Parp1 inhibitor compounds

Abstract

A PARP1 inhibitor compound has a structure of (I). Each R1 and R2 is independently absent, H, or an organic group. R3 is H or an organic group. Z1, Z2u, Z2l, and each Z3 is independently C or N. At least one of Z2u and Z2l is N. L is (II) b is absent or (III). Each R5A, R5B, R5C, and R6 is independently absent, H, or an organic group. Each X1 is C or N. Each X2 is C, N, O or S. n, m, p, q r and s are each integers in the range 0 to 6. m+n, p+q, and r+s are each in the range 2 to 6. QAE, QAB, and QBC are independently absent or an alkyl, alkenyl, ester, amine, or ketone linker. The compounds are useful for e.g. treating cancer. Also provided are compositions and kits including the compounds, and methods of synthesising the compounds.

Description

[0001] PARP1 Inhibitor Compounds 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 double- strand 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 BRCA1 / 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 double- strand 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, Y. et al. 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 2021.01.26.428337v1). 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, e15−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 (Farrés, 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. et al. 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 PARP1-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. Chem. 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 (Illuzzi, 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 compounds and pharmaceutical compositions for treating a cancer. It is also an aim to provide methods of synthesis of the compounds. Summary Provided herein are PARP1 inhibitor compounds for use in medicine. The PARP1 inhibitor compounds have a structure of: wherein: each R1is independently absent or selected from H and a substituted or unsubstituted organic group; R2is absent or selected from H and a substituted or unsubstituted organic group; R3is selected from H and a substituted or unsubstituted organic group; Z1is C or N; Z2uand Z2lare each selected from C and N, with the proviso that at least one of Z2uand Z2lis N; each Z3is independently selected from C and N; and L has a structure of: wherein: a dashed line represents a single bond or a double bond; each R5Aand each R5Cis independently absent or selected from H and a substituted or unsubstituted organic group; R6is absent or selected from H and a substituted or unsubstituted organic group; each X1is independently selected from C and N; each X2is independently selected from C, N, O and S; n is a number selected from 0, 1, 2, 3, 4, 5 and 6; and m is a number selected from 0, 1, 2, 3, 4, 5 and 6; with the proviso that m + n is a number selected from 2, 3, 4, 5, and 6; r is a number independently selected from 0, 1, 2, 3, 4, 5 and 6; and s is a number independently selected from 0, 1, 2, 3, 4, 5 and 6; with the proviso that r + s is a number selected from 2, 3, 4, 5, and 6; b is absent or a ring having a structure of: wherein: p is a number selected from 0, 1, 2, 3, 4, 5 and 6; and q is a number selected from 0, 1, 2, 3, 4, 5 and 6; with the proviso that p + q is a number selected from 2, 3, 4, 5, and 6; and each R5Bis independently absent or selected from H and a substituted or unsubstituted organic group; and QAE, QAB, and QBCare each independently absent or selected from: , wherein: t is a number selected from 0, 1, 2, 3, 4 and 5; and u is independently a number selected from 0, 1, 2, 3, 4 and 5; with the proviso that t + u is a number selected from 0, 1, 2, 3, 4, 5 and 6; and each R7and R8is independently selected from H and a substituted or unsubstituted organic group. Another aspect provides a pharmaceutical composition comprising a PARP1 inhibitor compound as defined herein. A further aspect provides a pharmaceutical kit for treating a cancer. The 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. Another aspect provides a method of treating a disease and / or a condition and / or a disorder, which method comprises administering to a patient a compound, a composition or a kit as provided herein. Still another aspect provides a compound having a structure of: where: Z1is C or N; one of Z2uand Z2lis C, and the other of Z2uand Z2lis N; each Z3is independently selected from C and N, each R1is independently absent or selected from H, a halogen (e.g., F), methyl, halomethyl (e.g., CF3), and CN; R5C2ois H, a methyl group, or a halogen; X2CMis N and R5C2Mis absent or X2CMis C and R5C2Mis H; and Typically, in these compounds, when a Z3is N, the corresponding R1is absent; and when a Z3is C, the corresponding R1is not absent. Optionally, R5C2ois H or a halogen such as F. Another aspect provides a method of synthesis of a PARP1 inhibitor compound as provided herein. The method comprises conducting a reaction between a first reactant comprising ring E bearing a first portion of group L and a second reactant comprising a remainder of group L, to form the PARP1 inhibitor compound. Certain more specific aspects of the invention are set out in the dependent claims. 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. Ionisable 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 µM in a suitable assay. A suitable assay may be conducted using 2 nM PARP1, 2 µM biotin-NAD+ assay solution in 20 mM HEPES (pH 7.5), 100 mM NaCl, 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 µM, 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 µM 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 NaCl, 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 µM 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. The expression “substituted or unsubstituted organic group” is used herein as a synonym for “substituent”. Example organic groups are discussed in more detail hereinbelow. Where it is said that an organic group is “substituted”, it is meant that an H in the organic group is replaced by a further organic group. A dotted line in a structural formula represents a covalent bond of any appropriate non-zero order, most typically 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. 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’ in a compound number denotes a racemic mixture. The suffix ‘a’ in a compound number 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’ in a compound number 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. Discussion Provided herein are PARP1 inhibitor compounds having a structure of: and typically: , with ring B being optional. Various aspects of this general structure are discussed in detail below. Substituents The expression “R5group” refers generally to groups R5A, R5B, and R5C. An “R5A” group is an R5group which is attached to ring A, and so on. Some of the formulae presented herein use more specific identifiers for R5groups. For example, “R5A1” identifies a subset of R5Agroups. In the compounds provided herein, various ones of the R1, R2, and R5groups may be absent. Dotted lines in the structural formulae presented herein representing covalent bonds of any non-zero order. As will be appreciated, the number of ring bonds and the number of substituents are selected such that the Z1, Z2, Z3, X1, and X2atoms 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 for nitrogen; and 4 for carbon). When an X1, X2, Z1, Z2u, Z2l, or Z3atom is N, that atom most preferably has a valency of 3. Compounds in which an X1, X2, Z1, Z2u, Z2l, or Z3atom is tetravalent N are also contemplated. Tetravalent N is positively charged, and such compounds may have a counterion. Preferably, the PARP1 inhibitor compound includes at most one tetravalent N, and more preferably no tetravalent N. Each R5group may be absent or present, and may be the same or different. For the avoidance of doubt, where the number of R5groups may vary according to the choice of corresponding X group, the following provisos typically apply: i) When an X1is N, its corresponding R5is absent. ii) When an X1is C and is double bonded to an adjacent ring atom, its corresponding R5is absent. iii) When an X1is C and is not double bonded to an adjacent ring atom, its corresponding R5is present. iv) When an X2is O, its corresponding R5 / R6groups are both absent. v) When an X2is S, its corresponding R5 / R6groups are both absent or are both selected from =O and =NR10, where R10is H or a substituted or unsubstituted organic group, preferably a C1 to C3 alkyl group. vi) When an X2is N and is double bonded to an adjacent ring atom, the or each corresponding R5 / R6is absent. vii) When an X2is N and not double bonded to an adjacent ring atom, exactly one corresponding R5 / R6is present. viii) When an X2is C and is double bonded to an adjacent ring atom, exactly one corresponding R5 / R6is present. ix) When an X2is C and is not double bonded to an adjacent ring atom, both corresponding R5groups or both the corresponding R5and R6groups are present. The substituents (i.e. R groups; R1, R2, R3, R5, R6, R7, and R8) are not especially limited, provided that they do not prevent the PARP1 inhibitory function from occurring. The substituents are selected from H and a substituted or unsubstituted organic group. Thus, both above and in the following, the terms ‘substituent’ and ‘organic group’ are not especially limited and may be any functional group or any atom, especially any functional group or atom common in organic chemistry. Any R5or R6group may form a ring with any other R5or R6group on an adjacent and / or proximal atom, although in most embodiments this is not preferred, except where explicitly stated. Thus, the following substituents may together form a ring: an R5Awith another R5A; an R5Bwith another R5B; an R5Cwith another R5C; or an R5Cwith R6. In the present context, an adjacent and / or proximal atom may mean another atom directly bonded to an atom (adjacent) or may be two atoms with only a single atom in between (proximal), or may mean two atoms close enough sterically to be capable of forming a ring (proximal). Preferably R5 / R6groups attached to the same atom do not together form a ring, although this is not excluded. A single R5or R6group on an atom, or two R5 / R6groups on the same atom, may form a group which is double bonded to that atom. Accordingly, an R5or R6group, or two R5 / R6groups attached to the same atom, may together form a =O group, or a =C(R’)2group (wherein each R’ group is the same or different and is H or an organic group, preferably H or a straight or branched C1-C6alkyl group). This is more typical in cases where the R groups are attached to a C atom, such that together they form a C=O group or a C=C(R’)2group. Thus in some cases an X2group which is C may bear a =O group. ‘Substituent’ and ‘organic group’ may have any of the following meanings. The organic group may comprise any one or more atoms from any of groups IIIA, IVA, VA, VIA or VIIA of the Periodic Table, such as a B, Si, N, P, O, or S atom (e.g. OH, OR, NH2, NHR, NR2, SH, SR, SO2R, SO3H, PO4H2) or a halogen atom (e.g. F, Cl, Br or I) where R is a linear or branched lower hydrocarbon (1-6 C atoms) or a linear or branched higher hydrocarbon (7 C atoms or more, e.g.7-40 C atoms). The organic group preferably comprises a hydrocarbon group. The hydrocarbon group may comprise a straight chain, a branched chain or a cyclic group. Independently, the hydrocarbon group may comprise an aliphatic or an aromatic group. Also independently, the hydrocarbon group may comprise a saturated or unsaturated group. When the hydrocarbon comprises an unsaturated group, it may comprise one or more alkene functionalities and / or one or more alkyne functionalities. When the hydrocarbon comprises a straight or branched chain group, it may comprise one or more primary, secondary and / or tertiary alkyl groups. When the hydrocarbon comprises a cyclic group it may comprise an aromatic ring, a non- aromatic ring, an aliphatic ring, a heterocyclic group, and / or fused ring derivatives of these groups. The ring may be fully saturated, partially saturated, or fully unsaturated. The cyclic group may thus comprise a benzene, naphthalene, anthracene, phenanthrene, phenalene, biphenylene, pentalene, indene, as-indacene, s-indacene, acenaphthylene, fluorene, fluoranthene, acephenanthrylene, azulene, heptalene, pyrrole, pyrazole, imidazole, 1,2,3- triazole, 1,2,4-triazole, tetrazole, pyrrolidine, furan, oxetane, tetrahydrofuran, 2-aza- tetrahydrofuran, 3-aza-tetrahydrofuran, oxazole, isoxazole, furazan, 1,2,4-oxadiazol, 1,3,4- oxadiazole, thiophene, isothiazole, thiazole, thiolane, pyridine, pyridazine, pyrimidine, pyrazine, piperidine, 2-azapiperidine, 3-azapiperidine, piperazine, pyran, tetrahydropyran, 2- azapyran, 3-azapyran, 4-azapyran, 2-aza-tetrahydropyran, 3-aza-tetrahydropyran, morpholine, thiopyran, 2-azathiopyran, 3-azathiopyran, 4-azathiopyran, thiane, indole, indazole, benzimidazole, 4-azaindole, 5-azaindole, 6-azaindole, 7-azaindole, isoindole, 4- azaisoindole, 5-azaisoindole, 6-azaisoindole, 7-azaisoindole, indolizine, 1-azaindolizine, 2- azaindolizine, 3-azaindolizine, 5-azaindolizine, 6-azaindolizine, 7-azaindolizine, 8- azaindolizine, 9-azaindolizine, purine, carbazole, carboline, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, quinoline, cinnoline, quinazoline, quinoxaline, 5- azaquinoline, 6-azaquinoline, 7-azaquinoline, isoquinoline, phthalazine, 6-azaisoquinoline, 7- azaisoquinoline, pteridine, chromene, isochromene, acridine, phenanthridine, perimidine, phenanthroline, phenoxazine, xanthene, phenoxanthiin, and / or thianthrene, as well as regioisomers of the above groups. These groups may generally be attached at any point in the group, and also may be attached at a hetero-atom or at a carbon atom. In some instances particular attachment points are preferred, such as at 1-yl, 2-yl and the like, and these are specified explicitly where appropriate. All tautomeric ring forms are included in these definitions. For example pyrrole is intended to include 1H-pyrrole, 2H-pyrrole and 3H-pyrrole. The number of carbon atoms in the hydrocarbon group is not especially limited, but preferably the hydrocarbon group comprises from 1-40 C atoms. The hydrocarbon group may thus be a lower hydrocarbon (1-6 C atoms) or a higher hydrocarbon (7 C atoms or more, e.g. 7-40 C atoms). The lower hydrocarbon group may be a methyl, ethyl, propyl, butyl, pentyl or hexyl group or regioisomers of these, such as isopropyl, isobutyl, tert-butyl, etc. The number of atoms in the ring of the cyclic group is not especially limited, but preferably the ring of the cyclic group comprises from 3-10 atoms, such as 3, 4, 5, 6, 7, 8, 9 or 10 atoms. The groups comprising heteroatoms described above, as well as any of the other groups defined above, may comprise one or more heteroatoms from any of groups IIIA, IVA, VA, VIA or VIIA of the Periodic Table, such as a B, Si, N, P, O, or S atom or a halogen atom (e.g. F, Cl, Br or I). Thus, the substituent may comprise one or more of any of the common functional groups in organic chemistry, such as hydroxy groups, carboxylic acid groups, ester groups, ether groups, aldehyde groups, ketone groups, amine groups, amide groups, imine groups, thiol groups, thioether groups, sulfate groups, sulfonic acid groups, sulfonyl groups, and phosphate groups etc. The substituent may also comprise derivatives of these groups, such as carboxylic acid anhydrides and carboxylic acid halides. In addition, any substituent may comprise a combination of two or more of the substituents and / or functional groups defined herein. Typically, when one or more of R1, R2, R3, R5A(e.g., R5A1, R5A2, R5A3), R5B(e.g., R5B1, R5B2, R5B3), R5C(e.g., R5C1), R6, R7, R51, and R52is a substituted or unsubstituted organic group, the or each substituted or unsubstituted organic group is independently selected from: deuterium; a halogen (such as –F, -Cl, -Br and –I); a nitrile group; a substituted or unsubstituted linear or branched C1-C6 alkyl group (such as Me, Et, Pr, i-Pr, n-Bu, i-Bu, t-Bu, pentyl and hexyl); a substituted or unsubstituted linear or branched C1-C6 alkyl-aryl group (such as –CH2Ph, -CH2(2,3 or 4)F-Ph, -CH2(2,3 or 4)Cl-Ph, -CH2(2,3 or 4)Br-Ph, -CH2(2,3 or 4)I-Ph, -CH2CH2Ph, -CH2CH2CH2Ph, -CH2CH2CH2CH2Ph, -CH2CH2CH2CH2CH2Ph, and -CH2CH2CH2CH2CH2CH2Ph); a substituted or unsubstituted linear or branched C1-C6 halogenated alkyl group (such as -CH2F, -CH2Cl, -CH2Br, -CH2I, -CHF2, -CF3, -CCl3 -CBr3, -CI3, -CH2CH2F, -CH2CF3, -CH2CCl3, -CH2CBr3, and -CH2CCI3); NH2 or a substituted or unsubstituted linear or branched primary secondary or tertiary C1-C6 amine group (such as -NMeH, -NMe2, -NEtH, -NEtMe, -NEt2, -NPrH, -NPrMe, -NPrEt, -NPr2, - NBuH, -NBuMe, -NBuEt, –CH2-NH2, -CH2-NMeH, -CH2-NMe2, -CH2-NEtH, - CH2-NEtMe, -CH2-NEt2, -CH2-NPrH, -CH2-NPrMe, and –CH2-NPrEt); a substituted or unsubstituted amino-aryl group (such as -NH-Ph, -NH-(2,3 or 4)F-Ph, -NH-(2,3 or 4)Cl-Ph, -NH-(2,3 or 4)Br-Ph, -NH-(2,3 or 4)I-Ph, -NH-(2,3 or 4)Me-Ph, -NH-(2,3 or 4)Et-Ph, -NH-(2,3 or 4)Pr-Ph, -NH-(2,3 or 4)Bu-Ph, NH-(2,3 or 4)OMe-Ph, -NH-(2,3 or 4)OEt-Ph, -NH-(2,3 or 4)OPr-Ph, -NH-(2,3 or 4)OBu-Ph, -NH-2,(3,4,5 or 6)F2-Ph, -NH-2,(3,4,5 or 6)Cl2-Ph, -NH-2,(3,4,5 or 6)Br2-Ph, -NH-2,(3,4,5 or 6)I2-Ph, -NH-2,(3,4,5 or 6)Me2-Ph, -NH-2,(3,4,5 or 6)Et2-Ph, -NH-2,(3,4,5, or 6)Pr2-Ph, -NH-2,(3,4,5 or 6)Bu2-Ph), a substituted or unsubstituted cyclic amine or amido group (such as pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, 2-keto-pyrrolidinyl, 3-keto-pyrrolidinyl, 2-keto-piperidinyl, 3-keto-piperidinyl, and 4-keto-piperidinyl); a substituted or unsubstituted cyclic C3-C8alkyl group (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl); an -OH group; a substituted or unsubstituted linear or branched C1-C6 alcohol group (such as –CH2OH, -CH2CH2OH, -CH(CH3)CH2OH, -C(CH3)2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, -CH(CH3)CH2CH2OH, -CH(CH3)CH(CH3)OH, -CH(CH2CH3)CH2OH, -C(CH3)2CH2OH, -CH2CH2CH2CH2CH2OH, and -CH2CH2CH2CH2CH2CH2OH); a substituted or unsubstituted linear or branched C1-C6 carboxylic acid group (such as -COOH, -CH2COOH, -CH2CH2COOH, -CH2CH2CH2COOH, -CH2CH2CH2CH2COOH, and -CH2CH2CH2CH2CH2COOH); a substituted or unsubstituted linear or branched carbonyl group (such as -(CO)Me, -(CO)Et, -(CO)Pr, -(CO)iPr, -(CO)nBu, -(CO)iBu, -(CO)tBu, -(CO)Ph, -(CO)CH2Ph, -(CO)CH2OH, -(CO)CH2OCH3, -(CO)CH2NH2, -(CO)CH2NHMe, -(CO)CH2NMe2, -(CO)-cyclopropyl, -(CO)-1,3-epoxypropan-2-yl; -(CO)NH2, -(CO)NHMe, -(CO)NMe2, -(CO)NHEt, -(CO)NEt2, -(CO)-pyrollidine-N-yl, -(CO)-morpholine-N-yl, -(CO)-piperazine-N-yl, -(CO)-N-methyl-piperazine-N-yl, -(CO)NHCH2CH2OH, -(CO)NHCH2CH2OMe, -(CO)NHCH2CH2NH2, -(CO)NHCH2CH2NHMe, and -(CO)NHCH2CH2NMe2); a substituted or unsubstituted linear or branched C1-C6carboxylic acid ester group (such as -COOMe, -COOEt, -COOPr, -COO-i-Pr, -COO-n-Bu, -COO-i-Bu, -COO-t-Bu, -CH2COOMe, -CH2CH2COOMe, -CH2CH2CH2COOMe, and -CH2CH2CH2CH2COOMe); a substituted or unsubstituted linear or branched C1-C6amide group (such as -CO-NH2, -CO-NMeH, -CO-NMe2, -CO-NEtH, -CO-NEtMe, -CO-NEt2, -CO-NPrH, -CO-NPrMe, and -CO-NPrEt); a substituted or unsubstituted linear or branched C1-C7amino carbonyl group (such as -NH-CO-Me, -NH-CO-Et, -NH-CO-Pr, -NH-CO-Bu, -NH-CO-pentyl, -NH-CO-hexyl, -NH-CO-Ph, -NMe-CO-Me, -NMe-CO-Et, -NMe-CO-Pr, -NMe-CO-Bu, -NMe-CO-pentyl, -NMe-CO-hexyl, -NMe-CO-Ph); a substituted or unsubstituted linear or branched C1-C7alkoxy or aryloxy group (such as –OMe, -OEt, -OPr, -O-i-Pr, -O-n-Bu, -O-i-Bu, -O-t-Bu, -O-pentyl, -O-hexyl, -OCH2F, -OCHF2, -OCF3, -OCH2Cl, -OCHCl2, -OCCl3, -O-Ph, -O-CH2-Ph, -O-CH2-(2,3 or 4)-F-Ph, -O-CH2-(2,3 or 4)-Cl-Ph, –CH2OMe, –CH2OEt, –CH2OPr, –CH2OBu, -CH2CH2OMe, -CH2CH2CH2OMe, -CH2CH2CH2CH2OMe, and -CH2CH2CH2CH2CH2OMe); a substituted or unsubstituted linear or branched aminoalkoxy group (such as –OCH2NH2, -OCH2NHMe, -OCH2NMe2, -OCH2NHEt, -OCH2NEt2, -OCH2CH2NH2, -OCH2CH2NHMe, -OCH2CH2NMe2, -OCH2CH2NHEt, and -OCH2CH2NEt2); a substituted or unsubstituted sulfonyl group (such as -SO2Me, -SO2Et, -SO2Pr, -SO2iPr, -SO2Ph, -SO2-(2,3 or 4)-F-Ph, -SO2-cyclopropyl, -SO2CH2CH2OCH3, -SO2NH2, -SO2NHMe, -SO2NMe2, -SO2NHEt, -SO2NEt2, -SO2-pyrrolidine-N-yl, -SO2-morpholine-N-yl, -SO2NHCH2OMe, and -SO2NHCH2CH2OMe); a substituted or unsubstituted aminosulfonyl group (such as –NHSO2Me, -NHSO2Et, - NHSO2Pr, -NHSO2iPr, -NHSO2Ph, -NHSO2-(2,3 or 4)-F-Ph, -NHSO2-cyclopropyl, -NHSO2CH2CH2OCH3); a substituted or unsubstituted aromatic group (such as Ph-, 2-F-Ph-, 3-F-Ph-, 4-F-Ph-, 2-Cl-Ph-, 3-Cl-Ph-, 4-Cl-Ph-, 2-Br-Ph-, 3-Br-Ph-, 4-Br-Ph-, 2-I-Ph-, 3-I-Ph, 4-I-Ph-, 2,(3,4,5 or 6)-F2-Ph-, 2,(3,4,5 or 6)-Cl2-Ph-, 2,(3,4,5 or 6)-Br2-Ph-, 2,(3,4,5 or 6)-I2-Ph-, 2,(3,4,5 or 6)-Me2-Ph-, 2,(3,4,5 or 6)-Et2-Ph-, 2,(3,4,5 or 6)-Pr2-Ph-, 2,(3,4,5 or 6)-Bu2-Ph-, 2,(3,4,5 or 6)-(CN)2-Ph-, 2,(3,4,5 or 6)-(NO2)2-Ph-, 2,(3,4,5 or 6)-(NH2)2-Ph-, 2,(3,4,5 or 6)-(MeO)2-Ph-, 2,(3,4,5 or 6)-(CF3)2-Ph-, 3,(4 or 5)-F2-Ph-, 3,(4 or 5)-Cl2-Ph-, 3,(4 or 5)-Br2-Ph-, 3,(4 or 5)-I2-Ph-, 3,(4 or 5)-Me2-Ph-, 3,(4 or 5)-Et2-Ph-, 3,(4 or 5)-Pr2-Ph-, 3,(4 or 5)-Bu2-Ph-, 3,(4 or 5)-(CN)2-Ph-, 3,(4 or 5)-(NO2)2-Ph-, 3,(4 or 5)-(NH2)2-Ph-, 3,(4 or 5)-(MeO)2-Ph-, 3,(4 or 5)-(CF3)2-Ph-, 2-Me-Ph-, 3-Me-Ph-, 4-Me-Ph-, 2-Et-Ph-, 3-Et-Ph-, 4-Et-Ph-, 2-Pr-Ph-, 3-Pr-Ph-, 4-Pr-Ph-, 2-Bu-Ph-, 3-Bu-Ph-, 4-Bu-Ph-, 2-(CN)-Ph-, 3-(CN)-Ph-, 4-(CN)-Ph-, 2-(NO2)-Ph-, 3-(NO2)-Ph-, 4-(NO2)-Ph-, 2-(NH2)-Ph-, 3-(NH2)-Ph-, 4-(NH2)-Ph-, 2-MeO-Ph-, 3-MeO-Ph-, 4-MeO-Ph-, 2-(NH2-CO)-Ph-, 3-(NH2-CO)-Ph-, 4-(NH2-CO)-Ph-, 2-CF3-Ph-, 3-CF3-Ph-, 4-CF3-Ph-, 2-CF3O-Ph-, 3-CF3O-Ph-, and 4-CF3O-Ph-); a saturated or unsaturated, substituted or unsubstituted, heterocyclic group, optionally an aromatic heterocyclic group or a non-aromatic heterocyclic group (such as pyrrole-1-yl, pyrrole-2-yl, pyrrole-3-yl, pyrazole-1-yl, pyrazole-3-yl, pyrazole-4-yl, pyrazole-5-yl, imidazole-1-yl, imidazole-2-yl, imidazole-4-yl, imidazole-5-yl, 1,2,3-triazole-1-yl, 1,2,3-triazole-4-yl, 1,2,3-triazole-5-yl, 1,2,4-triazole-1-yl, 1,2,4-triazole-3-yl, 1,2,4-triazole-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazine-3-yl, pyridazine-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, pyrazine-2-yl, pyrrolidine-1-yl, pyrrolidine-2-yl, pyrrolidine-3-yl, piperidine-1-yl, piperidine-2-yl, piperidine-3-yl, piperidine-4-yl, 2-azapiperidine-1-yl, 2-azapiperidine-3-yl, 2-azapiperidine-4-yl, 3-azapiperidine-1-yl, 3-azapiperidine-2-yl, 3-azapiperidine-4-yl, 3-azapiperidine-5-yl, piperazine-1-yl, piperazine-2-yl, furan-2-yl, furan-3-yl, pyran-2-yl, pyran-3-yl, pyran-4-yl, 2-azapyran-2-yl, 2-azapyran-3-yl, 2-azapyran-4-yl, 2-azapyran-5-yl, 2-azapyran-6-yl, 3-azapyran-2-yl, 3-azapyran-4-yl, 3-azapyran-5-yl, 3-azapyran-6-yl, 4-azapyran-2-yl, 4-azapyran-3-yl, 4-azapyran-4-yl, 4-azapyran-5-yl, 4-azapyran-6-yl, oxetan-2-yl, oxetan-3-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-2-yl, 2-aza-tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-4-yl, 2-aza-tetrahydrofuran-5-yl, 3-aza-tetrahydrofuran-2-yl, 3-aza-tetrahydrofuran-3-yl, 3-aza-tetrahydrofuran-4-yl, 3-aza-tetrahydrofuran-5-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, 2-aza-tetrahydropyran-2-yl, 2-aza-tetrahydropyran-3-yl, 2-aza-tetrahydropyran-4-yl, 2-aza-tetrahydropyran-5-yl, 2-aza-tetrahydropyran-6-yl, 3-aza-tetrahydropyran-2-yl, 3-aza-tetrahydropyran-3-yl, 3-aza-tetrahydropyran-4-yl, 3-aza-tetrahydropyran-5-yl, 3-aza-tetrahydropyran-6-yl, morpholine-2-yl, morpholine-3-yl, morpholine-4-yl, thiophen-2-yl, thiophen-3-yl, isothiazole-3-yl, isothiazole-4-yl, isothiazole-5-yl, thiazole-2-yl, thiazole-4-yl, thiazole-5-yl, thiopyran-2-yl, thiopyran-3-yl, thiopyran-4-yl, 2-azathiopyran-2-yl, 2-azathiopyran-3-yl, 2-azathiopyran-4-yl, 2-azathiopyran-5-yl, 2-azathiopyran-6-yl, 3-azathiopyran-2-yl, 3-azathiopyran-4-yl, 3-azathiopyran-5-yl, 3-azathiopyran-6-yl, 4-azathiopyran-2-yl, 4-azathiopyran-3-yl, 4-azathiopyran-4-yl, 4-azathiopyran-5-yl, 4-azathiopyran-6-yl, thiolane-2-yl, thiolane-3-yl, thiane-2-yl, thiane-3-yl, thiane-4-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, furazan-3-yl, (1,3,4-oxadiazol)-2-yl, (1,3,4-oxadiazol)-5-yl, (1,2,4-oxadiazol)-3-yl, (1,2,4-oxadiazol)-5-yl; and tetrazole-1-yl, tetrazole-2-yl, tetrazole-5-yl). A pair of R5Agroups attached to different atoms may together form a ring with ring A atoms. A pair of R5Bgroups attached to different atoms may together form a ring with ring B atoms. A pair of R5Cgroups attached to different atoms may together form a ring with ring C atoms. An R5Cgroup and an R6group attached to different atoms may together form a ring with ring C atoms. R5groups (R5A, such as R5A1, R5A2, R5A3; R5B; or R5C, such as R5C1) may in particular be absent or selected from: H, deuterium, a halogen (such as –F, -Cl, -Br, and –I; preferably F or Cl), a nitrile group, a substituted or unsubstituted C1-C6alkyl group, a substituted or unsubstituted linear or branched C1-C6halogenated alkyl group (preferably CF3or CHF2), a cyclopropyl group, an -OH group, a substituted or unsubstituted linear or branched C1-C6alcohol group, a substituted or unsubstituted linear or branched C1-C7 amino carbonyl group (such as -NH-CO-Me), an -NH2 group, a substituted or unsubstituted C1-C6 amino group, and a substituted or unsubstituted C1-C6 alkoxy group. When a pair of R5Agroups attached to different atoms together forms a ring with ring A atoms and / or a pair of R5Bgroups attached to different atoms together forms a ring with ring B atoms and / or a pair R5Cgroups attached to different atoms together forms a ring with ring C atoms, each of the pair of R5A, R5Bor R5Cgroups independently comprises -CH2- or -CH2CH2-, or the pair of groups together comprise -CH=CH-CH=CH- or -NH-CO-NH-. Rings D and E Rings D and E (also collectively referred to as the “head group”) of the compounds provided herein have a structure of: where: each R1is independently absent or selected from H and a substituted or unsubstituted organic group; R2is absent or selected from H and a substituted or unsubstituted organic group; R3is selected from H and a substituted or unsubstituted organic group; Z1is C or N; Z2uand Z2lare each selected from C and N, with the proviso that at least one of Z2uand Z2lis N; and each Z3is independently selected from C and N. When a Z3is C, the associated R1is present. When a Z3is N, the associated R1is most preferably absent. In compounds which include more than one R1group, each R1is independently selected. Examples of suitable R1groups include: H; a C1 to C6 alkyl, aminoalkyl, alkoxy or haloalkyl group; a C3 to C6 cycloalkyl group; a halogen group; a nitrile group; and wherein R22is selected from H, C1 to C6 alkyl, C3 to C6 cycloalkyl, C1 to C6 alkoxy, C1 to C6 haloalkyl, and a halogen (optionally F), and each R23is independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R23is independently selected from H, a C1 to C6 alkyl, aminoalkyl, alkoxy or haloalkyl group, and a halogen group, and further optionally wherein at least one R23is H. Preferably, each R1is independently absent or selected from H; a halogen, optionally Cl or F; a C1 to C3 alkyl group, optionally a methyl group; a C1 to C3 haloalkyl group, optionally a halomethyl group (-CH2F, -CHF2, or -CF3) or a haloethyl group (e.g., -CH2CF3); and a nitrile group. More preferably, each R1is independently absent or selected from: H, Cl, F, a methyl group, CF3, and a nitrile group. Typically, at least one R1is H. Optionally, no more than one R1is a substituted or unsubstituted organic group, with each other R1being H or absent. Z1may be C. When Z1is C, R2is present and may be selected from H; halogen, optionally F or Cl; C1 to C3 alkyl, optionally isopropyl or cyclopropyl; C1 to C3 haloalkyl, optionally -CH2F, - CHF2, -CF3, -CH2CF3, or -CH2CH2F; C1 to C3 alcohol, optionally -CH2CH2OH; C1 to C3 alkoxy, optionally methoxy, methoxymethyl, or methoxyethyl; or C1 to C3 aminoalkyl. In particular, R2may be H. Alternatively, Z1may be N. In such compounds, R2is absent. R3may be selected from H, C1 to C3 alkyl, and C1 to C3 haloalkyl, and is most preferably H. Each Z3atom is independently selected from C and N. Optionally, at least two Z3atoms are C. Typically, exactly one of Z2uand Z2lis C. Z2umay be C and Z2lmay be N, such that the PARP1 inhibitor compound has a structure of: . Optionally, no more than one Z3atom is N. For example, the PARP1 inhibitor compound may have a structure selected from: . More particularly, the PARP1 inhibitor compound may have a structure selected from: In accordance with another possibility, the PARP1 inhibitor compound may have a structure of: . Alternatively, Z2umay be N and Z2lmay be C, such that the PARP1 inhibitor compound has a structure of: . In such examples, optionally no more than one Z3atom is N. The PARP1 inhibitor compound may have a structure selected from: . More specific examples of PARP1 inhibitor compounds have structures selected from:

[0002] Rings A, B, and C - general Group L of the PARP1 inhibitor compounds has a structure of: .

[0003] The optional group b is most preferably present. In such examples, group L has a structure . Variable atoms which are part of the skeleton of the A, B and C rings are generically referred to as “X” atoms. Each X1atom is independently selected from C and N. Each X2atom is independently selected from C, N, O, and S; with C and N being particularly preferred. Each X1and X2atom is independently selected. One or more, and most preferably all, of the following provisos may apply: Typically, at least one X group per ring is C. When an A, B or C ring is 4-membered, that ring typically includes at most one heteroatom. When an A, B or C ring is 5 or 6- membered, that ring typically includes at most three heteroatoms, optionally at most two heteroatoms. Each of rings A, B, and C individually may comprise at most three heteroatoms. The compound is typically not a quaternary ammonium compound. An X1atom which is N typically does not bear an R5group. An X2atom which is N typically bears at most one R5group. The compound is free of O-O, S-S, and S-O bonds between X2atoms. When an X2is O or S, its adjacent ring atoms are C or N. More generally, the compound may be free of O-O bonds and S-S bonds. Each portion of group L is discussed in more detail below. Ring A Ring A of the PARP1 inhibitor compound has the general structure: X1AEis the X1atom that is connected to ring E via linker QAE. X2Adenotes an X2atom which is part of ring A. Each R5Ais independently absent or selected from H and a substituted or unsubstituted organic group. R5A1denotes the R5Aassociated with X1AE. R5A2denotes an R5Aassociated with an X2Aatom. X1AEmay be C or N, and is preferably C. When X1AEis N, R5A1is typically absent. Rings A and B are most typically not connected via an N-N bond. To this end, when QABis least 1. Each X2Aatom is independently selected from C, N, O, and S; with C and N being particularly preferred. The X2Aatoms are selected such that ring A is free of O-O, O-S, and S-S bonds. Optionally, at least one X2Aatom is C. Particularly preferably, all of the X2Aatoms are C. Ring A is a 4, 5, 6, 7, or 8 membered ring. To this end, n is 0 or an integer in the range 1 to 6; m is 0 or an integer in the range 1 to 6, and n and m sum to an integer in the range 2 to 6. In particular, ring A may be a 4, 5, or 6 membered ring, preferably a 5 or 6 membered ring. Put differently, n+m may sum to an integer in the range 2 to 4. Preferably, both n and m are at least 1. Ring A may be a saturated ring, an unsaturated non-aromatic ring, or an aromatic ring depending upon the number of R5Agroups present. Saturated and unsaturated non-aromatic rings are preferred. In particular, ring A may be a 5-membered (n+m=3) saturated ring. In most implementations, no more than two R5Agroups are substituted or unsubstituted organic groups. Most typically, no more than one R5Agroup is a substituted or unsubstituted organic group. Generally, when an R5Agroup is present, that R5Agroup is preferably H. Ring A may be a bicyclic ring, in which two R5Agroups are fused together. The bicyclic ring may be a bridged bicyclic ring. For example, ring A may be a bridged bicyclic ring having a structure of: where: x is 0 or an integer in the range 1 to 6 and y is 0 or an integer in the range 1 to 6, with the proviso that x and y sum to (n-1); i is 0 or an integer in the range 1 to 6 and j is 0 or an integer in the range 1 to 6, with the proviso that i and j sum to (m-1); h is an integer in the range 1 to 3; and n is an integer in the range 1 to 6 and m is an integer in the range 1 to 6, with the proviso that n and m sum to an integer in the range 2 to 6. Alternatively, ring A may be a bridged bicyclic ring have a structure of: where: i is 0 or an integer in the range 1 to 6 and j is 0 or an integer in the range 1 to 6, with the proviso that i and j sum to (n-1); h is an integer in the range 1 to 3; and n is an integer in the range 1 to 6 and m is 0 or an integer in the range 1 to 6, with the proviso that n and m sum to an integer in the range 2 to 6. The value of h may be selected as appropriate based on the values of i and m. h is typically 1 or 2. For example, ring A may be a bridged 5-membered ring in which h is 1, i is 1, j is 0, and m is 1. Preferred are bridged bicyclic A rings having the structure: . The most preferred bridged bicyclic A ring has a structure of: .

[0004] Ring A may comprise a substituted or unsubstituted 7-membered ring, optionally a homopiperidine. For example, ring A may be a homopiperidine having a structure selected from: . Alternatively, ring A may be a substituted or unsubstituted 6-membered aliphatic (i.e., saturated or unsaturated non-aromatic) heterocycle. For example, ring A may have a structure selected from: , , In still further examples, ring A may be a substituted or unsubstituted 5-membered aliphatic heterocycle. Examples of 5-membered aliphatic heterocycles include: In other examples, ring A is a 5-membered aromatic ring, optionally a pyrrole or pyrazole. Examples of suitable 5-membered aromatic rings include: In accordance with another possibility, ring A may be a substituted or unsubstituted azetidine, such as an azetidine having a structure of: . More specific examples of suitable ring A structures include: In particular, ring A may have a structure selected from: The preferred ring A structures are: . Ring B The PARP1 inhibitor compound optionally includes ring B. Though compounds which do not include a ring B are contemplated, ring B is usually present. When present, ring B has a structure of: . X1BAis the X1atom that connects to ring A via linker QAB. X1BCis the X1atom that connects to ring C via linker QBC. X1BAand X1BCare each independently selected from C and N. X2Bdenotes an X2atom which is part of ring B. Each X2Batom is independently selected from C, N, O, and S; with C and N being preferred. The X2Batoms are selected such that ring B is free of O-O, O-S, and S-S bonds. Optionally, at least one X2Batom is C. Preferably, all of the X2Batoms are C. Each R5Bis independently absent or selected from H and a substituted or unsubstituted organic group. R5B1denotes the R5Bassociated with X1BA. R5B2denotes an R5Bassociated with an X2Batom. R5B3denotes the R5Bassociated with X1BC. When X1BAis N, R5B1is absent. When X1BCis N, R5B3is absent. Rings A and B are typically not connected via an N-N bond. When X1BAis N and QABis , t is at least 1 and u is at least 1. Rings B and C are typically not connected via an N-N bond. When X1BCis N and QBCis , t is at least 1. When X1BCis N and X1CBof the C ring as identified below is N, QBCis not absent. It is preferable for X1BAto be C. X1BAmay be C and X1BCmay be N, such that ring B has a structure of: . Group L may have a structure of: . Ring B is a 4, 5, 6, 7, or 8 membered ring. To this end, p is 0 or an integer in the range 1 to 6; q is 0 or an integer in the range 1 to 6, and p and q sum to an integer in the range 2 to 6. Preferably, p and q are each at least 1. It is generally preferred for ring B to be a 5- or 6-membered ring. Put differently, p and q may sum to 3 or 4. More preferably, ring B is a 6-membered ring wherein p = 2 and q = 2. Ring B may be a saturated ring, an unsaturated non-aromatic ring, or an aromatic ring depending upon the number of R5Bgroups present. Saturated and unsaturated non-aromatic rings are preferred. When an R5Bis present, that R5Bis preferably H. In most examples, no more than one R5Bis a substituted or unsubstituted organic group. Two R5Bgroups may be fused such that ring B is a bridged bicyclic ring, similar to as described with reference to ring A. Most typically, ring B is not a bridged bicyclic ring. Ring B may be a 7-membered saturated heterocyclic ring, optionally having a structure of: wherein: each R5Bis independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5Bis H; X1BAis C and R5B1is selected from H and a substituted or unsubstituted organic group, and is optionally H; or X1BAis N and R5B1is absent; and X1BCis C and R5B3is selected from H and a substituted or unsubstituted organic group or X1BCis N and R5B3is absent. Alternatively, ring B may be a 6-membered saturated heterocyclic ring, optionally having a structure of: wherein: each R5Bis independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5Bis H; X1BAis C and R5B1is selected from H and a substituted or unsubstituted organic group, and is optionally H; or X1BAis N and R5B1is absent; and X1BCis C and R5B3is selected from H and a substituted or unsubstituted organic group or X1BCis N and R5B3is absent. In other examples, ring B is a 5-membered saturated heterocyclic ring, optionally having a structure of: each R5Bis independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5Bis H; X1BAis C and R5B1is selected from H and a substituted or unsubstituted organic group, and is optionally H; or X1BAis N and R5B1is absent; and X1BCis C and R5B3is selected from H and a substituted or unsubstituted organic group or X1BCis N and R5B3is absent. In the above examples of 5- 6- and 7-membered B rings, X1BAmay be C and R5B1may be selected from H and a substituted or unsubstituted organic group; and R5B1is optionally H. Alternatively or additionally, X1BCmay be N and R5B3may be absent. The most preferred B ring structure is: . Ring C Ring C of the PARP1 inhibitor compound has a structure of: . X1CBis the X1atom that connects to ring B via linker QBC. X1CBis selected from N and C, and is preferably C. When X1CBis N, R5C1is absent. Rings B and C are not connected by N-N bonds. To this end, When QBCis and u=0, X1CBis C. When atom X1BCof ring B is N and QBCis absent, X1CB is C. X2Cdenotes an X2atom which is part of ring C. X2CTis the X2Catom that bears R6. Each X2Catom is independently selected from C, N, O, and S; with C and N being preferred. The X2Catoms are selected such that ring C is free of O-O, O-S, and S-S bonds. Optionally, at least one X2Catom is C. All of the X2Catoms may be C. Preferably, exactly one X2Catom is N, and each other X2Catom is C. Each R5Cis independently absent or selected from H and a substituted or unsubstituted organic group. R5C1denotes the R5Cassociated with X1CB. R5C2denotes an R5Cassociated with an X2Catom. R5C3denotes the R5associated with X2CT. Two R5Cgroups, or an R5Cgroup and R6, may be fused such that ring C is a bridged ring system. When an R5Cgroup is present, that R5Cgroup may in particular be selected from H and a halogen. The preferred halogen is F. In most examples, no more than one R5Cis a substituted or unsubstituted organic group. Optionally, each R5Cthat is not absent is selected from H and a halogen. In such examples, a proviso that no more than one R5Cis a halogen may apply. Ring C may be a 4, 5, 6, 7, or 8 membered ring. To this end, r is 0 or an integer in the range 1 to 6; s is 0 or an integer in the range 1 to 6, and r and s sum to an integer in the range 2 to 6. It is preferable for each of r and s to be at least 1. Ring C is preferably a 5- or 6- membered ring, and is particularly preferably a 6-membered ring. Put differently, r and s may sum to 3 or 4, preferably 4. Depending upon the chosen number of R5Cgroups, ring C may be a saturated ring, an unsaturated non-aromatic ring, or an aromatic ring. Ring C may be a 6-membered aliphatic ring, optionally a 6-membered aliphatic ring having structure of: each R5Cand R5C1being independently selected from H and a substituted or unsubstituted organic group, preferably wherein R5C1is H, more preferably wherein R5C1and each R5Cis H. Alternatively, ring C may be 6-membered aromatic ring. For example, ring C may be an optionally-substituted phenyl group, optionally having a structure of: each R5Cbeing independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5Cis H. In accordance with another possibility, ring C may be a pyridine group, optionally having a structure selected from: each R5Cbeing independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5Cis H. Ring C may alternatively be a diazine group, optionally having a structure selected from: each R5Cbeing independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5Cis H. Compounds wherein ring C is a 5-membered aromatic ring are also contemplated. For example, ring C may be an imidazole group, optionally an imidazole group having a structure selected from: each R5Cbeing independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5Cis H. Ring C may be a thiophene group, optionally having a structure selected from: , each R5Cbeing independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5Cis H. Ring C may be a thiazole group, optionally having a structure selected from: each R5Cbeing independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5Cis H. Ring C may be a triazole, optionally a triazole having a structure of: , R5Cbeing selected from H and a substituted or unsubstituted organic group, optionally wherein R5Cis H. Examples of ring C structures include: Particularly preferably, ring C has a structure of: where: R5C2ois selected from H, a methyl group and a halogen; and i) X2CMis C and R5C2Mis H; or ii) X2CMis N and R5C2Mis absent. Optionally, R5C2ois selected from H and a halogen. In particular, R5C2omay be a halogen, with F being the most preferred halogen. In the PARP1 inhibitor compounds provided herein, R6is absent or selected from H and a substituted or unsubstituted organic group. Preferably, R6is selected from H, -F, -Cl, -Br, -I, - CN, -CONR51R51, -NR51COR52, -SO2NR51R51, -NR51SO2R52, -O-CR52R52R52, -CR52R52NR51R51, and any of the following structures: wherein R51and R52are each independently selected from H and a substituted or unsubstituted organic group. Optionally, R51and R52are each independently selected from H, a halogen, C1 to C3 optionally-deuterated alkyl, and C1 to C3 haloalkyl. More preferably, R6is selected from -F, -Cl, -CN, -CONH2, -CONHMe (optionally -CONHCD3), - CONHEt, -CONMe2, -CONHCOMe, -CONHCH2-CH2OMe, -CONH-CH2-CH2F, -CONH-CH2-CF3, - CONH-CH2-CHF2, -OCHF2, -NHCOMe, -NHSO2Me, In accordance with another possibility, R6may have a structure of: wherein R51is selected from: a C1 to C6 alkyl group, optionally a C3 to C6 cycloalkyl group, a C1 to C3 alkyl group, or a C1 to C3 deuterated alkyl group; a C1 to C3 haloalkyl group, optionally a C1 to C3 fluoroalkyl group; and a 4-, 5-, 6-, or 7-membered saturated heterocyclic group, optionally a 4-, 5- or 6- membered cyclic ether group. For example, R6may be selected from: Optionally, R6may be selected from: The most preferred R6groups are CONHMe (i.e. . When R6is a CONHMe group, the CONHMe group is optionally deuterated: Deuterating the CONHMe group may beneficially reduce the rate at which the compound is metabolised. Where a compound, L group, or C ring substructure is depicted as having R6= CONHMe or CONHCD3, replacement of the R6group with is contemplated. Where a compound, L group, or C ring substructure is depicted as having R6= , replacement of the R6group with CONHMe (optionally CONHCD3) is contemplated. Alternatively, R6may have a structure of: wherein: each X6is independently selected from C, N, and O; R61is absent or H; each R62is independently absent or selected from H; a halo group, such as F; an oxo group; a C1 to C3 alkyl group; a C1 to C3 haloalkyl group, optionally a C1 to C3 fluoroalkyl group; and -NHR63, wherein R63is H or a C1 to C3 alkyl group. Examples of such R6groups include: The most preferred C rings are: In accordance with another possibility, ring C may be selected from: . In accordance with still another possibility, ring C may be selected from: In variants of the PARP1 inhibitor compounds provided herein, R6and one R5Cgroup together form a ring. In other words, R6and one of the R5Cgroups may be fused to form a ring system. For example, ring C may have a structure of: where: each XFis independently selected from C, N, O and S, optionally C and N; each R5Fis independently absent or selected from H and a substituted or unsubstituted organic group; and w is 1 or 2. The XFatoms are typically selected such that ring F is free of O-O, O-S, and S-S bonds. Each R5Fis preferably absent or selected from H and a carbonyl group. X2CTand X2CFeach denote X2atoms which bridge rings C and F. X2CTand X2CFare preferably each C. An example class of fused ring systems useful as ring C has a structure of: In such examples, each R5Fis H or selected from a substituted or unsubstituted organic group. Preferably, each R5Fis H or C1 to C3 alkyl. As a more specific example, ring C may have a structure of: .

[0005] In other examples of fused ring systems, ring F is an optionally-substituted benzene ring: In such examples, each R5Fis H or selected from a substituted or unsubstituted organic group. Preferably, each R5Fis H. A more specific ring C group in the above class is: . Linkers (Q groups) As shown in the formula below, the E ring, A ring, optional B ring, and C ring are connected by linkers QAE, QAB, and QBC: . The linkers may be referred to herein generically as “Q groups”. QAE, QAB, QBCand rings A to C may be referred to collectively as group L. Each linker is optionally absent. When it is said that a linker is “absent”, the moieties on either side of the linker are directly bound via a covalent bond. For example, the expressions “QAEis absent” and “QAEis a bond” are equivalent. When QAB, ring B, and QBCare all absent, there is a covalent bond between ring A and ring C. Each linker is independently absent (i.e., a bond) or selected from: where: t is a number selected from 0, 1, 2, 3, 4 and 5; and u is independently a number selected from 0, 1, 2, 3, 4 and 5; with the proviso that t + u is a number selected from 0, 1, 2, 3, 4, 5 and 6; and each R7and R8is independently selected from H and a substituted or unsubstituted organic group. When a Q group are selected such that the Q group connects to the rings via C-N bonds and not N-N bonds. Typically, t is at least 1 and u is at least 1. For example, at least one of QAE, QAB, and QBCmay be: where t + u is at least one; and where R7is selected from H, a halogen (such as –F, -Cl, -Br, and –I, preferably -F), a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted linear or branched C1-C6 halogenated alkyl group (preferably CF3), an -NH2 group or a substituted or unsubstituted C1- C6 amino group, an -OH group or a substituted or unsubstituted linear or branched C1-C6 alcohol group and a substituted or unsubstituted C1-C6 alkoxy group. In particular, R7may be selected from H, a halogen (preferably F), a substituted or unsubstituted C1-C6 alkyl group or a substituted or unsubstituted linear or branched C1-C6 halogenated alkyl group. When at least one of QAE, QABand QBChas a structure of: R8may be selected from: H; a substituted or unsubstituted linear or branched C1-C6alkyl group (such as Me, Et, Pr, i-Pr, n-Bu, i-Bu, t-Bu, pentyl and hexyl); a substituted or unsubstituted linear or branched C1-C6 alkyl-aryl group (such as –CH2Ph, -CH2(2,3 or 4)F-Ph, -CH2(2,3 or 4)Cl-Ph, -CH2(2,3 or 4)Br-Ph, -CH2(2,3 or 4)I-Ph, -CH2CH2Ph, -CH2CH2CH2Ph, -CH2CH2CH2CH2Ph, -CH2CH2CH2CH2CH2Ph, and -CH2CH2CH2CH2CH2CH2Ph); a substituted or unsubstituted linear or branched C1-C6 halogenated alkyl group (such as -CH2F, -CF3, -CH2CH2F and -CH2CF3); a substituted or unsubstituted cyclic amine or amido group (such as pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, 2-keto-pyrrolidinyl, 3-keto-pyrrolidinyl, 2-keto-piperidinyl, 3-keto-piperidinyl, and 4-keto-piperidinyl); a substituted or unsubstituted cyclic C3-C8 alkyl group (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl); a substituted or unsubstituted linear or branched C2-C6alcohol group (such as -CH2CH2OH, -CH(CH3)CH2OH, -C(CH3)2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, -CH(CH3)CH2CH2OH, -CH(CH3)CH(CH3)OH, -CH(CH2CH3)CH2OH, -C(CH3)2CH2OH, -CH2CH2CH2CH2CH2OH, and -CH2CH2CH2CH2CH2CH2OH); a substituted or unsubstituted linear or branched C2-C6carboxylic acid group (such as -CH2COOH, -CH2CH2COOH, -CH2CH2CH2COOH, -CH2CH2CH2CH2COOH, and -CH2CH2CH2CH2CH2COOH); a substituted or unsubstituted linear or branched carbonyl group (such as -(CO)Me, -(CO)Et, -(CO)Pr, -(CO)-i_Pr, -(CO)-n-Bu, -(CO)-i-Bu, -(CO)-t-Bu, -(CO)Ph, -(CO)CH2Ph, -(CO)CH2OH, -(CO)CH2OCH3, -(CO)CH2NH2,-(CO)CH2NHMe, -(CO)CH2NMe2, -(CO)-cyclopropyl, -(CO)-1,3-epoxypropan-2-yl; -(CO)NH2, -(CO)NHMe , -(CO)NMe2, -(CO)NHEt, -(CO)NEt2, -(CO)-pyrollidine-N-yl, -(CO)-morpholine-N-yl, -(CO)-piperazine-N-yl, -(CO)-N-methyl-piperazine-N-yl, -(CO)NHCH2CH2OH, -(CO)NHCH2CH2OMe, -(CO)NHCH2CH2NH2, -(CO)NHCH2CH2NHMe, and -(CO)NHCH2CH2NMe2); a substituted or unsubstituted linear or branched C1-C6 carboxylic acid ester group (such as -COOMe, -COOEt, -COOPr, -COO-i-Pr, -COO-n-Bu, -COO-i-Bu, -COO-t- Bu, -CH2COOMe, -CH2CH2COOMe, -CH2CH2CH2COOMe, and -CH2CH2CH2CH2COOMe); a substituted or unsubstituted linear or branched C1-C6 amide group (such as -CO-NH2, -CO-NMeH, -CO-NMe2, -CO-NEtH, -CO-NEtMe, -CO-NEt2, -CO-NPrH, -CO-NPrMe, and -CO-NPrEt); a substituted or unsubstituted sulfonyl group (such as -SO2Me, -SO2Et, -SO2Pr, -SO2iPr, -SO2Ph, -SO2-(2,3 or 4)-F-Ph, -SO2-cyclopropyl, -SO2CH2CH2OCH3), -SO2NH2, -SO2NHMe, -SO2NMe2, -SO2NHEt, -SO2NEt2, -SO2-pyrrolidine-N-yl, -SO2-morpholine-N-yl, -SO2NHCH2OMe, and -SO2NHCH2CH2OMe); a substituted or unsubstituted aromatic group (such as Ph-, 2-F-Ph-, 3-F-Ph-, 4-F-Ph-, 2-Cl-Ph-, 3-Cl-Ph-, 4-Cl-Ph-, 2-Br-Ph-, 3-Br-Ph-, 4-Br-Ph-, 2-I-Ph-, 3-I-Ph, 4-I-Ph-, 2,(3,4,5 or 6)-F2-Ph-, 2,(3,4,5 or 6)-Cl2-Ph-, 2,(3,4,5 or 6)-Br2-Ph-, 2,(3,4,5 or 6)-I2-Ph-, 2,(3,4,5 or 6)-Me2-Ph-, 2,(3,4,5 or 6)-Et2-Ph-, 2,(3,4,5 or 6)-Pr2-Ph-, 2,(3,4,5 or 6)-Bu2-Ph-, 2,(3,4,5 or 6)-(CN)2-Ph-, 2,(3,4,5 or 6)-(NO2)2-Ph-, 2,(3,4,5 or 6)-(NH2)2-Ph-, 2,(3,4,5 or 6)-(MeO)2-Ph-, 2,(3,4,5 or 6)-(CF3)2-Ph-, 3,(4 or 5)-F2-Ph-, 3,(4 or 5)-Cl2-Ph-, 3,(4 or 5)-Br2-Ph-, 3,(4 or 5)-I2-Ph-, 3,(4 or 5)-Me2-Ph-, 3,(4 or 5)-Et2-Ph-, 3,(4 or 5)-Pr2-Ph-, 3,(4 or 5)-Bu2-Ph-, 3,(4 or 5)-(CN)2-Ph-, 3,(4 or 5)-(NO2)2-Ph-, 3,(4 or 5)-(NH2)2-Ph-, 3,(4 or 5)-(MeO)2-Ph-, 3,(4 or 5)-(CF3)2-Ph-, 2-Me-Ph-, 3-Me-Ph-, 4-Me-Ph-, 2-Et-Ph-, 3-Et-Ph-, 4-Et-Ph-, 2-Pr-Ph-, 3-Pr-Ph-, 4-Pr-Ph-, 2-Bu-Ph-, 3-Bu-Ph-, 4-Bu-Ph-, 2-(CN)-Ph-, 3-(CN)-Ph-, 4-(CN)-Ph-, 2-(NO2)-Ph-, 3-(NO2)-Ph-, 4-(NO2)-Ph-, 2-(NH2)-Ph-, 3-(NH2)-Ph-, 4-(NH2)-Ph-, 2-MeO-Ph-, 3-MeO-Ph-, 4-MeO-Ph-, 2-(NH2-CO)-Ph-, 3-(NH2-CO)-Ph-, 4-(NH2-CO)-Ph-, 2-CF3-Ph-, 3-CF3-Ph-, 4-CF3-Ph-, 2-CF3O-Ph-, 3-CF3O-Ph-, and 4-CF3O-Ph-); and a substituted or unsubstituted heterocyclic group (such as pyrrole-2-yl, pyrrole-3-yl, pyrazole-3-yl, pyrazole-4-yl, pyrazole-5-yl, imidazole-2-yl, imidazole-4-yl, imidazole-5-yl, 1,2,3-triazole-4-yl, 1,2,3-triazole-5-yl, 1,2,4-triazole-3-yl, 1,2,4-triazole-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazine-3-yl, pyridazine-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, pyrazine-2-yl, pyrrolidine-2-yl, pyrrolidine-3-yl, piperidine-2-yl, piperidine-3-yl, piperidine-4-yl, 2-azapiperidine-3-yl, 2-azapiperidine-4-yl, 3-azapiperidine-2-yl, 3-azapiperidine-4-yl, 3-azapiperidine-5-yl, piperazine-2-yl, furan-2-yl, furan-3- yl, pyran-2-yl, pyran-3-yl, pyran-4-yl, 2-azapyran-3-yl, 2-azapyran-4-yl, 2-azapyran-5-yl, 2-azapyran-6-yl, 3-azapyran-2-yl, 3-azapyran-4-yl, 3-azapyran-5-yl, 3-azapyran-6-yl, 4-azapyran-2-yl, 4-azapyran-3-yl, 4-azapyran-5-yl, 4-azapyran-6-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-4-yl, 2-aza-tetrahydrofuran-5-yl, 3-aza-tetrahydrofuran-2-yl, 3-aza-tetrahydrofuran-4-yl, 3-aza-tetrahydrofuran-5-yl, tetrahydropyran-2-yl, oxetan-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, 2-aza-tetrahydropyran-3-yl, 2-aza-tetrahydropyran-4-yl, 2-aza-tetrahydropyran-5-yl, 2-aza-tetrahydropyran-6-yl, 3-aza-tetrahydropyran-2-yl, 3-aza-tetrahydropyran-4-yl, 3-aza-tetrahydropyran-5-yl, 3-aza-tetrahydropyran-6-yl, morpholine-2-yl, morpholine-3-yl, thiophen-2-yl, thiophen-3-yl, isothiazole-3-yl, isothiazole-4-yl, isothiazole-5-yl, thiazole-2-yl, thiazole-4-yl, thiazole-5-yl, thiopyran-2-yl, thiopyran-3-yl, thiopyran-4-yl, 2-azathiopyran-3-yl, 2-azathiopyran-4-yl, 2-azathiopyran-5-yl, 2-azathiopyran-6-yl, 3-azathiopyran-2-yl, 3-azathiopyran-4-yl, 3-azathiopyran-5-yl, 3-azathiopyran-6-yl, 4-azathiopyran-2-yl, 4-azathiopyran-3-yl, 4-azathiopyran-5-yl, 4-azathiopyran-6-yl, thiolane-2-yl, thiolane-3-yl, thiane-2-yl, thiane-3-yl, thiane-4-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, furazan-3-yl, (1,3,4-oxadiazol)-2-yl, (1,3,4-oxadiazol)-5-yl, (1,2,4-oxadiazol)-3-yl, (1,2,4-oxadiazol)-5-yl; and tetrazole-5-yl). In particular, R8may be selected from H, a substituted or unsubstituted C1-C6 alkyl group or a substituted or unsubstituted linear or branched C1-C6 halogenated alkyl group. Preferably, QAEis absent or -CH2-. More preferably, QAEis absent. Preferably, QABis absent or -CH2-. More preferably, QABis absent. When QABis absent, group L may have a structure of: . Preferably, QBCis absent or -CH2-. More preferably, QBCis absent. Both QABand QBCmay be absent. In such examples, group L may have a structure of: .

[0006] Most preferably, ring b is present, and all of QAE, QAB, and QBCare absent. In such examples, the PARP1 inhibitor compound may have a structure of: Example L groups In particular, group L may have a structure selected from: ,

[0007] . R5A, R5B, R5C, and R6are as defined hereinabove. Especially preferred L groups are those in which: each R5A(e.g., R5A1) is H; each R5Bis H; each R5Cis independently selected from H, a methyl group and a halogen (preferably F), with the proviso that no more than one R5Cis a methyl group or a halogen; and Optionally, each R5Cis independently selected from H and a halogen (preferably F), with the proviso that no more than one R5Cis a halogen. Group L may in particular have a structure selected from: In accordance with another possibility, L may be: Example Compounds In particular, there are provided PARP1 inhibitor compounds having a structure of: where: Z1is C or N; one of Z2uand Z2lis C, and the other of Z2uand Z2lis N; each Z3is independently selected from C and N; R1is absent or selected from H, a halogen (e.g., F), methyl, halomethyl (e.g., CF3), and CN; R5C2ois H, a methyl group, or a halogen (e.g., F); X2CMis N and R5C2Mis absent or X2CMis C and R5C2Mis H; and Optionally, R5C2ois H or a halogen, such as F. R1may be selected from H, a halogen (e.g., F), methyl, halomethyl (e.g., CF3), and CN. Specific PARP1 inhibitor compounds include:

[0008] 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. 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. In particular, 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. 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 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-CTLA4, anti-PD1, 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-I 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. Pharmaceutical Compositions Another aspect provides a pharmaceutical composition comprising the PARP1 inhibitor compound as defined above. 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-PD1, 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-I 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-PD1, 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-I 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. Methods of synthesising PARP1 inhibitor compounds Also provided are methods for synthesising the PARP1 inhibitor compounds as defined herein. In general, the method comprises conducting a reaction between: i) a first reactant comprising rings D and E and bearing a first portion of group L and ii) a second reactant comprising a remainder of group L, to form the PARP1 inhibitor compound. The skilled person may select reaction conditions with reference to known synthesis techniques depending on the appropriate starting materials. The method may comprise one or more additional steps. Exemplary synthesis methodology is shown in the Examples hereinbelow. In one example method, the first reactant comprises rings D, E and A, and the second reactant comprises a QABprecursor bearing a reactive group, and the method comprises joining ring A to the QABprecursor. In this method, the reactive group of the QABprecursor may comprise a carbonyl group, an alkyl halide, or an alkyl sulfonate. The reaction may comprise alkylation, reductive amination, or amide formation so as to form group L. In some implementations of this example method, the first reactant has a structure of:

[0009] The first reactant may be prepared by deprotecting an intermediate product having a structure of: , where RPGis a protecting group. It will be appreciated that the R1, R2, R5, X, and Z groups are as previously defined with reference to the PARP1 inhibitor compound. The first reactant may be prepared by providing a precursor having a structure of: and performing a ring closure reaction by treating the precursor with NHR3or a conjugate acid thereof to form the first reactant. R3is as previously described with reference to the compound aspect. R9is a C1 to C6 alkyl group, optionally an ethyl group. RPGmay be Boc. R3may be H. Z2lmay be N and Z2umay be C. In some implementations, Z1is C and the precursor may have a structure of: .

[0010] In alternative implementations, Z1is N and the precursor has a structure of: . The above precursor may be obtained by: a) reacting a compound having a structure of: with a phenylhydroxylamine having a structure of: wherein EWG represents one or more electron withdrawing groups; in the presence of a base, such as sodium hydride, to obtain an intermediate product having a structure of: b) reacting the intermediate product with a carboxylic acid having a structure of: to obtain the precursor. In this method, the substituted phenyl hydroxylamine may be O-(2,4- dinitrophenyl)hydroxylamine: . An alternative method for preparing a first reactant having a structure of: comprises: a) providing a first precursor having a structure of: wherein R10is a C1 to C6 alkyl group, optionally a t-butyl group; b) providing a second precursor having a structure of: wherein RPGis a protecting group, optionally Boc; and c) coupling the first precursor and the second precursor using a catalyst, optionally a [Cp*RhCl2]2catalyst, to form the first reactant. The second reactant may have a structure of: . The second reactant may be prepared by: i) providing a first precursor of formula: wherein: a) X2CMis C and R5C2Mis H; or b) X2CMis N and R5C2Mis absent. ii) providing a second precursor of formula: iii) coupling the first and second precursor using a base, optionally a caesium base such as Cs2CO3, to obtain an intermediate product of formula: iv) treating the intermediate product with an acid to obtain the second reactant, wherein the second reactant has a structure of: . The second precursor is 1,4-dioxa-8-azaspiro[4.5]decane: . Conducting the reaction may comprise coupling the first reagent and the second reagent using a reducing agent in the presence of an acid. In another example method, the first reactant comprises rings A, B, D, and E, QAEand QAB, and the second reactant comprises a ring C derivative bearing a leaving group such as a halide or sulfonate. In this method, the reaction may comprise a nucleophilic substitution reaction, such as a nucleophilic aromatic substitution reaction, so as to form group L. The PARP1 inhibitor compound may be obtained as a mixture of structural isomers. In such implementations, the method may further comprise separating the structural isomers using chiral supercritical fluid chromatography and / or chiral high-performance liquid chromatography.

[0011] Examples Example 1: Synthesis of 1a / 1b Preparation of tert-butyl 3-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (1003) To a solution of 1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid 1001 (5.0 g, 0.0231 mol) in DCM (200 mL) were added N,O-dimethylhydroxylamine hydrochloride 1002 (4.5 g, 0.0462 mol), DIPEA (14.9 g, 0.115 mol) and HATU (17.6 g, 0.0462 mol). The mixture was stirred at rt for 2 h, diluted with water (1.6 L) and extracted with EtOAc (200 mL × 3). The combined organic layer was washed with brine, dried over Na2SO4, concentrated to obtain tert-butyl 3- (methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate 1003 (6.0 g, 80 % purity, 80 % yield) as a colourless oil. LCMS (ESI) calcd for C12H22N2O4 [M - 56 + H]+m / z 203.10, found 202.95. Preparation of tert-butyl 3-acetylpyrrolidine-1-carboxylate (1004) To a solution of tert-butyl 3-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate 1003 (6.0 g, 0.0231 mol) in THF (300 mL) at -78 °C under N2 atmosphere was added MeMgBr (38.5 mL, 0.1155 mol, 3 M in THF). The mixture was stirred at 0 °C for 1 h, quenched with saturated NH4Cl solution and extracted with EtOAc (100 mL × 3). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under vacuo to obtain tert-butyl 3- acetylpyrrolidine-1-carboxylate 1004 (3.5 g, 90 % purity, 63 % yield) as a colourless oil. LCMS (ESI) calcd for C11H19NO3[M - 56 + H]+m / z 158.08, found 158.00. Preparation of tert-butyl 3-(2-bromoacetyl)pyrrolidine-1-carboxylate (1005) To a solution of tert-butyl 3-acetylpyrrolidine-1-carboxylate 1004 (1.2 g, 5.6 mmol) in DCM / MeOH (2:1, 30 mL) was added TBABr3 (5.4 g, 11.2 mol) at rt. The mixture was kept stirring at rt for 16 h. The resulting mixture was diluted with water and extracted with DCM (30 mL × 3). The combined organic layer was dried over Na2SO4and concentrated under reduced pressure. The residue was purified by flash silica chromatography (eluting with EtOAc / PE, 30 % to 40 %) to give tert-butyl 3-(2-bromoacetyl)pyrrolidine-1-carboxylate 1005 (300 mg, 50 % purity, 8 % yield) as a colourless oil. LCMS (ESI) calcd for C11H18BrNO3[M - 56 + H]+m / z 235.99, found 235.85. Preparation of ethyl 1-(2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-2-oxoethyl)-5-methyl-1H- pyrrole-2-carboxylate (1007) To a solution of ethyl 5-methyl-1H-pyrrole-2-carboxylate 1006 (157 mg, 1.02 mmol) and Cs2CO3(667 mg, 2.05 mmol) in DMF (10 mL) was added tert-butyl 3-(2- bromoacetyl)pyrrolidine-1-carboxylate 1005 (300 mg, 1.02 mmol). The mixture was heated at 50 °C for 1 h. The reaction mixture was quenched with water and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with EtOAc / PE, 30 % to 50 %) to give ethyl 1-(2-(1-(tert-butoxycarbonyl)pyrrolidin-3- yl)-2-oxoethyl)-5-methyl-1H-pyrrole-2-carboxylate 1007 (130 mg, 50 % purity, 17 % yield) as a yellow oil. LCMS (ESI) calcd for C19H28N2O5 [M + H]+m / z 365.20, found 365.03. Preparation of tert-butyl 3-(6-methyl-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazin-3- yl)pyrrolidine-1-carboxylate (1008) A solution of ethyl 1-(2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-2-oxoethyl)-5-methyl-1H- pyrrole-2-carboxylate 1007 (130 mg, 0.35 mmol) in NH3-MeOH (7 M, 20 mL) was stirred at 110 °C for 16 h in a sealed tube. The resulting mixture was concentrated, and purified by silica gel column chromatography (eluting with EtOAc / PE, 50 % to 70 %) to give tert-butyl 3-(6- methyl-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazin-3-yl)pyrrolidine-1-carboxylate 1008 (60 mg, 90 % purity, 47 % yield) as a white solid. LCMS (ESI) calcd for C17H23N3O3[M + H]+m / z 318.18, found 318.15. Preparation of 6-methyl-3-(pyrrolidin-3-yl)pyrrolo[1,2-a]pyrazin-1(2H)-one hydrochloride (1009) A solution of tert-butyl 3-(6-methyl-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazin-3-yl)pyrrolidine- 1-carboxylate 1008 (60 mg, 0.19 mmol) in HCl-dioxane solution (4 M, 5 mL) was stirred at rt for 2 h. The mixture was concentrated under reduced pressure and triturated in DCM. The precipitate was collected and dried under vacuum to provide 6-methyl-3-(pyrrolidin-3- yl)pyrrolo[1,2-a]pyrazin-1(2H)-one hydrochloride 1009 (50 mg, 80 % purity, 83 % yield) as a white solid. LCMS (ESI) calcd for C12H15N3O [M + H]+m / z 218.12, found 218.15. Preparation of racemic N-methyl-5-(4-(3-(6-methyl-1-oxo-1,2-dihydropyrrolo[1,2- a]pyrazin-3-yl)pyrrolidin-1-yl)piperidin-1-yl)picolinamide (1rac) To a solution of 6-methyl-3-(pyrrolidin-3-yl)pyrrolo[1,2-a]pyrazin-1(2H)-one hydrochloride 1009 (50 mg, 0.20 mmol) in MeOH (5 mL) were added N-methyl-5-(4-oxopiperidin-1- yl)pyridine-2-carboxamide INT-1 (80 mg, 0.34 mmol), 2 drops of AcOH, NaBH3CN (14 mg, 0.23 mmol) and NaBH(OAc)3 (146 mg, 0.69 mmol). The reaction mixture was stirred at rt for 1 h, quenched with 2 drops of water and concentrated under reduced pressure. The residue was purified by prep-HPLC (Gemini 5 μm C18150 × 21.2 mm, eluting with 40 % to 80 % ACN / H2O containing 0.05 % NH3·H2O) to give N-methyl-5-(4-(3-(6-methyl-1-oxo-1,2- dihydropyrrolo[1,2-a]pyrazin-3-yl)pyrrolidin-1-yl)piperidin-1-yl)picolinamide 1rac, a racemic mixture of 1a and 1b (20 mg, 95 % purity, 22 % yield) as a white solid. Chiral separation of racemic N-methyl-5-(4-(3-(6-methyl-1-oxo-1,2-dihydropyrrolo[1,2- a]pyrazin-3-yl)pyrrolidin-1-yl)piperidin-1-yl)picolinamide (1rac) to obtain 1a and 1b The N-methyl-5-(4-(3-(6-methyl-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazin-3-yl)pyrrolidin-1- yl)piperidin-1-yl)picolinamide racemic mixture 1rac was separated by SFC (Column: Daicel Chiralpak IH 20 mm I.D. × 250 mm, 5 μm; Mobile phase: CO2 / MeOH (0.1 % NH3) = 70 / 30) and concentrated under reduced pressure to afford the first fraction as 1a (4.7 mg, 94 % purity, 100 % ee, white solid) and the second fraction as 1b (3.8 mg, 96 % purity, 100 % ee, white solid) 1a1H NMR (400 MHz, DMSO-d6, ppm) δ: 10.18 (s, 1 H), 8.46-8.31 (m, 1 H), 8.28 (d, J = 2.8 Hz, 1 H), 7.82 (d, J = 8.8 Hz, 1 H), 7.40 (dd, J = 8.8, 2.8 Hz, 1 H), 6.99 (s, 1 H), 6.75 (d, J = 3.6 Hz, 1 H), 6.28 (d, J = 4.0 Hz, 1 H), 3.93-3.71 (m, 2 H), 3.18-3.07 (m, 1 H), 2.99 (t, J = 11.6 Hz, 2 H), 2.90- 2.75 (m, 5 H), 2.73-2.64 (m, 2 H), 2.33 (s, 3 H), 2.20-2.13 (m, 1 H), 2.00-1.91 (m, 2 H), 1.89- 1.80 (m, 1 H), 1.62-1.50 (m, 2 H). LCMS (ESI) calcd for C24H30N6O2[M + H]+m / z 435.25, found 435.09. 1b1H NMR (400 MHz, DMSO-d6, ppm) δ: 10.17 (s, 1 H), 8.38 (q, J = 4.7 Hz, 1 H), 8.28 (d, J = 2.8 Hz, 1 H), 7.82 (d, J = 8.8 Hz, 1 H), 7.40 (dd, J = 8.8, 2.8 Hz, 1 H), 6.99 (s, 1 H), 6.75 (d, J = 3.6 Hz, 1 H), 6.28 (d, J = 3.6 Hz, 1 H), 3.85-3.74 (m, 2 H), 3.15-3.05 (m, 1 H), 2.99 (t, J = 11.6 Hz, 2 H), 2.90-2.81 (m, 2 H), 2.78 (d, J = 4.8 Hz, 3 H), 2.73-2.62 (m, 2 H), 2.33 (s, 3 H), 2.22-2.10 (m, 1 H), 2.01-1.90 (m, 2 H), 1.89-1.77 (m, 1 H), 1.61-1.45 (m, 2 H). LCMS (ESI) calcd for C24H30N6O2[M + H]+m / z 435.25, found 435.12. Example 2: Synthesis of 2rac Preparation of ethyl 1-(2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-2-oxoethyl)-3-methyl-1H- pyrazole-5-carboxylate (1102) To a solution of ethyl 3-methyl-1H-pyrazole-5-carboxylate 1101 (110 mg, 0.71 mmol) in DMF (5 mL) at room temperature were added tert-butyl 3-(2-bromoacetyl)pyrrolidine-1- carboxylate 1005 (230 mg, 0.78 mmol) and Cs2CO3 (465 mg, 1.43 mmol). The reaction mixture was stirred at rt for 1 h. The reaction solution was quenched with ice-water and extracted with EtOAc (30 mL x 3). The organic phase was concentrated under reduced pressure and the residue was purified by flash chromatography (eluting with PE / EtOAc = 100 : 0 to 70: 30) to give ethyl 1-(2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-2-oxoethyl)-3-methyl-1H-pyrazole-5- carboxylate 1102 (40 mg, 80 % purity, 12 % yield) as a yellow oil. LCMS (ESI) calcd for C18H27N3O5 [M + H]+m / z 366.20, found 366.35. Preparation of tert-butyl 3-(2-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]pyrazin-6- yl)pyrrolidine-1-carboxylate (1103) To a solution of ethyl 1-(2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-2-oxoethyl)-3-methyl-1H- pyrazole-5-carboxylate 1102 (40 mg, 0.11 mmol) in EtOH (3 mL) at room temperature was added NH4OAc (170 mg, 2.20 mmol). The reaction mixture was stirred at 110 °C for 8 h in a sealed tube. The reaction solution was concentrated under reduced pressure and the residue was purified by flash chromatography (eluting with PE / EtOAc = 100 : 0 to 30: 70) to obtain tert-butyl 3-(2-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]pyrazin-6-yl)pyrrolidine-1- carboxylate 1103 (23 mg, 80 % purity, 42 % yield) as a yellow oil. LCMS (ESI) calcd for C16H22N4O3 [M - t-Bu + H]+m / z 263.17, found 263.20. Preparation of 2-methyl-6-(pyrrolidin-3-yl)pyrazolo[1,5-a]pyrazin-4(5H)-one hydrochloride (1104) To a solution of tert-butyl 3-(2-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]pyrazin-6- yl)pyrrolidine-1-carboxylate 1103 (23 mg, 0.072 mmol) in DCM (2 mL) at room temperature was added 4 M HCl / dioxane (5 mL). The reaction mixture was stirred at rt for 1 h. The reaction solution was concentrated under reduced pressure to obtain 2-methyl-6-(pyrrolidin-3- yl)pyrazolo[1,5-a]pyrazin-4(5H)-one hydrochloride 1104 (20 mg, 80 % purity, 87 % yield) as a yellow solid. LCMS (ESI) calcd for C11H14N4O [M + H]+m / z 219.12, found 219.10. Preparation of racemic N-methyl-5-(4-(3-(2-methyl-4-oxo-4,5-dihydropyrazolo[1,5- a]pyrazin-6-yl)pyrrolidin-1-yl)piperidin-1-yl)picolinamide (2rac) To a solution of 2-methyl-6-(pyrrolidin-3-yl)pyrazolo[1,5-a]pyrazin-4(5H)-one hydrochloride 1104 (20 mg, 0.092 mmol) in MeOH (1 mL) was added TEA (1 mL) at rt and stirred for 5 mins, then the reaction was concentrated to dryness under reduced pressure. The residue was dissolved in MeOH (5 mL) and AcOH (0.1 mL) at room temperature. N-methyl-5-(4- oxopiperidin-1-yl)pyridine-2-carboxamide INT-1 (26 mg, 0.11 mmol) and NaBH3CN (12 mg, 0.19 mmol) were added at rt. The reaction mixture was then stirred at 50 °C for 1 h. The resulting reaction solution was concentrated under reduced pressure and the residue was purified by flash chromatography (eluting with DCM / MeOH = 100 : 0 to 90: 10) and prep-HPLC (Gemini 5 µm C18150 × 21.2 mm, mobile phase: ACN - H2O (0.1% FA), gradient: 40 - 95) to give N-methyl-5-(4-(3-(2-methyl-4-oxo-4,5-dihydropyrazolo[1,5-a]pyrazin-6-yl)pyrrolidin-1- yl)piperidin-1-yl)picolinamide racemic 2rac (6.9 mg, 98 % purity, 17 % yield) as a white solid. 1H NMR (400 MHz, DMSO-d6, ppm) δ: 11.03 (s, 1 H), 8.42-8.34 (m, 1 H), 8.28 (d, J = 2.8 Hz, 1 H), 8.14 (s, 0.9 H), 7.82 (d, J = 8.8 Hz, 1 H), 7.49 (s, 1 H), 7.40 (dd, J = 8.8, 2.8 Hz, 1 H), 6.70 (s, 1 H), 3.88-3.79 (m, 2 H), 3.20-3.13 (m, 1 H), 3.00-2.92 (m, 3 H), 2.88-2.82 (m, 1 H), 2.78 (d, J = 4.8 Hz, 3 H), 2.76-2.69 (m, 2 H), 2.44-2.40 (m, 1 H),2.31 (s, 3 H), 2.22-2.13 (m, 1 H), 2.00-1.92 (m, 2 H), 1.90-1.81 (m, 1 H), 1.60-1.47 (m, 2 H). LCMS (ESI) calcd for C23H29N7O2[M + H]+m / z 436.24, found 436.25.

[0012] Example 3: Synthesis of 6rac Preparation of 1H-pyrrole-1-carboxylic acid (1202) To an ice-cold solution of t-BuOK (4.23 g, 37.7 mmol) in 120 mL of Et2O / THF (1:1) was slowly added 1H-pyrrole 1201 (2.3 g, 34.3 mmol). The reaction mixture was warmed to room temperature and stirred for 30 min. Following this time, excess solid CO2was slowly added through the top of the flask causing vigorous bubbling and a drop in the reaction temperature. The reaction vessel was placed in a room temperature water bath and allowed to stand until no solid CO2remained at the bottom of the flask.300 mL of H2O was added, and the contents were transferred to a separatory funnel. The aqueous layer was collected, and the organic phase was washed with 300 mL of H2O. The combined aqueous extracts were acidified to pH < 1 with 1.0 M aqueous HCl. To this aqueous solution was then added 40 mL of Et2O and the contents were transferred again to a separatory funnel. The organic phase was collected, and the aqueous phase was extracted with 2 x 40 mL of Et2O. The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 1H-pyrrole- 1-carboxylic acid 1202 (1.6 g, 90 % purity, 37 % yield) as a white solid. LCMS (ESI) calcd for C5H5NO2 [M + H]+m / z 112.04, no MS signal. Preparation of N-(pivaloyloxy)-1H-pyrrole-1-carboxamide (1204) To a stirred solution of (COCl)2(1.26 g, 9.90 mmol) in THF (25 mL) was added DMF (0.070 g, 0.90 mmol) at 0 °C. The reaction mixture was stirred for 10 min and 1H-pyrrole-1-carboxylic acid 1202 (1.0 g, 9.00 mmol) was added at 0 °C in two portions. The reaction mixture was stirred for 15 min at 0 °C, cooling bath was removed and then the reaction mixture was stirred at rt for 30 min. The solvent was evaporated under reduced pressure to obtain a crude acid chloride. In another round bottom flask containing a stirred solution of Na2CO3(1.91 g, 18.00 mmol) in EtOAc (40 mL) and water (20 mL) was added O-pivaloylhydroxylamine trifluoromethanesulfonate 1203 (2.4 g, 9.00 mmol) at 0 °C, followed by the addition of the acid chloride in EtOAc (5 mL). The reaction mixture was stirred at 0 °C for 2 h, the progress of the reaction was monitored by TLC, and EtOAc (60 mL) was added to it. The two layers were separated, and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic layer was dried over sodium sulphate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluting with EtOAc / PE, 20 % to 40 %) to obtain N-(pivaloyloxy)-1H-pyrrole-1-carboxamide 1204 (0.60 g, 90 % purity, 28 % yield) as a white solid. LCMS (ESI) calcd for C10H14N2O3 [M - H] - m / z 209.09, found 209.10. Preparation of tert-butyl 3-(1-oxo-1,2-dihydropyrrolo[1,2-c]pyrimidin-3-yl)pyrrolidine-1- carboxylate (1206) and tert-butyl 3-(1-oxo-1,2-dihydropyrrolo[1,2-c]pyrimidin-4- yl)pyrrolidine-1-carboxylate (1206a) To a stirred solution of N-(pivaloyloxy)-1H-pyrrole-1-carboxamide 1204 (0.6 g, 2.85 mmol) in MeOH (20 mL) were added AcOCs (0.55 g, 2.85 mmol), [Rh(Cp*)Cl2]2 (0.17 g, 2.85 mmol) and tert-butyl 3-ethynylpyrrolidine-1-carboxylate 1205 (0.56 g, 2.85 mmol). The reaction mixture was stirred at rt for 1 h. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated and purified by flash chromatography (eluting with EtOAc / PE, 30 % to 60 %) to obtain tert-butyl 3-(1-oxo-1,2-dihydropyrrolo[1,2-c]pyrimidin-3-yl)pyrrolidine- 1-carboxylate 1206 (300 mg, 90 % purity, 31 % yield) and tert-butyl 3-(1-oxo-1,2- dihydropyrrolo[1,2-c]pyrimidin-4-yl)pyrrolidine-1-carboxylate 1206a (200 mg, 90 % purity, 21 % yield) as a yellow solid. 1206: LCMS (ESI) calcd for C16H21N3O3 [M + H]+m / z 304.16, found 303.97. 1206a: LCMS (ESI) calcd for C16H21N3O3[M + H]+m / z 304.16, found 303.95. Preparation of 3-(pyrrolidin-3-yl)pyrrolo[1,2-c]pyrimidin-1(2H)-one hydrochloride (1207) A solution of tert-butyl 3-(1-oxo-1,2-dihydropyrrolo[1,2-c]pyrimidin-3-yl)pyrrolidine-1- carboxylate 1206 (100 mg, 0.32 mmol) in HCl dioxane solution (4 M, 10 mL) was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure to provide 3-(pyrrolidin-3-yl)pyrrolo[1,2-c]pyrimidin-1(2H)-one hydrochloride 1207 (80 mg, 90 % purity, 94 % yield) as a brown solid. LCMS (ESI) calcd for C11H13N3O [M + H]+m / z 204.11, found 204.10. Preparation of racemic N-methyl-5-(4-(3-(1-oxo-1,2-dihydropyrrolo[1,2-c]pyrimidin-3- yl)pyrrolidin-1-yl)piperidin-1-yl)picolinamide (6rac) To a solution of 3-(pyrrolidin-3-yl)pyrrolo[1,2-c]pyrimidin-1(2H)-one hydrochloride 1207 (80 mg, 0.34 mmol) in MeOH (10 mL) were added N-methyl-5-(4-oxopiperidin-1-yl)picolinamide INT-1 (120 mg, 0.52 mmol), two drops of acetic acid, NaBH3CN (22 mg, 0.34 mmol) and NaBH(OAc)3(146 mg, 0.69 mmol) at rt. The reaction mixture was stirred at rt for 1 h. The resulting solution was quenched with water and concentrated under reduced pressure. The residue was purified by prep-HPLC (Gemini-C18150 x 21.2 mm, eluting with 15% to 45% ACN / H2O containing 0.05% NH3) to give N-methyl-5-(4-(3-(1-oxo-1,2-dihydropyrrolo[1,2- c]pyrimidin-3-yl)pyrrolidin-1-yl)piperidin-1-yl)picolinamide 6rac racemate (5.1 mg) as a white solid.1H NMR (400 MHz, DMSO-d6, ppm) δ: 10.70 (s, 1 H), 8.41-8.35 (m, 1 H), 8.31-8.28 (m, 1.4 H), 8.28-8.25 (m, 1 H), 7.82 (d, J = 8.8 Hz, 1 H), 7.44-7.35 (m, 2 H), 6.57 (t, J = 3.2 Hz, 1 H), 6.35 (s, 1 H), 6.22-6.17 (m, 1 H), 3.84-3.79 (m, 2 H), 3.13-3.08 (m, 1 H), 2.99-2.90 (m, 3 H), 2.81-2.74 (m, 4 H), 2.70-2.64 (m, 2 H), 2.37-2.32 (m, 1 H), 2.24-2.11 (m, 1 H), 1.99-1.91 (m, 2 H), 1.84- 1.76 (m, 1 H), 1.60-1.48 (m, 2 H). LCMS (ESI) calcd for C23H28N6O2[M + H]+m / z 421.23, found 421.35. Example 4: Synthesis of 8rac Preparation of 6-bromo-8-methoxyimidazo[1,2-a]pyrazine (1302) Sodium hydride (60 % dispersion in mineral oil, 173 mg, 4.333 mmol) was added portionwise to a mixture of 6,8-dibromoimidazo[1,2-a]pyrazine 1301 (1000 mg, 3.611 mmol) in MeOH (30 mL) and then the reaction was stirred at rt for 2 hours. The reaction mixture was quenched by water and most MeOH was removed by evaporation. The residue was extracted with EtOAc three times. The combined organic layers were washed with water and brine, concentrated in vacuo and purified by flash silica chromatography (eluting with MeOH / DCM, 0 to 8 %) to 6-bromo-8-methoxyimidazo[1,2-a]pyrazine 1302 (680 mg, 90 % purity, 74 % yield) as a yellow solid. LCMS (ESI) calcd for C7H6BrN3O [M + H]+m / z 227.97, found 227.85. Preparation of tert-butyl 3-(8-methoxyimidazo[1,2-a]pyrazin-6-yl)-2,5-dihydro-1H-pyrrole- 1-carboxylate (1304) A suspension of tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H- pyrrole-1-carboxylate 1303 (324 mg, 1.096 mmol), 6-bromo-8-methoxyimidazo[1,2- a]pyrazine 1302 (250 mg, 1.096 mmol), Na2CO3(228 mg, 2.192 mmol) and Pd(dppf)Cl2(80 mg, 0.109 mmol) in dioxane / H2O (4 / 1, 10 mL) was heated at 90 °C for 2 h under N2. After cooling to rt, the reaction mixture was poured into ice water and then extracted with EtOAc (50 mL × 3). The combined organic layers were washed with water, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash silica chromatography (eluting with EtOAc / PE, 0 to 85 %) to give tert-butyl 3-(8- methoxyimidazo[1,2-a]pyrazin-6-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate 1304 (220 mg, 90 % purity, 56 % yield) as a white solid. LCMS (ESI) calcd for C16H20N4O3 [M + H]+m / z 317.15, found 317.15. Preparation of tert-butyl 3-(8-methoxyimidazo[1,2-a]pyrazin-6-yl)pyrrolidine-1- carboxylate (1305) A solution of tert-butyl 3-(8-methoxyimidazo[1,2-a]pyrazin-6-yl)-2,5-dihydro-1H-pyrrole-1- carboxylate 1304 (220 mg, 0.693 mmol) and Pd / C (10 %, 147 mg) in MeOH (10 mL) was stirred at rt for 2 h under H2 atmosphere. The resulting solution was filtered and concentrated under reduced pressure to afford tert-butyl 3-(8-methoxyimidazo[1,2-a]pyrazin-6-yl)pyrrolidine-1- carboxylate 1305 (180 mg, 90 % purity, 73 % yield) as a white solid. LCMS (ESI) calcd for C16H22N4O3 [M + H]+m / z 319.17, found 319.25. Preparation of 6-(pyrrolidin-3-yl)imidazo[1,2-a]pyrazin-8(7H)-one (1306) A solution of tert-butyl 3-(8-methoxyimidazo[1,2-a]pyrazin-6-yl)pyrrolidine-1-carboxylate 1305 (180 mg, 0.563 mmol) in HBr in H2O (48 wt.%, 5 mL) was stirred at 100 °C for 2 h. The reaction mixture was concentrated. The residue was diluted with MeOH (5 mL), added TEA (1 mL) and stirred for 5 min, and then concentrated to dryness to obtain 6-(pyrrolidin-3- yl)imidazo[1,2-a]pyrazin-8(7H)-one 1306 (100 mg, 90 % purity, 78 % yield) as a yellow oil. LCMS (ESI) calcd for C10H12N4O [M + H]+m / z 205.10, found 205.00. Preparation of racemic N-methyl-5-(4-(3-(8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-6- yl)pyrrolidin-1-yl)piperidin-1-yl)picolinamide (8rac) To a solution of 6-(pyrrolidin-3-yl)imidazo[1,2-a]pyrazin-8(7H)-one 1306 (60 mg, 0.293 mmol) in MeOH (10 mL) and AcOH (0.01 mL) at rt were added N-methyl-5-(4-oxopiperidin-1- yl)picolinamide INT-1 (68 mg, 0.293 mmol) and NaBH3CN (37 mg, 0.587 mmol). The reaction mixture was stirred at 50 °C for 1 h. The reaction solution was concentrated under reduced pressure and the residue was purified by prep-HPLC (Gemini 5 um C18150 × 21.2 mm, mobile phase: ACN - H2O (0.1 % FA), gradient: 30 - 60) and SFC (Column: Daicel Chiralpak OJ-H 250 mm × 20 mm I.D., 5 μm; mobile phase: CO2 / MeOH (0.1 % NH3) = 70 / 30) to give N-methyl-5- (4-(3-(8-oxo-7,8-dihydroimidazo[1,2-a]pyrazin-6-yl)pyrrolidin-1-yl)piperidin-1- yl)picolinamide 8rac racemate (30.2 mg, 99 % purity, 24 % yield) as a white solid.1H NMR (400 MHz, DMSO-d6, ppm) δ: 11.01 (s, 1 H), 8.41-8.34 (m, 1 H), 8.27 (d, J = 2.4 Hz, 1 H), 7.82 (d, J = 8.8 Hz, 1 H), 7.73 (s, 1 H), 7.45-7.37 (m, 3 H), 3.87-3.78 (m, 2 H), 3.16-3.10 (m, 1 H), 3.00-2.88 (m, 3 H), 2.81-2.74 (m, 4 H), 2.71-2.63 (m, 2 H), 2.36-2.29 (m, 1 H), 2.24-2.14 (m, 1 H), 1.97-1.89 (m, 2 H),1.84-1.75 (m, 1 H), 1.58-1.45 (m, 2 H). LCMS (ESI) calcd for C22H27N7O2 [M + H]+m / z 422.22, found 422.15. Example 5: Synthesis of 10a / 10b SCHEME 5B

[0013] Preparation of ethyl 1-(2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-2-oxoethyl)-3-fluoro-1H- pyrrole-2-carboxylate (1403) A solution of ethyl 3-fluoro-1H-pyrrole-2-carboxylate 1401 (600 mg, 3.825 mmol), Cs2CO3 (2506 mg, 7.619 mmol) and tert-butyl 3-(2-bromoacetyl)pyrrolidine-1-carboxylate 1005 (740 mg, 2.543 mmol) in DMF (10 mL) was stirred for 2 h at rt. The reaction mixture was poured into water and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluting with DCM / MeOH, 100:0 to 90:10) to give ethyl 1-(2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-2-oxoethyl)-3-fluoro-1H-pyrrole-2- carboxylate 1403 (1000 mg, 90 % purity, 63 % yield) as a yellow oil. LCMS (ESI) calcd for C18H25FN2O5 [M – t-Bu + H]+m / z 313.17, found 313.10. Preparation of tert-butyl 3-(8-fluoro-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazin-3- yl)pyrrolidine-1-carboxylate (1404) To a solution of ethyl 1-(2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-2-oxoethyl)-3-fluoro-1H- pyrrole-2-carboxylate 1403 (1000 mg, 2.717 mmol) in EtOH (15 mL) added NH4OAc (20900 mg, 27.17 mmol). The mixture was stirred at 100 °C for 12 h in a steel bomb. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluting with DCM / MeOH, 100:0 to 90:10) to give tert-butyl 3- (8-fluoro-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazin-3-yl)pyrrolidine-1-carboxylate 1404 racemate (600 mg, 95 % purity, 65 % yield) as a yellow oil. LCMS (ESI) calcd for C16H20FN3O3 [M + H]+m / z 321.15, found 321.70. Preparation of tert-butyl 3-(8-fluoro-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazin-3- yl)pyrrolidine-1-carboxylate (1404-P1 and 1404-P2) 1404 racemate (300 mg, 0.934 mmol) was separated by SFC (Column: Daicel Chiralpak IH 20 mm I.D. × 250 mm, 5 μm; Mobile phase: CO2 / MeOH [0.1% (NH3)] = 60 / 40) and concentrated under reduced pressure to afford the first fraction as 1404-P1 (120 mg, 95 % purity, white solid) and the second fraction as 1404-P2 (90 mg, 95 % purity, white solid). Preparation of 8-fluoro-3-(pyrrolidin-3-yl)pyrrolo[1,2-a]pyrazin-1(2H)-one (1405-P1) A solution of tert-butyl 3-(8-fluoro-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazin-3-yl)pyrrolidine-1- carboxylate 1404-P1 (120 mg, 0.374 mmol) in HCl-dioxane (4 M, 2 mL) was stirred at rt for 2 h. The reaction mixture was concentrated. The residue was diluted with MeOH (5 mL) and TEA (1 mL). After stirring at rt for 5 min. The solution was concentrated to dryness to obtain 8-fluoro-3-(pyrrolidin-3-yl)pyrrolo[1,2-a]pyrazin-1(2H)-one 1405-P1 (100 mg, 70 % purity, 84 % yield) as a white solid. LCMS (ESI) calcd for C11H12FN3O [M + H]+m / z 222.10, found 222.30. Preparation of 6-fluoro-5-(4-(3-(8-fluoro-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazin-3- yl)pyrrolidin-1-yl)piperidin-1-yl)-N-methylpicolinamide (10a) To a solution of 8-fluoro-3-(pyrrolidin-3-yl)pyrrolo[1,2-a]pyrazin-1(2H)-one 1405-P1 (35 mg, 0.157 mmol) in MeOH (10 mL) were added 6-fluoro-N-methyl-5-(4-oxopiperidin-1- yl)picolinamide INT-2 (47 mg, 0.188 mmol), two drops of HOAc and NaBH(OAc)3 (33 mg, 0.157 mmol). The mixture was stirred at 50 °C for 30 min, added NaBH3CN (10 mg, 0.158 mmol) and stirred at 50 °C for 2 h. After cooling to rt, the reaction mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC (Gemini 5 um C18150 × 21.2 mm, mobile phase: ACN - H2O (0.1 % FA), gradient: 5 - 90) to give 6-fluoro-5-(4-(3-(8-fluoro- 1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazin-3-yl)pyrrolidin-1-yl)piperidin-1-yl)-N- methylpicolinamide 10a (37.2 mg, 98 % purity, 100 %ee, 52 % yield) as a white solid.1H NMR (400 MHz, DMSO-d6, ppm) δ: 10.22 (s, 1 H), 8.47-8.31 (m, 1 H), 7.83 (d, J = 8.0 Hz, 1 H), 7.58 (dd, J = 10.4, 8.0 Hz, 1 H), 7.26-7.17 (m, 1 H), 7.13 (s, 1 H), 6.36 (d, J = 2.8 Hz, 1 H), 3.57-3.45 (m, 2 H), 3.10-2.96 (m, 1 H), 2.93-2.81 (m, 3 H), 2.81-2.70 (m, 4 H), 2.69-2.57 (m, 2 H), 2.31-2.21 (m, 1 H), 2.22-2.08 (m, 1 H), 2.04-1.89 (m, 2 H), 1.84-1.68 (m, 1 H), 1.67-1.49 (m, 2 H). LCMS (ESI) calcd for C23H26F2N6O2[M + H]+m / z 457.21, found 457.30. Preparation of 8-fluoro-3-(pyrrolidin-3-yl)pyrrolo[1,2-a]pyrazin-1(2H)-one (1405-P2) A solution of tert-butyl 3-(8-fluoro-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazin-3-yl)pyrrolidine-1- carboxylate 1404-P2 (90 mg, 0.281 mmol) in HCl-dioxane (4 M, 2 mL) was stirred at rt for 2 h. The reaction mixture was concentrated, the residue was diluted with MeOH (5 mL) and TEA (1 mL). After stirring at rt for 5 min. The solution was concentrated to dryness to obtain 8- fluoro-3-(pyrrolidin-3-yl)pyrrolo[1,2-a]pyrazin-1(2H)-one 1405-P2 (70 mg, 70 % purity, 78 % yield) as a white solid. LCMS (ESI) calcd for C11H12FN3O [M + H]+m / z 222.10, found 222.25. Preparation of 6-fluoro-5-(4-(3-(8-fluoro-1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazin-3- yl)pyrrolidin-1-yl)piperidin-1-yl)-N-methylpicolinamide (10b) To a solution of 8-fluoro-3-(pyrrolidin-3-yl)pyrrolo[1,2-a]pyrazin-1(2H)-one 1405-P2 (35 mg, 0.157 mmol) in MeOH (10 mL) were added 6-fluoro-N-methyl-5-(4-oxopiperidin-1- yl)picolinamide INT-2 (47 mg, 0.188 mmol), two drops of HOAc and NaBH(OAc)3(33 mg, 0.157 mmol). The mixture was stirred at 50 °C for 30 min, added NaBH3CN (10 mg, 0.158 mmol) and stirred at 50 °C for 2 h. After cooling to rt, the reaction mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC (Gemini 5 µm C18150 × 21.2 mm, mobile phase: ACN - H2O (0.1 % FA), gradient: 5 - 90) to give 6-fluoro-5-(4-(3-(8-fluoro- 1-oxo-1,2-dihydropyrrolo[1,2-a]pyrazin-3-yl)pyrrolidin-1-yl)piperidin-1-yl)-N- methylpicolinamide 10b (36.3 mg, 98 % purity, 100% ee, 50 % yield) as a white solid.1H NMR (400 MHz, DMSO-d6, ppm) δ: 10.22 (s, 1 H), 8.47-8.30 (m, 1 H), 7.84 (d, J = 8.0 Hz, 1 H), 7.58 (dd, J = 10.4, 8.0 Hz, 1 H), 7.23-7.18 (m, 1 H), 7.13 (s, 1 H), 6.36 (d, J = 2.8 Hz, 1 H), 3.55-3.48 (m, 2 H), 3.09-2.97 (m, 1 H), 2.93-2.81 (m, 3 H), 2.81-2.74 (m, 4 H), 2.71-2.58 (m, 2 H), 2.35-2.22 (m, 1 H), 2.22-2.08 (m, 1 H), 2.04-1.90 (m, 2 H), 1.85-1.68 (m, 1 H), 1.66-1.49 (m, 2 H). LCMS (ESI) calcd for C23H26F2N6O2 [M + H]+m / z 457.21, found 457.30. SCHEME 6 Preparation of ethyl 2-methyl-1H-imidazole-5-carboxylate (1502) Ethyl 2-chloro-4,4,4-trifluoro-3-oxobutanoate 1501 (2.5 g, 0.0114 mol) was combined with formamidine (5.1 g, 0.114 mol) and water (5 mL). The mixture became warm and was heated to 130 °C for 2 h in a sealed tube. The mixture was then cooled to room temperature, and 100 mL of ice-water was added. The formed solids were collected and washed with water, then dried in vacuo to give ethyl 4-(trifluoromethyl)-1H-imidazole-5-carboxylate 1502 (0.8 g, 90 % purity, 30 % yield) as a brown solid. LCMS (ESI) calcd for C7H7F3N2O2 [M + H]+m / z 209.05, found 209.15. Preparation of ethyl 1-(2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-2-oxoethyl)-4- (trifluoromethyl)-1H-imidazole-5-carboxylate (1503) To a solution of ethyl 4-(trifluoromethyl)-1H-imidazole-5-carboxylate 1502 (250 mg, 1.2 mmol) in NMP (5 mL) were added tert-butyl 3-(2-bromoacetyl)pyrrolidine-1-carboxylate 1005 (528 mg, 1.8 mmol) and Cs2CO3 (782 mg, 2.4 mmol) slowly under N2. The mixture was stirred at rt for 2 hours. The resulting mixture was diluted with water (200 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with MeOH / DCM, 3 % to 10 %) to give ethyl 1-(2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-2- oxoethyl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylate 1503 (200 mg, 90 % purity, 35 % yield) as a yellow solid. LCMS (ESI) calcd for C18H24F3N3O5[M + H]+m / z 420.17, found 419.98. Preparation of tert-butyl 3-(8-oxo-1-(trifluoromethyl)-7,8-dihydroimidazo[1,5-a]pyrazin-6- yl)pyrrolidine-1-carboxylate (1504) A solution of ethyl 1-(2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-2-oxoethyl)-4- (trifluoromethyl)-1H-imidazole-5-carboxylate 1503 (200 mg, 0.49 mmol) in NH3-MeOH (7 M, 20 mL) was heated at 130 °C for 16 h in a steel bomb. The resulting mixture was concentrated and purified by silica gel column chromatography (eluting with MeOH / DCM, 3 % to 10 %) to give tert-butyl 3-(8-oxo-1-(trifluoromethyl)-7,8-dihydroimidazo[1,5-a]pyrazin-6- yl)pyrrolidine-1-carboxylate 1504 (120 mg, 90 % purity, 58 % yield) as a white solid. LCMS (ESI) calcd for C16H19F3N4O3[M + H]+m / z 373.14, found 373.10. Preparation of 6-(pyrrolidin-3-yl)-1-(trifluoromethyl)imidazo[1,5-a]pyrazin-8(7H)-one hydrochloride (1505) A solution of tert-butyl 3-(8-oxo-1-(trifluoromethyl)-7,8-dihydroimidazo[1,5-a]pyrazin-6- yl)pyrrolidine-1-carboxylate 1504 (120 mg, 0.32 mmol) in HCl dioxane solution (4 M, 5 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to provide 6-(pyrrolidin-3-yl)-1-(trifluoromethyl)imidazo[1,5-a]pyrazin-8(7H)-one hydrochloride 1505 (80 mg, 90 % purity, 72 % yield) as a white solid. LCMS (ESI) calcd for C11H11F3N4O [M + H]+m / z 273.09, found 273.15. Preparation of racemic N-methyl-5-(4-(3-(8-oxo-1-(trifluoromethyl)-7,8- dihydroimidazo[1,5-a]pyrazin-6-yl)pyrrolidin-1-yl)piperidin-1-yl)picolinamide (12rac) To a solution of 6-(pyrrolidin-3-yl)-1-(trifluoromethyl)imidazo[1,5-a]pyrazin-8(7H)-one hydrochloride 1505 (80 mg, 0.26 mmol) in MeOH (5 mL) were added N-methyl-5-(4- oxopiperidin-1-yl)picolinamide INT-1 (90 mg, 0.39 mmol), two drops of acetic acid, NaBH3CN (16 mg, 0.26 mmol) and NaBH(OAc)3(109 mg, 0.52 mmol) at room temperature. The reaction mixture was stirred at rt for 1 h. The resulting solution was quenched with water and concentrated under reduced pressure. The residue purified by prep-HPLC (Gemini-C18150 x 21.2 mm, eluting with 10 % to 40 % ACN / H2O containing 0.1 % FA) to give N-methyl-5-(4-(3- (8-oxo-1-(trifluoromethyl)-7,8-dihydroimidazo[1,5-a]pyrazin-6-yl)pyrrolidin-1-yl)piperidin-1- yl)picolinamide 12rac, a racemic mixture of 12a and 12b (30 mg, 95 % purity, 22 % yield) as a white solid. Chiral separation of N-methyl-5-(4-(3-(8-oxo-1-(trifluoromethyl)-7,8-dihydroimidazo[1,5- a]pyrazin-6-yl)pyrrolidin-1-yl)piperidin-1-yl)picolinamide to obtain 12a and 12b The 12rac racemic mixture was separated by SFC (Column: Regis (R,R)-Whelk-O120 mm × 250 mm I.D., 5 μm; Mobile phase: CO2 / MeOH [0.1 % (NH3)] = 60 / 40) and concentrated under reduced pressure to afford the first fraction as 12a (12.4 mg, 99 % purity, 100 %ee, white solid) and the second fraction as 12b (7.2 mg, 99 % purity, 100 %ee, white solid). 12a1H NMR (400 MHz, DMSO-d6, ppm) δ: 11.00 (s, 1 H), 8.43-8.34 (m, 1 H), 8.32 (s, 1 H), 8.28 (d, J = 2.8 Hz, 1 H), 7.82 (d, J = 8.8 Hz, 1 H), 7.47 (s, 1 H), 7.41-7.33 (m, 1 H), 3.88-3.78 (m, 2 H), 3.15-3.11 (m, 1 H), 2.99-2.86 (m, 3 H), 2.80-2.75 (m, 4 H), 2.66-2.62 (m, 2 H), 2.21-2.17 (m, 1 H), 1.97-1.91 (m, 2 H), 1.83-1.77 (m, 1 H), 1.58-1.45 (m, 2 H). LCMS (ESI) calcd for C23H26F3N7O2 [M + H]+m / z 490.21, found 490.15. 12b1H NMR (400 MHz, DMSO-d6, ppm) δ: 11.04 (s, 1 H), 8.41-8.35 (m, 1 H), 8.33 (s, 1 H), 8.28 (d, J = 2.8 Hz, 1 H), 7.82 (d, J = 8.8 Hz, 1 H), 7.48 (s, 1 H), 7.43-7.35 (m, 1 H), 3.87-3.80 (m, 2 H), 3.15-3.09 (m, 1 H), 3.00-2.85 (m, 3 H), 2.81-2.70 (m, 4 H), 2.70-2.61 (m, 2 H), 2.26-2.10 (m, 1 H), 1.98-1.88 (m, 2 H), 1.83-1.74 (m, 1 H), 1.58-1.44 (m, 2 H). LCMS (ESI) calcd for C23H26F3N7O2[M + H]+m / z 490.21, found 490.15. Example 7: synthesis of 15a / 15b Preparation of ethyl 1-amino-5-methyl-1H-pyrrole-2-carboxylate (1603) To a solution of ethyl 5-methyl-1H-pyrrole-2-carboxylate 1601 (2500 mg, 16.321 mmol) in DMF (50 mL) was added NaH (849 mg, 21.217 mmol, 60 % wt. in mineral oil) at 0 °C. After stirring at 0 °C for 30 min, a solution of O-(2,4-dinitrophenyl)hydroxylamine 1602 (3900 mg, 19.585 mmol) in DMF (5 mL) was added. The mixture was then stirred at rt for 2 h. The resulting reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain ethyl 1-amino-5-methyl-1H-pyrrole-2-carboxylate 1603 (3.2 g, 80 % purity, 95 % yield) as a white solid. LCMS (ESI) calcd for C8H12N2O2[M + H]+m / z 169.09, found 169.00 Preparation of ethyl 1-(1-(tert-butoxycarbonyl)pyrrolidine-3-carboxamido)-5-methyl-1H- pyrrole-2-carboxylate (1605) To a solution of ethyl 1-amino-5-methyl-1H-pyrrole-2-carboxylate 1603 (3.0 g, 17.837 mmol) in DCM (120 mL) were added 1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid 1604 (4.2 g, 19.620 mmol), DIPEA (6.9 g, 53.510 mmol) and T4P (15.4 g, 21.404 mmol, 50 % wt. in EtOAc). The mixture was stirred at rt for 3 h, concentrated and purified by flash silica chromatography (eluting with EtOAc / PE, 0 to 50 %) to obtain ethyl 1-(1-(tert- butoxycarbonyl)pyrrolidine-3-carboxamido)-5-methyl-1H-pyrrole-2-carboxylate 1605 (5.1 g, 93 % purity, 72 % yield) as an off-white solid. LCMS (ESI) calcd for C18H27N3O5[M + H]+m / z 366.20, found 366.15. 2-carboxylic acid (1606) To a solution of ethyl 1-(1-(tert-butoxycarbonyl)pyrrolidine-3-carboxamido)-5-methyl-1H- pyrrole-2-carboxylate 1605 (4.9 g, 0.013 mol) in MeOH / H2O (3:1, 120 mL) was added NaOH (1.6 g, 0.040 mol). The mixture was heated at 90 °C for 2 h, acidified with 1 M HCl and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4and concentrated. The residue was purified with flash silica chromatography (eluting with MeOH / DCM, 0 to 8 %) to obtain 1-(1-(tert-butoxycarbonyl)pyrrolidine-3-carboxamido)-5- methyl-1H-pyrrole-2-carboxylic acid 1606 (1.4 g, 80 % purity, 24 % yield) as a white solid. LCMS (ESI) calcd for C16H23N3O5 [M - Boc + H]+m / z 238.16, found 238.15. Preparation of tert-butyl 3-((2-carbamoyl-5-methyl-1H-pyrrol-1-yl)carbamoyl)pyrrolidine- 1-carboxylate (1607) To a solution of 1-(1-(tert-butoxycarbonyl)pyrrolidine-3-carboxamido)-5-methyl-1H-pyrrole- 2-carboxylic acid 1606 (1350 mg, 3.990 mmol) in THF (50 mL) were added (NH4)2CO3 (1533 mg, 15.958 mmol), EDCI (1147 mg, 5.984 mmol) and HOBT (269 mg, 1.995 mmol). The mixture was stirred at rt for 2 h, washed with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4and concentrated. The residue was purified with flash silica chromatography (eluting with EtOAc / PE, 0 to 80 %) to obtain tert-butyl 3-((2- carbamoyl-5-methyl-1H-pyrrol-1-yl)carbamoyl)pyrrolidine-1-carboxylate 1607 (535 mg, 80 % purity, 31 % yield) as a yellow solid. LCMS (ESI) calcd for C16H24N4O4[M + H]+m / z 337.18, found 337.00. Preparation of tert-butyl 3-(7-methyl-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2- yl)pyrrolidine-1-carboxylate (1608) A solution of tert-butyl 3-((2-carbamoyl-5-methyl-1H-pyrrol-1-yl)carbamoyl)pyrrolidine-1- carboxylate 1607 (500 mg, 1.482 mmol) in NH3·H2O (12 mL, 25 % wt.) was heated at 90 ℃ for 18 h in a sealed tube. The resulting mixture was concentrated and purified by flash silica chromatography (eluting with EtOAc / PE, 0 to 60 %) to obtain tert-butyl 3-(7-methyl-4-oxo- 3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidine-1-carboxylate 1608 (355 mg, 70 % purity, 52 % yield) as a yellow solid. LCMS (ESI) calcd for C16H22N4O3[M – t-Bu + H]+m / z 263.17, found 263.10. Preparation of 7-methyl-2-(pyrrolidin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one hydrochloride (1609) A solution of tert-butyl 3-(7-methyl-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2- yl)pyrrolidine-1-carboxylate 1608 (350 mg, 1.096 mmol) in HCl-dioxane (5 mL, 4 M) was stirred at rt for 30 min and then concentrated to obtain 7-methyl-2-(pyrrolidin-3- yl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one hydrochloride 1609 (290 mg, 80 % purity, 83 % yield) as a white solid. LCMS (ESI) calcd for C11H14N4O [M + H]+m / z 219.12, found 219.10. Preparation of N-methyl-5-(4-(3-(7-methyl-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2- yl)pyrrolidin-1-yl)piperidin-1-yl)picolinamide (15rac) To a solution of 7-methyl-2-(pyrrolidin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one hydrochloride 1609 (100 mg, 0.393 mmol) in MeOH (5 mL) was added TEA (2 mL). The mixture was stirred at rt for 30 min and concentrated. The residue was diluted with MeOH (5 mL) and N-methyl-5-(4-oxopiperidin-1-yl)picolinamide INT-1 (101 mg, 0.432 mmol) and NaBH3CN (37 mg, 0.589 mmol) were added. The mixture was stirred at rt for 2 h, concentrated and purified by flash silica chromatography (eluting with MeOH / DCM, 0 to 10 %) to obtain N-methyl-5-(4- (3-(7-methyl-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)pyrrolidin-1-yl)piperidin-1- yl)picolinamide racemic mixture 15rac (50 mg, 95 % purity, 27 % yield) as a white solid. Chiral resolution of N-methyl-5-(4-(3-(7-methyl-4-oxo-3,4-dihydropyrrolo[2,1- f][1,2,4]triazin-2-yl)pyrrolidin-1-yl)piperidin-1-yl)picolinamide (15rac) The racemic mixture 15rac was separated by SFC (Column: Daicel OJ-H 250 mm × 20 mm I.D., 5 μm; Mobile phase: CO2 / MeOH (0.1% NH3) = 60 / 40) and concentrated under reduced pressure to afford the first fraction as 15a (15.1 mg, 98 % purity, 100% ee, white solid) and the second fraction as 15b (13.5 mg, 98 % purity, 100 %ee, white solid). 15a1H NMR (400 MHz, DMSO-d6, ppm) δ: 11.32 (s, 1 H), 8.42-8.32 (m, 1 H), 8.27 (d, J = 2.8 Hz, 1 H), 7.81 (d, J = 8.4 Hz, 1 H), 7.39 (dd, J = 8.8, 2.8 Hz, 1 H), 6.77 (d, J = 4.0 Hz, 1 H), 6.32 (d, J = 4.0 Hz, 1 H), 3.87-3.76 (m, 2 H), 3.25-3.21 (m, 1 H), 3.03-2.91 (m, 3 H), 2.87-2.80 (m, 1 H), 2.78 (d, J = 4.8 Hz, 3 H), 2.74-2.66 (m, 2 H), 2.39-2.32 (m, 4 H), 2.20-2.07 (m, 2 H), 1.98-1.89 (m, 2 H), 1.59-1.45 (m, 2 H). LCMS (ESI) calcd for C23H29N7O2[M + H]+m / z 436.24, found 436.25. 15b1H NMR (400 MHz, DMSO-d6, ppm) δ: 11.32 (s, 1 H), 8.42-8.33 (m, 1 H), 8.27 (d, J = 2.8 Hz, 1 H), 7.81 (d, J = 8.8 Hz, 1 H), 7.39 (dd, J = 8.8, 2.8 Hz, 1 H), 6.77 (d, J = 4.4 Hz, 1 H), 6.32 (d, J = 4.4 Hz, 1 H), 3.87-3.75 (m, 2 H), 3.23-3.18 (m, 1 H), 3.04-2.90 (m, 3 H), 2.86-2.80 (m, 1 H), 2.78 (d, J = 4.8 Hz, 3 H), 2.74-2.66 (m, 2 H), 2.39-2.30 (m, 4 H), 2.19-2.06 (m, 2 H), 1.99-1.88 (m, 2 H), 1.58-1.45 (m, 2 H). LCMS (ESI) calcd for C23H29N7O2 [M + H]+m / z 436.24, found 436.25. Example 8: synthesis of INT-1 (a reference example) A method of synthesising INT-1, an intermediate product useful in some implementations of the synthetic methods of the invention, will now be described with reference to Scheme 8: Preparation of 5-{1,4-dioxa-8-azaspiro[4.5]decan-8-yl}-N-methylpyridine-2-carboxamide (2003) To a solution of 5-fluoro-N-methylpyridine-2-carboxamide 2001 (1.00 g, 6.50 mmol) in DMF (15 mL) was added 1,4-dioxa-8-azaspiro[4.5]decane 2002 (1.40 g, 9.75 mmol), then Cs2CO3 (2.12 g, 6.50 mmol) was added at room temperature. The reaction mixture was stirred at 150 °C using a microwave for 5 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 97 : 3) to give 5-{1,4-dioxa-8-azaspiro[4.5]decan-8-yl}- N-methylpyridine-2-carboxamide 2003 (1.50 g, 76 % yield ) as a white solid. LCMS (ESI) calcd for C14H19N3O3 [M + H]+m / z 278.14, found 278.14. Preparation of N-methyl-5-(4-oxopiperidin-1-yl)picolinamide (INT-1) To a solution of 5-{1,4-dioxa-8-azaspiro[4.5]decan-8-yl}-N-methylpyridine-2-carboxamide 2003 (1.50 g, 5.40 mmol) in H2O (10 mL) was added HCl in 1,4-dioxane (4 M, 20 mL) at room temperature. The reaction mixture 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 > 7 using NaHCO3 solution, then extracted with EtOAc (50 mL x 3), the organic phase dried by Na2SO4and concentrated to give N-methyl-5-(4-oxopiperidin-1- yl)picolinamide INT-1 (1.50 g, 76 % yield ) as a yellow solid. LCMS (ESI) calcd for C12H15N3O2[M + H]+m / z 234.12, found 234.18.

[0014] Example 9: synthesis of INT-2 (a reference example) A method of synthesising INT-2, an intermediate product useful in some implementations of the synthetic methods of the invention, will now be described with reference to Scheme 9: Preparation of 6-chloro-5-fluoro-N-methylpicolinamide (2102) To a solution of 6-chloro-5-fluoropicolinic acid 2101 (2.00 g, 11.40 mmol) in DMF (50 mL) was added methanamine (420 mg, 13.68 mmol), DIEA (4.42 g, 34.20 mmol) and HATU (6.50 g, 17.10 mmol) at room temperature successively. The mixture was kept stirring at room temperature for 1 h. The resulting mixture was diluted with water and extracted with EtOAc (200 mL x 3). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE / EtOAc = 100 : 0 to 70 : 30) to afford 6-chloro-5-fluoro-N-methylpicolinamide 2102 (2.00 g, 88 % yield) as a white solid. LCMS (ESI) calcd for C7H6ClFN2O [M + H]+m / z 189.02, found 188.90. Preparation of 6-chloro-N-methyl-5-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)picolinamide (2104) To a solution 6-chloro-5-fluoro-N-methylpicolinamide 2102 (2.00 g, 10.60 mmol) in DMF (20 mL) was added Cs2CO3(6.91 g, 21.20 mmol) and 1,4-dioxa-8-azaspiro[4.5]decane 2002 (3.04 g, 21.20 mmol). The mixture was stirred for 4 h under 120 °C using a sealed tube. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE / EtOAC = 100 : 0 to 50 : 50) to afford 6-chloro-N-methyl-5- (1,4-dioxa-8-azaspiro[4.5]decan-8-yl)picolinamide 2104 (1.60 g, 42 % yield) as a white solid. LCMS (ESI) calcd for C14H18ClN3O3[M + H]+m / z 312.10, found 311.95. Preparation of 6-fluoro-N-methyl-5-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)picolinamide (2105) To a solution 6-chloro-N-methyl-5-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)picolinamide 2104 (300 mg, 0.96 mmol) in DMF (20 mL) was added CsF (293 mg, 1.93 mmol). The mixture was stirred for 20 h at 150 °C using a microwave. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE / EtOAC = 100 : 0 to 30 : 70) to 6-fluoro-N-methyl-5-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)picolinamide 2105 (200 mg, 69 % yield) as a yellow solid. LCMS (ESI) calcd for C14H18FN3O3[M + H]+m / z 296.13, found 295.95. Preparation of 6-fluoro-N-methyl-5-(4-oxopiperidin-1-yl)picolinamide (INT-2) To the solution of 6-fluoro-N-methyl-5-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)picolinamide 2105 (200 mg, 0.68 mmol) in H2O (3 mL) was added formic acid (2 mL), stirred at 50 °C for 1 h, The aqueous solution was adjusted to pH 7-8 with aqueous NaHCO3solution. The mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL × 3). The combined organic layer was washed with brine (100 mL × 2), dried over Na2SO4, concentrated to give crude product of 6-fluoro-N-methyl-5-(4-oxopiperidin-1-yl)picolinamide INT-2 (100 mg, 47 % yield) as a yellow solid. LCMS (ESI) calcd for C12H14FN3O2 [M + H]+m / z 252.11, found 251.90. Example 10: synthesis of 21 SCHEME 10 Preparation of methyl 1-amino-3-(trifluoromethyl)-1H-pyrrole-2-carboxylate (1703) To a solution of methyl 3-(trifluoromethyl)-1H-pyrrole-2-carboxylate 1701 (900 mg, 4.66 mmol) in DMF (10 mL) was added NaH (186 mg, 4.66 mmol, 60 % wt. in mineral oil) slowly at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. Then O-(2,4- dinitrophenyl)hydroxylamine 1702 (1392 mg, 6.99 mmol) was added. The mixture was stirred at rt for 5 h. The mixture was quenched with water slowly, then extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (3 times), dried over Na2SO4, filtered and concentrated to afford methyl 1-amino-3-(trifluoromethyl)-1H-pyrrole-2- carboxylate 1703 (730 mg, 85 % purity, 63 % yield) as a yellow solid. LCMS (ESI) calcd for C7H7F3N2O2 [M + H]+m / z 209.05, found 209.15. Preparation of tert-butyl 4-((2-(methoxycarbonyl)-3-(trifluoromethyl)-1H-pyrrol-1- yl)carbamoyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (1705) To a solution of methyl 1-amino-3-(trifluoromethyl)-1H-pyrrole-2-carboxylate 1703 (730 mg, 3.51 mmol) in pyridine (9 mL) was added T4P (5345 mg, 7.42 mmol, 50 % wt. in EtOAc) then 2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-4-carboxylic acid 1704 (640 mg, 2.80 mmol) was added. The mixture was stirred at rt for 18 h. The mixture was concentrated and purified by flash silica chromatography (DCM / MeOH = 100:0 to 93:7) to afford tert-butyl 4- ((2-(methoxycarbonyl)-3-(trifluoromethyl)-1H-pyrrol-1-yl)carbamoyl)-2- azabicyclo[2.1.1]hexane-2-carboxylate 1705 (1180 mg, 85 % purity, 80 % yield) as a yellow solid. LCMS (ESI) calcd for C18H22F3N3O5[M + Na]+m / z 440.15, found 440.10. Preparation of 1-(2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-4-carboxamido)-3- (trifluoromethyl)-1H-pyrrole-2-carboxylic acid (1706) To a solution of tert-butyl 4-((2-(methoxycarbonyl)-3-(trifluoromethyl)-1H-pyrrol-1- yl)carbamoyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate 1705 (1.1 g, 0.0026 mol) in DME (15 mL) was added Sn(CH3)3OH (0.94 g, 0.0052 mol). The resulting mixture was stirred for 2 h at 80 °C. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with DCM / MeOH = 100 : 0 to 93 : 7) to obtain 1-(2-(tert- butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-4-carboxamido)-3-(trifluoromethyl)-1H-pyrrole- 2-carboxylic acid 1706 (900 mg, 90 % purity, 76 % yield) as a yellow solid. LCMS (ESI) calcd for C17H20F3N3O5 [M - H] - m / z 402.14, found 402.05. Preparation of tert-butyl 4-((2-carbamoyl-3-(trifluoromethyl)-1H-pyrrol-1-yl)carbamoyl)-2- azabicyclo[2.1.1]hexane-2-carboxylate (1707) To a solution of 1-(2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-4-carboxamido)-3- (trifluoromethyl)-1H-pyrrole-2-carboxylic acid 1706 (900 mg, 2.23 mmol) in THF (20 mL) was added (NH4)2CO3 (950 mg, 9.89 mmol), EDCI (711 mg, 3.70 mmol) and HOBT (167 mg, 1.23 mmol). The reaction mixture was stirred at rt for 3 h. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with DCM / MeOH = 100 : 0 to 96 : 4) to obtain tert-butyl 4-((2-carbamoyl-3-(trifluoromethyl)-1H- pyrrol-1-yl)carbamoyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate 1707 (915 mg, 90 % purity, 91 % yield) as a yellow solid. LCMS (ESI) calcd for C17H21F3N4O4[M - H] - m / z 401.15, found 401.10. Preparation of tert-butyl 4-(4-oxo-5-(trifluoromethyl)-3,4-dihydropyrrolo[2,1- f][1,2,4]triazin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (1708) A solution of tert-butyl 4-((2-carbamoyl-3-(trifluoromethyl)-1H-pyrrol-1-yl)carbamoyl)-2- azabicyclo[2.1.1]hexane-2-carboxylate 1707 (500 mg, 1.23 mmol) in NH3 ^H2O (10 mL, ~25 % wt.) was stirred at 90 °C for 2 h in a steel bomb. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with DCM / MeOH = 100 : 0 to 90 : 10) to obtain tert-butyl 4-(4-oxo-5-(trifluoromethyl)-3,4-dihydropyrrolo[2,1- f][1,2,4]triazin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate 1708 (230 mg, 80 % purity, 38 % yield) as a yellow solid. LCMS (ESI) calcd for C17H19F3N4O3 [M - H] - m / z 383.14, found 383.35. Preparation of 2-(2-azabicyclo[2.1.1]hexan-4-yl)-5-(trifluoromethyl)pyrrolo[2,1- f][1,2,4]triazin-4(3H)-one (1709) A solution of tert-butyl 4-(4-oxo-5-(trifluoromethyl)-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2- yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate 1708 (220 mg, 0.57 mmol) in HCl-dioxane (4 M, 6 mL) was stirred for 2 h at rt. The reaction mixture was concentrated under reduced pressure. The residue was diluted with MeOH (4 mL), added TEA (0.5 mL), and stirred at rt for 10 min. Then the mixture was concentrated under reduced pressure to obtain 2-(2- azabicyclo[2.1.1]hexan-4-yl)-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one 1709 (200 mg, 70 % purity, 86 % yield) as a yellow solid. LCMS (ESI) calcd for C12H11F3N4O [M + H]+m / z 285.09, found 285.15. Preparation of N-methyl-5-(4-(4-(4-oxo-5-(trifluoromethyl)-3,4-dihydropyrrolo[2,1- f][1,2,4]triazin-2-yl)-2-azabicyclo[2.1.1]hexan-2-yl)piperidin-1-yl)picolinamide (21) To a stirred solution of 2-(2-azabicyclo[2.1.1]hexan-4-yl)-5-(trifluoromethyl)pyrrolo[2,1- f][1,2,4]triazin-4(3H)-one 1709 (45 mg, 0.15 mmol) in MeOH (10 mL) were added AcOH (0.3 mL) and N-methyl-5-(4-oxopiperidin-1-yl)picolinamide INT-1 (55 mg, 0.23 mmol), then stirred at rt for 20 min. Then NaBH3CN (9 mg, 0.15 mmol) was added, the reaction mixture was stirred at rt for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (Gemini 5 µm C18 column, 150 × 21.2 mm, eluting with 15 % to 65 % MeCN / H2O containing 0.1 % FA) to obtain N-methyl-5-(4-(4-(4-oxo-5-(trifluoromethyl)-3,4- dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)-2-azabicyclo[2.1.1]hexan-2-yl)piperidin-1- yl)picolinamide 21 (0.22 FA salt, 20.3 mg, 97.13 % purity, 24 % yield) as a white solid.1H NMR (400 MHz, DMSO-d6, ppm) δ: 12.10 (s, 1 H), 8.45-8.33 (m, 1 H), 8.29 (d, J = 2.8 Hz, 1 H), 8.14 (s, 0.22 H), 7.82 (d, J = 8.8 Hz, 1 H), 7.69 (d, J = 2.8 Hz, 1 H), 7.42 (dd, J = 9.0, 2.6 Hz, 1 H), 6.90 (d, J = 2.8 Hz, 1 H), 3.95-3.83 (m, 2 H), 3.81-3.72 (m, 1 H), 3.13-3.02 (m, 2 H), 3.00- 2.86 (m, 2 H), 2.78 (d, J = 4.8 Hz, 3 H), 2.65-2.56 (m, 1 H), 2.20-2.07 (m, 2 H), 2.04-1.83 (m, 4 H), 1.57-1.39 (m, 2 H). LCMS (ESI) calcd for C24H26F3N7O2[M + H]+m / z 502.21, found 502.15.

[0015] Example 11: synthesis of 22 SCHEME 11 Preparation of 6-fluoro-N-methyl-5-(4-(4-(4-oxo-5-(trifluoromethyl)-3,4- dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)-2-azabicyclo[2.1.1]hexan-2-yl)piperidin-1- yl)picolinamide (22) To a stirred solution of 2-(2-azabicyclo[2.1.1]hexan-4-yl)-5-(trifluoromethyl)pyrrolo[2,1- f][1,2,4]triazin-4(3H)-one 1709 (45 mg, 0.15 mmol) in MeOH (10 mL) were added AcOH (0.3 mL) and 6-fluoro-N-methyl-5-(4-oxopiperidin-1-yl)picolinamide INT-2 (59 mg, 0.23 mmol), then the reaction mixture was stirred at rt for 20 min. Then NaBH3CN (9 mg, 0.15 mmol) was added, the reaction mixture was stirred at rt for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (Gemini 5 µm C18 column, 150 × 21.2 mm, eluting with 15 % to 65 % MeCN / H2O containing 0.1 % FA) to obtain 6-fluoro-N- methyl-5-(4-(4-(4-oxo-5-(trifluoromethyl)-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)-2- azabicyclo[2.1.1]hexan-2-yl)piperidin-1-yl)picolinamide 22 (0.63 FA salt, 19.3 mg, 96 % purity, 21 % yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6, ppm) δ: 12.23 (s, 1 H), 8.44-8.34 (m, 1 H), 8.16 (s, 0.63 H), 7.84 (d, J = 8.0 Hz, 1 H), 7.69 (d, J = 2.8 Hz, 1 H), 7.59 (dd, J = 10.6, 8.2 Hz, 1 H), 6.90 (d, J = 3.2 Hz, 1 H), 3.76-3.68 (m, 1 H), 3.59-3.51 (m, 2 H), 3.08-2.99 (m, 2 H), 2.90-2.81 (m, 2 H), 2.77 (d, J = 4.8 Hz, 3 H), 2.57-2.53 (m, 1 H), 2.15-2.06 (m, 2 H), 2.03-1.92 (m, 2 H), 1.91-1.82 (m, 2 H), 1.59- 1.45 (m, 2 H). LCMS (ESI) calcd for C24H25F4N7O2[M + H]+m / z 520.20, found 520.15. Example 12: synthesis of 26a / 26b ompounds 26a and 26b Preparation of 7-chloro-5-methoxyimidazo[1,2-c]pyrimidine (1802) A solution of 5,7-dichloroimidazo[1,2-c]pyrimidine 1801 (1 g, 0.0053 mol) and MeONa (570 mg, 0.0106 mol) in MeOH (20 mL) was stirred at rt for 2 h. The reaction solution was concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with PE / EtOAc = 100:0 to 80:20) to afford 7-chloro-5- methoxyimidazo[1,2-c]pyrimidine 1802 (790 mg, 90 % purity, 73 % yield) as a white solid. LCMS (ESI) calcd for C7H6ClN3O [M + H]+m / z 184.02, found 183.95. Preparation of tert-butyl 3-(5-methoxyimidazo[1,2-c]pyrimidin-7-yl)-2,5-dihydro-1H- pyrrole-1-carboxylate (1804) To a solution of 7-chloro-5-methoxyimidazo[1,2-c]pyrimidine 1802 (790 mg, 4.3029 mmol) in dioxane / H2O (15 mL, 10:1) was added tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-2,5-dihydro-1H-pyrrole-1-carboxylate 1803 (1.4 g, 4.7331 mmol), RuPhos Pd G3 (360 mg, 0.4302 mmol) and K2CO3 (1.78 g, 12.9087 mmol) successively. The reaction mixture was stirred at 80 °C for 2 h under N2atmosphere. The reaction solution was cooled to rt and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with PE / EtOAc = 100:0 to 60:40) to afford tert-butyl 3-(5- methoxyimidazo[1,2-c]pyrimidin-7-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate 1804 (900 mg, 90 % purity, 59 % yield) as a yellow solid. LCMS (ESI) calcd for C16H20N4O3[M + H]+m / z 317.15, found 317.25. Preparation of tert-butyl 3-(5-methoxyimidazo[1,2-c]pyrimidin-7-yl)pyrrolidine-1- carboxylate (1805) A solution of tert-butyl 3-(5-methoxyimidazo[1,2-c]pyrimidin-7-yl)-2,5-dihydro-1H-pyrrole-1- carboxylate 1804 (900 mg, 2.8359 mmol ) and Pd / C (302 mg, 10 % wt.) in MeOH (15 mL) was stirred under balloon pressure of H2at rt for 2 h. The mixture was filtered through a Celite pad, and the filtrate was concentrated to give tert-butyl 3-(5-methoxyimidazo[1,2- c]pyrimidin-7-yl)pyrrolidine-1-carboxylate 1805 (850 mg, 90 % purity, 84 % yield) as a colourless oil. LCMS (ESI) calcd for C16H22N4O3[M + H]+m / z 319.17, found 319.20. Preparation of tert-butyl 3-(3-iodo-5-methoxyimidazo[1,2-c]pyrimidin-7-yl)pyrrolidine-1- carboxylate (1806) To a solution of tert-butyl 3-(5-methoxyimidazo[1,2-c]pyrimidin-7-yl)pyrrolidine-1- carboxylate 1805 (850 mg, 2.6614 mmol) in DCM (30 mL) was added NIS (599 mg, 2.6614 mmol). The reaction mixture was stirred rt for 16 h. The reaction solution was concentrated under reduced pressure and purified by flash column chromatography (eluting with PE / EtOAc = 100:0 to 60:40) to afford tert-butyl 3-(3-iodo-5-methoxyimidazo[1,2-c]pyrimidin-7- yl)pyrrolidine-1-carboxylate 1806 (1.04 g, 90 % purity, 78 % yield) as a white solid. LCMS (ESI) calcd for C16H21IN4O3 [M + H]+m / z 445.07, found 445.05. Preparation of tert-butyl 3-(5-methoxy-3-(trifluoromethyl)imidazo[1,2-c]pyrimidin-7- yl)pyrrolidine-1-carboxylate (1808) To a solution of tert-butyl 3-(3-iodo-5-methoxyimidazo[1,2-c]pyrimidin-7-yl)pyrrolidine-1- carboxylate 1806 (500 mg, 1.1229 mmol) in DMF (15 mL) was added nano Cu (143 mg, 2.2458 mmol) and 5-(trifluoromethyl)-4a,10a-dihydro-5H-thianthren-5-ium 1807 (648 mg, 2.2458 mmol) successively. The reaction mixture was stirred at 100 °C for 6 h under N2. The reaction mixture was poured into water, then extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with PE / EtOAc = 100:0 to 50:50) to afford tert-butyl 3-(5-methoxy-3-(trifluoromethyl)imidazo[1,2- c]pyrimidin-7-yl)pyrrolidine-1-carboxylate 1808 (150 mg, 90 % purity, 30 % yield) as a white solid. LCMS (ESI) calcd for C17H21F3N4O3[M + H]+m / z 387.16, found 387.10. Preparation of 7-(pyrrolidin-3-yl)-3-(trifluoromethyl)imidazo[1,2-c]pyrimidin-5(6H)-one (1809) A solution of tert-butyl 3-(5-methoxy-3-(trifluoromethyl)imidazo[1,2-c]pyrimidin-7- yl)pyrrolidine-1-carboxylate 1808 (150 mg, 0.3862 mmol) in HBr (3 mL, 48 % in H2O) was stirred at 80 °C for 2 h. The reaction solution was cooled to rt and concentrated under reduced pressure. The residue was diluted with MeOH (3 mL) and TEA (0.5 mL), then stirred at rt for 5 min. The mixture was concentrated under reduced pressure to obtain 7-(pyrrolidin-3-yl)-3- (trifluoromethyl)imidazo[1,2-c]pyrimidin-5(6H)-one 1809 (115 mg, 90 % purity, 98 % yield) as a white solid. LCMS (ESI) calcd for C11H11F3N4O [M + H]+m / z 273.09, found 273.05. Preparation of N-methyl-5-(4-(3-(5-oxo-3-(trifluoromethyl)-5,6-dihydroimidazo[1,2- c]pyrimidin-7-yl)pyrrolidin-1-yl)piperidin-1-yl)picolinamide (26a / 26b racemic mixture) To a solution of 7-(pyrrolidin-3-yl)-3-(trifluoromethyl)imidazo[1,2-c]pyrimidin-5(6H)-one 1809 (115 mg, 0.4209 mmol) in MeOH (5 mL) was added N-methyl-5-(4-oxopiperidin-1- yl)picolinamide INT-1 (118 mg, 0.5050 mmol), AcOH (1 drop) and NaBH3CN (53 mg, 0.8418 mmol) successively. The reaction mixture was stirred at 50 °C for 1 h. The reaction mixture was quenched with water (2 mL) and concentrated under reduced pressure. The residue was purified by prep-HPLC (column : Gemini - C18150 × 21.2 mm, 5 µm; mobile phase : ACN - H2O (0.05 % NH3); gradient : 30 - 95) to give N-methyl-5-(4-(3-(5-oxo-3-(trifluoromethyl)-5,6- dihydroimidazo[1,2-c]pyrimidin-7-yl)pyrrolidin-1-yl)piperidin-1-yl)picolinamide 26a / 26b racemic mixture (70 mg, 95 % purity, 32 % yield) as a white solid. Chiral resolution of N-methyl-5-(4-(3-(5-oxo-3-(trifluoromethyl)-5,6-dihydroimidazo[1,2- c]pyrimidin-7-yl)pyrrolidin-1-yl)piperidin-1-yl)picolinamide (26a / 26b racemic mixture) The 26a / 26b racemic mixture was separated by SFC (Column: Daicel Chiralpak IH SFC; 20 mm I.D. × 250 mm, 5 μm; Mobile phase: CO2 / MeOH [0.1 % NH3(7 M Solution in MeOH)] = 70 / 30) and concentrated under reduced pressure to afford the first fraction as Compound 26a (27.8 mg, 96.88 % purity, 100 % ee, white solid) and the second fraction as Compound 26b (29.3 mg, 98.66 % purity, 100 % ee, white solid). Compound 26a1H NMR (400 MHz, DMSO-d6, ppm) δ: 8.41-8.35 (m, 1 H), 8.28 (d, J = 2.4 Hz, 1 H), 7.89 (s, 1 H), 7.82 (d, J = 8.8 Hz, 1 H), 7.40 (dd, J = 8.8, 2.8 Hz, 1 H), 6.59 (s, 1 H), 3.87-3.78 (m, 2 H), 3.29- 3.15 (m, 1 H), 3.04-2.88 (m, 3 H), 2.86-2.72 (m, 5 H), 2.72-2.60 (m, 1 H), 2.40-2.29 (m, 1 H), 2.26-2.14 (m, 1 H), 2.00-1.83 (m, 3 H), 1.60-1.46 (m, 2 H). LCMS (ESI) calcd for C23H26F3N7O2 [M + H]+m / z 490.21, found 490.10. Compound 26b1H NMR (400 MHz, DMSO-d6, ppm) δ: 8.43-8.33 (m, 1 H), 8.27 (d, J = 2.8 Hz, 1 H), 7.85-7.78 (m, 2 H), 7.40 (dd, J = 8.8, 3.0 Hz, 1 H), 6.51 (s, 1 H), 3.86-3.79 (m, 2 H), 3.26-3.13 (m, 1 H), 3.02-2.85 (m, 3 H), 2.78 (d, J = 4.8 Hz, 3 H), 2.76-2.65 (m, 3 H), 2.37-2.31 (m, 1 H), 2.24-2.10 (m, 1 H), 2.01-1.87 (m, 3 H), 1.61-1.44 (m, 2 H). LCMS (ESI) calcd for C23H26F3N7O2 [M + H]+m / z 490.21, found 490.10. Example 13: 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 13A. 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 ^g. Wells were then washed 3 x 5 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 3 x 5 min in coating wash buffer. For the assay 20 ^l 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 ^l of 10 ^M biotin-NAD+and 10 nM activation DNA (sequence shown below) in solution in 20 mM HEPES (pH 7.5), 100 mM NaCl, 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 ^l 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 ^l of a 1:1000 dilution of DELFIA Eu-N1 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 ^l 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 ^s; integration time 400 ^s). Typically compounds were tested from 20 ^M at 3-fold dilution intervals in 12-point concentration-response curves to determine IC50values. 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 IC50values. The IC50values for a variety of test compounds are shown in Table 1. Example 13B. 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 NaCl, 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 ^l 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 µs; integration time 400 µs) using the HTRF module. Typically compounds were tested from 58.5 ^M at factor 3 dilution intervals in 12-point concentration-response curves to determine IC50values. 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]))*KdTherefore Kd = IC50 / (1+[[probe concentration] / [Kmprobe])); using probe at 10 x Km, this equated to Kd = IC50 / 11 Example 13C. 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.

[0016] Cy5 probe structure: 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 PARP1-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. NanoBRETTMTE 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 µM at factor 3 dilution intervals in 12-point concentration- response 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 NanoBRETTMNano-Glo® 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 of Parp 1 / 2 assays for selected compounds (DELFIA and Probe Displacement HTRF) TABLE 2 Results of Parp 1 / 2 assays for selected compounds (NanoBRET) Key: DELFIA, Probe Displacement HTRF and NanoBRET assay categories: - indicates IC50or Kdvalue above 10 ^M + indicates IC50 or Kd value above 1 ^M up to 10 ^M ++ indicates IC50or Kdvalue above 100 nM up to 1 ^M +++ indicates IC50 or Kd value above 10 nM up to 100 nM ++++ indicates IC50 or Kd 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 Kd values for PARP1 and PARP2 inhibition as Kd (PARP2) / Kd (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

Claims 1. A PARP1 inhibitor compound for use in medicine, the PARP1 inhibitor compound having a structure of:wherein: each R1is independently absent or selected from H and a substituted or unsubstituted organic group; R2is absent or selected from H and a substituted or unsubstituted organic group; R3is selected from H and a substituted or unsubstituted organic group; Z1is C or N; Z2uand Z2lare each selected from C and N, with the proviso that at least one of Z2uand Z2lis N; each Z3is independently selected from C and N; and L has a structure of:wherein: a dashed line represents a single bond or a double bond; each R5Aand each R5Cis independently absent or selected from H and a substituted or unsubstituted organic group; R6is absent or selected from H and a substituted or unsubstituted organic group; each X1is independently selected from C and N;each X2is independently selected from C, N, O and S; n is a number selected from 0, 1, 2, 3, 4, 5 and 6; and m is a number selected from 0, 1, 2, 3, 4, 5 and 6; with the proviso that m + n is a number selected from 2, 3, 4, 5, and 6; r is a number independently selected from 0, 1, 2, 3, 4, 5 and 6; and s is a number independently selected from 0, 1, 2, 3, 4, 5 and 6; with the proviso that r + s is a number selected from 2, 3, 4, 5, and 6; b is absent or a ring having a structure of:wherein: p is a number selected from 0, 1, 2, 3, 4, 5 and 6; and q is a number selected from 0, 1, 2, 3, 4, 5 and 6; with the proviso that p + q is a number selected from 2, 3, 4, 5, and 6; and each R5Bis independently absent or selected from H and a substituted or unsubstituted organic group; and QAE, QAB, and QBCare each independently absent or selected from:wherein: t is a number selected from 0, 1, 2, 3, 4 and 5; and u is independently a number selected from 0, 1, 2, 3, 4 and 5; with the proviso that t + u is a number selected from 0, 1, 2, 3, 4, 5 and 6; and each R7and R8is independently selected from H and a substituted or unsubstituted organic group.

2. The PARP1 inhibitor compound for use according to claim 1, wherein L has a structure of:.

3. The PARP1 inhibitor compound for use according to claim 1 or claim 2, wherein each R1is independently absent or selected from: H; a C1 to C6 alkyl, aminoalkyl, alkoxy or haloalkyl group; a C3 to C6 cycloalkyl group; a halogen group; a nitrile group;wherein R22is selected from H, C1 to C6 alkyl, C3 to C6 cycloalkyl, C1 to C6 alkoxy, C1 to C6 haloalkyl, and a halogen (optionally F), and each R23is independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R23is independently selected from H, a C1 to C6 alkyl, aminoalkyl, alkoxy or haloalkyl group, and a halogen group, and further optionally wherein at least one R23is H.

4. The PARP1 inhibitor compound for use according to claim 3, wherein each R1is independently absent or selected from H; a halogen, optionally Cl or F; a C1 to C3 alkyl group, optionally a methyl group; a C1 to C3 haloalkyl group, optionally a halomethyl group (-CH2F, - CHF2, or -CF3) or a haloethyl group (e.g., -CH2CF3); and a nitrile group.

5. The PARP1 inhibitor compound for use according to claim 4, wherein each R1is independently absent or selected from: H, Cl, F, a methyl group, CF3, and a nitrile group.

6. The PARP1 inhibitor compound for use according to claim 4, wherein: exactly one R1is selected from Cl, F, a methyl group, CF3, and a nitrile group; and each other R1is H or absent.

7. The PARP1 inhibitor compound for use according to any preceding claim, wherein at least one R1is H.

8. The PARP1 inhibitor compound for use according to any preceding claim, wherein Z1is C.

9. The PARP1 inhibitor compound for use according to claim 8, wherein R2is selected from H; halogen, optionally F or Cl; C1 to C3 alkyl, optionally isopropyl or cyclopropyl; C1 to C3 haloalkyl, optionally -CH2F, -CHF2, -CF3, -CH2CF3, or -CH2CH2F; C1 to C3 alcohol, optionally -CH2CH2OH; C1 to C3 alkoxy, optionally methoxy, methoxymethyl, or methoxyethyl; or C1 to C3 aminoalkyl.

10. The PARP1 inhibitor compound for use according to claim 9, wherein R2is H.

11. The PARP1 inhibitor compound for use according to any of claims 1 to 7, wherein Z1is N and R2is absent.

12. The PARP1 inhibitor compound for use according to any preceding claim, wherein R3is selected from H, C1 to C3 alkyl, and C1 to C3 haloalkyl; preferably wherein R3is H.

13. The PARP1 inhibitor compound for use according to any preceding claim, wherein at least two Z3atoms are C.

14. The PARP1 inhibitor compound for use according to any preceding claim, wherein one of Z2uand Z2lis C.

15. The PARP1 inhibitor compound for use according to claim 13, having a structure of:.

16. The PARP1 inhibitor compound for use according to claim 15, having a structure selected from:.

17. The PARP1 inhibitor compound for use according to claim 15, having a structure selected from:

18. The PARP1 inhibitor compound for use according to claim 16, having a structure of:.

19. The PARP1 inhibitor compound for use according to claim 14, having a structure of:.

20. The PARP1 inhibitor compound for use according to claim 19, having a structure selected from:.

21. The PARP1 inhibitor compound for use according to claim 20, having a structure selected from:

22. The PARP1 inhibitor compound for use according to any preceding claim, wherein QAEis absent or -CH2-, optionally wherein QAEis absent.

23. The PARP1 inhibitor compound according to any preceding claim, wherein both n and m are at least 1.

24. The PARP1 inhibitor compound according to any preceding claim, wherein ring A has a structure of:where: i is a number selected from 0, 1, 2, 3, 4, 5, 6; and j is a number selected from 0, 1, 2, 3, 4, 5, 6, with the proviso that i and j sum to (n-1); h is a number selected from 1, 2, and 3; and n is at least 1.

25. The PARP1 inhibitor compound according to claim 24, wherein ring A has a structure.

26. The PARP1 inhibitor compound for use according to any of claims 1 to 23, wherein: i) ring A is a substituted or unsubstituted homopiperidine, further optionally a homopiperidine having a structure selected from:wherein: each R5Ais independently selected from H and a substituted or unsubstituted organic group; orii) ring A is a substituted or unsubstituted 6-membered aliphatic heterocycle, optionally having a structure selected from: , , ,wherein: each R5Ais independently selected from H and a substituted or unsubstituted organic group; oriii) ring A is a substituted or unsubstituted 5-membered aliphatic heterocycle, optionally having a structure selected from: ,wherein: each R5Ais independently selected from H and a substituted or unsubstituted organic group; or iv) ring A is a 5-membered aromatic ring, optionally a pyrrole or pyrazole, and further optionally having a structure selected from:, each R5Abeing independently selected from H and a substituted or unsubstituted organic group; or v) ring A is a substituted or unsubstituted azetidine, optionally having a structure of:wherein: each R5Ais independently selected from H and a substituted or unsubstituted organic group.

27. The PARP1 inhibitor compound for use according to claim 26, wherein ring A has a structure selected from:

28. The PARP1 inhibitor compound for use according to claim 27, wherein ring A has a29. The PARP1 inhibitor compound for use according to any preceding claim, wherein QABis absent or -CH2-, optionally wherein QABis absent.

30. The PARP1 inhibitor compound for use according to claim 29, wherein L has a structure of:.

31. The PARP1 inhibitor compound for use according to any preceding claim, wherein both p and q are at least 1; optionally wherein p and q sum to 3 or 4, and further optionally wherein p is 2 and q is 2.

32. The PARP1 inhibitor compound for use according to claim 31, wherein: i) ring B is a 7-membered saturated heterocyclic ring, optionally having a structure of:wherein: each R5Bis independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5Bis H; X1BAis C and R5B1is selected from H and a substituted or unsubstituted organic group, and is optionally H; or X1BAis N and R5B1is absent; and X1BCis C and R5B3is selected from H and a substituted or unsubstituted organic group or X1BCis N and R5B3is absent; or ii) ring B is a 6-membered saturated heterocyclic ring, optionally having a structure of:wherein: each R5Bis independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5Bis H; X1BAis C and R5B1is selected from H and a substituted or unsubstituted organic group, and is optionally H; or X1BAis N and R5B1is absent; and X1BCis C and R5B3is selected from H and a substituted or unsubstituted organic group or X1BCis N and R5B3is absent; oriii) ring B is a 5-membered saturated heterocyclic ring, optionally having a structure of:each R5Bis independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5Bis H; X1BAis C and R5B1is selected from H and a substituted or unsubstituted organic group, and is optionally H; or X1BAis N and R5B1is absent; and X1BCis C and R5B3is selected from H and a substituted or unsubstituted organic group or X1BCis N and R5B3is absent.

33. The PARP1 inhibitor compound for use according to claim 32, wherein X1BAis C and R5B1is selected from H and a substituted or unsubstituted organic group; optionally wherein R5B1is H.

34. The PARP1 inhibitor compound for use according to claim 32 or claim 33, wherein X1BCis N and R5B3is absent.

35. The PARP1 inhibitor compound for use according to claim 34, wherein ring B has a structure of:.

36. The PARP1 inhibitor compound for use according to any preceding claim, wherein QBCis absent or -CH2-, optionally wherein QBCis absent.

37. The PARP1 inhibitor compound for use according to claim 36, wherein L has a structure.

38. The PARP1 inhibitor compound for use according to any preceding claim, wherein both r and s are at least 1, optionally wherein r and s sum to 3 or 4.

39. The PARP1 inhibitor compound for use according to claim 38, wherein: i) ring C is a 6-membered aliphatic ring, optionally a 6-membered aliphatic ring having structure of:each R5Cand R5C1being independently selected from H and a substituted or unsubstituted organic group, preferably wherein R5C1is H, more preferably wherein R5C1and each R5Cis H;ii) ring C is a 6-membered aromatic ring, optionally selected from: iia) a phenyl group, optionally having a structure of:each R5Cbeing independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5Cis H; iib) a pyridine group, optionally having a structure selected from: ,each R5Cbeing independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5Cis H;iic) a diazine group, optionally having a structure selected from:each R5Cbeing independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5Cis H; or iii) ring C is a 5-membered aromatic ring, optionally selected from: iiia) an imidazole group, optionally an imidazole group having a structure selected from:each R5Cbeing independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5Cis H; iiib) a thiophene group, optionally having a structure selected from:,each R5Cbeing independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5Cis H; iiic) a thiazole group, optionally having a structure selected from: ,each R5Cbeing independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5Cis H; iiid) a triazole, optionally a triazole having a structure of:R5Cbeing selected from H and a substituted or unsubstituted organic group, optionally wherein R5Cis H.

40. The PARP1 inhibitor compound for use according to claim 39, wherein ring C has a structure selected from:

41. The PARP1 inhibitor compound for use according to claim 39, wherein ring C has a structure of:wherein: R5C2ois selected from H, a methyl group, and a halogen; and i) X2CMis C and R5C2Mis H; or ii) X2CMis N and R5C2Mis absent.

42. The PARP1 inhibitor compound for use according to claim 41, wherein R5C2ois selected from H and a halogen.

43. The PARP1 inhibitor compound for use according to claim 42, wherein R5C2ois a halogen, optionally wherein R5C2ois F.

44. The PARP1 inhibitor compound for use according to any of claims 41 to 43, wherein ring C has a structure selected from:.

45. The PARP1 inhibitor compound for use according to claim 41, wherein ring C has a structure of:.

46. The PARP1 inhibitor compound for use according to any of claims 41 to 45, wherein ring C has a structure selected from:

47. The PARP1 inhibitor compound for use according to any of claims 1 to 43, wherein R6is selected from H, -F, -Cl, -Br, -I, -CN, -CONR51R51, -NR51COR52, -SO2NR51R51, -NR51SO2R52, -O-CR52R52R52, -CR52R52NR51R51, and any of the following structures:wherein R51and R52are each independently selected from H and a substituted or unsubstituted organic group, optionally wherein R51and R52are each independently selected from H, a halogen, optionally-deuterated C1 to C3 alkyl, and C1 to C3 haloalkyl.

48. The PARP1 inhibitor compound for use according to claim 47, wherein R6has a structure of:wherein R51is selected from: a C1 to C6 alkyl group, optionally a C3 to C6 cycloalkyl group, a C1 to C3 alkyl group, or a C1 to C3 deuterated alkyl group; a C1 to C3 haloalkyl group, optionally a C1 to C3 fluoroalkyl group; and a 4-, 5-, 6-, or 7-membered saturated heterocyclic group, optionally a 4-, 5- or 6- membered cyclic ether group.

49. The PARP1 inhibitor compound for use according to claim 48, wherein R6is selected from:

51. The PARP1 inhibitor compound for use according to claim 50, wherein R6is CONHMe.. The PARP1 inhibitor compound according to claim 51, wherein R6is.

53. The PARP1 inhibitor compound for use according to claim 50, wherein R6is.

54. The PARP1 inhibitor compound for use according to any of claims 1 to 40, wherein R6has a structure of:wherein: each X6is independently selected from C, N, and O; R61is absent or H; each R62is independently absent or selected from H; a halo group, such as F; an oxo group; a C1 to C3 alkyl group; a C1 to C3 haloalkyl group, optionally a C1 to C3 fluoroalkyl group; and -NHR63, wherein R63is H or a C1 to C3 alkyl group.

55. The PARP1 inhibitor compound for use according to claim 54, wherein R6has a structure selected from:

56. The PARP1 inhibitor compound for use according to any of claims 1 to 39, wherein R6and one R5Cgroup together form a ring.

57. The PARP1 inhibitor compound for use according to any preceding claim, wherein each R5A(e.g., R5A1, R5A2, R5A3) is H.

58. The PARP1 inhibitor compound for use according to any preceding claim, wherein each R5B(e.g., R5B1, R5B3) is H.

59. The PARP1 inhibitor compound for use according to any preceding claim, wherein each R5C(e.g., R5C1) is selected from H and a halogen, with the proviso that no more than one R5Cis a halogen, optionally wherein the halogen is F.

60. The PARP1 inhibitor compound for use according to any preceding claim, wherein at least one of QAE, QAB, and QBCis:wherein t + u is at least 1; and wherein R7is selected from H, a halogen (such as –F, -Cl, -Br, and –I, preferably -F), a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted linear or branched C1-C6 halogenated alkyl group (preferably CF3), an -NH2 group or a substituted or unsubstituted C1-C6 amino group, an -OH group or a substituted or unsubstituted linear or branched C1-C6 alcohol group and a substituted or unsubstituted C1-C6 alkoxy group.

61. The PARP1 inhibitor compound for use according to claim 60, wherein R7is selected from: H; a halogen, optionally F; a substituted or unsubstituted C1-C6 alkyl group; or a substituted or unsubstituted linear or branched C1-C6 halogenated alkyl group.

62. The PARP1 inhibitor compound for use according to any preceding claim, wherein at least one of QAE, QABand QBChas a structure of:and wherein R8is selected from: H; a substituted or unsubstituted linear or branched C1-C6alkyl group (such as Me, Et, Pr, i-Pr, n-Bu, i-Bu, t-Bu, pentyl and hexyl); a substituted or unsubstituted linear or branched C1-C6alkyl-aryl group (such as –CH2Ph, -CH2(2,3 or 4)F-Ph, -CH2(2,3 or 4)Cl-Ph, -CH2(2,3 or 4)Br-Ph, -CH2(2,3 or 4)I-Ph, -CH2CH2Ph, -CH2CH2CH2Ph, -CH2CH2CH2CH2Ph, -CH2CH2CH2CH2CH2Ph, and -CH2CH2CH2CH2CH2CH2Ph); a substituted or unsubstituted linear or branched C1-C6halogenated alkyl group (such as -CH2F, -CF3, -CH2CH2F and -CH2CF3); a substituted or unsubstituted cyclic amine or amido group (such as pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, 2-keto-pyrrolidinyl, 3-keto-pyrrolidinyl, 2-keto-piperidinyl, 3-keto-piperidinyl, and 4-keto-piperidinyl);a substituted or unsubstituted cyclic C3-C8 alkyl group (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl); a substituted or unsubstituted linear or branched C2-C6 alcohol group (such as -CH2CH2OH, -CH(CH3)CH2OH, -C(CH3)2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, -CH(CH3)CH2CH2OH, -CH(CH3)CH(CH3)OH, -CH(CH2CH3)CH2OH, -C(CH3)2CH2OH, -CH2CH2CH2CH2CH2OH, and -CH2CH2CH2CH2CH2CH2OH); a substituted or unsubstituted linear or branched C2-C6carboxylic acid group (such as -CH2COOH, -CH2CH2COOH, -CH2CH2CH2COOH, -CH2CH2CH2CH2COOH, and -CH2CH2CH2CH2CH2COOH); a substituted or unsubstituted linear or branched carbonyl group (such as -(CO)Me, -(CO)Et, -(CO)Pr, -(CO)-i_Pr, -(CO)-n-Bu, -(CO)-i-Bu, -(CO)-t-Bu, -(CO)Ph, -(CO)CH2Ph, -(CO)CH2OH, -(CO)CH2OCH3, -(CO)CH2NH2, -(CO)CH2NHMe, -(CO)CH2NMe2, -(CO)-cyclopropyl, -(CO)-1,3-epoxypropan-2-yl; -(CO)NH2, -(CO)NHMe, -(CO)NMe2, -(CO)NHEt, -(CO)NEt2, -(CO)-pyrollidine-N-yl, -(CO)-morpholine-N-yl, -(CO)-piperazine-N-yl, -(CO)-N-methyl-piperazine-N-yl, -(CO)NHCH2CH2OH, -(CO)NHCH2CH2OMe, -(CO)NHCH2CH2NH2, -(CO)NHCH2CH2NHMe, and -(CO)NHCH2CH2NMe2); a substituted or unsubstituted linear or branched C1-C6carboxylic acid ester group (such as -COOMe, -COOEt, -COOPr, -COO-i-Pr, -COO-n-Bu, -COO-i-Bu, -COO-t- Bu, -CH2COOMe, -CH2CH2COOMe, -CH2CH2CH2COOMe, and -CH2CH2CH2CH2COOMe); a substituted or unsubstituted linear or branched C1-C6 amide group (such as -CO-NH2, -CO-NMeH, -CO-NMe2, -CO-NEtH, -CO-NEtMe, -CO-NEt2, -CO-NPrH, -CO-NPrMe, and -CO-NPrEt); a substituted or unsubstituted sulfonyl group (such as -SO2Me, -SO2Et, -SO2Pr, -SO2iPr, -SO2Ph, -SO2-(2,3 or 4)-F-Ph, -SO2-cyclopropyl, -SO2CH2CH2OCH3), -SO2NH2, -SO2NHMe, -SO2NMe2, -SO2NHEt, -SO2NEt2, -SO2-pyrrolidine-N-yl, -SO2-morpholine-N-yl, -SO2NHCH2OMe, and -SO2NHCH2CH2OMe);a substituted or unsubstituted aromatic group (such as Ph-, 2-F-Ph-, 3-F-Ph-, 4-F-Ph-, 2-Cl-Ph-, 3-Cl-Ph-, 4-Cl-Ph-, 2-Br-Ph-, 3-Br-Ph-, 4-Br-Ph-, 2-I-Ph-, 3-I-Ph, 4-I-Ph-, 2,(3,4,5 or 6)-F2-Ph-, 2,(3,4,5 or 6)-Cl2-Ph-, 2,(3,4,5 or 6)-Br2-Ph-, 2,(3,4,5 or 6)-I2-Ph-, 2,(3,4,5 or 6)-Me2-Ph-, 2,(3,4,5 or 6)-Et2-Ph-, 2,(3,4,5 or 6)-Pr2-Ph-, 2,(3,4,5 or 6)-Bu2-Ph-, 2,(3,4,5 or 6)-(CN)2-Ph-, 2,(3,4,5 or 6)-(NO2)2-Ph-, 2,(3,4,5 or 6)-(NH2)2-Ph-, 2,(3,4,5 or 6)-(MeO)2-Ph-, 2,(3,4,5 or 6)-(CF3)2-Ph-, 3,(4 or 5)-F2-Ph-, 3,(4 or 5)-Cl2-Ph-, 3,(4 or 5)-Br2-Ph-, 3,(4 or 5)-I2-Ph-, 3,(4 or 5)-Me2-Ph-, 3,(4 or 5)-Et2-Ph-, 3,(4 or 5)-Pr2-Ph-, 3,(4 or 5)-Bu2-Ph-, 3,(4 or 5)-(CN)2-Ph-, 3,(4 or 5)-(NO2)2-Ph-, 3,(4 or 5)-(NH2)2-Ph-, 3,(4 or 5)-(MeO)2-Ph-, 3,(4 or 5)-(CF3)2-Ph-, 2-Me-Ph-, 3-Me-Ph-, 4-Me-Ph-, 2-Et-Ph-, 3-Et-Ph-, 4-Et-Ph-, 2-Pr-Ph-, 3-Pr-Ph-, 4-Pr-Ph-, 2-Bu-Ph-, 3-Bu-Ph-, 4-Bu-Ph-, 2-(CN)-Ph-, 3-(CN)-Ph-, 4-(CN)-Ph-, 2-(NO2)-Ph-, 3-(NO2)-Ph-, 4-(NO2)-Ph-, 2-(NH2)-Ph-, 3-(NH2)-Ph-, 4-(NH2)-Ph-, 2-MeO-Ph-, 3-MeO-Ph-, 4-MeO-Ph-, 2-(NH2-CO)-Ph-, 3-(NH2-CO)-Ph-, 4-(NH2-CO)-Ph-, 2-CF3-Ph-, 3-CF3-Ph-, 4-CF3-Ph-, 2-CF3O-Ph-, 3-CF3O-Ph-, and 4-CF3O-Ph-); and a substituted or unsubstituted heterocyclic group (such as pyrrole-2-yl, pyrrole-3-yl, pyrazole-3-yl, pyrazole-4-yl, pyrazole-5-yl, imidazole-2-yl, imidazole-4-yl, imidazole-5-yl, 1,2,3-triazole-4-yl, 1,2,3-triazole-5-yl, 1,2,4-triazole-3-yl, 1,2,4-triazole-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazine-3-yl, pyridazine-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, pyrazine-2-yl, pyrrolidine-2-yl, pyrrolidine-3-yl, piperidine-2-yl, piperidine-3-yl, piperidine-4-yl, 2-azapiperidine-3-yl, 2-azapiperidine-4-yl, 3-azapiperidine-2-yl, 3-azapiperidine-4-yl, 3-azapiperidine-5-yl, piperazine-2-yl, furan-2-yl, furan-3- yl, pyran-2-yl, pyran-3-yl, pyran-4-yl, 2-azapyran-3-yl, 2-azapyran-4-yl, 2-azapyran-5-yl, 2-azapyran-6-yl, 3-azapyran-2-yl, 3-azapyran-4-yl, 3-azapyran-5-yl, 3-azapyran-6-yl, 4-azapyran-2-yl, 4-azapyran-3-yl, 4-azapyran-5-yl, 4-azapyran-6-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-4-yl, 2-aza-tetrahydrofuran-5-yl, 3-aza-tetrahydrofuran-2-yl,3-aza-tetrahydrofuran-4-yl, 3-aza-tetrahydrofuran-5-yl, tetrahydropyran-2-yl, oxetan-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, 2-aza-tetrahydropyran-3-yl, 2-aza-tetrahydropyran-4-yl, 2-aza-tetrahydropyran-5-yl, 2-aza-tetrahydropyran-6-yl, 3-aza-tetrahydropyran-2-yl, 3-aza-tetrahydropyran-4-yl, 3-aza-tetrahydropyran-5-yl, 3-aza-tetrahydropyran-6-yl, morpholine-2-yl, morpholine-3-yl, thiophen-2-yl, thiophen-3-yl, isothiazole-3-yl, isothiazole-4-yl, isothiazole-5-yl, thiazole-2-yl, thiazole-4-yl, thiazole-5-yl, thiopyran-2-yl, thiopyran-3-yl, thiopyran-4-yl, 2-azathiopyran-3-yl, 2-azathiopyran-4-yl, 2-azathiopyran-5-yl, 2-azathiopyran-6-yl, 3-azathiopyran-2-yl, 3-azathiopyran-4-yl, 3-azathiopyran-5-yl, 3-azathiopyran-6-yl, 4-azathiopyran-2-yl, 4-azathiopyran-3-yl, 4-azathiopyran-5-yl, 4-azathiopyran-6-yl, thiolane-2-yl, thiolane-3-yl, thiane-2-yl, thiane-3-yl, thiane-4-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, furazan-3-yl, (1,3,4-oxadiazol)-2-yl, (1,3,4-oxadiazol)-5-yl, (1,2,4-oxadiazol)-3-yl, (1,2,4-oxadiazol)-5-yl; and tetrazole-5-yl).

63. The PARP1 inhibitor compound for use according to claim 62, wherein R8is selected from H, a substituted or unsubstituted linear or branched C1-C6alkyl group, and a substituted or unsubstituted linear or branched C1-C6halogenated alkyl group.

64. The PARP1 inhibitor compound for use according to any of claims 1 to 59, wherein L has a structure selected from:,wherein: each R5A, R5A1, R5B, R5B1, R5C, and R6is independently selected from H and a substituted or unsubstituted organic group.

65. The PARP1 inhibitor compound for use according to claim 64, wherein L has a structure of:.

66. The PARP1 inhibitor compound according to any of claims 1 to 59, having a structure of:where: Z1is C or N; one of Z2uand Z2lis C, and the other of Z2uand Z2lis N;each Z3is independently selected from C and N, each R1is independently absent or selected from H, a halogen (e.g., F or Cl), methyl, halomethyl (e.g., CF3), and CN; R5C2ois H, a methyl group, or a halogen; X2CMis N and R5C2Mis absent or X2CMis C and R5C2Mis H; and67. The PARP1 inhibitor compound for use according to claim 66, wherein R5C2ois H or a halogen, optionally F.

68. The PARP1 inhibitor compound for use according to claim 67, wherein L has a structure selected from:

69. The PARP1 inhibitor compound for use according to claim 66, wherein L has a structure of:

70. The PARP1 inhibitor compound for use according to any of claims 66 to 69, wherein the compound has a structure selected from:

71. The PARP1 inhibitor compound for use according to any of claims 1 to 65, wherein when one or more of R1, R2, R3, R5A(e.g., R5A1, R5A2), R5B(e.g., R5B1, R5B3), R5C(e.g., R5C1), R6, R7, R51, and R52is a substituted or unsubstituted organic group, the or each substituted or unsubstituted organic group is independently selected from: deuterium; a halogen (such as –F, -Cl, -Br and –I); a nitrile group; a substituted or unsubstituted linear or branched C1-C6 alkyl group (such as Me, Et, Pr, i-Pr, n-Bu, i-Bu, t-Bu, pentyl and hexyl); a substituted or unsubstituted linear or branched C1-C6 alkyl-aryl group (such as –CH2Ph, -CH2(2,3 or 4)F-Ph, -CH2(2,3 or 4)Cl-Ph, -CH2(2,3 or 4)Br-Ph, -CH2(2,3 or 4)I-Ph, -CH2CH2Ph, -CH2CH2CH2Ph, -CH2CH2CH2CH2Ph, -CH2CH2CH2CH2CH2Ph, and -CH2CH2CH2CH2CH2CH2Ph); a substituted or unsubstituted linear or branched C1-C6 halogenated alkyl group (such as -CH2F, -CH2Cl, -CH2Br, -CH2I, -CHF2, -CF3, -CCl3 -CBr3, -CI3, -CH2CH2F, -CH2CF3, -CH2CCl3, -CH2CBr3, and -CH2CCI3);NH2 or a substituted or unsubstituted linear or branched primary secondary or tertiary C1-C6 amine group (such as -NMeH, -NMe2, -NEtH, -NEtMe, -NEt2, -NPrH, -NPrMe, -NPrEt, -NPr2, - NBuH, -NBuMe, -NBuEt, –CH2-NH2, -CH2-NMeH, -CH2-NMe2, -CH2-NEtH, - CH2-NEtMe, -CH2-NEt2, -CH2-NPrH, -CH2-NPrMe, and –CH2-NPrEt); a substituted or unsubstituted amino-aryl group (such as -NH-Ph, -NH-(2,3 or 4)F-Ph, -NH-(2,3 or 4)Cl-Ph, -NH-(2,3 or 4)Br-Ph, -NH-(2,3 or 4)I-Ph, -NH-(2,3 or 4)Me-Ph, -NH-(2,3 or 4)Et-Ph, -NH-(2,3 or 4)Pr-Ph, -NH-(2,3 or 4)Bu-Ph, NH-(2,3 or 4)OMe-Ph, -NH-(2,3 or 4)OEt-Ph, -NH-(2,3 or 4)OPr-Ph, -NH-(2,3 or 4)OBu-Ph, -NH-2,(3,4,5 or 6)F2-Ph, -NH-2,(3,4,5 or 6)Cl2-Ph, -NH-2,(3,4,5 or 6)Br2-Ph, -NH-2,(3,4,5 or 6)I2-Ph, -NH-2,(3,4,5 or 6)Me2-Ph, -NH-2,(3,4,5 or 6)Et2-Ph, -NH-2,(3,4,5, or 6)Pr2-Ph, -NH-2,(3,4,5 or 6)Bu2-Ph), a substituted or unsubstituted cyclic amine or amido group (such as pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, 2-keto-pyrrolidinyl, 3-keto-pyrrolidinyl, 2-keto-piperidinyl, 3-keto-piperidinyl, and 4-keto-piperidinyl); a substituted or unsubstituted cyclic C3-C8alkyl group (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl); an -OH group; a substituted or unsubstituted linear or branched C1-C6alcohol group (such as –CH2OH, -CH2CH2OH, -CH(CH3)CH2OH, -C(CH3)2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, -CH(CH3)CH2CH2OH, -CH(CH3)CH(CH3)OH, -CH(CH2CH3)CH2OH, -C(CH3)2CH2OH, -CH2CH2CH2CH2CH2OH, and -CH2CH2CH2CH2CH2CH2OH); a substituted or unsubstituted linear or branched C1-C6 carboxylic acid group (such as -COOH, -CH2COOH, -CH2CH2COOH, -CH2CH2CH2COOH, -CH2CH2CH2CH2COOH, and -CH2CH2CH2CH2CH2COOH);a substituted or unsubstituted linear or branched carbonyl group (such as -(CO)Me, -(CO)Et, -(CO)Pr, -(CO)iPr, -(CO)nBu, -(CO)iBu, -(CO)tBu, -(CO)Ph, -(CO)CH2Ph, -(CO)CH2OH, -(CO)CH2OCH3, -(CO)CH2NH2, -(CO)CH2NHMe, -(CO)CH2NMe2, -(CO)-cyclopropyl, -(CO)-1,3-epoxypropan-2-yl; -(CO)NH2, -(CO)NHMe, -(CO)NMe2, -(CO)NHEt, -(CO)NEt2, -(CO)-pyrollidine-N-yl, -(CO)-morpholine-N-yl, -(CO)-piperazine-N-yl, -(CO)-N-methyl-piperazine-N-yl, -(CO)NHCH2CH2OH, -(CO)NHCH2CH2OMe, -(CO)NHCH2CH2NH2, -(CO)NHCH2CH2NHMe, and -(CO)NHCH2CH2NMe2); a substituted or unsubstituted linear or branched C1-C6carboxylic acid ester group (such as -COOMe, -COOEt, -COOPr, -COO-i-Pr, -COO-n-Bu, -COO-i-Bu, -COO-t-Bu, -CH2COOMe, -CH2CH2COOMe, -CH2CH2CH2COOMe, and -CH2CH2CH2CH2COOMe); a substituted or unsubstituted linear or branched C1-C6amide group (such as -CO-NH2, -CO-NMeH, -CO-NMe2, -CO-NEtH, -CO-NEtMe, -CO-NEt2, -CO-NPrH, -CO-NPrMe, and -CO-NPrEt); a substituted or unsubstituted linear or branched C1-C7amino carbonyl group (such as -NH-CO-Me, -NH-CO-Et, -NH-CO-Pr, -NH-CO-Bu, -NH-CO-pentyl, -NH-CO-hexyl, -NH-CO-Ph, -NMe-CO-Me, -NMe-CO-Et, -NMe-CO-Pr, -NMe-CO-Bu, -NMe-CO-pentyl, -NMe-CO-hexyl, -NMe-CO-Ph); a substituted or unsubstituted linear or branched C1-C7alkoxy or aryloxy group (such as –OMe, -OEt, -OPr, -O-i-Pr, -O-n-Bu, -O-i-Bu, -O-t-Bu, -O-pentyl, -O-hexyl, -OCH2F, -OCHF2, -OCF3, -OCH2Cl, -OCHCl2, -OCCl3, -O-Ph, -O-CH2-Ph, -O-CH2-(2,3 or 4)-F-Ph, -O-CH2-(2,3 or 4)-Cl-Ph, –CH2OMe, –CH2OEt, –CH2OPr, –CH2OBu, -CH2CH2OMe, -CH2CH2CH2OMe, -CH2CH2CH2CH2OMe, and -CH2CH2CH2CH2CH2OMe); a substituted or unsubstituted linear or branched aminoalkoxy group (such as –OCH2NH2, -OCH2NHMe, -OCH2NMe2, -OCH2NHEt, -OCH2NEt2, -OCH2CH2NH2, -OCH2CH2NHMe, -OCH2CH2NMe2, -OCH2CH2NHEt, and -OCH2CH2NEt2); a substituted or unsubstituted sulfonyl group (such as -SO2Me, -SO2Et, -SO2Pr, -SO2iPr, -SO2Ph, -SO2-(2,3 or 4)-F-Ph,-SO2-cyclopropyl, -SO2CH2CH2OCH3, -SO2NH2, -SO2NHMe, -SO2NMe2, -SO2NHEt, -SO2NEt2, -SO2-pyrrolidine-N-yl, -SO2-morpholine-N-yl, -SO2NHCH2OMe, and -SO2NHCH2CH2OMe); a substituted or unsubstituted aminosulfonyl group (such as –NHSO2Me, -NHSO2Et, - NHSO2Pr, -NHSO2iPr, -NHSO2Ph, -NHSO2-(2,3 or 4)-F-Ph, -NHSO2-cyclopropyl, -NHSO2CH2CH2OCH3); a substituted or unsubstituted aromatic group (such as Ph-, 2-F-Ph-, 3-F-Ph-, 4-F-Ph-, 2-Cl-Ph-, 3-Cl-Ph-, 4-Cl-Ph-, 2-Br-Ph-, 3-Br-Ph-, 4-Br-Ph-, 2-I-Ph-, 3-I-Ph, 4-I-Ph-, 2,(3,4,5 or 6)-F2-Ph-, 2,(3,4,5 or 6)-Cl2-Ph-, 2,(3,4,5 or 6)-Br2-Ph-, 2,(3,4,5 or 6)-I2-Ph-, 2,(3,4,5 or 6)-Me2-Ph-, 2,(3,4,5 or 6)-Et2-Ph-, 2,(3,4,5 or 6)-Pr2-Ph-, 2,(3,4,5 or 6)-Bu2-Ph-, 2,(3,4,5 or 6)-(CN)2-Ph-, 2,(3,4,5 or 6)-(NO2)2-Ph-, 2,(3,4,5 or 6)-(NH2)2-Ph-, 2,(3,4,5 or 6)-(MeO)2-Ph-, 2,(3,4,5 or 6)-(CF3)2-Ph-, 3,(4 or 5)-F2-Ph-, 3,(4 or 5)-Cl2-Ph-, 3,(4 or 5)-Br2-Ph-, 3,(4 or 5)-I2-Ph-, 3,(4 or 5)-Me2-Ph-, 3,(4 or 5)-Et2-Ph-, 3,(4 or 5)-Pr2-Ph-, 3,(4 or 5)-Bu2-Ph-, 3,(4 or 5)-(CN)2-Ph-, 3,(4 or 5)-(NO2)2-Ph-, 3,(4 or 5)-(NH2)2-Ph-, 3,(4 or 5)-(MeO)2-Ph-, 3,(4 or 5)-(CF3)2-Ph-, 2-Me-Ph-, 3-Me-Ph-, 4-Me-Ph-, 2-Et-Ph-, 3-Et-Ph-, 4-Et-Ph-, 2-Pr-Ph-, 3-Pr-Ph-, 4-Pr-Ph-, 2-Bu-Ph-, 3-Bu-Ph-, 4-Bu-Ph-, 2-(CN)-Ph-, 3-(CN)-Ph-, 4-(CN)-Ph-, 2-(NO2)-Ph-, 3-(NO2)-Ph-, 4-(NO2)-Ph-, 2-(NH2)-Ph-, 3-(NH2)-Ph-, 4-(NH2)-Ph-, 2-MeO-Ph-, 3-MeO-Ph-, 4-MeO-Ph-, 2-(NH2-CO)-Ph-, 3-(NH2-CO)-Ph-, 4-(NH2-CO)-Ph-, 2-CF3-Ph-, 3-CF3-Ph-, 4-CF3-Ph-, 2-CF3O-Ph-, 3-CF3O-Ph-, and 4-CF3O-Ph-); a saturated or unsaturated, substituted or unsubstituted, heterocyclic group, optionally an aromatic heterocyclic group or a non-aromatic heterocyclic group (such as pyrrole-1-yl, pyrrole-2-yl, pyrrole-3-yl, pyrazole-1-yl, pyrazole-3-yl, pyrazole-4-yl, pyrazole-5-yl, imidazole-1-yl, imidazole-2-yl, imidazole-4-yl, imidazole-5-yl, 1,2,3-triazole-1-yl, 1,2,3-triazole-4-yl, 1,2,3-triazole-5-yl, 1,2,4-triazole-1-yl, 1,2,4-triazole-3-yl, 1,2,4-triazole-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazine-3-yl, pyridazine-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, pyrazine-2-yl, pyrrolidine-1-yl, pyrrolidine-2-yl, pyrrolidine-3-yl, piperidine-1-yl, piperidine-2-yl, piperidine-3-yl, piperidine-4-yl, 2-azapiperidine-1-yl, 2-azapiperidine-3-yl,2-azapiperidine-4-yl, 3-azapiperidine-1-yl, 3-azapiperidine-2-yl, 3-azapiperidine-4-yl, 3-azapiperidine-5-yl, piperazine-1-yl, piperazine-2-yl, furan-2-yl, furan-3-yl, pyran-2-yl, pyran-3-yl, pyran-4-yl, 2-azapyran-2-yl, 2-azapyran-3-yl, 2-azapyran-4-yl, 2-azapyran-5-yl, 2-azapyran-6-yl, 3-azapyran-2-yl, 3-azapyran-4-yl, 3-azapyran-5-yl, 3-azapyran-6-yl, 4-azapyran-2-yl, 4-azapyran-3-yl, 4-azapyran-4-yl, 4-azapyran-5-yl, 4-azapyran-6-yl, oxetan-2-yl, oxetan-3-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-2-yl, 2-aza-tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-4-yl, 2-aza-tetrahydrofuran-5-yl, 3-aza-tetrahydrofuran-2-yl, 3-aza-tetrahydrofuran-3-yl, 3-aza-tetrahydrofuran-4-yl, 3-aza-tetrahydrofuran-5-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, 2-aza-tetrahydropyran-2-yl, 2-aza-tetrahydropyran-3-yl, 2-aza-tetrahydropyran-4-yl, 2-aza-tetrahydropyran-5-yl, 2-aza-tetrahydropyran-6-yl, 3-aza-tetrahydropyran-2-yl, 3-aza-tetrahydropyran-3-yl, 3-aza-tetrahydropyran-4-yl, 3-aza-tetrahydropyran-5-yl, 3-aza-tetrahydropyran-6-yl, morpholine-2-yl, morpholine-3-yl, morpholine-4-yl, thiophen-2-yl, thiophen-3-yl, isothiazole-3-yl, isothiazole-4-yl, isothiazole-5-yl, thiazole-2-yl, thiazole-4-yl, thiazole-5-yl, thiopyran-2-yl, thiopyran-3-yl, thiopyran-4-yl, 2-azathiopyran-2-yl, 2-azathiopyran-3-yl, 2-azathiopyran-4-yl, 2-azathiopyran-5-yl, 2-azathiopyran-6-yl, 3-azathiopyran-2-yl, 3-azathiopyran-4-yl, 3-azathiopyran-5-yl, 3-azathiopyran-6-yl, 4-azathiopyran-2-yl, 4-azathiopyran-3-yl, 4-azathiopyran-4-yl, 4-azathiopyran-5-yl, 4-azathiopyran-6-yl, thiolane-2-yl, thiolane-3-yl, thiane-2-yl, thiane-3-yl, thiane-4-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, furazan-3-yl, (1,3,4-oxadiazol)-2-yl, (1,3,4-oxadiazol)-5-yl, (1,2,4-oxadiazol)-3-yl, (1,2,4-oxadiazol)-5-yl; and tetrazole-1-yl, tetrazole-2-yl, tetrazole-5-yl); wherein: a pair of R5Agroups attached to different atoms may together form a ring with ring A atoms; and / ora pair of R5Bgroups attached to different atoms may together form a ring with ring B atoms, and / or a pair of R5Cgroups attached to different atoms may together form a ring with ring C atoms; and / or an R5Cgroup and an R6group attached to different atoms may together form a ring with ring C atoms.

72. The PARP1 inhibitor compound for use according to claim 71, wherein each of R5A(e.g., R5A1, R5A2, R5A3), R5B(e.g., R5B1, R5B3), and R5C(e.g., R5C1) is independently absent or selected from: H, deuterium, a halogen (such as –F, -Cl, -Br, and –I; preferably F or Cl), a nitrile group, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted linear or branched C1-C6 halogenated alkyl group (preferably CF3 or CHF2), a cyclopropyl group, an -OH group, a substituted or unsubstituted linear or branched C1-C6 alcohol group, a substituted or unsubstituted linear or branched C1-C7 amino carbonyl group (such as -NH-CO-Me), an -NH2 group, a substituted or unsubstituted C1-C6 amino group, and a substituted or unsubstituted C1-C6 alkoxy group; wherein, when a pair of R5Agroups attached to different atoms together forms a ring with ring A atoms and / or a pair of R5Bgroups attached to different atoms together forms a ring with ring B atoms and / or a pair R5Cgroups attached to different atoms together forms a ring with ring C atoms, each of the pair of R5A, R5Bor R5Cgroups independently comprises -CH2- or -CH2CH2-, or the pair of groups together comprise -CH=CH-CH=CH- or -NH-CO-NH-.

73. The PARP1 inhibitor compound for use according to any preceding claim, which compound comprises: an isolated enantiomer, or a mixture of two or more enantiomers, or a mixture of two or more diastereomers, and / or epimers, or a racemic mixture, or a tautomer of the compound.

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

75. The PARP1 inhibitor compound for use according to any preceding claim, which is for use in treating a cancer.

76. The PARP1 inhibitor compound for use according to claim 75, 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 effusionlymphoma, 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.

77. The PARP1 inhibitor compound for use according to claim 75 or claim 76, wherein the cancer is deficient in a DNA damage response repair pathway, such as Homologous Recombination dependent DNA Double Strand Break DNA repair activity.

78. The PARP1 inhibitor compound for use according to any of claims 75 to 77, wherein the cancer is deficient in BRCA1 and / or BRCA2 function.

79. The PARP1 inhibitor compound for use according to any of claims 75 to 78, 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.

80. The PARP1 inhibitor compound for use according to claim 79, 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-PD1, 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-I 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.

81. A pharmaceutical composition comprising a PARP1 inhibitor compound as defined in any of claims 1 to 74.

82. A pharmaceutical composition according to claim 81, 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.

83. The pharmaceutical composition according to claim 81 or claim 82, 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 angiogenesis inhibitors, antibody-drug conjugates, immunotherapeutic agents, hormone deprivation therapy, proapoptotic agents, radioligand therapies, anti-angiogenic agents, and cell cycle signalling inhibitors.

84. The pharmaceutical composition according to claim 83, 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-PD1, 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-I 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.

85. The pharmaceutical composition according to any of claims 81 to 84, for use in treating a cancer.

86. A pharmaceutical kit for treating a cancer, which pharmaceutical kit comprises: a) a PARP1 inhibitor compound as defined in any of claims 1 to 74; and b) a further agent for treating cancer; wherein the 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-PD1, 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-I 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 tumour microenvironment modulator), proapoptotic agents, radioligand therapies, anti-angiogenic agents, and cell cycle signalling inhibitors.

87. A compound having a structure of:where: Z1is C or N; one of Z2uand Z2lis C, and the other of Z2uand Z2lis N;each Z3is independently selected from C and N, each R1is independently absent or selected from H, a halogen (e.g., F or Cl), methyl, halomethyl (e.g., CF3), and CN; R5C2ois H, a methyl group, or a halogen; X2CMis N and R5C2Mis absent or X2CMis C and R5C2Mis H; and88. The compound according to claim 87, wherein R5C2ois H or a halogen, optionally F.

89. The compound according to claim 87 or claim 88, wherein the compound has a structure selected from:

90. The compound according to any of claims 87 to 89, which compound comprises: an isolated enantiomer, or a mixture of two or more enantiomers, or a mixture of two or more diastereomers, and / or epimers, or a racemic mixture, or a tautomer of the compound.

91. 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.

92. The method according to claim 91, wherein the patient is an animal, preferably a mammal, optionally a human, canine, equine or feline; and preferably a human.

93. A method of synthesising a PARP1 inhibitor compound as defined in any of claims 1 to 74, which method comprises conducting a reaction between: i) a first reactant comprising rings D and E and bearing a first portion of group L and ii) a second reactant comprising a remainder of group L, to form the PARP1 inhibitor compound.

94. A method according to claim 93, wherein the first reactant comprises rings D, E and A, and the second reactant comprises a QABprecursor bearing a reactive group, which method comprises joining ring A to the QABprecursor.

95. A method according to claim 94, wherein the reactive group of the QABprecursor comprises a carbonyl group, an alkyl halide, or an alkyl sulfonate.

96. A method according to any of claims 93 to 95, wherein the reaction comprises alkylation, reductive amination or amide formation so as to form group L.

97. The method according to any of claims 93 to 96, further comprising preparing the first reactant by: a) providing a precursor having a structure of:wherein: R9is a C1 to C6 alkyl group; and RPGis a protecting group; b) performing a ring closure reaction by treating the precursor with NHR3or a conjugate acid thereof to form an intermediate product, the intermediate product having a structure of:c) deprotecting the intermediate product to obtain the first reactant, the first reactant having a structure of:.

98. The method according to claim 97, wherein Z2lis N and Z2uis C.

99. The method according to claim 98, wherein the precursor has a structure of:.

100. The method according to claim 98, wherein the precursor has a structure of:

101. The method according to claim 100, wherein providing the precursor comprises: a) reacting a compound having a structure of:with a phenylhydroxylamine having a structure of:wherein EWG represents one or more electron withdrawing groups; in the presence of a base, such as sodium hydride, to obtain an intermediate product having a structure of:b) reacting the intermediate product with a carboxylic acid having a structure of:to obtain the precursor.

102. The method according to claim 101, wherein the substituted phenyl hydroxylamine is O-(2,4-dinitrophenyl)hydroxylamine:.

103. The method according to any of claims 97 to 102, wherein R9is an ethyl group.

104. The method according to any of claims 97 to 103, wherein RPGis Boc.

105. The method according to any of claims 97 to 104, wherein R3is H.

106. The method according to any of claims 93 to 96, further comprising preparing the first reactant by: a) providing a first precursor having a structure of:wherein R10is a C1 to C6 alkyl group, optionally a t-butyl group;b) providing a second precursor having a structure of:wherein RPGis a protecting group, optionally Boc; and c) coupling the first precursor and the second precursor using a catalyst, optionally a [Cp*RhCl2]2 catalyst, to form the first reactant, the first reactant having a structure of:

107. The method according to any of claims 93 to 106, wherein the second reactant has a structure of:.

108. The method according to claim 107, further comprising preparing the second reactant by: i) providing a first precursor of formula:wherein: a) X2CMis C and R5C2Mis H; or b) X2CMis N and R5C2Mis absent. ii) providing a second precursor of formula:iii) coupling the first and second precursor using a base, optionally a caesium base such as Cs2CO3, to obtain an intermediate product of formula:iv) treating the intermediate product with an acid to obtain the second reactant, wherein the second reactant has a structure of:.

109. The method according to claim 108, wherein the second precursor is 1,4-dioxa-8- azaspiro[4.5]decane:.

110. The method according to any of claims 93 to 109, wherein conducting the reaction comprises coupling the first reagent and the second reagent using a reducing agent in the presence of an acid.

111. A method according to claim 93, wherein the first reactant comprises rings A, B, D, and E, QAEand QAB, and the second reactant comprises a ring C derivative bearing a leaving group such as a halide or sulfonate.

112. A method according to any of claims 93 to 111, wherein the reaction comprises a nucleophilic substitution reaction, such as a nucleophilic aromatic substitution reaction, so as to form group L.

113. The method according to any of claims 93 to 112, further comprising separating structural isomers of the PARP1 inhibitor compound using chiral supercritical fluid chromatography and / or chiral high-performance liquid chromatography.

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