(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`(19) World Intellectual Property
`Organization
`International Bureau
`
`(43) International Publication Date
`8 June 2017 (08.06.2017)
`
`WIPO!IPCT
`
`\=
`
`(10) International Publication Number
`WO 2017/093718 Al
`
`Agent: STRATAGEM IPM LIMITED; Meridian Court,
`Comberton Road, Toft, Cambridge Cambridgeshire CB23
`2RY (GB).
`
`Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY,
`BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM,
`DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT,
`HIN, HR, HU,ID,IL, IN, IR, IS, JP, KE, KG, KN, KP, KR,
`KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME,
`MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI NO, NZ,
`OM,PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA,
`SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, T,
`TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM,
`ZW.
`
`GD)
`
`International Patent Classification:
`C07D 401/12 (2006.01)
`A61K 31/433 (2006.01)
`C07D 417/04 (2006.01)
`A6LK 31/549 (2006.01)
`C07D 417/14 (2006.01)
`A6IP 35/00 (2006.01)
`C07D 487/04 (2006.01)
`A61P 25/00 (2006.01)
`C07D 513/04 (2006.01)
`
`(74)
`
`(81)
`
`(21)
`
`International Application Number:
`
`PCT/GB2016/053742
`
`(22)
`
`(25)
`
`(26)
`
`(30)
`
`(71)
`
`(72)
`
`International Filing Date:
`29 November 2016 (29.11.2016)
`
`Filing Language:
`
`Publication Language:
`
`Priority Data:
`1521109.7.
`30 November 2015 (30.11.2015)
`
`English
`
`English
`
`GB
`
`Applicant: MISSION THERAPEUTICS LIMITED
`[GB/GB]; Babraham Research Campus, Moneta (Building
`280), Cambridge Cambridgeshire CB22 3AT (GB).
`
`Inventors: KEMP, Mark Ian; c/o Mission Therapeutics
`Limited, Babraham Research Campus, Moneta (Building
`280), Cambridge Cambridgeshire CB22
`3AT (GB).
`STOCKLEY, Martin Lee; c/o Mission Therapeutics Lim-
`ited, Babraham Research Campus, Moneta (Building 280),
`Cambridge Cambridgeshire CB22 3AT (GB). MADIN,
`Andrew; c/o Mission Therapeutics Limited, Babraham Re-
`search Campus, Moneta (Building 280), Cambridge Cam-
`bridgeshire CB22 3AT (GB).
`
`(84)
`
`Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ,
`TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU,
`TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE,
`DK,EE, ES, FI, FR, GB, GR, HR, HU,IE, IS, IT, LT, LU,
`LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK,
`SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ,
`GW, KM, ML, MR,NE, SN, TD, TG).
`Published:
`
`with international search report (Art. 21(3))
`
`(54) Title: 1-CYANO-PYRROLIDINE DERIVATIVES AS INHIBITORS OF USP30.
`
`
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`(I)
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`2017/093718AXIMIRNATATIATTATA0TITEL
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`(57) Abstract: The present invention relates to novel compounds and methods for the manufacture of inhibitors of deubiquitylatin-
`genzymes (DUBs). In particular, the invention relates to the inhibition of ubiquitin C- terminal hydrolase 30 or Ubiquitin Specific
`Peptidase 30 (USP30). The invention further relates to the use of DUB inhibitors in the treatment of conditions involving mitochon-
`© drial dysfunction and cancer. Compounds of the invention include compounds having the formula (1) (1) or a pharmaceutically ac -
`WwW ceptable salt thereof, wherein R', R’, R*, m, L and X are as defined herein.
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`WO 2017/093718
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`PCT/GB2016/053742
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`1-CYANO-PYRROLIDINE DERIVATIVES AS INHIBITORS OF USP30.
`
`The present invention relates to novel compounds and methods for the manufacture of inhibitors of
`
`deubiquitylating enzymes (DUBs). In particular, the invention relates to the inhibition of ubiquitin C-
`
`terminal hydrolase 30 or Ubiquitin Specific Peptidase 30 (USP30). The invention further relates to
`
`the use of DUB inhibitors in the treatment of conditions involving mitochondrial dysfunction and in
`
`the treatment of cancer.
`
`
`Background to the Invention
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`The listing or discussion of an apparently prior-published document in this specification should not
`
`necessarily be taken as an acknowledgement that the document is part of the state of the art or is
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`common general knowledge.
`
`Ubiquitin is a small protein consisting of 76 amino acidsthat 1s important for the regulation of protein
`
`function in the cell. Ubiquitylation and deubiquitylation are enzymatically mediated processes by
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`which ubiquitin is covalently bound or cleaved from a target protein by deubiquitylating enzymes
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`(DUBs), of which there are approximately 95 DUBs in humancells, divided into sub-families based
`
`on sequence homology. The USP family are characterised by thcir common Cys and His boxcs which
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`contain Cys and His residues critical for their DUB activities. The ubiquitylation and deubiquitylation
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`processes have been implicated in the regulation of many cellular functions including cell cycle
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`progression, apoptosis, modification of cell surface receptors, regulation of DNA transcription and
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`DNA repair. Thus, the ubiquitin system has been implicated in the pathogenesis of numerous disease
`
`states including inflammation, viral infection, metabolic dysfunction, CNS disorders, and oncogenesis
`
`(Clague et al., Physiol Rev 93:1289-1315, 2013).
`
`Ubiquitin is a master regulator of mitochondrial dynamics. Mitochondria are dynamic organelles
`
`whose biogenesis, fusion and fission events are regulated by the post-translational regulation via
`
`ubiquitylation of many key factors such as mitofusins. While ubiquitin ligases such as parkin are
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`known to ubiquitylate a number of mitochondrial proteins, until recently, deubiquitylating enzymes
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`remained elusive. USP30 is a 517 amino acid protein which is found in the mitochondrial outer
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`membrane (Nakamura ct al., Mol Biol 19:1903-11, 2008).
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`It is the sole dcubiquitylating cnzyme
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`bearing a mitochondrial addressing signal and has been shown to deubiquitylate a number of
`
`mitochondrial proteins.
`
`It has been demonstrated that USP30 opposes parkin-mediated mitophagy
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`and that reduction of USP30 activity can rescue parkin-mediated defects in mitophagy (Bingolet al.,
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`Mitochondrial dysfunction can be defined as diminished mitochondrial content (mitophagy or
`
`mitochondrial biogenesis), as a dccrcasc in mitochondrial activity and oxidative phosphorylation, but
`
`also as modulation of reactive oxygen species (ROS) generation. Hence a role for mitochondrial
`
`dysfunctions in a very large number of aging processes and pathologies including but not limited to,
`
`neurodegenerative diseases (c.g. Parkinson’s disease (PD), Alzheimer’s disease, Huntington’s disease,
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`Amylotrophic Lateral Sclerosis (ALS), multiple sclerosis), cancer, diabetes, metabolic disorders,
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`cardio-vascular diseases, psychiatric diseases (e.g. Schizophrenia), and osteoarthnitis.
`
`For example, Parkinson’s disease affects around 10 million people worldwide (Parkinson’s Disease
`
`Foundation) and is characterised by the loss of dopaminergic neurons in the substantia nigra. The
`
`exact mechanisms underlying PD are unclear; however mitochondrial dysfunction is increasingly
`
`appreciated as a key determinant of dopaminergic neuronal susceptibility in PD and is a feature of
`
`both familial and sporadic disease, as well as in toxin-induced Parkinsonism. Parkin is one of a
`
`numberof proteins that have been implicated with carly onset PD. While most PD cases are linked to
`
`defects in alpha-synuclein, 10% of Parkinson’s cases are linked to specific genetic defects, one of
`
`which is in the ubiquitin E3 ligase parkin. Parkin and the protein kinase PTEN-induced putative
`
`kinase
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`1
`
`(PINK1) collaborate to ubiquitylate mitochondrial membrane proteins of damaged
`
`mitochondria resulting in mitophagy. Dysregulation of mitophagy results in increased oxidative
`
`stress, which has been described as a characteristic of PD.
`
`Inhibition of USP30 could therefore be a
`
`potential strategy for the treatment of PD. For example, PD patients with parkin mutations leading to
`
`reduced activity could be therapeutically compensated by inhibition of USP30.
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`It has been reported that depletion of USP30 enhances mitophagic clearance of mitochondna and also
`
`enhances
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`parkin-induced
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`cell
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`death
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`(Liang
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`et
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`al.
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`»
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`EMBO)
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`Reports
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`2015
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`DOL:
`
`10.15252/embr.201439820). USP30 has also been shown to regulate BAX/BAK-dependent apoptosis
`
`independently of parkin over expression. Depletion of USP30 sensitises cancer cells to BH-3
`
`mimetics such as ABT-737, without the need for parkin over expression. Thus, an anti-apoptotic role
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`has been demonstrated for USP30 and USP30 is therefore a potential target for anti-cancer therapy.
`
`The ubiquitin-proteasome system has gained interest as a target for the treatment of cancer following
`
`the approval of the proteasome inhibitor bortezomib (Velcade®) for the treatment of multiple
`
`myeloma. Extended treatment with bortezomib is
`
`limited by its associated toxicity and drug
`
`resistance. However, therapeutic strategies that target specific aspects of the ubiquitin-proteasome
`
`pathway upstrcam of the protcascomc, such as DUBs, are predicted to be better tolcrated (Bedford ct
`
`al., Nature Rev 10:29-46, 2011). Thus,
`
`there is a need for compounds and pharmaceutical
`
`compositions to inhibit DUBs such as USP30 for the treatment of indications where DUBactivity is
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`observed,
`cancer.
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`including, although not limited to, conditions involving mitochondrial dysfunction and
`
`Summary of the Invention
`
`In accordance with a first aspect of the invention there is provided a compound of formula (1)
`
`a
`
`or a pharmaceutically acceptable salt thereof, wherem:
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`m is an integer from 0 to 3;
`each occurrence of R'
`is independently selected from the group consisting of fluorine, cyano,
`
`hydroxyl, amino, optionally substituted C)-C. alkyl, optionally substituted C\-C, alkoxy or an
`
`optionally substituted 3 to 6 membered ring;
`R’ represents hydrogen, optionally substituted C)-Cs alkyl, an optionally substituted ring, or R’
`together with R* formsan optionally further substituted ring:
`R° represents hydrogen, optionally substituted C)-C. alkyl, an optionally substituted ring, or R°
`together with R* forms an optionally further substituted ring, or R* together with X forms an
`
`optionally substituted ring;
`
`L represents a bond, an optionally substituted C,-C, alkylene or optionally substituted -C-C,
`alkenylene linker or formspart of a ring with X and R’;
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`X represents hydrogen, optionally substituted C,-C, alkyl, an optionally substituted ring, or X together
`with R* forms an optionally substituted ring.
`
`In one aspect, the invention also relates to pharmaceutical compositions comprising the compounds of
`
`the present invention and one or more pharmaceutically acceptable excipients.
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`In another aspect, the compoundsof the invention are useful for the treatment of cancer or a disease or
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`condition involving mitochondrial dysfunction.
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`Brief Description of the Figures
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`Figure 1 is a graph showing protcolytic activity of USP30 measured using a fluorescence polarisation
`
`assay. Various volumes of purified USP30 as indicated were incubated with a TAMRA labelled
`
`peptide linked to ubiquitin via an isopeptide bond.
`
`
`Detailed Description of the Invention
`
`The definitions and explanations below are for the terms as used throughout this entire document
`
`including both the specification and the claims. Reference to compoundsas described herein (e.g. a
`
`compound of formula (1),
`
`includes reference to formula (I) and formula (II) including any sub-
`
`generic embodiments thereof, e.g. formula (IA), (IB) or (IC) (including all sub-generic embodiments
`
`thereof).
`
`Where any group of the compounds of formula (I) or (ID) have been referred to as optionally
`
`substituted, this group may be substituted or unsubstituted. Substitution may be by one or more of the
`
`specified substituents which may be the sameor different.
`
`It will be appreciated that the number and
`
`nature of substituents will be selected to avoid any sterically undesirable combinations.
`
`In the context of the present specification, unless otherwise stated an alkyl, alkylene, alkoxy, alkenyl,
`
`alkenylene or alkynyl substituent (or linker) group or an alkyl, alkenyl moiety in a substituent group
`
`may be linear or branched. Alkyl, alkylene, alkenyl and alkenylene chains may also include
`
`intervening heteroatoms such as oxygen,
`
`C,-C, alkyl refers to a saturated aliphatic hydrocarbon group having x-y carbon atoms which may be
`
`linear or branched. For example C,.C. alkyl contains from | to 6 carbon atoms and includes C,, C2,
`
`C3, Cu, Cs and Cs. “Branched” means that at least one carbon branch point is present in the group.
`
`For example, tert-butyl and isopropyl are both branched groups. Examples of C,-C, alkyl groups
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`include methyl, ethyl, propyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-
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`butyl, 2-methyl-3-butyl, 2,2-dimethyl-l-propyl, 2-methyl-pentyl, 3-methyl-l-pentyl, 4-methyl-1-
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`pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-
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`1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl and n-hexyl. C)-
`Cy alkyl, C\-C, alkyl and C.-C; alkyl within the definitions of R', R’, R’, R’, R”, R’”, R® R®, R® RY
`R°, RB‘, R&R" and R’‘, Q', Q’, Q*, X, and within the definition of substituents for R*, R° and R°, may be
`
`unsubstituted or substituted with one or more of the substituents defined herein.
`
`Examples of
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`substituted C\-C¢ alkyl therefore include CF3, CH2CF3, CH2CN, CH2OH and CH2CH2OH.
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`A C,-C, alkylene group or moiety may be linear or branched and refers to a divalent hydrocarbon
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`group having onc Icss hydrogen atom from C,.C, alkyl as defined above. C,-Cs alkylene may include
`
`intervening heteroatoms such as oxygen, and therefore includes alkyleneoxy groups. Alkyleneoxyas
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`employed herem also extends to embodiments in which the or an oxygen atom (c.g. a single oxygen
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`atom) is located within the alkylene chain, for example CH2CH2,OCH2 or CH2OCH2. Examples of C,.
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`C.e alkylene groups include methylene, methyleneoxy, ethylene, ethyleneoxy, n-propylene, n-
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`propyleneoxy, n-butylene, n-butyleneoxy, methylmethylene and dimethylmethylene. Unless stated
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`otherwise, Ci-C, alkylene, Ci-C, alkylene and C\-C; alkylene within the definitions of R’, R”, R”,
`R* R°, RS R° R° RY R%, R" and R', Q', Q’, Q’, L, and within the definition of substituents for R“, R°
`and R°, may be unsubstituted or substituted with one or more ofthe substituents defined herein.
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`C.-C, alkenyl refers to a linear or branched hydrocarbon chain radical containing at least two carbon
`
`atoms and at least one double bond. Examples of alkenyl groups include ethenyl, propenyl, 2-
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`propenyl, 1-butenyl, 2-butenyl, 1-hexenyl, 2-methyl-1-propenyl, 1,2-butadienyl, 1,3-pentadienyl, 1,4-
`pentadienyl and 1-hexadienyl. Unless stated otherwise, Co-C, alkenyl within the definitions of Q', Q’,
`Q*, and within the definition of substituents for R*, R° and R°, may be unsubstituted or substituted
`with one or more of the substituents defined herein.
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`C.-C, alkenylene refers to linear or branched hydrocarbon group having one less hydrogen atom
`
`from C,-C, alkenyl as defined above. Examples of C.-C, alkenylene include ethenylene, propenylene
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`and butenylene. Unless stated otherwise, C.-C, alkenylene and C2-C, alkenylene within the definition
`of substituents for Q’, Q’, Q*, Q*, Q’, Q° and L, may be unsubstituted or substituted with one or more
`
`of the substituents defined herein.
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`C.-C, alkynyl refers to a linear or branched hydrocarbon chain radical containing at least two carbon
`
`atoms and at least one triple bond. Examples of alkenyl groups include ethynyl, propynyl, 2-
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`propynyl, 1-butynyl, 2-butynyl and I-hexynyl. Unless specified otherwise, C2-C, alkynyl within the
`definitions of Q', Q’, Q*, and within the definition of substituents for R“, R° and R°, may be
`
`unsubstituted or substituted with one or more of the substituents defined herein.
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`C,-C, alkoxy refers to a group or part of a group having an -O-C,.C, alkyl group according to the
`
`definition of C,.C, alkyl above. C)-C, alkoxy contains from 1 to 6 carbon atoms and includes C), Co,
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`Cs, C4, Cs and Cs. Examples of C,-C, alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy,
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`pentoxy and hexoxy. Alkoxy as cmployed hcrcin also cxtends to cmbodiments in which the or an
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`oxygen atom (e.g. a single oxygen atom) is located within the alkyl chain, for example CH,CH,0CH;
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`or CH,OCH;. Thus the alkoxy may be linked through carbon to the remainder of the molecule, for
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`example, -CH,»CH2,OCHs, or alternatively, the alkoxy is linked through oxygen to the remainderof the
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`molecule, for cxample -OC,« alkyl.
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`In onc instance, the alkoxy is linked through oxygen to the
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`remainder of the molecule but the alkoxy group contains a further oxygen atom, for example —
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`OCH:;CH2OCH:;. Unless specified otherwise, C)-C, alkoxy and C,-C; alkoxy within the definitions
`R', R’,R’, RR”, R’”, Q', Q”, Q’ and X may be unsubstituted or substituted with one or more of the
`
`substituents defined herein. Examples of substituted C,-C, alkoxy therefore include OCF;, OCHF,
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`OCH:CF; and OCH,COCHs;. For example, OCF;, OCH2CF; and OCH,COCHs.
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`The term “halogen” or “halo” refers to chlorine, bromine, fluorine or iodine atoms,
`
`in particular
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`chlorine or fluorine atoms.
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`The term “oxo” means =O.
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`The term “amino” means —NH)>.
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`For the avoidance of doubtit will be understood that the cycloalkyl, heterocyclyl, aryl and heteroaryl
`rings disclosed herein and withinthe definitions of R', R’, R*, R*, R°, R®, R*, R®, RY, R& RY, RY RY, R"
`and R', X, ring A, ring B, ring C, and within the definition of substituents for R*, R° and R°, do not
`
`include any unstable ring structures or, in the case of heteroaryl and heterocyclic ring systems, any O-
`
`O, O-S or S-S bonds. The ring systems may be monocyclic, bicyclic or tricyclic. Bicyclic and
`
`tricyclic ring systems include bridged, fused and spiro ring systems. A substituent if present may be
`
`attached to any suitable ring atom which may be a carbon atom or, in the case of heteroaryl and
`
`heterocyclic ring systems, a heteroatom. Substitution on a ring may also include a changein the nng
`
`atomat the position of the substitution. For example, substitution on a phenyl ring may include a
`
`change in the ring atom at the position of substitution from carbon to nitrogen, resulting in a pyridine
`
`ring.
`
`“cycloalkyl” refers to a monocyclic saturated or partially unsaturated, non-aromatic ring, wherein all
`
`of the ring atoms are carbon, and having the number of ring atoms as indicated. For example C3-Cio
`
`cycloalkyl refers to a monocyclic or bicyclic hydrocarbon ring containing 3 to 10 carbon atoms.
`
`Examples of C3-Cy cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
`
`cyclooctyl and decahydronaphthalenyl. Bicyclic cycloalkyl groupsinclude bridged ring systems such
`
`as bicycloheptane and bicyclooctane. Unless specified otherwise, cycloalkyl within the definitions of
`R', R?, B®, R*, R’, R®, R® R®, RY, RY RY, RY, R&R" and RX, ring C, and within the definition of
`substituents for R*, R° and R°, may be unsubstituted or substituted with one or more of the
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`substituents defined herein.
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`An “aryl” group / moicty refcrs to any monocyclic or bicyclic hydrocarbon group compnising at Icast
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`one aromatic group and having from 5 to 10 carbon atom ring members. Examples of aryl groups
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`imclude phenyl and naphthyl. Bicyclic nngs may be fused aromatic rings where both rings are
`
`aromatic, for example, naphthalenyl. Preferred aryl groups are phenyl and naphthyl, more preferably
`phenyl. Unless specified otherwise, aryl within the definitions of R', R’, R’, R*, R°, R°®, R*, R°, R®, R%,
`R®, R4, R&, R" and R’', X, ring C, and within the definition of substituents for R*, R° and R°, may be
`
`unsubstituted or substituted with one or more of the substituents defined herein.
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`“Heteroaryl” as used herein means a polyunsaturated, monocyclic, bicyclic or tricyclic 5 to 14
`
`membered, or 4 to 10 membered, or 5 to 10 membered, aromatic moiety containing at least one and
`
`up to 5 heteroatoms,particular 1, 2 or 3 heteroatoms selected from N, O andS, and the remaining ring
`
`atoms are carbon atoms, in stable combinations known to the skilled person. Heteroaryl ring nitrogen
`
`and sulphur atoms are optionally oxidised, and the nitrogen atom(s) are optionally quaternized. A
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`heteroaryl ring can be a single aromatic ring or a fused bicyclic mng where the bicyclic ring system
`
`can be aromatic, or one of the fused rings is aromatic andthe otheris at least partially saturated.
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`In
`
`such instances, attachment of the bicyclic ring to the group it is a substituent of, e.g. with respect to
`
`the cyanopyrrolidine core,
`
`is via the aromatic ring of the bicycle.
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`In one example, a bicyclic
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`heteroaryl is one in whichthe entire fused ring system is aromatic. A bicyclic heteroaryl can have the
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`at least one heteroatom in either of the fused rings, ie.
`
`it can be attached to the group it is a
`
`substituent of either via a heteroatom containing ring or a carbon only containing nng. The point of
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`attachment of heteroaryl to the group it is a substituent of can be via a carbon atom or a heteroatom
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`(e.g. nitrogen).
`
`In instances where nng B of formula (IB) is a heteroaryl, the ring incorporating the
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`sulphamide nitrogen is an aromatic ring which may be fused to a further aromatic or partially
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`saturated ring.
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`In instances where ring C of formula (IC)is a heteroaryl, the ring is an aromatic ring
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`which may be fused to a further aromatic or partially saturated ring. Examples of heteroaryl rings
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`include pynidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl,
`
`tniazolyl,
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`tetrazolyl,
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`indolyl,
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`indolizinyl,
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`isomdolyl, purmnyl,
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`furazanyl,
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`imidazolyl,
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`indazolyl,
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`isothiazolyl,
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`isoxazolyl,
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`oxadiazolyl,
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`tetrazolyl,
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`thiadiazolyl, benzofuranyl,
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`isobenzofurany],
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`benzothiophenyl,
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`isobenzothiophenyl, benzimidazolyl, benzothiazolyl, napthyridinyl, pteridinyl,
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`pyrazinyl, quinolinyl,
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`isoquinolinyl,
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`cimnolinyl, phthalazinyl, quinazolinyl,
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`imidazopyndinyl,
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`triazinyl, dihydrophyridinyl, quinoxalinyl and carbazolyl.
`thiazolopyridinyl,
`pyrazolopynidinyl,
`Unless specified otherwise, heteroaryl within the definitions of R', R’?, R*, R*, R°, R®, R* R°, R®, RY
`R°, R*, R&R" and R', X, ring B, ring C, and within the definition of substitucnts for R*, R° and R°,
`
`maybe unsubstituted or substituted with one or more of the substituents defined herein.
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`“Heterocyclyl” or “heterocyclic” as used herein in describing a ring means, unless otherwise stated, a
`
`monocyclic saturated or partially unsaturatcd, non-aromatic nng, a bicyclic saturated or partially
`
`unsaturated ring, wherein the bicyclic ring system is non-aromatic, or a tricyclic partially unsaturated
`
`ring, the mono-, bi- or tricyclic ring having, for example, 3 to 14 members, or 3 to 10 members, or 4
`
`to 10 members, whereat least one member and up to 5 members, particularly 1, 2 or 3 members ofthe
`
`ring, are heteroatoms selected from N, O and S, and the remaining ring atoms are carbon atoms, in
`
`stable combinations known to those of skill in the art. Heterocyclic ring nitrogen and sulphur atoms
`
`are optionally oxidised, and the nitrogen atoms(s) are optionally quaternized. As used herein, the
`
`heterocyclic ring may be a fused ring to another ring system to form a bicycle, i.e. one or two of the
`
`heterocyclic ring carbons is commonto an additional ring system. In instances where the heterocyclyl
`
`is a bicyclic ring, attachment to the group it is a substituent of relative to the cyanopyrrolidine core is
`
`via the non-aromatic ring, wherein the non-aromatic ring may be fused to a further ring which may be
`aromatic or non-aromatic. For example, R’ and R* may together form a heterocylic ring which
`
`incorporates the sulphamide nitrogens and sulphur, and whichis also referred to as ring A in formula
`
`(IA).
`
`In the case where the heterocylcyl is a bicyclic ring, the second ring (i.e. the nng portion that
`
`does not include -N-S(O2)-N-) can be aromatic, e.g. a fused phenyl, pyridyl, pyrazolyl, or the like. In
`
`the case of a tricyclic heterocyclic ring, the heterocyclic ring may formthe central ring and be fused to
`
`two further ring systems which are preferably aromatic. The heterocyclyl may be linked through
`
`carbon or a heteroatom to the remainder of the molecule and the link may be via the central
`
`heterocyclyl or either of the fused terminal rings. Examples of heterocyclyl groups include azetidinyl,
`
`pytrolidinyl, piperidinyl,
`
`azepanyl, diazepanyl, dihydrofuranyl
`
`(e.g. 2,3-dihydrofuranyl, 2,5-
`
`dihydrofuranyl),
`
`dioxolanyl, morpholinyl,
`
`oxazolidinyl,
`
`oxazinanyl,
`
`indolinyl,
`
`isoimdolinyl,
`
`piperazinyl,
`
`tetrahydrofuranyl,
`
`thiomorpholinyl, dihydropyranyl
`
`(e.g. 3,4-dihydropyranyl, 3,6-
`
`dihydropyranyl), homopiperazinyl, dioxanyl, hexahydropynmidinyl, pyrazolinyl, pyrazolidinyl, 4H-
`
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`quinolizinyl, tetrahydropyridinyl,—tetrahydropynmidinyl,quinuclidinyl, tetrahydropyranyl,
`
`
`
`
`
`
`
`tetrahydrothiophenyl, thiazolidinyl, benzopyranyl, tetrahydrothiazolopyridinyl, tetrahydroquinolinyl,
`
`benzomorpholinyl, tetrahydroisoquinolinyl and carbazolyl. Unless specified otherwise, heterocyclyl
`within the definitions of R', R’, R*, R*, R*, R®, R*, R®, R®, RB“, R®, RY R® R" and R’, X,ring A, ring B,
`ring C, and within the definition of substituents for R*, R° and R®, may be unsubstituted or substituted
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`30
`
`with one or more of the substituents defined herein.
`
`Substituted heterocyclyl rings include for
`
`example 4,5-dihydro-1H-maleimido, tetramethylenesulfoxide and hydantoiny1.
`
`“Optionally substituted” as applied to any group means that the said group may if desired be
`
`substituted with onc or morc substitucnts (c.g., 1, 2, 3 or 4 substituents) which may bc the same or
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`Examples of suitable substituents for “substituted” and “optionally substituted” C,-C, alkyl (including
`
`C.-C, alkyl and C)-C; alkyl),Ci-C¢ alkoxy (including C)-C, alkoxy and C)-C; alkoxy), -C2-C, alkenyl
`and -C3-C, alkynyl, for example within the definitions of R', R’, R*, R’, R’”, R’”, R*, R®, R®, R°, RY, RB’
`R&, R" and R', Q', Q’, Q*, X, and within the definition of substituents for R*, R° and R®°, and Cy-C,
`
`alkylene (including C)-C3 alkylene) and C.-C. alkenylene, for example within the definitions of R’,
`R”, R’”, R*, R°, R°, RY R® RY Re R" and R’, Q', Q’, Q? and L, include C\-Cs alkoxy, halogen,
`
`hydroxyl, thiol, cyano, amino, nitro and SF; (a known mimetic of nitro),
`
`in particular, halogen
`
`(preferably fluorine or chlorine), hydroxyl and cyano. For example, suitable substituents include
`
`halogen, hydroxyl, thiol, cyano, amino, nitro and SFs, in particular, halogen (preferably fluorine or
`
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`
`chlorine), hydroxyl and cyano.
`
`Examples of suitable substituents for “substituted” and “optionally substituted” rings, 1.¢. cycloalkyl,
`heterocyclyl, aryl and heteroaryl rings, for example within the definitions of R', R’, R’, R*, R’, R°, R*,
`R®, R& RY R®, RR’, R&, R"and R‘, X, ring A, ring B,ring C, and within the definition of substituents for
`R*, R° and R°, include halogen, C)-C, alkyl or C\-C; alkyl, hydroxy, C)-Cs alkoxy or C)-C; alkoxy,
`
`cyano, amino, nitro or SF;
`
`(a known mimetic of nitro), aryl, heteroaryl, heterocyclyl, C3-C¢
`
`cycloalkyl, Ci; alkylamino, C2. alkenylamino, di-C)-C; alkylamimo, C)-C; acylamino, di-C-C;
`
`acylamino, carboxy, C)-C; alkoxycarbonyl, carboxamidyl, carbamoyl, mono-C,.3; carbamoyl, di-C,;
`
`carbamoyl or any of the above in which a hydrocarbyl moiety is itself substituted by halo.
`
`In groups
`
`containing an oxygen atom such as hydroxy and alkoxy,
`
`the oxygen atom can be replaced with
`
`sulphur to make groups such as thio (SH) and thio-alkyl (S-alkyl). Optional substituents therefore
`
`include groups such as S-methyl.
`
`In thio-alkyl groups, the sulphur atom may be further oxidised to
`
`make a sulfoxide or sulfone, and thus optional substituents therefore includes groups such as S(O)-
`
`alkyl and S(O)»-alkyl.
`
`Examples of suitable substituents for “substituted” and “optionally substituted” rings include in
`
`particular,
`
`fluorine, chlorine, oxo, cyano, C)-C; alkyl, C)-C3 alkoxy, heterocyclyl, cycloalkyl,
`
`heteroary or aryl, wherein the alkyl or alkoxyis optionally substituted with one or more (e.g. one, two
`
`or three) substituents independently selected from halogen, hydroxyl, thiol, cyano, amino, nitro and
`
`SF.
`
`In particular, suitable substituents for “substituted” and “optionally substituted” rings disclosed
`
`herein include fluorine, chlorine, oxo, cyano, C)-C; alkyl, Ci-C; alkoxy, wherein the alkyl or alkoxy is
`
`optionally substituted with one or more (e.g. one, two or three) substituents selected from halogen,
`
`hydroxyl, thiol, cyano, amino, nitro and SFs, in particular, one or more fluorine.
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`Substituted groups thus include for example Br, Cl, F, CN, Me, Et, Pr, OMe, OEt, OPr, C(CHs)s,
`
`CH(CH3)2, CF3, OCF3:3, C(O)NHCHs, cyclopropyl, phenyl, ctc.
`
`In the case of aryl groups, the
`
`substitutions may be in the form of rings from adjacent carbon atoms in the aryl ring, for example
`
`cyclic acetals such as O-CH;-O.
`
`The term "treat" or "treating" or “treatment” includes prophylaxis and means to ameliorate,
`
`alleviate symptoms, eliminate the causation of the symptoms either on a temporary or permanent
`
`basis, or to prevent or slow the appearance of symptoms of the named disorder or condition. The
`
`compoundsof the invention are useful in the treatment of humans and non-humananimals.
`
`The dose of the compound is that amount effective to prevent occurrence of the symptoms of the
`
`disorder or to treat some symptoms of the disorder from which the patient suffers. By "effective
`
`amount" or "therapeutically effective amount" or "effective dose" is meant that amount sufficient
`
`to elicit the desired pharmacological or therapeutic effects, thus resulting in effective prevention or
`
`treatment of the disorder. Prevention of the disorder is manifested by delaying the onset of the
`
`symptoms of the disorder to a medically significant extent. Treatment of the disorder is manifested by
`
`a decrease in the symptoms associated with the disorder or an amelioration of the reoccurrence of the
`
`symptoms of the disorder.
`
`Pharmaceutically acceptable salts of the compounds of the invention include but are not limited to
`
`addition salts (for example phosphates, nitrates, sulphates, borates, acetates, maleates, citrates,
`
`fumarates, succinates, methanesulphonates, benzoates, salicylates and hydrohalides), salts derived
`
`from organic bases (such as lithium, potasstum and sodium), salts of amino acids (such as glycine,
`
`alanine, valine,
`
`leucine,
`
`isoleucine, cysteine, methionine and proline),
`
`inorganic bases (such as
`
`triethylamine,
`
`hydroxide,
`
`choline,
`
`thiamine
`
`and N-N’-diacetylethylenediamine).
`
`Other
`
`pharmaceutically acceptable salts
`
`include ammonium salts,
`
`substituted ammonium salts and
`
`aluminium salts. Further pharmaceutically acceptable salts include quaternary ammoniumsalts of the
`
`compoundsof the invention.
`
`General methods for the production of salts are well known to the person skilled in the art. Such salts
`
`may be formed by conventional means, for example by reaction of a free acid or a free base form of a
`
`compound with one or more equivalents of an appropriate acid or base, optionally in a solvent, or ina
`
`medium in whichthesalt is insoluble, followed by removal of said solvent, or said medium, using
`
`standard techniqucs (c.g. in vacuo, by freeze-drying or byfiltration). Salts may also be prepared by
`
`exchanging a counter-ion of a compound in the form of a salt with another counter-ion, for example
`
`using a suitable ion exchange resin.
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`Where compoundsof the invention cxist in differcnt cnantiomcric and/or diastcrcoisomcric forms, the
`
`invention relates to these compounds prepared as isomeric mixtures or racemates whether present in
`
`an optically pure form or as mixtures with other isomers. Enantiomers differ only m their ability to
`
`rotate plane-polarized light by equal amounts in opposite directions and are denoted as the (+) / (S) or
`
`(-) /(2) forms respectively. Individual enantiomer