WO2022084479A1 - N-cyanopyrrolidines ayant une activité en tant qu'inhibiteurs de l'usp30 - Google Patents

N-cyanopyrrolidines ayant une activité en tant qu'inhibiteurs de l'usp30 Download PDF

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WO2022084479A1
WO2022084479A1 PCT/EP2021/079278 EP2021079278W WO2022084479A1 WO 2022084479 A1 WO2022084479 A1 WO 2022084479A1 EP 2021079278 W EP2021079278 W EP 2021079278W WO 2022084479 A1 WO2022084479 A1 WO 2022084479A1
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disease
compound
tautomer
fibrosis
deficiency
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Christopher Andrew Luckhurst
Mark Ian Kemp
Paul William Thompson
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Mission Therapeutics Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to a class of N-cyanopyrrolidines with activity as inhibitors of the deubiquitylating enzyme ubiquitin C-terminal hydrolase 30, also known as ubiquitin specific peptidase 30 (USP30), uses thereof, processes for the preparation thereof and composition containing said inhibitors.
  • ubiquitin C-terminal hydrolase 30 also known as ubiquitin specific peptidase 30 (USP30)
  • USP30 ubiquitin specific peptidase 30
  • These inhibitors have utility in a variety of therapeutic areas, including conditions involving mitochondrial dysfunction, cancer and fibrosis.
  • Ubiquitin is a small protein consisting of 76 amino acids that is important for the regulation of protein function in the cell. Ubiquitylation and deubiquitylation are enzymatically mediated processes by which ubiquitin is covalently bound or cleaved from a target protein by deubiquitylating enzymes (DUBs), of which there are approximately 100 DUBs in human cells, divided into sub-families based on sequence homology.
  • DUBs deubiquitylating enzymes
  • the USP family are characterised by their common Cys and His boxes which contain Cys and His residues critical for their DUB activities.
  • the ubiquitylation and deubiquitylation 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.
  • 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 the post-translational regulation via ubiquitylation of many key factors such as mitofusins. In humans, USP30 is a 517 amino acid protein which is found in the mitochondrial outer membrane (Nakamura et al, 2008, Mol Biol 19: 1903-11). It is the sole deubiquitylating enzyme bearing a mitochondrial addressing signal and has been shown to deubiquitylate a number of mitochondrial proteins.
  • USP30 A small proportion of USP30 has been localized to peroxisomes, which are generated through fusion of mitochondrial and ER vesicles, with USP30 potentially antagonizing the Pex2/pexophagy pathway (Riccio et al, 2019, J Cell Biol 218(3): 798-807).
  • the E3 Ub ligase March5 and the deubiquitinase USP30 associate with the translocase and regulate mitochondrial import, and while March5 opposes mitochondrial import and directs degradation of substrates, USP30 deubiquitinates substrates to promote their import (Phu et al, 2020, Molecular Cell 77, 1107-1123).
  • Mitochondrial dysfunction can be defined as diminished mitochondrial content (mitophagy or mitochondrial biogenesis), as a decrease in mitochondrial activity and oxidative phosphorylation, but also as modulation of reactive oxygen species (ROS) generation. Hence a role for mitochondrial dysfunctions in a very large number of aging processes and pathologies.
  • ROS reactive oxygen species
  • Parkinson’s disease affects around 10 million people worldwide (Parkinson’s Disease Foundation) and is characterised by the loss of dopaminergic neurons in the substantia nigra.
  • the exact mechanisms underlying PD are unclear; however mitochondrial dysfunction is increasingly appreciated as a key determinant of dopaminergic neuronal susceptibility in PD and is a feature of both familial and sporadic disease, as well as in toxin-induced Parkinsonism.
  • Parkin is one of a number of proteins that have been implicated with early onset PD. While most PD cases are linked to defects in alpha- synuclein, 10% of Parkinson’s cases are linked to specific genetic defects, one of which is in the ubiquitin E3 ligase parkin.
  • USP30 has been reported that depletion of USP30 enhances mitophagic clearance of mitochondria and also enhances parkin-induced cell death. USP30 has also been shown to regulate BAX/BAK-dependent apoptosis independently of parkin overexpression. Depletion of USP30 sensitises cancer cells to BH-3 mimetics such as ABT-737, without the need for parkin overexpression. Thus, an anti-apoptotic role has been demonstrated for USP30 and USP30 is therefore a potential target for anti -cancer therapy.
  • the ubiquitin-proteasome system has gained interest as a target for the treatment of cancer 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 that target specific aspects of the ubiquitin-proteasome pathway upstream of the proteasome, such as DUBs, 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 leading cause of morbidity and mortality and can affect all tissues and organ systems. Fibrosis is considered to be the result of acute or chronic stress on the tissue or organ, characterized by extracellular matrix deposition, reduction of vascular/tubule/duct/airway patency and impairment of function ultimately resulting in organ failure. Many fibrotic conditions are promoted by lifestyle or environmental factors; however, a proportion of fibrotic conditions can be initiated through genetic triggers or indeed are considered idiopathic (i.e., without a known cause).
  • Certain fibrotic disease such as idiopathic pulmonary fibrosis (IPF) can be treated with non-specific kinase inhibitor (nintedanib) or drugs without a well-characterized mechanism of action (pirfenidone).
  • nintedanib non-specific kinase inhibitor
  • Other treatments for organ fibrosis such as kidney or liver fibrosis, alleviate 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 diet control, may also influence the course and severity of disease.
  • Mitochondrial dysfunction has been implicated in a number of fibrotic diseases, with oxidative stress downstream of dysfunction being the key pathogenic mediator, alongside decreased ATP production.
  • disruption of the mitophagy pathway through mutation or knockout of either parkin or PINK1 exacerbates lung fibrosis and kidney fibrosis, with evidence of increased oxidative stress.
  • MMA methylmalonic acidemia
  • MMUT mitochondrial methylmalonyl -coenzyme A mutase
  • WO 2017/009650 (US 15/738900), WO 2017/093718 (US 15/776149), WO 2017/103614
  • WO 2018/060742 (US 16/336202), WO 2018/060689 (US 16/334836), WO 2018/060691
  • PCT/EP2021/064897 and PCT/EP2021/065112 are expressly incorporated herein by reference.
  • PCT application WO 2019/171042 discloses the use of N-cyanopyrrolidines as inhibitors of USP30 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 treating osteoporosis and other bone-resorption related conditions.
  • PCT application WO 2015/179190 refers to /V-acylethanolamine hydrolysing acid amidase inhibitors, with potential utility in treating ulcerative colitis and Crohn’s disease.
  • PCT application WO 2013/030218 refers to quinazolin-4-one compounds as inhibitors of ubiquitin specific proteases, such as USP7, with potential utility in treating cancer, neurodegenerative diseases, inflammatory disorders and viral infections.
  • PCT applications WO 2015/017502 and WO 2016/019237 refer to inhibitors of Bruton’s tyrosine kinase with potential utility in treating disease such as autoimmune disease, inflammatory disease and cancer.
  • PCT applications WO 2009/026197, WO 2009/129365, WO 2009/129370, and WO 2009/129371 refer to cyanopyrrolidines as inhibitors of Cathepsin C with potential utility in treating COPD.
  • United States patent application US 2008/0300268 refers to polyaromatic compounds as inhibitors of tyrosine kinase receptor PDGFR.
  • PCT application WO 2015/183987 refers to pharmaceutical compositions comprising deubiquitinase inhibitors and human serum albumin in methods of treating cancer, fibrosis, an autoimmune disease or condition, an inflammatory disease or condition, a neurodegenerative disease or condition or an infection.
  • deubiquitinases including UCHL5/UCH37, USP4, USP9X, USP11 and USP15, are said to have been implicated in the regulation of the TGF-beta signalling pathway, the disruption of which gives rise to neurodegenerative and fibrotic diseases, autoimmune dysfunction and cancer.
  • PCT application WO 2006/067165 refers to a method for treating fibrotic diseases using indolinone kinase inhibitors.
  • PCT application WO 2007/119214 refers to a method for treating early stage pulmonary fibrosis using an endothelin receptor antagonist.
  • PCT application WO 2012/170290 refers to a method for treating fibrotic diseases using THC acids.
  • PCT application WO 2018/213150 refers to sulfonamide USP30 inhibitors with potential utility in the treatment of 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, reviews the potential role of mitophagy in renal pathophysiology.
  • Acute Kidney Injury is defined as an abrupt decrease in kidney function occurring over 7 days or less, with severity of injury staged based on increased serum creatinine (SCr) and decreased urine output as described in the Kidney Disease Improving Global Outcomes (KDIGO) guidelines.
  • AKI occurs in about 13.3 million people per year, 85% of whom live in the developing world and it is thought to contribute to about 1.7 million deaths every year (Mehta et al, 2015, Lancet 385(9987): 2616-2643).
  • AKI more than likely results in permanent 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 developing incident CKD, progressive CKD, end-stage renal disease and cardiovascular events.
  • AKI has been found to be prevalent in patients hospitalised by COVID-19 and is strongly associated with hospital mortality, with mitochondrial damage and dysfunction 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 a continuum on the same disease spectrum (Chawla et al, 2017, Nat Rev Nephrol 13(4): 241-257). Patients undergoing coronary artery bypass graft (CABG) are at high risk for kidney injury. There is an obvious unmet medical need in the development of medicinal products for the treatment and/or prevention of AKI.
  • the kidney is a site of high metabolic demand, with high mitophagy rates demonstrated in vivo (McWilliams et al, 2018, Cell Metab 27(2): 439-449 e435). Renal Proximal Tubule Epithelial Cells (RPTECs), a cell type with 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.
  • RPTECs Renal Proximal Tubule Epithelial Cells
  • Mitochondrial dysfunction has been implicated in AKI/CKD mechanisms, both through multiple lines of evidence from preclinical AKI and CKD models and also 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 manifest 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).
  • Parkin knockout animals show exacerbated lung fibrosis in response to bleomycin (Kobayashi et al, 2016, J Immunol, 197:504-516).
  • airway epithelial cells from parkin knockout (KO) animals show exacerbated fibrotic and senescent responses to cigarette smoke (Araya et al, 2019, Autophagy 15(3): 510-526).
  • Preclinical models are available to study potential novel therapeutics, through their ability to model fibrosis pathology (e.g., collagen deposition) consistent with the human condition.
  • Preclinical models can be toxin-mediated (e.g., bleomycin for lung and skin fibrosis), surgical (e.g., ischemia/reperfiision injury model and unilateral ureter obstruction model for acute tubulointerstitial fibrosis), and genetic (e.g., diabetic (db/db) mice for diabetic nephropathy).
  • IPF treatments nintedanib and pirfenidone
  • both examples previously given for indicated IPF treatments show efficacy in the bleomycin lung fibrosis model.
  • the present invention is directed to compounds of formula (I) a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein: R 1 , R 2 and R 3 are each independently selected from hydrogen and fluorine.
  • the present invention is also directed to uses of the compounds of formula (I), particularly in the treatment of conditions involving mitochondrial dysfunction, cancer and fibrosis, and also processes for the preparation thereof and pharmaceutical compositions containing said compounds.
  • the present invention is directed to USP30 inhibitors that have suitable and/or improved properties in order to maximise efficacy against the target disease.
  • properties include, for example, potency, selectivity, physicochemical properties, ADME (absorption, distribution, metabolism and excretion) properties, including PK (pharmacokinetic) profile, and safety profile.
  • USP30 is a transmembrane protein located in the outer membrane of mitochondria, which are energyproducing organelles present inside cells. Therefore, being able to demonstrate cellular activity in vitro is advantageous, as this is one of a number of components that may indicate a greater ability to engage the target in its physiological setting, i.e., where the USP30 inhibitor compound is able to penetrate cells.
  • the USP30 cellular western blot (WB) assay aims to test the activity of compounds against USP30 in cells using an irreversible activity probe to monitor USP30 activity.
  • target engagement assessment (ex vivo) may be carried out in either brain or kidney tissue samples from compound-dosed animals. To extend target binding knowledge to downstream pharmacodynamics, assessment of TOM20 (an outer mitochondrial membrane protein) ubiquitylation may be made.
  • DUB enzymes for which the compounds of the present invention may be screened against are UCHU1, UCHU3, UCHU5, Y0D1, 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.
  • compounds of the invention have
  • targets for which the compounds of the present invention may be screened against 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 kinase and non-kinase enzymes.
  • compounds of the invention have insignificant affinity against targets of this screening panel.
  • targets for which the compounds of the present invention may be screened against are kinases of the Thermo Fisher SelectScreen kinase profiling panel, which includes 39 targets as a representative selection of kinase enzymes.
  • compounds of the invention have insignificant affinity against targets of this screening panel.
  • examples of a particular enzyme class for which the compounds of the present invention may be screened against are the cathepsins (e.g., cathepsins A, B, C, H, K, L, S, V and Z).
  • cathepsins e.g., cathepsins A, B, C, H, K, L, S, V and Z.
  • compounds of the invention have good selectivity for USP30 over one or more of these enzymes.
  • An orally administered drug should have good bioavailability; that is an ability to readily cross the gastrointestinal (GI) tract and not be subject to extensive metabolism as it passes from the GI tract into the systemic circulation. Once a drug is in the systemic circulation the rate of metabolism is also important in determining the time of residence of the drug in the body.
  • GI gastrointestinal
  • the Caco-2 assay is a widely accepted model for predicting the ability of a given molecule to cross the GI tract.
  • the majority of metabolism of drug molecules generally occurs in the liver, and in vitro assays using whole cell hepatocytes (animal or human) are widely accepted methods for measuring the susceptibility of a given molecule towards metabolism in the liver.
  • Such assays aim to predict in vivo clearance from the hepatocyte calculated clearance value.
  • Compounds which have good Caco-2 flux and are stable towards hepatocytes are predicted to have good oral bioavailability (good absorption across the GI tract and minimal extraction of compound as it passes through the liver) and a long residence time in the body that is sufficient for the drug to be efficacious.
  • the solubility of a compound is an important factor in achieving a desired concentration of drug in systemic circulation for the anticipated pharmacological response.
  • Low aqueous solubility is a problem encountered with formulation development of new chemical entities and to be absorbed a drug must be present in the form of solution at the site of absorption.
  • the kinetic solubility of a compound may be measured using a turbidimetric solubility assay, the data from which may also be used in conjunction with Caco-2 permeability data to predict dose dependent human intestinal absorption.
  • parameters that may be measured using standard assays that are indicative of a compound’s exposure profile include, for example plasma stability (half-life measurement), blood AUC, Cmax, and Tmax values.
  • CNS disorders including Alzheimer’s disease, Parkinson’s disease, and other disorders described herein
  • USP30 inhibitors that possess effective blood brain penetration properties and provide suitable residence time in the brain to be efficacious.
  • the probability that a compound can cross the blood brain barrier may be measured by an in vitro flux assay utilizing a MDR1-MDCK cell monolayer (Madin-Darby Canine Kidney cells transfected with MDR-1 resulting in overexpression of the human efflux transporter P -glycoprotein). Additionally, exposure may also be measured directly in brain and plasma using in vivo animal models.
  • a cell toxicity counter-screen may be used to assay the anti-proliferative/cytotoxic effect in a particular cell line (e.g., HCT116) by fluorometric detection of rezasurin (alamarBlueTM) to resofiirin in response to mitochondrial activity.
  • Toxicology and safety studies may also be conducted to identify potential target organs for adverse effects and define the Therapeutic Index to set the initial starting doses in clinical trials. Regulatory requirements generally require studies to be conducted in at least two laboratory animal species, one rodent (rat or mouse) and one nonrodent (rabbit, dog, non-human primate, or other suitable species).
  • the bacterial reverse mutation assay (Ames Test) may be used to evaluate the mutagenic properties of compounds of the invention, commonly by using the bacterial strain Salmonella typhimurium, which is mutant for the biosynthesis of the amino acid histidine.
  • micronucleus assay may be used to determine if a compound is genotoxic by evaluating the presence of micronuclei.
  • Micronuclei may contain chromosome fragments produced from DNA breakage (clastogens) or whole chromosomes produced by disruption of the mitotic apparatus (aneugens).
  • the hERG predictor assay provides valuable information about the possible binding of test compounds to the potassium channel and potential QT prolongation on echocardiogram. Inhibition of the hERG current causes QT interval prolongation resulting in potentially fatal ventricular tachyarrhythmia (Torsades de Pointes).
  • assay data may 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 in order to maximise efficacy against the target disease.
  • properties include, for example, potency, selectivity, physicochemical properties, ADME (absorption, distribution, metabolism and excretion) properties, including PK (pharmacokinetic) profile, and safety profile.
  • Examples 1 and 2 of the present invention are highly potent for USP30, as measured in the biochemical assay described herein. Both Examples of the present invention are significantly more selective for USP30 over 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.
  • the present invention provides a compound of formula (I) a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein: R 1 , R 2 and R 3 are each independently selected from hydrogen and fluorine.
  • the compound of formula (I) exists as a single stereoisomer with the absolute stereochemistry shown.
  • substituted means substituted by one or more defined groups.
  • groups may be selected from more than one alternative, the selected groups may be the same or different.
  • independently means that where more than one substituent is selected from more than one possible substituent, those substituents may be the same or different.
  • R 1 is hydrogen
  • R 2 is hydrogen
  • R 3 is hydrogen
  • the preferred compound of formula (I) of the present invention is:
  • the present invention is also directed to the compound of formula (I)(z) : which is 5-(5-cyano-2-cyclopropoxyphenyl)-N-((3R,5S)-l-cyano-5-(methoxymethyl)pyrrolidin-3-yl)- 1 , 3 ,4-oxadiazole -2 -carboxamide ; a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.
  • the present invention is also directed to uses of the compound of formula (I)(z), particularly in the treatment of conditions involving mitochondrial dysfunction, cancer and fibrosis, and also processes for the preparation thereof and pharmaceutical compositions containing said compounds.
  • References herein to the invention as directed to the compounds of formula (I) also encompass the compound of formula (I)(z) .
  • Pharmaceutical acceptable salts of the compounds of formula (I) include the acid addition and base salts (including di-salts) thereof.
  • Suitable acid addition salts are formed from acids which form non -toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulfate, camsylate, citrate, edisylate, esylate, fumarate, gluceptate, gluconate, glucuronate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, hydrogen phosphate, isethionate, D- and L-lactate, malate, maleate, malonate, mesylate, methylsulfate, 2-napsylate, nicotinate, nitrate, orotate, palmate, phosphate, saccharate, stearate, succinate sulfate, D-and L-tartrate, and tosylate salts.
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, ammonium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
  • a pharmaceutical acceptable salt of a compound of formula (I) may be readily prepared by mixing together solutions of the compound of formula (I) and the desired acid or base, as appropriate.
  • the salt may precipitate from solution and be collected by fdtration or may be recovered by evaporation of the solvent.
  • solvates in accordance with the invention include hydrates and solvates wherein the solvent of crystallization may be isotopically substituted, e.g., D2O, acetone-de, DMSO-de.
  • references to compounds of formula (I) include references to salts thereof and to solvates and clathrates of compounds of formula (I) and salts thereof.
  • the invention includes all polymorphs of the compounds of formula (I) as hereinbefore defined.
  • prodrugs of the compounds of formula (I).
  • certain derivatives of compounds of formula (I) which have little or no pharmacological activity themselves can, when metabolised upon administration into or onto the body, give rise to compounds of formula (I) having the desired activity.
  • Such derivatives are referred to as "prodrugs”.
  • Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of formula (I) with certain moieties known to those skilled in the art as “pro-moieties” as described, for example, in “Design of Prodrugs” by H Bundgaard (Elsevier, 1985). Finally, certain compounds of formula (I) may themselves act as prodrugs of other compounds of formula (I).
  • racemate or the racemate of a salt or derivative
  • HPLC high performance liquid chromatography
  • the racemate or a racemic precursor
  • a suitable optically active compound for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, a base or acid such as 1 -phenylethylamine or tartaric acid.
  • the resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.
  • Chiral compounds of the invention (and chiral precursors thereof) may 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 from 0 to 50% by volume of propan-2 -ol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1% diethylamine.
  • the present invention includes all crystal forms of the compounds of formula (I) including racemates and racemic mixtures (conglomerates) thereof. Stereoisomeric conglomerates may 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).
  • the compounds of formula (I) contain two chiral centres at the carbon atoms of the pyrrolidine ring that are substituted by methoxymethyl and the amide, and said stereocentres could exist in either the (R) or (.S') configuration.
  • the designation of the absolute configuration (R) and (.S') for stereoisomers in accordance with IUPAC nomenclature is dependent on the nature of the substituents and application of the sequence -rule procedure.
  • 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 (/?)-stcrcoccntrc and the pyrrolidine carbon atom of the methoxymethyl group exists as the (.S)-stcrcoccntrc .
  • the compound of formula (I) is isolated as a single stereoisomer and may exist with a stereoisomeric excess of at least 60%, preferably at least 80%, more preferably at least 90%, more preferably at least 95%, for example 96%, 97%, 98%, 99%, or 100%.
  • 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 an atomic mass different from the atomic mass usually found in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 13 C and 14 C, nitrogen, such as 15 N, oxygen, such as 17 O and 18 O, phosphorus, such as 32 P, sulfur, such as 35 S, fluorine, such as 18 F, and chlorine, such as 36 C1.
  • Substitution of the compounds of the invention with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo halflife or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Certain isotopic variations of the compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, and 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Isotopic variations of the compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using appropriate isotopic variations of suitable reagents.
  • the compounds of formula (I) are inhibitors of the deubiquitylating enzyme USP30.
  • 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.
  • the present invention provides a method of treatment or prevention of 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.
  • the disorder or condition is a CNS indication.
  • the disorder or condition is a peripheral indication.
  • the present invention provides 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 shown, to produce a beneficial effect.
  • the manufacture of a medicament may include, inter aha, 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.
  • the disorder or condition is a CNS indication.
  • the disorder or condition is a peripheral indication.
  • the present invention provides a method of inhibition of 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 said compound or tautomer.
  • the disorder or condition benefiting from USP30 activity is selected from a condition involving mitochondrial dysfunction, cancer and fibrosis.
  • the disorder or condition benefiting from USP30 activity is a condition involving mitochondrial dysfunction.
  • the condition involving mitochondrial dysfunction may be a CNS indication or a peripheral indication.
  • Mitochondrial dysfunctions result from defects of the mitochondria, which are specialized compartments present in every cell of the body except red blood cells. When mitochondria fail, less and less energy is generated within the cell and cell injury or even cell death will follow. If this process is repeated throughout the body the life of the subject in whom this is happening is severely compromised. Diseases of the mitochondria appear most often in organs that are very energy demanding such as the brain, heart, liver, skeletal muscles, kidney and the endocrine and respiratory system.
  • the condition involving mitochondrial dysfunction may 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.
  • 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's hereditary optic neuropathy (LHON); cancer (including, for example, breast, ovarian, prostate, lung, kidney, gastric, colon, testicular, head and neck, pancreas, brain, melanoma, bone or other cancers of tissue organs and cancers of the blood cells, such as lymphoma and leukaemia, multiple myeloma, metastatic carcinoma, osteosarcoma, chondosarcoma, Ewing’s 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 acid
  • 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, dementia with Lewy bodies, multiple system atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal dementia.
  • Parkinson’s disease Alzheimer’s disease
  • ALS amyotrophic lateral sclerosis
  • Huntington’s disease ischemia
  • stroke dementia with Lewy bodies
  • MSA multiple system atrophy
  • PSP progressive supranuclear palsy
  • CBD corticobasal degeneration
  • frontotemporal dementia frontotemporal dementia
  • the compounds of the invention may be useful in the treatment or prevention of Parkinson’s disease, including, but not limited to, PD related to mutations in a-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.
  • Parkinson’s disease including, but not limited to, PD related to mutations in a-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.
  • the compounds of the invention may be useful in 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 and major depressive disorders.
  • 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 and major depressive disorders.
  • 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 monoamino 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 anti-convulsant.
  • additional agents selected from levodopa, a dopamine agonist, a monoamino oxygenase (MAO) B inhibitor, a catechol O-methyltransferase (COMT) inhibitor, an anticholinergic, riluzole, amantadine,
  • the compounds may be combined with agents which reduce/remove pathogenic protein aggregates in neurodegenerative diseases, such as agents which reduce/remove alpha-synuclein in Parkinson’s disease, multiple system atrophy or dementia with Lewy bodies; agents which reduce/remove Tau in Alzheimer’s disease or progressive supranuclear palsy; agents which reduce/remove TDP-43 in ALS or frontotemporal dementia.
  • agents which reduce/remove pathogenic protein aggregates in neurodegenerative diseases such as agents which reduce/remove alpha-synuclein in Parkinson’s disease, multiple system atrophy or dementia with Lewy bodies; agents which reduce/remove Tau in Alzheimer’s disease or progressive supranuclear palsy; agents which reduce/remove TDP-43 in ALS or frontotemporal dementia.
  • the disorder or condition benefiting from USP30 activity 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, pancreas, brain, melanoma, bone or other cancers of tissue organs and cancers of the blood cells, such as lymphoma and leukaemia, multiple myeloma, metastatic carcinoma, osteosarcoma, chondosarcoma, Ewing’s sarcoma, nasopharyngeal carcinoma, colorectal cancer, colorectal cancer, and non-small cell lung carcinoma.
  • the compounds of the invention may be useful in the treatment or prevention of cancer where apoptotic pathways are dysregulated and more particularly where proteins of the BCL-2 family 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 may be treated by the compounds and compositions of the present invention include, inter alia, 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 kidney graft function, heart or vascular disease (cardiac fibrosis) and diseases of the eye; fibroproliferative disorders, for example, systemic and local scleroderma, keloids and hypertrophic scars, atherosclerosis, restenosis, and Dupuytren’s contracture; scarring associated
  • the present invention therefore relates to methods of treatment or prevention, and compounds and compositions used in said methods, of fibrosis/fibrotic disorders of and/or associated with the major organs, including for example, the lung, liver, kidney, heart, skin, eye, gastrointestinal tract, peritoneum and bone marrow, and other diseases/disorders herein described.
  • the compounds may be combined with agents which are used as treatments for kidney disease, including anti-diabetic agents, cardiovascular disease agents, and novel agents targeting disease relevant 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).
  • agents which are used as treatments for kidney disease including anti-diabetic agents, cardiovascular disease agents, and novel agents targeting disease relevant 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 includes disorders in which pulmonary inflammation and fibrosis are the final common pathways of pathology, for example, sarcoidosis, silicosis, drug reactions, infections, and collagen vascular diseases, such as rheumatoid arthritis and systemic sclerosis (scleroderma).
  • the fibrotic disorder of the lung includes, for example, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), usual interstitial pneumonitis (UIP), interstitial lung disease, cryptogenic fibrosing alveolitis (CFA), bronchiolitis obliterans, and bronchiectasis.
  • Idiopathic pulmonary fibrosis is the most common type of ILD and has no known cause.
  • the compounds may be combined with agents which 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 may be associated with diabetes, which can damage and scar the kidneys leading to a progressive loss of function, and also hypertensive diseases.
  • Kidney fibrosis may occur at any stage of kidney disease, from acute kidney disease (AKD) post injury and chronic kidney disease (CKD), such as incident CKD and progressive CKD, through to end-stage renal disease (ESRD).
  • Kidney fibrosis can develop as a result of cardiovascular disease such as hypertension or diabetes, both of which place immense strain on kidney function which promotes a fibrotic response.
  • kidney fibrosis can also be idiopathic (without a known cause), and certain genetic mitochondrial diseases also present kidney fibrosis manifestations and associated symptoms.
  • Heart disease may result in scar tissue that can impair the ability of the heart to pump.
  • Diseases of the eye include, for example, macular degeneration and retinal and vitreal retinopathy, which can impair vision.
  • the present invention is directed to the treatment or prevention of idiopathic pulmonary fibrosis (IPF).
  • IPF idiopathic pulmonary fibrosis
  • the present invention is directed to the treatment or prevention of kidney fibrosis.
  • the present invention is directed to the treatment or prevention of acute kidney injury (AKI), especially in high risk patients.
  • AKI acute kidney injury
  • organ transplantation such as due to ischemia reperfusion injury, delayed graft function
  • oncology such as AKI due to chemotherapy
  • contrast medium-induced nephropathy such as direct- tubular cytotoxicity, hemodynamic ischemia and osmotic effects
  • acute interstitial nephritis such as due to drugs or infection
  • AKI due to obstruction such as kidney stones
  • COVID-19-induced AKI A particular high risk patient sub-group are those undergoing cardiac surgery, for example, coronary artery bypass graft and/or valve surgery.
  • AKI AKI-related diabetes
  • CKD adults with an estimated glomerular filtration rate [eGFR] less than 60 ml/min/1.73 m2 are at particular risk
  • heart failure heart failure
  • liver disease history of AKI.
  • the present invention is directed to the treatment or prevention of acute kidney disease (AKD) or chronic kidney disease (CKD) stemming from such AKI, including for example, tubulointerstitial fibrosis and diabetic nephropathy.
  • AKI acute kidney disease
  • CKD chronic kidney disease
  • 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 including, for example, NAFLD, NASH, liver cirrhosis, portal hypertension, acute liver failure, and hepatocellular carcinoma.
  • Liver disease such as NAFLD and NASH may be associated with various metabolic conditions such as metabolic syndrome and Type II diabetes, which also would increase risk for various diabetes associated pathologies, including diabetic retinopathy and peripiheral neuropathies.
  • 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 liver disease and metabolic dysfunction, including metformin, sulfonylureas, DPP-4 inhibitors, GLP-1 agonists, PP AR agonists, SGLT2 inhibitors, angiotensin -converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs).
  • 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, PP AR 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 teenagers and adults. Leigh syndrome can be caused by mutations in nuclear DNA encoding for mitochondrial proteins, mutations in mitochondrial DNA (maternally inherited Leigh syndrome - MILS), or by deficiencies of an enzyme called pyruvate dehydrogenase located on the short arm of the X Chromosome (X-linked Leigh syndrome). Symptoms of Leigh syndrome usually progress rapidly. The earliest signs may be poor sucking ability, and the loss of head control and motor skills. These symptoms may be accompanied by loss of appetite, vomiting, irritability, continuous 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 impairment of respiratory and kidney function.
  • MILS maternally inherited Leigh syndrome
  • genetic mutations in mitochondrial DNA interfere with the energy sources that run cells in an area of the brain that plays a role in motor movements.
  • Genetic mutations in mitochondrial DNA result in a chronic lack of energy in these cells, which in turn affects the central nervous system and causes progressive degeneration of motor functions.
  • NARP neuropathy ataxia and retinitis pigmentosa
  • Leigh X-linked Leigh's disease
  • Leigh syndrome is also a form of Leigh syndrome which is called French Canadian variant, characterized by mutations in a gene called LRPPRC. Similar neurological symptoms are expressed as those for Leigh syndrome, although Liver Steatosis is commonly also observed in the French Canadian variant.
  • the present invention is directed to the treatment or prevention of Leigh syndrome or disease, including for example, X-linked Leigh's disease, Leigh syndrome French Canadian variant, and/or the symptoms associated with Leigh’s disease.
  • the compounds may be combined with novel agents which may be used as treatments for mitochondrial disease, including, but not limited to, nicotinamide riboside.
  • References to ‘treatment’ includes means to ameliorate, alleviate symptoms, eliminate the causation of the symptoms either on a temporary or permanent basis.
  • the compounds of the invention are useful in the treatment of the diseases disclosed herein in humans and other mammals.
  • the invention encompasses prophylactic therapy of the diseases disclosed herein and includes means to prevent or slow the appearance of symptoms of the named disorder or condition.
  • the compounds of the invention are useful in the prevention of the diseases disclosed herein in humans and other mammals.
  • a patient in need of treatment or prevention may, for example, be a human or other mammal suffering from the condition or at risk of suffering from the condition.
  • the present invention provides a pharmaceutical composition
  • 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.
  • compositions of the invention comprise any of the compounds of the invention combined with any pharmaceutically acceptable carrier, adjuvant or vehicle.
  • pharmaceutically acceptable carriers include, but are not limited to, preserving agents, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavouring agents, perfuming agents, 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.
  • composition in the context of this invention means a composition comprising an active agent and comprising additionally one or more pharmaceutically acceptable carriers.
  • the composition may further contain ingredients selected from, for example, diluents, adjuvants, excipients, vehicles, preserving agents, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavouring agents, perfuming agents, 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 combined with one or more additional pharmaceutical agents.
  • the compounds may be combined with an additional anti-tumour therapeutic agent, for example, chemotherapeutic drugs or inhibitors of other regulatory proteins.
  • the additional anti -tumour therapeutic agent is a BH-3 mimetic.
  • BH-3 mimetics may be selected from but not limited to one or more of ABT-737, ABT-199, ABT-263, and Obatoclax.
  • the additional anti-tumour agent is a chemotherapeutic agent.
  • Chemotherapeutic agents may be selected from but not limited to, olaparib, mitomycin C, cisplatin, carboplatin, oxaliplatin, ionizing radiation (IR), camptothecin, irinotecan, topotecan, temozolomide, taxanes, 5 -fluoropyrimidines, gemcitabine, and doxorubicin.
  • the compounds of the invention or pharmaceutical compositions thereof, as described herein may be used alone or combined 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.
  • 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.
  • the compounds of the invention or pharmaceutical compositions thereof, as described herein may be used alone or combined with one or more additional pharmaceutical agents selected from the group consisting of general immunosuppressive drugs, such as a corticosteroid, immunosuppressive or cytotoxic agents, or antifibrotics, such as pirfenidone or a non-specific kinase inhibitor (e.g., nintedanib).
  • general immunosuppressive drugs such as a corticosteroid, immunosuppressive or cytotoxic agents, or antifibrotics, such as pirfenidone or a non-specific kinase inhibitor (e.g., nintedanib).
  • compositions of the invention may be administered in any suitably effective manner, such as oral, parenteral, topical, inhaled, intranasal, rectal, intravaginal, ocular and aural.
  • Pharmaceutical compositions suitable for the delivery of 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 may be found, for example, in "Remington's Pharmaceutical Sciences", 19th Edition (Mack Publishing Company, 1995).
  • the compounds of the invention may be administered orally.
  • Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.
  • Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi-and nanoparticulates, gels, films (including muco- adhesive), ovules, sprays and liquid formulations.
  • Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
  • the compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986 by Liang and Chen (2001).
  • a typical tablet may be prepared using standard processes known to a formulation chemist, for example, by direct compression, granulation (dry, wet, or melt), melt congealing, or extrusion.
  • the tablet formulation may comprise one or more layers and may be coated or uncoated.
  • excipients suitable for oral administration include carriers, for example, cellulose, calcium carbonate, dibasic calcium phosphate, mannitol and sodium citrate, granulation binders, for example, poly vinylpyrrolidine, hydroxypropylcellulose, hydroxypropylmethylcellulose and gelatin, disintegrants, for example, sodium starch glycolat and silicates, lubricating agents, for example, magnesium stearate and stearic acid, wetting agents, for example, sodium lauryl sulfate, preservatives, anti-oxidants, flavours and colourants.
  • carriers for example, cellulose, calcium carbonate, dibasic calcium phosphate, mannitol and sodium citrate
  • granulation binders for example, poly vinylpyrrolidine, hydroxypropylcellulose, hydroxypropylmethylcellulose and gelatin
  • disintegrants for example, sodium starch glycolat and silicates
  • lubricating agents for example, magnesium stearate and stearic acid
  • wetting agents for
  • Solid formulations for oral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled dual-, targeted and programmed release. Details of suitable modified release technologies such as high energy dispersions, osmotic and coated particles are to be found in Verma et al, Pharmaceutical Technology On-line, 25 (2), 1-14 (2001). Other modified release formulations are described in US Patent No. 6,106,864.
  • the compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ.
  • Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrastemal, intracranial, intramuscular, and subcutaneous.
  • Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors, and infusion techniques.
  • Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates, and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
  • excipients such as salts, carbohydrates, and buffering agents (preferably to a pH of from 3 to 9)
  • a suitable vehicle such as sterile, pyrogen-free water.
  • parenteral formulations under sterile conditions may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
  • solubility of compounds of formula (I) used in the preparation of parenteral solutions may be increased by suitable processing, for example, the use of high energy spray -dried dispersions and/or using appropriate formulation techniques, such as the use of solubility -enhancing agents.
  • Formulations for parenteral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed, sustained, pulsed, controlled dual, targeted, and programmed release.
  • Pharmaceutical compositions of the present invention also include compositions and methods known in the art for bypassing the blood brain barrier or can be injected directly into the brain. Suitable areas for injection include the cerebral cortex, cerebellum, midbrain, brainstem, hypothalamus, spinal cord and ventricular tissue, and areas of the peripheral nervous system including the carotid body and the adrenal medulla.
  • the magnitude of an effective dose of a compound will, of course, vary with the nature of the severity of the condition to be treated and the route of administration. The selection of appropriate dosages is within the remit of the physician.
  • the daily dose range is about 10 pg to about 100 mg per kg body weight of a human and non-human animal and in general may be around 10 pg to 30 mg per kg body weight per dose. The above dose may be given from one to three times per day.
  • oral administration may require a total daily dose of from 5 mg to 1000 mg, such as from 5 to 500 mg, while an intravenous dose may only require from 0.01 to 30 mg/kg body weight, such as from 0. 1 to 10 mg/kg, more preferably from 0. 1 to 1 mg/kg body weight.
  • the total daily dose may be administered in single or divided doses.
  • compounds of the invention may be taken as a single dose on an "as required" basis (i.e., as needed or desired).
  • the present invention provides a process for the preparation of a compound of formula (I) comprising reacting a compound of formula (IV), where Y is OH with an amine of formula (V), where PG is a protecting group, such as BOC or Cbz, to give an amide of formula (III) (Scheme 1).
  • the amide -coupling reaction can be performed using standard methodology, for example by reaction using a coupling reagent such as DCC, HATU, HBTU, EDC or via a mixed anhydride.
  • the acid (IV), where Y is OH can be converted into the acid chloride (IV), where Y is Cl, using SOCE, PCh, or PCI5, which can then be reacted with the amine (V), preferably in a suitable solvent in the presence of a suitable base.
  • the compound (IV), where Y forms the ester can be reacted directly with the amine (V), preferably in a suitable solvent.
  • the compound of formula (III) may be deprotected using standard methods to give amine (II) which may then be reacted with cyanogen bromide to give the corresponding compound of formula (I).
  • the present invention provides a compound, which is selected from formulae (II) and (III): wherein PG is a protecting group and R 1 , R 2 and R 3 are as defined herein for the compound of formula (I) and preferred embodiments thereof, a tautomer thereof, or a salt of said compound or tautomer.
  • the present invention provides a compound, which is selected from formulae (II)(z) and (III)(z): wherein PG is a protecting group, a tautomer thereof, or a salt of said compound or tautomer.
  • 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 (Troc), 4 -nitrobenzene sulfonyl (Nosyl) and 2-nitrophenylsulfenyl (Nps). Most preferred are BOC and Cbz.
  • Dilution plates were prepared at 21 times the final concentration (2100 pM for a final concentration of lOOpM) 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 pM final. Reactions were performed in duplicate in black 384 well plates (small volume, Greiner 784076) in a final reaction volume of 21 pl. Either Ipl of 50% DMSO or diluted compound was added to the plate.
  • USP30 (Boston Biochem #E582) was diluted in reaction buffer (40 mM Tris, pH 7.5, 0.005% Tween 20, 0.5 mg/ml BSA, 5 mM beta-mercaptoethanol) to achieve a final assay concentration of 4 nM, and 10 pl of diluted USP30 was added to the compound. Enzyme and compound were incubated for 30 min at room temp. Reactions were initiated by the addition of 50 nM of TAMRA labelled peptide linked to ubiquitin via an isopeptide bond as fluorescence polarisation substrate. Reactions were read immediately after addition of substrate and following a 2-hour incubation at room temperature. Readings were performed on a Pherastar Plus (BMG Labtech). X Excitation 540 nm; X Emission 590 nm. Activity of exemplary compounds in USP30 biochemical IC50 assay:
  • Human cell lines can be challenged with mitochondrial depolarizing agents (ionophores (eg. CCCP, valinomycin), mitochondrial complex inhibitors (oligomycin, antimycin A)) to induce ubiquitylation of ionophores (eg. CCCP, valinomycin), mitochondrial complex inhibitors (oligomycin, antimycin A)) to induce ubiquitylation of ionophores (eg. CCCP, valinomycin), mitochondrial complex inhibitors (oligomycin, antimycin A)) to induce ubiquitylation of ionophores (eg. CCCP, valinomycin), mitochondrial complex inhibitors (oligomycin, antimycin A)) to induce ubiquitylation of ionophores (eg. CCCP, valinomycin), mitochondrial complex inhibitors (oligomycin, antimycin A)) to induce ubiquitylation of ionophores (eg. CCCP, valinomycin), mitochondrial complex inhibitors (oligomycin, antimycin
  • TOM20 which is then further promoted in the presence of USP30 inhibitors.
  • TOM20 ubiquitylation is subsequently assessed through western blotting of the cell lysates, with TOM20 ubiquitylation adduct detection possible due to an 8 kDa molecule weight increase for each molecule of ubiquitin added, resulting in laddering of a TOM20 immunoreactive band.
  • TOM20-ubiquitylation levels can be quantified using chemiluminescence densitometry of laddered immunoreactive bands.
  • log P partition coefficient; lipophilicity measurement.
  • log D distribution co-efficient; lipophilicity measurement.
  • TPSA topological polar surface area.
  • Turbidimetric solubility Test compound solution prepared in DMSO diluted into aqueous buffer. Turbidimetry is used as the end-point by measuring absorbance at 620 nm.
  • FaSSIF simulated intestinal fluid in fasted state measured at pH 6.5.
  • Hep Cl mouse in vitro hepatocyte clearance in mouse cells.
  • Hep Cl human in vitro hepatocyte clearance in human cells.
  • Plasma f u , p The free fraction of a compound in plasma preparation determined by in vitro equilibrium dialysis. It is understood that only unbound (free) compound is capable of engaging with the target.
  • Brain f Uj b r The free fraction of a compound in brain homogenate preparation determined by in vitro equilibrium dialysis. It is understood that only unbound (free) compound is capable of engaging with the target.
  • Cl u in vitro clearance.
  • Cl u as defined here is the scaled clearance, in turn calculated from the intrinsic clearance.
  • the intrinsic clearance is the predicted clearance due to hepatic metabolic reactions, determined from incubation of a compound in a hepatocyte preparation. The lower the value in mL/min/kg, the more stable the compound.
  • Cl in vivo clearance Pharmacokinetic measurement of the volume of plasma (or any matrix) from which a substance is completely removed per unit time. The lower the value in mL/min/kg, the more stable the compound.
  • Oral F Oral Bioavailability.
  • MDR1-MDCK Mesdin-Darby Canine Kidney cell monolayer
  • in vitro flux assay
  • WT-MDCK wild-type
  • Cell TE WB USP30 endogenous cellular target engagement western blot (WB) assay. Assays the activity of compounds against USP30 in cells using an irreversible activity probe to monitor USP30 activity.
  • TE ex vivo USP30 kidney tissue target engagement assay.
  • Kp uu is the ratio of unbound drug in brain to unbound drug in plasma and may be indicative of potential for treating peripheral and/or CNS indications.
  • Examples 1 and 2 possess beneficial properties demonstrating potential superiority over other compounds. For instance, the observed IV plasma clearance of 23 mL/min/kg, as measured in the mouse, is low, demonstrating valuable plasma stability, and the compound has good oral bioavailability of 25%.
  • Reference Examples A, B, C, D and E are known DUB inhibitors that have been identified as active as inhibitors of USP30 and share some structural similarity with the compounds of the present invention, possessing the cyanamide structural feature.
  • Reference Examples C, D and E are disclosed in WO 2016/046530 as having UCHL1 inhibitory activity.
  • Examples 1 and 2 of the present invention are more potent against USP30 than the Reference Examples, as measured in the biochemical assay, with Example 1 being 4.4 to 440-fold more potent.
  • Example 1 is significantly more selective for USP30 over 10 DUBs compared to Reference Examples A and B (USP2, USP6, USP10, USP16, USP21, USP22, USP25, USP28, USP35 and USP46).
  • Example 1 is, at a minimum, 290-fold more potent against USP30 than against each of the 10 DUBs.
  • Example 2 is significantly more selective for USP30 over 7 DUBs compared to Reference Examples A and B (USP2, USP6, USP10, USP16, USP21, USP25 and USP28; activity against USP22, USP35 and USP46 was not measured).
  • Example 2 is, at a minimum, 189-fold more potent against USP30 than against each of the 7 DUBs.
  • Examples 1 and 2 are 30000-fold and 8570-fold more potent, respectively, against USP30 than UCHL1 and are therefore significantly more selective compared to the Reference Examples.
  • Reference Examples C and D show inverse selectivity, being selective for UCHL1 over USP30.
  • Examples 1 and 2 are significantly more selective for USP30 over the cathepsins (B, K, L, S and V) compared to Reference Examples A and B.
  • Examples 1 and 2 are, at a minimum, 2870-fold and 417-fold more potent, respectively, against USP30 than against each of the cathepsins. This is a significant advantage over A and B, which against one cathepsin are 11 -fold and 22-fold more potent, respectively.
  • Examples 1 and 2 are significantly more selective for USP30 over Cathepsin L compared to Reference Examples C and D.
  • Examples 1 and 2 are 2870-fold and 1594-fold more potent, respectively, against USP30 than against Cathepsin L. This is a significant advantage over C and D, which are 0.48-fold and 3.2-fold more potent, respectively.
  • mice model effects on 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]

Abstract

La présente invention concerne une classe de N-cyanopyrrolidines ayant une activité en tant qu'inhibiteurs de l'enzyme de désubiquitinylation USP30, ayant une utilité dans une variété de champs thérapeutiques, y compris pour des états pathologiques impliquant un dysfonctionnement mitochondrial, un cancer et une fibrose : Formule (I).
PCT/EP2021/079278 2020-10-22 2021-10-21 N-cyanopyrrolidines ayant une activité en tant qu'inhibiteurs de l'usp30 WO2022084479A1 (fr)

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WO2023099561A1 (fr) 2021-12-01 2023-06-08 Mission Therapeutics Limited N-cyanopyrrolidines substituées ayant une activité en tant qu'inhibiteurs de l'usp30

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