(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`(19) World Intellectual Property
`Organization
`International Bureau
`
`(43) International Publication Date
`29 June 2017 (29.06.2017)
`
`WIPO!IPCT
`
`\=
`
`(10) International Publication Number
`WO 2017/109488 Al
`
`GD)
`
`International Patent Classification:
`C07D 403/12 (2006.01)
`CO7D 417/14 (2006.01)
`C07D 413/14 (2006.01)
`C07D 207/10 (2006.01)
`C07D 413/12 (2006.01)
`A61IK 31/40 (2006.01)
`C07D 417/12 (2006.01)
`A61P 35/00 (2006.01)
`
`2)
`
`International Application Number:
`
`(22)
`
`International Filing Date:
`
`PCT/GB2016/054022
`
`21 December 2016 (21.12.2016)
`
`(25) Filing Language:
`(26) Publication Language:
`(30) Priority Data:
`1522768.9
`23 December 2015 (23.12.2015)
`
`GB
`
`(71) Applicant: MISSION THERAPEUTICS LIMITED
`[GB/GB]; Moneta (Building 280), Babraham Research
`Campus, Cambridge CB22 3AT (GB).
`
`(72)
`
`Inventors: KEMP, Mark Ian; C/o Mission Therapeutics
`Limited, Moneta (Building 280), Babraham Research Cam-
`pus, Cambridge CB22 3AT (GB). WOODROW, Michael
`David; C/o Mission Therapeutics Limited, Moneta (Build-
`ing 280), Babraham Research Campus, Cambridge CB22
`3AT (GB).
`
`(81) 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, FL GB, GD, GE, GH, GM,GT,
`HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KH, 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, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN,
`ZA, ZM, ZW.
`English
`English (g4) 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, FL 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 (BEF, BJ, CF, CG, CI, CM, GA, GN, GQ,
`GW, KM,ML,MR,NE, SN, TD, TG).
`Published:
`
`with international search report (Art. 21(3))
`
`(74)
`
`Agent: STRATAGEM INTELLECTUAL PROPERTY
`MANAGEMENT LIMITED, Meridian Court, Comber-
`ton Road, Toft, Cambridge CB23 2RY (GB).
`
`(54) Title: CYANOPYRROLIDINE DERVIVATIVES AS INHIBITORS FOR DUBS
`
`
`
`we mg
`
`
`
`“GeRMRRESEOETES 4
`
`“AALAMAAEALAERPPLEEAEP
`
`
`
`a
`
`(1)
`
`
`
`2017/109488AiIMIIIMIITNATAIIATTATAHOAMERICAA
`
`(57) Abstract: The present invention relates to novel compounds and methods for the manufacture of inhibitors of deubiquitylating
`enzymes (DUBs). In particular, the inventionrelates to the inhibition of Cezanne 1 and ubiquitin C-terminal hydrolase 30 or Ubi-
`quitin Specific Peptidase 30 (USP30). The invention further relates to the use of DUB inhibitors in the treatment of cancer. Com -
`poundsof the invention include compounds having the formula (I): pharmaceutically acceptable salt thereof, wherein R'*, R', R',
`= RR Rand A are as defined herein.
`
`

`

`WO 2017/109488
`
`PCT/GB2016/054022
`
`CYANOPYRROLIDINE DERVIVATIVES AS INHBITORS FOR DUBS
`
`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 Cezanne 1.
`
`The invention further relates to the use of DUB inhibitors in the treatment of cancer.
`
`
`Background to the Invention
`
`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
`
`10
`
`commongeneral knowledge.
`
`Ubiquitin is a small protein consisting of 76 amino acids that is important for the regulation of protein
`
`function in the cell. Ubiquitylation and deubiquitylation are enzymatically mediated processes by
`
`which ubiquitin is covalently bound or cleaved from a target protein. These processes have been
`
`implicated in the regulation of many cellular functions including cell cycle progression, apoptosis,
`
`modification of cell surface receptors, regulation of DNA transcription and DNA repair. Thus, the
`
`ubiquitin system has been implicated in the pathogenesis of numerous disease states including
`
`inflammation, viral infection, metabolic dysfunction, CNS disorders, and oncogenesis.
`
`Ubiquitin molecules are cleaved from proteins by deubiquitylating enzymes (DUBs), of which there
`
`are approximately 95 DUBs in humancells, divided into sub- families based on sequence homology.
`
`The ovarian tumour (OTU) family consists of at least 14 active DUBs and are characterised by the
`
`presence of an OTU domainand the tendencyto cleave ubiquitin chains in a linkage specific manner.
`
`Cezanne |, also known as OTUD7B, is an 843 amino acid protein that was identified owing to its
`
`similarity to the OTU family member A20 that has been shown biochemically to have a strong
`
`preference for K11 ubiquitin chain linkages.
`
`Cezanne | has been shownto act as a negative regulator of both the canonical and the non-canonical
`
`NF-«B pathway. It has been shown that Cezanne | acts on the canonical pathway by processing K63
`
`chains on the RIP1 protein and on the non-canonical pathway by deubiquitylation of the inhibitory
`
`component TRAF3 (TNFreceptor associated factor 3).
`
`It has also been shown to have a role in
`
`hypoxia by regulating HIFla (hypoxia inducible factor la) protein levels. Cezanne 1 siRNA
`
`decreased HIFla protein levels under hypoxia, and accordingly decreased HIFloa target gene
`
`expression. Knockdown of Cezanne |
`
`led to higher levels of apoptosis following hypoxia. Since
`
`HIFla has oncogenic properties, and Cezanne | has a pro-survival role in hypoxia, Cezanne | has
`
`been suggested to be a goodtarget for pharmacological intervention.
`
`15
`
`20
`
`25
`
`30
`
`35
`
`

`

`WO 2017/109488
`
`PCT/GB2016/054022
`
`Cezanne | has been shownto have a role in cell proliferation, migration and invasion by antagonizing
`
`EGFR(epidermal growth factor receptor) internalisation and degradation. Cezanne 1 and Cezanne 2
`
`were identified in a genetic screen to find a DUB enzyme for EGFR. Cezanne | overexpressionled to
`
`higher levels of phosphorylated EGFR, lower levels of ubiquitylated EGFR and EGFRstabilization.
`
`In MDA-MB-231 breast cancer cells, knockdown of Cezanne 1
`
`led to decreased invasion and
`
`migration. Analysis of The Cancer Genome Atlas by Pareja et al., showed that Cezanne 1 was
`
`overexpressed in breast cancer and amplification of the gene was seen in a third of breast tumours.
`
`The level of Cezanne | expression correlated with poor prognosis.
`
`10
`
`Although there has been a handful of DUB inhibitors published in the literature, there is a continuing
`
`need for compounds and pharmaceutical compositions which inhibit DUBs such as Cezanne | and
`
`USP30 for the treatment of cancer and other indications where DUBactivity is observed.
`
`15
`
`Summary of the Invention
`
`In accordance with a first aspect of the invention there is provided a compound of formula (1)
`
`a
`
`oewe
`
`GRAAL
`
`LALALES
`
`(1)
`
`20
`
`or a pharmaceutically acceptable salt thereof, wherein:
`R'* RR" and R' each independently represent hydrogen or an optionally substituted C-C, alkyl,
`or R'is linked to R™ to form an optionally substituted cycloalkyl ring, or R'’ is linked to R'® or R" to
`
`form an optionally substituted cycloalkyl ring;
`R"° and R" each independently represent hydrogen, fluorine, cyano, hydroxyl, amino, optionally
`
`25
`
`substituted C,-C, alkyl, optionally substituted C,-C, alkoxy or an optionally substituted 5 or 6
`memberedaryl or heteroaryl ring, or R'® and R"together form an optionally substituted cycloalkyl
`ring, or R" is linked to R' to form an optionally substituted cycloalkyl ring;
`
`A is an optionally substituted 5 to 10 membered heteroaryl or aryl ring.
`
`30
`
`

`

`WO 2017/109488
`
`PCT/GB2016/054022
`
`A may represent a 5 to 10 membered heteroaryl or aryl ring substituted with onc or more of Q'-(R”)n.
`
`wherein:
`
`nis Oor 1;
`-
`-NR*COR*,
`-CONR’R*,
`-NR°R*,
`-SR’,
`-OR®,
`Q'
`represents halogen, cyano, oxo, nitro,
`NR*CONR'R’, -COR’, -C(O)OR*, -SO2R*, -SO:NR°R", -NR*SO,R*, -NR*SO.NR'R’, -NR°C(O)OR’,
`
`optionally substituted -C,-C, alkyl, optionally substituted -C,-C, alkoxy, optionally substituted —C2-C,
`
`alkenyl, optionally substituted —C2-C. alkynyl, a covalent bond, an oxygen atom, a sulphur atom, -SO-
`, “SO.-,
`-CO-,
`-C(O)O-,
`-CONR’*-,
`-NR*-,
`-NR*CO-,
`-NR*CONR"-,
`-SO2NR*-,
`-NR*SO,-,
`-
`NR’SO,NR*-,
`-NR°C(O)O-,
`-NR*C(O)OR*-, optionally substituted C)-C, alkylene or optionally
`
`10
`
`substituted -C2-C, alkenylene;
`R°, R‘ and R° each independently represent hydrogen, optionally substituted C\-C, alkyl or optionally
`
`substituted C,-C, alkylene.
`
`Whennis 1, R’ represents an optionally substituted 3 to 10 membered heterocyclyl, heteroaryl, aryl
`15
`or cycloalkyl ring. (When n is 0, Q; is present and R’is absent).
`
`R’ maybeoptionally substituted with onc or more substituents sclected from halogen, cyano, oxo,
`nitro, -OR®, -SR°, -NR°R’, -CONR®R’, -NR°COR’, -NR°CONR’R*, -COR®,-C(O)OR*®, -SO,R’,-
`SO;NR°R’, -NR°SO>R’, NR°SO,NR’R®, -NR°C(O)OR’, optionally substituted -C)-C, alkyl,
`
`optionally substituted -C)-C, alkoxy, optionally substituted —C.-C, alkenyl, optionally substituted -C2-
`Cs alkynyl, -Q’-R°, -Q’-NR°CONR’R®, -Q’-NR°R’, -Q?-COR®, -Q’-NR°COR’, -Q’-NR°C(O)OR’,-
`Q’-SO2R°, Q’-CONR‘’R’, -Q’-CO2R°, -Q’-SO,NR°R’, —Q’-NR°SO>R’ and -Q’-NR°SO,NR’R*;
`
`wherein
`
`Q’ represents a covalent bond, an oxygen atom, a sulphur atom, -SO-, -SO,-, -CO-, optionally
`
`substituted C,-C, alkylene or optionally substituted C2-C, alkenylene; and
`R°, R’, R® each independently represent hydrogen, optionally substituted C\-C, alkyl, optionally
`
`substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, or an optionally
`
`substituted cycloalkyl.
`
`In one aspect, the invention also relates to pharmaceutical compositions comprising the compounds of
`
`the present invention and one or more pharmaceutically acceptable excipients.
`
`In another aspect, the compoundsof the invention are useful for the treatment of cancer.
`
`20
`
`25
`
`30
`
`35
`
`

`

`WO 2017/109488
`
`PCT/GB2016/054022
`
`
`Bnicf Description of the Figures
`
`Figure | provides an image of Cezanne 1 purified from mammalian cells. FLAG-purified protein or
`
`the indicated concentrations of BSA were separated by SDS-PAGEandstained with Impenal (Pierce
`
`Biotechnology).
`
`Figure 2 is a graph showing proteolytic activity of Cezanne 1 measured using a fluorescence
`
`polarisation assay. Various volumes of purified Cezanne | as indicated were incubated with a
`
`TAMRA labelled peptide linked to ubiquitin via an isopeptide bond.
`
`10
`
`
`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 compounds as described herein (e.g. a
`
`compound of formula (I),
`
`includes reference to formula (1) and (IT)
`
`including any sub-generic
`
`embodiments thereof, e.g. formula (JA).
`
`15
`
`20
`
`25
`
`30
`
`35
`
`Where any group of the compounds of formula (I) have been referred to as optionally substituted, this
`
`group may be substitutcd or unsubstituted. Substitution may be by onc or morc of the spccificd
`
`substituents which may be the same ordifferent.
`
`It will be appreciated that the numberand 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,
`
`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,, Co,
`
`Cs, Ca, Cs and Cs. “Branched” meansthat 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
`
`include methyl, ethyl, propyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-
`
`butyl, 2-methyl-3-butyl, 2,2-dimethyl-l-propyl, 2-methyl-pentyl, 3-methyl-l-pentyl, 4-methyl-1-
`
`pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-
`
`1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl and n-hexyl. C,-
`Cz alkyl, C\-C, alkyl and Cj-C; alkyl within the definitions of R', R'’, R', R'?, R'®, RY, R’, RY R?,
`R°, R’, R®, Q', and within the definition of substituents for R’, may be unsubstituted or substituted
`
`

`

`WO 2017/109488
`
`PCT/GB2016/054022
`
`with onc or morc of the substituents defined herein. Examples of substituted Ci-Ce alkyl thercforc
`
`include CF3, CH,CFs, CH,CN, CH,OH and CH,CH,OH.
`
`A C,-C, alkylene group or moiety may be linear or branched and refers to a divalent hydrocarbon
`
`group having one less hydrogen atom from C,-C, alkyl as defined above. C)-C, alkylene may include
`
`intervening heteroatoms such as oxygen, and therefore includes alkyleneoxy groups. Alkyleneoxy as
`
`employed herein also extends to embodiments in which the or an oxygen atom (e.g. a single oxygen
`
`atom) is located within the alkylene chain, for example CH,CH,OCH, or CH,OCH;. Examples of Cy.
`
`C.s alkylene groups include methylene, methyleneoxy, ethylene, ethyleneoxy, n-propylene, n-
`
`propyleneoxy, n-butylene, n-butyleneoxy, methylmethylene and dimethylmethylene. Unless stated
`otherwise, C,-C, alkylene, C,-C, alkylene and C,-C; alkylene within the definitions of R?, RR’, Q'
`and Q’ may be unsubstituted or substituted with one or more of the substituents defined herein.
`
`C.-C, alkenyl refers to a linear or branched hydrocarbon chain radical containing at least two carbon
`
`atoms and at least one double bond and includes C,-C, alkenyl. Examples of alkenyl groups include
`
`ethenyl, propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1-hexenyl, 2-methyl-1-propenyl, 1,2-butadienyl,
`
`1,3-pentadicnyl, 1,4-pentadicnyl and 1-hcexadicnyl. Unless stated otherwise, C2-C¢ alkenyl and C2-C,
`alkenyl within the definitions of Q' and within the definition of substituents for R’, may be
`
`unsubstituted or substituted with one or more of the substituents defined herein.
`
`10
`
`15
`
`20
`
`C.-C, alkenylene refers to linear or branched hydrocarbon group having one less hydrogen atom
`
`from C2-C, alkenyl as defined above. Examples of C:-C, alkenylene include ethenylene, propenylene
`
`and butenylene. Unless stated otherwise, C:-C, alkenylene and C.-C, alkenylene within the definition
`of substituents for Q' and Q’, may be unsubstituted or substituted with one or more of the substituents
`
`25
`
`defined herein.
`
`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-
`
`propynyl, 1-butynyl, 2-butynyl and l-hexynyl. Unless specified otherwise, C3-C, alkynyl, within the
`definitions of Q' and within the definition of substituents for R’, may be unsubstituted or substituted
`
`30
`
`with one or more of the substituents defined herein.
`
`C,-Cg 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), C2,
`
`35
`
`Cs, C4, Cs and Cs. Examples of C)-C, alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy,
`
`pentoxy and hexoxy. Alkoxy as employed herein also extends to embodiments in which the or an
`
`

`

`WO 2017/109488
`
`PCT/GB2016/054022
`
`oxygen atom (c.g. a single oxygen atom) 1s located within the alkyl chain, for example CH2CH2,OCH3
`
`or CH,0CH;. Thus the alkoxy may be linked through carbon to the remainder of the molecule, for
`
`example, -CH,CH,OCHs, or alternatively, the alkoxy is linked through oxygento the remainder ofthe
`
`molecule, for example -OC, alkyl.
`
`In certain instances, the alkoxy may be linked through oxygen to
`
`the remainder of the molecule but the alkoxy group contains a further oxygen atom, for example —
`
`OCH:;CH.20OCH:;. Unless specified otherwise, C)-C, alkoxy and C,-C; alkoxy within the definitions
`R'*, RQ! and within the definition of substituents for R’, may be unsubstituted or substituted with
`
`one or more of the substituents defined herein. Examples of substituted C,-C, alkoxy therefore
`
`include OCF3, OCHF,, OCH2CF;, CH2CH2,OCH; and CH,CH,0CH2CHs.
`
`The term “halogen” or “halo” refers to chlorine, bromine, fluorine or iodine atoms,
`
`in particular
`
`chlorine or fluorine atoms.
`
`The term “oxo” means =O.
`
`For the avoidance of doubtit will be understood that the cycloalkyl, heterocyclyl, aryl and heteroaryl
`rings disclosed herein and within the definitions of R'*, R', R', R'! R'®, R'!, R?, R°, R’, R®ring A,
`and within the definition of substituents for R’, do not include any unstable ring structures or, in the
`
`case of heteroaryl and heterocyclic rings systems, any O-O, O-S or S-S bonds. The ring systems may
`
`be monocyclic or bicyclic. Bicyclic 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 change in the ring atom at the position of the substitution. For example, substitution on a
`
`phenyl ring may include a change in the nng atom at the position of substitution from carbon to
`
`10
`
`15
`
`20
`
`25
`
`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 numberof ring atoms as indicated. For example C3-Cjo
`
`cycloalkyl refers to a monocyclic or bicyclic hydrocarbon ring containing 3 to 10 carbon atoms.
`
`Examples of C3-Ciy cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
`
`cyclooctyl and decahydronaphthalenyl. Bicyclic cycloalkyl groups include bridged ring systems such
`
`as bicycloheptane and bicyclooctane. Unless specified otherwise, cycloalkyl within the definitions of
`R™ R’, RI RI RI RY R?, RR’, R® and within the definition of substituents for R’, may be
`unsubstituted or substituted with one or more of the substituents defined herein.
`
`30
`
`35
`
`

`

`WO 2017/109488
`
`PCT/GB2016/054022
`
`An “aryl” group / moicty refers to any monocyclic or bicyclic hydrocarbon group compnisingat Icast
`
`one aromatic group and having from 5 to 10 carbon atom ring members. Examples of aryl groups
`
`include phenyl and naphthyl. Bicyclic mnngs may be fused aromatic mngs where both mngs are
`
`aromatic, for example, naphthalenyl. Preferred aryl groups are phenyl and naphthyl, more preferably
`phenyl. Unless specified otherwise, aryl within the definitions of RR" R?, R° R’, RR’, ring, A, and
`within the definition of substituents for R’, may be unsubstituted or substituted with one or more of
`
`the substituents defined herein.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`“Heteroaryl” as used herein means a polyunsaturated, monocyclic or bicyclic 5 to 10 membered
`
`aromatic moiety containing at least one and up to 5 heteroatoms, particularly 1, 2 or 3 heteroatoms
`
`selected from N, O and S, and the remaining ring atoms are carbon atoms, in stable combinations
`
`knownto the skilled person. Heteroaryl ring nitrogen and sulphur atomsare optionally oxidised, and
`
`the nitrogen atom(s) are optionally quaternized. A heteroaryl ring can be a single aromatic ring or a
`
`fused bicyclic ring where the bicyclic mng system can be aromatic, or one of the fused rings is
`
`aromatic and the otheris at least partially saturated.
`
`In one example, a bicyclic heteroaryl is one in
`
`which the entire fused ring system is aromatic. Examples of fused rings where one of the rings is
`
`aromatic
`
`and the othcr
`
`is
`
`at
`
`lcast partially saturated include
`
` tctrahydropyridopyrazinyl,
`
`tetrahydroquinolinyl and tetrahydroisoquinolinyl. In such instances, attachmentof the bicyclic ring to
`
`the group it is a substituent of relative to the cyanopyrrolidine core, e.g. attachment of mng A via the
`
`amide group, is from the aromatic ring of the bicycle. A bicyclic heteroaryl can have the at least one
`
`heteroatom in either of the fused rings. For example, a bicyclic ring with an aromatic ring fused to a
`
`partially saturated ring may contain the at least one heteroatom in the aromatic ring or the partially
`
`saturated ring. Attachment of the bicyclic ring to the group it is a substituent of may be via either a
`
`heteroatom containing ring or a carbon only containing ring. The point of attachment of heteroaryl to
`
`the group it is a substituent of can be via a carbon atom or a heteroatom (e.g. nitrogen). Examples of
`
`heteroaryl
`
`rings include pyridinyl, pyrazinyl, pynmidinyl, pyridazinyl, furyl, pyrrolyl, oxazolyl,
`
`thiazolyl, pyrazolyl,
`
`tnazolyl,
`
`tetrazolyl,
`
`indolyl,
`
`indolizinyl,
`
`isoindolyl, purinyl,
`
`furazanyl,
`
`imidazolyl,
`
`indazolyl,
`
`isothiazolyl,
`
`isoxazolyl, oxadiazolyl,
`
`tetrazolyl,
`
`thiadiazolyl, benzofuranyl,
`
`isobenzofuranyl,
`
`benzothiophenyl,
`
`1sobenzothiophenyl,
`
`benzimidazolyl,
`
`benzothiazolyl,
`
`napthyndinyl, ptendinyl, pyrazinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl,
`
`imidazopynidinyl,
`
`pyrazolopyridinyl,
`
`thiazolopyridinyl,
`
`tnazinyl,
`
`dihydrophyridiny1,
`
`dihydropyrrolopyridinyl,
`
`indolinyl,
`
`isoindolinyl,
`
`quinoxalinyl,
`
`benzomorpholinyl,
`
`
`tetrahydropyndopyrazinyl, tetrahydroquinolinyl and_tetrahydroisoquinolinyl. Unless specified
`
`
`otherwise, heteroaryl within the definitions of R', RR? R®,R’, R® ring, A, and within the definition
`of substituents for R’, may be unsubstituted or substituted with one or more ofthe substituents defined
`
`35
`
`herein.
`
`

`

`WO 2017/109488
`
`PCT/GB2016/054022
`
`“Heterocyclyl’ or “heterocyclic” as used herein in describing a ring means, unless otherwise stated, a
`
`monocyclic saturated or partially unsaturated, non-aromatic ring or a bicyclic saturated or partially
`
`unsaturated ring, wherein the bicyclic ring system 1s non-aromatic, the mono- or bicyclic ring having,
`
`for example, 3 to 10 members, where at least one member and up to 5 members, particularly 1, 2 or 3
`
`members of the rng are heteroatoms selected from N, O and S, and the remaining ring atoms are
`carbon atoms, in stable combinations knownto those ofskill in the art. For example, R’ and R° may
`
`together form a heterocyclic ring which incorporates the amine nitrogen. Heterocyclic rng 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, 1.c.
`
`one or two of the heterocyclic ring carbons is common to an additional ring system.
`
`In instances
`
`wherethe heterocylcyl is a bicyclic ring, the second ring can be aromatic, e.g. a fused phenyl, pyridyl,
`
`pyrazolyl, or the like. The bicyclic heterocyclyl can have at least one heteroatom in either of the
`
`fused nngs. The heterocyclyl may be linked through carbon or a heteroatom to the remainder of the
`
`molecule and in instances where the heterocylyl is a bicyclic ring, the link may be via the heteroatom
`
`containing ring or the fused ring.
`
`In instances where the heterocyclyl is a bicyclic ring where the
`
`second ring is aromatic, attachment of the bicyclic group to the group it is a substituent of relative to
`
`the cyanopyrrolidine core is from the non-aromatic ring. Examples of heterocyclyl groups include
`
`azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, diazepanyl, dihydrofuranyl (e.g. 2,3-dihydrofuranyl,
`
`2,5-dihydrofuranyl), dioxolanyl, morpholinyl, oxazolidinyl, oxazinanyl,
`
`indolinyl,
`
`isoindolinyl,
`
`piperazinyl,
`
`tetrahydrofuranyl,
`
`thiomorpholinyl, dihydropyranyl
`
`(e.g. 3,4-dihydropyranyl, 3,6-
`
`dihydropyranyl), homopiperazinyl, dioxanyl, hexahydropynmidinyl, pyrazolinyl, pyrazolidinyl, 4H-
`
`10
`
`15
`
`20
`
`
`
`quinolizinyl, tetrahydropyndinyl,—tetrahydropyrimidinyl,quinuclidinyl, tetrahydropyranyl,
`
`
`
`
`
`25
`
`30
`
`35
`
`tetrahydrothiophenyl,
`thiazolidinyl, benzopyranyl,
`tetrahydroquinolinyl, benzomorpholinyl
`and
`tetrahydroisoquinolinyl. Unless specified otherwise, heterocyclyl within the definitions of R’, R°, R’,
`R® and within the definition of substituents for R’, may be unsubstituted or substituted with one or
`
`more of the substituents defined herein. Examples of substituted heterocyclyl mngs include for
`
`example 4,5-dihydro-1H-maleimido,tetramethylenesulfoxide and hydantoinyl.
`
`“Optionally substituted” as applied to any group means that the said group may if desired be
`
`substituted with one or more substituents (e.g., 1, 2, 3 or 4 substituents) which may be the same or
`
`different.
`
`Examplesof suitable substituents for “substituted” and “optionally substituted” C,-C, alkyl (including
`
`C.-C, alkyl, Ci-C; alkyl and C.-C, alkyl) and C,-C, alkoxy Gncluding C)-C, alkoxy, C)-C; alkoxy and
`
`C.-C, alkoxy) and C.-C, alkenyl
`
`(Gncluding C.-C, alkenyl) and C2-C, alkynyl Gincluding C.-C,
`
`

`

`WO 2017/109488
`
`PCT/GB2016/054022
`
`alkynyl), for cxample within the definitions of R', R', R', R'? R'*, R™ R®, R*, R°, R° RR’, R® Q',
`and within the definition of substituents for R’, and C.-C, alkylene (including C,-C; alkylene) and C,-
`C. alkenylene, for example within the definitions of R*, R*, R°, Q' and Q’, include halogen, hydroxyl,
`
`thiol, cyano, amino, nitro and SF; (a known mimetic of nitro), in particular, halogen (preferably
`
`fluorine or chlorine), hydroxyl and cyano.
`
`Examples of suitable substituents for “substituted” and “optionally substituted” rings, 1.c. cycloalkyl,
`heterocyclyl, aryl and heteroaryl rings, for example within the definitions of R'*, R', R', R'?, RY,
`R", R’, R°, R’, R*, ring A, and within the definition of substituents for R’, include halogen, cyano,
`
`oxo, nitro, amino, hydroxy, C,-C¢, alkyl or C-C3 alkyl, Ci-C¢ alkoxy or C)-C3 alkoxy, aryl, heteroaryl,
`
`heterocyclyl, C3-Cs cycloalkyl, C,; alkylamino, C2 alkenylamino, di-C,-C3; alkylamino, C,-C;
`
`acylamino, di-C,-C; acylamino, carboxy, C)-C; alkoxycarbonyl, carboxamidyl, carbamoyl, mono-C,.;
`
`carbamoyl, di-C).3 carbamoyl! or any of the above in which a hydrocarbyl moiety is itself substituted
`
`by halogen, e.g. fluorine, hydroxyl, cyano, amino, nitro or SFs (a known mimetic of nitro).
`
`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-mcthyl.
`
`In thio-alkyl groups, the sulphur atom may bc further oxidised to
`
`make a sulfoxide or sulfone, and thus optional substituents therefore includes groups such as S(O)-
`
`alkyl and S(O)s-alkyl.
`
`Examples of suitable substituents for “substituted” and “optionally substituted” rings include in
`
`particular,
`
`fluorine, chlorine, oxo, cyano, C)-C; alkyl, Ci-C; alkoxy, heterocyclyl, cycloalkyl,
`
`heteroary or aryl, 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 SF3.
`
`Substituted groups thus include for example Br, Cl, F, CN, Me, Et, Pr, Bu, 1-Bu, OMe, OEt, OPr,
`
`C(CHs3)3, CH(CHs3)2, CF3, OCF:, C(O)NHCHs;, cyclopropyl, phenyl, etc.
`
`In the case of aryl groups,
`
`the substitutions may be in the form of rings from adjacent carbon atomsin 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.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`

`

`WO 2017/109488
`
`PCT/GB2016/054022
`
`The dose of the compound is that amount cffective to prevent occurrence of thc 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 symptomsassociated 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 pharmaccutically acccptable 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 in a
`
`medium in whichthe salt is insoluble, followed by removal of said solvent, or said medium, using
`
`standard techniques (e.g. in vacuo, by freeze-drying or by filtration). 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 exchangeresin.
`
`Where compoundsof the invention exist in different enantiomeric and/or diastereoisomeric 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 in their ability to
`
`rotate plane-polarized light by equal amounts in opposite directions and are denotedas the (+) / (S) or
`
`(-) / (R) forms respectively. Individual enantiomers or isomers may be prepared by methods known in
`
`the art, such as optical resolution of products or intermediates (for example chiral chromatographic
`
`separation e.g. chiral HPLC, or an asymmetric synthesis approach). Similarly where compounds of
`
`the invention exist as alternative tautomeric forms e.g. keto/enol, amide/imidic acid, the invention
`
`relates to the individual tautomers in isolation, and to mixtures of the tautomers 1n all proportions.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`10
`
`

`

`WO 2017/109488
`
`PCT/GB2016/054022
`
`Included herein is the compound according to formula (ID
`
`v
`i
`,
`&
`SSA.
`Ae
`
`ce
`:
`‘
`3
`|a.
`oll,
`7 we —wea .
`iN
`
` ¥ ~ Ne,
`
`we
`
`ca
`
`(II)
`
`or a pharmaceutically acceptable salt thereof, wherein:
`R' R', R'° and R'* each independently represent hydrogen or an optionally substituted C,-C, alkyl,
`or R'is linked to R" to forman optionally substituted cycloalkyl ring, or R'is linked to R'* or R™to
`
`form an optionally substituted cycloalkyl ring;
`R" and R"each independently represent hydrogen, fluorine, cyano, hydroxyl, amino, optionally
`
`10
`
`substituted C,-C, alkyl, optionally substituted C)-C, alkoxy or an optionally substituted 5 or 6
`memberedring, or R'° and R"together form an optionally substituted cycloalkyl ring, or R'° is linked
`to R' to form an optionally substituted cycloalkylring;
`
`A is an optionally substituted 5 to 10 membered heteroaryl or aryl ring.
`
`15
`
`20
`
`25
`
`30
`
`Isotopes
`
`The compounds described herein may contain one or more isotopic substitutions, and a reference to a
`
`particular element includes within its scopeall isotopes of the element. For example, a reference to
`hydrogen includes within its scope 'H, 7H (D), and *H (T). Similarly, references to carbon and
`oxygen include within their scope respectively '"C, °C and "C and '°O and '*O. Examples of
`isotopes include *H, *H, 'C, °C, “C, *°Cl, °F, I, '7I, °N, °N, °O, ’O, O, *°P and *S.
`
`In an analogous manner, a reference to a particular function