N-CYANOPYRROLIDINES WITH ACTIVITY AS UBIQUITIN-SPECIFIC PEPTIDASE INHIBITORS 30

Abstract

The present invention relates to a class of N-cyanopyrrolidines with activity as inhibitors of the USP30 deubiquitination enzyme, which has utility in a variety of therapeutic areas, including conditions involving mitochondrial dysfunction, cancer, and fibrosis: (see Formulations).

Description

N-CYANOPYRROLIDINES WITH ACTIVITY AS UBIQUITIN-SPECIFIC PEPTIDASE INHIBITORS 30 FIELD OF INVENTION The present invention relates to a class of N-cyanopyrrolidines with activity as inhibitors of the deubiquitinating enzyme ubiquitin C-terminal hydrolase 30, also known as ubiquitin-specific peptidase 30 (USP30), uses thereof, processes for their preparation, and compositions containing such inhibitors. These inhibitors are useful in a variety of therapeutic areas, including conditions involving mitochondrial dysfunction, cancer, and fibrosis. All documents cited or specified below are expressly incorporated into this document for reference. BACKGROUND OF THE INVENTION Ubiquitin is a small protein consisting of 76 amino acids that is important for regulating protein function in the cell. Ubiquitination and deubiquitination are enzyme-mediated processes by which ubiquitin is covalently attached to or cleaved from a target protein by deubiquitinating enzymes (DUBs). There are approximately 100 DUBs in human cells, divided into subfamilies based on sequence homology. The USP family is characterized by its common Cys and His boxes, which contain Cys and His residues critical for its DUB activities. Ubiquitination and deubiquitination processes have been implicated in the regulation of many cellular functions, including cell cycle progression, apoptosis, modification of cell surface receptors, regulation of DNA transcription, and DNA repair.Thus, the ubiquitin system has been implicated in the pathogenesis of numerous disease states including inflammation, viral infection, metabolic dysfunction, CNS disorders, and oncogenesis. Ubiquitin is a master regulator of mitochondrial dynamics. Mitochondria are dynamic organelles whose biogenesis, fusion, and fission events are regulated by post-translational regulation via ubiquitination of many key factors such as mitofusins. In humans, USP30 is a 517-amino-acid protein located in the outer mitochondrial membrane (Nakamura et al., 2008, Mol Biol. 19:1903–11). It is the only deubiquitinating enzyme that carries a mitochondrial targeting signal and has been shown to deubiquitinate a number of mitochondrial proteins. USP30 has been shown to oppose parkin-mediated mitophagy and to inhibit parkin. USP30 depletion sensitizes cancer cells to BH-3 mimetics such as ABT-737, without requiring parkin overexpression. Thus, an anti-apoptotic role for USP30 has been demonstrated, making it a potential target for anti-cancer therapy. The ubiquitin-proteasome system has gained interest as a target for cancer treatment following the approval of the proteasome inhibitor bortezomib (Velcade®) for the treatment of multiple myeloma. Extended treatment with bortezomib is limited by its associated toxicity and drug resistance. However, therapeutic strategies targeting specific aspects of the ubiquitin-proteasome pathway upstream of the proteasome, such as DUB, are predicted to be better tolerated (Bedford et al, 2011, Nature Rev 10:29-46). Fibrotic diseases, including renal, hepatic, and pulmonary fibrosis, are a major cause of morbidity and mortality and can affect all tissue and organ systems. Fibrosis is considered to be the result of acute or chronic stress on the tissue or organ, characterized by deposition in the extracellular matrix, reduced vascular / tubular / ductal / airway patency, and impaired function, ultimately leading to organ failure. Many fibrotic conditions are promoted by lifestyle or environmental factors; however, a proportion of fibrotic conditions may be initiated through genetic activators or are in fact considered idiopathic (i.e., without a known cause). Certain fibrotic diseases, such as idiopathic pulmonary fibrosis (IPF), can be treated with a nonspecific kinase inhibitor (nintedanib) or drugs without a well-characterized mechanism of action (pirfenidone).Other treatments for organ fibrosis, such as renal or hepatic fibrosis, relieve pressure on the organ itself (e.g., beta-blockers for cirrhosis, angiotensin receptor blockers for chronic kidney disease). Attention to lifestyle factors, such as glucose and dietary control, can also influence the development and severity of the disease. Mitochondrial dysfunction has been implicated in a number of fibrotic diseases, with oxidative stress downstream of the dysfunction being the key pathogenic mediator, along with decreased ATP production. In preclinical models, disruption of the mitophagy pathway (through mutation or inactivation of either parkin or PINK1) exacerbates pulmonary and renal fibrosis, with evidence of increased oxidative stress. Kurita et al., 2017, Respiratory Research 18:114, describe the accumulation of profibrotic myofibroblasts as a crucial process for fibrotic remodeling in pulmonary fibrosis (PF). Recent findings suggest the involvement of autophagy / mitophagy, part of the lysosomal degradation machinery, in the pathogenesis of PF, and that mitophagy has been implicated in myofibroblast differentiation through the regulation of platelet-derived growth factor receptor (PDGFR) activation mediated by mitochondrial reactive oxygen species (ROS) frCZC Ln / Zznz / E / YIAI. Kurita's results suggested that pirfenidone induces PARK2-mediated mitophagy and also inhibits the development of pulmonary fibrosis in patients with insufficient mitophagy, which may at least partially explain the anti-fibrotic mechanisms for the treatment of PF. frC7C ίη / 77Π7 / E / YΙΛΙ Williams et al., 2015, Pharmacol Res. December; 102: 264-269, discuss the role of PINK1-Parkina-mediated autophagy in protecting against alcohol- and acetaminophen-induced liver injury by removing damaged mitochondria through mitophagy. They suggest that pharmacological stabilization of USP8 or inactivation of USP15 and USP30 may be potential therapeutic targets for upregulating Parkin-induced mitophagy and, in turn, protecting against drug-induced liver injury. However, they note that DUBs are regulated both transcriptionally and post-translationalally, which may make drug development for targeting these specific enzymes challenging, and furthermore, phosphorylated ubiquitin has been shown to be resistant to DUBs. The authors conclude that upregulating PINK1 stabilization or kinase activity may be a more effective target than inhibiting DUBs. Williams et al, 2015, Biomolecules 5, 2619-2642, and Williams et al, 2015, Am J Physiol Gastrointest Liver Physiol 309: G324-G340, reviewed the mechanisms involved in the regulation of mitochondrial homeostasis in the liver and how these mechanisms may protect against alcohol-induced liver disease. Luciani et al., 2020, Nat. Commun. 11, 970, report that dysregulation of the mitochondrial network in terminally differentiated cells contributes to a wide spectrum of disorders, including methylmalonic acidemia (MMA). MMA is one of the most common inherited metabolic disorders, due to a deficiency of mitochondrial methylmalonyl-coenzyme A mutase (MMUT). MMUT deficiency induces metabolic and mitochondrial alterations that are exacerbated by abnormalities in PINK1 / Parkina-mediated mitophagy, leading to the accumulation of dysfunctional mitochondria that activates epithelial stress and ultimately cell damage. A link between primary MMUT deficiency, diseased mitochondria, mitophagy dysfunction, and epithelial stress is suggested, and potential therapeutic perspectives for MMA are provided. Kluge et al, Bioorganic & Medicinal Chemistry Letters, 2018, 28 2655-2659, report that selective inhibitors of USP30 accelerate mitophagy. A series of N-cyano-substituted heterocycle derivatives are described as inhibitors of deubiquitination enzymes in applications WO 2016 / 046530 (US 15 / 513125, US 15 / 894025, US 16 / 448066), WO 2016 / 156816 (US 15 / 558632, US 16 / 297937, US 16 / 419558, US 16 / 419747, (US 15 / 776149), WO 2017 / 109488 US 16 / 788446), WO 2017 / 103614 (US 16 / 060299), WO 2017 / 009650 (US 15 / 781615), WO 2017 / 141036 (US 15 / 738900), WO 2017 / 149313 (US 16 / 070936), WO 2017 / 093718 (US 16 / 078518), WO 2017 / 163078 (US 16 / 087515), WO 2017 / 158381 (US 16 / 080229), WO 2017 / 158388 (US 16 / 080506), WO 2018 / 065768 (US 16 / 336685), WO 2018 / 060742 (US 16 / 336202), WO 2018 / 060689 (US 16 / 334836), WO 2018 / 060691 (US 16 / 336363), WO 2018 / 220355 (US 16 / 615040), WO 2018 / 234755 (US 16 / 615709), WO 2020 / 212350, WO 2020 / 212351, WO 2021 / 043870 and PCT / EP2021 / 064166, each of which is expressly incorporated herein by reference. PCT application WO 2019 / 171042 (US 16 / 977019), which is expressly incorporated herein by reference, describes the use of N-cyanopyrrolidines as USP30 inhibitors for the treatment of fibrotic diseases. Falgueyret et al., 2001, J. Med. Chem. 44, 94-104, and PCT application WO 01 / 77073 refer to cyanopyrrolidines as inhibitors of cathepsins K and L, with potential utility in the treatment of osteoporosis and other conditions related to bone resorption. PCT application WO 2015 / 179190 refers to acid amidase inhibitors that hydrolyze acylethanolamine, with potential utility in the treatment of ulcerative colitis and Crohn's disease. PCT application WO 2013 / 030218 refers to quinazolin-4-one compounds as inhibitors of specific ubiquitin proteases, such as USP7, with potential utility in the treatment of cancer, neurodegenerative diseases, inflammatory disorders, and viral infections. PCT applications WO 2015 / 017502 and WO 2016 / 019237 relate to Bruton's tyrosine kinase inhibitors with potential utility in the treatment of diseases such as autoimmune disease, inflammatory disease, and cancer.PCT applications WO 2009 / 026197, WO 2009 / 129365, WO 2009 / 129370, and WO 2009 / 129371 relate to cyanopyrrolidines as cathepsin C inhibitors with potential utility in the treatment of COPD. US patent application US 2008 / 0300268 relates to polyaromatic compounds as PDGFR tyrosine kinase receptor inhibitors. PCT applications WO 2019 / 222468, WO 2019 / 071073, WO 2020 / 036940 and WO 2020 / 072964, Rusilowicz-Jones et al, 2020, bioRxiv 2020.04.16.044206 (April 20, 2020), and Tsefou et al, bioRxiv 2021.02.02.429344 (February 2, 2021), refer to cyanamide-containing compounds as USP30 inhibitors. Yue et al, 2014, Cell Research, 24, 482-496, refer to a diterpenoid derivative, 15-oxospiramylactone, as a USP30 inhibitor that induced mitochondrial fusion. PCT application WO 2015 / 183987 relates to pharmaceutical compositions comprising deubiquitinase inhibitors and human serum albumin for the treatment of cancer, fibrosis, an autoimmune disease or condition, an inflammatory disease or condition, a neurodegenerative disease or condition, or an infection. It is noted that deubiquitinases, including UCHL5 / UCH37, USP4, USP9X, USP11, and USP15, are said to be involved in the regulation of the TGF-beta signaling pathway, disruption of which leads to neurodegenerative and fibrotic diseases, autoimmune dysfunction, and cancer. PCT application WO 2006 / 067165 relates to a method for treating fibrotic diseases using indolinone kinase inhibitors. PCT application WO 2007 / 119214 relates to a method for treating early-stage pulmonary fibrosis using an endothelin receptor antagonist. PCT application WO 2012 / 170290 relates to a method for treating fibrotic diseases using THC acids. PCT application WO 2018 / 213150 relates to sulfonamide USP30 inhibitors with potential utility in treating conditions involving mitochondrial defects. Larson-Casey et al., 2016, Immunity 44, 582-596, concerns macrophage Aktl kinase-mediated mitophagy, apoptosis resistance, and pulmonary fibrosis. Tang et al, 2015, Kidney Diseases 1, 71-79, review the potential role of mitophagy in renal pathophysiology. There is a need for safe, alternative, and / or improved methods and compositions for the treatment or prevention of conditions involving mitochondrial dysfunction, cancer, and fibrosis, and the various symptoms and conditions associated with them. Although not wishing to be limited by any particular theory or mechanism, it is believed that the compounds of the present invention act by inhibiting the USP30 enzyme, which in turn upregulates Parkin-induced mitophagy. Acute kidney injury (AKI) is defined as an abrupt decline in kidney function occurring over 7 days or less, with the severity of injury graded according to the increase in serum creatinine (SCr) and the decrease in urine output, as described in the Kidney Disease Improves Global Outcomes (KDIGO) guidelines. AKI occurs in approximately 13.3 million people per year, 85% of whom live in the developing world, and is thought to contribute to about 1.7 million deaths annually (Mehta et al., 2015, Lancet 385(9987): 2616–2643). AKI is most likely to result in kidney damage (i.e., chronic kidney disease; CKD) and may also result in damage to non-renal organs. AKI is a significant public health concern particularly when considering the absolute number of patients who develop incident CKD, progressive CKD, end-stage renal disease, and cardiovascular events.AKI has been found to be prevalent in patients hospitalized for COVID-19 and is strongly associated with hospital mortality, and mitochondrial damage and dysfunction have been reported as a potential pathophysiological mechanism and therapeutic target (Kellum et al, Nephrol Dial Transplant (2020) 35: 1652-1662). AKI and CKD are viewed as continuations on the same disease spectrum (Chawla et al, 2017, Nat Rev Nephrol 13(4): 241-257). Patients undergoing coronary artery bypass grafting (CABG) are at increased risk of kidney injury. There is a clear unmet medical need for the development of medicinal products for the treatment and / or prevention of AKI. frC7C ίη / 77Ω7 / Β / YΙΛΙ The kidney is a site of high metabolic demand, with high rates of mitophagy demonstrated in vivo (McWilliams et al, 2018, Cell Metab 27(2): 439-449 e435). Renal proximal tubule epithelial cells (RPTECs), a cell type with a significant ATP requirement for solute / ion exchange, are rich in mitochondria and are the primary effector cells of acute kidney injury (AKI) in the kidney. Mitochondrial dysfunction has been implicated in the mechanisms of AKI / CKD, both through multiple lines of evidence from preclinical models of AKI and CKD as well as through data demonstrating abnormal mitochondrial phenotypes in patient biopsies (Emma et al., 2016, Nat Rev Nephrol 12(5): 267-280; Eirin et al., 2017, Handb Exp Pharmacol 240: 229-250).Furthermore, primary mitochondrial disease often manifests in renal symptoms, such as focal segmental glomerulosclerosis (Kawakami et al, 2015, J Am Soc Nephrol 26(5): 1040-1052) in patients with MELAS / MIDD, and also primary tubular pathologies in patients with Coenzyme Q deficiencies. Mutations in mtDNA can cause maternally inherited tubulointerstitial disease (Connor et al, 2017, PLoS Genet 13(3): el006620). Regarding mitochondrial quality control in kidney injury (Tang et al., 2018, Autophagy 14(5): 880–897), researchers demonstrated that kidney injury was exacerbated after ischemic AKI in both PINK1 KO and PARK2 KO mice, suggesting that PINK1 / PARKINA-mediated mitophagy plays a protective role after IRI in the kidney. Furthermore, parkin / PINK1 mitophagy protects against cisplatin-induced kidney injury (Wang et al., 2018, Cell Death Dis. 9(11): 1113). While limited CKD models are available for mitophagy research, supporting evidence for mitochondrial quality control in fibrosis comes from studies in fibrotic lung conditions such as COPD and IPF. Parkin-deactivated animals show exacerbated pulmonary fibrosis in response to bleomycin (Kobayashi et al, 2016, J Immunol, 197:504-516).Similarly, airway epithelial cells from parkin-knocked-out (KO) animals show exacerbated fibrotic and senescent responses to cigarette smoke (Araya et al, 2019, Autophagy 15(3): 510526). Preclinical models are available for studying potential novel therapeutic agents by modeling fibrosis pathology (e.g., collagen deposition) consistent with the human condition. These models can be toxin-mediated (e.g., bleomycin for lung and skin fibrosis), surgical (e.g., ischemia / reperfusion injury model and unilateral urethral obstruction model for acute tubulointerstitial fibrosis), and genetic (e.g., diabetic (db / db) mice for diabetic nephropathy). For example, both previously mentioned examples of the indicated IPF treatments (nintedanib and pirfenidone) demonstrate efficacy in the bleomycin-induced lung fibrosis model. Consequently, there is a need for compounds that are USP30 inhibitors for the treatment or prevention of conditions where USP30 inhibition is indicated. In particular, there is a need for USP30 inhibitors that have suitable and / or enhanced properties to maximize efficacy against the target disease. BRIEF DESCRIPTION OF THE INVENTION frCZC Ln / Zznz / E / YIAI The present invention relates to a compound of formula (I), which is selected from formula (I)(¡) and formula (I)(i¡): a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from (C1-C4) alkyl, (C1-C4) fluoroalkyl and CH2OCH3; R2 is selected from (C1-C4) alkyl, CF3 and cyclopropyl; and R3, R4 and R5 are each independently selected from hydrogen and halogen. The present invention also relates to the uses of compounds of formula (I), particularly in the treatment of conditions involving mitochondrial dysfunction, cancer, and fibrosis, and also to processes for the preparation thereof and pharmaceutical compositions containing such compounds. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to USP30 inhibitors that have suitable and / or improved properties to maximize efficacy against the target disease. Such properties include, for example, potency, selectivity, physicochemical properties, ADME (absorption, distribution, metabolism, and excretion), including PK (pharmacokinetic) profile, and safety profile. It is generally desirable to maximize the potency of a drug molecule against the target enzyme in relevant assays to reduce the effective dosage to be administered to patients. The compounds of the invention can be tested for USP30 affinity using the in vitro biochemical fluorescence polarization (FP) assay described herein. USP30 is a transmembrane protein located in the outer membrane of mitochondria, energy-producing organelles within cells. Therefore, demonstrating cellular activity in vitro is advantageous, as this is one of several factors that can indicate a greater ability to bind to the target in its physiological configuration—that is, where the USP30-inhibiting compound can also penetrate cells. The USP30 cell western blot (WB) assay described herein is designed to test the activity of compounds against USP30 in cells using an irreversible activity probe to monitor USP30 activity. Analogous to the cell western blot assay, the assessment of target involvement (ex vivo) can be performed on brain or kidney tissue samples from animals that have been administered the compound dose. To extend target binding knowledge to downstream pharmacodynamics, one can assess the ubiquitination of TOM20 (an outer mitochondrial membrane protein). In general, it is important that a drug be as selective as possible for its desired target enzyme; additional activity increases the likelihood of side effects. The exact physiological role of many dendritic nucleotides (DUBs) has not yet been fully determined; however, regardless of the role these DUBs may or may not play, it is a sound principle of medicinal chemistry to ensure that any drug has selectivity for related mechanistic targets of unknown physiological function.Representative examples of DUB enzymes against which the compounds of the present invention can be selected are UCHL1, UCHL3, UCHL5, YOD1, SENP2, SENP6, TRABID, BAP1, Cezanne, MINDY2 / FAM63B, OTU1, OTUD3, OTUD5, OTUD6A, OTUD6B, OTUB1 / UBCH5B, OTUB2, CYLD, VCPIP, AMSH-LP, JOSD1, JOSD2, USP1 / UAF1, USP2, USP4, USP5, USP6, USP7, USP8, USP9x, USP10, USP11, USP12 / UAF1, USP13, USP14, USP15, USP16, USP19, USP20, USP21, USP22, USP24, USP25, USP28, USP32, USP34, USP35, USP36, USP45, USP46 / UAF1, USP47 and USP48. Preferably, the compounds of the invention have good selectivity for USP30 over one or more of these DUB enzymes. In addition to selectivity for other DUB enzymes, it is important that a drug have low affinity for other targets, and pharmacological profiling can be performed against panels of targets to assess the potential for, and to minimize, potential off-target effects. Examples of targets against which the compounds of the present invention can be screened are those of the industry-standard Eurofins-Cerep SafetyScreen44 panel, which includes 44 targets as a representative selection of GPCR receptors, transporters, ion channels, nuclear receptors, and kinases and non-kinase enzymes. Preferably, the compounds of the invention have negligible affinity for the targets on this screening panel.Other examples of targets against which the compounds of the present invention can be selected are the kinases in the Thermo Fisher SelectScreen kinase profiling panel, which includes 39 targets as a representative selection of kinase enzymes. Preferably, the compounds of the invention have negligible affinity for the targets in this selection panel. Furthermore, examples of a particular enzyme class against which the compounds of the present invention can be screened are the cathepsins (e.g., cathepsin A, B, C, H, K, L, L2, S, V, and Z). Preferably, the compounds of the invention have good selectivity for one or more of these enzymes. There is also a need for compounds with favorable pharmacokinetic properties that make them suitable for oral administration. An orally administered drug must have good bioavailability; this is the ability to readily cross the gastrointestinal (GI) tract and not undergo extensive metabolism as it passes from the GI tract into the systemic circulation. Once the drug is in the systemic circulation, the rate of metabolism is also important in determining the drug's residence time in the body. Thus, it is clearly advantageous for drug molecules to have the properties of being readily available to cross the GI tract and to be metabolized slowly in the body. The Caco-2 assay is a widely accepted model for predicting the ability of a given molecule to cross the GI tract. Most drug molecule metabolism generally occurs in the liver, and in vitro assays using whole-cell hepatocytes (animal or human) are widely accepted methods for measuring a given molecule's susceptibility to hepatic metabolism. Such assays aim to predict in vivo elimination based on the calculated hepatocyte clearance value. Compounds that have good Caco-2 flux and are stable into hepatocytes are predicted to have good oral bioavailability (good absorption through the GI tract and minimal extraction of the compound as it passes through the liver) and a long residence time in the body that is sufficient for the drug to be effective. The solubility of a compound is an important factor in achieving the desired drug concentration in the systemic circulation for the anticipated pharmacological response. Low water solubility is a problem encountered with the development of new chemical formulations, and for a drug to be absorbed, it must be present in solution at the absorption site. The kinetic solubility of a compound can be measured using a turbidimetric solubility assay, the data from which can also be used in conjunction with CaCO2 permeability data to predict dose-dependent intestinal absorption in humans. Other parameters that can be measured using standard assays that are indicative of a compound's exposure profile include, for example, plasma stability (measurement of frC7C ίη / 77P7 / E / YILI half-life), blood AUC values, Cmax, Cmin and Tmax. The treatment of CNS disorders, including Alzheimer's disease, Parkinson's disease, and other disorders described herein, requires drug molecules that target the brain, which necessitates adequate penetration of the blood-brain barrier. Therefore, there is a need for USP30 inhibitors that possess effective blood-brain penetration properties and provide sufficient residence time in the brain to be effective. The likelihood of a compound crossing the blood-brain barrier can be measured by an in vitro flow assay using an MDR1-MDCK cell monolayer (Madin-Darby Canine Kidney cells transfected with MDR-1 result in overexpression of human efflux transporter P-glycoprotein). Furthermore, exposure can also be measured directly in the brain and plasma using in vivo animal models. There is also a need for compounds with a favorable safety profile, which can be measured by a variety of standard in vitro and in vivo methods. Reverse cell toxicity screening can be used to analyze the antiproliferative / cytotoxic effect in a particular cell line (e.g., HCT116) by fluorometric detection of rezasurin (alamarBIue™) to resofurin in response to mitochondrial activity. Toxicology and safety studies can also be conducted to identify potential target organs for adverse effects and to define the Therapeutic Index for establishing initial starting doses in clinical trials. Regulatory requirements generally mandate that these studies be performed in at least two laboratory animal species: a rodent (rat or mouse) and a non-rodent (rabbit, dog, non-human primate, or other suitable species). The bacterial reverse mutation assay (Ames test) can be used to evaluate the mutagenic properties of the compounds of the invention, commonly by using the bacterial strain Salmonella typhimurium, which is mutating for the biosynthesis of the amino acid histidine. The micronucleus assay can be used to determine if a compound is genotoxic by assessing the presence of micronuclei. Micronuclei may contain chromosome fragments produced by DNA breakage (clastogens) or whole chromosomes produced by disruption of the mitotic apparatus (aneugens). The hERG prediction assay provides valuable information about the potential binding of test compounds to the potassium channel and the resulting QT prolongation on echocardiography. Inhibition of the hERG current leads to QT interval prolongation, resulting in a potentially fatal ventricular tachyarrhythmia (Torsades de Pointes). Typically, assay data can be generated from an automated patch-clamp assay platform. The present invention is therefore directed to USP30 inhibitors that have suitable and / or improved properties to maximize efficacy against the target disease. Such properties include, for example, potency, selectivity, physicochemical properties, ADME (absorption, distribution, metabolism, and excretion), including PK (pharmacokinetic) profile, and safety profile. The compounds of the present invention have been found to exhibit one or more of the aforementioned significant and unexpected properties. For example, Examples 1 through 12 of the present invention are highly potent for USP30, as measured by the biochemical assay described herein. All of these Examples (1 through 12) of the present invention are significantly more selective for USP30 than for other DUBs and cathepsins. The significant and unexpected properties of the compounds of the present invention make them particularly suitable for use in the treatment and / or prevention of diseases linked to USP30 activity. According to a first aspect, the present invention provides a compound of formula (I), which is selected from formula (I)(ii) and formula (I)(ii): frC7C ίη / 77Π7 / E / YΙΛΙ a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from (C1-C4) alkyl, (C1-C4) fluoroalkyl and CH2OCH3; R2 is selected from (C1-C4) alkyl, CF3 and cyclopropyl; and R3, R4 and R5 are each independently selected from hydrogen and halogen. The compound of formula (I) exists as a single stereoisomer with the absolute stereochemistry shown. Alkyl groups can be linear or branched and contain from 1 to 4 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and sec-butyl. Halogen means fluorine, chlorine, bromine, or iodine, particularly fluorine or chlorine. Fluoroalkyl groups can contain one or more fluorine substituents. Examples are fluoromethyl, difluoromethyl, and trifluoromethyl. Unless otherwise stated, the term 'substituted' means substituted by one or more defined groups. Where groups can be selected from more than one alternative, the selected groups may be the same or different. The term 'independently' means that when more than one substituent is selected from more than one possible substituent, those substituents may be the same or different. The preferred embodiments of the compound of formula (I) are defined below. Preferably, R1 is selected from methyl, CH2F, CHF2, CF3, and CH2OCH3. More preferably, R1 is selected from methyl, CH2F and CH2OCH3. Even more preferably, R1 is selected from methyl and CH2OCH3. Preferably, R2 is selected from methyl, CF3 and cyclopropyl. Even more preferably, R2 is selected from methyl and cyclopropyl. Preferably, R3 is selected from hydrogen, chlorine, and fluorine. More preferably, R3 is selected from hydrogen and fluorine. Even more preferably, R3 is hydrogen. Preferably, R4 and R5 are each selected independently from hydrogen and fluorine. Even more preferably, R4 and R5 are each hydrogen. According to one aspect of the invention, the compound of formula (I) has the formula (I)(i): frCZC Ln / Zznz / E / YIAI According to another aspect of the invention, the compound of formula (I) has the formula (I)(ii): According to a first preferred aspect of the invention, the compound is of formula (IA)(¡): R5O—R2 frC7C ίη / 77Π7 / E / YΙΛΙ R1(IA)(¡) a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from (C1-C4) alkyl, (C1-C4) fluoroalkyl and CH2OCH3; R2 is selected from (C1-C4) alkyl, CF3 and cyclopropyl; and R3, R4 and R5 are each independently selected from hydrogen and halogen. The preferred forms of the compound of formula (IA)(i) are defined below. Preferably, R1 is selected from methyl, CH2F, CHF2, CF3 and CH2OCH3. More preferably, R1 is selected from methyl, CH2F and CH2OCH3. Even more preferably, R1 is selected from methyl and CH2OCH3. Preferably, R2 is selected from methyl, CF3 and cyclopropyl. Even more preferably, R2 is selected from methyl and cyclopropyl. Preferably, R3 is selected from hydrogen, chlorine, and fluorine. More preferably, R3 is selected from hydrogen and fluorine. Even more preferably, R3 is hydrogen. Preferably, R4 and R5 are each selected independently from hydrogen and fluorine. Even more preferably, R4 and R5 are each hydrogen. The preferred components of the formula (IA) (i) of the present day are selected by: 5-(5-c¡ano-2-c¡clopropox¡fenil)-N-((3R,5R)-lc¡ano-5-met¡lp¡rrol¡d¡n-3-¡l)oxazol-2carboxamida; 5-(5-cyano-2-ciclopropoxifen¡l)-N-((3R,5S)-lc¡ano-5-(metox¡met¡l)p¡rrol¡din-3¡l)oxazol-2-carboxamida; 5-(5-cyano-2-c¡clopropoxifen¡l)-N-((3R,5S)-lc¡ano-5-(fluoromet¡l)p¡rrol¡din-3il)oxazol-2-carboxamida; 5-(5-c¡ano-2-metoxifen¡l)-N-((3R,5R)-lc¡ano-5-met¡lp¡rrol¡d¡n-3-¡l)oxazol-2carboxamida; 5-(5-c¡ano-2-metox¡fen¡l)-N-((3R,5S)-lc¡ano-5-(metox¡met¡l)pirrol¡d¡n-3-¡l)oxazol-2 carboxamida; 5-(5-c¡ano-2-(tr¡fluorometox¡)fen¡l)-N-((3R,5S)-l-cyano-5-(metoximetil)pirrol¡d¡n-3il)oxazol-2-carboxamida; 5-(5-Cano-2-(trfluorometox)fenl)-N-((3R,5R)-lcano-5-metallprroldn-3-l)oxazol·2carboxamide; y 5-(5-c¡ano-4-fluoro-2-metoxifen¡l)-N-((3R,5R)-lc¡ano-5-metilpinOlidin-3-il)oxazol-2carboxamida; or a pharmaceutically acceptable salt thereof. The most preferred compounds of formula (IA)(i) of the present invention are selected from: 5-(5-cyano-2-cyclopropoxyphenyl)-N-((3R,5R)-lcyano-5-methylpyrrolidin-3-l)oxazole-2carboxamide; and 5-(5-cyano-2-cyclopropoxyphenyl)-N-((3R,5S)-lcyane-5-(methoxymethyl)pyrrolidin-3yl)oxazole-2-carboxamide; or a pharmaceutically acceptable salt thereof. According to a second preferred aspect of the invention, the compound is of formula (IB)(i): frCZC Ln / Zznz / E / YIAI a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from (C1-C4) alkyl, (C1-C4) fluoroalkyl and CH2OCH3; R2 is selected from (C1-C4) alkyl, CF3 and cyclopropyl; and R3, R4 and R5 are each independently selected from hydrogen and halogen. The preferred forms of the formula compound are defined below. Preferably, R1 is selected from methyl, CH2F, CHF2, CF3 and CH2OCH3. More preferably, R1 is selected from methyl, CH2F and CH2OCH3. Even more preferably, R1es CH2OCH3. Preferably, R2 is selected from methyl, CF3 and cyclopropyl. Even more preferably, R2 is methyl. Preferably, R3 is selected from hydrogen, chlorine, and fluorine. More preferably, R3 is selected from hydrogen and fluorine. Even more preferably, R3 is hydrogen. Preferably, R4 and R5 are each selected independently from hydrogen and fluorine. Even more preferably, R4 and R5 are each hydrogen. The preferred compounds of formula (IB)(¡) of the present invention are selected from: 4-(5-cyano-2-methoxyphenyl)-N-((3R,5S)-l-cyano-5-(methoxymethyl)pyrrolidin-3-yl)oxazole-2carboxamide; and 4-(5-cyano-2-cyclopropoxyphenyl)-N-((3R,5S)-lcyane-5-(methoxymethyl)pyrrolydin-3yl)oxazole-2-carboxamide; or a pharmaceutically acceptable salt thereof. According to a third preferred aspect of the invention, the compound is of formula (IA)(ii): frCZC Ln / Zznz / E / YIAI a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from (C1-C4) alkyl, (C1-C4) fluoroalkyl and CH2OCH3; R2 is selected from (C1-C4) alkyl, CF3 and cyclopropyl; and R3, R4 and R5 are each independently selected from hydrogen and halogen. The preferred forms of the compound of formula (IA)(¡¡) are defined below. Preferably, R1 is selected from methyl, CH2F, CHF2, CF3 and CH2OCH3. More preferably, R1 is selected from methyl, CH2F and CH2OCH3. Even more preferably, R1 is selected from methyl and CH2OCH3. Preferably, R2 is selected from methyl, CF3 and cyclopropyl. Even more preferably, R2 is selected from methyl and cyclopropyl. Preferably, R3 is selected from hydrogen, chlorine, and fluorine. More preferably, R3 is selected from hydrogen and fluorine. Even more preferably, R3 is hydrogen. Preferably, R4 and R5 are each selected independently from hydrogen and fluorine. Even more preferably, R4 and R5 are each hydrogen. The preferred compounds of formula (IA)(ii) of the present invention are selected from: 5-(5-cyane-2-cyclopropoxyphenyl)-N-((3R,5R)-lcyane-5-(methoxymethyl)pyrrolidin-3¡l)oxazole-2-carboxamide; 5-(5-cyano-2-cyclopropoxyphenyl)-N-((3R,5S)-lcyano-5-methylpyrrolidin-3-l)oxazole-2carboxamide; 5-(5-c¡ano-2-methoxyphenyl)-N-((3R,5S)-lc¡ano-5-met¡lp¡rrolidin-3-¡l)oxazol-2carboxamida; 5-(5-c¡ano-2-methoxifen¡l)-N-((3R,5R)-l-cyano-5-(methox¡met¡l)pinOl¡d¡n-3-¡l)oxazol-2carboxamida; 5-(5-c¡ano-2-(trifluoromethox¡)phen¡l)-N-((3R,5R)-lc¡ano-5-(methox¡met¡l)p¡nOl¡d¡n-3yl)oxazol-2-carboxamida; 5-(5-c¡ano-2-(tr¡fluoromethox¡)phen¡l)-N-((3R,5S)-lc¡ano-5-met¡lp¡nOl¡d¡n-3-¡l)oxazol-2carboxamida; 5-(5-cyano-4-fluoro-2-methox¡phen¡l)-N-((3R,5S)-lc¡ano-5-methylpinOl¡d¡n-3-¡l)oxazol-2carboxamida; y 5-(5-cyano-2-c¡clopropoxyfen¡l)-N-((3R,5R)-lc¡ano-5-(fluoromet¡l)p¡rrol¡d¡n-3yl)oxazol-2-carboxamida; or a pharmaceutically acceptable sal de las mismas. Next, a fourth favorite aspect of the invention is the formula (IB)(i): frC7C ίη / 77Π7 / Ε / ΥΙΛΙ a tautómero of the same, or a pharmaceutically acceptable sal de dicho compuesto or tautómero, where: R1 is selected from (C1-C4) alkyl, (C1-C4) fluoroalkyl and CH2OCH3; R2 is selected from (C1-C4) alkyl, CF3 and cyclopropyl; and R3, R4 and R5 are each independently selected from hydrogen and halogen. The preferred forms of the compound of formula (IB)(¡¡) are defined below. Preferably, R1 is selected from methyl, CH2F, CHF2, CF3 and CH2OCH3. More preferably, R1 is selected from methyl, CH2F and CH2OCH3. Even more preferably, R1es CH2OCH3. Preferably, R2 is selected from methyl, CF3 and cyclopropyl. Even more preferably, R2 is methyl. Preferably, R3 is selected from hydrogen, chlorine, and fluorine. More preferably, R3 is selected from hydrogen and fluorine. Even more preferably, R3 is hydrogen. Preferably, R4 and R5 are each selected independently from hydrogen and fluorine. Even more preferably, R4 and R5 are each hydrogen. The preferred compounds of formula (IB)(¡¡) of the present invention are selected from: 4-(5-cyano-2-cyclopropoxyphenyl)-N-((3R,5R)-l-cyano-5-(methoxymethyl)pyrrolidin-3yl)oxazole-2-carboxamide; and 4-(5-cyane-2-methoxyphenyl)-N-((3R,5R)-lcyane-5-(methoxymethyl)pinOlidin-3-!l)oxazole-2carboxamide; or a pharmaceutically acceptable salt thereof. Pharmaceutically acceptable salts of compounds of formula (I) include acid and basic addition salts (including disalts) thereof. Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include acetate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate, camsylate, citrate, edisylate, esylate, fumarate, gluceptate, gluconate, glucuronate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, acid phosphate, isethionate, D- and L-lactate, malate, maleate, malonate, mesylate, methyl sulfate, 2-napsylate, nicotinate, nitrate, orotate, palmate, phosphate, saccharate, stearate, succinate sulfate, D- and L-tartrate, and tosylate salts. Suitable basic salts are formed from bases that form non-toxic salts. Examples include the salts of aluminum, ammonium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, and zinc. For a proper review of salts, see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Wiley-VCH, Weinheim, Germany (2002). A pharmaceutically acceptable salt of a compound of formula (I) can be readily prepared by mixing together solutions of the compound of formula (I) and the desired acid or base, as appropriate. The salt can be precipitated from the solution and collected by filtration or recovered by evaporation of the solvent. Acceptable pharmaceutical solvates according to the invention include hydrates and solvates wherein the crystallization solvent can be isotopically substituted, for example D2O, acetone-ds, DMSO-de. Also within the scope of the invention are clathrates, drug-host inclusion complexes in which, in contrast to the solvates mentioned above, the drug and host are present in non-stoichiometric amounts. For a review of such complexes, see Pharm Sci, 64 (8), 1269-1288 by Haleblian (August 1975). Henceforth all references to compounds of formula (I) include reference to the salts thereof and to the solvates and clathrates of compounds of formula (I) and salts thereof. The invention includes all polymorphs of compounds of formula (I) as defined above. Also within the scope of the invention are so-called prodrugs of compounds of formula (I). Thus, certain derivatives of compounds of formula (I) that have little or no pharmacological activity on their own can, when metabolized after administration into or onto the body, give rise to compounds of formula (I) that have the desired activity. Such derivatives are referred to as prodrugs. The prodrugs according to the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of any of the formula (I) with certain radicals known to those skilled in the art as pro-radicals as described, for example, in Design of Prodrugs by H Bundgaard (Elsevier, 1985). Finally, certain compounds of formula (I) can by themselves act as prodrugs of other compounds of formula (I). Certain derivatives of compounds of formula (I) containing a nitrogen atom can also form the corresponding AAxide, and such compounds are also within the scope of the present invention. Included within the scope of the present invention are all tautomeric forms of compounds of formula (I). Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high-performance liquid chromatography (HPLC). Alternatively, the racemate (or a racemic precursor) can be reacted with a suitable optically active compound, for example, an alcohol, or, where the compound of formula (I) contains an acidic or basic portion, a base or acid such as phenylethylamine or tartaric acid. The resulting diastereomeric mixture can be separated by chromatography and / or fractional crystallization, and one or both of the diastereomers can be converted to the corresponding pure enantiomer(s) by means well known to the person skilled in the art.The chiral compounds of the invention (and their chiral precursors) can be obtained in enantiomerically enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing 0 to 50% by volume of propan-2-ol, typically 2% to 20%, and 0 to 5% by volume of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate produces the enriched mixture. The present invention includes all crystalline forms of the compounds of formula (I), including racemates and racemic mixtures (clusters) thereof. The stereoisomeric clusters can be separated by conventional techniques known to those skilled in the art—see, for example, Stereochemistry of Organic Compounds by E.L. Eliel and S.H. Wilen (Wiley, New York, 1994). Compounds of formula (I) contain two chiral centers on the carbon atoms of the pyrrolidine ring that are substituted by R1 and the amide, and these stereocenters can exist in either ( / ?) or (S) configuration. The designation of the absolute configuration ( / ?) and (5) for stereoisomers according to IUPAC nomenclature depends on the nature of the substituents and the application of the sequence rule procedure. Compounds of formula (I) could, therefore, exist in four stereoisomeric forms. The compounds of formula (I) of the present invention exist as a single stereoisomer. The pyrrolidine carbon atom of the amide substituent exists as the ( / ?)stereocenter, while the designation of the pyrrolidine carbon atom of group R1 is dependent on the nature of the substituent. The compound of formula (I) is isolated as a single stereoisomer and can exist with a stereoisomeric excess of at least 60%, preferably at least 80%, more preferably at least 90%, and more preferably at least 95%, for example 96%, 97%, 98%, 99%, or 100%. Additional chiral centers may exist in compounds of formula (I) within the substituent R1 itself. Included within the scope of the present invention are all stereoisomeric forms of compounds of formula (I). The present invention also includes all pharmaceutically acceptable isotopic variations of a compound of formula (I). An isotopic variation is defined as one in which at least one atom is replaced by an atom having the same atomic number, but a different atomic mass from the atomic mass normally found in nature. frCZC Ln / Zznz / E / YIAI Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2H and 3H, carbon, such as 13C and 14C, nitrogen, such as 15N, oxygen, such as 17O and 18O, phosphorus, such as 32P, sulfur, such as 35S, fluorine, such as 18F, and chlorine, such as 36Cl. Replacing the compounds of the invention with isotopes such as deuterium may produce certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and may therefore be preferred in some circumstances. Certain isotopic variations of compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in tissue distribution studies of drugs and / or substrates. The radioactive isotopes tritium and 14C are particularly useful for this purpose due to their ease of incorporation and readily detectable by means of analysis. Isotopic variations of compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by procedures analogous to those described in the accompanying Examples and Preparations using appropriate isotopic variations of suitable reagents. Compounds of formula (I) are inhibitors of the USP30 deubiquitination enzyme. According to a further aspect, the present invention provides a compound of formula (I) as defined herein, a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer for use as a medicament. According to a further aspect, the present invention provides a method of treating or preventing a disorder or condition where inhibition of USP30 is known, or can be shown, to produce a beneficial effect, in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of formula (I) as defined herein, a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer. According to a further aspect, the present invention provides for the use of a compound of formula (I) as defined herein, a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, in the manufacture of a medicament for the treatment or prevention of a disorder or condition where inhibition of USP30 is known, or can be demonstrated, to produce a beneficial effect. The manufacture of a medicament may include, inter alia, the chemical synthesis of the compound of formula (I) or a salt thereof, or the preparation of a composition or formulation comprising the compound or salt, or the packaging of any medicament comprising the compound. According to another aspect, the present invention provides a method of inhibiting frC7C ίη / 77Ω7 / Β / YΙΛΙ USP30 in a patient comprising administering to the patient a therapeutically effective amount of a compound of formula (I) as defined herein, a tautomer thereof, or a pharmaceutically acceptable salt of such compound or tautomer. The disorder or condition that benefits from USP30 activity is selected from a condition involving mitochondrial dysfunction, cancer, and fibrosis. In a preferred embodiment of all aspects of the invention, the disorder or condition that benefits from the activity of USP30 is a condition involving mitochondrial dysfunction. Mitochondrial dysfunction results from defects in the mitochondria, which are specialized compartments present in every cell of the body except red blood cells. When the mitochondria fail, less and less energy is generated within the cell, leading to cell damage or even cell death. If this process is repeated throughout the body, the life of the affected individual is severely compromised. Mitochondrial diseases most often appear in organs that are highly energy-demanding, such as the brain, heart, liver, skeletal muscles, kidneys, and the endocrine and respiratory systems. The condition involving mitochondrial dysfunction can be selected from a condition involving a mitophagy defect, a condition involving a mutation in mitochondrial DNA, a condition involving mitochondrial oxidative stress, a condition involving a defect in mitochondrial membrane potential, mitochondrial biogenesis, a condition involving a defect in mitochondrial shape or morphology, and a condition involving a lysosomal storage defect. In particular, the condition involving mitochondrial dysfunction may be selected from a neurodegenerative disease; multiple sclerosis (MS); mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome; materially inherited diabetes and deafness (MIDD); Leber hereditary optic neuropathy (LHON); cancer (including, for example, breast, ovarian, prostate, lung, kidney, gastric, colon, testicular, head and neck, pancreatic, brain, melanoma, bone, or other cancers of tissue organs and cancers of blood cells, such as lymphoma and leukemia, multiple myeloma, metastatic carcinoma, osteosarcoma, chondrosarcoma, Ewing sarcoma, nasopharyngeal carcinoma, colorectal cancer, and non-small cell lung carcinoma); neuropathy, ataxia, retinitis pigmentosa, maternally inherited Leigh syndrome (NARP-MILS); Danon disease; diabetes; diabetic nephropathy;metabolic disorders; heart failure; ischemic heart disease leading to myocardial infarction; psychiatric illnesses, e.g., schizophrenia; multiple sulfatase deficiency (MSD); mucolipidosis II (ML II); mucolipidosis III (ML III); mucolipidosis IV (ML IV); GMI-gangliosidosis (GM1); neuronal ceroid lipofuscinosis (NCL1); Alpers disease; frC7C ίη / 77P7 / E / YILI Barth syndrome; beta-oxidation defects; carnitine-acyl-carnitine deficiency; carnitine deficiency; creatine deficiency syndromes; coenzyme Q10 deficiency; complex I deficiency; complex II deficiency; complex III deficiency; complex IV deficiency; complex V deficiency; COX deficiency; chronic progressive external ophthalmoplegia (CPEO) syndrome; CPT I deficiency; CPT II deficiency; glutaric aciduria type II; Kearns-Sayre syndrome; lactic acidosis; long-chain acyl-CoA dehydrogenase (LCHAD) deficiency; Leigh disease or syndrome; French-Canadian variant (LSFC) of Leigh syndrome; lethal infantile cardiomyopathy (LIC); Luft disease; medium-chain acyl-CoA dehydrogenase (MCAD) deficiency; myoclonic and ragged-red fiber epilepsy syndrome (IMERRF); mitochondrial cytopathy; recessive mitochondrial ataxia syndrome; mitochondrial DNA depletion syndrome;Myoneurogastric disorder and encephalopathy; Pearson syndrome; pyruvate dehydrogenase deficiency; pyruvate carboxylase deficiency; POLG mutations; medium / short-chain 3-hydroxyacyl-CoA dehydrogenase (M / SCHAD) deficiency; very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency; peroxisomal disorders; methylmalonic acidemia; mevalonate kinase deficiency; age-dependent decline in cognitive function and muscle strength; and cognitive impairment associated with neurodegenerative and neuropsychiatric disorders. The condition involving mitochondrial dysfunction may be a CNS disorder, for example a neurodegenerative disease. Neurodegenerative diseases include, but are not limited to, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, ischemia, stroke, Lewy body dementia, multiple system atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal dementia. In particular, the compounds of the invention may be useful in the treatment or prevention of Parkinson's disease, which includes, among others, PD related to mutations in o-synuclein, parkin, PINK1, GBA and LRRK2, and autosomal recessive juvenile Parkinson's disease (AR-JP) or early-onset Parkinson's disease (EOPD), where parkin or PINK1 is mutated, truncated or deleted. In particular, the compounds of the invention may be useful in the treatment of cognitive impairment associated with neurodegenerative and neuropsychiatric disorders, including, for example, cognitive impairment associated with Alzheimer's disease and Parkinson's disease, preclinical or prodromal forms of AD and PD, Huntington's disease, dementia with Lewy body disease, cognitive impairment associated with schizophrenia, mood disorders, bipolar disorder, and major depression. The compounds of the invention or pharmaceutical compositions thereof as described herein may be combined with one or more additional agents when used for the treatment or prevention of conditions involving mitochondrial dysfunction. The compounds may be combined with one or more additional agents selected from levodopa, a dopamine agonist, a monoamine oxygenase (MAO) B inhibitor, a catechol-O-methyltransferase (COMT) inhibitor, an anticholinergic, riluzole, amantadine, a cholinesterase inhibitor, memantine, tetrabenazine, an antipsychotic, diazepam, clonazepam, an antidepressant, and an anticonvulsant.The compounds can be combined with agents that reduce / remove pathogenic protein aggregates in neurodegenerative diseases, such as agents that reduce / remove alpha-synuclein in Parkinson's disease, atrophy or multiple systemic dementia with Lewy bodies; agents that reduce / remove Tau in Alzheimer's disease or progressive supranuclear palsy; agents that reduce / remove TDP-43 in ALS or frontotemporal dementia. In another preferred embodiment of all aspects of the invention, the disorder or condition that benefits from the activity of USP30 is cancer. The cancer may be linked to mitochondrial dysfunction. Preferred cancers include, for example, breast, ovarian, prostate, lung, kidney, gastric, colon, testicular, head and neck, pancreatic, brain, melanoma, bone or other organ tissue cancers, and blood cell cancers, such as lymphoma and leukemia, multiple myeloma, metastatic carcinoma, osteosarcoma, chondrosarcoma, Ewing sarcoma, nasopharyngeal carcinoma, colorectal cancer, and non-small cell lung carcinoma. In particular, the compounds of the invention may be useful in the treatment or prevention of cancer where apoptotic pathways are dysregulated and more particularly where BCL-2 family proteins are mutated, or over- or under-expressed. Fibrosis refers to the accumulation of extracellular matrix constituents that occurs following trauma, inflammation, tissue repair, immunological reactions, cellular hyperplasia, and neoplasia. Fibrotic disorders that can be treated with the compounds and compositions of the present invention include, but are not limited to, fibrosis / fibrotic disorders associated with major organ diseases, for example, interstitial lung disease (ILD), liver cirrhosis, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) (hepatic fibrosis), kidney disease (renal fibrosis), acute kidney injury (AKI), acute kidney disease (AKD), chronic kidney disease (CKD), delayed renal graft function, heart or vascular disease (cardiac fibrosis), and eye diseases;Fibroproliferative disorders, e.g., systemic and local scleroderma, keloids and hypertrophic scars, atherosclerosis, restenosis, and Dupuytren's contracture; scarring associated with trauma, e.g., surgical complications, chemotherapeutic drug-induced fibrosis (e.g., bleomycin-induced fibrosis), radiation-induced fibrosis, accidental injuries, and burns; retroperitoneal fibrosis (Ormond's disease); and peritoneal fibrosis / scarring in patients receiving peritoneal dialysis, usually following a kidney transplant. See, e.g., Wynn et al., 2004, Nat Rev Immunol. August.4(8): 583-594. The present invention relates therefore to methods of treatment or prevention, and compounds and compositions used in such methods, of fibrosis / fibrotic disorders of and / or associated with major organs, including for example the lung, liver, kidney, heart, skin, eye, gastrointestinal tract, peritoneum and bone marrow, and other diseases / disorders described herein. The compounds can be combined with agents used as treatments for kidney disease, including anti-diabetic agents, cardiovascular disease agents, and novel agents that target relevant disease pathways such as oxidative stress (including, but not limited to, the nrf2 / keap-l pathway) and anti-apoptotic pathways (including, but not limited to, anti-p53 agents). Interstitial lung disease (ILD) includes disorders in which pulmonary inflammation and fibrosis are the common final pathways of the pathology, for example, sarcoidosis, silicosis, drug reactions, infections, and collagen vascular diseases such as rheumatoid arthritis and systemic sclerosis (scleroderma). Fibrotic lung disorders include, for example, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), normal interstitial pneumonitis (UIP), interstitial lung disease, cryptogenic fibrosing alveolitis (CFA), bronchopulmonary obliterans, and bronchiectasis. Idiopathic pulmonary fibrosis (IPF) is the most common type of ILD and has no known cause. The compounds can be combined with agents that are treatments for IPF and potentially for ILD, including nintedanib and pirfenidone. Liver cirrhosis has similar causes to ILD and includes, for example, cirrhosis associated with viral hepatitis, schistosomiasis, and chronic alcoholism. Kidney disease can be associated with diabetes, which can damage and scar the kidneys, leading to a progressive loss of function, and also with hypertensive diseases. Renal fibrosis can occur at any stage of kidney disease, from post-injury acute kidney disease (AKD) and chronic kidney disease (CKD), including incident and progressive CKD, to end-stage renal disease (ESRD). Renal fibrosis can develop as a result of cardiovascular disease such as hypertension or diabetes, both of which place immense strain on kidney function, promoting a fibrotic response. However, renal fibrosis can also be idiopathic (without a known cause), and certain genetic mitochondrial diseases also present with manifestations of renal fibrosis and associated symptoms. Heart disease can result in scar tissue that can impair the heart's pumping ability. Eye diseases include, for example, macular degeneration and retinal and vitreous retinopathy, which can impair vision. In a preferred embodiment, the present invention is directed to the treatment or prevention of idiopathic pulmonary fibrosis (IPF). In another preferred embodiment, the present invention is directed to the treatment or prevention of renal fibrosis. In another preferred embodiment, the present invention is directed to the treatment or prevention of acute kidney injury (AKI), especially in high-risk patients. Examples include post-surgical AKI, for example, organ transplantation, such as due to ischemia reperfusion injury or delayed graft function; oncology, such as AKI due to chemotherapy; contrast-induced nephropathy, such as direct tubular cytotoxicity, hemodynamic ischemia, and osmotic effects; acute interstitial nephritis, such as that due to drugs or infection; AKI due to obstruction, such as kidney stones; and COVID-19-induced AKI. One particular subgroup of high-risk patients is that undergoing cardiac surgery, for example, coronary artery bypass grafting and / or valve surgery.There are established static risk factors for AKI, such as age 65 or older, insulin-dependent diabetes, CKD (adults with an estimated glomerular filtration rate [eGFR] below 60 ml / min / 1.73 m2 are at particular risk), heart failure, liver disease, and a history of AKI. In another preferred embodiment, the present invention is directed to the treatment or prevention of acute kidney disease (AKD) or chronic kidney disease (CKD) resulting from such AKI, which includes, for example, tubulointerstitial fibrosis and diabetic nephropathy. In another preferred embodiment, the present invention is directed to the treatment or prevention of liver diseases, including, for example, NAFLD, NASH, liver cirrhosis, portal hypertension, acute liver failure, and hepatocellular carcinoma. Liver diseases, such as NAFLD and NASH, can be associated with various metabolic conditions, such as metabolic syndrome and type II diabetes, which also increase the risk of various diabetes-related pathologies, including diabetic retinopathy and peripheral neuropathies. The compounds of the invention or their pharmaceutical compositions as described herein may be combined with one or more additional agents when used for the treatment or prevention of conditions involving liver disease and metabolic dysfunction, including metformin, sulfonylureas, DPP-4 inhibitors, GLP-1 agonists, PPAR agonists, SGLT2 inhibitors, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers (ARBs). Leigh syndrome is a rare inherited neurometabolic disorder that affects the central nervous system. This progressive disorder begins in infants between the ages of three months and two years. Rarely, it occurs in adolescents and adults. Leigh syndrome can be caused by mutations in nuclear DNA that encodes mitochondrial proteins, mutations in mitochondrial DNA (maternally inherited Leigh syndrome - MILS), or by deficiencies in an enzyme called pyruvate dehydrogenase located on the short arm of the X chromosome (X-linked Leigh syndrome). The symptoms of Leigh syndrome typically progress rapidly. The earliest signs may include poor sucking ability and loss of head control and motor skills. These symptoms may be accompanied by loss of appetite, vomiting, irritability, persistent crying, and seizures.As the disorder progresses, symptoms may also include generalized weakness, lack of muscle tone, and episodes of lactic acidosis, which can lead to deterioration of respiratory and kidney function. In maternally inherited Leigh syndrome (MILS), genetic mutations in mitochondrial DNA (at a high rate of >90%) interfere with the energy sources flowing through cells in a brain area that plays a role in motor movements. These mitochondrial DNA mutations result in a chronic lack of energy in these cells, which in turn affects the central nervous system and leads to progressive degeneration of motor function. When the mitochondrial DNA mutations that cause MILS are less prevalent (less than 90%), the condition is known as neuropathy, ataxia, and retinitis pigmentosa (NARP). There is also a form of Leigh disease (called X-linked Leigh disease) that results from mutations in a gene that produces another group of substances important for cellular metabolism.There is another variant of Leigh syndrome called the French-Canadian variant, characterized by mutations in a gene called LRPPRC. Neurological symptoms similar to those of Leigh syndrome are expressed, although hepatic steatosis is also commonly observed in the French-Canadian variant. In a preferred embodiment, the present invention is directed to the treatment or prevention of Leigh syndrome or disease, which includes, for example, X-linked Leigh disease, the French-Canadian variant of Leigh syndrome and / or symptoms associated with Leigh disease. The compounds can be combined with novel agents that can be used as treatments for mitochondrial disease, including, but not limited to, nicotinamide riboside. References to 'treatment' include means of lessening or alleviating symptoms, or eliminating the causes of symptoms, whether on a temporary or permanent basis. The compounds of the invention are useful in the treatment of the diseases described herein in humans and other mammals. frCZC Ln / Zznz / E / YIAI In another embodiment, the invention covers the prophylactic therapy of the diseases described herein and includes means for preventing or slowing the onset of symptoms of the named disorder or condition. The compounds of the invention are useful in the prevention of the diseases described herein in humans and other mammals. A patient in need of treatment or prevention may be, for example, a human or other mammal suffering from the condition or at risk of suffering from the condition. According to a further aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt of said compound or tautomer, together with a pharmaceutically acceptable diluent or carrier. The pharmaceutical compositions of the invention comprise any of the compounds of the invention combined with any pharmaceutically acceptable carrier, adjuvant, or vehicle. Examples of pharmaceutically acceptable carriers are known to those skilled in the art and include, but are not limited to, preservatives, fillers, disintegrants, wetting agents, emulsifying agents, suspending agents, sweeteners, flavoring agents, perfumers, antibacterial agents, antifungal agents, lubricating agents, and dispersing agents, depending on the nature of the mode of administration and dosage forms. The compositions may be in the form of, for example, tablets, capsules, powders, granules, elixirs, lozenges, suppositories, syrups, and liquid preparations, including suspensions and solutions.The term pharmaceutical composition in the context of this invention means a composition comprising an active agent and further comprising one or more pharmaceutically acceptable carriers. The composition may further contain ingredients selected from, for example, diluents, adjuvants, excipients, vehicles, preservatives, fillers, disintegrants, wetting agents, emulsifying agents, suspending agents, sweeteners, flavoring agents, perfumers, antibacterial agents, antifungal agents, lubricating agents, and dispersing agents, depending on the nature of the mode of administration and dosage forms. The compounds of the invention or pharmaceutical compositions thereof, as described herein, may be used alone or in combination with one or more additional pharmaceutical agents. The compounds may be combined with an additional antitumor therapeutic agent, for example, chemotherapeutic drugs or inhibitors of other regulatory proteins. In one embodiment, the additional antitumor therapeutic agent is a BH-3 mimetic. In a further embodiment, the BH-3 mimetics may be selected from, but not limited to, one or more of ABT737, ABT-199, ABT-263, and Obatoclax. In a further embodiment, the additional antitumor agent is a chemotherapeutic agent. Chemotherapeutic agents may be selected from, but are not limited to, olaparib, mitomycin C, cisplatin, carboplatin, oxaliplatin, ionizing radiation (IR), camptothecin, irinotecan, topotecan, temozolomide, taxanes, 5-fluoropyrimidines, gemcitabine, and doxorubicin. For the treatment or prevention of fibrotic disorders, for example, the compounds of the invention or pharmaceutical compositions thereof, as described herein, may be used alone or in combination with one or more additional pharmaceutical agents selected from the group consisting of anticholinergic agents, beta-2 mimetics, steroids, PDE-IV inhibitors, p38 MAP kinase inhibitors, NK1 antagonists, LTD4 antagonists, EGFR inhibitors, and endothelin antagonists. In particular, the compounds of the invention or pharmaceutical compositions thereof, as described herein, may be used alone or in combination with one or more additional pharmaceutical agents selected from the group consisting of additional immunosuppressive drugs, such as a corticosteroid, immunosuppressive or cytotoxic agents, or antifibrotic agents, such as pirfenidone or a non-specific kinase inhibitor (e.g., nintedanib). The pharmaceutical compositions of the invention can be administered in conveniently effective ways, such as orally, parenterally, topically, by inhalation, intranasally, rectally, intravaginally, ocularly, and aurally. Suitable pharmaceutical compositions for delivering the compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in Remington's Pharmaceutical Sciences, 19th edition (Mack Publishing Company, 1995). Oral administration The compounds of the invention can be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed, whereby the compound enters directly into the bloodstream from the mouth. Suitable formulations for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chewable, multi- and nano-particulate, gels, films (including muco-adhesive), ovules, sprays, and liquid formulations. Liquid formulations include suspensions, solutions, syrups, and elixirs. Such formulations can be used as fillings in soft or hard capsules and typically comprise a carrier, such as water, ethanol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying and / or suspending agents. Liquid formulations can also be prepared by reconstituting a solid, such as a sachet. The compounds of the invention can also be used in fast-dissolving, fast-disintegrating dosage forms of frC7C ίη / 77Ω7 / Β / YΙΛΙ such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986 by Liang and Chen (2001). A typical tablet can be prepared using standard procedures known to a formulation chemist, for example, by direct compression, granulation (dry, wet, or melt), melt coagulation, or extrusion. The tablet formulation may comprise one or more layers and may be coated or uncoated. Examples of excipients suitable for oral administration include carriers, e.g. cellulose, calcium carbonate, dibasic calcium phosphate, mannitol and sodium citrate, granulation binders, e.g. polyvinylpyrrolidine, hydroxypropylcellulose, hydroxypropylmethylcellulose and gelatin, disintegrants, e.g. sodium starch glycolate and silicates, lubricating agents, e.g. magnesium stearate and stearic acid, wetting agents, e.g. sodium lauryl sulfate, preservatives, antioxidants, flavors and colorants. Solid formulations for oral administration can be formulated for immediate and / or modified release. Modified-release formulations include delayed-release, sustained-release, pulsed-release, dual-controlled-release, targeted-release, and programmed-release. Details of suitable modified-release technologies such as high-energy dispersions, osmotic particles, and coated particles can be found in Verma et al., Pharmaceutical Technology Online, 25(2), 1-14 (2001). Other modified-release formulations are described in U.S. Patent No. 6,106,864. Parental Administration The compounds of the invention can also be administered directly into the bloodstream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intra-arterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, and subcutaneous. Suitable devices for parenteral administration include needle injectors (including microneedles), needle-free injectors, and infusion techniques. Parenteral formulations are typically aqueous solutions that may contain excipients such as salts, carbohydrates, and buffering agents (preferably at a pH of 3 to 9), but, for some applications, they may be more conveniently formulated as a sterile non-aqueous solution or as a dry form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water. The preparation of parenteral formulations under sterile conditions, for example by lyophilization, can be easily carried out using standard pharmaceutical techniques well known to those experts in the art. The solubility of the compounds of formula (I) used in the preparation of parenteral solutions frCZC Ln / Zznz / E / YIAI can be increased by appropriate processing, e.g., the use of high-energy spray-dried dispersions and / or by the use of appropriate formulation techniques, such as the use of solubility-enhancing agents. Parenteral formulations can be formulated for immediate and / or modified release. Modified-release formulations include delayed, sustained, pulsed, dual-controlled, targeted, and programmed release. The pharmaceutical compositions of the present invention also include compositions and methods known in the art for bypassing the blood-brain barrier or for direct injection into the brain. Suitable injection sites include the cerebral cortex, cerebellum, midbrain, brainstem, hypothalamus, spinal cord, and ventricular tissue, and areas of the nervous system including the carotid body and adrenal medulla. Dosage The magnitude of an effective dose of a compound will, of course, vary with the nature and severity of the condition being treated and the route of administration. The selection of appropriate dosages is within the physician's jurisdiction. The daily dosage range is approximately 10 pg to 100 mg per kg of body weight in both human and non-human animals, and generally, it can be approximately 10 pg to 30 mg per kg of body weight per dose. The above dosage may be given one to three times daily. For example, oral administration may require a total daily dose of 5 mg to 1000 mg, such as 5 to 500 mg, whereas an intravenous dose may only require 0.01 to 30 mg / kg of body weight, such as 0.1 to 10 mg / kg, more preferably 0.1 to 1 mg / kg of body weight. The total daily dose may be administered in single or divided doses. The person skilled in the art will also appreciate that, in the treatment or prevention of certain conditions, the compounds of the invention may be taken as a single dose on an as-required basis (i.e., as needed or desired). Synthesis methodologies Compounds of formula (I) can be prepared using methods as described below in the general chemical reaction and representative examples. Where appropriate, individual transformations within a chemical reaction can be completed in a different order. The invention is illustrated by the following non-limiting examples in which the following abbreviations and definitions are used. The compounds were characterized by liquid chromatography-mass spectroscopy (LC-MS) or 1H NMR or both. According to another aspect, the present invention provides a process for preparing a compound of formula (I)(i) comprising reacting a compound of formula (IV), where Y is OH, with an amine of formula (V)(i), where PG is a protecting group, such as BOC or CBZ, to give an amide of formula (III)(i) (Chemical Reaction 1). The amide coupling reaction can be carried out using standard methodology, for example, by reaction using a coupling reagent such as DCC, HATU, HBTU, EDC, or through a mixed anhydride. Alternatively, the acid (IV), where Y is OH, can be converted into the acid (IV) chloride, where Y is Cl, using SOCh, PCI3, or PCI5, which can then be reacted with the amine (V)(i), preferably in a suitable solvent in the presence of a suitable base.Alternatively, compound (IV), in which Y forms the ester, can be reacted directly with amine (V)(i), preferably in a suitable solvent. The compound of formula (III)(i) can be deprotected using standard methods to give amine (II)(i), which can then be reacted with cyanogen bromide to give the corresponding compound of formula (I)(i). Chemical Reaction 1 In another aspect, the present invention provides a compound, which is selected from formulas (II)(ii) and (III)(i): where PG is a protecting group, preferably BOC or CBZ, and R1, R2, R3, R4 and R5 are as defined herein for the compound of formula (I) and its preferred embodiments, a tautomer thereof or a salt of said compound or tautomer. When the compound of formula (I)(i) has the formula (IA)(i), the formulas (II)(i), (III)(i) and (IV) are (IIA)(i), (IIIA)(i) and (IVA), respectively. When the compound of formula (I)(i) has the formula (IB)(i), the formulas (II)(i), (III)(i) and (IV) are (IIB)(i), (IIIB)(i) and (IVB)(i), respectively. According to another aspect, the present invention provides a process for preparing a compound of formula (I)(iii) comprising reacting a compound of formula (IV), wherein Y is OH, with an amine of formula (V)(iii), where PG is a protecting group, such as BOC or CBZ, to give an amide of formula (III)(iii) (Chemical Reaction 2). The amide coupling reaction can be carried out using standard methodology, for example, by reaction using a coupling reagent such as DCC, HATU, HBTU, EDC, or through a mixed anhydride. Alternatively, the acid (IV), wherein Y is OH, can be converted into the acid (IV) chloride, wherein Y is Cl, using SOCl, PCh, or PCb, which can then be reacted with the amine (V)(ii), preferably in a suitable solvent in the presence of a suitable base. Alternatively, compound (IV), where Y forms the ester, can be reacted directly with amine (V)(ii), preferably in a suitable solvent.The compound of formula (III)(ii) can be deprotected using standard methods to give amine (II)(¡) which can then be reacted with cyanogen bromide to give the corresponding compound of formula (I)(¡). frC7C ίη / 77Π7 / E / YΙΛΙ Chemical Reaction 2 In another aspect, the present invention provides a compound, which is selected from formulas (II)(¡¡) and (III)(ii): R5R5 frCZC Ln / Zznz / E / YIAI where PG is a protecting group, preferably BOC or CBZ, and R1, R2, R3, R4 and R5 are as defined herein for the compound of formula (I) and its preferred embodiments, a tautomer thereof or a salt of said compound or tautomer. When the compound of formula (I)(¡¡) has the formula (IA)(¡¡), the formulas (II)(¡¡), (III)(¡¡) and (IV) are (IIA)(ii), (IIIA)(¡i) and (IVA), respectively. When the compound of formula (I)(¡¡) has the formula (IB)(ii), the formulas (II)(ii), (III)(¡i) and (IV) are (IIB)(¡¡), (IIIB)(¡¡) and (IVB)(i¡), respectively. The protecting groups are preferably selected from tert-butyloxycarbonyl (BOC), benzyloxycarbonyl (Cbz), p-methoxybenzyl carbonyl (MeOZ), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), carbamate, p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), trichloroethoxycarbonyl (Trac), 4-nitrobenzenesulfonyl (Nosil), and 2-nitrophenylsulfenyl (Nps). BOC and Cbz are the most preferred. Abbreviations br s broad singlet (NMR signal) MeOH methane CO carbon monoxide min minute(s) d doublet (NMR signal) N2 nitrogen dba dibenzylacetone NMP / V-methylpyrrolidone DCM dichloromethane rae racemic DMF / V-dimethylformamide rt room temperature DMSO dimethyl sulfoxide s singlet (NMR signal) ES electrosprayed SFC Supercritical fluid chromatography EtOAc ethyl acetate SOCI2 thionyl chloride h hour(s) TBD 1,5,7-triazabicyclo[4.4.0]dec-5-ene H2 hydrogen TEA triethylamine HPLC High-performance liquid chromatography TFA trifluoroacetic acid LCEM Liquid chromatography mass spectrometry THF tetrahydrofuran m multiplet (NMR signal) TsCl 4-toluenesulfonyl chloride MsCI methanesulfonyl chloride vol volumes MeCN acetonitrile frC7C ίη / 77Π7 / Ε / ΥΙΛΙ LCEM / HPLC / SFC methods Method C Mobile phase (A) 2 mM ammonium acetate and 0.1% formic acid in water (B) 0.1% formic acid in acetonitrile Instrument: Waters ACQUITY Class H with PDA and SQ detector Column: BEH C18 (50 mm x 2.1 mm) 1.7 pm Flow rate: 0.550 ml / min Column oven temperature: Ambient Run time: 3.0 min Gradient Time (min) Flow rate (ml / min) % A % B 0.01 0.55 98 2 0.30 0.55 98 2 0.60 0.55 22.6 22.6 1.10 0.55 25 75 2.00 0.60 0 100 2.70 0.60 0 100 2.71 0.55 98 2 3.00 0.55 98 2 Cl Method Mobile phase (A) 2 mM ammonium acetate and 0.1% formic acid in water (B) 0.1% formic acid in acetonitrile Instrument: Waters ACQUITY UPLC Class H with PDA and SQ detector Column: BEH C18 (50 mm x 2.1 mm) 1.7 pm Flow rate: 0.550 ml / min Column oven temperature: Ambient Run time: 2.0 min Gradient Time (min) Flow rate (ml / min) %A %B 0.00 0.55 95 5 0.60 0.60 30 70 0.80 0.65 10 90 1.10 0.65 0 100 1.70 0.65 0 100 1.71 0.55 95 5 2.00 0.55 95 5 bC7C ίΩ / 77Ω7 / Β / YILI Method C2 Mobile phase (A) 2 mM ammonium acetate and 0.1% formic acid in water and acetonitrile (90:10) (B) 0.1% formic acid in acetonitrile Instrument: Waters ACQUITY Class H with PDA and SQ detector Column: BEH C18 (50 mm x 2.1 mm) 1.7 pm Flow rate: 0.600 ml / min Column oven temperature: Ambient Run time: 1.5 min Gradient Time (min) Flow rate (ml / min) %A %B 0.01 0.600 95 5 0.40 0.600 0 100 0.50 0.650 0 100 1.30 0.700 0 100 1.31 0.600 95 5 1.50 0.600 95 5 Method H Mobile phase (A) 5 mM ammonium bicarbonate in water (B) 100% acetonitrile Instrument: Shimadzu Nexera UFLC with single quadrupole mass detector 2020 Column: Waters X-Bridge C18 (50 x 4.6 mm) 3.5 pm Column oven temperature: Ambient Flow rate: 1.0 ml / min Run time: 8.0 min Gradient Time (min) Flow rate (ml / min) % A % B 0.01 1.0 95 5 3.50 1.0 10 90 4.50 1.0 5 95 6.00 1.0 5 95 6.01 1.0 95 5 8.00 1.0 95 5 bCZC I η / 77Π7 / Β / YILI Method H1 Mobile phase (A) 5 mM ammonium bicarbonate in water (B) 100% acetonitrile Instrument: Shimadzu Nexera UFLC with single quadrupole mass detector 2020 Column: Waters X-Bridge C18 (50 x 4.6 mm) 3.5 pm Column oven temperature: Ambient Flow rate: 1.0 ml / min Run time: 6.0 min Gradient Time (min) Flow rate (ml / min) % A % B 0.01 1.0 95 5 2.80 1.0 15 85 3.50 1.0 5 95 5.00 1.0 5 95 5.01 1.0 95 5 6.00 1.0 95 5 Method J Mobile phase (A) 2 mM ammonium acetate and 0.1% formic acid in water (B) 0.1% formic acid in acetonitrile Instrument: Waters Acquity Class H with PDA and SQ detector Column: BEH C18 (50x2.1 mm) 1.7 pm Column oven temperature: Ambient Flow rate: 0.45 ml / min Run time: 8.0 min Gradient Time (min) Flow rate (ml / min) % A % B 0.01 0.45 98 2 0.50 0.45 98 2 5.00 0.45 10 90 6.00 0.45 5 95 7.00 0.45 5 95 7.01 0.45 98 2 8.00 0.45 98 2 bC7C ίη / 77Ω7 / Β / YILI Method F Mobile phase (A) 10 mM ammonium acetate in water (B) 100% acetonitrile Instrument: Agilent 1290 Infinity RRLC coupled with Agilent 6120 mass spectrometer and diode array detector Column: YMC TRAIT, C18 (150 mm x 4.6 mm), 5 pm Flow rate: 1.0 ml / min Column oven temperature: Ambient Run time: 12.0 min Gradient Time (min) Flow rate (ml / min) %A %B 0.01 1.0 90 10 5.00 1.0 10 90 7.00 1.0 0 100 11.00 1.0 0 100 11.01 1.0 90 10 12.00 1.0 90 10 Method P3 Mobile phase (A) 0.1% v / v (30% v / v aqueous ammonia) in water (B) 0.1% v / v (30% v / v aqueous ammonia) in acetonitrile Instrument: Waters e2695 HPLC with PDA detector Column: X-Bridge C8 (250 x 4.6 mm), 5 pm Column oven temperature: 25°C Flow rate: 1.0 ml / min Run time: 40.0 min Diluent: Acetonitrile: Water (8:2 v / v) Gradient Time (min) Flow rate (ml / min) % A % B 0.0 1.0 95 5 5.00 1.0 95 5 10.00 1.0 70 30 15.00 1.0 70 30 25.00 1.0 18.1 27.2 30.00 1.0 10 90 35.00 1.0 10 90 35.01 1.0 95 5 40.00 1.0 95 5 bC7C ίΩ / 77Ω7 / Β / YILI Method Y3 method used for analytical chiral SFC Mobile phase (A) Liquid carbon dioxide (B) 0.1% diethylamine in propan-2-ol:acetonitrile (50:50) Instrument: Waters SFC investigator and PDA detector Column: Chiralcel OJ-H (250 x 4.6 mm), 5 pm Flow rate: 4.0 ml / min Run time: 7.0 min Gradient Time (min) Flow rate (ml / min) %B start %B end 0 to 5 4.0 5 5 5 to 7 4.0 22.6 22.6 Method Y4 method used for analytical chiral SFC Mobile phase (A) Liquid carbon dioxide (B) 0.1% diethylamine in propan-2-ol:acetonitrile (50:50) Instrument: Waters SFC investigator and PDA detector Column: Chiralpak IH (250 x 4.6 mm), 5 pm Flow rate: 4.0 ml / min Run time: 10.0 min Gradient Time (min) Flow rate (ml / min) %B start %B end 0 to 5 4.0 5 5 5 to 10 4.0 22.6 22.6 Method Y5 method used for analytical chiral SFC Mobile phase (A) Liquid carbon dioxide (B) 0.1% diethylamine in propan-2-ol:acetonitrile (50:50) Instrument Waters SFC investigator and PDA detector Column Chiralpak AD-H (250 x 4.6 mm), 5 pm Flow rate 4.0 ml / min Run time 10.0 min Gradient Time (min) Flow rate (ml / min) %B start %B end 0 to 5 4.0 5 5 5 to 10 4.0 22.6 22.6 frCZC Ln / Zznz / E / YIAI Method Y6 method used for analytical chiral SFC Mobile phase (A) Liquid carbon dioxide (B) 0.1% diethylamine in methanol Instrument: Waters SFC investigator and PDA detector Column: Chiralcel OJ-H (250 x 4.6 mm), 5 pm Flow rate: 4.0 ml / min Run time: 7.0 min Gradient Time (min) Flow rate (ml / min) %B start %B end 0 to 5 4.0 5 22.6 5 to 7 4.0 22.6 22.6 Method Y7 method used for analytical chiral SFC Mobile phase (A) Liquid carbon dioxide (B) 0.1% diethylamine in propan-2-ol:acetonitrile (50:50) Instrument: Waters SFC investigator and PDA detector Column: Chiralcel OX-H (250 x 4.6 mm), 5 pm Flow rate: 4.0 ml / min Run time: 10.0 min Gradient Time (min) Flow rate (ml / min) %B start %B end Oa 5 4.0 5 22.6 5 to 10 4.0 22.6 22.6 Method Y8 method used for analytical chiral SFC Mobile phase (A) Liquid carbon dioxide (B) 0.1% diethylamine in propan-2-ol:acetonitrile (50:50) Instrument: Waters SFC investigator and PDA detector Column: Chiralpak IC (250 x 4.6 mm), 5 pm Flow rate: 4.0 ml / min Run time: 10.0 min Gradient Time (min) Flow rate (ml / min) %B start %B end 0 to 5 4.0 5 5 5 to 10 4.0 22.6 22.6 bCZC ίη / 77Π7 / E / YΙΛΙ Method Y12 Method used for analytical chiral SFC Mobile phase (A) Liquid carbon dioxide (B) 0.1% diethylamine in propan-2-ol:acetonitrile (50:50) Instrument: Waters SFC Investigator and PDA detector Column: Chiralcel OJ-H (250 x 4.6 mm), 5 pm Flow rate: 4.0 ml / min Run time: 8.0 min Gradient Time (min) Flow rate (ml / min) %B start %B end 0 to 5 4.0 5 22.6 5 to 8 4.0 22.6 22.6 Method Y15 Method used for analytical chiral HPLC Mobile phase (A) 0.1% Diethylamine in hexane (B) 0.1% Diethylamine in propan-2-ol:acetonitrile (70-30) Instrument Agilent 1260 Series HPLC and PDA Detector Column Chiralpak IC (250 x 4.6 mm), 5 pm Flow rate 1.0 ml / min Run time 25.0 min Gradient Time (min) Flow rate (ml / min) %A at start %B at finish 0.01 1.0 80 20 5.00 1.0 45 24.9 10.00 1.0 30 70 15.00 1.0 30 70 20.00 1.0 80 20 25.00 1.0 80 20 Method Y16 Method used for analytical chiral CFS Mobile phase (A) Liquid carbon dioxide (B) 0.1% diethylamine in methanol Instrument Waters SFC Investigator and PDA detector Column Chiralpak IB-N (250 x 4.6 mm), 5 pm Flow rate 4.0 ml / min Run time 8.0 min Gradient Time (min) Flow rate (ml / min) %B start %B end 0 to 5 4.0 5 22.6 5 to 8 4.0 22.6 22.6 frCZC Ln / Zznz / E / YIAI Intermediate A Ethyl 5-(5-Cyano-2-cyclopropoxyphenyl)oxazole-2-carboxylate (i) NaH, THF, 0°C, 2 hours; (ii) phenyltrimethylammonium tribromide, THF, from 0°C to room temperature, 16 hours; (iii) NaN(CHO)2, MeCN, 70°C, 1 hour, then concentrated HCl, 70°C, 16 hours; (iv) K2CO3, DCM, 0°C at room temperature, 2 hours; (v) POCI3, 100°C, 7 hours. Step (i) 3-Acetyl-4-acidpropoxybenzoniumtrile This reaction was performed in triplicate. To a stirred solution of cyclopropanol (CAS 16545-68-9, from Synthonix, 0.71 g, 12.27 mmol) in THF (6 mL), NaH (60% in oil, 0.49 g, 12.27 mmol) was added in portions at 0°C and stirred for 30 min. A solution of 3-acetyl-4-fluorobenzonitrile (CAS 267875-54-7, from Combi-blocks, 1.0 g, 6.13 mmol) in THF (4 mL) was added dropwise at 0°C, and the mixture was stirred at 0°C for 2 hours. The reaction mixture was combined with two more identical batches, poured into ice water (500 mL), and extracted with EtOAc (2 x 500 mL). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 12% EtOAc in n-hexanes) to produce 3-acetyl-4-cyclopropoxybenzenitryl (3.18 g, 15.82 mmol, 85% yield). LCEM: m / z without support; 2.50 (s, 3H), 0.81 0.93 (m, 4H). Step (i) 3-(2-Bromoacetyl)-4-ddopropoxybenzonitrile To a stirred solution of 3-acetyl-4-cyclopropoxybenzenitril (3.18 g, 15.82 mmol) in THF (40 mL) was added phenyltrimethylammonium tribromide (5.94 g, 15.82 mmol) at 0°C. The mixture was slowly heated to room temperature and stirred for 16 hours, then poured into water (200 mL) and extracted with EtOAc (2 x 200 mL). The combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure to give 3-(2-bromoacetyl)-4-cyclopropoxybenzenitril (4.3 g, 15.41 mmol, 97% yield). This crude material was used directly in the next step. LCEM: Method F, 6.61 min; EM: ES+: 297.0, 299.0 (M+18). Step (iii) 4-Cyclopropoxy-3-glycylbenzonitrite hydrochloride To a stirred solution of 3-(2-bromoacetyl)-4-cyclopropoxybenzonitrile (4.30 g, 15.41 mmol) in acetonitrile (43 mL), sodium diformylamide (1.75 g, 18.49 mmol) was added and heated at 70°C for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with MeOH (43 mL) and concentrated HCl (4.3 mL). The mixture was further heated at 70°C for 16 hours and then allowed to cool to room temperature. The mixture was concentrated under reduced pressure, and the residue was stirred with isopropyl alcohol (25 mL) to form a precipitate. The solid was collected by filtration under reduced pressure to give 4-cyclopropoxy-3-glycylbenzonitrile hydrochloride (5.0 g, quantitative yield). LCEM: Method C, 1.30 min; EM: ES+: 217.4. Step (iv) Ethyl 2-((2-(5-Cyano-2-cyclopropoxyphenyl)-2-oxoethH)amino)-2-oxoacetate To a stirred solution of HCl salt of 4-cyclopropoxy-3-glycylbenzenitrile (5.0 g, 19.80 mmol) in DCM (50 mL) K2CO3 (10.92 g, 79.2 mmol) was added at 0°C. Ethyloxalyl chloride (5.4 g, 4.43 mL, 39.60 mmol) was added dropwise at 0°C. The mixture was allowed to warm to room temperature, stirred for 2 hours, then poured into water (500 mL) and extracted with DCM (2 x 300 mL). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure to provide 2-((2-(5-cyano-2-cyclopropoxyphenyl)-2-oxoethyl)amino)-2-oxoacetate ethyl (5.0 g, quantitative yield). LCEM: Method C, 1.52 min; EM: ES+ 316.9. Step (v) Ethyl 5-(5-Cyano-2-cyclopropoxyphenyl)oxazole-2-carboxylate A stirred solution of ethyl 2-((2-(5-cyano-2-cyclopropoxyphenyl)-2-oxoethyl)amino)-2-oxoacetate (5.0 g, 15.81 mmol) in POCh (50 mL, 10 vol) was heated at 100°C for 7 hours. The mixture was cooled to room temperature, poured into ice water (500 mL), and extracted with EtOAc (2 x 200 mL). The combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was resuspended in MeOH (40 mL) and stirred at -78°C for 15 min. The solid was collected by reduced pressure filtration to provide 5-(5-cyano-2-cyclopropoxyphenyl)oxazol-2 frC7C ίη / 77P7 / E / YILI ethyl carboxylate (1.0 g, 3.35 mmol, 21% yield in three steps). LCEM: Method C, 1.77 min; EM: ES+: 299.5. frC7C ίη / 77Π7 / E / YΙΛΙ Intermediate B 5-(5-Cyano-2-methoxyphenH)oxazo / -2-carboxate ethyl / o Br CN CN (i) Zn(CN)2, Zn powder, PdCl2(dppf) DCM complex, DMA, 120°C, 16 hours; (ii) pyridinium tribromide, THF, from 0°C to room temperature, 16 hours; (iii) NaN(CHO)2, MeCN, 80°C, 5 hours, then concentrated HCl, 80°C, 16 hours; (iv) K2CO3, DCM, 0°C to room temperature, 4 hours; (v) POCh, 100°C, 16 hours. Step (i) 3-Acetyl-4-methoxybenzonitrile To a stirred solution of l-(5-bromo-2-methoxyphenyl)ethan-l-one (CAS 16740-73-1, from Combi-blocks, 60.0 g, 261.89 mmol) in DMA (600 mi) was added zinc cyanide (92.25 g, 785.67 mmol) and zinc powder (17.22 g, 261.89 mmol) at room temperature. The mixture was degassed with N2 gas for 30 min, followed by the addition of [l,l'-Bís(diphenylphosphino)ferrocene]dichloropalladium(II), complexed with DCM (10.69 g, 13.09 mmol). The mixture was heated at 120°C for 16 hours. The mixture was allowed to cool to room temperature, filtered through Celite Hyflow™, the filtrate poured into ice-cold water (800 mL), and extracted with EtOAc (2 x 1000 mL). The combined organic phases were washed with ice-cold water (4 x 1000 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography (60–120 µg silica gel, 15% EtOAc in n-hexanes) to produce 3-acetyl-4-methoxybenzenitrile (40.0 g, 228.57 mmol, 87% yield). LCEM: Method C, 1.52 min; EM: ES+: 176.08. Step (i) 3-(2-BromoacetH)-4-methoxybenzonitrHo To a stirred solution of 3-acetyl-4-methoxybenzenitrile (7.20 g, 41.14 mmol) in THF (72 mL) pyridinium tribromide (14.47 g, 45.25 mmol) at 0°C was added. The mixture was slowly heated to room temperature and stirred for 16 hours, then poured into water (400 mL) and extracted with EtOAc (2 x 400 mL). The combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure to give 3-(2-bromoacetyl)-4-methoxybenzenitrile (13.0 g, quantitative yield). This crude material was used directly in the next step. Step (ii) 3-Glycyl-4-methoxybenzonium hydrochloride To a stirred solution of 3-(2-bromoacetyl)-4-methoxybenzonitrile (10.5 g, 41.51 mmol) in acetonitrile (105 mL), sodium diformylamide (5.91 g, 62.26 mmol) was added, and the mixture was heated to 80°C for 8 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was diluted with MeOH (105 mL) and concentrated HCl (10.5 mL). The mixture was further heated to 80°C for 16 hours and then allowed to cool to room temperature. The mixture was concentrated under reduced pressure and the residue was stirred with isopropyl alcohol (40 ml) to form a precipitate, which was collected by filtration under reduced pressure to produce 3-glycyl-4-methoxybenzonitrile hydrochloride (9.0 g, 39.73 mmol, 95% yield). LCEM: Method C2, 0.40 min; MS: ES+: 191.0. Step (iv) Ethyl 2-((2-(5-Clano-2-methoxyphenyl)-2-oxoethyl)amino)-2-oxoacetate To a stirred solution of 3-glycyl-4-methoxybenzonitrile hydrochloride (HCl) (9.0 g, 39.73 mmol) in DCM (90 mL) K₂CO₃ (21.93 g, 158.92 mmol) was added at 0°C. Ethyloxalyl chloride (10.84 g, 8.89 mL, 79.46 mmol) was added dropwise at 0°C. The mixture was allowed to warm to room temperature and stirred for 4 hours. The mixture was poured into water (900 mL) and extracted with DCM (2 x 500 mL). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure to provide ethyl 2-((2-(5-cyano-2-methoxyphenyl)-2-oxoethyl)amino)-2-oxoacetate (9.0 g, 31.03 mmol, 78% yield). LCEM: Method C, 1.34 min; EM: ES+ 291.1. Step (v) Ethi / o 5-(5-Cyano-2-methoxyphenH)oxazole-2-carboxylate A stirred solution of ethyl 2-((2-(5-cyano-2-methoxyphenyl)-2-oxoethyl)amino)-2-oxoacetate (1.2 g, 4.14 mmol) in POCl3 (12 mL, 10 vol) was heated at 100°C for 2 hours. The mixture was cooled to room temperature, poured into ice water (200 mL), and extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with saturated NaHCCh solution (3 x 100 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by instant column chromatography (silica gel, 32% EtOAc in n-hexanes) to produce ethyl 5-(5-cyano-2-methoxyphenyl)oxazol-2-carboxylate (0.60 g, 2.20 mmol, 53% yield). LCEM: Method C, 1.53 min; EM: ES+: 272.6. Intermediate C Ethyl 5-(5-Bromo-2-(trifluoromethoxy)phenyl)oxazole-2-carboxylate frC7C ίη / 77Ω7 / Β / ΥΙΛΙ frCZC Ln / Zznz / E / YIAI (i) HATU, DIPEA, THF, from 0°C to room temperature, 3 hours; (ii) methyl magnesium bromide, THF, -10°C to 0°C, 4 hours; (iii) phenyltrimethylammonium tribromide, MeCN, from 0°C to room temperature, 9 hours; (iv) NaN(CHO)2, MeCN, 80°C, 1 hour, concentrated HCI luego, 80°C, 3 hours; (v) K2CO3, DCM, 0°C at room temperature, 3 hours; (vi) POCI3, 110°C, 16 hours. Step (i) 5-Bromo-N-methoxy-N-metH-2-(trifluoromethoxy)benzamide To a stirred solution of 5-bromo-2-(trifluoromethoxy)benzoic acid (CAS 40364647-9, from Combi-blocks, 10.0 g, 35.08 mmol) in THF (100 mL), DIPEA (13.57 g, 17.9 mL, 105.25 mmol) and HATL (20.0 g, 52.62 mmol) were added in portions at 0°C. After 30 min, N,O-dimethylhydroxylamine HCl (4.45 g, 45.61 mmol) was added at 0°C. The mixture was slowly heated to room temperature and stirred for 3 hours, then poured into ice water (300 mL) and extracted with EtOAc (3 x 150 mL). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure to produce 5-bromo-N-methoxy-N-methyl-2-(trifluoromethoxy)benzamide (12.2 g, quantitative yield). This crude material was used directly in the next step. LCEM: Method C, 1.69 min; MS: ES+: 327.8, 329.8. Step (Π l-(5-Bromo-2-(trifluoromethoxy)phenyl)ethane-l-one To a stirred solution of 5-bromo-N-methoxy-N-methyl-2-(trifluoromethoxy)benzamide (12.2 g, 37.31 mmol) in THF (130 mL) methylmagnesium bromide (3 M in diethyl ether, 24.9 mL, 74.62 mmol) was added dropwise at -10°C. The mixture was heated slowly to 0°C and stirred for 4 hours, then poured into a saturated solution of NH4Cl (300 mL) and extracted with EtOAc (3 x 200 mL). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure to give 1-(5-bromo-2-(trifluoromethoxy)phenyl)ethan-1-one (10.0 g, quantitative yield). This raw material was used directly in the next step. LCEM: Method C, m / z without support;ΧΗ NMR (400 MHz, CDCI3) δ ppm: 7.92 (s, 1H), 7.67 - 7.71 (m, 1H), 7.24 (d, 7 = 8.0 Hz, 1H), 2.62 (s, 3H). Step (iii) To a stirred solution of 5-bromo-2-fluoro-4-hydroxybenzonitrite (5.08 g, 23.63 mmol) in DMF (30 mL) at 0°C, K₂CO₃ (6.52 g, 47.26 mmol) was added. After 10 min, methyl iodide (5.03 g, 2.21 mL, 35.45 mmol) was added dropwise at 0°C. The mixture was heated slowly to room temperature and stirred for 3 hours, then poured into water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic phases were dried over Na₂SCl and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 2% EtOAc in n-hexanes) to produce 5-bromo-2-fluoro-4-methoxybenzonitrile (5.70 g, quantitative yield). LCEM: m / z without support;2H NMR (400 MHz, DMSO-úG) δ ppm: 8.30 (d, J= 7.2 Hz, 1H), 7.46 (d, J = 12.0 Hz, 1H), 4.01 (s, 3H). Step (iii) 5-(2-Bromoacetyl)-2-fluoro-4-methoxybenzonitrile A stirred solution of 5-bromo-2-fluoro-4-methoxybenzonitrile (5.70 g, 24.89 mmol) and tributyl(1-ethoxyvinyl)tin (CAS 97674-02-7, from Combi-blocks, 13.46 g, 37.34 mmol) in 1,4-dioxane (70 mL) was degassed with N2 for 15 min, followed by the addition of bis(triphenylphosphine)palladium(II) dichloride (0.87 g, 1.24 mmol) at room temperature. The mixture was heated to 100°C for 3 hours. The mixture was cooled to 0°C and THF:water (2:1, 120 mL) was added. Nbromosuccinimide (8.85 g, 49.78 mmol) was added at 0°C. The mixture was stirred at 0°C for 10 min, then poured into water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 2% EtOAc in n-hexanes) to produce 5-(2-bromoacetyl)2-fluoro-4-methoxybenzonitrile (6.3 g, 23.25 mmol, 98% yield in two steps). LCEM: m / z without support; Step (iv) 2-fluoro-5-glycyl-4-methoxybenzonitrite hydrochloride To a stirred solution of 5-(2-bromoacetyl)-2-fluoro-4-methoxybenzonitrile (6.30 g, 23.25 mmol) in acetonitrile (65 mL) sodium diformylamide (25.85 g, 27.9 mmol) was added, and the mixture was heated to 80°C for 2 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was diluted with MeOH (65 mL) and concentrated HCl (6.5 mL). The mixture was heated to 80°C for 16 hours, then allowed to cool to room temperature. The mixture was concentrated under reduced pressure and the residue was stirred with isopropyl alcohol (100 ml) to form a precipitate that was collected by filtration under reduced pressure to produce 2-fluoro-5-glycyl-4-methoxybenzonitrile hydrochloride (5.3 g, quantitative yield). LCEM: Method H, 1.96 min; EM: ES+: 209.1. frC7C ίη / 77Π7 / E / YΙΛΙ Step (v) Ethyl 2-((2-(5-Cyano-4-fluoro-2-methoxyphenyl)-2-oxoeth)amino)-2-oxoacetate To a stirred solution of HCl salt of 2-fluoro-5-glycyl-4-methoxybenzenitrile (5.30 g, 21.67 mmol) in DCM (60 ml) K2CO3 (11.96 g, 86.68 mmol) was added at 0°C. Ethyloxalyl chloride (5.89 g, 4.83 ml, 43.34 mmol) was added dropwise at 0°C. The mixture was allowed to warm to room temperature, stirred for 2 hours, then poured into water (150 ml) and extracted with EtOAc (2 x 150 ml). The combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure to provide ethyl 2-((2-(5-cyano-4-fluoro-2-methoxyphenyl)-2-oxoethyl)amino)-2-oxoacetate (4.20 g, 13.63 mmol, 58% yield in two steps). LCEM: Method C, 1.50 min; EM: ES+ 309.4. Step (vi) Ethyl 5-(5-Cyano-4-fluoro-2-methoxyphenyl)oxazole-2-carboxylate A stirred solution of ethyl 2-((2-(5-cyano-4-fluoro-2-methoxyphenyl)-2-oxoethyl)amino)-2-oxoacetate (4.2 g, 13.63 mmol) in POCl3 (42 mL, 10 vol) was heated at 100°C for 5 hours. The mixture was cooled to room temperature, poured into ice water (100 mL), and extracted with EtOAc (2 x 150 mL). The combined organic phases were washed with saturated NaHCO3 solution (2 x 100 mL), dried over NaZSO4, and concentrated under reduced pressure. The residue was resuspended in MeOH (30 mL) and stirred at -78°C for 15 min. The solid was collected by reduced pressure filtration to provide ethyl 5-(5-cyano-4-fluoro-2-methoxyphenyl)oxazol-2-carboxylate (1.60 g, 5.51 mmol, 40% yield). LCEM: Method C, 1.63 min; EM: ES+: 291.2. EXAMPLE 1 frCZC Ln / Zznz / E / YIAI 5-(5-Cyano-2-ddopropoxyphenyl)-N-((3R,5R)-l-dano-5-methylpyrrolidin-3-¡l)oxazole-2carboxamide frCZC Ln / Zznz / E / YIAI (i) TBD, THF, from 0°C to room temperature; (ii) TFA, DCM, from 0°C to room temperature; (iii) K2CO3, CNBr, THF, from O°C to room temperature. Step (i) (2R,4R)-4-(5-(5-Cyano-2-cyclopropoxyphen¡l)oxazole-2-carboxam¡do)-2-methylp¡rrolidin-lcarboxylate tere-butyl To a stirred solution of ethyl 5-(5-cyano-2-cyclopropoxyphenyl)oxazol-2-carboxylate (0.60 g, 2.01 mmol) and tert-butyl (2R,4R)-4-amino-2-methylpyrrolidine-carboxylate (CAS 348165-639, 0.60 g, 3.02 mmol) in THF (10 mL) TBD (0.42 g, 3.02 mmol) was added in portions at 0°C. The mixture was heated to room temperature and stirred for 1 hour, then poured into water (70 mL) and extracted with EtOAc (2 x 70 mL). The combined organic phases were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by instant column chromatography (silica gel, 30% EtOAc in z^hexanes) to produce (2R,4R)-4-(5-(5-cyano-2-cyclopropoxyphenyl)oxazol-2-carboxamido)-2-methylpyrrolidine-l-carboxylate of tere-butyl (0.32 g, 0.71 mmol, 35% yield). LCEM: Method C, 1.86 min; EM: ES- 451.4. Step (i) 5-(5-Cyane-2-cyclopropoxyphenyl)-N-((3R,5R)-5-methylpyrrolidine-3-yl)oxazol-2-carboxamide To a stirred solution of (2R,4R)-4-(5-(5-cyano-2-cyclopropoxyphenyl)oxazol-2-carboxamido)-2-methylpyrrolidine-1-carboxylate of tere-butyl (0.31 g, 0.68 mmol) in DCM (7 ml) TFA (0.93 ml, 3 vol) was added dropwise at 0°C. The mixture was allowed to warm to room temperature and stirred for 45 min, then concentrated under reduced pressure to produce TFA salt of 5-(5-cyano-2-cyclopropoxyphenyl)-N-((3R,5R)-5-methylpyrrolidine-3-yl)oxazol-2-carboxamide (0.3 g, 0.64 mmol, 94% yield). LCEM: Method C, 1.38 min; EM: ES+ 353.3. Step (iii) 5-(5-Cyano-2-cyclopropoxyphenyl)-N-((3R,5R)-l-cyano-5-methylpyrrolydin-3-l)oxazole-2carboxamide To a stirred solution of TFA salt of 5-(5-cyano-2-cyclopropoxyphenyl)-N-((3R,5R)-5-methylpyrrolidine-3-1)oxazol-2-carboxamide (0.3 g, 0.64 mmol) in THF (8 mL), K₂CO₃ (0.27 g, 1.93 mmol) was added at room temperature and the mixture was stirred for 10 min. Cyanogen bromide (0.07 g, 0.64 mmol) was added at 0°C and the mixture was stirred at room temperature for 45 min, then poured into water (70 mL) and extracted with EtOAc (2 x 70 mL). The combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by instant column chromatography (silica gel, 40% EtOAc in n-hexanes) to produce 5-(5-cyane-2-cyclopropoxyphenyl)-N-((3R,5R)-cyane-5-methylpyrrolidine-3-1)oxazol-2-carboxamide (0.1 g, 0.27 mmol, 42% yield). LCEM: Method H, 2.96 min; EM: ES+ 378.0; 1H), 4.21 - 4.23 (m, 1H), 3.89 - 3.95 (m, 1H), 3.77 - 3.81 (m, 1H), 3.43 - 3.46 (m, 1H), 2.16 - 2.18 (m, 1H), 1.76 - 1.83 (m, 1H), 1.26 (d, 7= 6.4 Hz, 3H), 0.92 (s, 4H). SFC quiral: Method Y5, 5.18 min. frC7C ίη / 77Π7 / Ε / ΥΙΛΙ EXAMPLE 2 5-(5-C¡ano-2-cidopropox¡phenyl)-N-((3R,5S)-lc¡ano-5-(methoxymethyl)p¡rrolidin-3¡l)oxazol-2-carboxamida (i) TBD, THF, de 0°C at room temperature; (¡i) TFA, DCM, de 0°C at room temperature; (iii) K2CO3, CNBr, THF, at 0°C at room temperature. Paso (i) (2S,4R)-4-(5-(5-Cyano-2-ddopropoxyphenyl)oxazol-2-carboxamido)-253 (methoxymethyl)pyrrolidin-l-carboxylate de tere-butyl To a stirred solution of ethyl 5-(5-cyano-2-cyclopropoxyphenyl)oxazol-2-carboxylate (0.50 g, 1.67 mmol) and tert-butyl-(2S,4R)-4-amino-2-(methoxymethyl)pyrrolidine-1-carboxylate (CAS 1207853-53-9, 0.46 g, 2.01 mmol) in THF (8 mL), TBD (0.35 g, 2.51 mmol) was added in portions at 0°C. The mixture was heated to room temperature and stirred for 3 hours, then poured into water (100 mL) and extracted with EtOAc (2 x 80 mL). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by instant column chromatography (silica gel, 55% EtOAc in n-hexanes) to produce tert-butyl (2S,4R)-4-(5-(5-cyane-2-cyclopropoxyphenyl)oxazol-2-carboxamido)-2-(methoxymethyl)pyrolidinyl-carboxylate (0.32 g, 0.66 mmol, 39% yield). LCEM: Cl Method, 1.35 min; EM: ES+ 483.4. Step (i) 5-(5-Cyano-2-cyclopropoxyphenyl)-N-((3R,5S)-5-(methoxymethyl)pyrrolidin-3-yl)oxazole-2carboxamide A stirred solution of (2S,4R)-4-(5-(5-cyano-2-cyclopropoxyphenyl)oxazol-2-carboxamido)-2-(methoxymethyl)pyrrolidine-1-carboxylate tert-butyl (0.32 g, 0.66 mmol) in DCM (8 ml) was added dropwise to TFA (0.96 ml, 3 vol) at 0°C. The mixture was allowed to warm to room temperature and stirred for 1 hour, then concentrated under reduced pressure to produce TFA salt of 5-(5-cyano-2-cyclopropoxyphenyl)-N-((3R,5S)-5-(methoxymethyl)pyrrolidine-3-1)oxazol-2-carboxamide (0.32 g, 0.64 mmol, 97% yield). LCEM: Method Cl, 1.06 min; EM: ES+ 383.4. Step (ii) 5-(5-C¡ano-2-cidopropoxy¡phenyl)-N-((3R,5S)-l-cyano-5-(methoxy¡methyl)pyrro¡din-3¡l)oxazole-2-carboxamide h a stirred solution of TFA salt of 5-(5-cyano-2-cyclopropoxyphenyl)-N-((3R,5S)-5(methoxymethyl)pyrrolidin-3-yl)oxazole-2-carboxamide (032 g, 0.64 mmol) in THF (8 ml) K2CO3 (0.27 g, 1.93 mmol) was added at room temperature and stirred for 10 min. Cyanogen bromide (0.07 g, 0.64 mmol) was added at 0°C. The mixture was stirred at room temperature for 1 hour, then poured into water (80 mL) and extracted with EtOAc (2 x 80 mL). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 70% EtOAc in hexanes) to produce 5-(5-cyano-2-cyclopropoxyphenyl)-N-((3R,5S)-cyano-5-(methoxymethyl)pyrrolidine-3-yl)oxazol-2-carboxamide (0.10 g, 0.24 mmol, 38% yield). LCEM: Metodo H, 2.94 min; EM: ES+ 408.2;7H RMN (400 MHz, DMSO-rá) δ ppm: 9.32 (d, 7 = 6.4 Hz, 1H), 8.26 (d, 7- 1.6 Hz, 1H), 7.98 (d, 7 = 8.8 Hz, 1H), 7.69 -7.70 (m, 2H), 4.47 frC7C ίη / 77Ω7 / Β / ΥΙΛΙ - 4.59 (m, 1H), 4.19 - 4.27 (m, 1H), 4.00 - 4.10 (m, 1H), 3.70 - 3.74 (m, 1H), 3.39 - 3.51 (m, 3H), 3.36 (s, 3H), 2.11 - 2.18 (m, 1H), 1.98 - 2.03 (m, 1H), 0.92 (s, 4H). SFC circuit: Metodo Y3, 3.56 min. Paso (iiñ sintesis alternativa 5-(5-C¡ano-2-dclopropox¡fenH)-N-((3R,5S)-lc¡ano-5-(metoximetil)p¡rrol¡d¡n-3il)oxazol-2-carboxamida In a nitrogen atmosphere, a stirred solution of TFA salt of 5-(5-cyano-2-cyclopropoxyphenyl)-N-((3R,5S)-5-(methoxymethyl)pyrrolidine-3-yl)oxazol-2-carboxamide (600.0 g, 1209.67 mmol) in THF (6 L) was mixed with K2CO3 (500.80 g, 3629.01 mmol) at room temperature in a nitrogen atmosphere and stirred for 15 to 20 min. A solution of cyanogen bromide (153.87 g, 1451.60 mmol) in THF (1.2 L) at 0°C was added dropwise. The mixture was allowed to warm to room temperature and stirred for 1 hour at room temperature. The progress of the reaction was monitored by TLC (mobile phase: 50% EtOAc in n-hexanes, product Rf 0.05; 10% MeOH / DCM product Rf 0.4). The mixture was quenched with water (3 L) and extracted with EtOAc (3 x 6 L). The combined organic phases were washed with brine solution (1.5 L), dried over anhydrous Na2SO4, and concentrated under reduced pressure to produce crude 5-(5-cyano-2-cyclopropoxyphenyl)-N-((3R,5S)-1-cyano-5-(methoxymethyl)pyrrolidine-3-yl)oxazol-2-carboxamide (505 g).The crude material (505 g) was suspended in IPA (5 L, 10 vol) and heated to 80°C to obtain a clear solution. The mixture was allowed to cool slowly to room temperature and then to 0°C to form a crystalline solid which was collected by filtration under reduced pressure, washed with cold IPA (505 mL) and dried under vacuum at 50°C to produce 5-(5-cyano-2-cyclopropoxyphenyl)N-((3R,5S)-1-cyano-5-(methoxymethyl)-pyrrolidine-3-1)oxazol-2-carboxamide as a white crystalline solid (400.0 g, 982.80 mmol). The IPA recrystallization material (400 g) was suspended in IPA (10 L, 25 vol), charcoal (100 g) was added, and the mixture was heated to 80°C for 1 hour. The hot mixture was filtered through Celite Hyflow™ and washed with hot IPA (800 ml, 2 vol). The filtrate was allowed to cool slowly to room temperature and then to 0°C to form a crystalline solid which was collected by suction filtration, washed with cold IPA (400 L, 1 vol) and vacuum dried at 50°C to produce 5-(5-cyano-2-cyclopropoxyphenyl)-N-((3R,5S)-1-cyano-5-(methoxymethyl)pyrrolidine-3-yl)oxazol-2-carboxamide as a white crystalline solid (320.0 g, 786.24 mmol, 63% yield). LCEM: Hl Method, 2.81 min, EM: ES+ 408.2; HPLC: Method P3, 24.22 min; Quiral HPLC: Method Y, 28.97 min; 3= 8.8 Hz, 1H), 7.65 (s, 1H), 4.48 - 4.58 (m, 1H), 4.18 - 4.22 (m, 1H), 4.01 - 4.07 (m, 1H), 3.70 - 3.74 (m, 1H), 3.40 - 3.51 (m, 3H), 3.35 (s, 3H), 2.12 - 2.18 (m, 1H), 1.97 - 2.03 (m, 1H), 0.88 - 0.96 (m, 4H); HPLC quiral: Method Y15, 15.11 min; 99.8% ee; HPLC: Method Y26, 27.87 min; maximum DSC temperature (fusion) - 132.7°C; High resolution EM: ES- 406.1521 (exact mass calculated 407.1594). The XRPD data in the following frC7C ίη / 77Π7 / Ε / ΥΙΛΙ panel were prepared in a Bruker AXS D8 Advance: Cu,ko: Kal(Á): 1.540598; Ka2(Á): 1.544426; bC7C ίΠ / 77Ω7 / Ε / ΥΙΛΙ Κα2 / Κα1=0.50. Peak Angle 2-Theta° Angstrom Intensity Value % Peak Angle 2-Theta° Angstrom Intensity Value % 1 6.1019 14.4829 16.4 25 23.9799 3.7080 38.9 2 9.1518 9.6553 4.7 26 24.1583 3.6810 32.8 3 9.9967 8.8411 2.6 12.2 24.8866 3.5749 32.0 400 10.3379 8.5500 3.5 28 25.0830 3.5475 26.4 5. 10.9032 8.1080 10.8 29 25.5443 3.4843 17.3 6 11.3251 7.8069 13.1 30 26.1307 3.4075 15.6 7 12.2208 7.2366 100.0 31 26.4530 3.3667 14.6 8 13.4827 6.5620 17.1 32 27.1747 3.2789 10.7 9 14.2466 6.2118 23.8 33 27.4419 3.2476 9.4 10 14.7766 5.9902 22.5 34 27.8223 3.2040 9.2 11 15.3381 5.7722 45.2 35 28.3928 3.1409 7.7 12 15.7537 5.6208 41.9 36 28.7031 3.1077 6.8 13 15.9125 5.5651 28.3 37 29.4677 3.0288 12.0 14 16.6015 5.3356 10.7 17.2 29.8598 2.9899 11.1 15 17.5713 5.0433 29.2 39 30.9607 2.8860 12.4 16 18.2473 4.8579 22.0 18.1 32.3735 2.7632 6.9 17 18.8069 4.7146 30.6 41 32.8863 2.7213 7.2 18 19.5552 4.5359 9.7 42 33.5633 2.6679 5.9 19 20.0896 4.4164 53.5 43 34.3472 2.6088 6.2 20 20.7701 4.2732 13.1 44 35 .8828 2.5006 6.5 21 21.3811 4.1525 13.7 20.4 37.2616 2.4112 6.6 22 21.8959 4.0560 22.1 46 38.7662 2.3210 5.2 23 22.7766 3.9011 45.7 47 39.5119 2.2789 5.4 24 23.5065 3.7816 26.8. Recristalización alternativa 5-(5-C¡ano-2-cyclopropoxy¡phenH)-N-((3R,5S)-lc¡ano-5-(methoxymethyl)p¡rrol¡d¡n-3yl)oxazol-2-carboxamida Crude 5-(5-Cyano-2-cyclopropoxyphenyl)-N-((3R,5S)-1-cyano-5-(methoxymethyl)pyrrolidine-3-yl)oxazol-2-carboxamide (134.4 g, 98.9% purity by LC) was suspended in ethanol (1340 mL, 10 vol) and heated from 55 to 65°C to form a brown solution. The mixture was allowed to cool to 40 to 45°C and seeding material (135 mg) from a smaller-scale analogous batch was added, and the mixture was stirred at 40 to 45°C for 30 min. The mixture was cooled to room temperature and stirred overnight. The beige suspension was filtered and the solid was collected, washed with ethanol (2 x 260 ml), the filter cake was dried and then dried at 60°C overnight to produce 5-(5-cyano-2-cyclopropoxyphenyl)-N-((3R,5S)-l-cyano-5-(methoxymethyl)pyrrolidine-3-l)oxazol-215 carboxamide as an off-white solid (116.2 g, 86% yield of crude). EM: ES+ 408.2; Y NMR (400 MHz, CDCh) δ ppm: 8.24 (d, J = 2.0 Hz, 1H), 7.66 (dd, = 8.8, 2.0 Hz, 1H), 7.56 (s, 1H), 7.47 (d, J = 8.4 Hz, 1H), 4.68 - 4.75 (m, 1H), 3.97 - 4.00 (m, 2H), 3.83 - 3.85 (m, 1H), 3.60 - 3.66 (m, 1H), 3.45 - 3.53 (m, 2H), 3.42 (s, 3H), 2.24 - 2.32 (m, 1H), 2.09 - 2.15 (m, 1H), 0.89 - 1.02 (m, 4H); residual solvents by NMR = EtOH (2260 ppm); HPLC purity of 99.6%; DSC peak temperature (melting) = 86.96°C. Example 2 was formulated as an aqueous suspension containing 0.1% (w / v) Tween-80 and 0.5% (w / v) hydroxypropyl methylcellulose. frC7C ίη / 77Π7 / E / YΙΛΙ EXAMPLE 3 5-(5-Cyano-2-cidopropoxyphenyl)-N-((3R,5S)-lcyano-5-(fluorometH)pyrrolidin-3yl)oxazole-2-carboxamide (i) TBD, THF, from 0°C to room temperature; (i) TFA, DCM, from 0°C to room temperature; (ii) K2CO3, CNBr, THF, from 0°C to room temperature. Step (i) tert-butUo (2S,4R)-4-(5-(5-Cyano-2-ddopropoxyphenyl)oxazole-2-carboxamido)-2(fluoromethH)pyrrolidine-l-carboxylate To a stirred solution of ethyl 5-(5-cyano-2-cyclopropoxyphenyl)oxazol-2-carboxylate (0.15 g, 0.50 mmol) and tert-butyl (2S,4R)-4-amino-2-(fluoromethyl)pyrrolidine-1-carboxylate (CAS 1207853-03-9, from Angene, 0.11 g, 0.50 mmol) in THF (4 mL) TBD (0.07 g, 0.50 mmol) was added in portions at 0°C. The mixture was heated to room temperature and stirred for 8 hours, then poured into water (40 mL) and extracted with EtOAc (2 x 50 mL). The combined organic phases were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by instant column chromatography (silica gel, 51% EtOAc in n-hexanes) to produce (2S,4R)-4-(5-(5-cyane-2-cyclopropoxyphenyl)oxazol-2-carboxamido)-2-(fluoromethyl)pyrrolidine n-1-carboxylate of tere-butyl (0.09 g, 0.19 mmol, 37% yield). LCEM: Method C, 1.76 min; EM: ES- 469.1. Step (i) 5-(5-Cyano-2-cyclopropoxyphenyl)-N-((3R,5S)-5-(fluoromethyl)pyrrolidin-3-yl)oxazole-2carboxamide To a stirred solution of (2S,4R)-4-(5-(5-cyano-2-cyclopropoxyphenyl)oxazol-2-carboxamido)-2-(fluoromethyl)pyrrolidine-3-1-carboxylate of tere-butyl (0.09 g, 0.19 mmol) in DCM (5 ml) TFA (0.9 ml, 10 vol) at 0°C was added dropwise. The mixture was allowed to warm to room temperature and stirred for 1 hour, then concentrated under reduced pressure to produce TFA salt of 5-(5-cyano-2-cyclopropoxyphenyl)-N-((3R,5S)-5-(fluoromethyl)pyrrolidine-3-1)oxazol-2-carboxamide (0.16 g, quantitative yield). LCEM: Method C, 1.35 min; EM: ES- 368.9. Step (iii) 5-(5-Cyano-2-cidopropoxyphenyl)-N-((3R,5S)-lcyano-5-(fluorometH)pyrrolidin-3yl)oxazole-2-carboxamide To a stirred solution of TFA salt of 5-(5-cyano-2-cyclopropoxyphenyl)-N-((3R,5S)-5-(fluoromethyl)pyrrolidine-3-1)oxazol-2-carboxamide (0.15 g, 0.32 mmol) in THF (5 mL), K₂CO₃ (0.13 g, 0.96 mmol) was added at room temperature, and the mixture was stirred for 10 min. Cyanogen bromide (0.03 g, 0.32 mmol) was added at 0°C. The mixture was stirred at room temperature for 1 hour, then poured into water (40 mL) and extracted with EtOAc (2 x 40 mL). The combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 69% EtOAc in 7-hexanes) to produce 5-(5cyane-2-cyclopropoxyphenyl)-N-((3R,5S)-l-dane-5-(fluoromethyl)-pyrrolidine-3-yl)oxazol-2-carboxamide (0.01 g, 0.03 mmol, 16% yield in two steps). LCEM: Method H, 2.96 min; EM: ES+ 396.1; NMR (400 MHz, DMSO-gú) δ ppm: 9.39 (d, 7= 6.8 Hz, 1H), 8.25 (s, 1H), 7.98 (d, J = 7.2 Hz, 1H), 7.68 - 7.70 (m, 2H), 4.41 - 4.69 (m, 3H), 4.10 - 4.26 (m, 2H), 3.61 - 3.80 (m, 1H), 3.43 - 3.53 (m, 1H), 2.12 - 2.25 (m, 1H), 1.95 - 2.07 (m, 1H), 0.92 (s, 4H). SFC quiral: Method Y4, 4.96 min. frC7C ίη / 77Ω7 / Β / ΥΙΛΙ EXAMPLE 4 frC7C ίη / 77Π7 / Ε / ΥΙΛΙ 5-(5-C¡ano-2-methoxifenH)-N-((3R,5R)-l-cyano-5-methylpyrrolidin-3-H)oxazol-2carboxamida (i) TBD, THF, de 0°C at room temperature; (¡i) TFA, DCM, de 0°C at room temperature; (ü¡) K2CO3, CNBr, THF, at 0°C at room temperature. Paso (i) (2R,4R)-4-(5-(5-Ciano-2-methoxifen¡l)oxazol-2-carboxam¡do)-2-met¡lp¡rrolidina-lcarboxüato de terc-butUo To a stirred solution of ethyl 5-(5-cyane-2-methoxyphenyl)oxazol-2-carboxylate (0.5 g, 1.84 mmol) and tert-butyl (2R,4R)-4-amino-2-methylpyrrolidine-carboxylate (CAS 348165-63-9, 0.37 g, 1.84 mmol) in THF (10 mL) TBD (0.38 g, 2.76 mmol) was added in portions at 0°C. The mixture was heated to room temperature and stirred for 2 hours, then poured into water (100 mL) and extracted with EtOAc (2 x 70 mL). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by instant column chromatography (silica gel, 30% EtOAc in 7-hexanes) to produce (2R,4R)-4-(5-(5-cyano-2-methoxyphenyl)oxazol-2-carboxamido)-2-methylpyrrolidine-1-carboxylate of tere-butyl (0.30 g, 0.70 mmol, 38% yield). LCEM: Method C, 1.61 min; EM: ES- 425.1. Step (i) 5-(5-Cyano-2-methoxyphenH)-N-((3R,5R)-5-methylpyrrolidine-3-H)oxazole-2-carboxamide To a stirred solution of (2R,4R)-4-(5-(5-cyano-2-methoxyphenyl)oxazol-2-carboxamido)-2-methylpyrrolidine-3-1-carboxylate of tert-butyl (0.30 g, 0.70 mmol) in DCM (6 ml) TFA (0.9 ml, 3 vol) at 0°C was added dropwise. The mixture was allowed to warm to room temperature and stirred for 1 hour, then concentrated under reduced pressure to produce TFA salt of 5-(5-cyano-2-methoxyphenyl)-N-((3R,5R)-5-methylpyrrolidine-3-1)oxazol-2-carboxamide (0.30 g, 0.68 mmol, 97% yield). LCEM: Method C, 1.22 min; EM: ES+ 327.1. Step (iii) 5-(5-Cyano-2-methoxyphenyl)-N-((3R,5R)-l-dano-5-methylpyrrolidin-3-yl)oxazole-2carboxamide To a stirred solution of TFA salt of 5-(5-cyano-2-methoxyphenyl)-N-((3R,5R)-5-methylpyrrolidine-3-1)oxazol-2-carboxamide (0.30 g, 0.68 mmol) in THF (7 mL), K₂CO₃ (0.28 g, 2.04 mmol) was added at room temperature and stirred for 10 min. Cyanogen bromide (0.07 g, 0.68 mmol) was added at 0°C. The mixture was stirred at room temperature for 1 hour, then poured into water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by instant column chromatography (silica gel, 1% MeOH in DCM) to produce 5-(5-cyano-2-methoxyphenyl)-N((3R,5R)-l-cyano-5-methylpyrrolidine-3-yl)oxazol-2-carboxamide (0.10 g, 0.28 mmol, 42% yield). LCEM: Method H, 2.73 min; EM: ES+ 352.2; Ή NMR (400 MHz, DMS0-6Ó) δ ppm: 9.35 (d, J= 6.8 Hz, 1H), 8.25 (s, 1H), 7.95 (d, J = 7.2 Hz, 1H), 7.84 (s, 1H), 7.41 (d, J = 8.4 Hz, 1H), 4.47 - 4.57 (m, 1H), 4.08 (s, 3H), 3.89 - 3.94 (m, 1H), 3.76 - 3.80 (m, 1H), 3.42 - 3.49 (m, 1H), 2.16 - 2.20 (m, 1H), 1.76 - 1.83 (m, 1H), 1.26 (d, J = 6.4 Hz, 3H). SFC quiral: Method Y6, 3.76 min. EXAMPLE 5 5-(5-C¡ano-2-methoxyphenyl)-N-((3R,5S)-l-dano-5-(methox¡met¡l)pyrrol¡din-3-¡l)oxazol-2carboxamida frC7C ίη / 77Ω7 / Β / ΥΙΛΙ frCZC Ln / Zznz / E / YIAI (i) TBD, THF, de 0°C at room temperature; (ii) TFA, DCM, de 0°C at room temperature; (i¡¡) K2CO3, CNBr, THF, at 0°C at room temperature. Paso (i) (2S,4R)-4-(5-(5-C¡ano-2-metoxifenH)oxazol-2-carboxam¡do)-2-(metox¡met¡l)p¡rrol¡d¡n1-carboxHato de terc-butUo To a stirred solution of ethyl 5-(5-cyano-2-methoxyphenyl)oxazol-2-carboxylate (0.80 g, 2.94 mmol) and tert-butyl (2S,4R)-4-amino-2-(methoxymethyl)pyrrolidine-1-carboxylate (CAS 1207853-53-9, 0.67 g, 2.94 mmol) in THF (20 mL) TBD (0.61 g, 4.41 mmol) was added in portions at 0°C. The mixture was stirred at 0°C for 6 hours, then poured into water (50 mL) and extracted with EtOAc (2 x 70 mL). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by instant column chromatography (silica gel, 50% EtOAc in hexanes) to produce tert-butyl (2S,4R)-4-(5-(5-cyano-2-methoxyphenyl)oxazol-2-carboxamido)-2-(methoxymethyl)pyrrolidine-1-carboxylate (0.25 g, 0.55 mmol, 18% yield). LCEM: Method Cl, 1.29 min; EM: ES+ 457.2. Step (i) 5-(5-Cyano-2-methoxyphenyl)-N-((3R,5S)-5-(methoxymethyl)pyrrolidin-3-yl)oxazole-2carboxamide To a stirred solution of (2S,4R)-4-(5-(5-cyano-2-methoxyphenyl)oxazol-2-carboxamido)-2(methoxymethyl)pyrrolidine-1-carboxylate of tert-butyl (0.25 g, 0.55 mmol) in DCM (5 ml) TFA (2.5 ml, 10 vol) was added dropwise at 0°C. The mixture was allowed to warm to room temperature and stirred for 2 hours, then concentrated under reduced pressure to produce TFA salt of 5-(5-cyano-2-methoxyphenyl)-N-((3R,5S)-5-(methoxymethyl)pyrrolidine-3-1)oxazol-2-carboxamide (0.32 g, quantitative yield). LCEM: Method Cl, 1.00 min; EM: ES+ 357.3. Step (ii) 5-(5-Cyano-2-methoxyphenH)-N-((3R,5S)-lcyane-5-(methoxymethyl)pyrrolidine-3-H)oxazole-2carboxamide To a stirred solution of TFA salt of 5-(5-cyano-2-methoxyphenyl)-N-((3R,5S)-5-(methoxymethyl)pyrrolidine-3-1)oxazol-2-carboxamide (0.31 g, 0.66 mmol) in THF (15 mL), K₂CO₃ (0.27 g, 1.98 mmol) was added at room temperature. After stirring for 10 min, cyanogen bromide (0.07 g, 0.66 mmol) was added to the mixture at 0°C. The mixture was stirred at 0°C for 0.5 hours, then poured into water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by instant column chromatography (silica gel, 60% EtOAc in n-hexanes) to produce 5-(5-cyano-2-methoxyphenyl)-N-((3R,5S)-cyano-5-(methoxymethyl)pyrolidin-3-yl)oxazol-2-carboxamide (0.11 g, 0.29 mmol, 52% yield in two steps). LCEM: Method H, 2.66 min; EM: ES+ 382.2;2H NMR (400 MHz, DMSO-rá) δ ppm: 9.34 (d, 7= 6.8 Hz, 1H), 8.25 (s, 1H), 7.96 (d, 7 = 8.0 Hz, 1H), 7.85 (s, 1H), 7.43 (d, 7= 8.8 Hz, 1H), 4.47 - 4.58 (m, 1H), 4.09 (s, 3H), 4.00 - 4.10 (m, 1H), 3.70 - 3.74 (m, 1H), 3.41 - 3.53 (m, 3H), 3.36 (s, 3H), 2.08 - 2.20 (m, 1H), 1.95 - 2.06 (m, 1H). SFC quiral: Method Y7, 5.42 min. frC7C ίη / 77Π7 / Ε / ΥΙΛΙ EXAMPLE 6 4-(5-C¡ano-2-methoxifen¡l)-N-((3R,5S)-l-cyano-5-(methox¡met¡l)p¡rrol¡d¡n-3-¡l)oxazol-2carboxamida (i) AgOTf, EtOAc, 80°C; (i) LÍOH.H2O, H2O, THF, 0°C at room temperature; (ii) POCl3, pyridine, 0°C at room temperature; (iv) TFA, DCM, 0°C at room temperature; (v) K2CO3, CNBr, THF, 0°C at room temperature. Step (i) 4-(5-Cyano-2-metoxifenil)oxazol-2-carbox¡lato de etilo To a stirred solution of ethyl 5-(5-cyano-2-methoxyphenyl)oxazol-2-carboxylate (3.5 g, 13.83 mmol) and ethyloxamate (CAS 617-36-7, from Sigma-Aldrich, 4.86 g, 41.51 mmol) in EtOAc (35 mL) silver triflate (CAS 2923-28-6, from Combi-blocks, 10.66 g, 41.51 mmol) at room temperature was added. The mixture was heated to 80°C for 24 hours, then poured into water (120 mL), filtered through Celite Hyflow™, and the filtrate extracted with EtOAc (3 x 70 mL). The combined organic phases were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by instant column chromatography (silica gel, 16% EtOAc in nhexanes) to produce ethyl 4-(5-cyano-2-methoxyphenyl) oxazol-2-carboxylate (0.53 g, 1.95 mmol, 14% yield). LCEM: Method C, 1.65 min; EM: ES+ 273.1. Step (i) 4-(5-cyano-2-methoxyphenyl)oxazole-2-carboxyHco acid To a stirred solution of ethyl 4-(5-cyano-2-methoxyphenyl)oxazol-2-carboxylate (0.50 g, 1.84 mmol) in THF:water (1:1, 10 mL), lithium hydroxide monohydrate (0.23 g, 5.51 mmol) was added in portions at 0°C. The mixture was stirred at 0°C for 2 hours, then poured into water (70 mL), acidified with 1 N HCl, and extracted with DCM (3 x 70 mL). The combined organic phases were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to produce 4-(5-cyano-2-methoxyphenyl)oxazol-2-carboxylic acid (0.15 g, 0.61 mmol, 33% yield). LCEM: Method C2, 0.81 min; EM: ES+ 245.1. Step (iii) Tere-butyl (2S,4R)-4-(4-(5-Cyano-2-methoxyphenH)oxazole-2-carboxamido)-2-(methoxymethyl)pyrrolidine1-carboxyate POCh (0.3 g, 0.18 mL, 1.97 mmol) was added dropwise at 0°C to a stirred solution of 4-(5-cyano-2-methoxyphenyl)oxazol-2-carboxylic acid (0.16 g, 0.65 mmol) and tert-butyl (2S,4R)-4-amino-2-(methoxymethyl)pyrrolidine-1-carboxylate (CAS 120785353-9, 0.15 g, 0.65 mmol) in pyridine (3 mL). The mixture was stirred at 0°C for 10 min, then poured into water (50 mL) and extracted with EtOAc (2 x 30 mL). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by instant column chromatography (silica gel, 22% EtOAc in n-hexanes) to produce (2S,4R)-4-(4-(5-cyano-2-methoxyphenyl)oxazol-2-carboxamido)-2-(methoxymethyl)pyrrolidine-1-carboxylate of tere-butyl (0.18 g, 0.39 mmol, 60% yield). LCEM: Method C, 1.70 min; EM: ES- 455.1. Step (iv) 4-(5-Cyano-2-methoxypheníl)-N-((3R,55)-5-(methoxymethyl)pyrrolídin-3-H)oxazole-2carboxamide frCZC Ln / Zznz / E / YIAI To a stirred solution of (2S,4R)-4-(4-(5-cyano-2-methoxyphenyl)oxazol-2-carboxamido)-2-(methoxymethyl)pyrrolidine-3-1-carboxylate of tert-butyl (0.17 g, 0.37 mmol) in DCM (5 ml) TFA (0.85 ml, 5 vol) at 0°C was added dropwise. The mixture was allowed to warm to room temperature and stirred for 1 hour, then concentrated under reduced pressure to produce TFA salt of 4-(5-cyano-2-methoxyphenyl)-N-((3R,5S)-5-(methoxymethyl)pyrrolidine-3-1)oxazol-2-carboxamide (0.25 g, quantitative yield). LCEM: Method C, 1.32 min; EM: ES+ 357.1. Step (v) 4-(5-Cyano-2-methoxyphenyl)-N-((3R,5S)-l-cyano-5-(methoxymethyl)pyrrolidin-3-l)oxazole-2carboxamide To a stirred solution of TFA salt of 4-(5-cyano-2-methoxyphenyl)-N-((3R,5S)-5-(methoxymethyl)pyrrolidine-3-1)oxazol-2-carboxamide (0.24 g, 0.51 mmol) in THF (5 mL) K₂CO₃ (0.21 g, 1.53 mmol) at room temperature was added and stirred for 10 min. Cyanogen bromide (0.04 g, 0.41 mmol) was added at 0°C. The mixture was stirred at room temperature for 1 hour, then poured into water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by instant column chromatography (silica gel, 71% EtOAc in 7-hexanes) to produce 4-(5-cyane-2-methoxyphenyl)-N-((3R,5S)-1-cyano-5-(methoxymethyl)pyrrolidine-3-1)oxazol-2-carboxamide (0.05 g, 0.14 mmol, 36% yield in two steps). LCEM: Method H, 2.80 min; EM: ES- 380.1;XH NMR (400 MHz, DMSO-ok) δ ppm: 9.25 (d, 7 = 6.8 Hz, 1H), 8.72 (s, 1H), 8.44 (d, 7 = 1.6 Hz, 1H), 7.89 (dd, 7= 8.8, 2.0 Hz, 1H), 7.37 (d, 7 = 8.8 Hz, 1H), 4.47 - 4.58 (m, 1H), 4.07 (s, 3H), 4.00 - 4.18 (m, 1H), 3.69 - 3.73 (m, 1H), 3.43 - 3.50 (m, 3H), 3.34 (s, 3H), 2.09 - 2.19 (m, 1H), 1.96 - 2.02 (m, 1H). Chiral SFC: Method Y3, 3.49 min. EXAMPLE 5-(5-Cyano-2-(trifluoromethoxy)phen¡l)-N-((3R / 5S)-lc¡ano-5-(methoxymetH)p¡rrolidin-3yl)oxazol-2-carboxamide frC7C ίη / 77Π7 / Ε / ΥΙΛΙ frCZC Ln / Zznz / E / YIAI (i) TBD, THF, 0°C at room temperature; (ii) Zn(CN)2, Zn, Pd2(dba)3, phosphine ligand, DMA, 140°C; (i¡¡) TFA, DCM, from 0°C to room temperature; (iv) K2CO3, CNBr, THF, from 0°C to room temperature. Step (i) (2S,4R)-4-(5-(5-Bromo-2-(trifluoromethox¡)phenyl)oxazol-2-carboxam¡do)-2(methoxymetH)pyrrolidine-l-carboxylate of tere-butyl To a stirred solution of ethyl 5-(5-bromo-2-(trifluoromethoxy)phenyl)oxazol-2-carboxylate (0.70 g, 1.84 mmol) and tert-butyl (2S,4R)-4-amino-2-(methoxymethyl)pyrrolidine-carboxylate (CAS 1207853-53-9, 0.42 g, 1.84 mmol) in THF (8 mL) TBD (0.38 g, 2.77 mmol) was added in portions at 0°C. The mixture was stirred at 0°C for 2 hours, then poured into water (100 mL) and extracted with EtOAc (3 x 70 mL). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by instant column chromatography (silica gel, 25% EtOAc in n-hexanes) to produce (2S,4R)-4-(5-(5-bromo-2(trifluoromethoxy)phenyl)oxazol-2-carboxamido)-2-(methoxymethyl)pyrrolidine-1-carboxylate of tere-butyl (0.37 g, 0.66 mmol, 35% yield). LCEM: Method C, 2.00 min; EM: ES+ 564.4, 566.4. Step (ii) (2S,4R)-4-(5-(5-Cyan-2-(trifluoromethoxy)phenH)oxazol-2-carboxamido)-2-(methoxymethyl)pyrrolidine-tere-butyl carboxylateTo a stirred solution of (2S,4R)-4-(5-(5-bromo-2-(trifluoromethoxy)phenyl)oxazol-2-carboxamido)-2-(methoxymethyl)pyrrolidine-1-carboxylate tert-butyl (0.35 g, 0.62 mmol) in DMA (3 ml) zinc cyanide (0.18 g, 1.55 mmol), zinc powder (0.02 g, 0.31 mmol) and 1,1'-ferrocenedyl-bis(diphenylphosphine) (0.07 g, 0.12 mmol) was added at room temperature. The mixture was degassed with N2 for 15 min, followed by the addition of tris(dibenzylideneacetone)dipalladium(O) (0.11 g, 0.12 mmol). The mixture was microwaved at 140°C for 1 hour, then allowed to cool to room temperature, poured into ice water (70 ml), and extracted with EtOAc (3 x 70 ml). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure.The residue was purified by instant column chromatography (silica gel, 22% EtOAc in n-hexanes) to produce tert-butyl (2S,4R)-4-(5-(5-cyano-2-(trifluoromethoxy)-phenyl)oxazol-2-carboxamido)-2-(methoxymethyl)pyrrolidine carboxylate (0.25 g, 0.5 mmol, 80% yield). LCEM: Method C, 1.83 min; EM: ES+: 511.4. Step (iii) 5-(5-Cyano-2-(trifluoromethoxy)phenyl)-N-((3R,5S)-5-(methoxymethyl)pyrrolydin-3-l)oxazole-2carboxamide To a stirred solution of (2S,4R)-4-(5-(5-cyano-2-(trifluoromethoxy)phenyl)oxazol-2-carboxamido)-2-(methoxymethyl)pyrrolidine-3-1) tert-butyl carboxylate (0.25 g, 0.49 mmol) in DCM (3 ml) TFA (1.25 ml, 5 vol) at 0°C was added dropwise. The mixture was allowed to warm to room temperature and stirred for 2 hours, then concentrated under reduced pressure to produce TFA salt of 5-(5-cyano-2-(trifluoromethoxy)phenyl)-N-((3R,5S)-5-(methoxymethyl)pyrrolidine-3-1)oxazol-2-carboxamide (0.39 g, quantitative yield). LCEM: Method C, 1.38 min; EM: ES+ 411.1. Step (iv) 5-(5-Cyan-2-(trífíuoromethoxi)phenH)-N-((3R,5S)-l -cyano-5-(methoximetH)p¡rroHdin-3il)oxazol-2-carboxamida To a stirred solution of TFA salt of 5-(5-cyano-2-(trifluoromethoxy)phenyl)-N-((3R,5S)5-(methoxymethyl)pyrrolidine-3-yl)oxazol-2-carboxamide (0.39 g, 0.74 mmol) in THF (5 mL), K₂CO₃ (0.31 g, 2.23 mmol) was added at room temperature and stirred for 10 min. Cyanogen bromide (0.06 g, 0.59 mmol) was added at 0°C. The mixture was stirred at room temperature for 1 hour, then poured into water (70 mL) and extracted with EtOAc (3 x 70 mL). The combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 40% EtOAc in 7-hexanes) to produce 5-(5-cyane-2-(trifluoromethoxy)phenyl)-N-((3R,5S)-cyane-5-(methoxymethyl)pyrrolidine-3-yl)oxazol-2-carboxamide (0.14 g, 0.33 mmol, 66% yield in two steps). LCEM: Method H, 3.03 min; EM: ES- 434.1; NMR (400 MHz, DMSO-ra) δ ppm: 9.40 (d, 7 = 6.8 Hz, 1H), 8.51 (d, 7= 1.6 Hz, 1H), 8.12 (dd, 7= 8.8, 2.0 Hz, 1H), 7.86 (s, 1H), 7.82 (d, 7 =). 8.4 Hz, 1H), 4.51 - 4.55 (m, 1H), 3.99 - 4.08 (m, 1H), 3.69 - 3.74 (m, 1H), 3.42 - 3.51 (m, 3H), 3.34 (s, 3H), 2.11 - 2.17 (m, 1H), - 2.03 (m, 1H). Chiral SFC: Method Y4, 3.57 min. EXAMPLE 5-(5-C¡ano-2-(triphiuoromethoxy)phen¡l)-N-((3R,5R)-lc¡ano-5-methylpyrrol¡din-3-H)oxazol-2frCZC Ln / Zznz / E / YIAI carboxamide frCZC Ln / Zznz / E / YIAI (i) TBD, THF, 0°C at room temperature; (i) Zn(CN)2, Zn, Pd2(dba)3, phosphine ligand, DMA, 140°C; (iii) TFA, DCM, from 0°C to room temperature; (iv) K2CO3, CNBr, THF, from 0°C to room temperature. Step (i) (2R,4R)-4-(5-(5-Bromo-2-(trifluoromethoxy)phenyl)oxazol-2-carboxamido)-2methylpyrrolidine-l-carboxylate of tere-butyl To a stirred solution of ethyl 5-(5-bromo-2-(trifluoromethoxy)phenyl)oxazol-2-carboxylate (0.40 g, 1.05 mmol) and tert-butyl (2R,4R)-4-amino-2-methylpyrrolidine-1-carboxylate (CAS 348165-63-9, 0.23 g, 1.16 mmol) in THF (8 mL) TBD (0.22 g, 1.57 mmol) was added in portions at 0°C. The mixture was allowed to warm to room temperature and stirred for 3 hours, then poured into water (50 mL) and extracted with EtOAc (3 x 60 mL). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by instant column chromatography (silica gel, 32% EtOAc in n-hexanes) to produce (2R,4R)-4-(5-(5-bromo-2-(trifluoromethoxy)phenyl)oxazol-2-carboxamido)-2-methylpyrrolidine-l-carboxylate of tere-butyl (0.14 g, 0.26 mmol, 24% yield). LCEM: Method C, 2.01 min; EM: ES+ 534.2, 536.2. Step (i) (2R,4R)-4-(5-(5-cyano-2-(trifluoromethoxy)phenyl)oxazol-2-carboxamido)-2-methylpyrrolidine-1-carboxylate of tere-butyl Zinc cyanide (0.07 g, 0.61 mmol), zinc powder (0.01 g, 0.12 mmol) and l,l'-ferrocenedi¡l bis(diphenylphosphine) (0.03 g, 0.05 mmol) at room temperature. The mixture was degassed with N2 for 10 min, followed by the addition of tris(dibenzeneacetone)d¡palladium(0) (0.04 g, 0.05 mmol). The mixture was microwaved at 140°C for 1 hour, then cooled to room temperature, poured into water (20 ml), and extracted with EtOAc (3 x 30 ml). The combined organic phases were dried over Na2S4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 38% EtOAc in n-hexanes) to produce tert-butyl (2R,4R)-4-(5-(5-cyano-2-(trifluoromethoxy)phenyl)-oxazol-2-carboxamido)-2-methylpyrrolidine n-1-carboxylate (0.05 g, 0.10 mmol, 42% yield). LCEM: Method C, 1.88 min; EM: ES+: 425.6 (M-56). Step (iii) 5-(5-Cyano-2-(trifluoromethoxy¡)phen¡l)-N-((3R,5R)-5-met¡lprrolidin-3-yl)oxazole-2carboxamide To a stirred solution of (2R,4R)-4-(5-(5-cyano-2-(trifluoromethoxy)phenyl)oxazol-2-carboxamido)-2-methylpyrrolidine-1-carboxylate of tert-butyl (0.05 g, 0.1 mmol) in DCM (2 ml) TFA (0.15 ml, 3 vol) at 0°C was added dropwise. The mixture was allowed to warm to room temperature and stirred for 1 hour, then concentrated under reduced pressure to produce TFA salt of 5-(5-cyano-2-(trifluoromethoxy)phenyl)-N-((3R,5R)-5-methylpyrrolidine-3-yl)oxazol-2-carboxamide (0.08 g, quantitative yield). LCEM: Method C, 1.38 min; EM: ES+ 381.2. Step (iv) 5-(5-Cyano-2-(trifluoromethoxy)phenyl)-N-((3R,5R)-lcyane-5-methylpyrrolidine-3-H)oxazole-2carboxamide To a stirred solution of TFA salt of 5-(5-cyano-2-(trifluoromethoxy)phenyl)-N-((3R,5R)5-methylpyrrolidine-3-1)oxazol-2-carboxamide (0.08 g, 0.16 mmol) in THF (4 mL), K₂CO₃ (0.07 g, 0.48 mmol) was added at room temperature and stirred for 10 min. Cyanogen bromide (0.02 g, 0.16 mmol) was added at 0°C. The mixture was stirred at room temperature for 1 hour, then poured into water (20 mL) and extracted with EtOAc (3 x 25 mL). The combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 47% EtOAc in 7-hexanes) to produce 5-(5-cyano-2-(trifluoromethoxy)phenyl)-N-((3R,5R)-1-cyano-5-methylpyrrolidine-3-yl)oxazol-2-carboxamide (0.02 g, 0.05 mmol, 47% yield in two steps). LCEM: Method H, 3.02 min; EM: ES-404.0; NMR (400 MHz, DMSO-ck) δ ppm: 9.43 (d, 7 = 6.8 Hz, 1H), 8.51 (s, 1H), 8.11 (d, 7 = 8.4 Hz, 1H), 7.84 (s, 1H), 7.82 (d, 7= 8.4 Hz, 1H), 4.48 - 4.57 (m, 1H), 3.89 - 3.94 (m, 1H), 3.76 - 3.80 (m, 1H), 3.42 - 3.46 (m, 1H), 2.15 - 2.18 (m, 1H), 1.76 - 1.83 (m, 1H), 1.25 (d, 7= 6.4 Hz, 3H). SFC quiral: Method Y8, 5.02 min. frC7C ίη / 77Ω7 / Β / ΥΙΛΙ EXAMPLE 9 frC7C ίη / 77Π7 / Ε / ΥΙΛΙ 5-(5-Cyano-4-fluoro-2-methoxyphenyl)-N-((3R,5R)-1-cyano-5-methylpyrrol¡d¡n-3-H)oxazol-2carboxamide (i) TBD, THF, de 0°C at room temperature; (¡i) TFA, DCM, de 0°C at room temperature; (iii) K2CO3, CNBr, THF, at 0°C at room temperature. Paso (i) (2R, 4R)-4-(5-(5-Cyano-2-ddopropoxyphenyl)oxazol-2-carboxamido)-2-met¡lp¡rroHdina1-carboxylato de tere-butyl To a stirred solution of ethyl 5-(5-cyane-2-cyclopropoxyphenyl)oxazol-2-carboxylate (0.50 g, 1.72 mmol) and tert-butyl (2R,4R)-4-amino-2-methylpyrrolidine-1-carboxylate (CAS 348165-639, 0.27 g, 1.38 mmol) in THF (10 mL) TBD (0.29 g, 2.07 mmol) was added in portions at 0°C. The mixture was heated to room temperature and stirred for 2 hours, then poured into water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by instant column chromatography (silica gel, 40% EtOAc in 7-hexanes) to produce (2R,4R)-4-(5-(5-cyano-2-cyclopropoxyphenyl)oxazol-2-carboxamido)-2-methylpyrrolidine-1-carboxylate of tere-butyl (0.3 g, 0.67 mmol, 38% yield). LCEM: Method C, 1.78 min; EM: ES+ 389.3 (M-56). Step (i) 5-(5-Cyano-2-acidopropoxyphenyl)-N-((3R,5R)-5-methylpyrrolidine-3-yl)oxazol-2-carboxamide A stirred solution of (2R,4R)-4-(5-(5-cyano-2-cyclopropoxyphenyl)oxazol-2-carboxamido)-2-methylpyrrolidine-1-carboxylate of tere-butyl (0.3 g, 0.67 mmol) in DCM (7 ml) TFA (0.9 ml, 3 vol) at 0°C was added dropwise. The mixture was allowed to heat to room temperature and stirred for 1 hour, then concentrated under reduced pressure to produce TFA salt of 5-(5-cyano-2-cyclopropoxyphenyl)-N-((3R,5R)-5-methylpyrrolidine-3-1)oxazol-2-carboxamide (0.29 g, quantitative yield). LCEM: Method C, 1.39 min; EM: ES+ 345.3. Step (iii) 5-(5-Cyano-4-fluoro-2-methoxyphenyl)-N-((3R,5R)-l-cyano-5-methylpyrrolidin-3-yl)oxazole-2carboxamide To a stirred solution of TFA salt of 5-(5-cyano-2-cyclopropoxyphenyl)-N-((3R,5R)-5-methylpyrrolidine-3-1)oxazol-2-carboxamide (0.29 g, 0.63 mmol) in THF (7 ml) K2CO3 (0.26 g, 1.89 mmol) was added at room temperature and stirred for 10 min. Cyanogen bromide (0.07 g, 0.63 mmol) was added at 0°C. The mixture was stirred at room temperature for 1 hour, then poured into water (70 ml) to form a precipitate and the solid was collected by filtration under reduced pressure to produce 5-(5-cyano-4-fluoro-2-methoxyphenyl)-N-((3R,5R)-l-cyano-5-methylpyrrolidine-3-yl)oxazol-2-carboxamide (0.13 g, 0.35 mmol, 52% yield in two steps). LCEM: Method H, 2.75 min; EM: ES+ 370.1;XH NMR (400 MHz, DMSO-based) δ ppm: 9.31 (d, J= 6.4 Hz, 1H), 8.28 - 8.31 (m, 1H), 7.79 - 7.82 (m, 1H), 7.49 - 12, (H 4.47 - 4.59 (m, 1H), 4.08 (s, 3H), 3.85 - 3.99 (m, 1H), 3.76 - 3.80 (m, 1H), 3.42 - 3.45 (m, 1H), 2.12 - 2.23 (m, 1H), 1.83 (m, 1H), . 1H), 1.24 -1.29 (m, 3H). Chiral SFC: Method Y5, 4.98 min. EXAMPLE 10 4-(5-Cano-2-cyclopropoxyphen¡l)-N-((3R,5S)-lcano-5-(methoxymethl)p¡rrol¡n-3yl)oxazole-2-carboxamide frC7C ίη / 77Π7 / Ε / ΥΙΛΙ frC7C ίη / 77Π7 / Ε / ΥΙΛΙ 4-(5-Cyane-2-dipropoxyphenyl)oxazol-2-carboxylate was mixed with a stirred solution of 3-(2-bromoacetyl)-4-cyclopropoxybenzenitryl (0.70 g, 2.50 mmol) and ethyl oxamate (CAS 617-36-7, from Sigma-Aldrich, 0.66 g, 3.75 mmol) in EtOAc (10 mL). Silver triflate (CAS 2923-28-6, from Combi-blocks, 0.96 g, 3.75 mmol) was added at room temperature. The mixture was heated to 80°C for 16 hours. An identical batch was combined and then poured into water (100 mL), filtered through Celite Hyflow™, and the filtrate was extracted with EtOAc (2 x 100 mL). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 10% EtOAc in n-hexanes) to produce ethyl 4-(5-cyane-2-cyclopropoxyphenyl)oxazol-2-carboxylate (0.35 g, 1.17 mmol, 23% yield). LCEM: Hl method, 3.40 min; EM: ES+ 299.0. Step (i) tert-butUo (2S,4R)-4-(4-(5-Cyano-2-ddopropoxyphenH)oxazole-2-carboxamido)-2(methoxymethyl)pyrrolidine-l-carboxylate To a stirred solution of ethyl 4-(5-cyane-2-cyclopropoxyphenyl)oxazol-2-carboxylate (0.32 g, 1.07 mmol) and tert-butyl (2S,4R)-4-amino-2-(methoxymethyl)pyrrolidine-1-carboxylate (CAS 1207853-53-9, 0.25 g, 1.07 mmol) in DMF (7 mL) TBD (0.18 g, 1.28 mmol) was added in portions at 0°C. The mixture was allowed to warm to room temperature and stirred for 2 hours, then poured into water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 30% EtOAc in n-hexanes) to produce (2S,4R)-4-(4-(5-cyane-2-cyclopropoxyphenyl)oxazol-2-carboxamido)-2-(methoxymethyl)pyrrolidine 1-tere-butyl carboxylate (0.10 g, 0.22 mmol, 20% yield). LCEM: Hl method, 3.51 min; EM: ES- 481.3. Step (iii) 4-(5-Cyano-2-cyclopropoxyphenH)-N-((3R,5S)-5-(methoxymethyl)pyrrolidin-3yl)oxazole-2-carboxamide TFA salt To a stirred solution of (2S,4R)-4-(4-(5-cyano-2-cyclopropoxyphenyl)oxazol-2-carboxamido)-2-(methoxymethyl)pyrrolidine-1-carboxylate tert-butyl (0.1 g, 0.22 mmol) in DCM (5 ml) TFA (1 ml, 10 vol) at 0°C was added dropwise. The mixture was allowed to warm to room temperature and stirred for 1 hour, then concentrated under reduced pressure to produce TFA salt of 4-(5-cyano-2-cyclopropoxyphenyl)-N-((3R,5S)-5-(methoxymethyl)pyrrolidine-3-1)oxazol-2-carboxamide (0.14 g, quantitative yield). LCEM: Method J, 3.61 min; EM: ES+ 383.0. Step (iv) 4-(5-Cyano-2-ddopropoxyphenyl)-N-((3R,5S)-l-dano-5-(methoxymethyl)pyrrolidin-3yl)oxazole-2-carboxamide a stirred solution of TFA salt 4-(5-cyano-2-cyclopropoxyphenyl)-N-((3R,5S)-5(methoxy¡methyl)pyrrolidin-3-¡l)oxazole-2-carboxamide (0.14 g, 0.28 mmol) in THF (5 ml) K2CO3 (0.12 g, 0.84 mmol) was added at room temperature and stirred for 5 min. Cyanogen bromide (0.03 g, 0.28 mmol) was added at 0°C. The mixture was stirred at room temperature for 1 hour, then poured into water (30 ml) and extracted with EtOAc (2 x 30 ml). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 45% EtOAc in n-hexanes) to produce 4-(5-cyano-2-cyclopropoxyphenyl)-N-((3R,5S)-cyano-5-(methoxymethyl)pyrrolidine-3-yl)oxazol-2-carboxamide (0.04 g, 0.09 mmol, 47% yield, in two steps). LCEM: Método Hl, 2.97 min; EM: ES- 406.2;2H NMR (400 MHz, DMSO-ok) δ ppm: 9.24 (d, J = 6.8 Hz, 1H), 8.52 (s, 1H), 8.43 (d, J = 2.0 Hz, 1H), 7.92 (dd, J = 8.8, 2.0 Hz, 1H), 7.64 (d, 7 = 8.4 Hz, 1H), 4.48 - 4.56 (m, 1H), 4.15 - 4.23 (m, 1H), 4.0 - 4.08 (m, 1H), 3.68 - 3.72 (m, 1H), 3.42 - 3.50 (m, 3H), 3.32 (s, 3H), 2.10 - 2.15 (m, 1H), 1.96 - 2.01 (m, 1H), 0.86 - 0.97 (m, 4H). HPLC quiral: Method Y15, 10.0 min. frC7C ίη / 77Π7 / Ε / ΥΙΛΙ EXAMPLE 11 frC7C ίη / 77Π7 / Ε / ΥΙΛΙ 5-(5-C¡ano-2-ddopropoxyphenH)-N-((3R,5R)-l-dano-5-(methoxymethyl)plrrol¡d¡n-3yl)oxazol-2-carboxamida Paso (i) (2R,4R)-4-(5-(5-Cano-2-ddopropoxyphenyl)oxazol-2-carboxamdo)-2(methoxymethyl)p¡rrol¡d¡nl-carbox¡lato de terc-butUo To a stirred solution of ethyl 5-(5-cyane-2-cyclopropoxyphenyl)oxazol-2-carboxylate (0.25 g, 0.83 mmol) and tert-butyl (2R,4R)-4-amino-2-(methoxymethyl)pyrrolidine-1-carboxylate (CAS 1123305-98-5, 0.19 g, 0.83 mmol) in toluene (5 mL), TBD (0.12 g, 0.83 mmol) was added in portions at 0°C. The mixture was allowed to warm to room temperature and stirred for 1 hour, then poured into water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by instant column chromatography (silica gel, 35% EtOAc in n-hexanes) to produce (2R,4R)-4-(5-(5-cyane-2-cyclopropoxyphenyl)oxazol-2-carboxamido)-2-(methoxymethyl)pyrrolidine n-1-carboxylate of tere-butyl (0.08 g, 0.16 mmol, 19% yield). LCEM: Method Cl, 1.41 min; EM: ES+ 483.4. Step (Ί0) 5-(5-Dano-2-ddopropoxy¡phenH)-N-((3R,5R)-5-(methoxy¡metH)p¡rroHd¡n-3yl)oxazole-2-carboxamide TFA salt To a stirred solution of (2R,4R)-4-(5-(5-cyano-2-cyclopropoxyphenyl)oxazol-2-carboxamido)-2-(methoxymethyl)pyrrolidine-3-yl-carboxylate of tert-butyl (0.07 g, 0.15 mmol) in DCM (1 ml) TFA (0.22 ml, 3 vol) at 0°C was added dropwise. The mixture was allowed to warm to room temperature and stirred for 1 hour, then concentrated under reduced pressure to produce TFA salt of 5-(5-cyano-2-cyclopropoxyphenyl)-N-((3R,5R)-5-(methoxymethyl)pyrrolidine-3-yl)oxazol-2-carboxamide (0.10 g, quantitative yield). LCEM: Method Cl, 1.06 min; EM: ES+ 383.2. Step (iii) 5-(5-Cyano-2-cyclopropoxyphenyl)-N-((3R,5R)-l-cyano-5-(methoxymetH)pyrrolidin-3yl)oxazole-2-carboxamide To a stirred solution of TFA salt of 5-(5-cyano-2-cyclopropoxyphenyl)-N-((3R,5R)-5-(methoxymethyl)pyrrolidine-3-1)oxazol-2-carboxamide (0.10 g, 0.20 mmol) in THF (5 mL), K₂CO₃ (0.08 g, 0.60 mmol) was added at room temperature and stirred for 5 min. Cyanogen bromide (0.02 g, 0.20 mmol) was added at 0°C. The mixture was stirred at room temperature for 1 hour, then poured into water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic phases were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by instant column chromatography (silica gel, 45% EtOAc in n-hexanes) to produce 5-(5-cyane-2-cyclopropoxyphenyl)-N-((3R,5R)-cyane-5-(methoxymethyl)pyrrolidine-3-1)oxazol-2-carboxamide (0.02 g, 0.04 mmol, 29% yield, in two steps). LCEM: Método Hl, 2.94 min; EM: ES+ 408.2; 4.61 (m, 1H), 4.15 - 4.25 (m, 1H), 3.88 - 3.97 (m, 1H), 3.63 - 3.72 (m, 1H), 3.46 - 3.60 (m, 2H), 3.37 - 3.41 (m, 4H), 2.27 - 2.38 (m, 1H), 1.80 - 1.90 (m, 1H), 0.83 - 0.98 (m, 4H). SFC series: Método Y12, 3.53 min. frC7C ίη / 77Ω7 / Β / ΥΙΛΙ EJEMPLO 12 frCZC Ln / Zznz / E / YIAI 4-(5-Ciano-2-c¡clopropox¡fenil)-N-((3R,5R)-lc¡ano-5-(metoximetH)p¡rrolidin-3il)oxazol-2-carboxamida Paso(i)(2R / 4R)-4-(4-(5-C¡ano-2-ciclopropox¡fen¡l)oxazol-2-carboxamido)-2(metoximetH)pirrolidin-l-carboxilato de terc-butUo To a stirred solution of ethyl 4-(5-cyano-2-cyclopropoxyphenyl)oxazol-2-carboxylate (0.40 g, 1.34 mmol) [Example 10; Step (i)] and tert-butyl (2R,4R)-4-amino-2-(methoxymethyl)pyrrolidine-1-carboxylate (CAS 1123305-98-5, 0.31 g, 1.34 mmol) in toluene (5 mL) TBD (0.19 g, 1.34 mmol) was added in portions at 0°C. The mixture was allowed to warm to room temperature and stirred for 4 hours, then poured into water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 40% EtOAc in n-hexanes) to produce tert-butyl (2R,4R)-4-(4-(5-cyano-2-cyclopropoxyphenyl)oxazol-2-carboxamido)-2-(methoxymethyl)pyrrolidine carboxylate (0.22 g, 0.46 mmol, 34% yield). LCEM: Method Cl, 1.42 min, EM: ES+ 483.3. Step (iii) 4-(5-C¡ane-2-cyclopropoxy¡phen¡l)-N-((3R,5R)-5-(methoxy¡methyl)pyrrolídin-3¡l)oxazole-2-carboxamide TFA salt To a stirred solution of (2R,4R)-4-(4-(5-cyano-2-cyclopropoxyphenyl)oxazol-2-carboxamido)-2-(methoxymethyl)pyrrolidine-1-carboxylate tert-butyl (0.22 g, 0.46 mmol) in DCM (5 ml) TFA (0.66 ml, 3 vol) at 0°C was added dropwise. The mixture was allowed to warm to room temperature and stirred for 1 hour, then concentrated under reduced pressure to produce TFA salt of 4-(5-cyano-2-cyclopropoxyphenyl)-N-((3R,5R)-5-(methoxymethyl)pyrrolidine-3-1)oxazol-2-carboxamide (0.28 g, quantitative yield). LCEM: Method Cl, 1.09 min. EM: ES+ 383.2. Step (iii) 4-(5-Cyano-2-cyclopropoxyphenyl)-N-((3R,5R)-l-cyano-5-(methoxymethyl)pyrrolidin-3yl)oxazole-2-carboxamide To a stirred solution of TFA salt of 4-(5-cyano-2-cyclopropoxyphenyl)-N-((3R,5R)-5-(methoxymethyl)pyrrolidine-3-1)oxazol-2-carboxamide (0.28 g, 0.56 mmol) in THF (5 mL) K₂CO₃ (0.23 g, 1.69 mmol) at room temperature was added and stirred for 5 min. Cyanogen bromide (0.06 g, 0.56 mmol) was added at 0°C. The mixture was stirred at room temperature for 1 hour, then poured into water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic phases were dried over Na₂S₄ and concentrated under reduced pressure. The residue was purified by instant column chromatography (silica gel, 65% EtOAc in n-hexanes) to produce 4-(5cyane-2-cyclopropoxyphenyl)-N-((3R,5R)-l-dane-5-(methoxymethyl)pyrolidin-3-l)oxazol-2-carboxamide (0.06 g, 0.14 mmol, 31% yield, in two steps). LCEM: Hl Method, 3.01 min; EM: ES+ 408.2; Ή NMR (400 MHz, DMSO-¿A) δ ppm: 9.10 (d, J= 7.6 Hz, 1H), 8.52 (s, 1H), 8.38 (s, 1H), 7.91 (d, J = 8.4, 2.0 Hz, 1H), 7.64 (d, 7= 8.8 Hz, 1H), 4.51 - 4.56 (m, 1H), 4.16 - 4.23 (m, 1H), 3.88 - 3.97 (m, 1H), 3.63 - 3.67 (m, 1H), 3.46 - 3.56 (m, 2H), 3.38 - 3.41 (m, 4H), 2.29 - 2.36 (m, 1H), 1.83 - 1.90 (m, 1H), 0.92 (br s, 4H). SFC quiral: Method Y16, 5.11 min. EXAMPLE 13 5-(5-Cyano-2-cidopropoxyphenH)-N-((3R, 5S)-1 -dano-5-methylpyrrolid¡n-3-yl)oxazol-2carboxamida frC7C ίη / 77Π7 / Ε / ΥΙΛΙ The composition of the title can be prepared by a similar method to Example 1 using (2S,4R)-4-amino-2-methylp¡rrol¡d¡nl-carbox¡lato de tere-butilo (CAS 708274-468) in El Paso (i). EXAMPLE 14 frCZC ίη / ΖΖΩΖ / Ε / ΥΙΛΙ 5-(5-Cyano-2-methoxifenH)-N-((3R,5S)-l-cyano-5-methylpyrrolidin-3-H)oxazol-2carboxamida The title compound can be prepared by a method analogous to that of Example 4 using tere-butyl (2S,4R)-4-amino-2-methylpyrrolidine carboxylate (CAS 708274-468) in Step (i). EXAMPLE 15 5-(5-Cyano-2-methoxyphenH)-N-((3R,5R)-l-cyano-5-(methoxymethyl)pyrrolidin-3-yl)oxazole-2carboxamide The title compound can be prepared by a method analogous to that of Example 5 using tere-butyl (2R,4R)-4-amino-2-(methoxymethyl)pyrolidinyl-carboxylate (CAS 1123305-98-5) in Step (i). EXAMPLE 16 4-(5-Cyano-2-methoxyphenyl)-N-((3R,5R)-l -cyano-5-(methoxymethyl)pyrrolidin-3-yl)oxazole-2carboxamide The title compound can be prepared by a method analogous to that of Example 6 using tert-butyl (2R,4R)-4-amino-2-(methoxymethyl)pyrrolidine-1-carboxylate (CAS 1123305-98-5) in Step (iii). frCZC Ln / Zznz / E / YIAI EXAMPLE 17 5-(5-Cyano-2-(trifluoromethoxy)phenyl)-N-((3R,5R)-lcyano-5-(methoxymetH)pyrrolidin-3¡l)oxazole-2-carboxamide ocf3 The title compound can be prepared by a method analogous to that of Example 7 using tert-butyl (2R,4R)-4-amino-2-(methoxymethyl)pyrrolidine-1-carboxylate (CAS 1123305-98-5) in Step (i). EXAMPLE 18 5-(5-Cyano-2-(trifluoromethoxy)phenyl)-N-((3R,5S)-l-dano-5-methylpyrrolidin-3-yl)oxazole-2carboxamide The title compound can be prepared by a method analogous to that of Example 8 using tert-butyl (2S,4R)-4-amino-2-methylpyrrolidine carboxylate (CAS 708274-468) in Step (i). EXAMPLE 19 5-(5-Cyano-4-fluoro-2-methoxyphenyl)-N-((3R,5S)-l-cyano-5-methylpyrolydin-3-l)oxazole-2carboxamide The compound in the title can be prepared by a method analogous to that of Example 9 using (2S,4R)-4-amino-2-methylpyrrolidine α-butyl carboxylate (CAS 708274-468) in Step (i). Biological Activity of the Compounds of the Invention Abbreviations: TAMRA carboxytetramethylrhodamine PCR polymerase chain reaction Phosphate-regulated saline PBS EDTA ethylenediaminetetraacetic acid Tris 2-amino-2-(hydroxymethyl)-1,3-propanediol NP-40 Nonidet P-40, octylphenoxypolyethoxyethanol BSA bovine serum albumin PNS peripheral nervous system BH3 Bcl-2 domain homology 3 PTEN phosphatase and tensin homologue SDS-PAGE sodium dodecyl sulfate polyacrylamide gel electrophoresis DMSO Dimethyl sulfoxide YFP Yellow fluorescent protein VME Methyl vinyl ester HA Hemagglutinin Ahx Aminohexanoic Acid USP30 Biochemical ICso Assay Dilution plates were prepared at 21 times the final concentration (2100 μM for a final concentration of 100 μM) in 50% DMSO in a 96-well polypropylene V-bottom plate (Greiner #651201). A typical 8-point dilution series would be 100, 30, 10, 3, 1, 0.3, 0.1, 0.03 μM final. Reactions were performed in duplicate in 384-well black plates (small volume, Greiner 784076) in a final reaction volume of 21 μL. Either 50% DMSO or the diluted compound was added to the plate. USP30 (Boston Biochem #E582) was diluted in reaction pH buffer (Tris 40 mM, pH 7.5, Tween 20 0.005%, BSA 0.5 mg / ml, betamercaptoethanol 5 mM) to achieve a final assay concentration of 4 nM, and 10 μL of diluted USP30 was added to the compound. The enzyme and compound were incubated for 30 min at room temperature.The reactions were initiated by adding 50 nM of TAMRA-labeled peptide linked to ubiquitin via an isopeptide bond as a fluorescence polarization substrate. Reactions were read immediately after substrate addition and after a 2-hour incubation at room temperature. Readings were performed on a Pherastar Plus (BMG Labtech). frC7C ίη / 77Ω7 / Β / ΥΙΛΙ λ Excitation 540 nm; λ Emission 590 nm. Exemplary compound activity in the USP30 biochemical ICso assay: Example IC50 (nM) Example IC50 (nM) 1 3 7 3 2 3 8 400 3 1 9 2 400 2 10 400 5 3 11 10 6 2 0.30 68 Reference examples Exemplary compound activity in the USP30 biochemical ICso assay: Reference example Structure Origin USP30 ICso (nM) AH H3C0 [Α\Ι^=Ν WO 2016 / 156816 Example 221 68 B Nc / yy ? A7 CF3O H 1 n^n WO 2016 / 046530 Example 219 172 C NCxy^N o Ή h3co h I n—=n WO 2016 / 046530 Example 220 160 D AV / Χ o \= / \A Λ S Χ'Ύ H | N—=N WO 2016 / 046530 Example 1 310 E XXgUN 0 HN—=N \ WO 2016 / 046530 Example 88 4400 Off-target pharmacology Example 2 underwent pharmacological profiling on the Eurofins CEREP SafetyScreen44 panel. At a single concentration of 10 μM, less than 50% inhibition of enzyme binding or activity was observed against all targets on the panel. Example 1 has a low probability of off-target interactions due to its low affinity for the targets in this assay. Safety Pharmacology Example 2 was evaluated for its effects on the hERG potassium channel in stably expressing 15CHO cells at concentrations between 0.01 and 30 μM. Example 2 produced a maximum inhibition value of 35% of the hERG current amplitude at 30 μM, indicating little propensity to affect the QT interval. Genetic Toxicity Example 2 was evaluated in the bacterial reverse mutation assay (Ames) and the in vitro micronucleus assay. All tests were performed with and without exogenous metabolic activation using concentrations up to those limited by cytotoxicity or insolubility. Example 2 did not induce mutations when tested at up to 5000 pg / plate with and without metabolic activation in the reverse mutation assay against Salmonella typhimurium strains TA98, TA100, TA1535, and TA97a and Escherichia coli strain WP2 uvrA pKMIOl. The induction of chromosome damage was evaluated using the in vitro micronucleus assay in TK6 cells. Example 2 was negative for micronucleus induction when incubated for 3 hours in the presence of exogenous metabolic activation followed by 27 hours of recovery, and also when incubated for 27 hours in the absence of exogenous metabolic activation followed by 27 hours of recovery. USP30 Endogenous Cell Target Engagement Assay HeLa cells stably overexpressing YFP-Parkina were seeded in 6-well plates. Once attached, the cells were treated with appropriate concentrations of the test or vehicle control compounds for 1 hour at 37°C, 5% CO2. Whole cells were prepared by clipping the cells in cold PBS, centrifuging, and using a pH buffer for lysis (Tris-base 50 mM, pH 7.5, NaCl 50 mM, 1% NP-40 / Igepal CA-630, MgCb 2 mM, 10% Glycerol, beta-mercaptoethanol 5 mM, cOmplete mini tablets without EDTA (Roche), PhosStop tablets (Roche)) for 10 mins. The equivalent of 20 pg of protein from the clean cell sample was incubated with a final concentration of HA-Ahx-Ahx-Ub-VME probe at room temperature. The reaction was stopped by adding 5x SDS-PAGE to the sample loading buffer, and proteins were separated by SDS-PAGE and Western blotting.USP30 was detected using an anti-USP30 Sheep antibody S746D (MRC PPU Reagents and Services) and a radish peroxidase conjugate and rabbit anti-sheep (H+L) secondary IgG (Thermo #31480) and visualized using ECL reagent (GE #RPN2109) on a GE LAS4000 image reader. Target binding was measured by quantifying the bands corresponding to USP30 and USP30 bound to the Ub-VME probe and the expression of this proportion compared to the vehicle-treated control. TOM20 ubiquitination assay Human cell lines can be challenged with mitochondrial depolarizing agents (ionophores (e.g., CCCP, valinomycin), mitochondrial complex inhibitors (oligomycin, antimycin A)) to induce TOM20 ubiquitination, which is further promoted in the presence of USP30 inhibitors. TOM20 ubiquitination is subsequently assessed by Western blot of the cells, with detection of the TOM20 ubiquitination adduct possible due to an 8 kDa increase in molecular weight for each added ubiquitin molecule, resulting in the formation of an immunoreactive ladder band of TOM20. TOM20 ubiquitination levels can be quantified using chemiluminescence densitometry of the immunoreactive ladder bands. In Vitro Cytotoxicity (ToxCel): Measured in human HCT116 colorectal carcinoma cells using alamarBIue™ as the assay endpoint. Compound cytotoxicity was measured over a continuous 96-hour exposure period. Additional studies log P: partition coefficient; lipophilicity measurement. log D: Distribution coefficient; measurement of lipophilicity. TPSA: topological polar surface area. Turbidimetric solubility: The test compound solution was prepared in DMSO diluted in aqueous pH buffer. Turbidimetry was used as the endpoint by measuring the absorbance at 620 nm. FaSSIF: simulated intestinal fluid in a fasting state measured at pH 6.5. Mouse Hep Cl: in vitro elimination of hepatocytes in mouse cells. Human Hep Cl: in vitro elimination of hepatocytes in human cells. Plasma fu,P: The free fraction of a compound in the plasma preparation determined by in vitro equilibrium dialysis. Brain fu,br: The free fraction of a compound in the brain homogenate preparation determined by in vitro equilibrium dialysis. CL: in vitro elimination. CL, as defined here, is the escalated elimination, calculated from the intrinsic elimination. Intrinsic elimination is the predicted elimination due to hepatic metabolic reactions, determined by incubating a compound in a hepatocyte preparation. The lower the value in ml / min / kg, the more stable the compound. In vivo Cl elimination: Pharmacokinetic measurement of the volume of plasma (or any matrix) from which a substance is completely removed per unit of time. The lower the value in ml / min / kg, the more stable the compound. F Oral: Oral bioavailability. MDR1-MDCK (MadinDarby Canine Kidney Cell Monolayer) flow assay (in vitro). In vitro flow WT-MDCK (wild type). Kpu,u is the ratio of unbound drug in the brain to unbound drug in plasma and may be indicative of potential for the treatment of peripheral and / or CNS indications. frC7C ίη / 77Π7 / E / YΙΛΙ Studies Example 1 Example 2 TE WB Cellular ECso of endogenous USP30 (pM) 0.002 0.003 Cell Tox ECso of HCT116 (μM) 23.8 27.1, > 30 Physicochemical Log D measured at pH 7.4 2.5 2.2 TPSA 116 125 Turbidimetric solubility (pM) 65 > 100 FaSSIF (pM) measured at pH 6.5 - 34 Mouse hepatocyte Cl Clu scaled (ml / min / kg) 117 105 Human hepatocyte Cl CL scaled (ml / min / kg) 18.6 5.0 Mouse plasma ty2 stability (min) > 120 > 120 MDR1-MDCK Effective efflux ratio - 15 WT-MDCK Efflux ratio (AB flux Papp (10 6 cm / s)) - 0.7 (10.7) frC7C ίη / 77Π7 / E / YΙΛΙ Studies Example 1 Example 2 Mouse Binding Plasma fu,P / brain fu,br 0.09 / 0.06 0.07 / 0.20 Mouse PK 2 mg / kg IV Plasma Cl (ml / min / kg) 41 20 Mouse PK 10 mg / kg F oral (%) 37 47 TOM20-Ub 1.5-fold gain Mitophagy activator antimycin A / oligomycin EC1.5x (pM) 0.006 0.007 Cellular potency Cmax / TOM20-Ub free plasma (10 mg / kg oral dose - mouse) 45 140 Kpuu 2 mg / kg IV dose - mouse 0.02 0.01 The examples possess beneficial properties that demonstrate potential superiority over other compounds. For example, for Examples 1 and 2, plasma clearance The observed IV of 41 and 20 ml / min / kg, respectively, measured in the mouse, is low, demonstrating 5 valuable plasma stability, and the compounds have a very good oral bioavailability of and 47%, respectively. Compound Ex. 1 Ex. 2 Ex. 4 Ex. 6 ICso of DUB (pM) USP30 0.003 0.003 0.002 0.002 IC50 of DUB (pM) USP2, USP6, USP10, USP15, USP16, USP21, USP25, USP28, USP46 / UAF1 1.2-80 1.1 - 130 1.0- > 300 1.4 - 258 DUB Selectivity Preference for USP30 v 9 DUB > 400 > 367 > 500 > 700 Compound Ex. 1 Ex-2 Ex. 4 Ex.6 IC50 of Cathepsin (μΜ) Cathepsin B 106.6 > 300 > 300 52.1 Cathepsin K 10.5 18.9 164.8 40.4 Cathepsin L 9.9 23.6 294.3 39.8 Cathepsin S 54.4 91.2 > 300 64.8 Cathepsin V 30.9 60.6 > 300 91.6 B, K, L, S, V > 9.9 > 18.9 > 164.8 > 39.8 Selectivity preference for cathepsins USP30 v > 3300 > 6300 > 82400 > 19900 frCZC Ln / Zznz / E / YIAI Compound Ex. 7 Ex. 11 Ex. 12 Ex. of ref. A IC50 of DUB (pM) USP30 0.003 0.010 0.068 0.068 IC50 of DUB (pM) USP2, USP6, USP10, USP15, USP16, USP21, USP25, USP28, USP46 / UAF1 4.0- > 300 (exc. ​​USP15) 78.2> 300 7.5 > 300 0.15-22.4 DUB Selectivity Preference for USP30 v 9 DUB > 1333 > 7820 > 110 > 2.2 Compound Ex-7 Ex. 11 Ex. 12 Ref. Ex. A IC50 of Cathepsin (MM) Cathepsin B 60.9 83.0 > 300 4.5 Cathepsin K 14.9 100.2 > 300 0.79 Cathepsin L 13.8 15.4 > 300 2.9 Cathepsin S > 30 129.7 > 300 8.8 Cathepsin V 12.1 > 100 189.6 5.8 B, K, L, S, V > 12.1 > 15.4 > 189 0.79 - 8.8 Selectivity preference for cathepsins USP30 v > 4033 > 1540 > 2788 11.6-129 Composite Ex. 1, 2, 4, 6, 7, 11 Ex. 12 Ref. Ex. B Example of ref. C Ref. D Example of ref. E IC50 of DUB (μΜ) USP30 0.002 0.010 0.068 0.172 0.160 0.31 4.4 UCHL1 > 300 > 300 0.52 0.21 0.25 6.8 DUB selectivity preference for USP30 v UCHL1 > 30000 > 4412 3.0 1.3 0.8 1.5 Comparative data Reference Examples A, B, C, D, and E are known DUB inhibitors that have been identified as active inhibitors of USP30 and share some structural similarity with the compounds of the present invention, which possess the cyanamide structural feature. Reference Examples B, C, D, and E are described in WO 2016 / 046530 with UCHL1 inhibitory activity. Power for USP30 Examples 1 through 11 of the present invention are significantly more potent against USP30 than Reference Examples A, B, C, D, and E, as measured by biochemical assay. Example 12 is significantly more potent against USP30 than Reference Examples B, C, D, and E. For example, Examples 1 through 11 are 6.8 to 34 times more potent than Reference Example A, 16 to 155 times more potent than Reference Examples B, C, and D, and at least 440 times more potent than Reference Example E. Selectivity for USP30 over other DUBs The data provided demonstrate that Examples 1, 2, 4, 6, 7, 11, and 12 are significantly more selective for USP30 against nine DUBs (USP2, USP6, USP10, USP15, USP16, USP21, USP25, USP28, and USP46) compared to Reference Example A. These examples are at least 110 to 7820 times more potent against USP30 than against each of the nine DUBs (Example 7 not tested against USP15). This is a significant selectivity advantage over Reference Example A, which is as low as 2.2 times more potent. Selectivity for USP30 on UCHL1 The data provided demonstrate that Examples 1, 2, 4, 6, 7, 11, and 12 are significantly more selective for USP30 than for UCHL1 compared to Reference Examples B, C, D, and E. Examples 1, 2, 4, 6, 7, and 11 are more than 30,000 times more powerful against USP30 than UCHL1, with Example 12 being more than 4,412 times more powerful, while Reference Examples B, C, D, and E are only 3.0, 1.3, 0.8, and 1.5 times more powerful, respectively; 'C is more selective for UCHL1. Selectivity for USP30 on cathepsins B, K, L, S and V The data provided demonstrate that Examples 1, 2, 4, 6, 7, 11, and 12 are significantly more selective for USP30 over the cathepsins (B, K, L, S, and V) compared to Reference Example A. These examples are all more than 1540 times more potent against USP30 than against each of the cathepsins. This is a significant selectivity advantage over Reference Example A, which is only 11.6 times more potent against cathepsin K. The advantages identified above of the compounds of the invention over the reference examples of the prior art are both significant and unexpected. On their own, and particularly in combination, this superiority makes the compounds of the invention particularly suitable for use in the treatment or prevention of diseases linked to USP30 activity. In vitro preclinical model (a) Human renal proximal tubule cell cisplatin injury model, modified to test renal protective agents. frC7C ίη / 77Π7 / E / YΙΛΙ Primary human PTCs are isolated from kidneys rejected for transplantation. Isolated cells were seeded onto 96-well Transwell inserts (surface area = 0.143 cm2) at a density of 20,000 cells per insert. The medium was refreshed 24 hours after initial seeding and also on days 3 and 5 of culture. The monolayers demonstrated TEER in a range of 80-120 Q.cm2 before being used in experiments. Human PTC monolayers were pre-exposed to Example 2 (0.01, 0.03, 0.1, 0.3, 1.0, and 3.0 pM) for 1 hour on the apical and basolateral sides of the cell layer before exposing the cells to cisplatin (20 pM). Subsequently, the cells were exposed to both Example 2 (0.01, 0.03, 0.1, 0.3, 1.0, and 3.0 μM) and cisplatin (20 μM) on both the apical and basolateral sides for 24 and 48 hours. In addition, negative controls (Example 2 only, 0.5% DMSO for Example 2, 0.2% dimethylformamide (DMF) for the cisplatin solvent control, a positive control (cisplatin 20 μM), and cisplatin plus a cisplatin uptake inhibitor (dolutegravir 100 μM)) were included in parallel. Experiments were performed in triplicate in human cell monolayers (n=3) and in three different donors (N=3). Cell viability assays based on ATP production and LDH release were performed on monolayers treated with the test compound in 96-well Transwell inserts. Example 2 protected against cisplatin-induced ATP loss in a concentration-dependent manner. Example 2 also reduced cisplatin-induced LDH elevation. These data demonstrate that Example 2 can protect against cisplatin-induced toxicity to human proximal tubule epithelial cells. In vivo preclinical models The compounds of the invention can be tested for efficacy in representative in vivo disease models, using standard study procedures from the published literature, including, for example: (a) Bleomycin-induced pulmonary fibrosis model, which is a leading preclinical in vivo model of Idiopathic Pulmonary Fibrosis. [Kobayashi et al, 2016, J Immunol, 197(2):504-516]. (b) Diet-induced model of NAFLD and glucose homeostasis. [Nishida et al, 2013, Lab Invest; Feb;93(2):230-41]. (c) MPTP model of Parkinson's disease, which is a paradigm commonly used to look for neurodegeneration in the brain's dopaminergic system that is activated by chemically induced mitochondrial dysfunction. [Karuppagouner et al, 2014, Sci Rep. 2014 May 2;4:4874]. frCZC Ln / Zznz / E / YIAI (d) Ndufs4KO model of Leigh syndrome. [Kruse et al, 2008, Cell Metab. Apr;7(4):312-20]. (e) Aging rodent model: effects on hippocampal, cognitive, and motor function. [Kobilo et al, 2014, Learn Mem. Jan 17;21(2): 119-26; Creed et al, 2019, Neuroscience. Jun 15;409:169-179; Van Skike et al, 2020, Aging Cell. 19; el3057]. (f) The unilateral urethral obstructive kidney disease (UUO) model. [Chevalier et al, 2009, Kidney Int 75(11): 1145-1152]. UUO causes kidney injury characterized by tubular cell injury, interstitial inflammation, and fibrosis. It serves as a model of irreversible post-renal acute kidney injury (AKI). Experimental UUO has illustrated the molecular mechanisms of apoptosis, inflammation, and fibrosis, all of which are key processes in kidney injury, regardless of the primary insult. Consequently, the UUO model provides researchers with insights beyond obstruction (Chevalier et al., 2009, Kidney Int. 75(11): 1145–1152). Example 2 was evaluated in the UUO model to determine the compound's ability to attenuate progressive tubulointerstitial fibrosis and chronic kidney disease (CKD). On day 1 of the study, adult C57BL / 6 mice were dosed via oral gavage according to one of the following dosing regimens: Vehicle, 5 or 1.5 mg / kg of Example 2 BID. Two hours post-dosing on day 1, the study mice underwent surgery to ligate the left urethra at two points. Successful UUO surgery was later confirmed by observation of renal pelvis dilation due to hydronephrosis. The animals were dosed according to a prescribed regimen for 10 days, at which point the kidneys were harvested for histopathological evaluation and protein / RNA assessment. Picrosirius Red staining was performed to assess the degree of collagen deposition, and IHC was used to assess α-Smooth Muscle Actin (α-SMA) expression. The results demonstrated that 5 and 1.5 mg / kg of Example 2 (po) administered twice daily (BID) statistically reduced collagen deposition, as evidenced by a reduction in picrosirius red staining in ligated kidneys. Evaluation of α-SMA staining revealed that oral dosing of 5 and 1.5 mg / kg of Example 2 BID resulted in a statistically significant reduction in α-SMA levels in UUO-injured kidneys compared to vehicle-treated controls. (g) AKI can be induced by bilateral renal pedicle clamping resulting in ischemia reperfusion injury (IRI) leading to severe loss of renal function, tubular damage and inflammation [Lu et al. 2012. J Nephrol. 25 (5): 738-45]. Prophylactic administration: Example 2 was administered to C57BL / 6 mice at 5 and 1.5 mg / kg BID (po) and compared with vehicle treatment from day -1 to day +21. On day 0, mice were anesthetized and their left renal pedicle was clamped for 45 min and then released to induce IRI. On day +21, the kidneys were harvested. Morphology and fibrosis were assessed. Body weight was similar between groups and remained constant throughout the observation periods. Masson's trichome staining revealed significantly less tubular atrophy and collagen content in the outer medulla of animals treated with Example 2 (both dose levels) on day +21. Fibronectin expression in the cortex and outer medulla was significantly reduced in animals treated with Example 2 (both dose levels) on day +21. Example 2 demonstrated efficacy in this IR-induced CKD model. Daily treatment has shown significant benefits in attenuating tubular atrophy and reducing fibrosis. Post-injury management: On day 0, C57BL / 6 mice were anesthetized, and their left renal pedicle was clamped for 45 min and then released to induce IRI. Mice were then administered either vehicle or Example 2; 5 mg / kg (orally) twice daily for 21 days, with the first treatment beginning five hours after IRI surgery (i.e., therapeutic dosage). Mice were monitored, and kidneys were harvested on day +21. Kidney sections were quantitatively assessed for relative cell morphology and fibrosis using blinded histological scoring methods. Body weight was similar between groups and remained constant throughout the observation periods. Fibronectin staining in the cortex was significantly reduced in mice treated with Example 2 on day +21. Example 2 demonstrated partial efficacy in this IR-induced CKD model when therapeutically dosed. Initiating treatment after the establishment of ischemia-reperfusion injury has shown significant benefits in reducing cortical fibrosis. Paragraphs of the invention frCZC Ln / Zznz / E / YIAI The present invention is directed to the following: 1. A compound of formula (I), which is selected from formula (I)(¡) and formula (I)(ü): frC7C ίη / 77Π7 / E / YΙΛΙ a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from (C1-C4) alkyl, (C1-C4) fluoroalkyl and CH2OCH3; R2 is selected from (C1-C4) alkyl, CF3 and cyclopropyl; and R3, R4 and R5 are each independently selected from hydrogen and halogen. 2. The compound according to paragraph 1, wherein R1 is selected from methyl, CH2F, CHF2, CF3 and CH2OCH3. 3. The compound according to paragraph 2, wherein R1 is selected from methyl and CH2OCH3. 4. The compound according to any of paragraphs 1 to 3, wherein R2 is selected from methyl, CF3 and cyclopropyl. 5. The compound according to paragraph 4, wherein R2 is selected from methyl and cyclopropyl. 6. The compound according to any of paragraphs 1 to 5, wherein R3 is selected from hydrogen and fluorine. 7. The compound according to paragraph 6, in which R3 is hydrogen. 8. The compound according to any of paragraphs 1 to 7, wherein R4 and R5 are each hydrogen. 9. The compound according to any of paragraphs 1 to 8, which has the formula (D(¡): a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer. 10. The compound according to paragraph 9, which has the formula (IA)(¡): frCZC ίη / ZZOΩZ / E / YILI a tautomer thereof, or a pharmaceutically acceptable salt thereof or tautomer. 11. The compound according to paragraph 10, which is selected from: 5-(5-cyane-2-cyclopropoxyphenyl)-N-((3R,5R)-lcyane-5-methylpinOlidin-3-l)oxazole-2carboxamide; 5-(5-cyano-2-cyclopropoxyphenyl)-N-((3R,5S)-l-cyano-5-(methoxymethyl)pyrrolidin-3yl)oxazole-2-carboxamide; 5-(5-cyane-2-cyclopropoxyphenyl)-N-((3R,5S)-lcyane-5-(fluoromethyl)pyrrolydin-3yl)oxazole-2-carboxamide; 5-(5-cyano-2-methoxyphenyl)-N-((3R,5R)-lcyano-5-methylpyrrolidin-3-l)oxazole-2carboxamide; 5-(5-cyane-2-methoxyphenyl)-N-((3R,5S)-lcyane-5-(methoxymethyl)pinOlidin-3-l)oxazole-2carboxamide; 5-(5-cyane-2-(trifluoromethoxy)phenyl)-N-((3R,5S)-lcyane-5-(methoxymethyl)pyrrolidin-3yl)oxazole-2-carboxamide; 5-(5-cyane-2-(tnfluoromethoxy¡)phenyl)-N-((3R,5R)-lcyane-5-methylpyrrolidine-3-¡l)oxazole-2carboxamide; and 5-(5-cyane-4-fluoro-2-methoxyphenyl)-N-((3R,5R)-lcyane-5-methylpinOlidin-3-l)oxazole-2carboxamide; or a pharmaceutically acceptable salt thereof. 12. The compound according to paragraph 9, which has the formula (IB)(¡): a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer. 13. The compound according to paragraph 12, which is selected from: 4-(5-cyane-2-methoxyphenyl)-N-((3 / ?,55)-lcyane-5-(methoxymethyl)pyrrolidin-3-l)oxazole-2 carboxamide 4-(5-cyano-2-cyclopropoxyphenyl)-N-((3R,5S)-l-cyano-5-(methoxymethyl)pyrrolidin-3-l)oxazole-2carboxamide; or a pharmaceutically acceptable salt thereof. 14. The compound according to any of paragraphs 1 to 8, having the formula (I)(¡¡): frC7C ίη / 77Ω7 / Β / YΙΛΙ a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer. 15. The compound according to paragraph 14, which has the formula (IA)(¡¡): a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer. 16. The compound according to paragraph 15, which is selected from: 5-(5-cyano-2-cyclopropoxyphenyl)-N-((3R,5R)-l-cyano-5-(methoxymethyl)pyrrolidin-3yl)oxazole-2-carboxamide; 5-(5-cyano-2-cyclopropoxyphenyl)-N-((3R,5S)-lcyano-5-methylpyrrolidin-3-l)oxazole-2carboxamide; 5-(5-cyano-2-methoxyphenyl)-N-((3R,5S)-l-cyano-5-methylpyrrolidin-3-yl)oxazole-2carboxamide; 5-(5-c¡ano-2-methoxifen¡l)-N-((3R,5R)-lc¡ano-5-(methox¡met¡l)pinOlid¡n-3-¡l)oxazol-2carboxamida; 5-(5-c¡ano-2-(tr¡fluoromethox¡)phen¡l)-N-((3R,5R)-l-cyano-5-(methoximeth¡l)p¡nOl¡d¡n-3yl)oxazol-2-carboxamida; 5-(5-c¡ano-2-(tr¡fluoromethox¡)phenyl)-N-((3R,5S)-lc¡ano-5-met¡lp¡rrol¡d¡n-3-¡l)oxazol-2carboxamida; 5-(5-cyano-4-fluoro-2-methox¡fen¡l)-N-((3R,5S)-l-cyano-5-met¡lp¡rrol¡d¡n-3-¡l)oxazol-2 carboxamida; y 5-(5-cyano-2-c¡clopropox¡phen¡l)-N-((3R,5R)-lc¡ano-5-(fluoromet¡l)p¡rrol¡d¡n-3yl)oxazol-2-carboxamida; or a pharmaceutically acceptable sal de las mismas. 17. The composition follows paragraph 14, which has the formula (IB)(¡¡): frC7C ίη / 77Ω7 / Β / ΥΙΛΙ a tautómero of the same, or a sal pharmaceutically acceptable de dicho compuesto or tautómero. 18. The composition follows paragraph 17, which is selected from: 4-(5-cyano-2-cyclopropoxyphenyl)-N-((3R,5R)-l-cyano-5-(methoxymethyl)pnOlidin-3yl)oxazole-2-carboxamide; and 4-(5-cyane-2-methoxyphenyl)-N-((3R,5R)-lcyane-5-(methoxymethyl)pyrrolidin-3-l)oxazole-2carboxamide; or a pharmaceutically acceptable salt thereof. 19. A compound according to any of paragraphs 1 to 18, a tautomer thereof, or a pharmaceutically acceptable salt of such compound or tautomer, for use as a medicament. 20. A compound according to any of paragraphs 1 to 18, a tautomer thereof, or a pharmaceutically acceptable salt of such compound or tautomer, for use in the treatment or prevention of a condition involving mitochondrial dysfunction, cancer, or fibrosis. 21. A use of a compound in accordance with any of paragraphs 1 to 18, a tautomer thereof, or a pharmaceutically acceptable salt of such compound or tautomer, in the manufacture of a drug for use in the treatment or prevention of a condition involving mitochondrial dysfunction, cancer, or fibrosis. 22. A method for the treatment or prevention of a condition involving mitochondrial dysfunction, cancer, or fibrosis, comprising the step of administering an effective amount of a compound according to any of paragraphs 1 to 18, a tautomer thereof, or a pharmaceutically acceptable salt of such compound or tautomer, to a patient in need. 23. The compound, use, or method, in accordance with paragraphs 20 to 22, wherein the condition involving mitochondrial dysfunction is selected from a CNS disorder; neurodegenerative disease; Parkinson's disease; Alzheimer's disease; amyotrophic lateral sclerosis; Huntington's disease; ischemia; stroke; Lewy body dementia; frontotemporal dementia; multiple sclerosis; mitochondrial encephalopathy, lactic acidosis, and stroke-like episode syndrome; materially inherited diabetes and deafness; Leber hereditary optic neuropathy; maternally inherited neuropathy, ataxia, retinitis pigmentosa-Leigh syndrome; Danon disease; diabetes; diabetic nephropathy; metabolic disorders; heart failure; ischemic heart disease leading to myocardial infarction; psychiatric disorders, schizophrenia; multiple sulfatase deficiency; mucolipidosis II; mucolipidosis III; mucolipidosis IV; GMI-gangliosidosis;neuronal ceroid lipofuscinosis; Alpers disease; Barth syndrome; beta-oxidation defects; carnitine-acylcarnitine deficiency; carnitine deficiency; creatine deficiency syndromes; coenzyme Q10 deficiency; complex I deficiency; complex II deficiency; complex III deficiency; complex IV deficiency; complex V deficiency; COX deficiency; chronic progressive external ophthalmoplegia syndrome; CPT I deficiency; CPT II deficiency; glutaric aciduria type II; Kearns-Sayre syndrome; lactic acidosis; long-chain acyl-CoA dehydrogenase deficiency; Leigh disease or syndrome; French-Canadian variant of Leigh syndrome; lethal infantile cardiomyopathy; Luft disease; medium-chain acyl-CoA dehydrogenase deficiency; myoclonic epilepsy and ragged-red fiber syndrome; mitochondrial cytopathy; recessive mitochondrial ataxia syndrome; mitochondrial DNA depletion syndrome;Myoneurogastrointestinal disorder and encephalopathy; Pearson syndrome; pyruvate dehydrogenase deficiency; pyruvate carboxylase deficiency; POLG mutations; medium / short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency; very long-chain acyl-CoA dehydrogenase deficiency; peroxisomal disorders; methylmalonic acidemia; mevalonate kinase deficiency; age-dependent decline in cognitive function and muscle strength; and cognitive impairment associated with all neurodegenerative and neuropsychiatric disorders. 24. The compound, use or method, according to paragraph 23, wherein the neurodegenerative disease is selected from Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, ischemia, stroke, Lewy body dementia, multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, frontotemporal dementia; and Parkinson's disease related to mutations in α-synuclein, parkin, PINK1, GBA and LRRK2, and autosomal recessive juvenile Parkinson's disease or early-onset Parkinson's disease (EOPD), wherein parkin or PINK1 is mutated, truncated or deleted. 25. The compound, use or method, as defined in paragraph 23, wherein the neurodegenerative disease is Leigh syndrome or disease, X-linked Leigh disease, the French-Canadian variant of Leigh syndrome and / or symptoms associated with Leigh disease. frCZC Ln / Zznz / E / YIAI 26. The compound, use, or method, according to paragraphs 20 to 22, wherein the cancer is selected from breast, ovarian, prostate, lung, kidney, gastric, colon, testicular, head and neck, pancreatic, brain, melanoma, bone, liver, soft tissue, tissue organ cancers, blood cell cancers, CML, AML, mantle cell lymphoma, neuroblastoma, melanoma, soft tissue sarcoma, liposarcoma, fibroblastic sarcoma, leiomyosarcoma, hepatocellular carcinoma, osteosarcoma, esophageal cancer, leukemia, lymphoma, multiple myeloma, metastatic carcinoma, osteosarcoma, chondrosarcoma, Ewing sarcoma, nasopharyngeal carcinoma, colorectal cancer, non-small cell lung carcinoma, cancer where apoptotic pathways are dysregulated, and cancer where BCL-2 family proteins are mutated, or on or underexpressed. 27. The compound, use, or method, as defined in paragraphs 20 to 22, wherein fibrosis is selected from fibrosis or a fibrotic disorder associated with the accumulation of extracellular matrix constituents that occurs following trauma, inflammation, tissue repair, immunological reactions, cellular hyperplasia, and neoplasia. 28. The compound, use or method, as per paragraph 27, wherein the fibrosis is selected from fibrosis or a fibrotic disorder associated with major organ diseases, fibroproliferative disorders and scarring associated with trauma. 29. The compound, use or method, according to paragraph 28, wherein the fibrosis is selected from fibrosis or a fibrotic disorder associated with interstitial lung disease, liver cirrhosis, non-alcoholic fatty liver disease, non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, kidney disease, acute kidney disease, acute kidney injury, chronic kidney disease, delayed renal graft function, heart or vascular disease, eye diseases, systemic and local scleroderma, keloids, hypertrophic scars, atherosclerosis, restenosis, Dupuytren's contracture, surgical complications, chemotherapeutic drug-induced fibrosis, radiation-induced fibrosis, accidental injuries and burns, retroperitoneal fibrosis and peritoneal fibrosis / peritoneal scarring. 30. The compound, use or method, according to paragraph 29, wherein the fibrosis associated with interstitial lung disease is selected from sarcoidosis, silicosis, drug reactions, infections, collagen vascular diseases, rheumatoid arthritis, systemic sclerosis, scleroderma, pulmonary fibrosis, idiopathic pulmonary fibrosis, habitual interstitial pneumonitis, interstitial lung disease, cryptogenic fibrosing alveolitis, bronchiolitis obliterans and bronchiectasis. 31. The compound, use or method, as defined in paragraph 29, where kidney disease is acute kidney disease, acute kidney injury or chronic kidney disease. 32. A pharmaceutical composition comprising a compound of formula (I) frC7C ίη / 77Ω7 / Β / YΙΛΙ as defined in any of paragraphs 1 to 18, a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, together with one or more pharmaceutically acceptable excipients. 33. A compound, selected from formulas (II)(i), (III)(i), (II)(¡) and (III)(i¡): frC7C ίη / 77Π7 / E / YΙΛΙ a tautomer thereof, or a salt of said compound or tautomer; where R1, R2, R3, R4 and R5 are as defined for the compound of formula (I) in any of paragraphs 1 to 18; and PG is a protecting group, preferably selected from tert-butyloxycarbonyl, benzyloxycarbonyl, p-methoxybenzylcarbonyl, 9-fluorenylmethyloxycarbonyl, acetyl, benzoyl, benzyl, carbamate, p-methoxybenzyl, 3,4-dimethoxybenzyl, p-methoxyphenyl, tosyl, trichloroethoxycarbonyl, 4-nitrobenzenesulfonyl and 2-nitrophenylsulfenyl.

Claims

1. A compound of formula (I), which is selected from formula (I)(ii) and formula (I)(ü): a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein: R1 is selected from (C1-C4) alkyl, (C1-C4) fluoroalkyl and CH2OCH3; R2 is selected from (C1-C4) alkyl, CF3 and cyclopropyl; and R3, R4 and R5 each independently are selected from hydrogen and halogen.

2. The compound according to claim 1, further characterized in that R1 is selected from methyl, CH2F, CHF2, CF3 and CH2OCH3.

3. The compound according to claim 2, further characterized in that R1 is selected from methyl and CH2OCH3.

4. The compound according to any of claims 1 to 3, further characterized in that R2 is selected from methyl, CF3 and cyclopropyl.

5. The compound according to claim 4, further characterized in that R2 is selected from methyl and cyclopropyl.

6. The compound according to any of claims 1 to 5, further characterized in that R3 is selected from hydrogen and fluorine.

7. The compound according to claim 6, further characterized in that R3 is hydrogen.

8. The compound according to any one of claims 1 to 7, further characterized in that each of R4 and R5 is hydrogen.

9. The compound according to any of claims 1 to 8, further characterized in that it has the formula (I) (i): R5 R? A. ,0= „ Xa rC T \ IH r4 VV <X\ [| I N—ΞΝ 0 Ay R1 (I)(¡) un tautómero del mismo, o una sal farmacéuticamente aceptable de dicho compuesto o tautómero.

10. The compound according to claim 9, further characterized in that it formulates (IA)(i): frC7C ίη / 77Π7 / E / YΙΛΙ a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.

11. The form of compliance with the indication 10, characterized also by selecting: 5-(5-cyano-2-c¡clopropoxyfen¡l)-N-((3R,5R)-l-cyano-5-met¡lp¡rrol¡din-3¡l)oxazol-2-carboxamida; 5-(5-cyano-2-cyclopropoxyphenol)-N-((3R,5S)-lcano-5-(methoxymethyl)prroldin3-l)oxazol-2-carboxamida; 5-(5-cyano-2-cyclopropoxyfen¡l)-N-((3R,5S)-lc¡ano-5-(fluoromet¡l)p¡rrolid¡n-3-¡l)oxazol-2-carboxam¡da; 5-(5-cyano-2-methoxyphenol)-N-((3R,5R)-lcano-5methylprroldin-3-yl)oxazol-2-carboxamida; 5-(5-cyano-2-methoxifen¡l)-N-((3R,5S)-lc¡ano-5(methoximet¡l)p¡rrolid¡n-3-¡l)oxazol-2-carboxam¡da; 5-(5-cyano-2-(trifluoromethoxy)phenyl)-N-((3R,5S)-lc¡ano-5-(methox¡met¡l)p¡rrolid¡n-3-yl)oxazol-2-carboxam¡da; 5-(5-cyano-2-(trifluoromethox¡)phen¡l)-N((3R,5R)-lc¡ano-5-met¡lpyrrol¡d¡n-3-¡l)oxazol-2-carboxamida; y 5-(5-cyano-4-fluoro-2-methoxyfen¡l)-N((3R,5R)-1-cyano-5-methylpyrrolidin-3-yl)oxazol-2-carboxamida; or a pharmaceutically acceptable sal de las mismas.

12. The compound according to claim 9, further characterized in that the formula (IB)(¡):

13. The compound according to claim 12, further characterized frCZC Ln / Zznz / E / YIAI in that it is selected from: 4-(5-cyano-2-methoxyphen¡l)-N-((3 / ?,55)-lc¡ane-5-(methoxymethyl)pyrrolid¡n-35 yl)oxazole-2-carboxamide and 4-(5-cyano-2-cyclopropoxyphenyl)-N-((3R,5S)-l-dane-5(methoxymethyl)pyrrolidin-3-l)oxazole-2-carboxamide; or a pharmaceutically acceptable salt thereof.

14. The compound according to any of claims 1 to 8, further characterized in that formula (I)(¡¡): a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.

15. The compound according to claim 14, further characterized in that formula (IA)(ii): 15 a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.

16. The requirement for compliance with the indication 15, also characterized by the selection of: 5-(5-cyano-2-cyclopropoxyphenol)-N-((3R,5R)-l-cyano-5-(methoxymethyl)prroldn3-l)oxazol-2-carboxamida; 5-(5-cyano-2-c¡clopropox¡phen¡l)-N-((3R,5S)-lc¡ano-5-met¡lp¡rrol¡d¡n-3¡l)oxazol-2-carboxamida; 5-(5-cyano-2-methoxyfen¡l)-N-((3R,5S)-lc¡ano-5-methylp¡rrol¡d¡n-3-yl)oxazol-2 carboxamida; 5-(5-dano-2-methox¡phen¡l)-N-((3R,5R)-lc¡ano-5-(methox¡met¡l)pinOl¡d¡n-3-¡l)oxazol-2carboxamida; 5-(5-cyano-2-(tnfluoromethox¡)fen¡l)-N-((3R,5R)-l-cyano-5-(methoximet¡l)pinOl¡d¡n-3yl)oxazol-2-carboxamida; 5-(5-c¡ano-2-(tr¡fluoromethox¡)phen¡l)-N-((3R,5S)-lc¡ano-5-met¡lp¡rrol¡din-3¡l)oxazol-2-carboxamida; 5-(5-cyano-4-fluoro-2-methoxyphenyl)-N-((3R,5S)-lc¡ano-5-methylp¡nOl¡d¡n-3yl)oxazol-2-carboxamida; y 5-(5-cyano-2-cyclopropoxyphenol)-N-((3R,5R)-lcano-5(fluoromethyl)prrolid-3-l)oxazol-2-carboxamda; or a pharmaceutically acceptable sal de las mismas.

17. The compound according to claim 14, further characterized in that the formula (IB)(¡¡): frC7C ίη / 77Π7 / E / YΙΛΙ is a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.

18. The compound according to claim 17, further characterized in that it is selected from: 4-(5-cyano-2-cyclopropoxyphenyl)-N-((3R,5R)-Icyano-5-(methoxymethyl)pyrolidin3-1)oxazol-2-carboxamide; and 4-(5-cyano-2-methoxyphenyl)-N-((3R,5R)-Icyano-5-(methoxymethyl)pyrolidin3-1)oxazol-2-carboxamide; or a pharmaceutically acceptable salt thereof.

19. The compound according to any of claims 1 to 18, a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, for use as a medicament.

20. The compound according to any of claims 1 to 18, a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, for use in the treatment or prevention of a condition involving mitochondrial dysfunction, cancer, or fibrosis.

21. The use of a compound according to any one of claims 1 to 18, a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, in the manufacture of a medicament for use in the treatment or prevention of a condition involving mitochondrial dysfunction, cancer, or fibrosis.

22. The compound or use according to claim 20 or 21, wherein the condition involving mitochondrial dysfunction is selected from a CNS disorder; neurodegenerative disease; Parkinson's disease; Alzheimer's disease; amyotrophic lateral sclerosis; Huntington's disease; ischemia; stroke; Lewy body dementia; frontotemporal dementia; multiple sclerosis; mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes; inherited diabetes and deafness; Leber hereditary optic neuropathy; maternally inherited neuropathy, ataxia, retinitis pigmentosa-Leigh syndrome; Danon disease; diabetes; diabetic nephropathy; metabolic disorders; heart failure; ischemic heart disease leading to myocardial infarction; psychiatric disorders, schizophrenia; multiple sulfatase deficiency; mucolipidosis II; mucolipidosis III; mucolipidosis IV; GMI-gangliosidosis;neuronal ceroid lipofuscinosis; Alpers disease; Barth syndrome; beta-oxidation defects; carnitine-acylcarnitine deficiency; carnitine deficiency; creatine deficiency syndromes; coenzyme Q10 deficiency; complex I deficiency; complex II deficiency; complex III deficiency; complex IV deficiency; complex V deficiency; COX deficiency; chronic progressive external ophthalmoplegia syndrome; CPT I deficiency; CPT II deficiency; glutaric aciduria type II; Kearns-Sayre syndrome; lactic acidosis; long-chain acyl-CoA dehydrogenase deficiency; Leigh disease or syndrome; French-Canadian variant of Leigh syndrome; lethal infantile cardiomyopathy; Luft disease; medium-chain acyl-CoA dehydrogenase deficiency; myoclonic epilepsy and ragged-red fiber syndrome; mitochondrial cytopathy; recessive mitochondrial ataxia syndrome; mitochondrial DNA depletion syndrome;Myoneurogastrointestinal disorder and encephalopathy; Pearson syndrome; pyruvate dehydrogenase deficiency; pyruvate carboxylase deficiency; POLG mutations; medium / short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency; very long-chain acyl-CoA dehydrogenase deficiency; peroxisomal disorders; methylmalonic acidemia; mevalonate kinase deficiency; age-dependent decline in cognitive function and muscle strength; and cognitive impairment associated with all neurodegenerative and neuropsychiatric disorders.

23. The compound or use according to claim 22, wherein the neurodegenerative disease is selected from Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, ischemia, stroke, Lewy body dementia, multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, frontotemporal dementia; and Parkinson's disease related to mutations in asynuclein, parkin, PINK1, GBA, and LRRK2, and autosomal recessive juvenile Parkinson's disease or early-onset Parkinson's disease (EOPD), wherein parkin or PINK1 is mutated, truncated, or deleted.

24. The compound or use according to claim 22, wherein the neurodegenerative disease is Leigh syndrome or disease, X-linked Leigh disease, the French-Canadian variant of Leigh syndrome and / or symptoms associated with Leigh disease.

25. The compound or use, according to claim 20 or 21, in frCZC Ln / Zznz / E / YIAI 100 wherein the cancer is selected from breast, ovarian, prostate, lung, kidney, gastric, colon, testicular, head and neck, pancreatic, brain, melanoma, bone, liver, soft tissue, tissue organ cancers, blood cell cancers, CML, AML, mantle cell lymphoma, neuroblastoma, melanoma, soft tissue sarcoma, liposarcoma, fibroblastic sarcoma, leiomyosarcoma, hepatocellular carcinoma, osteosarcoma, esophageal cancer, leukemia, lymphoma, multiple myeloma, metastatic carcinoma, osteosarcoma, chondrosarcoma, Ewing sarcoma, nasopharyngeal carcinoma, colorectal cancer, non-small cell lung carcinoma, cancer wherein apoptotic pathways are dysregulated and cancer where the BCL-2 family proteins are mutated, or over- or under-expressed.

26. The compound or use according to claim 20 or 21, wherein fibrosis is selected from fibrosis or a fibrotic disorder associated with the accumulation of extracellular matrix constituents that occurs following trauma, inflammation, tissue repair, immunological reactions, cellular hyperplasia, and neoplasia.

27. The compound or use according to claim 26, wherein fibrosis is selected from fibrosis or a fibrotic disorder associated with major organ diseases, fibroproliferative disorders, and scarring associated with trauma.

28. The compound or use according to claim 27, wherein fibrosis is selected from fibrosis or a fibrotic disorder associated with interstitial lung disease, hepatic cirrhosis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, kidney disease, acute kidney disease, acute kidney injury, chronic kidney disease, delayed renal graft function, heart or vascular disease, eye diseases, systemic and local scleroderma, keloids, hypertrophic scars, atherosclerosis, restenosis, Dupuytren's contracture, surgical complications, chemotherapeutic drug-induced fibrosis, radiation-induced fibrosis, accidental injuries and burns, retroperitoneal fibrosis, and peritoneal fibrosis / peritoneal scarring.

29. The compound or use according to claim 28, wherein the fibrosis associated with interstitial lung disease is selected from sarcoidosis, silicosis, drug reactions, infections, collagen vascular diseases, rheumatoid arthritis, systemic sclerosis, scleroderma, pulmonary fibrosis, idiopathic pulmonary fibrosis, normal interstitial pneumonitis, interstitial lung disease, cryptogenic fibrosing alveolitis, bronchopulmonary obliterans, and bronchiectasis.

30. The compound or use, according to claim 29, wherein kidney disease is acute kidney disease, acute kidney injury, or chronic kidney disease.

31. A pharmaceutical composition comprising a compound of formula (I) as defined in any of claims 1 to 18, a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, together with one or more pharmaceutically acceptable excipients.

32. A compound, selected from formulas (II)(i), (III)(i), (II)(iii) and (III)(iii): frC7C ίη / 77Π7 / E / YILI, a tautomer thereof, or a salt of said compound or tautomer; wherein R1, R2, R3, R4 and R5 are as defined for the compound of formula (I) in any one of claims 1 to 18; and PG is a protecting group, which is preferably selected from tert-butyloxycarbonyl, benzyloxycarbonyl, 10 p-methoxybenzylcarbonyl, 9-fluorenylmethyloxycarbonyl, acetyl, benzoyl, benzyl, carbamate, p-methoxybenzyl, 3,4-dimethoxybenzyl, p-methoxyphenyl, tosyl, trichloroethoxycarbonyl, 4-nitrobenzenesulfonyl and 2-nitrophenylsulfenyl.