Parp1 inhibitor compounds

Abstract

A PARP1 inhibitor compound has a structure of: Formula (I), R1 and R4 are independently selected from H and an organic group. R2 and R3 are independently absent, H, or an organic group. Z1 and Z2 are independently C or N. L has the structure: Formula (II). Each X1 is independently selected from C and N. Each X2 is independently selected from C, N, O and S. n, m, p, q, r and s are each in the range 0 to 6. m+n, p+q, and r+s are each in the range 2 to 6. Each R5A, R5B, R5C, and R6 is independently absent, H, or an organic group. Qa, Qb, Qc are each independently a bond or an organic linker. The compounds are for use in medicine, e.g. for use in treating cancer. Also provided are compositions and kits comprising 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 In one aspect, there is provided a PARP1 inhibitor compound for use in medicine. The PARP1 inhibitor compound has the following structure: wherein: R1is selected from H and a substituted or unsubstituted organic group; R2is absent or selected from H and a substituted or unsubstituted organic group; R3is absent or selected from H and a substituted or unsubstituted organic group; R4is selected from H and a substituted or unsubstituted organic group; Z1and Z2are each independently selected from C and N; and L is a group having the following structure: wherein: 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 1, 2, 3, 4, 5, and 6; 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 1, 2, 3, 4, 5, and 6; r is a number independently selected from 0, 1, 2, 3, 4, 5 and 6; 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; each R5A, R5B, and R5Cis independently absent or selected from H and a substituted or unsubstituted organic group; and R6is absent or selected from H and a substituted or unsubstituted organic group; the lines forming rings A, B and C each independently represent single or double bonds such that each ring is independently saturated, unsaturated, or aromatic; and each of Qa, Qb, and Qc is independently selected from a bond and a group having a structure independently 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. Typically, p + q is a number selected from 2, 3, 4, 5, and 6. Optionally, p + q is a number selected from 2, 3, 4, 5, and 6; and m + n is a number selected from 2, 3, 4, 5 and 6. 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 selected from: 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. 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 ring in which all bonds between ring atoms are single bonds. 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 suffixes ‘cis’ and ‘trans’ denotes compounds which are A ring cis and A ring trans, as explained in the section “stereochemistry” hereinbelow. In the case of diastereomeric compounds, the cis and trans suffixes may refer to pairs of diastereomers having the indicated configuration of the A ring. Nuclear Overhauser Effect nuclear magnetic resonance spectroscopy (“NOE NMR”) may be used to determine the stereochemistry of compounds as described herein. 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. Some structural formulae presented herein illustrate stereochemistry assigned by the applicant. In the event of any discrepancy between order of elution (as represented by compound numbering) and assigned stereochemistry, the order of elution takes precedence. By way of illustration, Example 3 hereinbelow describes the synthesis of compound 6. Compound 6 is obtained as a mixture of diastereomers. In a first separation step, the diastereomers are separated into two fractions by prep-HPLC. The first fraction to be eluted comprises a pair of enantiomers 6cis-a and 6cis-b. The second fraction comprises a pair of enantiomers 6trans-a and 6trans-b. In a second separation step, the mixture of 6cis-a and 6cis-b is passed through a Regis (R,R)-Whelk-O chiral chromatography column under the conditions indicated above. The first fraction to be eluted in the second separation step comprises compound 6cis-a, and the second fraction comprises compound 6cis-b. Separately, the mixture of 6trans-a and 6trans-b is passed through a Daicel CHIRALPAK chiral chromatography column under the conditions indicated above to obtain compounds 6trans- a (eluted first) and 6trans-b (eluted second). Discussion Provided herein are PARP1 inhibitor compounds having monocyclic head groups. Also provided are kits and compositions comprising such compounds, and medical uses of the compounds, compositions, and kits. The PARP1 inhibitor compounds have a structure according to the following general formula: wherein: R1is selected from H and a substituted or unsubstituted organic group; R2is absent or selected from H and a substituted or unsubstituted organic group; R3is absent or selected from H and a substituted or unsubstituted organic group; R4is selected from H and a substituted or unsubstituted organic group; Z1and Z2are each independently selected from C and N; and L is a group having the following structure: wherein: 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 1, 2, 3, 4, 5, and 6; 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 1, 2, 3, 4, 5, and 6; r is a number independently selected from 0, 1, 2, 3, 4, 5 and 6; 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; each R5A, R5B, and R5Cis independently absent or selected from H and a substituted or unsubstituted organic group; and R6is absent or selected from H and a substituted or unsubstituted organic group; the lines forming rings A, B and C each independently represent single or double bonds such that each ring is independently saturated, unsaturated, or aromatic; and each of Qa, Qb, and Qc is independently selected from a bond and a group having a structure independently 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. Typically, p + q is a number selected from 2, 3, 4, 5, and 6. Optionally, p + q is a number selected from 2, 3, 4, 5, and 6; and m + n is a number selected from 2, 3, 4, 5 and 6. The PARP1 inhibitor compounds provided herein may be selective for PARP1 over PARP2. Selective inhibition of PARP1 over PARP2 reduces PARP2 associated side effects including one or more haematological toxicities such as anaemia, neutropenia and thrombocytopenia. This may enable treatment of cancer patients with reduced haematological side effects. Alternatively or additionally, this may enable higher doses of PARP1 inhibitors to be administered to patients and for such inhibitors to be administered in combination with chemotherapeutic agents. The PARP1 inhibitor compounds provided herein have monocyclic head groups. Comparative compounds have bicyclic head groups, with the groups at positions R1and R2being fused to form a ring. Without wishing to be bound by theory, it is believed that the PARP1 inhibitor compounds with monocyclic head groups may have improved physicochemical and pharmacokinetic properties, and potentially central nervous system (“CNS”) penetrating activity. Compounds provided herein may therefore be particularly useful for the treatment of a cancer of the brain (such as gliomas, glioblastomas, medulloblastomas, craniopharyngioma, ependymoma, and astrocytoma) or spinal cord. The improved pharmacokinetics and improved CNS penetration may at least in part be due to improved physicochemical properties of the molecules compared to those having bicyclic head groups, as well as modifying the conformation of the molecule: the head groups of bicyclic head groups tend to be flatter and more lipophilic. 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 R2, R3, and R5groups may be absent, with 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, 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 X1or X2atom is N, that atom most preferably has a valency of 3. Compounds in which an X1or X2atom is tetravalent N are also contemplated. Tetravalent N is positively charged, and such compounds may have a counterion. Typically, each of rings A, B, and C includes at most a single tetravalent N. 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 doubled bonded to an adjacent ring atom, the or each corresponding R5 / R6is absent. vii) When an X2is N and not doubled 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 R6are present. The substituents (i.e. R groups; R1, R2, R3, R4, 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. The PARP1 inhibitor compounds provided herein have monocyclic head groups. None of R1, R2, R3, and R4forms a ring with any other R group. 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, R4, R5A(e.g., R5A1, R5A2, R5A3), R5B, 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-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, -CH2Cl, -CH2Br, -CH2I, -CHF2, -CF3, -CCl3-CBr3, -CI3, -CH2CH2F, -CH2CF3, -CH2CCl3, -CH2CBr3, and -CH2CI3); NH2or a substituted or unsubstituted linear or branched primary secondary or tertiary C1-C6amine 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-C6carboxylic 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. R5 groups (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-C7amino carbonyl group (such as -NH-CO-Me), an -NH2group, a substituted or unsubstituted C1-C6amino group, and a substituted or unsubstituted C1-C6alkoxy 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-. Ring E Ring E (also referred to as the “head group”) of the compounds provided herein has a structure of: where: Z1and Z2are each independently selected from C and N; R1is selected from H and a substituted or unsubstituted organic group; R2is absent or selected from H and a substituted or unsubstituted organic group; R3is absent or selected from H and a substituted or unsubstituted organic group; and R4is selected from H and a substituted or unsubstituted organic group. Ring E may have a structure of: R1, R2and R4each being independently selected from H and a substituted or unsubstituted organic group. Alternatively, ring E may have a structure of: R1, R3and R4each being independently selected from H and a substituted or unsubstituted organic group; In accordance with another possibility, ring E may have a structure of: R1, R2, R3and R4each being independently selected from H and a substituted or unsubstituted organic group. Generally, the following provisos apply to the selection of R2and R3: R2is absent when Z1is N. R2is selected from H and a substituted or unsubstituted organic group, and is preferably H, when Z1is C. R3is absent when Z2is N. R3is selected from H and a substituted or unsubstituted organic group, and is preferably H, when Z2is C. R1and R2may each be independently selected from: H; a C1 to C6 alkyl, aminoalkyl, alkoxy or haloalkyl group; a C3 to C6 cycloalkyl group; a halogen group; and wherein R22is selected from H, a C1 to C6 alkyl, cycloalkyl, alkoxy, or haloalkyl group, and a halogen group, and each R23is independently selected from H and a substituted or unsubstituted organic group, and each R23is preferably selected from H, a C1 to C6 alkyl, aminoalkyl, alkoxy or haloalkyl group, and a halogen group. Usually, at least one R23is H. In most implementations, at least one of R1and R2is not H. Preferably, R1is a substituted or unsubstituted organic group and R2is H. Preferably, at least one of R1, R2, R3and R22is selected from -CH3, -CH2CH3, -CH2CH2CH3, -CH2F, -CHF2, -CF3, -F, -Cl, -CH2CF3, -CH2CH2F, -CH2CH2OH, methoxy, methoxymethyl, methoxyethyl, isopropyl, cyclopropyl or cyclopropylmethyl. At least one of R1and R2may be with each R23being independently selected from H, F, C1 to C3 alkyl, and C1 to C3 fluoroalkyl. Optionally, R3is as defined further below, and at least one of R1, R2, and R22is selected from -CH3, -CH2CH3, -CH2CH2CH3, -CH2F, -CHF2, -CF3, -F, -Cl, -CH2CF3, -CH2CH2F, -CH2CH2OH, methoxy, methoxymethyl, methoxyethyl, isopropyl, cyclopropyl or cyclopropylmethyl. R1may be selected from H, C1 to C3 alkyl, C1 to C3 alkoxy, and C1 to C3 haloalkyl. Alternatively, R1may be selected from a halogen group, optionally Cl; a C1 to C4 alkyl group; and a C1 to C4 haloalkyl group, optionally a C1 to C4 fluoroalkyl group. For instance, R1may be selected from Most preferably, R1is an ethyl group. R2may in particular be selected from H, CH3, -CH2CH3, -CH2CH2CH3, -CH2F, -CHF2, -CF3, -F, -Cl, -CH2CF3, -CH2CH2F, -CH2CH2OH, methoxy, methoxymethyl, methoxyethyl, isopropyl, cyclopropyl and cyclopropylmethyl. R2is most preferably H. R3may in particular be selected from H, halogen, C1 to C3 alkyl, C1 to C3 haloalkyl, C1 to C3 alcohol, and C1 to C3 aminoalkyl. R3is most preferably H. R4may in particular be selected from H, C1 to C3 alkyl, and C1 to C3 haloalkyl. R4is most preferably H. In one class of example compounds, Z1and Z2are each C; and R2and R3are each independently selected from H, a halogen, C1 to C3 alkyl, and C1 to C3 haloalkyl. Optionally, R2and R3are each independently selected from H, C1 to C3 alkyl, and C1 to C3 haloalkyl. In compounds of this class, R2and R3are optionally each H. The E ring may have a structure selected from:

[0002] In accordance with another possibility, ring E may have a structure of: Ring E is preferably selected from: The most preferred E ring has the structure: Rings A, B, and C - general Rings A and C are each independently carbocylic or heterocyclic. 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. Ring A Ring A of the PARP1 inhibitor compound has the general structure: X1AEis the X1atom that is connected to ring E via linker Qa, and X1ABis the X1atom that is connected to ring B via linker Qb. X2Adenotes an X2atom which is part of ring A. X1AEmay be C or N, and is preferably C. When Qa is and u=0, X1AEis C. When X1AEis N, R5A1is typically absent. X1ABmay be C or N, and is preferably C. Rings A and B are most typically not connected via an N-N bond. To this end, when Qb is a bond or and t=0, X1ABis C. When X1ABis N, R5A3is typically absent. Each X2Aatom is independently selected from C, N, O, and S; with C and N being particularly preferred. The X2Agroups are selected such that ring A is free of O-O, O-S, and S-S bonds. Particularly preferably, all of the X2Aatoms are C. Ring A is typically 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, and is 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. In other words, it is preferable for X1AEand X1ABto be non-adjacent. In accordance with another possibility, ring A may be a 3-membered ring. For example, ring A may be: When ring A is a 3-membered ring, Qb is preferably not a bond. For example, ring A is a 3- membered ring Qb may be -CH2-. The R5Agroups (R5A1, R5A2, and R5A3) are each independently absent or selected from H and a substituted or unsubstituted organic group. Ring A may be a saturated ring, an unsaturated non-aromatic ring, or an aromatic ring depending upon the number of R5Agroups present. In most implementations, no more than one of the R5Agroups is a substituted or unsubstituted organic group. When an R5Agroup is present, that R5Agroup is most preferably H. Ring A may have a structure of: wherein: n is 1, 2 or 3; m is 0, 1, or 2; X1is C or N; each X2is independently selected from C, O, and N; and each R5A1, R5A2, and R5A3is independently absent or selected from H and a substituted or unsubstituted organic group; with the proviso that R5A1is absent when X1 is N; and R5A2is absent when the corresponding X2 is O. Optionally, R5A1and R5A3are each independently H or absent. Optionally, each R5A2is independently absent, H, an oxo group, or a methyl group. Further optionally, each R5A1, R5A2, and R5A3is independently H or absent. For example, each R5A1, R5A2, and R5A3may be H. Alternatively, exactly two groups selected from the R5A1, R5A2, and R5A3groups together represent a C1 to C3 alkyl group bridging ring A. For example, two groups selected from the R5A1, R5A2, and R5A3groups may together represent a -CH2- group. In such compounds, the remaining ones of the R5A1, R5A2, and R5A3groups are preferably H. Examples of bridged ring A structures include: Alternatively, two R5A2groups on adjacent X2atoms may together represent a phenyl group. For example, ring A may have a structure of: Preferably, ring A is monocyclic. For example, ring A may have a structure of: where: m is 1 or 2; n is 1 or 2; each R5A2and R5A3independently is absent or selected from H and a substituted or unsubstituted organic group; and i) X1 is C and R5A1is absent or selected from H and a substituted or unsubstituted organic group; or ii) X1 is N and R5A1is absent. In such compounds, ring A is preferably an aliphatic ring (i.e., all bonds between X atoms are single bonds) and R5A3is H. Optionally, each R5A2is H. Optionally, ring A may have a structure selected from: In accordance with another possibility, ring A may have a structure selected from:

[0003] For example, ring A may be: In other examples, ring A is a substituted or unsubstituted 7-membered aliphatic carbocycle or heterocycle, optionally a cycloheptane, further optionally a cycloheptane having structure selected from: each R5Aand R5A3being independently selected from H and a substituted or unsubstituted organic group, wherein R5A3is most preferably H.

[0004] Alternatively, ring A may be a substituted or unsubstituted 6-membered aliphatic carbocycle or heterocycle, optionally a cyclohexane or tetrahydropyran and further optionally having a structure selected from: , , , , , each R5Aand R5A3being independently selected from H and a substituted or unsubstituted organic group, wherein R5A3is most preferably H. In accordance with another possibility, ring A may be a substituted or unsubstituted 5- membered aliphatic carbocycle or heterocycle, optionally a cyclopentane, cyclopentene, or a tetrahydrofuran, and further optionally having a structure selected from: , , or each R5Aand R5A3being independently selected from H and a substituted or unsubstituted organic group, wherein R5A3is most preferably H. In still further examples, ring A may be 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. Other example compounds include those in which ring A is a substituted or unsubstituted cyclobutane, optionally having a structure of: each R5Aand R5A3being independently selected from H and a substituted or unsubstituted organic group, wherein R5A3is most preferably H. Alternatively, the substituted or unsubstituted cyclobutane may have a structure of: Examples of ring A structures include:

[0005] Ring B Ring B of the PARP1 inhibitor compound has a structure of: X1BCis the X1atom that is connected to ring C via linker Qc. X2Bdenotes an X2atom which is part of ring B. X1BCmay be C or N, and is preferably N. When X1BCis N, R5B3is typically absent. Rings B and C are most typically not connected via an N-N bond. When Qc is and t=0, X1BCis C. When Qc is a bond, no more than one of X1BCand X1CBis N. 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. Particularly preferably, all of the X2Batoms are C. Ring B may be 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. In particular, ring B may be a 5- or 6-membered ring, and is particularly preferably a 6- membered ring. Put differently, p and q may sum to 3 or 4, preferably 4. Preferably, both p and q are at least 1. In other words, X1BCis preferably not adjacent to the N atom that connects to linker Qa. When ring B is a 6-membered ring, it is preferable for p to be 2 and q to be 2. The R5Bgroups (R5B2, R5B3) are each independently absent or selected from H and a substituted or unsubstituted organic group. Ring B may be a saturated ring, an unsaturated non-aromatic ring, or an aromatic ring depending upon the number of R5Bgroups present. Ring B is preferably a saturated heterocycle. In most implementations, no more than one of the R5Bgroups is a substituted or unsubstituted organic group. When an R5Bgroup is present, that R5Bgroup is most preferably H. Preferably, all R5Bgroups are present and all R5Bgroups are H. Two R5Bgroups may together bridge ring B.

[0006] Ring B may be a 7-membered saturated heterocyclic ring, optionally a homopiperazine having a structure: each R5Bbeing independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5Bis H. Alternatively, ring B may be a 6-membered saturated heterocyclic ring, optionally a piperazine, further optionally a piperazine having a structure: each R5Bbeing independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5Bis H. In accordance with another possibility, ring B may be a 5-membered saturated heterocyclic ring, optionally an imidazolidine, further optionally an imidazolidine having a structure: each R5Bbeing independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5Bis H. Alternatively, ring B may be an azepane, optionally having a structure of: each R5Bbeing independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5Bis H. In accordance with another possibility, ring B may be a piperidine, optionally having a structure of: each R5Bbeing independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5Bis H. Alternatively, ring B may be ring B is a pyrrolidine, optionally having a structure of: each R5Bbeing independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5Bis H. In accordance with still another possibility, ring B may have a structure of: each R5Bbeing independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5Bis H. Preferably, ring B may have a structure selected from: It is particularly preferred for ring B to have a structure of: Ring C Ring C of the PARP1 inhibitor compound has a structure of: X1CBdenotes the X1atom of ring C which connects to ring B via linker Qc. X2Cdenotes an X2atom of ring C. X1CBmay be C or N, and is preferably C. When X1CBis N, R5C1is typically absent. When Qc is and u=0, X1CBis C. When atom X1BCof ring B is N and Qc is a bond, X1CBis C. 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. In particular, ring C may be a 5 or 6 membered ring, and is particularly preferably a 6 membered ring. Put differently, p and q may sum to 3 or 4, preferably 4. Ring C may be a 6-membered aliphatic ring, optionally a 6-membered aliphatic ring having structure: 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 a 6-membered aromatic ring, optionally selected from: iia) a phenyl group, optionally having formula: 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 formula selected from: , each R5Cbeing independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5Cis H; and iic) a diazine group, optionally having a formula selected from: , each R5Cbeing independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5Cis H. In further examples, ring C may be a 5-membered aromatic ring, optionally selected from: iiia) an imidazole group, optionally an imidazole group having a structure of: 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; and iiid) a triazole, optionally a triazole of formula: R5Cbeing selected from H and a substituted or unsubstituted organic group, optionally wherein R5Cis H. For example, ring C may have a structure selected from: It is preferable for ring C to be a 6-membered aromatic ring. For instance, ring C may have a structure of: wherein: each XCis independently selected from C and N; and when an XCis N, the corresponding R5COor R5CMgroup is absent; and when an XCis C, the corresponding R5COor R5CMgroup is H or an organic group selected from a halo group; -CN; a C1 or C2 alkyl group; and a C1 or C2 haloalkyl group. When an XCis C, the corresponding R5COor R5CMgroup may be H or an organic group selected from H, -Cl, -F, and -CN. Ring C may have exactly one substituent. In other words, either exactly one R5COor exactly one R5CMgroup may be an organic group. Optionally, no more than two XCatoms are N. In particular, ring C may have a structure of: where: R5C2ois selected from H and a halogen; and i) X2CMis C and R5C2is H; or ii) X2CMis N and R5C2Mis absent. Preferably, R5C2ois a halogen, with F being the preferred halogen. Ring C may have a structure selected from: In accordance with another possibility, ring C may be: In further examples, ring C may be selected from: Substituent R6In 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, -CR52R52NR51R51and any of the following structures:

[0007] wherein R51and R52are each independently selected from H and a substituted or unsubstituted organic group. R51and R52are preferably each independently selected from H, a halogen, C1 to C3 alkyl, and C1 to C3 haloalkyl. For example, R51and R52may each be H. R6may be selected from -F, -Cl, -CN, -CONH2, -CONHMe, -CONHEt, -CONMe2, -CONHCOMe, -CONHCH2-CH2OMe, -CONH-CH2-CH2F, -CONH-CH2-CF3, -CONH-CH2-CHF2, -OCHF2, -NHCOMe, -NHSO2Me, -SO2NHMe, -CONHSO2Me, 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: or R6may be selected from: The preferred R6groups are: The most preferred R6groups are CONHMe (i.e. ) and . Where a compound, L group, or C ring substructure is depicted as having R6= CONHMe, replacement of the R6group with is contemplated. Likewise, where a compound, L group, or C ring substructure is depicted as having replacement of the R6 group with CONHMe 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: In other examples, R6and one R5Cgroup together form a ring. For example, ring C may have a structure selected from: Typically however, ring C is not a fused ring system and no R5Cgroup forms a ring with another R5Cor R6group. In accordance with still another possibility, R6may be selected from -H, -F, -Cl, and -CN. Linkers (Q groups) As shown in the formula below, the E, A, B, and C rings are connected by linkers Qa, Qb, and Qc: The linkers may be referred to herein generically as “Q groups”. Qa, Qb, and Qc and rings A to C may be referred to collectively as group L. Each linker is independently selected from a bond and a group having a structure independently 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 is , t and u 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 Qa, Qb, and Qc may 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 -NH2group or a substituted or unsubstituted C1- C6amino group, an -OH group or a substituted or unsubstituted linear or branched C1-C6alcohol group and a substituted or unsubstituted C1-C6alkoxy group. In particular, R7may be selected from H, a halogen (preferably F), a substituted or unsubstituted C1-C6alkyl group or a substituted or unsubstituted linear or branched C1-C6halogenated alkyl group. When at least one of Qa, Qb and Qc has 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-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-C8alkyl 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-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 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-C6alkyl group or a substituted or unsubstituted linear or branched C1-C6halogenated alkyl group. Optionally, Qa is a bond or -CH2-, and preferably Qa is a bond. Group L may have a structure of: and optionally group L may have a structure of: Optionally, Qb is a bond or -CH2-, and preferably Qb is a bond. When ring A is 5-, 6-, or 7- membered ring, Qb is preferably a bond. When ring A is a 3-membered ring, Qb is preferably -CH2-. When ring A is a 4-membered ring, Qb may be -CH2- or a bond. Optionally, Qc is a bond or -CH2-, and preferably Qc is a bond. In particular, when ring B is a 5-, 6-, or 7-membered ring, Qc may be a bond. When ring B is a 3- or 4-membered ring, Qc may be selected from -CH2-; -O-; and -NR8-. R8is H or a substituted or unsubstituted organic group, optionally H or a C1 to C3 alkyl group. In particular, when ring B is a 3- or 4-membered ring, Qc may be -O- or -NH-. Preferably, Qa, Qb and Qc are each independently selected from a bond and -CH2-. Most preferably, Qa, Qb, and Qc are each bonds. Stereochemistry Various ones of the PARP1 inhibitor compounds provided herein may include one or more chiral centres. Without wishing to be bound by theory, it is believed that the configuration of rings E and B with respect to the A ring may influence the activity of the PARP1 inhibitor compound.

[0008] In the context of the present disclosure, where it is said that a PARP1 inhibitor compound is “A ring cis” or has a cis configuration of the A ring this means that the L group of the compound has a structure of: where ring A is a saturated or unsaturated aliphatic carbocycle or heterocycle. Where it is said that a PARP1 inhibitor compound is “A ring trans” or has a trans configuration of the A ring, this means that the L group of the compound has a structure of: where ring A is a saturated or unsaturated aliphatic carbocycle or heterocycle. When the PARP1 inhibitor compound is A ring trans and the A ring is a cyclopentane (e.g., if ring A has structure A9), both X1atoms of ring A may have an R configuration or both X1atoms of ring A may have an S configuration. In other words, the A ring may have an (R,R) configuration or an (S,S) configuration. In some examples, the (S,S) enantiomer may be more active than the (R,R) enantiomer. In some of the compounds provided herein, ring A is an aromatic ring. When ring A is aromatic, the PARP1 inhibitor compound is neither A ring cis nor A ring trans. The PARP1 inhibitor compounds described herein may be provided in the form of an isolated enantiomer, a mixture of two or more enantiomers, a mixture of two or more diastereomers and / or epimers, or a racemic mixture. Example L groups In particular, group L may have a structure of: where: m is 1 or 2; n is 1 or 2; X1AEis C and R5A1is H, or X1AEis N and R5A1is absent; each R5A2is independently absent or H; R5A3is absent or H; p is 1 or 2; q is 1 or 2; X1BCis C and R5B3is H, or X1BCis N and R5B3is absent; R5C2ois H or a halogen, optionally F; X2CMis N and R5C2Mis absent, or X2CMis C and R52CMis H; and R6is selected from: In a variant, exactly two groups selected from R5A1, the R5A2groups, and R5A3represent a -CH2- group bridging ring A. Optionally, R6may be selected from . p may be 2 and q may be 2, such that group L has a structure of: Preferably, X1BCis N and R5B3is absent. Ring A is preferably selected from: cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, and cyclohexenyl. Group L may be selected from:

[0009] Group L may in particular be selected from: ; Example Compounds Example PARP1 inhibitor compounds provided herein include those having a structure of: where: each R23is independently selected from H or a halogen (e.g., F); R22is selected from H, methyl, and halomethyl (e.g., CH2F, CHF2, CF3); Z2is C and R3is H, or Z2is N and R3is absent; m is 1 or 2; n is 1 or 2; X1AEis C and R5A1is absent or H, or X1AEis N and R5A1is absent; each R5A2is independently absent or H; R5A3is absent or H; p is 1 or 2; q is 1 or 2; X1BCis C and R5B3is H, or X1BCis N and R5B3is absent; R5C2ois H or a halogen, optionally F; X2CMis N and R5C2Mis absent, or X2CMis C and R52CMis H; and R6is selected from: In variants, exactly two groups selected from R5A1, the R5A2groups, and R5A3represent a -CH2- group bridging ring A. Optionally, R6may be selected from . Preferably, each R23is H and R22is methyl. Preferably, Z2is C and R3is H. Preferably, X1AEis C and R5A1is H. Ring A is preferably selected from cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, and cyclohexenyl. Ring B is preferably a piperazine: Further examples of PARP1 inhibitor compounds provided herein are those having a structure of: wherein: Z1and Z2are each independently selected from C and N; when Z1is N: R2is absent; when Z1is C: R2is H; when Z2is N: R3is absent; when Z2is C: R3is H; each XCis independently selected from C and N; and when an XCis N, the corresponding R5COor R5CMgroup is absent; and when an XCis C, the corresponding R5COor R5CMgroup is H or an organic group selected from a halo group; -CN; a C1 or C2 alkyl group; and a C1 or C2 haloalkyl group; two R5Agroups together represent a -CH2- group, each other R5Agroup being independently H or absent with the proviso that ring A is non-aromatic; or preferably each R5Agroup is independently H or absent with the proviso that ring A is non-aromatic. R6is as defined hereinabove. For example, R6 may be selected from: The PARP1 inhibitor compound may have a structure selected from:

[0010] 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 ring E 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 ring E and ring A, and the second reactant comprises a Qb precursor bearing a reactive group, which method comprises joining ring A to the Qb precursor. In this method, the reactive group of the Qb precursor 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 another example method, the first reactant comprises ring E, ring A, Qa, and ring B, 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. A particularly preferred method is for synthesising a PARP1 inhibitor compound where L is a group having a structure of: . In the preferred method, the first reactant has a structure of: where R9 is a protecting group. R9 is most typically a methyl group. Other examples of protecting groups include acetyl, tert-butyl, benzoyl; benzyl; p-methoxybenzyl; p- methoxyphenyl, methoxymethyl, ethoxyethyl, methoxyethoxymethyl; methylthiomethyl, trityl; methoxytrityl; dimethoxytrityl, pivaloyl, tetrahydropyranyl, tetrahydrofuran, and silyl groups (such as trimethylsilyl, tert-butyldimethylsilyl, tri-iso-propylsilyloxymethyl, and triisopropylsilyl). The second reactant in the preferred method has a structure of: . In the preferred method, conducting the reaction comprises: i) coupling the first reagent and the second reagent using a reducing agent in the presence of an acid to obtain an intermediate product having a structure of: ii) subsequently deprotecting ring E’ to form the PARP1 inhibitor compound. The reducing agent and acid used in step i) may be selected as appropriate. Examples of suitable reducing agents include sodium borohydride, sodium cyanoborohydride, and sodium triacetoxyborohydride. The acid may be a weak acid, optionally a weak organic acid such as acetic acid. The conditions used for deprotection step ii) may be selected as appropriate based on the nature of the protecting group R9. For example, in implementations where R9is a methyl group, deprotection may be performed trimethylsilyl iodide (“TMSI”) or boron tribromide in an appropriate solvent (such as dichloromethane, acetonitrile, or chloroform). Other acids or Lewis acids may be used. In some implementations of the preferred method, rings A, B’, and B are all saturated rings, and optionally the X1 of rings B and B’ is N. The PARP1 inhibitor compound may be obtained in the form of a mixture of two or more structural isomers. The method may further comprise separating the structural isomers. For example, the method may further comprise comprising separating structural isomers of the PARP1 inhibitor compound using chiral supercritical fluid chromatography (“SFC”) and / or chiral high-performance liquid chromatography (“HPLC”). When the PARP1 inhibitor compound is diastereomeric, separation may proceed in two stages. In a first stage, two pairs of stereoisomers may be isolated by HPLC. In a second stage, individual stereoisomers may be isolated from the pairs of stereoisomers by SFC.

[0011]

[0012] Preparation of 6-bromo-3-iodo-2-methoxypyridine (1002) The following three solutions A-C were prepared: A: a solution of NaNO2(3.4 g, 0.049 mol) in H2O (100 mL). B: a solution of 6-bromo-2-methoxypyridin-3-amine 1001 (10 g, 0.049 mol) in conc. HCl: H2O = 1:1 (80 mL). C: a solution of KI (24.56 g, 0.15 mol) in H2O (450 mL). A was added to B dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 20 min. Then the reaction mixture was added to C dropwise at 0 °C. The mixture was heated at 60 °C for 2 h. The resulting mixture was diluted with water (200 mL) and extracted with EtOAc (500 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 EtOAc / PE, 0 % to 50 %) to give 6-bromo-3-iodo-2-methoxypyridine 1002 (8.9 g, 90 % purity, 58 % yield) as a white solid. LCMS (ESI) calcd for C6H5BrINO [M + H]+m / z 313.86, no MS signal found. Preparation of 6-bromo-2-methoxy-3-vinylpyridine (1004) To a solution of 6-bromo-3-iodo-2-methoxypyridine 1002 (1 g, 0.0032 mol) in DMF / H2O = 5:1 (50 mL) was added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane 1003 (0.50 g, 0.0032 mol), Na2CO3(1.01 g, 0.0096 mol) and Pd(dppf)Cl2·DCM (0.26 g, 0.00032 mol) under N2. The mixture was heated at 65 °C for 2 hours. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (100 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 EtOAc / PE, 0 % to 100 %) to give 6-bromo-2-methoxy-3- vinylpyridine 1004 (600 mg, 90 % purity, 78 % yield) as a white solid. LCMS (ESI) calcd for C8H8BrNO [M + H]+m / z 213.98, no signal found. Preparation of 7-(6-methoxy-5-vinylpyridin-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonane (1006) To a solution of 6-bromo-2-methoxy-3-vinylpyridine 1004 (600 mg, 0.0028 mol) and 1,4- dioxa-7-azaspiro[4.4]nonane 1005 (0.41 g, 0.0031 mol) in Dioxane (20 mL) was addedtBuONa (0.89 g, 0.0084 mol) and RuPhos Pd G3 (0.24 g, 0.00024 mol) in a sealed tube. The mixture was heated at 100oC for 2 hours. The resulting mixture was concentrated and purified by silica gel column chromatography (eluting with EtOAc / PE, 0 % to 100 %) to give 7-(6-methoxy- 5-vinylpyridin-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonane 1006 (250 mg, 90 % purity, 30 % yield) as a white solid. LCMS (ESI) calcd for C14H18N2O3[M + H]+m / z 263.13, found 262.92. Preparation of 7-(5-ethyl-6-methoxypyridin-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonane (1007) To a solution of 7-(6-methoxy-5-vinylpyridin-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonane 1006 (250 mg, 0.96 mmol) in MeOH (20 mL) was added 10 % Pd / C (25 mg). The mixture was evacuated and backfilled with hydrogen three times and then charged with hydrogen. The resulting mixture was stirred at room temperature for 2 hours. Then the mixture was filtered through celite and concentrated under vacuum to give crude 7-(5-ethyl-6-methoxypyridin-2-yl)-1,4- dioxa-7-azaspiro[4.4]nonane 1007 (250 mg, 90 % purity, 90 % yield) which was used directly in next step without further purification. LCMS (ESI) calcd for C14H20N2O3[M + H]+m / z 265.15, found 264.95. Preparation of 1-(5-ethyl-6-methoxypyridin-2-yl)pyrrolidin-3-one (1008) A solution of 7-(5-ethyl-6-methoxypyridin-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonane 1007 (200 mg, 0.76 mmol) in conc. HCl (12 mL) was stirred at 50 ιC for 12 h. Then the resulting mixture was adjusted to pH 7-8 with aq. NaHCO3and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated to give crude 1-(5-ethyl-6-methoxypyridin-2-yl)pyrrolidin-3-one 1008 (130 mg, 90 % purity, 70 % yield) as a white solid. LCMS (ESI) calcd for C12H16N2O2[M + H]+m / z 221.12, found 221.20. Preparation of 5-(4-(1-(5-ethyl-6-methoxypyridin-2-yl)pyrrolidin-3-yl)piperazin-1-yl)-N- methylpicolinamide (1010) To a solution of 1-(5-ethyl-6-methoxypyridin-2-yl)pyrrolidin-3-one 1008 (120 mg, 0.45 mmol) and N-methyl-5-(piperazin-1-yl)picolinamide 1009 (117 mg, 0.45 mmol) in MeOH (10 mL) was added AcOH (0.1 mL). Then NaBH3CN (29 mg, 0.45 mmol) was added to the mixture. The mixture was heated at 50 °C for 1 hour. The resulting mixture was quenched with water (1 mL), concentrated, and purified by silica gel column chromatography (eluting with MeOH / DCM, 0 % to 10 %) to give 5-(4-(1-(5-ethyl-6-methoxypyridin-2-yl)pyrrolidin-3- yl)piperazin-1-yl)-N-methylpicolinamide 1010 (100 mg, 90 % purity, 38 % yield) as a white solid. LCMS (ESI) calcd for C23H32N6O2[M + H]+m / z 425.26, found 425.25. Preparation of 5-(4-(1-(5-ethyl-6-oxo-1,6-dihydropyridin-2-yl)pyrrolidin-3-yl)piperazin-1- yl)-N-methylpicolinamide (3rac) To a solution of 5-(4-(1-(5-ethyl-6-methoxypyridin-2-yl)pyrrolidin-3-yl)piperazin-1-yl)-N- methylpicolinamide 1010 (100 mg, 0.24 mmol) in DCM (10 mL) was added BBr3(118 mg, 0.47 mmol) at 0 °C. The mixture was stirred at rt for 2 hours. The resulting mixture was diluted with water (10 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 prep-HPLC (Gemini 5 μm C18 column, 150 × 21.2 mm, eluting with 5 % to 95 % MeCN / H2O containing 0.1% FA) to give 5-(4-(1-(5-ethyl-6-oxo-1,6-dihydropyridin-2-yl)pyrrolidin-3-yl)piperazin-1-yl)- N-methylpicolinamide 3rac (11.9 mg, 99 % purity, 13 % yield) as a white solid.1H NMR (400 MHz, DMSO-d6, ppm) δ: 10.20 (s, 1 H), 8.44-8.36 (m, 1 H), 8.28 (d, J = 2.4 Hz, 1 H), 7.83 (d, J = 8.8 Hz, 1 H), 7.44-7.37 (m, 1 H), 7.11 (d, J = 7.6 Hz,1 H), 5.39 (s, 1 H), 3.65-3.57 (m, 1 H), 3.52-3.42 (m, 1 H), 3.37-3.33 (m, 3 H), 3.30-3.22 (m, 2 H), 3.19-3.09 (m, 1 H), 2.94 (d, J = 4.8 Hz, 1 H), 2.78 (d, J = 4.8 Hz, 3 H), 2.68-2.60 (m, 2 H), 2.60-2.53 (m, 2 H), 2.34-2.25 (m, 2 H), 2.23-2.14 (m, 1 H), 1.89-1.77 (m, 1 H), 1.03 (t, J = 7.4 Hz, 3 H). LCMS (ESI) calcd for C22H30N6O2[M + H]+m / z 411.24, found 411.25. Example 2: Synthesis of 4cis Preparation of 3-(benzyloxy)-1-(5-ethyl-6-methoxypyridin-2-yl)cyclobutan-1-ol (1103) To a solution of 6-bromo-3-ethyl-2-methoxypyridine 1101 (800 mg, 12.41 mmol) in THF (15 mL) was added n-BuLi (2.5 M in hexane, 2.22 mL, 5.55 mmol) dropwise at -78°C under an atmosphere of N2. After addition, the solution was stirred at -78 °C for 30 minutes. Then 3- (benzyloxy)cyclobutan-1-one (1102, 984 mg, 5.55 mmol) was added dropwise. The resulting solution was slowly warmed to room temperature and stirred for 2 hours. The final mixture was quenched with saturated aqueous NH4Cl solution and extracted with EtOAc. (20 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE / EtOAc = 100 : 0 to 80 : 20) to give 3-(benzyloxy)-1-(5-ethyl-6-methoxypyridin-2- yl)cyclobutan-1-ol 1103 (400 mg, 32 % yield ) as a colourless oil. LCMS (ESI) calcd for C19H24NO3[M + H]+m / z 314.17, found 314.10. Preparation of 6-(3-(benzyloxy)cyclobut-1-en-1-yl)-3-ethyl-2-methoxypyridine (1104) To a solution of 3-(benzyloxy)-1-(5-ethyl-6-methoxypyridin-2-yl)cyclobutan-1-ol (1103, 400 mg, 1.27 mmol) and TEA (257 mg, 2.54 mmol) in DCM (10 mL) was added MsCl (292 mg, 2.54 mmol) at 0°C. The resulting solution was slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was added to water and then extracted with EtOAc (10 mL × 3). The combined organic layer was washed with brine, dried over Na2SO4and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE / EtOAc = 100 : 0 to 90: 10) to give 6-(3-(benzyloxy)cyclobut-1-en-1-yl)-3-ethyl-2- methoxypyridine 1104 (120 mg, 30 % yield) as a colourless oil. LCMS (ESI) calcd for C19H22NO2[M + H]+m / z 296.16, found 296.05. Preparation of 3-(5-ethyl-6-methoxypyridin-2-yl)cyclobutan-1-ol (1105) To a solution of 6-(3-(benzyloxy)cyclobut-1-en-1-yl)-3-ethyl-2-methoxypyridine 1104 (120 mg, 0.40 mmol) in MeOH (10 mL) was added Pd / C (5 mg, 0.04 mmol). The mixture was stirred at room temperature under H2for 2 h. The reaction mixture was concentrated under reduced pressure to give 3-(5-ethyl-6-methoxypyridin-2-yl)cyclobutan-1-ol 1105 (70 mg, 60 % yield) as a yellow solid. LCMS (ESI) calcd for C12H18NO2[M + H]+m / z 208.13, found 208.05. Preparation of 3-(5-ethyl-6-methoxypyridin-2-yl)cyclobutan-1-one (1106) To a solution of 3-(5-ethyl-6-methoxypyridin-2-yl)cyclobutan-1-ol 1105 (60 mg, 0.29 mmol) in DCM (5 mL) was added Dess-Martin reagent (368 g, 0.87 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was added into sodium hypochlorite solution and then extracted with EtOAc (5 mL × 3). The combined organic layer was washed with brine, dried over Na2SO4and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE / EtOAc = 100 : 0 to 80: 20) to give 3-(5-ethyl-6-methoxypyridin-2-yl)cyclobutan-1-one 1106 (35 mg, 37 % yield ) as a yellow oil. LCMS (ESI) calcd for C12H16NO2[M + H]+m / z 206.11, found 205.94. Preparation of 5-(4-(3-(5-ethyl-6-methoxypyridin-2-yl)cyclobutyl)piperazin-1-yl)-N- methylpicolinamide (1107) To a solution of give 3-(5-ethyl-6-methoxypyridin-2-yl)cyclobutan-1-one 1106 (30 mg, 0.15 mmol) and N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide 1009 (32 mg, 0.15 mmol) in MeOH (5 mL) was added sodium triacetoxyborohydride (77 mg, 0.37 mmol). The mixture was stirred at 50 °C for 1 h. Sodium cyanoborohydride (11 mg, 0.18 mmol) was added at 50 °C. The mixture was stirred at 50 °C for 3 h. Saturated NH4Cl aqueous (2 mL) was added. 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-(4-(3-(5-ethyl-6- methoxypyridin-2-yl)cyclobutyl)piperazin-1-yl)-N-methylpicolinamide 1107 (40 mg, 7 % yield) as a white solid. LCMS (ESI) calcd for C23H32N5O2 [M + H]+m / z 409.25, found 410.72. Preparation of 5-(4-((1s,3s)-3-(5-ethyl-6-oxo-1,6-dihydropyridin-2-yl)cyclobutyl)piperazin-1- yl)-N-methylpicolinamide (4cis) To a solution of 5-(4-(3-(5-ethyl-6-methoxypyridin-2-yl)cyclobutyl)piperazin-1-yl)-N- methylpicolinamide 1107 (40 mg, 0.10 mmol) in ACN (5 mL) was added TMSI (58.65 mg, 0.29 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (Column: Gemini 5um C18 150*21.2mm; Mobile phase: ACN / H2O [0.1 %(FA)] = 20 / 80) to give 5-(4- ((1s,3s)-3-(5-ethyl-6-oxo-1,6-dihydropyridin-2-yl)cyclobutyl)piperazin-1-yl)-N- methylpicolinamide 4cis (5 mg, 13 % yield) as a white solid.1HNMR(400 MHz, DMSO-d6) δ 11.53 (s, 1 H), 8.40 (q, J = 4.4 Hz, 1 H), 8.29 (d, J = 2.4 Hz, 1 H), 7.84 (d, J = 8.8 Hz, 1 H), 7.41 (dd, J = 8.8, 2.4 Hz, 1 H), 7.19 (d, J = 7.2Hz, 1H), 5.98 (d, J = 6.8 Hz, 1 H), 3.49-3.37 (m, 4 H), 3.05-2.97 (m, 1 H), 2.87-2.74 (m, 4 H), 2.59-2.52 (m, 2 H), 2.48- 2.40 (m, 4 H), 2.34 (q, J = 7.2 Hz, 2 H), 2.08-1.84 (m, 2 H), 1.06 (t, J = 7.2 Hz, 3 H). LCMS (ESI) calcd for C22H30N5O2[M + H]+m / z 396.23, found 396.25.

[0013] Example 3: Synthesis of 6cis-a, 6cis-b, 6trans-a, 6trans-b Preparation of 3-(5-ethyl-6-methoxypyridin-2-yl)cyclopent-2-en-1-one (1203) To a solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-2-en-1-one 1201 (200 mg, 0.96 mmol) and 6-chloro-3-ethyl-2-methoxypyridine 1202 (197 mg, 1.15 mmol) in dioxane (5 mL) and H2O (0.5 mL) was added Pd(dppf)Cl2(70 mg, 0.10 mmol) and sodium carbonate (255 mg, 2.40 mmol) at room temperature. The reaction mixture stirred under nitrogen at 95 °C for 6 h. After cooling to ambient temperature, the mixture was filtered through celite and the filtrate was concentrated under vacuum. The residue was diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by flash chromatography (eluting with PE / EtOAc = 100 : 0 to 85 : 15) to give product of 3-(5- ethyl-6-methoxypyridin-2-yl)cyclopent-2-en-1-one 1203 (90 mg, 43 % yield ) as a white solid. LCMS (ESI) calcd for C13H15NO2[M + H]+m / z 218.12, found 218.00. Preparation of 5-(4-(3-(5-ethyl-6-methoxypyridin-2-yl)cyclopent-2-en-1-yl)piperazin-1-yl)- N-methylpicolinamide (1204) To a solution of 3-(5-ethyl-6-methoxypyridin-2-yl)cyclopent-2-en-1-one 1203 (90 mg, 0.42 mmol) and N-methyl-5-(piperazin-1-yl)picolinamide 1009 (110 mg, 0.50 mmol) in MeOH (5 mL) was added two drops of acetic acid at room temperature and stirred for 10 min. NaBH(OAc )3(220 mg, 1.04 mmol) was added to the reaction mixture and stirred at 60 °C for 1 h. NaBH3CN (261 mg, 4.15 mmol) was added to the reaction mixture and stirred at 60 °C for 15h. 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 95 : 5) to give product of 5-(4-(3-(5-ethyl-6-methoxypyridin-2- yl)cyclopent-2-en-1-yl)piperazin-1-yl)-N-methylpicolinamide 1204 (85 mg, 49 % yield) as pale yellow oil. LCMS (ESI) calcd for C24H31N5O2[M + H]+m / z 422.26, found 422.25. Preparation of 5-(4-(3-(5-ethyl-6-methoxypyridin-2-yl)cyclopentyl)piperazin-1-yl)-N- methylpicolinamide (1205) To a solution of 5-(4-(3-(5-ethyl-6-methoxypyridin-2-yl)cyclopent-2-en-1-yl)piperazin-1-yl)-N- methylpicolinamide 1204 (85 mg, 0.20 mmol) in MeOH (5 mL) was added Pd(OH)2 / C (20 mg). The mixture was evacuated and backfilled with hydrogen three times and then charged with hydrogen. The resulting mixture was stirred at 50 °C for 3 h. Then the mixture was filtered through celite and concentrated under vacuum to give crude 5-(4-(3-(5-ethyl-6- methoxypyridin-2-yl)cyclopentyl)piperazin-1-yl)-N-methylpicolinamide 1205 (80 mg, 93 % yield) as pale yellow oil. LCMS (ESI) calcd for C24H33N5O2[M + H]+m / z 424.27, found 424.15. Preparation of 5-(4-(3-(5-ethyl-6-oxo-1,6-dihydropyridin-2-yl)cyclopentyl)piperazin-1-yl)-N- methylpicolinamide (6cis-a, 6cis-b, 6trans-a, 6trans-b) To a solution of 5-(4-(3-(5-ethyl-6-methoxypyridin-2-yl)cyclopentyl)piperazin-1-yl)-N- methylpicolinamide 1205 (80 mg, 0.19 mmol) in ACN (4 mL) was added TMSI (113 mg, 0.57 mmol). The mixture was stirred at 50 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (Gemini 5 μm C18150*21.2 mm, mobile phase: ACN - H2O (0.1 % FA), gradient: 2 % - 95 %) to afford the first fraction as 6cis-a / 6cis-b racemic mixture (cis stereochemistry assumed across cyclopentane based on NOE experiments) (10 mg, 95 % purity, white solid) and the second fraction as 6trans-a / 6trans-b racemic mixture (trans stereochemistry assumed across cyclopentane based on NOE experiments) (3 mg, 95 % purity, white solid). 6cis-a / 6cis-b racemic mixture1H NMR (400 MHz, CDCl3, ppm) δ 8.19 (d, J = 2.4 Hz, 1 H), 8.10 (d, J = 8.8 Hz, 1 H), 7.83 (d, J = 4.8 Hz, 1 H), 7.69 (d, J = 7.2 Hz, 1 H), 7.29 (d, J = 2.4 Hz, 1 H), 6.82 (d, J = 7.2 Hz, 1 H), 4.20-3.36 (m, 8 H), 3.24 (dt, J = 14.8, 10.8 Hz, 2 H), 3.02 (d, J = 5.2 Hz, 3 H), 2.66-2.54 (m, 3 H), 2.39 (dd, J = 22.0, 11.2 Hz, 2H), 2.31-2.19 (m, 2H), 2.10-2.00 (m, 1H), 1.22 (t, J = 7.4 Hz, 3H). LCMS (ESI) calcd for C23H31N5O2[M + H]+m / z 410.26, found 410.20. 6trans-a / 6trans-b racemic mixture1H NMR (400 MHz, CDCl3, ppm) δ 11.74 (s, 1 H), 8.17 (s, 1 H), 8.06 (dd, J = 8.4, 2.4 Hz, 1 H), 7.78 (s, 1 H), 7.25-7.15 (m, 2 H), 6.02 (dd, J = 6.4, 2.0 Hz, 1 H), 3.37 (s, 3 H), 3.22-2.96 (m, 5 H), 2.71 (s, 3 H), 2.57-2.48 (m, 2 H), 2.27-1.98 (m, 4 H), 1.86-1.58 (m, 4 H), 1.18 (td, J = 7.2, 2.4 Hz, 3 H). LCMS (ESI) calcd for C23H31N5O2[M + H]+m / z 410.26, found 410.40. The 6cis-a / 6cis-b racemic mixture was separated by SFC (Column: Regis (R,R)-Whelk-O 1, 250 mm × 20 mm I.D., 5 μmm; Mobile phase: CO2 / MeOH[0.1 %(NH3)(7 M solution in MeOH)] = 65 / 35) and concentrated under reduced pressure to afford the first fraction as 6cis-a (white solid) and the second fraction as 6cis-b (white solid). The 6trans-a / 6trans-b racemic mixture was separated by SFC (Column: Daicel CHIRALPAK IJ SFC 250 mm × 20 mm I.D., 5 μmm; Mobile phase: CO2 / MeOH[0.1 %(NH3)(7 M solution in MeOH)] = 60 / 40) and concentrated under reduced pressure to afford the first fraction as 6trans-a (white solid) and the second fraction as 6trans-b (white solid).

[0014] Preparation of 3-oxocyclopent-1-en-1-yl pivalate (1302) To a solution of cyclopentane-1,3-dione 1301 (8 g, 81.6 mmol) and DIPEA (21.09 g, 163.2 mmol) in DCM (160 mL) was added pivaloyl chloride (10.77 g, 89.8 mmol) slowly at 0 °C. The reaction mixture stirred at room temperature for 16 h. The mixture was diluted with water (400 mL) and extracted with EtOAc (400 mL × 3). The combined organic layer was washed with brine (100 mL × 2), dried over Na2SO4, filtered and concentrated in vacuo to get crude product, which was purified by flash column chromatography (PE / EtOAc = 100: 0 to 70: 30) to afford product of 3-oxocyclopent-1-en-1-yl pivalate 1302 (12 g, 81 % yield) as a pale yellow oil. LCMS (ESI) calcd for C10H14O3[M + H]+m / z 183.12, found 183.00. Preparation of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-2-en-1-one (1303) To a solution of 3-oxocyclopent-1-en-1-yl 2,2-dimethylpropanoate 1302 (8 g, 43.9 mmol), B2Pin2(22.3 g, 87.9 mmol), palladium diacetate (863 mg, 3.52 mmol) and Tri-o-tolylphosphine (1.2 g, 3.9 mmol) in acetone (80 mL) and H2O (8 mL) was added 1,3,5-trimethoxybenzene (3.7 g, 22.0 mmol). The reaction mixture was stirred at 60 °C for 18 hours. After cooling to room temperature, the reaction mixture was poured into water (800 mL), The aqueous phase was washed with EtOAc (600 mL) 3 times. The water layers were concentrated under reduced pressure to give product of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-2-en-1- one 1303 (2 g, 22 % yield) as a white solid. LCMS (ESI) calcd for C24H31N5O2[M-72 + H]+m / z 126, found N / A. Preparation of 3-(5-ethyl-6-methoxypyridin-2-yl)cyclopent-2-en-1-one (1305) To a solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-2-en-1-one 1303 (2.0 g, 9.6 mmol) and 6-chloro-3-ethyl-2-methoxypyridine 1304 (1.6 g, 9.6 mmol) in dioxane (50 mL) and H2O (5 mL) were added Pd(dppf)Cl2(351 mg, 0.48 mmol) and sodium carbonate (2.5 g, 24.0 mmol) at room temperature. The reaction mixture stirred under nitrogen at 95 °C for 8 h. After cooling to ambient temperature, the mixture was filtered through celite and the filtrate was concentrated under vacuum. The residue was diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by flash chromatography (eluting with PE / EtOAc = 100 : 0 to 85 : 15) to give product of 3-(5-ethyl-6- methoxypyridin-2-yl)cyclopent-2-en-1-one 1305 (450 mg, 22 % yield) as a white solid. LCMS (ESI) calcd for C13H15NO2[M + H] + m / z 218.12, found 218.00. Preparation of 5-(4-(3-(5-ethyl-6-methoxypyridin-2-yl)cyclopent-2-en-1-yl)piperazin-1-yl)-6- fluoro-N-methylpicolinamide (1307) To a solution of 3-(5-ethyl-6-methoxypyridin-2-yl)cyclopent-2-en-1-one 1305 (186 mg, 0.85 mmol) and 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide 1306 (243 mg, 1.02 mmol) in MeOH (5 mL) was added two drops of acetic acid at room temperature and stirred for 10 min. NaBH (OAc )3(433 mg, 2.04 mmol) was added to the reaction mixture and stirred at 60 °C for 1 h. NaBH3CN (534 mg, 8.5 mmol) was added to the reaction mixture and stirred at 60 °C for 2 days. 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 95 : 5) to give crude product of 5-(4-(3-(5-ethyl-6-methoxypyridin-2- yl)cyclopent-2-en-1-yl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide 1307 (200 mg, 54 % yield) as a pale yellow oil. LCMS (ESI) calcd for C24H30FN5O2[M + H]+m / z 440.25, found 440.20. Preparation of 5-(4-(3-(5-ethyl-6-methoxypyridin-2-yl)cyclopentyl)piperazin-1-yl)-6-fluoro- N-methylpicolinamide (1308) To a solution of 5-(4-(3-(5-ethyl-6-methoxypyridin-2-yl)cyclopent-2-en-1-yl)piperazin-1-yl)-6- fluoro-N-methylpicolinamide 1307 (200 mg, 0.46 mmol) in MeOH (5 mL) was added Pd(OH)2 / C (80 mg). The mixture was evacuated and backfilled with hydrogen three times and then charged with hydrogen. The resulting mixture was stirred at 50 °C for 5 h. Then the mixture was filtered through celite and concentrated under vacuum to give crude product. The crude product was purified by flash chromatography (eluting with DCM / MeOH = 100 : 0 to 95 : 5) to give product of 5-(4-(3-(5-ethyl-6-methoxypyridin-2-yl)cyclopentyl)piperazin-1- yl)-6-fluoro-N-methylpicolinamide 1308 (125 mg, 63 % yield) as a pale yellow oil. LCMS (ESI) calcd for C24H32FN5O2[M + H]+m / z 442.26, found 442.25. Preparation of 5-(4-(3-(5-ethyl-6-oxo-1,6-dihydropyridin-2-yl)cyclopentyl)piperazin-1-yl)-6- fluoro-N-methylpicolinamide (7trans-a / 7trans-b / 7cis-a / 7cisb) To a solution of 5-(4-(3-(5-ethyl-6-methoxypyridin-2-yl)cyclopentyl)piperazin-1-yl)-6-fluoro- N-methylpicolinamide 1308 (125 mg, 0.283 mmol) in ACN (5 mL) was added TMSI (170 mg, 0.85 mmol). The mixture was stirred at 50 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (Gemini 5 μm C18 150*21.2mm, mobile phase: ACN - H2O (0.05 % NH3.H2O), gradient: 25 % - 95 %) to afford the first fraction as a racemic mixture of 7trans-a and 7trans-b (23 mg, white solid) and the second fraction as a racemic mixture of 7cis-a and 7cis-b (33 mg, white solid). 7trans-a / 7trans-b LCMS (ESI) calcd for C23H3FN5O2[M + H]+m / z 428.25, found 428.20. 7cis-a / 7cis-b LCMS (ESI) calcd for C23H3FN5O2[M + H]+m / z 428.25, found 428.20. Preparation of 5-(4-(3-(5-ethyl-6-oxo-1,6-dihydropyridin-2-yl)cyclopentyl)piperazin-1-yl)-6- fluoro-N-methylpicolinamide (7trans-a, 7trans-b, 7cis-a and 7cis-b) The racemic mixture of 7trans-a and 7trans-b was separated by SFC (Column: Daicel CHIRALPAK IH SFC 250 mm × 20 mm I.D., 5 μmm; 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 7trans-a (3.85 mg, 99 % purity, ee%: 100, white solid) and the second fraction as 7trans-b (5.43 mg, 99 % purity, ee%: 100, white solid). 7trans-a1H NMR (400 MHz, MeOD, ppm) δ 7.90 (dd, J = 8.0, 1.2 Hz, 1 H), 7.52 (dd, J = 10.4, 8.4 Hz, 1 H), 7.35 (d, J = 7.2 Hz, 1 H), 6.23 (d, J = 7.2 Hz, 1 H), 3.29-3.24 (m, 4 H), 3.17-3.09 (m, 1 H), 2.96-2.87 (m, 4 H), 2.79-2.68 (m, 4 H), 2.48 (q, J = 7.6 Hz, 2 H), 2.18-2.04 (m, 3 H), 2.00-1.92 (m, 1H), 1.78-1.59 (m, 2 H), 1.16 (t, J = 7.6 Hz, 3 H). Assigned trans-stereochemistry based on NOE experiments. LCMS (ESI) calcd for C23H3FN5O2[M + H]+m / z 428.25, found 428.20. 7trans-b1H NMR (400 MHz, MeOD, ppm) δ 7.90 (d, J = 8.0 Hz, 1 H), 7.61-7.42 (m, 1 H), 7.35 (d, J = 7.2 Hz, 1 H), 6.22 (d, J = 6.8 Hz, 1 H), 3.29-3.22 (m, 4 H), 3.17-3.08 (m, 1 H), 2.99-2.83 (m, 4 H), 2.80-2.65 (m, 4 H), 2.48 (q, J = 7.6 Hz, 2 H), 2.20-2.04 (m, 3 H), 2.00-1.91 (m, 1 H), 1.78-1.58 (m, 2 H), 1.16 (t, J = 7.6 Hz, 3 H). Assigned trans-stereochemistry based on NOE experiments. LCMS (ESI) calcd for C23H3FN5O2[M + H]+m / z 428.25, found 428.20. The racemic mixture of 7cis-a and 7cis-b was separated by SFC (Column: Daicel CHIRALPAK IH SFC 250 mm × 20 mm I.D., 5 μmm; 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 7cis- a (6.20 mg, 98 % purity, ee%: 100, white solid) and the second fraction as 7cis-b (5.34 mg, 98 % purity, ee%: 99, white solid). 7cis-a1H NMR (400 MHz, MeOD, ppm) δ 7.91 (dd, J = 8.0, 1.2 Hz, 1 H), 7.57 (dd, J = 10.4, 8.2 Hz, 1 H), 7.31 (d, J = 6.8 Hz, 1 H), 6.21 (d, J = 6.8 Hz, 1 H), 3.54-3.42 (m, 2 H), 3.40-3.33 (m, 2 H), 3.19-3.11 (m, 1 H), 2.91 (s, 3 H), 2.84-2.72 (m, 5 H), 2.46 (q, J = 7.6 Hz, 2 H), 2.25-2.14 (m, 2 H), 2.05-1.98 (m, 1 H), 1.90-1.79 (m, 2 H), 1.76-1.65 (m, 1 H), 1.14 (t, J = 7.6 Hz, 3 H). Assigned cis-stereochemistry based on NOE experiments. LCMS (ESI) calcd for C23H3FN5O2 [M + H]+m / z 428.25, found 428.20. 7cis-b1H NMR (400 MHz, MeOD, ppm) δ 7.91 (d, J = 8.0 Hz, 1 H), 7.57 (dd, J = 10.4, 8.2 Hz, 1 H), 7.31 (d, J = 6.8 Hz, 1 H), 6.21 (d, J = 6.8 Hz, 1 H), 3.52-3.42 (m, 2 H), 3.40-3.33 (m, 2 H), 3.19-3.11 (m, 1 H), 2.91 (s, 3 H), 2.84-2.74 (m, 5H), 2.46 (q, J = 7.6 Hz, 2 H), 2.25-2.14 (m, 2 H), 2.05-1.98 (m, 1 H), 1.89-1.79 (m, 2 H), 1.76-1.64 (m, 1 H), 1.14 (t, J = 7.6 Hz, 3 H). Assigned cis-stereochemistry based on NOE experiments. LCMS (ESI) calcd for C23H3FN5O2[M + H]+m / z 428.25, found 428.20.

[0015] Example 5: Synthesis of 12cis-a / 12cis-b / 12trans-a / 12trans-b Preparation of methyl 5-bromo-6-methoxypicolinate (1402) To the solution of 5-bromo-6-methoxypicolinic acid 1401 (5.00 g, 21.65 mmol) in MeOH (200 mL) was added dropwise SOCl2(7.67 g, 64.47 mmol). The resulting mixture was stirred for 2 h at 0 °C. The reaction solution was concentrated under reduced pressure, then adjusted to pH 9 with an aqueous solution of Na2CO3, the aqueous layer was extracted with EtOAc (300mL x 3). The combined organic layer was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE / EtOAc = 100: 0 to 80: 20) to give methyl 5- bromo-6-methoxypicolinate 1402 (4.50 g, 85 % yield) as a white solid. LCMS (ESI) calcd for C8H8BrNO3[M + H]+m / z 245.97, found 245.95. Preparation of methyl 5-ethyl-6-methoxypicolinate (1403) To a solution of methyl 5-bromo-6-methoxypicolinate 1402 (4.50 g, 18.29 mmol) in 1,4- dioxane (200 mL) were added diethylzinc (1 M, 90 mL) and Pd(dppf)Cl2(1.34 g, 1.83 mmol) successively at room temperature. The reaction mixture was stirred at 80 ^ for 18 h under N2. The mixture was diluted with water (50 mL) and extracted with EtOAc (300 mL × 3). The combined organic layer was washed with brine (100 mL × 2), dried over Na2SO4, filtered and concentrated in vacuo to get a crude product, which was purified by flash column chromatography (PE / EtOAc = 100: 0 to 80: 20) to afford methyl 5-ethyl-6-methoxypicolinate 1403 (2.30 g, 64 % yield) as a yellow solid. LCMS (ESI) calcd for C10H13NO3[M + H]+m / z 196.09, found 196.05. Preparation of (5-ethyl-6-methoxypyridin-2-yl)methanol (1404) To a solution of methyl 5-ethyl-6-methoxypicolinate 1403 (2.30 g, 11.78 mmol) in THF (100 mL) was added LiAlH4 (11.8 mL, 11.78 mmol, 1 M) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched with cold water and then extracted with EtOAC (200 mL×3). The combined organic layer was concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with PE / EtOAc = 100:0 to 60:40) to afford (5-ethyl-6-methoxypyridin-2-yl)methanol 1404 (1.70 g, 86 % yield) as a colourless oil. LCMS (ESI) calcd for C9H13NO2[M + H]+m / z 168.09, found 168.05. Preparation of 5-ethyl-6-methoxypicolinaldehyde (1405) To a solution of (5-ethyl-6-methoxypyridin-2-yl)methanol 1404 (1.70 g, 10.17 mmol) in DCM (50 mL) was added Dess-Martin reagent (6.47 g, 15.25 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water and then extracted with DCM (100 mL×3). The organic layer was concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with PE / EtOAC = 100:0 to 80:20) to afford 5-ethyl-6-methoxypicolinaldehyde 1405 (1.50 g, 89 % yield) as a colourless oil. LCMS (ESI) calcd for C9H11NO2[M + H]+m / z 166.08, found 166.05. Preparation of 1-(5-ethyl-6-methoxypyridin-2-yl)but-3-en-1-ol (1406) To a solution of 5-ethyl-6-methoxypicolinaldehyde 1405 (1.50 g, 9.08 mmol) in THF (50 mL) was added bromo(prop-2-en-1-yl)magnesium (1.45 g, 9.99 mmol) dropwise at room temperature. The reaction mixture was stirred at 0 °C for 2 h under N2. 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, filtered and concentrated in vacuo to get crude product, which was purified by flash column chromatography (PE / EtOAc = 100: 0 to 80: 20) to afford 1-(5-ethyl-6-methoxypyridin-2-yl)but-3-en-1-ol 1406 (1.40 g, 74 % yield) as a yellow oil. LCMS (ESI) calcd for C12H17NO2[M + H]+m / z 208.13, found 208.05. Preparation of 4-(5-ethyl-6-methoxypyridin-2-yl)butane-1,2,4-triol (1407) To a solution of 1-(5-ethyl-6-methoxypyridin-2-yl)but-3-en-1-ol 1406 (1.40 g, 6.75 mmol) in THF / H2O (5:1, 48 mL) were added K2OsO4y2H2O (124 mg, 0.34 mmol) and NMO (7.92 g, 67.54 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 h. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL × 3). The combined organic layer was washed with brine and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with DCM / MeOH = 100: 0 to 90 : 10) to give 4-(5-ethyl-6-methoxypyridin-2-yl)butane-1,2,4-triol 1407 (1.00 g, 61 % yield) as a yellow oil. LCMS (ESI) calcd for C12H19NO4[M + H]+m / z 242.13, found 242.05. Preparation of 5-(5-ethyl-6-methoxypyridin-2-yl)tetrahydrofuran-3-ol (1408) To a solution of 4-(5-ethyl-6-methoxypyridin-2-yl)butane-1,2,4-triol 1407 (1.00 g, 4.14 mmol) in toluene (50 mL) was added PTSA (2.26 g, 12.43 mmol) at room temperature. The reaction mixture was stirred at 120 °C for 6 h. The reaction mixture was quenched with cold water and then extracted with DCM (80 mL× 3). The combined organic layer was concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with DCM / MeOH = 100:0 to 90:10) to afford 5-(5-ethyl-6-methoxypyridin-2-yl)tetrahydrofuran-3- ol 1408 (450 mg, 49 % yield) as a colourless oil. LCMS (ESI) calcd for C12H17NO3[M + H]+m / z 224.12, found 224.05. Preparation of 5-(5-ethyl-6-methoxypyridin-2-yl)dihydrofuran-3(2H)-one (1409) To a solution of 5-(5-ethyl-6-methoxypyridin-2-yl)tetrahydrofuran-3-ol 1408 (450 mg, 2.01 mmol) in DCM (30 mL) was added Dess-Martin reagent (1.28 g, 3.02 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water and then extracted with DCM (100 mL×3). The organic layer was concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with PE / EtOAC = 100:0 to 80:20) to afford 5-(5-ethyl-6- methoxypyridin-2-yl)dihydrofuran-3(2H)-one 1409 (220 mg, 49 % yield) as a colourless oil. LCMS (ESI) calcd for C12H15NO3 [M + H]+m / z 222.11, found 222.05. Preparation of 5-(4-(5-(5-ethyl-6-methoxypyridin-2-yl)tetrahydrofuran-3-yl)piperazin-1-yl)- 6-fluoro-N-methylpicolinamide (1410) To a solution of 5-(5-ethyl-6-methoxypyridin-2-yl)dihydrofuran-3(2H)-one 1409 (110 mg, 0.50 mmol) in MeOH (20 mL) was added 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide 1306 (130 mg, 0.55 mmol), then two drops of acetic acid and NaBH(OAc)3(211 mg, 1.00 mmol) were added at room temperature. The reaction mixture was stirred for 1 h then NaBH3CN (16 mg, 0.25 mmol) was added. The reaction mixture stirred at 50 ^ for 12 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with DCM / MeOH = 100:0 to 90:10) to afford 5-(4-(5-(5-ethyl-6-methoxypyridin-2-yl)tetrahydrofuran-3-yl)piperazin-1-yl)- 6-fluoro-N-methylpicolinamide 1410 (120 mg, 54 % yield) as a yellow solid. LCMS (ESI) calcd for C23H30FN5O3[M + H]+m / z 444.23, found 444.24. Preparation of 5-(4-(5-(5-ethyl-6-oxo-1,6-dihydropyridin-2-yl)tetrahydrofuran-3- yl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide (12cis-a / 12cis-b / 12trans-a / 12trans-b) To a solution of 5-(4-(5-(5-ethyl-6-methoxypyridin-2-yl)tetrahydrofuran-3-yl)piperazin-1-yl)- 6-fluoro-N-methylpicolinamide 1410 (120 mg, 0.27 mmol) in ACN (30 mL) was added TMSI (162 mg, 0.81 mmol) at room temperature. The mixture was kept stirring at 50 ^ for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by C18column (mobile phase: ACN - H2O (0.1% FA), gradient: 10 - 95) to give 5-(4-(5-(5-ethyl-6-oxo-1,6-dihydropyridin-2-yl)tetrahydrofuran-3- yl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide 12cis-a / 12cis-b / 12trans-a / 12trans-b mixture (70 mg, 60 % yield) as a yellow solid. LCMS (ESI) calcd for C22H28FN5O3[M + H]+m / z 430.22, found 430.20. Chiral resolution of 5-(4-(5-(5-ethyl-6-oxo-1,6-dihydropyridin-2-yl)tetrahydrofuran-3- yl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide (12cis-a / 12cis-b / 12trans-a / 12trans-b) The 12cis-a / 12cis-b / 12trans-a / 12trans-b mixture was separated by SFC (Column: Daicel Chiralpak AS-H-30 % D 250 mm × 20 mm I.D., 5 μmm; Mobile phase: CO2 / MeOH[0.1 %(NH3)] = 70 / 30) and concentrated under reduced pressure to afford the first fraction as 12cis-rac, a racemic mixture of 12cis-a and 12cis-b (32.4 mg, racemate, 98 % purity, white solid) and the second fraction as 12trans-a (6.2 mg, 98 % purity, ee%: 100, white solid) and the third fraction as 12trans-b (6.0 mg, 99 % purity, ee%: 100, white solid). 12cis-rac1H NMR (400 MHz, MeOD-d4, ppm) δ: 7.91 (d, J = 8.0 Hz, 1 H), 7.59-7.55 (m, 1 H), 7.34 (d, J = 6.8 Hz, 1 H), 6.30 (d, J = 6.8 Hz, 1 H), 4.83-4.81 (m, 1 H), 4.32 (d, J = 10.4 Hz, 1 H), 3.81-3.77 (m, 1 H), 3.57-3.51 (m, 4 H), 3.05 (s, 1 H), 2.91 (s, 3 H), 2.83 (t, J = 4.8 Hz, 4 H), 2.56-2.44 (m, 3H), 2.19-2.14 (m, 1 H), 1.15 (t, J = 7.6 Hz, 3 H). Assigned cis-stereochemistry based on NOE experiments. LCMS (ESI) calcd for C22H28FN5O3[M + H]+m / z 430.22, found 430.25. 12trans-a1H NMR (400 MHz, MeOD-d4, ppm) δ: 7.90 (dd, J = 7.0 Hz, 1.0 Hz, 1 H), 7.58-7.47 (m, 1 H), 7.38 (d, J = 7.2 Hz, 1 H), 6.31 (d, J = 7.0 Hz, 1 H), 4.97-4.91 (m, 1 H), 4.28-4.21 (m, 1 H), 3.83-3.79 (m, 1 H), 3.26 (t, J = 5.0 Hz, 4 H), 3.18-3.13 (m, 1 H), 2.91 (s, 3H), 2.78-2.72 (m, 2 H), 2.66-2.61 (m, 2 H), 2.52-2.47 (m, 2 H), 2.43-2.35 (m, 1 H), 2.16-2.08 (m, 1 H), 1.17 (t, J = 7.6 Hz, 3 H). Assigned trans-stereochemistry based on NOE experiments. LCMS (ESI) calcd for C22H28FN5O3[M + H]+m / z 430.22, found 430.25. 12trans-b1H NMR (400 MHz, MeOD-d4, ppm) δ: 7.90 (d, J = 8.0 Hz, 1 H), 7.53-7.49 (m, 1 H), 7.38 (d, J = 7.2 Hz, 1 H), 6.31 (d, J = 7.2 Hz, 1 H), 4.97-4.91 (m, 1 H), 4.27-4.23 (m, 1 H), 3.86-3.78 (m, 1 H), 3.26 (t, J = 4.8 Hz, 4 H), 3.18-3.13 (m, 1 H), 2.91 (s, 3 H), 2.79-2.72 (m, 2 H), 2.68-2.61 (m, 2 H), 2.52-2.47 (m, 2 H), 2.43-2.35 (m, 1 H), 2.16-2.09 (m, 1 H), 1.16 (t, J = 7.6 Hz, 3 H). Assigned trans-stereochemistry based on NOE experiments. LCMS (ESI) calcd for C22H28FN5O3[M + H]+m / z 430.22, found 430.20.

[0016] Example 6 – Synthesis of 17cis-a / 17cis-b / 17trans-a / 17trans-b Preparation of 2,4-dichloro-5-ethylpyrimidine (1502) To a solution of 5-ethyl-1,3-dihydropyrimidine-2,4-dione 1501 (10.00 g, 0.07 mol) in POCl3(55.00 g, 0.36 mol) at 0°C was added DIEA (23.00 g, 0.18 mol). Then the mixture was stirred for 2 h at 120 °C. The reaction mixture was poured into iced water and the aqueous layer was extracted with EA (50 mL × 3). The combined organic layers were dried over Na2SO4. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE / EtOAc = 100 : 0 to 92 : 8) to give 2,4-dichloro-5- ethylpyrimidine 1502 (4.80 g, 38 % yield) as a white solid. LCMS (ESI) calcd for C6H6Cl2N2[M + H]+m / z 176.99, found 177.20 Preparation of 2-chloro-5-ethyl-4-(2-methoxy-5-methylphenoxy)pyrimidine (1504) To a solution of (4-methoxyphenyl) methanol 1503 (4.54 g, 32.90 mmol) in THF (20 mL) was added tBuOLi (2.30 g, 28.75 mmol) at 70 °C for 15 min. Then 2,4-dichloro-5-ethylpyrimidine 1502 (4.80 g, 27.27 mmol) was added to the reaction mixture at 0 °C. The mixture was stirred for 3 h at 70 °C. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE / EtOAc = 100 : 0 to 93 : 7) to give 2- chloro-5-ethyl-4-(2-methoxy-5-methylphenoxy)pyrimidine 1504 (4.00 g, 53 % yield) as a white solid. LCMS (ESI) calcd for C14H15ClN2O2[M + H]+m / z 279.08, found 279.25. Preparation of 3-(5-ethyl-4-((4-methoxybenzyl)oxy)pyrimidin-2-yl)cyclopent-2-en-1-one (1505) To a solution of 2-chloro-5-ethyl-4-(2-methoxy-5-methylphenoxy)pyrimidine 1504 (400 mg, 1.43 mmol) in 1,4-dioxane:H2O=5:1 (25 mL) was added 3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)cyclopent-2-en-1-one 1303 (447 mg, 2.15 mmol). Then Pd(dppf)Cl2(105 mg, 0.14 mmol) and Na2CO3(608 mg, 5.7 mmol) were added at room temperature. Then the mixture was stirred for 3 h at 80 °C. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE / EA = 100 : 0 to 80 : 20) to give 3-(5-ethyl-4-((4-methoxybenzyl)oxy)pyrimidin-2-yl)cyclopent-2-en-1-one 1505 (400 mg, 85 % yield) as a white solid. LCMS (ESI) calcd for C19H20N2O3[M + H]+m / z 325.15, found 325.20. Preparation of 5-(4-(3-(5-ethyl-4-((4-methoxybenzyl)oxy)pyrimidin-2-yl)cyclopent-2-en-1- yl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide (1506) To a solution of 3-(5-ethyl-4-((4-methoxybenzyl)oxy)pyrimidin-2-yl)cyclopent-2-en-1-one 1505 (400 mg, 1.23 mmol) in EtOH (10 mL) was added 4-fluoro-N-methyl-5-(piperazin-1- yl)picolinamide 1306 (323 mg, 1.35 mmol), then two drops of acetic acid and NaBH(OAc)3(1.3 g, 6.15 mmol) were added at room temperature. After stirring at 90 °C for 30 min NaBH3CN (772 mg, 12.32 mmol) was added. The reaction mixture stirred at 90 °C for 12 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 95: 5) to give 5-(4-(3-(5-ethyl-4-((4-methoxybenzyl)oxy)pyrimidin-2-yl)cyclopent-2-en-1-yl)piperazin- 1-yl)-6-fluoro-N-methylpicolinamide 1506 (200 mg, 29 % yield) as a white solid. LCMS (ESI) calcd for C30H35FN6O3[M + H]+m / z 547.28, found 547.30. Preparation of 5-(4-(3-(5-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)cyclopentyl)piperazin-1-yl)- 6-fluoro-N-methylpicolinamide (17cis-a / 17cis-b / 17trans-a / 17trans-b) To a solution of 5-(4-(3-(5-ethyl-4-((4-methoxybenzyl)oxy)pyrimidin-2-yl)cyclopent-2-en-1- yl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide 1506 (200 mg, 0.36 mmol) in MeOH (10 mL) was added Pd / C (51.18 mg, 0.36 mmol). The reaction mixture was stirred at 50 °C for 3 h under hydrogen. The solution was filtered and concentrated under reduced pressure to give 5-(4-(3-(5-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)cyclopentyl)piperazin-1-yl)-6-fluoro-N- methylpicolinamide 17cis-a / 17cis-b / 17trans-a / 17trans-b mixture (100 mg, 64 % yield) as a white solid. LCMS (ESI) calcd for C22H29FN6O2[M + H]+m / z 429.23.16, found 429.20. Chiral resolution of 5-(4-(3-(5-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)cyclopentyl)piperazin- 1-yl)-6-fluoro-N-methylpicolinamide (17cis-a / 17cis-b / 17trans-a / 17trans-b) The 17cis-a / 17cis-b / 17trans-a / 17trans-b mixture was separated by SFC (Column: DAICEL IJ 4.6mmI.D.*250 mmL 5 μm; Mobile phase: CO2 / MeOH [0.1 % (NH3)] = 65 / 35) and concentrated under reduced pressure to afford the first fraction as 17cis-rac, a racemic mixture of 17cis-a and 17 cis-b (52 mg, 99 % purity, white solid); the second fraction as 17trans-a (12 mg, 99 % purity, ee%: 100, white solid); and the third fraction as 17trans-b (11 mg, 99 % purity, ee%: 99, white solid). 17cis-rac1H NMR (400 MHz, DMSO) δ 12.49 (s, 1 H), 8.44-8.31 (m, 1 H), 7.85 (d, J = 8.0 Hz, 1H), 7.72 (s, 1 H), 7.56 (m, 1 H), 3.24-3.14 (m, 4 H), 3.08-2.98 (m, 1 H), 2.77 (d, J = 4.8 Hz, 3 H), 2.71-2.66 (m, 1 H), 2.65-2.55 (m, 4 H), 2.34-2.28 (m, 2 H), 2.18-2.08 (m, 1 H), 2.02-1.92 (m, 1 H), 1.85- 1.73 (m, 3 H), 1.73-1.62 (m, 1 H), 1.07 (t, J = 7.2 Hz, 3 H). LCMS (ESI) calcd for C22H29FN6O2[M + H]+m / z 429.23, found 429.15. 17trans-a1H NMR (400 MHz, DMSO) δ 12.27 (s, 1 H), 8.45-8.31 (m, 1 H), 7.94-7.79 (m, 1 H), 7.72 (s, 1 H), 7.61-7.51 (m, 1 H), 3.20-3.12 (m, 4 H), 3.12-3.06 (m, 1 H), 2.85-2.72 (m, 4 H), 2.61-2.53 (m, 4 H), 2.34-2.28 (m, 2 H), 2.06-1.76 (m, 5 H), 1.54-1.44 (m, 1 H), 1.07 (t, J = 7.6 Hz, 3 H). LCMS (ESI) calcd for C22H29FN6O2[M + H]+m / z 429.23, found 429.25. 17trans-b1H NMR (400 MHz, DMSO) δ 12.28 (s, 1 H), 8.51-8.25 (m, 1 H), 7.84 (d, J = 8.0 Hz, 1 H), 7.73 (s, 1 H), 7.60-7.51 (m, 1 H), 3.18-3.13 (m, 4 H), 3.12- 3.07 (m, 1 H), 2.79-2.73 (m, 4 H), 2.60-2.54 (m, 4 H), 2.34-2.29 (m, 2 H), 2.05-1.75 (m, 5 H), 1.52-1.44 (m, 1 H), 1.07 (t, J = 7.6 Hz, 3 H). LCMS (ESI) calcd for C22H29FN6O2[M + H]+m / z 429.23, found 429.25.

[0017] Example 7 - Synthesis of 28cis-a / 28cis-b / 28trans-a / 28trans-b Preparation of 3-(6-methoxy-5-(trifluoromethyl)pyridin-2-yl)cyclopent-2-en-1-one (1602) To a solution of 6-chloro-2-methoxy-3-(trifluoromethyl)pyridine 1601 (700 mg, 60 % purity, 1.99 mmol) in dioxane: H2O = 5: 1 (15 mL) was added 3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)cyclopent-2-en-1-one 1303 (900 mg, 4.33 mmol), Pd(dppf)Cl2(70 mg, 0.10 mmol) and K2CO3(700 mg, 5.07 mmol). The reaction mixture stirred under N2at 90 °C 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 PE / EtOAc = 100: 0 to 85: 15) to give 3-(6-methoxy-5-(trifluoromethyl)pyridin-2-yl)cyclopent-2-en-1-one 1602 (400 mg, 78 % yield) as a yellow solid. LCMS (ESI) calcd for C12H10F3NO2[M + H]+m / z 258.07, found 257.89. Preparation of 5-(4-(3-(6-methoxy-5-(trifluoromethyl)pyridin-2-yl)cyclopent-2-en-1- yl)piperazin-1-yl)-N-methylpicolinamide (1603) To a solution of 3-(6-methoxy-5-(trifluoromethyl)pyridin-2-yl)cyclopent-2-en-1-one 1602 (400 mg, 1.55 mmol) in MeOH (20 mL) was added N-methyl-5-(piperazin-1-yl)picolinamide 1009 (800 mg, 3.63 mmol) and 3 drops of HOAc.10 mins later, NaBH3CN (900 mg, 14.51 mmol) was added. The reaction mixture stirred at 100 °C for 4 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 92: 8) to give 5-(4-(3-(6-methoxy- 5-(trifluoromethyl)pyridin-2-yl)cyclopent-2-en-1-yl)piperazin-1-yl)-N-methylpicolinamide 1603 (600 mg, 83 % yield) as a yellow solid. LCMS (ESI) calcd for C23H26F3N5O2[M + H]+m / z 462.20, found 462.20. Preparation of 5-(4-(3-(6-methoxy-5-(trifluoromethyl)pyridin-2-yl)cyclopentyl)piperazin-1- yl)-N-methylpicolinamide (1604) To a solution of 5-(4-(3-(6-methoxy-5-(trifluoromethyl)pyridin-2-yl)cyclopent-2-en-1- yl)piperazin-1-yl)-N-methylpicolinamide 1603 (600 mg, 1.30 mmol) in MeOH (100 mL) was added Pd(OH)2 / C (200 mg, 1.42 mmol). The reaction mixture stirred under H2 at 50 °C for 15 h. After cooling to room temperature, the mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to give 5-(4-(3-(6-methoxy-5- (trifluoromethyl)pyridin-2-yl)cyclopentyl)piperazin-1-yl)-N-methylpicolinamide 1604 (550 mg, 91 % yield) as a yellow solid. LCMS (ESI) calcd for C23H28F3N5O2[M + H]+m / z 464.22, found 464.20. Preparation of N-methyl-5-(4-(3-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-2- yl)cyclopentyl)piperazin-1-yl)picolinamide (28cis racemic mixture and 28trans racemic mixture) To the solution of 5-(4-(3-(6-methoxy-5-(trifluoromethyl)pyridin-2-yl)cyclopentyl)piperazin-1- yl)-N-methylpicolinamide 1604 (550 mg, 1.18 mmol) in ACN (20 mL) was added TMSI (550 mg, 2.75 mmol). The reaction mixture stirred at 50 °C for 3 h. the mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Gemini 5 μm C18150 × 21.2 mm, mobile phase: ACN - H2O (0.1 % FA), gradient: 10 - 25) to give 6-(3-(4-(4- chlorophenyl)piperazin-1-yl)cyclopentyl)-3-ethylpyridin-2(1H)-one 28cis racemic mixture (60 mg, 99 % purity, 11 % yield) and 6-(3-(4-(4-chlorophenyl)piperazin-1-yl)cyclopentyl)-3- ethylpyridin-2(1H)-one 28trans racemic mixture (40 mg, 99 % purity, 7 % yield) as white solid. LCMS (ESI) calcd for C22H26F3N5O2[M + H]+m / z 450.20, found 450.09. Preparation of N-methyl-5-(4-(3-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-2- yl)cyclopentyl)piperazin-1-yl)picolinamide (28cis-a and 28cis-b) N-methyl-5-(4-(3-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-2-yl)cyclopentyl)piperazin-1- yl)picolinamide 28cis racemic mixture (60 mg, 0.13 mmol) was separated by SFC (Column: DAICEL AD-H 4.6mm *250mmL 5μm; Mobile phase: CO2 / MeOH [0.1 % NH3(7 M Solution in MeOH)]=60 / 40) and concentrated under reduced pressure to afford the first fraction as 28cis- a (11 mg, 99 % purity, ee%: 100, white solid) and the second fraction as 28cis-b (11 mg, 99 % purity, ee%: 100, white solid) 28cis-a1H NMR (400 MHz, MeOD) δ 8.31 (d, J = 2.8 Hz, 1 H), 7.91 (d, J = 8.8 Hz, 1 H), 7.83 (d, J = 7.6 Hz, 1 H), 7.40 (dd, J = 8.8, 2.8 Hz, 1 H), 6.33 (d, J = 7.6 Hz, 1 H), 3.68-3.58 (m, 2 H), 3.55-3.45 (m, 2 H), 3.27-2.21 (m, 1 H), 2.93 (s, 3 H), 2.89-2.74 (m, 5 H), 2.30-2.20 (m, 2 H), 2.13-2.04 (m, 1 H), 1.98-1.81 (m, 1 H), 1.80-1.66 (m, 1 H). Assigned cis-stereochemistry based on NOE experiments LCMS (ESI) calcd for C22H26F3N5O2[M + H]+m / z 450.20, found 450.15. 28cis-b1H NMR (400 MHz, MeOD) δ 8.33 (d, J = 2.8 Hz, 1 H), 7.93 (d, J = 8.8 Hz, 1 H), 7.85 (d, J = 7.6 Hz, 1 H), 7.42 (dd, J = 8.8, 2.8 Hz, 1 H), 6.35 (d, J = 7.2 Hz, 1 H), 3.68-3.59 (m, 2 H), 3.57-3.48 (m, 2 H), 3.31-3.23 (m, 1 H), 2.95 (s, 3 H), 2.89-2.76 (m, 5 H), 2.33-2.21 (m, 2 H), 2.17-2.05 (m, 1 H), 2.01-1.82 (m, 1 H), 1.81-1.69 (m, 1 H). Assigned cis-stereochemistry based on NOE experiments LCMS (ESI) calcd for C22H26F3N5O2[M + H]+m / z 450.20, found 450.20. Preparation of N-methyl-5-(4-(3-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-2- yl)cyclopentyl)piperazin-1-yl)picolinamide (28trans-a and 28trans-b) N-methyl-5-(4-(3-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-2-yl)cyclopentyl)piperazin-1- yl)picolinamide 28trans racemic mixture (40 mg, 0.09 mmol) was separated by SFC (Column: DAICEL IH 4.6 mm * 250 mmL 5μm; 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 28trans-a (9 mg, 99 % purity, ee%: 100, white solid) and the second fraction as 28trans-b (8 mg, 99 % purity, ee%: 100, white solid). 28trans-a1H NMR (400 MHz, MeOD) δ 8.29 (d, J = 2.4 Hz, 1 H), 7.95-7.84 (m, 2 H), 7.38 (dd, J = 8.8, 2.8 Hz, 1 H), 6.35 (d, J = 7.2 Hz, 1 H), 3.43-3.36 (m, 4 H), 3.23-3.14 (m, 1 H), 2.98-2.86 (m, 4 H), 2.78-2.68 (m, 4 H), 2.26-2.08 (m, 3 H), 2.07-1.94 (m, 1 H), 1.83-1.60 (m, 2 H). Assigned trans-stereochemistry based on NOE experiments. LCMS (ESI) calcd for C22H26F3N5O2[M + H]+m / z 450.20, found 450.20. 28trans-b1H NMR (400 MHz, MeOD) δ 8.29 (d, J = 2.8 Hz, 1 H), 7.94-7.84 (m, 2 H), 7.38 (dd, J = 8.8, 2.8 Hz, 1 H), 6.35 (d, J = 7.6 Hz, 1 H), 3.46-3.37 (m, 4 H), 3.24-3.14 (m, 1 H), 2.96-2.87 (m, 4 H), 2.76-2.69 (m, 4 H), 2.24-2.08 (m, 3 H), 2.05-1.95 (m, 1 H), 1.83-1.60 (m, 2 H). Assigned trans-stereochemistry based on NOE experiments. LCMS (ESI) calcd for C22H26F3N5O2[M + H]+m / z 450.20, found 450.25. Example 8: Synthesis of 51cis-a / 51cis-b / 51trans-a / 51trans-b Preparation of tert-butyl 4-(2-fluoro-6-(methoxycarbonyl)pyridin-3-yl)piperazine-1- carboxylate (1702) To a solution of methyl tert-butyl 4-(2-bromo-6-(methoxycarbonyl)pyridin-3-yl)piperazine-1- carboxylate 1701 (10.00 g, 25.00 mmol) in DMSO (100 mL) was added CsF (15.19 g, 100.00 mmol) and 18-Crown-6 (13.20 g, 50.00 mmol). The reaction mixture was stirred at 100 ^ for 5 h. The mixture was diluted with water (200 mL) and extracted with EtOAc (200 mL × 3). The combined organic layer was washed with brine (200 mL × 3), dried over Na2SO4, filtered and concentrated in vacuo to get crude product, which was purified by flash column chromatography (PE / EtOAc = 100:0 to 46:54) to afford tert-butyl 4-(2-fluoro-6- (methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate 1702 (7.00 g, 82 % yield) as a yellow solid. LCMS (ESI) calcd for C16H22FN3O4[M + H]+m / z 340.16, found 340.20. Preparation of 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-fluoropicolinic acid (1703) To a solution of tert-butyl 4-(2-fluoro-6-(methoxycarbonyl)pyridin-3-yl)piperazine-1- carboxylate 1702 (1.00 g, 2.95 mmol) in THF / H2O = 1:1 (10 mL) was added LiOH (140 mg, 5.90 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was acidified to pH 6 with 1 M HCl. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layer was washed with brine (100 mL × 3), dried over Na2SO4, filtered and concentrated in vacuo to get crude product, which was purified by flash column chromatography (PE / EtOAc = 100:0 to 50:50) to afford 5-(4-(tert- butoxycarbonyl)piperazin-1-yl)-6-fluoropicolinic acid 1703 (950 mg, 99 % yield) as a yellow solid. LCMS (ESI) calcd for C15H20FN3O4[M + H]+m / z 326.14, found 326.15. Preparation of tert-butyl 4-(2-fluoro-6-((2-fluoroethyl)carbamoyl)pyridin-3-yl)piperazine-1- carboxylate (1704) To a solution of 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-fluoropicolinic acid 1703 (950 mg, 2.92 mmol) and 2-fluoroethanamine (275 mg, 4.36 mmol) in DMF (20 mL) was added HATU (1.66 g, 4.37 mmol) and DIEA (1.50 g, 11.60 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layer was washed with brine (100 mL × 3), dried over Na2SO4, filtered and concentrated in vacuo to get crude product, which was purified by flash column chromatography (PE / EtOAc = 100:0 to 50:50) to afford tert-butyl 4-(2-fluoro-6-((2- fluoroethyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate 1704 (1.00 g, 99 % yield) as a yellow oil. LCMS (ESI) calcd for C17H24F2N4O3[M + H]+m / z 371.18, found 371.30. Preparation of 6-fluoro-N-(2-fluoroethyl)-5-(piperazin-1-yl)picolinamide (1705) Tert-butyl 4-(2-fluoro-6-((2-fluoroethyl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate 1704 (1.00 g, 2.70 mmol) was added to HCl in dioxane (10 mL) and the mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure to give 6- fluoro-N-(2-fluoroethyl)-5-(piperazin-1-yl)picolinamide 1705 (790 mg, 99 % yield) as a yellow solid. LCMS (ESI) calcd for C12H16F2N4O [M + H]+m / z 271.13, found271.20. Preparation of 5-(4-(3-(5-ethyl-6-methoxypyridin-2-yl)cyclopent-2-en-1-yl)piperazin-1-yl)-6- fluoro-N-(2-fluoroethyl)picolinamide (1706) To a solution of 6-fluoro-N-(2-fluoroethyl)-5-(piperazin-1-yl)picolinamide 1705 (790 mg, 2.93 mmol), 3-(5-ethyl-6-methoxypyridin-2-yl)cyclopent-2-en-1-one 1305 (300 mg, 1.38 mmol) and NaBH(OAc)3(439 mg, 6.99 mmol) in MeOH (20 mL) was added 2 drops of AcOH at room temperature and the mixture was stirred for 10 min. Then NaBH3CN (434 mg, 2.05 mmol) was added. The reaction mixture was stirred at 100 °C for 12 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with DCM / MeOH = 100 : 0 to 90 : 10) to afford 5-(4-(3- (5-ethyl-6-methoxypyridin-2-yl)cyclopent-2-en-1-yl)piperazin-1-yl)-6-fluoro-N-(2- fluoroethyl)picolinamide 1706 (650 mg, 99 % yield) as a yellow oil. LCMS (ESI) calcd for C25H31F2N5O2[M + H]+m / z 472.25, found 474.45. Preparation of 5-(4-(3-(5-ethyl-6-methoxypyridin-2-yl)cyclopentyl)piperazin-1-yl)-6-fluoro- N-(2-fluoroethyl)picolinamide (1707) A mixture of 5-(4-(3-(5-ethyl-6-methoxypyridin-2-yl)cyclopent-2-en-1-yl)piperazin-1-yl)-6- fluoro-N-(2-fluoroethyl)picolinamide 1706 (650 mg, 1.38 mmol) and Pd / C (270 mg) in MeOH (5 mL) was degassed with H2and stirred at room temperature for 5 h under H2atmosphere. The resulting solution was filtered, and the filtrate was concentrated under reduced pressure to afford 5-(4-(3-(5-ethyl-6-methoxypyridin-2-yl)cyclopentyl)piperazin-1-yl)-6-fluoro-N-(2- fluoroethyl)picolinamide 1707 (650 mg, 99 % yield) as a yellow oil. LCMS (ESI) calcd for C25H33F2N5O2[M + H]+m / z 474.26, found 474.20. Preparation of 5-(4-(3-(5-ethyl-6-oxo-1,6-dihydropyridin-2-yl)cyclopentyl)piperazin-1-yl)-6- fluoro-N-(2-fluoroethyl)picolinamide (51cis-a / 51cis-b / 51trans-a / 51trans-b) To a solution of 5-(4-(3-(5-ethyl-6-methoxypyridin-2-yl)cyclopentyl)piperazin-1-yl)-6-fluoro- N-(2-fluoroethyl)picolinamide 1707 (650 mg, 1.37 mmol) in ACN (30 mL) was added TMSI (825 mg, 4.13 mmol). The reaction mixture was stirred at 50 ^ for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by C18 column (mobile phase: ACN - H2O (0.05 % NH3), gradient: 30 - 95) to give 5-(4-(3-(5-ethyl-6-oxo-1,6-dihydropyridin-2-yl)cyclopentyl)piperazin-1-yl)-6-fluoro-N-(2- fluoroethyl)picolinamide 51cis-a / 51cis-b racemic mixture (110 mg, 32 % yield) and 51trans- a / 51trans-b racemic mixture (90 mg, 32 % yield) as a white solid. LCMS (ESI) calcd for C24H31F2N5O2[M + H]+m / z 460.24, found 460.80. Chiral resolution of 5-(4-(3-(5-ethyl-6-oxo-1,6-dihydropyridin-2-yl)cyclopentyl)piperazin-1- yl)-6-fluoro-N-(2-fluoroethyl)picolinamide (51cis-a / 51cis-b racemic mixture and 51trans-a / 51trans-b racemic mixture) The 51cis-a / 51cis-b racemic mixture was separated by SFC (Column: IB N-54.6 mm × 250 mmL, 5 μm; Mobile phase: CO2 / MeOH[0.1 % (NH3)] = 60 / 40) and concentrated under reduced pressure to afford the first fraction as 51cis-a (31 mg, 98 % purity, ee%: 100, white solid ) and the second fraction as 51cis-b (28 mg, 99% purity, ee%: 100, white solid). The 51trans-a / 51trans-b racemic mixture was separated by SFC (Column: (R, R)-Whelk-O1 4.6 mm × 250 mmL, 5 μm; Mobile phase: CO2 / MeOH[0.1 %(NH3)] = 60 / 40) and concentrated under reduced pressure to afford the and the third fraction as 51trans-a (31 mg, 99 % purity, ee%: 100, white solid) and the first fraction as 51trans-b ((31 mg, 97 % purity, ee%: 100, white solid). 51cis-a1H NMR (400 MHz, MeOD-d4, ppm) δ: 7.93 (dd, J = 8.0, 1.2 Hz, 1 H), 7.61-7.55 (m, 1 H), 7.31 (d, J = 7.2 Hz, 1 H), 6.21 (d, J = 7.2 Hz, 1 H), 4.60 (t, J = 5.2 Hz, 1 H), 4.48 (t, J = 5.2 Hz, 1 H), 3.71 (t, J = 5.2 Hz, 1 H), 3.64 (t, J = 5.2 Hz, 1 H), 3.51-3.45 (m, 2 H), 3.41-3.34 (m, 2 H), 3.19- 3.12 (m, 1 H), 2.83-2.76 (m, 5 H), 2.46 (q, J = 7.2 Hz, 2 H), 2.25-2.14 (m, 2 H), 2.06-1.99 (m, 1 H), 1.88-1.80 (m, 2 H), 1.75-1.66 (m, 1 H), 1.14 (t, J = 7.6 Hz, 3 H). Assigned cis-stereochemistry based on NOE experiments. LCMS (ESI) calcd for C24H31F2N5O2[M + H]+m / z 460.24, found 460.45. 51cis-b1H NMR (400 MHz, MeOD-d4, ppm) δ: 7.93 (dd, J = 8.0, 1.2 Hz, 1 H), 7.62-7.54 (m, 1 H), 7.31 (d, J = 6.8 Hz, 1 H), 6.21 (d, J = 7.2 Hz, 1 H), 4.60 (t, J = 5.2 Hz, 1 H), 4.48 (t, J = 5.2 Hz, 1 H), 3.71 (t, J = 5.2 Hz, 1 H), 3.64 (t, J = 5.2 Hz, 1 H), 3.52-3.45 (m, 2 H), 3.41-3.34 (m, 2 H), 3.19-3.11 (m, 1 H), 2.83-2.76 (m, 5 H), 2.46 (q, J = 7.6 Hz, 2 H), 2.25-2.15 (m, 2 H), 2.04-1.98 (m, 1 H), 1.89- 1.80 (m, 2 H), 1.75-1.65 (m, 1 H), 1.14 (t, J = 7.6 Hz, 3 H). Assigned cis-stereochemistry based on NOE experiments. LCMS (ESI) calcd for C24H31F2N5O2[M + H]+m / z 460.24, found 460.45. 51trans-a1H NMR (400 MHz, MeOD-d4, ppm) δ: 7.92 (dd, J = 8.0, 0.8 Hz, 1 H), 7.58-7.49 (m, 1 H), 7.35 (d, J = 6.8 Hz, 1 H), 6.23 (d, J = 7.2 Hz, 1 H), 4.59 (t, J = 5.2 Hz, 1 H), 4.47 (t, J = 4.8 Hz, 1 H), 3.70 (t, J = 5.2 Hz, 1 H), 3.64 (t, J = 4.8 Hz, 1 H), 3.29-3.23 (m, 4 H), 3.16-3.09 (m, 1 H), 2.96- 2.88 (m, 1 H), 2.77-2.70 (m, 4 H), 2.48 (q, J = 7.2 Hz, 2 H), 2.19-2.05 (m, 3 H), 2.00-1.92 (m, 1 H), 1.79-1.60 (m, 2 H), 1.16 (t, J = 7.2 Hz, 3 H). Assigned trans-stereochemistry based on NOE experiments. LCMS (ESI) calcd for C24H31F2N5O2[M + H]+m / z 460.24, found 460.45. 51trans-b1H NMR (400 MHz, MeOD-d4, ppm) δ: 7.92 (dd, J = 8.0, 1.2 Hz, 1 H), 7.53 (dd, J = 10.0, 8.0 Hz, 1 H), 7.35 (d, J = 7.2 Hz, 1 H), 6.23 (d, J = 7.2 Hz, 1 H), 4.59 (t, J = 5.2 Hz, 1 H), 4.47 (t, J = 5.2 Hz, 1 H), 3.70 (t, J = 5.2 Hz, 1 H), 3.64 (t, J = 5.2 Hz, 1 H), 3.29-3.23 (m, 4 H), 3.17-3.09 (m, 1H), 2.96-2.87 (m, 1 H), 2.77-2.69 (m, 4 H), 2.48 (q, J = 7.6 Hz, 2 H), 2.19-2.05 (m, 3 H), 2.00-1.92 (m, 1 H), 1.77-1.58 (m, 2 H), 1.16 (t, J = 7.2 Hz, 3 H). Assigned trans-stereochemistry based on NOE experiments. LCMS (ESI) calcd for C24H31F2N5O2[M + H]+m / z 460.24, found 460.45.

[0018] Example 9: Synthesis of 79cis-a / 79cis-b / 79trans-a / 79trans-b Preparation of 6-bromo-3-chloro-2-methoxypyridine (1802) The following solutions A and B were prepared: A: a solution of NaNO2(3.4 g, 0.049 mol) in H2O (100 mL). B: a solution of 6-bromo-2-methoxypyridin-3-amine 1801 (5 g, 0.025 mol) in conc. HCl / H2O = 1:1 (80 mL). A was added to B dropwise at 0 °C, the reaction mixture was stirred at 0 °C for 20 min. Then CuCl (4.87 g, 0.049 mol) was added to the mixture at 0 °C. The mixture was stirred at 0 °C for 2 h. The resulting mixture was diluted with water (200 mL) and extracted with EtOAc (500 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 EtOAc / PE, 0 to 50 %) to give 6-bromo-3-chloro-2-methoxypyridine 1802 (3 g, 90 % purity, 49 % yield) as a white solid. LCMS (ESI) calcd for C6H5BrClNO [M + H]+m / z 221.92, no MS signal found. Preparation of 3-(5-chloro-6-methoxypyridin-2-yl)cyclopent-2-en-1-one (1803) To a solution of 6-bromo-3-chloro-2-methoxypyridine 1802 (2.8 g, 0.013 mol) in Dioxane / H2O = 5:1 (100 mL) was added 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-2-en-1- one 1303 (2.62 g, 0.013 mol), Na2CO3(2.67 g, 0.025 mol) and Pd(dppf)Cl2·DCM (1.03 g, 0.0012 mol) under N2. The mixture was heated at 100 °C for 5 hours. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (100 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 EtOAc / PE, 0 to 100 %) to give 3-(5-chloro-6- methoxypyridin-2-yl)cyclopent-2-en-1-one 1803 (1.2 g, 90 % purity, 38 % yield) as a white solid. LCMS (ESI) calcd for C11H10ClNO2[M + H]+m / z 224.04, found 223.75. Preparation of 5-(4-(3-(5-chloro-6-methoxypyridin-2-yl)cyclopent-2-en-1-yl)piperazin-1-yl)- 6-fluoro-N-methylpicolinamide (1804) To a solution of 3-(5-chloro-6-methoxypyridin-2-yl)cyclopent-2-en-1-one 1803 (500 mg, 2.23 mmol) and 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide 1306 (586 mg, 2.46 mmol) in EtOH (20 mL) was added AcOH (0.1 mL) and NaBH(OAc)3(946 mg, 4.46 mmol). The mixture was heated at 50 °C for 10 min. Then NaBH3CN (211 mg, 3.35 mol) was added to the mixture. The mixture was heated at 90 °C for 15 hours. The resulting mixture was quenched with water (1 mL), concentrated, and purified by silica gel column chromatography (eluting with MeOH / DCM, 0 to 10 %) to give 5-(4-(3-(5-chloro-6-methoxypyridin-2-yl)cyclopent-2-en-1- yl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide 1804 (700 mg, 90 % purity, 63 % yield) as a white solid. LCMS (ESI) calcd for C22H25ClFN5O2[M + H]+m / z 446.17, found 446.10. Preparation of 5-(4-(3-(5-chloro-6-methoxypyridin-2-yl)cyclopentyl)piperazin-1-yl)-6-fluoro- N-methylpicolinamide (1805) To a solution of 5-(4-(3-(5-chloro-6-methoxypyridin-2-yl)cyclopent-2-en-1-yl)piperazin-1-yl)- 6-fluoro-N-methylpicolinamide 1804 (700 mg, 1.57 mmol) in toluene (20 mL) was added Rh(PPh3)3Cl2(145 mg, 0.16 mmol). The mixture was evacuated and backfilled with hydrogen three times and then charged with hydrogen. The resulting mixture was stirred at 100 ι^ for 18 hours. Then the mixture was purified by silica gel column chromatography (eluting with MeOH / DCM, 0 to 10 %) to give 5-(4-(3-(5-chloro-6-methoxypyridin-2- yl)cyclopentyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide 1805 (500 mg, 90 % purity, 64 % yield) as a white solid. LCMS (ESI) calcd for C22H27ClFN5O2[M + H]+m / z 448.18, found 448.15. Preparation of 5-(4-(3-(5-chloro-6-oxo-1,6-dihydropyridin-2-yl)cyclopentyl)piperazin-1-yl)- 6-fluoro-N-methylpicolinamide (79cis-a / 79cis-b / 79trans-a / 79trans-b) To a solution of 5-(4-(3-(5-chloro-6-methoxypyridin-2-yl)cyclopentyl)piperazin-1-yl)-6-fluoro- N-methylpicolinamide 1805 (500 mg, 1.12 mmol) in ACN (20 mL) was added TMSI (894 mg, 4.46 mmol). The mixture was heated at 50 °C for 2 hours. The resulting mixture was concentrated, and purified by silica gel column chromatography (eluting with MeOH / DCM, 0 to 10 %), then prep-HPLC (Gemini 5 μm C18 column, 150 × 21.2 mm, eluting with 5 % to 95 % MeCN / H2O containing 0.1 % FA) to give 5-(4-(3-(5-chloro-6-oxo-1,6-dihydropyridin-2- yl)cyclopentyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide 79cis-a / 79cis-b / 79trans-a / 79trans-b (50 mg, 99 % purity, 9 % yield) as a white solid. Chiral resolution of 5-(4-(3-(5-chloro-6-oxo-1,6-dihydropyridin-2-yl)cyclopentyl)piperazin-1- yl)-6-fluoro-N-methylpicolinamide (79cis-a / 79cis-b / 79trans-a / 79trans-b) Stereoisomers of 79 were separated by SFC (Column: DAICEL IH 20 mm I.D. × 250 mmL, 5 μm; Mobile phase: CO2 / MeOH [0.1% NH3(7 M Solution in MeOH)] = 80 / 20) and concentrated under reduced pressure to afford the first fraction as 79cis-a (13.4 mg, 99.64 % purity, ee%: 100, white solid), the second fraction as 79cis-b (10.7 mg, 99.72 % purity, ee%: 100, white solid), the third fraction as 79trans-rac, a racemic mixture of 79trans-a and 79trans-b (12.3 mg, 99.94 % purity, white solid). 79cis-a1H NMR (400 MHz, DMSO-d6, ppm) δ: 12.57 (s, 1 H), 8.45-8.35 (m, 1 H), 7.86 (d, J = 8.0 Hz, 1 H), 7.63-7.54 (m, 2 H), 6.11 (d, J = 7.6 Hz, 1 H), 3.32-3.26 (m, 2 H), 3.25-3.16 (m, 2 H), 3.10- 3.01 (m, 1 H), 2.77 (d, J = 4.8 Hz, 3 H), 2.71-2.59 (m, 5 H), 2.17-2.02 (m, 2 H), 1.86-1.66 (m, 3 H), 1.64-1.52 (m, 1 H). Assigned cis-stereochemistry based on NOE experiments. LCMS (ESI) calcd for C21H25ClFN5O2[M + H]+m / z 434.17, found 433.94. 79cis-b1H NMR (400 MHz, DMSO-d6, ppm) δ: 12.58 (s, 1 H), 8.45-8.36 (m, 1 H), 7.86 (d, J = 8.0 Hz, 1 H), 7.66-7.51 (m, 2 H), 6.11 (d, J = 7.6 Hz, 1 H), 3.31-3.26 (m, 2 H), 3.24-3.18 (m, 2 H), 3.11- 3.00 (m, 1 H), 2.77 (d, J = 4.8 Hz, 3 H), 2.71-2.60 (m, 5 H), 2.15-2.01 (m, 2 H), 1.87-1.67 (m, 3 H), 1.65-1.54 (m, 1 H). Assigned cis-stereochemistry based on NOE experiments. LCMS (ESI) calcd for C21H25ClFN5O2[M + H]+m / z 434.17, found 433.97. 79trans-rac1H NMR (400 MHz, DMSO-d6, ppm) δ: 12.07 (s, 1 H), 8.46-8.35 (m, 1 H), 7.84 (d, J = 8.0 Hz, 1 H), 7.63 (d, J = 7.6 Hz, 1 H), 7.58-7.50 (m, 1 H), 6.08 (d, J = 7.6 Hz,1 H), 3.19-3.10 (m, 4 H), 3.05- 2.97 (m, 1 H), 2.87-2.80 (m, 1 H), 2.76 (d, J = 4.8 Hz, 3 H), 2.61-2.52 (m, 4 H), 2.06-1.89 (m, 3 H), 1.80-1.70 (m, 1 H), 1.66-1.43 (m, 2 H). Assigned trans-stereochemistry based on NOE experiments. LCMS (ESI) calcd for C21H25ClFN5O2[M + H]+m / z 434.17, found 433.95. Example 10: Synthesis of 75cis-a / 75 cis-b / 75trans-a / 75trans-b Preparation of 5-bromo-3-methoxy-2-vinylpyrazine (1903) To a solution of 5-bromo-2-iodo-3-methoxypyrazine 1901 (30 g, 95.3 mmol) and 4,4,5,5- tetramethyl-2-vinyl-1,3,2-dioxaborolane 1902 (22 g, 142.8 mmol) in Dioxane / H2O (500 mL, v / v = 10: 1) were added Pd(dppf)Cl2.DCM (6.98 g, 9.5 mmol) and K2CO3(39.45 g, 285.9 mmol) at room temperature. The reaction mixture was stirred at 80 °C for 2 h. After cooling to room temperature, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE / EtOAc = 100: 0 to 90: 10) to give 5-bromo-3-methoxy-2-vinylpyrazine 1903 (15 g, 90 % purity, 65 % yield) as a yellow oil. LCMS (ESI) calcd for C7H7BrN2O [M + H]+m / z 214.97, found 214.95. Preparation of 5-bromo-2-ethyl-3-methoxypyrazine (1904) To a solution of 5-bromo-3-methoxy-2-vinylpyrazine 1903 (15 g, 69.8 mmol) in EtOAc (500 mL) was added PtO2(1.59 g) at room temperature. The mixture was evacuated and backfilled with hydrogen three times and then charged with hydrogen. The mixture was stirred at room temperature for 4 h. Then the mixture was filtered through celite and concentrated under vacuum to give crude product. The residue was purified by flash chromatography (eluting with PE / EtOAc = 100: 0 to 90: 10) to give 5-bromo-2-ethyl-3-methoxypyrazine 1904 (10 g, 90 % purity, 59 % yield) as a yellow oil. LCMS (ESI) calcd for C7H9BrN2O [M + H]+m / z 216.99, found 217.05. Preparation of 3-(5-ethyl-6-methoxypyrazin-2-yl)cyclopent-2-en-1-one (1905) To a solution of 5-bromo-2-ethyl-3-methoxypyrazine 1904 (10 g, 46.1 mmol) in 1,4- dioxane / H2O = 10:1 (250 mL) were added 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)cyclopent-2-en-1-one 1303 (14.3 g, 69.1 mmol), K2CO3(19 g, 138.3 mmol) and RuPhos Pd G3 ((2-dicyclohexylphosphino-2ʹ,6ʹ-diisopropoxy-1,1ʹ-biphenyl)[2-(2ʹ-amino-1,1ʹ- biphenyl)]palladium(II) methanesulfonate, 3.86 g, 4.6 mmol) successively at room temperature. The reaction mixture was stirred at 100 ^ for 4 h under N2. The mixture was filtered and concentrated in vacuo to get crude product, which was purified by flash column chromatography (PE / EtOAc = 100: 0 to 50: 50) to afford 3-(5-ethyl-6-methoxypyrazin-2- yl)cyclopent-2-en-1-one 1905 (10 g, 90 % purity, 89 % yield) as a yellow solid. LCMS (ESI) calcd for C12H14N2O2[M + H]+m / z 219.11, found 219.15. Preparation of 5-(4-(3-(5-ethyl-6-methoxypyrazin-2-yl)cyclopent-2-en-1-yl)piperazin-1-yl)- 6-fluoro-N-methylpicolinamide (1906) To a solution of 3-(5-ethyl-6-methoxypyrazin-2-yl)cyclopent-2-en-1-one 1905 (1000 mg, 4.6 mmol) in EtOH (150 mL) was added 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide 1306 (2.1 g, 9.2 mmol), then two drops of acetic acid was added at room temperature. After 1 h, NaBH(OAc)3(1950 g, 9.2 mmol) and NaBH3CN (290 mg, 4.6 mmol) were added. The reaction mixture stirred at 100 ιC for 12 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with DCM / MeOH = 100:0 to 95:5) to afford 5-(4-(3-(5-ethyl-6- methoxypyrazin-2-yl)cyclopent-2-en-1-yl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide 1906 (1000 mg, 90 % purity, 43 % yield) as a yellow solid. LCMS (ESI) calcd for C23H29FN6O2[M + H]+m / z 441.23, found 443.20. Preparation of 5-(4-(3-(5-ethyl-6-methoxypyrazin-2-yl)cyclopentyl)piperazin-1-yl)-6-fluoro- N-methylpicolinamide (1907) To a solution of 5-(4-(3-(5-ethyl-6-methoxypyrazin-2-yl)cyclopent-2-en-1-yl)piperazin-1-yl)-6- fluoro-N-methylpicolinamide 1906 (1000 mg, 2.3 mmol) in MeOH (100 mL) was added Pd(OH)2 / C (300 mg). The mixture was evacuated and backfilled with hydrogen three times and then charged with hydrogen. The resulting mixture was stirred at 50 °C for 15 hours. Then the mixture was filtered through celite and concentrated under vacuum to give crude product, which was purified by flash column chromatography (DCM / MeOH = 100: 0 to 95: 5) to afford 5-(4-(3-(5-ethyl-6-methoxypyrazin-2-yl)cyclopentyl)piperazin-1-yl)-6-fluoro-N- methylpicolinamide 1907 (1000 mg, 90 % purity, 86 % yield) as a yellow solid. LCMS (ESI) calcd for C23H31FN6O2[M + H]+m / z 443.25, found 443.15. Preparation of 5-(4-(3-(5-ethyl-6-oxo-1,6-dihydropyrazin-2-yl)cyclopentyl)piperazin-1-yl)-6- fluoro-N-methylpicolinamide (75cis-a / 75cis-b / 75trans-a / 75trans-b) 5-(4-(3-(5-ethyl-6-methoxypyrazin-2-yl)cyclopentyl)piperazin-1-yl)-6-fluoro-N- methylpicolinamide 1907 (1000 mg, 2.3 mmol) was mixed with 33 wt.% HBr in water (30 mL) at room temperature. The mixture was stirring at 70 °C for 0.5 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography (DCM / MeOH = 100: 0 to 95: 5) to afford 5-(4-(3-(5-ethyl-6-oxo-1,6-dihydropyrazin-2-yl)cyclopentyl)piperazin-1-yl)-6-fluoro-N- methylpicolinamide 75cis-a / 75cis-b / 75trans-a / 75trans-b as a mixture of diastereomers (200 mg, 90 % purity, 17 % yield), in the form of a white solid. Chiral resolution of 5-(4-(3-(5-ethyl-6-oxo-1,6-dihydropyrazin-2-yl)cyclopentyl)piperazin-1- yl)-6-fluoro-N-methylpicolinamide (75cis-a / 75cis-b / 75trans-a / 75trans-b) The mixture of diastereomers of 75 was separated by SFC (Column: (R,R)-Whelk-O1250 mmL × 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 75trans-rac, a racemic mixture of 75trans-a and 75trans-b (80 mg, 99 % purity, white solid), the second fraction as 75cis-a (48.5 mg, 95.07 % purity, ee%: 100, white solid) and the third fraction as 75cis-b (43.4 mg, 96.63 % purity, ee%: 100, white solid). 75cis-a LCMS (ESI) calcd for C22H29FN6O2[M + H]+m / z 429.23, found 429.45.1H NMR (400 MHz, DMSO-d6, ppm) δ: 12.60-12.36 (m, 1 H), 8.44-8.36 (m, 1 H), 7.89-7.82 (m, 1 H), 7.61-7.52 (m, 1 H), 7.21-7.07 (m, 1 H), 3.30-3.14 (m, 4 H), 3.05-2.93 (m, 1 H), 2.77 (d, J = 4.8 Hz, 3 H), 2.73-2.69 (m, 1 H), 2.68-2.57 (m, 6 H), 2.15-1.99 (m, 2 H), 1.88-1.70 (m, 3 H), 1.69- 1.57 (m, 1 H), 1.11 (t, J = 7.6 Hz, 3 H). Assigned cis-stereochemistry based on NOE experiments. 75cis-b LCMS (ESI) calcd for C22H29FN6O2[M + H]+m / z 429.23, found 429.35.1H NMR (400 MHz, DMSO-d6, ppm) δ: 12.57-12.34 (m, 1 H), 8.45-8.34 (m, 1 H), 7.90-7.80 (m, 1 H), 7.63-7.51 (m, 1 H), 7.21-7.05 (m, 1 H), 3.30-3.14 (m, 4 H), 3.05-2.93 (m, 1 H), 2.77 (d, J = 4.8 Hz, 3 H), 2.74-2.69 (m, 1 H), 2.68-2.55 (m, 6 H), 2.16-1.98 (m, 2 H), 1.88-1.69 (m, 3 H), 1.69- 1.58 (m, 1 H), 1.11 (t, J = 7.6 Hz, 3 H). Assigned cis-stereochemistry based on NOE experiments. Chiral resolution of 5-(4-(3-(5-ethyl-6-oxo-1,6-dihydropyrazin-2-yl)cyclopentyl)piperazin-1- yl)-6-fluoro-N-methylpicolinamide (75trans-a / 75trans-b racemic mixture) The 75trans-a / 75trans-b racemic mixture was separated by SFC (Column: DAICEL AS-H 250 mmL × 20 mm I.D., 5 μm; Mobile phase: CO2 / MeOH [0.1 % (NH3)] = 80 / 20) and concentrated under reduced pressure to afford the first fraction as 75trans-a (23.9 mg, 99.84 % purity, ee%: 100, white solid) and the second fraction as 75trans-b (26.3 mg, 99.74 % purity, ee%: 95, white solid). 75trans-a LCMS (ESI) calcd for C22H29FN6O2[M + H]+m / z 429.23, found 429.35.1H NMR (400 MHz, DMSO-d6, ppm) δ: 12.10-11.88 (m, 1 H), 8.44-8.35 (m, 1 H), 7.88-7.81 (m, 1 H), 7.61-7.49 (m, 1 H), 7.22-7.05 (m, 1 H), 3.20-3.11 (m, 4 H), 3.03-2.92 (m, 1 H), 2.91-2.81 (m, 1 H), 2.76 (d, J = 4.8 Hz, 3 H), 2.64-2.55 (m, 6 H), 2.04-1.92 (m, 3 H), 1.85-1.75 (m, 1 H), 1.72-1.60 (m, 1 H), 1.57-1.45 (m, 1 H), 1.11 (t, J = 7.6 Hz, 3 H). Assigned trans-stereochemistry based on NOE experiments. 75trans-b LCMS (ESI) calcd for C22H29FN6O2[M + H]+m / z 429.23, found 429.35.1H NMR (400 MHz, DMSO-d6, ppm) δ: 12.09-11.89 (m, 1 H), 8.43-8.36 (m, 1 H), 7.88-7.81 (m, 1 H), 7.61-7.52 (m, 1 H), 7.22-7.07 (m, 1 H), 3.20-3.10 (m, 4 H), 3.03-2.92 (m, 1 H), 2.90-2.81 (m, 1 H), 2.76 (d, J = 4.8 Hz, 3 H), 2.66-2.55 (m, 6 H), 2.04-1.91 (m, 3 H), 1.86-1.75 (m, 1 H), 1.73-1.59 (m, 1 H), 1.58-1.46 (m, 1 H), 1.11 (t, J = 7.6 Hz, 3 H). Assigned trans-stereochemistry based on NOE experiments. Example 11: Synthesis of 82 Preparation of 3-(4-((benzyloxy)carbonyl)piperazin-1-yl)bicyclo[2.1.1]hexane-1-carboxylic acid (2003) To a solution of 3-oxobicyclo[2.1.1]hexane-1-carboxylic acid 2001 (1.2 g, 8.60 mmol) in MeOH (20 mL) was added benzyl piperazine-1-carboxylate 2002 (2.0 g, 9.03 mmol), NaBH(OAc)3(3.7 g, 17.20 mmol) and NaBH3CN (540 mg, 8.60 mmol) successively. The reaction mixture was stirred at 50 °C for 1 h. The reaction mixture was quenched with water (20 mL), the mixture was adjusted to pH = 3 with aq. HCl (2 N) and extracted with EtOAc (50 mL × 5). The combined organic layers were concentrated under reduced pressure to give 3-(4- ((benzyloxy)carbonyl)piperazin-1-yl)bicyclo[2.1.1]hexane-1-carboxylic acid 2003 (1.7 g, 90 % purity, 51 % yield) as a white solid. LCMS (ESI) calcd for C19H24N2O4[M + H]+m / z 345.17, found 345.05. Preparation of benzyl 4-(4-carbamoylbicyclo[2.1.1]hexan-2-yl)piperazine-1-carboxylate (2004) To a solution of 3-(4-((benzyloxy)carbonyl)piperazin-1-yl)bicyclo[2.1.1]hexane-1-carboxylic acid 2003 (1.7 g, 4.90 mmol) in DCM (30 mL) were added NH4Cl (520 mg, 9.80 mmol), DIPEA (2.5 g, 19.60 mmol) and HATU (3.7 g, 9.80 mmol) successively at rt. The reaction mixture was stirred at rt for 1 h. The reaction was diluted with H2O and extracted with DCM (50 mL × 2). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with DCM / MeOH = 100:0 to 97:3) to afford benzyl 4-(4-carbamoylbicyclo[2.1.1]hexan-2- yl)piperazine-1-carboxylate 2004 (1.2 g, 80 % purity, 57 % yield) as a white solid. LCMS (ESI) calcd for C19H25N3O3[M + H]+m / z 344.19, found 344.05. Preparation of benzyl 4-(4-carbamimidoylbicyclo[2.1.1]hexan-2-yl)piperazine-1- carboxylate (2005) To a solution of benzyl 4-(4-carbamoylbicyclo[2.1.1]hexan-2-yl)piperazine-1-carboxylate 2004 (1.2 g, 3.50 mmol) in DCM (15 mL) was added Me3O+BF4- (1.0 g, 7.00 mmol). The reaction mixture was stirred at rt for 2 h under N2. Solvent was removed under reduced pressure and the residue was dissolved in NH3-MeOH (15 mL, 7 M). The reaction mixture was stirred at rt for 16 h. The reaction solution was concentrated under reduced pressure to give benzyl 4-(4- carbamimidoylbicyclo[2.1.1]hexan-2-yl)piperazine-1-carboxylate 2005 (1.2 g, 50 % purity, 51 % yield) as a brown oil. LCMS (ESI) calcd for C19H26N4O2[M + H]+m / z 343.21, found 343.15. Preparation of benzyl 4-(4-(6-oxo-1,6-dihydropyrimidin-2-yl)bicyclo[2.1.1]hexan-2- yl)piperazine-1-carboxylate (2007) To a solution of benzyl 4-(4-carbamimidoylbicyclo[2.1.1]hexan-2-yl)piperazine-1-carboxylate 2005 (1.2 g, 3.50 mmol) in DMF (15 mL) was added methyl 3-methoxyacrylate 2006 (810 mg, 7.00 mmol) and K2CO3(1.45 g, 10.50 mmol). The reaction mixture was stirred at 120 °C for 6 h under N2atmosphere. The reaction solution was cooled to rt and was poured into water, then extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with DCM / MeOH = 100:0 to 95:5) to afford benzyl 4- (4-(6-oxo-1,6-dihydropyrimidin-2-yl)bicyclo[2.1.1]hexan-2-yl)piperazine-1-carboxylate 2007 (0.48 g, 90 % purity, 31 % yield) as a colourless oil. LCMS (ESI) calcd for C22H26N4O3[M + H]+m / z 395.20, found 395.15. Preparation of benzyl 4-(4-(5-bromo-6-oxo-1,6-dihydropyrimidin-2-yl)bicyclo[2.1.1]hexan- 2-yl)piperazine-1-carboxylate (2008) To a solution of benzyl 4-(4-(6-oxo-1,6-dihydropyrimidin-2-yl)bicyclo[2.1.1]hexan-2- yl)piperazine-1-carboxylate 2007 (480 mg, 1.22 mmol) in AcOH (5 mL) was added Br2(584 mg, 3.65 mmol) at 0 °C. The reaction mixture was stirred at 0 ^ for 1 h. The reaction mixture was quenched with aq. Na2S2O3, then extracted with EtOAc (20 mL × 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with DCM / MeOH = 100:0 to 97:3) to afford benzyl 4-(4-(5-bromo-6- oxo-1,6-dihydropyrimidin-2-yl)bicyclo[2.1.1]hexan-2-yl)piperazine-1-carboxylate 2008 (330 mg, 80 % purity, 45 % yield) as colourless oil. LCMS (ESI) calcd for C22H25BrN4O3[M + H]+m / z 473.11, found 472.82. Preparation of benzyl 4-(4-(6-oxo-5-vinyl-1,6-dihydropyrimidin-2-yl)bicyclo[2.1.1]hexan-2- yl)piperazine-1-carboxylate (2010) To a solution of benzyl 4-(4-(5-bromo-6-oxo-1,6-dihydropyrimidin-2-yl)bicyclo[2.1.1]hexan-2- yl)piperazine-1-carboxylate 2008 (330 mg, 0.70 mmol) in ACN (10 mL) was added tributyl(vinyl)stannane 2009 (332 mg, 1.05 mmol) and Pd(AMPHOS)Cl2(49 mg, 0.07 mmol) successively. The reaction mixture was stirred at 100 °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 DCM / MeOH = 100:0 to 95:5) to afford benzyl 4-(4-(6-oxo-5-vinyl-1,6-dihydropyrimidin-2-yl)bicyclo[2.1.1]hexan-2-yl)piperazine-1- carboxylate 2010 (210 mg, 80 % purity, 57 % yield) as a colourless oil. LCMS (ESI) calcd for C24H28N4O3[M + H]+m / z 421.22, found 421.08. Preparation of 5-ethyl-2-(3-(piperazin-1-yl)bicyclo[2.1.1]hexan-1-yl)pyrimidin-4(3H)-one (2011) A mixture of benzyl 4-(4-(6-oxo-5-vinyl-1,6-dihydropyrimidin-2-yl)bicyclo[2.1.1]hexan-2- yl)piperazine-1-carboxylate 2010 (210 mg, 0.50 mmol ) and PtO2 (57 mg, 0.25 mmol) in MeOH (5 mL) was stirred under balloon pressure of H2at rt for 16 h. The mixture was filtered through a Celite pad, and the filtrate was concentrated to give 5-ethyl-2-(3-(piperazin-1- yl)bicyclo[2.1.1]hexan-1-yl)pyrimidin-4(3H)-one 2011 (150 mg, 20 % purity, 20 % yield) as colourless oil. LCMS (ESI) calcd for C16H24N4O [M + H]+m / z 289.20, found 289.25. Preparation of methyl 6-bromo-5-(4-(4-(5-ethyl-6-oxo-1,6-dihydropyrimidin-2- yl)bicyclo[2.1.1]hexan-2-yl)piperazin-1-yl)picolinate (2013) To a solution of 5-ethyl-2-(3-(piperazin-1-yl)bicyclo[2.1.1]hexan-1-yl)pyrimidin-4(3H)-one 2011 (150 mg, 0.52 mmol) in ACN (5 mL) was added methyl 6-bromo-5-fluoropicolinate 2012 (122 mg, 0.52 mmol) and DIPEA (202 mg, 1.56 mmol). The reaction mixture was stirred at 75 °C for 6 h. The reaction solution was cooled to rt and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with DCM / MeOH = 100:0 to 95:5) to afford methyl 6-bromo-5-(4-(4-(5-ethyl-6-oxo-1,6-dihydropyrimidin-2- yl)bicyclo[2.1.1]hexan-2-yl)piperazin-1-yl)picolinate 2013 (20 mg, 80 % purity, 6 % yield) as a colourless oil. LCMS (ESI) calcd for C23H28BrN5O3[M + H]+m / z 502.14, found 502.05. Preparation of 6-bromo-5-(4-(4-(5-ethyl-6-oxo-1,6-dihydropyrimidin-2- yl)bicyclo[2.1.1]hexan-2-yl)piperazin-1-yl)-N-methylpicolinamide (2014) A solution of methyl 6-bromo-5-(4-(4-(5-ethyl-6-oxo-1,6-dihydropyrimidin-2- yl)bicyclo[2.1.1]hexan-2-yl)piperazin-1-yl)picolinate 2013 (20 mg, 0.04 mmol) in MeNH2(5 mL, 30 wt.% in MeOH) was stirred at 100 ιC for 2 h in a steel bomb. The reaction solution was cooled to rt and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with DCM / MeOH = 100:0 to 95:5) to afford 6-bromo-5-(4- (4-(5-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)bicyclo[2.1.1]hexan-2-yl)piperazin-1-yl)-N- methylpicolinamide 2014 (20 mg, 80 % purity, 80 % yield) as a colourless oil. LCMS (ESI) calcd for C23H29BrN6O2[M + H]+m / z 501.15, found 501.25. Preparation of 5-(4-(4-(5-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)bicyclo[2.1.1]hexan-2- yl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide (82) To a solution of 6-bromo-5-(4-(4-(5-ethyl-6-oxo-1,6-dihydropyrimidin-2- yl)bicyclo[2.1.1]hexan-2-yl)piperazin-1-yl)-N-methylpicolinamide 2014 (20 mg, 0.04 mmol) in DMSO (2 mL) was added 18-Crown-6 (21 mg, 0.08 mmol) and CsF (24 mg, 0.16 mmol) successively. The reaction mixture was stirred at 100 °C for 16 h under N2atmosphere. The reaction solution was cooled to rt and poured into water, then extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, 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: 20 - 60) to obtain 5-(4-(4-(5-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)bicyclo[2.1.1]hexan-2- yl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide 82 racemate (2.7 mg, 97.60 % purity, 15 % yield) as a white solid. 1H NMR (400 MHz, DMSO-d6, ppm) δ: 8.48-8.35 (m, 1 H), 7.90-7.80 (m, 1 H), 7.65-7.51 (m, 2 H), 3.21-3.12 (m, 4 H), 2.76 (d, J = 4.8 Hz, 3 H), 2.60-2.56 (m, 4 H), 2.53-2.52 (m, 2 H), 2.28- 2.20 (m, 2 H), 2.05-1.96 (m, 1 H), 1.95-1.89 (m, 1 H), 1.83-1.72 (m, 2 H), 1.71-1.64 (m, 1 H), 1.43-1.31 (m, 1 H), 1.03 (t, J = 7.6 Hz, 3 H). LCMS (ESI) calcd for C23H29FN6O2[M + H]+m / z 441.23, found 441.35. Example 12 - 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 12A. 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 / HCO3coating buffer at pH 9.6, overnight at 4 °C, in order to achieve a final immobilisation per well of 0.3 Pg. 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 4oC. Prior to assay, wells were washed 3 x 5 min in coating wash buffer. For the assay 20 μl 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 μl of 10 PM 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 Pl of 12 mM NAD+quenching solution. After 30 min at room temperature, assay solution was removed and following washing 5 times for 3 min, 100 Pl of a 1:1000 dilution of DELFIA Eu-N1 Streptavidin reagent was added. Plates were then incubated for 30 min at room temperature. Reaction mixture was removed and plates washed 5 times for 3 min prior to the addition of 25 μl 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 Ps; integration time 400 Ps). Typically compounds were tested from 20 PM 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 12B. 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 Pl of this reaction mixture was then transferred to each well of a black non-binding surface 384-well plate and 35 nl of compound solution in DMSO was then added using pintool technology. Following incubation for 1 h at room temperature, fluorescence was measured on a Pherastar FS (Ex 337 nm, Em620 nm, em665 nm; integration start 60 μs; integration time 400 μs) using the HTRF module. Typically compounds were tested from 58.5 PM at factor 3 dilution intervals in 12-point concentration-response curves to determine 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 Kdvalues 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 12C. 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. 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 (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. 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) *The suffixes X and Y denote isomers having different, but unassigned, stereochemistry across ring A. TABLE 2 Results of Parp 1 / 2 assays for selected compounds (NanoBRET)

[0019] Key DELFIA, Probe Displacement HTRF and NanoBRET assay categories: - indicates IC50or Kdvalue above 10 PM + indicates IC50or Kdvalue above 1 PM up to 10 PM ++ indicates IC50or Kdvalue above 100 nM up to 1 PM +++ indicates IC50or Kdvalue above 10 nM up to 100 nM ++++ indicates IC50or Kdvalue 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 NT: not tested. The selectivity values relate to the selectivity preference of PARP1 over PARP2. They are calculated from the ratio of Kdvalues for PARP1 and PARP2 inhibition as Kd(PARP2) / Kd(PARP1). 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, which compound comprises a structure of:wherein: R1is selected from H and a substituted or unsubstituted organic group; R2is absent or selected from H and a substituted or unsubstituted organic group; R3is absent or selected from H and a substituted or unsubstituted organic group; R4is selected from H and a substituted or unsubstituted organic group; Z1and Z2are each independently selected from C and N; and L is a group having a structure of:wherein: 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 1, 2, 3, 4, 5, and 6; 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 1, 2, 3, 4, 5, and 6;r is a number selected from 0, 1, 2, 3, 4, 5 and 6; s is a number 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; each R5A, R5B, and R5Cis independently absent or selected from H and a substituted or unsubstituted organic group; and R6is absent or selected from H and a substituted or unsubstituted organic group; the lines forming rings A, B and C each independently represent single or double bonds such that each ring is independently saturated, unsaturated, or aromatic; and each of Qa, Qb, and Qc is independently selected from a bond and a group having a structure independently selected from:wherein: t is a number selected from 0, 1, 2, 3, 4 and 5; and u is 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 p + q is a number selected from 2, 3, 4, 5, and 6; and optionally m + n is a number selected from 2, 3, 4, 5 and 6.

3. The PARP1 inhibitor compound for use according to claim 1 or claim 2, wherein each X2is independently selected from C and N.

4. The PARP1 inhibitor compound for use according to any preceding claim, wherein the compound has a structure selected from:R1, R2and R4each being independently selected from H and a substituted or unsubstituted organic group;R1, R3and R4each being independently selected from H and a substituted or unsubstituted organic group; and:R1, R2, R3and R4each being independently selected from H and a substituted or unsubstituted organic group.

5. The PARP1 inhibitor compound for use according to claim 4, having a structure of:wherein R1, R2, R3and R4are each independently selected from H and a substituted or unsubstituted organic group.

6. The PARP1 inhibitor compound for use according to claim 4, having a structure of:wherein R1, R3and R4are each independently selected from H and a substituted or unsubstituted organic group.

7. The PARP1 inhibitor compound for use according to any preceding claim, wherein R1and R2are each independently selected from: H; a C1 to C6 alkyl, aminoalkyl, alkoxy or haloalkyl group; a C3 to C6 cycloalkyl group; a halogen group; andwherein R22is selected from H, a C1 to C6 alkyl, cycloalkyl, alkoxy, or haloalkyl group, and a halogen group, and each R23is independently selected from H and a substituted or unsubstituted organic group, preferably wherein each R23is independently selected from H, a C1 to C6 alkyl, aminoalkyl, alkoxy or haloalkyl group, and a halogen group, and preferably wherein at least one R23is H; with the proviso that at least one of R1and R2is not H.

8. The PARP1 inhibitor compound for use according to any preceding claim, wherein R2is absent or H; preferably wherein R2is H.

9. The PARP1 inhibitor compound for use according to claim 7, wherein at least one of R1, R2, R3and R22is selected from -CH3, -CH2CH3, -CH2CH2CH3, -CH2F, -CHF2, -CF3, -F, -Cl, - CH2CF3, -CH2CH2F, -CH2CH2OH, methoxy, methoxymethyl, methoxyethyl, isopropyl, cyclopropyl or cyclopropylmethyl; optionally wherein at least one of R1, R2, and R22is selected from -CH3, -CH2CH3, - CH2CH2CH3, -CH2F, -CHF2, -CF3, -F, -Cl, -CH2CF3, -CH2CH2F, -CH2CH2OH, methoxy, methoxymethyl, methoxyethyl, isopropyl, cyclopropyl or cyclopropylmethyl.

10. The PARP1 inhibitor compound for use according to any preceding claim, having a structure selected from:,or having a structure of:

11. The PARP1 inhibitor compound for use according to any of claims 7 to 10, wherein at least one of R1and R2isand each R23is independently selected from H, F, C1 to C3 alkyl or C1 to C3 fluoroalkyl.

12. The PARP1 inhibitor compound for use according to any preceding claim, wherein R1is selected from a halogen group, optionally Cl; a C1 to C4 alkyl group; and a C1 to C4 haloalkyl group, optionally a C1 to C4 fluoroalkyl group.

13. The PARP1 inhibitor compound for use according to claim 12, wherein R1is selected from -CH2CH3, -CF3,CH2CH2F, Cl, and CH2CF3.

14. The PARP1 inhibitor compound for use according to any preceding claim, wherein R1is selected from H, C1 to C3 alkyl, C1 to C3 alkoxy, and C1 to C3 haloalkyl.

15. The PARP1 inhibitor compound for use according to claim 14, wherein R1is an ethyl group.

16. The PARP1 inhibitor compound for use according to any preceding claim, wherein R3is selected from H, halogen, C1 to C3 alkyl, C1 to C3 haloalkyl, C1 to C3 alcohol or C1 to C3 aminoalkyl; optionally wherein R3is H.

17. The PARP1 inhibitor compound for use according to claim 16, wherein: Z1and Z2are each C; and R2and R3are each independently selected from H, a halogen, C1 to C3 alkyl, and C1 to C3 haloalkyl; optionally wherein R2and R3are each independently selected from H, C1 to C3 alkyl, and C1 to C3 haloalkyl.

18. The PARP1 inhibitor compound for use according to claim 17, wherein R2and R3are each H.

19. The PARP1 inhibitor compound for use according to any preceding claim, wherein R4is selected from H, C1 to C3 alkyl, and C1 to C3 haloalkyl. preferably wherein R4is H.

20. The PARP1 inhibitor compound according to any preceding claim, having a structure selected from:

21. The PARP1 inhibitor compound for use according to any preceding claim, wherein ring A is a non-aromatic ring.

22. The PARP1 inhibitor compound for use according to claim 21, wherein L has a structure of: andwherein ring A is a saturated or unsaturated aliphatic carbocycle or heterocycle.

23. The PARP1 inhibitor compound for use according to any of claims 1 to 21, wherein L has a structure of:wherein ring A is a saturated or unsaturated aliphatic carbocycle or heterocycle; optionally wherein ring A is a cyclopentyl group and each X1atom of ring A has an R configuration or each X1atom of ring A has an S configuration; further optionally wherein each X1atom of ring A has an S configuration.

24. The PARP1 inhibitor compound for use according to any preceding claim, wherein ring A is a 5-membered saturated or unsaturated aliphatic carbocycle or heterocycle.

25. The PARP1 inhibitor compound for use according to any of claims 1 to 23, wherein ring A is a 6-membered saturated or unsaturated aliphatic carbocycle or heterocycle.

26. The PARP1 inhibitor compound for use according to any preceding claim, wherein Qa is a bond or -CH2-, optionally wherein Qa is a bond.

27. The PARP1 inhibitor compound for use according to any preceding claim, wherein L is a group having a structure of:.

28. The PARP1 inhibitor compound for use according to claim 27, wherein L is a group having a structure of:.

29. The PARP1 inhibitor compound for use according to any preceding claim, wherein ring B is a saturated heterocycle.

30. The PARP1 inhibitor compound according to any preceding claim, wherein ring A is selected from:

31. The PARP1 inhibitor compound according to claim 30, wherein Qb is -CH2-.

32. The PARP1 inhibitor compound according to any of claims 1 to 29, wherein both n and m are at least 1.

33. The PARP1 inhibitor compound for use according to claim 32, wherein: i) ring A is a substituted or unsubstituted 7-membered aliphatic carbocycle or heterocycle, optionally a cycloheptane, further optionally a cycloheptane having a structure selected from:each R5Aand R5A3being independently selected from H and a substituted or unsubstituted organic group, wherein R5A3is most preferably H; orii) wherein ring A is a substituted or unsubstituted 6-membered aliphatic carbocycle or heterocycle, optionally a cyclohexane, cyclohexene, or tetrahydropyran and further optionally having a structure selected from: , , ,,,each R5Aand R5A3being independently selected from H and a substituted or unsubstituted organic group, wherein R5A3is most preferably H; or iii) ring A is a substituted or unsubstituted 5-membered aliphatic carbocycle or heterocycle, optionally a cyclopentane, cyclopentene, or a tetrahydrofuran, and further optionally having a structure selected from: , ,each R5Aand R5A3being independently selected from H and a substituted or unsubstituted organic group, wherein R5A3is most preferably H; 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; and v) ring A is a substituted or unsubstituted cyclobutane, optionally having a structure of:; each R5Aand R5A3being independently selected from H and a substituted or unsubstituted organic group, wherein R5A3is most preferably H.

34. The PARP1 inhibitor compound for use according to claim 33, wherein ring A has a structure selected from:

35. The PARP1 inhibitor compound for use according to any preceding claim, wherein ring A has a structure of:wherein: n is 1, 2 or 3; m is 0, 1, or 2; X1is C or N; each X2is independently selected from C and O; and each R5A1, R5A2, and R5A3is independently absent or selected from H and a substituted or unsubstituted organic group; with the proviso that R5A1is absent when X1is N; and R5A2is absent when the corresponding X2is O.

36. The PARP1 inhibitor compound for use according to claim 35, wherein: exactly two groups selected from the R5A1, R5A2, and R5A3groups together represent a C1 to C3 alkyl group bridging ring A, or together represent a phenyl group fused to ring A; and each other group of the R5A1, R5A2, and R5A3groups is independently absent, H, or an oxo group.

37. The PARP1 inhibitor compound for use according to claim 35, wherein each R5A1, R5A2, and R5A3is independently H or absent; optionally wherein each R5A1, R5A2, and R5A3is H.

38. The PARP1 inhibitor compound for use according to any of claims 35 to 37, wherein ring A has a structure of:wherein: m is 1 or 2; n is 1 or 2; each R5A2and R5A3independently is absent or selected from H and a substituted or unsubstituted organic group, preferably wherein the ring A is an aliphatic ring and R5A3is H; and wherein: i) X1is C and R5A1is selected from H and a substituted or unsubstituted organic group; or ii) X1is N and R5A1is absent.

39. The PARP1 inhibitor compound for use according to claim 38, wherein each R5A2independently is absent, H, an oxo group, or forms a -CH2- group together with one other group selected from another R5A2group, R5A1, and R5A3; optionally wherein each R5A2is independently absent or H.

40. The PARP1 inhibitor compound for use according to claim 39, wherein ring A has a structure selected from: ,41. The PARP1 inhibitor compound according to claim 40, wherein ring A is:

42. The PARP1 inhibitor compound for use according to any of claims 1 to 29, wherein ring A has a structure selected from:

43. The PARP1 inhibitor compound for use according to any preceding claim, wherein Qb is a bond or -CH2-, optionally wherein Qb is a bond.

44. 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.

45. The PARP1 inhibitor compound for use according to any preceding claim, wherein: i) ring B is a 7-membered saturated heterocyclic ring, optionally a homopiperazine having a structure of:each R5Bbeing independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5Bis H; or ii) ring B is a 6-membered saturated heterocyclic ring, optionally a piperazine, further optionally a piperazine having a structure of:each R5Bbeing independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5Bis H; or iii) ring B is a 5-membered saturated heterocyclic ring, optionally an imidazolidine, further optionally an imidazolidine having a structure of:each R5Bbeing independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5Bis H; oriv) ring B is a 4-membered saturated heterocyclic ring, optionally having a structure of:each R5Bbeing independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5Bis H.

46. The PARP1 inhibitor compound for use according to claim 45, wherein ring B is selected from:

47. The PARP1 inhibitor compound for use according to claim 46, wherein ring B has a structure of:

48. The PARP1 inhibitor compound for use according to claim 45, wherein: i) ring B is an azepane, optionally having a structure of:each R5Bbeing independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5Bis H; orii) ring B is a piperidine, optionally having a structure of:each R5Bbeing independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5Bis H; or iii) ring B is a pyrrolidine, optionally having a structure of:each R5Bbeing independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5Bis H.

49. The PARP1 inhibitor compound according to any of claims 1 to 44, wherein ring B has a structure of:each R5Bbeing independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5Bis H.

50. The PARP1 inhibitor compound for use according to any preceding claim, wherein Qc is a bond or -CH2-, optionally wherein Qc is a bond.

51. The PARP1 inhibitor compound for use according to any of claims 1 to 46, wherein ring B is a 4-membered ring, and wherein Qc is selected from -CH2-; -O-; and -NR8-, optionally wherein R8is H or a C1 to C3 alkyl group.

52. The PARP1 inhibitor compound for use according to claim 51, wherein Qc is -O- or -NH-.

53. 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.

54. The PARP1 inhibitor compound for use according to any preceding claim, wherein each R5Cis independently absent, H, or an organic group selected from a halo group; -CN; a C1 to C3 alkyl group; and a C1 to C3 haloalkyl group; optionally wherein each R5Cis independently absent, H, or an organic group selected from -Cl, -F, and -CN.

55. The PARP1 inhibitor compound for use according to claim 54, wherein exactly one R5Cis an organic group, each other R5Cbeing absent or H.

56. The PARP1 inhibitor compound for use according to any of claims 53 to 55, 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;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.

57. The PARP1 inhibitor compound for use according to claim 56, wherein ring C has a structure selected from:

58. The PARP1 inhibitor compound for use according to any preceding claim, wherein ring C has a structure of:wherein: each XCis independently selected from C and N; and when an XCis N, the corresponding R5COor R5CMgroup is absent; and when an XCis C, the corresponding R5COor R5CMgroup is H or an organic group selected from a halo group; -CN; a C1 or C2 alkyl group; and a C1 or C2 haloalkyl group.

59. The PARP1 inhibitor compound for use according to claim 58, wherein when an XCis C, the corresponding R5COor R5CMgroup is H or an organic group selected from H, -Cl, -F, and -CN.

60. The PARP1 inhibitor compound for use according to claim 58 or claim 59, wherein no more than two XCatoms are N.

61. The PARP1 inhibitor compound for use according to any of claims 58 to 60, wherein exactly one group selected from the R5COand R5CMgroups is an organic group.

62. The PARP1 inhibitor compound for use according to any of claims 58 to 61, wherein ring C has a structure of:wherein: R5C2ois selected from H and a halogen; and i) X2CMis C and R5C2Mis H; or ii) X2CMis N and R5C2Mis absent.

63. The PARP1 inhibitor compound for use according to claim 62, wherein R5C2ois a halogen, optionally wherein R5C2ois F.

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

65. The PARP1 inhibitor compound for use according to claim 56, wherein ring C is:

66. The PARP1 inhibitor compound for use according to any preceding claim, 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 orunsubstituted organic group, optionally wherein R51and R52are each independently selectedfrom H, a halogen, C1 to C3 alkyl, and C1 to C3 haloalkyl.

67. The PARP1 inhibitor compound for use according to claim 66, 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.

68. The PARP1 inhibitor compound for use according to claim 67, wherein R6is selected from:or wherein R6is selected from:or wherein R6is selected from:

69. The PARP1 inhibitor compound for use according to claim 68, wherein R6is CONHMe.

70. The PARP1 inhibitor compound for use according to claim 68, wherein R6is.

71. The PARP1 inhibitor compound for use according to any of claims 1 to 65, 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.

72. The PARP1 inhibitor compound for use according to claim 71, wherein R6is selected from:

73. The PARP1 inhibitor compound for use according to claim 66, wherein R6is H or selected from -F, -Cl, -CN, -CONH2, -CONHMe, -CONHEt, -CONMe2, -CONHCOMe, -CONHCH2- CH2OMe, -CONH-CH2-CH2F, -CONH-CH2-CF3, -CONH-CH2-CHF2, -OCHF2, -NHCOMe, -NHSO2Me,- ,74. The PARP1 inhibitor compound according to claim 73, wherein R6is selected from -H, -F, -Cl, and -CN.

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

76. The PARP1 inhibitor compound for use according to any of claims 1 to 57, wherein R6and one R5Cgroup together form a ring.

77. The PARP1 inhibitor compound for use according to any preceding claim, having a structure of:Z1and Z2are each independently selected from C and N; when Z1is N: R2is absent; when Z1is C: R2is H; when Z2is N: R3is absent; when Z2is C: R3is H; each XCis independently selected from C and N; and when an XCis N, the corresponding R5COor R5CMgroup is absent; and when an XCis C, the corresponding R5COor R5CMgroup is H or an organic group selected from a halo group, -CN, a C1 or C2 alkyl group, and a C1 or C2 haloalkyl group; two R5Agroups together represent a -CH2- group, and each other R5Agroup is H; or each R5Agroup is H.

78. The PARP1 inhibitor compound for use according to any of claims 1 to 20, wherein group L is selected from:

79. The PARP1 inhibitor compound for use according to claim 78, wherein group L is selected from:

80. The PARP1 inhibitor compound for use according to claim 1, wherein the compound has a structure selected from:

81. The PARP1 inhibitor compound for use according to any preceding claim, wherein when one or more of R1, R2, R3, R4, R5A(e.g., R5A1, R5A2, R5A3), R5B, R5C, R6, R7, R51, R52, R53is 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-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, -CH2Cl, -CH2Br, -CH2I, -CHF2, -CF3, -CCl3-CBr3, -CI3, -CH2CH2F, -CH2CF3, -CH2CCl3, -CH2CBr3, and -CH2CI3); NH2or a substituted or unsubstituted linear or branched primary secondary or tertiary C1-C6amine 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-C6carboxylic 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-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-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 / or a 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.

82. The PARP1 inhibitor compound for use according to any preceding claim, wherein each of R5A(e.g., R5A1, R5A2, R5A3), R5B, and R5Cis 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-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 -NH2group,a substituted or unsubstituted C1-C6amino group, and a substituted or unsubstituted C1-C6alkoxy 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-.

83. The PARP1 inhibitor compound for use according to any preceding claim, wherein at least one of Qa, Qb, and Qc is:wherein t + u is at least 1; and wherein R7is selected from H, a halogen (such as –F, -Cl, -Br, and –I, preferably -F), asubstituted or unsubstituted C1-C6alkyl group, a substituted or unsubstituted linear orbranched C1-C6halogenated alkyl group (preferably CF3), an -NH2group or a substituted or unsubstituted C1-C6amino group, an -OH group or a substituted or unsubstituted linear or branched C1-C6alcohol group and a substituted or unsubstituted C1-C6alkoxy group.

84. The PARP1 inhibitor compound for use according to claim 83, wherein R7is selected from: H; a halogen, optionally F; a substituted or unsubstituted C1-C6alkyl group; or a substituted or unsubstituted linear or branched C1-C6halogenated alkyl group.

85. The PARP1 inhibitor compound for use according to any preceding claim, wherein at least one of Qa, Qb and Qc has 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-C8alkyl 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-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 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).

86. The PARP1 inhibitor compound for use according to claim 85, 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.

87. 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.

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

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

90. The PARP1 inhibitor compound for use according to claim 89, wherein the cancer is selected from: a cancer of the eye, brain (such as gliomas, glioblastomas, medulloblastomas, craniopharyngioma, ependymoma, and astrocytoma), spinal cord, kidney, mouth, lip, throat, oral cavity, nasal cavity, small intestine, colon, parathyroid gland, gall bladder, head and neck, breast, bone, bile duct, cervix, heart, hypopharyngeal gland, lung, bronchus, liver, skin, ureter, urethra, testicles, vagina, anus, laryngeal gland, ovary, thyroid, oesophagus, nasopharyngeal gland, pituitary gland, salivary gland, prostate, pancreas, adrenal glands; an endometrial cancer, oral cancer, melanoma, neuroblastoma, gastric cancer, an angiomatosis, a hemangioblastoma, a pheochromocytoma, a pancreatic cyst, a renal cell carcinoma, Wilms’tumour, squamous cell carcinoma, sarcoma, osteosarcoma, Kaposi sarcoma, rhabdomyosarcoma, hepatocellular carcinoma, PTEN Hamartoma-Tumor Syndromes (PHTS) (such as Lhermitte-Duclos disease, Cowden syndrome, Proteus syndrome, and Proteus-like syndrome), leukaemias and lymphomas (such as acute lymphoblastic leukaemia, chronic lymphocytic leukaemia, acute myelogenous leukaemia, chronic myelogenous leukaemia, hairy cell leukaemia, T-cell prolymphocytic leukaemia (T-PLL), large granular lymphocytic leukaemia, adult T-cell leukaemia, juvenile myelomonocytic leukaemia, Hodgkin lymphoma, non-Hodgkin lymphoma, mantle lymphoma, follicular lymphoma, primary effusion lymphoma, AIDS-related lymphoma, diffuse B cell lymphoma, Burkitt lymphoma, cutaneous T-cell lymphoma, nasopharyngeal and gastrointestinal cancers; optionally wherein the cancer is a cancer of the brain or spinal cord.

91. The PARP1 inhibitor compound for use according to claim 89 or claim 90, wherein the cancer is deficient in a DNA damage response repair pathway, such as Homologous Recombination dependent DNA Double Strand Break DNA repair activity.

92. The PARP1 inhibitor compound for use according to any of claims 89 to 91, wherein the cancer is deficient in BRCA1 and / or BRCA2 function.

93. The PARP1 inhibitor compound for use according to any of claims 89 to 92, 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.

94. The PARP1 inhibitor compound for use according to claim 93, 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.

95. A pharmaceutical composition comprising a PARP1 inhibitor compound as defined in any of claims 1 to 88.

96. A pharmaceutical composition according to claim 95, 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.

97. The pharmaceutical composition according to claim 95 or claim 96, 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.

98. The pharmaceutical composition according to claim 97, 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.

99. The pharmaceutical composition according to any of claims 95 to 98, for use in treating a cancer.

100. A pharmaceutical kit for treating a cancer, which pharmaceutical kit comprises: a) a PARP1 inhibitor compound as defined in any of claims 1 to 88; and b) a further agent for treating cancer; wherein the compound and the further agent are suitable for administration simultaneously, sequentially or separately; and 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, 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.

101. 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.

102. The method according to claim 101, wherein the patient is an animal, preferably a mammal, optionally a human, canine, equine or feline; and preferably a human.

103. A compound selected from:

104. The compound according to claim 103, 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.

105. A method of synthesising a PARP1 inhibitor compound as defined in any of claims 1 to 88, which method comprises conducting a reaction between: i) a first reactant comprising ring E bearing a first portion of group L and ii) a second reactant comprising a remainder of group L, to form the PARP1 inhibitor compound.

106. A method according to claim 105, wherein the first reactant comprises ring E and ring A, and the second reactant comprises a Qb precursor bearing a reactive group, which method comprises joining ring A to the Qb precursor.

107. A method according to claim 106, wherein the reactive group of the Qb precursor comprises a carbonyl group, an alkyl halide, or an alkyl sulfonate.

108. A method according to any of claims 105 to 107, wherein the reaction comprises alkylation, reductive amination or amide formation so as to form group L.

109. A method according to claim 108, wherein the first reactant comprises ring E, ring A, Qa, and ring B, and the second reactant comprises a ring C derivative bearing a leaving group such as a halide or sulfonate.

110. A method according to claim 106 or claim 107, wherein the reaction comprises a nucleophilic substitution reaction, such as a nucleophilic aromatic substitution reaction, so as to form group L.

111. The method according to any of claims 105 to 110, which method is to synthesise a PARP1 inhibitor compound wherein L is a group having a structure of:wherein the first reactant has a structure of:R9being a protecting group, optionally a C1 to C6 alkyl group, and preferably a methyl group; wherein the second reactant has a structure of:wherein conducting the reaction comprises: i) coupling the first reagent and the second reagent using a reducing agent in the presence of an acid to obtain an intermediate product having a structure of: ;ii) subsequently deprotecting ring E’ to form the PARP1 inhibitor compound.

112. The method according to claim 111, wherein rings A, B’, and B are all saturated rings.

113. The method according to claim 112, wherein the X1 of rings B and B’ is N.

114. The method according to any of claims 111 to 113, 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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