NZ746531B2 - Spiro-condensed pyrrolidine derivatives as deubiquitylating enzymes (dub) inhibitors - Google Patents

Abstract

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. (Figure (I))

Description

SPIRO-CONDENSED PYRROLIDINE DERIVATIVES AS DEUBIQUITYLATING ENZYMES (DUB) INHIBITORS The present invention relates to novel compounds and methods for the manufacture of inhibitors of deubiquitylating enzymes (DUBs). In ular, the invention relates to the inhibition of Cezanne l.

The invention fithher relates to the use ofDUB inhibitors in the treatment of cancer. ound 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 common l knowledge.

Ubiquitin is a small protein ting of 76 amino acids that is important for the regulation of protein fiinction in the cell. Ubiquitylation and deubiquitylation are enzymatically mediated processes by which ubiquitin is covalently bound or d from a target protein. These processes have been implicated in the regulation of many cellular fimctions 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 enesis of us disease states including inflammation, viral infection, metabolic dysfiinction, CNS disorders, and oncogenesis.

Ubiquitin molecules are cleaved from proteins by deubiquitylating enzymes (DUBs), of which there are imately 95 DUBs in human cells, 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 domain and the tendency to cleave ubiquitin chains in a linkage specific manner.

Cezanne 1, also known as , is an 843 amino acid protein that was fied owing to its rity to the OTU family member A20 that has been shown biochemically to have a strong preference for Kll ubiquitin chain linkages.

Cezanne 1 has been shown to act as a negative regulator of both the canonical and the nonical NF-KB pathway. It has been shown that Cezanne 1 acts on the canonical pathway by processing K63 chains on the RIPl protein and on the non-canonical pathway by deubiquitylation of the inhibitory component TRAF3 (TNF or associated factor 3). It has also been shown to have a role in hypoxia by regulating HIFla (hypoxia ble factor la) protein levels. Cezanne l siRNA decreased HIFla protein levels under hypoxia, and accordingly decreased HIFla target gene expression. Knockdown of e 1 led to higher levels of apoptosis following hypoxia. Since HIFla has oncogenic properties, and Cezanne 1 has a pro-survival role in hypoxia, Cezanne 1 has been suggested to be a good target for pharmacological intervention.

Cezanne 1 has been shown to facilitate T cell activation and inflammatory responses by regulating ZAP70 ubiquitination (Hu et al 2016 Journal of Exploratory Medicine). This shows that inhibition of Cezanne 1 would lead to a ion in inflammatory response. There is a continued need for nds which inhibit DUBs such as Cezanne for the treatment of inflammation.

Cezanne 1 has been shown to 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 fied in a genetic screen to find a DUB enzyme for EGFR. Cezanne 1 overexpression led to higher levels of orylated EGFR, lower levels of ubiquitylated EGFR and EGFR stabilization.

In -231 breast cancer cells, own of Cezanne 1 led to decreased invasion and migration. Analysis of The Cancer Genome Atlas by Pareja et al. (2012) 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 1 expression correlated with poor prognosis. Although there has been a handful of DUB inhibitors published in the literature, there is a uing need for compounds and pharmaceutical compositions which inhibit DUBs such as Cezanne 1 and USP30 for the treatment of cancer or other indications where DUB activity is ed.

Summary of the Invention In a first aspect, the present invention provides a compound of formula I: a tautomer thereof, or a pharmaceutically acceptable salt of said nd or tautomer, wherein: R1a, R1b, R1c, R1d R1e and R1f each represent hydrogen; ring A is a 5 to 11-membered monocyclic or bicyclic heterocyclyl ring, which in addition to the amide nitrogen optionally comprises 1, 2 or 3 heteroatoms each ndently selected from N, O and S; wherein, when ring A is bicyclic, the ring fused to the amide-containing ring is aromatic; and which may be ally substituted with one -Q1-(R2)n wherein n is 1; and optionally one, two or three -Q1- (R2)n, wherein n is 0; wherein each -Q1-(R2)n is the same or different: when n is 0, Q1 represents halogen, cyano, oxo, hydroxyl, , -CONR3R4, -NR3COR4, - NR3CONR4R4a, -COR3, -C(O)OR3, -C1-C6 alkyl, or -C1-C6 alkoxy; wherein the alkyl and alkoxy groups are optionally substituted with one to four halogen substituents; when n is 1, Q1 ents a covalent bond, an oxygen atom, a sulphur atom, -SO-, -SO2-, -CO-, - C(O)O-, -CONR3-, -NR3-, -NR3CO-, -NR3CONR4-, SO2NR3-, 2-, -NR3SO2NR4-, -NR3C(O)O- , -NR3C(O)OR5-, C1-C6 ne, or -C2-C6 alkenylene; R2 represents a phenyl ring or a a 5 to bered heterocyclyl or heteroaryl ring, wherein said heterocyclyl and heteroaryl rings comprise 1, 2 or 3 heteroatoms, each ndently selected from N, O and S; wherein said R2 ring is optionally substituted with one to two tuents independently selected from halogen, cyano, oxo, hydroxyl, -NR6R7, R7, R7, -NR6CONR7R7a, - COR6, -C(O)OR6, -C1-C6 alkyl, -C1-C6 alkoxy, -Q2a-R8, -Q2b-CONR6-Q2c-R8, and –Q2-NR6SO2-Q2c- R8; wherein the alkyl and alkoxy groups are optionally substituted with one to four substituents selected from halogen and hydroxyl; Q2a represents a covalent bond, an oxygen atom, a sulphur atom, -SO-, -SO2-, -CO-, or C1-C6 alkylene; Q2b and Q2c each represent a covalent bond; R3, R4 and R4a each independently represent hydrogen or C1-C6 alkyl; R6, R7 and R7a each independently represent hydrogen or C1-C6 alkyl; R8 is selected from phenyl, piperazinyl, cyclopropyl, morpholinyl and piperidinyl; wherein R8 is optionally substituted by fluorine, chlorine, oxo, cyano, C1-C3 alkyl, or C1-C3 alkoxy.

In a second , the present invention es use of the compound, the tautomer thereof, or a pharmaceutically able salt of said compound or tautomer according to the first aspect in the manufacture of a medicament for the ent of cancer linked to Cezanne 1 activity.

In a third aspect, the present invention provides use of the compound, the tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer according to the first aspect in the manufacture of a medicament for the treatment of inflammation.

In a fourth aspect, the present invention provides use of the compound, the tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer according to the first aspect in the cture of a medicament for the ent of a condition involving mitochondrial dysfunction.

In a fifth aspect, the present invention provides a pharmaceutical composition comprising the compound, the tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer according to the first aspect, together with one or more pharmaceutically acceptable excipients. 2b (followed by page 3) A further aspect disclosed herein relates to a compound of formula (I) or a pharmaceutically acceptable salt f, wherein: R1a, R1b, R1c and R1d each independently represent en or an ally substituted C1-C6 alkyl, or R1a and R1b together form an optionally substituted cycloalkyl ring, R1c and R1d together form an optionally substituted cycloalkyl ring, or R1d together with R1e forms an optionally substituted cycloalkyl ring; R1e and R1f each independently represent hydrogen, fluorine, cyano, hydroxyl, amino, optionally substituted C1-C6 alkyl, ally substituted C1-C6 alkoxy or an optionally substituted 5 or 6 membered heteroaryl or aryl ring, or R1e forms an optionally substituted cycloalkyl ring with R1f or ring A is a 5 to 11 membered monocyclic or bicyclic heterocyclyl ring which may be optionally further tuted.

In another aspect, the invention also relates to pharmaceutical compositions comprising the compounds of the present invention and one or more pharmaceutically acceptable excipients.

In r aspect, the compounds of the invention are useful for the treatment of cancer.

Brief Description of the Figures Figure 1 provides an image of Cezanne 1 purified from mammalian cells. FLAG-purified protein or the indicated concentrations of BSA were separated by SDS-PAGE and stained with Imperial protein stain (Pierce Biotechnology).

Figure 2 is a graph showing proteolytic activity of Cezanne 1 measured using a fluorescence polarisation assay. s s of purified Cezanne 1 as indicated were incubated with a TAMRA labelled peptide linked to ubiquitin via an tide bond.

Detailed Description of the Invention The definitions and ations below are for the terms as used throughout this entire document including both the ication and the claims. Reference to nds as described herein (e.g. a compound of Formula I), includes reference to Formula I and II ing any neric embodiments thereof.

Where any group of the compounds of formula I have been referred to as optionally substituted, this group may be tuted or unsubstituted. Substitution may be by one or more of the specified substituents which may be the same or 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, or alkynyl substituent (or linker) group or an alkyl, alkenyl moiety in a substituent group may be linear or branched.

Cx-Cy alkyl refers to a saturated aliphatic hydrocarbon group having x-y carbon atoms which may be linear or branched. For example C1-C6 alkyl contains from 1 to 6 carbon atoms and includes C1, C2, C3, C4, C5 and C6. "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 C1-C6 alkyl groups include methyl, ethyl, , 2-methylpropyl, 2-methylpropyl, 2-methylbutyl, 3-methyl butyl, 2-methylbutyl, 2,2-dimethylpropyl, 2-methyl-pentyl, 3-methylpentyl, yl pentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,2-dimethylbutyl, 3,3-dimethyl- l, 2-ethylbutyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl and n-hexyl. C1- C6 alkyl, C1-C4 alkyl and C1-C3 alkyl within the definitions of R1a, R1b, R1c, R1d, R1e, R1f, R3, R4, R4a, R6, R7, R7a, Q1, and within the definition of substituents for R2, may be unsubstituted or substituted with one or more of the substituents d herein. Examples of substituted C1-C6 alkyl therefore e CF3, CH2CF3, CH2CN, CH2OH and CH2CH2OH.

A Cx-Cy alkylene group or moiety may be linear or branched and refers to a divalent hydrocarbon group having one less hydrogen atom from Cx-Cy alkyl as defined above. 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 CH2CH2OCH2 or CH2OCH2. Examples of C 1-C6 alkylene or alkyleneoxy groups include methylene, methyleneoxy, ethylene, ethyleneoxy, npropylene , n-propyleneoxy, n-butylene, n-butyleneoxy, methylmethylene and dimethylmethylene.

Unless stated otherwise, C1-C6 alkylene, C1-C4 alkylene and C1-C3 alkylene within the tions of R5, Q1, Q2a, Q2b and Q2c may be unsubstituted or substituted with one or more of the substituents defined herein.

C2-C6 alkenyl refers to a linear or branched hydrocarbon chain radical containing at least two carbon atoms and at least one double bond and includes C2-C4 alkenyl. Examples of alkenyl groups include ethenyl, propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1-hexenyl, 2-methylpropenyl, 1,2-butadienyl, 1,3-pentadienyl, 1,4-pentadienyl and 1-hexadienyl. Unless stated otherwise, C2-C6 alkenyl within the definitions of Q1 and within the tion of substituents for R2, may be unsubstituted or substituted with one or more of the substituents defined herein.

C2-C6 alkenylene refers to linear or branched hydrocarbon group having one less hydrogen atom from C2-C6 l as defined above. Examples of C2-C6 alkenylene include ethenylene, propenylene and lene. Unless stated ise, C2-C6 alkenylene within the definitions of Q1, Q2a, Q2b and Q2c may be unsubstituted or substituted with one or more of the substituents defined .

C2-C6 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 l, propynyl, 2- yl, 1-butynyl, 2-butynyl and 1-hexynyl. Unless specified otherwise, C2-C6 alkynyl, within the definitions of Q1 and within the definition of substituents for R2, may be unsubstituted or tuted with one or more of the substituents defined herein.

C1-C6 alkoxy refers to a group or part of a group having an Cy alkyl group according to the definition of CX_Cy alkyl above. C1_C6 alkoxy contains from 1 to 6 carbon atoms and includes C1, C2, C3, C4, C5 and C6. Examples of C1_C6 alkoxy include methoxy, ethoxy, propoxy, poxy, butoxy, pentoxy and hexoxy. Alkoxy as employed herein also extends to embodiments in which the or an oxygen atom (e.g. a single oxygen atom) is located within the alkyl chain, for example CHZCHZOCHg or CH20CH3. Thus the alkoxy may be linked h carbon to the remainder of the molecule, for example, -CH2CH20CH3, or atively, the alkoxy is linked through oxygen to the remainder of the molecule, for example -OC1_6 alkyl. In one instances, the alkoxy is linked through oxygen to the remainder of the molecule but the alkoxy group contains a fithher oxygen atom, for example — OCHZCHZOCHg. Unless specified otherwise, C1-C6 alkoxy and C1-C3 alkoxy within the definitions R15, R", Q, and within the definition of substituents for R2, may be tituted or substituted with one or more of the substituents defined herein. Examples of tuted C1-C6 alkoxy ore LIdC OCF3, OCHFz, OCH2CF3, CH2CH20CH3 and 0CH2CH3.

The term "halogen" or "halo" refers to chlorine, bromine, fluorine or iodine atoms, in particular chlorine or fluorine atoms.

The term "oxo" means =0.

The term "amino" means —NR'R" wherein R' and R" each independently represent hydrogen or C1-C3 alkyl.

The term " means —C(O)NR'R" wherein R' and R" each independently represent hydrogen or C1-C3 alkyl.

For the avoidance of doubt it will be understood that the cycloalkyl, heterocyclyl, aryl and heteroaryl rings disclosed herein and within the definitions of R2, R8, ring A, do not include any unstable ring structures or, in the case of heteroaryl and heterocyclic rings systems, any 0-0, 0-8 or 8-8 bonds.

The ring systems may be monocyclic or bicyclic. ic ring systems include bridged, filSCd 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, tution 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-C10 cycloalkyl refers to a monocyclic or bicyclic hydrocarbon ring containing 3 to 10 carbon atoms.

Examples of C3-C10 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 R13, Rlb, R", R", R15, R", R2, R8, may be unsubstituted or substituted with one or more of the substituents defined herein.

An "aryl" group / moiety refers to any monocyclic or bicyclic hydrocarbon group comprising at least one ic group and haVing from 5 to 10 carbon atom ring members. Examples of aryl groups include phenyl and naphthyl. Bicyclic rings may be filSCd aromatic rings where both rings are aromatic, for example, alenyl. Preferred aryl groups are phenyl and naphthyl, more preferably . Unless specified otherwise, aryl within the definitions of R15, R", R2, R8, may be unsubstituted or substituted with one or more of the substituents defined herein. oaryl" as used herein means a polyunsaturated, monocyclic or bicyclic 5 to 10 membered ic moiety containing at least one and up to 5 heteroatoms, ularly 1, 2 or 3 heteroatoms selected from N, O and S, and the remaining ring atoms are carbon atoms, in stable combinations known to the skilled person. Heteroaryl ring en and sulphur atoms are optionally oxidised, and the nitrogen atom(s) are optionally ized. A heteroaryl ring can be a single aromatic ring or a filSCd bicyclic ring where the bicyclic ring system can be aromatic, or one of the filSCd rings is aromatic and the other is at least partially saturated. In one example, a bicyclic heteroaryl is one in which the entire filSCd ring system is aromatic. 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 filSCd to a partially saturated ring may contain the at least one heteroatom in the ic ring or the partially saturate ring. ment of the bicyclic ring to the group it is a substituent of may be Via either a heteroatom ning 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). In instances where ring A is a heteroaryl, the ring is an aromatic ring and may be filSCd to a fithher aromatic or partially saturated ring. Examples include pyridinyl, pyrazinyl, dinyl, zinyl, fiiryl, pyrrolyl, yl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, indolyl, indolizinyl, isoindolyl, indolinyl, purinyl, nyl, imidazolyl, indazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazinanyl, tetrazolyl, thiadiazolyl, benzofuranyl, isobenzofiJranyl, tetrahydrofuranyl, benzothiophenyl, isobenzothiophenyl, benzimidazolyl, benzothiazolyl, napthyridinyl, pteridinyl, pyrazinyl, 4H-quinolizinyl, inyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, opyridinyl, pyrazolopyridinyl, thiazolopyridinyl, indolinyl, isoindolinyl, triazinyl, dihydrophyridinyl, quinoxalinyl and dihydrobenzoxazinyl. Unless specified otherwise, heteroaryl within the definitions of R15, R", R2, R8, may be unsubstituted or substituted with one or more of the substituents defined herein.

"Heterocyclyl" or ocyclic" as used herein in describing a ring means, unless otherwise stated, a monocyclic ted or partially unsaturated, non-aromatic ring or a ic saturated or partially unsaturated ring, wherein the bicyclic ring system is 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 ring are heteroatoms selected from e.g., N, O and S and the remaining ring atoms are carbon atoms, in stable ations known to those of skill in the art. Heterocyclic ring nitrogen and sulphur atoms are ally ed, and the nitrogen atoms(s) are optionally ized. As used herein, the heterocyclic ring may be a filSCd ring to another ring system to form a bicycle, i.e. one or two of the heterocyclic ring carbons is common to an additional ring system. In instances where the heterocylcyl is a bicyclic ring, the second ring can be aromatic, e.g. a filSCd phenyl, pyridyl, lyl, or the like. 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 ning ring or the filSCd ring. The heterocyclyl of ring A is a 5 to 11 membered clic or bicyclic ring. When ring A is bicyclic, the second ring (i.e. the portion that does not include —NH-C(O)-) can be aromatic, e.g. a filSCd phenyl or nyl. When ring A is bicyclic, lly any fithher substituents will be on the second ring. Examples of heterocyclyl groups include azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, diazepanyl, dihydrofiJranyl (e.g. 2,3- dihydrofiJranyl, 2,5-dihydrofiJranyl), dioxolanyl, morpholinyl, oxazolidinyl, piperazinyl, tetrahydrofuranyl, thiomorpholinyl, dihydropyranyl (e. g. 3,4-dihydropyranyl, hydropyranyl), homopiperazinyl, dioxanyl, hexahydropyrimidinyl, pyrazolinyl, pyrazolidinyl, 4H-quinolizinyl, quinuclidinyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, thiazolidinyl, benzopyranyl, tetrahydroquinolinyl, dihydrobenzoxazinyl and tetrahydroisoquinolinyl.

Examples of heterocyclyl ring A include from piperidinone, indolineone, piperazineone, pyrrolidin-2—one, 3,4-dihydroquinolin-2(lH)-one, lH-pyrido[2,3-b][l,4]oxazin-2(3H)-one, 3,4- dihydropyrido[2,3-b]pyrazine-2(lH)-one, l,5-diydrobenzo[e][l,4]oxazepin-2(3H)-one, 3,4-dihydro- 1,5 -naphthyridin-2( lH)-one, 3 ,4-dihydro- l ,6-naphthyridin-2( lH)-one, 3 ,4-dihydro- l ,7-naphthyridin- 2(lH)-one, 3,4-dihydro-l,8-naphthyridin-2(lH)-one and 3,4-dihydropyrazino[2,3-b]pyrazine-2(lH)- one and l,2,3,5-tetrahydro-4H-pyrido[2,3-b][l,4]diazepinone. Unless specified otherwise, heterocyclyl within the definitions of R2 and R8, may be unsubstituted or substituted with one or more of the substituents defined herein. es of substituted heterocyclyl rings include 4,5-dihydro- lH-maleimido, tetramethylenesulfoxide and hydantoinyl. The monocyclic or bicyclic heterocycle ring A may be optionally fithher substituted as described herein.

"Optionally tuted" as applied to any group means that the said group may if desired be substituted with one or more substituents (e.g., l, 2, 3 or 4 substituents) which may be the same or different.

Examples of suitable substituents for "substituted" and nally substituted" C1-C6 alkyl (including C1-C4 alkyl, C1-C3 alkyl and C1-C2 alkyl) and C1-C6 alkoxy (including C1-C4 alkoxy, C1-C3 alkoxy and C1-C2 alkoxy) and C2-C6 l (including C2-C4 alkenyl) and C2-C6 alkynyl (including C2-C4 alkynyl) within the definitions of R13, R", R": R", R", R", R3, R4, R43, R6, R7, R", Q, and within the definition of substituents for R2, and C1-C6 alkylene (including C1-C3 alkylene) and C2-C6 alkenylene within the definitions of R5, Q1, Q23, Q2b and Q", include halogen, hydroxyl, thiol, cyano, amino, nitro and SF5 (a known mimetic of nitro), in particular, halogen (preferably fluorine or chlorine), hydroxyl and cyano. Other le substituents include amido, C1_3 alkylamino, CH alkenylamino, dl'Cng alkylamino, C1-C3 ino, dl'Cl'C3 acylamino, y, C1-C3 carbonyl, carboxamidyl, carbamoyl, mono-CH oyl, di-C1_3 carbamoyl wherein any hydrocarbyl moiety may itself be substituted by halogen, e.g. fluorine, hydroxyl, cyano, amino, nitro or SF5 (a known mimetic of nitro).

Examples of le substituents for "substituted" and "optionally substituted" rings, i.e. cycloalkyl, heterocyclyl, aryl and aryl rings, within the definitions of R13, Rlb, R", R", R15, R", R2, R8, ring A, e halogen, cyano, oxo, nitro, amino, hydroxy, C1-C6 alkyl or C1-C3 alkyl, C1-C6 alkoxy or C1-C3 alkoxy, aryl, heteroaryl, heterocyclyl, C3-C6 cycloalkyl, amino, C13 alkylamino, C26 alkenylamino, dl'Cng alkylamino, C1-C3 acylamino, dl'Cl'C3 acylamino, carboxy, C1-C3 alkoxycarbonyl, carboxamidyl, carbamoyl, mono-CH carbamoyl, di-C1_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 SF5.

Examples of suitable substituents for "substituted" and "optionally substituted" rings include in particular, fluorine, chlorine, oxo, cyano, C1-C3 alkyl, C1-C3 alkoxy, amino, amido, heterocyclyl, lkyl, 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 Substituted groups thus e for example Br, Cl, F, CN, Me, Et, Pr, t-Bu, OMe, OEt, OPr, C(CH3)3, CH(CH3)2, CF3, OCF3, C(O)NHCH3, cyclopropyl, phenyl, etc. 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-CHz-O.

In groups ning an oxygen atom such as hydroxy and alkoxy, the oxygen atom can be replaced with r to make groups such as thio (SH) and thio-alkyl (S-alkyl). Optional substituents ore include groups such as S-methyl. In thio-alkyl groups, the sulphur atom may be fithher oxidised to make a sulfoxide or e, and thus optional substituents therefore es groups such as S(O)-alkyl and S(O)2-alkyl.

The term "treat" or "treating" or "treatment" includes laxis and means to ameliorate, alleviate symptoms, eliminate the causation of the symptoms either on a ary or permanent basis, or to prevent or slow the appearance of symptoms of the named disorder or condition. The compounds of the invention are usefiil in the treatment of humans and non-human animals.

The dose of the compound is that amount effective to t 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 ms ated with the disorder or an ration 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, potassium and sodium), salts of amino acids (such as glycine, alanine, valine, leucine, isoleucine, cysteine, methionine and proline), inorganic bases (such as triethylamine, hydroxide, e, thiamine and iacetylethylenediamine). Other pharmaceutically acceptable salts include ammonium salts, substituted ammonium salts and aluminium salts. Further pharmaceutically acceptable salts include quaternary ammonium salts of the compounds of 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 lents of an appropriate acid or base, ally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said , using standard techniques (e. g. in vacuo, by freeze-drying or by tion). 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.

Where compounds of the ion exist in different enantiomeric and/or diastereoisomeric forms, the invention relates to these compounds ed as ic mixtures or racemates whether present in an optically pure form or as es with other isomers. Enantiomers differ only in their ability to rotate polarized light by equal amounts in opposite directions and are denoted as 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 tographic separation e.g. chiral HPLC, or an asymmetric synthesis approach). Similarly where nds of the invention exist as alternative tautomeric forms e.g. keto/enol, imidic acid, the invention relates to the dual tautomers in isolation, and to mixtures of the tautomers in all proportions.

Isotopes The compounds described herein may contain one or more isotopic substitutions, and a reference to a particular element includes within its scope all isotopes of the element. For example, a reference to hydrogen includes within its scope 1H, 2H (D), and 3H (T). Similarly, references to carbon and oxygen include within their scope respectively 12C, 13C and 14C and 16O and 180. Examples of isotopes include 2H, 3H, "C, 13C, 14C,36C1, 18F, 1231, 1251, 13N, 15N, 150, 170, 180,321) and 35s.

In an analogous manner, a reference to a particular fiinctional group also includes within its scope isotopic variations, unless the context indicates otherwise. For example, a reference to an alkyl group such as an ethyl group also covers variations in which one or more of the hydrogen atoms in the group is in the form of a deuterium or m isotope, e.g. as in an ethyl group in which all five hydrogen atoms are in the deuterium isotopic form (a perdeuteroethyl group).

The isotopes may be radioactive or non-radioactive. In one embodiment, the compounds contain no radioactive es. Such compounds are preferred for eutic use. In another embodiment, however, the compounds may contain one or more radioisotopes. Compounds ning such radioisotopes may be usefiil in a diagnostic context.

Certain isotopically labelled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes i.e. 3H and 14C are particularly usefiil for this e in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes i.e. 2H, may afford certain therapeutic advantages resulting from greater metabolic ity, for example, increased in viva half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as 11C, 18F, 15O and 13N, can be useful in Positron Emission Topography (PET) s for examining receptor occupancy. Isotopically labelled nds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples and preparations using an appropriate isotopically labelled reagent in place ofthe non-labelled reagent previously employed.

Crystalline and amorphous forms The compounds of formula (I) may exist in crystalline or amorphous form and some of the crystalline forms may exist as polymorphs, which are included within the scope of the present invention.

Polymorphic forms of compounds of formula (I) may be characterised and differentiated using a number of conventional analytical ques, including, but not limited to, infra-red spectra, Raman spectra, X-ray powder diffraction, differential scanning calorimetry, thermogravimetric analysis and solid state nuclear magnetic resonance.

Accordingly, in fithher ments, the invention provides a compound according to any bed embodiments in a crystalline form. The compound may be from 50% to 100% crystalline, and more particularly is at least 50% crystalline, or at least 60% crystalline, or at least 70% crystalline, or at least 80% crystalline, or at least 90% lline, or at least 95% crystalline, or at least 98% crystalline, or at least 99% crystalline, or at least 99.5% crystalline, or at least 99.9% crystalline, for example 100% crystalline. The compound may atively be in an amorphous form.

The invention described herein relates to all crystal forms, solvates and hydrates of any of the disclosed compounds however so prepared. To the extent that any of the compounds sed herein have acid or basic centres such as carboxylates or amino groups, then all salt forms of said compounds are included herein. In the case of pharmaceutical uses, the salt should be seen as being a pharmaceutically able salt.

The invention s to any solvates of the compounds and their salts. Preferred solvates are solvates formed by the incorporation into the solid state structure (e. g. crystal structure) of the compounds of the invention of molecules of a non-toxic ceutically acceptable solvent (referred to below as the ing solvent). Examples of such solvents e water, alcohols (such as ethanol, isopropanol and butanol) and dimethylsulfoxide. Solvates can be prepared by recrystallising the compounds of the invention with a solvent or mixture of solvents containing the solvating solvent. r or not a solvate has been formed in any given instance can be determined by subjecting crystals of the compound to is using well known and standard techniques such as thermogravimetric analysis (TGE), differential scanning calorimetry (DSC) and X-ray crystallography.

The solvates can be stoichiometric or non-stoichiometric solvates. Particular solvates may be hydrates, and examples of hydrates include hemihydrates, monohydrates and dihydrates. For a more detailed discussion of solvates and the methods used to make and characterise them, see Bryn et al., Solid-State Chemistry of Drugs, Second Edition, hed by SSCI, Inc ofWest Lafayette, IN, USA, 1999, ISBN 006710-3.

The invention relates to pharmaceutically fiinctional derivatives of compounds as defined herein including ester derivatives and/or derivatives that have, or provide for, the same biological fianction and/or activity as any relevant nd of the invention. Thus, for the es of this invention, the term also includes prodrugs of compounds as defined herein.

The term "prodrug" of a relevant compound includes any compound that, following oral or parenteral administration, is metabolised in vivo to form that compound in an experimentally-detectable amount, and within a predetermined time (e.g. within a dosing interval of between 6 and 24 hours (i.e. once to four times daily).

Prodrugs of compounds may be prepared by ing onal groups present on the compound in such a way that the modifications are cleaved, in vivo when such prodrug is administered to a mammalian t. The cations typically are achieved by synthesizing the parent compound with a prodrug substituent. Prodrugs include compounds wherein a hydroxyl, amino, dryl, carboxyl or carbonyl group in a compound is bonded to any group that may be cleaved in vivo to regenerate the free yl, amino, sulfllydryl, yl or carbonyl group, respectively.

Examples of prodrugs include, but are not limited to, esters and carbamates of hydroxyl fiinctional groups, ester groups of carboxyl fiinctional groups, N-acyl derivatives and N-Mannich bases. General information on prodrugs may be found e.g. in Bundegaard, H. "Design of Prodrugs" p. l-92, Elsevier, New York-Oxford (1985).

Compounds of the ion may be metabolised in vivo. Metabolites of compounds of formula (I) are also within the scope of the present invention. The term ‘metabolites’ refers to all molecules derived from any of the compounds according to the present invention in a cell or organism, preferably mammal. Preferably the term relates to molecules which differ from any molecule which is present in any such cell or organism under logical ions.

A treatment defined herein may be applied as a sole y of may involve, in addition to the compounds of the invention, conventional surgery or radiotherapy or chemotherapy. Furthermore, compounds of a (I) can also be used in combination with eXisting therapeutic agents for the treatment of conditions associated with cancer, including small molecule therapeutics or antibody based therapeutics.

In accordance with a first aspect ofthe invention there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: R", Rlb, R1‘: and R1d each independently represent hydrogen or an optionally substituted C1-C6 alkyl, or Rla and R1b together form an ally substituted cycloalkyl ring, R1‘: and R1d together form an optionally substituted cycloalkyl ring, or R1d together with R15 forms an ally substituted cycloalkyl ring, R15 and R1f each independently represent hydrogen, fluorine, cyano, hydroxyl, amino, optionally substituted C1-C6 alkyl, ally substituted C1-C6 alkoxy or an ally substituted 5 or 6 membered heteroaryl or aryl ring, or R15 forms an optionally substituted cycloalkyl ring with R1f or ring A is a 5 to 11 membered monocyclic or bicyclic heterocyclyl ring which may be optionally fithher substituted.

Rla may represent hydrogen. Rla may represent C1-C6 alkyl. Rla may represent hydrogen or C1-C3 alkyl, for example, methyl or ethyl. When R1a ents C1-C6 alkyl, Rlb, R", R", R16 and R" may each represent hydrogen. The alkyl may be unsubstituted or substituted with one or more substituents selected from halogen, hydroxyl, thiol, cyano, amino, nitro and SF5, in particular fluorine.

R1b may represent hydrogen. R1b may ent C1-C6 alkyl. R1b may represent hydrogen or C1-C3 alkyl, for example, methyl or ethyl. When R1b represents C1-C6 alkyl, R13, R", R", R16 and R" may each represent hydrogen. The alkyl may be unsubstituted or substituted with one or more substituents selected from halogen, yl, thiol, cyano, amino, nitro and SF5, in particular fluorine.

R1c may represent hydrogen. R1c may represent C1-C6 alkyl. R1c may ent hydrogen or C1-C3 alkyl, for example, methyl or ethyl. When R1‘: represents C1-C6 alkyl, R", Rlb, R", R16 and R" may each represent hydrogen. The alkyl may be unsubstituted or substituted with one or more substituents selected from halogen, hydroxyl, thiol, cyano, amino, nitro and SF5, in particular fluorine.

R1d may represent hydrogen. R1d may represent C1-C6 alkyl. R1d may represent hydrogen or C1-C3 alkyl, for e, methyl or ethyl. When R1d ents C1-C6 alkyl, R", Rlb, R", R16 and R" may each represent hydrogen. The alkyl may be unsubstituted or substituted with one or more substituents selected from halogen, hydroxyl, thiol, cyano, amino, nitro and SF5, in particular fluorine.

Alternatively, Rla and R1b may together form a cycloalkyl ring. In addition or alternatively, but preferably alternatively, R1‘: and R1d may together form a cycloalkyl ring. The cycloalkyl ring can contain 3, 4, 5 or 6 atoms, in particular 3 or 4 atoms. When Rla and R1b together form a C3-C6 cycloalkyl ring, R", R", R13 and R1f may be hydrogen. When R1‘: and R1d together form a cycloalkyl ring, R", Rlb, R13 and R" may each be hydrogen.

R13 may represent hydrogen, fluorine, cyano, hydroxyl, amino, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, or an optionally tuted 5 or 6 membered heteroaryl or aryl ring. The alkyl and alkoxy may be substituted with one or more substituents ed from halogen, hydroxyl, thiol, cyano, amino, nitro and SF5. The heteroaryl or aryl ring may be unsubstituted or substituted with halogen, cyano, nitro, amino, hydroxy, C1-C6 alkyl or C1-C3 alkyl, C1-C6 alkoxy or C1-C3 alkoxy, aryl, heteroaryl, heterocyclyl, C3-C6 cycloalkyl, C1_3 alkylamino, CH alkenylamino, di- C1-C3 alkylamino, C1-C3 acylamino, dl'Cl'C3 acylamino, carboxy, C1-C3 alkoxycarbonyl, carboxamidyl, carbamoyl, mono-C13 carbamoyl, di-C1_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 SF5. In particular, the heteroaryl or aryl ring may be substituted with halogen, cyano, amino, C1-C3 alkoxy, C1-C6 alkyl. R15 can represent en, fluorine, unsubstituted or tuted C1-C3 alkyl or unsubstituted or tuted C1-C3 alkoxy. R15 can represent en or methyl. R15 can represent hydrogen. R15 can represent fluorine. R15 can represent methyl. R15 can represent methoxy. R15 can represent CF3. R15 can ent OCF3. When R15 represents fluorine, cyano, hydroxyl, amino, optionally substituted C1-C6 alkyl or optionally tuted C1-C6 alkoxy or an optionally substituted 5 or 6 membered heteroaryl or aryl ring, R", Rlb, R16, R1d and R" may each represent hydrogen. le may represent hydrogen, fluorine, cyano, hydroxyl, amino, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, or an optionally tuted 5 or 6 ed heteroaryl or aryl ring. The alkyl and alkoxy may be substituted with one or more substituents selected from halogen, hydroxyl, thiol, cyano, amino, nitro and SF5. The heteroaryl or aryl ring may be unsubstituted or substituted with halogen, cyano, oxo, nitro, amino, hydroxy, C1-C6 alkyl or C1-C3 alkyl, C1-C6 alkoxy or C1-C3 , aryl, heteroaryl, cyclyl, C3-C6 cycloalkyl, C1_3 alkylamino, CH alkenylamino, dl'Cl'C3 alkylamino, C1-C3 ino, dl'Cl'C3 acylamino, carboxy, C1-C3 alkoxycarbonyl, amidyl, carbamoyl, mono-C13 carbamoyl, di-C1_3 oyl or any of the above in which a arbyl moiety is itself substituted by halogen, e.g. fluorine, hydroxyl, cyano, amino, nitro or SF5. In particular, the heteroaryl or aryl ring may be substituted with halogen, cyano, amino, C1-C3 alkoxy, C1-C6 alkyl. R" can ent en, fluorine, unsubstituted or substituted C1-C3 alkyl or unsubstituted or substituted C1-C3 alkoxy. R" can represent hydrogen or methyl. R" can represent hydrogen. R" can represent fluorine. R" can represent methyl. R" can represent methoxy. R" can represent CF3. R1f can represent OCF3. When R1f ents fluorine, cyano, hydroxyl, amino, optionally substituted C1-C6 alkyl or optionally substituted C1-C6 alkoxy or an optionally substituted 5 or 6 membered heteroaryl or aryl ring, R", Rlb, R16, R1d and R15 may each represent en.

When R16 is hydrogen, le may represent hydrogen, fluorine, cyano, hydroxyl, amino, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, or an optionally substituted 5 or 6 membered heteroaryl or aryl ring.

Alternatively, R15 and R1f may together form a cycloalkyl ring. Alternatively, R13 and R1d may together form a cycloalkyl ring. The cycloalkyl ring can contain 3, 4, 5 or 6 atoms, in particular 3 or 4 atoms. When R15 and R1f together form a C3-C6 cycloalkyl ring, R", Rlb, R1‘: and R1d may be hydrogen. When R15 and R1d together form a C3-C6 cycloalkyl ring, R", Rlb, R1‘: and R1f may each be hydrogen.

The cycloalkyl rings within the definitions of R13, R": R": R", R16 and R" may be unsubstituted or substituted with one or more substituents ed from n, cyano, oxo, nitro, amino, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1_3 alkylamino, CH alkenylamino, C1-C3 acylamino, carboxy, C1-C3 alkoxycarbonyl, carboxamidyl, carbamoyl, mono-CH carbamoyl and di-C1_3 carbamoyl wherein any hydrocarbyl moiety may itself be substituted by one or more halogen, hydroxyl, cyano, amino, nitro or SF5, in particular fluorine. In ular, the cycloalkyl ring may be unsubstituted or substituted with one or two substituents selected from halogen, cyano, oxo, nitro, amino, hydroxy, C1-C3 alkyl and C1-C3 alkoxy, wherein the alkyl and alkoxy may be substituted with one or more halogen, in particular fluorine.

The compounds may be in the form where R", Rlb, R", R", R15 and R1f each ent hydrogen. In such cases the compounds may be of formula: ‘2<5 ,H- uuuuuu- («a'w/ or a pharmaceutically acceptable salt thereof, n ring A is a 5 to 11 membered monocyclic or bicyclic heterocyclyl ring which may be optionally r substituted.

Ring A may be monocyclic or bicyclic. Where the ring is bicyclic, the second ring (i.e. the ring not directly attached to the pyrrolidine ring) may be aromatic, saturated or may be partly saturated.

Preferably, the second ring is aromatic.

Ring A represents a 5 to 11 membered (e.g. 5, 6, 7, 8, 9, 10 or 11 membered) heterocyclyl ring which may be optionally fithher substituted with one or more (e.g. one, two, three or four) of 2)n.

Ring A may represent a 5 or 6 membered cyclyl ring which may be optionally fithher substituted with one or more (e.g. one, two, three or four) of —Q1(R2)n.

Alternatively, ring A may represent a 9, 10 or 11 membered filSCd bicyclic heterocyclic ring which may be optionally fithher substituted with one or more (e.g. one, two, three or four) of —Q1(R2)n.

Ring A may comprise one or more (e.g. l, 2 or 3) heteroatoms in addition to the amide en, wherein the additional heteroatom(s) are independently selected from nitrogen, oxygen and sulphur.

In particular, ring A may fithher comprise one or more additional heteroatoms selected from en and oxygen. When ring A is a bicyclic ring, the additional heteroatoms may be in first ring (i.e. the ring containing —NH-C(O)-) and/or the second ring (i.e. the filSCd ring portion not containing —NH- C(O)-).

Ring A may be selected from piperidinone, indolineone, piperazine-2—one, pyrrolidin-2—one, hydroquinolin-2(lH)-one, ido[2,3-b][l,4]oxazin-2(3H)-one, 3,4-dihydropyrido[2,3- b]pyrazine-2(lH)-one, l,5-diydrobenzo[e][l,4]oxazepin-2(3H)-one, 3,4-dihydro-l,5-naphthyridin- 2(lH)-one, 3,4-dihydro-l,6-naphthyridin-2(lH)-one, 3,4-dihydro-l,7-naphthyridin-2( lH)-one, 3,4- dihydro-l,8-naphthyridin-2(lH)-one and 3,4-dihydropyrazino[2,3-b]pyrazine-2( e and l,2,3,5- tetrahydro-4H-pyrido [2,3 -b] [ l ,4]diazepinone.

More particularly, ring A is selected from pyrrolidin-2—one, piperazine2-one, 3,4-dihydroquinolin- 2(1H)-one, 1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one, 3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-one, 1,5 -dihydrobenzo[e][1,4]oxazepin-2(3H)-one and 1,2,3 ,5 -tetrahydro-4H-pyrido [2,3 -b] iazepin- 4-one.

In all case described herein, ring A may be filI'tl’lCI‘ substituted with one or more —Q1-(R2)11 wherein each occurrence of —Q1-(R2)11 is the same or different, and wherein: n is 0 or 1, Q1 ents halogen, cyano, oxo, nitro, hydroxyl, -SR3, -NR3R4, -CONR3R4, -NR3COR4, - NR3CONR4R43, -COR3, -C(O)OR3, -sozR3, -SOZNR3R4, -NR3SOZR4, NR3SOZNR4R4a, -NR3C(O)OR4, optionally substituted -C1-C6 alkyl, optionally substituted -C1-C6 alkoxy, optionally substituted —C2-C6 l, ally substituted —C2-C6 l, a covalent bond, an oxygen atom, a sulphur atom, - OR5-, -SO-, -SOz-, -CO-, -C(O)O-, -C0-C3 alkylene-CONR3-C0-C3 alkylene, -C0-C3 alkylene-NR3-C0- C3 alkylene, -C0-C3 alkylene-NR3CO-C0-C3 alkylene, -C0-C3 alkylene-NR3CONR4-C0-C3 alkylene, - SOZNR3-, -NR3SOZ-, -NR3SOZNR4-, -NR3C(O)O-, -NR3C(O)OR5-, optionally substituted C1-C6 ne or optionally substituted -C2-C6 alkenylene, R3, R4 and R461 each independently represent en or optionally substituted C1-C6 alkyl, and R5 represents optionally substituted C1-C6 alkylene.

When n is 1, R2 represents an optionally substituted 3 to 10 membered heterocyclyl, cycloalkyl, heteroaryl or aryl ring (when n is 0, Q1 is present and R2 is absent).

Ring A may be filI'tl’lCI‘ substituted with one, two, three or four of —Q1-(R2)n. Substitution is in addition to the oxo substitution which forms part ofthe amide.

In particular, ring A may not be further tuted or may be filI'tl’lCI‘ tuted with one, two or three of —Q1-(R2)n. Ring A may be further substituted with one or two of —Q1-(R2)n. Each occurrence of —Q1-(R2)11 may be the same or different. Alternatively, ring A may be filI'tl’lCI‘ substituted with one of —Q1-(R2)n. Q, R2 and n are as defined herein. In certain ces, ring A may not be further substituted.

In certain embodiments, ring A is substituted with a filI'tl’lCI‘ optionally tuted ring, i.e. ring A is substituted with one or more —Q1-(R2)11 moieties where n is 1 for at least one of the moieties.

Generally, ring A will only be substituted with one -Q1-(R2)11 moiety where n is 1, i.e. ring A will only be substituted with one ring, which may be in addition to other ng substituents.

In all cases described herein, Q1 may be selected from halogen (e.g. fluorine, chlorine or bromine), cyano, oxo, nitro, hydroxyl, -SR3 (e.g. thiol), -NR3R4 (e.g. amino or N,N—dimethylamino), -CONR3R4 (e.g. amido), -NR3COR4 tyl), -NR3CONR4R4a, -COR3 (e.g. acetyl), -C(O)OR3 (e.g. methoxycarbonyl or ethoxycarbonyl), -SOZR3 (e.g. methyl sulphonyl), -SOZNR3R4 (e.g. dimethylaminosulphonyl), -NR3SOZR4, NR4R4a, -NR3C(O)OR4, optionally substituted -C1-C4 alkyl (e.g. propyl, isobutyl or tert butyl), optionally substituted C1-C2 alkyl (e.g. methyl or eithyl), optionally substituted -C1-C6 alkoxy, optionally substituted —C2-C6 alkenyl, optionally substituted — C2-C6 alkynyl, a covalent bond, an oxygen atom, a sulphur atom, -OR5-, -SO-, -SOz-, -CO-, -C(O)O-, -C0-C3 alkylene-CONR3-C0-C3 alkylene, -C0-C3 alkylene-NR3-C0-C3 alkylene (e.g. methylamino), - C0-C3 ne-NR3CO-C0-C3 alkylene, -NR3CONR4-, -SOZNR3-, -NR3SOZ-, ZNR4-, - NR3C(O)O-, -NR3C(O)OR5-, optionally substituted C1-C4 alkylene (e.g. methylene or ethylene) or optionally substituted -C2-C4 alkenylene (e,g. , wherein R3, R4, R461 and R5 are as defined above.

In one embodiment, Q1 is selected from halogen, cyano, oxo, nitro, hydroxyl, -SR3, , - CONR3R4, -NR3COR4, -NR3CONR4R43, -COR3, -C(O)OR3, -sozR3, -SOZNR3R4, -NR3SOZR4, NR3SOZNR4R43, -NR3C(O)OR4, optionally substituted -C1-C4 alkyl, optionally substituted C1-C2 alkyl, ally substituted -C1-C6 alkoxy, optionally substituted —C2-C6 alkenyl, optionally substituted —C2-C6 alkynyl, a covalent bond, an oxygen atom, a sulphur atom, -OR5-, -SO-, -SOz-, - CO-, -C(O)O-, -CONR3-, -NR3-, -NR3CO-, -NR3CONR4-, -SOZNR3-, -NR3SOZ-, -NR3SOZNR4-, - NR3C(O)O-, -NR3C(O)OR5-, ally substituted C1-C4 alkylene or optionally substituted -C2-C4 alkenylene, n R3, R4, R461 and R5 are as defined above.

When n is 0, ring A may be fithher substituted with one or more (e.g. one, two, three or four) Q1 tuents independently selected from halogen (e.g. fluorine, chlorine or bromine), cyano, oxo, nitro, hydroxyl, -SR3, -NR3R4, -CONR3R4, -NR3C(O)R4, -NR3C(O)NR4R43, -C(O)R3, -C(O)OR3, - $02113, -SOZNR3R4, -NR3SOZR4, NR3SOZNR4R4a, -NR3C(O)OR4, -C1-C6 alkyl, -C1-C6 alkoxy,—C2-C6 alkenyl, or —C2-C6 alkynyl, wherein alkyl, alkoxy, alkenyl or alkynyl, may be unsubstituted or substituted with one or more substituents ed from n, hydroxyl, thiol, cyano, amino, nitro and SF5, and wherein R3, R4, R461 and R5 are as defined above.

In particular, when n is 0, Q1 may represent oxo, methyl, ethyl, CF3, methoxy, n (e.g. e or chlorine), -C(O)NR3R4, wherein R3 and R4 are each independently represent hydrogen or .

In particular examples, n is 0 and ring A represents a 5 or 6 membered heterocyclyl ring which is optionally substituted with one or more (e.g. one, two, three or four) Q1 substituents independently selected from n (e.g. fluorine or chlorine), oxo, C1-C6 alkyl or C1-C3 alkyl optionally substituted with one or more fluorine, e.g. CF3.

Alternatively, n is 0 and ring A represents a 9 or 10 ed heterocyclyl ring which is optionally substituted with one or more (e.g. one, two, three or four) Q1 substituents independently selected from halogen (e.g. fluorine or chlorine), C1-C6 alkyl or C1-C3 alkyl or C1-C6 alkoxy or C1-C3 alkoxy, wherein the alkyl or alkoxy is optionally substituted with one or more fluorine, e.g. CF3, or C(O)NR3R4 wherein R3 and R4 are each independently represent hydrogen and methyl.

When n is 1, Q1 is a nt bond or a linker selected from an oxygen atom, a sulphur atom, -OR5-, - SO-, -SOz-, -CO-, -C(O)O-, -C0-C3 alkylene-CONR3-C0-C3 alkylene, -C0-C3 alkylene-NR3-C0-C3 alkylene, -C0-C3 alkylene-NR3CO-C0-C3 alkylene, -NR3CONR4-, -SOZNR3-, -NR3SOz-, -NR3SOZNR4- or wherein the or , -NR3C(O)O-, -NR3C(O)OR5-, C1-C6 alkylene -C2-C6 alkenylene, alkylene alkenylene is optionally substituted with one or more substituents selected from halogen, hydroxyl, thiol, cyano, amino, nitro and SF5, and wherein R3, R4 and R5 are as defined above.

In particular, when n is 1, Q1 may be selected from a covalent bond or a linker ed from covalent bond, an oxygen atom, a r atom, -OR5-, -SO-, -SOz-, -CO-, -C(O)O-, -CONR3-, -NR3-, - NR3CO-, -NR3CONR4-, -SOZNR3-, -NR3SOz-, -NR3SOZNR4-, -NR3C(O)O-, -NR3C(O)OR5-, C1-C6 alkylene or -C2-C6 alkenylene, wherein the ne or alkenylene is optionally substituted with one or more substituents selected from halogen, hydroxyl, thiol, cyano, amino, nitro and SF5, and wherein R3, R4 and R5 are as defined above.

In particular, when n is 1, Q1 is a nt bond or C1-C6 alkylene, e.g. C1-C3 alkylene, wherein the alkylene is optionally substituted with one or more substituents selected from halogen, yl, thiol, cyano, amino, nitro and SF5.

It is preferred that ring A is substituted with a filI'tl’lCl‘ ring either directly or via a linker, i.e. ring A is substituted with at least one —Q1-(R2)11 wherein n is 1.

In all cases bed herein, R2 ents a 3 to 10 membered heterocyclyl, cycloalkyl, heteroaryl or aryl ring. R2 may be selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, decahydronaphthalenyl, phenyl, naphthyl, naphthalenyl, pyridinyl, nyl, pyrimidinyl, pyridazinyl, fierl, pyrrolyl, yl, thiazolyl, pyrazolyl, tetrazolyl, indolyl, indolizinyl, isoindolyl, nyl, purinyl, fiJrazanyl, imidazolyl, indazolyl, isothiazolyl, olyl, oxadiazolyl, tetrazolyl, thiadiazolyl, benzofiiranyl, isobenzofiiranyl, benzothiophenyl, isobenzothiophenyl, benzimidazolyl, benzothiazolyl, napthyridinyl, pteridinyl, pyrazinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, imidazopyridinyl, pyrazolopyridinyl, thiazolopyridinyl, isoindolinyl, triazinyl, dihydrophyridinyl, quinoxalinyl, azetidinyl, pyrrolidinyl, piperidinyl, yl, diazepanyl, dihydrofiiranyl (eg. 2,3-dihydrofuranyl, 2,5-dihydrofiJranyl), dioxolanyl, morpholinyl, oxazolidinyl, oxazinanyl, indolinyl, isoindolinyl, piperazinyl, ydrofuranyl, thiomorpholinyl, dihydropyranyl (eg. 3,4-dihydropyranyl, hydropyranyl), homopiperazinyl, dioxanyl, hexahydropyrimidinyl, pyrazolinyl, pyrazolidinyl, 4H-quinolizinyl, quinuclidinyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, thiazolidinyl, benzopyranyl, tetrahydroquinolinyl, dihydrobenzoxazinyl and tetrahydroisoquinolinyl.

R2 may represent an optionally substituted 5 or 6 membered clic heterocyclyl, cycloalkyl, heteroaryl or aryl ring. atively, R2 may represent an optionally substituted 9 or 10 membered bicyclic heterocyclyl, cycloalkyl, heteroaryl or aryl ring.

In particular, R2 is selected from , pyrazolyl, indazolyl, pyridinyl, benzothiazolyl and pyrimidinyl. More particularly, R2 is phenyl.

In all cases described herein, R2 may be optionally substituted with one or more substituents selected from halogen, cyano, oxo, nitro, hydroxyl -SR6, -NR6R7, -CONR6R7, -NR6COR7, -NR6CONR7R7a, - COR6, -C(O)OR6, -sozR6, -SOZNR6R7, -NR6SOZR7, NR6SOZNR7R7a, -NR6C(O)OR7, -C1-C6 alkyl, — C1-C6 ,—C2-C6 alkenyl, -C2-C6, -Q2a-R8, -Q2b-NR6CONR7R7a, -Q2b-NR6CONR7-Q2"-R8, -Q2b- NR6R7, —Q2b—NR6—Q2‘=—R8, -Q2b-COR6, o-Q2°-R8, -Q2b-NR6COR7, -Q2b-NR6CO-Q2°-R8, -Q2b- NR6C(O)OR7, -Q2b-NR6C(O)O-Q2°-R8, -Q2b-SOZR6, -Q2b-SOZ-Q2°-R8, -Q2b-CONR6R7, -Q2b-CONR6- QZC-RS, -Q2b-C02R6, -Q2b-C02-Q2°-R8, -Q2b-s02NR6R7, 02NR6-Q2C-R8, —Q2-NR6802R7, —Q2- NR6SOZ-QZC-R8, -Q2b-NR6SOZNR7R7a and -Q2b-NR6SOZNR7-QZC-R8 n the alkyl, alkoxy, alkenyl or alkynyl are optionally substituted with one or more substituents selected from halogen, hydroxyl, thiol, cyano, amino, nitro and SF5, wherein Q261 represents a covalent bond, an oxygen atom, a sulphur atom, -SO-, -SOz-, -CO-, optionally tuted C1-C6 alkylene or optionally substituted C2-C6 alkenylene, Q2b and Q2‘: each independently represent a covalent bond, optionally substituted C1-C6 alkylene or optionally substituted C2-C6 nylene, R6, R7 and R761 each independently represent hydrogen or ally substituted C1-C6 alkyl, and R8 represents optionally substituted heterocyclyl, optionally tuted heteroaryl, optionally substituted aryl, or an optionally substituted cycloalkyl.

R2 may be substituted with one or more (e.g. one, two, three or four), in particular one or two, substituents independently selected from halogen, cyano, oxo, nitro, hydroxyl, -SR6, -NR6R7, - CONR6R7, -NR6COR7, -NR6CONR7R7a, -COR6, -C(O)OR6, -sozR7, -SOZNR6R7, -NR6SOZR7, NR6SOZNR7R7a, -NR6C(O)OR7, -C1-C6 alkyl, -C1-C6 alkoxy,—C2-C6 l, -C2-C6 l, -Q2b- NR6CONR7R7a, -Q2b-NR6R7, -Q2b-C(O)R6, -Q2b-NR6C(O)R7, -Q2b-NR6C(O)OR7, -Q2b-SOZR6, QZb- C(O)NR6R7, 02R6, -Q2b-s02NR6R7, —Q2b-NR6s02R7 and -Q2b-NR6s02NR7R7a, wherein Q2b ents a covalent bond, optionally substituted C1-C6 alkylene or optionally substituted C2-C6 alkenylene, and wherein R6, R7 and R761 each independently represent hydrogen or optionally substituted C1-C6 alkyl, wherein any alkyl, alkoxy, alkenyl, alkynyl, alkylene or alkenylene is optionally substituted with one or more (e.g. one, two, three or four) substituents selected from halogen, hydroxyl, thiol, cyano, amino, nitro and SF5.

In particular, R2 may be substituted with one or more substituents selected from halogen (e.g. fluorine), cyano, oxo, C1-C3 alkyl or C1-C3 alkoxy wherein the alkyl or alkoxy is optionally substituted with e, -CONR6R7, -NR6COR7, -Q2a-R8, —Q2b-NR6SOZ-Q2°-R8, n Q23 is a covalent bond, an oxygen atom, -CO-, -SOZ- or -C1-C3 alkylene, Q2b is a covalent bond or C1-C3 alkylene and Q2‘: is a covalent bond, and wherein R6 and R7 are each independently selected from hydrogen or C1-C3 alkyl, and R8 is a 3 to 10 membered optionally substituted cycloalkyl, heterocyclcyl, aryl or heteroaryl ring, in particular a 3 to 6 membered monocyclic cycloalkyl, heterocyclyl, heteroaryl or aryl ring. More particularly, R8 is selected from phenyl, piperazinyl, cyclopropyl, morpholinyl and piperidinyl.

More particularly, R2 may be substituted with one or more substituents selected from n (e.g. chlorine or fluorine), cyano, oxo, methyl, i-propyl, OMe, OCF3, O-i-propyl, -C(O)NHMe, - C(O)N(CH3)2, -NHC(O)Me, piperidinyl,—NHSOz-cyclopropyl, Qza-phenyl n Q261 is a covalent bond, an oxygen atom or methyleneoxy, perazinyl wherein Q261 is a covalent bond or —CO- and Qza-morpholinyl n Q261 is —CO- or —SOz-.

In particular, R2 is unsubstituted, mono-substituted or disubstituted.

In certain instances, R2 is ally substituted with a 3 to 10 membered heterocyclyl, lkyl, aryl or aryl ring, either ly attached or via a linking group. The linking group may be an oxygen atom, carbonyl, -SOz-, -NHSOz-, or an optionally substituted C1-C3 ne. The linking group may be oxygen, -CO- or an alkylene chain, for example, methylene or methyleneoxy. For example, R2 may be substituted with a 5 or 6 membered ring selected from phenyl, piperidinyl, piperazinyl and morpholinyl. R2 may be fithher substituted, in addition to the ring substitution, with one or more non-ring substituents selected from halogen, cyano, oxo, C1-C3 alkyl, C1-C3 alkoxy wherein the alkyl or alkoxy may be optionally substituted with fluorine, -C(O)NHMe, -C(O)N(CH3)2 and -NHC(O)Me.

In certain instances, R2 represents a 3 to 10 membered heterocyclyl, cycloalkyl, heteroaryl or aryl ring selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, dronaphthalenyl, phenyl, naphthyl, naphthalenyl, pyridinyl, nyl, pyrimidinyl, pyridazinyl, fierl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, tetrazolyl, indolyl, indolizinyl, isoindolyl, indolinyl, purinyl, fiJrazanyl, imidazolyl, indazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, tetrazolyl, thiadiazolyl, benzofiiranyl, zofiJranyl, benzothiophenyl, isobenzothiophenyl, benzimidazolyl, benzothiazolyl, napthyridinyl, pteridinyl, pyrazinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, imidazopyridinyl, pyrazolopyridinyl, thiazolopyridinyl, isoindolinyl, nyl, dihydrophyridinyl, quinoxalinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, diazepanyl, ofiJranyl (e.g. 2,3-dihydrofuranyl, 2,5-dihydrofiJranyl), dioxolanyl, morpholinyl, oxazolidinyl, oxazinanyl, indolinyl, isoindolinyl, piperazinyl, tetrahydrofuranyl, thiomorpholinyl, dihydropyranyl (e.g. 3,4-dihydropyranyl, 3,6-dihydropyranyl), homopiperazinyl, dioxanyl, hexahydropyrimidinyl, pyrazolinyl, pyrazolidinyl, 4H-quinolizinyl, quinuclidinyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, thiazolidinyl, benzopyranyl, tetrahydroquinolinyl, dihydrobenzoxazinyl and tetrahydroisoquinolinyl, which is either unsubstituted or substituted with one or more (e.g. one, two or three) substituents selected from halogen (e.g. fluorine or ne), cyano, oxo, nitro, hydroxyl, -SR6, -NR6R7, -CONR6R7, -NR6COR7, -NR6CONR7R73, -COR6, - 6, -sozR6, -SOZNR6R7, -NR6SOZR7, NR6SOZNR7R7a, -NR6C(O)OR7, -C1-C6 alkyl, -C1-C6 alkoxy,—C2-C6 alkenyl, -C2-C6 alkynyl, 8, -Q2b-NR6CONR7R73, -Q2b-NR6C0NR7-Q2°-R8, -Q2b- NR6R7, R6—Q2‘=—R8, -Q2b-COR6, -Q2b-Co-Q2°-R8, R6COR7, -Q2b-NR6CO-Q2°-R8, -Q2b- )OR7, -Q2b-NR6C(O)O-Q2°-R8, -Q2b-SOZR6, OZ-Q2°-R8, QZb-CONR6R7, -Q2b-CONR6- QZC-R8,-Q2b-C02R6, -Q2b-C02-Q2°-R8, -Q2b-s02NR6R7, -Q2b-s02NR6-Q2‘=-R8, —Q2b-NR6s02R7, —Q2b- NR6SOZ-Q2c-R8, -Q2-NR6SOZNR7R8 and -Q2b-NR6SOZNR7-QZC-R8, wherein the alkyl, alkoxy, alkenyl or alkynyl are ally substituted with one or more substituents selected from n, hydroxyl, thiol, cyano, amino, nitro and SF5, wherein Q261 ents a covalent bond, an oxygen atom, a sulphur atom, -SO-, -SOz-, -CO-, C1-C6 alkylene or optionally substituted C2-C6 alkenylene, Q2b and Q2‘: each independently represent a covalent bond, optionally substituted C1-C6 alkylene or optionally substituted C2-C6 alkylenylene, R6, R7 and R761 each independently ent hydrogen or ally substituted C1-C6 alkyl, and R8 represents optionally substituted heterocyclyl, ally substituted heteroaryl, optionally substituted aryl, or an optionally tuted cycloalkyl.

In particular, R2 may be selected from phenyl, pyrazolyl, indazolyl, pyridinyl, benzothiazolyl and pyrimidinyl, wherein the ring is unsubstituted or substituted with one or more (e.g. one, two or three) subsitutents ed from halogen, cyano, oxo, C1-C3 alkyl or C1-C3 alkoxy wherein the alkyl or alkoxy is optionally substituted with fluorine, -CONR6R7, -NR6COR7, -Q2a-R8, —Q2b-NR6SOZ-QZC-R8, wherein Q261 is a covalent bond, an oxygen atom, -CO-, -SOZ- or -C1-C3 alkylene, Q2b is a nt bond or C1-C3 alkylene and Q2‘: is a covalent bond and wherein R6 and R7 are each independently selected from hydrogen or C1-C3 alkyl and R8 is a 3 to 10 membered ally substituted cycloalkyl, heterocyclcyl, aryl or heteroaryl ring.

The t ion fithher relates to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein: R", Rlb, R1‘: and R1d are each independently selected from hydrogen and C1-C3 alkyl which may be optionally substituted with fluorine, R15 and R" are each independently selected from hydrogen, fluorine, C1-C3 alkyl or C1_C3 alkoxy wherein the alkyl or alkoxy is optionally tuted with fluorine, Ring A is a monocyclic or bicyclic 5 to 10 membered heterocyclyl ring which is optionally fithher substituted with one, two, or three of —Q1-(R2)11 wherein Q, R2 and n are as defined herein.

The present invention fithher relates to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein: R", Rlb, R", R", R13 and R" each represent hydrogen, Ring A is selected from pyrrolidin-2—one, piperazine2-one, 3,4-dihydroquinolin-2(lH)-one, 1H- [2,3-b][l,4]oxazin-2(3H)-one, 3,4-dihydropyrido[2,3-b]pyrazine-2(lH)-one, 1,5- dihydrobenzo [e] [ l ,4]oxazepin-2(3H)-one and 1,2,3 ,5 -tetrahydro-4H-pyrido [2,3 -b] [ l ,4]diazepin rein the ring is optionally fithher substituted with one, two or three of —Q1-(R2)11 wherein Q, R2 and n are as defined herein.

The present invention fithher relates to compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein: R", Rlb, R", R", R13 and R" each represent hydrogen, Ring A ents a monocyclic or bicyclic 5 to 10 membered cyclyl ring which is optionally fithher tuted with one, two or three of —Q1-(R2)n, wherein n is 0 or 1, R2 is selected from piperidiniyl, pyrrolyl, phenyl, pyrazolyl, isoxazolyl, indazolyl, nyl, dihidropyridinyl, benzothiazolyl and pyrimidinyl, Q1 is as defined herein.

Examples of the monocyclic and bicyclic heterocyclyl ring represented by A include those shown below: :."mNmm 2.3 J \..,., W \333333.:fimxxxxxxxxxhw x .Pv33333.5 Pmohd.maawne P.mm10.1na_m indolin-Z-one _....$333sz __. xx .\\\\\\\\.5 .,\ .,..

P.1pau.1n"A.U_me 1H-pyrido [2,3 -b][1,4]oxazin- 3,4-dihydroquinolin-2(1H)-one 2(3H)-one 33333! .2. \\\\\\\\\\\. x... f\\\\\\\\\\\\\\ .\\\\\\\\\\\5xi. 1,5 -dihydrobenzo[e][1,4]oxazepin- 3 4_dmydw , Pw.d0Q3: _ 2Bm;_on6 3 ydro-1,5 -naphthyridin- b]pwu.mmy[AW_mc 2(1H)-one rill/titttt/ {I} 5:1 3 ,4-dihydro- l 3 ,4-dihydro- l thyridin- 3 ,4-dihydro- l , , thyridin- , 6-naphthyridin- 2( lH)-one 2( lH)-one 2( lH)-one "(111111" .-.. (‘3 \. is, a H. \ $.51?f "ar x, .' ‘-. -:, l: 'u N \y‘i‘I-fi'F-"v‘fifl' WWW—Vi Eva." "" 1'." ‘51 HEN s i > NE\-\ u‘ m!s¢,,,,,,,,,,,}\, fauna": l,2,3,5-tetrahydro-4H-pyrido[2,3- b] [ l ,4]diazepinone 3,4-dihydropyrazino[2,3- b]pyrazine-2( lH)-one wherein * represents the point of attachment to the remainder of the molecule, i.e. to the pyrrolidine cyanamide to form a ycle, and wherein the rings are optionally substituted with one or more of -Q1-(R2)n.

Examples of novel compounds of formula I include: 2'-oxo- l ihydro-2'H-spiro [pyrrolidine-3 ,3 '-quinoline] - l -carbonitrile 7'-chloro-2'-oxo- l ',4'-dihydro-2'H-spiro [pyrrolidine-3 ,3 '-quinoline] - l -carbonitrile 7'-methoxy-2'—oxo- l ihydro-2'H-spiro [pyrrolidine-3 ,3 '-quinoline] - l -carbonitrile 7'—(5 -isopropylmethoxyphenyl)-2'-oxo- l ihydro-2'H-spiro [pyrrolidine-3 ,3 '-quinoline] - l - carbonitrile 7'-([ l , l '-biphenyl] yl)-2'—oxo- l ',4'-dihydro-2'H-spiro [pyrrolidine-3 ,3 '-quinoline] - l nitrile 7'—(4-(benzyloxy)phenyl)-2'-oxo- l ',4'-dihydro-2'H-spiro [pyrrolidine-3 ,3 '-quinoline] - l -carbonitrile 7'-(2-fluoro-5 -methylphenyl)-2'—oxo- l ',4'-dihydro-2'H-spiro [pyrrolidine-3 ,3 '-quinoline] - l -carbonitrile 7'—(3 -cyanophenyl)-2'-oxo- l ',4'-dihydro-2'H-spiro [pyrrolidine-3 ,3 '-quinoline] - l -carbonitrile methy1-1H-pyrazol-5 -y1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile 2'-0X0-7 '-(4-phenoxypheny1)- 1 ',4'-dihydro-2'H-spiro [pyrrolidine-3 , 3'-quinoline]—1-carbonitrile methyl-1H-pyrazolyl)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile 7'-(4-cyanophenyl)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile 7'-(2-chloro-5 -(trifluoromethoxy)pheny1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile -(1-cyano-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 3 olin] -7' -y1)-N-methy1picolinamide 7'—(2-(benzyloxy)pheny1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 inoline]—1-carbonitrile 4-(1-cyano-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinolin] -7' -y1)-N-methy1benzamide 7'—(3 -((2-ch1orobenzyl)oxy)pheny1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile 7'-(4-(4-methy1piperaziny1)pheny1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile 7'-(6-methoxypyridin-3 -y1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 inoline]carbonitrile 7'—(5 -fluoroisopropoxypheny1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile 7'—(3 -methy1-1H-indazolyl)-2'—oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile 7'-(4-(4-methy1piperazinecarbony1)pheny1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '- quinoline]—1-carbonitrile 7'-(1-methy1-1H-indazol-5 -y1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile 7'—(5 -methy1-1H-indazolyl)-2'—oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 oline] itrile N—(3 -(1-cyano-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinolin] -7'- yl)pheny1)cyclopropanesulfonamide 7'—(3 -methyl-1H-pyrazolyl)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile 2'-0X0-7'-(pyrimidin-5 -yl)-1',4'-dihydro-2'H-spiro[pyrrolidine-3 3 '-quinoline] carbonitrile N—(3 -(1-cyano-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinolin] -7'-y1)pheny1)acetamide 3 -(1-cyano-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 3 '-quinolin] -7' -y1)-N,N-dimethy1benzamide N—(4-(1-cyano-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinolin] -7'-y1)pheny1)acetamide 7'-(4-(morpholinosulfony1)pheny1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile 7'—(3 ,5 -dimethyl-1H-pyrazoly1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile 7'-(2-methy1pyridiny1)-2'-OXO- 1 ',4'-dihydro-2'H-spiro [pyrrolidine-3 ,3'-quinoline]—1-carbonitrile -7 '-(3 -(piperidiny1)pheny1)-1',4'-dihydro-2'H-spiro[pyrrolidine-3 , 3'-quinoline]—1-carbonitrile N—(2-(1-cyano-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinolin] -7'-y1)pheny1)acetamide 7'-(4-(morpholinecarbony1)pheny1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile 7'—(3 -(morpholinosulfony1)pheny1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile 7'-(1-methylOXO-1,6-dihydropyridin-3 -y1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '- quinoline]—1-carbonitrile 7'-(2-methy1benzo [d]thiazol-5 -y1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 oline] carbonitrile 2'-0X0-6'-pheny1-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile 6'—(4-cyanophenyl)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] - 1 nitrile 6'—(3 -cyanophenyl)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile 6'—(4-fluoropheny1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile 6'—(3 -fluoropheny1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile 1-cyano-N,N—dimethy1-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] -7'—carboxamide 1-cyano-N—methyl-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] -7'-carboxamide 1,2-dihydrospiro[pyrido[2,3 -b][1,4]oxazine-3 rrolidine]—1'—carbonitrile 2-0X0pheny1-1,2—dihydrospiro[pyrido[2,3 -b][1,4]oxazine-3 ,3'-pyrrolidine]-1'—carbonitrile 7-(4-cyanopheny1)0X0-1,2-dihydrospiro[pyrido[2,3 -b] [1,4]oxazine-3 ,3'-pyrrolidine]-1'—carbonitrile 7-(3 -cyanopheny1)0X0- 1 ,2—dihydroSpiro [pyrido [2,3 -b] [1,4]oxazine-3 ,3'-pyrrolidine]-1'—carbonitrile uoropheny1)0X0- 1 ,2—dihydroSpiro [pyrido [2,3 -b] [1,4]oxazine-3 ,3'-pyrrolidine]-1'—carbonitrile 7-(3 -fluoropheny1)0X0-1,2—dihydrospiro[pyrido[2,3 -b] [1,4]oxazine-3 ,3'-pyrrolidine]-1'—carbonitrile 2-0X0pheny1-1,2—dihydrospiro[pyrido[2,3 -b][1,4]oxazine-3 ,3'-pyrrolidine]-1'—carbonitrile 2-0X0-1,4-dihydro-2H-spiro[pyrido[2,3 -b]pyrazine-3 ,3'-pyrrolidine]—1'-carbonitrile 6-(trifluoromethy1)-1,4-dihydro-2H-spiro[pyrido[2,3 -b]pyrazine-3 ,3 '-pyrrolidine] - 1 '- carbonitrile 2-0X0pheny1-1,4-dihydro-2H-spiro[pyrido[2,3 -b]pyrazine-3 ,3'-pyrrolidine]—1'—carbonitrile 7-(4-cyanopheny1)0X0-1,4-dihydro-2H-spiro[pyrido[2,3 -b]pyrazine-3 rrolidine]-1'—carbonitrile 7-(4-fluoropheny1)0X0-1,4-dihydro-2H-spiro[pyrido[2,3 -b]pyrazine-3 ,3 '-pyrrolidine] - 1 '- carbonitrile 7-(3 -fluoropheny1)0X0- 1 ,4-dihydro-2H-spiro [pyrido [2,3 -b]pyrazine-3 ,3 '-pyrrolidine] - 1 '- carbonitrile 3 -0X0-3 ,4-dihydro-1H-spiro[pyrido[2,3 -b]pyrazine-2,3'-pyrrolidine]—1'-carbonitrile 6-0X0-2,7-diazaspiro [4 . 4]nonanecarbonitrile (R)oxo-2,7-diazaspiro [4 . 4]nonanecarbonitrile (S)0X0pheny1-1,2-dihydrospiro[pyrido[2,3 -b] [1,4]oxazine-3 ,3'-pyrrolidine]-1'—carbonitrile (S)0X0-1,2-dihydrospiro[pyrido[2,3 -b][1,4]oxazine-3 ,3'-pyrrolidine]-1'—carbonitrile (S)0X0-1,4-dihydro-2H-spiro[pyrido[2,3 -b]pyrazine-3 ,3'-pyrrolidine]-1'—carbonitrile -0X0-6'-phenyl-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile (S)0X0pheny1-1,4-dihydro-2H-spiro[pyrido[2,3 -b]pyrazine-3 ,3'-pyrrolidine]-1'—carbonitrile (S)(3 -fluoropheny1)0X0-1,2-dihydrospiro[pyrido[2,3 -b] [1,4]oxazine-3 ,3 '-pyrrolidine] - 1 '- carbonitrile (S)(4-cyanopheny1)0X0- 1 ,2-dihydrospiro [pyrido [2,3 -b] [1,4]oxazine-3 ,3 '-pyrrolidine] - 1 '- carbonitrile (S)(3 -cyanopheny1)0X0- 1 ,2-dihydrospiro [pyrido [2,3 -b] [1,4]oxazine-3 ,3 olidine] - 1 '- carbonitrile (S)(4-fluoropheny1)0X0- 1 ,4-dihydro-2H-spiro [pyrido [2,3 -b]pyrazine-3 ,3'-pyrrolidine]-1'— carbonitrile (S)(3 -fluoropheny1)0X0- 1 ,4-dihydro-2H-spiro o [2,3 -b]pyrazine-3 ,3'-pyrrolidine]-1'— carbonitrile (S)(4-fluoropheny1)0X0- 1 ,2-dihydrospiro [pyrido [2,3 -b] [1,4]oxazine-3 ,3 '-pyrrolidine] - 1 '- carbonitrile (S)(3 -cyanopheny1)0X0- 1 ,4-dihydro-2H-spiro [pyrido [2,3 -b]pyrazine-3 ,3'-pyrrolidine]-1'— carbonitrile -methy1—7, 10-dioxo-2,6,9-triazaspiro [4.5]decanecarbonitrile 7,10-dioxo-2,6,9-triazaspiro[4.5]decanecarbonitrile (8 S)methy1-7,10-dioxo-2,6,9-triazaspiro[4.5]decanecarbonitrile 7, 10-dioxopheny1-2,6,9-triazaspiro [4.5]decanecarbonitrile 8-ethy1oxo-2,7-diazaspiro [4 . 4]nonanecarbonitrile 8-benzy10X0-2,7-diazaspiro [4 . 4]nonanecarbonitrile 8-methy10X0-2,7-diazaspiro [4 .4]nonanecarbonitrile 2-0X0-1,5 ro-2H-spiro [benzo [6] [1,4]oxazepine-3 ,3'-pyrrolidine]-1'—carbonitrile 2-0X0-1,2,4,5 -tetrahydrospiro [pyrido [2,3 -b][1,4]diazepine-3 ,3 '-pyrrolidine] - 1 '-carbonitrile 8-methy1-7, 10-dioxopheny1—2, 6,9-triazaspiro [4 . 5 ] decanecarbonitrile -1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile 7'-chloro-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile hoxy-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] - 1 nitrile 7'—(5 -isopropylmethoxypheny1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3'-quinoline] carbonitrile ,1'-bipheny1]y1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile 7'—(4-(benzyloxy)pheny1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 inoline]—1-carbonitrile 7'-(2-fluoro-5 -methylphenyl)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3'-quinoline]—1-carbonitrile 7'—(3 -cyanophenyl)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile 7'-(1-methy1-1H-pyrazol-5 -y1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 oline] carbonitrile 2'-0X0-7 '-(4-phenoxypheny1)- 1 ',4'-dihydro-2'H-spiro [pyrrolidine-3 , 3'-quinoline]—1-carbonitrile 7'-(1-methyl-1H-pyrazolyl)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile 7'-(4-cyanophenyl)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile 7'-(2-chloro-5 -(trifluoromethoxy)pheny1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile -(1-cyano-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 3 '-quinolin] -7' -y1)-N-methy1picolinamide 7'—(2-(benzyloxy)pheny1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3'-quinoline]—1-carbonitrile 4-(1-cyano-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 olin] -7' -y1)-N-methy1benzamide 7'—(3 -((2-chlorobenzyl)oxy)pheny1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 oline] carbonitrile 7'-(4-(4-methy1piperaziny1)pheny1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile 7'-(6-methoxypyridin-3 -y1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3'-quinoline]carbonitrile 7'—(5 -fluoroisopropoxypheny1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile 7'—(3 -methy1-1H-indazolyl)-2'—oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile 7'-(4-(4-methy1piperazinecarbony1)pheny1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '- ine]—1-carbonitrile 7'-(1-methy1-1H-indazol-5 -y1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile 7'—(5 -methy1-1H-indazolyl)-2'—oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile N—(3 -(1-cyano-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 olin] -7'- yl)pheny1)cyclopropanesulfonamide 7'—(3 -methyl-1H-pyrazolyl)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile 2'-0X0-7'-(pyrimidin-5 -yl)-1',4'-dihydro-2'H-spiro[pyrrolidine-3 3 oline] carbonitrile N—(3 -(1-cyano-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinolin] -7'-y1)pheny1)acetamide 3 -(1-cyano-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 3 '-quinolin] -7' -y1)-N,N-dimethy1benzamide N—(4-(1-cyano-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinolin] -7'-y1)pheny1)acetamide 7'-(4-(morpholinosulfony1)pheny1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile 7'—(3 ,5 hyl-1H-pyrazoly1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile 7'-(2-methy1pyridiny1)-2'-OXO- 1 ',4'-dihydro-2'H-spiro [pyrrolidine-3 ,3'-quinoline]—1-carbonitrile 2'-0X0-7'-(3 -(piperidiny1)pheny1)-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile N—(2-(1-cyano-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinolin] -7'-y1)pheny1)acetamide 7'-(4-(morpholinecarbony1)pheny1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile 7'—(3 -(morpholinosulfony1)pheny1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile 7'-(1-methylOXO-1,6-dihydropyridin-3 '-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '- quinoline]—1-carbonitrile 7'-(2-methy1benzo [d]thiazol-5 -y1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile 2'-0X0-6'-pheny1-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile 6'—(4-cyanophenyl)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile 6'—(3 -cyanophenyl)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile 6'—(4-fluoropheny1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] - 1 nitrile 6'—(3 -fluoropheny1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile 1-cyano-N,N—dimethy1-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] -7'—carboxamide 1-cyano-N—methyl-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] -7'-carboxamide 1,2-dihydrospiro[pyrido[2,3 -b][1,4]oxazine-3 rrolidine]—1'—carbonitrile 2-0X0pheny1-1,2—dihydrospiro[pyrido[2,3 -b][1,4]oxazine-3 ,3'-pyrrolidine]-1'—carbonitrile 7-(4-cyanopheny1)0X0-1,2-dihydrospiro[pyrido[2,3 -b] [1,4]oxazine-3 ,3'-pyrrolidine]-1'—carbonitrile 7-(3 -cyanopheny1)0X0-1,2—dihydrospiro[pyrido[2,3 -b] [1,4]oxazine-3 rrolidine]-1'—carbonitrile 7-(4-fluoropheny1)0X0- 1 ,2—dihydroSpiro [pyrido [2,3 -b] [1,4]oxazine-3 ,3'-pyrrolidine]-1'—carbonitrile 7-(3 -fluoropheny1)0X0-1,2—dihydrospiro[pyrido[2,3 -b][1,4]oxazine-3 ,3'-pyrrolidine]-1'—carbonitrile 2-0X0pheny1-1,2—dihydrospiro[pyrido[2,3 -b][1,4]oxazine-3 ,3'-pyrrolidine]-1'—carbonitrile 1,4-dihydro-2H-spiro[pyrido[2,3 azine-3 ,3'-pyrrolidine]—1'-carbonitrile 2-0X0(trifluoromethy1)-1,4-dihydro-2H-spiro[pyrido[2,3 -b]pyrazine-3 ,3 '-pyrrolidine] - 1 '- carbonitrile 2-0X0pheny1-1,4-dihydro-2H-spiro[pyrido[2,3 -b]pyrazine-3 ,3'-pyrrolidine]—1'—carbonitrile 7-(4-cyanopheny1)0X0-1,4-dihydro-2H-spiro[pyrido[2,3 -b]pyrazine-3 rrolidine]-1'—carbonitrile 7-(4-fluoropheny1)0X0-1,4-dihydro-2H-spiro[pyrido[2,3 -b]pyrazine-3 ,3 '-pyrrolidine] - 1 '- carbonitrile 7-(3 -fluoropheny1)0X0- 1 ydro-2H-spiro [pyrido [2,3 -b]pyrazine-3 ,3 '-pyrrolidine] - 1 '- carbonitrile 3 -0X0-3 ,4-dihydro-1H-spiro[pyrido[2,3 -b]pyrazine-2,3'—pyrrolidine]—1'-carbonitrile 6-0X0-2,7-diazaspiro [4 . 4]nonanecarbonitrile (R)oxo-2,7-diazaspiro [4 . 4]nonanecarbonitrile (S)0X0pheny1-1,2-dihydrospiro[pyrido[2,3 -b] [1,4]oxazine-3 ,3'—pyrrolidine]—1'—carbonitrile (S)0X0-1,2-dihydrospiro[pyrido[2,3 -b][1,4]oxazine-3 ,3'—pyrrolidine]—1'—carbonitrile (S)0X0-1,4-dihydro-2H-spiro[pyrido[2,3 -b]pyrazine-3 ,3'—pyrrolidine]—1'—carbonitrile (R)-2'-0X0-6'-phenyl-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile (S)0X0pheny1-1,4-dihydro-2H-spiro[pyrido[2,3 azine-3 ,3'—pyrrolidine]—1'—carbonitrile (S)(3 -fluoropheny1)0X0-1,2-dihydrospiro[pyrido[2,3 -b] [1,4]oxazine-3 ,3 '-pyrrolidine] - 1 '- carbonitrile (S)(4-cyanopheny1)0X0- 1 ,2-dihydrospiro [pyrido [2,3 -b] [1,4]oxazine-3 ,3 olidine] - 1 '- itrile (S)(3 -cyanopheny1)0X0- 1 ,2-dihydrospiro [pyrido [2,3 -b] [1,4]oxazine-3 ,3 '-pyrrolidine] - 1 '- carbonitrile (S)(4-fluoropheny1)0X0- 1 ,4-dihydro-2H-spiro [pyrido [2,3 -b]pyrazine-3 ,3 '-pyrrolidine] - 1 '- itrile (3 -fluoropheny1)0X0-1,4-dihydro-2H-spiro[pyrido[2,3 -b]pyrazine-3 ,3 '-pyrrolidine] - 1 '- carbonitrile (S)(4-fluoropheny1)0X0- 1 ,2-dihydrospiro [pyrido [2,3 -b] [1,4]oxazine-3 ,3 '-pyrrolidine] - 1 '- carbonitrile (S)(3 -cyanopheny1)0X0- 1 ,4-dihydro-2H-spiro [pyrido [2,3 -b]pyrazine-3 ,3 '-pyrrolidine] - 1 '- carbonitrile (8R)methy1—7, 10-dioxo-2,6,9-triazaspiro [4.5]decanecarbonitrile 7,10-dioxo-2,6,9-triazaspiro[4.5]decanecarbonitrile (8 S)methy1-7,10-dioxo-2,6,9-triazaspiro[4.5]decanecarbonitrile 7, xopheny1-2,6,9-triazaspiro [4.5]decanecarbonitrile 8-ethy1oxo-2,7-diazaspiro [4 . 4]nonanecarbonitrile 8-benzy10X0-2,7-diazaspiro [4 . 4]nonanecarbonitrile 8-methy10X0-2,7-diazaspiro [4 .4]nonanecarbonitrile 2-0X0-1,5 -dihydro-2H-spiro [benzo [6] [1,4] oxazepine-3 ,3 '-pyrrolidine] - 1 '-carbonitrile 2-0X0-1,2,4,5 -tetrahydrospiro [pyrido [2,3 -b][1,4]diazepine-3 ,3 olidine] - 1 '-carbonitrile 8-methy1-7, xopheny1—2, 6,9-triazaspiro [4 . 5 ] decanecarbonitrile 2-0X0pheny1-1,4-dihydro-2H-spiro[pyrido[2,3 azine-3 ,3'—pyrrolidine]—1'—carbonitrile 7-(5 -methyl-1H-indazoly1)0X0-1,4-dihydro-2H-spiro[pyrido[2,3 -b]pyrazine-3 ,3 '-pyrrolidine] - 1' carbonitrile 7-(1,4-dimethy1-1H-pyrazol-5 -y1)0X0-1,4-dihydro-2H-spiro[pyrido[2,3 -b]pyrazine-3 ,3 '- pyrrolidine]—1'—carbonitrile (R)-7'-(5 -methy1-1H-indazolyl)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] itrile -(4-(4-methylpiperaziny1)pheny1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile 7'-(1H-indazoly1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile 6'—(1H-indazoly1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile (R)-7'-(1H-indazoly1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3'-quinoline]carbonitrile (S)-7'-(1H-indazoly1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile (R)-6'—(1H-indazoly1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3'-quinoline]carbonitrile 1'-cyano-N—(4-fluoropheny1)0X0-1,2—dihydrospiro[pyrido[2,3 -b][1,4]oxazine-3 ,3 '-pyrrolidine] amide 2-0X0(piperidinecarbony1)-1,2-dihydrospiro[pyrido[2,3 -b][1,4]oxazine-3 ,3 '-pyrrolidine] - 1 '- carbonitrile 7-(1H-indazolyl)0X0-1,2-dihydrospiro[pyrido[2,3 -b] [1,4]oxazine-3 ,3 '-pyrrolidine] - 1 '- carbonitrile 6-(1H-indazolyl)0X0-1,2-dihydrospiro[pyrido[2,3 -b] [1,4]oxazine-3 ,3 '-pyrrolidine] - 1 '- carbonitrile (S)(1H-indazoly1)0X0-1,2—dihydrospiro[pyrido[2,3 -b] [1,4]oxazine-3 ,3 '-pyrrolidine] - 1 '- carbonitrile (S)(1H-indazoly1)0X0-1,2—dihydrospiro[pyrido[2,3 -b] [1,4]oxazine-3 ,3 '-pyrrolidine] - 1 '- carbonitrile (S)-1'-cyano-N-(4-fluoropheny1)oxo-1,2-dihydrospiro[pyrido[2,3-b] [ 1,4]oxazine-3,3'-pyrrolidine] 6-carboxamide 1'-cyano0X0-N-phenyl-1,2-dihydrospiro[pyrido[2,3 -b] [1,4]oxazine-3 ,3 '-pyrrolidine] carboxamide no-N—(2-fluoropheny1)0X0-1,2—dihydrospiro[pyrido[2,3 -b][1,4]oxazine-3 ,3 '-pyrrolidine] carboxamide 7-(1-methyl-1H-indazoly1)-2—oxo-1,2—dihydrospiro[pyrido[2,3 -b][1,4]oxazine-3 ,3 '-pyrrolidine] - 1' itrile (R)(1-methy1-1H-indazolyl)0X0-1,2—dihydrospiro[pyrido[2,3 -b][1,4]oxazine-3 ,3 '- pyrrolidine]—1'—carbonitrile (S)(1-methy1-1H-indazolyl)0X0-1,2-dihydrospiro[pyrido[2,3 4]oxazine-3 ,3 '- pyrrolidine]—1'—carbonitrile 7-(1-(2-hydroxyethy1)-1H-indazoly1)0X0-1,2-dihydrospiro[pyrido[2,3 4]oxazine-3 ,3 '- pyrrolidine]—1'—carbonitrile (R)(1-(2-hydroxyethyl)-1H-indazolyl)0X0-1,2-dihydrospiro[pyrido[2,3 -b][1,4]oxazine-3 ,3 '- pyrrolidine]—1'—carbonitrile (1-(2-hydroxyethy1)-1H-indazoly1)0X0-1,2-dihydrospiro[pyrido[2,3 -b][1,4]oxazine-3 ,3 '- pyrrolidine]—1'—carbonitrile 7-(1-(2-methoxyethyl)-1H-indazoly1)0X0-1,2-dihydrospiro[pyrido[2,3 -b] [1,4]oxazine-3 ,3 '- pyrrolidine]—1'—carbonitrile (R)(1-(2-methoxyethy1)-1H-indazoly1)0X0-1,2-dihydrospiro[pyrido[2,3 -b] [1,4]oxazine-3 ,3 '- pyrrolidine]—1'—carbonitrile (S)(1-(2-methoxyethyl)-1H-indazolyl)0X0-1,2-dihydrospiro[pyrido[2,3 -b][1,4]oxazine-3 ,3 '- pyrrolidine]—1'—carbonitrile 7-(6-methoxymethy1pyridin-3 -y1)0X0-1,2-dihydrospiro[pyrido[2,3 -b] [1,4]oxazine-3 ,3 '- pyrrolidine]—1'—carbonitrile (R)(6-methoxymethy1pyridin-3 -y1)0X0-1,2-dihydrospiro[pyrido[2,3 -b] [1,4]oxazine-3 ,3 '- pyrrolidine]—1'—carbonitrile (S)(6-methoxymethy1pyridin-3 -y1)0X0-1,2-dihydrospiro[pyrido[2,3 -b] [1,4]oxazine-3 ,3 '- pyrrolidine]—1'—carbonitrile 2'-0X0-7 '-(3 uoromethoxy)pheny1)-1',4'-dihydro-2'H-spiro[pyrrolidine-3 3 '-quinoline] carbonitrile 4-(1-cyano-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinolin] -7' -y1)-N,N-dimethy1benzamide 7'—(3 -(4-methy1piperazinecarbony1)pheny1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '- quinoline]—1-carbonitrile 7'-(1-methy1-1H-pyrrolyl)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 inoline]—1-carbonitrile 6'—([1,1'-bipheny1]y1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] - 1 nitrile 6'—(4-(benzyloxy)pheny1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3'—quinoline]—1-carbonitrile 6'-(1-methy1-1H-pyrazol-5 '-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile 2'-0X0-6 '-(3 -(trifluoromethoxy)pheny1)-1',4'-dihydro-2'H-spiro[pyrrolidine-3 3 '-quinoline] carbonitrile 2'-0X0-6 '-(4-phenoxypheny1)- 1 ',4'-dihydro-2'H-spiro [pyrrolidine-3 , noline]—1-carbonitrile 6'-(1-methyl-1H-pyrazolyl)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile -(1-cyano-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 3 '-quinolin] -6' -methy1picolinamide 6'—(2-(benzyloxy)pheny1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3'—quinoline]—1-carbonitrile 4-(1-cyano-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinolin] -6' -y1)-N-methy1benzamide 6'—(5 -isopropylmethoxypheny1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile 6'—(3 -((2-ch1orobenzyl)oxy)pheny1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile 6'-(6-methoxypyridin-3 -y1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3'—quinoline]carbonitrile 6'—(5 -fluoroisopropoxypheny1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile 6'—(3 -methy1-1H-indazolyl)-2'—oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile 6'-(4-(4-methy1piperazinecarbony1)pheny1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '- quinoline]—1-carbonitrile 6'-(1-methy1-1H-indazol-5 -y1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile 6'—(5 -methy1-1H-indazolyl)-2'—oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile N—(3 -(1-cyano-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinolin] -6'— yl)pheny1)cyclopropanesulfonamide 4-(1-cyano-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinolin] -6' -y1)-N,N-dimethy1benzamide -6'-(pyrimidin-5 -yl)-1',4'-dihydro-2'H-spiro[pyrrolidine-3 3 '-quinoline] - 1 nitrile N—(3 -(1-cyano-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinolin] -6'-y1)pheny1)acetamide 1-cyano-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinolin] -6'-y1)pheny1)acetamide 6'—(3 -(4-methy1piperazinecarbony1)pheny1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '- quinoline]—1-carbonitrile 6'-(1-methy1-1H-pyrrolyl)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3'—quinoline]—1-carbonitrile 6'-(4-(morpholinosulfony1)pheny1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile 6'—(3 ,5 -dimethyl-1H-pyrazoly1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 oline] carbonitrile -6 '-(3 -(piperidiny1)pheny1)-1',4'-dihydro-2'H-spiro[pyrrolidine-3 , 3'—quinoline]—1-carbonitrile N—(2-(1-cyano-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinolin] -6'-y1)pheny1)acetamide 6'-(4-(morpholinecarbony1)pheny1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile 6'—(3 -(morpholinosulfony1)pheny1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 oline] carbonitrile 6'—(1-methylOXO-1,6-dihydropyridin-3 -y1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '- quinoline]—1-carbonitrile 6'-(2-methy1benzo [d]thiazol-5 -y1)-2'-0X0-1',4'-dihydro-2'H-spiro[pyrrolidine-3 ,3 '-quinoline] carbonitrile 6'—(3 , 5 -dimethylisoxazolyl)-2'-0X0- 1 ',4'-dihydro-2'H-spiro [pyrrolidine-3 , 3 '-quinoline] - l - carbonitrile 6'-(2-chloro-5 -(trifluoromethoxy)phenyl)-2'-0X0- 1 ',4'-dihydro-2'H-spiro [pyrrolidine-3 ,3 '-quinoline] - l - itrile (4-methylpiperazin- l -yl)phenyl)-2'—oxo- l ',4'-dihydro-2'H-spiro [pyrrolidine-3 ,3 '-quinoline] - l - carbonitrile N-benzyl( l -2'-oxo- l ',4'-dihydro-2'H-spiro [pyrrolidine-3 ,3 '-quinolin] -6'-yl)benzamide 6'—(3 -methyl- lH-pyrazol-4 -yl)-2'-oxo- l ',4'-dihydro-2'H-spiro lidine-3 ,3 oline] - l - carbonitrile 6'-(4-(morpholinomethyl)phenyl)-2'-oxo- l ',4'-dihydro-2'H-spiro [pyrrolidine-3 ,3 '-quinoline] - l - carbonitrile 3 -( l -cyano-2'-0X0- 1 ',4'-dihydro-2'H-spiro [pyrrolidine-3 3 '-quinolin] -6' -yl)-N,N-dimethylbenzamide methylpyridinyl)-2'-0X0- 1 ',4'-dihydro-2'H-spiro [pyrrolidine-3 ,3 '-quinoline] - l -carbonitrile.

It should be noted that each of the al compounds listed above represents a particular and independent aspect of the invention.

According to a fithher aspect of the invention there is provided a process for the preparation of a compound of formula I or a pharmaceutically acceptable salt thereof comprising the steps of reacting an amine of formula II with cyanogen bromide to form N-CN compounds: A NH 0 R1d Where Rla — R" and A are as defined elsewhere.

According to a fithher aspect of the invention there is provided a pharmaceutical composition comprising a compound of the invention.

Pharmaceutical compositions of this invention comprise any of the nds of the invention combined with any pharmaceutically acceptable carrier, adjuvant or vehicle. Examples of ceutically acceptable carriers, are known to those skilled in the art and include but are not limited to preserving agents, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, ing agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispersing agents, depending on the nature of the mode of administration and dosage forms. The compositions may be in the form of, for e, tablets, capsules, powders, granules, elixirs, lozenges, suppositories, syrups and liquid preparations including suspensions and solutions. The term "pharmaceutical composition" in the context of this invention means a ition comprising an active agent and comprising additionally one or more pharmaceutically acceptable rs. The composition may fithher contain ingredients selected from, for example, ts, adjuvants, excipients, vehicles, preserving agents, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavouring agents, perfiJming agents, antibacterial agents, antifiJngal agents, lubricating agents and dispersing agents, depending on the nature ofthe mode of administration and dosage forms.

The nds of the invention may be used in the treatment of disorders and diseases related to DUB inhibition, particularly e l and USP30 inhibition.

According to a fithher aspect of the ion there is provided a compound of formula (I) or pharmaceutical ition thereof for use in therapy. In particular, the compounds of the invention have use in the treatment of cancer and more particularly in the treatment of cancer linked to DUB activity. Compounds of the invention may be USCfill against any DUB , ing but not limited to Cezanne l and USP30.

The compounds described herein may be used in the manufacture of a medicament for the treatment of cancer linked to DUB activity.

In a fithher aspect of the ion there is provided a method of treatment or prevention of cancer linked to Cezanne l or USP30 activity, the method comprising administering a pharmaceutically effective amount of a compound of the invention or a pharmaceutical composition thereof to an individual ing from cancer linked to e l or USP30 activity.

The compounds or compositions disclosed herein may be used to treat . References to "cancer" or "tumour" include but are not limited to , ovarian, prostate, lung, kidney, gastric, colon, testicular, head and neck, pancreas, brain, melanoma, bone or other cancers of tissue organs and cancers of the blood cells such as lymphomas and leukaemias. Particular cancers e lymphoma, multiple myeloma, colorectal cancer, and non-small cell lung carcinoma.

The compounds or compositions disclosed herein may be used to treat additional es linked to Cezanne 1 activity.

The compounds of the invention or pharmaceutical compositions thereof as described herein may be combined with one or more additional . The compounds may be combined with one or more additional anti-tumour therapeutic , for example chemotherapeutic drugs or inhibitors of other regulatory ns. In one embodiment the one or more anti-tumour therapeutic agent is a chemotherapeutic agent. Chemotherapeutic agents may be selected from olaparib, mitomycin C, cisplatin, carboplatin, oxaliplatin, ionizing radiation (IR), camptothecin, irinotecan, topotecan, temozolomide, taxanes, 5-fluoropyrimidines, abine, and doxorubicin. In a fithher embodiment the additional anti-tumour therapeutic agent is a BH-3 mimetic. In a finther ment BH-3 mimetics may be selected from but not limited to one or more of ABT-737, ABT-l99, 3, and ObatoclaX.

As ned above, tion of Cezanne 1 would lead to a reduction in inflammatory response, and therefore the compounds of the invention (Formula (I)) may be used in the treatment of inflammation.

As discussed above, the compounds of the invention may be USCfill in the treatment of disorders and es related to USP30 inhibition. The compounds of the invention may therefore be useful in the treatment of disorders or diseases having a component relating to mitochondrial dysfiJnction.

Mitochondrial dysfiJnctions result from defects of the mitochondria, which are specialized compartments present in every cell of the body except red blood cells. When mitochondria fail, less and less energy is generated Within the cell and cell injury or even cell death will follow. If this s is repeated throughout the body the life of the subject in Whom this is happening is ly compromised. Diseases of the mitochondria appear most often in organs that are very energy demanding such as the brain, heart, liver, skeletal muscles, kidney and the endocrine and respiratory system.

The condition involving mitochondrial ction may be selected from a condition involving a mitophagy defect, a condition involving a mutation in mitochondrial DNA, a condition involving mitochondrial oxidative stress, a condition involving a defect in mitochondrial membrane potential, mitochondrial biogenesis, a ion ing a defect in mitochondrial shape or morphology, and a condition involving a lysosomal storage defect.

In particular, the condition ing mitochondrial dysfirnction may be selected from a neurodegenerative disease; multiple sclerosis (MS), mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, Leber's hereditary optic neuropathy (LHON), cancer, athy, , retinitis pigmentosa-maternally inherited Leigh syndrome (NARP-MILS), Danon disease, diabetes, diabetic nephropathy, metabolic disorders, heart failure, ischemic heart disease leading to myocardial infarction, psychiatric diseases, for example schizophrenia, multiple sulfatase deficiency (MSD), pidosis II (ML II), pidosis III (ML III), pidosis IV (ML IV), GMl-gangliosidosis (GMl), neuronal ceroid-lipofirscinoses , Alpers disease, Barth syndrome, Beta-oxidation s, camitine-acyl-camitine deficiency, ne deficiency, creatine deficiency syndromes, yme Q10 deficiency, x I deficiency, x II deficiency, x III ncy, complex IV deficiency, complex V deficiency, COX deficiency, chronic progressive external ophthalmoplegia syndrome (CPEO), CPT I deficiency, CPT II deficiency, glutaric aciduria type II, Keams-Sayre syndrome, lactic acidosis, hain acyl-CoA dehydrogenase deficiency (LCHAD), Leigh disease or syndrome, lethal infantile cardiomyopathy (LIC), Luft disease, glutaric aciduria type II, medium-chain acyl-CoA dehydrogenase deficiency (MCAD), myoclonic epilepsy and ragged-red fiber (MERRF) syndrome, mitochondrial cytopathy, mitochondrial recessive ataxia syndrome, mitochondrial DNA depletion syndrome, myoneurogastointestinal disorder and encephalopathy, Pearson me, pyruvate dehydrogenase deficiency, pyruvate carboxylase ncy, POLG mutations, medium/short-chain 3-hydroxyacyl- CoA dehydrogenase (M/SCHAD) deficiency, and very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, and age-dependent decline in cognitive firnction and muscle strength.

The condition involving mitochondrial dysfirnction may be a CNS disorder, for example a neurodegenerative disease. Neurodegenerative diseases include, but are not limited to, Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), Huntington’s disease, ischemia, stroke, dementia with Lewy bodies, and frontotemporal dementia.

Dosage Forms The pharmaceutical compositions of the invention may be designed for administration by the oral, parenteral or mucosal route and the choice or the specific form of composition is dependent on the administration route. Thus for oral administration the composition may be in the form, for example, of tablets, lozenges, dragees, films, powders, elixirs, syrups, liquid preparations including dispersions, suspensions, emulsions, ons or sprays, cachets, granules, es, etc. For administration to mucosa the composition may be in the form of sprays, inhalants, dispersions, sions, emulsions, ons, gels, patches, films, ointrnents, creams, s, suppositories etc. For parenteral administration the composition is in the form of a liquid preparation such as a solution, dispersion, emulsion or suspension including me compositions.

Preparations according to the invention for parenteral stration include sterile aqueous, aqueousorganic , and organic ons, suspensions and emulsions.

Such dosage forms are prepared according to techniques known in the art of ceutical formulation. When in the form of sprays or inhalants the pharmaceutical compositions may be stered nasally. Suitable formulations for this purpose are known to those skilled in the art.

The pharmaceutical compositions of the invention may be administered by injection and may be in the form of a sterile liquid preparation for injection, including liposome preparations. The pharmaceutical compositions of the invention may also be in the form of suppositories for rectal administration.

These are ated so that the pharmaceutical composition is solid at room temperature and liquid at body temperature to allow release of the active compound.

The dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the remit of the person skilled in the skill of the art. Generally, treatment is initiated with smaller s which are less than the optimal dose ofthe compound. Thereafter the dosage is increased by small increments until the m effect under the circumstances is reached.

The magnitude of an effective dose of a compound will, of course, vary with the nature of the severity of the condition to be treated and with the ular compound and its route of administration. The selection of riate dosages is within the ability of one of ordinary skill in this art, without undue burden. The daily dose range is about lOug to about 100 mg per kg body weight of a human and non- human animal and in general may be around 10ug to 30mg per kg body weight per dose. The above dose may be given from one to three times per day.

Synthetic ologies Compounds of the invention may be prepared via a variety of synthetic routes. Exemplary routes to certain compounds of the invention are shown below. Representative compounds of the present invention can be synthesized in accordance with the general synthetic s described below and are illustrated more particularly in the schemes that follow. Since the schemes are an illustration, the invention should not be construed as being limited by the chemical reactions and conditions sed. The preparation of the various starting materials used in the schemes is well within the skill of persons versed in the art. Those skilled in the art iate that, where appropriate, the individual transformations within a scheme can be completed in a different order. The following schemes describe general synthetic methods y ediate and target compounds of the present invention may be ed. Additional representative compounds and stereoisomers, racemic mixtures, diastereomers and enantiomers thereof can be synthesized using the intermediates prepared in accordance to the general schemes and other materials, compounds and reagents known to those skilled in the art. All such compounds, isomers, racemic mixtures, diastereomers and enantiomers thereof are intended to be encompassed within the scope ofthe present ion.

All single enantiomers listed were prepared from the corresponding racemic mixture by chiral preparative HPLC or Supercritical Fluid Chromatography (SFC).

All the compounds were characterised by liquid chromatography-mass spectroscopy (LCMS) and/or 1HNMR Abbreviations: ABPR Automated back pressure tor AIBN Azobisisobutyronitrile Boc Tert-butoxycarbonyl br Broad (NMR signal) CAS Chemical Abstracts e d Doublet (NMR signal) DCM Dichloromethane DIPEA Diisopropylethylamine DMF N,N-Dimethylformamide DMSO Dimethylsulphoxide dppf l, l ’ -Bis(diphenylphosphino)ferrocene ES Electrospray EtOAc Ethyl acetate h Hour(s) HATU l-[Bis(dimethylamino)methylene]-lH-1,2,3 -triazolo [4,5 -b]pyridinium3 -oxid hexafluorophosphate HPLC High performance liquid chromatography IPA Propanol LCMS Liquid tography-mass ometry LiHMDS Lithium bis(trimethylsilyl)amide m Multiplet (NMR signal) MeCN Acetonitrile MeOH Methanol MTBE Methyl tert-butyl ether NBS N—Bromosuccinimide n-Bu n-butyl NMR nuclear magnetic resonance PE Petroleum Ether Ph Phenyl Prep Preparative psi Pounds per square inch rt Room temperature RT Retention time s Singlet (NMR signal) t Triplet (NMR signal) TBD Triazabicyclo[4.4.0]decene TEA Triethylamine TFA Trifluoroacetic acid THF TetrahydrofiJran TLC Thin layer chromatography LCMS Methods Method 1 Column BEH C18, mm, 1.7um or equivalent Mobile Phase (A) 5mM Ammonium Acetate + 0.1% Formic Acid in Water (B) 0.1% Formic Acid in MeCN Flow Rate 0.55 mL/min Gradient Time %B 0.0 1 5 0.40 5 0.80 35 1.20 55 2.50 100 3 .30 100 3 .3 1 5 4.00 5 Method 2 Column BEH C18, 50X2.1mm, 1.7um or equivalent Mobile Phase (A) 5mM Ammonium Acetate + 0.1% Formic Acid in Water (B) 0.1% Formic Acid in MeCN Flow Rate 0.45 mL/min Gradient Time %B 0.01 2 0.50 2 .00 90 6.00 95 7.00 95 7.01 2 8.00 2 Method 3 Column X-bridge C18, 50X4.6mm, 3.5um or equivalent Mobile Phase (A) 0.1% Ammonia in Water (B) 0.1% Ammonia in MeCN Flow Rate 1.0 mL/min nt Time %B 0.01 5 .00 90 .80 95 7.20 95 7.21 5 .00 5 Method 4 Column X-bridge C18, 250X4.6mm, 5pm or equivalent Mobile Phase (A) 0.1% Ammonia in Water (B) 0.1% Ammonia in MeCN Flow Rate 1.0 mL/min Gradient Time %B 0.01 5 .00 5 .00 30 .00 30 .00 60 .00 90 .00 90 .01 5 40.00 5 Method 5 Column CHIRALPAK IC, 250X4.6mm, 5 pm or equivalent Mobile Phase (A) 5mM Ammonium Acetate + 0.1% Formic Acid in Water (B) 0.1% Formic Acid in IPA Flow Rate 3 mL/min Gradient Time %B 0.01 55 .00 55 .01 95 1 1.00 95 1 1.01 2 12.00 2 Method 6 Column Chiral ART SA 250X4.6 mm, 5 pm or equivalent Mobile Phase (A) Liquid C02 (B) 0.1% Ammonia in IPA Flow Rate 3.0 mL/min Gradient Time %B 0.01 2 2.00 2 .00 50 .00 50 Method 7 Column Xbridge C18, 150x19 mm, Sum or lent Mobile Phase (A) 20mM Ammonium Acetate in water (B) MeCNzMeOH (50:50) Flow Rate 15 mL/min Gradient Time %B 0.01 0 32.00 10 32.01 100 .00 100 .01 0 40.00 0 Method 8 Column Agilent TC-C18, 50X2.1mm, 5pm or equivalent Mobile Phase (A) 0.04% TFA in water (B) 0.02% TFA in MeCN Flow Rate 0.8 mL/min Gradient Time %B 0.00 1 0.40 1 3.40 100 4.00 100 4.01 1 4.50 1 Method 9 Column YMC Triart C18 150X4.6 mm, 5pm or lent Mobile Phase (A) 10mM Ammonium Acetate in water (B) MeCN Flow Rate 1.0 mL/min Gradient Time %B 0.01 0 .00 0 .00 30 13.00 70 .00 90 17.00 90 17.01 0 .00 0 Method 10 Column XBridge RP18, 2.1X50mm, 5um or equivalent Mobile Phase (A) 0.05% NH3.H20 in water (B) MeCN Flow Rate 0.80 mL/min Gradient Time %B 0.01 5 3.40 100 4.00 100 4.01 5 4.50 5 Method 11 Column Agilent TC-C18, 2.1X50mm, 5pm or equivalent Mobile Phase (A) 0.04% TFA in water (B) 0.02% TFA in MeCN Flow Rate 0.80 mL/min Gradient Time %B 0.01 10 3.40 100 4.00 100 4.01 10 4.50 10 Intermediate A Methyl 3-amin0benzylpyrrolidinecarboxylate \_ b c E O ,Boc O /0\n/\N,Boc —> O —» / #m _. / mN H : O O O Step a. To a stirred solution of methyl (tert-butoxycarbonyl)-L-serinate (CAS Number 27660; 30 g, 136.9 mmol) in DCM (600 ml) was added pyridine (27.03 g, 342.1 mmol) at -50°C. Benzyl chloroformate (23.35 g, 136.9 mmol) was added slowly to the reaction mixture at -50°C and the reaction mixture was stirred at rt for 16 h. The ing mixture was poured into 10% citric acid solution (1500 ml) and the organic phase was separated and aqueous phase was re-extracted with DCM (2 x 300 ml). The combined organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (20% EtOAc in hexane) yielding methyl O-((benzyloxy)carbonyl)-N-(tert-butoxycarbonyl)-L-serinate (22.0 g, 62.323 mmol). LCMS: Method 3, 4.98 min, MS: ES+ 3542, 1H NMR (400 MHz, DMSO-d6) 5 ppm: 7.49 (d, J=7.2 Hz, 1 H), 7.36 - 7.39 (m, 5 H), 5.16 (s, 2 H), 4.35 - 4.40 (m, 2 H), 4.21 - 4.27 (m, 1 H), 3.64 (s, 3 H), 1.38 (s, 9 H).

Step b. To a stirred solution of methyl nzyloxy)carbonyl)-N-(tert-butoxycarbonyl)-L-serinate (22.0 g, 62.3 mmol) in DMF (150 ml) was added K2C03 (17.2 g, 124.6 mmol) at rt and the reaction mixture was stirred at 65°C for 1 h. The mixture was cooled to It, poured into water (2000 ml) and extracted with EtOAc (2 x 500 ml). The combined organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (5% EtOAc in ) yielding methyl rt-butoxycarbonyl)amino)acrylate (11.0 g, 54.726 mmol). 1H NMR (400 MHz, DMSO-d6) 5 ppm: 8.39 (s, 1 H), 5.60 (s, 1 H), 5.49 (s, 1 H), 3.72 (s, 3 H), 1.42 (s, 9 H).

Step c. To a stirred solution of methyl 2-((tert-butoxycarbonyl)amino)acrylate (11 g, 54.726 mmol) and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (CAS Number 931027, 12.97 g, 54.7 mmol) in DCM (250 ml) was added TFA (0.3 ml) at 0°C under nitrogen atmosphere. The reaction e was stirred at rt for 16 h. The resulting reaction mixture was diluted with DCM (200 ml) and washed with saturated NaHC03 solution (1500 ml). The organic layer ted and aqueous layer was re-extracted with DCM (2 x 200 ml). The combined organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (5-20% EtOAc in hexane) to afford methyl 1-benzyl((tert- butoxycarbonyl)amino)pyrrolidinecarboxylate (9.0 g, 26.9 mmol). LCMS: Method 3, 4.69 min, MS: ES+ 3351, 1H NMR (400 MHz, DMSO-d6) 5 ppm: 7.59 (s, 1 H), 7.28 (m, 4 H), 7.22 - 7.26 (m, 1 H), 3.57 - 3.63 (m, 5 H), 2.99 (d, J=10.0 Hz, 1 H), 2.68 (d, J=10.0 Hz, 1 H), 2.58 - 2.61 (m, 1 H), 2.47 - 2.49 (m, 1 H), 2.17 - 2.21 (m, 1 H), 1.97 - 1.99 (m, 1 H), 1.36 (s, 9 H).

Step (1. To a stirred solution of methyl 1-benzyl((tert-butoxycarbonyl)amino)pyrrolidine carboxylate (0.8 g, 2.39 mmol) in DCM (15 ml) was added TFA (4 ml) at 0°C. The reaction mixture was stirred at rt for 16 h. The reaction e was trated under reduced pressure and opically distilled using DCM (2 x 20 ml). The ing residue was dissolved into EtOAc (50 ml) and washed with saturated NaHC03 solution (3 x 50 ml). The organic phase was separated, dried over Na2SO4, filtered and trated under reduced pressure yielding methyl 3-amino pyrrolidinecarboxylate (0.57 g, quantitative). This material was used directly for the next step without fithher purification. LCMS: Method 1, 0.90 min, MS: ES+ 2353, 1H NMR (400 MHz, DMSO-d6) 8 ppm: 7.22 - 7.33 (m, 5 H), 3.63 (s, 3 H), 3.58 (s, 2 H), 2.88 (d, J=9.2 Hz, 1 H), 2.68 (q, J=7.2 Hz, 1 H), 2.54 - 2.58 (m, 1 H), 2.38 (d, J=9.6 Hz, 1 H), 2.21 - 2.25 (m, 1 H), 1.61 - 1.68 (m, 1 Intermediate B Terr-bulyl 7'-br0m0-2'-0x0-1 C4 '-dihydr0-2'H-spirofilyrrolidine-i3 '-quinoline] carboxylate HN N—Boc Reagents and conditions: a) NBS, AIBN, CCl4, 76°C, 16h b) LiHMDS, THF, -78°C, 1h, rt, 16h c) Fe, NH4Cl, THF/water, 60°C,16 h.

Step a. To a mixture of 4-bromomethylnitro-benzene (60 g, 277 mmol, 1.0 eq) and NBS (59.3 g, 333 mmol, 1.2 eq) in CCl4 (600 mL) was added AIBN (5.47 g, 33.3 mmol, 0.12 eq) at rt under N2.

The mixture was stirred at 76°C for 16 h. The reaction e was filtered and the filtrate was washed with 2M NaHC03 (2 x 250 ml) and brine (400 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (0~5% EtOAc/PE) to provide 4-bromo(bromomethyl)nitro-benzene (40 g, 135 mmol, 48.8% yield) as a yellow solid. 1H NMR (400 MHz, CDC13) 5 ppm: 8.19 (d, J=1.6 Hz, 1H), 7.75 (dd, J=8.4, 2.0 Hz, 1H), 7.47 (d, J=8.4 Hz, 1H), 4.78 (s, 2H).

Step b. To a mixture of 1-(tert-butyl ) 3-methyl pyrrolidine-1,3-dicarboxylate (31.1 g, 135 mmol, 1.0 eq) in THF (450 ml) was added dropwise LiHMDS (1 M, 203 ml, 1.5 eq) at -78°C under N2. The mixture was stirred at -78°C for 30 min, then a solution of 4-bromo(bromomethyl)nitro-benzene (40 g, 135 mmol, 1.0 eq) in THF (150 ml) was added dropwise at -78°C. The mixture was d at - 78°C for 1 h, then d at rt for 16 h. LCMS showed the desired compound was detected. The reaction mixture was quenched by addition saturated NH4Cl solution (500 ml) at It, and then extracted with EtOAc (5 x 500 ml). The combined organic layers were washed with brine (2 x 1000 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was d by silica gel chromatography (0~30% PE). 1-(Tert-butyl) 3-methyl 3-[(4-bromonitro-phenyl)methyl]- idine-1,3-dicarboxylate (15 g, 33.8 mmol, 24.9% yield) was obtained as a yellow liquid. 1H NMR (400 MHz, CDC13) 8 ppm: 8.04 (d, J=10.0 Hz, 1H), 7.61-7.68 (m, 1H), 7.13 (dd, J=8.0, 2.0 Hz, 1H), 3.70-3.76 (m, 1H), 3.64 (s, 3H), 3.23-3.49 (m, 5H), 2.25-2.37 (m, 1H), .92 (m, 1H), 1.46 (s, 9H).

Step c. To a mixture of t-butyl) 3-methyl 3-[(4-bromonitro-phenyl)methyl]pyrrolidine-1,3- dicarboxylate (15 g, 33.8 mmol, 1.0 eq) in THF (250 ml) and water (250 ml) was added Fe (18.9 g, 338 mmol, 10.0 eq) and NH4Cl (18.1 g, 338 mmol, 11.8 ml, 10.0 eq) at 0°C. The mixture was stirred at 60°C for 16 h. The reaction mixture was filtered, and the filtrate was diluted with water (50 ml) and extracted with EtOAc (5 x 50 ml). The combined organic layers were washed with brine (2 x 60 ml), dried over NaZSO4, filtered and concentrated under reduced pressure to give a e. The residue was purified by silica gel chromatography (Eluent of 0~5% DCM/MeOH). Tert-butyl 7'-bromo-2'- oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline]carboxylate (12 g, 31.4 mmol, 93.0% yield) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) 5 ppm: 10.34 (s, 1H), 7.07-7.16 (m, 2H), 7.03 (s, 1H), 3.50-3.57 (m, 1H), 3.24-3.34 (m, 1H), 3.06 (dd, J=10.8, 2.8 Hz, 1H), 2.89 (q, J=11.6 Hz, 2H), 1.94-2.02 (m, 1H), .75 (m, 1H), 1.37 (s, 9 H).

Intermediate C 1-(Tert—bulyl) 3-methyl 3-hydr0xypyrrolidine-1,3-dicarb0xylate O/‘/::N a N b O \ Boc _ \ Boc _> H><:'\j \(ID—ISISC/N’Boc —> (ID—ISISC/NH —> Reagents and ions: a) NaCN, NaHCOg, EtZO, water, b) HCl, 1,4-dioxane, water, c) BocZO, EtOAc, NaHC03 (aq), d) Cs2C03, DMF, e) Fe, NH4Cl, THF, water, f) TFA, DCM, g) CNBr, K2C03, Step a. To a stirred solution of N-Boc-3 -pyrrolidinone (CAS Number 1013857, 4.0 g, 21.6 mmol) in diethyl ether (50 ml) and water (8 ml) was added NaHC03 (3.6 g, 43 mmol) in water (5 ml) at 0°C.

NaCN (3.17 g, 64.8 mmol) was added to the on mixture at 0°C. The reaction mixture was d at rt for 24 h. The resulting reaction mixture was poured into water (500 ml) and extracted with diethyl ether (2 x 300 ml). The combined organic phase was dried over NaZSO4, filtered and concentrated under reduced pressure yielding utyl 3-cyanohydroxypyrrolidinecarboxylate (4.21 g, 19.9 mmol). This material was used directly for the next step without fithher purification. 1H NMR (400 MHz, DMSO-d6) 5 ppm: 6.90 (s, 1 H), 3.48 - 3.63 (m, 2 H), 3.36 - 3.44 (m, 1 H), 3.20 - 3.32 (m, 1 H), 2.27 - 2.33 (m, 1 H), 2.13 - 2.20 (m, 1 H), 1.42 (s, 9 H).

Step b. To a stirred solution of tert-butyl 3-cyanohydroxypyrrolidinecarboxylate (4.2 g, 19.8 mmol) in MeOH (10.5 ml) was added 4M HCl in 1,4-dioxane (42 ml) at 0°C. The reaction mixture was stirred at rt for 3 h. The excess of solvent was distilled under d pressure yielding methyl 3- hydroxypyrrolidinecarboxylate HCl salt (4.2 g, quantitative). This material was used directly for the next step t fithher purification. LCMS: Method 3, 1.140 min, MS: ES+ 146.07.

Step c. To a stirred solution of methyl 3-hydroxypyrrolidinecarboxylate HCl salt (4.2 g, 23.204 mmol) in EtOAc (42 ml) was added saturated NaHC03 solution (42 ml) at rt. Boc anhydride (10.12 g, 46.4 mmol) was added to the reaction e at It. The reaction mixture was stirred at rt for 16 h.

The ing reaction e was poured into saturated NaHC03 (200 ml) and extracted with EtOAc (2 x 100 ml). The combined organic phase was dried over NaZSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash tography (30% EtOAc in hexane) yielding l-(tert-butyl) 3-methyl 3-hydroxypyrrolidine-1,3-dicarboxylate (2.2 g, 8.979 mmol).

LCMS: Method 1, 1.90 min, MS: ES+ 2462, 1H NMR (400 MHz, DMSO-d6) 5 ppm: 5.87 (s, 1 H), 3.68 (s, 3 H), 3.41 - 3.52 (m, 2 H), 3.28 - 3.32 (M, 2 H), 2.09 - 2.18 (m, 1 H), 1.91 - 1.94 (m, 1 H), 1.39 (s, 9 H).

Intermediate D ulyl 7-br0m00x0-1,2-dihydr0spir0[pyrid0[2,3-b][1,4]0xazine-3,3'- pyrrolidine]-1 '-carb0xylate \O% _ N 9 Br Br \ H N / 2 / N\ F \ \ \N Boc | I \ a \ b C / \ \O N—Boc O O N N‘ 0 Boo Boo Step a. To a stirred solution of 1-(tert-butyl) 3-methyl 3-hydroxypyrrolidine-1,3-dicarboxylate (Intermediate C, 0.5 g, 2.04 mmol) in THF (30 ml) was added sodium bis(trimethylsilyl)amide solution (1M in THF, 2.04 ml, 2.04 mmol) dropwise at -78°C. The reaction mixture was stirred at - 78°C for 5 min. A solution of 2-fluoronitrobromopyridine (CAS Number 8863721, 0.493 g, 2.24 mmol) in THF (1 ml) was added to the reaction mixture at -78°C. The on mixture was stirred at -78°C to -40°C for 5 h. The resulting on mixture was quenched by slow addition of saturated ammonium chloride on (20 ml) at -40°C. The resulting reaction mixture was warmed to rt and combined with three other batches on the same scale prepared by an identical method. The reaction mixture was diluted with water (50 ml) and extracted with EtOAc (3 x 50 ml). The combined organic phase was ted and washed with brine (30 ml). The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (12% EtOAc in hexane) d 1-(tert-butyl) 3-methyl 3-((5-bromo nitropyridinyl)oxy)pyrrolidine-1,3-dicarboxylate (1.65 g, 3.697 mmol). LCMS: Method 1, 2.539 min, MS: ES+ 390.2, 392.2 (M-2) (M-56), 1H NMR (400 MHz, DMSO-d6) 5 ppm: 8.78 (s, 1 H), 8.63 (s, 1 H), 4.00 (d, J=12.0 Hz, 1 H), 3.70 (d, J=12.8 Hz, 1 H), 3.65 (s, 3 H), 3.48 - 3.54 (m, 1 H), 3.37 - 3.46 (m, 1 H), 2.39 - 2.45 (m, 2 H), 1.39 (d, J=6.4 Hz, 9 H).

Step b. To a stirred solution of 1-(tert-butyl) 3-methyl 3-((5-bromonitropyridin yl)oxy)pyrrolidine-1,3-dicarboxylate (0.8 g, 1.793 mmol) in THszater (1:1, 8 ml), was added iron powder (1.0 g, 17.927 mmol) and ammonium chloride (0.957 g, 17.93 mmol) at It. The reaction mixture was heated at 70°C for 18 h. The resulting reaction mixture was cooled to rt and combined with one other batch on the same scale prepared by an identical method. The reaction mixture was filtered through celite hyflow. The celite bed was washed with EtOAc (100 ml). The combined filtrate was poured into water (50 ml). The organic phase was ted and the aqueous phase was re- extracted with EtOAc (3 x 50 ml). The combined organic phase was washed with brine (50 ml). The combined organic phase was separated, dried over , filtered and concentrated under reduced pressure yielding an approximately 2:3 mixture of tert-butyl 7-bromooxo-1,2- dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3'-pyrrolidine]-1'-carboxylate and 1-(tert-butyl) 3-methyl 3- ((3-amino-5 -bromopyridinyl)oxy)pyrrolidine-1,3-dicarboxylate (1.45 g, quantitative). The obtained mixture was used for the next step without fithher purification. LCMS: Method 1, 2.218 min, 2.429 min, MS: ES+ 328.0, 329.0 (M+2) (M-56), 416.1, 418.1 Step c. To a stirred solution of an imately 2:3 mixture of tert-butyl 7-bromooxo-1,2- dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3'-pyrrolidine]-1'-carboxylate and 1-(tert-butyl) 3-methyl 3- ((3-aminobromopyridinyl)oxy)pyrrolidine-1,3-dicarboxylate (0.7 g, 1.689 mmol) in THF (20 ml) was added 1,5,7-triazabicyclo[4.4.0]decene (0.235 g, 1.689 mmol) at It. The on e was stirred at rt for 3 h. The resulting reaction mixture was combined with one other batch prepared on the same scale by an identical method. The ed reaction mixture was concentrated under vacuum and the e was purified by flash tography (25% EtOAc in hexane) yielding tert- butyl 7-bromooxo-1,2-dihydrospiro[pyrido[2,3 -b][1,4]oxazine-3 ,3 '-pyrrolidine] - 1 '-carboxylate (1.3 g, 3.618 mmol). LCMS: Method 1, 2.125 min, MS: ES+ 328.0, 330.0 (M+2) (M-56), 1H NMR (400 MHz, DMSO-d6) 5 ppm: 11.21 (s, 1 H), 7.96 (d, J=2.0 Hz, 1 H), 7.40 (d, J=2.4 Hz, 1 H), 3.68 - 3.75 (m, 1 H), 3.52 - 3.60 (m, 2 H), 3.64 - 3.44 (m, 1 H), 2.32 - 2.36 (m, 1 H), 2.20 - 2.22 (m, 1 H), 1.40 (d, J=10.0 Hz, 9 H).

Intermediate E Methyl 3-amin0benzylpyrrolidinecarboxylate TFA salt Step a. To a solution of Boc-L-serine methyl ester (CAS Number 27660, 30.0 g, 136.9 mmol) in DCM (300 ml) was added pyridine (28.8 ml, 342 mmol) at -50°C and stirred for 15 minutes. Benzyl chloroformate (25.67 g, 150.5 mmol) was added dropwise to the on mixture at -50°C. The temperature of the reaction mixture was gradually increased to rt. The resulting reaction mixture was stirred at rt for 15 h. After 15 h more pyridine (22.0 ml, 274 mmol) and benzyl chloroformate (23.3 g, 136.9 mmol) was added at -50°C and the reaction mixture was stirred at rt for 5 h. The resulting reaction mixture was quenched with 50% citric acid solution (500 ml) and extracted with EtOAc (3 x 100 ml). The combined organic phase was collected and washed with saturated NaHC03 solution (50 ml), dried over Na2SO4, filtered and trated under d pressure. The obtained residue was triturated with n-hexane (200 ml) yielding methyl O-((benzyloxy)carbonyl)-N-(tert-butoxycarbonyl)- L-serinate (33.25 g, 94.155 mmol). LCMS: Method 3, 4.94 min, MS: ES+ 354.1, 1H NMR (400 MHz, DMSO-d6) 5 ppm: 7.48 (d, J=7.2 Hz, 1 H), 7.32 - 7.41 (m, 5 H), 5.14 (s, 2H), 4.36 - 4.40 (m, 2H), 4.23 - 4.26 (m, 1H), 3.63 (s, 3H), 1.37 (S, 9H).

Step b. To a solution of methyl O-((benzyloxy)carbonyl)-N-(tert-butoxycarbonyl)-L-serinate (33.0 g, 93.48 mmol) in DMF (330 ml) was added K2C03 (25.88 g, 186.97 mmol) at It. The reaction mixture was heated at 65°C for l h. The resulting reaction mixture was poured into water (1000 ml) and extracted with EtOAc (3 x 150 ml). The combined c phase was washed with brine solution (3 x 50 ml), dried over NaZSO4, filtered and concentrated under reduced pressure. The resulting e was purified by column tography (3% EtOAc in hexane) yielding methyl 2-((tert- carbonyl)amino)acrylate (10.39 g, 51.66 mmol). LCMS: Method 1, 2.25 min. 1H NMR (400 MHz, DMSO-d6) 5 ppm: 8.37 (s, 1H), 5.64 (s, 1H), 5.49 (s, 1), 3.72 (s, 3H), 1.41 (s, 9H).

Step c. To a solution of rt-butoxycarbonyl)amino)acrylate (10.3 g, 51.24 mmol) in DCM (103 ml) was added TFA (0.26 ml) at 0°C. N-(Methoxymethyl)-N-(trimethylsilylmethyl)-benzylamine (13.35 g, 56.37 mmol) was slowly added to the reaction mixture at 0°C. The reaction mixture was stirred at 0°C for 15 min and then stirred at rt for 15 h. After 15 h unreacted starting al was observed so again N-(Methoxymethyl)-N-(trimethylsilylmethyl)-benzylamine (3.64 g, 15.373 mmol) was slowly added to the reaction mixture at 0°C. The reaction e was stirred at rt for a fithher 15 h. The resulting reaction mixture was poured into water (250 ml) and basified using Na2C03. The resulting mixture was extracted with DCM (2 x 150 ml) and the combined organic phase was washed with brine solution (50 ml), dried over NaZSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (20% EtOAc in hexane) yielding methyl 1- benzyl((tert-butoxycarbonyl)amino)pyrrolidinecarboxylate (13.80 g, 41.294 mmol). LCMS: Method 3, 4.68 min, MS: ES+ 335.3, 1H NMR (400 MHz, DMSO-d6) 5 ppm: 7.59 (s, 1H), 7.21 - 7.33 (m, 5H), 3.57 - 3.62 (m, 5H), 2.99 (d, J=10 Hz, 1 H), 2.67 (d, J=10 Hz, 1 H), 2.50 -2.61 (m, 2H), 2.14 - 2.18 (m, 1H), 1.98 - 1.99 (m, 1H), 1.35 (s, 9H).

Step d. To a solution of methyl l-benzyl((tert-butoxycarbonyl)amino)pyrrolidinecarboxylate (2.00 g, 5.99 mmol) in DCM (20 ml) was added TFA (2 ml) at rt. The reaction mixture was stirred at rt for 1 h. The resulting reaction e was concentrated under reduced pressure and the obtained residue was triturated with diethyl ether (2 x 10 ml) yielding methyl 3-amino-l-benzylpyrrolidine carboxylate TFA salt (2.50 g. quantitative). This material was used directly for the next step without fithher purification. LCMS: Method 1, 0.70 min, MS: ES+ 235.4.

Intermediate F 2-(4-(4, 4, 5, 5-tetramethyl-1, 3, ab0rolanyl)-1H—indazolyl)ethanol Br 0, B/O , L. N,’ _b- N, N l N \ H H N HO H Step a. To a solution of 4-bromo-lH-indazole (CAS Number 1864079, 1.000 g, 5.076 mmol) in DMF (20 ml) were added 2-bromoethanol (0.43 ml, 6.091 mmol) and K2C03 (1.400 g, 10.145 mmol) at It. The reaction mixture was heated to 100°C for 3 h. The resulting mixture was poured into ice cold water (50 ml). The resulting precipitate was collected by ion, washed with hexane (50 ml) and dried under high vacuum. The obtained solid material contained a 2:1 regioisomeric ratio by LCMS. The desired product was isolated by column chromatography (23% EtOAc in hexane) yielding 2-(4-bromo-1H-indazolyl)ethanol (0.700 g, 2.904 mmol). LCMS: Method 1, 1.629 min, MS: ES+ 241.20, 243.20, 1H NMR (400 MHz, DMSO-d6) 5 ppm: 8.03 (s, 1 H), 7.71 (d, J: 8.0 Hz, 1 H), 7.28 - 7.36 (m, 2 H), 4.87 (t, J: 5.6 Hz, 1 H), 4.62 (t, J: 5.2 Hz, 2 H), 3.78 - 3.82 (m, 2 H).

Step b. To a solution of 2-(4-bromo-1H-indazolyl) ethanol (0.700 g, 2.904 mmol) in 1,4- e (10 ml) were added nacolato)diborane (1.102 g, 4.356 mmol) and KOAc (0.569 g, .808 mmol) at rt. The reaction mixture was degassed for 10 min at rt before addition of dppf) (0.212 g, 0.290 mmol). The reaction e was heated at 100°C for 1 h. The resulting mixture was cooled to rt and concentrated under reduced pressure. The obtained residue was washed with n-hexane (10 ml) yielding 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-indazolyl)ethanol (1.0 g). LCMS: Method 1, 1.880 min, MS: ES+ 289.50 [M+1]. This material was ly used for next step without filI'tl’lCl‘ purification.

Intermediate G Terr-bulyl 6-br0m00x0-1,2-dihydr0spir0[pyrid0[2,3-b][1,4]0xazine-3,3'— pyrrolidine]-1 '-carb0xylate I N HNYENO o 0+ This was prepared in a similar way to Intermediate D, using 2,6-dibromonitropyridine (CAS Number 553048). LCMS: Method 1, 1.892 min, MS: ES+ 384.40, 386.40, 1H NMR (400 MHz, DMSO-d6) 5 ppm: 11.23 (br s, 1 H), 7.31 (d, J: 8.0 Hz, 1 H), 7.23 (d, J: 8.0 Hz, 1 H), 3.69 - 3.74 (m, 1 H), 3.52 - 3.62 (m, 3 H), 2.33 - 2.39 (m, 1 H), 2.21 - 2.24 (m, 1 H), 1.42 (d, J: 10.4 Hz, 9 H).

Scheme 1 Reagents and conditions: a) i) LiHMDS, hexane, THF, b) 10% Pd/C, H2, MeOH OR Fe, NH4C1, THF, water, c) TFA, DCM, d) CNBr, K2C03, THF Example 1 2 '-Ox0-1 C4 '-dihydr0-2 'H-spiro[pyrrolidine-3, 3 '-quin01ine]-1 nim'le Synthesis according to Scheme 1 HN N’_:N Step a. To a stirred solution of tert-butyl methyl pyrrolidine-l,3-dicarboxy1ate (CAS Number 122684- 33-7, 1.0 g, 4.367 mmol) in dry THF (15 ml) was added 1M LiHMDS in hexane (1.08 g, 6.55 mmol) at -78°C. The reaction mixture was stirred at -78°C for 0.5 h then 2-nitrobenzy1 bromide (1.03 g, 4.803 mmol) was added at -78°C. The resulting reaction mixture was warmed to rt and stirred for 16 h. The mixture was then poured into ted ammonium chloride solution (20 m1), diluted with water (100 m1) and extracted with EtOAc (5 x 50 ml). The combined organic phase was dried over , filtered and concentrated under d pressure. The resulting crude material was purified by flash chromatography (6% EtOAc in hexane) to afford 1-(tert-buty1) 3-methy1 3-(2- nitrobenzy1)pyrrolidine-1,3-dicarboxy1ate (0.48 g, 1.319 mmol). LCMS: Method 1, 2.41 min, MS: ES+ 3654, 1H NMR (400 MHz, DMSO-d6) 5 ppm: 7.93 (d, J=8.0 Hz, 1 H), 7.68 (t, J=7.2 Hz, 1 H), 7.53 (t, J=8.0 Hz, 1 H), 7.36 - 7.41 (m, 1 H), 3.57 - 3.64 (m, 1 H), 3.34 - 3.42 (m, 6 H), 3.11 - 3.20 (m, 2 H), 2.15 - 2.19 (m, 1 H), 1.88 - 1.93 (m, 1 H), 1.39 (s, 9 H).

Step b. To a d solution of 1-(tert-buty1) 3-methy1 3-(2-nitrobenzy1)pyrrolidine-1,3-dicarboxy1ate (0.2 g, 0.549 mmol) in MeOH (10 ml) was added 10% dry Pd/C (0.2 g) at It. The reaction mixture was purged with H2 gas at rt for 0.5 h. The resulting reaction mixture was carefiilly filtered through celite hyflow and concentrated under reduced pressure to afford utyl 2'-oxo-1',4'-dihydro-2'H- spiro[pyrrolidine-3,3'-quinoline]—1-carboxylate (0.14 g, 0.463 mmol). LCMS: Method 1, 2.20 min, MS: ES+ 247.4 (M-56), 1H NMR (400 MHz, MeOD) 5 ppm: 7.19 - 7.24 (m, 2 H), 7.02 (t, J=7.2 Hz, 1 H), 6. 90 (d, J=8.0 Hz, 1 H), 3.71 - 3.76 (m, 2 H), 3.49 - 3.69 (m, 2 H), 2.93 - 3.06 (m, 2 H), 2.14 - 2.24 (m, 1 H), 1.77 - 1.89 (m, 1 H) 1.47 (s, 9 H).

Step c. To a stirred on of tert-butyl 2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline] carboxylate (0.13 g, 0.43 mmol) in DCM (1 ml) was added TFA (1 m1) at It. The reaction mixture was stirred at rt for 2 h. The resulting reaction mixture was concentrated under reduced pressure ng 1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinolin]-2'-one TFA salt (0.09 g, 0.285 mmol). This material was used directly for the next step without fithher purification. LCMS: Method 1, 1.46 min, MS: ES+ 203.3.

Step (1. To a stirred solution of 1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinolin]-2'-one TFA salt (0.08 g, 0.253 mmol) in THF (10 ml) was added K2C03 (0.174 g, 1.265 mmol) at It. Cyanogen bromide (0.032 g, 0.304 mmol) was added to the reaction mixture at rt and the mixture was stirred at rt for 0.5 h. The resulting reaction mixture was filtered and excess THF was d under d pressure. The resulting residue was purified by flash chromatography (30% EtOAc in hexane) yielding 2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline]carbonitrile (0.022 g, 0.096 mmol). LCMS: Method 2, 3.26 min, MS: ES+ 2284, 1H NMR (400 MHz, DMSO-d6) 5 ppm: 10.36 (s, 1 H), 7.16 - 7.20 (m, 2 H), 6.93- 6.97 (m, 1 H), 6.88 (d, J=7.6 Hz, 1 H), 3.67 (d, J=9.6 Hz, 1 H), 3.51 - 3.55 (m, 1 H), 3.38 - 3.44 (m, 1 H), 3.22 (d, J: 9.6 Hz, 1 H), 3.02 (d, J: 16 Hz, 1 H), 2.89 (s, J=15.6 Hz, 1 H), 1.97 - 2.04 (m, 1 H), 1.72 - 1.79 (m, 1 H). :35:me - "133.35 "HHH u H TB "w 63 "H5 H "H5 Rm "N: é *3 mom "HHH 3N .QHH % 8.1: 8a w: - - "H5 w o.oH "HHH H "HHH H3 H "H5 a: 66-835 um H m: w: H "HHH "N: m3 AHH - "NHH é "H5 "N: "HHH H - H: H N.» $.m 2% "N: "N: :uw a 3H "H5 Nm2 "138.59: - E "HHH é "w 8a Manx "EH H 31w: é $.15 - «$138.59: 2% é "H5 00$ 6 "N: 8.0 Hem 3H "HHH cam 8a HHH>Hz H "H5 A: "HHH - "HHH "N: A: 3H HHH "a H Nm.m H H would "NHH "a E - "NHH "N: 8.1m "HS "HHH $2 a: Nd a: was {mum N we 2% a mH>H +5 . . 2953mm mom ommomm 5H 0: How mH>HoH EH5 . m Ea conuomoc mH>HoH 8:65 N m 8 ENHHom 032 m5 HonHHHHHZ w 3:85 -mmHHmNm -mmaHme 0:68on - Jigéégméfibé .Mw-§§3§§§% mHEEQfiS-Hésmessw _ - u. km a iménés we"? was/H _ mam: wigs?miwhwgém:3:an me . m 9:9? mNEEoQ‘Su-TFEBEEQ 28g -m Ho -002 mcqsomfioo 0 H 21 N m m 28g OHHHEQm mm Scheme 2 Br—T/ Ar Ar Ar a b 0 —> —> —> HN N—Boc HN -—Boc HN HN NH N—E—N O O O 0 Reagents and conditions: a) )2, CS2CO3, Pd(PPh3)4, 1,4-dioxane, water, b) TFA, DCM or HCl/ EtOAc, c) CNBr, K2C03, THF or CNBr, NaHCOg, EtOH Example 4 2 '-Ox0- 7'-phenyl-1 ', 4 '-dihydr0-2 'H—spiro[pyrrolidine-3, 3 '-quin01ine]-1 -carb0nim'le Synthesis according to Scheme 2 HN N—EN Step a. To a stirred solution of tert-butyl 7'-bromo-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'- quinoline]—1-carboxy1ate (Intermediate B, 0.25 g, 0.655 mmol) in 1,4-dioxane:water (8:2, 10 ml) was added phenylboronic acid (0.16 g, 1.311 mmol) and Cs2C03 (0.427 g, 1.311 mmol) at rt. The reaction mixture was degassed for 20 min at rt before addition of Pd(PPh3)4 (0.075 g, 0.065 mmol). The reaction mixture was heated at 80°C for 8 h. The resulting reaction e was cooled to It, poured into water (30 m1) and ted with EtOAc (5 X 25 ml). The combined organic phase was separated and washed with brine (2 X 20 ml). The organic phase was separated, dried over NaZSO4, filtered and concentrated under reduced re. The resulting residue was purified by flash chromatography (18% EtOAc in hexane) yielding tert-butyl 2'-oxo-7'-pheny1—1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'- quinoline]—1-carboxy1ate (0.21g, 0.552 mmol). LCMS: Method 1, 2.54 min, MS: ES+ 323.4 (M-56).

Steps b-c. The title compound was synthesised using the above intermediate following a ure similar to steps c-d of Example 1. LCMS: Method 2, 4.23 min, MS: ES+ 304.3, 1H NMR (400 MHz, DMSO-d6) 5 ppm 10.45 (s, 1 H), 7.57 - 7.59 (m, 2 H), 7.45 - 7.49 (m, 2 H), 7.35 - 7.39 (m, 1 H), 7.25 - 7.28 (m, 2 H), 7.14 (d, J=1.6 Hz, 1 H), 3.71 (d, J=9.6 Hz, 1 H), 3.52 - 3.57 (m, 1 H), 3.40 - 3.46 (m, 1 H), 3.26 (d, J=10.0 Hz, 1 H), 3.07 (d, J=16.0 Hz, 1 H), 2.95 (d, J=16.0 Hz, 1 H), 2.03 - 2.09 (m, 1H), 1.77 - 1.84 (m, 1 H).

Example 5 7'-(5-Is0pr0pylmethoxyphenyl)-2 1 ', 4 '-dihydr0-2 'H—spiro[pyrr01idine-3,3'- quinoline]-1 -carb0nim'le sis according to Scheme 2 Step a. To a on of tert-butyl 7'-bromo-2'—oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'- quinoline]—1-carboxylate (Intermediate B, 0.2mmol), (5-isopropylmethoxyphenyl)boronic acid (0.2 mmol) and Cs2C03 (0.6 mmol, 3eq) in 1,4-dioxane (1 ml) and water (0.2 ml) were added Pd(PPh3)4 (0.2 eq) at rt under nitrogen. The reaction mixture was stirred at 100°C for 16h. The resulting mixture was concentrated under reduced pressure. The resulting residue was d by prep-TLC (PE/EtOAc=1: 1) yielding tert-butyl 7'—(5 -isopropylmethoxyphenyl)-2'-oxo-2',4'-dihydro- 1'H-spiro [pyrrolidine-3 ,3 '-quinoline] - 1 xylate.

Step b. To a solution of tert-butyl 7'-(5-isopropylmethoxyphenyl)-2'-oxo-2',4'-dihydro-1'H- spiro[pyrrolidine-3,3'-quinoline]carboxylate in EtOAc (1 ml) was added HCl/EtOAc (4 M, 1 ml).

The reaction e was d at rt for 2h. The resulting mixture was concentrated under reduced pressure. The residue 7'—(5-isopropylmethoxyphenyl)-1'H-spiro[pyrrolidine-3,3'-quinolin]-2'(4'H)- one was used for next step directly without filI'tl’lCl‘ purification.

Step c. To a solution of 7'-(5-isopropylmethoxyphenyl)-1'H-spiro[pyrrolidine-3,3'-quinolin]- 2'(4'H)-one in EtOH (2 ml) was added cyanogen bromide (0.2 mmol) and NaHC03 (0.6 mmol). The reaction mixture was stirred at rt for 16h. The resulting mixture was concentrated under reduced pressure. The crude was purified by preparative reverse phase HPLC (A: 0.078% CH3COONH4 in water, B: MeCN) to get 7'-(5-isopropylmethoxyphenyl)-2'-oxo-2',4'-dihydro-1'H-spiro[pyrrolidine- 3,3'-quinoline]—1-carbonitrile (37.25mg, 99.2 umol). LCMS: Method 8, 3.353 min, MS: ES+ 376.1.

Compounds in Table 2 were synthesised using a procedure r to that bed for Example 5.

Table 2 Boronic acid LCMS MS Example R Name RT CAS method ES+ (min) Number 7’-([1 1 ’-Biphenyl]yl)-2’- Ph , , , . , 6 0x9'1’4'd’hzvdm'2H, 51221 11 2.862 380.1 Sp1r0[pyrrolldme-3,3 - ine]-1 -carb0nitrile 301d. LCMS MS Example R Name RT CAS method ES+ (mm).

Number 7’-(4-(Benzyloxy)phenyl)-2 ’- Ph 0 V 0x0-1’,4’-dihydr0-2’H— 146631- 7 11 2 835 410 1 Spir0[pyrrolidine-3, 3 ’- 00-7 ' ' ‘ quinoline]-1 -carb0nitrile 7’-(2-Flu0r0methylpheny0- gF 2’-0x0-1 ’, 4 ’-dihydro-2 ’H— 166328- 8 8 3214 3361 spiro[pyrrolidine-3,3’- 16-1 ‘ quinoline]-1 nitrile 7’-(3-Cyan0phenyl)-2 ’-0x0- 1 ’, 4 ’-dihydr0-2 ’H— 1072945- 9 p 8 2761 329 \ Spir0[pyrrolidine-3,3 ’- 82-4 N / quinoline]-1 -carb0nitrile / 7’-(1-Methyl-1H—pyrazol N ‘ N yl)-2 1 ’, 4 dro-2 ’H— 847818- <7L \ 10 2'59 308'1 Spir0[pyrrolidine-3,3 ’- 74-0 ‘ quinoline]-1 -carb0nitrile 2’-Ox0-7’-(4-phen0)qyphenyl)- Ph/ 1 ’, 4 ’-dihydr0-2 ’H— 38- 11 \(:L 11 2848 3961 spiro[pyrrolidine-3,3’- 0 ‘ quinoline]-1 -carb0nitrile 7’-(1-Methyl-1H—pyrazol y 0x0-1’4’-d'h dl y r0-2’H— 1022151- 12 "N;\, , 10 2567 308'1 spiro[pyrrolidine-3,3’- 50-3 quinoline]-1 -carb0nitrile N 7’-(4-Cyan0phenyl)-2 ’-0x0- 1 ’, 4 ’-dihydr0-2 ’H— 126747- 13 8 2974 329'1 Spir0[pyrrolidine-3,3 ’- 14-6 \ quinoline]-1 -carb0nitrile 7’-(2-Chloro CI (trifluoromethow)phenyl)-2’- 1022922_ 14 0x0-1’,4’-dihydr0-2’H— 11 3.133 422.1 F3C 16-2 \O \ \ Spir0[pyrrolidine-3,3 ’- quinoline]-1 -carb0nitrile O 5-(1-Cyan0-2’-0x0-1 ’,4 ’- dihydro-2 ’H— \N N\ 1006876' spir0[pyrrolidine-3,3 '— 10 2.615 362.1 H I qumolmj-7 -yl)-N—. . 27-2 \ methylpicolinamide 7’-(2-(Benzyloxy)phenyl)-2 ’- <10 Ph V 0x0-1’,4’-dihydr0-2’H— 190661- 16 11 3'104 410'1 spiro[pyrrolidine-3,3’- 29-1 ‘ quinoline]-1 -carb0nitrile O 4-(1-Cyan0-2’-0x0-1 ’,4 ’- dihydro-2 ’H— 17 \N Spir0[pyrrolidine-3,3 ’- 8 2.702 361 H quinolin]-7’-yl)-N— \ methylbenzamide 7'-(3-((2- Q ChlorobenzyDomdphenyDJ’- 84555 1_ 18 \ 0x0-1’,4’-dihydr0-2’H— 11 3.244 444.1 Spir0[pyrrolidine-3, 3 ’- quinoline]-1 -carb0nitrile Boronic acid LCMS MS Example R Name RT CAS method ES+ Number \Nfi 7’-(7-(Z-Melth§{plper;12212-I-"p my)‘ ""0" ' ’ 229009- 19 K/N dihydro-2 ’H— 8 2.492 402.2 . . . 40-9 Sp1r0[pyrrolldme-3,3 -, ‘ quinoline]-1 nitrile 7’-(6—Meth0xypyridinyl)-2 ’- M Oe N \ ,4’-dihydr0-2’H— 13472 I 8 2 875 335 1 ' ' / Spir0[pyrrolidine-3,3 ’- 2 ‘ quinoline]-1 nitrile 7’-(5-F[Moro O isopropowphenyD-Z-oxo- 480438- 21 1’,4’-dihydr0-2’H— 8 3 .271 380.1 . . . 63-9 F \ Sp1r0[pyrrolldme-3,3 -, quinoline]-1 -carb0nitrile [/V‘NH 7’-(3-Methyl-1H—indazol-6—yl)- 2’-0x0-1 ’, 4 ’-dihydro-2 ’H— 1245816- 22 8 2853 358'1 Spir0[pyrrolidine-3,3 ’- 26-5 \ quinoline]-1 -carb0nitrile 7’-(4-(4-Methylpiperazine-1 - carbonyl)phenyD-2 ’-0x0-1 ’, 4 ’- 8321 14_ 23 (\N dihydro-2’H— 8 2.148 430 Spir0[pyrrolidine-3,3 ’- / \ \ quinoline]-1 -carb0nitrile N— 7’-(1-Methyl-1H—indazolyl)- /N -1’,4’-dihydr0-2H— 590418- 24 8 2688 358 pyrrolidine-3,3 ’- 08-9 \ quinoline]-1 -carb0nitrile 7’-(5-Methyl-1H—indazolyl)- 2’-0x0-1 ’, 4 ’-dihydro-2 ’H— 1245816- 8 2'87 358'1 Spir0[pyrrolidine-3,3 ’- 10-7 quinoline]-1 -carb0nitrile N—(3-(1-Cyan0-2’-0x0-1’,4’- dihydro-2 ’H— Spir0[pyrrolidine-3,3 ’- 1072945- 26 8 2.486 423 ("1171011."ij 67-5 prhenyl)cyclopropanesulfon amide 7’-(3-Methyl-1H—pyrazol , yl)-2’-0x0-1’,4’-dihydro-2’H— 936250- 27 10 2045 308 / pyrrolidine-3,3 ’- 20-3 ‘ quinoline]-1 -carb0nitrile 2 ’-Ox0-7’-(pyrimidinyl)- 28 f \ .1’4 "wk/V734 1:3, pyrr0 1 me- 1.921 306 - 107982? N / - ‘ quinoline]-1 -carb0nitrile N—(3-(1-Cyan0-2’-0x0-1’,4’- O dihydro-2 ’H— 29 )L O\\ Spir0[pyrrolidine-3, 3 ’- 5201303?- 8 2.278 361 quinolin]-7’- prhenyDacetamide Boronic 301d. LCMS MS Example R Name RT CAS method ES+ Number 3-(1-Cyan0-2’-0x0-1 ’,4 ’- I dihydro-2 ’H— /N \ Spir0[pyrrolidine-3,3 ’- 371343124_ 10 2.291 375 quinolin]-7’-yl)-N,N— O dimethylbenzamide N—(4-(1-Cyan0-2’-0x0-1’,4’- N dihydro-2 ’H— 31 \n/ 101251 spiro[pyrrolidine-3,3’- 8 2.459 361 . . 09-6 0 \ qumolmj-7 -, prhenyl)acetamide 7"(4' \\ I, linosulfonybphenyb- 32 furs 2’-0x0-1’,4’-dihydro-2H— 4:681? 8 2.701 453 0d \ Spir0[pyrrolidine-3,3 ’- quinoline]-1 -carb0nitrile N\ 7’-(3, 5-Dimethyl-1H—pyrazol- HNI 4-yl)-2’-0x0-1 ’,4 ’-dihydr0-2 ’H— 857530-

Claims (17)

1. A compound of formula I: (I) 5 a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein: R 1a, R1b, R1c , R 1d , R 1e and R1f each represent hydrogen; ring A is a 5 to 11-membered monocyclic or bicyclic heterocyclyl ring, which in addition to 10 the amide nitrogen optionally comprises 1, 2 or 3 heteroatoms each independently selected from N, O and S; wherein, when ring A is bicyclic, the ring fused to the amide-containing ring is aromatic; and which may be optionally substituted with one -Q 1 -(R2 )n wherein n is 1; and optionally one, two or three -Q 1 -(R2 )n, wherein n is 0; wherein each -Q 1 -(R2 )n is the same or different; when n is 0, Q1 represents halogen, cyano, oxo, hydroxyl, -NR3R 4 , -CONR3R 4 , -NR3COR4 15 , - NR3CONR4R 4a , -COR3 , -C(O)OR3 , -C1-C6 alkyl, or -C1-C6 alkoxy; wherein the alkyl and alkoxy groups are optionally substituted with one to four halogen substituents; when n is 1, Q1 represents a covalent bond, an oxygen atom, a sulphur atom, -SO-, -SO2-, - CO-, -C(O)O-, -CONR3 -, -NR3 -, -NR3CO-, -NR3CONR4 -, SO2NR3 -, -NR3SO2-, - NR3SO2NR4 -, -NR3C(O)O-, -NR3C(O)OR5 20 -, C1-C6 alkylene, or -C2-C6 alkenylene; R 2 represents a phenyl ring or a a 5 to 10-membered heterocyclyl or heteroaryl ring, wherein said heterocyclyl and heteroaryl rings comprise 1, 2 or 3 heteroatoms, each independently selected from N, O and S; wherein said R2 ring is optionally substituted with one to two substituents independently selected from halogen, cyano, oxo, hydroxyl, -NR6R 7 , -CONR6R 7 , -NR6COR7 , -NR6CONR7R 7a , -COR6 , -C(O)OR6 , -C1-C6 alkyl, -C1-C6 alkoxy, -Q 2a -R 8 , -Q 2b 25 - CONR6 -Q 2c -R 8 , and –Q 2 -NR6SO2-Q 2c -R 8 ; wherein the alkyl and alkoxy groups are optionally substituted with one to four substituents selected from halogen and hydroxyl;Q 2a represents a covalent bond, an oxygen atom, a sulphur atom, -SO-, -SO2-, -CO-, or C1-C6 alkylene; 108 Q 2b and Q2c each represent a covalent bond; R 3 , R4 and R4a each independently represent hydrogen or C1-C6 alkyl; R 6 , R7 and R7a each independently represent hydrogen or C1-C6 alkyl; R 8 is selected from phenyl, piperazinyl, cyclopropyl, morpholinyl and piperidinyl; wherein R8 5 is optionally substituted by fluorine, chlorine, oxo, cyano, C1-C3 alkyl, or C1-C3 alkoxy.

2. The compound according to claim 1, wherein ring A is a 9, 10, or 11-membered fused bicyclic heterocyclyl ring. 10 3. The compound according to claim 2, wherein ring A is selected from indolineone,

3. ,4-dihydroquinolin-2(1H)-one, 1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one, 3,4- dihydropyrido[2,3-b]pyrazine-2(1H)-one, 1,5-dihydrobenzo[e][1,4]oxazepin-2(3H)-one, 3,4- dihydro-1,5-naphthyridin-2(1H)-one, 3,4-dihydro-1,6-naphthyridin-2(1H)-one, 3,4-dihydro1,7-naphthyridin-2(1H)-one, 3,4-dihydro-1,8-naphthyridin-2(1H)-one, 3,4- 15 dihydropyrazino[2,3-b]pyrazine-2(1H)-one and 1,2,3,5-tetrahydro-4H-pyrido[2,3- b][1,4]diazepinone.

4. The compound according to claim 1, wherein ring A is a 5 or 6-membered monocyclic heterocyclyl ring. 20

5. The compound according to claim 4, wherein ring A is selected from piperidinone, piperazineone and pyrrolidinone.

6. The compound according to claim 1, wherein n is 1; and Q 1 is selected from a 25 covalent bond and C1-C3 alkylene.

7. The compound according to claim 1, wherein R2 is optionally substituted phenyl, or a 5 or 6-membered monocyclic, or a 9 or 10-membered bicyclic, optionally substituted, heterocyclyl or heteroaryl ring. 30

8. The compound according to claim 7, wherein R2 is selected from optionally substituted piperidinyl, pyrrolyl, phenyl, pyrazolyl, isoxazolyl, indazolyl, pyridinyl, dihydropyridinyl, benzothiazolyl and pyrimidinyl. 109

9. The compound according to claim 1, wherein R2 is unsubstituted, or substituted with one or two substituents selected from halogen, cyano, oxo, C1-C3 alkyl, C1-C3 alkoxy, - CONR6R 7 , -NR6COR7 , -Q 2a -R 8 , and -Q 2b -NR6SO2-Q 2c -R 8 ; wherein alkyl and alkoxy are 5 optionally substituted with fluorine; Q 2a is a covalent bond, an oxygen atom, -CO-, -SO2- or -C1-C3 alkylene; and R 6 and R7 are each independently selected from hydrogen and C1-C3 alkyl.

10. The compound according to claim 1, wherein n is 0; Q1 is selected from oxo, methyl, ethyl, CF3, methoxy, halogen and -C(O)NR3R 4 ; and R3 and R4 10 are each independently selected from hydrogen and methyl.

11. The compound according to claim 1 selected from the group consisting of: 2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline]carbonitrile; 15 7'-chloro-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline]carbonitrile; 7'-methoxy-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline]carbonitrile; 7'-(5-isopropylmethoxyphenyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline]- 1-carbonitrile; 7'-([1,1'-biphenyl]yl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline] 20 carbonitrile; 7'-(4-(benzyloxy)phenyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline] carbonitrile; 7'-(2-fluoromethylphenyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline] carbonitrile; 25 7'-(3-cyanophenyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline]carbonitrile; 7'-(1-methyl-1H-pyrazolyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline] carbonitrile; 2'-oxo-7'-(4-phenoxyphenyl)-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline] carbonitrile; 30 7'-(1-methyl-1H-pyrazolyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline] carbonitrile; 7'-(4-cyanophenyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline]carbonitrile; 7'-(2-chloro(trifluoromethoxy)phenyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'- quinoline]carbonitrile; 110 5-(1-cyano-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinolin]-7'-yl)-Nmethylpicolinamide; 7'-(2-(benzyloxy)phenyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline] carbonitrile; 5 4-(1-cyano-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinolin]-7'-yl)-Nmethylbenzamide; 7'-(3-((2-chlorobenzyl)oxy)phenyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'- quinoline]carbonitrile; 7'-(4-(4-methylpiperazinyl)phenyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'- 10 quinoline]carbonitrile; 7'-(6-methoxypyridinyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline] carbonitrile; 7'-(5-fluoroisopropoxyphenyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline]- 1-carbonitrile; 15 7'-(3-methyl-1H-indazolyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline] carbonitrile; 7'-(4-(4-methylpiperazinecarbonyl)phenyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'- quinoline]carbonitrile; 7'-(1-methyl-1H-indazolyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline] 20 carbonitrile; 7'-(5-methyl-1H-indazolyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline] carbonitrile; N-(3-(1-cyano-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinolin]-7'- yl)phenyl)cyclopropanesulfonamide; 25 7'-(3-methyl-1H-pyrazolyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline] carbonitrile; 2'-oxo-7'-(pyrimidinyl)-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline]carbonitrile; N-(3-(1-cyano-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinolin]-7'- yl)phenyl)acetamide; 30 3-(1-cyano-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinolin]-7'-yl)-N,Ndimethylbenzamide; N-(4-(1-cyano-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinolin]-7'- yl)phenyl)acetamide; 111 7'-(4-(morpholinosulfonyl)phenyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline]- 1-carbonitrile; 7'-(3,5-dimethyl-1H-pyrazolyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline]- 1-carbonitrile; 5 7'-(2-methylpyridinyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline] carbonitrile; 2'-oxo-7'-(3-(piperidinyl)phenyl)-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline] carbonitrile; N-(2-(1-cyano-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinolin]-7'- 10 yl)phenyl)acetamide; 7'-(4-(morpholinecarbonyl)phenyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'- quinoline]carbonitrile; 7'-(3-(morpholinosulfonyl)phenyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline]- 1-carbonitrile; 15 7'-(1-methyloxo-1,6-dihydropyridinyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'- quinoline]carbonitrile; 7'-(2-methylbenzo[d]thiazolyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline]- 1-carbonitrile; 2'-oxo-6'-phenyl-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline]carbonitrile; 20 6'-(4-cyanophenyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline]carbonitrile; 6'-(3-cyanophenyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline]carbonitrile; 6'-(4-fluorophenyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline]carbonitrile; 6'-(3-fluorophenyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline]carbonitrile; 1-cyano-N,N-dimethyl-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline]-7'- 25 carboxamide; 1-cyano-N-methyl-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline]-7'-carboxamide; 2-oxo-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3'-pyrrolidine]-1'-carbonitrile; 2-oxophenyl-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3'-pyrrolidine]-1'-carbonitrile; 7-(4-cyanophenyl)oxo-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3'-pyrrolidine]-1'- 30 carbonitrile; 7-(3-cyanophenyl)oxo-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3'-pyrrolidine]-1'- carbonitrile; 7-(4-fluorophenyl)oxo-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3'-pyrrolidine]-1'- carbonitrile; 112 7-(3-fluorophenyl)oxo-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3'-pyrrolidine]-1'- carbonitrile; 2-oxophenyl-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3'-pyrrolidine]-1'-carbonitrile; 2-oxo-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1'-carbonitrile; 5 2-oxo(trifluoromethyl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1'- carbonitrile; 2-oxophenyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1'-carbonitrile; 7-(4-cyanophenyl)oxo-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1'- carbonitrile; 10 7-(4-fluorophenyl)oxo-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1'- carbonitrile; 7-(3-fluorophenyl)-;2-oxo-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1'- carbonitrile; 3-oxo-3,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-2,3'-pyrrolidine]-1'-carbonitrile; 15 6-oxo-2,7-diazaspiro[4.4]nonanecarbonitrile; (R)oxo-2,7-diazaspiro[4.4]nonanecarbonitrile; (S)oxophenyl-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3'-pyrrolidine]-1'- carbonitrile; (S)oxo-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3'-pyrrolidine]-1'-carbonitrile; 20 (S)oxo-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1'-carbonitrile; (R)-2'-oxo-6'-phenyl-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline]carbonitrile; (S)oxophenyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1'- carbonitrile; (S)(3-fluorophenyl)oxo-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3'-pyrrolidine]- 25 1'-carbonitrile; (S)(4-cyanophenyl)oxo-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3'-pyrrolidine]- 1'-carbonitrile; (S)(3-cyanophenyl)oxo-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3'-pyrrolidine]- 1'-carbonitrile; 30 (S)(4-fluorophenyl)oxo-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]- 1'-carbonitrile; (S)(3-fluorophenyl)oxo-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]- 1'-carbonitrile; 113 (S)(4-fluorophenyl)oxo-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3'-pyrrolidine]- 1'-carbonitrile; (S)(3-cyanophenyl)oxo-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]- 1'-carbonitrile; 5 (8R)methyl-7,10-dioxo-2,6,9-triazaspiro[4.5]decanecarbonitrile; 7,10-dioxo-2,6,9-triazaspiro[4.5]decanecarbonitrile; (8S)methyl-7,10-dioxo-2,6,9-triazaspiro[4.5]decanecarbonitrile; 7,10-dioxophenyl-2,6,9-triazaspiro[4.5]decanecarbonitrile; 8-ethyloxo-2,7-diazaspiro[4.4]nonanecarbonitrile; 10 8-benzyloxo-2,7-diazaspiro[4.4]nonanecarbonitrile; 8-methyloxo-2,7-diazaspiro[4.4]nonanecarbonitrile; 2-oxo-1,5-dihydro-2H-spiro[benzo[e][1,4]oxazepine-3,3'-pyrrolidine]-1'-carbonitrile; 2-oxo-1,2,4,5-tetrahydrospiro[pyrido[2,3-b][1,4]diazepine-3,3'-pyrrolidine]-1'-carbonitrile; 8-methyl-7,10-dioxophenyl-2,6,9-triazaspiro[4.5]decanecarbonitrile; 15 2-oxophenyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'-pyrrolidine]-1'-carbonitrile; 7-(5-methyl-1H-indazolyl)oxo-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'- pyrrolidine]-1'-carbonitrile; 7-(1,4-dimethyl-1H-pyrazolyl)oxo-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3'- pyrrolidine]-1'-carbonitrile; 20 (R)-7'-(5-methyl-1H-indazolyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline]- 1-carbonitrile; (R)-7'-(4-(4-methylpiperazinyl)phenyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'- quinoline]carbonitrile; 7'-(1H-indazolyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline]carbonitrile; 25 6'-(1H-indazolyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline]carbonitrile; (R)-7'-(1H-indazolyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline] carbonitrile; (S)-7'-(1H-indazolyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline] carbonitrile; 30 (R)-6'-(1H-indazolyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline] carbonitrile; 1'-cyano-N-(4-fluorophenyl)oxo-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3'- pyrrolidine]carboxamide; 114 2-oxo(piperidinecarbonyl)-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3'- pyrrolidine]-1'-carbonitrile; 7-(1H-indazolyl)oxo-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3'-pyrrolidine]-1'- carbonitrile; 5 6-(1H-indazolyl)oxo-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3'-pyrrolidine]-1'- carbonitrile; (S)(1H-indazolyl)oxo-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3'-pyrrolidine]- 1'-carbonitrile; (S)(1H-indazolyl)oxo-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3'-pyrrolidine]- 10 1'-carbonitrile; (S)-1'-cyano-N-(4-fluorophenyl)oxo-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3'- pyrrolidine]carboxamide; 1'-cyanooxo-N-phenyl-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3'-pyrrolidine] carboxamide; 15 1'-cyano-N-(2-fluorophenyl)oxo-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3'- pyrrolidine]carboxamide; 7-(1-methyl-1H-indazolyl)oxo-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3'- pyrrolidine]-1'-carbonitrile; (R)(1-methyl-1H-indazolyl)oxo-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3'- 20 pyrrolidine]-1'-carbonitrile; (S)(1-methyl-1H-indazolyl)oxo-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3'- pyrrolidine]-1'-carbonitrile; 7-(1-(2-hydroxyethyl)-1H-indazolyl)oxo-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine3,3'-pyrrolidine]-1'-carbonitrile; 25 (R)(1-(2-hydroxyethyl)-1H-indazolyl)oxo-1,2-dihydrospiro[pyrido[2,3- b][1,4]oxazine-3,3'-pyrrolidine]-1'-carbonitrile; (S)(1-(2-hydroxyethyl)-1H-indazolyl)oxo-1,2-dihydrospiro[pyrido[2,3- b][1,4]oxazine-3,3'-pyrrolidine]-1'-carbonitrile; 7-(1-(2-methoxyethyl)-1H-indazolyl)oxo-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine30 3,3'-pyrrolidine]-1'-carbonitrile; (R)(1-(2-methoxyethyl)-1H-indazolyl)oxo-1,2-dihydrospiro[pyrido[2,3- b][1,4]oxazine-3,3'-pyrrolidine]-1'-carbonitrile; (S)(1-(2-methoxyethyl)-1H-indazolyl)oxo-1,2-dihydrospiro[pyrido[2,3- b][1,4]oxazine-3,3'-pyrrolidine]-1'-carbonitrile; 115 7-(6-methoxymethylpyridinyl)oxo-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3'- pyrrolidine]-1'-carbonitrile; (R)(6-methoxymethylpyridinyl)oxo-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine3,3'-pyrrolidine]-1'-carbonitrile; 5 (S)(6-methoxymethylpyridinyl)oxo-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine3,3'-pyrrolidine]-1'-carbonitrile; 2'-oxo-7'-(3-(trifluoromethoxy)phenyl)-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline] carbonitrile; 4-(1-cyano-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinolin]-7'-yl)-N,N10 dimethylbenzamide; 7'-(3-(4-methylpiperazinecarbonyl)phenyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'- quinoline]carbonitrile; 7'-(1-methyl-1H-pyrrolyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline] carbonitrile; 15 6'-([1,1'-biphenyl]yl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline] carbonitrile; 6'-(4-(benzyloxy)phenyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline] carbonitrile; 6'-(1-methyl-1H-pyrazolyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline] 20 carbonitrile; 2'-oxo-6'-(3-(trifluoromethoxy)phenyl)-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline] carbonitrile; 2'-oxo-6'-(4-phenoxyphenyl)-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline] carbonitrile; 25 6'-(1-methyl-1H-pyrazolyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline] carbonitrile; 5-(1-cyano-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinolin]-6'-yl)-Nmethylpicolinamide; 6'-(2-(benzyloxy)phenyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline] 30 carbonitrile; 4-(1-cyano-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinolin]-6'-yl)-Nmethylbenzamide; 6'-(5-isopropylmethoxyphenyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline]- 1-carbonitrile; 116 6'-(3-((2-chlorobenzyl)oxy)phenyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'- quinoline]carbonitrile; 6'-(6-methoxypyridinyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline] carbonitrile; 5 6'-(5-fluoroisopropoxyphenyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline]- 1-carbonitrile; 6'-(3-methyl-1H-indazolyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline] carbonitrile; 6'-(4-(4-methylpiperazinecarbonyl)phenyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'- 10 quinoline]carbonitrile; 6'-(1-methyl-1H-indazolyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline] carbonitrile; 6'-(5-methyl-1H-indazolyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline] carbonitrile; 15 N-(3-(1-cyano-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinolin]-6'- yl)phenyl)cyclopropanesulfonamide; 4-(1-cyano-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinolin]-6'-yl)-N,Ndimethylbenzamide; 2'-oxo-6'-(pyrimidinyl)-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline]carbonitrile; 20 N-(3-(1-cyano-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinolin]-6'- yl)phenyl)acetamide; N-(4-(1-cyano-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinolin]-6'- yl)phenyl)acetamide; 6'-(3-(4-methylpiperazinecarbonyl)phenyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'- 25 quinoline]carbonitrile; 6'-(1-methyl-1H-pyrrolyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline] carbonitrile; 6'-(4-(morpholinosulfonyl)phenyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline]- 1-carbonitrile; 30 6'-(3,5-dimethyl-1H-pyrazolyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline]- 1-carbonitrile; 2'-oxo-6'-(3-(piperidinyl)phenyl)-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline] carbonitrile; 117 N-(2-(1-cyano-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinolin]-6'- yl)phenyl)acetamide; 6'-(4-(morpholinecarbonyl)phenyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'- quinoline]carbonitrile; 5 6'-(3-(morpholinosulfonyl)phenyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline]- 1-carbonitrile; 6'-(1-methyloxo-1,6-dihydropyridinyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'- quinoline]carbonitrile; 6'-(2-methylbenzo[d]thiazolyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline]- 10 1-carbonitrile; 6'-(3,5-dimethylisoxazolyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline] carbonitrile; 6'-(2-chloro(trifluoromethoxy)phenyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'- quinoline]carbonitrile; 15 6'-(4-(4-methylpiperazinyl)phenyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'- quinoline]carbonitrile; N-benzyl(1-cyano-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinolin]-6'- yl)benzamide; 6'-(3-methyl-1H-pyrazolyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline] 20 carbonitrile; 6'-(4-(morpholinomethyl)phenyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline]- 1-carbonitrile; 3-(1-cyano-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinolin]-6'-yl)-N,Ndimethylbenzamide; and 25 6'-(2-methylpyridinyl)-2'-oxo-1',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline] carbonitrile; a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.

12. Use of the compound, the tautomer thereof, or a pharmaceutically acceptable salt of 30 said compound or tautomer according to any one of claims 1 to 11 in the manufacture of a medicament for the treatment of cancer linked to Cezanne 1 activity.

13. The use according to claim 12, wherein the cancer is selected from breast, ovarian, prostate, lung, kidney, gastric, colon, testicular, head and neck, pancreas, brain, melanoma, 118 bone, cancers of tissue organs, cancers of the blood cells, leukaemia, lymphoma, multiple myeloma, colorectal cancer, and non-small cell lung carcinoma.

14. Use of the compound, the tautomer thereof, or a pharmaceutically acceptable salt of 5 said compound or tautomer according to any one of claims 1 to 11 in the manufacture of a medicament for the treatment of inflammation.

15. Use of the compound, the tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer according to any one of claims 1 to 11 in the manufacture of a 10 medicament for the treatment of a condition involving mitochondrial dysfunction.

16. The use according to claim 15, wherein the condition involving mitochondrial dysfunction is selected from a CNS disorder; neurodegenerative disease; Parkinson’s disease; Alzheimer’s disease; amyotrophic lateral sclerosis; Huntington’s disease; ischemia; stroke; 15 dementia with Lewy bodies; frontotemporal dementia; multiple sclerosis; mitochondrial encephalopathy, lactic acidosis and stroke-like episodes syndrome; Leber's hereditary optic neuropathy; cancer; neuropathy, ataxia, retinitis pigmentosa-maternally inherited Leigh syndrome; Danon disease; diabetes; diabetic nephropathy; metabolic disorders; heart failure; ischemic heart disease leading to myocardial infarction; psychiatric diseases, schizophrenia; 20 multiple sulfatase deficiency; mucolipidosis II; mucolipidosis III; mucolipidosis IV; GMlgangliosidosis; neuronal ceroid-lipofuscinoses; Alpers disease; Barth syndrome; Betaoxidation defects; carnitine-acyl-carnitine deficiency; carnitine deficiency; creatine deficiency syndromes; co-enzyme Q10 deficiency; complex I deficiency; complex II deficiency; complex III deficiency; complex IV deficiency; complex V deficiency; COX 25 deficiency; chronic progressive external ophthalmoplegia syndrome; CPT I deficiency; CPT II deficiency; glutaric aciduria type II; Kearns-Sayre syndrome; lactic acidosis; long-chain acyl-CoA dehydrogenase deficiency; Leigh disease or syndrome; lethal infantile cardiomyopathy; Luft disease; medium-chain acyl-CoA dehydrogenase deficiency; myoclonic epilepsy and ragged-red fiber syndrome; mitochondrial cytopathy; mitochondrial 30 recessive ataxia syndrome; mitochondrial DNA depletion syndrome; myoneurogastrointestinal disorder and encephalopathy; Pearson syndrome; pyruvate dehydrogenase deficiency; pyruvate carboxylase deficiency; POLG mutations; medium/short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency; very long-chain acyl- 119 CoA dehydrogenase deficiency; and age-dependent decline in cognitive function and muscle strength.

17. A pharmaceutical composition comprising the compound, the tautomer thereof, or a 5 pharmaceutically acceptable salt of said compound or tautomer according to any one of claims 1 to 11, together with one or more pharmaceutically acceptable excipients.