Oxazolo[4,5-b]pyrazine and oxazolo[4,5-b]pyridine derivatives as nlrp3 inhibitors for the treatment of e.g. inflammatory diseases

Description

"OXAZOLO[4,5-B]PYRAZINE AND OXAZOLO[4,5B]PYRIDINE DERIVATIVES AS NLRP3 INHIBITORS FOR THE TREATMENT OF, FOR EXAMPLE, INFLAMMATORY DISEASES Field of the Invention"

[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 new compounds of formula I Ry In which, R1 is cyano, halo or haloalkyl, and R9 is H, or R1e R9e the atoms to which they are attached form a 5-membered cycloalkyl group or a 5-membered heterocycle comprising 1 heteroatom O; R2 is alkyl, hydroxyalkyl, alkoxyalkyl, or cyano, where if R1 is cyano, then R2 is not cyano; A1 is -CR10- or -N-; R10 is H, fluoro or alkoxy; Rxé H, alkyl, heteroarylalkyl, hydroxyalkyl or COOH-alkyl, wherein the heteroaryl group of the heteroarylalkyl is oxazolyl, tetrazolyl or oxadiazolyl; Ry is H or -OH; Petition 870250094781, dated 10 / 16 / 2025, pp. 188 / 378 2 / 167 where, if R1 is haloalkyl, then Rx is hydroxyalkyl or COOH-alkyl and Ry is -OH; and pharmaceutically acceptable salts thereof, provided that the compound is not a compound selected from: 5-chloro-2-[2-[[(3R)-1-ethyl-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-phenol; 5-chloro-2-[2-[[(3R)-1-ethyl-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxybenzonitrile; 5-chloro-2-[2-[[(3R)-1-ethyl-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3(methoxymethyl)phenol; 2,2,2-trifluoroacetic acid; 5-chloro-2-[2-[[(3R)-1-ethyl-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3(methoxymethyl)phenol; 5-chloro-3-methyl-2-[2-[[(3R)-1-methyl-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]fenol; 5-chloro-3-methyl-2-[2-[[(3R)-1-propil-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]fenol; (3S,5R)-5-[[5-(4-chloro-2-hidroxi-6-metilfenil)oxazolo[4,5-b]piridin-2-il]amino]-1-metil-piperidin3-ol; 5-chloro-2-[2-[[(3R,5S)-1-etyl-5-fluoro-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]-3-methyl-fenol; (3R,5R)-5-[[5-(4-chloro-2-hidroxi-6-metilfenil)oxazolo[4,5-b]piridin-2-il]amino]-1-etil-piperidin-3ol;ácido fórmico; (3R,5R)-5-[[5-(4-chloro-2-hidroxi-6-methylfenil)oxazolo[4,5-b]piridin-2-il]amino]-1-etil-piperidin-3ol; Petition: 870250094781, on 10 / 16 / 2025, p. 189 / 378 3 / 167 5-chloro-2-[2-[[(3R)-1-(3,3-difluoropropil)-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]-3-metil-phenol; 5-chloro-2-[2-[[(3R)-1-(2-hidroxietil)-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]-3-methyl-fenol; 5-chloro-3-(hidroximetil)-2-[2-[[(3R)-1-methyl-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]fenol; 5-chloro-2-[2-[[(3R)-1-(3-hidroxipropil)-3-piperidil]amino]oxazolo[4,5-b]piridin-5-il]-3-methyl-fenol; 5-chloro-3-metil-2-[2-[[(3R)-1-(2-hidroxipropil)3-piperidil]amino]oxazolo[4,5-b]piridin-5-il]fenol; (3S,5R)-5-[[5-[4-chloro-2-hidroxi-6(metoximetil)fenil]oxazolo[4,5-b]piridin-2-il]amino]-1metil-piperidin-3-ol; 5-chloro-2-[2-[[(3R)-1-etil-3piperidil]amino]oxazolo[4,5-b]pirazin-5-il]-3-metilfenol;ácido 2,2,2-trifluoroacético; 5-chloro-2-[2-[[(3R)-1-[[trans-2hidroxiciclobutil]metil]-3-piperidil]amino]oxazolo[4,5b]piridin-5-il]-3-methyl-fenol or 5-chloro-2-[2-[[(3R)-1[[cis-2-hidroxiciclobutil]metil]-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]-3-metil-fenol; (3S,5R)-5-[[5-(4-chloro-2-hidroxi-6-metilfenil)oxazolo[4,5-b]piridin-2-il]amino]-1-etil-piperidin-3ol; 2-[2-[[(3R)-1-etil-3-piperidil]amino]oxazolo[4,5b]piridin-5-il]-5-fluoro-3-methyl-fenol; 5-fluoro-3-methyl-2-[2-[[(3R)-1-methyl-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]fenol; 4-[2-[[(3R)-1-etil-3-piperidil]amino]oxazolo[4,5b]piridin-5-il]-3-hidroxi-5-metil-benzonitrila; Petition: 870250094781, on 10 / 16 / 2025, p. 190 / 378 4 / 167 3-hidroxi-5-metil-4-[2-[[(3R)-1-metil-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]benzonitrila; 4-[2-[[(3R,5S)-1-etil-5-hidroxi-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]-3-hidroxi-5metil-benzonitrila;ácido fórmico; 4-[2-[[(3R,5S)-1-etil-5-hidroxi-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]-3-hidroxi-5metil-benzonitrila; 3-hidroxi-4-[2-[[(3R,5S)-5-hidroxi-1-metil-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]-5-methylbenzonitrila; 4-[2-[[(3R,5R)-1-etil-5-hidroxi-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]-3-hidroxi-5metil-benzonitrila; 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyetil)-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-metilbenzonitrila; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5b]pyrazin-5-yl]-3-hydroxy-5-metil-benzonitrila; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5b]pyrazin-5-yl]-3-hydroxy-5-metil-benzonitrila;acido 2,2,2trifluoroacetico; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5b]pyridin-5-yl]-3-hydroxy-5-(methoxymethyl)benzonitrile; 2,2,2-trifluoroacetic acid 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5b]pyridin-5-yl]-3-hydroxy-5-(methoxymethyl)benzonitrile; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]-7-methoxyoxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-metilbenzonitrila; acido 2,2,2-trifluoroacetico; Petition 870250094781, de 16 / 10 / 2025, pág. 191 / 378 5 / 167 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]-7-methoxyoxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 5-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5b]pyridin-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; 5-chloro-3-methyl-2-[2-[[(3R)-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol; dihydrochloride; 5-chloro-3-methyl-2-[2-[[(3R)-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol; and pharmaceutically acceptable salts thereof.

[0003] Additionally, the invention includes all racemic mixtures, all their enantiomers and / or corresponding optical isomers. Background of the Invention

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

[0005] NLRP3 is an intracellular signaling molecule that detects many pathogen-derived, environmental, and host-derived factors. Upon activation, NLRP3 binds to apoptosis-associated particle-like protein containing an activation and recruitment domain for caspase (ASC). The ASC then polymerizes to form a large aggregate known as an ASC particle. The polymerized ASC, in turn, interacts with the cysteine ​​protease caspase-1 to form a complex. Petition 870250094781, dated 10 / 16 / 2025, page 192 / 378 6 / 167 called the inflammasome. This results in the activation of caspase-1, which cleaves the precursor forms of the pro-inflammatory cytokines IL-1β and IL-18 (referred to as pro-IL-1β and pro-IL-18, respectively) to activate these cytokines. Caspase-1 also mediates a type of inflammatory cell death known as pyroptosis. The ASC particle can also recruit and activate caspase-8, which can process pro-IL-1β and pro-IL-18 and trigger apoptotic cell death.

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

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

[0008] Active cytokines derived from NLRP3 inflammasome activation are important drivers of inflammation and interact with other cytokine pathways to shape the immune response to infection and injury. For example, the Petition 870250094781, dated 10 / 16 / 2025, pp. 193 / 378 7 / 167 IL-1β signaling induces the secretion of the proinflammatory cytokines IL-6 and TNF. IL-1β and IL-18 act synergistically with IL-23 to induce IL-17 production by CD4 Th17 memory cells and γδ T cells in the absence of T cell receptor engagement. IL-18 and IL-12 also act synergistically to induce IFN-γ production from memory T cells and NK cells, triggering a Th1 response.

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

[0010] A role for NLRP3 in central nervous system diseases is emerging, and pulmonary diseases have also been shown to be influenced by NLRP3. It has also been suggested that NLRP3 plays a role in a number of central nervous system conditions, including Parkinson's disease (PD), Alzheimer's disease (AD), dementia, Huntington's disease, cerebral malaria, and pneumococcal meningitis brain injury (Walsh et al., Nature Reviews, 15: 84-97, 2014, and Dempsey et al. Brain. Behav. Immun. 201761: 306-316). NLRP3 has also been shown to play a role in a number of lung diseases, including chronic obstructive pulmonary disease (COPD), asthma (including steroid-resistant asthma), asbestosis, and silicosis (De Nardo et al., Am. J. Pathol., 184: 42-54, 2014). Petition 870250094781, dated 10 / 16 / 2025, pp. 194 / 378 8 / 167 and Kim et al. Am J Respir Crit Care Med. 2017 196 (3): 283-97). Additionally, NLRP3 plays a role in the development of liver disease, kidney disease, and aging. Many of these associations have been defined using Nlrp3- / - mice, but there have also been insights into the specific activation of Nlrp3- / - in these diseases. In type 2 diabetes mellitus (T2D), islet amyloid polypeptide deposition in the pancreas activates NLRP3 and IL-1β signaling, resulting in cell death and inflammation.

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

[0012] Current treatments for NLRP3-related diseases include biological agents that target IL-1. These are the recombinant IL-1 receptor antagonist anakiran, the IL1β-neutralizing antibody canakinumab, and the soluble IL-1 receptor decoy rilonacept. These approaches have proven successful in treating CAPS, and these biological agents have been used in clinical trials for other IL-1-associated diseases.

[0013] Document WO2023 / 066825 discloses useful compounds as NLRP3 inhibitors. However, there is a need to provide compounds with improved pharmacological and / or physiological and / or physicochemical properties and / or those that provide a useful alternative. Petition 870250094781, dated 10 / 16 / 2025, pp. 195 / 378 9 / 167 to known compounds. Additionally, in the development of an NLRP3 inhibitor to treat peripheral indications, it is advantageous to minimize the brain exposure of an NLRP3 inhibitor compound relative to systemic exposure to minimize the risk of potential central nervous system (CNS) side effects. P-gp (P-glycoprotein) is an important transporter expressed in capillary endothelial cells that make up the blood-brain barrier and the blood-testis barrier, where it pumps xenobiotics back into the capillaries and limits brain exposure. The compounds of formula I achieve peripheral preference by showing increased efflux in a transcellular assay expressing active P-gp transporters and / or reduced passive permeability without compromising systemic distribution. By slightly increasing the polar surface area, the compounds of formula I surprisingly exhibit the desired profile and demonstrate lower permeability.Furthermore, there was a need for compounds that showed a reduced risk of phospholipidosis for chronic indications, with compounds exhibiting a combination of increased polarity and adjusted pKa. Summary of the Invention

[0014] The present invention provides new compounds of formula I Petition 870250094781, dated 10 / 16 / 2025, pp. 196 / 378 10 / 167 Ry In which, R1 is cyano, halo or haloalkyl, and R9 is H, or R1e R9e the atoms to which they are attached form a 5-membered cycloalkyl group or a 5-membered heterocycle comprising 1 heteroatom O; R2 is alkyl, hydroxyalkyl, alkoxyalkyl, or cyano, where if R1 is cyano, then R2 is not cyano; A1 is -CR10- or -N-; R10 is H, fluoro or alkoxy; Rxé H, alkyl, heteroarylalkyl, hydroxyalkyl or COOH-alkyl, wherein the heteroaryl group of the heteroarylalkyl is oxazolyl, tetrazolyl or oxadiazolyl; Ry is H or -OH; where R1 is haloalkyl, then Rx is hydroxyalkyl or COOH-alkyl and Ry is -OH; and pharmaceutically acceptable salts thereof, provided that the compound is not a compound selected from: 5-chloro-2-[2-[[(3R)-1-ethyl-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-phenol; 5-chloro-2-[2-[[(3R)-1-ethyl-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxybenzonitrile; 5-chloro-2-[2-[[(3R)-1-ethyl-3-] Petition 870250094781, dated 10 / 16 / 2025, page 197 / 378 11 / 167 piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3(methoxymethyl)phenol; 2,2,2-trifluoroacetic acid; 5-chloro-2-[2-[[(3R)-1-ethyl-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3(methoxymethyl)phenol; 5-chloro-3-methyl-2-[2-[[(3R)-1-methyl-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol; 5-chloro-3-methyl-2-[2-[[(3R)-1-propyl-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol; (3S,5R)-5-[[5-(4-chloro-2-hidroxi-6-metilfenil)oxazolo[4,5-b]piridin-2-il]amino]-1-metil-piperidin3-ol; 5-chloro-2-[2-[[(3R,5S)-1-etyl-5-fluoro-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]-3-methyl-fenol; (3R,5R)-5-[[5-(4-chloro-2-hidroxi-6-metilfenil)oxazolo[4,5-b]piridin-2-il]amino]-1-etil-piperidin-3ol;ácido fórmico; (3R,5R)-5-[[5-(4-chloro-2-hidroxi-6-methylfenil)oxazolo[4,5-b]piridin-2-il]amino]-1-etil-piperidin-3ol; 5-chloro-2-[2-[[(3R)-1-(3,3-difluoropropil)-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]-3-metil-phenol; 5-chloro-2-[2-[[(3R)-1-(2-hidroxietil)-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]-3-methyl-fenol; 5-chloro-3-(hidroximetil)-2-[2-[[(3R)-1-methyl-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]fenol; 5-chloro-2-[2-[[(3R)-1-(3-hidroxipropil)-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]-3-methyl-fenol; 5-chloro-3-methyl-2-[2-[[(3R)-1-(2-hidroxipropil)3-piperidil]amino]oxazolo[4,5-b]piridin-5-il]fenol; Petition: 870250094781, on 10 / 16 / 2025, p. 198 / 378 12 / 167 (3S,5R)-5-[[5-[4-chloro-2-hidroxi-6(metoximetil)fenil]oxazolo[4,5-b]piridin-2-il]amino]-1metil-piperidin-3-ol; 5-chloro-2-[2-[[(3R)-1-etil-3piperidil]amino]oxazolo[4,5-b]pirazin-5-il]-3-metilfenol;ácido 2,2,2-trifluoroacético; 5-chloro-2-[2-[[(3R)-1-[[trans-2hidroxiciclobutil]metil]-3-piperidil]amino]oxazolo[4,5b]piridin-5-il]-3-metil-fenol or 5-chloro-2-[2-[[(3R)-1[[cis-2-hidroxiciclobutil]metil]-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]-3-metil-fenol; (3S,5R)-5-[[5-(4-chloro-2-hidroxi-6-metilfenil)oxazolo[4,5-b]piridin-2-il]amino]-1-etil-piperidin-3ol; 2-[2-[[(3R)-1-etil-3-piperidil]amino]oxazolo[4,5b]piridin-5-il]-5-fluoro-3-methyl-fenol; 5-fluoro-3-methyl-2-[2-[[(3R)-1-methyl-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]fenol; 4-[2-[[(3R)-1-etil-3-piperidil]amino]oxazolo[4,5b]piridin-5-il]-3-hidroxi-5-metil-benzonitrila; 3-hidroxi-5-metil-4-[2-[[(3R)-1-metil-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]benzonitrila; 4-[2-[[(3R,5S)-1-etil-5-hidroxi-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]-3-hidroxi-5metil-benzonitrila;ácido fórmico; 4-[2-[[(3R,5S)-1-etil-5-hidroxi-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]-3-hidroxi-5metil-benzonitrila; 3-hidroxi-4-[2-[[(3R,5S)-5-hidroxi-1-metil-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]-5-metilPetição 870250094781, on 16 / 10 / 2025, page. 199 / 378 13 / 167 benzonitrile; 4- [2- [[(3R,5R)-1-etil-5-hidroxi-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]-3-hidroxi-5metil-benzonitrila; 3-hidroxi-4-[2-[[(3R)-1-(2-hidroxietil)-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]-5-methylbenzonitrila; 4-[2-[[(3R)-1-etil-3-piperidil]amino]oxazolo[4,5b]pirazin-5-il]-3-hidroxi-5-metil-benzonitrila; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5b]pyrazin-5-yl]-3-hydroxy-5-metil-benzonitrila;acido 2,2,2trifluoroacetico; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5b]pyridin-5-yl]-3-hydroxy-5-(methoxymethyl)benzonitrile; 2,2,2-trifluoroacetic acid 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5b]pyridin-5-yl]-3-hydroxy-5-(methoxymethyl)benzonitrile; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]-7-methoxyoxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-metilbenzonitrila; acido 2,2,2-trifluoroacetico; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]-7-methoxyoxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 5-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5b]pyridin-5-yl]-6-metil-2,3-di-hidrobenzofuran-4-ol; 5-chloro-3-metil-2-[2-[[(3R)-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol; dicloridrato; 5-chloro-3-metil-2-[2-[[(3R)-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol; and pharmaceutically acceptable salts thereof. Petition 870250094781, dated 10 / 16 / 2025, pp. 200 / 378 14 / 167

[0015] The term alkyl denotes a monovalent, linear or branched saturated hydrocarbon group of 1 to 6 carbon atoms. In some embodiments, if not otherwise described, alkyl comprises 1 to 6 carbon atoms (C1-6-alkyl) or 1 to 4 carbon atoms (C14-alkyl). Examples of C1-6-alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and pentyl. Particular alkyl groups are methyl and ethyl.

[0016] The term alkoxy denotes a group of the formula -O-R', where R' is a C1-6-alkyl group. Examples of C1-6-alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy.

[0017] 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. The particular alkoxyalkyl is methoxymethyl.

[0018] The term cycloalkyl denotes a monocyclic or polycyclic hydrocarbon, saturated or partially unsaturated, non-aromatic. 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.

[0019] The terms halogen, halide and halo are used interchangeably in this document and denote Petition 870250094781, dated 10 / 16 / 2025, page 201 / 378 15 / 167 fluorine, chlorine, bromine or iodine.

[0020] The term haloalkyl denotes an alkyl group in which one or more hydrogen atoms of the alkyl group have been replaced by halo. Examples of haloalkyl are trifluoromethyl, difluoromethyl, and fluoromethyl. A particular example is trifluoromethyl.

[0021] The term heteroaryl denotes a monovalent aromatic monocyclic or bicyclic ring system of 4 to 9 ring atoms, comprising 1, 2, 3 or 4 ring heteroatoms selected from N and O, the remaining ring atoms being carbon. Examples of heteroaryl are thiazolyl, pyridyl, oxazolyl, tetrazolyl, oxadiazolyl and the like.

[0022] The term heteroarylalkyl denotes an alkyl group in which one of the hydrogen atoms of the alkyl group has been replaced by a heteroaryl group. Examples are oxyzolyethyl, tetrazolyethyl, and oxadiazolylethyl. A particular example is oxazolylethyl.

[0023] The term heterocyclic ring denotes a monovalent saturated or partially unsaturated mono- or bicyclic ring system of 4 to 9 ring atoms, comprising 1, 2, or 3 ring heteroatoms selected from N, O, and S, the remaining ring atoms being carbon. Examples of saturated monocyclic heterocyclic rings are azetidinyl, diazepanyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, and piperazinyl. Examples of saturated polycyclic heterocyclic rings are azaspiro-heptanyl, diazaspiro Petition 870250094781, dated 10 / 16 / 2025, page 202 / 378 16 / 167 heptanyl, azaspiro-octanyl, diazospiro-octanyl, diazaspirononanyl, oxa-azaspiro-octanyl and oxadiazaspirononanil.

[0024] The term hydroxyl denotes a -OH group.

[0025] The term hydroxyalkyl denotes an alkyl group in which at least one of the hydrogen atoms of the alkyl group has been replaced by a hydroxyl group. Examples of hydroxyalkyl include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxymethylethyl, hydroxymethylpropyl, and dihydroxypropyl. A particular example of a hydroxyalkyl is hydroxyethyl.

[0026] The term cyan denotes a group -C=N.

[0027] The term pharmaceutically acceptable salts refers to salts that retain the biological efficacy and properties of free bases or free acids that are not biologically or otherwise undesirable. Salts are formed with 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-acetylcysteine. Furthermore, these salts can be prepared by adding an inorganic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not limited to, sodium salts, Petition 870250094781, dated 10 / 16 / 2025, pp. 203 / 378 17 / 167 potassium, lithium, ammonium, calcium, and magnesium. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion-exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, and polyamine resins. The compound of formula I may also be present in the form of zwitterions. Particularly preferred pharmaceutically acceptable salts of compounds of formula I are the salts formed with formic acid and the salts formed with hydrochloric acid yielding a hydrochloride, dihydrochloride, or trihydrochloride salt.

[0028] The abbreviation μM stands for microMolar and is equivalent to the symbol μM.

[0029] The abbreviation μl stands for microliter and is equivalent to the symbol μ^

[0030] The abbreviation μg stands for microgram and is equivalent to the symbol μg.

[0031] Compounds of formula I may contain several asymmetric centers and may be present in the form of optically pure enantiomers, mixtures of enantiomers, such as racemates, optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates.

[0032] According to the CahnIngold-Prelog Convention, the asymmetric carbon atom can be of the R or S configuration. Petition 870250094781, dated 10 / 16 / 2025, pp. 204 / 378 18 / 167

[0033] Also, an embodiment of the present invention provides compounds according to formula I, as described in this document, and pharmaceutically acceptable salts or esters thereof, in particular compounds according to formula I, as described in this document, and pharmaceutically acceptable salts thereof, more particularly compounds according to formula I, as described in this document.

[0034] One embodiment of the present invention provides compounds according to formula I Ry In which, R1 is cyano, halo or haloalkyl, and R9 is H, or R1e R9e the atoms to which they are attached form a 5-membered cycloalkyl group or a 5-membered heterocycle comprising 1 heteroatom O; R2 is alkyl, hydroxyalkyl, alkoxyalkyl, or cyano, where if R1 is cyano, then R2 is not cyano; A1é -CR10- or -N-; R10 is H, fluoro or alkoxy; Rxé H, alkyl, heteroarylalkyl, hydroxyalkyl or COOH-alkyl, wherein the heteroaryl group of the heteroarylalkyl is oxazolyl, tetrazolyl or oxadiazolyl; Ry is H or -OH; Petition 870250094781, dated 10 / 16 / 2025, pp. 205 / 378 19 / 167 where, if R1 is haloalkyl, then Rx is hydroxyalkyl or COOH-alkyl and Ry is -OH; and pharmaceutically acceptable salts thereof, provided that the compound is not a compound selected from: 5-chloro-2-[2-[[(3R)-1-ethyl-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methyl-phenol; 5-chloro-2-[2-[[(3R)-1-ethyl-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxybenzonitrile; 5-chloro-2-[2-[[(3R)-1-ethyl-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3(methoxymethyl)phenol; 2,2,2-trifluoroacetic acid; 5-chloro-2-[2-[[(3R)-1-ethyl-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3(methoxymethyl)phenol; 5-chloro-3-methyl-2-[2-[[(3R)-1-methyl-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]fenol; 5-chloro-3-methyl-2-[2-[[(3R)-1-propil-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]fenol; (3S,5R)-5-[[5-(4-chloro-2-hidroxi-6-metilfenil)oxazolo[4,5-b]piridin-2-il]amino]-1-metil-piperidin3-ol; (3R,5R)-5-[[5-(4-chloro-2-hidroxi-6-metilfenil)oxazolo[4,5-b]piridin-2-il]amino]-1-etil-piperidin-3ol;ácido fórmico; (3R,5R)-5-[[5-(4-chloro-2-hidroxi-6-methylfenil)oxazolo[4,5-b]piridin-2-il]amino]-1-etil-piperidin-3ol; 5-chloro-2-[2-[[(3R)-1-(3,3-difluoropropil)-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]-3-metil-phenol; Petition: 870250094781, on 10 / 16 / 2025, p. 206 / 378 20 / 167 5-chloro-2-[2-[[(3R)-1-(2-hidroxietil)-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]-3-methyl-fenol; 5-chloro-3-(hidroximetil)-2-[2-[[(3R)-1-methyl-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]fenol; 5-chloro-2-[2-[[(3R)-1-(3-hidroxipropil)-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]-3-methyl-fenol; 5-chloro-3-methyl-2-[2-[[(3R)-1-(2-hidroxipropil)3-piperidil]amino]oxazolo[4,5-b]piridin-5-il]fenol; (3S,5R)-5-[[5-[4-chloro-2-hidroxi-6(metoximetil)fenil]oxazolo[4,5-b]piridin-2-il]amino]-1metil-piperidin-3-ol; 5-chloro-2-[2-[[(3R)-1-etil-3piperidil]amino]oxazolo[4,5-b]pirazin-5-il]-3-metilfenol;ácido 2,2,2-trifluoroacético; 5-chloro-2-[2-[[(3R)-1-etil-3piperidil]amino]oxazolo[4,5-b]pirazin-5-il]-3-methyl-fenol; (3S,5R)-5-[[5-(4-chloro-2-hidroxi-6-metilfenil)oxazolo[4,5-b]piridin-2-il]amino]-1-etil-piperidin-3ol; 2-[2-[[(3R)-1-etil-3-piperidil]amino]oxazolo[4,5b]piridin-5-il]-5-fluoro-3-methyl-fenol; 5-fluoro-3-methyl-2-[2-[[(3R)-1-methyl-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]fenol; 4-[2-[[(3R)-1-etil-3-piperidil]amino]oxazolo[4,5b]piridin-5-il]-3-hidroxi-5-metil-benzonitrila; 3-hidroxi-5-metil-4-[2-[[(3R)-1-metil-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]benzonitrila; 4-[2-[[(3R,5S)-1-etil-5-hidroxi-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]-3-hidroxi-5metil-benzonitrila;ácido fórmico; Petition: 870250094781, on 10 / 16 / 2025, p. 207 / 378 21 / 167 4-[2-[[(3R,5S)-1-etil-5-hidroxi-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]-3-hidroxi-5metil-benzonitrila; 3-hidroxi-4-[2-[[(3R,5S)-5-hidroxi-1-metil-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]-5-methylbenzonitrila; 4-[2-[[(3R,5R)-1-etil-5-hidroxi-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]-3-hidroxi-5metil-benzonitrila; 3-hidroxi-4-[2-[[(3R)-1-(2-hidroxietil)-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]-5-methylbenzonitrila; 4-[2-[[(3R)-1-etil-3-piperidil]amino]oxazolo[4,5b]pirazin-5-il]-3-hidroxi-5-metil-benzonitrila; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5b]pyrazin-5-yl]-3-hydroxy-5-metil-benzonitrila;acido 2,2,2trifluoroacetico; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5b]pyridin-5-yl]-3-hydroxy-5-(methoxymethyl)benzonitrile; 2,2,2-trifluoroacetic acid 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5b]pyridin-5-yl]-3-hydroxy-5-(methoxymethyl)benzonitrile; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]-7-methoxyoxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-metilbenzonitrila; acido 2,2,2-trifluoroacetico; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]-7-methoxyoxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 5-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5b]pyridin-5-yl]-6-metil-2,3-di-hidrobenzofuran-4-ol; 5-chloro-3-metil-2-[2-[[(3R)-3Petição 870250094781, de 16 / 10 / 2025, pág. 208 / 378 22 / 167 piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol; dicloridrato; 5-chloro-3-methyl-2-[2-[[(3R)-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol; and pharmaceutically acceptable salts thereof.

[0035] One embodiment of the present invention provides compounds according to formula I, as described herein, wherein R1 is cyano or haloalkyl, and R9 is H, or R1 and R9 and the atoms to which they are attached form a 5-membered heterocycle comprising 1 heteroatom O.

[0036] An embodiment of the present invention provides compounds according to formula I, as described in this document, wherein R1 is cyano and R9 is H, or R1 and R9 and the atoms to which they are attached form a 5-membered heterocycle comprising 1 heteroatom O.

[0037] One embodiment of the present invention provides compounds according to formula I, as described in this document, wherein R1 is cyano and R9 is H.

[0038] One embodiment of the present invention provides compounds according to formula I, as described herein, wherein R1 and R9 and the atoms to which they are attached form a 5-membered heterocycle comprising 1 heteroatom O.

[0039] One embodiment of the present invention provides compounds according to formula I, as described herein, wherein R2 is alkyl or alkoxyalkyl.

[0040] One embodiment of the present invention provides compounds according to formula I, such as Petition 870250094781, dated 10 / 16 / 2025, pp. 209 / 378 23 / 167 described in this document, where Ai is -N-.

[0041] One embodiment of the present invention provides compounds according to formula I, as described herein, wherein R10 is H or alkoxy.

[0042] One embodiment of the present invention provides compounds according to formula I, as described in this document, where R10 is H.

[0043] An embodiment of the present invention provides compounds according to formula I, as described herein, wherein Rx is H, alkyl, heteroarylalkyl, hydroxyalkyl or COOH-alkyl, wherein the heteroaryl of heteroarylalkyl is oxazolyl.

[0044] An embodiment of the present invention provides compounds according to formula I, as described herein, wherein Rx is H, alkyl, heteroarylalkyl or hydroxyalkyl, wherein the heteroaryl of heteroarylalkyl is oxazolyl.

[0045] An embodiment of the present invention provides compounds according to formula I, as described herein, wherein Rx is alkyl, heteroarylalkyl or hydroxyalkyl, wherein the heteroaryl of heteroarylalkyl is oxazolyl.

[0046] One embodiment of the present invention provides compounds according to formula I, as described herein, wherein Rx is alkyl or hydroxyalkyl.

[0047] One embodiment of the present invention provides compounds according to formula I, as described herein, wherein Rx is hydroxyalkyl.

[0048] An embodiment of the present invention Petition 870250094781, dated 10 / 16 / 2025, pp. 210 / 378 24 / 167 provides compounds according to formula I, as described in this document, where Ry is H.

[0049] One embodiment of the present invention provides compounds according to formula I, as described herein, wherein, R1 is cyano or haloalkyl, and R9 is H, or R1e R9e the atoms to which they are attached form a 5-membered heterocycle comprising 1 O heteroatom; R2 is alkyl or alkoxyalkyl; A1é -CR10- or -N-; R10 is H or alkoxy; Rxé H, alkyl, heteroarylalkyl, hydroxyalkyl or COOH-alkyl, where the heteroaryl group of the heteroarylalkyl is oxazolyl; Ryé H or -OH; where, if R1 is haloalkyl, then Rx is hydroxyalkyl or COOH-alkyl and Ry is -OH; and pharmaceutically acceptable salts thereof.

[0050] One embodiment of the present invention provides compounds according to formula I, as described in this document, wherein, R1 is cyan and R9 is H, or R1e R9e the atoms to which they are attached form a 5-membered heterocycle comprising 1 O heteroatom; R2 is alkyl or alkoxyalkyl; A1é -CR10- or -N-; R10 is H or alkoxy; Rxé alkyl or hydroxyalkyl; Ryé H or -OH; and pharmaceutically acceptable salts thereof. Petition 870250094781, dated 10 / 16 / 2025, pp. 211 / 378 25 / 167

[0051] One embodiment of the present invention provides compounds according to formula I, as described in this document, wherein R1 is cyano and R9 is H, or R1e R9e the atoms to which they are attached form a 5-membered heterocycle comprising 1 O heteroatom; R2 is alkyl or alkoxyalkyl; A1é -CR10- or -N-; R10 is H; Rxé hydroxyalkyl; Ry is H; and pharmaceutically acceptable salts thereof.

[0052] One embodiment of the present invention provides compounds according to formula I, as described in this document, wherein, R1 and R9 and the atoms to which they are attached form a 5-membered heterocycle comprising 1 O heteroatom; R2 is alkyl or alkoxyalkyl; A1é -CR10- or -N-; R10 is H; Rxé hydroxyalkyl; Ry is H; and pharmaceutically acceptable salts thereof.

[0053] One embodiment of the present invention provides compounds according to formula I, as described in this document, wherein, R1e R9e the atoms to which they are attached form a 5-membered heterocycle comprising 1 O heteroatom; R2 is alkyl or alkoxyalkyl; A1é -N-; Petition 870250094781, dated 10 / 16 / 2025, pp. 212 / 378 26 / 167 R10 is H; Rxé hydroxyalkyl; Ry is H; and pharmaceutically acceptable salts thereof.

[0054] One embodiment of the present invention provides compounds according to formula I, as described herein, wherein R1 is cyano and R9 is H; R2 is alkyl or alkoxyalkyl; A1é -CR10- or -N-; R10 is H or alkoxy; Rxé H, alkyl, heteroarylalkyl or hydroxyalkyl, where the heteroaryl group of the heteroarylalkyl is oxazolyl; Ry is H or -OH; and pharmaceutically acceptable salts thereof.

[0055] One embodiment of the present invention provides compounds according to formula I, as described in this document, wherein R1 is cyano and R9 is H; R2 is alkyl or alkoxyalkyl; A1é -N-; R10 is H or alkoxy; Rxé H, alkyl, heteroarylalkyl or hydroxyalkyl, where the heteroaryl group of the heteroarylalkyl is oxazolyl; Ryé H or -OH; and pharmaceutically acceptable salts thereof.

[0056] One embodiment of the present invention provides compounds according to formula I, such as Petition 870250094781, dated 10 / 16 / 2025, pp. 213 / 378 27 / 167 described in this document, in which, R1 is cyan and R9 is H; R2 is alkyl or alkoxyalkyl; A1é -CR10- or -N-; R10 is H; Rxé alkyl, heteroarylalkyl or hydroxyalkyl, where the heteroaryl group of the heteroarylalkyl is oxazolyl; Ry is H or -OH; and pharmaceutically acceptable salts thereof.

[0057] One embodiment of the present invention provides compounds according to formula I, as described herein, wherein R1 is cyano and R9 is H; R2 is alkyl or alkoxyalkyl; A1é -N-; R10 is H; Rxé alkyl, heteroarylalkyl or hydroxyalkyl, wherein the heteroaryl group of the heteroarylalkyl is oxazolyl; Ry is H or -OH; and pharmaceutically acceptable salts thereof.

[0058] Particular examples of compounds of formula I, as described in this document, are selected from 3-hydroxy-5-methyl-4-[2-[[(3R)-1-(2-oxazol-2ylethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5yl]benzonitrile; 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5(methoxymethyl)benzonitrile; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3 Petition 870250094781, dated 10 / 16 / 2025, pp. 214 / 378 28 / 167 piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-3-hydroxy-5methyl-benzonitrile; 2,2,2-trifluoroacetic acid; 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-5-methylbenzonitrile; 2,2,2-trifluoroacetic acid; and pharmaceutically acceptable salts thereof.

[0059] Other particular examples of compounds of formula I, as described in this document, are selected from 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-3-hydroxy-5methyl-benzonitrile; 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-5-methylbenzonitrile; and pharmaceutically acceptable salts thereof.

[0060] Other particular examples of compounds of formula I, as described in this document, are selected from 4-[(3S,5R)-3-hydroxy-5-[[5-[2-hydroxy-6-methyl-4(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]amino]-1-piperidyl]butanoic acid; (3S,5R)-1-(2-hydroxyethyl)-5-[[5-[2-hydroxy-6methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2yl]amino]piperidin-3-ol; 3-hydroxy-4-[2-[[(3R,5S)-5-hydroxy-1-methyl-3-piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-5-methylbenzonitrile; 2,2,2-trifluoroacetic acid; 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]-7-methoxyoxazolo[4,5-b]pyridin-5-yl]-5 Petition 870250094781, de 16 / 10 / 2025, p. 215 / 378 29 / 167 methylbenzonitrile;acido 2,2,2-trifluoroacetico; 3-hydroxy-4-[2-[[(3R,5S)-5-hydroxy-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-methylbenzonitrile; 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-5-methylbenzonitrile; e sais farmaceutamente aceitáveis ​​destes.

[0061] Other particular examples of compounds of formula I, as described herein, are selected from (3S,5R)-1-(2-hydroxyethyl)-5-[[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2yl]amino]piperidin-3-ol; 3-hydroxy-4-[2-[[(3R,5S)-5-hydroxy-1-methyl-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-5-methylbenzonitrile; 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridin-5-yl]-5methyl-benzonitrile; and pharmaceutically acceptable salts thereof.

[0062] Other particular examples of compounds of formula I, as described in this document, are selected from 5-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-6(methoxymethyl)-2,3-dihydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6(methoxymethyl)-2,3-dihydrobenzofuran-4-ol; Petition 870250094781, dated 10 / 16 / 2025, pp. 216 / 378 30 / 167 5-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; and pharmaceutically acceptable salts thereof.

[0063] Other particular examples of compounds of formula I, as described in this document, are selected from 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-5(methoxymethyl)benzonitrile; 2,2,2-trifluoroacetic acid; 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-5(methoxymethyl)benzonitrile; 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridin-5-yl]-5methyl-benzonitrile; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-3-hydroxy-5metil-benzonitrila; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-6-methyl-indan4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]7-methoxy-oxazolo[4,5-b]pyridin-5-yl]-6-methyl-indan-4-ol; 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridin-5-yl]-5(methoxymethyl)benzonitrile; Petition 870250094781, de 16 / 10 / 2025, pág. 217 / 378 31 / 167 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino] 7-methoxy-oxazolo[4,5-b]pyridin-5-yl]-6-(methoxymethyl)-2,3dihydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]7-methoxy-oxazolo[4,5-b]pyridin-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; 4-[2-[[(3R,5S)-1-etil-5-hidroxi-3piperidil]amino]oxazolo[4,5-b]pyrazin-5-yl]-3-hidroxi-5(methoxymetil)benzonitrila;acido 2,2,2-trifluoroacetico; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-3-hydroxy-5(methoxymethyl)benzonitrile; (3S,5R)-1-(2-hydroxyethyl)-5-[[5-(4-hydroxy-6-methyl-2,3-dihydrobenzofuran-5-yl)oxazolo[4,5-b]pyrazin-2yl]amino]piperidin-3-ol; (3S,5R)-1-ethyl-5-[[5-(4-hydroxy-6-metil-2,3-dihydrobenzofuran-5-yl)oxazolo[4,5-b]pyrazin-2yl]amino]piperidin-3-ol; 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-5(methoxymethyl)benzonitrile; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3piperidyl]amino]-7-fluoro-oxazolo[4,5-b]pyridin-5-yl]-3hydroxy-5-metil-benzonitrila; 3-hydroxy-5-metil-4-[2-[[(3R)-1-(3-oxazol-2ylpropyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5yl]benzonitrila; 4-[7-fluoro-2-[[(3R)-1-(2-hydroxyetil)-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5metil-benzonitrila; Petition 870250094781, de 16 / 10 / 2025, pág. 218 / 378 32 / 167 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridin-5-yl]-3hydroxy-5-methyl-benzonitrile; (3S,5R)-1-ethyl-5-[[5-(4-hydroxy-6-methyl-2,3-dihydrobenzofuran-5-yl)oxazolo[4,5-b]pyridin-2yl]amino]piperidin-3-ol; and you are pharmaceutically oiled from these.

[0064] Preferred examples of composts of formula I, as described in this document, are selected from 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-3-hydroxy-5methyl-benzonitrile;2,2,2-trifluoroacetic acid; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-3-hydroxy-5methyl-benzonitrile; 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-5-methylbenzonitrile;2,2,2-trifluoroacetic acid; 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-5-methylbenzonitrile; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-6(methoxymethyl)-2,3-di-hydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6(methoxymethyl)-2,3-di-hydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyrazine-5-yl]-6-methyl-2,3-di Petition 870250094781, of 16 / 10 / 2025, p. 219 / 378 33 / 167 hydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; and pharmaceutically acceptable six of these.

[0065] Other preferred examples of compounds of Formula I, as described herein, are selected from 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-3-hydroxy-5methyl-benzonitrile; teacher 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-5-methylbenzonitrile.

[0066] Most preferred examples of composts of formula I, as described in this document, only selected from 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-5-methylbenzonitrile;2,2,2-trifluoroacetic acid; 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-5-methylbenzonitrile; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-6(methoxymethyl)-2,3-di-hydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6(methoxymethyl)-2,3-di-hydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3Petição 870250094781, dated 10 / 16 / 2025, p. 220 / 378 34 / 167 piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; and pharmaceutically acceptable six of these.

[0067] The most preferred examples of compounds of Formula I, as described herein, are selected from 5-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-6(methoxymethyl)-2,3-di-hydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6(methoxymethyl)-2,3-di-hydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; and pharmaceutically acceptable six of these.

[0068] A more preferred example of a compound of formula I, as described herein, is 5[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5b]pyrazin-5-yl]-6-(methoxymethyl)-2,3-dihydrobenzofuran-4-ol, or a pharmaceutically acceptable salt thereof.

[0069] Another embodiment of the invention provides a pharmaceutical composition or medicament containing a compound of the invention and a vehicle, diluent or excipient. Petition 870250094781, dated 10 / 16 / 2025, pp. 221 / 378 35 / 167 therapeutically inert, as well as a method of using the compounds of the invention to prepare such a composition and medicament. In one example, the compound of formula I can be formulated by mixing at room temperature at the appropriate pH and desired degree of purity, with physiologically acceptable vehicles, i.e., vehicles that are not toxic to receptors at the dosages and concentrations employed in a galenic administration form. The pH of the formulation depends mainly on the particular use and the concentration of the compound, but preferably varies in the range of about 3 to about 8. In one example, a compound of formula I is formulated in an acetate buffer, at pH 5. In another embodiment, the compound of formula I is sterile. The compound can be stored, for example, as a solid or amorphous composition, as a lyophilized formulation, or as an aqueous solution.

[0070] The compositions are formulated, dosed, and administered in a manner consistent with good medical practice. Factors for consideration in this context include the particular disorder to be treated, the particular mammal to be treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the administration schedule, and other factors known to physicians.

[0071] The compounds of the invention can be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, epidural and intranasal and, if desired for local treatment, Petition 870250094781, dated 10 / 16 / 2025, pp. 222 / 378 36 / 167 Intralesional administration. Parenteral infusions include intramuscular, intravenous, intra-arterial, intraperitoneal, or subcutaneous administration.

[0072] The compounds of the present invention can be administered in any convenient administrative form, for example, tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain conventional components in pharmaceutical preparations, for example, diluents, vehicles, pH modifiers, sweeteners, bulking agents and additional active agents.

[0073] A typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, for example, Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005.The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, glidants, processing aids, colorants, sweeteners, fragrance agents, flavoring agents, diluents, and other known additives to provide an elegant presentation of the product. Petition 870250094781, dated 10 / 16 / 2025, pp. 223 / 378 37 / 167 drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or assist in the manufacture of the pharmaceutical product (i.e., medicine).

[0074] The compounds of formula I and their pharmaceutically acceptable salts may be processed with pharmaceutically inert, inorganic or organic excipients for the production of tablets, coated tablets, dragees, hard gelatin capsules, injectable solutions or topical formulations. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts, etc., may be used, for example, as such excipients for tablets, dragees and hard gelatin capsules.

[0075] Suitable excipients for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols, etc.

[0076] Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, etc.

[0077] Suitable adjuvants for injectable solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.

[0078] Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols, etc.

[0079] Suitable adjuvants for topical ocular formulations are, for example, cyclodextrins, mannitol, or many other vehicles and excipients known in the art.

[0080] In addition, pharmaceutical preparations may contain preservatives, solubilizers, substances that Petition 870250094781, dated 10 / 16 / 2025, pp. 224 / 378 38 / 167 increase viscosity, stabilizers, humectants, emulsifiers, sweeteners, colorings, flavorings, salts to vary osmotic pressure, buffers, masking agents or antioxidants. They may also contain other therapeutically valuable substances.

[0081] Dosage may vary within wide limits and will, of course, be adjusted to individual requirements in each particular case. In general, for oral administration, a daily dosage of approximately 0.1 mg to 20 mg per kg of body weight, preferably approximately 0.5 mg to 4 mg per kg of body weight (e.g., approximately 300 mg per person), divided into preferably 1 to 3 individual doses, which may consist, for example, of the same amounts, if appropriate. For topical administration, the formulation may contain 0.001% to 15% by weight of medication and the required dose, which may be between 0.1 and 25 mg, may be administered as a single dose per day or per week, or in multiple doses (2 to 4) per day, or in multiple doses per week. However, it will be clear that the upper or lower limit determined in this document may be exceeded when this is shown to be indicated.

[0082] One embodiment of the present invention is a compound according to formula I, as described herein, for use as a therapeutically active substance.

[0083] An embodiment of the present invention is a compound according to formula I, as described herein, for use in the treatment or prevention of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition. Petition 870250094781, dated 10 / 16 / 2025, pp. 225 / 378 39 / 167

[0084] An embodiment of the present invention is a compound according to formula I, as described herein, for the treatment or prophylaxis of a disease, disorder or condition, wherein the disorder or condition is responsive to NLRP3 inhibition.

[0085] As used in this document, the term “NLRP3 inhibition” refers to the complete or partial reduction in the level of NLRP3 activity and includes, for example, inhibition of active NLRP3 and / or inhibition of NLRP3 activation.

[0086] There is evidence of a role for NLRP3-induced IL-1 and IL-18 in inflammatory responses that occur in connection with, or as a result of, a multitude of different disorders (Menu et al., Clinical and Experimental Immunology, 166: 1-15, 2011; Strowig et al., Nature, 481: 278-286, 2012).

[0087] In one realization, the disease, disorder, or condition is selected from: (i) inflammation; (ii) an autoimmune disease; (iii) cancer; (iv) an infection; (v) a metabolic disease; (vi) a cardiovascular disease; (vii) a respiratory disease; (viii) a liver disease; (ix) a kidney disease; (x) an eye disease; (xi) a skin disease; (xii) a lymphatic condition; Petition 870250094781, dated 10 / 16 / 2025, pp. 226 / 378 40 / 167 (xiii) graft-versus-host disease; (xiv) allodynia; (xv) a condition associated with diabetes; and (xvi) any disease where an individual has been determined to carry a non-silent germline or somatic mutation in NLRP3

[0088] In another embodiment, the disease, disorder, or condition is selected from: (i) cancer; (ii) an infection; (iii) a cardiovascular disease; (iv) a liver disease; (v) an eye disease; and (vi) a skin disease.

[0089] In a typical further embodiment of the invention, the disease, disorder, or condition is inflammation. Examples of inflammation that can be treated or prevented include inflammatory responses that occur in connection with, or as a result of:

[0090] (i) a skin condition, 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;

[0091] (ii) a joint condition 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., spondylitis) Petition 870250094781, dated 10 / 16 / 2025, pp. 227 / 378 41 / 167 ankylosing spondylitis, psoriatic arthritis or Reiter's disease);

[0092] (iii) a muscular condition such as polymyositis or myasthenia gravis;

[0093] (iv) a condition of the gastrointestinal tract, such as inflammatory bowel disease (including Crohn's disease and ulcerative colitis), colitis, gastric ulcer, celiac disease, proctitis, pancreatitis, eosinopic gastroenteritis, mastocytosis, antiphospholipid syndrome or a food allergy that may have effects distant from the intestine (e.g., migraine, rhinitis or eczema);

[0094] (v) a condition of the respiratory system, such as chronic obstructive pulmonary disease (COPD), asthma (including eosinophilic, bronchial, allergic, intrinsic, extrinsic or dust asthma and, in particular, chronic or inveterate asthma, such as late-onset asthma and airway hyperresponsiveness), bronchitis, rhinitis (including acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis, caseous rhinitis, hypertrophic rhinitis, pumlenta rhinitis, dry rhinitis, drug-induced rhinitis, membranous rhinitis, seasonal rhinitis, for example, hay fever and vasomotor rhinitis), sinusitis, idiopathic pulmonary fibrosis (IPF), sarcoidosis, farmer's lung, silicosis, asbestosis, volcanic ash-induced inflammation, adult respiratory distress syndrome, hypersensitivity pneumonitis or idiopathic interstitial pneumonia;

[0095] (vi) a vascular condition, such as atherosclerosis, Behçet's disease, vasculitis or Wegener's granulomatosis; Petition 870250094781, dated 10 / 16 / 2025, pp. 228 / 378 42 / 167

[0096] (vii) an autoimmune condition, such as systemic lupus erythematosus, Sjogren's syndrome, systemic sclerosis, Hashimoto's thyroiditis, type I diabetes, idiopathic thrombocytopenic purpura or Graves' disease;

[0097] (viii) an eye condition, such as uveitis, allergic conjunctivitis or vernal conjunctivitis;

[0098] (ix) an infection or infection-related condition, such as Acquired Immunodeficiency Syndrome (AIDS), acute or chronic bacterial infection, acute or chronic parasitic infection, acute or chronic viral infection, acute or chronic fungal infection, meningitis, hepatitis (A, B or C or other viral hepatitis), peritonitis, pneumonia, epiglottitis, malaria, dengue hemorrhagic fever, leishmaniasis, streptococcal myositis, Mycobacterium tuberculosis (including Mycobacterium tuberculosis and HIV co-infection), Mycobacterium avium intracellulare, Pneumocystis carinii pneumonia, orchitis / epididymitis, legionella, Lyme disease, influenza A, Epstein-Barr virus infection, viral encephalitis / aseptic meningitis or pelvic inflammatory disease;

[0099] (x) a kidney condition, such as mesangial proliferative glomerulonephritis, nephrotic syndrome, nephritis, glomerular nephritis, obesity-related glomerulopathy, acute renal failure, acute kidney injury, uremia, nephritic syndrome, renal fibrosis, including chronic crystal nephropathy, or renal hypertension;

[00100] (xi) a lymphatic condition, such as Castleman's disease;

[00101] (xii) a condition of, or Petition 870250094781, dated 10 / 16 / 2025, pp. 229 / 378 43 / 167 involving the immune system, such as hyper-IgE syndrome, lepromatous leprosy, familial hemophagocytic lymphohistiocytosis, or graft-versus-host disease;

[00102] (xiii) a liver condition, such as chronic active hepatitis, non-alcoholic steatohepatitis (NASH), alcohol-induced hepatitis, non-alcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH), primary biliary cirrhosis, fulminant hepatitis, liver fibrosis or liver failure;

[00103] (xiv) a cancer, including the cancers listed above;

[00104] (xv) a burn, wound, trauma, hemorrhage or stroke;

[00105] (xvi) exposure to radiation;

[00106] (xvii) a metabolic disease, such as type 2 diabetes (T2D), atherosclerosis, obesity, gout or pseudogout; and / or

[00107] (xiii) pain such as inflammatory hyperalgesia, pelvic pain, allodynia, neuropathic pain or cancer-induced bone pain.

[00108] An embodiment of the present invention is a compound according to formula I, as described herein, for the treatment or prophylaxis of a disease, disorder or condition selected from: inflammation; an autoimmune disease; Cancer; an infection; a metabolic disease; Petition 870250094781, dated 10 / 16 / 2025, pp. 230 / 378 44 / 167 a cardiovascular disease; a respiratory disease; a liver disease; a kidney disease; an eye disease; a skin disease; a lymphatic condition; graft-versus-host disease; allodynia; a condition associated with diabetes; and any disease where an individual has been determined to carry a non-silent germline or somatic mutation in NLRP3.

[00109] One embodiment of the present invention is the use of a compound according to formula I, as described herein, in the treatment or prophylaxis of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

[00110] One embodiment of the present invention is the use of a compound according to formula I, as described herein, for use in the treatment or prophylaxis of a disease, disorder or condition selected from asthma and COPD.

[00111] One embodiment of the present invention is the use of a compound according to formula I, as described herein, for use in the treatment or prophylaxis of a cardiovascular disease, disorder or condition.

[00112] One embodiment of the present invention is the use of a compound according to formula I, as Petition 870250094781, dated 10 / 16 / 2025, pp. 231 / 378 45 / 167 described in this document, for use in the treatment or prophylaxis of a cardiometabolic disease, disorder or condition.

[00113] One embodiment of the present invention is the use of a compound according to formula I, as described herein, for use in the treatment or prophylaxis of a disease, disorder or condition selected from periodic syndromes associated with cryopyrin.

[00114] One embodiment of the present invention 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.

[00115] One embodiment of the present invention is a compound according to formula I, as described herein, for the treatment or prophylaxis of a cardiovascular disease, disorder or condition.

[00116] One embodiment of the present invention is a compound according to formula I, as described herein, for the treatment or prophylaxis of a cardiometabolic disease, disorder or condition.

[00117] An embodiment of the present invention is a compound according to formula I, as described herein, for the treatment or prophylaxis of a disease, disorder or condition selected from periodic syndromes associated with cryopyrin.

[00118] One embodiment of the present invention is the use of a compound according to formula I, as described herein, for the preparation of a medicament for the treatment or prophylaxis of a disease, Petition 870250094781, dated 10 / 16 / 2025, pp. 232 / 378 46 / 167 disorder or condition selected from asthma and COPD.

[00119] One embodiment of the present invention is the use of a compound according to formula I, as described herein, for the preparation of a medicament for the treatment or prophylaxis of a cardiovascular disease, disorder or condition.

[00120] One embodiment of the present invention is the use of a compound according to formula I, as described herein, for the preparation of a medicament for the treatment or prophylaxis of a cardiometabolic disease, disorder or condition.

[00121] One embodiment of the present invention is the use of a compound according to formula I, as described herein, for the preparation of a medicament for the treatment or prophylaxis of a disease, disorder or condition selected from periodic syndromes associated with cryopyrin.

[00122] An embodiment of the present invention is a method of treating or prophylactically treating a disease, disorder or condition selected from asthma and COPD, the method comprising administering an effective amount of a compound according to formula I, as described herein.

[00123] One embodiment of the present invention is a method of treating or preventing a cardiovascular disease, disorder or condition, wherein the method comprises administering an effective amount of a compound according to formula I, as described herein.

[00124] One embodiment of the present invention is a method of treatment or prophylaxis of a disease, disorder Petition 870250094781, dated 10 / 16 / 2025, pp. 233 / 378 47 / 167 or cardiometabolic condition, the method of which comprises administering an effective amount of a compound according to formula I, as described in this document.

[00125] An embodiment of the present invention is a method of treating or prophylactically treating a disease, disorder or condition selected from cryopyrin-associated periodic syndromes, the method comprising administering an effective amount of a compound according to formula I, as described herein.

[00126] One embodiment of the present invention relates to a method for inhibiting NLRP3, which method comprises administering an effective amount of a compound according to formula I, as described herein.

[00127] Also, an embodiment of the present invention are compounds of formula I, as described herein, when manufactured according to any of the processes described.

[00128] One embodiment of the present invention is a pharmaceutical composition comprising a compound according to formula I, as described herein, and a therapeutically inert carrier. Test Procedures NLRP3 and Pyroptosis

[00129] It is well established that the activation of NLRP3 leads to cellular pyroptosis, and this characteristic plays an important part in the manifestation of the clinical disease (Yan-gang Liu et al., Cell Death & Disease, 2017, 8(2), e2579; Alexander Wree et al., Hepatology, 2014, 59(3), 898-910; Alex Baldwin et al., Journal of Medicinal Chemistry, 2016, 59(5), 1691-1710; Ema Ozaki et al., Journal of Petition 870250094781, dated 10 / 16 / 2025, pp. 234 / 378 48 / 167 Inflammation Research, 2015, 8, 15-27; Zhen Xie & Gang Zhao, Neuroimmunology Neuroinflammation, 2014, 1(2), 60-65; Mattia Cocco et al., Journal of Medicinal Chemistry, 2014, 57(24), 10366-10382; T. Satoh et al., Cell Death & Disease, 2013, 4, e644). Therefore, NLRP3 inhibitors are expected to block pyroptosis as well as the release of pro-inflammatory cytokines (e.g., IL-1β) from the cell. THP-1 Cells: Culture and Preparation

[00130] 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 passed and grown to confluence (~106 cells / ml). On the day of the experiment, THP-1 cells were harvested and resuspended in RPMI medium (without FBS). Cells were then counted and viability (>90%) verified by Trypan blue (Sigma # T8154). Appropriate dilutions were made to provide a concentration of 625,000 cells / ml. To this diluted cell solution, LPS (Sigma # L4524) was added to provide a Final Assay Concentration (FAC) of 1 g / ml. 40 g / ml of the final preparation were aliquoted into each well of a 96-well plate. The plate thus prepared was used for compound screening. Piroptosis assay in THP-1 cells

[00131] The following step-by-step assay method was followed for compound screening.

[00132] THP-1 cell seeds (25,000 cells / well) containing 1.0 g / ml of LPS in 40 g / ml of medium Petition 870250094781, dated 10 / 16 / 2025, pp. 235 / 378 49 / 167 RPMI (without FBS) in 96-well cell culture plates, with black walls and transparent bottom, coated with polyD-lysine (VWR # 734-0317)

[00133] Add 5 pl of compound (half logarithm dilution of 8 points, with a maximum dose of 10 μM) or vehicle (DMSO 0.1% FAC) to the appropriate wells.

[00134] Incubate for 3 hours at 37°C, 5% CO2

[00135] Add 5 μl of nigericin (Sigma # N7143) (FAC at 5 μm) to all wells

[00136] Incubate for 1 hour at 37°C, 5% CO2

[00137] At the end of the incubation period, centrifuge the plates at 300xg for 3 minutes and remove the supernatant.

[00138] Next, add 50 μL of resazurin (Sigma # R7017) (FAC 100 μM of resazurin in RPMI medium without FBS) and incubate the plates for an additional 1 to 2 hours at 37°C and 5% CO2.

[00139] The plates were read on an Envision reader at Ex 560 nm and Em 590 nm

[00140] IC50 data are fitted to a non-linear regression equation (log inhibitor vs. slope of 4-parameter response variable)

[00141] The pyroptosis assay results are summarized in Table 1 below as THP IC50. IL-Iβ Release Assay in Human Whole Blood

[00142] For systemic delivery, the ability to inhibit NLRP3 when compounds are present within the bloodstream is of great importance. For this reason, the NLRP3 inhibitory activity of a number of compounds in human whole blood was investigated according to the following Petition 870250094781, dated 10 / 16 / 2025, pp. 236 / 378 50 / 167 protocol.

[00143] Whole human blood in Liheparin tubes was obtained from healthy donors from a volunteer donor panel.

[00144] Place 80 μL of whole blood containing 1 pg / ml of LPS in a 96-well clear-bottom cell culture plate (Corning # 3585)

[00145] Add 10 pl of compound (half logarithm dilution of 8 points with a maximum dose of 10 μM) or vehicle (DMSO 0.1% FAC) to the appropriate wells.

[00146] Incubate for 3 hours at 37°C, 5% CO2

[00147] Add 10 pl of nigericin (Sigma # N7143) (FAC at 10 μM) to all wells

[00148] Incubate for 1 hour at 37°C, 5% CO2

[00149] At the end of the incubation period, centrifuge the plates at 300xg for 5 minutes to pelletize cells and remove 20 µl of supernatant and add to 96-well V-bottom plates for IL-β analysis (note: these plates containing the supernatants can be stored at -80°C for analysis at a later date)

[00150] IL-1β was measured according to the manufacturer's protocol (Perkin Elmer-AlphaLisa IL-1 Kit AL220F-5000)

[00151] IC50 data are fitted to a nonlinear regression equation (log inhibitor vs. slope of 4-parameter response variable)

[00152] The results of the human whole blood assay are summarized in Table 1 below as HWB IC50. Microsomal Stability:

[00153] Incubations of test compounds at 1 μM Petition 870250094781, dated 10 / 16 / 2025, pp. 237 / 378 51 / 167 microsomes (0.5 mg / ml) plus NADPH cofactor are performed in 96-well plates at 37°C in a TECAN automated liquid handling system (Tecan Group Ltd, Switzerland). After a 10-minute pre-incubation step of the test compound with microsomes, the enzymatic reaction is initiated by the addition of cofactors. At 1, 3, 6, 9, 15, 25, 35, and 45 minutes, aliquots from the incubations are removed and quenched with an internal standard containing 1:3 (v / v) acetonitrile. The samples are then cooled and centrifuged before supernatant analysis by LC-MS / MS 2. Metabolic Stability in Hepatocytes: Assay Descriptions:

[00154] Biological materials. Cryopreserved hepatocytes [mouse, rat, rabbit, monkey, and human (male and female; mixed)] are obtained. Hepatocyte viability after reconstitution is at least 80% throughout the study. Ready-to-use HepatoPac® rat / human cultures [long-term hepatocyte co-cultures; pooled (n=5 for males n=5 for females for humans)] with mouse stromal fibroblasts (negative control; pooled) with incubation plates, application medium, and maintenance medium are acquired.

[00155] Metabolism by suspended hepatocytes. Primary cryopreserved pooled hepatocytes are reconstituted in pre-warmed Williams E media containing 10% FCS, 0.05 mg / ml streptomycin, 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 1x10⁶ cells / ml. Incubation was performed in a completely closed manner. Petition 870250094781, dated 10 / 16 / 2025, pp. 238 / 378 The 52 / 167 automated liquid handling system (Tecan) is equipped with a CO2 incubator with an orbital shaker. After adding a test compound at, for example, 1 μM, to the wells (1x10⁵ cells / well), the 96-well hepatocyte suspension culture plates are incubated in 5% CO₂ at 37 °C. Samples are quenched by adding acetonitrile (including an internal standard) to the incubation well at the designed time points for up to 2 h.

[00156] Metabolism by HepatoPac®. Incubations for a test article (e.g., 1 μM, 0.1% v / v DMSO), as conducted in suspension assays, are performed in 96-well plates containing a co-culture of adherent hepatocytes with mouse fibroblast control cells or control cells alone (5% CO2 atmosphere and 37°C). The incubation medium in Human HepatoPac® is identical to those in suspended hepatocytes. At defined time points (2, 18, 26, 48, 72 and 96 h), entire wells are quenched with ice-cold acetonitrile containing an internal standard.

[00157] The samples are then centrifuged appropriately and the supernatant is analyzed by LC-MS / MS. Incubation is conducted at n=1 or 2. hERG screening assay

[00158] In the process of developing small molecule drugs, one of the most frequent adverse side effects leading to drug failure is cardiac arrhythmia. This failure is usually related to the drug's ability to inhibit the human ether-to-go gene-related cardiac potassium channel (hERG). Having no or low inhibition of the hERG cardiac potassium channel is, Petition 870250094781, dated 10 / 16 / 2025, pp. 239 / 378 53 / 167 therefore, considered beneficial. Cells

[00159] A CHO crelox hERG cell line (ATCC reference No. PTA-6812, female Chinese hamster cells) was generated and validated at Roche. Instant frozen, ready-to-use CHO-hERG cells were cryopreserved at Evotec (Germany) and used directly in the experiments. Experimental solutions

[00160] The extracellular solution contains (in mM): NaCl 150; KCl 4; CaCl2 1; MgCl2 1; HEPES 10; pH 7.2-7.4 with NaOH, osmolarity of 290-330 mOsm. The internal solution contains (in mM): KCl, 10; KF, 100; NaCl, 10; HEPES, 10; EGTA, 20; pH = 7.0-7.4 with KOH, osmolarity of 260-300 mOsm. Electrophysiology

[00161] The effects of a compound on hERG K+ current parameters will be evaluated at 2 concentrations in at least 4 cells.

[00162] The hERG test is performed using the SynchroPatch® 384 automated patch clamping system (Nanion Technologies GmbH, Germany). K+ currents are measured using the patch-voltage-clamping technique in the whole-cell configuration at 35-37°C.

[00163] The cells were maintained at a resting voltage of -80 mV and were stimulated by a voltage pattern shown in Figure 1 (pulse pattern used to obtain external K+ current at 35-37°C) to activate hERG channels and conduct external IKhERG current, at a stimulation frequency of 0.1 Hz (6 bpm) Petition 870250094781, dated 10 / 16 / 2025, pp. 240 / 378 54 / 167 Data analysis

[00164] IKhERG amplitudes were recorded at each drug concentration and compared to vehicle control values ​​(taken as 100%) to define fractional blocks. Concentration-response data were fitted with the following relationship: l(C )= / 0° 1 + (C / IC 5°)h where C is the concentration, IC50 is the concentration that produces 50% blockage, and h is the Hill coefficient.

[00165] Concentration-response curves were fitted by nonlinear regression analysis using the EworkBook package (ID Business Solutions Ltd, UK). Data fitting was performed using the 4-Parameter Logistic Model (fit = (A+(B / (1+((x / C)AD)))), where A=0 and B=100).

[00166] The hERG assay results are summarized in Table 2 below as hERG IC20. P-gp Transcellular Assay:

[00167] The general assay uses transfected LLC-PK1 cells (porcine renal epithelial cells) with overexpression of human or mouse P-gp, which were cultured in 96-well semipermeable filter membrane plates, where they form a polarized monolayer with tight junctions and act as a barrier between the apical and basolateral compartments.

[00168] P-gp is expressed on the membrane facing the apical part of the monolayer. The rigidity of the cell monolayer and the functional activity of P-gp are confirmed by Petition 870250094781, dated 10 / 16 / 2025, pp. 241 / 378 55 / 167 addition of a cell-impermeable marker, Lucifer Yellow, and a reference P-gp substrate, edoxaban, respectively. J. Pharmacol. Exp Ther., 2021, 376, 322329. PAMPA:

[00169] PAMPA (Parallel Artificial Membrane Permeability Assay) is a first-line permeability screening tool for drug candidates. The PAMPA assay mimics transcellular absorption conditions using an artificial phospholipid membrane. This assay determines a permeability value that can be used for compound optimization and classification purposes, as well as input parameters for in silico models to predict intestinal absorption.

[00170] The donor concentration is measured at the beginning-t (reference) and compared with the donor and acceptor concentrations after a certain time (final-t) to calculate the extent of passage of the compound through the membrane. Bacterial Reverse Mutation Test (AMES):

[00171] Compound testing is conducted as indicated in this guidance: Test No. 471: Bacterial Reverse Mutation Test | OECD Guidelines for Testing of Chemicals, Section 4: Health Effects | OECD Library (oecd-library.org) Bacterial culture:

[00172] The bacterial strains used are TA98, TA100, TA1535, TA97a, and TA102. Batches of each strain are kept as frozen stocks. The ampoules are thawed and used to inoculate cultures in nutrient broth. The Petition 870250094781, dated 10 / 16 / 2025, pp. 242 / 378 56 / 167 cultures are placed in an incubator set to 37°C with shaking for approximately 10 hours to provide a working culture of at least 108 cells per ml.

[00173] To ensure that the cultures are at the appropriate growth stage and culture density, a sample is taken from each culture at the end of the incubation period and assessed for culture density by viability plating or OD650 assessment. Treatment:

[00174] 3 replicates per compound concentration and positive controls and 6 replicates per vehicle controls are included.

[00175] The formulations are prepared using DMSO to allow maximum exposure up to the solubility limit or 1000 μg / well for a freely soluble test item. This concentration is equivalent to 5000 μg / plate, as used in the usual Ames plate embedding assay.

[00176] Concentrations are usually separated by half-logarithm intervals in a single experiment. For soluble compounds, the concentrations will be 0, 3.2, 10, 32, 100, 320, 1000 μg / well. The positive controls used are: Abbreviation Name Used for strain 2NF 2-Nitrofluorene TA98-S-9 NaN3 Sodium Azide TA100 and TA1535 -S-9 AAC 9-Aminoacridine TA97a -S-9 MMC Mitomycin C TA102 -S-9 B[a]P Benzo[a]pyrene TA98 +S-9 AAN Aminoanthracene TA100, TA1535,TA97a and TA102 +S-9 Petition 870250094781, dated 10 / 16 / 2025, pp. 243 / 378 57 / 167

[00177] Plating will be achieved by the following sequence of additions to 400 μL of molten agar supplemented at 45±1°C: • 20 μL of bacterial culture • 20 μL of test article / vehicle control / positive control solution • 100 μL of 10% S-9 mixture or buffer solution followed by rapid mixing and pouring into mutation plates (wells).

[00178] Once set, the plates will be inverted and incubated protected from light for 2 to 3 days in an incubator set to 37°C. Toxicity:

[00179] Toxicity is detected by the following parameters: • Reduced background field • Marked reduction in revertants compared to simultaneous vehicle controls • Reduction in mutagenic response.

[00180] Scoring: Bacterial colony scoring is performed manually or electronically using an automated colony counter. In Vitro Mammalian Cell Micronucleus Test:

[00181] Compound testing is conducted as indicated in this guidance: Test No. 487: In Vitro Mammalian Cell Micronucleus Test | OECD Guidelines for Chemical Testing, Section 4: Health Effects | OECD Library (oecd-library.org) Cell culture:

[00182] The cultures are kept in flasks of Petition 870250094781, dated 10 / 16 / 2025, pp. 244 / 378 58 / 167 Tissue culture containing HEPES-buffered RPMI 1640 medium with GlutaMAX-1 including 10% (v / v) heat-inactivated fetal calf serum, 100 units / ml / 100 pg / ml penicillin / streptomycin in a humidified incubator set to 37°C, 5% (v / v) CO2 in the air. Subculture of cells at low to medium density will be performed at least once before treatment.

[00183] The day before treatment, subcultures will be performed on the cells at a density of approximately 7 x 10⁴ cells / ml. The cells will be maintained at 37°C, 5% (v / v) CO₂ in air, in a humidified environment before treatment. Treatment:

[00184] Human TK6 lymphoblastoid cells in which culture has been performed will be exposed to the compound for 3 hours in the presence of S-9, followed by a 24-hour recovery period. In addition, a continuous 27-hour treatment in the absence of S-9 will be included as a number of chemicals have been reported to only exert positive effects after prolonged treatment. This is equivalent to approximately 1.5-2.0 times the average generation time of TK6 cells used in this laboratory (cell cycle of approximately 15 hours). All cultures will be collected 27 hours after the start of treatment.

[00185] Dilutions will be prepared in DMSO that allow maximum exposure up to the solubility limit, 1 mM or 500 pg / ml, whichever is lower.

[00186] Typically, at least 12 concentrations separated by intervals of 0.7 times, varying below the upper limit (for soluble compounds with MW > 500, as Petition 870250094781, dated 10 / 16 / 2025, pp. 245 / 378 59 / 167 concentrations will be 9.887, 14.12, 20.18, 28.82, 41.18, 58.82, 84.04, 120.1, 171.5, 245, 350, and 500 μς / πιΣ). The final DMSO concentration will be 1% v / v. Positive controls are Noscapine in the absence of S-9 and Cyclophosphamide in the presence of S-9. Two replicates per compound concentration and multiple simultaneous positive and vehicle controls will be included per treatment in 96-well plates and incubated for the treatment time at 37°C, 5% (v / v) CO2. The 3-hour treatment cultures will be washed once and incubated again with fresh medium for 24 hours. Harvest:

[00187] At the designated sample collection time, an aliquot of cell suspension from designed cultures will be taken for cell number determination using a Coulter Counter. The cultures designated for analysis will be centrifuged at approximately 200 g for 5 minutes. The cells will be resuspended in 0.075 M KCl before fixation in fresh, cold methanol / glacial acetic acid (7:1 v / v). The fixed cells will be stored in fixative at 2-8°C before slide preparation. The slides will be air-dried before staining by immersion in 12.5 μg / ml of Acridine Orange in phosphate-buffered saline (PBS), pH 6.8 for approximately 10 minutes, followed by washing with PBS (with agitation) for a few seconds. Cytotoxicity reading and concentration selection:

[00188] Toxicity is expressed as Population Doubling (PD) relative to vehicle controls. PD will be calculated for each concentration as follows: PD = [log (N / X0)] / log 2 where N = final average cell count / culture in each Petition 870250094781, dated 10 / 16 / 2025, pp. 246 / 378 60 / 167 concentration Xo = initial count (baseline)

[00189] The highest concentration for micronucleus analysis should not exceed (approximately) 50% cytotoxicity, be the highest concentration tested, or be the lowest precipitating concentration observed with the naked eye at the end of the treatment incubation period. Slides from the highest selected concentration and at least two lower concentrations will be analyzed so that a range of cytotoxicity, from maximum to little or none, is covered, when appropriate. A minimum of 1000 mononuclear cells from each culture (2000 per concentration) will be analyzed for micronuclei. Evaluation criteria:

[00190] The compound will be considered to induce clastogenic and / or aneugenic events if: - A statistically significant increase in the frequency of MNMON cells was observed at one or more concentrations. The incidence of cells with micronuclei at such a concentration exceeds the normal range in both replicates. - An increase related to the concentration in the proportion of cells with micronuclei was observed (positive trend test).

[00191] The compound will be considered positive in this assay if all the above criteria are met.

[00192] The compound will be considered negative in this assay if none of the above criteria are met.

[00193] Results that only partially meet the above criteria will be treated on a basis Petition 870250094781, dated 10 / 16 / 2025, pp. 247 / 378 61 / 167 on a case-by-case basis, but, in the context of the screening study, will be concluded as positive, negative, or ambiguous. Evidence of a concentration-related effect is considered useful, but not essential in evaluating a positive result. Biological relevance will be taken into consideration, for example, consistency of response within and between concentrations and (if applicable) between experiments, or effects that occur only at very toxic concentrations. Pharmacokinetic profile of test substances in minipigs:

[00194] The pharmacokinetics of the test substance were determined in minipigs after intravenous and oral administration. The experimental design consisted of three male minipigs, each of which received a single intravenous bolus dose and a single oral dose of the test item. Intravenous doses were administered at a nominal dose volume of 1 ml / kg. Oral doses were administered by gavage at a nominal dose volume of 5 ml / kg. There was a treatment suspension period of at least 7 days between the last sample collection occasion and the next dosing occasion in the same animal. The content of all formulations was within the desired range of 85 to 115% of the nominal content. After dosing, blood samples (1 ml) were taken from the saphenous vein (using a cannula) or jugular vein of each animal at pre-dose, 5, 15, 30 min, 1, 2, 4, 8, 24 hours after IV dosing and at pre-dose, 15, 30 min, 1, 2, 4, 6, 8, 24, 48 hours after oral dosing.At all time points, hematocrit was determined. The blood:plasma partition factor was determined at the time points. Petition 870250094781, dated 10 / 16 / 2025, pp. 248 / 378 62 / 167 doses were administered at 2 and 4 hours, and urine was collected as a single sample for 24 hours after dose administration. Blood samples (nominally 1 ml) were withdrawn from the saphenous vein (via cannula) or jugular vein of each animal into polypropylene tubes containing K2EDTA anticoagulant and centrifuged (1500 g, 10 min, 4°C) to prepare plasma for analysis. Residual blood cells were discarded. Plasma ampoules were capped and stored on moist ice for no more than 60 minutes before being transferred to storage at <-50°C (nominally -80°C) prior to analysis with a specific LC-MS method. Test Substance Toxicity Assessment in Miniature Pigs

[00195] The maximum tolerated dose (MTD) of the test item is determined after once-daily oral administration (gavage) to the miniature pig. The toxicity of repeated daily administration for 14 days is then evaluated. In addition, the toxicokinetic profile of the test item is characterized. Gottingen miniature pigs bred sufficiently for this purpose are obtained from Ellegaard Gottingen, Dalmose, Denmark (Animals: age range 2 to 3 months and weight range 4 to 6 kg). At the start of dosing, the animals are 4 to 5 months old and weigh between 6 and 9.5 kg. A dose volume of 10 ml / kg is used. Individual dose volumes are calculated from the most recent body weights for each animal to achieve dose levels of 30, 100 and 300 mg / kg / day or others depending on non-MTD results.Blood samples are collected on day 1 and day 14 to determine plasma drug concentration and derived toxicokinetic parameters. The animals are not fed on the scheduled necropsy day. Each animal is... Petition 870250094781, dated 10 / 16 / 2025, pp. 249 / 378 63 / 167 anesthetized by intramuscular injection of a Zoletil mixture and then killed by exsanguination. All tissues are preserved in the appropriate fixative(s). Additional analyses include food intake, body weight, clinical pathology, and complete histopathological examination of target organs. Table 1: Inhibitory activity of NLRP3 Example No. THP-1 Pyroptosis Assay IC50 (nM) Human whole blood IL-Ιβ Assay IC50 (nM) 1 3.3 24.2 2 4.3 19.6 3 27.9 35.2 4 26.1 192.3 5 51 432 6 12 95 7 10 17 8 11 28 9 45 84 10 5 29 11 4 8 12 8 15 13 0.8 19 14 0.6 22 15 34 33 16 8 22 Petition 870250094781, dated 10 / 16 / 2025, pp. 250 / 378 64 / 167 Example No. THP-1 Pyroptosis Assay IC50 (nM) Human whole blood IL-Ιβ Assay IC50 (nM) 17 3 18 18 2 19 4 20 75 68 21 9 22 5 39 23 44 34 24 19 53 25 2 16 27 6 95 28 23 86 29 7 124 30 13 48 Table 2: Human P-gp transcellular assay: Example No. Permeability [nm / s] ER 1 26 4.4 2 29 3.0 3 19 2.9 11 26 3.3 Petition 870250094781, dated 10 / 16 / 2025, pp. 251 / 378 65 / 167 Example No. Permeability [nm / s] ER 13 83 3.5 14 135 4.0 16 37 5 22 122 9 31 112 3 * ER = efflux rate Table 3: hERG inhibitory activity Example No. hERG IC20 [μΜ] 1 > 10 3 6 11 > 10 12 > 10 13 > 10 15 > 10 16 > 10 17 > 10 18 6.3 following

[00196] The invention will now be illustrated by examples which are not limiting in nature.

[00197] If the preparatory examples are Petition 870250094781, dated 10 / 16 / 2025, pp. 252 / 378 66 / 167 obtained as a mixture of enantiomers or diastereomers, the pure enantiomers or diastereomers can be obtained by methods described in this document or by methods known to those skilled in the art, such as, for example, chiral chromatography or crystallization. The salt-free compounds can be transformed into analogues of the examples described, producing salts. Experimental Methods Abbreviations ACN Acetonitrile Aq. Aqueous DCE Dichloroethane DCM Dichloromethane DIEA N,N-Diisopropylethylamine DMF Dimethylformamide ESI Electrospray ionization EtOH Ethanol EtOAC Ethyl acetate eq Equivalent h, hours Hour(s) HPLC High-performance liquid chromatography LCMS Liquid chromatography-mass spectrometry MeCN Acetonitrile MeOH Methanol mins Minutes MTBE Methyl tert-butyl ether PE Petroleum ether ta Room temperature Petition 870250094781, dated 10 / 16 / 2025, pp. 253 / 378 67 / 167 TEA Triethylamine TBAF Tetrabutylammonium fluoride THF Tetrahydrofuran TFA Sat. Trifluoroacetic acid Saturated SFC Supercritical fluid chromatography Intermediate Preparation Intermediate 1 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5(2-trimethylsilylethoxymethoxy)benzonitrile \i ' O —C^ô£ Step A: 4-bromo-2-:methoxy-6-:methyl-aniline

[00198] A solution of 2-methoxy-6-methylaniline (CAS # 50868-73-0, 50.0 g, 364.5 mmol, 1.0 eq) in methanol (150 ml) and acetic acid (50.0 ml, 874.2 mmol, 2.4 eq) Br2 (22.4 ml, 437.4 mmol, 1.2 eq) was slowly added dropwise at 0 °C. The mixture was then stirred at 25 °C for 2 h. After the reaction was complete, the above reaction solution was diluted with water (300 ml) and extracted with ethyl acetate (3 x 100 ml). The combined organic phase was washed with brine (100 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under pressure and purified by silica gel column chromatography (PE / EtOAc, 1:0 to 10:1) to generate the title compound (30.3 Petition 870250094781, dated 10 / 16 / 2025, pp. 254 / 378 68 / 167 g, yield of 38%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 6.82 (d, 1H), 6.78 (d, 1H), 4.57 (m, 2H), 3.77 (s, 3H), 2.06 (s, 3H). Step B: 4-amino-3-:methoxy-5-methylbenzonitrile

[00199] To a solution of 4-bromo-2-methoxy-6-methylaniline (30.3 g, 140.2 mmol, 1.0 eq) and Zn(CN)2 (16.5 g, 140.51 mmol, 1.0 eq) in DMF (260 ml) was added Pd(PPh3)4 (32.4 g, 28.1 mmol, 0.2 eq) under N2. The mixture was stirred at 100°C for 12 h under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled to 20°C, poured into water (500 ml) and extracted with ethyl acetate (3 x 300 ml). The organic phase was washed with brine (3 x 200 ml), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude was purified by silica gel column chromatography (PE / EtOAc, 1:0 to 5:1) to yield the title compound (22.0 g, 97% yield) as a pink solid. 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 7.05 (s, 2H), 5.48 (s, 2H), 3.81 (s, 3H), 2.09 (s, 3H). Step C: 4-bromo-3-methoxy-5-methylbenzonitrile

[00200] To a solution of 4-amino-3-methoxy-5-methylbenzonitrile (22.0 g, 135.6 mmol, 1.0 eq) and CuBr (29.2 g, 203.5 mmol, 1.5 eq) in MeCN (220 ml), butyl nitrite (20.9 ml, 203.5 mmol, 1.5 eq) was added dropwise at 25°C. Then, the mixture was stirred at 65°C for 2 h. After the reaction was complete, the mixture was cooled to 20°C, diluted with MeCN (150 ml), filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (hexane / EtOAc, 1:0 to 5:1). Next, the residue was mixed with a mixture of ethyl acetate. Petition 870250094781, dated 10 / 16 / 2025, pp. 255 / 378 69 / 167 (30 ml) and petroleum ether (3 ml), filtered and the cake was collected to yield the title compound (18.0 g, 59% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 7.46 (s, 1H), 7.43 (s, 1H), 3.91 (s, 3H), 2.39 (s, 3H). Step D: 4-bromo-3-hydroxy-5-:methylbenzonitrile

[00201] To a solution of 4-bromo-3-methoxy-5-methylbenzonitrile (6.0 g, 26.5 mmol, 1.0 eq) in DCM (30 ml), BBr3 (30.0 ml, 316.1 mmol, 11.9 eq) was added at 0°C, then stirred at 25°C for 1 h. After completion of the reaction, it was combined with another batch (10 g) and diluted with water (500 ml). The mixture was extracted with ethyl acetate (3 x 150 ml) and the combined organic phase was washed with brine (200 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (hexane / EtOAc, 1:0 to 10:1) to yield the title compound (13.3 g, 89% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 10.15 (s, 1H), 6.42 (d, 1H), 6.24 (d, 1H), 1.51 (s, 3H). Step E: 4-bromo-3-methyl-5-(2trimethylsilylethoxymethoxy)benzonitrile

[00202] To a solution of 4-bromo-3-hydroxy-5-methylbenzonitrile (13.3 g, 62.7 mmol, 1.0 eq) in DMF (60 ml) was added Cs2CO3 (33.3 g, 102.1 mmol, 1.6 eq) at 0 °C, then stirring continued at 20 °C for 0.5 h. Then, 2-(trimethylsilyl)ethoxymethyl chloride (CAS # 76513-69-4, 15.5 ml, 87.8 mmol, 1.4 eq) was added dropwise at 0 °C, then stirred at 20 °C for 1 h. After the reaction was complete, water (200 ml) was added and the mixture was extracted. Petition 870250094781, dated 10 / 16 / 2025, pp. 256 / 378 70 / 167 with MTBE (3 x 150 ml). The combined organic phase was washed with brine (150 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (hexane / EtOAc, 1:0 to 10:1) to yield the title compound (16.3 g, 76% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ [ppm]: 7.27 (d, 1H), 7.18 (d, 1H), 5.30 (s, 2H), 3.77 (t, 2H), 2.44 (s, 3H), 0.95 (t, 2H), 0.00 (s, 9H). Step F: 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)-5-(2-trimethylsilylethoxy-methoxy)benzonitrile

[00203] To a solution of 4-bromo-3-methyl-5-(2-trimethylsilethoxymethoxy)benzonitrile (10.0 g, 29.2 mmol, 1.0 eq) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (14.8 g, 58.43 mmol, 2.0 eq) in 1,4-dioxane (100 ml) was added Cs2CO3 (19.04 g, 58.43 mmol, 2.0 eq), tris(4-methoxy-3,5-dimethylphenyl)phosphane (CAS # 12189864-4, 1.28 g, 2.92 mmol, 0.1 eq), Pd(OAc)2 (0.66 g, 2.92 mmol, 0.1 eq) and the mixture was stirred at 95°C for 5 h under N2. After the reaction was complete, the mixture was cooled to room temperature, diluted with water (150 ml) and ethyl acetate (50 ml), filtered, and the filtrate was extracted with ethyl acetate (3 x 100 ml).The combined organic phase was washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EtOAc, 1:0 to 10:1) (17 g), then triturated with MeOH (51 ml), filtered, and the cake was collected to yield the title compound (8.38 g, 74% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ [ppm]: 7.13 (s, 1H), 7.07 (s, 1H). Petition 870250094781, dated 10 / 16 / 2025, pp. 257 / 378 71 / 167 5.18 (s, 2H), 3.72 (t, 2H), 2.36 (s, 3H), 1.38 (s, 12H), 0.94 (t, 2H), 0.00 (s, 9H). Intermediate 2 4-(6-amino-5-benzyloxy-pyrazin-2-yl)-3-methyl-5-(2trimethylsilylethoxymethoxy)-benzonitrile Step A: 3-benzyloxy-6-chloro-pyrazine-2-amine

[00204] To a stirred solution of benzyl alcohol (4.49 ml, 43.2 mmol, 1.0 eq) in THF (90 ml) at room temperature, NaH (1.73 g, 43.18 mmol, 1.0 eq 60% in mineral oil) was added and stirring continued for 10 minutes. Then, 3-bromo-6-chloropyrazine-2-amine (CAS # 212779-21-0, 9.0 g, 43.2 mmol, 1.0 eq) was added and the reaction mixture was heated to 70°C for 4 h. The reaction mixture was cooled to room temperature. Ethyl acetate (60 ml) and water (80 ml) were added and the layers were separated. The aqueous phase was extracted with ethyl acetate (80 ml x 2). The combined extracts were washed with brine (80 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1 to 1:1), then purified by normal phase flash (column: Welch Ultimate XB-CN 250*70*10um; condition: hexane-EtOH Start B 12 End B 12; gradient time (min): 15 100% B; holding time). Petition 870250094781, dated 10 / 16 / 2025, pp. 258 / 378 72 / 167 (min) 5; flow rate (ml / min) 140) to generate the title compound (2.3 g, 23% yield) as a yellow solid. LCMS: m / z 236.0 [M+H]+, ESI pos. Step B: 4-(6-amino-5-benzyloxy-pyrazin-2-yl)-3-methyl-5-(2-trimethylsilethoxymethoxy)-benzonitrile

[00205] To a solution of the above-mentioned 3-benzyloxy-6-chloropyrazin-2-amine (2000 mg, 8.49 mmol, 1.0 eq) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-5-(2-trimethylsilethoxymethoxy)-benzonitrile (3965.2 mg, 10.2 mmol, 1.2 eq), CsF (2578.2 mg, 16.9 mmol, 2.0 eq) in 1,4-dioxane (30 ml) and water (3 ml) was added XPhos Pd G3 (719.2 mg, 0.85 mmol, 0.1 eq) under N2. Then, the mixture was stirred at 95°C for 2 h. After the reaction was complete, the reaction mixture was cooled to room temperature. Ethyl acetate (150 ml) and water (150 ml) were added and the layers were separated. The aqueous phase was extracted with ethyl acetate (150 ml x 2). The combined extracts were washed with brine (250 ml), dried over Na2SO4, filtered, and concentrated under vacuum to provide a residue.The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1 to 1:1) to give the title compound (2.70 g, 69% yield) as a yellow solid. LCMS: m / z 463.2 [M+H]+, ESI pos. Intermediate 3 (3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]piperidin-3amine Petition 870250094781, dated 10 / 16 / 2025, pp. 259 / 378 73 / 167 Step A: Benzyl N-[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3piperidyl]carbamate

[00206] To a solution of benzyl N-[(3R)-3-piperidyl]carbamate (CAS # 478646-32-1, 2.0 g, 8.54 mmol, 1.0 eq) in methanol (30 ml) was added (tert-butyldimethylsilyloxy)acetaldehyde (1.64 g, 9.39 mmol, 1.1 eq), followed by NaBH3CN (1.35 g, 21.3 mmol, 2.5 eq). The mixture was stirred at 20°C for 3 hours. The mixture was quenched with water (50 ml) and then concentrated under vacuum to remove methanol. Then, EtOAc (100 ml) was added and the layers were separated. The aqueous phase was extracted with EtOAc (300 ml x 2). The combined extracts were washed with brine (50 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc; PE = 77% at 33%) to give the title compound (2100.0 mg, 63% yield) as a colorless oil. LCMS m / z 393.3 [M+H]+, ESI pos. Step B: (3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]piperidin-3-amine

[00207] To a solution of N-[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]benzyl carbamate (2.1 g, 5.35 mmol, 1.0 eq) in methanol (30 ml) Pd / C (10%, 200 mg) and Pd(OH)2 (10%, 200 mg) were added under N2. Then, the suspension was degassed under vacuum and purged with H2 several times and stirred under a H2 flask at 50°C for 16 h. The suspension was filtered through a Celite pad and the filter cake was washed with MeOH (3 x 50 ml). The combined filtrates were concentrated under vacuum to provide the desired compound (1100.0 mg, 80% yield). Petition 870250094781, dated 10 / 16 / 2025, pp. 260 / 378 74 / 167 as a yellow oil.1H NMR (400 MHz, CD3OD) δ [ppm]: 3.79 (t, 2H), 2.93 - 2.91 (m, 1H), 2.83 - 2.76 (m, 2H), 2.54 (t, 2H), 2.11 - 2.06 (m, 1H), 1.92 - 1.84 (m, 2H), 1.73 - 1.68 (m, 1H), 1.61 - 1.55 (m, 1H), 1.15 - 1.06 (m, 1H), 0.90 (s, 9H), 0.83 (s, 6H). Intermediate 4 3-(methoxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-5-((2-(trimethylsilyl)ethoxy)methoxy)benzonitrile Step A: Methyl 2-amino-5-bromo-3-methoxybenzoate

[00208] A solution of methyl 2-amino-3-methoxybenzoate (10.0 g, 55.2 mmol, 1.0 eq CAS # 5121-346) in methanol (40 ml) was added dropwise to a solution of Br2 (3.4 ml, 66.2 mmol, 1.2 eq) in acetic acid (20 ml) at 0 to 10°C. The reaction mixture was stirred at 20°C for 2 h. The reaction mixture was poured into aqueous NaHSO3 (20 ml) and extracted with EtOAc (150 ml x 3). The organic phase was washed with brine (20 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1) to give the title compound (10.0 g, 70% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 7.43 (d, 1H), 7.10 (d, 1H), 6.46 (br. s, 1H), 3.85 (s, 3H), 3.80 (s, 3H). Petition 870250094781, dated 10 / 16 / 2025, pp. 261 / 378 75 / 167 Step B: Methyl 2-amino-5-cyano-3-methoxybenzoate

[00209] To a solution of methyl 2-amino-5-bromo-3-methoxybenzoate (10.0 g, 38.45 mmol, 1.0 eq) in MPN (50 ml) was added CuCN (4.13 g, 46.1 mmol, 1.2 eq). The mixture was stirred at 180°C for 2 h in a microwave. The reaction mixture was poured into water (10 ml) and extracted with ethyl acetate (100 ml x 3). The organic phase was washed with brine (100 ml x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0 to 5:1) to yield the title compound (6.0 g, 76% yield) as a white solid. LCMS: m / z 207.1 [M+H]+, ESI pos. Step C: Methyl 2-bromo-5-cyano-3-methoxybenzoate

[00210] To a solution of methyl 2-amino-5-cyano-3-methoxybenzoate (5.7 g, 27.64 mmol, 1.0 eq), CuBr (5.95 g, 41.5 mmol, 1.5 eq) in MeCN (80 ml) was added butyl nitrite (4.28 g, 41.5 mmol, 1.5 eq). The mixture was stirred at 65°C for 2 hours. The reaction mixture was poured into water (10 ml) and extracted with ethyl acetate (100 ml x 3). The organic phase was washed with brine (100 ml x 3), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0 to 5:1) to generate the title compound (4.0 g, 54% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 7.78 (d, 1H), 7.74 (d, 1H), 3.96 (s, 3H), 3.88 (s, 3H). Step D: 2-bromo-5-cyano-3-hydroxybenzoic acid

[00211] To a solution of 2-bromo-5-cyano-3 Petition 870250094781, dated 10 / 16 / 2025, pp. 262 / 378 76 / 167 Methyl methoxybenzoate (3.8 g, 14.1 mmol, 1.0 eq) in DCM (20 ml) was added to BBr3 (13.6 ml, 140.7 mmol, 10.0 eq) at -65°C. The mixture was then stirred at 25°C for 16 h. The reaction mixture was poured into water (10 ml) and extracted with ethyl acetate (100 ml x 3). The organic phase was washed with brine (100 ml x 3), dried over N2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 2:1) to yield the title compound (2.9 g, 85% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 13.76 (br. s, 1H), 11.41 (s, 1H), 7.52 (d, 1H), 7.33 (d, 1H). Step E: 2-trimethylsilethoxymethoxybenzoate

[00212] A solution of 2-bromo-5-cyano-3-(2-trimethylsilethoxymethyl)benzoate (2.9 g, 11.9 mmol, 1.0 eq), Cs2CO3 (7.81 g, 23.96 mmol, 2.0 eq) in DMF (50 ml) was stirred for 10 min at 25°C. Then, SEM-Cl (4.0 g, 23.96 mmol, 2.0 eq) was added and stirred at 25°C for 2 h. The reaction mixture was poured into water (10 ml) and extracted with ethyl acetate (100 ml x 3). The organic phase was washed with brine (100 ml x 3), dried over N2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 1:0 to 2:1) to generate the title compound (3.60 g, 60% yield) as a white solid. 1H NMR (400 MHz, DMSO-d) δ [ppm]: 7.83 (d, 1H), 7.78 (d, 1H), 5.49 (d, 4H), 3.82 - 3.73 (m, 4H), 0.96 - 0.87 (m, 4H), -0.01 (s, 9H), 0.07 (s, 9H). Petition 870250094781, dated 10 / 16 / 2025, pp. 263 / 378 77 / 167 Step F: 4-bromo-3-(hydroxymethyl)-5-((2(trimethylsilyl)ethoxy)methoxy)benzonitrile

[00213] To a solution of 2-bromo-5-cyano-3-(2-trimethylsilylethoxymethoxy)benzoate of 2-trimethylsilylethoxymethyl (3.0 g, 5.97 mmol, 1.0 eq) in THF (20 ml), NaBH4 (903.31 mg, 23.9 mmol, 4.0 eq) was added and stirred for 16 h at 25°C. The reaction mixture was poured into water (10 ml) and extracted with ethyl acetate (100 ml x 3). The organic phase was washed with brine (100 ml x 3), dried over N2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 1:0 to 5:1) to generate the title compound (1.6 g, 75% yield) as a white solid. 1H NMR (CD3OD, 400 MHz) δ [ppm]: 7.55 (d, 1H), 7.48 (d, 1H), 5.65 (t, 1H), 5.43 (s, 2H), 4.52 (d, 2H), 3.73 (t, 2H), 0.88 (t, 2H), -0.05 (s, 9H). Step G: 4-bromo-3-(methoxymethyl)-5-((2-trimethylsilyl)ethoxy)methoxy)benzonitrile

[00214] To a solution of 4-bromo-3-(hydroxymethyl)-5-(2-trimethylsilylethoxymethoxy)benzonitrile (200 mg, 0.56 mmol, 1.0 eq) in THF (3 ml), NaH (44.7 mg, 1.12 mmol, 2.0 eq, 60%) was added and stirred for 10 min at 25°C. Then, MeI (0.1 ml, 1.61 mmol, 2.88 eq) was added and stirred for 2 hours at 25°C. The mixture was quenched with water (30 ml), and extracted with EtOAc (30 ml x 3). The organic phase was washed with brine (30 ml x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EtOAc, 50:1 to 10:1) to provide the compound of Petition 870250094781, dated 10 / 16 / 2025, pp. 264 / 378 78 / 167 titer (130 mg, 63% yield), obtained as colorless oil. 1H NMR (DMSO-d6, 400 MHz) δ [ppm]: 7.60 (s, 1H), 7.46 (s, 1H), 5.44 (s, 2H), 4.48 (s, 2H), 3.74 (t, 2H), 3.39 (s, 1H), 0.88 (t, 2H), -0.04 (s, 9H). Step H: 3-(methoxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-5-((2(trimethylsilyl)ethoxy)methoxy)benzonitrile 0.35 mmol, 1.0 eq), 4,4,4', 4', 5.5, 5', 5'octamethyl-2,2'-bi(1,3,2-dioxaborolane) (441.68 mg, 1.75 mmol, 5.0 eq) in 1,4-dioxane (4 ml) was added KOAc (102.8 mg, 1.05 mmol, 3.0 eq) and Pd(dppf)Cl2 (25.5 mg, 0.03 mmol, 0.1 eq) was added, and the mixture was then stirred at 95 °C for 4 hours. The reaction mixture was poured into water (10 ml) and extracted with ethyl acetate (100 ml x 3). The organic phase was washed with brine (100 ml x 3), dried over N2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAC = 1:0 to 10:1) to yield the title compound (20.0 mg, 14% yield) as a white solid.1H NMR (CD3OD, 400 MHz) δ [ppm]: 7.31 (s, 1H), 7.26 (s, 1H), 5.30 (s, 2H), 4.49 (s, 2H), 3.84 - 3.76 (m, 2H), 3.32 (s, 3H), 1.40 (s, 12H), 0.99 - 0.92 (m, 2H), 0.01 (s, 9H). Intermediate 5 5-bromo-2-chloro-oxazolo[4,5-b]pyridine o JTX^Cl Br ^N X'-'N Step A: 5-bromo-oxazolo[4,5-b]pyridine-2-thiol Petition 870250094781, dated 10 / 16 / 2025, pp. 265 / 378 79 / 167

[00216] To a mixture of 2-amino-6-bromopyridin-3-ol (CAS # 934758-27-7, 5.0 g, 26.45 mmol, 1.0 eq) in DMF (50 ml), 1,1'-thiocarbonyldi-imidazole (6.13 g, 34.4 mmol, 1.3 eq) was added and stirred for 16 h at 20°C. Ethyl acetate (100 ml) and water (100 ml) were added and the layers were separated. The aqueous phase was extracted with ethyl acetate (2 x 100 ml). The combined extracts were washed with aqueous HCl solution. 1N (2 x 150 ml), followed by brine (2 x 200 ml), dried over Na2SO4, filtered and concentrated under vacuum to give the title compound (10.0 g, 96% yield) as a yellow solid. LCMS: m / z 230, 9 [M+H]+, ESI pos. Step B: 5-bromo-2-chloro-oxazolo[4,5-b]pyridine

[00217] To a mixture of 5-bromo-oxazolo[4,5b]pyridine-2-thiol (9.0 g, 22.86 mmol, 1.0 eq) and DMF (0.1 ml) oxalyl chloride (29.02 g, 228.63 mmol, 10.0 eq) was added and stirred for 1 hour at 50°C under N2. The reaction mixture was cooled to room temperature. Ethyl acetate (100 ml) and ice water (50 ml) were added and the layers were separated. The aqueous phase was extracted with ethyl acetate (2 x 100 ml). The combined extracts were washed with brine (2 x 200 ml), dried over Na2SO4, filtered and concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate gradient = 100:1 to 10:1) to give the title compound (4.0 g, 75% yield) as a yellow solid. LCMS: m / z 234.9 [M+H]+, ESI pos. Intermediate 6 (3R)-3-[(3-benzyloxy-6-chloro-pyrazin-2-yl)carbamothioylamino]piperidine-1-benzyl carboxylate Petition 870250094781, dated 10 / 16 / 2025, pp. 266 / 378 80 / 167 Step A: Benzyl (3R)-3-isothiocyanatopiperidine-1-carboxylate

[00218] To a solution of (R)-3-aminopiperidine-1-carboxylate benzyl (CAS # 1044560-96-4, 1.0 g, 4.27 mmol, 1.0 eq) in DCM (5 ml) a solution of thiophosgene (0.490 g, 4.27 mmol, 1.0 eq) in DCM (5 ml) was added dropwise at 0°C, then stirred at 20°C for 2 h. The above reaction mixture was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0 to 5:1) to yield the title compound (0.85 g, 72% yield) as a yellow oil. 1H NMR (DMSO-d6, 400 MHz) δ [ppm]: 7.45 - 7.27 (m, 5H), 5.12 (s, 2H), 4.06 - 3.98 (m, 1H), 3.96 - 3.62 (m, 2H), 3.44 - 3.36 (m, 1H), 3.28 - 2.95 (m, 1H), 1.95 - 1.82 (m, 2H), 1.69 - 1.45 (m, 2H). Step B: (3R)-3-[(3-benzyloxy-6-chloro-pyrazin-2-yl)carbamothioylamino]piperidine-1-carboxylate benzyl

[00219] To a solution of the above-mentioned 3-benzyloxy-6-chloropyrazin-2-amine (Intermediate 2, Step A) (0.600 g, 2.55 mmol, 1.0 eq) in THF (6 ml) was added NaH (203.67 mg, 5.09 mmol, 2.0 eq, 60% in mineral oil) and stirred at 0°C for 0.5 h, then a solution of (3R)-3isothiocyanatopiperidine-1-carboxylate benzyl (0.703 g, 2.55 mmol, 1.0 eq) in THF (3 ml) was left and stirred at 20°C for 1 hour. The above reaction solution was quenched with saturated ammonium chloride (100 ml), extracted with acetate of Petition 870250094781, dated 10 / 16 / 2025, pp. 267 / 378 81 / 167 ethyl (3 x 20 ml). The combined organic phase was washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0 to 5:1) to generate the title compound (0.500 g, 36% yield) as gum yellow. LCMS: m / z 512.1, [M+H]+, ESI pos. Intermediate 7 (4-cyano-2-hydroxy-6-methylphenyl)boronic acid Stage A: 4-amino-3-methoxy-5-methyl-benzonitrile

[00220] Two batches were carried out in parallel. To a solution of 4-bromo-2-methoxy-6-methylaniline (25.0 g, 115 mmol, 1.0 eq) in DMF (250 ml) was added Zn(CN)2 (13.5 g, 115 mmol, 7.34 ml, 1.00 eq) and Pd(PPh3)4 (66.8 g, 57.8 mmol, 0.50 eq). The reaction mixture was stirred at 100°C for 12 hours. The reaction mixture was poured into H2O (1.50 L) and extracted with ethyl acetate (1.00 L χ 3). The organic phase was washed with brine (1.00 L χ 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to provide a residue, which was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to yield the title compound (28.0 g, 75% yield) as a yellow solid. Step B: 4-bromo-3-methoxy-5-methyl-benzonitrile

[00221] To a solution of CuBr (46.4 g, 323 mmol, 9.86 ml, 1.50 eq) in MeCN (180 ml), t-BuONO (33.3 g, 323 mmol, 38.5 ml, 1.50 eq) was added and stirred at 65°C. Then, Petition 870250094781, dated 10 / 16 / 2025, pp. 268 / 378 82 / 167 A solution of 4-amino-3-methoxy-5-methyl-benzonitrile (35.0 g, 215 mmol, 1.00 eq) in MeCN (180 ml) at 65°C was added. The mixture was stirred at 65°C for 3.5 h. After cooling to room temperature, saturated aqueous Na2SO3 (400 ml) and saturated aqueous NH4Cl (200 ml) were added to the mixture and extracted with ethyl acetate (500 ml x 3). The organic phase was washed with brine (500 ml x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to provide a residue. The residue was purified by column chromatography (S1O2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1, Rf = 0.75) to give the title compound (20.7 g, 42% yield) as a white solid. Step C: 3-methoxy-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolane-2-yl)benzonitrile

[00222] To a solution of 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 h. Pd(dppf)Cl2*CH2Cl2 (13.0 g, 15.9 mmol, 0.20 eq) was added. The mixture was stirred at 100°C for 12 h. After cooling to room temperature, the mixture was filtered with diatomaceous earth and diluted with H2O (500 ml) and extracted with ethyl acetate (800 ml x 3). The organic phase was washed with brine (800 ml x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue 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, 83% yield) as a white solid. Step D: (4-cyano-2-hydroxy-6-:methylphenyl)boronic acid

[00223] A solution of 3-methoxy-5-methyl-4(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzonitrile Petition 870250094781, dated 10 / 16 / 2025, pp. 269 / 378 83 / 167 (17.0 g, 96.0 mmol, 1.00 eq) in DCM (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, and the cake was collected and triturated with ethyl acetate (20 ml) to give the title compound (4.67 g, 42% yield) as a gray solid. LCMS: m / z 178.1 [M+H]+, ESI pos. Intermediate 8 6-(methoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-2,3-dihydrobenzofuran-4-ol Step A: 2-[2,6-dibromo-4-(methoxymethyl)phenyl]ethanol

[00224] To a solution of 1,3-dibromo-5(methoxymethyl)benzene (171 g, 610 mmol, 1.00 eq, CAS# 164631410-4) in THF (750 ml) was added LDA (2.00 M, 366 ml, 1.20 eq) at -78°C and stirring continued for 30 min. Then, a solution of 1,3,2-dioxathiolane of 2,2-dioxide (98.5 g, 794 mmol, 1.30 eq, CAS# 1072-53-3) in THF (750 ml) was added to the mixture at -78°C. The mixture was heated and stirred at 25°C for 1 h. The reaction mixture was quenched by the addition of aqueous HCl (12.0 M, 170 mL) at 0°C and then diluted with water (500 mL) and extracted with EtOAc (500 mL x 3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1). Petition 870250094781, dated 10 / 16 / 2025, pp. 270 / 378 84 / 167 to 10 / 1) to produce the title compound (60.0 g, 30% yield) as a white NLRP solid. Step B: 4-bromo-6-(methoxymethyl)-2,3-dihydrobenzofuran

[00225] To a solution of 2-[2,6-dibromo-4-(methoxymethyl)phenyl]ethanol (60.0 g, 185 mmol, 1.00 eq) in dioxane (600 ml) was added t-BuOLi (44.4 g, 555 mmol, 50.0 ml, 3.00 eq) and CuI (3.53 g, 18.5 mmol, 0.10 eq) under a N2 atmosphere. The mixture was stirred at 100°C for 5 hours. The reaction mixture was quenched by the addition of water (1.00 L) and then diluted with ethyl acetate (500 ml) and extracted with ethyl acetate (500 ml x 3). The combined organic layers were washed with brine (500 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure. The title compound (50.0 g, crude) was obtained as a yellow oil and used without further purification in the next step. Step C: 6-(methoxymethyl)-2,3-dihydrobenzofuran-4-ol

[00226] To a solution of 4-bromo-6(methoxymethyl)-2,3-dihydrobenzofuran (48.0 g, 197 mmol, 1.00 eq) in dioxane (250 ml) and H2O (250 ml) was added t-BuXphos (16.7 g, 39.4 mmol, 0.20 eq), Pd2(dba)3 (9.04 g, 9.87 mmol, 0.05 eq) and KOH (33.2 g, 592 mmol, 3.00 eq). The mixture was stirred at 80°C for 16 h under a N2 atmosphere. The mixture was adjusted to pH = 5 with aqueous HCl. (12 M), and then extracted with ethyl acetate (500 ml x 3). The combined organic layers were washed with brine (500 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1 to 5 / 1) to yield the title compound (26 g, 74% yield) as a white solid. Petition 870250094781, dated 10 / 16 / 2025, pp. 271 / 378 85 / 167 Step D: 5-bromo-6-(methoxymethyl)-2,3-dihydrobenzofuran-4-ol

[00227] To a solution of 6-(methoxymethyl)-2,3-dihydrobenzofuran-4-ol (25.0 g, 138 mmol, 1.00 eq) in DCM (250 ml) was added NBS (22.2 g, 124 mmol, 0.90 eq) at 0°C. The mixture was stirred at 0°C for 5 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate: 50 / 1 to 10 / 1) to yield the title compound (16.0 g, 45% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ [ppm]: 6.56 (s, 1H), 5.72 (s, 1H), 4.63 (t, 2H), 4.44 (s, 2H), 3.43 (s, 3H), 3.22 (t, 2H). Step E: 4-benzyloxy-5-bromo-6-(methoxymethyl)-2,3-dihydrobenzofuran

[00228] To a solution of 5-bromo-6(methoxymethyl)-2,3-dihydrobenzofuran-4-ol (15.0 g, 57.8 mmol, 1.00 eq) in MeCN (150 ml) was added BnBr (10.8 g, 63.6 mmol, 7.56 ml, 1.10 eq) and K2CO3 (16.0 g, 115 mmol, 2.00 eq). The mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (100 ml) and extracted with EtOAc (50 ml x 3). The combined organic layers were washed with brine (50 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was ground with petroleum ether (50.0 ml) at 25°C for 16 h. The title compound (10.0 g, 74% yield) was obtained as a white solid. LCMS: m / z 350.0 [M+H]+, ESI pos. Step F: 2-[4-benzyloxy-6-(methoxymethyl)-2,3-diPetition 870250094781, dated 16 / 10 / 2025, p. 272 / 378 86 / 167 hydrobenzofuran-5-yl]-4,4,5,5-tetramethyl-1,3,2dioxaborolane

[00229] To a solution of 4-benzyloxy-5-bromo-6(methoxymethyl)-2,3-dihydrobenzofuran (1.5 g, 4.08 mmol, 1.00 eq) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.19 g, 1.3 ml, 6.37 mmol, 1.56 eq) in tetrahydrofuran (15 ml) was added dropwise 1.6 M n-butyllithium solution in hexane (4 ml, 6.4 mmol, 1.57 eq) at 76 °C and stirring continued at -76 °C for 2.25 h. The reaction mixture was heated to -60 °C, quenched with aqueous NH4Cl solution. Saturated (~10 ml) at -60°C, heated to room temperature, and then extracted with ethyl acetate (~70 ml) and saturated aqueous NH4Cl solution (~10 ml). The aqueous layer was back-extracted with ethyl acetate (~70 ml). The organic layers were washed with brine (~10 ml). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo.The crude product was purified by flash chromatography (silica gel, 25 g, gradient from 0% to 20% ethyl acetate in heptane) to yield the title compound (1.26 g, 74% yield) as a colorless oil. LCMS: m / z 397.3 [M+H]+, ESI pos. Step F: 6-(methoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-4-ol

[00230] A solution of 2-[4-benzyloxy-6(methoxymethyl)-2,3-dihydrobenzofuran-5-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolan (1.24 g, 2.98 mmol, 1.00 eq) in ethyl acetate (15 ml) and methanol (2.5 ml) was evacuated and purged with argon alternately three times. Palladium in activated charcoal, 10% Pd base (136 mg, 127.8 pmol, 0.043 eq) was carefully added. The reaction flask was Petition 870250094781, dated 10 / 16 / 2025, pp. 273 / 378 87 / 167 evacuated, purged with argon, evacuated and purged with hydrogen. The reaction mixture was stirred under a hydrogen atmosphere (flask) at room temperature for 3 h. Then, the reaction mixture was filtered and rinsed with ethyl acetate / methanol. The filtrate was concentrated in vacuo to yield the title compound (929 mg, 97% yield) as a light brown solid. LCMS: m / z 307.2 [M+H]+, ESI pos. The compound was used without further purification. Intermediate 9 (3S,5R)-5-[(5-bromo-oxazolo[4,5-b]pyrazin-2-yl)amino]-1-ethyl-piperidin-3-ol HO Step A: 2-benzyloxy-5-bromo-3-isothiocyanatopyrazine

[00231] To a solution of 3-benzyloxy-6-bromopyrazine-2-amine (2.0 g, 7.14 mmol, 1.0 eq; CAS# 2767116-118) in DCM (20 ml) was added 1,1'-thiocarbonyldipyridin2(1H)-one (1.99 g, 8.57 mmol, 1.2 eq). The reaction mixture was stirred at 30°C for 16 hours. After completion of the reaction, the reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1 to 50:1) to give the title compound (1.2 g, 51% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d) δ [ppm]: 8.39 (s, 1H), 7.52-7.50 (m, 2H), 7.43-7.35 (m, 3H), 5.47 (s, 2H). Step B: tert-butyl (3R,5S)-3-[(3-benzyloxy-6-bromo-pyrazin-2yl)carbamothioylamino]-5-hydroxy-piperidine-1-carboxylate Petition 870250094781, dated 10 / 16 / 2025, pp. 274 / 378 88 / 167

[00232] A mixture of tert-butyl (3R,5S)-3-amino-5-hydroxy-piperidine-1-carboxylate (671.3 mg, 3.1 mmol, 1.0 eq) and DIEA (0.81 ml, 4.66 mmol, 1.5 eq) in DCM (10 ml) was added dropwise to a solution of 2-benzyloxy-5-bromo-3-isothiocyanatopyrazine (1000.0 mg, 3.1 mmol, 1.0 eq) in DCM (10 ml). The reaction mixture was stirred at 20°C for 1 hour under N2. After the reaction was complete, the reaction mixture was quenched with water (30 ml) and extracted with ethyl acetate (50 ml x 2). The organic phases were washed with brine (50 ml x 2), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 59% ~ 41%) to yield the title compound (1580.0 mg, 95% yield) as a yellow oil. LCMS: m / z 484.1 [M-C4H8+H]+, ESI pos.1H NMR (400 MHz, DMSO-de) δ [ppm]: 10.47 (d, 1H), 8.86 (s, 1H), 7.99 (s, 1H), 7.51 - 7.49 (m, 2H), 7.43 - 7.34 (m, 3H), 5.48 - 5.40 (m, 2H), 5.08 (br s, 1H), 4.36 - 4.26 (m, 1H), 3.71. - 3.67 (m, 1H), 3.56 - 3.54 (m, 1H), 3.44 - 3.35 (m, 1H), 3.23 - 3.22 (m, 1H), 3.29 - 3.22 (m, 1H), 2.15 - 2.05 (m, 1H), 1.68 - 1.58 (m, 1H), 1.25 (br s, 9H). Step C: 1-(6-bromo-3-hydroxy-pyrazin-2-yl)-3-[(3R,5S)-5hydroxy-3-piperidyl]thiourea

[00233] To a solution of (3R,5S)-3-[(3benzyloxy-6-bromo-pyrazin-2-yl)carbamothioylamino]-5-hydroxy-piperidine-1-carboxylate tert-butyl (1800.0 mg, 3.34 mmol, 1.0 eq) in anisole (3 ml) was added TFA (3 ml) and the mixture was stirred at 70°C for 2 hours under N2. After the reaction was complete, the mixture was concentrated in vacuum. The residue was purified by prep-HPLC (column: Xtimate C18, Petition 870250094781, dated 10 / 16 / 2025, pp. 275 / 378 89 / 167 50mm*50mm*10μm, mobile phase: [water (0.1% ammonium hydroxide v / v)-MeCN]; B%: 5%-39%, 15 minutes), the eluent was lyophilized to provide the title compound (750.0 mg, 65% yield) as a yellow solid. LCMS: m / z 350, 0[M+2+H]+, ESI pos. Step D: (3S,5R)-5-[(5-bromo-oxazolo[4,5-b]pyrazin-2yl)amino]piperidin-3-ol

[00234] To a solution of 1-(6-bromo-3-hydroxypyrazin-2-yl)-3-[(3R,5S)-5-hydroxy-3-piperidyl]thiourea (50.0 mg, 0.14 mmol, 1.0 eq), tetrabutylammonium iodide (10.6 mg, 0.03 mmol, 0.2 eq) in THF (2 ml) and methanol (0.2 ml) was added H2O2 (240.0 mg, 2.12 mmol, 14.74 eq, purity: 30% in water). The resulting mixture was stirred at 20°C for 1 hour. After the reaction was complete, the mixture was quenched with saturated aqueous Na2SO3 solution (0.2 ml) and concentrated under vacuum. The residue was purified by prep-HPLC (column: Phenomenex Gemini, 150 mm*30 mm*15 µm; mobile phase: [water (0.1% TFA, V / V)-MeCN]; B%: 22%-40%, 10 min), the eluent was lyophilized to provide the title compound (10.0 mg, 22% yield) as a white solid. LCMS: m / z 314.1 [M+H]+, ESI pos. Step E: (3S,5R)-5-[(5-bromo-oxazolo[4,5-b]pyrazin-2yl)amino]-1-ethyl-piperidin-3-ol

[00235] To a solution of (3S,5R)-5-[(5-bromooxazolo[4,5-b]pyrazin-2-yl)amino]piperidin-3-ol (110.0 mg, 0.26 mmol, 1.0 eq), DIEA (0.09 ml, 0.51 mmol, 2.0 eq) in DMF (1 ml) was added CH3CH2I (0.02 ml, 0.26 mmol, 1.0 eq). The reaction mixture was stirred at 20°C for 1 hour under nitrogen. After completion of the reaction, the mixture was purified by prep-HPLC (column: Xtimate C18, Petition 870250094781, dated 10 / 16 / 2025, pp. 276 / 378 90 / 167 50mm*50mm*10μm, mobile phase: [water (0.1% ammonium hydroxide v / v)-MeCN]; B%: 10%-45%, 8 minutes), the eluent was lyophilized to provide the title compound (40.0 mg, 26% yield) as a yellow solid. LCMS: m / s 343, 9[M+H]+, ESI pos. Intermediate 10 2,5-dichloro-7-fluoro-oxazolo[4,5-b]pyridine Step B: 6-chloro-4-fluoro-2-nitro-pyridin-3-ol

[00236] To a solution of 6-chloro-4-fluoropyridin-3-ol (4.3 g, 29.15 mmol, 1.0 eq; CAS# 1211530-63-0) in sulfuric acid (40.0 ml, 116.59 mmol, 4.0 eq.) HNO3 (7.06 g, 100.86 mmol, 3.46 eq.) was slowly added at 0°C, then the mixture was stirred at 20°C for 4 hours. After completion of the reaction, the above reaction solution was diluted with water (200 ml), and extracted with ethyl acetate (100 ml x 3). The combined organic phases were washed with brine (200 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 1:1 to 10:1) to yield the title compound (5.0 g) as a yellow solid. 1H NMR (400 MHz, DMSO-d) δ [ppm]: 8.03 (d, 1H). Step C: 2-amino-6-chloro-4-fluoro-pyridin-3-ol

[00237] To a solution of 6-chloro-4-fluoro-2-nitropyridin-3-ol (2.1 g, 10.91 mmol, 1.0 eq.) in ethanol (30 ml) and water (30 ml) was added Na2S2O4 (11.39 g, 65.44 mmol, 6.0 eq.), then stirred at 70°C for 3 hours. After the Petition 870250094781, dated 10 / 16 / 2025, pp. 277 / 378 91 / 167 Upon completion of the reaction, the above reaction solution was cooled to room temperature, diluted with water (100 ml), and extracted with ethyl acetate (50 ml x 3). The combined organic phases were washed with brine (100 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 1:1 to 0:1) to yield the title compound (1.27 g, 71% yield) as a yellow solid. LCMS: m / z 163.1, [M+H]+, ESI+ pos. Step D: 5-chloro-7-fluoro-oxazolo[4,5-b]pyridine-2-thiol

[00238] To a solution of 2-amino-6-chloro-4-fluoro-pyridin-3-ol (500.0 mg, 3.08 mmol, 1.0 eq.) in DMF (5 ml) was added 1,1'-thiocarbonyldi-imidazole (603.0 mg, 3.38 mmol, 1.1 eq.), then the mixture was stirred at 50°C for 2 hours. After completion of the reaction, the above reaction solution was cooled to room temperature, diluted with water (20 ml) and extracted with ethyl acetate (20 ml x 3). The combined organic phases were washed with 1M HCl (50 ml), brine (50 ml), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 1:0 to 1:1) to generate the title compound (320.0 mg, 47% yield) as a white solid. LCMS: m / z 205.0, [M+H]+, ESI+ pos. Step E: 2,5-dichloro-7-fluorooxazolo[4,5-b]pyridine

[00239] To a solution of 5-chloro-7-fluorooxazolo[4,5-b]pyridine-2-thiol (320.0 mg, 1.56 mmol, 1.0 eq.) in oxalyl dichloride (4.0 ml, 46.96 mmol, 30.0 eq.) was added DMF (11.4 mg, 0.16 mmol, 0.1 eq.). And then, Petition 870250094781, dated 10 / 16 / 2025, pp. 278 / 378 The 92 / 167 mixture was stirred at 50°C for 1 hour. After the reaction was complete, the above reaction solution was cooled to room temperature, diluted with water (20 ml), and extracted with ethyl acetate (10 ml x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 1:0 to 10:1) to yield the title compound (300.0 mg, 93% yield) as a yellow solid. Intermediate 11 1-(6-bromo-3-hydroxy-pyrazin-2-yl)-3-[(3R)-1-(2hydroxyethyl)-3-piperidyl]thiourea Step A: 1-(3-benzyloxy-6-bromo-pyrazin-2-yl)-3-[(3R)-1-(2hydroxyethyl)-3-piperidyl]-thiourea

[00240] To a solution of 1-(6-bromo-3-hydroxypyrazin-2-yl)-3-[(3R)-3-piperidyl]thiourea hydrochloride (2600.0 mg, 7.03 mmol, 1.0 eq) in DCE (30 ml) and methanol (3 ml) was added CH3COONa (1730.73 mg, 21.1 mmol, 3.0 eq) followed by CH3COOH (42.2 mg, 0.7 mmol, 0.1 eq) to adjust the pH to 5.0 and (tert-butyldimethylsilyloxy)acetaldehyde (1838.97 mg, 10.55 mmol, 1.5 eq) and the mixture was stirred for 10 min before the addition of NaBH(OAc)3 (4471.67 mg, 21.1 mmol, 3.0 (eq). Stirring at 20 °C continued for 1 hour under N2. Then, the mixture was quenched with water (30 ml), and extracted with EtOAc. Petition 870250094781, dated 10 / 16 / 2025, pp. 279 / 378 93 / 167 (60 ml x 2), the organic phase was washed with brine (60 ml x 2), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by C18 column chromatography (0.1% TFA-CAN = 54%~46% to 36%~64%) to give 1-(6-bromo-3-hydroxypyrazin-2-yl)-3-[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]thiourea (100.0 mg, 3% yield) as a yellow solid (LCMS m / z: 492.2 [M+2+H]+, ESIpos) and the title compound (1200.0 mg, 24% yield) as a yellow solid. LCMS m / z: 466.2 [M+H]+, ESI pos. Step B: 1-(6-bromo-3-hydroxy-pyrazin-2-yl)-3-[(3R)-1-(2hydroxyethyl)-3-piperidyl]thiourea

[00241] A solution of 1-(3-benzyloxy-6-bromopyrazin-2-yl)-3-[(3R)-1-(2-hydroxyethyl)-3-piperidyl]thiourea (1200.0 mg, 2.57 mmol, 1.0 eq) in TFA (2 ml) was stirred at 70°C for 2 hours under N2. After completion of the reaction, the mixture was concentrated under vacuum to provide a residue, which was then purified by C18 column chromatography (0.1% NH3*H2O-CAN = 54%~46%) to provide the title compound (300.0 mg, 21% yield) as a white solid. LCMS m / z: 376.1 [M+H]+, ESI pos. Preparing Examples Example 1 3-hydroxy-4-[2-[[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-5-methylbenzonitrile;2,2,2-trifluoroacetic acid Petition 870250094781, dated 10 / 16 / 2025, pp. 280 / 378 94 / 167 Step A: 1-(6-chloro-3-hydroxy-pyrazin-2-yl)-3-[(3R)-3piperidyl]thiourea

[00242] A solution of (3R)-3-[(3-benzyloxy-6-chloro-pyrazin-2-yl)carbamothioylamino]piperidine-1-benzyl carboxylate (1.5 g, 2.93 mmol, 1.0 eq) in TFA (15.0 ml, 197.37 mmol, 67.37 eq), anisole (7.5 ml, 69.01 mmol, 23.56 eq) and the reaction mixture was stirred at 75°C for 12 h. The mixture was then concentrated under reduced pressure and purified by reverse-phase flash (water-MeCN condition of CombiFlash NH3-H2O) to give the title compound (320.0 mg, 22% yield) as a yellow solid. LCMS: m / z 288.2 [M+H]+, ESI pos. Step B: 1-[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3piperidyl]-3-(6-chloro-3-hydroxy-pyrazin-2-yl)thiourea

[00243] To a solution of 1-(6-chloro-3-hydroxypyrazin-2-yl)-3-[(3R)-3-piperidyl]thiourea (270.0 mg, 0.94 mmol, 1.0 eq) in methanol (5 ml) / DCE (10 ml) was added (tert-butyldimethylsilyloxy)acetaldehyde (CAS # 102191-92-4, 327.1 mg, 1.88 mmol, 2.0 eq) followed by NaBH(OAc)3 (994.3 mg, 4.69 mmol, 5.0 eq) and stirring continued at 20°C for 1.5 h. The above reaction mixture was poured onto ice (20 ml) and extracted with ethyl acetate (3 x 50 ml). The combined organic phase was washed with brine (3 x 50 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified over... Petition 870250094781, dated 10 / 16 / 2025, pp. 281 / 378 95 / 167 silica gel column chromatography (hexane / EtOAc, 1:0 to 0:1) to give the title compound (220.0 mg, 49% yield) as a yellow solid. LCMS: m / z 446.1 [M+H]+, ESI pos. Step C: N-[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3piperidyl]-5-chloro-oxazolo[4,5-b]pyrazin-2-amine

[00244] To a mixture of 1-[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]-3-(6-chloro-3-hydroxy-pyrazin-2-yl)thiourea (220.0 mg, 0.49 mmol, 1.0 eq) and tetrabutylazanium iodide (200.4 mg, 0.54 mmol, 1.1 eq) in THF (10 ml), H2O2 (111.8 mg, 0.99 mmol, 2.0 eq) was added and the mixture was stirred at 25°C for 2 h. The residue was purified by silica gel column chromatography (EtOAc / MeOH = 1:0 to 10:1) to yield the title compound (80.0 mg, 40% yield) as a yellow solid. LCMS: m / z 412.1 [M+H]+, ESI pos. Step D: 4-[2-[[(3R)-1-[2-[tertbutyl(dimethyl)silyl]oxyethyl]-3-piperidyl]amino]oxazolo[4,5b]pyrazin-5-yl]-3-methyl-5-(2trimethylsilylethoxymethoxy)benzonitrile

[00245] To a mixture of 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(2-trimethylsililetoxymethoxy)benzonitrile Intermediate 1 (79.4 mg, 0.2 mmol, 1.2 eq), N-[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]-5-chlorooxazolo[4,5-b]pyrazine-2-amine (step C) (70.0 mg, 0.17 mmol, 1.0 eq), CsF (77.42 mg, 0.51 mmol, 3.0 eq) in 1,4-dioxane (4 ml) / water (0.5 ml) was added Pd-PEPPSI-iHeptCl (CAS # 905459-27-0, 14.4 mg, 0.02 mmol, 0.1 eq) under N2 and stirred for 3 hours at 95°C. The above reaction mixture was cooled to Petition 870250094781, dated 10 / 16 / 2025, pp. 282 / 378 96 / 167 at room temperature, poured over ice (10 ml) and extracted with ethyl acetate (3 x 50 ml). The combined organic phase was washed with brine (3 x 50 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse-phase flash (water-MeCN condition of CombiFlash 0.1% TFA) to give the title compound (30.0 mg, 26% yield) as a yellow solid. LCMS: m / z 639.4 [M+H]+, ESI pos. Step E: 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-5-methylbenzonitrile; 2,2,2-trifluoroacetic acid

[00246] To a mixture of 4-[2-[[(3R)-1-[2-[tertbutyl(dimethyl)silyl]oxyethyl]-3-piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-3-methyl-5-(2trimethylsilylethoxymethoxy)benzonitrile (step D) (25.0 mg, 0.04 mmol, 1.0 eq) in DCM (0.1 ml) was added to TFA (0.1 ml) and stirred for 1 h at 25°C. The above reaction mixture was concentrated under reduced pressure. The crude product was purified by reverse-phase flash (MeCN condition of CombiFlash 0.1% TFA water) to yield the title compound (14.3 mg, 71% yield) as a yellow solid. LCMS: m / z 395.1 [M+H]+, ESI pos. Example 2 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-3-hydroxy-5methyl-benzonitrile;2,2,2-trifluoroacetic acid Petition 870250094781, dated 10 / 16 / 2025, pp. 283 / 378 97 / 167 Step A: tert-butyl (3R,5S)-3-amino-5-[tert-butyl(diphenyl)silyl]oxypiperidine-1-carboxylate

[00247] To a solution of (3R,5S)-3-amino-5-hydroxy-piperidine-1-carboxylate tert-butyl (CAS # 1932513-59-1, 400 mg, 1.85 mmol, 1.0 eq) and 1H-imidazole (378 mg, 5.55 mmol, 3.0 eq) in DMF (2 ml) was added tert-butylchlorodiphenylsilane (1029 mg, 3.74 mmol, 2.0 eq). The mixture was then stirred at 20°C for 48 h. After the reaction was complete, ethyl acetate (40 ml) and water (20 ml) were added and the layers were separated. The aqueous phase was extracted with ethyl acetate (40 ml x 2). The combined extracts were washed with brine (50 ml), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:2 to 0:1) to give the title compound (230.0 mg, 27% yield) as a yellow oil. LCMS: m / z 455.4 [M+H]+, ESI pos. Step B: (3S,5R)-3-[tert-butyl(diphenyl)silyl]oxy-5-isothiocyanato-piperidine-1-carboxylate tert-butyl

[00248] To a stirring solution of TEA (102 mg, 1.01 mmol, 2.0 eq) and (3R,5S)-3-amino-5-[tert-butyl(diphenyl)silyl]oxy-piperidine-1-carboxylate tert-butyl (230.0 mg, 0.51 mmol, 1.0 eq) in DCM (2 ml), a thiophosgene solution (174.5 mg, 1.52 mmol, Petition 870250094781, dated 10 / 16 / 2025, pp. 284 / 378 98 / 167 3.0 eq) at 0°C, dropwise, and stirring continued for 2 hours at 25°C. After completion of the reaction, the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1 to 4:1) to give the title compound (130.0 mg, 52% yield) as a yellow oil. LCMS: m / z 519.3 [M+Na]+, ESI pos. Step C: (3R,5S)-3-[[3-benzyloxy-6-[4-cyano-2-methyl-6-(2-trimethylsilethoxymethoxy)phenyl]pyrazine-2-yl]carbamothioylamino]-5-[tert-butyl(diphenyl)silyl]oxypiperidine-1-carboxylate tert-butyl

[00249] To a solution of 4-(6-amino-5-benzyloxypyrazine-2-yl)-3-methyl-5-(2-trimethylsilethoxymethoxy)benzonitrile Intermediate 2 (100.0 mg, 0.22 mmol, 1.0 eq) in THF (7 ml) was added NaH (60% in mineral oil, 17.3 mg, 0.43 mmol, 2.0 eq) was added and stirred at 20 °C for 0.5 h. Then, a solution of (3S,5R)3-[tert-butyl(diphenyl)silyl]oxy-5-isothiocyanato-piperidine1-carboxylate tert-butyl (108.0 mg, 0.22 mmol, 1.01 eq) in THF (2 ml) was added dropwise at 0 °C and the reaction was stirred at 20 °C for 4 h. As the reaction mixture was insoluble, additional DMF (10.0 ml) was added and stirring continued at 20 °C for 1 h. After completion of the reaction, the reaction mixture was cooled to room temperature. Ethyl acetate (50 ml) and saturated aqueous CaCl2 solution (50 ml) were added and the layers were separated. The aqueous phase was extracted with ethyl acetate (30 ml x 2). The combined extracts were washed with saturated aqueous CaCl2 solution (50 ml), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether). Petition 870250094781, dated 10 / 16 / 2025, pages 285 / 378 99 / 167 : ethyl acetate = 1:1 to 1:2) to give the title compound (100.0 mg, 48% yield) as yellow oil. LCMS: m / z 959.2 [M+H]+, ESI pos. Step D: 1-[(3R,5S)-5-[tert-butyl(diphenyl)silyl]oxy-3piperidyl]-3-[6-(4-cyano-2-hydroxy-6-:methyl-phenyl)-3hydroxy-pyrazin-2-yl]thiourea

[00250] (3R,5S)-3-[[3-benzyloxy-6-[4-cyano-2-methyl-6-(2-trimethylsilethoxymethoxy)-phenyl]pyrazin-2-yl]carbamothioylamino]-5-[tert-butyl-(diphenyl)silyl]oxypiperidine-1-carboxylate tert-butyl (100.0 mg, 0.1 mmol, 1.0 eq) was dissolved in TFA (3.0 ml, 39.5 mmol, 378.7 eq) and stirred at 20°C for 2 h. Then, the mixture was concentrated under vacuum and the residue was dissolved with methanol (2 ml) and the pH was adjusted to 7 with NH3*H2O. Subsequently, the crude was purified by reversed-phase flash (CombiFlash condition 0.1% aqueous NH3*H2O-ACN) to yield the title compound (40.0 mg, 60% yield) as a white solid. LCMS: m / z 639.3 [M+H]+, ESI pos. Step E: 1-[(3R,5S)-5-[tert-butyl(diphenyl)silyl]oxy-1-ethyl3-piperidyl]-3-[6-(4-cyano-2-hydroxy-6-methyl-phenyl)-3hydroxy-pyrazin-2-yl]thiourea

[00251] To a solution of 1-[(3R,5S)-5-[tert-butyl(diphenyl)silyl]oxy-3-piperidyl]-3-[6-(4-cyano-2-hydroxy-6-methylphenyl)-3-hydroxypyrazin-2-yl]thiourea (40 mg, 0.06 mmol, 1.0 eq) in methanol (0.1 ml) and DCE (1 ml) was added acetaldehyde (0.04 ml, 0.19 mmol, 3.0 eq). The mixture was stirred for 15 min, then NaBH(OAc)3 (53 mg, 0.25 mmol, 4.0 eq) was added and stirred at 20°C for 1.5 h. The mixture was purified by reverse-phase flash (CombiFlash condition 0.1% aqueous NH3*H2O-MeCN) to Petition 870250094781, dated 10 / 16 / 2025, pp. 286 / 378 100 / 167 generate the title compound (25.0 mg, 60% yield) as a white solid. LCMS: m / z 667.3 [M+H]+, ESI pos. Step F: 4-[2-[[(3R,5S)-5-[tert-butyl(diphenyl)silyl]oxy-1ethyl-3-piperidyl]amino]oxazolo-[4,5-b]pyrazin-5-yl]-3hydroxy-benzonitrile,'2,2,2-trifluoroacetic acid

[00252] A solution of 1-[(3R,5S)-5-[tert-butyl(diphenyl)silyl]oxy-1-ethyl-3-piperidyl]-3-[6-(4-cyano-2-hydroxy-6-methyl-phenyl)-3-hydroxy-pyrazin-2-yl]thiourea (30.0 mg, 0.04 mmol, 1.0 eq) and tetrabutylazanium iodide (16.6 mg, 0.04 mmol, 1.0 eq) in THF (1 ml) H2O2 (70.0 mg, 0.62 mmol, 13.7 eq) was added and stirring continued at 25°C for 1 h. The mixture was then concentrated under vacuum. The residue was then purified by reverse-phase flash (CombiFlash condition 0.1% aqueous TFA-MeCN) to yield the title compound (20.0 mg, 60% yield) as a yellow solid. LCMS: m / z 633.2 [M+H]+, ESI pos. Step G: 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-3-hydroxy-5methyl-benzonitrile,'2,2,2-trifluoroacetic acid

[00253] To a solution of 4-[2-[[(3R,5S)-5-[tert-butyl(diphenyl)silyl]oxy-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-3-hydroxybenzonitrile;2,2,2-trifluoroacetic acid (15.0 mg, 0.02 mmol, 1.0 eq) in THF (1 ml) was added TBAF (0.42 ml, 0.42 mmol, 21.1 eq). Then, the mixture was stirred at 20°C for 16 h. Subsequently, the solvent was removed under vacuum and the residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10um; Condition: Water (TFA)-MeCN; Initial B: 14, Final B: 44; Gradient Time (min): 10, 100% B; Holding Time (min): 3, Flow Rate (ml / min): 25) to generate the compound Petition 870250094781, dated 10 / 16 / 2025, pp. 287 / 378 101 / 167 of the title (3.89 mg, 37% yield) as a white solid. LCMS: m / z 395.4 [M+H]+, ESI pos. Example 3 3-hydroxy-4-[2-[[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5(methoxymethyl)benzonitrile THE OH H N Step A: 5-bromo-N-[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]oxazolo[4,5b]pyridin-2-amine

[00254] To a solution of (3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]piperidin-3-amine Intermediate 3 (200.0 mg, 0.77 mmol, 1.0 eq) in MeCN (2 ml), DIEA (0.26 ml, 1.55 mmol, 2.0 eq) was added, followed by a solution of 5-bromo-2-chloro-oxazolo[4,5-b]pyridine Intermediate 5 (180.6 mg, 0.77 mmol, 1.0 eq) in MeCN (2 ml) and the mixture was stirred at 25°C for 2 h. Next, the reaction mixture was concentrated under vacuum and the residue was purified by C18 column chromatography (column: Waters Xbridge 150*25mm*5µm; mobile phase: A for H2O (0.1% NH3*H2O v / v) and B for acetonitrile; gradient: B 78%-28% in 9 min linearly; flow rate: 25 ml / mini column; temperature: ta; wavelength: 220 nm / 254 nm) to yield the title compound (210.0 mg, 40% yield) as a colorless foam. LCMS m / z 455.1 [M+H]+, ESI pos. Step B: 4-[2-[[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]amino]oxazolo[4.5 Petition 870250094781, dated 10 / 16 / 2025, pages 288 / 378 102 / 167 b]pyridin-5-yl]-3-(methoxymethyl)-5-(2trimethylsilylethoxymethoxy)benzonitrile

[00255] To a solution of 5-bromo-N-[(3R)-1-[2[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]oxazolo[4,5b]pyridin-2-amine (100.0 mg, 0.22 mmol, 1.0 eq) and 3(methoxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2yl)-5-((2-(trimethylsilyl)ethoxy)methoxy)benzonitrile Intermediate 4 (110.5 mg, 0.26 mmol, 1.2 eq) in 1,4-dioxane (1 ml) and water (0.2 ml) was added CsF (133.4 mg, 0.88 mmol, 4.0 eq) and XPhos Pd G3 (37.2 mg, 0.04 mmol, 0.2 eq), and the reaction mixture was stirred at 95°C for 2 h under a nitrogen atmosphere. The mixture was then cooled to room temperature and diluted with ethyl acetate (10 ml), filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE:EtOAc, PE: 54% to 46%) to yield the title compound (90.0 mg, 61% yield) as a yellow oil. LCMS m / z 668.4 [M+H]+, ESI pos. Step C: 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5(methoxymethyl)benzonitrile

[00256] To a solution of 4-[2-[[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]amino]oxazolo[4,5b]pyridin-5-yl]-3-(methoxymethyl)-5-(2-trimethylsililetoxymethoxy)benzonitrile (45.0 mg, 0.07 mmol, 1.0 eq) in DCM (1 ml) was added TFA (1.5 ml) and stirring continued at 20°C for 2 h. After completion of the reaction, the mixture was diluted with DCM (3 ml) and MeOH (1 ml), and the pH was adjusted to about 8 with NH3*H2O, filtered, and the filtrate was concentrated under reduced pressure. The crude product was then Petition 870250094781, dated 10 / 16 / 2025, pp. 289 / 378 103 / 167 purified by preparative HPLC (Column: Waters Xbridge 150*25mm*5um; Condition: water (0.1% NH3*H2O)-MeCN; Start B 5 End B 35; Gradient time (min): 10; Holding time 100% B (min): 2; Flow rate (ml / min) 25) to provide the title compound as a whitish solid (25.9 mg, 89% yield). LCMS m / z 424.3 [M+H]+, ESI pos. Example 4 3-hydroxy-5-methyl-4-[2-[[(3R)-1-(2-oxazol-2-ylethyl)-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]benzonitrile Step A: tert-butyl (3R)-3-[(5-chloro-oxazolo[4,5-b]pyridin-2yl)amino]piperidine-1-carboxylate

[00257] To a mixture of 5-chloro-2(methylthio)oxazolo[4,5-b]pyridine (CAS # 1783370-92-2, 600 mg, 2.84 mmol, 1.00 eq) in 1,4-dioxane (5.7 ml) was added tert-butyl (3R)-3-aminopiperidine-1-carboxylate (CAS # 188111-79-7, 720 mg, 3.59 mmol, 1.27 eq) followed by triethylamine (334 mg, 0.46 ml, 3.30 mmol, 1.16 eq). The brown solution was stirred at 110°C for 16 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and saturated aqueous NaHCO3 solution. The aqueous layer was back-extracted with ethyl acetate. The organic layers were washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Petition 870250094781, dated 10 / 16 / 2025, pp. 290 / 378 104 / 167 crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 40 g, 0% to 70% ethyl acetate gradient in heptane) to generate the title compound (991 mg, 94% yield) as a whitish foam. LCMS: m / z 353.1 [M+H]+, ESI pos. Step B: 5-chloro-N-[(3R)-3-piperidyl]oxazolo[4,5-b]pyridin2-amine

[00258] To a solution of tert-butyl (3R)-3-[(5-chlorooxazolo[4,5-b]pyridin-2-yl)amino]piperidine-1-carboxylate (Example 4, step A) (227 mg, 0.61 mmol, 1.00 eq) in dichloromethane (1.8 ml) and methanol (0.90 ml) was added dropwise 4 M HCl in dioxane (1.8 g, 1.5 ml, 6.00 mmol, 9.82 eq). The reaction mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was dissolved in a small amount of dichloromethane plus a few drops of methanol, then carefully added to saturated aqueous NaHCO3 solution and extracted three times with a dichloromethane / methanol mixture (9:1). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to yield the title compound (137 mg, 88% yield) as a whitish solid. LCMS: m / z 253.0 [M+H]+, ESI pos. Step C: methyl 3-[(3R)-3-[(5-chloro-oxazolo[4,5-b]pyridin-2-yl)amino]-1-piperidyl]propanoate

[00259] To a mixture of 5-chloro-N-[(3R)-3-piperidyl]oxazolo[4,5-b]pyridin-2-amine (Example 4, step B) (68 mg, 0.27 mmol, 1.00 eq) in tetrahydrofuran (1.2 ml) and N,N-dimethylformamide (1.2 ml) was added N,N-diisopropylethylamine (86 mg, 0.116 ml, 0.66 mmol, 2.49 eq) Petition 870250094781, dated 10 / 16 / 2025, pp. 291 / 378 105 / 167 followed by dropwise addition of methyl 3-bromopropanoate (CAS # 3395-91-3, 57 mg, 0.037 ml, 0.34 mmol, 1.27 eq). The reaction mixture was stirred at 60 °C for 16 hours. The reaction mixture was cooled to room temperature and then extracted with ethyl acetate and 10% aqueous LiCl solution. The aqueous layer was back-extracted with ethyl acetate. The organic layers were washed twice with 10% aqueous LiCl solution, once with water, and once with brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient from 0% to 10% methanol in ethyl acetate) to yield the title compound (74 mg, 78% yield) as a colorless viscous oil. LCMS: m / z 339, 1 [M+H]+, ESI pos. Step D: 3-[(3R)-3-[(5-chlorooxazolo[4,5-b]pyridin-2-yl)amino]-1-piperidyl]-N-(2,2-dimethoxyethyl)propanamide

[00260] To a solution of 3-[(3R)-3-[(5-chlorooxazolo[4,5-b]pyridin-2-yl)amino]-1-piperidyl]propanoate (Example 4, Step C) (74 mg, 0.21 mmol, 1.00 eq) in tetrahydrofuran (0.80 ml) and methanol (0.80 ml) was added dropwise 1M aqueous lithium hydroxide solution (0.27 ml, 0.27 mmol, 1.30 eq). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo. The residue was collected twice in toluene, concentrated in vacuo, and then placed under high vacuum. The residue was suspended in N,N-dimethylformamide (1.0 ml). Aminoacetaldehyde dimethyl acetal (CAS # 22483-09-6, 34 mg, 0.035 ml, 0.32 mmol, 1.55 eq) was added followed by N,N-diisopropylethylamine (85 mg, Petition 870250094781, dated 10 / 16 / 2025, pp. 292 / 378 106 / 167 0.115 ml, 0.66 mmol, 3.17 eq) and HATU (100 mg, 0.26 mmol, 1.27 eq). The reaction mixture was stirred at room temperature for 2.5 hours. The reaction mixture was extracted with ethyl acetate and 5% aqueous LiCl solution. The aqueous layer was back-extracted with ethyl acetate. The organic layers were washed three times with 5% aqueous LiCl solution, once with water, and once with brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was adsorbed onto ISOLUTE HMN and purified by flash chromatography (silica gel, 12 g, gradient from 0% to 5% methanol in dichloromethane) to yield the title compound (56 mg, 62% yield) as a yellow viscous oil. LCMS: m / z 412.1 [M+H]+, ESI pos. Step E: 5-chloro-N-[(3R)-1-(2-oxazol-2-ylethyl)-3-piperidyl]oxazolo[4,5-b]pyridin-2-amine

[00261] A solution of 3-[(3R)-3-[(5-chlorooxazolo[4,5-b]pyridin-2-yl)amino]-1-piperidyl]-N-(2,2-dimethoxyethyl)propanamide (Example 4, Step D) (56 mg, 0.13 mmol, 1.00 eq) in Eaton reagent (CAS # 39394-84-8, 1.24 g, 0.82 ml, 5.22 mmol, 40.4 eq) was stirred at 100°C for 16 h. The reaction mixture was added dropwise to aqueous NaHCO3 solution. The saturated solution (20 ml) was then extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient from 0% to 10% methanol in dichloromethane and then 10% to 100% (dichloromethane:methanol:NH4OH 9:1:0.05) in dichloromethane) to yield the title compound (13 mg, 23% yield, 80% purity) as a viscous brown oil. Petition 870250094781, dated 10 / 16 / 2025, pp. 293 / 378 107 / 167 LCMS: m / z 348.1 [M+H]+, ESI pos. Etapa F: 3-hidroxi-5-metil-4-[2-[[(3R)-1-(2-oxazol-2ylethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5yl]benzonitrila

[00262] A mixture of 5-chloro-N-[(3R)-1-(2-oxazol-2-ylethyl)-3-piperidyl]oxazolo[4,5-b]pyridin-2-amine (Example 4, step E) (13 mg, 0.03 mmol, 1.00 eq, 80% purity), (4-cyano-2-hydroxy-6-methylphenyl)boronic acid, Intermediate 7, (8 mg, 0.05 mmol, 1.51 eq), cesium carbonate (31 mg, 0.10 mmol, 3.18 eq) and XPhos Pd G3 (5 mg, 0.01 mmol, 0.20 eq) in 1,4-dioxane (0.30 ml) and water (0.075 ml) was purged with argon and stirred at 100°C for 2.5 hours and The reaction mixture was infused at room temperature for 16 hours. The reaction mixture was extracted with ethyl acetate and semi-saturated aqueous NH4Cl solution. The aqueous layer was back-extracted with ethyl acetate. The organic layers were washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 12 g, gradient from 0% to 10% methanol in dichloromethane).All fractions containing the product were combined and concentrated in vacuo to generate the title compound (6 mg, 41% yield, 90% purity) as a light yellow solid. LCMS: m / z 445.1 [M+H]+, ESI pos. Example 5: 4-[(3S,5R)-3-hydroxy-5-[[5-[2-hydroxy-6-methyl-4(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]amino]-1piperidyl]butanoic acid Petition 870250094781, dated 10 / 16 / 2025, pp. 294 / 378 108 / 167 Step A: methyl 4-[(3S,5R)-3-hydroxy-5-[[5-[2-hydroxy-6-methyl-4(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]amino]-1-piperidyl]butanoate

[00263] To a suspension of (3S,5R)-5-[[5-[2hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5b]pyridin-2-yl]amino]piperidin-3-ol;dihydrochloride (example 6, step C) (90 mg, 0.18 mmol, 1.0 eq) in dichloromethane (4 ml) was added at 0°C methyl 4-ketobutyric acid ester ((CAS # 13865-19-5), 57 mg, 0.05 ml, 0.44 mmol, 2.50 eq) followed by sodium acetate ((CAS # 127-09-3), 36 mg, 0.44 mmol, 2.50 eq) and sodium triacetoxyborohydride ((CAS # 56553-60-7) 68 mg, 0.32 mmol, 1.80 eq). The reaction mixture was stirred at 0°C for 5 min and at room temperature for 3 hours. Saturated NaHCO3 solution (30 ml) was added to the reaction mixture and extracted with dichloromethane (3 x 50 ml). The organic phase was separated and washed with water (20 ml) and brine (20 ml). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo.The crude product was purified by flash chromatography (silica gel, 12 g, gradient from 0% to 50% (dichloromethane:methanol:NH4OH 110:10:1) in dichloromethane) to generate the title compound (78 mg, 82% yield) as a white foam. LCMS: m / z 507.1. Petition 870250094781, dated 10 / 16 / 2025, pp. 295 / 378 109 / 167 [MH]-, ESI neg. Step B: 4-[(3S,5R)-3-hydroxy-5-[[5-[2-hydroxy-6-:methyl-4(trifluoromethyl)phenyl]-oxazolo[4,5-b]pyridin-2-yl]amino]-1piperidyl]butanoic acid

[00264] To a solution of the above-mentioned 4-[(3S,5R)-3-hydroxy-5[[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5b]pyridin-2-yl]amino]-1-piperidyl]methylbutanoate (76 mg, 0.14 mmol, 1.0 eq) in tetrahydrofuran (1.0 ml) and methanol (0.5 ml) was added 1 M aqueous lithium hydroxide solution (0.28 ml, 0.28 mmol, 2.0 eq). Stirred at 23 °C for 16 hours. All organic solvents were evaporated. The crude product was then purified by preparative HPLC (Column: Gemini NX, 12 nm, 5 µm, 100 x 30 mm; Condition: MeCN / water + 0.1% HCOOH; Gradient: 20-60 MeCN in water, run time 11 min) to yield the title compound (34 mg, 46% yield) as a white solid. LCMS: m / z 495.2 [M+H]+, ESI pos. Example 6 (3S,5R)-1-(2-hydroxyethyl)-5-[[5-[2-hydroxy-6-methyl-4(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2yl]amino]piperidin-3-ol Step A (3R,5S)-3-[(5-chloro-oxazolo[4,5-b]pyridin-2yl)amino]-5-hydroxy-piperidine-1-carboxylate tert-butyl

[00265] A mixture of 5-chloro-2 Petition 870250094781, dated 10 / 16 / 2025, page 296 / 378 110 / 167 (methylthio)oxazolo[4,5-b]pyridine (CAS # 1783370-92-2, 387 mg, 1.83 mmol, 1.0 eq) in 1,4-dioxane (4 ml) was added tert-butyl ester of (3R,5S)-3-amino-5-hydroxypiperidine-1-carboxylic acid (CAS # 1932513-59-1, 476 mg, 2.2 mmol, 1.20 eq), followed by triethylamine (278 mg, 0.38 ml, 2.75 mmol, 1.50 eq). The reaction mixture was stirred at 110°C for 48 hours. The reaction mixture was extracted with ethyl acetate (3 x 80 ml) and 1 M Na2CO3 (80 ml). The organic layers were washed with water (30 ml) and brine (30 ml). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo.

[00266] The crude product was purified by flash chromatography (silica gel, 12 g, gradient from 0% to 50% (dichloromethane:methanol:NH4OH 110:10:1) in dichloromethane) to generate the title compound (535 mg, 75% yield) as a colorless oil. LCMS: m / z 369.1 ([{35Cl}M+H]+), 371.1 ([{37Cl}M+H]+), ESI pos. Step B: tert-Butyl-(3S,5R)-3-hydroxy-5-[[5-[2-hydroxy-6methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2yl]amino]piperidine-1-carboxylate

[00267] In a sealable tube, a mixture of tert-butyl-(3R,5S)-3-[(5-chloro-oxazolo[4,5-b]pyridin-2-yl)amino]-5-hydroxy-piperidine-1-carboxylate mentioned above (step A) (150 mg, 0.39 mmol, 1.0 eq), 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol (163 mg, 0.54 mmol, 1.40 eq) and cesium carbonate (378 mg, 1.16 mmol, 3.0 eq) in 1,4-dioxane (4 ml) and water (1 ml) was placed under argon, and xphos-g3palladaciclo (CAS # 1445085-55-1, 49 mg, 0.05 mmol, 0.150 eq) was finally added. The reaction mixture was Petition 870250094781, dated 10 / 16 / 2025, pp. 297 / 378 111 / 167 was stirred at 90°C in a sealed tube for 4 hours. The reaction mixture was cooled to room temperature. It was quenched with water (20 ml) and saturated NH4Cl solution (20 ml), then extracted with ethyl acetate (2 x 40 ml). The organic layers were washed with brine (40 ml), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 12 g, gradient from 0% to 50% ethyl acetate in heptane; then ethyl acetate:methanol 9:1 (v / v) to generate the title compound (169 mg, 86% yield) as a light brown foam. LCMS: m / z 509.1 [M+H]+, ESI pos. Step C: (3S,5R)-5-[[5-[2-hydroxy-6-methyl-4(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2yl]amino]piperidin-3-ol;dihydrochloride

[00268] To a solution of tert-butyl-(3S,5R)-3hydroxy-5-[[5-[2-hydroxy-6-methyl-4(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2yl]amino]piperidine-1-carboxylate (step B) (169 mg, 0.33 mmol, 1.0 eq) in dichloromethane (8 ml) and methanol (2 ml) was added dropwise at room temperature 4 M HCl in 1,4-dioxane (997 mg, 0.83 ml, 3.32 mmol, 10.0 eq). The reaction mixture was stirred at 23°C for 16 hours. Evaporation of the reaction mixture yielded the title compound (158 mg, 94%) as a pale yellow foam. LCMS: m / z 409.1 [M+H]+, ESI pos. Step D: (3S,5R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5[[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5b]pyridin-2-yl]amino]piperidin-3-ol

[00269] To a suspension of (3S,5R)-5-[[5-[2hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5] Petition 870250094781, dated 10 / 16 / 2025, page 298 / 378 112 / 167 b]pyridin-2-yl]amino]piperidin-3-ol;dihydrochloride (step C) (68 mg, 0.13 mmol, 1.0 eq) in dichloromethane (3 ml) was added at 0°C 2-((tert-butyldimethylsilyl)oxy)acetaldehyde (CAS # 102191-92-4, 65 mg, 0.07 ml, 336 mmol, 2.50 eq) followed by sodium acetate ((CAS # 127-09-3), 28 mg, 0.34 mmol, 2.50 eq) and sodium triacetoxyborohydride (CAS # 56553-60-7, 51 mg, 0.24 mmol, 1.80 eq). The reaction mixture was stirred at 0°C for 5 min and at 23°C for 3 hours. To the reaction mixture, a saturated NaHCO3 solution (30 ml) was added and extracted with dichloromethane (3 x 50 ml). The organic phase was separated and washed with water (20 ml) and brine (20 ml). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to yield the title compound (170 mg; 98% yield) as a light brown oil. LCMS: m / z 565.2 [MH]-, ESI neg. Step E: (3S,5R)-1-(2-hydroxyethyl)-5-[[5-[2-hydroxy-6methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2yl]amino]piperidin-3-ol

[00270] Dropwise addition of 1 M tetrabutylammonium fluoride in THF (CAS # 429-41-4, 234 mg, 0.26 ml, 0.26 mmol, 2.0 eq) to a solution of (3S,5R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-[[5-[2-hydroxy-6-methyl-4(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2yl]amino]piperidin-3-ol (step D) (170 mg, 0.13 mmol, 1.0 eq) in tetrahydrofuran (3.52 ml). The reaction mixture was stirred at 23°C for 2 hours. The reaction mixture was extracted with ethyl acetate (2 x 30 ml). The organic layers were washed with water (30 ml) and brine (30 ml). The combined organic extracts were dried over sodium sulfate. Petition 870250094781, dated 10 / 16 / 2025, pp. 299 / 378 113 / 167 filtered and evaporated. The crude product was then purified by preparative HPLC (Column: Gemini NX, 12 nm, 5 µm, 100 x 30 mm; Condition: MeCN / water + 0.1% TEA; Gradient: 5-10100 MeCN in water, run time 15 min) to yield the title compound (24 mg, 38% yield) as a white solid. LCMS: m / z 453.3 [M+H]+, ESI pos. Example 7 3-hydroxy-4-[2-[[(3R,5S)-5-hydroxy-1-methyl-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-5-methylbenzonitrile;2,2,2-trifluoroacetic acid Step A: 4-(5-(benzyloxy)-6-isothiocyanatopyrazin-2-yl)-3-methyl-5-((2-(trimethylsilyl)ethoxy)methoxy)benzonitrile

[00271] To a solution of 1,1'thiocarbonyldipyridin-2(1H)-one (773 mg, 3.33 mmol, 1.1 eq) in DCM (16 ml) was added 4-(6-amino-5-benzyloxypyrazin-2-yl)-3-methyl-5-(2-trimethylsilylethoxymethoxy)benzonitrile (1400 mg, 3.03 mmol, 1.0 eq). The reaction mixture was stirred at 25°C for 2 hours. After the reaction was complete, the reaction mixture was concentrated under vacuum and purified by silica gel column chromatography (petroleum ether / ethyl acetate 20:1 to 10:1) to give the title compound as yellow oil. LCMS: m / z 505.2 [M+H]+, ESI pos. Petition 870250094781, dated 10 / 16 / 2025, pages 300 / 378 114 / 167 Step B: (3R,5S)-3-(3-(3-(enzyloxy)-6-(4-cyano-2-methyl-6((2-(trimethylsilyl)ethoxy)methoxy)phenyl)pyrazin-2yl)thioureido)-5-hydroxypiperidine-1-carboxylate tertbutyl

[00272] To a solution of (3R,5S)-3-amino-5-hydroxy-piperidine-1-carboxylate tert-butyl (157 mg, 0.73 mmol, 1.05 eq) and DIEA (0.18 ml, 1.04 mmol, 1.5 eq) in DCM (5 ml) was added dropwise a solution of 4-(5-benzyloxy-6-isothiocyanato-pyrazin-2-yl)-3-methyl-5-(2-trimethylsilylethyloxymethoxy)benzonitrile (350 mg, 0.69 mmol, 1.0 eq) in DCM (5 ml). The reaction mixture was stirred at 20°C for 2 h. After completion of the reaction, the reaction mixture was concentrated under vacuum to provide a residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate 10:1 to 2:1) to yield the title compound (450 mg, 90% yield) as a yellow oil. LCMS: m / z 721.3 [M+H]+, ESI pos. Step C: 1-(6-(4-cyano-2-hydroxy-6-methylphenyl)-3hydroxypyrazin-2-yl)-3-((3R,5S)-5-hydroxypiperidin-3yl)thiourea

[00273] A solution of tert-butyl (3R,5S)-3-[[3-benzyloxy6-[4-cyano-2-methyl-6-(2-trimethylsilethyleneoxymethoxy)phenyl]pyrazine-2-yl]carbamothioylamino]-5-hydroxypiperidine-1-carboxylate (450 mg, 0.62 mmol, 1.0 eq) in TFA (4.5 ml, 60.49 mmol, 97 eq) was stirred at 25°C for 2 h. After the reaction was complete, the reaction mixture was concentrated under vacuum and dissolved in MeCN (1 ml), and the pH was adjusted to pH = 78 by the addition of NH3^H2O. The residue was purified by C18 column chromatography (20 g, 0.1% of Petition 870250094781, dated 10 / 16 / 2025, pp. 301 / 378 115 / 167 NH3-H2O in water / MeCN, MeCN: 30%-40%) to give the title compound (180 mg, 72% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ [ppm]: 7.16 - 7.13 (m, 1H), 7.07 (s, 1H), 7.04 (s, 1H), 4.48 - 4.36 (m, 1H), 3.76 - 3.64 (m, 1H), 3.27 (m, 1H), 3.08 - 2.94 (m, 1H), 2.57 - 2.45 (m, 1H), 2.44 - 2.36 (m, 1H), 2.33 (s, 1H), 2.29 (s, 3H), 1.39 - 1.33 (m, 1H). Step D: 1-(6-(4-cyano-2-hydroxy-6-methylphenyl)-3hydroxypyrazin-2-yl)-3-((3R,5S)-5-hydroxy-1-methylpiperidin3-yl)thiourea

[00274] To a solution of 1-[6-(4-cyano-2-hydroxy-6-methylphenyl)-3-hydroxypyrazin-2-yl]-3-[(3R,5S)5-hydroxy-3-piperidyl]thiourea (100 mg, 0.25 mmol, 1.0 eq) in methanol (1 ml) / DCE (5 ml) formaldehyde (61 mg, 0.75 mmol, 3.0 eq) was added and stirred at 20°C for 0.5 h, then NaBH(OAc)3 (132 mg, 0.62 mmol, 2.5 eq) was added. The reaction mixture was stirred at 20°C for 2 hours. After completion of the reaction, the reaction mixture was concentrated under vacuum. The residue was purified by reverse-phase flash (CombiFlash condition 0.1% aqueous TFA-MeCN) to give the title compound (100 mg, 76% yield) as a yellow solid. LCMS: m / z 415.2 [M+H]+, ESI pos. Step E: 3-hydroxy-4-[2-[[(3R,5S)-5-hydroxy-1-methyl-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-5-methylbenzonitrile,'2,2,2-trifluoroacetic acid

[00275] A solution of 1-[6-(4-cyano-2-hydroxy-6-methylphenyl)-3-hydroxypyrazine-2-yl]-3-[(3R,5S)5-hydroxy-1-methyl-3-piperidyl]thiourea, 2,2,2-trifluoroacetic acid (100 mg, 0.19 mmol, 1.0 eq) and tetrabutylazanium iodide (84 mg, 0.23 mmol, 1.2 eq) in THF Petition 870250094781, dated 10 / 16 / 2025, pp. 302 / 378 116 / 167 (2 ml) was added dropwise to H2O2 (35 mg, 0.38 mmol, 2.00 eq) and stirred at 20°C for 0.5 hours. After the reaction was complete, the reaction mixture was quenched with saturated aqueous Na2SO3 solution (1 ml) and then concentrated under vacuum. The residue was purified by reverse-phase flash (condition: CombiFlash 0.1% aqueous NH3^H2O-MeCN) to give the crude product (60 mg). It was then purified again by preparative HPLC (Column: Phenomenex luna C18 150*25mm*10um; Condition: water(TFA)-MeCN; Start: B, 14, End B: 44; Gradient Time (min): 10; 100% of B Time Waiting time (min): 3; Flow rate (ml / min): 25.) to generate the title compound (22.1 mg, 23% yield) as a white solid. LCMS: m / z 381.1 m / z 395.1 [M+H]+, ESI pos. Example 8 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]7-methoxy-oxazolo[4,5-b]pyridin-5-yl]-5-methylbenzonitrile;2,2,2-trifluoroacetic acid THE H ^<_O H Step A: 6-chloro-4-iodo-2-nitropyridin-3-ol [0027 6] In a round-bottomed flask with three necks, 6-chloro-4-iodo-pyridin-3-ol (5.0 g, 19.57 mmol, 1.0 eq, CAS # 877133-58-9) in acetic acid (50 ml) was added, fuming nitric acid (2.65 ml, 63.5 mmol, 3.24 Petition 870250094781, dated 10 / 16 / 2025, pp. 303 / 378 117 / 167 eq) at 20°C, then the mixture was stirred at 20°C for 2 h. After the reaction was complete, the reaction mixture was slowly pipetted into ice-cold water (150 ml). EtOAc (150 ml) was added and the layers were separated. The aqueous phase was extracted with EtOAc (3 x 150 ml). The combined extracts were washed with saturated NaHCO3 (3 x 100 ml), dried over Na2SO4, filtered, and concentrated under vacuum to provide a residue that was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 2:1) to yield the title compound (2.90 g, 49% yield) as a yellow solid. LCMS: m / z 298.9 [MH]-, ESI neg. Step B: 6-chloro-4-:methoxy-2-nitropyridin-3-ol

[00277] To a solution of 6-chloro-4-iodo-2-nitropyridin-3-ol (1.3 g, 4.33 mmol, 1.0 eq) in methanol (13 ml) was added sodium methoxide (4.95 ml, 21.63 mmol, 5.0 eq) and Cul (0.99 g, 5.19 mmol, 1.2 eq). The reaction mixture was stirred at 80 °C for 3 h. After completion of the reaction, the reaction mixture was cooled to room temperature and water (30 ml) was added, acidified to pH = 5-6 with 1N HCl. EtOAc (50 ml) was added and the layers were separated. The aqueous phase was extracted with EtOAc (3 x 50 ml). The combined extracts were washed with brine (3 x 30 ml), dried over Na2SO4, filtered, and concentrated under vacuum to provide a residue that was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1 to 2:1) to the title compound (500.0 mg, 56% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 11.43 - 11.14 (m, 1H), 7.48 (s, 1H), 4.00 (s, 3H). Petition 870250094781, dated 10 / 16 / 2025, pp. 304 / 378 118 / 167 Step C: 2-amino-6-chloro-4-methoxypyridin-3-ol

[00278] To a solution of 6-chloro-4-methoxy-2-nitro-pyridin-3-ol (100.0 mg, 0.49 mmol, 1.0 eq) in methanol (1 ml) was added tin(II) chloride (278.06 mg, 1.47 mmol, 3.0 eq). The reaction mixture was stirred at 70°C for 2 h. After completion of the reaction, the reaction mixture was cooled to room temperature and water (20 ml) was added, basified to pH = 7 with NaHCO3. EtOAc (20 ml) was added and the layers were separated. The aqueous phase was extracted with EtOAc (3 x 20 ml). The combined extracts were washed with brine (2 x 10 ml), dried over Na2SO4, filtered, and concentrated under vacuum to provide a residue that was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1 to 1:2) to generate the title compound (45.0 mg, 53% yield) as a white solid. LCMS: m / z 175.0 [M+H]+, ESI pos. Step D: 5-Chloro-7-methoxyoxazolo[4,5-b]pyridine-2-thiol

[00279] To a solution of 2-amino-6-chloro-4-methoxypyridin-3-ol (40.0 mg, 0.23 mmol, 1.0 eq) in DMF (0.5 ml) was added di(1H-imidazol-1-yl)methathenthione (40.83 mg, 0.23 mmol, 1.0 eq) and stirred at 20°C for 16 hours. After completion of the reaction, the reaction mixture was quenched with water (10 ml) and acidified to pH = 2-3 with 1N HCl. EtOAc (10 ml) and water (10 ml) were added and the layers were separated. The aqueous phase was extracted with EtOAc (3 x 10 ml). The combined extracts were washed with saturated CaCl2 solution (2 x 10 ml), dried over Na2SO4, filtered, and concentrated under vacuum to yield the title compound (30.0 mg, 60% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 7.12 (s, 1H), 4.04 (s, 3H). Petition 870250094781, dated 10 / 16 / 2025, pages 305 / 378 119 / 167 Step E: 2,5-dichloro-7-methoxyoxazolo[4,5-b]pyridine

[00280] To a mixture of 5-chloro-7-methoxyoxazolo[4,5-b]pyridine-2-thiol (30.0 mg, 0.14 mmol, 1.0 eq) in oxalyl chloride (1.0 ml, 11.8 mmol, 85 eq), DMF (1.01 mg, 0.01 mmol, 0.1 eq) was added, then the mixture was stirred at 50°C for 1 h. After completion of the reaction, the reaction mixture was cooled to 20°C and then concentrated under vacuum, ice-cold water (5 ml) was added, and extracted with EtOAc (2 x 10 ml). The combined extracts were washed with brine (10 ml), dried over Na2SO4, filtered, and concentrated under vacuum to provide a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1 to 8:1) to generate the title compound (16.0 mg, 53% yield) as a yellow solid. LCMS: m / z 218.9 [M+H]+, ESI pos. Step F: (R)-N-(1-(2-((tertbutyldimethylsilyl)oxy)ethyl)piperidin-3-yl)-5-chloro-7methoxyoxazolo[4,5-b]pyridin-2-amine, also known as N-[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3piperidyl]-5-chloro-7-:methoxy-oxazolo[4,5-b]pyridin-2-amine

[00281] A solution of (3R)-1-[2-[tertbutyl(dimethyl)silyl]oxyethyl]piperidin-3-amine (21.2 mg, 0.08 mmol, 1.2 eq) and N-ethyl-N-isopropylpropan-2-amine (17.67 mg, 0.14 mmol, 2.0 eq) in acetonitrile (1 A solution of 2,5-dichloro-7-methoxy-oxazolo[4,5-b]pyridine (15.0 mg, 0.07 mmol, 1.0 eq) in acetonitrile (0.5 ml) was added dropwise at 20°C. The mixture was then stirred at 20°C for 1 h. After the reaction was complete, the mixture was concentrated under vacuum to yield the residue, which was purified by prepTLC (EtOAc:MeOH = 10:1) to generate the title compound (15.0 Petition 870250094781, dated 10 / 16 / 2025, pp. 306 / 378 120 / 167 mg, equivalent to 50%) combined with amarelo. 1H RMN (400 MHz, CD3OD) δ [ppm]: 6.79 (s, 1H), 4.05 (s, 3H), 3.96 - 3.88 (m, 1H), 3.82 (t, 2H), 3.22 - 3.14 (m, 1H), 2.86 - 2.77 (m, 1H), 2, 66 - 2.58 (m, 2H), 2.36 - 2.24 (m, 2H), 2.05 - 1.96 (m, 1H), 1.87 - 1.77 (m, 1H), 1.73 - 1.63 (m, 1H), 1.53 - 1.42 (m, 1H), 0.87 (s, 9H), 0.07(s, 6H). Etapa G: (R)-N-(1-(2-((tercbutildimetilsilil)oxi)etil)piperidin-3-il)-5-chloro-7metoxioxazolo[4,5-b]piridin-2-amina

[00282] To a solution of N-[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]-5-chloro-7-methoxyoxazolo[4,5-b]pyridin-2-amine (14.0 mg, 0.03 mmol, 1.0 eq) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolano-2-yl)5-(2-trimethylsililetoxymethoxy)benzonitrile (14.8 mg, 0.04 mmol, 1.2 eq), K2CO3 (10.97 mg, 0.08 mmol, 2.5 eq) in 1,4-dioxane (0.5 ml) and water (0.1 ml) was added Xphos Pd G3 (5.38 mg, 0.01 mmol, 0.2 eq) and stirred at 90°C for 4 h. After completion of the reaction, the reaction mixture was cooled to room temperature, concentrated under vacuum to provide a residue, which was purified by preparative TLC (EtOAc / MeOH = 10:1) to yield the title compound (12.0 mg, 57% yield) as a colorless oil.1H RMN (400 MHz, CD3OD) δ [ppm]: 7.38 (s, 1H), 7.32 (s, 1H), 6.66 (s, 1H), 5.17 (s, 2H), 4.06 (s, 3H), 3.98 - 3.91 (m, 1H), 3.81 (t, 2H), 3.59 (t, 2H), 3.24 - 3.17 (m, 1H), 2.83 - 2.77 (m, 1H), 2.63 - 2.56 (m, 2H), 2.33 - 2.22 (m, 2H), 2.13 (s, 3H), 2.05 - 2.00 (m, 1H), 1.85 - 1.78 (m, 1H), 1.74 - 1.65 (m, 1H), 1.48 (m, 1H), 0.87 (s, 8H), 0.84 (m, 2H), 0.07 (d, 6H), 0.05 (s, 9H). Etapa H: 3-hidroxi-4-[2-[[(3R)-1-(2-hidroxietil)-3 Petition: 870250094781, on 10 / 16 / 2025, p. 307 / 378 121 / 167 piperidil]amino]-7-metoxy-oxazolo[4,5-b]piridin-5-il]-5metil-benzonitrila,'ácido 2,2,2-trifluoroacético

[00283] A solution of 4-[2-[[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]amino]-7-methoxyoxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(2-trimethylsililetoxymethoxy)benzonitrile (10.0 mg, 0.01 mmol, 1.0 eq) in TFA (0.83 ml, 11.2 mmol, 748 eq) was stirred at 40°C for 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and concentrated under vacuum to provide a residue that was purified by preparative HPLC (Phenomenex luna C18 column 150*25mm*10µm; Condition: water(TFA)-MeCN; Start B: 14; End B: 34; Gradient Time (min): 7; 100% B Holding Time (min): 3; Flow Rate (ml / min): 25.) to yield the title compound (3.9 mg, 48% yield) as a white solid. LCMS: m / z 424.2 [M+H]+, ESI pos. Example 9 3-hydroxy-4-[2-[[(3R,5S)-5-hydroxy-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-methylbenzonitrile Step A: (3R,5S)-3-[(5-chloro-oxazolo[4,5-b]pyridin-2yl)amino]-5-hydroxy-piperidine-1-carboxylate tert-butyl

[00284] A mixture of 5-chloro-2(methylthio)oxazolo[4,5-b]pyridine (CAS # 1783370-92-2, 150 Petition 870250094781, dated 10 / 16 / 2025, pages 308 / 378 122 / 167 mg, 0.71 mmol, 1.00 eq) in 1,4-dioxane (1.4 ml) was added (3R, 5S)-3-amino-5-hydroxy-piperidine-1-tert-butylcarboxylate (CAS # 1932513-59-1, 177 mg, 0.82 mmol, 1.15 eq), followed by triethylamine (83 mg, 0.115 ml, 0.83 mmol, 1.16 eq). The reaction mixture was stirred at 110°C for 16 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and saturated aqueous NaHCO3 solution. The aqueous layer was back-extracted with ethyl acetate. The organic layers were washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient from 0% to 5% methanol in dichloromethane) to yield the title compound (251 mg, 86% yield, 90% purity) as a pale yellow oil. LCMS: m / z 369.1 [M+H]+, ESI pos. Step B: tert-butyl (3R,5S)-3-[[5-(4-cyano-2-hydroxy-6-methylphenyl)oxazolo[4,5-b]pyridin-2-yl]amino]-5-hydroxypiperidine-1-carboxylate

[00285] A mixture of tert-butyl (3R,5S)-3-[(5-chlorooxazolo[4,5-b]pyridin-2-yl)amino]-5-hydroxy-piperidine-1carboxylate (Example 9, step A) (251 mg, 0.61 mmol, 1.00 eq, 90% purity), (4-cyano-2-hydroxy-6-methylphenyl)boronic acid, Intermediate 7, (164 mg, 0.93 mmol, 1.51 eq), cesium carbonate (635 mg, 1.95 mmol, 3.18 eq) and XPhos Pd G3 (102 mg, 0.12 mmol, 0.20 eq) in 1,4-dioxane (6.0 ml) and water (1.5 ml) was purged with argon and stirred at 100°C for 3 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and Petition 870250094781, dated 10 / 16 / 2025, pp. 309 / 378 123 / 167 semi-saturated aqueous NH4Cl solution. The aqueous layer was back-extracted with ethyl acetate. The organic layers were washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient from 0% to 100% ethyl acetate in heptane to generate the title compound (188 mg, 63% yield) as a whitish solid. LCMS: m / z 466.3 [M+H]+, ESI pos. Step C: 3-hydroxy-4-[2-[[(3R,5S)-5-hydroxy-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-methylbenzonitrile

[00286] To a solution of (3R,5S)-3-[[5-(4-cyano-2-hydroxy-6-methyl-phenyl)oxazolo[4,5-b]pyridin-2-yl]amino]5-hydroxy-piperidine-1-carboxylate tert-butyl (Example 9, step B) (188 mg, 0.38 mmol, 1.00 eq) in dichloromethane (3 ml) was added dropwise at 0°C trifluoroacetic acid (992 mg, 0.67 ml, 8.70 mmol, 22.7 eq). Then, the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. The residue was dissolved in dichloromethane / methanol and carefully basified with saturated aqueous NaHCO3 solution and extracted three times with a dichloromethane / methanol mixture (9:1). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by SFC (Chiral IH column, eluent B: 20% methanol + 0.2% diethylamine) to yield the title compound (25 mg, 17% yield) as a white powder. LCMS: m / z 366, 1 [M+H]+, ESI pos. Petition 870250094781, dated 10 / 16 / 2025, pp. 310 / 378 124 / 167 Example 10 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-5-methylbenzonitrile Step A: tert-butyl (3R)-3-[(3-benzyloxy-6-bromo-pyrazin-2yl)carbamothioylamino]piperidine-1-carboxylate

[00287] To a solution of 3-benzyloxy-6-bromopyraz-2-amine (2700.0 mg, 9.64 mmol, 1.0 eq) in THF (15 ml) was added NaH (578.32 mg, 14.46 mmol, 1.5 eq) and stirred for 20 min, then a solution of (3R)-3isothiocyanatopiperidine-1-carboxylate tert-butyl (CAS # 2824986-69-6, 2803.02 mg, 11.6 mmol, 1.2 eq) in THF (5 ml) was added dropwise and stirring continued at 20°C for 4h under N2. After the reaction was complete, the mixture was quenched with NH4Cl (60 ml) and extracted with EtOAc (100 ml x 2). The organic phase was washed with brine (100 ml x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, PE:EtOAc, 87% to 13%) to give the title compound (3700.0 mg, 73% yield) as a yellow oil. LCMS (de-BOC) m / z: 466, 1 [M+H]+, ESI pos. Step B: 1-(6-bromo-3-hydroxy-pyrazin-2-yl)-3-[(3R)-3Petition 870250094781, of 10 / 16 / 2025, p. 311 / 378 125 / 167 piperidyl]thiourea

[00288] To a solution of (3R)-3-[(3-benzyloxy-6-bromo-pyrazin-2-yl)carbamothioylamino]piperidine-1-tert-butylcarboxylate (3700.0 mg, 7.08 mmol, 1.0 eq) in anisole (20 ml) was added TFA (20 ml) and stirred at 70°C for 2 h under N2. After completion of the reaction, the mixture was concentrated under vacuum, diluted with MeOH (6 ml) and the pH was adjusted to 8.0. The residue was purified by C18 column chromatography (0.1% NH3*H2O-MeCN=54%~46%), the eluent was lyophilized to give the title compound (1400.0 mg, 60% yield) as a white solid. LCMS m / z: 334.0 [M+2+H]+, ESI pos. Step C: 1-(6-bromo-3-hydroxy-pyrazin-2-yl)-3-[(3R)-1-[2[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]thiourea

[00289] To a solution of 1-(6-bromo-3-hydroxypyrazin-2-yl)-3-[(3R)-3-piperidyl]thiourea (570.0 mg, 1.72 mmol, 1.0 eq) in DCE (10 ml) and methanol (1 ml) was added CH3COOH (10.3 mg, 0.17 mmol, 0.1 eq) stirred for 20 min, then NaBH(OAc)3 (1.82 g, 8.58 mmol, 5.0 eq) was added and the mixture stirred at 20°C for 1 hr. After the reaction was complete, the mixture was quenched with H2O (30 ml), and extracted with EtOAc (30 ml x 2). The organic phase was washed with brine (30 ml x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate, 61% to 39%) to yield the title compound (540.0 mg, 64% yield) as yellow oil. LCMS m / z: 492.2 [M+2+H]+, ESI pos. Step D: 5-bromo-N-[(3R)-1-[2-[tertbutyl(dimethyl)silyl]oxyethyl]-3-piperidyl]oxazolo[4,5b]pyrazin-2-amine Petition 870250094781, dated 10 / 16 / 2025, pp. 312 / 378 126 / 167

[00290] To a solution of 1-(6-bromo-3-hydroxypyrazin-2-yl)-3-[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]thiourea (540.0 mg, 1.1 mmol, 1.0 eq) in THF (20 ml) was added tetrabutylammonium iodide (406.6 mg, 1.1 mmol, 1.0 eq) then dropwise H2O2 (390.0 mg, 3.44 mmol, 3.13 eq) and stirred at 25°C for 1 h. After the reaction was complete, the mixture was quenched with H2O (30 ml) and Na2SO3 (30 ml), and extracted with EtOAc (20 ml x 2). The organic phase was washed with Na2SO3 (30 ml), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate, 65% to 35%) to give the title compound (169.0 mg, 34% yield) as yellow oil. LCMS m / z: 456.3 [M+H]+, ESI pos. Step E: 4-[2-[[(3R)-1-[2-[tertbutyl(dimethyl)silyl]oxyethyl]-3-piperidyl]amino]oxazolo[4,5b]pyrazin-5-yl]-3-methyl-5-(2trimethylsilylethoxymethoxy)benzonitrile

[00291] To a solution of 5-bromo-N-[(3R)-1-[2[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]oxazolo[4,5b]pyrazine-2-amine (269.0 mg, 0.59 mmol, 1.0 eq) and 3-methyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolano-2-yl)-5-(2-trimethylsililetoxymethoxy)benzonitrile (344.2 mg, 0.88 mmol, 1.5 eq) in 1,4-dioxane (4 ml) and water (0.8 ml) was added CsF (358.08 mg, 2.36 mmol, 4.0 eq) and XPhos Pd G3 (99.9 mg, 0.12 mmol, 0.2 eq), then, The mixture was stirred at 95°C for 2 h under N2. After the reaction was complete, the above reaction was concentrated under reduced pressure, diluted with EtOAc (3 ml), filtered, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (SiO2, PE:EtOAc = 1:1) to Petition 870250094781, dated 10 / 16 / 2025, pp. 313 / 378 127 / 167 provide the title compound (70.0 mg, 19% yield) as a yellow oil. LCMS m / z: 639.5 [M+H]+, ESI pos. Additionally, these compounds were also isolated: 2[(3R)-3-[(5-bromo-oxazolo[4,5-b]pyrazin-2-yl)amino]-1-piperidyl]ethanol (30.0 mg, 9.7% yield) as a yellow oil. LCMS m / z: 342.1 [M+H]+, ESI pos.; as well as 4-[2[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5b]pyrazin-5-yl]-3-methyl-5-(2-trimethylsilethylenethoxymethoxy)benzonitrile (30.0 mg, 10% yield) as a yellow solid. LCMS m / z: 525.3 [M+H]+, ESI pos. Step F: 4-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-3-methyl-5-(2trimethylsilylethoxymethoxy)benzonitrile

[00292] To a solution of the above-mentioned 2-[(3R)-3-[(5-bromooxazolo[4,5-b]pyrazin-2-yl)amino]-1-piperidyl]ethanol (30.0 mg, 0.09 mmol, 1.0 eq) and 3-methyl-4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(2-trimethylsilethoxymethoxy)benzonitrile (51.2 mg, 0.13 mmol, 1.5 eq) in 1,4-dioxane (1 ml) and water (0.2 ml) was added CsF (53.27 mg, 0.35 mmol, 4.0 eq) and xphos Pd g3 (14.9 mg, 0.02 mmol, 0.2 eq), then stirred at 95°C for 2 h under N2. After the reaction was complete, the above reaction was concentrated by reduced pressure, diluted with EtOAc (2 ml), filtered, and the filtrate was concentrated under vacuum. The residue was purified by prep-TLC (EA:MeOH=3:1) to give the title compound (10.0 mg, 22% yield) as yellow oil. Step G: 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-5-methylbenzonitrile Petition 870250094781, dated 10 / 16 / 2025, pp. 314 / 378 128 / 167

[00293] To a solution of 4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]3-methyl-5-(2-trimethylsilethylenethoxymethoxy)benzonitrile (10.0 mg, 0.02 mmol, 1.0 eq) in DCM (0.5 ml) was added TFA (0.5 ml) and stirred at 40°C for 2 hours. After completion of the reaction, the mixture was diluted with DCM (2 ml) and MeOH (1 ml), and the pH was adjusted to about 8 with NH3*H2O, then filtered and the filtrate was concentrated under reduced pressure. The crude product purified by prep-HPLC (Column: Waters Xbridge 150*25mm*5um; Condition: water (0.1% NH3*H2O)-ACN, Start B 7 End B 38; Gradient time (min): 10; 100% B Holding time (min): 2; Flow rate (ml / min) 25), to give the title compound (2.12 mg, 27% yield) as a white solid. LCMS m / z: 395.2 [M+H]+, ESI pos. Example 11 5- [2- [[(3R) -1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-6(methoxymethyl)-2,3-dihydrobenzofuran-4-ol Step A: 2-[(3R)-3-[(5-bromo-oxazolo[4,5-b]pyrazin-2yl)amino]piperidine]ethanol; 2,2,2-trifluoroacetic acid

[00294] A solution of 5-Bromo-N-[(3R)-1-[2[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]oxazolo[4.5b]pyrazin-2-amine (290.0 mg, 0.64 mmol, 1.0 eq, Example 10, Step D) in TFA (3.0 ml, 40.4 mmol, 63.6 eq) and DCM (3ml) Petition 870250094781, dated 10 / 16 / 2025, pp. 315 / 378 129 / 167 was stirred at 40°C for 1 h. Then, the reaction mixture was concentrated under vacuum to provide a residue. For purification, 2 batches were combined (adding 170 mg) and the crude was purified by C18 column chromatography (20 g, 0.1% NH3·H2O in water / MeCN, MeCN: 40%-50%) to provide the title compound (370.9 mg, 79% yield) as a yellow solid. LCMS m / z: 341.9 [M+H]+, ESI pos. Step B: 5-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-6(methoxymethyl)-2,3-di-hydrobenzofuran-4-ol

[00295] A mixture of 2-[(3R)-3-[(5-bromooxazole[4,5-b]pyrazin-2-yl)amino]piperidino]ethanol;2,2,2-trifluoroacetic acid (324 mg, 710.2 pmol, 1.0 eq), 6(methoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2yl)-2,3-di-hydrobenzofuran-4-ol Intermediate 8 (365 mg, A mixture of 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane dichloride (1.13 mmol, 1.6 eq), potassium carbonate (405 mg, 2.93 mmol, 4.126 eq) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane dichloride complex (89 mg, 109 pmol, 0.15 eq) in 1,4-dioxane (5.6 ml) and water (2.8 ml) was purged with argon and stirred at 90°C for 2 h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and semi-saturated aqueous NH4Cl solution. The aqueous layer was back-extracted twice with ethyl acetate. The organic layers were washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 25 g, gradient from 0% to 10% methanol in dichloromethane) to yield the title compound (297 mg) as a brown foam. After combining with another batch (35 mg), the Petition 870250094781, dated 10 / 16 / 2025, pp. 316 / 378 Compound 130 / 167 was purified again by flash chromatography (Si-amine, 12 g, gradient from 0% to 10% methanol in ethyl acetate) followed by trituration with ethyl acetate / heptane to generate the title compound (206 mg, 63% yield) as a light yellow powder. LCMS m / z: 442.4 [M+H]+, ESI pos. Example 12 5-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6(methoxymethyl)-2,3-dihydrobenzofuran-4-ol

[00296] A mixture of 2-[(3R)-3-[(5-chlorooxazolo[4,5-b]pyridin-2-yl)amino]piperidino]ethanol (124 mg, 397 gmol, 1.00 eq; CAS# 2923540-56-9), 6-(methoxymethyl)-5(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-4-ol Intermediate 8 (230 mg, 714 gmol, 1.80 eq), potassium carbonate (209 mg, 1.51 mmol, 3.81 eq) and potassium dichloride complex 1,1'-bis(diphenylphosphine)ferrocenepalladium(ii) dichloromethane (50 mg, 61.23 gmol, A solution of 0.15 eq) in 1,4-dioxane (2.8 ml) and water (1.4 ml) was purged with argon and stirred at 95°C overnight. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and semi-saturated aqueous NH4Cl solution. The aqueous layer was back-extracted with ethyl acetate. The organic layers were washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was... Petition 870250094781, dated 10 / 16 / 2025, pp. 317 / 378 131 / 167 purified by flash chromatography (silica gel, 12 g, gradient from 0% to 10% methanol in dichloromethane). All fractions containing the product were combined and concentrated in vacuo and purified again by flash chromatography (Si-amine, 12 g, gradient from 0% to 10% methanol in ethyl acetate) to generate the title compound (73 mg, 40% yield) as a whitish foam. LCMS m / z: 441.3 [M+H]+, ESI pos. Example 13 5- [2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol OH Step A: 5-[2-[[(3R)-1-[2-[tertbutyl(dimethyl)silyl]oxyethyl]-3-piperidyl]amino]oxazolo[4,5b]pyrazin-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol

[00297] To a solution of 5-Bromo-N-[(3R)-1-[2[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]oxazolo[4,5b]pyrazin-2-amine (400.0 mg, 0.88 mmol, 1.0 eq, Example 10, Step D) in 1,4-dioxane (10 ml) and water (2 ml) was added 6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-4-ol (290.39 mg, 1.05 mmol, 1.2 eq; CAS# 2923540-54-7) and CsF (332.79 mg, 2.19 mmol, 2.5 eq) were added. Then, XphosPdG3 (74.27 mg, 0.09 mmol, 0.1 eq) was added to the above mixture. The reaction mixture was stirred at 80°C for 4 h under N2. After the reaction was complete, the reaction mixture Petition 870250094781, dated 10 / 16 / 2025, pp. 318 / 378 132 / 167 was cooled to room temperature. EtOAc (10 ml) and brine (3 ml) were added to the mixture and the layers were separated. The aqueous phase was extracted with EtOAc (10 ml x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1 to 0:1) to yield the title compound (300 mg, 63% yield) as a yellow solid. LCMS m / z: 526.3 [M+H]+, ESI pos. Step B: 5-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol

[00298] A solution of 5-[2-[[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]amino]oxazolo[4,5b]pyrazin-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol (300.0 mg, 0.57 mmol, 1.0 eq) in DCM (3 ml) and TFA (3.0 ml, 40.39 mmol, 70.78 eq) was stirred at 40 °C for 2 hours. After completion of the reaction, the reaction mixture was concentrated under vacuum and dissolved in MeOH (2 ml), basified to pH = 7 by addition of saturated aqueous NaHCO3 solution. Then, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Method: Waters Xbridge column 150 x 25 mm x 5 µm; Condition: water (ammonium hydroxide v / v)-MeCN; Start B: 0; End B: 30; Gradient Time (min): 10; 100% B Holding Time (min): 4; Flow Rate (ml / min): 25) to yield the title compound (145.3 mg, 60% yield) as a white solid. LCMS m / z: 412.2 [M+H]+, ESI pos. Example 14 5-[2-[[(3R)-1-(2-hydroxyethyl)-3Petition 870250094781, of 16 / 10 / 2025, p. 319 / 378 133 / 167 piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol

[00299] A mixture of 2-[(3R)-3-[(5-chlorooxazolo[4,5-b]pyridin-2-yl)amino]piperidino]ethanol (70 mg, 224.1 pmol, 1.00 eq; CAS# 2923540-56-9), 6-methyl-5-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)coumaran-4-ol (129 mg, 350.4 pmol, 1.56 eq; CAS# 2923540-54-7), potassium carbonate (146 mg, 1.06 mmol, 4.71 eq) and potassium dichloride complex 1,1'-bis(diphenylphosphine)ferrocene-palladium(ii) dichloromethane (28 mg, 34.3 pmol, A solution of 0.15 eq) in 1,4-dioxane (1.5 ml) and water (750 µl) was purged with argon and stirred at 95°C overnight. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and semi-saturated aqueous NH4Cl solution. The aqueous layer was back-extracted with ethyl acetate. The organic layers were washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 12 g, gradient from 0% to 10% methanol in dichloromethane).All fractions containing the product were combined and concentrated in vacuo. The residue (52 mg) was subjected to further purification by SFC (Column: 4-Ethyl Pyridine achiral, 12 nm, 5 pm, 250 x 20 mm, Eluent B: 15% MeOH + 0.2% DEA) to generate the title compound (16 mg, 17% yield) as a yellow solid. Petition 870250094781, dated 10 / 16 / 2025, pp. 320 / 378 134 / 167 of course. LCMS m / z: 411.1 [M+H]+, ESI pos. Example 15 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-5(methoxymethyl)benzonitrile;2,2,2-trifluoroacetic acid HOO H\F1 <fa o n q xxx«-X^Z^OH N Step A: 2-[(3R)-3-[(5-bromo-oxazolo[4,5-b]pyrazin-2yl)amino]-1-piperidyl]ethanol

[00300] A solution of 1-(6-bromo-3-hydroxypyrazin-2-yl)-3-[(3R)-1-(2-hydroxyethyl)-3-piperidyl]thiourea Intermediate 11 (200.0 mg, 0.53 mmol, Tetrabutylammonium iodide (39.3 mg, 0.11 mmol, 0.2 eq) in THF (5 ml) was added to H2O2 (180.8 mg, 1.59 mmol, 3.0 eq, purity: 30% in water) and stirred at 20°C for 1 h. After completion of the reaction, the mixture was quenched with saturated aqueous Na2SO3 solution (3 ml), then the mixture was concentrated under vacuum. The residue was purified by prep-HPLC (column: Xtimate C18, 2 50mm*50mm*10μm; mobile phase: [water (0.1% ammonium hydroxide v / v)-MeCN]; B%: 5%-35%, 10 minutes), the eluent was lyophilized to yield the title compound (80.0 mg, 39% yield) as a yellow solid. LCMS: m / z 344.0 [M+2+H]+, ESI pos. Step B: 4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-3-(methoxymethyl)-5-(2-trimethylsilethoxymethoxy)benzonitrile

[00301] To a solution mentioned above of 2 Petition 870250094781, dated 10 / 16 / 2025, pp. 321 / 378 135 / 167 [(3R)-3-[(5-bromo-oxazolo[4,5-b]pyrazin-2-yl)amino]-1-piperidyl]ethanol (50.0 mg, 0.15 mmol, 1.0 eq) and 3(methoxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-5-(2-trimethylsilethoxymethoxy)benzonitrile (91.9 mg, 0.22 mmol, 1.5 eq; CAS# 2923541-74-4), CsF (66.6 mg, 0.44 mmol, 3.0 eq) in 1,4-dioxane (2 ml) and water (0.4 ml) was added Xphos Pd G3 (24.8 mg, 0.03 mmol, 0.2 eq). Next, the mixture was stirred at 80°C for 2 h under nitrogen. After the reaction was complete, the above reaction mixture was cooled to room temperature, poured onto ice (20 ml), and extracted with ethyl acetate (50 ml*3). The combined organic phases were washed with brine (50 ml*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1 to 1:1) to yield the title compound (30.0 mg, 37% yield) as a yellow solid.1H RMN (400 MHz, CD3OD) δ [ppm]: 7.78 (s, 1H), 7.56 (s, 1H), 7.54 (s, 1H), 5.22 (s, 2H), 4.31 (s, 2H), 4.07 (s, 1H), 3.71 - 3.67 (m, 2H), 3.60 (t, 2H), 3.25 (s, 3H), 3.00 - 2.96 (m, 1H), 2.61 - 2.59 (m, 1H), 2.59 - 2.56 (m, 2H), 2.47 - 2.45 (m, 2H), 1.89 -1.83 (m, 2H), 1.70 - 1,66 (m, 2H), 0.86 (t, 2H), -0.05 (s, 9H). Etapa C: 3-hidroxi-4-[2-[[(3R)-1-(2-hidroxietil)-3piperidil]amino]oxazolo[4,5-b]pirazin-5-il]-5(metoximetil)benzonitrila,'ácido 2,2,2-trifluoroacético

[00302] A uma solução de 4-[2-[[(3R)-1-(2hidroxietil)-3-piperidil]amino]oxazolo[4,5-b]pirazin-5-il]3-(metoximetil)-5-(2-trimetilsililetoximetoxi)benzonitrila acima mencionada (15,0 mg, 0,03 mmol, 1,0 eq) em DCM (0,5 ml) foi adicionado TFA (0,5 ml). Então, a mistura foi agitada Petition: 870250094781, on 10 / 16 / 2025, p. 322 / 378 136 / 167 at 20°C for 1 h. After completion of the reaction, the above reaction mixture was concentrated under vacuum. The residue was purified by prep-HPLC (column: Phenomenex Gemini, 150mm*30mm*15µm; mobile phase: [water (0.1% TFA, V / V)-MeCN]; B%: 22%-52%, 12 mins), the eluent was lyophilized to generate the title compound (12.8 mg, 110% yield, TFA salt) as a yellow oil. LCMS: m / z 425.3 [M+H]+, ESI pos. Example 16 = Example 8 as free salt 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]7-methoxy-oxazolo[4,5-b]pyridin-5-yl]-5-methyl-benzonitrile THE N \_O H Example 17 = Examples 2 as free salt 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-3-hydroxy-5methyl-benzonitrile,OH THE Example 18 5-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-6-methyl-indan4-ol NODE OHO OH Step A: N-[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3Petition 870250094781, of 16 / 10 / 2025, p. 323 / 378 137 / 167 piperidyl]-5-[6-methyl-4-(2-trimethylsilylethoxymethoxy)indan5-yl]oxazolo[4,5-b]pyrazine-2-amine

[00303] To a solution of 5-bromo-N-[(3R)-1-[2[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]oxazolo[4,5b]pyrazine-2-amine (110.0 mg, 0.11 mmol, 1.0 eq; Example 10, Step D), trimethyl-[2-[[6-methyl-5-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)indan-4-yl]oxymethoxy]ethyl]silane (53.2 mg, 0.13 mmol, 1.2 eq; Example 19, Step G), CsF (66.6 mg, 0.44 mmol, 4.0 eq) in 1,4-dioxane (1 ml) and water (0.2 ml) was added Xphos Pd G3 (18.6 mg, 0.02 mmol, 0.2 eq). The reaction vessel was sealed and microwaved at 95°C for 3 h. After the reaction was complete, the reaction mixture was cooled to room temperature, then diluted with water (20 ml) and extracted with ethyl acetate (30 ml *3). The combined organic phases were washed with brine (30 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (ethyl acetate) to yield the title compound (50.0 mg, 42% yield) as gum yellow.LCMS: m / z 654.4 [M+H]+, ESI pos. Step B: 5-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-6-methyl-indan4-ol

[00304] A solution of N-[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]-5-[6-methyl-4-(2-trimethylsilethyleneoxymethoxy)indan-5-yl]oxazolo[4,5-b]pyrazin-2-amine (50.0 mg, 0.08 mmol, 1.0 eq) in HCl / dioxane (1.0 mL, 2 M) was stirred at 25°C for 1 h. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex). Petition 870250094781, dated 10 / 16 / 2025, pp. 324 / 378 138 / 167 Gemini, 150mm * 25mm * 10um; mobile phase: [water (0.1% NH4HCO3, V / V)-MeCN]; B%: 22%-55%, 10 min), then lyophilized to generate the title compound (5.1 mg, 16.0% yield) as a white solid. LCMS: m / z 410.3 [M+H]+, ESI pos. Example 19 5-[2-[[(3R)-1-(2-hidroxyetil)-3-piperidil]amino]-7-metoxioxazolo[4,5-b]pyridin-5-yl]-6-methyl-indan-4-ol O' H ~Ϋ_Ο H Step A: 2-vinylcyclopenteno-1-carbaldeido

[00305] To a solution of 2-bromocyclopentene-1-carbaldehyde (30.0 g, 171.4 mmol, 1.0 eq; CAS # 89466-25-1), Cs2CO3 (167.6 g, 514.23 mmol, 3.0 eq) and potassium vinyltrifluoroborate (29.9 g, 222.8 mmol, 1.3 eq), PPh3 (4.5 g, 17.1 mmol, 0.1 eq) in THF (500 ml) and water (100 ml) Pd(OAc)2 (1.92 g, 8.57 mmol, 0.05 eq) was added, the mixture was degassed with N2 three times and stirred at 50°C for 12 h. The reaction mixture was diluted with water (500 ml) and extracted with EtOAc (300 ml x 2). The combined organic phases were washed with brine (50 ml*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1 / 0) to yield the title compound (15.0 g, 64% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ [ppm]: 10.21 (s, 1H), 7.31 - 7.24 (m, 1H), 5.57 (d, 1H), 5.54 (s, 1H), 2.78 (t, 2H), 2.67 (t, 2H), 1.95 - 1.88 (m, 2H). Petition 870250094781, dated 10 / 16 / 2025, pages 325 / 378 139 / 167 Step B: 3-:methyl-1-(2-vinylcyclopenten-1-yl)but-3-en-1-ol

[00306] To the aforementioned solution of 2-vinylcyclopentene-1-carbaldehyde (6.0 g, 49.1 mmol, 1.0 eq) in THF (20 ml), 2-methylallylmagnesium chloride (197.0 ml, 98.5 mmol, 2.01 eq) was added at 0°C under N2, the mixture was stirred at 25°C for 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution (150 ml), and extracted with EtOAc (100 ml x 2). The combined organic layers were washed with brine (100 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1 / 0-10 / 1) to generate the title compound (2.5 g, 29% yield) as yellow oil. 1H NMR (400 MHz, CDCl3) δ [ppm]: 6.78 - 6.71 (m, 1H), 5.16 - 5.10 (m, 2H), 4.88 (m, 1H), 4.85 - 4.82 (m, 2H), 2.69 - 2.59 (m, 1H), 2.57 - 2.43 (m, 4H), 2.20 (dd, 1H), 1.90 - 1.82 (m, 2H), 1.79 (s, 3H). Step C: 3-methyl-1-(2-vinylcyclopenten-1-yl)but-3-en-1-one

[00307] To the aforementioned solution of 3-methyl-1-(2-vinylcyclopenteno-1-yl)but-3-en-1-ol (2.5 g, 14.02 mmol, 1.0 eq) in DCM (200 ml), Dess-Martin periodinan (11896.1 mg, 28.1 mmol, 2.0 eq) was added at 0°C. The mixture was stirred at 25°C for 0.5 h. The reaction mixture was quenched with saturated aqueous Na2SO3 solution (150 ml), extracted with EtOAc (150 ml x 2). The combined organic layers were washed with brine (100 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1 / 0 to 10 / 1) to generate the compound of Petition 870250094781, dated 10 / 16 / 2025, pp. 326 / 378 140 / 167 title (2.0 g, 65% yield) as yellow oil. 1H NMR (400 MHz, CDCla) δ [ppm]: 7.41 (dd, 1H), 5.49 - 5.41 (m, 2H), 4.94 (s, 1H), 4.76 (d, 1H), 3.24 (s, 2H), 2.80 (t, 2H), 2.68 (t, 2H), 1.94 - 1.87 (m, 2H), 1.78 (s, 3H). Step D: 6-methylindan-4-ol

[00308] To a solution of the above-mentioned 3-methyl-1-(2-vinylcyclopenteno-1-yl)but-3-en-1-one (2000.0 mg, 11.4 mmol, 1.0 eq) in toluene (1000 ml), Hoveyda-Grubbs (567.9 mg, 0.91 mmol, 0.08 eq) was added, the mixture was degassed with N2 three times and stirred at 80°C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1 to 5:1) to yield the title compound (1.2 g) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 6.67 (s, 1H), 6.46 (s, 1H), 4.54 - 4.51 (m, 1H), 2.89 (t, 2H), 2.82 (t, 2H), 2.29 (s, 3H), 2.14 - 2.06 (m, 2H). Step E: 5-bromo-6-methylindan-4-ol

[00309] To the aforementioned solution of 6-methylindan-4-ol (1.2 g, 8.1 mmol, 1.0 eq) and i-Pr2NH (163.6 mg, 1.62 mmol, 0.2 eq) in DCM (20 ml), NBS (1441.2 mg, 8.1 mmol, 1.0 eq) was added at 0°C. The mixture was stirred at 0°C for 1 h. The reaction mixture was diluted with DCM (50 ml) and washed with brine (40 ml). The organic layers were separated and dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50:1 to 10:1) to yield the title compound (1.0 g, 54% yield) as a white solid. 1H NMR (400 MHz, CDCl3): δ 6.73 (s, 1H), 5.58 (s, 1H), 2.93 Petition 870250094781, dated 10 / 16 / 2025, pp. 327 / 378 141 / 167 2.83 (m, 4H), 2.37 (s, 3H), 2.14 - 2.06 (m, 2H). Step F: 2-[(5-bromo-6-:methyl-indan-4-yl)oxymethoxy]ethyltrimethyl-silane

[00310] To the above-mentioned solution of 5-bromo-6-methyl-indan-4-ol (300.0 mg, 1.32 mmol, 1.0 eq) in DMF (5 ml) was added CS2CO3 (860.8 mg, 2.64 mmol, 2.0 eq) at 0°C, then the mixture was stirred at 0°C for 0.5 h. Then, 2-(trimethylsilyl)ethoxymethyl chloride (0.26 ml, 1.45 mmol, 1.1 eq) was added to the above mixture, dropwise, at 0°C, then the resulting mixture was stirred at 20°C for 1 h. After completion of the reaction, the above reaction solution was diluted with water (10 ml), extracted with ethyl acetate (20 ml*3). The combined organic phases were washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether: ethyl acetate = 1:0 to 0:1) to yield the title compound (440.0 mg, 84% yield) as a colorless oil. 1H NMR (400 MHz, DMSO-de): δ 6.99 (s, 1H), 5.10 (s, (2H), 3.89 - 3.77 (m, 2H), 2.90 (t, 2H), 2.79 (t, 2H), 2.31 (s, 3H), 2.02 - 1.97 (m, 2H), 0.95 - 0.85 (m, 2H), 0.01 (s, 9H). Etapa G: Trimetil-[2-[[6-metil-5-(4,4,5,5-tetrametil-1,3,2dioxaborolan-2-il)indan-4-il]oximetoxi]etil]silano 00311 'octametil-2,2'-bi(1,3,2-dioxaborolano) (625,5 mg, 2,46 mmol, 2,0 eq), Cs2CO3 (802,4 mg, 2,46 mmol, 2,0 eq) e tris(4-metoxi3,5-dimetilfenil)fosfano (107,5 mg, 0,25 mmol, 0,2 eq) em Petition: 870250094781, on 10 / 16 / 2025, p. 328 / 378 142 / 167 1,4-dioxane (10 ml) was added to Pd(OAc)2 (55.3 mg, 0.25 mmol, 0.2 eq) under N2. The mixture was stirred at 95°C for 3 h. After the reaction was complete, the above reaction mixture was cooled to room temperature, then diluted with water (30 ml) and ethyl acetate (20 ml), filtered, and the filtrate was extracted with ethyl acetate (20 ml*3). The combined organic phases were washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (petroleum ether: ethyl acetate = 20:1) to generate the title compound (330.0 mg, 66% yield) as colorless oil. 1H NMR (400 MHz, CD3OD) δ [ppm]: 6.81 (s, 1H), 5.07 (s, 2H), 4.60 (s, 2H), 3.75 - 3.88 (m, 2H), 2.75 - 3.03 (m, 4H), 2.30 (s, 3H), 1.92 - 2.11 (m, 2H), 1.37 (s, 12H), 1.34 - 1.43 (m, 1H), 0.82 - 1.00 (m, 2H), 0.00 (s, 9H). Step H: 7-methoxy-5-[6-methyl-4-(2trimethylsilylethoxymethoxy)indan-5-yl]-N-[(3R)-1-[2-[tertbutyl(dimethyl)silyl]oxyethyl]-3-piperidyl]oxazolo[4.5b]pyridin-2-amine

[00312] To a solution of N-[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]-5-chloro-7-methoxyoxazolo[4,5-b]pyridin-2-amine (110.0 mg, 0.13 mmol, 1.0 eq, Example 8, Step F), in 1,4-dioxane (2 ml) and water (0.400 ml) was added the aforementioned trimethyl-[2-[[6-methyl-5(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indan-4yl]oxymethoxy]ethyl]silane (63.8 mg, 0.16 mmol, 1.2 eq), CsF (39.9 mg, 0.26 mmol, 2.0 eq) and Xphos Pd G3 (22.3 mg, 0.03 mmol, 0.2 eq). The reaction vessel was sealed and microwaved at 95°C for 3 h. After the reaction was complete, the above reaction mixture was cooled to room temperature, then diluted. Petition 870250094781, dated 10 / 16 / 2025, pp. 329 / 378 143 / 167 with water (20 ml), extracted with ethyl acetate (30 ml * 3). The combined organic phases were washed with brine (30 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (ethyl acetate) to generate the title compound (70.0 mg, 26% yield) as gum yellow. LCMS: m / z 683.6 [M+H]+, ESI pos. Step I: 5-[2-[[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]7-:methoxy-oxazolo[4,5-b]pyridin-5-yl]-6-methyl-indan-4-ol

[00313] A solution of 7-methoxy-5-[6-methyl-4-(2trimethylsilylethoxymethoxy)indan-5-yl]-N- [rac-(3R)-1-[2[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]oxazolo[4,5b]pyridin-2-amine (70.0 mg, 0.1 mmol, 1.0 eq) in HCl / 1,4dioxane (1.0 ml, 2 M) was stirred at 25 ° C for 1 h. After the reaction was complete, the above mixture was concentrated under pressure, then adjusted to pH = 7 with a saturated aqueous solution of NaHCO3 at 0°C, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC column: Phenomenex Gemini, 150 mm * 25 mm * 10 µm; mobile phase: [water (0.1% NH4HCO3, V / V)-MeCN]; B%: 22%-52%, 12 min), then lyophilized to yield the title compound (10.1 mg, 22% yield) as a white solid. LCMS: m / z 439.3 [M+H]+, ESI pos. Example 20 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridin-5-yl]-5(methoxymethyl)benzonitrile Petition 870250094781, de 16 / 10 / 2025, pág. 330 / 378 144 / 167 OH Step A: 3-(methoxymethyl)-4-[7-:methoxy-2-[[(3R)-1-[2-[tertbutyl(dimethyl)silyl]oxyethyl]-3-piperidyl]amino]oxazolo[4,5b]pyridin-5-yl]-5-(2-trimethylsilylethoxymethoxy)benzonitrile

[00314] To a solution of N-[(3R)-1-[2-[tertbutyl(dimethyl)silyl]oxyethyl]-3-piperidyl]-5-chloro-7-methoxyoxazolo[4,5-b]pyridin-2-amine (60.0 mg, 0.14 mmol, 1.0 eq; Example 8, Step F), 3-(methoxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(2-trimethylsilethoxymethoxy)benzonitrile (68.5 mg, 0.16 mmol, 1.2 eq; CAS # 2923541-74-4), CsF (41.3 mg, 0.27 mmol, 2.0 eq) in 1,4-dioxane (2 ml) and water (0.4 ml) was added Xphos Pd G3 (23.1 mg, 0.03 mmol, 0.2 eq). The reaction vessel was sealed and microwaved at 95°C for 1.5 h under nitrogen. After completion of the reaction, the above reaction mixture was cooled to room temperature and diluted with water (20 ml), extracted with ethyl acetate (30 ml*3).The combined organic phases were washed with brine (30 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (ethyl acetate) to yield the title compound (50.0 mg, 35% yield) as gum yellow. 1H NMR (400 MHz, CD3OD) δ [ppm]: 7.55 - 7.52 (m, 1H), 7.51 - 7.48 (m, 1H), 6.72 (s, 1H), 5.20 (s, 2H), 4.86 (s, 1H), 4.25 (s, 2H), 4.06 (s, 3H), 3.98 - 3.92 (m, 1H), 3.82 (t, 2H), 3.59 (t, 2H), 3.34 - 3.32 (m, 1H), 3.27 (s,. Petition 870250094781, dated 10 / 16 / 2025, pp. 331 / 378 145 / 167 3H), 3.25 - 3.18 (m, 1H), 2.86 - 2.74 (m, 1H), 2.66 - 2.55 (m, 2H), 2.35 - 2.23 (m, 2H), 2.06 - 1.99 (m, 1H), 1.86 1.77 (m, 1H), 1.74 - 1.65 (m, 1H), 1.55 - 1.42 (m, 1H), 0.87 (s, 9H), 0.07 (s, 6H), 0.00 (s, 9H). Step B: 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridin-5-yl]-5(methoxymethyl)benzonitrile

[00315] The above-mentioned solution of 3(methoxymethyl)-4-[7-methoxy-2-[[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]amino]oxazolo[4,5b]pyridin-5-yl]-5-(2-trimethylsililetoxymethoxy)benzonitrile (50.0 mg, 0.07 mmol, 1.0 eq) in HCl / 1,4-dioxane (1.0 ml, 2M) was stirred at 25°C for 1 h. After completion of the reaction, the above mixture was adjusted to pH = 7 with saturated aqueous NaHCO3 solution at 0°C, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Gemini, 150 mm*25 mm*10 µm; mobile phase: [water (0.1% NH4HCO3, V / V)-MeCN]; B%: 22%-52%, 11 min), then lyophilized to yield the title compound (18.7 mg, 58% yield) as a white solid. LCMS: m / z 454.3 [M+H]+, ESI pos. Example 21 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]-7-methoxyoxazolo[4,5-b]pyridin-5-yl]-6-(methoxymethyl)-2,3-dihydrobenzofuran-4-ol Petition 870250094781, dated 10 / 16 / 2025, pp. 332 / 378 146 / 167 Step A: 6-(methoxymethyl)-5-[7-methoxy-2-[[(3R)-1-[2-[tertbutyl(dimethyl)silyl]oxyethyl]-3-piperidyl]amino]oxazolo[4,5b]pyridin-5-yl]-2,3-dihydrobenzofuran-4-ol

[00316] A solution of 6-(methoxymetil)-5(4,4,5,5-tetrametil-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-4-ol Intermediário 8 (58.3 mg, 0.19 mmol, 1.2 eq) and N-[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]3-piperidyl]-5-chloro-7-methoxy-oxazolo[4,5-b]pyridin-2-amine (70.0 mg, 0.16 mmol, 1.0 eq; Example 8, Step F), K2CO3 (54.8 mg, 0.4 mmol, 2.5 eq) in 1,4-dioxane (1 ml) and water (0.200 ml) was added Xphos-PdG3 (13.5 mg, 0.02 mmol, 0.1 eq). Then, the reaction mixture was stirred at 95°C for 4 h under N2. After the reaction was complete, the reaction mixture was cooled to room temperature. Ethyl acetate (10 ml) and water (5 ml) were added and the layers were separated. The aqueous phase was extracted with ethyl acetate (20 ml x 3). The combined extracts were washed with brine (30 ml), dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1 to 0:1) to yield the title compound (70.0 mg, 60% yield) as a yellow solid. LCMS: m / z 585.3 [M+H]+, ESI pos. Step B: 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]7-methoxy-oxazolo[4,5-b]pyridin-5-yl]-6-(methoxymethyl)-2,3 Petition 870250094781, dated 10 / 16 / 2025, pp. 333 / 378 147 / 167 dihydrobenzofuran-4-ol

[00317] A solution of the aforementioned 6(methoxymethyl)-5-[7-methoxy-2-[[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]amino]oxazolo[4,5b]pyridin-5-yl]-2,3-dihydrobenzofuran-4-ol (70.0 mg, 0.12 mmol, 1.0 eq) in HCl / dioxane (2M, 1.0 ml) was stirred at 25°C for 30 min. After completion of the reaction, the reaction mixture was concentrated under vacuum. The residue was purified by prepHPLC (column: Xtimate C18, 150 mm * 2 5 mm * 5 μm; mobile phase: [water (0.1% ammonium hydroxide v / v)-MeCN]; B%: 10%-40%, 5 minutes) and lyophilized to yield the title compound (43.9 mg, 78% yield) as a white solid. LCMS: m / z 471.2 [M+H]+, ESI pos. Example 22 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]-7-methoxyoxazolo[4,5-b]pyridin-5-yl]-6-methyl-2,3-di-hydrobenzofuran4-ol YOU ARE WITH Step A: 5-[7-methoxy-2-[[(3R)-1-[2-[tercbutyl(dimethyl)silyl]oxyethyl]-3-piperidyl]amino]oxazolo[4,5b]pyridin-5-yl]-6-:methyl-2,3-di-hydrobenzofuran-4-4-ol

[0038] A solution N-[(3R )-1-[2-[tercbutyl(dimethyl)silyl]oxyethyl]-3-piperidyl]-5-chloro-7-methoxyoxazolo[4,5-b]pyridin-2-amine (50.0 mg, 0.11 mmol, 1.0 equiv; Example 8, step F) e 6-methyl-5-(4,4,5,5-tetramethyl-1,3,2 Petition 870250094781, of 16 / 10 / 2025, p. 334 / 378 148 / 167 dioxaborolan-2-yl)-2,3-dihydrobenzofuran-4-ol (37.6 mg, 0.14 mmol, 1.2 eq; CAS # 2923540-54-7), K2CO3 (39.2 mg, 0.28 mmol, 2.5 eq) in 1,4-dioxane (1 ml) and water (0.2 ml) was added to Xphos-PdG3 (9.6 mg, 0.01 mmol, 0.1 eq). The reaction mixture was stirred at 90°C for 2 h under N2. After completion of the reaction, the reaction mixture was cooled to room temperature. Ethyl acetate (10 ml) and water (15 ml) were added to the reaction mixture and the layers were separated. The aqueous phase was extracted with ethyl acetate (10 ml x 3). The combined extracts were washed with brine (5 ml x 2), dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by prep-TLC (EtOAc) to yield the title compound (50.0 mg, 77% yield) as a yellow solid. LCMS: m / z 555.3 [M+H]+, ESI pos. Step B: 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]7-:methoxy-oxazolo[4,5-b]pyridin-5-yl]-6-:methyl-2,3-dihydrobenzofuran-4-ol

[00319] A solution of the aforementioned 5-[7methoxy-2-[[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol (45.0 mg, 0.08 mmol, 1.0 eq) in HCl / dioxane (2M, 1.0 ml) was stirred at 25°C for 10 min. After completion of the reaction, the reaction mixture was concentrated under vacuum. The residue was dissolved in methanol (1 ml) and basified to pH = 7 with saturated aqueous NaHCO3 solution, then filtered, and the filtrate was concentrated under vacuum. The residue was purified by prep-HPLC (column: Xtimate C18, 150mm*25mm*5um; mobile phase: [water (0.1% ammonium hydroxide v / v)-MeCN]; B%: 15%-45%, 10 minutes) and lyophilized to generate the title compound (16.9 mg, 46% yield). Petition 870250094781, dated 10 / 16 / 2025, pages 335 / 378 149 / 167 as a white solid. LCMS: m / z 441.2 [M+H]+, ESI pos. Example 23 4-[2-[[(3R,5S)-1-etil-5-hidroxi-3piperidil]amino]oxazolo[4,5-b]pyrazin-5-il]-3-hidroxi-5(methoxymetil)benzonitrila;acido 2,2,2-trifluoroacetico OH O n H FF. d OH f The Step A: 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-3(methoxymethyl)-5-(2-trimethylsilylethoxymethoxy)benzonitrile

[00320] To a solution of Intermediate 9 (3S,5R)-5-[(5-bromo-oxazolo[4,5-b]pyrazin-2-yl)amino]-1ethyl-piperidin-3-ol (16.0 mg, 0.05 mmol, 1.0 eq), 3(methoxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-5-(2-trimethylsilylethoxymethoxy)benzonitrile (21.57 mg, 0.05 mmol, 1.1 eq; CAS# 2923541-74-4), K2CO3 (18.1 mg, 0.13 mmol, 2.8 eq) in 1,4-dioxane (1 ml) and water (0.2 ml) was added Xphos-PdG3 (7.9 mg, 0.01 mmol, 0.2 eq). Then, the reaction mixture was stirred at 95°C for 2 h under N2. After completion of the reaction, the above reaction mixture was cooled to room temperature, diluted with methanol (2 ml), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (methanol: ethyl acetate = 1:5) to yield the title compound (16.0 mg, 55% yield) as a white solid. LCMS: m / z 555.3, [M+H]+, ESI pos. Step B: 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-3-hydroxy-5Petition 870250094781, dated 16 / 10 / 2025, p. 336 / 378 150 / 167 (methoxymethyl)benzonitrile; 2,2,2-trifluoroacetic acid

[00321] To a solution of 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-3(methoxymethyl)-5-(2-trimethylsilyletoxymethoxy)benzonitrile (14.0 mg, 0.03 mmol, 1.0 eq) in DCM (1 ml), trifluoroacetic acid (1.0 ml) was added, then the mixture was stirred at 20°C for 1 h. After completion of the reaction, the above reaction solution was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Gemini, 150 mm*30 mm*15 µm; mobile phase: [water (0.1% TFA, V / V)-MeCN]; B%: 22%-50%, 11 min), and lyophilized to yield the title compound (10.45 mg, 77% yield) as gum yellow. LCMS: m / z 425, 3, [M+H]+, ESI pos. Example 24 (3S,5R)-1-(2-hydroxyethyl)-5-[[5-(4-hydroxy-6-methyl-2,3-dihydrobenzofuran-5-yl)oxazolo[4,5-b]pyrazin-2yl]amino]piperidin-3-ol HO Step A: (3S,5R)-5-[(5-bromo-oxazolo[4,5-b]pyrazin-2yl)amino]-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]piperidin3-ol

[00322] To a solution of (3S,5R)-5-[(5-bromooxazolo[4,5-b]pyrazin-2-yl)amino]piperidin-3-ol (120.0 mg, 0.22 mmol, 1.0 eq; Intermediate 9, Step D), CH3COOH (33.7 mg, 0.56 mmol, 2.5 eq), CH3COONa (55.2 mg, 0.67 mmol, 3.0 eq) in DCM (2 ml) and methanol (0.200 ml) was added (third Petition 870250094781, dated 10 / 16 / 2025, pp. 337 / 378 151 / 167 butyldimethylsilyloxy)acetaldehyde (58.6 mg, 0.34 mmol, 1.5 eq). The reaction mixture was stirred at 20°C for 5 min. Then, NaBH(OAc)3 (237.6 mg, 1.12 mmol, 5.0 eq) was added to the above reaction mixture and stirred at 20°C for 30 min. After completion of the reaction, the reaction mixture was quenched with water (10 ml) and extracted with ethyl acetate (10 ml x 4). The combined extracts were washed with brine (10 ml x 2), dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (ethyl acetate: methanol = 1:0 to 10:1) to generate the title compound (30.0 mg, 35% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ [ppm]: 7.90 (s, 1H), 4.04 - 3.96 (m, 1H), 3.81 (t, 2H), 3.26 - 3.20 (m, 1H), 3.09 - 3.01 (m, 1H), 2.64 (t, 2H), 2.36 2.29 (m, 1H), 2.18 - 2.04 (m, 2H), 1.46 - 1.27 (m, 2H), 0.88 (s, 9H), 0.08 (s, 6H)). Step B: (3S,5R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5[[5-(4-hydroxy-6-methyl-2,3-dihydrobenzofuran-5yl)oxazolo[4,5-b]pyrazin-2-yl]amino]piperidin-3-ol

[00323] To the above-mentioned solution of (3S,5R)-5-[(5-bromo-oxazolo[4,5-b]pyrazin-2-yl)amino]-1-[2[tert-butyl(dimethyl)silyl]oxyethyl]piperidin-3-ol (20.0 mg, 0.04 mmol, 1.0 eq) and 6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-4-ol (14.0 mg, 0.05 mmol, 1.2 eq; CAS# 2923540-54-7), K2CO3 (14.6 mg, 0.11 mmol, 2.5 eq) in 1,4-dioxane (1 ml) and water (0.2 ml) was added XphosPdG3 (7.2 mg, 0.01 mmol, 0.2 eq). The reaction mixture was stirred at 90°C for 2 h under N2. After the reaction was complete, the reaction mixture was cooled to room temperature. Ethyl acetate (10 ml) and water (5 ml) Petition 870250094781, dated 10 / 16 / 2025, pages 338 / 378 152 / 167 were added to the mixture and the layers were separated. The aqueous phase was extracted with ethyl acetate (10 ml x 4). The combined extracts were washed with brine (30 ml), dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by prep-TLC (EtOAc) to yield the title compound (20.0 mg, 1.0 eq) as yellow oil. LCMS: m / z 542.2 [M+H]+, ESI pos. Step C: (3S,5R)-1-(2-hydroxyethyl)-5-[[5-(4-hydroxy-6methyl-2,3-dihydrobenzofuran-5-yl)oxazolo[4,5-b]pyrazin-2yl]amino]piperidin-3-ol

[00324] A solution of (3S,5R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-[[5-(4-hydroxy-6-methyl-2,3-dihydrobenzofuran-5-yl)oxazolo[4,5-b]pyrazin-2yl]amino]piperidin-3-ol (20.0 mg, 0.04 mmol, 1.0 eq) and TFA (0.5 ml) in DCM (0.5 ml) was stirred at 40°C for 2 h. After the reaction was complete, the reaction mixture was concentrated under vacuum. The residue was dissolved in methanol (1 ml) and basified to pH = 7 with saturated aqueous NaHCO3 solution, then the mixture was purified by prep-HPLC (column: Xtimate C18, 2 50mm*50mm*10μm; mobile phase: [water (0.1% ammonium hydroxide v / v)-MeCN]; B%: 5%-45%, 12 minutes) and lyophilized to yield the title compound (12.2 mg, 77% yield) as a yellow solid. LCMS: m / z 428.2 [M+H]+, ESI pos. Example 25 (3S,5R)-1-ethyl-5-[[5-(4-hydroxy-6-methyl-2,3-dihydrobenzofuran-5-yl)oxazolo[4,5-b]pyrazin-2yl]amino]piperidin-3-ol Petition 870250094781, dated 10 / 16 / 2025, pp. 339 / 378 153 / 167 HO

[00325] To a solution of Intermediate 9 (3S,5R)-5-[(5-bromo-oxazolo[4,5-b]pyrazin-2-yl)amino]-1-ethyl-piperidin-3-ol (20.0 mg, 0.06 mmol, 1.0 eq), 6-methyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-4-ol (19.4 mg, 0.07 mmol, 1.2 eq; CAS# 2923540-54-7), K2CO3 (22.7 mg, 0.16 mmol, 2.8 eq) in 1,4-dioxane (1 ml) and water (0.2 ml) was added Xphos-PdG3 (9.9 mg, 0.01 mmol, 0.2 eq), The mixture was then stirred at 90°C for 1 h under N2. After the reaction was complete, the above reaction mixture was cooled to room temperature, diluted with methanol (2 ml), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Gemini, 150 mm*25 mm*10 µm; mobile phase: [water (0.1% NH4HCO3, V / V)-MeCN]; B%: 22%-52%, 12 min), then the eluent was lyophilized to yield the title compound (7.28 mg, 30% yield) as a white solid. LCMS: m / z 412.2 [M+H]+, ESI pos. Example 26 = Example 15 as free salt 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-5(methoxymethyl)benzonitrile OH Petition 870250094781, de 16 / 10 / 2025, pág. 340 / 378 154 / 167 Example 27 4-[2-[[(3R,5S)-1-etil-5-hidroxi-3-piperidil]amino]-7fluoro-oxazolo[4,5-b]pyridin-5-yl]-3-hidroxi-5-metilbenzonitrila HO Etapa A: (3R,5S)-3-[(5-chloro-7-fluoro-oxazolo[4,5b]pyridin-2-yl)amino]-5-hydroxy-piperidina-1-carboxilato de tert-butila

[00326] To a solution of (3R,5S)-3amino-5-hydroxy-piperidine-1-tert-butyl carboxylic acid ester (275.8 mg, 1.28 mmol, 1.2 eq), 2,5-dichloro-7-fluorooxazolo[4,5-b]pyridine (220.0 mg, 1.06 mmol, 1.0 eq) in MeCN (4 ml) was added DIPEA (274.2 mg, 2.13 mmol, 2.0 eq), then the mixture was stirred at 20°C for 0.5 hours. After completion of the reaction, the above reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 1:0 to 0:1) to yield the title compound (380.0 mg, 97% yield) as a yellow solid. LCMS: m / z 387.1, [M+H]+, ESI pos. Step B: tert-butyl (3R,5S)-3-[[5-[4-cyano-2-methyl-6-(2trimethylsilylethoxymethoxy)phenyl]-7-fluoro-oxazolo[4,5b]pyridin-2-yl]amino]-5-hydroxy-piperidine-1-carboxylate

[00327] A solution of (3R,5S)-3-[(5-chloro-7fluoro-oxazolo[4,5-b]pyridin-2-yl)amino]-5-hydroxypiperidine-1-carboxylate tert-butyl (370.0 mg, 0.96 Petition 870250094781, dated 10 / 16 / 2025, pp. 341 / 378 155 / 167 mmol, 1.0 eq), Intermediate 1 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(2-trimethylsilethoxymethoxy)benzonitrile (558.7 mg, 1.43 mmol, 1.5 eq), K2CO3 (371.0 mg, 2.68 mmol, 2.8 eq) in 1,4-dioxane (8 ml) and water (1 ml) was added XphosPdG3, (121.6 mg, 0.14 mmol, 0.15 eq), then the mixture was stirred at 95°C for 2 hours under N2. After the reaction was complete, the above reaction solution was cooled to room temperature, diluted with water (100 ml), and extracted with ethyl acetate (50 ml x 3). The combined organic phases were washed with brine (100 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 1:0 to 0:1) to yield the title compound (500.0 mg, 82% yield) as a yellow solid. LCMS: m / z 614.3, [M+H]+, ESI pos. Step C: 4-[7-fluoro-2-[[(3R,5S)-5-hydroxy-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5methyl-benzonitrile

[00328] To a solution of (3R,5S)-3-[[5-[4-cyano-2-methyl-6-(2-trimethylsilethoxymethoxy)phenyl]-7-fluorooxazolo[4,5-b]pyridin-2-yl]amino]-5-hydroxy-piperidine-1-carboxylate tert-butyl (100.0 mg, 0.16 mmol, 1.0 eq) in DCM (1 ml) was added TFA (1.0 ml), then the mixture was stirred at 20°C for 1 hour. After completion of the reaction, the above reaction solution was concentrated under reduced pressure to generate the title compound (TFA salt, 81.0 mg, 0.16 mmol, 99.95% yield) as gum yellow. LCMS: m / z 384.1, [M+H]+, ESI pos. Step D: 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-Petition 870250094781, dated 10 / 16 / 2025, page 342 / 378 156 / 167 piperidyl]amino]-7-fluoro-oxazolo[4,5-b]pyridin-5-yl]-3hydroxy-5-methyl-benzonitrile

[00329] To a solution of 4-[7-fluoro-2[[(3R,5S)-5-hydroxy-3-piperidyl]amino]oxazolo[4,5b]pyridin-5-yl]-3-hydroxy-5-methylbenzonitrile (TFA salt, 81.0 mg, 0.16 mmol, 1.0 eq), DIPEA (84.1 mg, 0.65 mmol, 4.0 eq) in DMF (1 ml) was added iodoethane (24.5 mg, 0.16 mmol, 1.0 eq), then the mixture was stirred at 20 °C for 12 hours. After completion of the reaction mixture, the reaction mixture was concentrated under vacuum. The residue was purified by prep-HPLC (column: Xtimate C18, 2 50mm*50mm*10μm, mobile phase: [water (0.1% ammonium hydroxide v / v)-MeCN]; B%: 5%-35%, 10 minutes) and followed by lyophilization to generate the title compound (10.02 mg, 0.02 mmol, yield 14.66%) as a white solid. LCMS: m / z 412.1, [M+H]+, ESI pos. Example 28 Chiral 3-hydroxy-5-methyl-4-[2-[[(3R)-1-(3-oxazol-2-ylpropyl)-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]benzonitrile O \-N Step A: (E)-3-oxazol-2-ylprop-2-enoate methyl

[00330] To a chilled solution of diethylphosphonoacetate methyl (CAS # 1067-74-9, 1.12 g, 0.97 ml, 5.15 mmol, 1.05 eq) in tetrahydrofuran (15.2 ml) Petition 870250094781, dated 10 / 16 / 2025, pp. 343 / 378 To 157 / 167, 60% sodium hydride in mineral oil (206 mg, 5.15 mmol, 1.05 eq) was added and the mixture was stirred at this temperature for 10 minutes. A solution of oxazol-2-carbaldehyde (CAS # 65373-52-6, 500 mg, 4.89 mmol, 1.00 eq) in tetrahydrofuran (34.2 ml) was added dropwise. Stirring was continued at 0°C for 1.5 hours. The reaction mixture was extracted with ethyl acetate and water. The aqueous layer was back-extracted with ethyl acetate. The organic layers were washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 24 g, 0% to 50% ethyl acetate gradient in heptane) to yield the title compound (591 mg, 75% yield) as a white solid. LCMS: m / z 153.9 [M+H]+, ESI pos. Step B: Methyl 3-oxazol-2-ylpropanoate

[00331] A solution of methyl (E)-3-oxazol-2-ylprop-2-enoate (Example 28, step A) (591 mg, 3.67 mmol, 1.00 eq) in methanol (18 ml) and ethyl acetate (9 ml) was evacuated and purged with argon alternately three times. Palladium in activated charcoal (195 mg, 0.18 mmol, 0.05 eq, 10% purity) was carefully added. The reaction flask was evacuated, purged with argon, evacuated, and purged with hydrogen. The reaction mixture was stirred under a hydrogen atmosphere (flask) at room temperature for 3 hours. The reaction mixture was filtered over celite and thoroughly rinsed with ethyl acetate / methanol. The filtrate was concentrated to yield the title compound (346 mg, 58% yield) as a colorless oil, which was used without purification. Petition 870250094781, dated 10 / 16 / 2025, pp. 344 / 378 158 / 167 additional. LCMS: m / z 155.9 [M+H]+, ESI pos. Step C: 3-oxazol-2-ylpropan-1-ol

[00332] A solution of methyl 3-oxazol-2-ylpropanoate (Example 28, step B) (150 mg, 0.92 mmol, 1.00 eq) in tetrahydrofuran (5.8 ml) was cooled to 0°C before lithium aluminum hydride (1.0 M solution in tetrahydrofuran) (1.0 ml, 1.00 mmol, 1.09 eq) was added dropwise at 0°C (gas evolution observed). The reaction mixture was stirred at 0°C for 2 hours. Sodium sulfate decahydrate was carefully added to quench the reaction. When no bubbling was detected, the ice bath was removed, sodium sulfate was added, and the mixture was stirred for 1 hour at room temperature. The suspension was filtered over celite and rinsed with ethyl acetate / methanol. The filtrate was concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 4 g, gradient from 0% to 100% ethyl acetate in heptane) to yield the title compound (45 mg, 35% yield, 90% purity) as a colorless oil.LCMS: m / z 128.1 [M+H]+, ESI pos. Step D: 3-oxazol-2-ylpropyl 4-:methylbenzenesulfonate

[00333] To a solution of 3-oxazol-2-ylpropan-1-ol (Example 28, step C) (45 mg, 0.32 mmol, 1.00 eq, 90% purity) in dichloromethane (1.0 ml) was added triethylamine (81 mg, 0.11 ml, 0.80 mmol, 2.51 eq) followed by p-toluenesulfonyl chloride (73 mg, 0.38 mmol, 1.20 eq). The reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was poured into saturated aqueous NaHCO3 solution and extracted three times with dichloromethane. The combined organic layers were washed with brine. Petition 870250094781, dated 10 / 16 / 2025, pages 345 / 378 159 / 167 dried over sodium sulfate, filtered and concentrated in vacuo to generate the title compound (108 mg, 84% yield, 70% purity) as a light red oil, which was used without further purification. LCMS: m / z 282.2 [M+H]+, ESI pos. Step E: 5-chloro-N-[(3R)-1-(3-oxazol-2-ylpropyl)-3-piperidyl]oxazolo[4,5-b]pyridin-2-amine

[00334] To a mixture of 5-chloro-N-[(3R)-3-piperidyl]oxazolo[4,5-b]pyridin-2-amine (Example 4, Step B) (55 mg, 0.21 mmol, 1.00 eq) and 3-oxazol-2-ylpropyl 4-methylbenzenesulfonate (Example 28, Step D) (108 mg, 0.27 mmol, 1.30 eq, 70% purity) in tetrahydrofuran (1.0 ml) and N,N-dimethylformamide (1.0 ml) was added N,N-diisopropylethylamine (80 mg, 0.11 ml, (0.62 mmol, 2.99 eq). The reaction mixture was stirred at 50°C for 16 hours and at 70°C for 6 hours. The reaction mixture was cooled to room temperature and then extracted with ethyl acetate and 10% aqueous LiCl solution. The aqueous layer was back-extracted with ethyl acetate. The organic layers were washed twice with 10% aqueous LiCl solution, once with water, and once with brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo.The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient from 0% to 10% methanol in ethyl acetate) to yield the title compound (34 mg, 39% yield, 85% purity) as a colorless oil. LCMS: m / z 362.2 [M+H]+, ESI pos. Step F: 3-hydroxy-5-methyl-4-[2-[[(3R)-1-(3-oxazol-2ylpropyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5Petition 870250094781, dated 16 / 10 / 2025, p. 346 / 378 160 / 167 il]benzonitrile

[00335] A mixture of 5-chloro-N-[(3R)-1-(3oxazol-2-ylpropyl)-3-piperidyl]oxazolo[4,5-b]pyridin-2-amine (Example 28, step E) (34 mg, 0.09 mmol, 1.00 eq), (4-cyano-2-hydroxy-6-methylphenyl)boronic acid, Intermediate 7, (26 mg, 0.15 mmol, 1.56 eq), cesium carbonate (98 mg, A mixture of 0.30 mmol, 3.19 eq) and XPhos Pd G3 (15 mg, 0.02 mmol, 0.19 eq) in 1,4-dioxane (0.94 ml) and water (0.24 ml) was purged with argon and stirred at 100°C for 5 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and semi-saturated aqueous NH4Cl solution. The aqueous layer was back-extracted with ethyl acetate. The organic layers were washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient from 0% to 10% methanol in dichloromethane) to yield the title compound (25 mg, 55% yield) as a pale yellow solid. LCMS: m / z 459, 3 [M+H]+, ESI pos. Example 29 4-[7-fluoro-2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5methyl-benzonitrile F Step A: N-[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3 Petition 870250094781, dated 10 / 16 / 2025, pp. 347 / 378 161 / 167 piperidyl]-5-chloro-7-fluoro-oxazolo[4,5-b]pyridin-2-amine

[00336] To a solution of ((3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]piperidin-3-amine (164.8 mg, 0.64 mmol, 1.2 eq), DIPEA (137.1 mg, 1.06 mmol, 2.0 eq) in MeCN (2 ml) was added Intermediate 10 2,5-dichloro-7fluoro-oxazolo[4,5-b]pyridine (110.0 mg, 0.53 mmol, 1.0 eq), then the mixture was stirred at 20°C for 2 hours. After completion of the reaction, the above reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (20 ml x 3). The combined organic phases were washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 1:1 to 0:1) to yield the title compound (200.0 mg, 82% yield) as a yellow solid. LCMS: m / z 429.1, [M+H]+, ESI pos. Step B: 4-[2-[[(3R)-1-[2-[tertbutyl(dimethyl)silyl]oxyethyl]-3-piperidyl]amino]-7-fluorooxazolo[4,5-b]pyridin-5-yl] - 3-:methyl-5-(2trimethylsilylethoxymethoxy)benzonitrile

[00337] To a solution of N-[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]-5-chloro-7-fluorooxazolo[4,5-b]pyridin-2-amine (200.0 mg, 0.47 mmol, 1.0 eq), Intermediate 1 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(2-trimethylsililetoxymethoxy)benzonitrile (272.3 mg, 0.7 mmol, 1.5 eq), K2CO3 (180.8 mg, 1.31 mmol, 2.8 eq) in 1,4-dioxane (4 ml) and water (0.5 ml) was added and XphosPdG3 (59.3 mg, 0.07 mmol, 0.15 eq). Then, the mixture was stirred at 95°C for 2 hours under N2. After the reaction was complete, the solution of Petition 870250094781, dated 10 / 16 / 2025, pages 348 / 378 The above reaction (162 / 167) was cooled to room temperature, diluted with water (100 ml), and extracted with ethyl acetate (50 ml x 3). The combined organic phases were washed with brine (100 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 1:1 to 0:1) to yield the title compound (300.0 mg, 93% yield) as a yellow solid. LCMS: m / z 656.3, [M+H]+, ESI pos. Step C: 4-[7-fluoro-2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5methyl-benzonitrile

[00338] A solution of 4-[2-[[(3R)-1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-piperidyl]amino]-7-fluorooxazolo[4,5-b]pyridin-5-yl]-3-methyl-5-(2-trimethylsililetoxymethoxy)benzonitrile (100.0 mg, 0.15 mmol, 1.0 eq) in trifluoroacetic acid (2.0 ml) was stirred at 45 °C for 3 hours. After completion of the reaction, the above reaction solution was concentrated under reduced pressure, and then the residue was dissolved with DMF (1 ml) and the pH adjusted to 8 with NHa*H2O (25% in water), then purified by reverse-phase flash (CombiFlash [water (0.1% ammonium hydroxide v / v)MeCN]) to yield 4-[7-fluoro-2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methylbenzonitrile (34.39 mg, 0.08 mmol, yield 54.17%) as a white solid. LCMS: m / z 412.1, [M+H]+, ESI pos. Example 30 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]-7methoxy-oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methylPetition 870250094781, of 10 / 16 / 2025, p. 349 / 378 163 / 167 benzonitrile HO Step A: tert-butyl (3R,5S)-3-[(5-chloro-7-methoxy-oxazolo[4,5b]pyridin-2-yl)amino]-5-hydroxy-piperidine-1-carboxylate

[00339] To a solution of tert-butyl (3R,5S)-3-amino-5-hydroxypiperidine-1-carboxylate (54.3 mg, 0.25 mmol, 1.1 eq CAS:1932513-59-1) and 2,5-dichloro-7-methoxyoxazolo[4,5-b]pyridine (50.0 mg, 0.23 mmol, 1.0 eq, Example 8, Step E) in MeCN (0.5 ml) was added DIEA (58.9 mg, 0.46 mmol, 2.0 eq). Then, the mixture was stirred at 20°C for 0.5 hours. After the reaction was complete, the mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:3 to 1:5) to yield the title compound (75.0 mg, 82% yield) as a white solid. LCMS: m / z 399, 2 [M+H]+, ESI pos. Step B: (3S,5R)-5-[(5-chloro-7-methoxy-oxazolo[4,5b]pyridin-2-yl)amino]piperidin-3-ol

[00340] To a solution of tert-butyl (3R,5S)-3-[(5-chloro-7-methoxy-oxazolo[4,5-b]pyridin-2-yl)amino]-5-hydroxypiperidine-1-carboxylate (75.0 mg, 0.19 mmol, 1.0 eq) in DCM (0.5 ml) was added TFA (0.5 ml). The mixture was stirred at 20°C for 2 hours. After the reaction was complete, the reaction mixture was concentrated under vacuum. The Petition 870250094781, dated 10 / 16 / 2025, pages 350 / 378 164 / 167 residue was purified by reversed-phase flash (CombiFlash, mobile phase: [water (0.1% TFA v / v)-MeCN]; B%: 30%-40%) and followed by lyophilization to generate the title compound (TFA salt, 67.0 mg, 86% yield) as a colorless oil. LCMS: m / z 299.1 [M+H]+, ESI pos. Step C: (3S,5R)-5-[(5-chloro-7-methoxy-oxazolo[4,5b]pyridin-2-yl)amino]-1-ethyl-piperidin-3-ol

[00341] To a solution of (3S,5R)-5-[(5-chloro-7-methoxy-oxazolo[4,5-b]pyridin-2-yl)amino]piperidin-3-ol (TFA salt, 67.0 mg, 0.16 mmol, 1.0 eq) and TEA (16.4 mg, 0.16 mmol, 1.0 eq), AcOH (14.6 mg, 0.24 mmol, 1.5 eq) in DCM (1 ml) / methanol (0.2 ml) was added acetaldehyde (0.16 ml, 0.81 mmol, 5.0 eq). The mixture was stirred at 20°C for 0.5 hours. Then, NaBH(OAc)3 (103.2 mg, 0.49 mmol, 3.0 eq) was added to the above reaction mixture. The mixture was then stirred at 20°C for 1 hour under nitrogen. After the reaction was complete, the mixture was concentrated under vacuum. The residue was purified by reversed-phase flash (CombiFlash, mobile phase: [water (0.1% TFA v / v)-MeCN]; B%: 35%-50%) and followed by lyophilization to generate the title compound (TFA salt, 35.0 mg, 41% yield) as yellow oil. LCMS: m / z 327.1 [M+H]+, ESI, pos. Step D: 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridin-5-yl]-3methyl-5-(2-trimethylsilylethoxymethoxy)benzonitrile

[00342] A solution of (3S,5R)-5-[(5-chloro-7-methoxy-oxazolo[4,5-b]pyridin-2-yl)amino]-1-ethyl-piperidin3-ol (TFA salt, 35.0 mg, 0.07 mmol, 1.0 eq) and Intermediate 1 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5(2-trimethylsilethoxymethoxy)benzonitrile (39.6 mg, 0.1 mmol, Petition 870250094781, dated 10 / 16 / 2025, pp. 351 / 378 165 / 167 1.5 eq) in 1,4-dioxane (1 ml) / water (0.1 ml) was added K2CO3 (26.3 mg, 0.19 mmol, 2.8 eq) and Xphos-PdG3 (5.8 mg, 0.01 mmol, 0.1 eq) under N2. The reaction mixture was stirred at 95°C for 12 hours. After completion of the reaction, the mixture was cooled to 20°C and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:2 to 0:1) to yield the title compound (25.0 mg, 63% yield) as a yellow oil. LCMS: m / z 554.3 [M+H]+, ESI pos. Step E: 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridin-5-yl]-3hydroxy-5-methyl-benzonitrile

[00343] A mixture of 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridin5-yl]-3-methyl-5-(2-trimethylsilethylenethoxymethoxy)benzonitrile (23.0 mg, 0.04 mmol, 1.0 eq), TFA (0.1 ml) in DCM (1.0 ml) was stirred at 40°C for 2 hours. After the reaction was complete, the mixture was cooled to 20°C and concentrated under vacuum. The residue was dissolved with MeOH (2 ml) and adjusted to pH=8 with NH3*H2O (25% in water). Then, the mixture was purified by prep-HPLC (Method: Column: Waters Xbridge 150*25mm*5um, mobile phase: [water (0.1% ammonium hydroxide v / v)-MeCN]; B%: 14%-44%, 10 minutes). The eluent was lyophilized to yield the title compound (6.1 mg, 34% yield) as a white solid. LCMS: m / z 424.1 [M+H]+, ESI pos. Example 31 (3S,5R)-1-ethyl-5-[[5-(4-hydroxy-6-methyl-2,3-dihydrobenzofuran-5-yl)oxazolo[4,5-b]pyridin-2yl]amino]piperidin-3-ol Petition 870250094781, dated 10 / 16 / 2025, pp. 352 / 378 166 / 167 HO

[00344] A mixture of (3S,5R)-5-[(5-chlorooxazolo[4,5-b]pyridin-2-yl)amino]-1-ethyl-piperidin-3-ol (CAS # 2923539-98-2, 65 mg, 0.20 mmol, 1.00 eq, 90% purity), 6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)-2,3-dihydrobenzofuran-4-ol (CAS # 2923540-54-7, 117 mg, 0.32 mmol, 1.61 eq, 75% purity), potassium carbonate (120 mg, 0.87 mmol, 4.40 eq) and sodium dichloride complex 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii)dichloromethane (25 mg, 0.03 mmol, 0.16 eq) in 1,4-dioxane (1.4 ml) and water (0.70 ml) was purged with argon and stirred at 95 °C for 16 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate and semi-saturated aqueous NH4Cl solution. The aqueous layer was back-extracted with ethyl acetate. The organic layers were washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo.The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient from 0% to 10% methanol in dichloromethane). All fractions containing the product were combined and concentrated in vacuo. The residue was subjected to further purification by SFC (achiral DEA column; eluent B: 15% methanol) to yield the title compound (24 mg, 28% yield) as a light yellow solid. LCMS: m / z 411.3 [M+H]+, ESI pos. Petition 870250094781, dated 10 / 16 / 2025, pp. 353 / 378 167 / 167 Example A

[00345] A compound of formula I can be used in a manner known per se as the active ingredient for the production of tablets of the following composition: Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg 425 mg Example B

[00346] A compound of formula I can be used in a manner known per se as the active ingredient for the production of capsules of the following composition: Per capsule Active ingredient 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0 mg< / fa>

Claims

1. Compound of formula I Ry I characterized in that, R1 is cyano, halo or haloalkyl, and R9 is H, or R1 and R9 and the atoms to which they are attached form a 5-membered cycloalkyl or a 5-membered heterocycle comprising 1 heteroatom O; R2 is alkyl, hydroxyalkyl, alkoxyalkyl or cyano, wherein if R1 is cyano, then R2 is not cyano; A1 is -CR10- or -N-; R10 is H, fluoro or alkoxy; Rx is H, alkyl, heteroarylalkyl, hydroxyalkyl or COOH-alkyl, wherein the heteroaryl of the heteroarylalkyl is oxazolyl, tetrazolyl or oxadiazolyl; Ry is H or -OH; wherein, if R1 is haloalkyl, then Rx is hydroxyalkyl or COOH-alkyl and Ry is -OH; and pharmaceutically acceptable salts thereof, provided that the compound is not a compound selected from: 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-methylphenol; 5-chloro-2-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxybenzonitrile;5-chloro-2-[2-[[(3R)-1-etil-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]-3(metoximetil)phenol;ácido 2,2,2-trifluoroacético; 5-chloro-2-[2-[[(3R)-1-etil-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]-3(metoximetil)phenol; 5-chloro-3-metil-2-[2-[[(3R)-1-metil-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]phenol; 5-chloro-3-methyl-2-[2-[[(3R)-1-propyl-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]fenol; (3S,5R)-5-[[5-(4-chloro-2-hidroxi-6-metilfenil)oxazolo[4,5-b]piridin-2-il]amino]-1-metil-piperidin-3-ol; (3R,5R)-5-[[5-(4-chloro-2-hidroxi-6-metilfenil)oxazolo[4,5-b]piridin-2-il]amino]-1-etil-piperidin-3ol; acid formic acid; (3R,5R)-5-[[5-(4-chloro-2-hidroxi-6-methylfenil)oxazolo[4,5-b]piridin-2-il]amino]-1-etyl-piperidin-3ol; 5-chloro-2-[2-[[(3R)-1-(3,3-difluoropropyl)-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]-3-metil-fenol; 5-chloro-2-[2-[[(3R)-1-(2-hidroxietil)-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]-3-metil-fenol;5-chloro-3-(hidroximetil)-2-[2-[[(3R)-1-methyl-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]fenol; 5-chloro-2-[2-[[(3R)-1-(3-hidroxipropil)-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]-3-methyl-fenol; 5-chloro-3-metil-2-[2-[[(3R)-1-(2-hidroxipropil)Petição 870250094781, de 16 / 10 / 2025, pág. 356 / 378 3 / 17 3-piperidil]amino]oxazolo[4,5-b]piridin-5-il]fenol; (3S,5R)-5-[[5-[4-chloro-2-hidroxi-6(metoximetil)fenil]oxazolo[4,5-b]piridin-2-il]amino]-1metil-piperidin-3-ol; 5-chloro-2-[2-[[(3R)-1-etil-3piperidil]amino]oxazolo[4,5-b]pirazin-5-il]-3-metilfenol;ácido 2,2,2-trifluoroacético; 5-chloro-2-[2-[[(3R)-1-etil-3piperidil]amino]oxazolo[4,5-b]pirazin-5-il]-3-metil-phenol; (3S,5R)-5-[[5-(4-chloro-2-hidroxi-6-methylfenil)oxazolo[4,5-b]piridin-2-il]amino]-1-etyl-piperidin-3ol; 2-[2-[[(3R)-1-etyl-3-piperidil]amino]oxazolo[4,5-b]piridin-5-il]-5-fluoro-3-methyl-fenol; 5-fluoro-3-metil-2-[2-[[(3R)-1-metil-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]fenol;4-[2-[[(3R)-1-etil-3-piperidil]amino]oxazolo[4,5b]piridin-5-il]-3-hidroxi-5-metil-benzonitrila; 3-hidroxi-5-metil-4-[2-[[(3R)-1-metil-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]benzonitrila; 4-[2-[[(3R,5S)-1-etil-5-hidroxi-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]-3-hidroxi-5metil-benzonitrila; acid formic acid; 4-[2-[[(3R,5S)-1-etil-5-hidroxi-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]-3-hidroxi-5metil-benzonitrila; 3-hidroxi-4-[2-[[(3R,5S)-5-hidroxi-1-metil-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]-5-metilbenzonitrila; 4-[2-[[(3R,5R)-1-etil-5-hidroxi-3 Petição 870250094781, de 16 / 10 / 2025, pág. 357 / 378 4 / 17 piperidil]amino]oxazolo[4,5-b]piridin-5-il]-3-hidroxi-5-methyl-benzonitrile; 3-hidroxi-4-[2-[[(3R)-1-(2-hidroxietil)-3piperidil]amino]oxazolo[4,5-b]piridin-5-il]-5-metilbenzonitrile; 4-[2-[[(3R)-1-etil-3-piperidil]amino]oxazolo[4,5b]pirazin-5-il]-3-hidroxi-5-metil-benzonitrile; 4-[2-[[(3R)-1-etil-3-piperidil]amino]oxazolo[4,5b]pirazin-5-il]-3-hidroxi-5-metil-benzonitrila;2,2,2-trifluoroacetic acid; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5b]pyridin-5-yl]-3-hydroxy-5-(methoxymethyl)benzonitrile; 2,2,2-trifluoroacetic acid 4-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5b]pyridin-5-yl]-3-hydroxy-5-(methoxymethyl)benzonitrile; 4-[[(3R)-1-ethyl-3-piperidyl]amino]-7-methoxyoxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methylbenzonitrile; 2,2,2-trifluoroacetic acid; 4-[2-[[(3R)-1-ethyl-3-piperidyl]amino]-7-methoxyoxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5-methyl-benzonitrile; 5-[[(3R)-1-ethyl-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; 5-chloro-3-methyl-2-[2-[[(3R)-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol; dihydrochloride; 5-chloro-3-methyl-2-[2-[[(3R)-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]phenol; and pharmaceutically acceptable salts thereof.; 2. Compound according to claim 1, characterized in that R1 is cyano or haloalkyl, and R9 is H, or R1 and R9 and the atoms to which they are attached form a 5-membered heterocycle comprising 1 heteroatom O.

3. A compound according to any one of claims 1 to 2, characterized in that R1 is cyano and R9 is H, or R1 and R9 and the atoms to which they are attached form a 5-membered heterocycle comprising 1 O heteroatom.

4. A compound according to any one of claims 1 to 3, characterized in that R1 and R9 and the atoms to which they are attached form a 5-membered heterocycle comprising 1 heteroatom O.

5. Compound according to any one of claims 1 to 4, characterized in that R2 is alkyl or alkoxyalkyl.

6. Compound according to any one of claims 1 to 5, characterized in that R10 is H or alkoxy.

7. Compound according to any one of claims 1 to 6, characterized in that R10 is H.

8. Compound according to any one of claims 1 to 7, characterized in that Rx is H-alkyl, heteroarylalkyl, hydroxyalkyl or COOH-alkyl, wherein the heteroaryl group of heteroarylalkyl is oxazolyl.

9. Compound according to any one of claims 1 to 8, characterized in that Rx is H, alkyl, heteroarylalkyl or hydroxyalkyl, wherein the heteroaryl of heteroarylalkyl is oxyzolyl.

10. Compound, according to any one of claims 1 to 9, characterized in that Rx is Petition 870250094781, dated 10 / 16 / 2025, p. 359 / 378 6 / 17 alkyl, heteroarylalkyl or hydroxyalkyl, wherein the heteroaryl of the heteroarylalkyl is oxyzolyl.

11. Compound according to any one of claims 1 to 10, characterized in that Rx is alkyl or hydroxyalkyl.

12. Compound according to any one of claims 1 to 11, characterized in that Rx is hydroxyalkyl.

13. Compound, according to any one of claims 1 to 12, characterized in that Ry is H.

14. Compound according to claim 1, characterized in that R1 is cyano or haloalkyl, and R9 is H, or R1 and R9 and the atoms to which they are attached form a 5-membered heterocycle comprising 1 heteroatom O; R2 is alkyl or alkoxyalkyl; A1 is -CR10- or -N-; R10 is H or alkoxy; Rx is H, alkyl, heteroarylalkyl, hydroxyalkyl or COOH-alkyl, wherein the heteroaryl of the heteroarylalkyl is oxazolyl; Ry is H or -OH; wherein, if R1 is haloalkyl, then Rx is hydroxyalkyl or COOH-alkyl and Ry is -OH; and pharmaceutically acceptable salts thereof.

15. Compound according to claim 1, characterized in that R1 is cyano and R9 is H, or R1 and R9 and the atoms to which they are attached form Petition 870250094781, 10 / 16 / 2025, p. 360 / 378 7 / 17 a 5-membered heterocycle comprising 1 heteroatom O; R2 is alkyl or alkoxyalkyl; Ai is -CR10- or -N-; R10 is H or alkoxy; Rx is alkyl or hydroxyalkyl; Ry is H or -OH; and pharmaceutically acceptable salts thereof.

16. Compound according to claim 1, characterized in that R1 is cyano and R9 is H, or R1 and R9 and the atoms to which they are attached form a 5-membered heterocycle comprising 1 heteroatom O; R2 is alkyl or alkoxyalkyl; A1 is -CR10- or -N-; R10 is H; Rx is hydroxyalkyl; Ry is H; and pharmaceutically acceptable salts thereof.

17. Compound according to claim 1, characterized in that R1 and R9 and the atoms to which they are attached form a 5-membered heterocycle comprising 1 heteroatom O; R2 is alkyl or alkoxyalkyl; A1 is -N-; Rx is hydroxyalkyl; Ry is H; and pharmaceutically acceptable salts thereof.

18. Compound according to any one of claims 1 to 17, characterized in that it is selected from Petition 870250094781, dated 10 / 16 / 2025, pp. 361 / 378 8 / 17 3-hydroxy-5-methyl-4-[2-[[(3R)-1-(2-oxazol-2-ylethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]benzonitrile; 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-(methoxymethyl)benzonitrile; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-3-hydroxy-5-methylbenzonitrile; 2,2,2-trifluoroacetic acid; 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-5-methylbenzonitrile; 2,2,2-trifluoroacetic acid; and pharmaceutically acceptable salts thereof.

19. A compound according to any one of claims 1 to 17, characterized in that it is selected from 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-3-hydroxy-5-methylbenzonitrile; 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-5-methylbenzonitrile; and pharmaceutically acceptable salts thereof.

20. Compound, according to any one of claims 1 to 17, characterized in that it is selected from 4-[(3S,5R)-3-hydroxy-5-[[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]amino]-1-piperidyl]butanoic acid; (3S,5R)-1-(2-hydroxyethyl)-5-[[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2-yl]amino]piperidin-3-ol; 3-hydroxy-4-[2-[[(3R,5S)-5-hydroxy-1-methyl-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-5-methylbenzonitrile; 2,2,2-trifluoroacetic acid; 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridin-5-yl]-5methyl-benzonitrile; 2,2,2-trifluoroacetic acid; 3-hydroxy-4-[2-[[(3R,5S)-5-hydroxy-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-5-methylbenzonitrile; 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-5-methylbenzonitrile; and pharmaceutically acceptable salts thereof.

21. A compound according to any one of claims 1 to 17, characterized in that it is selected from (3S,5R)-1-(2-hydroxyethyl)-5-[[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]oxazolo[4,5-b]pyridin-2yl]amino]piperidin-3-ol; 3-hydroxy-4-[2-[[(3R,5S)-5-hydroxy-1-methyl-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-5-methylbenzonitrile; 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridin-5-yl]-5-methylbenzonitrile; and pharmaceutically acceptable salts thereof.

22. Compound, according to any one of claims 1 to 17, characterized in that it is selected from 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-6(methoxymethyl)-2,3-dihydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6(methoxymethyl)-2,3-dihydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; and pharmaceutically acceptable salts thereof.

23. Composto, de accordo com qualquer uma das reivindicações 1 a 17, characterized by the facto de que é sélectionnada a partir de 3-hidroxi-4-[2-[[(3R)-1-(2-hidroxietil)-3piperidil]amino]oxazolo[4,5-b]pyrazin-5-yl]-5(methoxymetil)benzonitrila;acido 2,2,2-trifluoroacetico; 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyetil)-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-5(methoxymetil)benzonitrila; 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyetil)-3piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridin-5-yl]-5metil-benzonitrila; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-3-hydroxy-5metil-benzonitrila; 5-[2-[[(3R)-1-(2-hydroxyetil)-3Petição 870250094781, de 16 / 10 / 2025, pág. 364 / 378 11 / 17 piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-6-methyl-indan4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]7-methoxy-oxazolo[4,5-b]pyridin-5-yl]-6-methyl-indan-4-ol; 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridin-5-yl]-5(methoxymethyl)benzonitrile;5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]7-methoxy-oxazolo[4,5-b]pyridin-5-yl]-6-(methoxymethyl)-2,3di-hydrobenzofuran-4-ol; 5-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]7-methoxy-oxazolo[4,5-b]pyridin-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; 4-[[(3R,5S)-1-ethyl-5-hydroxy-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-3-hydroxy-5(methoxymethyl)benzonitrile; 2,2,2-trifluoroacetic acid; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-3-hydroxy-5(methoxymethyl)benzonitrile; (3S,5R)-1-(2-hydroxyethyl)-5-[[5-(4-hydroxy-6methyl-2,3-dihydrobenzofuran-5-yl)oxazolo[4,5-b]pyrazin-2yl]amino]piperidin-3-ol; (3S,5R)-1-ethyl-5-[[5-(4-hydroxy-6-methyl-2,3-dihydrobenzofuran-5-yl)oxazolo[4,5-b]pyrazin-2yl]amino]piperidin-3-ol; 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-5(methoxymethyl)benzonitrile;4-[2-[[(3R,5S)-1-etil-5-hydroxy-3piperidil]amino]-7-fluoro-oxazolo[4,5-b]pyridin-5-yl]-3 Petição 870250094781, de 16 / 10 / 2025, pág. 365 / 378 12 / 17 hydroxy-5-metil-benzonitrila; 3-hydroxy-5-metil-4-[2-[[(3R)-1-(3-oxazol-2ylpropyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5yl]benzonitrila; 4-[7-fluoro-2-[[(3R)-1-(2-hydroxyetil)-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-3-hydroxy-5metil-benzonitrila; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3piperidyl]amino]-7-methoxy-oxazolo[4,5-b]pyridin-5-yl]-3hydroxy-5-methyl-benzonitrile; (3S,5R)-1-ethyl-5-[[5-(4-hydroxy-6-methyl-2,3-dihydrobenzofuran-5-yl)oxazolo[4,5-b]pyridin-2yl]amino]piperidin-3-ol; and pharmaceutically acceptable salts thereof.; 24. Compound, according to any one of claims 1 to 17, characterized in that it is selected from 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-3-hydroxy-5-methylbenzonitrile; 2,2,2-trifluoroacetic acid; 4-[2-[[(3R,5S)-1-ethyl-5-hydroxy-3-piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-3-hydroxy-5-methylbenzonitrile; 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-5-methylbenzonitrile; 2,2,2-trifluoroacetic acid; 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-5-methylbenzonitrile; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3Petition 870250094781, dated 16 / 10 / 2025, p.366 / 378 13 / 17 piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-6(methoxymethyl)-2,3-dihydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6(methoxymethyl)-2,3-dihydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; e sais farmaceuticamente aceitáveis ​​destes.

25. Compound, according to any one of claims 1 to 17, characterized in that it is selected from 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-5-methylbenzonitrile; 2,2,2-trifluoroacetic acid; 3-hydroxy-4-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-5-methylbenzonitrile; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-6-(methoxymethyl)-2,3-dihydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6(methoxymethyl)-2,3-dihydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; Petition 870250094781, dated 10 / 16 / 2025, p. 367 / 378 14 / 17 5-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; and pharmaceutically acceptable salts thereof.

26. Compound, according to any one of claims 1 to 17, characterized in that it is selected from 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-6-(methoxymethyl)-2,3-dihydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6-(methoxymethyl)-2,3-dihydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3-piperidyl]amino]oxazolo[4,5-b]pyrazin-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; 5-[2-[[(3R)-1-(2-hydroxyethyl)-3piperidyl]amino]oxazolo[4,5-b]pyridin-5-yl]-6-methyl-2,3-dihydrobenzofuran-4-ol; and pharmaceutically acceptable salts thereof.

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

28. Pharmaceutical composition, characterized in that it comprises a compound, as defined in any one of claims 1 to 26, and a therapeutically inert vehicle.

29. Use of a compound, as defined in Petition 870250094781, dated 10 / 16 / 2025, pp. 368 / 378 15 / 17, any of claims 1 to 26, characterized in that it is for the treatment or prophylaxis of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

30. A compound, according to any one of claims 1 to 26, characterized in that it is for the treatment or prophylaxis of a disease, disorder or condition selected from Asthma or COPD.

31. A compound, according to any one of claims 1 to 26, characterized in that it is for the treatment or prophylaxis of a cardiovascular disease, disorder or condition.

32. A compound, according to any one of claims 1 to 26, characterized in that it is for the treatment or prophylaxis of a cardiometabolic disease, disorder or condition.

33. Use of a compound, as defined in any one of claims 1 to 26, characterized in that it is for the treatment or prophylaxis of a disease, disorder or condition selected from Asthma or COPD.

34. Use of a compound, as defined in any one of claims 1 to 26, characterized in that it is for the treatment or prophylaxis of a cardiovascular disease, disorder or condition.

35. Use of a compound, as defined in any one of claims 1 to 26, characterized in that it is for the treatment or prophylaxis of a cardiometabolic disease, disorder or condition.

36. Use of a compound, as defined in any of claims 1 to 26, characterized by the fact that it is for the preparation of a medicament for the treatment or prophylaxis of a disease, disorder or condition selected from Asthma or COPD.

37. Use of a compound, as defined in any one of claims 1 to 26, characterized in that it is for the preparation of a medicament for the treatment or prophylaxis of a cardiovascular disease, disorder or condition.

38. Use of a compound, as defined in any one of claims 1 to 26, characterized in that it is for the preparation of a medicament for the treatment or prophylaxis of a cardiometabolic disease, disorder or condition.

39. A method for inhibiting NLRP3, which method is characterized by comprising administering an effective amount of a compound, as defined in any one of claims 1 to 26, to inhibit NLRP3.

40. A method for the treatment or prophylaxis of a disease, disorder or condition, the method being characterized in that it comprises administering an effective amount of a compound, as defined in any one of claims 1 to 26, wherein the disease, disorder or condition is selected from Asthma or COPD.

41. A method for the treatment or prophylaxis of a cardiovascular disease, disorder or condition, the method being characterized in that it comprises administering an effective amount of a compound, as defined in any one of claims 1 to 26.

42. Method for the treatment or prophylaxis of a cardiometabolic disease, disorder or condition, which Petition 870250094781, dated 10 / 16 / 2025, pp. 370 / 378 17 / 17 method is characterized in that it comprises administering an effective amount of a compound, as defined in any one of claims 1 to 26.

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