Deuterated PARP1 inhibitor compounds

Abstract

A compound according to formula (I), wherein Z1, Z2 and Z3 are C or N, R1 and R2 either together form an optionally substituted 5- or 6-membered ring or are each independently absent or selected from

Description

Technical Field The present invention relates to PARP1 inhibitor compounds, and in particular to PARP1 inhibitor compounds for use in medicine. The inhibitors of the invention may be used in pharmaceutical compositions, and in particular pharmaceutical compositions for treating a cancer. The invention also relates to methods of manufacture of such inhibitors, and methods of treatment using such inhibitors. Background The family of poly(ADP-ribose) polymerases (PARPs) consists of 17 PARP proteins that catalyse the transfer of ADP-ribose to target proteins, a posttranslational process termed PARylation. Target protein modification by PARylation causes significant changes to function and as such PARPs play an important role in many cellular processes such as chromatin remodelling, transcription, replication, recombination, cell cycle progression and DNA damage repair (Kamaletdinova, T. et al. Cell. 2019; 8: 1625). PARP1 and 2 are the most widely studied PARP enzymes, primarily due to their role in DNA damage repair, in particular in the base excision repair (BER) process of DNA single-strand breaks (Ngoi, YL. et al. Cancer J. 2021; 27: 521-528). PARP1 is activated by DNA damage breaks, and the subsequent PARylation of target proteins leads to recruitment of additional factors that initiate repair of DNA lesions. Auto-PARylation of PARP triggers the release of bound PARP from the DNA allowing other DNA repair proteins access to complete lesion repair. This highlights the critical role PARP plays in enabling a cancer cell to repair DNA damage caused by exogenous agents such as radiation therapy and chemotherapeutic agents. Inhibition of PARP enzymes has been utilised as a strategy to selectively kill cancer cells that harbour genetic defects in complementary DNA damage repair pathways (Farmer, H. et al. Nature. 2005; 434: 917-921). This synthetic lethality approach has been demonstrated successfully in tumours with epigenetic modifications or deleterious mutations in BRCA1 and BRCA2, two functionally redundant tumour suppressor proteins involved in DNA doublestrand break (DSB) repair by homologous recombination (HR) (Lord, CJ. and Ashworth, A. Science. 2017; 355: 1152-1158). Such tumours with HR deficiency (HRD) are dependent on PARP function for survival - following PARP inhibition in these tumours, DSB breaks will be processed by alternative error-prone repair pathways leading to genomic instability and cancer cell death. The inhibition of PARP can trap the inactivated PARP at the sites of DNA damage. This leads to replication fork stalling and subsequent collapse in S-phase when the fork reaches the site of the trapped PARP, resulting in the generation of genotoxic DNA double-strand breaks. It is believed that this PARP1-DNA trapping can lead to the selective death of cancer cells harbouring HRD (Farmer, H. et al. Nature. 2005; 434: 917-921). This strategy has led to the successful approval of several PARP inhibitors for the treatment of cancers with HRD, such as in BRCAl / 2-mutated breast, ovarian and prostate cancer, as well as in ovarian and prostate cancer harbouring genomic consequences of HRD, and ovarian cancer in the maintenance setting where platinum sensitivity acts as a surrogate for HRD (Fong, PC. et al. N. Engl. J. Med. 2009; 361:123-134). It has recently been shown that genomic instability, in the form of unrepaired DNA doublestrand breaks or micronuclei disruption can trigger innate immune system activation via the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS), leading to generation of cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) and induction of dimerization of Stimulator of interferon genes (STING). STING subsequently translocates from the endoplasmic reticulum to the Golgi where it recruits and activates TANK-binding kinase 1 (TBK1). TBK1 phosphorylates interferon regulatory transcription factor 3 (IRF3) which drives the production of type I interferons and supports the induction of an adaptive immune response (Zhu, ¥. etaL Mol. Cancer. 2019,18:152). For example, PARP inhibitor-induced STING pathway activation and anti-tumour immune responses have been demonstrated in multiple tumour models, providing rationale for exploiting combinations of PARP inhibitors with immunotherapies for improved therapeutic efficacy (Sen, T. et al. Cancer Discov. 2019; 9: 646-661). For example, the PARP inhibitor Olaparib was also recently shown to induce synthetic lethal effects in combination with a synthetic cyclic dinucleotide STING agonist in DNA damage repair deficient cancer cells and a BRCA-deficient breast cancer model (Pantelidou, C. et al. 2021: bioRxiv 2021.01.26.428337vl). Overall, modulation of nucleic acid sensing pathways via multiple mechanisms has been shown to promote anti-tumour efficacy in a variety of cell and animal models thus demonstrating therapeutic potential for augmenting efficacy of immunotherapies and overcoming resistance to immune checkpoint blockade through use of PARP inhibitors. There are numerous clinical trials ongoing combining PARP inhibitors with immunotherapies (reviewed in Chabanon, RM, et al. Nat. Rev. Cancer. 2021; 21: 701-717). Recently, PARP1 has also been shown to bind the Epstein Barr Virus (EBV) genome and that PARP1 inhibition can alter EBV chromatin structure and latent gene expression (Morgan, SM. et al. Nat. Commun. 2022; 13:187). Hence, PARP1 inhibitors may play a role in cancers where EBV plays a contributing role such as Burkitt's lymphoma, Hodgkin's lymphoma, nasopharyngeal and gastrointestinal cancers. Interestingly, EBV has also been shown to be a causative factor in multiple sclerosis (MS) whereby EBV infection greatly increases the risk of subsequent MS (Bjornevik, K. et al. Science (2021); 375: 296-301). First-generation PARP inhibitors generally demonstrate non-selective activity at PARP1 and 2. Haematological toxicities such as anaemia, neutropenia and thrombocytopenia are associated with clinical use of these molecules which restricts their use in combination with cytotoxic chemotherapies and other targeted agents due to dose-limiting cytopenias (LaFargue, CJ. et al. Lancet Oncol. 2019, 20, el5-e28). Evidence from pre-clinical mouse studies strongly suggests that PARP2 inhibition is a major driver of these haematological toxicities, with PARP2 being particularly linked to erythrogenesis in mice (Farres, J. et al. Blood. 2013; 122: 44-54). In addition, PARP2 function has been shown to be dispensable for anti-tumour activity in HRD mouse cancer models (Ronson, G E. etal. Nat. Commun. 2018, 9: 746). Taken together, these data suggest an unmet medical need for the development of inhibitors with improved selectivity for PARP1 over PARP2 and other PARPs, thus providing expanded therapeutic utility (1) as single agents and (2) in combination with other anti-cancer agents. To date, two PARPl-selective inhibitors, AZD5305 and AZD9574, have entered clinical development. AZD5305 was described as a potent PARP1 inhibitor and trapper with 500-fold selectivity over PARP2 and less off-target activity against secondary pharmacology targets than first-generation PARP inhibitors (Johannes, JW. et al. J. Med. Chern. 2021; 64: 14498-14512). Importantly, significantly less haematotoxicity was observed for AZD5305 in rodent models than with first-generation PARP inhibitors, confirming the reported pathogenic role of PARP2 in haematologic toxicity (111uzzi, G. et al. Clin. Cancer Res. 2022; CCR-22-0301). Having regard to the above, it is an aim of the present invention to provide PARP1 inhibitors, and in particular PARP1 inhibitors for use in medicine. It is a further aim to provide pharmaceutical compositions comprising such inhibitors, and in particular to provide compoundsand pharmaceutical compositions for treating a cancer. It is also an aim to provide methods of synthesis of the compounds. Summary In one aspect, there is provided a PARP1 inhibitor compound having a structure of: where: A dotted line indicates a bond selected from a single bond and a double bond; Z1, Z2, and Z3 are each independently selected from C and N. Rxand R2: i) together form an optionally-substituted 5- or 6-membered ring; or ii) are each independently absent or selected from H; D; a halogen; a nitrile group; a Cl to C6 alkyl group, optionally a C3 to C6 cycloalkyl group; a Cl to C6 aminoalkyl group; a Cl to C6 alkoxy group; and a Cl to C6 haloaIkyl group; R3 is absent or selected from H, D, a halogen, a Cl to C3 alkyl group, a Cl to C3 haloalkyl group, a Cl to C3 alcohol group, and a Cl to C3 aminoalkyl group; R4 is selected from H, a Cl to C3 alkyl group, and a Cl to C3 haloalkyl group; L has a structure of: R where: each X2 is independently selected from C, N, O and S; each X3 is independently selected from C and N; n is 1 or 2, and m is (3-n); p is selected from 1, 2, and 3, and q is (4-p); r is selected from 1, 2, and 3, and s is (4-r); ring C is an aromatic ring, optionally a heteroaromatic ring; each R5A group is independently: i) absent, with the proviso that ring A is non-aromatic; or ii) a member of a pair of R5A groups which together form a bridging group, the bridging group being selected from a Cl to C6 alkyl group, a Cl to C6 haloalkyl group, a Cl to C6 alcohol group, a Cl to C7 amino carbonyl group, a Cl to C6 amino group, and a Ci-Ce alkoxy group; or iii) selected from H; D; a halogen; a carbonyl group; a nitrile group; a Cl to C6 alkyl group, optionally a C3 to C6 cycloalkyl group; a Cl to C6 haloalkyl group; an -OH group; a Cl to C6 alcohol group; a Cl to C7 amino carbonyl group; an -NH2 group; a Cl to C6 amino group; and a Cl to C6 alkoxy group, optionally an oxetane group; each R5B and R5C is independently absent or selected from: H; D; a halogen; a carbonyl group; a nitrile group; a Cl to C6 alkyl group, optionally a C3 to C6 cycloalkyl group; a Cl to C6 haloalkyl group; an -OH group; a Cl to C6 alcohol group; a Cl to C7 amino carbonyl group; an -NH2 group; a Cl to C6 amino group; and a Cl to C6 alkoxy group, optionally an oxetane group; with the proviso that ring B is non-aromatic. A related aspect provides a PARP1 inhibitor compound as defined herein, for use in medicine. For example, the PARP1 inhibitor compound may be for use in treating cancer. Another aspect provides a pharmaceutical composition comprising a PARP1 inhibitor compound as defined herein. Still another aspect provides a pharmaceutical kit for treating a cancer. The pharmaceutical kit comprises a PARP1 inhibitor compound as defined herein, and a further agent for treating cancer. The PARP1 inhibitor compound and the further agent are suitable for administration simultaneously, sequentially or separately. Also described is a method of treating a disease and / or a condition and / or a disorder, which method comprises administering to a patient a PARP1 inhibitor compound, a composition or a kit as defined herein. This Summary is provided to introduce a selection of concepts in a simplified form that are further described below in the Detailed Description. This Summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used to limit the scope of the claimed subject matter. Nor is the claimed subject matter limited to implementations that solve any or all of the disadvantages noted herein. Detailed Description General Definitions The verb 'to comprise' is used herein as shorthand for 'to include or to consist of'. In other words, although the verb 'to comprise' is intended to be an open term, the replacement of this term with the closed term 'to consist of' is explicitly contemplated, particularly where used in connection with chemical compositions. It will be appreciated that some compounds disclosed herein may be ionisable, i.e. some compounds may be weak acids, weak bases, or ampholytes. Representations of the free forms of ionisable compounds are intended to encompass the corresponding ionised forms, lonisable compounds may be in free form, or in the form of a pharmaceutically-acceptable salt. A compound is considered to be a PARP1 inhibitor if its presence is capable of preventing or reducing the ability of immobilised PARP1 to undergo auto-poly-ADP ribosylation (AutoPARylation) following incubation with biotinylated-NAD+ as compared to the same process in its absence. Typically, the compound is considered to be a PARP1 inhibitor if it has an IC50 <10 pM in a suitable assay. A suitable assay may be conducted using 2 nM PARP1, 2 pM biotin-NAD+ assay solution in 20 mM HEPES (pH 7.5), 100 mM NaCI, 2 mM DTT, 0.1 % BSA (w / v), 0.02 % Tween (v / v) assay buffer. PARylation may take place for 2 h at room temperature and may be detected using a dissociation-enhanced lanthanide fluorescence immunoassay (DELFIA) readout. A particularly suitable assay is described in the Examples below. Preferably, the compound has an IC50 <1 pM, more preferably <100 nM and most preferably <10 nM in the PARP1 inhibitor assay. A compound is considered to be a selective PARP1 inhibitor if its presence is capable of displacing or reducing the ability of a high affinity Cy5 fluorescent dye-labelled chemical probe to bind to PARP1 whilst displacing the same chemical probe at PARP2 with at least 10-fold weaker activity. Typically, the compound is considered to be a selective PARP1 inhibitor if it has an IC50 <10 pM in this assay at PARP1 with at least 10-fold selectivity preference over PARP2. A suitable such assay may be conducted for 1 h at room temperature using 10 nM PARP1 or PARP2, Tb-cryptate antibody and PARP1 / 2 binding probe in 20 mM HEPES (pH 7.5), 100 mM NaCI, 2 mM DTT, 0.1 % BSA (w / v), 0.02 % Tween (v / v) assay buffer. Probe binding displacement may be detected using homogeneous time-resolved fluorescence. A particularly suitable assay is described in the Examples below. Preferably the selectivity preference of PARP1 over PARP2 is at least 50-fold, more preferably at least 100-fold. A compound is also considered to be a selective PARP1 inhibitor if it has an IC50 <10 pM at PARP1 with at least 10-fold selectivity preference over PARP2 in NanoBRET assays demonstrating cellular target engagement. These assays are based on bioluminescence resonance energy transfer (BRET) between a Nano-luc-tagged protein (e.g. PARP1 or PARP2) and a fluorescent group on a high affinity NAD+ competitive binding probe. Such cellular probe displacement assays can be utilised to measure inhibitor affinities and selectivity ratios at PARP1 and 2. A particularly suitable assay is described in the Examples below. Preferably the selectivity preference of PARP1 over PARP2 is at least 50-fold, more preferably at least 100-fold. A dotted line in a structural formula represents a single bond or a double bond. As will be appreciated, systems comprising multiple double bonds may be conjugated or aromatic. Except where the configuration of a particular bond is directly illustrated, all formulae herein are shown in non-stereoisomeric form and are intended to represent all possible stereoisomers of a particular structure, including all possible isolated enantiomers corresponding to the formula, all possible mixtures of enantiomers corresponding to the formula, all possible mixtures of diastereomers corresponding to the formula, all possible mixtures of epimers corresponding to the formula and all possible racemic mixtures corresponding to the formula. In addition to this, all formulae herein are intended to represent all tautomeric forms equivalent to the corresponding formula. The term "aliphatic ring" is used herein in the broad sense of a non-aromatic ring. An aliphatic ring may be carbocylic or heterocyclic, and may be substituted or unsubstituted. Substituent R groups may, where appropriate, be linear, branched, cyclic, or may include a combination of linear or branched portion(s) and cyclic portion(s). For instance, examples of C4 alkyl groups include a linear butyl group; a t-butyl group; a cyclobutyl group; and Compound numbering Various ones of the compounds provided herein are enantiomeric or diastereomeric. Where a suffix is applied to a compound number, the suffix indicates stereochemistry. A compound number without a suffix denotes a compound having the indicated structural formula without defining stereochemistry. The suffix 'rac' denotes a racemic mixture. The suffix 'a' denotes an enantiomer eluted as a first fraction when a mixture of two enantiomers is separated by supercritical fluid chromatography ("SFC") using a chiral column. The suffix 'b' denotes an enantiomer eluted as a second fraction when a mixture of two enantiomers is separated by supercritical fluid chromatography ("SFC") using a chiral column. The suffix 'S' denotes an S-enantiomer, and the suffix 'R' denotes an R-enantiomer. Discussion Provided herein are PARP1 inhibitor compounds having a structure of: "Head group" where: a dotted line indicates a bond selected from a single bond and a double bond; Z1, Z2, and Z3 are each independently selected from C and N; Rxand R2: i) together form an optionally-substituted 5- or 6-membered ring; or ii) are each independently absent or selected from H; D; a halogen; a nitrile group; a Cl to C6 alkyl group, optionally a C3 to C6 cycloalkyl group; a Cl to C6 aminoalkyl group; a Cl to C6 alkoxy group; and a Cl to C6 haloaIkyl group; R3 is absent or selected from H, D, a halogen, a Cl to C3 alkyl group, a Cl to C3 haloalkyl group, a Cl to C3 alcohol group, and a Cl to C3 aminoalkyl group; R4 is selected from H, a Cl to C3 alkyl group, and a Cl to C3 haloalkyl group; each X2 is independently selected from C, N, O and S; each X3 is independently selected from C and N; n is 1 or 2, and m is (3-n); p is selected from 1, 2, and 3, and q is (4-p); r is selected from 1, 2, and 3, and s is (4-r); ring C is an aromatic ring, optionally a heteroaromatic ring; each R5A group is independently: i) absent, with the proviso that ring A is non-aromatic; or ii) a member of a pair of R5A groups which together form a bridging group, the bridging group being selected from a Cl to C6 alkyl group, a Cl to C6 haloalkyl group, a Cl to C6 alcohol group, a Cl to C7 amino carbonyl group, a Cl to C6 amino group, and a Ci-Ce alkoxy group; or iii) selected from H; D; a halogen; a carbonyl group; a nitrile group; a Cl to C6 alkyl group, optionally a C3 to C6 cycloalkyl group; a Cl to C6 haloalkyl group; an -OH group; a Cl to C6 alcohol group; a Cl to C7 amino carbonyl group; an -NH2 group; a Cl to C6 amino group; and a Cl to C6 alkoxy group, optionally an oxetane group; each R5B and R5C is independently absent or selected from: H; D; a halogen; a carbonyl group; a nitrile group; a Cl to C6 alkyl group, optionally a C3 to C6 cycloalkyl group; a Cl to C6 haloalkyl group; an -OH group; a Cl to C6 alcohol group; a Cl to C7 amino carbonyl group; an -NH2 group; a Cl to C6 amino group; and a Cl to C6 alkoxy group, optionally an oxetane group; with the proviso that ring B is non-aromatic. Without wishing to be bound by theory, it is believed that providing the -C(O)NHD3 moiety on ring C of the compound may modify how the compound is metabolised in vivo in comparison with analogous compounds bearing a -C(O)NHC1H3 moiety. Specifically, the stability of the compound with respect to certain metabolic pathways may be improved. Some of the PARP1 inhibitor compounds provided herein include one or more chiral centres. Such compounds may be provided in the form of an isolated enantiomer; a mixture of two or more enantiomers; a mixture of two or more diastereomers or epimers; or a racemic mixture. Some PARP1 inhibitor compounds may be capable of tautomerism. Such compounds may be provided in the form of any possible tautomer. Head group - general The head group of the PARP1 inhibitor compound has a structure of: Z1, Z2, and Z3 are each independently selected from C and N. Optionally, Z1 and Z2 are each C. R1 and R2 may together represent an optionally-substituted 5- or 6- membered ring. In such examples, the head group of the compound is termed a bicyclic head group. Alternatively, R1 and R2 may each independently be absent or selected from H; D; a halogen; a nitrile group; a Cl to C6 alkyl group, optionally a C3 to C6 cycloalkyl group; a Cl to C6 aminoalkyl group; a Cl to C6 alkoxy group; and a Cl to C6 haloalkyl group. In other words, the head group may be monocyclic. The dotted line between Z1 and Z2 may represent a single bond or a double bond, depending upon the selection of Z1, Z2, R1, and R2. Most typically, the dotted line represents a double bond. Z3 may be N. In such variants, R3 is most typically absent. Alternatively, Z3 may be C. In such variants, R3 is present and is selected from H, D, a halogen, a Cl to C3 alkyl group, a Cl to C3 haloalkyl group, a Cl to C3 alcohol group, and a Cl to C3 aminoalkyl group. When R3 is present, R3 is preferably H. R4 is selected from H, a Cl to C3 alkyl group, and a Cl to C3 haloalkyl group. Most preferably, R4is H. Head group - bicyclic variants The head group of the PARP1 inhibitor compound may be bicyclic. In such variants, R1 and R2 together form an optionally-substituted 5- or 6-membered ring D, and the PARP1 inhibitor compound has a structure of: In the above formula: each X1 is independently selected from C, N, O and S, optionally C and N; k is 1 or 2; and each R6 is independently absent or selected from H, D, a halogen, a nitrile group, an OH group, a Cl to C6 alkyl group (optionally a C3 to C6 cycloalkyl group, further optionally a spiro-cyclopropyl group), an -NHz group; a Cl to C6 aminoalkyl group, a Cl to C6 alkoxy group, and a Cl to C6 haloalkyl group. Ring D may be saturated, unsaturated, or aromatic depending upon the X1 atoms and R6 groups chosen. As will be appreciated, the number of ring bonds and the number of substituents are selected such that the X1 atoms maintain a stable valency. Maintaining a stable valency means ensuring that an atom has its normal (typically most common) valency in organic compounds (i.e. 2 for oxygen; 2 or 6 for sulfur; 3 or 4 and most preferably 3 for nitrogen; and 4 for carbon). An X1 which is N is trivalent, and bears at most one R6 group. An X1 which is C is tetravalent, and bears one or two R6 groups. An X1 which is O or S is divalent and bears no R6 groups. The X1 atoms are in general selected such that ring D is free of O-O, S-S and S-0 bonds. Optionally, each R6 is independently absent or selected from H; a halogen, optionally Cl or F; a nitrile group; a Cl to C3 alkyl group, optionally a methyl group; and a Cl to C3 haloalkyl group, optionally a halomethyl group (-CH2F, -CHF2, or -CF3) or a haloethyl group (e.g., -CH2CF3). For example, each R6 may independently be absent or selected from: H, Cl, F, a methyl group, CF3, and a nitrile group. When an R6 group is present, that R6 group is preferably H or F. At least one R6 group may be H. Exactly one R6 may be F, with the remaining R6 groups being absent or H. Alternatively, each R6 group may be either absent or H. Ring D may be a 6-membered ring. In other words, k may be 2. Ring D is optionally an aromatic ring. Ring D may be a 6-membered aromatic ring. In such examples, The PARP1 inhibitor compound has a structure of: 5 Optionally, each XI is independently selected from C and N. Further optionally, each X1 may be C. Ring D may be a carbocycle, with each X1, Z1 and Z2 being C. The PARP1 inhibitor compound may preferably have a structure of: 10 The most preferred bicyclic head group structures are: following: More specific examples of PARP1 inhibitor compounds with bicyclic head groups include: specific examples, each R6 is present. Examples of PARP1 inhibitor compounds with bicyclic head groups include: Head group - monocyclic variants The head group of the PARP1 inhibitor compound may be monocyclic. Compounds with monocyclic head groups have a structure of: where R1 and R2 are each independently absent or selected from H; D; a halogen; a nitrile 10 group; a Cl to C6 alkyl group, optionally a C3 to C6 cycloalkyl group; a Cl to C6 aminoalkyl group; a Cl to C6 alkoxy group; and a Cl to C6 haloalkyl group. In the monocyclic variants, R1 and R2 are not fused to form a ring. 15 R1 is preferably present. R1 is more preferably selected from a halogen; a nitrile group; a Cl to C6 alkyl group, optionally a C3 to C6 cycloalkyl group; a Cl to C6 aminoalkyl group; a Cl to C6 alkoxy group; or a Cl to C6 haloalkyl group. In the compounds with monocyclic head groups, R1 is most preferably an ethyl group. The preferred R2 group in compounds with monocyclic head groups is H. In the compounds with monocyclic head groups, R1 and R2 are preferably both present with at most one of R1 and R2 being H. A PARP1 inhibitor compound with a monocyclic head group may in particular have a structure 10 selected from: Examples of PARP1 inhibitor compounds with monocyclic head groups include: The most preferred monocyclic head group has a structure of: O Group L - general Group L of the PARP1 inhibitor compounds provided herein has a structure of: 10 where: each X2 is independently selected from C, N, O and S; each X3 is independently selected from C and N; n is 1 or 2, and m is (3-n); p is selected from 1, 2, and 3, and q is (4-p); r is selected from 1, 2, and 3, and s is (4-r); ring C is an aromatic ring, optionally a heteroaromatic ring; each R5A group is independently: i) absent, with the proviso that ring A is non-aromatic; or ii) a member of a pair of R5A groups which together form a bridging group, the bridging group being selected from a Cl to C6 alkyl group, a Cl to C6 haloalkyl group, a Cl to C6 alcohol group, a Cl to C7 amino carbonyl group, a Cl to C6 amino group, and a Ci-Ce alkoxy group; or iii) selected from H; D; a halogen; a carbonyl group; a nitrile group; a Cl to C6 alkyl group, optionally a C3 to C6 cycloalkyl group; a Cl to C6 haloalkyl group; an -OH group; a Cl to C6 alcohol group; a Cl to C7 amino carbonyl group; an -NH2 group; a Cl to C6 amino group; and a Cl to C6 alkoxy group, optionally an oxetane group; each R5B and R5C is independently absent or selected from: H; D; a halogen; a carbonyl group; a nitrile group; a Cl to C6 alkyl group, optionally a C3 to C6 cycloalkyl group; a Cl to C6 haloalkyl group; an -OH group; a Cl to C6 alcohol group; a Cl to C7 amino carbonyl group; an -NH2 group; a Cl to C6 amino group; and a Cl to C6 alkoxy group, optionally an oxetane group; with the proviso that ring B is non-aromatic. Preferably, each X2 is selected from C and N. Group L- ring A Group L includes ring A: n is 1 or 2, and m is (3-n). In other words, ring A is a 5-membered ring. The ring A atoms which are bonded to rings E and B are not adjacent to one other, i.e. not in 1,2 relationship. Each X2 is independently selected from C, N, O and S. Of these, C and N are preferred. In 10 particular, each X2 may be C. For instance, when ring A is saturated and each X2 is C, ring A has a structure of: 15 When each X2 is C and ring A is unsaturated, ring A may have a structure selected from: The PARP1 inhibitor compound may have an S-configuration with respect to ring A: Where it is said herein that a compound is an S-enantiomer, this means that the compound has an S-configuration of the carbon atom in the A ring which is bonded to ring E. In many instances of structurally-related compounds, it has been observed that S-enantiomers of PARP1 inhibitor compounds have greater activity than the corresponding R-enantiomers. Each R5Agroup (e.g., R5A1, R5A2) may be absent or present. The R5A groups are selected such that ring A is saturated or unsaturated and non-aromatic. When present, an R5A group may be selected from H; D; a halogen; a carbonyl group; a nitrile group; a Cl to C6 alkyl group, optionally a C3 to C6 cycloalkyl group; a Cl to C6 haloalkyl group; an -OH group; a Cl to C6 alcohol group; a Cl to C7 amino carbonyl group; an -NH2 group; a Cl to C6 amino group; and a Cl to C6 alkoxy group, optionally an oxetane group. Of these, the preferred groups are H and halogen groups, with F being the preferred halogen group. Two R5A groups attached to different ring A atoms may together form a bridging group. The bridging group may be selected from a Cl to C6 alkyl group, a Cl to C6 haloalkyl group, a Cl to C6 alcohol group, a Cl to C7 amino carbonyl group, a Cl to C6 amino group, and a Ci-Ce alkoxy group. In particular, the bridging group may be a methylene (i.e., -CH2-) group. Generally, ring A includes no more than one bridging group. Examples of ring A structures which include a bridging group include: Preferred bridged A rings have a structure of Examples of bridged A rings include: The preferred bridged A ring is: Examples of non-bridged ring A structures include: The preferred non-bridged ring A structure is: Group L- ring B Ring B of group L has a structure of: 5B2 5B2 R 5B2 R R 5B2 p is selected from 1, 2, and 3, and q is (4-p). In other words, ring B is a 6-membered ring in which the atoms which are bound to rings A and C are non-adjacent. Optionally, p is 1 or 2; and further optionally p is 2. Each X2 is independently selected from C, N, O and S. Of these, C and N are preferred. All of the X2 groups of ring B may be C. Each R5B (e.g., R5B1, R5B2) may be absent or present. The number of R5B groups is selected such that ring B is saturated or unsaturated and non-aromatic. Each R5B which is not absent is independently selected from H; D; a halogen; a carbonyl group; a nitrile group; a Cl to C6 alkyl group, optionally a C3 to C6 cycloalkyl group; a Cl to C6 haloalkyl group; an -OH group; a Cl to C6 alcohol group; a Cl to C7 amino carbonyl group; an -NH2 group; a Cl to C6 amino group; and a Cl to C6 alkoxy group, optionally an oxetane group. Preferably, each R5B is independently absent or H. Ring B may be a 6-membered saturated ring, optionally a piperidine having a structure of: with each R5B being independently selected from H; D; a halogen, optionally F; a nitrile group; a Cl to C6 alkyl group; a Cl to C6 haloalkyl group; an -OH group; a Cl to C6 alcohol group; a Cl to C7 amino carbonyl group; an -NH2 group; a Cl to C6 amino group; and a Cl to C6 alkoxy group; optionally wherein each R5B is H. The most preferred ring B structure is: Group L- ring C 15 Ring C is a 6-membered aromatic ring bearing a C(O)NHCD3 substituent: 5C R r is selected from 1, 2, and 3, and s is (4-r). In other words, the C(O)NHCD3 substituent and the bond to ring B are meta or para. Each X3 is independently selected from C and N. In particular, ring C may be a phenyl ring, pyridine, or a diazine. Each R5C is independently absent or selected from: H; D; a halogen; a carbonyl group; a nitrile group; a Cl to C6 alkyl group, optionally a C3 to C6 cycloalkyl group; a Cl to C6 haloalkyl group; an -OH group; a Cl to C6 alcohol group; a Cl to C7 amino carbonyl group; an -NH2 group; a Cl to C6 amino group; and a Cl to C6 alkoxy group, optionally an oxetane group. In particular, each R5C may be absent or selected from H and a halogen, optionally F. For instance, each R5Cmay be absent or H. In other examples, each R5C may be absent, H, or F; optionally wherein exactly one R5C is F. When an X3 is C, the corresponding R5C is present. When an X3 is N, the corresponding R5C is absent. Ring C may be a phenyl group having a structure of: Alternatively, ring C may be a pyridine group having a structure selected from: In accordance with a still further possibility, ring C may be a diazine group having a structure selected from: Examples of ring C structures include: 5 Ring C may have a structure of: wherein: R5cortho js selected from H and a halogen (optionally F); and 10 i) X3meta is C and R5Cmeta is H; or ii) x3meta is N and R5Cmeta is absent. Particularly preferably, ring C may have a structure of: or Group L - examples Group L may in particular have a structure selected from: f N 0 optionally D D ; and 10 F F optionally D Example Compounds Examples of PARP1 inhibitor compounds provided herein include: 3 Medical Uses The compounds described herein may be for use in medicine. In the context of the present invention, the medicinal use is not especially limited, provided that it is a use which is facilitated by the PARP1 inhibitory effect of the compound. Thus, the compounds of the invention may be for use in any disease, condition or disorder that may be prevented, ameliorated or treated using a PARP1 inhibitor. The PARP1 inhibitor compounds provided herein may be selective for PARP1 over PARP2. As such, the PARP1 inhibitor compounds may have reduced toxicity. PARP2 inhibition is believed to be a major driver of haematological toxicities such as anaemia, neutropenia and thrombocytopenia. The PARP1 inhibitor compound may be for use in treating a cancer. The nature of the cancer is not especially limited, provided that the cancer is one which may be treated, prevented or ameliorated by using a PARP1 inhibitor. The cancer may comprise a solid or liquid tumour. For example, the cancer selected from: a cancer of the eye, brain (such as gliomas, glioblastomas, medulloblastomas, craniopharyngioma, ependymoma, and astrocytoma), spinal cord, kidney, mouth, lip, throat, oral cavity, nasal cavity, small intestine, colon, parathyroid gland, gall bladder, head and neck, breast, bone, bile duct, cervix, heart, hypopharyngeal gland, lung, bronchus, liver, skin, ureter, urethra, testicles, vagina, anus, laryngeal gland, ovary, thyroid, oesophagus, nasopharyngeal gland, pituitary gland, salivary gland, prostate, pancreas, adrenal glands; an endometrial cancer, oral cancer, melanoma, neuroblastoma, gastric cancer, an angiomatosis, a hemangioblastoma, a pheochromocytoma, a pancreatic cyst, a renal cell carcinoma, Wilms' tumour, squamous cell carcinoma, sarcoma, osteosarcoma, Kaposi sarcoma, rhabdomyosarcoma, hepatocellular carcinoma, PTEN Hamartoma-Tumor Syndromes (PHTS) (such as Lhermitte-Duclos disease, Cowden syndrome, Proteus syndrome, and Proteus-like syndrome), leukaemias and lymphomas (such as acute lymphoblastic leukaemia, chronic lymphocytic leukaemia, acute myelogenous leukaemia, chronic myelogenous leukaemia, hairy cell leukaemia, T-cell prolymphocytic leukaemia (T-PLL), large granular lymphocytic leukaemia, adult T-cell leukaemia, juvenile myelomonocytic leukaemia, Hodgkin lymphoma, non-Hodgkin lymphoma, mantle lymphoma, follicular lymphoma, primary effusion lymphoma, AIDS-related lymphoma, diffuse B cell lymphoma, Burkitt lymphoma, cutaneous T-cell lymphoma, nasopharyngeal and gastrointestinal cancers. For instance, the cancer may be a cancer of the brain or spinal cord. In addition, the compounds described herein may be of use in cancers where Epstein Barr Virus, EBV, plays a contributing role such as Burkitt's lymphoma, Hodgkin's lymphoma, nasopharyngeal and gastrointestinal cancers. The compounds described herein may be provided for use in for treating a cancer which is deficient in one or more DNA damage response repair pathways, in particular in Homologous Recombination ("HR") dependent DNA Double Strand Break ("DSB") DNA repair activity. Components of HR dependent DNA DSB repair pathways and other DNA damage response pathways include but are not limited to the following proteins: ATM, ATR, ERCC1, XRCC1, XRCC2, XRCC3, RAD51, RAD51L1, RAD51C, RAD51D, RAD51L3, DMC1, RAD52, RAD54L, RAD54B, RAD50, MRE11A, NBS1, BRCA1, BRCA2, FANCP (SLX4), FEN1, PALB2, PBRM1, SMARCA4, ARID1A, ARID1B, FANCD2, BLM. Other components involved in HR dependent DNA DSB repair include regulatory factors such as ESMY (Hughes-Davies, L. et al. Cell. 2003; 115: 523-535). A cancer which is deficient in HR-dependent DNA DSB repair typically becomes dependent on alternative DSB pathway repair mechanisms. Such cancers include but are not limited to cancers of the ovary, prostate, breast, lung, gastrointestine, blood and pancreas. The cancer cells may have a BRCA1 and / or BRCA2 deficient phenotype, i.e. the cancer cells may be deficient in BRCA1 and / or 2 function. The deficiency may arise by means of mutation, polymorphism or epigenetic silencing in the encoding nucleic acids or by means of mutation, polymorphism, amplification in a gene encoding a regulatory factor, e.g. the ESMY gene which encodes a BRCA2 regulatory factor (Hughes-Davies, L. et al. Cell. 2003; 115: 523-535). Amplification of the ESMY gene is associated with breast and ovarian cancer. Carriers of mutations in the tumour suppressor BRCA1 and / or BRCA2 genes are known to have an elevated risk of developing certain cancers including ovarian, prostate and breast. Wild-type alleles of BRCA1 and / or BRCA2 are frequently lost in tumours of heterozygous carriers (Jasin, M. et al. Oncogene. 2002; 21: 8981-93) and their detection, as a means of patient selection, is well known in the art (Radice, PJ. et al. Exp. Clin. Cancer. Res. 2002; 21: 9-12; Chappnis, PO and Foulkes WO. Cancer Treat Res. 2002; 107: 29-59). The compounds provided herein may be administered to a patient who is undergoing radiotherapy and / or chemotherapy using a further agent for treating cancer. For example, the PARP1 inhibitor compound may be administered in conjunction with a further agent for treating cancer. The further agent for treating cancer may be selected from: anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase I inhibitors, topoisomerase II inhibitors, antimetabolites, senolytic agents, hormones and hormone analogues, signal transduction pathway inhibitors, other DNA damage repair pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, antibody-drug conjugates, immunotherapeutic agents, hormone deprivation therapy, proapoptotic agents, radioligand therapies, anti-angiogenic agents, and cell cycle signalling inhibitors. In particular, the further agent may comprise an immunotherapeutic agent selected from: an anti-tumour vaccine; an oncolytic virus; an immune stimulatory antibody such as anti-CTI_A4, anti-PDl, anti-PDL-1, anti-OX40, anti-41BB, anti-CD27, anti-CD40, anti-LAG3, anti-TIM3, and anti-GITR; a pattern recognition receptor agonist such as a STING, TLR-9 or RIG-1 Helicase agonist; an IDO orTDO inhibitor; a novel adjuvant; a peptide; a cytokine; a chimeric antigen receptor T cell therapy (CAR-T); a small molecule immune modulator; and a tumour microenvironment modulator. Pharmaceutical Compositions Another aspect provides a pharmaceutical composition comprising a PARP1 inhibitor compound as defined herein. Typically, the composition includes a pharmaceutically acceptable additive and / or excipient. In the pharmaceutical composition, the PARP1 inhibitor compound as defined above may be present in the form described above, but may alternatively be in a form suitable for improving bioavailability, solubility, and / or activity, and / or may be in a form suitable for improving formulation. Thus, the compound may be in the form of a pharmaceutically acceptable salt, hydrate, acid, ester, or other alternative suitable form. Typically, the composition is for use in medicine, e.g. for use in treating a disease, condition or disorder as defined above. For example, the pharmaceutical composition may be for use in treating a cancer. The composition may further comprise a further agent for treating cancer. The further agent for treating cancer is not especially limited, provided that it affords some utility for cancer treatment. The further agent for treating cancer may comprise one or more chemotherapeutic agents such as anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase I inhibitors, topoisomerase II inhibitors, antimetabolites, senolytic agents, hormones and hormone analogues, signal transduction pathway inhibitors, other DNA damage repair pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, antibody-drug conjugates, immunotherapeutic agents, hormone-deprivation therapies, proapoptotic agents, radioligand therapies, anti-angiogenic agents, and cell cycle signalling inhibitors. In particular, the further agent for treating cancer may comprise an immunotherapeutic agent selected from: an anti-tumour vaccine; an oncolytic virus; an immune stimulatory antibody such as anti-CTLA4, anti-PDl, anti-PDL-1, anti-OX40, anti-41BB, anti-CD27, anti-CD40, anti-LAG3, anti-TIM3, and anti-GITR; a pattern recognition receptor agonist such as a STING, TLR-9 or RIG-1 Helicase agonist; an IDO or TDO inhibitor; a novel adjuvant; a peptide; a cytokine; a chimeric antigen receptor T cell therapy (CAR-T); a small molecule immune modulator; and a tumour microenvironment modulator. Kits Another aspect provides a pharmaceutical kit for treating a cancer. The pharmaceutical kit comprises a PARP1 inhibitor compound as defined herein, and a further agent for treating cancer. The compound and the further agent are suitable for administration simultaneously, sequentially or separately. The further agent for treating cancer may be any of the further agents for treating cancer identified above in the discussion of the pharmaceutical composition. In particular, the further agent for treating cancer may comprise one or more chemotherapeutic agents selected from: anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase I inhibitors, topoisomerase II inhibitors, antimetabolites, senolytic agents, hormones and hormone analogues, signal transduction pathway inhibitors, other DNA damage repair pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, antibody-drug conjugates, hormone-deprivation therapies, radioligand therapies, antiangiogenic agents, immunotherapeutic agents (such as selected from an anti-tumour vaccine, an oncolytic virus, an immune stimulatory antibody such as anti-CTLA4, anti-PDl, anti-PDL-1, anti-OX40, anti-41BB, anti-CD27, anti-CD40, anti-LAG3, anti-TIM3, and anti-GITR, a pattern recognition receptor agonist such as a STING, TLR-9 or RIG-1 Helicase agonist, an IDO or TDO inhibitor, a novel adjuvant, a peptide, a cytokine, a chimeric antigen receptor T cell therapy (CAR-T), a small molecule immune modulator, tumour microenvironment modulators), proapoptotic agents and cell cycle signalling inhibitors. Methods of Treatment Another aspect of the invention provides a method of treating a disease and / or a condition and / or a disorder, which method comprises administering to a patient (or subject) a PARP1 inhibitor compound, or a composition, or a kit as defined herein. The method is typically a method for treating any disease condition or disorder mentioned herein. In typical embodiments, the method is a method for treating a cancer. The patient may be any animal, preferably a mammal. For example, the patient may be a human, canine, equine or feline; and is preferably a human. The method may comprise administering to the patient (or subject) a compound or a composition as defined above and a further agent for treating cancer as defined above. The compound or composition and the further agent may be administered simultaneously, sequentially or separately, depending upon the agents and patients involved, and the disease to be treated (e.g., the type of cancer to be treated). The patient may be undergoing treatment using ionising radiation. Examples Example 1 - synthesis of IS The synthesis of compound IS: F 0 via an intermediate product 8-fluoro-3-(pyrrolidin-3-yl)isoquinolin-l(2H)-one (INT-1) will now be described. a) Synthesis of 8-fluoro-3-(pvrrolidin-3-yl)isoquinolin-l(2H)-one (INT-1) INT-1 was prepared in accordance with Scheme 1A: 105 racemate INT-1 (S-enantiomer) SCHEME 1A Chiral-SFC DAICEL Preparation of N,N-diethyl-2-fluoro-6-methylbenzamide (103) To a solution of 2-fluoro-6-methylbenzoic acid 101 (230 g, 1.5 mol) and diethylamine 102 (218 g, 3.0 mol) in DCM (5000 mL) were added DIPEA (385 g, 3.0 mol) and HATU (851 g, 2.2 mol) successively at rt. The reaction mixture was stirred at rt for 1 h. The reaction solution was quenched with water (3000 mL) and extracted with DCM (3000 mL x 2). The combined organic phase was concentrated and purified by silica gel column chromatography (eluting with PE / EtOAc = 100 : 0 to 70 : 30) to afford N,N-diethyl-2-fluoro-6-methylbenzamide 103 (310 g, 90 % purity, 89 % yield) as a white solid. LCMS (ESI) calcd for Ci2Hi6FNO [M + H]+ m / z 210.12, found 209.92. Preparation of tert-butyl 3-(8-fluoro-l-oxo-l,2-dihydroisoquinolin-3-yl)pyrrolidine-l-carboxylate (105 racemate) To a solution of N,N-diethyl-2-fluoro-6-methylbenzamide 103 (40 g, 191.1 mmol) in THF (1000 mL) was added LDA (143.3 mL, 286.6 mmol, 2 M in THF) at -78 °C under N2. The reaction mixture was stirred at -78 °C for 1 h. A solution of tert-butyl 3-cyanopyrrolidine-l-carboxylate 104 (41 g, 210.2 mmol) in THF (100 mL) was added dropwise to the reaction mixture at -78 °C. After this addition was complete, the reaction mixture was warmed to rt and stirred at rt for a further 15 h. The reaction solution was quenched with aq. NH4CI, then the aqueous layer was extracted with EtOAc (2000 mL x 2). The combined organic layers were concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with PE / EtOAc = 100 : 0 to 50 : 50) and triturated with ACN (50 mL) to afford tert-butyl 3-(8-fluoro-l-oxo-l,2-dihydroisoquinolin-3-yl)pyrrolidine-l-carboxylate 105 racemate (38 g, 80 % purity, 52 % yield) as a yellow solid. LCMS (ESI) calcd for C18H21FN2O3 [M + H] + m / z 333.15, found 333.05. Chiral resolution of tert-butyl 3-(8-fluoro-l-oxo-l,2-dihydroisoquinolin-3-yl)pyrrolidine-l-carboxylate (105 racemate) Compound 105 racemate (96 g, 93 % purity) was separated by SFC (Column: CHIRALPAK IC (IC00CE-BN011); 0.46 cm I.D. x 25 cm L; Mobile phase: DCM / MeOH = 80 / 20) and concentrated under reduced pressure to afford the first fraction as 105 (S-enantiomer) (40 g, 99 % purity, 100 %ee, white solid). Preparation of8-fluoro-3-(pyrrolidin-3-yl)isoquinolin-l(2H)-one (INT-1, S-enantiomer) A solution of tert-butyl 3-(8-fluoro-l-oxo-l,2-dihydroisoquinolin-3-yl)pyrrolidine-l-carboxylate 105 (S-enantiomer) (35 g, 84.2 mmol) in HCI-Dioxane (4 M, 800 mL) was stirred at rt for 1 h. The reaction solution was concentrated under reduced pressure. The residue was dissolved in MeOH (300 mL), then EtsN (20 mL) was added dropwise. The reaction mixture was stirred at rt for 10 min. The reaction solution was concentrated under reduced pressure to give 8-fluoro-3-(pyrrolidin-3-yl)isoquinolin-l(2H)-one INT-1 (S-enantiomer) (23 g, 95 % purity, 99 % yield) as a white solid. LCMS (ESI) calcd for C13H13FN2O [M + H] + m / z 233.10, found 233.00. b) Synthesis of IS using I NT-1 Compound IS was prepared in accordance with Scheme IB: 1001 LiOH THF, H2O, rt T F O 1S SCHEME IB D h2n—(-D HCI D T4P, DIPEA DCM, rt Preparation of methyl 5-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)picolinate (1003) To a solution of methyl 5-fluoropicolinate 1001 (2 g, 0.0129 mol) in DMSO (30 mL) were added l,4-dioxa-8-azaspiro[4.5]decane 1002 (1.85 g, 0.0129 mol) and DIPEA (4.99 g, 0.0387 mol) at rt. The resulting mixture was stirred at 100 °C for 3 h. After cooling to room temperature, the reaction mixture was poured into water and then extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (150 mL x 3), dried over NazSOA, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with PE / EtOAc = 100 : 0 to 50 : 50) to afford methyl 5-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)picolinate 1003 (3.5 g, 90 % purity, 87 % yield) as white solid. LCMS (ESI) calcd for C14H18N2O4 [M + H]+ m / z 279.13, found 279.10. Preparation of methyl 5-(4-oxopiperidin-l-yl)picolinate (1004) A solution of methyl 5-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)picolinate 1003 (2 g, 0.0072 mol) in formic acid (10 mL) and H2O (10 mL) was stirred at 50 °C for 5 h. The mixture was concentrated under reduced pressure. The residue was adjusted to pH = 8-9 with aqueous NaHCOs at 0 °C and then extracted with EtOAc (100 mL x 3). The combined organic layers were concentrated under reduced pressure to afford methyl 5-(4-oxopiperidin-l-yl)picolinate 1004 (1.5 g, 90 % purity, 80 % yield) as yellow oil. LCMS (ESI) calcd for C12H14N2O3 [M + H] + m / z 235.10, found 235.20. Preparation of methyl 5-(4-(3-(8-fluoro-l-oxo-l,2-dihydroisoquinolin-3-yl)pyrrolidin-l-yl)piperidin-l-yl)picolinate 1005 (S-enantiomer) To a solution of methyl 5-(4-oxopiperidin-l-yl)picolinate 1004 (400 mg, 1.7076 mmol) in MeOH (20 mL) was added 8-fluoro-3-(pyrrolidin-3-yl)isoquinolin-l(2H)-one INT-1 (S-enantiomer) (396 mg, 1.7076 mmol), then AcOH (0.05 mL) and NaBHsCN (214 mg, 3.4152 mmol) were added at rt. The reaction mixture stirred at 50 °C for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with DCM / MeOH = 100 : Oto 90 :10) to provide methyl 5-(4-(3-(8-fluoro-l-oxo-l,2-dihydroisoquinolin-3-yl)pyrrolidin-l-yl)piperidin-l-yI)picolinate 1005 (S-enantiomer) (425 mg, 90 % purity, 49 % yield) as a white solid. LCMS (ESI) calcd for C25H27FN4O3 [M + H] + m / z 451.21, found 451.20. Preparation of 5-(4-(3-(8-fluoro-l-oxo-l,2-dihydroisoquinolin-3-yl)pyrrolidin-l-yl)piperidin-l-yl)picolinic acid (1006, S-enantiomer) To a solution of methyl 5-(4-(3-(8-fluoro-l-oxo-l,2-dihydroisoquinolin-3-yl)pyrrolidin-l-yI)piperidin-l-yl)picolinate 1005 (S-enantiomer) (425 mg, 0.9434 mmol) in THF / H2O = 1:1 (20 mL) was added LiOH (45 mg,1.8868 mmol) at rt. The mixture was stirred at rt for 1 h, acidified with 1 M HCI and extracted with DCM (50 mL x 3). The aqueous phase was concentrated under reduced pressure, and the residue was purified by prep-HPLC (Gemini 5 urn Cis 150 x 21.2 mm, mobile phase: ACN - H2O (0.05% NH3), gradient: 40 - 60) to give 5-(4-(3-(8-fluoro-l-oxo-l,2-dihydroisoquinolin-3-yl)pyrrolidin-l-yl)piperidin-l-yl)picolinic acid 1006 (S- enantiomer) (102 mg, 99 % purity, 100 %ee, 24 % yield) as a white solid. XH NMR (400 MHz, DMSO-de, ppm) 6: 11.09 (s, 1 H), 8.37 (d, J = 2.8 Hz, 1 H), 7.85 (d, J = 8.8 Hz, 1 H), 7.65-7.54 (m, 1 H), 7.40-7.32 (m, 2 H), 7.14-7.05 (m, 1 H), 6.46 (s, 1 H), 3.92-3.84 (m, 2 H), 3.20-3.17 (m, 1 H), 3.07-2.89 (m, 4 H), 2.87-2.60 (m, 4 H), 2.41-2.36 (m, 1 H), 2.26-2.19 (m, 1 H), 2.00-1.92 (m, 2 H), 1.87-1.78 (m, 1 H), 1.59-1.47 (m, 2 H). LCMS (ESI) calcd for C24H25FN4O3 [M + H]+ m / z 437.19, found 437.20. Preparation of 5-(4-(3-(8-fluoro-l-oxo-l,2-dihydroisoquinolin-3-yl)pyrrolidin-l-yl)piperidin-l-yl)-N-(methyl-d3)picolinamide (Compound 1, S-enantiomer} 5-(4-(3-(8-fluoro-l-oxo-l,2-dihydroisoquinolin-3-yl)pyrrolidin-l-yl)piperidin-l-yl)picolinic acid 1006 (S-enantiomer) (60 mg, 0.1375 mmol), DIPEA (88 mg, 0.6875 mmol) and T4P (50 % in EtOAc, 99 mg, 0.1375 mmol) were added to a solution of methan-ds-amine hydrochloride (20 mg, 0.2750 mmol) in DCM (10 mL). After stirring at rt for 30 min, the reaction mixture was concentrated and purified by flash silica chromatography (eluting with MeOH / DCM, Oto 15 %) and prep-HPLC (Gemini 5 urn Cis 150 x 21.2mm, mobile phase: ACN - H2O (0.1 % FA), gradient: 40 - 80) to provide 5-(4-(3-(8-fluoro-l-oxo-l,2-dihydroisoquinolin-3-yl)pyrrolidin-l-yl)piperidin-l-yl)-N-(methyl-d3)picolinamide 1 (S-enantiomer) (0.6 FA salt, 37.3 mg, 99 % purity, 100 %ee, 58 % yield) as a yellow solid. TH NMR (400 MHz, DMSO-d6, ppm) 5:11.09 (s, 1 H), 8.36 (s, 1 H), 8.28 (d, J = 2.8 Hz, 1 H), 8.18 (s, 0.6 H), 7.82 (d, J = 8.8 Hz, 1 H), 7.64-7.57 (m, 1 H), 7.43-7.33 (m, 2 H), 7.10 (dd, J = 11.6, 8.0 Hz, 1 H), 6.46 (s, 1 H), 3.86-3.77 (m, 2 H), 3.22-3.16 (m, 1 H), 3.01-2.91 (m, 3 H), 2.85-2.79 (m, 5 1 H), 2.75-2.65 (m, 2 H), 2.39-2.31 (m, 1 H), 2.27-2.17 (m, 1 H), 1.99-1.91 (m, 2 H), 1.88-1.80 (m, 1H), 1.61-1.49 (m, 2 H). LCMS (ESI) calcd for C25H25D3FN5O2 [M + H] + m / z 453.24, found 453.20. 10 Example 2: synthesis of 2 Compound 2: 0 was prepared using intermediate product 2-(2-azabicyclo[2.1.1]hexan-4-yl)-6- 15 fluoroquinazolin-4(3H)-one INT-2. a) Synthesis of INT-2 HCI-Dioxane DCM, rt, 1h SCHEME 2A Preparation of tert-butyl 4-((2-carbamoyl-4-fluorophenyl)carbamoyl)-2-azabicyclo[2.1.1 ]hexane-2-carboxylate (203) To a solution of 2-amino-5-fluorobenzamide 201 (30 mg, 2.21 mmol) and 2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-4-carboxylic acid 202 (520 mg, 2.20 mmol) in pyridine (20 mL) was added EDCI (423 mg, 2.21 mmol). Then the mixture was stirred for 18 h at room temperature. The reaction mixture was quenched with water, the aqueous layer was extracted with EtOAc (150 mL x 3). The combined organic layers was washed by IM HCI solution and brine, dried over Na2SO4, concentrated under reduced pressure to give product of tert-butyl 4-((2-carbamoyl-4-fluorophenyl)carbamoyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate 203 (500 mg, 56 % yield) as a white solid. LCMS (ESI) calcd for Ci8H22FN3O4 [M + Na] + m / z 386.16, found 385.95. Preparation of tert-butyl      4-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-2- azabicyclo[2.1.1 ]hexane-2-carboxylate (204) To a solution of tert-butyl 4-((2-carbamoyl-4-fluorophenyl)carbamoyl)-2- azabicyclo[2.1.1]hexane-2-carboxylate 203 (500 mg, 1.38 mmol) in DME (50 mL) was added KOH (154 mg, 2.75 mmol), the reaction mixture was then stirred at 60 °C for 2 h. After cooling to room temperature the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with DCM / MeOH = 100 : 0 to 90 :10) to give tert-butyl 4-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-azabicyclo[2.1.1]hexane-2-5 carboxylate 204 (400 mg, 76 % yield ) as a white solid. LCMS (ESI) calcd for Ci8H2oFN303 [M + H] + m / z 346.15, found 345.85. Preparation of 2-(2-azabicyclo[2.1.1]hexan-4-yl)-6-fluoroquinazolin-4(3H)-one (INT-2) 10 To a solution of tert-butyl 4-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate 204 (400 mg, 1.16 mmol) in DCM (10 mL) was added HCI in dioxane (4 M, 20 mL). The mixture was stirred for 1 h at room temperature. The reaction mixture was concentrated under reduced pressure to give product of 2-(2-azabicyclo[2.1.1]hexan-4-yl)-6-fluoroquinazolin-4(3H)-one INT-2 (200 mg, 63 % yield ) as a 15 white solid. LCMS (ESI) calcd for C15H17N3O [M + H] + m / z 246.10, found 245.95. b) Synthesis of 2 Compound 2 SCHEME 2B 5 Preparation of methyl 6-bromo-5-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)picolinate(1102) To a solution of methyl 5-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)picolinate 1101 (1.5 g, 0.0054 mol) in DMF (15 mL) at 0 °C was added N-bromosuccinimide (1.3 g, 0.0059 mol). The reaction mixture was stirred at 0 °C for 1 h. The reaction solution was quenched with ice-water and 10 extracted with EtOAc (50 mL x 3). The organic phase was washed with brine (50 mL x 2) and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE / EtOAc = 100 : 0 to 20: 80) to give methyl 6-bromo-5-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)picolinate 1102 (1.8 g, 90 % purity, 83 % yield) as white solid. 15 LCMS (ESI) calcd for Ci4Hi7BrN2O4 [M + H] + m / z 357.04, found 357.05. Preparation of 6-bromo-5-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)picolinic acid (1103) A solution of methyl 6-bromo-5-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)picolinate 1102 (200 mg, 0.562 mmol) and LiOH (54.0 mg, 2.248 mmol) in MeOH / fW = 1:1 (10 mL) was stirred at rt for 2 h. The resulting mixture was adjusted to pH = 3 by addition of 1 M HCI and then extracted with EtOAc (50 mL x 3). The combined organic phase was concentrated under reduced pressure to give 6-bromo-5-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)picolinic acid 1103 (160 mg, 90 % purity, 74 % yield) as white solid. LCMS (ESI) calcd for Ci3Hi5BrN2O4 [M + H] + m / z 343.02, found 342.90. Preparation of 6-bromo-N-(methyl-d3)-5-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)picolinamide (1104) A solution of 6-bromo-5-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)picolinic acid 1103 (160 mg, 0.468 mmol), methan-d3-amine hydrochloride (49 mg, 0.695 mmol), HATU (356 mg, 0.936 mmol) and DIPEA (120 mg, 0.936 mmol) in DMF (10 mL) was stirred at rt for 2 h. The resulting mixture was diluted with water and extracted with EtOAc (50 mL x 3). The combined organic phase was concentrated under reduced pressure and the residue was purified by flash chromatography (eluting with PE / EtOAc = 100: 0 to 50: 50) to give 6-bromo-N-(methyl-d3)-5-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)picolinamide 1104 (160 mg, 90 % purity, 85 % yield) as yellow oil. LCMS (ESI) calcd for Ci4Hi5D3BrN3O3 [M + H] + m / z 359.07, found 359.00. Preparation of 6-fluoro-N-(methyl-d3)-5-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)picolinamide (1105) A solution of 6-bromo-N-(methyl-d3)-5-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)picolinamide 1104 (160 mg, 0.447 mmol), CsF (272 mg, 1.788 mmol) and 18-crown-6 (236 mg, 0.894 mmol) in DMSO (10 mL) was stirred at 100 °C for 15 h. The reaction solution was cooled to rt, added into water (50 mL) and then extracted with EtOAc (100 mL x 3). The combined organic phase was concentrated under reduced pressure and the residue was purified by flash chromatography (eluting with PE / EtOAc = 100: 0 to 40: 60) to give 6-fluoro-N-(methyl-d3)-5- (l,4-dioxa-8-azaspiro[4.5]decan-8-yl)picolinamide 1105 (100 mg, 90 % purity, 67 % yield) as yellow oil. LCMS (ESI) calcd for C14H15D3FN3O3 [M + H]+ m / z 299.15, found 298.95. Preparation of 6-fluoro-N-(methyl-d3)-5-(4-oxopiperidin-l-yl)picolinamide (1106) A solution of 6-fluoro-N-(methyl-d3)-5-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)picolinamide 1105 (100 mg, 0.335 mmol) in formic acid / FW = 1:1 (10 mL) was stirred at 50 °C for 1 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was adjusted to pH = 9 with saturated NaHCOs aqueous solution and then extracted with EtOAc (50 mL x 3). The combined organic phase washed with brine (50 mL) and dried over Na2SO4 and concentrated under reduced pressure to give 6-fluoro-N-(methyl-d3)-5-(4-oxopiperidin-l-yl)picolinamide 1106 (70 mg, 90 % purity, 74 % yield) as a yellow oil. LCMS (ESI) calcd for C12H11D3FN3O2 [M + H]+ m / z 255.13, found 255.00. Preparation of 6-fluoro-5-(4-(4-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-azabicyclo[2.1.1 ]hexan-2-yl)piperidin-l-yl)-N-(methyl-d3)picolinamide / Compound 2) To a solution of 2-(2-azabicyclo[2.1.1]hexan-4-yl)-6-fluoroquinazolin-4(3H)-one INT-2 (25 mg, 0.102 mmol) in MeOH (5 mL) was added 6-fluoro-N-(methyl-d3)-5-(4-oxopiperidin-l-yl)picolinamide 1106 (39 mg, 0.153 mmol) and 2 drops of AcOH. The reaction was stirred for 10 min at 50 °C, then NaBHsCN (8 mg, 0.125 mmol) was added and the reaction mixture was stirred for 2 h. The reaction mixture was concentrated under vacuum, purified by prep-HPLC (Gemini 5 urn Cis column, 150 x 21.2 mm, eluting with 15 % to 85 % MeCN / H2O containing 0.1 % FA) to afford 6-fluoro-5-(4-(4-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-azabicyclo[2.1.1]hexan-2-yl)piperidin-l-yl)-N-(methyl-d3)picolinamide Compound 2 (0.32 FA salt, 13.2 mg, 98 % purity, 26 % yield) as a white solid. XH NMR (400 MHz, DMSO-d6, ppm) 6:12.36 (s, 1 H), 8.38 (s, 1 H), 7.85 (d, J = 8.4 Hz, 1 H), 7.82-7.76 (m, 1 H), 7.74-7.66 (m, 2 H), 7.65-7.56 (m, 1 H), 3.96 (s, 1 H), 3.66-3.54 (m, 2 H), 3.43-3.35 (m, 2 H), 2.93-2.75 (m, 3 H), 2.36-2.25 (m, 2 H), 2.15-1.89 (m, 4 H), 1.72-1.51 (m, 2 H). LCMS (ESI) calcd for C25H23D3F2N6O2 [M + H] + m / z 484.23, found 484.20. Example 3: Synthesis of 3S Pd / C, H2 MeOH, rt,18 h Compound 3 (S-enantiomer) SCHEME 3 Preparation of 6-chloro-2-methoxy-3-vinylpyridine (302) 10 To a solution of PPhsCHsBr (62.30 g, 175 mmol) in dry THF (300 mL) was added n-BuLi (70 mL, 175 mmol, 2.5 M) at 0 °C under nitrogen and the reaction mixture was stirred for 1 h. 6-chloro-2-methoxynicotinaldehyde 301 (25.00 g, 175 mmol) was added to the mixture which was stirred for 15 h at room temperature. The reaction mixture was quenched with ammonium chloride aqueous solution. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography (eluting with PE / EtOAc = 100 : 0 to 99 : 1) to give product of 6-chloro-2-methoxy-3-vinylpyridine 302 (18.00 g, 73% yield ) as a colorless oil. LCMS (ESI) calcd for C8H8CINO [M + H] + m / z 170.04, found 169.95. Preparation of tert-butyl 3-(6-methoxy-5-vinylpyridin-2-yl)-2,5-dihydro-lH-pyrrole-l-carboxylate (304) To a solution of 6-chloro-2-methoxy-3-vinylpyridine 302 (18.00 g, 106 mmol) and tert-butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,5-dihydro-lH-pyrrole-l-carboxylate 303 (34.52 g, 117 mmol) in dioxane (200 mL) and H2O (20 mL) was added Pd(dppf)Clz (2.00 g) and NazCOs (28.20 g, 266 mmol) at room temperature. The reaction mixture stirred under nitrogen at 90 °C for 5 h. After cooling to ambient temperature, the mixture was filtered and the filtrate was concentrated under vacuum. The residue was diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by flash chromatography (eluting with PE / EtOAc = 100 : 0 to 94 : 6) to give product of tert-butyl 3-(6-methoxy-5-vinylpyridin-2-yl)-2,5-dihydro-lH-pyrrole-l-carboxylate 304 (24.00 g, 75 % yield) as a white solid. LCMS (ESI) calcd for C17H22N2O3 [M + H] + m / z 303.17, found 303.05. Preparation of tert-butyl 3-(5-ethyl-6-methoxypyridin-2-yl) pyrrolidine-l-carboxylate (305) To a solution of tert-butyl 3-(6-methoxy-5-vinylpyridin-2-yl)-2,5-dihydro-lH-pyrrole-l-carboxylate 304 (24.00 g, 80 mmol) in MeOH (60 mL) was added Pd / C (2.40 g). The mixture was evacuated and backfilled with hydrogen three times and then charged with hydrogen. The resulting mixture was stirred at room temperature for 18 h. Then the mixture was filtered and concentrated under vacuum to give crude product of tert-butyl 3-(5-ethyl-6-methoxypyridin-2-yl) pyrrolidine-l-carboxylate 305 (24.00 g, 98 % yield) as a white solid. LCMS (ESI) calcd for C17H26N2O3 [M + H] + m / z 307.20, found 307.05. Preparation of 3-ethyl-6-(pyrrolidin-3-yl) pyridin-2(lH)-one (INT-3, S-enantiomer) Tert-butyl 3-(5-ethyl-6-methoxypyridin-2-yl) pyrrolidine-l-carboxylate 305 (24.00 g, 78 mmol) was added to HBr (48 % in water, 80 mL), and the mixture was stirred at 100 °C for 2 h. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in MeOH (80 mL), then adjusted to pH >7 using ammonia methanol. The mixture was concentrated under reduced pressure to give racemic 3-ethyl-6-(pyrrolidin-3-yl)pyridin-2(lH)-one 306 (13.50 g, 90 % yield) as a light yellow solid. Racemic 3-ethyl-6-(pyrrolidin-3-yl)pyridin-2(lH)-one 306 was separated by SFC (Column: Daicel Chiralpak IC-10, 250 mm x 20 mm I.D., 5 pmm; Mobile phase: CO2 / MeOH[0.1 %(NH3)] = 60 / 40) and concentrated under reduced pressure to afford the first fraction as INT-3 (S-enantiomer) (5.60 g, 99 % purity, ee%: 100, white solid). LCMS (ESI) calcd for CnHi6N2O [M + H] + m / z 193.13, found 193.05. Preparation of 5-(4-(3-(5-ethyl-6-oxo-l,6-dihydropyridin-2-yl)pyrrolidin-l-yl)piperidin-l-yl)-6-fluoro-N-(methyl-d3)picolinamide (Compound 3, S-enantiomer) To a solution of 3-ethyl-6-(pyrrolidin-3-yl)pyridin-2(lH)-one INT-3 (S-enantiomer) (30 mg, 0.156 mmol) in MeOH (5 mL) was added 6-fluoro-N-(methyl-d3)-5-(4-oxopiperidin-l-yl)picolinamide 1106 (48 mg, 0.189 mmol) and 2 drops of AcOH. The reaction was stirred for 10 min at 50 °C, then NaBHsCN (10 mg, 0.156 mmol) was added and the reaction mixture was stirred for 2 h. The reaction mixture was concentrated under vacuum, purified by prep-HPLC (Gemini 5 urn Cis column, 150 x 21.2 mm, eluting with 10 % to 40 % MeCN / H2O containing 0.1 % FA) to afford 5-(4-(3-(5-ethyl-6-oxo-l,6-dihydropyridin-2-yl)pyrrolidin-l-yl)piperidin-l-yl)-6-fluoro-N-(methyl-d3)picolinamide Compound 3, S-enantiomer (0.75 FA salt, 21.2 mg, 99 % purity, 100 %ee, 30 % yield) as a white solid. LCMS (ESI) calcd for C23H27D3FN5O2 [M + H] + m / z 431.26, found 431.20. Example 4: Assays Exemplary compounds of the invention were prepared and tested to determine their effect as PARP1 and PARP2 inhibitors. Typical assays are described below. Example 4A. PARP1 biochemical dissociation-enhanced lanthanide fluorescence immunoassay (DELFIA assay) Optiplate HB 384-well plates were coated with anti-FLAG antibody, supplied as a 4 mg / ml solution, using a Na2CO3 / HCO3 coating buffer at pH 9.6, overnight at 4 °C, in order to achieve a final immobilisation per well of 0.3 ng. Wells were then washed 3x5 min in coating wash buffer (PBS / 0.05 % Tween (v / v)), and blocked with 2 % BSA (w / v) in coating wash buffer overnight at 4°C. Prior to assay, wells were washed 3x5 min in coating wash buffer. For the assay 20 pl of 2.5 nM recombinant full length human N-terminally FLAG-tagged PARP1 was added to each well of the 384-well plate for 30 min at room temperature followed by addition of 50 nL of compound solution in DMSO using pintool technology. Following incubation for 30 min at room temperature, 5 pl of 10 pM biotin-NAD+ and 10 nM activation DNA (sequence shown below) in solution in 20 mM HEPES (pH 7.5), 100 mM NaCI, 2 mM DTT, 0.1 % BSA (w / v), 0.02 % Tween (v / v) assay buffer. Auto-PARylation proceeded for 2 h at room temperature prior to the addition of 5 pl of 12 mM NAD+ quenching solution. After 30 min at room temperature, assay solution was removed and following washing 5 times for 3 min, 100 pl of a 1:1000 dilution of DELFIA Eu-Nl Streptavidin reagent was added. Plates were then incubated for 30 min at room temperature. The reaction mixture was removed and the plates washed 5 times for 3 min prior to the addition of 25 |ul DELFIA enhancement solution. Following incubation for 30 min at room temperature, fluorescence was measured on a Pherastar FS (Ex337 nm, Em620 nm; integration start 60 us; integration time 400 us). Typically compounds were tested from 20 pM at 3-fold dilution intervals in 12-point concentration-response curves to determine IC50 values. Data was analysed using ActivityBase software and replicate values for the low (without enzyme, 0.2 % DMSO) and high (0.2 % DMSO) % controls were averaged and the data obtained from the test compounds expressed as a % of 100 % using the below formulae: % value = 100-(100*((high control - unknown) / (high control - low control)) % data was fitted to a non-linear regression equation (log inhibitor vs response-variable slope 4-parameters) to obtain IC50 values. The IC50 values for a variety of test compounds are shown in Table 1. Activation DNA sequence: Dyphx Sewi^ (SEQ ID NO:1) S'ATCACCTTGTTCTCCAHGCCCACAGCAGGGT^' (SEQ ID NO:2) 5 ’ “ -3 ’(SEQ ID NO:3) I m i n n h m n u h Example 4B. PARP1 probe displacement homogeneous time-resolved fluorescence assay (HTRF assay) 10 nM full length N-terminally FLAG-tagged PARP1 was incubated with 2 nM Anti-FLAG Tb-cryptate antibody and PARP1 / 2 Cy5 fluorescent dye-labelled binding probe (10-fold probe Kd = 270 nM) in 20 mM HEPES (pH 7.5), 100 mM NaCI, 2 mM DTT, 0.1 % BSA (w / v), 0.02 % Tween (v / v) assay buffer for 40 min at room temperature. A Cy5-labelled binding probe is shown below and described in Papeo, G. et al. J. Biomol. Screen. 2014; 19:1212-1219. 6 pl of this reaction mixture was then transferred to each well of a black non-binding surface 384-well plate and 35 nl of compound solution in DMSO was then added using pintool technology. Following incubation for 1 h at room temperature, fluorescence was measured on a Pherastar FS (Ex 337 nm, Em620 nm, em665 nm; integration start 60 ps; integration time 400 ps) using the HTRF module. Typically compounds were tested from 58.5 pM at factor 3 dilution intervals in 12-point concentration-response curves to determine IC50 values. Data was analysed using ActivityBase software and replicate values for the low (without enzyme but with probe and Tb-cryptate antibody, 0.6 % DMSO) and high (0.6 % DMSO) % controls were averaged and the data obtained from the test compounds expressed as a % of 100 % using the below formulae: %activity = 100*(value - low control) / (high control - low control) %activity data was fitted to a non-linear regression equation to obtain IC50 values. Kd values were calculated using Cheng-Prussoff formula: IC50 = (1+ ([probe concentration] / [KmProbe]))*Kd Therefore Kd = IC50 / (l+[[probe concentration] / [Kmprobe])); using probe at 10 x Km, this equated to Kd = IC50 / H Example 4C. PARP2 probe displacement homogeneous time-resolved fluorescence assay (HTRF assay) This assay was performed under identical conditions as for PARP1, except that N-terminally FLAG-tagged PARP2 (amino acids 1-583) was used instead of PARP1, and PARP1 / 2 binding probe was used at 10-fold probe Kd = 540 nM. Data analysis was performed identical as for PARP1. NanoBRET cellular target occupancy assay NanoBRET assays were employed to demonstrate cellular target engagement and selectivity at PARP1 and PARP2. These assays are based on bioluminescence resonance energy transfer (BRET) between a Nano-luc-tagged protein (eg PARP1 or PARP2) and a fluorescent group on a high affinity NAD+ competitive binding probe. Such cellular probe displacement assays can be utilised to measure inhibitor affinities and selectivity ratios at PARP1 and 2. Frozen HEK293 cells transiently transfected with either PARPl-NanoLuc® fusion or PARP2-NanoLuc® fusion constructs (Promega) were thawed and dispensed as a suspension in 384-well microplates each at a density of 1750 cells per well. NanoBRET™ TE PARP Tracer-01 was then added to final concentrations of 11 and 2 nM for PARP1 and PARP2 assays, respectively. Compounds were added from 25 pM at factor 3 dilution intervals in 12-point concentrationresponse curves and plates were incubated for 2 hours at 37 °C. BRET ratios were then measured using a NanoBRET module (LUM 610-LP 450-80) and PHERAstar FS or FSX reader following addition of NanoBRET™ Nano-Gio® Substrate and Extracellular NanoLuc® Inhibitor according to manufacturer's instructions. Kd values were calculated using Cheng-Prussoff formula: IC50 = (1+ ([tracer concentration] / [Kmtracer])) * Kd Binned potency, affinity and selectivity data for a variety of test compounds are shown in Table 1 where DELFIA and Probe Displacement HTRF assays were used. Binned potency, affinity and selectivity data for a subset of test compounds where the NanoBRET assay was used are shown in Table 1. TABLE 1 Results ofParp 1 / 2 assays for selected compounds (DELFIA and Probe Displacement HTRF) Compound PARP1 DELFIA PARP1 HTRF PARP2 HTRF Selectivity Is ++++ ++++ +++ ++ 2 ++++ ++++ ++ +++ 3s ++++ ++++ ++ +++ TABLE 2 Results ofParp 1 / 2 assays for selected compounds (NanoBRET) Compound PARP1 NanoBRET PARP2 NanoBRET Selectivity Is ++++ +++ +++ 2 ++++ + +++ Key DELFIA, Probe Displacement HTRF and NanoBRET assay categories: - indicates IC50 or Ka value above 10 pM + indicates IC50 or Ka value above 1 pM up to 10 pM ++ indicates IC50 or Ka value above 100 nM up to 1 pM +++ indicates IC50 or Ka value above 10 nM up to 100 nM ++++ indicates IC50 or Ka value of 10 nM or less Selectivity categories: - indicates a value of less than 10 + indicates a value of 10 to less than 50 ++ indicates a value of 50 to less than 100 +++ indicate a value of at least 100 The selectivity values relate to the selectivity preference of PARP1 over PARP2. They are calculated from the ratio of Ka values for PARP1 and PARP2 inhibition as Ka (PARP2) / Ka (PARP1). It will be appreciated that the above embodiments have been described by way of example only. Other variants or use cases of the disclosed techniques may become apparent to the person skilled in the art once given the disclosure herein. The scope of the disclosure is not limited by the described embodiments but only by the accompanying claims.

Claims

1. A PARP1 inhibitor compound having a structure of:wherein:a dotted line indicates a bond selected from a single bond and a double bond;Z1, Z2, and Z3 are each independently selected from C and N;R1 and R2:i) together form an optionally-substituted 5- or 6-membered ring; orii) are each independently absent or selected from H; D; a halogen; a nitrilegroup; a Cl to C6 alkyl group, optionally a C3 to C6 cycloalkyl group; a Cl to C6aminoalkyl group; a Cl to C6 alkoxy group; and a Cl to C6 haloaIkyl group;R3 is absent or selected from H, D, a halogen, a Cl to C3 alkyl group, a Cl to C3 haloalkyl group, a Cl to C3 alcohol group, and a Cl to C3 aminoalkyl group;R4 is selected from H, a Cl to C3 alkyl group, and a Cl to C3 haloalkyl group;L has a structure of:wherein:each X2 is independently selected from C, N, O and S;each X3 is independently selected from C and N;n is 1 or 2, and m is (3-n);p is selected from 1, 2, and 3, and q is (4-p);r is selected from 1, 2, and 3, and s is (4-r);ring C is an aromatic ring, optionally a heteroaromatic ring;each R5A group is independently:i) absent, with the proviso that ring A is non-aromatic; orii) a member of a pair of R5A groups which together form a bridging group, the bridging group being selected from a Cl to C6 alkyl group, a Cl to C6 haloalkyl group, a Cl to C6 alcohol group, a Cl to C7 amino carbonyl group, a Cl to C6 amino group, and a Ci-Ce alkoxy group; or iii) selected from H; D; a halogen; a carbonyl group; a nitrile group; a Cl to C6 alkyl group, optionally a C3 to C6 cycloalkyl group; a Cl to C6 haloalkyl group; an -OH group; a Cl to C6 alcohol group; a Cl to C7 amino carbonyl group; an -NH2 group; a Cl to C6 amino group; and a Cl to C6 alkoxy group, optionally an oxetane group;each R5B and R5C is independently absent or selected from: H; D; a halogen; a carbonyl group; a nitrile group; a Cl to C6 alkyl group, optionally a C3 to C6 cycloalkyl group; a Cl to C6 haloalkyl group; an -OH group; a Cl to C6 alcohol group; a Cl to C7 amino carbonyl group; an -NH2 group; a Cl to C6 amino group; and a Cl to C6 alkoxy group, optionally an oxetane group;with the proviso that ring B is non-aromatic.

2. The PARP1 inhibitor compound according to claim 1, wherein Z1 and Z2 are each C.

3. The PARP1 inhibitor compound according to claim 1 or claim 2, wherein Z3 is N and R3is absent.

4. The PARP1 inhibitor compound according to claim 1 or claim 2, wherein Z3 is C and R3 is selected from H, D, a halogen, a Cl to C3 alkyl group, a Cl to C3 haloalkyl group, a Cl to C3 alcohol group, and a Cl to C3 aminoalkyl group,optionally wherein R3 is H.

5. The PARP1 inhibitor compound according to any preceding claim, wherein R4 is H.

6. The PARP1 inhibitor compound according to any preceding claim, wherein each X2 isselected from C and N.

7. The PARP1 inhibitor compound according to any preceding claim, wherein R1 and R2 together form an optionally-substituted 5- or 6-membered ring D, the PARP1 inhibitor compound having a structure of:wherein:each X1 is independently selected from C, N, O and S, optionally C and N;k is 1 or 2; andeach R6 is independently absent or selected from H, D, a halogen, a nitrile group, an OH group, a Cl to C6 alkyl group (optionally a C3 to C6 cycloalkyl group, further optionally a spiro-cyclopropyl group), an -NH2 group, a Cl to C6 aminoalkyl group, a Cl to C6 alkoxy group, and a Cl to C6 haloalkyl group.

8. The PARP1 inhibitor compound according to claim 7, wherein each R6 is independently absent or selected from H; a halogen, optionally Cl or F; a nitrile group; a Cl to C3 alkyl group, optionally a methyl group; and a Cl to C3 haloalkyl group, optionally a halomethyl group (-CH2F, -CHF2, or -CF3) or a haloethyl group (e.g., -CH2CF3).

9. The PARP1 inhibitor compound according to claim 8, wherein each R6 is independently absent or selected from: H, Cl, F, a methyl group, CF3, and a nitrile group.

10. The PARP1 inhibitor compound according to claim 9, wherein each R6 is independently absent or selected from H and F, optionally wherein exactly one R6 is F.

11. The PARP1 inhibitor compound according to any of claims 7 to 10, wherein at least one R6 is H, optionally wherein each R6 is absent or H.

12. The PARP1 inhibitor compound according to any of claims 7 to 11, wherein k is 2.

13. The PARP1 inhibitor compound according to any of claims 7 to 12, wherein ring D isan aromatic ring.

14. The PARP1 inhibitor compound according to claim 13, having a structure of:

15. The PARP1 inhibitor compound according to claim 14, having a structure of:

16. The PARP1 inhibitor compound according to claim 15, having a structure of:

17. The PARP1 inhibitor compound according to any of claims 7 to 13, having a structureselected from:

18. The PARP1 inhibitor compound according to claim 17, having a structure selectedfrom:wherein each R6 not absent.19.The PARP1 inhibitor compound according to claim18, having a structure selectedfrom:

20. The PARP1 inhibitor compound according to any of claims 1 to 6, wherein R1 and R2 are each independently absent or selected from H; D; a halogen; a nitrile group; a Cl to C6 alkyl group, optionally a C3 to C6 cycloalkyl group; a Cl to C6 aminoalkyl group; a Cl to C6 alkoxy group; and a Cl to C6 haloaIkyI group.

21. The PARP1 inhibitor compound according to claim 20, wherein R1 is selected from a halogen; a nitrile group; a Cl to C6 alkyl group, optionally a C3 to C6 cycloalkyl group; a Cl to C6 aminoalkyl group; a Cl to C6 alkoxy group; or a Cl to C6 haloalkyl group22. The PARP1 inhibitor compound according to claim 21, wherein R1 is an ethyl group.

23. The PARP1 inhibitor compound for use according to any of claims 20 to 22, whereinR2isH.

24. The PARP1 inhibitor compound according to any of claims 20 to 23, wherein thecompound has a structure selected from:

25. The PARP1 inhibitor compound according to claim 24, having a structure selectedfrom:

26. The PARP1 inhibitor compound of claim 25, having a structure of:

27. The PARP1 inhibitor compound according to any preceding claim, wherein ring A hasa structure of:

28. The PARP1 inhibitor compound according to claim Tl, having an s-configuration of ringA:

29. The PARP1 inhibitor compound according to claim 27 or claim 28, wherein ring A has30. The PARP1 inhibitor compound according to claim T1 or claim 28, wherein ring A hasa structure selected from:preferably wherein ring A has a structure of:

31. The PARP1 inhibitor compound according to any of claims 1 to 29, wherein a pair of R5A groups together form a bridging group, the bridging group being selected from a Cl to C6 alkyl group, a Cl to C6 haloalkyl group, a Cl to C6 alcohol group, a Cl to C7 amino carbonyl group, a Cl to C6 amino group, and a Ci-Ce alkoxy group.

32. The PARP1 inhibitor compound according to claim 31, wherein ring A has a structureoptionally wherein ring A has a structure of33. The PARP1 inhibitor compound according to claim 32, wherein ring A has a structureselected from:and preferably wherein ring A has a structure of:

34. The PARP1 inhibitor compound according to any of claims 1 to 29 or 32, wherein each R5A is selected from H and a halogen, optionally wherein each R5A is selected from H and F.

35. The PARP1 inhibitor compound according to any preceding claim, wherein p is 1 or 2;optionally wherein p is 2.

36. The PARP1 inhibitor compound according to any preceding claim, wherein ring B is a6-membered saturated heterocyclic ring, optionally having a structure of:wherein each R5B is independently selected from H; D; a halogen, preferably F; a nitrile group; a Cl to C6 alkyl group; a Cl to C6 haloalkyl group; an -OH group; a Cl to C6 alcohol group; a Cl to C7 amino carbonyl group; an -NH2 group; a Cl to C6 amino group; and a Cl to C6 alkoxy group.

37. The PARP1 inhibitor compound according to any preceding claim, wherein each R5B is H.

38. The PARP1 inhibitor compound according to claim 37, wherein ring B has a structure39. The PARP1 inhibitor compound according to any preceding claim, wherein ring C is aphenyl group having a structure of:pyridine group having a structure selected from:diazine group having a structure selected from:

42. The PARP1 inhibitor compound according to any preceding claim, wherein each R5C isselected from H and a halogen, optionally F.

43. The PARP1 inhibitor compound according to claim 42, wherein each R5C is H.

44. The PARP1 inhibitor compound according to claim 42, wherein each R5C is selected from H and F, optionally wherein exactly one R5C is F.a structure of:wherein:Rscortho js se|ectec| from h and a halogen; and i) X3meta is C and R5Cmeta is H; orii) X3meta is N and R5Cmeta js absent.

47. The PARP1 inhibitor compound according to claim 46, wherein R5Cortho is a halogen, optionally wherein R5C°rth°js F.

48. The PARP1 inhibitor compound according to claim 47, wherein ring C has a structureof:

49. The PARP1 inhibitor compound according to any preceding claim, wherein group L hasa structure selected from:FoptionallyFoptionallyF50. The PARP1 inhibitor compound according to claim 1, having a structure selected from:F o3S51. The PARP1 inhibitor compound according to any preceding claim, which is in the form of:an isolated enantiomer, ora mixture of two or more enantiomers, ora mixture of two or more diastereomers, and / or epimers, ora racemic mixture, ora tautomer of the compound.

52. The PARP1 inhibitor compound according to any preceding claim, which is selective for PARP1 over PARP2.

53. The PARP1 inhibitor compound of any preceding claim, for use in medicine.

54. The PARP1 inhibitor compound for use according to claim 53, which is for use in treating a cancer.

55. The PARP1 inhibitor compound for use according to claim 54, wherein the cancer is selected from: a cancer of the eye, brain (such as gliomas, glioblastomas, medulloblastomas, craniopharyngioma, ependymoma, and astrocytoma), spinal cord, kidney, mouth, lip, throat, oral cavity, nasal cavity, small intestine, colon, parathyroid gland, gall bladder, head and neck, breast, bone, bile duct, cervix, heart, hypopharyngeal gland, lung, bronchus, liver, skin, ureter, urethra, testicles, vagina, anus, laryngeal gland, ovary, thyroid, oesophagus, nasopharyngeal gland, pituitary gland, salivary gland, prostate, pancreas, adrenal glands; an endometrial cancer, oral cancer, melanoma, neuroblastoma, gastric cancer, an angiomatosis, a hemangioblastoma, a pheochromocytoma, a pancreatic cyst, a renal cell carcinoma, Wilms' tumour, squamous cell carcinoma, sarcoma, osteosarcoma, Kaposi sarcoma, rhabdomyosarcoma, hepatocellular carcinoma, PTEN Hamartoma-Tumor Syndromes (PHTS) (such as Lhermitte-Duclos disease, Cowden syndrome, Proteus syndrome, and Proteus-like syndrome), leukaemias and lymphomas (such as acute lymphoblastic leukaemia, chronic lymphocytic leukaemia, acute myelogenous leukaemia, chronic myelogenous leukaemia, hairy cell leukaemia, T-cell prolymphocytic leukaemia (T-PLL), large granular lymphocytic leukaemia, adult T-cell leukaemia, juvenile myelomonocytic leukaemia, Hodgkin lymphoma, non-Hodgkin lymphoma, mantle lymphoma, follicular lymphoma, primary effusion lymphoma, AIDS-related lymphoma, diffuse B cell lymphoma, Burkitt lymphoma, cutaneous T-cell lymphoma, nasopharyngeal and gastrointestinal cancers;optionally wherein the cancer is a cancer of the brain or spinal cord.

56. The PARP1 inhibitor compound for use according to claim 54 or claim 55, wherein the cancer is deficient in a DNA damage response repair pathway, such as Homologous Recombination dependent DNA Double Strand Break DNA repair activity.

57. The PARP1 inhibitor compound for use according to any of claims 54 to 56, wherein the cancer is deficient in BRCA1 and / or BRCA2 function.

58. The PARP1 inhibitor compound for use according to any of claims 54 to 57, which is to be administered in conjunction with a further agent for treating cancer; optionally wherein the further agent for treating cancer is selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase I inhibitors, topoisomerase II inhibitors, antimetabolites, senolytic agents, hormones and hormone analogues, signal transduction pathway inhibitors, other DNA damage repair pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, antibody-drug conjugates, immunotherapeutic agents, hormone deprivation therapy, proapoptotic agents, radioligand therapies, cell cycle signalling inhibitors, and anti-angiogenic agents.

59. The PARP1 inhibitor compound for use according to claim 58, wherein the further agent is an immunotherapeutic agent selected from: an anti-tumour vaccine; an oncolytic virus; an immune stimulatory antibody such as anti-CTLA4, anti-PDl, anti-PDL-1, anti-OX40, anti-41BB, anti-CD27, anti-CD40, anti-LAG3, anti-TIM3, and anti-GITR; a pattern recognition receptor agonist such as a STING, TLR-9 or RIG-1 Helicase agonist; an IDO or TDO inhibitor; a novel adjuvant; a peptide; a cytokine; a chimeric antigen receptor T cell therapy (CAR-T); a small molecule immune modulator; and a tumour microenvironment modulator.

60. A pharmaceutical composition comprising a PARP1 inhibitor compound as defined in any of claims 1 to 52.

61. A pharmaceutical composition according to claim 60, further comprising a pharmaceutically acceptable additive and / or excipient, and / or wherein the compound is in the form of a pharmaceutically acceptable salt, hydrate, acid, ester, or other alternative form of the compound.

62. The pharmaceutical composition according to claim 60 or claim 61, further comprising a further agent for treating cancer; optionally wherein the further agent for treating cancer is selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase I inhibitors, topoisomerase II inhibitors, antimetabolites, senolytic agents, hormones and hormone analogues, signal transduction pathway inhibitors, other DNA damage repair pathway inhibitors, non-receptor tyrosine kinase angiogenesisinhibitors, antibody-drug conjugates, immunotherapeutic agents, hormone deprivation therapy, proapoptotic agents, radioligand therapies, anti-angiogenic agents, and cell cycle signalling inhibitors.

63. The pharmaceutical composition according to claim 62, wherein the further agent comprises an immunotherapeutic agent selected from: an anti-tumour vaccine; an oncolytic virus; an immune stimulatory antibody such as anti-CTLA4, anti-PDl, anti-PDL-1, anti-OX40, anti-41BB, anti-CD27, anti-CD40, anti-LAG3, anti-TIM3, and anti-GITR; a pattern recognition receptor agonist such as a STING, TLR-9 or RIG-1 Helicase agonist; an IDO or TDO inhibitor; a novel adjuvant; a peptide; a cytokine; a chimeric antigen receptor T cell therapy (CAR-T); a small molecule immune modulator; and a tumour microenvironment modulator.

64. The pharmaceutical composition according to any of claims 61 to 63, for use in treating a cancer.

65. A pharmaceutical kit for treating a cancer, which pharmaceutical kit comprises:a) a PARP1 inhibitor compound as defined in any of claims 1 to 52; andb) a further agent for treating cancer;wherein the PARP1 inhibitor compound and the further agent are suitable for administration simultaneously, sequentially or separately; andoptionally wherein the further agent for treating cancer is selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase I inhibitors, topoisomerase II inhibitors, antimetabolites, senolytic agents, hormones and hormone analogues, signal transduction pathway inhibitors, other DNA damage repair pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, antibody-drug conjugates, hormone-deprivation therapy, immunotherapeutic agents (such as selected from an anti-tumour vaccine; an oncolytic virus; an immune stimulatory antibody such as anti-CTLA4, anti-PDl, anti-PDL-1, anti-OX40, anti-41BB, anti-CD27, anti-CD40, anti-LAG3, anti-TIM3, and anti-GITR; a pattern recognition receptor agonist such as a STING, TLR-9 or RIG-1 Helicase agonist; an IDO or TDO inhibitor; a novel adjuvant; a peptide; a cytokine; a chimeric antigen receptor T cell therapy (CAR-T); a small molecule immune modulator; a tumourmicroenvironment modulator), proapoptotic agents, radioligand therapies, anti-angiogenic agents, and cell cycle signalling inhibitors.

66. A method of treating a disease and / or a condition and / or a disorder, which method comprises administering to a patient a PARP1 inhibitor compound, a composition or a kit as defined in any preceding claim.

67. The method according to claim 66, wherein the patient is an animal, preferably a mammal, optionally a human, canine, equine or feline; and preferably a human.104