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WO2025021711A1 - Composés pharmaceutiques - Google Patents

Composés pharmaceutiques Download PDF

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WO2025021711A1
WO2025021711A1 PCT/EP2024/070617 EP2024070617W WO2025021711A1 WO 2025021711 A1 WO2025021711 A1 WO 2025021711A1 EP 2024070617 W EP2024070617 W EP 2024070617W WO 2025021711 A1 WO2025021711 A1 WO 2025021711A1
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methyl
diazaspiro
carbonyl
difluorophenyl
decan
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Matthew Duncan HELM
Adam Piotr TREDER
James Samuel Shane Rountree
Mary Mcfarland
Steven David SHEPHERD
Natalia Wanda SALEWSKA
Frank Burkamp
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Almac Discovery Ltd
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Almac Discovery Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D411/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D415/00—Heterocyclic compounds containing the thiamine skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention concerns inhibitors of ubiquitin specific protease 19 (USP19) and methods of use thereof.
  • USP19 ubiquitin specific protease 19
  • Ub conjugation I deconjugation machinery Interfering with the ubiquitin (Ub) conjugation I deconjugation machinery, for instance at the level of the Ubiquitin Specific Proteases (USPs), would allow for the development of improved therapeutics with enhanced specificity and reduced toxicity profiles.
  • USPs are the largest subfamily of the deubiquitinating enzymes (DUBs) family with over 60 family members reported to date (Komander D. etal., Nat. Rev. Mol. Cell Biol. (2009), 10, 550-563; Clague M. etal., Physiol. Rev. (2013), 93, 1289-1315). USPs are typically cysteine proteases that catalyse the removal of Ub from specific target substrates thus preventing their induced degradation by the proteasome, or regulating their activation and/or subcellular localization (Daviet L. etal., Biochimie (2008), 90, 270-283; Nicholson B. etal., Cell Biochem. Biophys. (2011), 60, 61-68). It is now well established that USPs regulate the stability and activation of numerous proteins involved in the pathogenesis of human diseases including both oncogenes and tumour suppressors. As such, USPs represent an emerging and attractive target class for pharmacological intervention.
  • DRBs
  • USP19 is an important member due to its association with a number of important pathways with implications for pathological conditions including but not restricted to cancer, neurodegeneration and degenerative diseases as well as antiviral immune response.
  • USP19 expresses as multiple isoforms varying in length from 71.09 kDa (isoform 2) to 156.03 kDa (isoform 5) with the canonical sequence (isoform 1) of 145.65 kDa in size (uniprot.org).
  • the cellular localisation of USP19 may be cytosolic or bound to the endoplasmic reticulum (Lee J. etal., J. Biol. Chem. (2014), 289, 3510-3517; Lee J.
  • USP19 is a key component of the endoplasmic reticulum-associated degradation (ERAD) pathway (Hassink B. etal., EMBO Rep. (2009), 10, 755-761 ; Lee J. etal., J. Biol. Chem. (2014), 289, 3510-3517; Lee J. etal., Nat. Cell Biol. (2016), 18, 765-776).
  • ERAD endoplasmic reticulum-associated degradation pathway
  • USP19 has also been demonstrated to regulate the stability of the E3 ligases MARCH6 and HRD1 (Nakamura N. etal., Exp. Cell Res. (2014), 328, 207-216; Harada K. etal., Int. J. Mol. Sci. (2016), 17, 1829).
  • USP19 has recently been implicated in the stabilisation of multiple and potentially important protein substrates. For instance, USP19 interacts with SIAH proteins to rescue HIF1a from degradation under hypoxic conditions (Altun M. etal., J. Biol. Chem. (2012), 287, 1962-1969; Velasco K. etal., Biochem. Biophys. Res. Commun. (2013), 433, 390-395).
  • USP19 also stabilises the KPC1 ubiquitin ligase which is involved in the regulation of the p27 Kip1 cyclin-dependent kinase inhibitor (Lu Y. etal., Mol. Cell Biol. (2009), 29, 547-558). Knock-out of USP19 by RNAi leads to p27 Kip1 accumulation and inhibition of cell proliferation (Lu Y. etal., PLoS ONE (2011), 6, e15936). USP19 was also found to interact with the inhibitors of apoptosis (lAPs) including C-IAP1 and C-IAP2 (Mei Y. etal., J. Biol. Chem. (2011), 286, 35380-35387).
  • lAPs inhibitors of apoptosis
  • Knockdown of USP19 decreases the total levels of these c-IAPs whilst overexpression increases the levels of both BIRC2/clAP1 and BIRC3/clAP2. Knockdown of USP19 also enhances TNFa-induced caspase activation and apoptosis in a BIRC2/C-IAP1 and BIRC3/C-IAP2 dependent manner. In addition to some direct involvement in regulating hypoxia response and ER stress, USP19 has also been implicated recently as a positive regulator of autophagy and negative regulator of type I interferon signalling (IFN, antiviral immune response) by deubiquitinating Beclin-1.
  • IFN type I interferon signalling
  • USP19 was found to stabilise Beclin-1 at the post-translational level by removing the K11 -linked ubiquitin chains of Beclin-1 at Lysine 437 (Jin S. eta!., EMBOJ. (2016), 35, 866-880). USP19 negatively regulates type I IFN signalling pathway, by blocking RIG-I-MAVS interaction in a Beclin-1 dependent manner. Depletion of either USP19 or Beclin-1 inhibits autophagic flux and promotes type I IFN signalling as well as cellular antiviral immunity (Jin S. etal., EMBO J. (2016), 35, 866-880; Cui J. etal., Autophagy (2016), 12, 1210-1211).
  • USP19 may negatively affect the cellular antiviral type I IFN signalling by regulating the TRAF3 substrate (Gu Z. etal., Future Microbiol. (2017), 12, 767-779). USP19 has also been recently implicated in the Wnt signalling pathway by stabilising the coreceptor LRP6 (Perrody E. etal., eLife (2016), 5, e19083) and in the DNA repair processes, most particularly chromosomal stability and integrity, by regulating the HDAC1 and HDAC2 proteins (Wu M. etal., Oncotarget (2017), 8, 2197-2208).
  • USP19 has been linked in gene knock-out studies to muscle-wasting syndromes and other skeletal muscle atrophy disorders (Wing S., Int. J. Biochem. Cell Biol. (2013), 45, 2130-2135; Wing S., Int. J. Biochem. Cell Biol. (2016), 79, 426-468; Wiles B. etal., Mol. Biol. Cell (2015), 26, 913-923; Combaret L. etal., Am. J. Physiol. Endocrinol. Metab. (2005), 288, E693-700, each of which is incorporated herein by reference).
  • Muscle wasting associated with conditions such as cachexia is known to impair quality of life and response to therapy, which increase morbidity and mortality of cancer patients. Muscle wasting is also associated with other serious illnesses such as HIV/AIDS, heart failure, rheumatoid arthritis and chronic obstructive pulmonary disease (Wiles B. etal., Mol. Biol. Ce// (2015), 26, 913-923). Muscle wasting is also a prominent feature of aging.
  • USP19 may also have implications in the pathogenesis of degenerative diseases including but not restricted to Parkinson’s disease and other prion-like transmission disorders by regulating important substrates such as a- synuclein or polyglutamine-containing proteins, Ataxin3, Huntington (He W. etal., PLoS ONE (2016), 11 , e0147515; Bieri G. etal., Neurobiol Dis. (2016), 109B, 219-225).
  • important substrates such as a- synuclein or polyglutamine-containing proteins, Ataxin3, Huntington (He W. etal., PLoS ONE (2016), 11 , e0147515; Bieri G. etal., Neurobiol Dis. (2016), 109B, 219-225).
  • coronin 2A C0R02A
  • RAR retinoic acid receptor
  • WO 2022/200523 A1 discloses compounds that are useful as inhibitors of the activity of the ubiquitin specific protease USP19 and also relates to pharmaceutical compositions comprising these compounds and to methods of using these compounds in therapy.
  • R 1 is optionally substituted C1 -C6 alkyl, optionally substituted amino, optionally substituted 3 to 11 membered heterocycloalkyl, optionally substituted aryl, or optionally substituted 5 to 8 membered heteroaryl;
  • R 2 and R 3 are each independently selected from H and C1 -C6 alkyl, or wherein R 2 and R 3 together form C3-C8 cycloalkyl, C3-C8 cycloalkenyl or 3 to 8 membered heterocycloalkyl together with the carbon to which they are attached;
  • M is N or CR a wherein R a is H, halo, optionally substituted C3-C8 cycloalkyl, or optionally substituted C1-C6 alkyl;
  • A, D, E and G are absent and
  • X is NR 15 or CH
  • Y is CR 4 or N or absent
  • Z is CR 5 , NR 6 or O
  • R 4 is halo, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted 5 to 8 membered heteroaryl, 4 to 10 membered fused-ring heterocyclyl, optionally substituted C1 -C6 alkylsulfanyl, sulfoxide, sulfone, sulfoximine, optionally substituted amino, optionally substituted 3 to 8 membered heterocycloalkyl, or OR 20 ; wherein R 20 is optionally substituted C1 -C6 alkyl;
  • R 5 is H, optionally substituted C1 -C6 alkyl, optionally substituted aryl, optionally substituted 5 to 8 membered heteroaryl, optionally substituted 3 to 8 membered heterocycloalkyl, amido, sulfoximine, CN, halo, C(O)OR 21 , OR 22 , or NR 23 R 24 ; wherein R 21 is selected from H and C1 -C6 alkyl;
  • R 22 is selected from H and C1-C6 alkyl
  • R 23 and R 24 are independently selected from H and optionally substituted C1 -C6 alkyl
  • R 15 is H or C1 -C6 alkyl; or R 4 and R 5 together form 3 to 8 membered heterocycloalkyl or aryl together with Y and Z to which they are attached; or R 4 and R 15 together form 5 membered cycloalkyl, heterocycloalkyl, or heteroaryl together with X and Y to which they are attached; R 6 is H, C1 -C6 alkyl, optionally substituted aryl, or C3-C8 cycloalkyl; or A is CR 12 or N, D is CR 7 or N, E is CR 13 or N and G is CR 14 or N and
  • X is N or C
  • Y is C
  • Z is CR 20 , N, NR 11 , or O, wherein R 11 is H, optionally substituted 01-06 alkyl, optionally substituted 03-08 cycloalkyl, optionally substituted aryl, or optionally substituted 5 to 8 membered heteroaryl; wherein R 20 is H, optionally substituted 01-06 alkyl, optionally substituted aryl, optionally substituted 5 to 8 membered heteroaryl, optionally substituted 3 to 8 membered heterocycloalkyl, amido, sulfoximine, ON, halo, C(O)OR 25 , OR 26 , or NR 27 R 28 ; wherein R 25 is selected from H and 01 -06 alkyl;
  • R 26 is selected from H and 01-06 alkyl
  • R 27 and R 28 are independently selected from H and 01-06 alkyl
  • R 7 is H, halo, 01 -06 alkyl, or OR 19 ; wherein R 19 is optionally substituted 01 -06 alkyl;
  • R 12 is H, halo, or 01 -06 alkyl
  • R 13 is H, halo, 01-06 alkyl, OR 16 ; or NR 17 R 18 ; wherein R 16 is optionally substituted 01 -06 alkyl,
  • R 17 and R 18 are independently selected from H and 01-06 alkyl or wherein R 17 and R 18 together form 5 to 6 membered heterocycloalkyl with the nitrogen atom to which they are attached;
  • R 14 is H, halo, or C1 -C6 alkyl; or a stereoisomer, tautomer, hydrate, /V-oxide derivative or pharmaceutically acceptable salt thereof.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound, stereoisomer, tautomer, hydrate, /V-oxide derivative or pharmaceutically acceptable salt according to the first aspect, and a pharmaceutically acceptable carrier or diluent.
  • the invention provides the compound, stereoisomer, tautomer, hydrate, M-oxide derivative or pharmaceutically acceptable salt according to the first aspect or the pharmaceutical composition according to the second aspect for use in therapy.
  • the invention provides the compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt according to the first aspect or the pharmaceutical composition according to the second aspect for use as a medicament.
  • the invention provides the compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt according to the first aspect or the pharmaceutical composition according to the second aspect for use in treating muscular atrophy, obesity, insulin resistance, or type II diabetes.
  • the invention provides the compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt according to the first aspect or the pharmaceutical composition according to the second aspect for use in treating muscular atrophy, cachexia or sarcopenia, wherein the muscular atrophy, cachexia and sarcopenia are associated with or induced by cancer.
  • the invention provides a method of treating obesity, insulin resistance, type II diabetes, or muscular atrophy, comprising administering to a subject in need thereof an effective amount of a compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt according to the first aspect or a pharmaceutical composition according to the second aspect.
  • the invention provides a method of reducing loss of muscle mass in a subject comprising administering to a subject in need thereof an effective amount of a compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt according to the first aspect or a pharmaceutical composition according to the second aspect.
  • USP19 has been associated with a number of diseases and conditions including (but not limited to) cancer and neoplastic conditions. Knock-out of USP19 by RNAi leads to p27 Kip1 accumulation and inhibition of cell proliferation (Lu Y. eta!., PLoS ONE (2011), 6, e15936). USP19 was also found to interact with the inhibitors of apoptosis (lAPs) including C-IAP1 and C-IAP2 (Mei Y. etal., J. Biol. Chem. (2011), 286, 35380-35387).
  • lAPs inhibitors of apoptosis
  • Knockdown of USP19 decreases the total levels of these c-IAPs whilst overexpression increases the levels of both BIRC2/clAP1 and BIRC3/clAP2. Knockdown of USP19 also enhances TNFa-induced caspase activation and apoptosis in a BIRC2/C-IAP1 and BIRC3/C-IAP2 dependent manner. USP19 has also been recently implicated in the Wnt signalling pathway by stabilising the coreceptor LRP6 (Perrody E. etal., eLife (2016), 5, e19083) and in the DNA repair processes, most particularly chromosomal stability and integrity, by regulating the HDAC1 and HDAC2 proteins (Wu M. etal., Oncotarget (2017), 8, 2197-2208).
  • USP19 inhibitor compounds as described in relation to the first aspect exhibit cell permeability and potent target engagement in cancer cell lines.
  • the cell permeability and target engagement in cancer cells is comparable to that observed in muscle cells.
  • USP19 inhibitors exhibit potent in vivo therapeutic effects on muscle wasting.
  • pharmacological USP19 inhibitors will be effective at exerting therapeutic effects in cancer, due to the association of USP19 and oncogenic processes described above.
  • USP19 is also implicated in muscular atrophy, muscle-wasting syndromes and other skeletal muscle atrophy disorders (Wing S., Int. J. Biochem. Cell Biol. (2013), 45, 21 SO- 2135; Wing S., Int. J. Biochem. Cell Biol. (2016), 79, 462-468; Wiles B. eta!., Mol. Biol. Cell (2015), 26, 913-923; Combaret L. etal., Am. J. Physiol. Endocrinol. Metab. (2005), 288, E693-700). This was supported for instance by studies which demonstrated that USP19- silencing induced the expression of myofibrillar proteins and promoted myogenesis (Sundaram P. etal., Am. J.
  • mice lacking the USP19 gene were resistant to muscle wasting in response to both glucocorticoids, a common systemic cause of muscle atrophy, as well as in response to denervation, a model of disuse atrophy (Bedard N. etal., FASEB J. (2015), 29, 3889-3898, which is incorporated herein by reference).
  • USP19 inhibitors reduce fat deposition in an in vivo model, indicating that USP19 inhibitors can be an effective treatment for obesity.
  • USP19 inhibitors can reduce loss of muscle mass in an in vivo model of muscular atrophy.
  • USP19 inhibitors can treat the symptoms of insulin resistance, as indicated by an improved response to glucose.
  • the compounds according to the invention are able to selectively inhibit USP19 activity.
  • the Examples demonstrate that compounds which potently inhibit USP19 activity can be effective therapeutic compounds.
  • the compounds of the invention are therefore suitable for use in methods of treatment.
  • Indications suitable for treatment with compounds of the invention include: the treatment and prevention of cancer and neoplastic conditions; immunological and inflammatory conditions for example by promoting antiviral immune response; treatment and prevention of muscular atrophy, for example cachexia and sarcopenia; treatment and prevention of obesity; treatment and prevention of insulin resistance, for example diabetes; treatment and prevention of neurodegenerative diseases including Parkinson’s disease and other prion-based disorders.
  • the cancer to be treated is breast cancer or neuroblastoma.
  • a method of treating cancer comprising administering to a subject an effective amount of a compound, or a stereoisomer, tautomer, hydrate, /V-oxide derivative or pharmaceutically acceptable salt thereof, according to the first aspect or a pharmaceutical composition according to the second aspect.
  • a method of treating muscular atrophy comprising administering to a subject an effective amount of a compound, or a stereoisomer, tautomer, hydrate, /V-oxide derivative or pharmaceutically acceptable salt thereof, according to the first aspect, or a pharmaceutical composition according to the second aspect.
  • a method of treating Parkinson’s Disease comprising administering to a subject an effective amount of a compound, or a stereoisomer, tautomer, hydrate, /V-oxide derivative or pharmaceutically acceptable salt thereof, according to the first aspect, or a pharmaceutical composition according to the second aspect.
  • the compounds, or stereoisomers, tautomers, hydrates, /V-oxide derivatives or pharmaceutically acceptable salts thereof, may be used as monotherapy or as combination therapy with radiation and/or additional therapeutic agents.
  • compounds of the present invention exhibit improved in vitro physicochemical properties such as higher kinetic solubility (KSol) and improved in vitro ADME properties such as higher metabolic stability (demonstrated by lower estimated intrinsic clearance, CLnt, using human liver microsome data) and lower CYP3A4 inhibition compared to analogues having the presence of a nitrogen atom between position ‘M’ and the carbonyl group.
  • KSol kinetic solubility
  • ADME properties such as higher metabolic stability (demonstrated by lower estimated intrinsic clearance, CLnt, using human liver microsome data)
  • lower CYP3A4 inhibition compared to analogues having the presence of a nitrogen atom between position ‘M’ and the carbonyl group.
  • compounds of the present invention exhibit improved in vitro physicochemical properties such as higher kinetic solubility (KSol) and improved in vitro ADME properties such as lower hERG inhibition and lower CYP3A4 inhibition compared to analogues having the presence of a nitrogen atom between position ‘M’ and the carbonyl group.
  • KSol kinetic solubility
  • ADME in vitro ADME
  • FIG. 1 Effect of USP19 pharmacological inhibition on tibialis anterior mass.
  • A Tibialis anterior mass (mg) from mice treated with vehicle or USP19 inhibitor compound ADC-141 . Mass is given for the muscle from limb that had undergone sciatic nerve denervation (DEN) and also from the innervated limb (INN).
  • B Percentage loss of tibialis anterior muscle mass as a result of denervation in vehicle and USP19 inhibitor (ADC-141) treated mice. Percentage calculated as a proportion of the mass of the muscle from the innervated limb of the same mouse.
  • C Loss of tibialis anterior muscle mass (in mg) as a result of denervation in vehicle treated and USP19 inhibitor (ADC-141) treated mice. P ⁇ 0.025.
  • Figure 2 Effect of USP19 pharmacological inhibition on gastrocnemius muscle mass.
  • A gastrocnemius muscle mass (mg) from mice treated with vehicle or USP19 inhibitor compound ADC-141. Mass is given for the muscle from limb that had undergone sciatic nerve denervation (DEN) and also from the innervated limb (INN).
  • B Percentage loss of gastrocnemius muscle mass as a result of denervation in vehicle and USP19 inhibitor (ADC-141) treated mice. Percentage calculated as a proportion of the mass of the muscle from the innervated limb of the same mouse.
  • C Loss of gastrocnemius muscle mass (in mg) as a result of denervation in vehicle treated and USP19 inhibitor (ADC-141) treated mice.
  • FIG. 3 (A) Effect of USP19 pharmacological inhibition on fat mass. The epididymal fat pad was collected from vehicle and USP19 inhibitor (ADC-141) treated mice, with USP19 inhibitor treated mice showing a significant reduction in fat mass. (B) Effect of USP19 pharmacological inhibition on liver mass. The liver was collected from vehicle and USP19 inhibitor (ADC-141) treated mice. An increase in liver mass was observed, likely due to accumulation of drug compound in the liver. (C) Percentage change in overall body weight in vehicle-treated control DIO mice. USP19 inhibitor 5 mg/kg i.p. BID, USP19 inhibitor 25 mg/kg i.p. BID, or positive control liraglutide 0.1 mg/kg s.c.
  • Figure 4 Cellular target engagement of USP19 inhibitor compound in breast cancer, neuroblastoma and skeletal muscle cell lines. ECso was determined by densitometry.
  • Figure 5 Response to oral glucose tolerance test (OGTT) in obese mice.
  • A Timeline of plasma glucose response in vehicle-treated control mice (circles), USP19 inhibitor 5 mg/kg i.p. BID (triangle), USP19 inhibitor 25 mg/kg i.p. BID (solid circle), or positive control liraglutide 0.1 mg/kg s.c. BID (diamond);
  • B Glucose AUG (mM.h) and
  • C insulin AUG (ng.h/mL) for vehicle, USP19 inhibitor 5 mg/kg, USP19 inhibitor 25 mg/kg, and liraglutide (left to right, respectively). ** p ⁇ 0.01 vs vehicle; ***p ⁇ 0.001 vs vehicle.
  • alkyl group (alone or in combination with another term(s)) means a straight-or branched-chain saturated hydrocarbon substituent typically containing 1 to 15 carbon atoms, such as 1 to 10, 1 to 8, 1 to 6, or 1 to 4 carbon atoms.
  • a “C n alkyl” group refers to an aliphatic group containing n carbon atoms.
  • a C1-C10 alkyl group contains 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Attachment to the alkyl group occurs through a carbon atom.
  • substituents include methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl, pentyl (branched or unbranched), hexyl (branched or unbranched), heptyl (branched or unbranched), octyl (branched or unbranched), nonyl (branched or unbranched), and decyl (branched or unbranched).
  • alkenyl group means a straight-or branched-chain hydrocarbon substituent containing one or more double bonds and typically 2 to 15 carbon atoms; such as 2 to 10, 2 to 8, 2 to 6 or 2 to 4 carbon atoms.
  • substituents include ethenyl (vinyl), 1 -propenyl, 3-propenyl, 1 ,4-pentadienyl, 1 ,4- butadienyl, 1 -butenyl, 2-butenyl, 3-butenyl, pentenyl and hexenyl.
  • alkynyl group (alone or in combination with another term(s)) means a straight-or branched-chain hydrocarbon substituent containing one or more triple bonds and typically 2 to 15 carbon atoms; such as 2 to 10, 2 to 8, 2 to 6 or 2 to 4 carbon atoms.
  • substituents include ethynyl, 1-propynyl, 3-propynyl, 1-butynyl, 3-butynyl and 4- butynyl.
  • heteroalkyl group (alone or in combination with another term(s)) means a straight-or branched-chain saturated hydrocarbyl substituent typically containing 1 to 15 atoms, such as 1 to 10, 1 to 8, 1 to 6, or 1 to 4 atoms, wherein at least one of the atoms is a heteroatom (i.e. oxygen, nitrogen, or sulfur), with the remaining atoms being carbon atoms.
  • a “C n heteroalkyl” group refers to an aliphatic group containing n carbon atoms and one or more heteroatoms, for example one heteroatom.
  • a C1-C10 heteroalkyl group contains 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms in addition to one or more heteroatoms, for example one heteroatom. Attachment to the heteroalkyl group occurs through a carbon atom or through a heteroatom.
  • heteroalkenyl group (alone or in combination with another term(s)) means a straight-or branched-chain hydrocarbon substituent containing one or more carbon-carbon double bonds and typically 2 to 15 atoms; such as 2 to 10, 2 to 8, 2 to 6 or 2 to 4 atoms, wherein at least one of the atoms is a heteroatom (i.e. oxygen, nitrogen, or sulfur), with the remaining atoms being carbon atoms.
  • a “C n heteroalkenyl” group refers to an aliphatic group containing n carbon atoms and one or more heteroatoms, for example one heteroatom.
  • a C2-C10 heteroalkenyl group contains 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms in addition to one or more heteroatoms, for example one heteroatom. Attachment to the heteroalkenyl group occurs through a carbon atom or through a heteroatom.
  • heteroalkynyl group (alone or in combination with another term(s)) means a straight-or branched-chain hydrocarbon substituent containing one or more carbon-carbon triple bonds and typically 2 to 15 carbon atoms; such as 2 to 10, 2 to 8, 2 to 6 or 2 to 4 carbon atoms, wherein at least one of the atoms is a heteroatom (i.e. oxygen, nitrogen, or sulfur), with the remaining atoms being carbon atoms.
  • a “C n heteroalkynyl” group refers to an aliphatic group containing n carbon atoms and one or more heteroatoms, for example one heteroatom.
  • a C2-C10 heteroalkynyl group contains 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms in addition to one or more heteroatoms, for example one heteroatom. Attachment to the heteroalkynyl group occurs through a carbon atom or through a heteroatom.
  • carbocyclyl group (alone or in combination with another term(s)) means a saturated cyclic (i.e. "cycloalkyl"), partially saturated cyclic (i.e. “cycloalkenyl”), or completely unsaturated (i.e. "aryl”) hydrocarbon substituent containing from 3 to 14 carbon ring atoms ("ring atoms” are the atoms bound together to form the ring or rings of a cyclic substituent).
  • a carbocyclyl may be a single-ring (monocyclic) or polycyclic ring structure.
  • a carbocyclyl may be a single ring structure, which typically contains 3 to 8 ring atoms, more typically 3 to 7 ring atoms, and more typically 5 to 6 ring atoms.
  • Examples of such single-ring carbocyclyls include cyclopropyl (cyclopropanyl), cyclobutyl (cyclobutanyl), cyclopentyl (cyclopentanyl), cyclopentenyl, cyclopentadienyl, cyclohexyl (cyclohexanyl), cyclohexenyl, cyclohexadienyl, and phenyl.
  • a carbocyclyl may alternatively be polycyclic (i.e. may contain more than one ring).
  • polycyclic carbocyclyls include bridged, fused, and spirocyclic carbocyclyls.
  • a spirocyclic carbocyclyl one atom is common to two different rings.
  • An example of a spirocyclic carbocyclyl is spiropentanyl.
  • a bridged carbocyclyl the rings share at least two common non-adjacent atoms.
  • bridged carbocyclyls include bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]hept-2-enyl, and adamantanyl.
  • a bridged azepane may be 8-oxa-3-azabicyclo[3.2.1]octan-3-yl.
  • a fused- ring carbocyclyl system two or more rings may be fused together, such that two rings share one common bond.
  • two- or three-fused ring carbocyclyls include naphthalenyl, tetrahydronaphthalenyl (tetralinyl), indenyl, indanyl (dihydroindenyl), anthracenyl, phenanthrenyl, and decalinyl.
  • cycloalkyl group (alone or in combination with another term(s)) means a saturated cyclic hydrocarbon substituent containing 3 to 14 carbon ring atoms.
  • a cycloalkyl may be a single carbon ring, which typically contains 3 to 8 carbon ring atoms and more typically 3 to 6 ring atoms. It is understood that attachment to a cycloalkyl group is via a ring atom of the cycloalkyl group.
  • single-ring cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • a cycloalkyl may alternatively be polycyclic or contain more than one ring.
  • Polycyclic cycloalkyls include bridged, fused, and spirocyclic cycloalkyls.
  • alkylcycloalkyl refers to a cycloalkyl substituent attached via an alkyl chain.
  • alkylcycloalkyl substitent include cyclohexylethane, where the cyclohexane is attached via an ethane linker.
  • Other examples include cyclopropylethane, cyclobutylethane, cyclopentylethane, cycloheptylethane, cyclohexylmethane.
  • Cn includes the carbon atoms in the alkyl chain and in the cycloalkyl ring.
  • cyclohexylethane is a C8 alkylcycloalkyl.
  • aryl group (alone or in combination with another term(s)) means an aromatic carbocyclyl containing from 5 to 14 carbon ring atoms, optionally 5 to 8, 5 to 7, optionally 5 to 6 carbon ring atoms.
  • a “C n aryl” group refers to an aromatic group containing n carbon atoms.
  • a C6-C10 aryl group contains 6, 7, 8, 9 or 10 carbon atoms. Attachment to the aryl group occurs through a carbon atom.
  • An aryl group may be monocyclic or polycyclic (i.e. may contain more than one ring).
  • aryl groups include phenyl, naphthyl, acridinyl, indenyl, indanyl, and tetrahydronapthyl.
  • arylalkyl refers to an aryl substituent attached via an alkyl chain.
  • Examples of an arylalkyl substitent include benzyl and phenylethane/ethylbenzene, where the ethane chain links to a phenyl group to the point of attachment.
  • C n includes the carbon atoms in the alkyl chain and in the aryl group.
  • ethylbenzene is a 08 arylalkyl.
  • heterocyclyl group (alone or in combination with another term(s)) means a saturated (i.e. "heterocycloalkyl"), partially saturated (i.e. “heterocycloalkenyl”), or completely unsaturated (i.e. "heteroaryl”) ring structure containing a total of 3 to 14 ring atoms, wherein at least one of the ring atoms is a heteroatom (e.g. oxygen, nitrogen, or sulfur), with the remaining ring atoms being carbon atoms.
  • a heterocyclyl group may, for example, contain one, two, three, four or five heteroatoms. Attachment to the heterocyclyl group may occur through a carbon atom and/or one or more heteroatoms that are contained in the ring.
  • a heterocyclyl may be a single-ring (monocyclic) or polycyclic ring structure.
  • a heterocyclyl group may be a single ring, which typically contains from 3 to 7 ring atoms, more typically from 3 to 6 ring atoms, and even more typically 5 to 6 ring atoms.
  • single-ring heterocyclyls include furanyl, di hydrofuranyl, tetrahydrofuranyl, thiophenyl (thiofuranyl), dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, oxazolyl, oxazolidinyl, isoxazolidinyl, isoxazolidinyl, isoxazolidinyl, isoxazolyl, thiazolyl, isothi
  • a heterocyclyl group may alternatively be polycyclic (i.e. may contain more than one ring).
  • polycyclic heterocyclyl groups include bridged, fused, and spirocyclic heterocyclyl groups.
  • a spirocyclic heterocyclyl group one atom is common to two different rings.
  • a bridged heterocyclyl group the rings share at least two common non- adjacent atoms.
  • two or more rings may be fused together, such that two rings share one common bond.
  • fused ring heterocyclyl groups containing two or three rings include indolizinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl (including pyrido[3,4-b]-pyridinyl, pyrido[3,2-b]- pyridinyl, or pyrido[4,3-b]-pyridinyl), and pteridinyl.
  • fused-ring heterocyclyl groups include benzo-fused heterocyclyl groups, such as indolyl, isoindolyl (isobenzazolyl, pseudoisoindolyl), indoleninyl (pseudoindolyl), isoindazolyl (benzpyrazolyl), benzazinyl (including quinolinyl (1-benzazinyl) or isoquinolinyl (2-benzazinyl)), phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl (including cinnolinyl (1 ,2-benzodiazinyl) or quinazolinyl (1 ,3-benzodiazinyl)), benzopyranyl (including chromanyl or isochromanyl), and benzisoxazinyl (including 1 ,2-benzisoxazinyl or 1 ,4-benzisoxazinyl).
  • heterocycloalkyl group (alone or in combination with another term(s)) means a saturated heterocyclyl.
  • An “x to y membered heterocycloalkyl” group refers to a cyclic aliphatic group containing x to y ring atoms, including at least one heteroatom (e.g. nitrogen), with the remainder being carbon atoms.
  • a 3 to 8 membered heterocycloalkyl group contains a total of 3 to 8 ring atoms, wherein at least one of the ring atoms is a heteroatom (e.g. nitrogen, oxygen, sulfur) with the remaining atoms being carbon atoms. Attachment to the heterocycloalkyl group occurs through a carbon atom or one of the at least one heteroatoms.
  • heteroaryl group (alone or in combination with another term(s)) means an aromatic heterocyclyl containing from 5 to 14 ring atoms.
  • An “x to y membered heteroaryl” group refers to an aromatic group containing x to y ring atoms, including at least one heteroatom (e.g. nitrogen), with the remainder being carbon atoms.
  • a 5 to 8 membered heteroaryl group contains a total of 5 to 8 ring atoms, wherein at least one of the ring atoms is a heteroatom (e.g. nitrogen, oxygen, sulfur) with the remaining atoms being carbon atoms. Attachment to the heteroaryl group occurs through a carbon atom or through a heteroatom.
  • a heteroaryl group may be monocyclic or polycyclic.
  • a heteroaryl may be a single ring or 2 or 3 fused rings.
  • monocyclic heteroaryl groups include 6-membered rings such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and 1 ,3,5-, 1 ,2,4- or 1 ,2,3-triazinyl; 5-membered rings such as imidazolyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1 ,2,3-, 1 ,2,4-, 1 ,2,5-, or 1 ,3,4-oxadiazolyl and isothiazolyl.
  • Polycyclic heteroaryl groups may be 2 or 3 fused rings.
  • Examples of polycyclic heteroaryl groups include 6/5-membered fused ring groups such as benzothiofuranyl, benzisoxazolyl, benzoxazolyl, and purinyl; and 6/6-membered fused ring groups such as benzopyranyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and benzoxazinyl.
  • 6/5-membered fused ring groups such as benzothiofuranyl, benzisoxazolyl, benzoxazolyl, and purinyl
  • 6/6-membered fused ring groups such as benzopyranyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and benzoxazinyl.
  • polycyclic heteroaryl groups only one ring in the polycyclic system is
  • amino group refers to the -NR’R” group.
  • the amino group can be optionally substituted.
  • R’ and R are hydrogen.
  • R’ and R each independently may be, but are not limited to, hydrogen, an alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl, alkoxy, sulfonyl, alkenyl, alkanoyl, aryl, arylalkyl, or a heteroaryl group, provided R’ and R” are not both hydrogen.
  • R’ and R may cyclise to form a cyclic amino group, e.g. a pyrrolidine group or a piperidine group.
  • a cyclic amino group may incorporate other heteroatoms, for example to form a piperazine or morpholine group.
  • Such a cyclic amino group may be optionally substituted, e.g. with an amino group, a hydroxyl group or an oxo group.
  • alkylamino refers to the -R a NR’R” group, wherein R a is an alkyl chain as defined above and NR’R” is an optionally substituted amino group as defined above.
  • C n alkylamino refers to a group containing n carbon atoms.
  • a C1-C10 alkylamino group contains 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • the amino group of the alkylamino group is a substituted amino group, the number of carbon atoms includes any carbon atoms in the substituent groups. Attachment to the alkylamino group occurs through a carbon atom of the R a alkyl group.
  • alkylamino substituents include methylamine, ethylamine, methylaminomethyl, dimethylaminomethyl, methylaminoethyl, dimethylaminoethyl, methylpyrrolidine, and ethylpyrrolidine
  • alkylsulfanyl refers to the -SR a group, wherein R a is an alkyl chain as defined above.
  • C n alkylsulfanyl group refers to a group containing n carbon atoms.
  • a C1-C10 alkylsulfanyl group contains 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Attachment to the alkylsulfanyl group occurs through the sulfur atom of the SR a group.
  • the alkylsulfanyl group may be optionally substituted.
  • alkylsulfanyl substituents examples include SMe (a methylsulfanyl group), an ethylsulfanyl group, a propylsulfanyl group and a benzylsulfanyl group.
  • sulfoximine refers to sulfoximine substituents that are either S-linked or N-linked - that is, attachment may be through the sulfur or nitrogen atom.
  • the sulfoximine group may be attached as a substituent via the sulfur atom, in which case the sulfur has a single R group in addition to the oxo group and the sulfur-bound nitrogen atom has one R group attached -that is the group is -S(O)(R)NR’.
  • the sulfoximine group may be attached as a substituent via the nitrogen atom, in which case the sulfur atom has two attached R groups in addition to the oxo group - that is, the group is -NS(O)RR’.
  • each of R and R’ are H.
  • the sulfoximine group may be substituted at one or both of R and R’, for example to form a dimethyl sulfoximine, where both R and R’ are methyl.
  • ether refers to an -O-alkyl group or an — alkyl-O-alkyl group, for example a methoxy group, a methoxymethyl group or an ethoxyethyl group.
  • the alkyl chain(s) of an ether can be linear, branched or cyclic chains.
  • the ether group can be optionally substituted (a "substituted ether") with one or more substituents.
  • a C n ether refers to an ether group having n carbons in all alkyl chains of the ether group. For example, a CH(CH3)-O-C6H11 ether is a Cs ether group.
  • alkoxy group refers to an -O-alkyl group.
  • the alkoxy group can refer to linear, branched, or cyclic, saturated or unsaturated oxy-hydrocarbon chains, including, for example, methoxyl, ethoxyl, propoxyl, isopropoxyl, butoxyl, t-butoxyl and pentoxyl.
  • the alkoxy group can be optionally substituted (a "substituted alkoxy") with one or more alkoxy group substituents.
  • aryloxy group refers to an -O-aryl group, for example a phenoxy group.
  • An aryloxy substituent may itself be optionally substituted, for example with a halogen.
  • alkylester refers to a -C(O)OR group, where R is an alkyl group as defined herein.
  • R is an alkyl group as defined herein.
  • An example of an alkylester is ethyl methanoate - i.e. R is an ethyl group.
  • hydroxyl refers to an -OH group.
  • halo refers to a substituent selected from chlorine, fluorine, bromine and iodine.
  • the halo substituent is selected from chlorine, fluorine and bromine. More preferably, the halo substituent is selected from chlorine and fluorine.
  • alkyl, alkenyl, alkynyl, carbocyclyl (including cycloalkyl, cycloalkenyl and aryl), heterocyclyl (including heterocycloalkyl, heterocyloalkenyl, heteroaryl, nitrogen-containing heterocyclyl), amino, amido, ester, ether, alkoxy, or sulfonamide group can be optionally substituted with one or more substituents, which can be the same or different.
  • a substituent can be attached through a carbon atom and/or a heteroatom in the alkyl, alkenyl, alkynyl, carbocyclyl (including cycloalkyl, cycloalkenyl and aryl), heterocyclyl (including heterocycloalkyl, heterocyloalkenyl, heteroaryl, nitrogen-containing heterocyclyl, nitrogen- containing heteroaryl), amino, amido, ester, ether, alkoxy, or sulfonamide group.
  • substituted alkyl includes but is not limited to alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, aralkyl, substituted aralkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halo, hydroxyl, cyano, amino, amido, alkylamino, arylamino, carbocyclyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, nitro, thio, alkanoyl, hydroxyl, aryloxyl, alkoxyl, alkylthio, arylthio, aralkyloxyl, aralkylthio, carboxyl, alkoxycarbonyl,
  • the substituent is alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halo, hydroxyl, cyano, amino, amido, alkylamino, arylamino, carbocyclyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, nitro, thio, alkanoyl, hydroxyl, aryloxyl, alkoxyl, alkylthio, arylthio, aralkyloxyl, aralkylthio, carboxyl, alkoxycarbonyl, oxo, alkylsulfonyl and arylsulfonyl.
  • a group for example an alkyl group, is “optionally substituted”, it is understood that the group has one or more substituents attached (substituted) or does not have any substituents attached (unsubstituted).
  • first substituent may itself be either unsubstituted or substituted.
  • the compounds of the present invention may possess some aspect of stereochemistry.
  • the compounds may possess chiral centres and/or planes and/or axes of symmetry.
  • the compounds may be provided as single stereoisomers, single diastereomers, mixtures of stereoisomers or as racemic mixtures, unless otherwise specified.
  • Stereoisomers are known in the art to be molecules that have the same molecular formula and sequence of bonded atoms, but which differ in their spatial orientations of their atoms and/or groups.
  • the compounds of the present invention may exhibit tautomerism. Each tautomeric form is intended to fall within the scope of the invention.
  • the compounds of the present invention may be provided as a pro-drug. Pro- drugs are transformed, generally in vivo, from one form to the active forms of the drugs described herein.
  • a hydrogen atom may be 1 H, 2 H (deuterium) or 3 H (tritium).
  • the compounds of the present invention may be provided in the form of their pharmaceutically acceptable salts or as co-crystals.
  • pharmaceutically acceptable salt refers to ionic compounds formed by the addition of an acid to a base.
  • the term refers to such salts that are considered in the art as being suitable for use in contact with a patient, for example in vivo and pharmaceutically acceptable salts are generally chosen for their non-toxic, non-irritant characteristics.
  • co-crystal refers to a multi- component molecular crystal, which may comprise non-ionic interactions.
  • Pharmaceutically acceptable salts and co-crystals may be prepared by ion exchange chromatography or by reacting the free base or acidic form of a compound with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid or base in one or more suitable solvents, or by mixing the compound with another pharmaceutically acceptable compound capable of forming a co-crystal.
  • Salts known in the art to be generally suitable for use in contact with a patient include salts derived from inorganic and/or organic acids, including the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate and tartrate. These may include cations based on the alkali and alkaline earth metals, such as sodium, potassium, calcium and magnesium, as well as ammonium, tetramethylammonium, tetraethylammonium. Further reference is made to the number of literature sources that survey suitable pharmaceutically acceptable salts, for example the handbook of pharmaceutical salts published by IUPAC. In addition, the compounds of the present invention may sometimes exist as zwitterions, which are considered as part of the invention.
  • a USP19 inhibitor refers to a compound which acts on USP19 so as to decrease the activity of the enzyme.
  • Examples of USP19 inhibitors are exemplified compounds herein.
  • a USP19 inhibitor exhibits an IC50 of less than 5 ⁇ M, preferably less than 0.5 ⁇ M.
  • obesity refers to the medical condition characterised by excess body fat.
  • Obesity can be characterised by, for example, a body mass index (BMI) of greater than 30.
  • BMI body mass index
  • Treatment of obesity may be indicated by, for example, the reduction of body fat, in percentage and/or absolute mass terms. Treatment of obesity may also be exemplified by a reduction in the rate of body fat accumulation by a subject compared to before treatment.
  • insulin resistance refers to the medical condition characterised by an abnormally weak response to insulin. Since insulin resistance is typically not treated by exogenous insulin treatment, the resistance is typically to insulin produced by the body of the subject, though the subject may also be resistant to exogenous insulin. “Insulin resistance” encompasses the conditions “prediabetes” and Type II diabetes. Insulin resistance may be indicated, for example, by a glucose tolerance test (GTT) glycaemia of 7.8 mmol/L or greater. Type II diabetes is typically diagnosed following a glucose tolerance test (GTT) glycaemia of 11 .1 mmol/L or greater.
  • GTT glucose tolerance test
  • Treatment of insulin resistance may be indicated by an improvement (i.e. reduction) in the subject’s GTT glycaemia compared to before treatment. Treatment may also be indicated by a reduction in the subject’s blood sugar concentration under normal conditions compared to before treatment.
  • muscle atrophy and “muscle-wasting” are used interchangeably to refer to decrease in muscle mass in a subject, including in the context of cachexia or sarcopenia, for example.
  • Muscular atrophy can be as a result of temporary or permanent disability, temporary or permanent immobilisation of a limb, extended bedrest, cachexia (for example as a result of cancer, heart failure, or COPD), or sarcopenia.
  • Treatment of muscular atrophy may be characterised as the slowing of the rate of atrophy - that is, treatment results in less muscle mass lost over a given period of time. Preferably, successful treatment results in no loss of muscle mass.
  • R 1 is optionally substituted C1 -C6 alkyl, optionally substituted amino, optionally substituted 3 to 11 membered heterocycloalkyl, optionally substituted aryl, or optionally substituted 5 to 8 membered heteroaryl;
  • R 2 and R 3 are each independently selected from H and C1 -C6 alkyl, or wherein R 2 and R 3 together form C3-C8 cycloalkyl, C3-C8 cycloalkenyl or 3 to 8 membered heterocycloalkyl together with the carbon to which they are attached;
  • M is N or CR a wherein R a is H, halo, optionally substituted C3-C8 cycloalkyl, or optionally substituted C1-C6 alkyl;
  • A, D, E and G are absent and
  • X is NR 15 or CH
  • Y is CR 4 or N or absent
  • Z is CR 5 , NR 6 or O
  • R 4 is halo, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted 5 to 8 membered heteroaryl, 4 to 10 membered fused-ring heterocyclyl, optionally substituted C1-C6 alkylsulfanyl (optionally SMe), sulfoxide, sulfone, sulfoximine, optionally substituted amino, optionally substituted 3 to 8 membered heterocycloalkyl, or OR 20 ; wherein R 20 is optionally substituted C1-C6 alkyl;
  • R 5 is H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted 5 to 8 membered heteroaryl, optionally substituted 3 to 8 membered heterocycloalkyl, amido, sulfoximine, CN, halo, C(O)OR 21 , OR 22 , or NR 23 R 24 ; wherein R 21 is selected from H and C1-C6 alkyl;
  • R 22 is selected from H and C1-C6 alkyl
  • R 23 and R 24 are independently selected from H and optionally substituted C1-C6 alkyl
  • R 15 is H or C1-C6 alkyl; or R 4 and R 5 together form 3 to 8 membered heterocycloalkyl or aryl together with Y and Z to which they are attached; or R 4 and R 15 together form 5 membered cycloalkyl, heterocycloalkyl, or heteroaryl together with X and Y to which they are attached;
  • R 6 is H, C1-C6 alkyl, optionally substituted aryl or C3-C8 cycloalkyl; or A is CR 12 or N, D is CR 7 or N, E is CR 13 or N and G is OR 14 or N and
  • X is N or C
  • Y is C
  • Z is CR 20 , N, NR 11 , or O, wherein R 11 is H, optionally substituted 01-06 alkyl, optionally substituted 03-08 cycloalkyl, optionally substituted aryl, or optionally substituted 5 to 8 membered heteroaryl; wherein R 20 is H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted 5 to 8 membered heteroaryl, optionally substituted 3 to 8 membered heterocycloalkyl, amido, sulfoximine, CN, halo, C(O)OR 25 , OR 26 , or NR 27 R 28 ; wherein R 25 is selected from H and C1 -C6 alkyl;
  • R 26 is selected from H and C1-C6 alkyl
  • R 27 and R 28 are independently selected from H and C1-C6 alkyl
  • R 7 is H, halo, C1 -C6 alkyl, or OR 19 ; wherein R 19 is optionally substituted C1 -C6 alkyl;
  • R 12 is H, halo, or C1 -C6 alkyl
  • R 13 is H, halo, C1-C6 alkyl, OR 16 ; or NR 17 R 18 ; wherein R 16 is optionally substituted C1 -C6 alkyl,
  • R 17 and R 18 are independently selected from H and C1-C6 alkyl or wherein R 17 and R 18 together form 5 to 6 membered heterocycloalkyl with the nitrogen atom to which they are attached;
  • Dotted lines in formula (I) indicate optional bonds. That is, the dotted lines indicate the ring including positions X, Y, Z, M can be aliphatic (for example saturated or partially unsaturated) or aromatic. Similarly, in formula (I) dotted lines indicate that, when present, the ring including positions A, D, E and G can be aliphatic (for example saturated or partially unsaturated) or aromatic.
  • each of the one or more optional substituents is independently selected from alkyl, alkoxy, oxo, halo, cycloalkyl, heterocycloalkyl, aryl, aryl substituted by one or more halo, aryl substituted by halo and alkyl, aryl substituted by halo and alkoxy, heteroaryl, hydroxyl, CR 8 R 9 R 10 , NR 8 , NR 8 R 9 , NHC(O)R 8 , NHCR 8 R 9 R 10 , NHCH2CR 8 R 9 R 10 and NHCH2C(O)R 8 , wherein R 8 , R 9 and R 10 are each independently selected from H, halo, hydroxyl, alkyl, cycloalkyl, cycloalkyl substituted by one or more halo or alkyl, heterocycloalkyl substituted by one or more alkyl or oxo, heteroaryl, alkoxy, CH2OH
  • R 1 is optionally substituted C1 -C6 alkyl, optionally substituted amino, optionally substituted 3 to 8 membered heterocycloalkyl, optionally substituted aryl, or optionally substituted 5 to 8 membered heteroaryl.
  • R 1 is optionally substituted 3 to 11 membered heterocycloalkyl. More preferably, R 1 is optionally substituted 3 to 8 membered heterocycloalkyl. More preferably, R 1 is optionally substituted 5 to 8 membered heterocycloalkyl. More preferably still R 1 is optionally substituted 5 to 6 membered heterocycloalkyl.
  • R 1 is optionally substituted morpholine, bridged azepane, diazepane, thiomorpholine, pyrrolidine, piperazine, or piperidine.
  • R 1 is optionally substituted morpholine, thiomorpholine, pyrrolidine, piperazine, or piperidine.
  • R 1 is optionally substituted piperidine.
  • R 1 is substituted by one or more alkyl, oxo, cycloalkyl, heterocycloalkyl, aryl, aryl substituted by one or more halo, heteroaryl, NR 8 , NR 8 R 9 , NHC(O)R 8 , NHCR 8 R 9 R 10 , NHCH2CR 8 R 9 R 10 and NHCH2C(O)R 8 , wherein R 8 , R 9 and R 10 are each independently selected from H, halo, hydroxyl, alkyl, cycloalkyl, cycloalkyl substituted by one or more halo or alkyl, heterocycloalkyl substituted by one or more alkyl or oxo, heteroaryl, and alkoxy.
  • R 1 is substituted by NR 8 R 9 , NHC(O)R 8 , or NHCH2CR 8 R 9 R 10 , wherein R 8 , R 9 and R 10 are each independently selected from H, C1-C6 alkyl, fluoro-substituted C1-C6 alkyl, C1-C6 alkoxy, CH2OH, CH2CH2OH, fluoro- substituted C3-C6 cycloalkyl, C3-C6 cycloalkyl substituted by C1 -C6 alkyl, and pyridine- substituted C1 -C6 alkyl.
  • R 1 is substituted by phenyl or phenyl substituted by one or more halo, and wherein R 1 is optionally substituted with one or more further substituents.
  • R 1 is substituted by phenyl or phenyl substituted by one or more fluoro, wherein R 1 is optionally substituted with one or more further substituents. In certain preferred embodiments R 1 is substituted by difluoro-phenyl.
  • R 1 is substituted by phenyl substituted by halo and C1- C6 alkyl, wherein R 1 is optionally substituted with one or more further substituents. In certain preferred embodiments R 1 is substituted by phenyl substituted by halo and C1 -C6 alkoxy, wherein R 1 is optionally substituted with one or more further substituents. In certain preferred embodiments R 1 is substituted by phenyl substituted by fluoro and methyl, wherein R 1 is optionally substituted with one or more further substituents. In certain preferred embodiments R 1 is substituted by phenyl substituted by fluoro and methoxy, wherein R 1 is optionally substituted with one or more further substituents.
  • R 1 is optionally substituted amino. More preferably, R 1 is amino substituted with phenyl substituted by one or more halo or benzyl substituted by one or more halo.
  • R 1 is NR b R c or NR b CH2R c , wherein R b and R c are independently selected from H, methyl, ethyl, propyl, CF3, optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted cyclohexyl, optionally substituted phenyl, optionally substituted benzyl, optionally substituted pyridinyl, pyrazole, imidazole, furan, benzodioxol, optionally substituted oxadiazole, thiazole, and thiophene, wherein each of the one or more optional substituents are independently selected from halo, methyl, cyclopropyl and CN, optionally wherein R 1 is NR a CH2R b and the methylene group is substituted with CF3.
  • R 1 is NR b R c and R b and R c together form an optionally substituted C3-C9 heterocycle together with the N to which they are attached.
  • R 1 is NR b R c and R b and R c together form an optionally substituted C3-C9 heterocycle together with the N to which they are attached, wherein each of the one or more optional substituents is selected from OH, oxo, C1-C3 alkyl optionally substituted with OH and/or halo, optionally substituted phenyl, optionally substituted benzyl, C1-C3 alkoxy, NR m R n , NHC(O)R m , and NHCH2R n , wherein R m and R" are independently selected from H; C1 -C3 alkyl optionally substituted with OH, methoxy or halo; C3-C4 cycloalkyl optionally substituted with methyl and/or halo; C3-C4 heterocycloalkyl optionally substituted with oxo, methyl or fluoro-methyl; C3-C5 heteroaryl optionally substituted with each of the one
  • R 1 is NR b R c and R b and R c together form an optionally substituted
  • each of the one or more optional substituents is selected from optionally halo-substituted phenyl, NR m R n , NHC(O)R m , and NHCH2R n , wherein R m and R n are independently selected from H; C1 -C3 alkyl optionally substituted with OH, methoxy or halo; C3-C4 cycloalkyl optionally substituted with methyl and/or halo; C3-C4 heterocycloalkyl optionally substituted with oxo, methyl or fluoro-methyl; C3-C5 heteroaryl optionally substituted with methyl; and Boc; and/or wherein R n is further selected from CH2OCH3, COOH and COOCH3, or wherein R m and R n form a C3-C5 heterocyclyl group together with the N to which they are attached, optionally wherein R m
  • R 1 is NR b R c and R b and R c form an optionally substituted heterocycle together with the N to which they are attached, wherein the heterocycle is selected from pyrrolidinyl, pyrimidinyl, piperidinyl, morpholino, piperazinyl, and thiomorpholino.
  • the heterocycle is optionally substituted with one or more substituents independently selected from methyl, spiro-cyclopropyl, C1-C3 aminoalkyl, NH2, CH2OH, CH2CF3, oxo, thiophene, phenyl optionally substituted with F or CF3, and OH provided the same ring carbon is not also substituted with methyl.
  • R 1 is NR b R c and R b and R c form a heterocycle together with the N to which they are attached, wherein the heterocycle is selected from pyrrolidinyl, piperidinyl, morpholino, piperazinyl, and thiomorpholino, wherein the heterocycle is optionally substituted with one or more substituents independently selected from methyl, NH2, C1 or C2 aminoalkyl, CH2CF3, oxo, thiophene, phenyl optionally substituted with F or CF3, and OH provided the same ring carbon is not also substituted with methyl.
  • the heterocycle is selected from pyrrolidinyl, piperidinyl, morpholino, piperazinyl, and thiomorpholino
  • the heterocycle is optionally substituted with one or more substituents independently selected from methyl, NH2, C1 or C2 aminoalkyl, CH2CF3, oxo, thiophene, phenyl optionally
  • R 1 is NR b R c and R b and R c form a heterocycle together with the N to which they are attached, wherein the heterocycle is selected from piperidinyl and piperazinyl, wherein the heterocycle is optionally substituted with one or more substituents independently selected from methyl, NH2, C1 or C2 aminoalkyl, CH2CF3, oxo, thiophene, phenyl optionally substituted with F or CF3, and OH provided the same ring carbon is not also substituted with methyl.
  • R 1 is NR b R c and R b and R c form an optionally substituted heterocycle together with the N to which they are attached, wherein the heterocycle is selected from piperidinyl and piperazinyl.
  • the piperazinyl group is optionally further substituted with methyl.
  • the piperazinyl group is optionally further substituted with CH2OH or spiro-cyclopropyl.
  • R 1 is NR b R c and R b and R c form an optionally substituted heterocycle, wherein the heterocycle is a piperidinyl group substituted with phenyl, wherein the phenyl is optionally substituted with one or more halo (e.g. fluoro) substituents.
  • the piperidinyl group is optionally further substituted with NH2 or NHCH3.
  • R 1 is NR b R c and R b and R c together with the N to which they are attached form a piperidinyl group optionally substituted with phenyl, fluoro-phenyl, or difluoro-phenyl, and wherein the piperidinyl group is optionally further substituted with NR m R n , NHC(O)R m , or NHCH2R n , wherein R m and R n are independently selected from H; C1 -C3 alkyl optionally substituted with OH, methoxy or halo; C3-C4 cycloalkyl optionally substituted with methyl and/or halo; C3-C4 heterocycloalkyl optionally substituted with oxo, methyl or fluoro-methyl; C3-C5 heteroaryl optionally substituted with methyl; and Boc; and/or wherein R n is further selected from CH2OCH3, COOH and COOCH3, or where
  • R 1 is NR b R c and R b and R c together with the N to which they are attached form a piperidinyl group optionally substituted with phenyl, fluoro-phenyl, or difluoro-phenyl, and wherein the piperidinyl group is optionally further substituted with NR m R n , NHC(O)R m , or NHCH2R n , wherein R m is selected from H; C1 -C3 alkyl optionally substituted with OH or halo; C3-C4 cycloalkyl optionally substituted with methyl and/or halo; C3-C4 heterocycloalkyl optionally substituted with oxo, methyl or fluoro-methyl; C3-C5 heteroaryl optionally substituted with methyl; and Boc; and wherein R n is selected from H; C1 -C3 alkyl optionally substituted with OH or halo; C3-C
  • the piperidinyl ring formed by R 1 is substituted with NR m R n , wherein R m and R n are independently selected from H; C1-C3 alkyl optionally substituted with OH or halo (preferably F); C3-C4 cycloalkyl optionally substituted with methyl and/or halo (preferably F); C3-C4 heterocycloalkyl optionally substituted with oxo, methyl or fluoro-methyl; C3-C5 heteroaryl optionally substituted with methyl; and Boc.
  • R m and R n are independently selected from H; C1-C3 alkyl optionally substituted with OH or halo (preferably F); C3-C4 cycloalkyl optionally substituted with methyl and/or halo (preferably F); C3-C4 heterocycloalkyl optionally substituted with oxo, methyl or fluoro-methyl; C3-C5 heteroaryl optionally substituted with methyl; and Boc
  • R 1 is substituted with NR m R n , R m is H.
  • the piperidinyl ring formed by R 1 is substituted with NHC(O)R m , wherein R m is selected from H; C1-C3 alkyl optionally substituted with OH or halo (preferably F); C3-C4 cycloalkyl optionally substituted with methyl and/or halo (preferably F); C3-C4 heterocycloalkyl optionally substituted with oxo, methyl or fluoro- methyl; C3-C5 heteroaryl optionally substituted with methyl; and Boc.
  • R m is selected from H; C1-C3 alkyl optionally substituted with OH or halo (preferably F); C3-C4 cycloalkyl optionally substituted with methyl and/or halo (preferably F); C3-C4 heterocycloalkyl optionally substituted with oxo, methyl or fluoro- methyl; C3-C5 heteroaryl optionally substituted with methyl; and Boc.
  • R m is selected from C1 -C3 alkyl, C3-C4 cycloalkyl, and C4-C5 heteroaryl, for example pyridine.
  • R 1 is NR b R c and R b and R c together with the N to which they are attached form a piperidinyl group optionally substituted with phenyl, fluoro-phenyl, or difluoro-phenyl, and wherein the piperidinyl group is optionally further substituted with NH2, NHCH3 or NHCH2CH3.
  • the heterocycle formed by R 1 is substituted at the ortho position and the para position (2,4 position).
  • the heterocycle formed by R 1 is substituted at the meta position (3 position). In certain such embodiments, the heterocycle formed by R 1 is substituted at the ortho position and the meta position (2,3 position).
  • the heterocycle formed by R 1 is substituted at the 3,5 position.
  • R 1 is NR b R c and R b and R c together with the N to which they are attached form a piperidinyl group, wherein the piperidinyl group is substituted at the 4 position with NR m R n , NHC(O)R m , and NHCH2R n , and is further substituted at the 2 position with phenyl, fluoro-phenyl, or difluoro-phenyl.
  • R m and R n are as defined above and elsewhere herein.
  • R 1 is a heterocycle substituted (e.g. by phenyl) at the ortho or 2 position and is chiral, the compound is the (Reconfiguration at this position.
  • R 1 is substituted (e.g. by phenyl) at the ortho or 2 position and is chiral
  • the compound is the ( ⁇ -configuration at this position.
  • R 1 is a heterocycle substituted at the ortho or 2 position and at the meta or 3 position and is chiral
  • the compound is the ( ⁇ -configuration at the ortho position and the ( ⁇ -configuration at the meta position.
  • R 1 is substituted at the ortho or 2 position and at the meta or 3 position and is chiral
  • the compound is the ( ⁇ -configuration at the ortho position and the (Reconfiguration at the meta position.
  • R 1 is a heterocycle substituted at the 3,4 position.
  • the compound is the (/ ⁇ -configuration at the 3 position and the (/ ⁇ -configuration at the 4 position.
  • R 1 is a heterocycle substituted at the 3,5 position.
  • the compound is the (/ ⁇ -configuration at the 3 position and the ( ⁇ -configuration at the 5 position.
  • R 1 is a heterocycle substituted at the 1 ,2,5 position.
  • the compound is the ( ⁇ -configuration at the 1 position, the (Reconfiguration at the 2 position and the (Reconfiguration at the 5 position.
  • R 1 is a heterocycle substituted (e.g. by NH2 or C1- C2 alkylamino) at the ortho or 2 position and at the para or 4-position and is chiral
  • the compound is the (Reconfiguration at the para position and the ( ⁇ -configuration at the ortho position.
  • R 1 is substituted (e.g. by NH2 or C1 - C2 alkylamino) at the ortho or 2 position and at the para or 4-position and is chiral
  • the compound is the (S)-configuration at the para position and the (Reconfiguration at the ortho position.
  • R 1 forms a piperazinyl group substituted with phenyl, fluoro-phenyl, difluoro-phenyl, or thiophenyl.
  • R 1 forms a 4-aminopiperidinyl group substituted with phenyl, fluoro-phenyl, difluoro-phenyl, or thiophenyl.
  • R 1 forms a piperazinyl or 4-aminopiperidinyl group substituted with phenyl.
  • R 1 forms a piperazinyl or 4-aminopiperidinyl group substituted with fluoro-phenyl.
  • R 1 forms a piperazinyl or 4-aminopiperidinyl group substituted with difluoro-phenyl.
  • R 1 is substituted with difluoro-phenyl
  • the substituent is 2,5 difluoro-phenyl or 3,5 difluoro-phenyl.
  • the piperazinyl or 4-aminopiperidinyl group is optionally further substituted with one or two, preferably one, /V-alkyl groups, such as methyl or ethyl.
  • R 1 is:
  • R 1 is:
  • R 1 is: In certain preferred embodiments, R 1 is:
  • the phenyl ring is mono- or di-substituted with fluoro.
  • R 1 is selected from:
  • R 1 is NR b R c or NR b CH2R c , wherein R b and R c are independently selected from H, methyl, ethyl, propyl, CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, pyridinyl, pyrazole, imidazole, or wherein R b and R c together form a C3-C5 heterocycle together with the N to which they are attached, optionally substituted with OH, CH2OH, CH2OCH3, methyl, ethyl, propyl, CF3, phenyl, or benzyl.
  • R 1 is NR b CH2R°, wherein R b is H or methyl and R c is selected from cyclobutyl optionally substituted with F, cyclohexyl, phenyl optionally substituted with F, furan and thiophene, optionally wherein the methylene group is substituted with CF3.
  • R c is phenyl or fluoro-substituted phenyl.
  • R 2 and R 3 are each independently H or methyl, or R 2 and R 3 together form C3-C6 cycloalkyl, cyclopentenyl or 4 to 6 membered heterocycloalkyl together with the carbon to which they are attached. In certain such embodiments, R 2 and R 3 together form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, oxetanyl or oxanyl together with the carbon to which they are attached. More preferably, R 2 and R 3 are each independently H or methyl, or R 2 and R 3 together form cyclopentyl. More preferably, R 2 and R 3 together form cyclopentyl together with the carbon to which they are attached.
  • M is N or CR a wherein R a is H, halo, cyclopropyl, or optionally substituted C1-C6 alkyl.
  • M is N or CR a wherein R a is H, fluoro, chloro, cyclopropyl, or C1 -C6 alkyl optionally substituted with one or more halo groups.
  • M is N or CR a wherein R a is H, fluoro, chloro, cyclopropyl, CF 3 or C1 -C6 alkyl.
  • M is N or CR a wherein R a is H, or optionally substituted C1 -C6 alkyl. More preferably, M is N or CR a wherein R a is H, or C1-C6 alkyl.
  • M is CR a .
  • R a is H, cyclopropyl, CF 3 or methyl.
  • R a is H or methyl. More preferably, R a is H.
  • M is N.
  • R 15 is H or methyl.
  • A, D, E and G are absent and
  • X is NR 15 or CH
  • Y is CR 4 , N or absent
  • Z is CR 5 , NR 6 or O;
  • R 4 is halo, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted 5 to 8 membered heteroaryl, 4 to 10 membered fused-ring heterocyclyl or C1-C6 alkylsulfanyl;
  • R 5 is H, optionally substituted C1 -C6 alkyl, optionally substituted aryl, optionally substituted 5 to 8 membered heteroaryl, optionally substituted 3 to 8 membered heterocycloalkyl, amido, sulfoximine, CN or halo; or R 4 and R 5 together form 3 to 8 membered heterocycloalkyl or aryl together with Y and Z to which they are attached;
  • R 6 is H, C1 -C6 alkyl, aryl or C3-C8 cycloalkyl
  • R 15 is H or C1 -C6 alkyl; or R 4 and R 15 together form 5 membered heterocycloalkyl, or heteroaryl together with X and Y to which they are attached, optionally wherein R 4 and R 15 together form dihydrothiazole with X and Y to which they are attached; or A is CR 12 or N, D is CR 7 or N, E is CR 13 or N and G is OR 14 or N and
  • X is N or C
  • Y is C
  • Z is CH, N, NR 11 , or O, wherein R 11 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, or optionally substituted 5 to 8 membered heteroaryl;
  • R 7 is H, halo, C1 -C6 alkyl
  • R 12 is H, halo, or C1 -C6 alkyl
  • R 13 is H, halo, C1-C6 alkoxy, or C1-C6 alkyl; and R 14 is H, halo, or C1 -C6 alkyl; or a stereoisomer, tautomer, hydrate, /V-oxide derivative or pharmaceutically acceptable salt thereof.
  • A, D, E and G are absent and
  • X is NH or CH
  • Y is CR 4 or N.
  • A, D, E and G are absent and
  • X is NH or CH
  • Y is CR 4 or N
  • Z is CR 5 , NR 6 or O
  • R 4 is halo, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted 5 to 8 membered heteroaryl, 4 to 10 membered fused-ring heterocyclyl, C1-C6 alkylsulfanyl (optionally SMe), sulfoxide, sulfone, sulfoximine, optionally substituted amino, or optionally substituted 3 to 8 membered heterocycloalkyl;
  • R 5 is H, optionally substituted C1 -C6 alkyl, optionally substituted aryl, optionally substituted 5 to 8 membered heteroaryl, optionally substituted 3 to 8 membered heterocycloalkyl, amido, sulfoximine, CN, or halo; or R 4 and R 5 together form 3 to 8 membered heterocycloalkyl or aryl together with Y and Z to which they are attached; and
  • R 6 is H, C1 -C6 alkyl, or C3-C8 cycloalkyl.
  • Z is CR 5 or NR 6 .
  • R 6 is H or 01-06 alkyl.
  • R 4 is halo, optionally substituted 01 -06 alkyl, optionally substituted 03-08 cycloalkyl, optionally substituted aryl, optionally substituted 5 to 8 membered heteroaryl, 4 to 10 membered fused-ring heterocyclyl, SMe, sulfoxide, sulfone, sulfoximine, optionally substituted amino, optionally substituted pyrrolidine, optionally substituted piperidine, optionally substituted morpholine, or optionally substituted piperazine.
  • R 4 is halo, optionally substituted C1 -C6 alkyl, optionally substituted 03-08 cycloalkyl, optionally substituted aryl, optionally substituted 5 to 8 membered heteroaryl, or 4 to 10 membered fused-ring heterocyclyl.
  • R 5 is H.
  • Y is OR 4 .
  • X is NH
  • X is CH.
  • R 4 is 01 -06 alkyl, 01- 06 alkyl substituted by one or more halo groups, halo, cycloalkyl, cycloalkyl substituted by one or more 01-06 alkyl, heteroaryl, heteroaryl substituted by 01 -06 alkyl, dihydrobenzofuran, phenyl, or phenyl substituted by one or more 01 -06 alkyl, alkoxy (optionally 01 -06 alkoxy), or halo.
  • R 4 is methyl, CF3, CHF2, chloro, cyclopropyl, methyl substituted cyclopropyl, thiophene, methyl substituted pyrazole, 2,3-dihydrobenzofuran, phenyl, or phenyl substituted by methyl, methoxy, or fluoro.
  • R 4 is phenyl or phenyl substituted by methyl, methoxy, or fluoro.
  • R 4 and R 5 together form
  • Z is CH.
  • Z is NR 6 .
  • R 6 when A, D, E and G are absent, R 6 is H, methyl or cyclopropyl. More preferably, when A, D, E and G are absent, R 6 is H or methyl.
  • Y is CR 4 wherein R 4 is C1-C6 alkylsulfanyl, preferably SMe, and Z is CR 5 wherein R 5 is CN.
  • M is N
  • X is CH
  • Y is CR 4
  • Z is NH
  • R 4 is phenyl
  • A, D, E and G are absent;
  • X is CH
  • Y is CR 4 ;
  • Z is NR 6 ;
  • M is CR a or N, wherein R a , R 4 and R 6 are as defined herein above.
  • A, D, E and G are absent;
  • X is NH
  • Y is CR 4 ;
  • Z is CR 5 ; and M is CR a , wherein R a , R 4 and R 5 are as defined herein above.
  • A, D, E and G are absent;
  • X is NH
  • Y is OR 4 ;
  • M is CR a ;
  • Z is N, wherein R a and R 4 are as defined herein above.
  • A is OR 12 or N
  • D is CR 7 or N
  • E is CR 13 or N
  • G is OR 14 or N and
  • X is N or C
  • Y is C
  • Z is CH, N, NR 11 , or O, wherein R 11 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, or optionally substituted 5 to 8 membered heteroaryl;
  • R 7 is H, halo, or C1-C6 alkyl
  • R 12 is H, halo, or C1 -C6 alkyl
  • R 13 is H, halo, C1-C6 alkoxy, or C1-C6 alkyl
  • R 14 is H, halo, or C1 -C6 alkyl.
  • A when A is CR 12 or N, D is CR 7 or N, E is CR 13 or N and G is CR 14 or N, Z is CH, N, or NR 11 . In certain preferred embodiments, when A is OR 12 or N, D is OR 7 or N, E is OR 13 or N and G is CR 14 or N, Z is CH, N, or O.
  • A is CR 12 or N
  • D is CR 7 or N
  • E is CR 13 or N
  • G is CR 14 or N
  • R 7 is H, methyl or halo.
  • A is CR 12 or N
  • D is CR 7 or N
  • E is CR 13 or N
  • G is CR 14 or N
  • R 12 is H.
  • A is CR 12 or N
  • D is CR 7
  • E is CR 13 or N
  • G is CR 14 or N.
  • A is CR 12 or N
  • D is CR 7 or N
  • E is CR 13
  • G is CR 14 or N.
  • A is CR 12 or N
  • D is CR 7 or N
  • E is CR 13 or N
  • G is CR 14 or N
  • R 13 is H.
  • A is CR 12 or N
  • D is CR 7 or N
  • E is CR 13 or N
  • G is CR 14 .
  • A is CR 12 or N
  • D is CR 7 or N
  • E is CR 13 or N
  • G is CR 14 or N
  • R 14 is H.
  • A is CR 12 or N
  • D is CR 7 or N
  • E is CR 13 or N
  • G is CR 14 or N
  • X is N.
  • A is CH
  • D is CR 7 or N
  • E is CR 13 or N
  • G is CR 14 or N.
  • A is N
  • D is CR 7 or N
  • E is CR 13 or N
  • G is CR 14 or N.
  • R 7 is H or halo, optionally fluoro.
  • A is OR 12 or N
  • D is OR 7 or N
  • E is CR 13 or N
  • G is OR 14 or N
  • Z is CH.
  • A is CR 12 or N
  • D is CR 7 or N
  • E is CR 13 or N
  • G is CR 14 or N
  • Z is N.
  • A is CR 12 or N
  • D is CR 7 or N
  • E is CR 13 or N
  • G is CR 14 or N
  • Z is O.
  • A is CR 12 or N
  • D is CR 7 or N
  • E is CR 13 or N
  • G is CR 14 or N
  • Z is NR 11 .
  • R 11 is H, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, or 5 to 7 membered heteroaryl. More preferably, when A is CR 12 or N, D is CR 7 or N, E is CR 13 or N, G is CR 14 or N, and Z is NR 11 , R 11 is methyl. More preferably, when A is CR 12 or N, D is CR 7 or N, E is CR 13 or N, G is CR 14 or N, and Z is NR 11 , R 11 is H.
  • X and Y are each C; Z is O; A, E, G and M are each CH; and D is CR 7 , wherein R 7 is as defined herein above.
  • X and Y are each C; Z is NR 11 ; A, E, G and M are each CH; and D is N, wherein R 11 is as defined herein above.
  • X and Y are each C; Z is NH; E is N; and A, D, G and M are each CH.
  • A, D, E and G are absent; X is NR 15 ; Y is CR 4 ; Z is N; M is CH; and R 4 and R 15 together form 5 membered heterocycloalkyl with X and Y to which they are attached. In certain preferred embodiments, R 4 and R 15 together form dihydrothiazole with X and Y to which they are attached.
  • A, D, E and G are absent
  • X is NH or CH
  • Y is CR 4 ;
  • Z is CR 5 or NR 6 ;
  • R 1 is optionally substituted piperidine or piperazine
  • R 2 and R 3 together form cyclopentyl together with the carbon to which they are attached
  • R 4 is phenyl
  • R 5 is H
  • R 6 is H or methyl, wherein each optional substituent is selected from phenyl, difluoro-phenyl, NHCH3, NHCH2CH3, NHCH(CH3)2, NHC(O)CH3, N(CH3)2, NHCH2CHF2, NHCH2CH2F, NHCH2CH2OH and NHCH2CH2OCH3.
  • A, D, E and G are absent;
  • X is NH or CH
  • Y is CR 4 ;
  • Z is CR 5 or NR 6 ;
  • R 1 is piperidine or piperazine each substituted by difluoro-phenyl and further substituted by amino optionally substituted by one or more C1-C3 alkyl, oxo- substituted C1 -C3 alkyl, fluoro-substituted C1-C3 alkyl, CH2CH2OH, C1-C3 alkoxy, fluoro-substituted C3-C6 cycloalkyl, C3-C6 cycloalkyl substituted by C1-C3 alkyl, or pyridine-substituted C1-C3 alkyl;
  • R 2 and R 3 are each methyl, or together form cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, oxetanyl or oxanyl together with the carbon to which they are attached;
  • R 4 is methyl, dihydrobenzofuran, phenyl, phenyl substituted by methyl, phenyl substituted by F, phenyl substituted by OMe, phenyl substituted by SMe, phenyl substituted by OH, or thiophene;
  • R 5 is H, methyl or CN; and R 6 is H or methyl.
  • X is N or C
  • Y is C
  • Z is N, NR 11 or O, wherein R 11 is H or methyl;
  • M is CR a wherein R a is H, methyl or cyclopropyl
  • A is C
  • D is CR 7 , wherein R 7 is H, methyl, F, Cl, Br;
  • E is N or CR 13 , wherein R 13 is H, Cl or OMe;
  • G is C
  • R 1 is piperidine or piperazine each substituted by difluoro-phenyl and further substituted by amino optionally substituted by one or more C1-C3 alkyl, fluoro- substituted C1-C3 alkyl, CH2CH2OH, C1-C3 alkoxy; and
  • R 2 and R 3 are each methyl, or together form cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, oxetanyl or oxanyl together with the carbon to which they are attached.
  • a compound, stereoisomer, tautomer, hydrate, N- oxide derivative or pharmaceutically acceptable salt as described above that is an inhibitor of USP19, preferably human USP19.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound, stereoisomer, tautomer, hydrate, /V-oxide derivative or pharmaceutically acceptable salt according to the first aspect, and a pharmaceutically acceptable carrier or diluent.
  • compositions may be formulated according to their particular use and purpose by mixing, for example, excipient, binding agent, lubricant, disintegrating agent, coating material, emulsifier, suspending agent, solvent, stabilizer, absorption enhancer and/or ointment base.
  • the composition may be suitable for oral, injectable, rectal or topical administration.
  • Suitable pharmaceutically acceptable excipients would be known by the person skilled in the art, for example: fats, water, physiological saline, alcohol (e.g. ethanol), glycerol, polyols, aqueous glucose solution, extending agent, disintegrating agent, binder, lubricant, wetting agent, stabilizer, emulsifier, dispersant, preservative, sweetener, colorant, seasoning agent or aromatizer, concentrating agent, diluent, buffer substance, solvent or solubilizing agent, chemical for achieving storage effect, salt for modifying osmotic pressure, coating agent or antioxidant, saccharides such as lactose or glucose; starch of corn, wheat or rice; fatty acids such as stearic acid; inorganic salts such as magnesium metasilicate aluminate or anhydrous calcium phosphate; synthetic polymers such as polyvinylpyrrolidone or polyalkylene glycol; alcohols such as stearyl alcohol or benzyl alcohol; synthetic
  • the pharmaceutical composition may be administered orally, such as in the form of tablets, coated tablets, hard or soft gelatine capsules, solutions, emulsions, or suspensions.
  • Administration can also be carried out rectally, for example using suppositories, locally or percutaneously, for example using ointments, creams, gels or solution, or parenterally, for example using injectable solutions.
  • the compounds of the present invention may be admixed with pharmaceutically inert, inorganic or organic excipients.
  • suitable excipients include lactose, maize starch or derivatives thereof, talc or stearic acid or salts thereof.
  • suitable excipients for use with soft gelatine capsules include, for example, vegetable oils, waxes, fats and semi-solid or liquid polyols.
  • excipients include, for example, water, polyols, saccharose, invert sugar and glucose.
  • excipients include, for example, water, alcohols, polyols, glycerine and vegetable oil.
  • excipients include, for example, natural or hardened oils, waxes, fats and semi-solid or liquid polyols.
  • the pharmaceutical compositions may also contain preserving agents, solublizing agents, stabilizing agents, wetting agents, emulsifiers, sweeteners, colorants, odorants, buffers, coating agents and/or antioxidants.
  • the second drug may be provided in pharmaceutical composition with the present invention or may be provided separately.
  • a pharmaceutical formulation for oral administration may, for example, be granule, tablet, sugar-coated tablet, capsule, pill, suspension or emulsion.
  • a sterile aqueous solution may be provided that may contain other substances including, for example, salts and/or glucose to make to solution isotonic.
  • the anti-cancer agent may also be administered in the form of a suppository or pessary, or may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder.
  • the invention provides a compound according to the first aspect, including a stereoisomer, tautomer, hydrate, /V-oxide derivative or pharmaceutically acceptable salt thereof, for use in therapy.
  • the invention provides a pharmaceutical composition according to the second aspect for use in therapy.
  • the invention provides a compound according to any embodiment of the first aspect, or a stereoisomer, tautomer, hydrate, /V-oxide derivative or pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of cancer.
  • the invention provides a pharmaceutical composition according to the second aspect for use in the treatment and/or prevention of cancer.
  • the invention provides a method of treating or preventing cancer comprising administering to a subject a compound, including a stereoisomer, tautomer, hydrate, /V-oxide derivative or pharmaceutically acceptable salt thereof, according to any embodiment of the first aspect of the invention or a pharmaceutical composition according to any embodiment of the second aspect of the invention.
  • the invention provides a use of a compound, including a stereoisomer, tautomer, hydrate, /V-oxide derivative or pharmaceutically acceptable salt thereof, according to any embodiment of the first aspect in the manufacture of a medicament for treating or preventing cancer.
  • Cancers or neoplastic conditions suitable to be treated with the compounds or compositions according to the invention include, for example: prostate cancer, colon cancer, breast cancer, lung cancer, kidney cancer, CNS cancers (e.g. neuroblastomas, glioblastomas), osteosarcoma, haematological malignancies (e.g. leukaemia, multiple myeloma and mantle cell lymphoma).
  • the cancer is associated with p53 dysregulation.
  • the cancer is selected from a haematological malignancy (e.g. mantle cell lymphoma, multiple myeloma), prostate cancer, a neuroblastoma, or a glioblastoma. In certain preferred embodiments, the cancer is neuroblastoma or breast cancer.
  • a haematological malignancy e.g. mantle cell lymphoma, multiple myeloma
  • prostate cancer e.g. mantle cell lymphoma, multiple myeloma
  • a neuroblastoma e.g. glioblastoma
  • the cancer is neuroblastoma or breast cancer.
  • a compound according to the first aspect or a pharmaceutically acceptable salt, tautomer, stereoisomer or /V-oxide derivative thereof, for use in a method of treating obesity.
  • composition according to the second aspect for use in a method of treating obesity.
  • Also provided in accordance with the invention is a method of treating obesity comprising administering to a subject in need thereof an effective amount of a compound, pharmaceutically acceptable salt, tautomer, stereoisomer or N-oxide derivative according to the first aspect, or an effective amount of a pharmaceutical composition according to the second aspect.
  • a compound as defined in relation to the first aspect of the invention or a pharmaceutically acceptable salt, tautomer, stereoisomer or /V-oxide derivative thereof, for use in a method of treating insulin resistance.
  • a compound as defined in relation to the first aspect of the invention or a pharmaceutically acceptable salt, tautomer, stereoisomer or N- oxide derivative thereof, for use in a method of treating type II diabetes.
  • composition according to the second aspect for use in a method of treating insulin resistance.
  • composition according to the second aspect for use in a method of treating type II diabetes.
  • Also provided in accordance with the invention is a method of treating insulin resistance comprising administering to a subject in need thereof an effective amount of a compound, pharmaceutically acceptable salt, tautomer, stereoisomer or /V-oxide derivative as defined in relation to the first aspect of the invention, or an effective amount of a pharmaceutical composition comprising a compound, pharmaceutically acceptable salt, tautomer, stereoisomer or /V-oxide derivative as defined in relation to the first aspect of the invention.
  • Also provided in accordance with the invention is a method of treating type II diabetes comprising administering to a subject in need thereof an effective amount of a compound, pharmaceutically acceptable salt, tautomer, stereoisomer or N-oxide derivative as defined in relation to the first aspect of the invention, or an effective amount of a pharmaceutical composition comprising a compound, pharmaceutically acceptable salt, tautomer, stereoisomer or /V-oxide derivative as defined in relation to the first aspect of the invention.
  • a compound as defined in relation to the first aspect of the invention or a pharmaceutically acceptable salt, tautomer, stereoisomer or N-oxide derivative thereof, for use in a method of treating muscular atrophy.
  • the invention provides a compound as defined in relation to the first aspect, or a pharmaceutically acceptable salt, tautomer, stereoisomer or /V-oxide derivative thereof, for use in a method of treating cachexia or sarcopenia.
  • composition according to the second aspect for use in a method of treating muscular atrophy.
  • composition according to the second aspect for use in a method of treating cachexia or sarcopenia.
  • Also provided in accordance with the invention is a method of treating muscular atrophy comprising administering to a subject in need thereof an effective amount of a compound, pharmaceutically acceptable salt, tautomer, stereoisomer or /V-oxide derivative as defined in relation to the first aspect of the invention, or an effective amount of a pharmaceutical composition comprising a compound, pharmaceutically acceptable salt, tautomer, stereoisomer or /V-oxide derivative as defined in relation to the first aspect of the invention.
  • Also provided in accordance with the invention is a method of treating cachexia or sarcopenia comprising administering to a subject in need thereof an effective amount of a compound, pharmaceutically acceptable salt, tautomer, stereoisomer or N-oxide derivative as defined in relation to the first aspect of the invention, or an effective amount of a pharmaceutical composition comprising a compound, pharmaceutically acceptable salt, tautomer, stereoisomer or /V-oxide derivative as defined in relation to the first aspect of the invention.
  • Muscle atrophy, cachexia or sarcopenia may be associated with or induced by HIV infection/AIDS, heart failure, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, multiple sclerosis, motor neuron disease (MND), Parkinson’s disease, dementia, or cancer.
  • HIV infection/AIDS HIV infection/AIDS
  • heart failure rheumatoid arthritis
  • COPD chronic obstructive pulmonary disease
  • cystic fibrosis cystic fibrosis
  • MND motor neuron disease
  • Parkinson’s disease dementia
  • dementia dementia
  • the invention provides a compound or composition according to any embodiment of the first aspect or second aspect for use in the treatment and/or prevention of Parkinson’s Disease.
  • the invention provides a method of treating or preventing Parkinson’s Disease comprising administering an effective amount of a compound, pharmaceutically acceptable salt, tautomer, stereoisomer or N-oxide derivative thereof, or pharmaceutical composition according to the invention to a subject.
  • the invention provides the use of a compound according to the invention, or a pharmaceutically acceptable salt, tautomer, stereoisomer or N-oxide derivative thereof, in the manufacture of a medicament for the treatment of Parkinson’s Disease.
  • the compound or composition of the invention may be used in monotherapy and/or a combination modality.
  • Suitable agents to be used in such combination modalities with compounds or compositions according to the invention include one or more of anti-cancer agents, anti-inflammatory agents, immuno-modulatory agents, for example immuno- suppressive agents, neurological agents, anti-diabetic agents, anti-viral agents, anti- bacterial agents and/or radiation therapy.
  • Agents used in combination with the compounds of the present invention may target the same or a similar biological pathway to that targeted by the compounds of the present invention or may act on a different or unrelated pathway. Depending on the disease to be treated, a variety of combination partners may be coadministered with the compounds of the present invention.
  • the second active ingredient may include, but is not restricted to: alkylating agents, including cyclophosphamide, ifosfamide, thiotepa, melphalan, chloroethylnitrosourea and bendamustine; platinum derivatives, including cisplatin, oxaliplatin, carboplatin and satraplatin; antimitotic agents, including vinca alkaloids (vincristine, vinorelbine and vinblastine), taxanes (paclitaxel, docetaxel), epothilones and inhibitors of mitotic kinases including aurora and polo kinases; topoisomerase inhibitors, including anthracyclines, epipodophyllotoxins, camptothecin and analogues of camptothecin; antimetabolites, including 5-fluorouracil, capecitabine, cytarabine, gemcitabine, 6-mercaptopurine, 6-thioguanine, fludarabine, met
  • the compounds may be administered to the subject in need of treatment in an “effective amount”.
  • effective amount refers to the amount or dose of a compound which, upon single or multiple dose administration to a subject, provides therapeutic efficacy in the treatment of disease.
  • Therapeutically effective amounts of a compound according to the invention can comprise an amount in the range of from about 0.1 mg/kg to about 20 mg/kg per single dose.
  • a therapeutic effective amount for any individual patient can be determined by the healthcare professional by methods understood by the skilled person.
  • the amount of compound administered at any given time point may be varied so that optimal amounts of the compound, whether employed alone or in combination with any other therapeutic agent, are administered during the course of treatment. It is also contemplated to administer compounds according to the invention, or pharmaceutical compositions comprising such compounds, in combination with any other cancer treatment, as a combination therapy.
  • the second drug may be provided in pharmaceutical composition with the present invention or may be provided separately.
  • treatment according to the invention comprises administering the therapeutic agent (that is, the compound, pharmaceutically acceptable salt, tautomer, stereoisomer or /V-oxide derivative, or pharmaceutical composition for use according to the invention) parenterally.
  • the therapeutic agent that is, the compound, pharmaceutically acceptable salt, tautomer, stereoisomer or /V-oxide derivative, or pharmaceutical composition for use according to the invention
  • the therapeutic agent is administered orally.
  • the therapeutic agent is administered intravenously. In certain preferred embodiments, the therapeutic agent is administered intraperitoneally. In certain preferred embodiments, the therapeutic agent is administered subcutaneously.
  • treatment comprises administering the therapeutic agent (that is, the compound, pharmaceutically acceptable salt, tautomer, stereoisomer or /V-oxide derivative, or pharmaceutical composition for use according to the invention) at a dose in the range of from 10 to 150 mg/kg.
  • the dose refers to the amount of the active ingredient administered to the subject per single administration.
  • treatment comprises administering the therapeutic agent at a dose in the range of from 25 to 125 mg/kg. In certain preferred embodiments, treatment comprises administering the therapeutic agent at a dose in the range of from 50 to 100 mg/kg.
  • the method comprises administering the therapeutic agent at a dose of 75 mg/kg.
  • treatment comprises administering the therapeutic agent (that is, the compound, pharmaceutically acceptable salt, tautomer, stereoisomer or N- oxide derivative, or pharmaceutical composition for use according to the invention) 1 , 2, 3 or 4 times daily.
  • the therapeutic agent is administered once or twice daily, most preferably twice daily.
  • the therapeutic agent is administered at a daily dosage in the range of from 10 to 300 mg/kg. That is, the total amount of active agent administered to the subject in one day is in the range of from 10-300 mg/kg. In such embodiments, the therapeutic agent may be administered once or multiple times per day as described herein, provided the total daily dosage is in the indicated range.
  • the therapeutic agent is administered at a daily dosage in the range of from 50 to 250 mg/kg. In certain preferred embodiments, the therapeutic agent is administered at a daily dosage in the range of from 75 to 250 mg/kg. In certain preferred embodiments, the therapeutic agent is administered at a daily dosage in the range of from 100 to 200 mg/kg. In certain preferred embodiments, the therapeutic agent is administered at a daily dosage of 150 mg/kg.
  • the therapeutic agent for example a compound as provided herein
  • the therapeutic agent is administered at a dose of 75 mg/kg twice daily.
  • the subject to be treated is human.
  • the invention provides the compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt according to the first aspect or the pharmaceutical composition according the second aspect for use as a medicament.
  • the invention provides the compound, stereoisomer, tautomer, hydrate, M-oxide derivative or pharmaceutically acceptable salt according to the first aspect or the pharmaceutical composition according to the second aspect for use in treating muscular atrophy, obesity, insulin resistance, or type II diabetes.
  • the invention provides a method of treating obesity, insulin resistance, type II diabetes, or muscular atrophy, comprising administering to a subject in need thereof an effective amount of a compound, stereoisomer, tautomer, hydrate, N-oxide derivative or pharmaceutically acceptable salt according to the first aspect or a pharmaceutical composition according to the second aspect.
  • the invention provides a method of reducing loss of muscle mass in a subject comprising administering to a subject in need thereof an effective amount of a compound, stereoisomer, tautomer, hydrate, /V-oxide derivative or pharmaceutically acceptable salt according to according to the first aspect or a pharmaceutical composition according to the second aspect.
  • USP19 activity was determined in a fluorescence polarisation (FP) homogeneous assay using the isopeptide Ubiquitin-Lys-TAMRA substrate (either AIIB-101 , Almac Sciences Scotland Limited, or U-558, Boston Biochem, both of which gave identical results).
  • Full- length USP19 was purchased from Boston Biochem (E-576). Unless otherwise stated, all other reagents were purchased from Sigma. Enzymatic reactions were conducted in black flat bottom polystyrene 384-well plates (Nunc) and 30 pL total volume.
  • USP19 (2.5 nM, 10 pL) was incubated in assay buffer (50 mM HEPES (pH 7.4), 150 mM NaCI, 5 mM DTT, 0.05% BSA (w/v), 0.05% CHAPS) in the presence or absence of inhibitor (10 pL).
  • Inhibitors were stored as 10 mM DMSO stocks in an inert environment (low humidity, dark, low oxygen, rt) using the StoragePod® system (Roylan Developments) and serial dilutions were prepared in buffer just prior to the assay (from 200 ⁇ M to 2 pM, 8-18 data point curve).
  • Test compounds (5 pL of 10 mM DMSO stock) were added to 245 pL of phosphate- buffered saline (PBS) buffer solution at pH 7.4 (Dulbecco A) in a MultiScreen® Solubility filter plate (Millipore) and mixed at 300 rpm at rt on a plate shaker for 90 min. Meanwhile 5- point calibration curves for each compound were established in a mixture of acetonitrile/PBS buffer (top concentration 200 pM). After filtration and matrix match, the calibration and assay plates were analysed on a BioTek Synergy 4 plate reader (240-400 nm). Final concentration of the test compound in the filtrate was calculated using the slope of the calibration curve.
  • PBS phosphate- buffered saline
  • CYP inhibition was assessed simultaneously for 5 major isoforms (CYP1 A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) using a commercially available mixture of the isoforms heterogeneously expressed in E. coll (Cypex). The method was adapted from Weaver R. et al., Drug Metab. Dispos. (2003), 31 , 955-966. Activity of each isoform was assessed by measuring the appearance of an isoform-specific metabolite using a selective and FDA accepted substrate for each isoform at a concentration around its published K m .
  • Test compounds were assayed over a range of 8 concentrations (half-log dilutions) typically in the range of 50 pM to 0.023 pM final concentration.
  • Test compounds at 4x the desired final concentration in 0.1 M PBS buffer solution at pH 7.4 (Dulbecco A) were incubated at 37 °C for 3 min with a 2x mixture of GYP isoforms and substrate mix.
  • 4 mM NADPH solution in 0.1 M PBS buffer solution at pH 7.4 (Dulbecco A) was then added to start the reaction.
  • the GYP activities for test compounds at each concentration were converted to % of control activity (GA) and the log (concentration) vs activity was plotted and used to generate a pseudo-Hill plot.
  • the slope and y axis intercept were used to calculate the IC 5o values for test compounds against each GYP isoform according to the following equation: hERG ion channel inhibition assay
  • Test compounds were assayed at an external provider for human Ether-a-go-go- Related Gene (hERG) inhibition using the QPatch II (Sophion Bioscience) automated patch-clamp.
  • hERG Ether-a-go-go- Related Gene
  • QPatch II Sophion Bioscience
  • a sham operation was carried out in the opposite leg as a control.
  • mice were randomised into Vehicle or Test groups, with all animals weighed to ensure a similar mean weight in each group.
  • ADC-141 a USP19 inhibitory compound at 75 mg/kg or Vehicle was administered i.p. twice daily starting from the evening post-operation.
  • mice were sacrificed 14 days later. Fat pads, liver, gastrocnemius and tibialis anterior muscles were harvested. Tissue masses were measured in both groups.
  • the diet-induced obese (DIO) mouse is a well characterised model of obesity which exhibits increased adiposity, insulin resistance and glucose intolerance.
  • mice Male C57BL6/J mice were continuously provided with high-fat diet (D12451 , 45% kcal as fat; Research Diets, New Jersey, USA) and filtered tap water ad libitum for the duration of the study. From day 0, mice were administered vehicle i.p. BID, USP19 inhibitor (ADC-141) i.p. BID at 5 mg/kg or 25 mg/kg, or positive control liraglutide 0.1 mg/kg s.c. BID.
  • high-fat diet D12451 , 45% kcal as fat; Research Diets, New Jersey, USA
  • ADC-141 USP19 inhibitor
  • mice positive control liraglutide 0.1 mg/kg s.c. BID.
  • Body weight was measured daily. On Day 13, body composition was be assessed by DEXA. On Day 15, fasting glucose and insulin levels were measured before and during an oral glucose tolerance test (OGTT) to assess improvements in glucose control. The OGTT was performed following an overnight fast. Hence, on Day 14 food (but not water) was removed beginning at approximately 16:45, immediately after the PM dose. An OGTT was performed the following morning ( ⁇ 16 h post fast). Mice were dosed with vehicle or test compound (starting at 08.45) to a timed schedule 30 min prior to the administration of the glucose challenge (2.0 g/kg p.o.). Blood samples were taken immediately prior to dosing (B1), immediately prior to glucose administration (B2) and 15, 30, 60 and 120 min after glucose administration.
  • ADC-141 is 1 -(((S)-7-((R)-3-cyclohexyl-2-methylpropanoyl)-10-hydroxy-7- azaspiro[4.5]decan-10-yl)methyl)-4-phenyl-5-(piperazine-1 -carbonyl)pyridin-2(1 H)-one, corresponding to exemplary compound 212 provided in WO2018/020242.
  • Both ADC-141 and the compounds provided herein are shown to have USP19 inhibitory activity using the fluorescence polarisation assay described above. It is therefore expected that the USP19 inhibitor compounds provided herein will show levels of efficacy similar to that described below for ADC-141 .
  • mice receiving a USP19 inhibitor had a significantly lower loss of muscle mass in the tibialis anterior muscle compared to mice receiving vehicle only.
  • the sparing of muscle atrophy was evident both in terms of percentage mass (Figure 1 B) and absolute muscle mass (Figure 1C).
  • Figure 3A shows the mass of the epididymal fat pad in mice following 2 weeks of receiving a USP19 inhibitor or vehicle alone. As shown in Figure 3, mice which received the USP19 inhibitor had significantly smaller fat pads compared to vehicle treated mice.
  • Figure 3B shows an increase in liver mass in mice treated with a USP19 inhibitor. This is thought to be as a result of drug accumulation in the liver.
  • Figure 3C shows that mice receiving USP19 inhibitor exhibited a reduction in overall body weight gain when on a high-fat diet.
  • Figures 3D and 3E show that this is due to a reduction in fat mass, but that lean body mass is preserved.
  • DIO mice treated with USP19 inhibitor also exhibited a reduction in cumulative food intake compared to vehicle control mice.
  • the data shown in Figure 3 demonstrates that pharmacological inhibition of USP19 can reduce fat accumulation in a wild-type background.
  • Gene knockout studies have described a possible association between USP19 and fat accumulation (Coyne E. etal., Diabetologia (2019), 62, 136-146, incorporated herein by reference).
  • acute or chronic pharmacological inhibition of an enzyme does not always result in similar physiological outcomes to genetic ablation.
  • Figure 5 shows the results of an oral glucose tolerance test (OGTT) in mice with diet- induced obesity.
  • Untreated mice exhibit the symptoms of insulin-resistance characterised by elevated plasma glucose and plasma insulin levels.
  • Mice treated with a USP19 inhibitor exhibit a dose-dependent improvement in OGTT response characterised by decreased plasma glucose and decreased plasma insulin.
  • the system uses reagent cartridges that allow for the appropriate reactant(s) to be subjected to various synthetic reaction procedures (including /V-heterocycle formation, reductive amination, Mitsunobu, amide formation, deoxyfluorination, Suzuki, among others) in an automated manner that includes reaction, work-up and purification steps to give the desired reaction products.
  • the system gives good reproducibility and allows for modification of some reaction parameters (e.g. time and temperature).
  • Microwave experiments were carried out using a Biotage InitiatorTM Eight instrument.
  • the system gives good reproducibility and control at temperature ranges from 60-250 °C and pressures of up to a maximum of 20 bar.
  • LCMS Liquid Chromatography Mass Spectrometry experiments to determine retention times (RT) and associated mass ions were performed using the following methods: Method A: The system consisted of an Agilent Technologies 6140 single quadrupole mass spectrometer linked to an Agilent Technologies 1290 Infinity LG system with UV diode array detector and autosampler. The spectrometer consisted of a multimode ionization source (electrospray and atmospheric pressure chemical ionizations) operating in positive and negative ion mode. LCMS experiments were performed on each sample submitted using the following conditions: LC Column: Zorbax Eclipse Plus C18 RRHD, 1.8 ⁇ m, 50 x 2.1 mm maintained at 40 °C. Mobile phases: A) 0.1% (v/v) formic acid in water; B) 0.1% (v/v) formic acid in MeCN.
  • Method A The system consisted of an Agilent Technologies 6140 single quadrupole mass spectrometer linked to an Agilent Technologies 1290 Infinity LG system
  • Method B The system consisted of an Agilent Technologies 6130 quadrupole mass spectrometer linked to an Agilent Technologies 1290 Infinity LC system with UV diode array detector and autosampler.
  • the spectrometer consisted of an electrospray ionization source operating in positive and negative ion mode.
  • LCMS experiments were performed on each sample submitted using the following conditions: LC Column: Agilent Eclipse Plus C18 RRHD, 1 .8 ⁇ m, 50 x 2.1 mm maintained at 40 °C. Mobile phases: A) 0.1% (v/v) formic acid in water; B) 0.1% (v/v) formic acid in MeCN.
  • Method C The system consisted of a Waters ACQUITY QDa mass spectrometer linked to a Waters ACQUITY l-Class UPLC system with TUV detector.
  • the spectrometer consisted of an electrospray ionization source operating in positive and negative ion mode.
  • LCMS experiments were performed on each sample submitted using the following conditions: LC Column: Zorbax Eclipse Plus C18 RRHD, 1.8 ⁇ m, 50 x 2.1 mm maintained at 40 °C. Mobile phases: A) 0.1% (v/v) formic acid in water; B) 0.1% (v/v) formic acid in MeCN.
  • the system consisted of either an Agilent Technologies 1100 Series LC/MSD system with UV diode array detector and evaporative light scattering detector (DAD/ELSD) and Agilent LC/MSD VL (G1956A), SL (G1956B) mass spectrometer or an Agilent 1200 Series LC/MSD system with DAD/ELSD and Agilent LC/MSD SL (G6130A), SL (G6140A) mass spectrometer. All of the LCMS data were obtained using the atmospheric pressure chemical ionization mode with positive and negative ion mode switching with a scan range of mlz 80-1000.
  • LCMS experiments were performed on each sample submitted using the following conditions: LC Column: Zorbax SB-C18 RRHD, 1 .8 ⁇ m, 4.6 x 15 mm. Mobile phases: A) 0.1% (v/v) formic acid in water; B) 0.1% (v/v) formic acid in MeCN.
  • LCMS/MS API 2000 instruments Spectrometer ionization technique: ESI using API source operating in positive ion mode.
  • LCMS experiments were performed on each sample submitted using the following conditions: LC Column: XBridge C18, 5 ⁇ m, 4.6 x 50 mm maintained at 25 °C. Mobile phases: A) 10 mM ammonium acetate (aq); B) MeCN.
  • Method F The system consisted of a Waters ACQUITY SQD 2 mass spectrometer linked to a Waters ACQUITY H-Class UPLC system with TUV detector.
  • the spectrometer consisted of an electrospray ionization source operating in positive and negative ion mode.
  • LCMS experiments were performed on each sample submitted using the following conditions: LC Column: XBridge C18, 3.5 ⁇ m, 3.0 x 50 mm maintained at 50 °C. Mobile phases: A) 5 mM ammonium acetate (aq); B) 5 mM ammonium acetate in 9:1 MeCN/water.
  • the system consisted of an Agilent Technologies 6120 single quadrupole mass spectrometer linked to an Agilent Technologies 1200 Preparative LG system with multiple wavelength detector and autosampler.
  • the mass spectrometer used a multimode ionization source (electrospray and atmospheric pressure chemical ionizations) operating in positive and negative ion mode. Fraction collection was mass-triggered (multimode positive and negative ion). Purification experiments, unless otherwise stated, were performed under basic conditions at an appropriate solvent gradient that was typically determined by the retention time found using an appropriate LCMS method. In cases where the basic conditions were unsuccessful, acidic conditions were employed.
  • the separation of mixtures of stereoisomers was performed using the following general procedure.
  • the mixture of stereoisomers was dissolved to 50 mg/mL in MeOH and purified by SFC under the stated conditions.
  • Combined fractions of each of stereoisomer were evaporated to near dryness using a rotary evaporator, transferred into final vessels using DCM, which was removed under a stream of compressed air at 40 °C, before being stored in a vacuum oven at 40 °C and 5 mbar for 16 h.
  • the separation of mixtures of stereoisomers was performed using the following general procedure.
  • the mixture of stereoisomers was dissolved to 66 mg/mL in MeOH and purified by HPLC under the stated conditions.
  • Combined fractions of each of stereoisomer were evaporated to near dryness using a rotary evaporator, transferred into final vessels using MeOH, which was removed under a stream of compressed air at 35 °C, before being stored in a vacuum oven at 35 °C and 5 mbar for 16 h.
  • each stereoisomer was analysed to determine chiral purity using appropriate analytical SFC or HPLC methods under the stated conditions.
  • the Boc protected amine (1 equiv.) was dissolved in DOM. TFA or 4 M HOI in 1 ,4-dioxane was added (as stated). The reaction was stirred at rt for 1-24 h. The mixture was loaded onto a pre-equilibrated SCX-2 cartridge. The column was washed with a 4:1 mixture of DCM/MeOH and the basic compound was eluted using a 4:1 mixture of DCM/7 M NH3 in MeOH. The ammoniacal fractions were concentrated in vacuo to give the desired product that was used directly in the next step or repurified under the stated conditions, as necessary.
  • the Cbz protected amine (e.g. 1 .0 mmol) was dissolved in EtOAc (20 mL)/EtOH (20 mL) and the solution was passed through an H-Cube® Pro hydrogenation flow reactor containing a 10%w/w Pd/C cartridge with a flow rate of 1 mL/min at 60 °C and using the “controlled mode” setting for 1 bar of hydrogen. Reaction completion was determined by LCMS and the material was passed through the system again, if necessary, until complete reaction. The solvents were removed in vacuo and the remaining residue was purified by flash chromatography to give the desired product.
  • Step 1 3-(Hydroxymethyl)-6-phenylpyridin-2(1H)-one: To a solution of 2-oxo-6-phenyl-1 ,2- dihydropyridine-3-carboxylic acid (53.3 g, 248 mmol) [commercially available] in THF (1200 mL) was added 1 M borane. DMS complex in THF solution (991 ml_, 991 mmol), and the suspension was stirred at rt. After 18 h, MeOH was slowly added until gas evolution ceased.
  • Step 2 2-Oxo-6-phenyl-1 ,2-dihydropyridine-3-carbaldehyde: To a stirred solution of 3- (hydroxymethyl)-6-phenylpyridin-2(1 H)-one (8.0 g, 40 mmol) in DCM (250 mL) at 0 °C was added Dess-Martin periodinane (22.0 g, 52 mmol). After 10 h, 2 M Na2CO3(aq> (300 mL) was added. After 2 h, the resultant precipitate was filtered and dried under vacuum to give the title compound (7.2 g, 90%).
  • Step 3 tert-Butyl 4-((2-oxo-6-phenyl-1,2-dihydropyridin-3-yl)methyl)piperazine-1- carboxylate: To a stirred solution of 2-oxo-6-phenyl-1 ,2-dihydropyridine-3-carbaldehyde (1.5 g, 7.5 mmol) in DCM (50 mL) was added tert-butyl piperazine-1 -carboxylate (2.1 g, 11 .2 mmol) followed by sodium triacetoxyborohydride (4.8 g, 22.5 mmol). After 3 h, the reaction mixture was heated to 55 °C.
  • Step 4 6-Phenyl-3-(piperazin-1 -ylmethyl)pyridin-2(1 H)-one dihydrochloride: Prepared according to General Procedure 1 using tert-butyl 4-((2-oxo-6-phenyl-1 ,2-dihydropyridin-3- yl)methyl)piperazine-1-carboxylate (50.0 mg, 0.14 mmol), 4 M HCI in 1 ,4-dioxane (3 mL) and DCM (4 mL) but without SCX-2 purification to give the title compound (46.3 mg, quantitative) [assumed dihydrochloride salt].
  • Step 1 3-(Chloromethyl)-6-phenylpyridin-2(1H)-one: To a stirred solution of 3- (hydroxymethyl)-6-phenylpyridin-2(1 H)-one (33.0 g, 165 mmol) in DCM (1200 mL) was added thionyl chloride (200 mL, 2.78 mol). The reaction mixture was heated to 40 °C. After 24 h, the volatiles were removed in vacuo using MeCN to assist with coevaporation to give the title compound (36.2 g, quantitative) that was used directly in the next step without purification.
  • Step 2 tert-Butyl 6-((2-oxo-6-phenyl-1,2-dihydropyridin-3-yl)-methyl)-6,9- diazaspiro[4.5]decane-9-carboxylate: To a solution of 3-(chloromethyl)-6-phenylpyridin- 2(1 H)-one (8.5 g, 39 mmol) in MeCN (300 mL) was added DIPEA (15 g, 116 mmol) and tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate (9.3 g, 39 mmol) [commercially available] and the suspension was stirred at 80 °C for 18 h.
  • Step 3 3-((6,9-Diazaspiro[4.5]decan-6-yl)methyl)-6-phenylpyridin-2(1H)-one: Prepared according to General Procedure 1 using fert-butyl 6-((2-oxo-6-phenyl-1 ,2-dihydropyridin-3- yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (100.0 mg, 0.24 mmol), TFA (1.1 mL) and anhydrous DOM (1 mL) to give the title compound (75.5 mg, 99%).
  • Step 1 tert-Butyl 6-((2-oxo-1,2-dihydroquinolin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9- carboxylate: To a solution of 2-oxo-1 ,2-dihydroquinoline-3-carbaldehyde [commercially available] (1 .50 g, 8.7 mmol) in 1 ,2-dichloroethane (50 mL) was added tert-butyl 6,9- diazaspiro[4.5]decane-9-carboxylate (3.10 g, 13.5 mmol) followed by portionwise addition of sodium triacetoxyborohydride (5.50 g, 26.1 mmol) and the suspension was stirred at 60 °C.
  • 2-oxo-1 ,2-dihydroquinoline-3-carbaldehyde [commercially available] (1 .50 g, 8.7 mmol) in 1 ,2-dichloroethane (50
  • Step 2 3-((6,9-Diazaspiro[4.5]decan-6-yl)methyl)quinolin-2(1H)-one: Prepared according to General Procedure 1 using tert-butyl 6-((2-oxo-1 ,2-dihydroquinolin-3-yl)methyl)-6,9- diazaspiro[4.5]decane-9-carboxylate (100.0 mg, 0.25 mmol), TFA (0.5 mL) and anhydrous DCM (1 mL) to give the title compound (75.1 mg, quantitative).
  • Step 2 3-((6,9-Diazaspiro[4.5]decan-6-yl)methyl)- 1,5, 7,8-tetrahydro-2H-pyrano[4,3- b]pyridin-2-one: Prepared according to General Procedure 1 using terf-butyl 6-((2-oxo- 1 ,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9- carboxylate (100 mg, 0.25 mmol), TFA (0.5 mL) and DCM (1 mL) to give the title compound (30 mg, 40%).
  • Step 1 2-(2,5-Difluorophenyl)isonicotinic acid: To a solution of methyl 2-bromoisonicotinate (250 g, 1.16 mol) and (2,5-difluorophenyl)boronic acid (200 g, 1.27 mol) in 1 ,4-dioxane (8.0 L) and water (2.6 L) was added Pd(dppf)Cl2 (47.5 g, 5 mol%) and potassium phosphate tribasic (735 g, 3.46 mol). The reaction mixture was refluxed for 16 h and evaporated to dryness. The residue was dissolved in hot water (4 L) and filtered.
  • Step 2 rac-(2S,4R)-2-(2,5-Difluorophenyl)piperidine-4-carboxylic acid: To a well stirred suspension of 2-(2,5-difluorophenyl)isonicotinic acid (60.0 g, 0.255 mol) in MeOH (2.4 L) was added 10% w/w Pd/C (6.0 g, 10%w/w) and the resultant mixture was reacted with hydrogen (50 atm) at 50 °C in an autoclave.
  • Step 3 rac-(2S,4R)-1-((Benzyloxy)carbonyl)-2-(2,5-difluorophenyl)piperidine-4-carboxylic acid: To a suspension of rac-(2S,4F?)-2-(2,5-difluorophenyl)piperidine-4-carboxylic acid (284 g, assumed 1.11 mol, contaminated with Pd/C) in 1 ,4-dioxane (5.0 L) and water (2.5 L) added NaOH (221 g, 5.54 mol). The reaction mixture was cooled to 0 °C followed by dropwise addition of benzyl chloroformate (282 g, 1.66 mol).
  • Step 4 rac-Benzyl (2S,4R)-2-(2,5-difluorophenyl)-4-(((2- (trimethylsilyl)ethoxy)carbonyl)amino)piperidine-1-carboxylate:To a suspension of rac- (2S,4R)-1 -((benzyloxy)carbonyl)-2-(2,5-difluorophenyl)piperidine-4-carboxylic acid (313 g, 0.834 mol) in toluene (4.0 L) was added triethylamine (253 g, 2.50 mol), followed by DPPA (298 g, 1 .08 mol).
  • reaction mixture heated at 75 °C for 4 h until gas evolution ceased, followed by addition of 2-(trimethylsilyl)ethanol (296 g, 2.50 mol).
  • the reaction mixture was heated at 110 °C for 24 h.
  • the reaction mixture was extracted using 15% w/v NaOH (aq ) (2 x 2 L), the organic phase was dried (Na2SO4), filtered, and evaporated to dryness to give the title compound (375 g, 92%).
  • Step 5 rac-Benzyl (2S,4R)-4-((tert-butoxycarbonyl)amino)-2-(2,5-difluorophenyl)piperidine- 1 -carboxylate-.
  • rac-benzyl (2S,4R)-2-(2,5-difluorophenyl)-4-(((2- (trimethylsilyl)ethoxy)carbonyl)amino)piperidine-1 -carboxylate (375 g, 0.764 mol) in THF (3.0 L) was added 1 M TBAF in THF solution (2292 mL, 2.29 mol) and the resultant mixture was heated at 55 °C for 48 h.
  • Step 6 rac-(2S,4R)-Benzyl 4-((tert-butoxycarbonyl)(methyl)amino)-2-(2,5- difluorophenyl)piperidine-1 -carboxylate: To a stirred solution of rac-benzyl (2S,4R)-4-((tert- butoxycarbonyl)amino)-2-(2,5-difluorophenyl)piperidine-1 -carboxylate (25 g, 56 mmol) in DMF (200 ml_) at 0 °C was added NaH (55% in mineral oil, 2.7 g, 61.7 mmol).
  • Step 7 Benzyl (2S,4R)-4-((tert-butoxycarbonyl)(methyl)amino)-2-(2,5- difluorophenyl)piperidine- 1 -carboxylate: rao-(2S,4R)-benzyl 4-((tert- butoxycarbonyl)(methyl)amino)-2-(2,5-difluorophenyl)piperidine-1 -carboxylate (18.0 g) was resolved into the single stereoisomers by chiral HPLC using a CHIRALCEL® OJ-H (20 mm x 250 mm, 5 pm) column with isocratic solvent conditions: 90:5:5 hexane/IPA/MeOH.
  • Step 8 tert-Butyl ((2S,4R)-2-(2,5-difluorophenyl)piperidin-4-yl)(methyl)carbamate: Benzyl (2S,4R)-4-((tert-butoxycarbonyl)(methyl)amino)-2-(2,5-difluorophenyl)piperidine-1- carboxylate (6.95 g, 15.1 mmol) was dissolved in MeOH (150 mL) and to this solution was added 10%w/w Pd/C (0.7 g) and the reaction mixture was hydrogenated ( ⁇ 1 atm, balloon) at rt.
  • Step 1 5-(Hydroxymethyl)-2-phenylpyridin-4(1H)-one: To a solution of ethyl 4-oxo-6- phenyl-1 ,4-dihydropyridine-3-carboxylate (30.4 g, 125 mmol) [prepared according to Chem.Pharm.Bull., 1995, 43, p450-460] in THF (1100 mL) was added 1.0 M borane.DMS complex in THF solution (485 mL, 485 mmol), and the suspension was stirred at rt. After 18 h, MeOH was slowly added until gas evolution ceased.
  • Step 2 5-(Chloromethyl)-2-phenylpyridin-4(1H)-one: To a solution of 5-(hydroxymethyl)-2- phenylpyridin-4(1 Hj-one (16.3 g, 82 mmol) in DCM (600 mL) was added thionyl chloride (100 mL, 1 .39 mol) and the suspension was stirred at 40 °C. After 24 h, the volatiles were removed in vacuo using MeCN to assist with coevaporation to give the title compound (18.0 g, quantitative) that was used directly in the next step without purification.
  • Step 3 tert-Butyl 6-((4-oxo-6-phenyl-1,4-dihydropyridin-3-yl)-methyl)-6,9- diazaspiro[4.5]decane-9-carboxylate: To a solution of 5-(chloromethyl)-2-phenylpyridin- 4(1 H)-one (8.5 g, 39 mmol) in MeCN (300 mL) was added DIPEA (15 g, 116 mmol) and tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate (9.3 g, 39 mmol), and the resulting suspension was stirred at 80 °C.
  • Step 4 tert-Butyl 6-((1-methyl-4-oxo-6-phenyl-1,4-dihydropyridin-3-yl)methyl)-6,9- diazaspiro[4.5]decane-9-carboxylate:To a solution of tert-butyl 6-((4-oxo-6-phenyl-1 ,4- dihydropyridin-3-yl)-methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (0.212 mg, 0.5 mmol) in DMF (2 mL) under argon was added sodium hydride (55% in mineral oil, 28 mg, 0.65 mmol).
  • Step 5 5-((6,9-Diazaspiro[4.5]decan-6-yl)methyl)-1-methyl-2-phenylpyridin-4(1H)-one: Prepared according to General Procedure 1 using tert-butyl 6-((1-methyl-4-oxo-6-phenyl- 1 ,4-dihydropyridin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (60.2 mg, 0.14 mmol), TFA (0.5 mL) and anhydrous DCM (1 mL) to give the title compound (49.5 mg, quantitative).
  • Step 1 rac-Benzyl (2S,4R)-4-((tert-butoxycarbonyl)(2-methoxyethyl)amino)-2-(2,5- difluorophenyl)piperidine-1 -carboxylate: To a solution of rac-benzyl (2S,4R)-4-((tert- butoxycarbonyl)amino)-2-(2,5-difluorophenyl)piperidine-1 -carboxylate (4.50 g, 10.2 mmol) in DMF (120 mL) at 0 °C was added sodium hydride (55% in mineral oil, 0.78 g, 13.3 mmol).
  • Step 2 Benzyl (2S,4R)-4-((tert-butoxycarbonyl)(2-methoxyethyl)amino)-2-(2,5- difluorophenyl)piperidine- 1 -carboxylate: rao-Benzyl (2S,4R)-4-((tert-butoxycarbonyl) (2- methoxyethyl)amino)-2-(2,5-difluorophenyl)piperidine-1 -carboxylate (2.98 g) was resolved into the single stereoisomers by chiral HPLC using a CHIRALPAK® AD-H (4.6 mm x 250 mm, 5 pm) column with isocratic solvent conditions: 95:2.5:2.5 hexane/IPA/MeOH.
  • Step 3 tert-Butyl ((2S,4R)-2-(2,5-difluorophenyl)piperidin-4-yl)(2-methoxyethyl)carbamate: Benzyl (2S,4R)-4-((ferf-butoxycarbonyl)(2-methoxyethyl)amino)-2-(2,5- difluorophenyl)piperidine-1 -carboxylate (1.21 g, 2.4 mmol) was dissolved in MeOH (50 mL) and 10%w/w Pd/C (0.12 g) and the reaction mixture was hydrogenated ( ⁇ 1 atm, balloon) at rt.
  • Step 1 tert-Butyl 3,3-dimethyl-4-((4-oxo-6-phenyl-1,4-dihydropyridin-3- yl)methyl)piperazine-1 -carboxylate:
  • the title compound was prepared similarly to tert-butyl 6-((4-oxo-6-phenyl-1 ,4-dihydropyridin-3-yl)-methyl)-6,9-diazaspiro[4.5]decane-9- carboxylate (Intermediate 7, Steps 1 to 3) except using tert-butyl 3,3-dimethylpiperazine-1 - carboxylate instead of tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate.
  • Step 2 5-((2,2-Dimethylpiperazin-1-yl)methyl)-2-phenylpyridin-4(1H)-one: Prepared according to General Procedure 1 using tert-butyl 3,3-dimethyl-4-((4-oxo-6-phenyl-1 ,4- dihydropyridin-3-yl)methyl)piperazine-1 -carboxylate (60.0 mg, 151 pmol), TFA (0.13 mL) and DCM (2 mL) to give the title compound (44.0 mg, 98%).
  • Step 1 tert-Butyl (2S)-2-(2,5-difluorophenyl)-4-(pyrrolidin-1-yl)piperidine-1 -carboxylate: To a stirred solution of tert-butyl (S)-2-(2,5-difluorophenyl)-4-oxopiperidine-1 -carboxylate (1.5 g, 4.82 mmol) [prepared according to W02022200523 Intermediate 19, Step 5] in MeOH (10 mL) were added acetic acid (3 drops) and pyrrolidine (0.6 mL, 7.23 mmol) at rt. After 2 h, NaBH 3 CN (0.9 g, 14.5 mmol) was added.
  • Step 2 tert-Butyl (2S,4R)-2-(2,5-difluorophenyl)-4-(pyrrolidin- 1 -yl)piperidine- 1 -carboxylate: tert-Butyl (2S)-2-(2,5-difluorophenyl)-4-(pyrrolidin-1-yl)piperidine-1 -carboxylate (1.6 g) was separated into the single stereoisomers by reversed phase preparative HPLC (C18 column) to give tert-butyl (2S,4S)-2-(2,5-difluorophenyl)-4-(pyrrolidin-1-yl)piperidine-1- carboxylate (first eluting isomer: 200 mg).
  • Step 1 Methyl 4-oxo-6-(thiophen-3-yl)-1,4-dihydropyridine-3-carboxylate: To a solution of (Z)-ethyl 2-(aminomethylene)-3-oxobutanoate (13.6 g, 87 mmol) in THF (400 ml_) was added sodium hydride (55% in mineral oil, 10.0 g, 226 mmol) at 0 °C under argon atmosphere.
  • Step 3 5-(Chloromethyl)-2-(thiophen-3-yl)pyridin-4(1H)-one: To a stirred solution of 5- (hydroxymethyl)-2-(thiophen-3-yl)pyridin-4(1 H)-one (6.0 g, 29 mmol) in DCM (200 mL) was added thionyl chloride (40 mL, 0.55 mol) at 40 °C. After 24 h, the solvents were removed in vacuo using MeCN to assist with coevaporation to give the title compound (6.5 g, quantitative) that was used directly in the next step without further purification.
  • Step 4 tert-Butyl 6-((4-oxo-6-(thiophen-3-yl)-1,4-dihydropyridin-3-yl)methyl)-6,9- diazaspiro[4.5]decane-9-carboxylate: To a solution of 5-(chloromethyl)-2-(thiophen-3- yl)pyridin-4(1 H)-one (2.1 g, 9.3 mmol) in MeCN (90 mL) was added DIPEA (3.6 g, 28 mmol) and tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate (2.7 g, 11 mmol) and the suspension was stirred at 80 °C.
  • the title compound was prepared similarly to 3-((6,9-diazaspiro[4.5]decan-6-yl)methyl)-6- phenylpyridin-2(1 H)-one (Intermediate 3) except using 3-(hydroxymethyl)-6-methyl-5- phenylpyridin-2(1 H)-one (prepared similarly to 3-(hydroxymethyl)-6-phenylpyridin-2(1 /-/)- one except using 6-methyl-2-oxo-5-phenyl-1 ,2-dihydropyridine-3-carboxylic acid [commercially available] instead of 2-oxo-6-phenyl-1 ,2-dihydropyridine-3-carboxylic acid) instead of 3-(hydroxymethyl)-6-phenylpyridin-2(1 H)-one to give the title compound.
  • Step 1 3-Bromo-4H-pyrido[1,2-a]pyrimidin-4-one: To a stirred solution of 4/7-pyrido[1 ,2- a]pyrimidin-4-one (6.00 g, 41 mmol) [commercially available] in DCM (200 mL) was added NBS (8.05 g, 45 mmol, 1.1 eq.) portionwise at rt. After 10 h, 1 M sodium carbonate (aq) solution (150 mL) was added. After a further 2 h, the biphasic mixture was separated, the organic phase was dried (Na2SO4), and the solvents were removed in vacuo to give the title compound (6.2 g, 69%).
  • 1 H NMR 400 MHz, CDCI 3 ): ⁇ 9.07 (d, 1 H), 8.55 (s, 1 H), 7.78 (t, 1 H), 7.67 (d, 1 H), 7.22 (t, 1 H).
  • Step 2 3-(Hydroxymethyl)-4H-pyrido[1,2-a]pyrimidin-4-one: To a stirred solution of 3- bromo-4H-pyrido[1 ,2-a]pyrimidin-4-one (4.40 g, 19 mmol) in 1 ,4-dioxane (250 mL) was added tributylstannylmethanol (9.25 g, 29 mmol) and XPhos-Pd-G2 (1.62 g, 2.0 mmol).
  • Step 3 3-(Chloromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one: To a stirred solution of 3- (hydroxymethyl)-4H-pyrido[1 ,2-a]pyrimidin-4-one (3.0 g, 17 mmol) in DCM (200 mL) was added thionyl chloride (40 mL, 0.55 mol) at 40 °C. After 24 h, the solvents were removed in vacuo using MeCN to assist with coevaporation to give the title compound (3.2 g, quantitative) that was used directly in the next step without further purification.
  • Step 4 tert-Butyl 6-((4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)methyl)-6,9- diazaspiro[4.5]decane-9-carboxylate: To a stirred solution of 3-(chloromethyl)-4H- pyrido[1 ,2-a]pyrimidin-4-one (3.0 g, 16 mmol) in MeCN (150 mL) was added DIPEA (6.2 g, 48 mmol) and tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate (3.4 g, 16 mmol) at 80 °C.
  • Step 5 3-((6,9-Diazaspiro[4.5]decan-6-yl)methyl)-4H-pyrido[ 1 ,2-a]pyrimidin-4-one: Prepared according to General Procedure 1 using tert-butyl 6-((4-oxo-4H-pyrido[1 ,2- a]pyrimidin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (120 mg, 300 pmol), TFA (0.7 mL) and DCM (1 .5 mL) to give the title compound (85.0 mg, 95%).
  • Step 4 a 2:1 mixture of tert-butyl 6-((6-(2-methoxyphenyl)-4-oxo-1 ,4-dihydropyridin-3-yl)methyl)-6,9- diazaspiro[4.5]decane-9-carboxylate/tert-butyl 6-((6-(2-hydroxyphenyl)-4-oxo-1 ,4- dihydropyridin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate was obtained that required RP preparative HPLC purification].
  • Step 1 3-(Hydroxymethyl)-4H-chromen-4-one: To a stirred solution of 4-oxo-4H-chromene- 3-carbaldehyde (500 mg, 2.87 mmol) [commercially available] in DCM (12 mL) was added NaBH(OAc)3 (1 .80 g, 8.61 mmol) at 0 °C and the resultant mixture was allowed to warm to rt. After 16 h, the reaction mixture was diluted with water and extracted with DCM (2 x 100 mL).
  • Step 2 3-(Chloromethyl)-4H-chromen-4-one: To a stirred solution of 3-(hydroxymethyl)-4H- chromen-4-one (1 .00 g, 5.67 mmol) in DCM (20 mL) was added dropwise SOCI2 (1 .2 mL, 17.0 mmol) at 0 °C and the resultant mixture was allowed to warm to rt. After 3 h, the reaction mixture was diluted with water and extracted with DCM (2 x 200 mL). The combined organic phase was washed with brine (200 mL), dried (NaaSCU) and the solvents were removed in vacuo to give the title compound (640 mg, 58%) which was used next step without further purification.
  • Step 3 tert-Butyl 6-((4-oxo-4H-chromen-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9- carboxylate: To a stirred of 3-(chloromethyl)-4H-chromen-4-one (640 mg, 3.28 mmol) in MeCN (20 mL) were added tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate (869 mg, 3.61 mmol) followed by addition of CS2CO3 (2.10 g, 6.57 mmol) at rt. The resultant mixture was heated to 90 °C.
  • Step 4 3-((6,9-Diazaspiro[4.5]decan-6-yl)methyl)-4H-chromen-4-one hydrochloride: Prepared according to General Procedure 1 using tert-butyl 6-((4-oxo-4H-chromen-3- yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (60.0 mg, 151 nmol), 4M HCI in 1 ,4- dioxane (0.38 mL) and 1 ,4-dioxane (1 mL) and omitting the SCX-2 purification to give the title compound (50 mg, 99%).
  • the title compound was prepared similarly to 3-((6,9-diazaspiro[4.5]decan-6-yl)methyl)-6- phenylpyridin-2(1 Hj-one (Intermediate 3) except using 1 -cyclopropyl-5-(hydroxymethyl)-2- methylpyridin-4(1 Hj-one (prepared similarly to 3-(hydroxymethyl)-6-phenylpyridin-2(1 Hj- one except using 1 -cyclopropyl-6-methyl-4-oxo-1 ,4-dihydropyridine-3-carboxylic acid [commercially available] instead of 2-oxo-6-phenyl-1 ,2-dihydropyridine-3-carboxylic acid) instead of 3-(hydroxymethyl)-6-phenylpyridin-2(1 Hj-one and using 4M HCI in 1 ,4- dioxane/1 ,4-dioxane instead of TFA/DCM and omitting the SCX-2 purification in the final step to give the title compound
  • Step 1 6-Fluoro-3-(hydroxymethyl)quinolin-4(1H)-one: To a stirred solution of ethyl 6- fluoro-4-oxo-1 ,4-dihydroquinoline-3-carboxylate (1.5 g, 6.38 mmol) [commercially available] in dimethoxyethane (45 mL) was added a 2M solution of UAIH4 in THF (3.2 mL, 6.4 mmol) at rt. The reaction mixture was heated to 75 °C. After 2 h, the reaction mixture was cooled, quenched with saturated Na2SO4(aq) solution (50 mL) and filtered using Celite®.
  • Step 2 3-(Chloromethyl)-6-fluoroquinolin-4(1H)-one: To a stirred solution of 6-fluoro-3- (hydroxymethyl)quinolin-4(1 H)-one (100 mg, 0.52 mmol) in DCM (6 mL) was added SOCI2 (0.11 mL, 1 .55 mmol) at 0 °C. The reaction mixture was heated to 50 °C. After 16 h, the solvents were removed in vacuo to give title compound (101 mg, 92%).
  • Step 3 tert-Butyl 6-((6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl)methyl)-6,9- diazaspiro[4.5]decane-9-carboxylate: To a stirred solution of 3-(chloromethyl)-6- fluoroquinolin-4(1 H)-one (380 mg, 1 .79 mmol) in MeCN (76 mL) were added tert-butyl 6,9- diazaspiro[4.5]decane-9-carboxylate (647 mg, 2.96 mmol) and CS2CO3 (1 .17 g, 3.59 mmol) at rt.
  • Step 4 3-((6,9-Diazaspiro[4.5]decan-6-yl)methyl)-6-fluoroquinolin-4(1H)-one hydrochloride: Prepared according to General Procedure 1 using tert-butyl 6-((6-fluoro-4-oxo-1 ,4- dihydroquinolin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (58 mg, 140 nmol), 4M HCI in 1 ,4-dioxane (0.42 mL) and DCM (1 .0 mL) but without SCX-2 purification to give the title compound (49 mg, quantitative).
  • Step 1 3-Bromo-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one: To a stirred solution of 7-fluoro- 4H-pyrido[1 ,2-a]pyrimidin-4-one (4.50 g, 27 mmol) [commercially available] in DCM (120 mL) was added NBS (5.37 g, 30 mmol) portionwise at rt. After 10 h, 1 M sodium carbonate (aq) solution (150 mL) was added. After a further 2 h, the biphasic mixture was separated, the organic phase was dried (Na2SO4), and the solvents were removed in vacuo to give the title compound (4.9 g, 75%).
  • 1 H NMR 400 MHz, CDCI 3 ): ⁇ 8.98 (m, 1 H), 8.67 (s, 1 H), 8.15 (m, 1 H), 7.86 (m, 1 H).
  • Step 2 3-Hydroxymethyl-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one: To a stirred solution of 3-bromo-7-fluoro-4H-pyrido[1 ,2-a]pyrimidin-4-one (4.40 g, 18 mmol) in 1 ,4-dioxane (250 mL) was added (tributylstannyl)methanol (9.25 g, 29 mmol) and XPhos-Pd-G2 (1.62 g, 2.0 mmol). The reaction mixture was degassed and back-filled with argon and then heated at 100 °C.
  • Step 3 3-Chloromethyl-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one: To a stirred solution of 3- hydroxymethyl-7-fluoro-4A/-pyrido[1 ,2-a]pyrimidin-4-one [contaminated with 7-fluoro-4A/- pyrido[1 ,2-a]pyrimidin-4-one] (3.2 g crude, assumed 6 mmol) in DCM (200 ml_) was added thionyl chloride (40 mL, 0.55 mol) at 40 °C. After 24 h, the solvents were removed in vacuo using MeCN to assist with coevaporation to give the crude title compound (3.2 g crude) that was used directly in the next step without further purification.
  • Step 4 tert-Butyl 6-((7-fluoro-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)methyl)-6,9- diazaspiro[4.5]decane-9-carboxylate: To a stirred solution of 3-chloromethyl-7-fluoro-4A/- pyrido[1 ,2-a]pyrimidin-4-one (3.0 g, assumed 6 mmol) in MeCN (150 mL) was added DIPEA (2.3 g, 18 mmol) and tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate (1.28 g, 6 mmol) at 80 °C.
  • Step 5 3-((6,9-Diazaspiro[4.5]decan-6-yl)methyl)-7-fluoro-4H-pyrido[ 1 ,2-a]pyrimidin-4-one hydrochloride: Prepared according to General Procedure 1 using tert-butyl 6-((7-fluoro-4- oxo-4A/-pyrido[1 ,2-a]pyrimidin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (60 mg, 144 pmol), 4M HCI in 1 ,4-dioxane (0.36 mL) and 1 ,4-dioxane (2 mL) but without SCX-2 purification to give the title compound (51 mg, 97%).
  • the title compound was prepared similarly to 3-((6,9-diazaspiro[4.5]decan-6-yl)methyl)-6- phenylpyridin-2(1 Aft-one (Intermediate 3) except using 3-(hydroxymethyl)-5- (trifluoromethyl)pyridin-2(1 Aft-one (prepared similarly to 3-(hydroxymethyl)-6-phenylpyridin- 2(1 Aft-one except using 2-oxo-5-(trifluoromethyl)-1 ,2-dihydropyridine-3-carboxylic acid [commercially available] instead of 2-oxo-6-phenyl-1 ,2-dihydropyridine-3-carboxylic acid) instead of 3-(hydroxymethyl)-6-phenylpyridin-2(1 H)-one and using 4M HCI in 1 ,4- dioxane/1 ,4-dioxane instead of TFA/DCM and omitting the SCX-2 purification in the final step to give the title compound.
  • Step 1 2-Oxo-6-(m-tolyl)-1 ,2-dihydropyridine-3-carboxylic acid: To a solution of 6-bromo-2- oxo-1 ,2-dihydropyridine-3-carboxylic acid (3.3 g, 15 mmol) in 1 ,4-dioxane (150 mL) and water (50 mL) was added m-tolylboronic acid (2.3 g, 16.5 mmol), Pd(dppf)Cl2 (0.62 g, 0.8 mmol) and sodium carbonate (4.8 g, 45.6 mmol). The reaction mixture was degassed and backfilled with argon before heating to reflux.
  • Step 2 3-(Hydroxymethyl)-6-(m-tolyl)pyridin-2(1H)-one: To a stirred solution of 2-oxo-6-(m- tolyl)-1 ,2-dihydropyridine-3-carboxylic acid (2.9 g, 12.6 mmol) in THF (120 mL) was added 1 M borane.DMS complex in THF solution (39 mL, 39 mmol) at rt. After 18 h, MeOH was slowly added until gas evolution ceased. The resulting solution was partitioned between EtOAc and brine, separated, the organic phase was dried (Na2SO4), and the solvents were removed in vacuo.
  • Step 3 3-(Chloromethyl)-6-(m-tolyl)pyridin-2(1H)-one: To a solution of 3-(hydroxymethyl)-6- (m-tolyl)pyridi n-2( 1 H)-one (2.5 g, 11 .6 mmol) in DCM (100 mL) was added thionyl chloride (20 mL, 0.278 mol), and the suspension was stirred at 40 °C. After 24 h, the solvents were removed under vacuum, the reside was dissolved in MeCN and reevaporated to give the title compound (2.5 g, 92%) as a brown solid that was used directly in the next step without further purification.
  • Step 4 tert-Butyl 6-((2-oxo-6-(m-tolyl)-1,2-dihydropyridin-3-yl)methyl)-6,9- diazaspiro[4.5]decane-9-carboxylate: To a solution of 3-(chloromethyl)-6-(m-tolyl)pyridin- 2(1 H)-one (2.4 g, 10 mmol) in MeCN (100 mL) was added DIPEA (3.9 g, 30 mmol) and tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate (2.4 g, 10 mmol). The resultant suspension was stirred at 80 °C.
  • Step 5 3-((6,9-Diazaspiro[4.5]decan-6-yl)methyl)-6-(m-tolyl)pyridin-2(1H)-one hydrochloride: Prepared according to General Procedure 1 using tert-butyl 6-((2-oxo-6-(m- tolyl)-1 ,2-dihydropyridin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (60 mg, 137 pmol), 4M HCI in 1 ,4-dioxane (0.411 mL) and DCM (1 .0 mL) but without SCX-2 purification to give the title compound (51 mg, 99%).
  • Step 1 tert-Butyl 6-((1-methyl-4-oxo-6-(thiophen-3-yl)-1,4-dihydropyridin-3-yl)methyl)-6,9- diazaspiro[4.5]decane-9-carboxylate:To a solution of tert-butyl 6-((4-oxo-6-(thiophen-3-yl)- 1 ,4-dihydropyridin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (429 mg, 1 mmol) in DMF (2 mL) under argon was added 55% sodium hydride in mineral oil (56 mg, 1.3 mmol).
  • Step 2 5-((6,9-Diazaspiro[4.5]decan-6-yl)methyl)-1-methyl-2-(thiophen-3-yl)pyridin-4(1H)- one hydrochloride: Prepared according to General Procedure 1 using tert-butyl 6-((1- methyl-4-oxo-6-(thiophen-3-yl)-1 ,4-dihydropyridin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9- carboxylate (50 mg, 113 pmol), 4M HOI in 1 ,4-dioxane (0.338 mL) and DCM (1 .0 mL) but without SCX-2 purification to give the title compound (42 mg, 98%).
  • Step 1 tert-Butyl 4-((6-chloro-2-(2-(trimethylsilyl)ethoxy)pyridin-3-yl)methyl)-3,3- dimethylpiperazine-1 -carboxylate: To a stirred solution of (6-chloro-2-(2- (trimethylsilyl)ethoxy)pyridin-3-yl)methanol (260 mg, 1.00 mmol) [prepared according to WO2018195321] in DCM (10 mL) under an atmosphere of N 2 at 0 °C were sequentially added triethylamine (167 ⁇ L, 1.20 mmol) and methanesulfonyl chloride (85.7 ⁇ L, 1.10 mmol).
  • Step 2 tert-Butyl 3,3-dimethyl-4-((6-(1-methyl-1H-pyrazol-5-yl)-2-(2- (trimethylsilyl)ethoxy)pyridin-3-yl)methyl)piperazine-1 -carboxylate'.
  • Step 3 3-((2,2-Dimethylpiperazin- 1 -yl)methyl)-6-(1 -methyl- 1 H-pyrazol-5-yl)pyridin-2( 1 H)- one hydrochloride'.
  • Step 1 (R)-5-(((tert-Butyldiphenylsilyl)oxy)methyl)dihydrofuran-2(3H)-one:To a stirred solution of (R)-5-(hydroxymethyl)dihydrofuran-2(3H)-one (1.00 g, 8.61 mmol) and imidazole (1.17 g, 17.2 mmol) in DMF (10 mL) at 0 °C was added tert-butylchlorodiphenylsilane (2.91 mL, 11 .2 mmol). The reaction mixture was allowed to warm to rt.
  • Step 2 (5R)-5-(((tert-Butyldiphenylsilyl)oxy)methyl)tetrahydrofuran-2-ol: To a stirred solution of (fl)-5-(((tert-butyldiphenylsilyl)oxy)methyl)dihydrofuran-2(3H)-one (2.74 g, 7.72 mmol) in diethyl ether (40 mL) at -78 °C under nitrogen and was added a 1 M solution of diisobutylaluminium hydride in DCM (11.6 mL, 11.6 mmol). After 5 h at -78 °C, the reaction mixture was quenched by the addition of MeOH (5 mL).
  • Step 3 (R)-tert-Butyl((2,3-dihydrofuran-2-yl)methoxy)diphenylsilane:To a stirred solution of (5R)-5-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydrofuran-2-ol (2.75 g, 7.71 mmol) and triethylamine (4.09 mL, 29.3 mmol) in DCM (50 mL) at -50 °C under nitrogen was added methanesulfonyl chloride (748 ⁇ L, 9.64 mmol).
  • Step 4 (R)-(2,3-Dihydrofuran-2-yl)methyl 4-methylbenzenesulfonate:To (R)-tert-butyl((2,3- dihydrofuran-2-yl)methoxy)diphenylsilane (1.37 g, 4.05 mmol) was added a 1 M TBAF in THF solution (4.05 mL, 4.05 mmol) and the resulting mixture was stirred at rt for 1 h.
  • Step 5 (R)-2-((2,3-Dihydrofuran-2-yl)methyl)isoindoline-1 ,3-dione: A mixture of (F?)-(2,3- dihydrofuran-2-yl)methyl 4-methylbenzenesulfonate (858 mg, 3.74 mmol) and potassium 1 ,3-dioxoisoindolin-2-ide (937 mg, 5.06 mmol) in DMF (13 mL) under nitrogen was stirred at 75 °C for 19 h. Upon cooling to rt, the reaction mixture was diluted with EtOAc (50 ml_) and washed with 1 :1 brine/water (3 x 50 mL).
  • Step 6 (R)-(2,3-Dihydrofuran-2-yl)methanamine:To (R)-2-((2,3-dihydrofuran-2- yl)methyl)isoindoline-1 , 3-dione (310 mg, 1.35 mmol) in MeOH (5.5 mL) was added hydrazine monohydrate (250 ⁇ L, 8.1 mmol) and the resulting mixture was heated at 60 °C for 2 h. Upon cooling to rt, a 2M sodium hydroxide ⁇ ) solution (10 mL) was added and the resulting mixture was extracted using DCM (3 x 20 mL).
  • Step 7 (1S,2R,5R)-2-(2,5-Difluorophenyl)-8-oxa-3-azabicyclo[3.2.1]octane:To crude (R)- (2,3-dihydrofuran-2-yl)methanamine (134 mg, 1.35 mmol) and 2,5-difluorobenzaldehyde (192 mg, 1 .35 mmol) in DCM (1.4 mL) was added 3A molecular sieves (300 mg) at rt. After 16 h, the reaction mixture was filtered (syringe filter) and the volatiles were evaporated under reduced pressure (40 °C, 210 mbar).
  • Step 1 6-Fluoro-3-(hydroxymethyl)-1-methylquinolin-4(1H)-one:To a stirred solution of 6- fluoro-3-(hydroxymethyl)quinolin-4(1 /-/)-one (965 mg, 5.00 mmol) in water (40 mL) were added NaOH (260 mg, 6.49 mmol), followed by dimethyl sulfate (1.40 ml_,19.0 mmol) at rt. After 3 h, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (0.79 g, 76%) as an off-white solid.
  • Step 2 3-(Chloromethyl)-6-fluoro-1-methylquinolin-4(1H)-one: To a stirred solution of 6- fluoro-3-(hydroxymethyl)-1-methylquinolin-4(1 H)-one (300 mg 1.45 mmol) in DCM (10 mL) was added SOCI 2 (0.31 mL, 4.34 mmol) at 50 °C. After 16 h, the solvents were evaporated under reduced pressure to yield the title compound (0.32 g, 98%) that was used in the next step without further purification.
  • Step 3 tert-Butyl 6-((6-fluoro-1-methyl-4-oxo-1,4-dihydroquinolin-3-yl)methyl)-6,9- diazaspiro[4.5]decane-9-carboxylate:To a stirred solution of 3-(chloromethyl)-6-fluoro-1- methylquinolin-4(1 F/)-one (0.32 g, 1.42 mmol) in MeCN (40 mL) were added tert-butyl 6,9- diazaspiro[4.5]decane-9-carboxylate (0.511 g, 2.13 mmol) and DIPEA (0.74 mL, 4.25 mmol) at rt.
  • Step 4 3-((6,9-Diazaspiro[4.5]decan-6-yl)methyl)-6-fluoro-1-methylquinolin-4(1H)-one: Prepared according to General Procedure 1 using tert-butyl 6-((6-fluoro-1-methyl-4-oxo- 1 ,4-dihydroquinolin-3-yl)methyl)-6,9-diazaspiro[4.5]decane-9-carboxylate (50 mg, 116 pmol), TFA (0.5 mL) and DCM (1.0 mL) to give the title compound (35.7 mg, 93%).

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Abstract

La présente invention concerne des composés de formule (I) qui sont utiles en tant qu'inhibiteurs de l'activité de la protéase spécifique de l'ubiquitine USP19. La présente invention concerne également des compositions pharmaceutiques comprenant lesdits composés et des méthodes d'utilisation desdits composés en thérapie.
PCT/EP2024/070617 2023-07-21 2024-07-19 Composés pharmaceutiques Pending WO2025021711A1 (fr)

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EP1431293A1 (fr) * 2001-09-26 2004-06-23 Kowa Co., Ltd. Derives de phenylpyridazine solubles dans l'eau et medicaments contenant ceux-ci
WO2006128562A1 (fr) * 2005-06-02 2006-12-07 Merck Patent Gmbh Utilisation de derives de chromone
WO2009072643A1 (fr) 2007-12-03 2009-06-11 Takeda Pharmaceutical Company Limited Composé hétérocyclique contenant de l'azote et son utilisation
WO2010117040A1 (fr) * 2009-04-10 2010-10-14 富士フイルム株式会社 Composé hétérocyclique à cinq chaînons
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