Parp1 inhibitor compounds

Abstract

A PARP1 inhibitor compound has a structure of: Formul (i) A dotted line represents a single bond or a double bond, y is 0, 1, or 2. Each XD is selected from C, O, and N. No more than one XD is O. When an XD is O or N, ring D is non-aromatic. Each R1 is absent, H, or an organic group. Each R4 is absent; H; a halogen; C(R9)o-3; OR9; or S(R9)1-5. Each R9 is H or an organic group. R2 and R3 are each H or an organic group. L is: Formul (ii) Each X1, X3, X4 and X5 is C or N. Each X2 is C, N, O, or S. n+m and r+s are 2 to 5. p and q are each 1 to 3. p+q is 2 to 5. Each R5A, R5B, R5C, and R6 is absent, H, or an organic group. Q1 and Q2 are each independently a bond or linking group.

Description

[0001] PARP1 Inhibitor Compounds

[0002] Technical Field

[0003] 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.

[0004] Background

[0005] 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).

[0006] 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.

[0007] Inhibition of PARP enzymes has been utilised as a strategy to selectively kill cancer cells that harbour genetic defects in complementary DNA damage repair pathways (Farmer, H. et al. Nature. 2005; 434: 917-921). This synthetic lethality approach has been demonstrated successfully in tumours with epigenetic modifications or deleterious mutations in BRCA1 and BRCA2, two functionally redundant tumour suppressor proteins involved in DNA doublestrand break (DSB) repair by homologous recombination (HR) (Lord, CJ. and Ashworth, A. Science. 2017; 355: 1152-1158). Such tumours with HR deficiency (HRD) are dependent on PARP function for survival - following PARP inhibition in these tumours, DSB breaks will be processed by alternative error-prone repair pathways leading to genomic instability and cancer cell death.

[0008] 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).

[0009] This strategy has led to the successful approval of several PARP inhibitors for the treatment of cancers with HRD, such as in BRCAl / 2-mutated breast, ovarian and prostate cancer, as well as in ovarian and prostate cancer harbouring genomic consequences of HRD, and ovarian cancer in the maintenance setting where platinum sensitivity acts as a surrogate for HRD (Fong, PC. et al. N. Engl. J. Med. 2009; 361: 123-134).

[0010] It has recently been shown that genomic instability, in the form of unrepaired DNA doublestrand breaks or micronuclei disruption can trigger innate immune system activation via the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS), leading to generation of cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) and induction of dimerization of stimulator of interferon genes (STING). STING subsequently translocates from the endoplasmic reticulum to the Golgi where it recruits and activates TANK-binding kinase 1 (TBK1). TBK1 phosphorylates interferon regulatory transcription factor 3 (IRF3) which drives the production of type I interferons and supports the induction of an adaptive immune response (Zhu, Y. et al. Mol. Cancer. 2019, 18: 152).

[0011] 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).

[0012] 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).

[0013] 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).

[0014] First-generation PARP inhibitors generally demonstrate non-selective activity at PARP1 and 2. Haematological toxicities such as anaemia, neutropenia and thrombocytopenia are associated with clinical use of these molecules which restricts their use in combination with cytotoxic chemotherapies and other targeted agents due to dose-limiting cytopenias (LaFargue, CJ. et al. Lancet Oncol. 2019, 20, el5-e28). Evidence from pre-clinical mouse studies strongly suggests that PARP2 inhibition is a major driver of these haematological toxicities, with PARP2 being particularly linked to erythrogenesis in mice (Farres, J. et al. Blood. 2013; 122: 44-54). In addition, PARP2 function has been shown to be dispensable for anti-tumour activity in HRD mouse cancer models (Ronson, G E. 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.

[0015] To date, two PARPl-selective inhibitors, AZD5305 and AZD9574, have entered clinical development. AZD5305 was described as a potent PARP1 inhibitor and trapper with 500-fold selectivity over PARP2 and less off-target activity against secondary pharmacology targets than first-generation PARP inhibitors (Johannes, JW. et al. J. Med. 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 (llluzzi, G. et al. Clin. Cancer Res. 2022; CCR-22-0301).

[0016] 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 fortreating a cancer. It is also an aim to provide methods of synthesis of the compounds.

[0017] Summary

[0018] In one aspect, the present invention provides a PARP1 inhibitor compound having a structure of: wherein: a dotted line represents a bond selected from a single bond and a double bond; y is 0, 1, or 2; ring D is aromatic or non-aromatic; each XDis independently selected from C, O, and N; with the provisos that: no more than one XDis O; and when an XDis O or N, ring D is non-aromatic; each R1is independently absent, or present and selected from H and a substituted or unsubstituted organic group; each R4is independently absent or selected from:

[0019] H; a halogen; C(R9)i, wherein i is an integer in the range 1 to 3;

[0020] OR9; and

[0021] S(R9)j, where j is an integer in the range 1 to 5; wherein each R9is independently selected from H and a substituted or unsubstituted organic group; R2and R3are each independently selected from H and a substituted or unsubstituted organic group; and

[0022] L is a group having a structure of: wherein:

[0023] X1, X3, X4and X5are each independently selected from C and N; each X2is independently selected from C, N, O, and S; n is 0, 1, 2, 3, 4, or 5; m is 0, 1, 2, 3, 4, or 5, with the proviso that n + m is in the range 1 to 5 (optionally

[0024] 2 to 5); p is 1, 2 or 3; q is 1, 2 or 3, with the proviso that p + q is in the range 2 to 5; r is 0, 1, 2, 3, 4, or 5; s is 0, 1, 2, 3, 4, or 5, with the proviso that r + s is in the range 2 to 5; each R5A, R5B, and R5Cis independently absent or selected from H and a substituted or unsubstituted organic group; R6is absent or selected from H and a substituted or unsubstituted organic group; and Q1and Q2are each independently a bond or a linking group having a structure selected from: wherein: t is 0, 1, 2, 3, 4 or 5; u is 0, 1, 2, 3, 4 and 5, with the proviso that t + u is in the range 0 to 6; and each R7and R8is independently selected from H and a substituted or unsubstituted organic group.

[0025] Optionally, Q1is a bond and m + n is in the range 2 to 5.

[0026] The PARP1 inhibitor compound may be for use in medicine. For instance, the PARP1 inhibitor compound may be for use in treating a cancer.

[0027] Another aspect of the invention provides a pharmaceutical composition comprising a PARP1 inhibitor compound as defined herein.

[0028] A further aspect of the invention provides a pharmaceutical kit for treating a cancer. The pharmaceutical kit comprises a PARP1 inhibitor compound as defined herein, and a further agent for treating cancer. The PARP1 inhibitor compound and the further agent are suitable for administration simultaneously, sequentially or separately. Still 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 a PARP1 inhibitor compound, a composition or a kit as defined herein.

[0029] Another aspect of the invention provides a method of synthesising a PARP1 inhibitor compound as defined herein. The method comprises conducting a reaction between: i) a first reactant comprising rings D and E and bearing a first portion of group L, and ii) a second reactant comprising a remainder of group L, to form the PARP1 inhibitor compound.

[0030] 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.

[0031] Detailed Description

[0032] General Definitions

[0033] 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.

[0034] It will be appreciated that some compounds disclosed herein may be ionisable, i.e. some compounds may be weak acids, weak bases, or ampholytes. Representations of the free forms of ionisable compounds are intended to encompass the corresponding ionised forms, lonisable compounds may be in free form, or in the form of a pharmaceutically-acceptable salt. A compound is considered to be a PARP1 inhibitor if its presence is capable of preventing or reducing the ability of immobilised PARP1 to undergo auto-poly-ADP ribosylation (AutoPARylation) following incubation with biotinylated-NAD+ as compared to the same process in its absence. Typically, the compound is considered to be a PARP1 inhibitor if it has an IC50 < 10 pM in a suitable assay. A suitable assay may be conducted using 2 nM PARP1, 2 pM biotin-NAD+ assay solution in 20 mM HEPES (pH 7.5), 100 mM NaCI, 2 mM DTT, 0.1 % BSA (w / v), 0.02 % Tween (v / v) assay buffer. PARylation may take place for 2 h at room temperature and may be detected using a dissociation-enhanced lanthanide fluorescence immunoassay (DELFIA) readout. A particularly suitable assay is described in the Examples below. Preferably, the compound has an IC50 < 1 pM, more preferably < 100 nM and most preferably < 10 nM in the PARP1 inhibitor assay.

[0035] A compound is considered to be a selective PARP1 inhibitor if its presence is capable of displacing or reducing the ability of a high affinity Cy5 fluorescent dye-labelled chemical probe to bind to PARP1 whilst displacing the same chemical probe at PARP2 with at least 10-fold weaker activity. Typically, the compound is considered to be a selective PARP1 inhibitor if it has an IC50 < 10 pM in this assay at PARP1 with at least 10-fold selectivity preference over PARP2. A suitable such assay may be conducted for 1 h at room temperature using 10 nM PARP1 or PARP2, Tb-cryptate antibody and PARP1 / 2 binding probe in 20 mM HEPES (pH 7.5), 100 mM NaCI, 2 mM DTT, 0.1 % BSA (w / v), 0.02 % Tween (v / v) assay buffer. Probe binding displacement may be detected using homogeneous time-resolved fluorescence. A particularly suitable assay is described in the Examples below. Preferably the selectivity preference of PARP1 over PARP2 is at least 50-fold, more preferably at least 100-fold.

[0036] A compound is also considered to be a selective PARP1 inhibitor if it has an IC50 < 10 pM at PARP1 with at least 10-fold selectivity preference over PARP2 in NanoBRET assays demonstrating cellular target engagement. These assays are based on bioluminescence resonance energy transfer (BRET) between a Nano-luc-tagged protein (e.g. PARP1 or PARP2) and a fluorescent group on a high affinity NAD+ competitive binding probe. Such cellular probe displacement assays can be utilised to measure inhibitor affinities and selectivity ratios at PARP1 and 2. A particularly suitable assay is described in the Examples below. Preferably the selectivity preference of PARP1 over PARP2 is at least 50-fold, more preferably at least 100-fold.

[0037] The expression "substituted or unsubstituted organic group" is used herein as a synonym for "substituent". Example organic groups are discussed in more detail hereinbelow.

[0038] 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.

[0039] 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.

[0040] 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.

[0041] Where stereochemistry is depicted, the stereochemistry shown is relative stereochemistry rather than absolute stereochemistry.

[0042] The term "aliphatic ring" is used herein in the broad sense of a non-aromatic ring. An aliphatic ring may be carbocylic or heterocyclic, and may be substituted or unsubstituted.

[0043] Compound numbering

[0044] 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.

[0045] The suffix 'rac' in a compound number denotes a racemic mixture.

[0046] 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 referto 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.

[0047] 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.

[0048] 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.

[0049] Discussion

[0050] Provided herein are PARP1 inhibitor compounds having a structure of: a dotted line represents a bond selected from a single bond and a double bond; y is 0, 1, or 2; ring D is aromatic or non-aromatic; each XDis independently selected from C, O, and N; with the provisos that: no more than one XDis O; and when an XDis O or N, ring D is non-aromatic; each R1is independently absent, or present and selected from H and a substituted or unsubstituted organic group; each R4is independently absent or selected from:

[0051] H; a halogen;

[0052] C(R9)i, wherein i is an integer in the range 1 to 3;

[0053] OR9; and

[0054] S(R9)j, where j is an integer in the range 1 to 5; wherein each R9is independently selected from H and a substituted or unsubstituted organic group;

[0055] R2and R3are each independently selected from H and a substituted or unsubstituted organic group; and

[0056] X1, X3, X4and X5are each independently selected from C and N; each X2is independently selected from C, N, O, and S; n is 0, 1, 2, 3, 4, or 5; m is 0, 1, 2, 3, 4, or 5, with the proviso that n + m is in the range 1 to 5; p is 1, 2 or 3; q is 1, 2 or 3, with the proviso that p + q is in the range 2 to 5; r is 0, 1, 2, 3, 4, or 5; s is 0, 1, 2, 3, 4, or 5, with the proviso that r + s is in the range 2 to 5; each R5A, R5B, and R5Cis independently absent or selected from H and a substituted or unsubstituted organic group;

[0057] R6is absent or selected from H and a substituted or unsubstituted organic group; and Q1and Q2are each independently a bond or a linking group having a structure selected from: wherein: t is 0, 1, 2, 3, 4 or 5; u is 0, 1, 2, 3, 4 and 5, with the proviso that t + u is in the range 0 to 6; and each R7and R8is independently selected from H and a substituted or unsubstituted organic group.

[0058] Optionally, Q1is a bond and m+n is in the range 2 to 5.

[0059] The PARP1 inhibitor compounds provided herein may be selective for PARP1 over PARP2.

[0060] Various aspects of the above general structure will now be discussed in more detail.

[0061] Stereochemistry

[0062] Some of the PARP1 inhibitor compounds provided herein include one or more chiral centres. Such compounds may be provided in the form of an isolated enantiomer; a mixture of two or more enantiomers; a mixture of two or more diastereomers or epimers; or a racemic mixture.

[0063] Some PARP1 inhibitor compounds may be capable of tautomerism. Such compounds may be provided in the form of any possible tautomer.

[0064] When ring A of the PARP1 inhibitor compounds is a cycloalkane, the compound may exhibit cis-trans isomerism. In the context of the present disclosure, unless expressly stated otherwise, a "cis" compound has a cis configuration across ring A:

[0065] And a "trans" compound has a trans configuration across ring A:

[0066] Substituents - general

[0067] The expression "R5group" refers generically 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. The expression "X atom" refers generically to any variable ring atom (XD, X1, X2, X3, X4, X5).

[0068] In the compounds provided herein, R6and various ones of the R1, R4, and R5groups may be absent. Dotted lines in the structural formulae presented herein representing covalent bonds of any non-zero order. As will be appreciated, the number of ring bonds and the number of substituents are selected such that the atoms of the rings 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).

[0069] When an X atom is N, that atom most preferably has a valency of 3. Compounds containing tetravalent N atoms are also contemplated. Preferably, the PARP1 inhibitor compound includes at most one tetravalent N, and more preferably no tetravalent N atoms.

[0070] The PARP1 inhibitor compounds are typically free of 0-0 bonds. When an X atom is O, its two immediately adjacent ring atoms are not O.

[0071] When an X atom is S, its corresponding Rgroups may both be absent or selected from =0 and =NR10, where R10is H or a substituted or unsubstituted organic group, preferably a Cl to C3 alkyl group.

[0072] Each R1, R4and R5group may independently be absent or present, and may be the same or different.

[0073] The substituents (i.e. R groups; R1, R2, 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.

[0074] 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 sterica lly 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.

[0075] A single R1, R4, R5or R6group on an atom, or two R1 / R4 / R5groups on the same atom, may form a group which is double bonded to that atom. Accordingly, an R1, R4, R5or R6group, or two R1 / R4 / R5groups attached to the same atom, may together form a =0 group, or a =C( R' h group (wherein each R' group is the same or different and is H or an organic group, preferably H or a straight or branched Ci-Ce alkyl 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')2 group. Thus in some cases an X2group which is C may bear a =0 group.

[0076] For example, a pair of R5Agroups attached to the same atom may together represent a carbonyl group. Likewise, a pair of R4 groups attached to the same atom may together represent a carbonyl group.

[0077] 'Substituent' and 'organic group' may have any of the following meanings.

[0078] The organic group may comprise any one or more atoms from any of groups IIIA, IVA, VA, VIA or VI I A 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).

[0079] 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.

[0080] 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.

[0081] When the hydrocarbon comprises a cyclic group it may comprise an aromatic ring, a nonaromatic 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-tetra hydropyran, 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 1 / 7-pyrrole, 2 / 7-pyrrole and 3 / 7-pyrrole.

[0082] 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.

[0083] 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 111 A, IVA, VA, VIA or VI I A 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.

[0084] In addition, any substituent may comprise a combination of two or more of the substituents and / or functional groups defined herein.

[0085] Where it is said that a substituent (R1, R2, R3, R4, R5A(e.g. R5A1, R5A2, R5A3), R5B, R5C(e.g., R5C1), R6, R7, R8, R51, and / or R52) is a substituted or unsubstituted organic group, the or each substituted or unsubstituted organic group may in particular be independently selected from: deuterium; a halogen (such as -F, -Cl, -Br and -I); a nitrile group; a substituted or unsubstituted linear or branched Ci-Ce alkyl group

[0086] (such as Me, Et, Pr, i-Pr, n-Bu, i-Bu, t-Bu, pentyl and hexyl); a substituted or unsubstituted linear or branched Ci-Ce a Ikyl-a ryl group

[0087] (such as -CH2Ph, -CH2(2,3 or 4)F-Ph, -CH2(2,3 or 4)CI-Ph, -CH2(2,3 or 4)Br-Ph, -CH2(2,3 or 4)l-Ph, -CH2CH2Ph, -CH2CH2CH2Ph,

[0088] -CH2CH2CH2CH2Ph, -CH2CH2CH2CH2CH2Ph, and -CH2CH2CH2CH2CH2CH2Ph); a substituted or unsubstituted linear or branched Ci-Ce halogenated alkyl group (such as -CH2F, -CH2CI, -CH2Br, -CH2I, -CHF2, -CF3, -CCI3-CBr3, -CCI3, -CH2CH2F, -CH2CF3, -CH2CCI3, -CH2CBr3, and -CH2CH2CCI3);

[0089] NH2or a substituted or unsubstituted linear or branched primary secondary or tertiary Ci-Ce amine group

[0090] (such as -NMeH, -NMe2, -NEtH, -NEtMe, -NEt2, -NPrH, -NPrMe, -NPrEt, -NPr2, - NBuH, -NBuMe, -NBuEt, -CH2-NH2, -CH2-NMeH, -CH2-NMe2, -CH2-NEtH, - CH2-NEtMe,

[0091] -CH2-NEt2, -CH2-NPrH, -CH2- NPrMe, and -CH2-NPrEt); a substituted or unsubstituted amino-aryl group

[0092] (such as -NH-Ph, -NH-(2,3 or 4)F-Ph, -NH-(2,3 or 4)CI-Ph, -NH-(2,3 or 4)Br-Ph,

[0093] -NH-(2,3 or 4)I-Ph, -NH-(2,3 or 4)Me-Ph, -NH-(2,3 or 4)Et-Ph,

[0094] -NH-(2,3 or 4)Pr-Ph, -NH-(2,3 or 4)Bu-Ph, NH-(2,3 or 4)OMe-Ph,

[0095] -NH-(2,3 or 4)OEt-Ph, -NH-(2,3 or 4)OPr-Ph, -NH-(2,3 or 4)OBu-Ph,

[0096] -NH-2,(3,4,5 or 6)F2-Ph, -NH-2,(3,4,5 or 6)CI2-Ph, -NH-2,(3,4,5 or 6)Br2-Ph,

[0097] -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

[0098] (such as pyrrolidin-l-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-l-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-Cs alkyl group

[0099] (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl); an -OH group; a substituted or unsubstituted linear or branched Ci-Ce alcohol group

[0100] (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 Ci-Ce carboxylic acid group (such as -COOH, -CH2COOH, -CH2CH2COOH,

[0101] -CH2CH2CH2COOH, -CH2CH2CH2CH2COOH, and -CH2CH2CH2CH2CH2COOH); a substituted or unsubstituted linear or branched carbonyl group

[0102] (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)-l,3-epoxypropan-2-yl; -(CO)NH2, -(CO)NHMe, -(CO)NMe2, -(CO)NHEt, -(CO)NEt2,

[0103] -(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 Ci-Ce 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 Ci-Ce amide group

[0104] (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-C7 amino 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-C7 alkoxy 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, -OCH2CI, -OCHCI2, -OCCI3, -O-Ph, -O-CH2-Ph, -O-CH2-(2,3 or 4)-F-Ph, -O-CH2-(2,3 or 4)-CI-Ph, -CH2OMe, -CH2OEt, -CH2OPr, -CH2OBU, -CH2CH2OMe, -CH2CH2CH2OMe, -CH2CH2CH2CH2OMe, and -CH2CH2CH2CH2CH2OMe); a substituted or unsubstituted linear or branched aminoalkoxy group

[0105] (such as -OCH2NH2, -OCH2NHMe, -OCH2NMe2, -OCH2NHEt, -OCH2NEt2, -OCH2CH2NH2, -OCH2CH2NHMe, -OCH2CH2NMe2, -OCH2CH2NHEt, and -OCH2CH2NEt2); a substituted or unsubstituted sulfonyl group

[0106] (such as -SO2Me, -SO2Et, -SO2Pr, -SO2iPr, -SO2Ph, -SO2-(2,3 or 4)-F-Ph, -SO2-cyclopropyl, -SO2CH2CH2OCH3, -SO2NH2, -SO2NHMe, -SO2NMe2,

[0107] -SChNHEt, -SO2NEt2, -SO2-pyrrolidine-N-yl,

[0108] -SO2-morpholine-N-yl, -SO2NHCH2OMe, and -SO2NHCH2CH2OI\ / le); a substituted or unsubstituted aminosulfonyl group

[0109] (such as -NHSO2Me, -NHSO2Et, - NHSO2Pr, -NHSO2iPr, -NHSO2Ph, -NHSO2-(2,3 or 4)-F-Ph, -NHSO2-cyclopropyl, -NHSO2CH2CH2OCH3); a substituted or unsubstituted aromatic group

[0110] (such as Ph-, 2-F-Ph-, 3-F-Ph-, 4-F-Ph-, 2-CI-Ph-, 3-CI-Ph-, 4-CI-Ph-, 2-Br-Ph-,

[0111] 3-Br-Ph-, 4-Br-Ph-, 2-l-Ph-, 3-l-Ph, 4-l-Ph-, 2, (3, 4, 5 or 6)-F2-Ph-,

[0112] 2, (3,4,5 or 6)-CI2-Ph-, 2, (3,4,5 or 6)-Br2-Ph-, 2, (3,4,5 or 6)-l2-Ph-,

[0113] 2, (3,4,5 or 6)-Me2-Ph-, 2, (3, 4, 5 or 6)-Et2-Ph-, 2, (3, 4, 5 or 6)-Pr2-Ph-,

[0114] 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-,

[0115] 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-,

[0116] 3,(4 or 5)-F2-Ph-, 3,(4 or 5)-CI2-Ph-, 3,(4 or 5)-Br2-Ph-, 3,(4 or 5)-l2-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-,

[0117] 3,(4 or 5)-(MeO)2-Ph-, 3,(4 or 5)-(CF3)2-Ph-, 2-Me-Ph-, 3-Me-Ph-, 4-Me-Ph-,

[0118] 2-Et-Ph-, 3-Et-Ph-, 4-Et-Ph-, 2-Pr-Ph-, 3-Pr-Ph-, 4-Pr-Ph-, 2-Bu-Ph-, 3-Bu-Ph-,

[0119] 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-,

[0120] 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

[0121] (such as pyrrole-l-yl, pyrrole-2-yl, pyrrole-3-yl, pyrazole-l-yl, pyrazole-3-yl, pyrazole-4-yl, pyrazole-5-yl, imidazole-l-yl, imidazole-2-yl, imidazole-4-yl, imidazole-5-yl, 1,2,3-triazole-l-yl, l,2,3-triazole-4-yl, l,2,3-triazole-5-yl, 1,2,4-triazole-l-yl, l,2,4-triazole-3-yl, l,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-l-yl, pyrrolidine-2-yl, pyrrolidine-3-yl, piperidine-l-yl, piperidine-2-yl, piperidine-3-yl, piperidine-4-yl, 2-azapiperidine-l-yl, 2-azapiperidine-3-yl, 2-azapiperidine-4-yl, 3-azapiperidine-l-yl, 3-azapiperidine-2-yl,

[0122] 3-azapiperidine-4-yl, 3-azapiperidine-5-yl, piperazine-l-yl, piperazine-2-yl, furan-2-yl, furan-3-yl, pyran-2-yl, pyran-3-yl, pyran-4-yl, 2-azapyran-2-yl,

[0123] 2-azapyran-3-yl, 2-azapyran-4-yl, 2-azapyran-5-yl, 2-azapyran-6-yl,

[0124] 3-azapyran-2-yl, 3-azapyran-4-yl, 3-azapyran-5-yl, 3-azapyran-6-yl,

[0125] 4-azapyran-2-yl, 4-azapyran-3-yl, 4-azapyran-4-yl, 4-azapyran-5-yl,

[0126] 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,

[0127] 2-aza-tetrahydrofuran-4-yl, 2-aza-tetrahydrofuran-5-yl,

[0128] 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,

[0129] 2-aza-tetrahydropyran-5-yl, 2-aza-tetrahydropyran-6-yl,

[0130] 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,

[0131] 2-azathiopyran-6-yl, 3-azathiopyran-2-yl, 3-azathiopyran-4-yl,

[0132] 3-azathiopyran-5-yl, 3-azathiopyran-6-yl, 4-azathiopyran-2-yl,

[0133] 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, (l,3,4-oxadiazol)-2-yl, (l,3,4-oxadiazol)-5-yl, (l,2,4-oxadiazol)-3-yl, (l,2,4-oxadiazol)-5-yl; and tetrazole-l-yl, tetrazole-2-yl, tetrazole-5-yl).

[0134] With the exception of R4, pairs of substituent groups with matching identifiers may together form a ring. For example, a pair of substituent groups attached to different atoms of the same ring may be connected to form a ring. 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.

[0135] It is also contemplated that an R5Cgroup and an R6group attached to different atoms may together form a ring with ring C atoms.

[0136] Preferably, each R5group (R5A, R5B, R5C) is independently absent or selected from:

[0137] H, deuterium, a halogen (such as -F, -Cl, -Br, and -I; preferably F or Cl), a nitrile group, a Ci-Ce alkyl group, a Ci-Ce halogenated alkyl group (preferably CF3 or CHF2), a cyclopropyl group, an -OH group, a Ci-Ce alcohol group, a C1-C7 amino carbonyl group (such as -NH-CO-Me), an -NH2 group, a Ci-Ce amino group, and a Ci-Ce alkoxy group.

[0138] When a pair of R5groups forms a ring, the pair of R5groups may together represent a group selected from -CH2-, -CH2CH2-, -CH=CH-CH=CH-, or -NH-CO-NH-.

[0139] In particular, it is contemplated that two R5Agroups may together represent an alkyl group bridging ring A. Various ones of the substituent groups may be bonded to a nitrogen atom. For example, when Q1or Q2is:

[0140] R8is bonded to a nitrogen. In some instances, an R1, R4, or R5Aor R5Bgroup may be attached to a ring atom which is N; and R3is attached to an N. The preferred substituents for N atoms are:

[0141] H; a substituted or unsubstituted linear or branched Ci-Ce alkyl group (such as Me, Et, Pr, i-Pr, n-Bu, i-Bu, t-Bu, pentyl and hexyl); a substituted or unsubstituted linear or branched Ci-Ce a Ikyl-a ryl group

[0142] (such as -CH2Ph, -CH2(2,3 or 4)F-Ph, -CH2(2,3 or 4)CI-Ph, -CH2(2,3 or 4)Br-Ph, -CH2(2,3 or 4)l-Ph, -CH2CH2Ph, -CH2CH2CH2Ph,

[0143] -CH2CH2CH2CH2Ph, -CH2CH2CH2CH2CH2Ph, and -CH2CH2CH2CH2CH2CH2Ph); a substituted or unsubstituted linear or branched Ci-Ce halogenated alkyl group (such as -CH2F, -CF3, -CH2CH2F and -CH2CF3); a substituted or unsubstituted cyclic amine or amido group

[0144] (such as pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, 2-keto-pyrrolidinyl,

[0145] 3-keto-pyrrolidinyl, 2-keto-piperidinyl, 3-keto-piperidinyl, and

[0146] 4-keto-piperidinyl); a substituted or unsubstituted cyclic C3-Cs alkyl group

[0147] (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl); a substituted or unsubstituted linear or branched C2-Ce alcohol group (such as -CH2CH2OH, -CH(CH3)CH2OH, -C(CH3)2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, -CH(CH3)CH2CH2OH, -CH(CH3)CH(CH3)OH, -CH(CH2CH3)CH2OH, -C(CH3)2CH2OH, -CH2CH2CH2CH2CH2OH, and -CH2CH2CH2CH2CH2CH2OH); a substituted or unsubstituted linear or branched C2-C6 carboxylic acid group

[0148] (such as -CH2COOH, -CH2CH2COOH, -CH2CH2CH2COOH, -CH2CH2CH2CH2COOH, and -CH2CH2CH2CH2CH2COOH); a substituted or unsubstituted linear or branched carbonyl group

[0149] (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)-l,3-epoxypropan-2-y I; -(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 Ci-Ce 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 Ci-Ce amide group

[0150] (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

[0151] (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,

[0152] -SO2-morpholine-N-yl, -SO2NHCH2OMe, and -SO2NHCH2CH2OI\ / le); a substituted or unsubstituted aromatic group

[0153] (such as Ph-, 2-F-Ph-, 3-F-Ph-, 4-F-Ph-, 2-CI-Ph-, 3-CI-Ph-, 4-CI-Ph-, 2-Br-Ph-, 3-Br-Ph-, 4-Br-Ph-, 2-l-Ph-, 3-l-Ph, 4-l-Ph-, 2, (3, 4, 5 or 6)-F2-Ph-, 2, (3,4,5 or 6)-CI2-Ph-, 2, (3,4,5 or 6)-Br2-Ph-, 2, (3,4,5 or 6)-l2-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-,

[0154] 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-,

[0155] 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-,

[0156] 3,(4 or 5)-F2-Ph-, 3,(4 or 5)-CI2-Ph-, 3,(4 or 5)-Br2-Ph-, 3,(4 or 5)-l2-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-,

[0157] 3,(4 or 5)-(MeO)2-Ph-, 3,(4 or 5)-(CF3)2-Ph-, 2-Me-Ph-, 3-Me-Ph-, 4-Me-Ph-,

[0158] 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-,

[0159] 3-CF3-Ph-, 4-CF3-Ph-, 2-CF3O-Ph-, 3-CF3O-Ph-, and 4-CF3O-Ph-); and a substituted or unsubstituted heterocyclic group

[0160] (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, l,2,3-triazole-4-yl, l,2,3-triazole-5-yl, l,2,4-triazole-3-yl, l,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,

[0161] 2-azapiperidine-3-yl, 2-azapiperidine-4-yl, 3-azapiperidine-2-yl,

[0162] 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,

[0163] 2-azapyran-5-yl, 2-azapyran-6-yl, 3-azapyran-2-yl, 3-azapyran-4-yl,

[0164] 3-azapyran-5-yl, 3-azapyran-6-yl, 4-azapyran-2-yl, 4-azapyran-3-yl,

[0165] 4-azapyran-5-yl, 4-azapyran-6-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-4-yl,

[0166] 2-aza-tetrahydrofuran-5-yl, 3-aza-tetrahydrofuran-2-yl,

[0167] 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,

[0168] 2-aza-tetrahydropyran-5-yl, 2-aza-tetrahydropyran-6-yl,

[0169] 3-aza-tetrahydropyran-2-yl, 3-aza-tetrahydropyran-4-yl,

[0170] 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,

[0171] 3-azathiopyran-6-yl, 4-azathiopyran-2-yl, 4-azathiopyran-3-yl,

[0172] 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, (l,3,4-oxadiazol)-2-yl, (l,3,4-oxadiazol)-5-yl, (l,2,4-oxadiazol)-3-yl, (l,2,4-oxadiazol)-5-yl; and tetrazole-5-yl).

[0173] Optionally, R8, or any R1, R4, or R5Aor R5Bthat is attached to a ring nitrogen, may preferably be selected from H, a substituted or unsubstituted linear or branched Ci-Ce alkyl group, and a substituted or unsubstituted linear or branched Ci-Ce halogenated alkyl group.

[0174] An R1or R4attached to a N is preferably selected from H, a Cl to C3 alkyl group, and a Cl to C3 fluoroalkyl group, such as CH2CF3.

[0175] Head group - general

[0176] The head group of the PARP1 inhibitor compound comprises rings D and E, as shown in the general formula below:

[0177] A dotted line represents a bond selected from a single bond and a double bond. Ring D may be a saturated ring, an unsaturated non-aromatic ring, or an aromatic ring. y is 0, 1, or 2. In other words, ring D may be a 5-, 6-, or 7-membered ring. In particular, ring D may be a 5-membered ring (y=0) or a 6-membered ring (y=l). Compounds having 6- membered D-rings (y=l) are particularly preferred.

[0178] Each individual XDis selected from C, O, and N. No more than one XDis O. When an XDis O or N, ring D is non-aromatic. Optionally, each XDis C.

[0179] Each R1is independently absent, H, or a substituted or unsubstituted organic group.

[0180] Each R4is independently absent or selected from:

[0181] H; a halogen;

[0182] C(R9)i, wherein i is an integer in the range 1 to 3;

[0183] OR9; and

[0184] S(R9)j, where j is an integer in the range 1 to 5.

[0185] Each R9is independently selected from H and a substituted or unsubstituted organic group.

[0186] When R4is C(R9)i and i is 1, R9may be a nitrile nitrogen,

[0187] Each R1and each R4may in particular be absent or selected from:

[0188] H; a halogen; a nitrile group; a Cl to C6 alkyl group, such as a C3 to C6 cycloalkyl group; a Cl to C6 alkoxy group; a Cl to C6 haloalkoxy group, such as -OCF3 or OCHF2; a haloalkyl group; and

[0189] R22being selected from H, a halogen, a Cl to C6 alkyl group, a C3 to C6 cycloalkyl group, a Cl to C6 alkoxy group, a Cl to C6 haloalkyl group, and each R23being independently selected from H, a halogen, a Cl to C6 linear or branched alkyl group, a Cl to C6 linear or branched aminoalkyl group, a Cl to C6 alkoxy group, a Cl to C6 haloalkoxy group, such as -OCF3 or OCHF2; and a Cl to C6 haloalkyl group.

[0190] Optionally, each R1and each R4is independently absent or selected from H; a halogen, optionally Cl or F; a Cl to C3 alkyl group, optionally a methyl group; a Cl to C3 haloalkyl group, optionally a halomethyl group such as -CH2F, -CHF2, or -CF3; a haloethyl group, such as - CH2CF3; and a nitrile group.

[0191] Further optionally, each R1and each R4is independently absent or selected from: H; Cl; F; a halomethyl group, such as CF3; and a nitrile group.

[0192] Preferably, each R1and each R4is independently absent or selected from H and F. Optionally, exactly one R1or exactly one R4is F. For example, each R4may be H, and exactly one R1may be F.

[0193] R2and R3are each independently selected from H and a substituted or unsubstituted organic group.

[0194] R2may in particular be selected from H; a halogen, optionally F or Cl; a Cl to C3 alkyl group, optionally an isopropyl group or a cyclopropyl group; a Cl to C3 haloalkyl group, optionally - CH2F, -CHF2, -CF3, -CH2CF3, or -CH2CH2F; a Cl to C3 alcohol group, optionally -CH2CH2OH; a Cl to C3 alkoxy group, optionally a methoxy group, a methoxymethyl group, or methoxyethyl group; and a Cl to C3 aminoalkyl group. Most preferably, R2is H. R3is typically selected from H, a Cl to C3 alkyl group, and a Cl to C3 haloalkyl group. Most preferably, R3is H.

[0195] Head groups - aromatic examples

[0196] When each XDatom is C, and y is 1, ring D may be an aromatic ring. In such examples, the

[0197] PARP1 inhibitor compound has a structure of: The PARP1 inhibitor compound optionally has a structure of:

[0198] In such examples, each R1is preferably selected from H and F. More preferably, the PARP1 inhibitor compound may have a structure selected from: The most preferred structures with aromatic D rings are: Further examples of PARP1 inhibitor compounds with aromatic D rings include those having the following structures:

[0199]

[0200] Head groups - non-aromatic examples

[0201] Alternatively, ring D may be non-aromatic. In such compounds, ring D may be a carbocycle or a heterocycle.

[0202] The PARP1 inhibitor compound may, for example, have a structure selected from: each R1and each R4being present.

[0203] In particular, the compound may have a structure of:

[0204] Alternatively, one XDatom may be O. In such examples, the PARP1 inhibitor compound may have a structure selected from: each R1and each R4being present. Of these, the following structures are preferred:

[0205] In accordance with another possibility, the PARP1 inhibitor compound may have a structure of:

[0206] The PARP1 inhibitor compound may in particular have a structure of:

[0207] Alternatively, one XDatom may be N. In such examples, the PARP1 inhibitor compound may have a structure selected from: Of these, the following structure is preferred:

[0208] In accordance with another possibility, the PARP1 inhibitor compound may have a structure selected from:

[0209] Further examples of PARP1 inhibitor compounds include: The most preferred general structures for PARP1 inhibitor compounds with non-aromatic head groups are:

[0210] L group - general

[0211] Group L of the PARP1 inhibitor compounds provided herein has a structure according to general formula: where:

[0212] X1, X3, X4and X5are each independently selected from C and N; each X2is independently selected from C, N, O, and S; n is 0, 1, 2, 3, 4, or 5; m is 0, 1, 2, 3, 4, or 5, with the proviso that n + m is in the range 1 to 5 (typically 2 to

[0213] 5); p is 1, 2 or 3; q is 1, 2 or 3, with the proviso that p + q is in the range 2 to 5; r is 0, 1, 2, 3, 4, or 5; s is 0, 1, 2, 3, 4, or 5, with the proviso that r + s is in the range 2 to 5; each R5A, R5B, and R5Cis independently absent or selected from H and a substituted or unsubstituted organic group; R6is absent or selected from H and a substituted or unsubstituted organic group; and Q1and Q2are each independently a bond or a linking group having a structure selected from: wherein: t is 0, 1, 2, 3, 4 or 5; u is 0, 1, 2, 3, 4 and 5, with the proviso that t + u is in the range 0 to 6; and each R7and R8is independently selected from H and a substituted or unsubstituted organic group.

[0214] Optionally, Q1is a bond and group L has a structure of:

[0215] One or more, and most preferably all, of the following provisos may apply: i) At least one X atom per ring is C. When ring A or ring B is 4-membered, that ring typically includes at most one heteroatom. When ring A or ring B is 5- or 6-membered, that ring typically includes at most three heteroatoms, optionally at most two heteroatoms. ii) Each of rings A, B, and C individually may comprise at most three heteroatoms. iii) The compound is not a quaternary ammonium compound. iv) The compound is free of O-O, S-S, and S-0 bonds.

[0216] Each portion of group L is discussed in more detail below. Ring A of the PARP1 inhibitor compound has the general structure: n is 0, 1, 2, 3, 4, or 5; and m is 0, 1, 2, 3, 4, or 5, with the proviso that n + m is in the range 1 to 5, typically 2 to 5, and optionally 2 to 4. In other words, ring A may be a 3-, 4-, 5-, 6-, or 7- membered ring. Ring A is typically a 4-, 5-, 6-, or 7-membered ring, optionally a 4-, 5-, or 6 membered ring. Preferably, ring A is a 5-membered ring (n + m = 3) or a 6-membered ring (n + m = 4). Most preferably, ring A is a 5-membered ring (n + m = 3)

[0217] Preferably, both n and m are at least 1. In other words, the atoms which connect ring A to rings E and B are preferably non-adjacent.

[0218] X1is bonded to ring E, and is selected from C and N. When X1is N, R5A1is absent. When X1is C, R5A1may be present or absent, and is preferably present.

[0219] Each X2is independently selected from C, N, O, and S. Optionally, each X2 may be selected from C, N, and O. Further optionally, each X2is independently selected from C and N. Most preferably, each X2is C.

[0220] Each R5Agroup (i.e., R5A1, R5A2, R5A3) is independently absent or selected from H and a substituted or unsubstituted organic group. The number of R5Agroups may be selected such that ring A is saturated, unsaturated and non-aromatic, or aromatic. Typically, ring A is nonaromatic. Preferably, ring A is saturated. In most implementations, no more than two R5Agroups are substituted or unsubstituted organic groups. Most typically, no more than one R5Agroup is a substituted or unsubstituted organic group.

[0221] Generally, when an R5Agroup is present, that R5Agroup is preferably H.

[0222] Ring A may be a bicyclic ring, in which two R5Agroups are fused together. The bicyclic ring may be a bridged bicyclic ring.

[0223] R5A3is most typically H.

[0224] It is preferable that, when present, each R5Ais independently selected from H; a halogen, optionally F; a hydroxyl group; a carbonyl group; and a Cl to C3 alkyl group, optionally wherein a pair of R5Agroups form a ring, further optionally wherein the ring bridges ring A.

[0225] Particularly preferably: i) one pair of R5Agroups forms -CH2- group bridging ring A, with each other R5Abeing H; or ii) each R5Ais H.

[0226] Ring A may be a 7-membered ring. For example, ring A may be a cycloheptane having a structure selected from: each R5Abeing present. Alternatively, ring A may be a 6-membered non-aromatic ring, such as a cyclohexane, cyclohexene, or tetrahydropyran. Ring A may for example have a structure selected from: each R5Abeing present.

[0227] In accordance with another possibility, ring A may be a 5-membered non-aromatic ring, such as a cyclopentane, cyclopentene, or a tetrahydrofuran. Ring A may for example have a structure selected from: each R5Abeing present. In other examples, ring A may be a 4-membered ring having a structure of: each R5Aand R5A3being present. In accordance with still another possibility, ring A may be a bridged ring. Examples of suitable bridged ring structures include: each R5Abeing present. Ring A typically includes no more than one bridging group. In the three examples immediately above, no R5Agroups are fused to form a further ring, and each R5Agroup is preferably H.

[0228] Further examples of suitable bridged ring structures include:

[0229] In the six examples immediately above, no R5Agroups are fused to form a further ring, and each R5Agroup is preferably H.

[0230] Examples of suitable structures for ring A include:

[0231] A26

[0232]

[0233] Additional examples of suitable structures for ring A include:

[0234] A47

[0235] A54

[0236] Ring A may have a structure of: where: n is 1, 2 or 3; m is 0, 1, or 2;

[0237] 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 provisos that:

[0238] R5A1is absent when X1is N; and

[0239] R5A2is absent when the corresponding X2is O. In an example, one X2atom is O and ring A is a tetrahydrofuran or a tetrahydropyran. In accordance with another possibility, ring A may have 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 R5A3is H; and wherein: i) XI is C and R5A1is selected from H and a substituted or unsubstituted organic group; or ii) XI is N and R5A1is absent.

[0240] Each R5A1, R5A2and R5A3may independently be absent or selected from H; a halogen, optionally F; a hydroxyl group; a carbonyl group (in other words, an oxo group =0); and a Cl to C3 alkyl group, optionally wherein a pair of R5Agroups form a Cl to C3 alkyl group (optionally -CH2- or -CH2-CH2-) bridging ring A. Preferably, each R5A1, R5A2and R5A3is absent or H.

[0241] In accordance with another possibility R5A1is absent, H, or forms a -CH2- or -CH2CH2- group together with an R5A2group or R5A3; each R5A2is independently absent, H, an oxo group (carbonyl group; =0), or forms a -CH2- or -CH2CH2- group together with R5A1, R5A3, or another R5A2; and R5A3is H or forms a -CH2- or -CH2CH2- group together with R5A1or an R5A2group.

[0242] In accordance with still another possibility, exactly two groups selected from the R5A1, R5A2, and R5A3groups 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. Preferred A ring structures include:

[0243] A12 A13 A14

[0244] Additional preferred A ring structures include: Most preferably, ring A has a structure of: Ring B of group L has a general structure of:

[0245] Each X2is independently selected from C, N, O and S. X3is selected from C and N, and optionally X3is N. p is 1, 2 or 3; and q is 1, 2 or 3, with the proviso that p + q is in the range 2 to 5. In other words, ring B may be a 4-, 5-, 6- or 7-membered ring. Preferably, ring B is a 6-membered ring, and most preferably p and q are both equal to 2.

[0246] Each R5Bis independently absent or selected from H and a substituted or unsubstituted organic group. Preferably, each R5Bis independently absent or H.

[0247] Depending upon the number of R5Bgroups present, ring B may be saturated or unsaturated.

[0248] Preferably, ring B is a saturated ring.

[0249] Preferably, each X2is C, and ring B has a structure of: X3is preferably N. In such examples, ring B may have a structure of:

[0250] Alternatively, X3may be C. In such examples, 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 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.

[0251] In accordance with 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.

[0252] Ring B may have a general structure selected from:

[0253] More specific examples of suitable ring B structures include:

[0254] When ring B has a structure of:

[0255] Q2is optionally -O-. Most preferably, ring B has a structure of:

[0256] Linkers - groups Q1and Q2

[0257] Ring A is coupled to ring B via a first linker Q1, and ring B is coupled to ring C via a second linker Q2:

[0258] Optionally, Q1is a bond such that ring A is directly connected to ring B:

[0259] In particular, Q1may be a bond when ring A is a 4-, 5-, 6-, or 7-membered ring. For example, Q1may be a bond and ring A may be selected from Al, A3, A4, A5, A6, A12, A13 and A14 as defined hereinabove.

[0260] When ring A is 3- or 4-membered ring, Q1may be a linking group. For example, when ring A is:

[0261] Q1may be -CH2-.

[0262] Q2may be a bond. In other words, atom X3may be directly connected to ring C. Q1and Q2are each independently selected from a bond and a linking group 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.

[0263] Optionally, t+u is at least 1.

[0264] Preferably, each R7is independently selected from H; a halogen, optionally F; a Cl to C6 alkyl group; and a Cl to C6 haloalkyl group.

[0265] Typically, rings are not connected by N-N bonds. To this end, when Q1is When Q1or Q2is:

[0266] R8may be selected from:

[0267] H; a substituted or unsubstituted linear or branched Ci-Ce alkyl group

[0268] (such as Me, Et, Pr, i-Pr, n-Bu, i-Bu, t-Bu, pentyl and hexyl); a substituted or unsubstituted linear or branched Ci-Ce a Ikyl-a ryl group

[0269] (such as -CH2Ph, -CH2(2,3 or 4)F-Ph, -CH2(2,3 or 4)CI-Ph, -CH2(2,3 or 4)Br-Ph,

[0270] -CH2(2,3 or 4)l-Ph, -CH2CH2Ph, -CH2CH2CH2Ph,

[0271] -CH2CH2CH2CH2Ph, -CH2CH2CH2CH2CH2Ph, and -CH2CH2CH2CH2CH2CH2Ph); a substituted or unsubstituted linear or branched Ci-Ce halogenated alkyl group (such as -CH2F, -CF3, -CH2CH2F and -CH2CF3); a substituted or unsubstituted cyclic amine or amido group

[0272] (such as pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, 2-keto-pyrrolidinyl,

[0273] 3-keto-pyrrolidinyl, 2-keto-piperidinyl, 3-keto-piperidinyl, and

[0274] 4-keto-piperidinyl); a substituted or unsubstituted cyclic C3-Cs alkyl group

[0275] (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl); a substituted or unsubstituted linear or branched C2-Ce alcohol group

[0276] (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-Ce carboxylic acid group

[0277] (such as -CH2COOH, -CH2CH2COOH, -CH2CH2CH2COOH, -CH2CH2CH2CH2COOH, and -CH2CH2CH2CH2CH2COOH); a substituted or unsubstituted linear or branched carbonyl group

[0278] (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)-l,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 Ci-Ce 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 Ci-Ce amide group

[0279] (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

[0280] (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,

[0281] -SO2-morpholine-N-yl, -SO2NHCH2OMe, and -SO2NHCH2CH2OMe); a substituted or unsubstituted aromatic group

[0282] (such as Ph-, 2-F-Ph-, 3-F-Ph-, 4-F-Ph-, 2-CI-Ph-, 3-CI-Ph-, 4-CI-Ph-, 2-Br-Ph-, 3-Br-Ph-, 4-Br-Ph-, 2-l-Ph-, 3-l-Ph, 4-l-Ph-, 2, (3, 4, 5 or 6)-F2-Ph-,

[0283] 2, (3,4,5 or 6)-CI2-Ph-, 2, (3,4,5 or 6)-Br2-Ph-, 2, (3,4,5 or 6)-l2-Ph-,

[0284] 2, (3,4,5 or 6)-Me2-Ph-, 2, (3, 4, 5 or 6)-Et2-Ph-, 2, (3, 4, 5 or 6)-Pr2-Ph-,

[0285] 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-,

[0286] 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-,

[0287] 3,(4 or 5)-F2-Ph-, 3,(4 or 5)-CI2-Ph-, 3,(4 or 5)-Br2-Ph-, 3,(4 or 5)-l2-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-,

[0288] 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

[0289] (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, l,2,3-triazole-4-yl, l,2,3-triazole-5-yl, l,2,4-triazole-3-yl, l,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,

[0290] 2-azapiperidine-3-yl, 2-azapiperidine-4-yl, 3-azapiperidine-2-yl,

[0291] 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,

[0292] 2-azapyran-5-yl, 2-azapyran-6-yl, 3-azapyran-2-yl, 3-azapyran-4-yl,

[0293] 3-azapyran-5-yl, 3-azapyran-6-yl, 4-azapyran-2-yl, 4-azapyran-3-yl,

[0294] 4-azapyran-5-yl, 4-azapyran-6-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-4-yl,

[0295] 2-aza-tetrahydrofuran-5-yl, 3-aza-tetrahydrofuran-2-yl,

[0296] 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,

[0297] 2-aza-tetrahydropyran-5-yl, 2-aza-tetrahydropyran-6-yl,

[0298] 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,

[0299] 2-azathiopyran-4-yl, 2-azathiopyran-5-yl, 2-azathiopyran-6-yl,

[0300] 3-azathiopyran-2-yl, 3-azathiopyran-4-yl, 3-azathiopyran-5-yl,

[0301] 3-azathiopyran-6-yl, 4-azathiopyran-2-yl, 4-azathiopyran-3-yl,

[0302] 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, (l,3,4-oxadiazol)-2-yl, (l,3,4-oxadiazol)-5-yl, (l,2,4-oxadiazol)-3-yl, (l,2,4-oxadiazol)-5-yl; and tetrazole-5-yl).

[0303] In particular, R8may be selected from H, a substituted or unsubstituted Ci-Ce alkyl group or a substituted or unsubstituted linear or branched Ci-Ce halogenated alkyl group.

[0304] Preferably, Q2is a bond or -CH2-. Most preferably, Q2is a bond.

[0305] When ring B is a 4-membered ring, Q2may be -O-.

[0306] Ring C

[0307] Ring C of the PARP1 inhibitor compound has a structure of:

[0308] X4and X5are each independently selected from C and N. Preferably, X4is C and X5is C.

[0309] Rings B and C are not connected by N-N bonds. When Q2is:

[0310] When atom X3of ring B is N and Q is a bond, X4is C. In accordance with another possibility, X3is C and X4is C.

[0311] Each X2is independently selected from C, N, O, and S, with C and N being preferred. The X2atoms are selected such that ring C is free of O-O, O-S, and S-S bonds. Optionally, at least one X2atom is C.

[0312] Ring C is preferably a heterocycle. Optionally, one X2atom is N, and each other X2atom is C.

[0313] Alternatively, each X2atom is C.

[0314] Each R5Cis independently absent or selected from H and a substituted or unsubstituted organic group. Two R5Cgroups, or an R5Cgroup and R6, may be fused such that ring C is a bridged ring system.

[0315] Each R5Cmay independently be absent, H, or an organic group selected from a halogen, preferably F; a Cl to C3 alkyl group, optionally a cyclopropyl group; a Cl to C3 haloalkyl group, optionally a fluoromethyl group such as CF2H or CF3; a Cl to C3 alkoxy group; and a nitrile group. Optionally, each R5Cmay independently be absent, H, or an organic group selected from a halogen, preferably F; a Cl to C3 alkyl group; a Cl to C3 haloalkyl group, optionally a fluoromethyl group such as CF2H or CF3; and a nitrile group.

[0316] When an R5Cgroup is present, that R5Cgroup may in particular be selected from H and a halogen. The preferred halogen is F. Optionally, exactly one R5Cis an organic group. That organic group is most preferably F. r is 0, 1, 2, 3, 4, or 5 and s is 0, 1, 2, 3, 4, or 5, with the proviso that r + s is in the range 2 to 5. In other words, ring C may be a 4-, 5-, 6-, or 7-membered ring. Typically, r is at least 1 and s is at least 1. Optionally, ring C is a 5-membered ring (r + s = 3) or a 6-membered ring (r + s= 4), with 6-membered rings being preferred.

[0317] Depending upon the chosen number of R5Cgroups, ring C may be a saturated ring, an unsaturated non-aromatic ring, or an aromatic ring. Preferably, ring C is an aromatic ring. Most preferably, ring C is a 6-membered aromatic ring.

[0318] Ring C may be a 6-membered saturated ring, optionally 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.

[0319] In accordance with another possibility, ring C may be a 6-membered saturated ring having a structure of: each R5Cand R5C1being independently selected from H and a substituted or unsubstituted organic group, preferably wherein R5C1is H, more preferably wherein R5C1and each R5Cis H. Alternatively, ring C may be a 6-membered aromatic ring.

[0320] For example, ring C may be an optionally-substituted phenyl group, optionally having a structure of: each R5Cbeing independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5Cis H.

[0321] In accordance with another possibility, ring C may be a pyridine group, optionally having a structure selected from: each R5Cbeing independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5Cis H.

[0322] Alternatively, ring C may be a diazine group, optionally having a structure selected from: each R5Cbeing independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5Cis H.

[0323] Compounds wherein ring C is a 5-membered aromatic ring are also contemplated.

[0324] For example, ring C may be an imidazole group, optionally an imidazole group having a structure selected from: each R5Cbeing independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5Cis H. Alternatively, ring C may be a thiophene group, optionally having a structure selected from: each R5Cbeing independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5Cis H. In accordance with another possibility, ring C may be 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.

[0325] In still other examples, ring C may be a triazole, optionally having a structure of: R5Cbeing selected from H and a substituted or unsubstituted organic group, optionally wherein R5Cis H.

[0326]

[0327] Additional examples of suitable ring C structures include:

[0328] C37

[0329] C38 Ring C optionally has a structure selected from C3, C8, CIO, Cll, C13, C14, C15, C18, C19, C21, C25, C28, C36, C37, and C38 as defined above.

[0330] In accordance with another possibility, ring C may have a structure of: wherein: each Xcatom is selected from C and N, with the proviso that at least two Xcatoms are C; when an Xcis N, the corresponding R5Cis absent; when an Xcis C, the corresponding R5Cis H, or a substituent selected from a halogen, such as F or Cl; -CN; a methyl group; and a halomethyl group, such as -CHF2; optionally wherein no more than one R5Cis a substituent.

[0331] For example, ring C may have a structure of: wherein:

[0332] XCoand XCmare each selected from C and N, preferably wherein exactly one of XCoand XCmis N; when XCois C, RCois H or a halogen, optionally F; when XCois N, RCois absent; when XCmis C, RCmis H or a halogen, optionally F; and when XCmis N, RCmis absent. When present, RCois preferably H or F. When present, RCmis preferably H.

[0333] Most preferably, ring C has a structure selected from:

[0334] Ring C may have a structure selected from:

[0335]

[0336] Terminal substituent R6

[0337] Ring C bears a substituent R6, which is selected from H and a substituted or unsubstituted organic group.

[0338] R6may in particular be selected from H, -F, -Cl, -Br, -I, -CN, -CONR51R51, -NR51COR52, -SO2NR51R51, -NR51SO2R52, -O-CR52R52R52, -CR52R52NR51R51, and any of the following structures:

[0339]

[0340] R51and R52are each independently selected from H and a substituted or unsubstituted organic group. Optionally, R51and R52are each independently selected from H, a halogen, optionally-deuterated Cl to C3 alkyl, and Cl to C3 haloalkyl.

[0341] Optionally, R6is selected from -F, -Cl, -CN, -CONH2, -CONHMe (optionally -CONHCD3),

[0342] -CONHEt, -CONMe2, -CONHCOMe, -CONHCH2-CH2OMe, -CONH-CH2-CH2F, -CONH-CH2-CF3,

[0343] In accordance with another possibility, R6may have a structure of: wherein R51is selected from: a Cl to C6 alkyl group, optionally a C3 to C6 cycloalkyl group, a Cl to C3 alkyl group, or a Cl to C3 deuterated alkyl group; a Cl to C3 haloalkyl group, optionally a Cl 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. R6may be selected from:

[0344] Particularly preferably, R6is selected from: i) CONHMe; ia) CONHCD3; ii) Cl; and iii) CN.

[0345] Where a compound is depicted with an R6group selected from i) to iii) as defined immediately above, replacement of the R6group with any other one of groups i) to iii) is explicitly contemplated. In some examples, R6is F.

[0346] In accordance with still another possibility, R6may have a structure of: wherein: each X6is independently selected from C, N, and O;

[0347] R61is absent or H; each R62is independently absent or selected from H; a halo group, such as F; an oxo group; a Cl to C3 alkyl group; a Cl to C3 haloalkyl group, optionally a Cl to C3 fluoroalkyl group; and -NHR63, wherein R63is H or a Cl to C3 alkyl group.

[0348] Examples of R6groups in this class include: Example L groups

[0349] Group L of the PARP1 inhibitor compound may, for example, have a structure selected from:

[0350] with R6being as defined hereinabove.

[0351] Group L of the PARP1 inhibitor compound may in particular be selected from:

[0352]

[0353] Further examples of L group structures include:

[0354]

[0355] Rings E and B of the PARP1 inhibitor compound may be in a cis configuration with respect to ring A. In such compounds, group L may be selected from: Further examples of group L structures having a cis configuration include: Alternatively, rings E and B may be in a trans configuration with respect to ring A. In such compounds, group L may be selected from:

[0356] Further examples of group L structures having a trans configuration include:

[0357]

[0358]

[0359] Example Compounds

[0360] Provided herein are PARP1 inhibitor compounds having a structure of: each Z independently represents -CH2- or a heteroatom-containing fragment selected from -O- and -N(RD)-, with the proviso that no more than one Z is a heteroatomcontaining fragment; wherein RDis H or a Cl to C3 alkyl group;

[0361] XC1and XC2are each independently selected from C and N; when XC1is N, R5C1is absent; when XC1is C, R5C1is selected from H and a halogen, preferably F; when XC2is N, R5C2is absent; when XC2is C, R5C2is selected from H and a halogen, preferably F;

[0362] R6is selected from -CONHMe, -Cl, and -CN.

[0363] When present, RDis preferably a methyl group.

[0364] When present, R5C1is preferably H or F.

[0365] When present, R5C2is preferably H or F.

[0366] XC2is preferably N. More preferably, XC1is C and XC2is N.

[0367] R6is preferably -CONHMe, e.g. -CONHCD3. The compound may have a cis configuration:

[0368] Examples of compounds in this class include the following: ltrans 6 Also provided herein are PARP1 inhibitor compounds according to general formula: wherein:

[0369] RD1and RD2are each independently selected from H and F; two R5Agroups together represent a -CH2- group bridging ring A, and each other R5Agroup is H; or each R5Ais H; each Xcatom is selected from C and N, with the proviso that at least two Xcatoms are C; when an Xcis N, the corresponding R5Cis absent; when an Xcis C, the corresponding R5Cis H, or a substituent selected from a halogen, such as F or Cl; -CN; a methyl group; and a halomethyl group, such as

[0370] -CHF2;

[0371] R6is selected from a halogen, -CN, and wherein R51is selected from a Cl to C3 alkyl group; a Cl to C3 deuterated alkyl group; a Cl to C3 fluoroalkyl group; a tetrahydrofuranyl group; and a tetrahydropyranyl group. For example, the PARP1 inhibitor compound may have a structure of:

[0372] RD1and RD2are each independently selected from H and F; XC1and XC2are each independently selected from C and N; when XC1is N, R5C1is absent; when XC1is C, R5C1is selected from H and a halogen, preferably F; when XC2is N, RC2is absent; when XC2is C, R5C2is selected from H and a halogen, preferably F; R6is selected from -CONHMe, -Cl, and -CN.

[0373] Preferably, exactly one of RD1and RD2is F.

[0374] Preferably, exactly one of XC1and XC2is N. For instance, XC1may be C and XC2may be N. Alternatively, XC2may be C and XC1may be N; in such examples, R5C2is preferably H.

[0375] The compound may have a cis configuration: or a trans configuration:

[0376] Examples of PARP1 inhibitor compounds in this class include:

[0377] lOtrans Provided herein are the following PARP1 inhibitor compounds:

[0378] 3 3cis

[0379] 6cis 6trans

[0380]

[0381] 23trans 24

[0382]

[0383] 29trans

[0384]

[0385] 42cis 42trans

[0386]

[0387] 45 45cis

[0388]

[0389] 48cis

[0390]

[0391] 50cis

[0392] 52trans 53

[0393]

[0394] 55trans

[0395]

[0396] 59cis

[0397]

[0398] Medical Uses

[0399] 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.

[0400] The PARP1 inhibitor compounds provided herein may be selective for PARP1 over PARP2. As such, the PARP1 inhibitor compounds may have reduced toxicity. PARP2 inhibition is believed to be a major driver of haematological toxicities such as anaemia, neutropenia and thrombocytopenia.

[0401] 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.

[0402] For example, the cancer may be selected from: a cancer of the eye, brain (such as gliomas, glioblastomas, medulloblastomas, craniopharyngioma, ependymoma, and astrocytoma), spinal cord, kidney, mouth, lip, throat, oral cavity, nasal cavity, small intestine, colon, parathyroid gland, gall bladder, head and neck, breast, bone, bile duct, cervix, heart, hypopharyngeal gland, lung, bronchus, liver, skin, ureter, urethra, testicles, vagina, anus, laryngeal gland, ovary, thyroid, oesophagus, nasopharyngeal gland, pituitary gland, salivary gland, prostate, pancreas, adrenal glands; an endometrial cancer, oral cancer, melanoma, neuroblastoma, gastric cancer, an angiomatosis, a hemangioblastoma, a pheochromocytoma, a pancreatic cyst, a renal cell carcinoma, Wilms' tumour, squamous cell carcinoma, sarcoma, osteosarcoma, Kaposi sarcoma, rhabdomyosarcoma, hepatocellular carcinoma, PTEN Hamartoma-Tumor Syndromes (PHTS) (such as Lhermitte-Duclos disease, Cowden syndrome, Proteus syndrome, and Proteus-like syndrome), leukaemias and lymphomas (such as acute lymphoblastic leukaemia, chronic lymphocytic leukaemia, acute myelogenous leukaemia, chronic myelogenous leukaemia, hairy cell leukaemia, T-cell prolymphocytic leukaemia (T- PLL), large granular lymphocytic leukaemia, adult T-cell leukaemia, juvenile myelomonocytic leukaemia, Hodgkin lymphoma, non-Hodgkin lymphoma, mantle lymphoma, follicular lymphoma, primary effusion lymphoma, AIDS-related lymphoma, diffuse B cell lymphoma, Burkitt lymphoma, cutaneous T-cell lymphoma, nasopharyngeal and gastrointestinal cancers. For instance, the cancer may be a cancer of the brain or spinal cord.

[0403] 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.

[0404] The compounds described herein may be provided for use in for treating a cancer which is deficient in one or more DNA damage response repair pathways, in particular in Homologous Recombination ("HR") dependent DNA Double Strand Break ("DSB") DNA repair activity. Components of HR dependent DNA DSB repair pathways and other DNA damage response pathways include but are not limited to the following proteins: ATM, ATR, ERCC1, XRCC1, XRCC2, XRCC3, RAD51, RAD51L1, RAD51C, RAD51D, RAD51L3, DMC1, RAD52, RAD54L, RAD54B, RAD50, MRE11A, NBS1, BRCA1, BRCA2, FANCP (SLX4), FEN1, PALB2, PBRM1, SMARCA4, ARID1A, ARID1B, FANCD2, BLM. Other components involved in HR dependent DNA DSB repair include regulatory factors such as ESMY (Hughes-Davies, L. et al. Cell. 2003; 115: 523-535). A cancer which is deficient in HR-dependent DNA DSB repair typically becomes dependent on alternative DSB pathway repair mechanisms. Such cancers include but are not limited to cancers of the ovary, prostate, breast, lung, gastrointestine, blood and pancreas. The cancer cells may have a BRCA1 and / or BRCA2 deficient phenotype, i.e. the cancer cells may be deficient in BRCA1 and / or 2 function. The deficiency may arise by means of mutation, polymorphism or epigenetic silencing in the encoding nucleic acids or by means of mutation, polymorphism, amplification in a gene encoding a regulatory factor, e.g. the ESMY gene which encodes a BRCA2 regulatory factor (Hughes-Davies, L. et al. Cell. 2003; 115: 523-535). Amplification of the ESMY gene is associated with breast and ovarian cancer. Carriers of mutations in the tumour suppressor BRCA1 and / or BRCA2 genes are known to have an elevated risk of developing certain cancers including ovarian, prostate and breast. Wild-type alleles of BRCA1 and / or BRCA2 are frequently lost in tumours of heterozygous carriers (Jasin, M. et al. Oncogene. 2002; 21: 8981-93) and their detection, as a means of patient selection, is well known in the art (Radice, PJ. et al. Exp. Clin. Cancer. Res. 2002; 21: 9-12; Chappnis, PO and Foulkes WO. Cancer Treat Res. 2002; 107: 29-59).

[0405] The compounds provided herein may be administered to a patient who is undergoing radiotherapy and / or chemotherapy using a further agent for treating cancer.

[0406] For example, the PARP1 inhibitor compound may be administered in conjunction with a further agent for treating cancer.

[0407] 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, cell cycle signalling inhibitors, and anti-angiogenic agents.

[0408] 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-PDl, anti-PDL-1, anti-OX40, anti-41BB, anti-CD27, anti-CD40, anti-LAG3, anti-TIM3, and anti-GITR; a pattern recognition receptor agonist such as a STING, TLR-9 or RIG-1 Helicase agonist; an IDO or TDO inhibitor; a novel adjuvant; a peptide; a cytokine; a chimeric antigen receptor T cell therapy (CAR-T); a small molecule immune modulator; and a tumour microenvironment modulator.

[0409] Pharmaceutical Compositions

[0410] Another aspect provides a pharmaceutical composition comprising a PARP1 inhibitor compound as defined herein.

[0411] Typically, the composition includes a pharmaceutically acceptable additive and / or excipient.

[0412] 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.

[0413] Typically, the composition is for use in medicine, e.g. for use in treating a disease, condition or disorder as defined above.

[0414] 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.

[0415] 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 fortreating cancer may comprise an immunotherapeutic agent selected from: an anti-tumour vaccine; an oncolytic virus; an immune stimulatory antibody such as anti-CTLA4, anti-PDl, anti-PDL-1, anti-OX40, anti-41BB, anti-CD27, anti-CD40, anti- LAG3, anti-TIM3, and anti-GITR; a pattern recognition receptor agonist such as a STING, TLR- 9 or RIG-1 Helicase agonist; an IDO or TDO inhibitor; a novel adjuvant; a peptide; a cytokine; a chimeric antigen receptor T cell therapy (CAR-T); a small molecule immune modulator; and a tumour microenvironment modulator.

[0416] Kits

[0417] 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.

[0418] 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.

[0419] In particular, the further agent for treating cancer may comprise one or more chemotherapeutic agents selected from: anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase I inhibitors, topoisomerase II inhibitors, antimetabolites, senolytic agents, hormones and hormone analogues, signal transduction pathway inhibitors, other DNA damage repair pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, antibody-drug conjugates, hormone-deprivation therapies, radioligand therapies, antiangiogenic agents, immunotherapeutic agents (such as selected from an anti-tumour vaccine, an oncolytic virus, an immune stimulatory antibody such as anti-CTLA4, anti-PDl, anti-PDL-1, anti-OX40, anti-41BB, anti-CD27, anti-CD40, anti- LAG3, anti-TIM3, and anti-GITR, a pattern recognition receptor agonist such as a STING, TLR- 9 or RIG-1 Helicase agonist, an IDO or TDO inhibitor, a novel adjuvant, a peptide, a cytokine, a chimeric antigen receptor T cell therapy (CAR-T), a small molecule immune modulator, tumour microenvironment modulators), proapoptotic agents and cell cycle signalling inhibitors.

[0420] Methods of Treatment

[0421] 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.

[0422] 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.

[0423] 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).

[0424] The patient may be undergoing treatment using ionising radiation.

[0425] Methods of synthesising PARP1 inhibitor compounds

[0426] Also provided are methods for synthesising the PARPl inhibitor compounds as defined herein. In general, the method comprises conducting a reaction between: (i) a first reactant comprising rings D and E and bearing a first portion of group L, and (ii) a second reactant comprising a remainder of group L, to form the PARP1 inhibitor compound. The skilled person may select reaction conditions with reference to known synthesis techniques depending on the appropriate starting materials. The method may comprise one or more additional steps. Exemplary synthesis methodology is shown in the Examples hereinbelow. In one example method, the first reactant comprises rings D, E and ring A, and the second reactant comprises a ring B precursor bearing a reactive group, which method comprises joining ring A to the ring B precursor. In this method, the reactive group of the ring B 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.

[0427] In another example method, the first reactant comprises rings D, E, ring A, 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.

[0428] 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").

[0429] 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.

[0430] Examples SCHEME 1

[0431] Preparation of 8-fluoro-2-(4-methoxybenzyl)-3-(3-oxocyclopent-l-en-l-yl)isoquinolin- l(2H)-one (1003)

[0432] A suspension of 3-chloro-8-fluoro-2-(4-methoxybenzyl)isoquinolin-l(2H)-one 1001 (1800 mg, 5.6650 mmol), 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclopent-2-en-l-one 1002

[0433] (1178 mg, 5.6650 mmol), Na2CO3(1201 mg, 11.3300 mmol) and Pd(dppf)CI2(462 mg, 0.5665 mmol) in dioxane (100 mL) was heated at 100 °C for 8 h under N2. After cooling to rt, the reaction mixture was poured into ice water and then extracted with EtOAc (200 mL x 3). The combined organic layers were washed with water, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash silica chromatography (eluting with EtOAc / PE, 0 to 15 %) to give 8-fluoro-2-(4-methoxybenzyl)-3-(3-oxocyclopent-l-en-l- yl)isoquinolin-l(2H)-one 1003 (800 mg, 80 % purity, 31 % yield) as a yellow oil. LCMS (ESI) calcd for C22H18FNO3 [M + H]+m / z 364.13, found 364.00.

[0434] Preparation of 5-(4-(3-(8-fluoro-2-(4-methoxybenzyl)-l-oxo-l,2-dihydroisoquinolin-3- yl)cyclopent-2-en-l-yl)piperazin-l -yl)-N-methylpicolinamide ( 1005)

[0435] To a solution of 8-fluoro-2-(4-methoxybenzyl)-3-(3-oxocyclopent-l-en-l-yl)isoquinolin-l(2H)- one 1003 (300 mg, 0.8256 mmol) in MeOH (6 mL) were added N-methyl-5-(piperazin-l- yl)picolinamide 1004 (218 mg, 0.9907 mmol), NaBH(OAc)3 (875 mg, 4.1280 mmol) and NaBHsCN (259 mg, 4.1280 mmol) successively. The reaction mixture was stirred at 60 °C for 48 h. The reaction mixture was quenched with water and 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-(8-fluoro-2-(4-methoxybenzyl)-l-oxo-l,2- dihydroisoquinolin-3-yl)cyclopent-2-en-l-yl)piperazin-l-yl)-N-methylpicolinamide 1005 (220 mg, 90 % purity, 42 % yield) as a colourless oil.

[0436] LCMS (ESI) calcd for C33H34FN5O3 [M + H]+m / z 568.26, found 568.30.

[0437] Preparation of 5-(4-(3-(8-fluoro-2-(4-methoxybenzyl)-l-oxo-l,2-dihydroisoquinolin-3- yl)cyclopentyl)piperazin-l-yl)-N-methylpicolinamide (1006)

[0438] A solution of 5-(4-(3-(8-fluoro-2-(4-methoxybenzyl)-l-oxo-l,2-dihydroisoquinolin-3- yl)cyclopent-2-en-l-yl)piperazin-l-yl)-N-methylpicolinamide 1005 (200 mg, 0.3523 mmol) and Pd(OH)2 / C (99 mg, 0.7046 mmol) in MeOH (5 mL) was stirred at 50 °C for 48 h under H2 atmosphere. The resulting solution was filtered through diatomaceous earth and the filter cake was washed with DCM (10 mL). The filtrate was concentrated under reduced pressure to give 5-(4-(3-(8-fluoro-2-(4-methoxybenzyl)-l-oxo-l,2-dihydroisoquinolin-3- yl)cyclopentyl)piperazin-l-yl)-N-methylpicolinamide 1006 (180 mg, 85 % purity, 76 % yield) as a colourless oil.

[0439] LCMS (ESI) calcd for C33H36FN5O3 [M + H]+m / z 570.28, found 570.35.Preparation of 5-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)cyclopentyl)piperazin-1-yl)-N-methylpicolinamide (5cis-a, 5cis-b, 5trans-a, and 5trans-b) A solution of 5-(4-(3-(8-fluoro-2-(4-methoxybenzyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)cyclopentyl)piperazin-1-yl)-N-methylpicolinamide 1006 (180 mg, 0.3160 mmol) in TFA (3mL) and TfOH (0.3 mL) was stirred at 100 °C for 10 min. The reaction solution was cooled tort and the reaction solution was adjusted to pH 8 with aq. NaHCO3 and extracted with EtOAc(100 mL × 2). The combined organic layers were concentrated under reduced pressure andpurified by prep-HPLC (column : Gemini - C18150 × 21.2 mm, 5 µm; mobile phase: ACN - H2O(0.05 % NH3); gradient : 25 - 70) to obtain 5-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)cyclopentyl)piperazin-1-yl)-N-methylpicolinamide 5cis-a / 5cis-b racemic mixture (27.6 mg,95 % purity, 18 % yield) as a white solid and 5-(4-(3-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)cyclopentyl)piperazin-1-yl)-N-methylpicolinamide 5trans-a / 5trans-b racemic mixture (7.5mg, 98 % purity, 5 % yield) as a white solid.5cis-a / 5cis-b racemic mixture1H NMR (400 MHz, DMSO-d6, ppm) δ: 11.63 (s, 1 H), 8.44-8.36 (m, 1 H), 8.29 (d, J = 2.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1 H), 7.64-7.57 (m, 1 H), 7.42 (dd, J = 8.8, 2.8 Hz, 1 H), 7.36 (d, J = 7.6Hz, 1 H), 7.11-7.04 (m, 1 H), 6.45 (s, 1 H), 3.52-3.35 (m, 4 H), 3.12-2.99 (m, 1 H), 2.79 (d, J =4.8 Hz, 3 H), 2.72-2.61 (m, 5 H), 2.2-2.05 (m, 2 H), 1.89-1.63 (m, 4 H).NOE experiments suggested a cis stereochemistry for this pair of enantiomers.LCMS (ESI) calcd for C25H28FN5O2 [M + H] + m / z 450.22, found 450.40.5trans-a / 5trans-b racemic mixture1H NMR (400 MHz, DMSO-d6, ppm) δ: 11.17 (s, 1 H), 8.43-8.34 (m, 1 H), 8.27 (d, J = 2.8 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1 H), 7.65-7.57 (m, 1 H), 7.43-7.34 (m, 2 H), 7.13-7.05 (m, 1 H), 6.42 (s,1 H), 3.36-3.32 (m, 4 H), 3.10-2.96 (m, 1 H), 2.90-2.81 (m, 1 H), 2.78 (d, J = 4.8 Hz, 3 H), 2.65-2.54 (m, 4 H), 2.13-1.94 (m, 3 H), 1.92-1.80 (m, 1 H), 1.77-1.64 (m, 1 H), 1.61-1.48 (m, 1 H).NOE experiments suggested a trans stereochemistry for this pair of enantiomers. LCMS (ESI) calcd for C25H28FN5O2 [M + H]+m / z 450.22, found 450.25.

[0440] Example 2: synthesis of2cis-a, 2cis-b, 2trans-a, 2trans-b 2

[0441] SCHEME 2

[0442] Preparation of 3-chloro-7-fluoro-l -methoxyisoquinoline (1102)

[0443] To a solution of l,3-dichloro-7-fluoroisoquinoline 1101 (1.0 g, 4.65 mmol) in MeOH (15 mL) was added MeONa (251 mg, 4.65 mmol) under N2. The reaction mixture was stirred at 60 °C for 16 h. The reaction solution was cooled to rt, quenched with water, and extracted with EtOAc (100 mL x 4). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE / EtOAc = 100: 0 to 50: 50) to give 3-chloro-7-fluoro-l-methoxyisoquinoline 1102 (900 mg, 80 % purity, 73 % yield) as a white solid.

[0444] LCMS (ESI) calcd for C10H7CIFNO [M + H]+m / z 212.02, found 212.10.

[0445] Preparation of 3-( 7-fluoro-l-methoxyisoquinolin-3-yl)cyclopent-2-en-l -one (1103)

[0446] To a solution of 3-chloro-7-fluoro-l-methoxyisoquinoline 1102 (900 mg, 4.25 mmol), 3- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclopent-2-en-l-one 1002 (1.06 g, 5.11 mmol) and RuPhos Pd G3 (357 mg, 0.43 mmol) in dioxane / FhO = 10 : 1 (15 mL) was added Na2COs (901 mg, 8.50 mmol) under N2. The reaction mixture was stirred at 90 °C for 2 h. The reaction solution was cooled to rt, quenched with water, and extracted with EtOAc (100 mL x 4). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE / EtOAc = 100: 0 to 50: 50) to give 3-(7-fluoro-l-methoxyisoquinolin-3-yl)cyclopent-2-en-l-one 1103 (800 mg, 90 % purity, 66 % yield) as a white solid.

[0447] LCMS (ESI) calcd for C15H12FNO2 [M + H]+m / z 258.09, found 258.10.

[0448] Preparation of 5-(4-(3-(7-fluoro-l-methoxyisoquinolin-3-yl)cyclopent-2-en-l-yl)piperazin-l- yl)-N-methylpicolinamide (1104)

[0449] To a solution of 3-(7-fluoro-l-methoxyisoquinolin-3-yl)cyclopent-2-en-l-one 1103 (460 mg, 1.79 mmol) in MeOH (20 mL) was added N-methyl-5-(piperazin-l-yl)picolinamide hydrochloride 1004 (1.37 g, 5.40 mmol) and 2 drops of AcOH, then NaBHsCN was added (1.12 g, 17.9 mmol). The reaction mixture was added to stir at 60 °C for 48 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (eluting with DCM / MeOH = 100 : 0 to 90: 10) to give 5-(4-(3-(7-fl uoro-1- methoxyisoquinolin-3-yl)cyclopent-2-en-l-yl)piperazin-l-yl)-N-meth-ylpicolinamide 1104 (530 mg, 70 % purity, 44 % yield) as a white solid.

[0450] LCMS (ESI) calcd for C26H28FN5O2 [M + H]+m / z 462.22, found 462.20. Preparation of 5-(4-(3-(7-fluoro-l-methoxyisoquinolin-3-yl)cyclopentyl)piperazin-l-yl)-N- methylpicolinamide (1105)

[0451] To a solution of 5-(4-(3-(7-fluoro-l-methoxyisoquinolin-3-yl)cyclopent-2-en-l-yl)piperazin-l- yl)-N-meth-ylpicolinamide 1104 (530 mg, 1.14 mmol) in MeOH (20 mL) was added Pd(0H)2 / C (160 mg) under H2. The reaction mixture was stirred at 50 °C for 4 h. The resulting solution was filtered through a celite pad, and the filtrate was concentrated under reduced pressure to give 5-(4-(3-(7-fluoro-l-methoxyisoquinolin-3-yl)cyclopentyl)piperazin-l-yl)-N- methylpicolinamide 1105 (320 mg, 70 % purity, 42 % yield) as a white solid.

[0452] LCMS (ESI) calcd for C26H30FN5O2 [M + H]+m / z 464.24, found 464.30.

[0453] Preparation of 5-(4-(3-(7-fluoro-l-oxo-l,2-dihydroisoquinolin-3-yl)cyclopentyl)piperazin-l- yl)-N-methylpicolinamide (2cis-a, 2cis-b, 2trans-a, 2trans-b)

[0454] To a solution of 5-(4-(3-(7-fluoro-l-methoxyisoquinolin-3-yl)cyclopentyl)piperazin-l-yl)-N- methylpicolinamide 1105 (320 mg, 0.69 mmol) in ACN (20 mL) was added TMSI (414 mg, 2.07 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 (columns: Gemini 5 pm C18 150 x 21.2 mm, mobile phase: ACN - H2O (0.05 % NH3), gradient: 30 - 65) to give 5-(4-(3-(7-fl uoro- l-oxo-l,2-dihydroisoquinolin-3-yl)cyclopentyl)piperazin-l-yl)-N-methylpicolinamide 2cis-a, 2cis-b racemic mixture (cis, 38 mg, 95 % purity, 10 % yield) and 5-(4-(3-(7-fluoro-l-oxo-l,2- dihydroisoquinolin-3-yl)cyclopentyl)piperazin-l-yl)-N-methylpicolinamide 2trans-a, 2trans-b racemic mixture (trans, 68 mg, 98 % purity, 21 % yield) as a white solid.

[0455] Preparation of 5-(4-(3-(7-fluoro-l-oxo-l,2-dihydroisoquinolin-3-yl)cyclopentyl)piperazin-l- yl)-N-methylpicolinamide (2cis-a and 2cis-b) 5-(4-(3-(7-fluoro-l-oxo-l,2-dihydroisoquinolin-3-yl)cyclopentyl)piperazin-l-yl)-N- methylpicolinamide 2cis-a, 2cis-b racemic mixture (38 mg, 0.08 mmol) was separated by SFC (Column: DAICEL IH 20 mm I.D. x 250 mm, 5 pm; 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 2cis-a (8.6 mg, 95.49 % purity, ee%: 100, white solid) and the second fraction as 2cis-b (10.7 mg, 97.15 % purity, ee%: 100, white solid). 2cis-a1H NMR (400 MHz, DMSO-d6, ppm) δ: 11.80 (s, 1 H), 8.44-8.35 (m, 1 H), 8.29 (d, J = 2.4 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1 H), 7.75 (dd, J = 9.2, 2.4 Hz, 1 H), 7.71-7.63 (m, 1 H), 7.59-7.51 (m, 1H), 7.42 (dd, J = 8.8, 2.8 Hz, 1 H), 6.50 (s, 1 H), 3.53-3.35 (m, 4 H), 3.14-3.01 (m, 1 H), 2.79 (d,J = 4.8 Hz, 3 H), 2.75-2.69 (m, 1 H), 2.69-2.60 (m, 4 H), 2.23-2.06 (m, 2 H), 1.93-1.83 (m, 1 H),1.82-1.72 (m, 2 H), 1.71-1.59 (m, 1 H).NOE experiments suggested cis stereochemistry for this compound.LCMS (ESI) calcd for C25H28FN5O2 [M + H] + m / z 450.22, found 450.40.2cis-b1H NMR (400 MHz, DMSO-d6, ppm) δ: 11.80 (s, 1 H), 8.48-8.35 (m, 1 H), 8.29 (d, J = 2.4 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1 H), 7.75 (dd, J = 9.2, 2.4 Hz, 1 H), 7.70-7.63 (m, 1 H), 7.59-7.50 (m, 1H), 7.42 (dd, J = 8.8, 2.8 Hz, 1 H), 6.50 (s, 1 H), 3.52-3.35 (m, 4 H), 3.14-3.00 (m, 1 H), 2.79 (d,J = 4.8 Hz, 3 H), 2.75-2.69 (m, 1 H), 2.69-2.61 (m, 4 H), 2.23-2.05 (m, 2 H), 1.94-1.82 (m, 1 H),1.81-1.72 (m, 2 H), 1.71-1.58 (m, 1 H).NOE experiments suggested cis stereochemistry for this compound.LCMS (ESI) calcd for C25H28FN5O2 [M + H] + m / z 450.22, found 450.40.Preparation of 5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)cyclopentyl)piperazin-1-yl)-N-methylpicolinamide (2trans-a and 2trans-b)5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)cyclopentyl)piperazin-1-yl)-N-methylpicolinamide 2trans-a, 2trans-b racemic mixture (68 mg, 0.15 mmol) was separated bySFC (Column: DAICEL IH 20 mm I.D. × 250 mmL, 5 μm; Mobile phase: CO2 / MeOH [0.1 % NH3(7 M Solution in MeOH)] = 60 / 40) and concentrated under reduced pressure to afford the firstfraction as 2trans-a (18.0 mg, 98.04 % purity, ee%: 100, white solid) and the second fractionas 2trans-b (16.0 mg, 97.86 % purity, ee%: 100, white solid). 2trans-a1H NMR (400 MHz, DMSO-d6, ppm) δ: 11.32 (s, 1 H), 8.43-8.33 (m, 1 H), 8.27 (d, J = 2.8 Hz, 1H), 7.86-7.80 (m, 1 H), 7.77 (dd, J = 9.6, 2.8 Hz, 1 H), 7.72-7.65 (m, 1 H), 7.59-7.50 (m, 1 H),7.39 (dd, J = 8.8, 2.8 Hz, 1 H), 6.47 (s, 1 H), 3.35-3.32 (m, 4 H), 3.11-2.99 (m, 1 H), 2.90-2.80(m, 1 H), 2.78 (d, J = 4.8 Hz, 3 H), 2.61-2.55 (m, 4 H), 2.12-1.95 (m, 3 H), 1.91-1.80 (m, 1 H),1.76-1.64 (m, 1 H), 1.62-1.48 (m, 1 H).NOE experiments suggested trans stereochemistry for this compound.LCMS (ESI) calcd for C25H28FN5O2 [M + H] + m / z 450.22, found 450.40.2trans-b1H NMR (400 MHz, DMSO-d6, ppm) δ: 11.32 (s, 1 H), 8.42-8.33 (m, 1 H), 8.27 (d, J = 2.4 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1 H), 7.77 (dd, J = 9.2, 2.4 Hz, 1 H), 7.73-7.64 (m, 1 H), 7.60-7.51 (m, 1H), 7.39 (dd, J = 8.8, 2.8 Hz, 1 H), 6.47 (s, 1 H), 3.35-3.32 (m, 4 H), 3.12-3.00 (m, 1 H), 2.89-2.81(m, 1 H), 2.78 (d, J = 4.8 Hz, 3 H), 2.61-2.55 (m, 4 H), 2.12-1.93 (m, 3 H), 1.90-1.80 (m, 1 H),1.76-1.64 (m, 1 H), 1.60-1.48 (m, 1 H).NOE experiments suggested trans stereochemistry for this compound.LCMS (ESI) calcd for C25H28FN5O2 [M + H] + m / z 450.22, found 450.40.

[0456] Example 3: synthesis oflcis-a, Icis-b, Itrans-a, Itrans-b

[0457] SCHEME 3

[0458] Preparation of 3-chloro-l-methoxyisoquinoline (1202)

[0459] To a solution of 1,3-dichloroisoquinoline 1201 (5.0 g, 25.2 mmol) in MeOH (100 mL) was added MeONa (4.1 g, 75.6 mmol). The mixture was heated at 80 °C for 16 hours. The resulting mixture was diluted with water (500 mL) and extracted with EtOAc (200 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, 30 % to 60 %) to give 3-chloro-l-methoxyisoquinoline 1202 (5.0 g, 90 % purity, 92 % yield) as a white solid.

[0460] LCMS (ESI) calcd for CI0H8CINO [M + H]+m / z 194.03, found 193.90.

[0461] Preparation of 3-(l-methoxyisoquinolin-3-yl)cyclopent-2-en-l-one (1203)

[0462] A mixture of 3-chloro-l-methoxyisoquinoline 1202 (1.00 g, 5.20 mmol), 3-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)cyclopent-2-en-l-one 1002 (1.62 g, 7.80 mmol), RuPhos Pd G3 (CAS No. 1445085-77-7, 0.44 g, 0.52 mmol), RuPhos (CAS No. 787618-22-8, 0.73 g, 1.56 mmol) and Na2COs (1.65 g, 15.60 mmol) in dioxane (30 mL) and H2O (3 mL) was heated at 100 °C for 2 hours under an atmosphere of N2. 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 phases were washed with water and brine, dried over sodium sulfate, concentrated under vacuum, and purified by flash chromatography (eluting with EtOAc / PE, 30 % to 60 %) to obtain 3-(l-methoxyisoquinolin-3- yl)cyclopent-2-en-l-one 1203 (1 g, 90 % purity, 73 % yield) as a white solid.

[0463] LCMS (ESI) calcd for C15H13NO2 [M + H]+m / z 240.10, found 239.90.

[0464] Preparation of benzyl 4-(3-(l-methoxyisoquinolin-3-yl)cyclopent-2-en-l-yl)piperazine-l- carboxylate (1205)

[0465] To a solution of 3-(l-methoxyisoquinolin-3-yl)cyclopent-2-en-l-one 1203 (1.0 g, 4.2 mmol) in MeOH (30 mL) were added benzyl piperazine-l-carboxylate 1204 (1.4 g, 6.3 mmol), AcOH (0.5 g, 8.4 mmol) and NaBHsCN (2.64 g, 41.9 mmol) at room temperature. The reaction mixture was stirred at 60 °C for 24 h. The resulting solution was quenched with water and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with EtOAc / PE, 50 % to 70 %) to give a mixture of benzyl 4-(3-(l-methoxyisoquinolin- 3-yl)cyclopent-2-en-l-yl)piperazine-l-carboxylate 1205 and benzyl 4-(3-(l- methoxyisoquinolin-3-yl)cyclopentyl)piperazine-l-carboxylate 1205a (1.2 g, 90 % purity, ~57 % yield) as a white solid. LCMS (ESI) calcd for C27H29N3O3 [M + H] + m / z 444.22, found 444.05.

[0466] Preparation of l-methoxy-3-(3-(piperazin-l-yl)cyclopentyl)-5,6,7,8-tetrahydroisoquinoline (1206)

[0467] To a solution of a mixture of benzyl 4-(3-(l-methoxyisoquinolin-3-yl)cyclopent-2-en-l- yl)piperazine-l-carboxylate 1205 and benzyl 4-(3-(l-methoxyisoquinolin-3- yl)cyclopentyl)piperazine-l-carboxylate 1205a (1.2 g, ~2.7 mmol) in TFA (20 mL) was added PtC>2 (0.6 g, 2.7 mmol). The mixture was evacuated and backfilled with hydrogen three times and then charged with hydrogen. The resulting mixture was stirred at room temperature for 16 hours under H2 atmosphere. The mixture was filtered through celite, and the filtrate was concentrated under vacuum to give crude l-methoxy-3-(3-(piperazin-l-yl)cyclopentyl)- 5,6,7,8-tetrahydroisoquinoline 1206 (1.2 g, 60 % purity, 85 % yield) as a yellow oil which was used directly in next step without further purification.

[0468] LCMS (ESI) calcd for C19H29N3O [M + H]+m / z 316.23, found 316.20.

[0469] Preparation of methyl 5-(4-(3-(l-methoxy-5,6,7,8-tetrahydroisoquinolin-3- yl)cyclopen tyl)piperazin-l -yl)picolin ate (1208)

[0470] To a solution of l-methoxy-3-(3-(piperazin-l-yl)cyclopentyl)-5,6,7,8-tetrahydroisoquinoline 1206 (1.1 g, 3.5 mmol) in DMSO (30 mL) were added methyl 5-fluoropicolinate 1207 (0.8 g, 5.2 mmol) and DIPEA (2.3 g, 17.5 mmol). The mixture was heated at 100 °C for 1 h. The resulting mixture was diluted with water (200 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, 50 % to 80 %) to give methyl 5-(4-(3-(l-methoxy-5,6,7,8-tetrahydroisoquinolin-3-yl)cyclopentyl)piperazin-l- yl)picoli nate 1208 (500 mg, 90 % purity, 28 % yield) as a white solid.

[0471] LCMS (ESI) calcd for C26H34N4O3 [M + H]+m / z 451.27, found 451.20. Preparation of 5-(4-(3-(l-methoxy-5,6,7,8-tetrahydroisoquinolin-3- yl)cyclopentyl)piperazin-l-yl)-N-methylpicolinamide (1209)

[0472] A solution of methyl 5-(4-(3-(l-methoxy-5,6,7,8-tetrahydroisoquinolin-3- yl)cyclopentyl)piperazin-l-yl)picolinate 1208 (500 mg, 1.1 mmol) in MeNH2-MeOH (10 mL, 30% wt.) was heated at 80 °C for 2 hours. The resulting mixture was concentrated to give 5- (4-(3-(l-methoxy-5,6,7,8-tetrahydroisoquinolin-3-yl)cyclopentyl)piperazin-l-yl)-N- methylpicolinamide 1209 (500 mg, 90 % purity, 90 % yield) as a yellow solid.

[0473] LCMS (ESI) calcd for C26H35N5O2 [M + H]+m / z 450.28, found 450.30.

[0474] Preparation of N-methyl-5-(4-(3-(l-oxo-l,2,5,6,7,8-hexahydroisoquinolin-3- yl)cyclopentyl)piperazin-l-yl)picolinamide (Icis-a / lcis-b / ltrans-a / Itrans-b)

[0475] To a solution of 5-(4-(3-(l-methoxy-5,6,7,8-tetrahydroisoquinolin-3-yl)cyclopentyl)piperazin- l-yl)-N-methylpicolinamide 1209 (500 mg, 1.11 mmol) in ACN (20 mL) was added TMSI (667 mg, 3.34 mmol). The mixture was heated at 50 °C for 2 hours. The resulting mixture was diluted with water (200 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 MeOH / DCM, 5 % to 10 %). The resulting solid was separated by SFC (Column: Torus 2-PIC OBD 20 mm LD. x 250 mm, 5 pm; Mobile phase: CCh / MeOH [0.1 % (NH3)] = 25 / 75) to afford the first fraction as N-methyl-5-(4-(3-(l-oxo- l,2,5,6,7,8-hexahydroisoquinolin-3-yl)cyclopentyl)piperazin-l-yl)picolinamide lcis-a / lcis-b racemic mixture (cis, 20 mg, 90 % purity, 3 % yield, white solid) and the second fraction as N- methyl-5-(4-(3-(l-oxo-l,2,5,6,7,8-hexahydroisoquinolin-3-yl)cyclopentyl)piperazin-l- yl)picolinamide ltrans-a / ltrans-b racemic mixture (trans, 20 mg, 90 % purity, 3 % yield, white solid).

[0476] Preparation of N-methyl-5-(4-(3-(l-oxo-l,2,5,6,7,8-hexahydroisoquinolin-3- yl)cyclopentyl)piperazin-l-yl)picolinamide (lcis-a and lcis-b) lcis-a / lcis-b racemic mixture was separated by SFC (Column: Daicel Chiralpak-IH 20 mm LD. x 250 mm, 5 pm; Mobile phase: CCh / MeOH [0.1 % (NH3)] = 70 / 30) and concentrated under reduced pressure to afford the first fraction as lcis-a (4.0 mg, 99.00 % purity, 100 % ee, white solid) and the second fraction as lcis-b (4.0 mg, 95.74 % purity, 100 % ee, white solid). 1cis-a1H NMR (400 MHz, DMSO-d6, ppm) δ: 11.50 (s, 1 H), 8.45-8.33 (m, 1 H), 8.28 (s, 1 H), 7.84 (d,J = 8.8 Hz, 1 H), 7.47-7.34 (m, 1 H), 5.81 (s, 1 H), 3.48-3.35 (m, 4 H), 3.02-2.89 (m, 1 H), 2.78(d, J = 4.8 Hz, 3 H), 2.69-2.60 (m, 5 H), 2.45-2.40 (m, 2 H), 2.28-2.21 (m, 2 H), 2.13-1.96 (m, 2H), 1.86-1.72 (m, 2 H), 1.68-1.53 (m, 6 H).NOE experiments suggested cis stereochemistry for this compound.LCMS (ESI) calcd for C25H33N5O2 [M + H] + m / z 436.27, found 436.20.1cis-b1H NMR (400 MHz, DMSO-d6, ppm) δ: 11.50 (s, 1 H), 8.40 (q, J = 4.6 Hz, 1 H), 8.27 (d, J = 2.8Hz, 1 H), 7.84 (d, J = 8.8 Hz, 1 H), 7.40 (dd, J = 8.8, 2.8 Hz, 1 H), 5.81 (s, 1 H), 3.50-3.40 (m, 4H), 3.01-2.88 (m, 1 H), 2.78 (d, J = 4.8 Hz, 3 H), 2.67-2.58 (m, 5 H), 2.45-2.41 (m, 2 H), 2.29-2.22 (m, 2 H), 2.12-1.98 (m, 2 H), 1.85-1.71 (m, 2 H), 1.67-1.53 (m, 6 H).NOE experiments suggested cis stereochemistry for this compound.LCMS (ESI) calcd for C25H33N5O2 [M + H] + m / z 436.27, found 436.25.Preparation of N-methyl-5-(4-(3-(1-oxo-1,2,5,6,7,8-hexahydroisoquinolin-3-yl)cyclopentyl)piperazin-1-yl)picolinamide (1trans-a and 1trans-b)1trans-a / trans-b racemic mixture was separated by SFC (Column: Daicel Chiralpak-IH 20 mmI.D. × 250 mm, 5 μm; Mobile phase: CO2 / MeOH [0.1 % (NH3)] = 70 / 30) and concentrated underreduced pressure to afford the first fraction as 1trans-a (5.2 mg, 99.16 % purity, 100% ee,white solid) and the second fraction as 1trans-b (5.2 mg, 99.39 % purity, 100% ee, white solid).1trans-a1H NMR (400 MHz, DMSO-d6, ppm) δ: 11.11 (s, 1 H), 8.48-8.35 (m, 1 H), 8.26 (d, J = 2.8 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1 H), 7.39 (dd, J = 8.8, 2.8 Hz, 1 H), 5.77 (s, 1 H), 3.31-3.28 (m, 4 H), 2.99-2.87 (m, 1 H), 2.85-2.74 (m, 4 H), 2.57-2.53 (m, 4 H), 2.46-2.41 (m, 2 H), 2.29-2.23 (m, 2 H),2.03-1.88 (m, 3 H), 1.82-1.68 (m, 1 H), 1.67-1.44 (m, 6 H).NOE experiments suggested trans stereochemistry for this compound.LCMS (ESI) calcd for C25H33N5O2 [M + H] + m / z 436.27, found 436.25.1trans-b1H NMR (400 MHz, DMSO-d6, ppm) δ: δ 11.12 (s, 1 H), 8.49-8.32 (m, 1 H), 8.26 (s, 1 H), 7.83(d, J = 8.4 Hz, 1 H), 7.48-7.26 (m, 1 H), 5.77 (s, 1 H), 3.31-3.29 (m, 4 H), 2.96-2.88 (m, 1 H),2.81-2.72 (m, 4 H), 2.57-2.53 (m, 4 H), 2.46-2.42 (m, 2 H), 2.30-2.23 (m, 2 H), 2.00-1.91 (m, 3H), 1.79-1.71 (m, 1 H), 1.64-1.46 (m, 6 H).NOE experiments suggested trans stereochemistry for this compound.LCMS (ESI) calcd for C25H33N5O2 [M + H] + m / z 436.27, found 436.25.

[0477] Example 4: synthesis of 16cis-a, 16cis-b, 16trans-a, 16trans-b F F SCHEME 4Preparation of 3-chloro-7-fluoro-1-methoxyisoquinoline (1302)To a solution of 1,3-dichloro-7-fluoroisoquinoline 1301 (5 g, 0.023 mol) in MeOH (100 mL)was added CH3ONa (4.99 g, 0.092 mol). The mixture was stirred at 65 °C for 4 h. The reactionsolution was concentrated under reduced pressure. The residue was purified by flashchromatography (eluting with DCM / MeOH = 100: 0 to 90: 10) to give 3-chloro-7-fluoro-1-methoxyisoquinoline 1302 (4.5 g, 90 % purity, 83 % yield) as a white solid.LCMS (ESI) calcd for C10H7ClFNO [M + H] + m / z 212.02, found 211.85.Preparation of 3-(7-fluoro-1-methoxyisoquinolin-3-yl)cyclohex-2-en-1-one (1304)To a solution of 3-chloro-7-fluoro-1-methoxyisoquinoline 1302 (3000 mg, 14.18 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-en-1-one 1303 (4093 mg, 18.43mmol) and RuPhos Pd G3 (CAS No. 1445085-77-7) (1187 mg, 1.42 mmol) in dioxane / H2O = 10: 1 (60 mL) was added Na2CO3 (4508 mg, 42.53 mmol) under N2. The reaction mixture wasstirred at 100 °C for 3 h. The reaction solution was cooled to rt, quenched with water, andextracted with EtOAc (200 mL × 4). The combined organic layer was washed with brine, driedover Na2SO4, and concentrated under reduced pressure. The residue was purified by flashchromatography (eluting with PE / EtOAc = 100: 0 to 50: 50) to give 3-(7-fluoro-1-methoxyisoquinolin-3-yl)cyclohex-2-en-1-one 1304 (3200 mg, 80 % purity, 67 % yield) as ayellow solid. LCMS (ESI) calcd for C16H14FNO2[M + H]+m / z 272.10, found 271.90.Preparation of 5-(4-(3-(7-fluoro-1-methoxyisoquinolin-3-yl)cyclohex-2-en-1-yl)piperazin-1-yl)-N-methylpicolinamide (1305)To a solution of 3-(7-fluoro-1-methoxyisoquinolin-3-yl)cyclohex-2-en-1-one 1304 (1500 mg,5.53 mmol) in EtOH (40 mL) was added N-methyl-5-(piperazin-1-yl)picolinamide 1004 (1462mg, 6.64 mmol) and 10 drops of HOAc, then NaBH(OAc)3 (2344 mg, 11.06 mmol) was added.The reaction was stirred for 10 min, then NaBH3CN (347 mg, 5.53 mmol) was added and themixture was stirred at 100 °C for 16 h. The reaction mixture was concentrated under reducedpressure and the residue was purified by flash chromatography (eluting with DCM / MeOH =100 : 0 to 90: 10) to give a mixture of 1305 and 1306 (1100 mg, 80 % purity, 33 % yield) as ayellow solid.LCMS (ESI) calcd for C27H30FN5O2 [M + H] + m / z 476.24, found 476.20.Preparation of 5-(4-(3-(7-fluoro-1-methoxyisoquinolin-3-yl)cyclohexyl)piperazin-1-yl)-N-methylpicolinamide (1306)To a mixture of 1305 and 1306 (1000 mg) in MeOH (20 mL) was added Pd(OH)2 / C (500 mg).The reaction mixture was degassed with H2 and stirred at 50 °C for 16 h under H2. The resultingsolution was filtered through a celite pad, and the filtrate was concentrated under reducedpressure to give 5-(4-(3-(7-fluoro-1-methoxyisoquinolin-3-yl)cyclohexyl)piperazin-1-yl)-N-methylpicolinamide 1306 (1000 mg, 60 % purity, 60 % yield) as a yellow solid.LCMS (ESI) calcd for C27H32FN5O2[M + H]+m / z 478.25, found 478.35. Preparation of 5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)cyclohexyl)piperazin-1- yl)-N-methylpicolinamide (16cis-rac and 16trans-rac) To a solution of 5-(4-(3-(7-fluoro-1-methoxyisoquinolin-3-yl)cyclohexyl)piperazin-1-yl)-N-methylpicolinamide 1306 (1000 mg, 2.09 mmol) in ACN (20 mL) was added TMSI (1676 mg,8.38 mmol). The mixture was stirred at 50 °C for 2 h. The mixture was concentrated underreduced pressure. The residue was purified by flash chromatography (eluting with DCM / MeOH = 100 : 0 to 90: 10) to give 5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)cyclohexyl)piperazin-1-yl)-N-methylpicolinamide 16cis-rac (80 mg, 95 % purity, 8 % yield)as a white solid and 16trans-rac (40 mg, 95 % purity, 4 % yield) as a white solid.Preparation of 5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)cyclohexyl)piperazin-1- yl)-N-methylpicolinamide (16cis-a and 16cis-b)16cis-rac was separated by SFC (Column: DAICEL AS-H 20 mm I.D. × 250 mmL 5 μm; Mobilephase: CO2 / MEOH [0.1 % NH3 (7 M Solution in MeOH)]=60 / 40) and concentrated underreduced pressure to afford the first fraction as 16cis-a (cis, 33.7 mg, 99 % purity, ee%: 100, 3% yield, white solid) and the second fraction as 16cis-b (cis, 30.6 mg, 99 % purity, ee%: 100, 3% yield, white solid).16cis-a1H NMR (400 MHz, DMSO-d6, ppm) δ: 11.33 (s, 1 H), 8.47-8.35 (m, 1 H), 8.26 (d, J = 2.8 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1 H), 7.77 (dd, J = 9.6, 2.8 Hz, 1 H), 7.72-7.65 (m, 1 H), 7.60-7.52 (m, 1H), 7.39 (dd, J = 9.0, 3.0 Hz, 1 H), 6.44 (s, 1 H), 3.31-3.27 (m, 4 H), 2.78 (d, J = 4.8 Hz, 3 H), 2.73- 2.65 (m, 4 H), 2.55-2.51 (m, 2 H), 2.10-2.03 (m, 1 H), 1.92-1.80 (m, 3 H), 1.55-1.43 (m, 1 H), 1.40-1.19 (m, 3 H). Cis stereochemistry assigned based on NOE experiments. LCMS (ESI) calcd for C26H30FN5O2 [M + H]+m / z 464.24, found 464.10. 16cis-b1H NMR (400 MHz, DMSO-d6, ppm) δ: 11.33 (s, 1 H), 8.44-8.33 (m, 1 H), 8.28-8.22 (m, 1 H), 7.85-7.79 (m, 1 H), 7.79-7.75 (m, 1 H), 7.72-7.64 (m, 1 H), 7.60-7.51 (m, 1 H), 7.42-7.34 (m, 1H), 6.44 (s, 1 H), 3.31-3.24 (m, 4 H), 2.78 (d, J = 4.8 Hz, 3 H), 2.73-2.63 (m, 4 H), 2.56-2.51 (m,2 H), 2.11-2.01 (m, 1 H), 1.92-1.80 (m, 3 H), 1.56-1.43 (m, 1 H), 1.41-1.21 (m, 3 H). Cis stereochemistry assigned based on NOE experiments. LCMS (ESI) calcd for C26H30FN5O2[M + H]+m / z 464.24, found 464.05. Preparation of 5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)cyclohexyl)piperazin-1- yl)-N-methylpicolinamide (16trans-a and 16trans-b)16trans-rac was separated by SFC (Column: DAICEL AS-H 20 mm I.D. × 250 mmL 5 μm; Mobilephase: CO2 / MeOH [0.1 % NH3 (7 M Solution in MeOH)] = 60 / 40) and concentrated underreduced pressure to afford the first fraction as 16trans-a (trans, 11.8 mg, 99 % purity, ee%:100, 3 % yield, white solid) and the second fraction as 16trans-b (trans-, 12.7 mg, 99 % purity,ee%: 100, 1 % yield, white solid).16trans-a1H NMR (400 MHz, DMSO-d6, ppm) δ: 11.34 (s, 1 H), 8.47-8.34 (m, 1 H), 8.28 (d, J = 2.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1 H), 7.77 (dd, J = 9.4, 2.6 Hz, 1 H), 7.73-7.65 (m, 1 H), 7.60-7.52 (m, 1H), 7.41 (dd, J = 8.8, 2.8 Hz, 1 H), 6.45 (s, 1 H), 3.46-3.33 (m, 4 H), 2.97-2.86 (m, 1 H), 2.78 (d,J = 4.8 Hz, 3 H), 2.70-2.55 (m, 4 H), 2.39-2.35 (m, 1 H), 2.16-2.07 (m, 1 H), 2.02-1.85 (m, 2 H),1.81-1.66 (m, 2 H), 1.64-1.38 (m, 3 H). Trans stereochemistry assigned based on NOE experiments. LCMS (ESI) calcd for C26H30FN5O2 [M + H]+m / z 464.24, found 464.10. 16trans-b1H NMR (400 MHz, DMSO-d6, ppm) δ: 11.34 (s, 1 H), 8.46-8.36 (m, 1 H), 8.28 (d, J = 2.8 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1 H), 7.77 (dd, J = 9.4, 2.6 Hz, 1 H), 7.73-7.66 (m, 1 H), 7.60-7.53 (m, 1H), 7.41 (dd, J = 8.8, 2.8 Hz, 1 H), 6.45 (s, 1 H), 3.46-3.33 (m, 4 H), 2.99-2.86 (m, 1 H), 2.78 (d,J = 4.8 Hz, 3 H), 2.70-2.55 (m, 4 H), 2.39-2.35 (m, 1 H), 2.16-2.07 (m, 1 H), 2.02-1.85 (m, 2 H),1.80-1.66 (m, 2 H), 1.64-1.39 (m, 3 H). Trans stereochemistry assigned based on NOE experiments. LCMS (ESI) calcd for C26H30FN5O2[M + H]+m / z 464.24, found 464.10.

[0478] Example 5: synthesis of26cis and 26trans Preparation of N-methoxy-N-methyl-3-oxocyclobutane-l-carboxamide (1402)

[0479] To a solution of 3-oxocyclobutane-l-carboxylic acid 1401 (5 g, 43.86 mmol) and N,O- dimethylhydroxylamine hydrochloride (15 g, 154.64 mmol) in DCM (100 mL) were added DIEA (10 g, 77.52 mmol) and T4P (50 % wt in EtOAc, 40 g, 55.56 mmol) successively. The reaction mixture was stirred at rt for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with DCM / MeOH = 100:0 to 99:1) to afford N-methoxy-N-methyl-3-oxocyclobutane-l-carboxamide 1402 (5 g, 72 % yield) as a colourless oil.

[0480] LCMS (ESI) calcd for C7H11NO3 [M + H]+m / z 158.07, found 158.00.

[0481] Preparation of benzyl 4-(3-(methoxy(methyl)carbamoyl)cyclobutyl)piperazine-l- carboxylate (1403)

[0482] To a solution of N-methoxy-N-methyl-3-oxocyclobutane-l-carboxamide 1402 (5 g, 31.85 mmol) and benzyl piperazine-l-carboxylate (10 g, 63.69 mmol) in MeOH (60 mL) was added 10 drops of acetic acid, then after 10 mins NaBHsCN (3 g, 48.39 mmol) was added. The reaction mixture was stirred at rt for 1 h. The reaction mixture was 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-(3-

[0483] (methoxy(methyl)carbamoyl)cyclobutyl)piperazine-l-carboxylate 1403 (5 g, 43 % yield) as a yellow oil.

[0484] LCMS (ESI) calcd for C17H27N3O4 [M + H]+m / z 362.20, found 362.10.

[0485] Preparation of benzyl 4-(3-formylcyclobutyl)piperazine-l-carboxylate (1404)

[0486] To a solution of benzyl 4-(3-(methoxy(methyl)carbamoyl)cyclobutyl)piperazine-l-carboxylate 1403 (5 g, 13.85 mmol) in THF (80 mL) was added DIBAL-H (IM in Hexane, 20 mL, 20 mmol) at -78 °C . The reaction mixture was stirred at -78 °C for 1 h. The reaction mixture was quenched with water, then extracted with EtOAc (100 mL x 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 96:4) to afford benzyl 4-(3- formylcyclobutyl)piperazine-l-carboxylate 1404 (2.8 g, 66 % yield) as a yellow oil. LCMS (ESI) calcd for C11H17NO3 [M + H]+m / z 303.16, found 303.10.

[0487] Preparation of benzyl 4-(3-ethynylcyclobutyl)piperazine-l-carboxylate (1406)

[0488] To a solution of benzyl 4-(3-formylcyclobutyl)piperazine-l-carboxylate 1404 (1.4 g, 4.64 mmol) in MeOH (30 mL) was added dimethyl (l-diazo-2-oxopropyl)phosphonate 1405 (2.8 g, 14.58 mmol) and K2CO3 (2.0 g, 14.49 mol) successively. The reaction mixture was stirred at rt for 1 h. The reaction was quenched with water and the aqueous layer was extracted with EtOAc (100 mL x 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 96:4) to afford benzyl 4-(3-ethynylcyclobutyl)piperazine-l-carboxylate 1406 (800 mg, 57 % yield) as a yellow oil.

[0489] LCMS (ESI) calcd for C18H22N2O2 [M + H]+m / z 299.17, found 299.10.

[0490] Preparation of benzyl 4-(3-(8-chloro-7-fluoro-l-oxo-l,2-dihydroisoquinolin-3- yl)cyclobutyl)piperazine-l-carboxylate (1408)

[0491] To a solution of benzyl 4-(3-ethynylcyclobutyl)piperazine-l-carboxylate 1406 (800 mg, 2.68 mol) in MeOH (35 mL) were added tert-butyl 4-ethynyl-2-azabicyclo[2.1.1]hexane-2- carboxylate 1407 (1 g, 3.66 mmol), AcOCs (1 g, 5.21 mol) and [Rh(Cp*)Cl2]2 (150 mg, 0.24 mol) successively. The reaction mixture was stirred at 45 °C for 18 h. The reaction solution was concentrated under reduced pressure and the residue was purified by flash column chromatography (eluting with DCM / MeOH = 100:0 to 96:4) to afford benzyl 4-(3-(8-chloro-7- fluoro-l-oxo-l,2-dihydroisoquinolin-3-yl)cyclobutyl)piperazine-l-carboxylate 1408 (200 mg, 15 % yield) as a yellow solid.

[0492] LCMS (ESI) calcd for C25H25FCIN3O3 [M + H]+m / z 470.16, found 470.15.

[0493] Preparation of 7-fluoro-3-(3-(piperazin-l-yl)cyclobutyl)isoquinolin-l(2H)-one (1409)

[0494] To a solution of benzyl 4-(3-(8-chloro-7-fluoro-l-oxo-l,2-dihydroisoquinolin-3- yl)cyclobutyl)piperazine-l-carboxylate 1408 (200 mg, 0.43 mol) in IPA (30 mL) was added Pd / C (50 mg, 0.47 mmol). The reaction mixture was stirred under H2 at 70 °C for 18 h. The mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to afford 7-fluoro-3-(3-(piperazin-l-yl)cyclobutyl)isoquinolin-l(2H)-one 1409 (100 mg, 77 % yield) as a yellow solid.

[0495] LCMS (ESI) calcd for C17H20FN3O [M + H]+m / z 302.16, found 302.10.

[0496] Preparation of methyl 5-(4-(3-(7-fluoro-l-oxo-l,2-dihydroisoquinolin-3- yl)cyclobutyl)piperazin-l-yl)picolinate (1411)

[0497] To a solution of 7-fluoro-3-(3-(piperazin-l-yl)cyclobutyl)isoquinolin-l(2H)-one 1409 (100 mg, 0.33 mol) in DMSO (10 mL) was added methyl 5-fluoropicolinate 1410 (100 g, 0.64 mmol) and DIEA (2.5 mL) successively. The reaction mixture was stirred at 120 °C for 18 h. The reaction was quenched with water and the aqueous layer was extracted with EtOAc (100 mL x 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 94:6) to afford methyl 5-(4-(3-(7-fluoro-l-oxo-l,2-dihydroisoquinolin-3-yl)cyclobutyl)piperazin-l- yl)picoli nate 1411 (70 mg, 48 % yield) as a yellow solid.

[0498] LCMS (ESI) calcd for C24H25FN4O3 [M + H]+m / z 437.19, found 437.10.

[0499] Preparation of 5-(4-(3-(7-fluoro-l-oxo-l,2-dihydroisoquinolin-3-yl)cyclobutyl)piperazin-l- yl)-N-methylpicolinamide (26cis / trans mixture)

[0500] Methyl 5-(4-(3-(7-fluoro-l-oxo-l,2-dihydroisoquinolin-3-yl)cyclobutyl)piperazin-l- yl)picolinate 1411 (70 mg, 0.16 mmol) was added to MeNFh in MeOH (30-33 % wt, 10 mL) portionwise. The reaction mixture was stirred in a sealed tube at 100 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column : Gemini - C18 150 x 21.2 mm, 5 urn; mobile phase : ACN - H2O (0.05 % NH3); gradient : 30 - 85) to give 5-(4-(3-(7-fluoro-l-oxo-l,2-dihydroisoquinolin-3-yl)cyclobutyl)piperazin-l- yl)-N-methylpicolinamide 26cis / trans mixture (25 mg, 35 % yield) as a white solid.

[0501] LCMS (ESI) calcd for C24H26FN5O2 [M + H]+m / z 436.21, found 436.15. Preparation of 5-(4-((1s,3s)-3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)cyclobutyl)piperazin-1-yl)-N-methylpicolinamide (26cis) &5-(4-((1r,3r)-3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)cyclobutyl)piperazin-1-yl)-N-methylpicolinamide(26trans) 5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)cyclobutyl)piperazin-1-yl)-N-methylpicolinamide 26cis / trans mixture (25 mg, 0.05 mmol) was separated by SFC (Column:DAICEL OJ-H 4.6mm *250 mmL 5μm; Mobile phase: CO2 / MeOH[0.1 % NH3 (7 M solution inMeOH)]=65 / 35) and concentrated under reduced pressure to afford as a first fraction 26cis(12 mg, 99 % purity, white solid), and as a second fraction 26trans (0.9 mg, 97 % purity, whitesolid). 26cis1H NMR (400 MHz, DMSO) δ 11.50 (s, 1 H), 8.39 (q, J = 4.4 Hz, 1 H), 8.31-8.25 (m, 1 H), 7.88-7.80 (m, 1 H), 7.79-7.67 (m, 2 H), 7.60-7.50 (m, 1 H), 7.45-7.37 (m, 1 H), 6.47 (s, 1 H), 3.38-3.32 (m, 4 H), 3.11-3.00 (m, 1 H), 2.83-2.72 (m, 4 H), 2.48-2.44 (m, 6 H), 2.00-1.88 (m, 2 H). Cis stereochemistry assigned based on NOE experiments. LCMS (ESI) calcd for C24H26FN5O2[M + H]+m / z 436.21, found 436.15. 26trans1H NMR (400 MHz, DMSO) δ 11.64 (s, 1 H), 8.40 (q, J = 4.8 Hz, 1 H), 8.31-8.25 (s, 1 H), 7.96 (d,J = 8.0 Hz, 1 H), 7.83 (d, J = 8.8 Hz, 1 H), 7.59-7.49 (m, 1 H), 7.46-7.38 (m, 2 H), 6.38 (s, 1 H),3.38-3.34 (m, 4 H), 3.15-3.07 (m, 1 H), 2.83-2.74 (m, 4 H), 2.56-2.54 (m, 2 H), 2.49-2.47 (m, 4 H), 2.02-1.93 (m, 2 H). Trans stereochemistry assigned based on NOE experiments. LCMS (ESI) calcd for C24H26FN5O2 [M + H]+m / z 436.21, found 436.15. Example 6: synthesis of31cis-a, 31cis-b, 31trans-a, 31trans-b '^

[0502] 31

[0503] SCHEME 6

[0504] Preparation of 3-chloro-7-fluoro-l-methoxyisoquinoline (1502)

[0505] To a solution of l,3-dichloro-7-fluoroisoquinoline 1501 (20 g, 92.60 mmol) in MeOH (300 mL) was added MeONa (5.5 g, 101.86 mmol). The mixture was stirred at 60 °C for 4 h. The mixture was quenched with water and extracted with EtOAc (300 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (PE / EtOAc = 100: 0 to 90: 10) to afford 3-chloro-7-fluoro-l- methoxyisoquinoline 1502 (14 g, 90 % purity, 64 % yield) as a white solid.

[0506] LCMS (ESI) calcd for C10H7CIFNO [M + H]+m / z 212.02, found 211.90.

[0507] Preparation of 7-fluoro-l-methoxy-3-vinylisoquinoline (1504)

[0508] To a solution of 3-chloro-7-fluoro-l-methoxyisoquinoline 1502 (14 g, 66.20 mmol) in ACN (200 mL) was added tributyl(vinyl)stannane 1503 (31.5 g, 99.30 mmol) and Pd(amphos)Cl2 (4.7 g, 6.62 mmol). The reaction mixture was stirred at 100 °C for 16 h under N2 atmosphere. The reaction solution was cooled to rt and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with PE / EtOAc = 100:0 to 70:30) to afford 7-fluoro-l-methoxy-3-vinylisoquinoline 1504 (9 g, 90 % purity, 60 % yield) as a white solid.

[0509] LCMS (ESI) calcd for C12H10FNO [M + H]+m / z 204.07, found 204.00.

[0510] Preparation of 7-fluoro-l-methoxyisoquinoline-3-carbaldehyde (1505)

[0511] To a solution of 7-fluoro-l-methoxy-3-vinylisoquinoline 1504 (9 g, 44.30 mmol) in dioxane / FhO (200 mL, 2:1) was added foOsCU^FhO (820 mg, 2.22 mmol) and NaICU (38 g, 177.20 mmol). The reaction mixture was stirred at rt for 6 h. The mixture was filtered through a Celite pad and the filtrate was diluted with water. The aqueous layer was extracted with EtOAc (300 mL x 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with PE / EtOAc = 100:0 to 60:40) to afford 7-fluoro-l-methoxyisoquinoline-3-carbaldehyde 1505 (3.5 g, 90 % purity, 34 % yield) as a white solid.

[0512] LCMS (ESI) calcd for CnH8FNO2[M + H] + m / z 206.05, found 206.00.

[0513] Preparation of l-(7-fluoro-l-methoxyisoquinolin-3-yl)but-3-en-l-ol (1507)

[0514] To a solution of 7-fluoro-l-methoxyisoquinoline-3-carbaldehyde 1505 (3.5 g, 17.10 mmol) in THF (80 mL) was added allylmagnesium bromide 1506 (34.2 mL, 34.2 mmol, 1 M in THF) at 0 °C under an N2 atmosphere. The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with aq. NH4CI and the aqueous layer was extracted with EtOAc (100 mL x 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with PE / EtOAc = 100:0 to 40:60) to afford l-(7-fluoro-l-methoxyisoquinolin-3-yl)but-3-en-l-ol 1507 (2.4 g, 90 % purity, 50 % yield) as a white solid.

[0515] LCMS (ESI) calcd for C14H14FNO2 [M + H]+m / z 248.10, found 248.00.

[0516] Preparation of4-(7-fluoro-l-methoxyisoquinolin-3-yl)butane-l,2,4-triol (1508)

[0517] To a solution of l-(7-fluoro-l-methoxyisoquinolin-3-yl)but-3-en-l-ol 1507 (2.4 g, 9.70 mmol) in THF / H2O (50 mL, 5:1) was added NMO (11.4 g, 97.0 mmol) and K2OsO4-2H2O (180 mg, 0.49 mmol). The reaction mixture was stirred at rt for 6 h. The reaction was diluted with H2O and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with DCM / MeOH = 100:0 to 90:10) to afford 4-(7-fluoro-l-methoxyisoquinolin-3-yl)butane-l,2,4-triol 1508 (1.3 g, 90 % purity, 43 % yield) as a colourless oil.

[0518] LCMS (ESI) calcd for CI4HI6FNO4[M + H]+m / z 282.11, found 282.05.

[0519] Preparation of 5-(7-fluoro-l-methoxyisoquinolin-3-yl)tetrahydrofuran-3-ol (1509)

[0520] To a solution of 4-(7-fluoro-l-methoxyisoquinolin-3-yl)butane-l,2,4-triol 1508 (1.3 g, 4.60 mmol) in toluene (15 mL) was added CMBP (2.2 g, 9.20 mmol). The reaction mixture was stirred at 100 °C for 2 h in a sealed tube. The reaction solution was cooled to rt and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with PE / EtOAc = 100:0 to 20:80) to afford 5-(7-fluoro-l- methoxyisoquinolin-3-yl)tetrahydrofuran-3-ol 1509 (750 mg, 90 % purity, 56 % yield) as a yellow solid.

[0521] LCMS (ESI) calcd for C14H14FNO3 [M + H]+m / z 264.10, found 264.10. Preparation of 5-(7-fluoro-l-methoxyisoquinolin-3-yl)dihydrofuran-3(2H)-one (1510)

[0522] To a solution of 5-(7-fluoro-l-methoxyisoquinolin-3-yl)tetrahydrofuran-3-ol 1509 (750 mg, 2.85 mmol) in DCM (25 mL) was added Dess-Martin periodinane (3.6 g, 8.55 mmol) at rt. The reaction mixture was stirred at rt for 6 h. The reaction mixture was quenched with aq. NaHCCh and the aqueous layer was extracted with DCM (50 mL x 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with PE / EtOAc = 100:0 to 50:50) to afford 5-(7-fluoro-l- methoxyisoquinolin-3-yl)dihydrofuran-3(2H)-one 1510 (520 mg, 90 % purity, 62 % yield) as a yellow solid.

[0523] LCMS (ESI) calcd for C14H12FNO3 [M + H]+m / z 262.08, found 262.05.

[0524] Preparation of 5-(4-(5-(7-fluoro-l-methoxyisoquinolin-3-yl)tetrahydrofuran-3-yl)piperazin- l-yl)-N-methylpicolinamide (1511)

[0525] To a solution of 5-(7-fluoro-l-methoxyisoquinolin-3-yl)dihydrofuran-3(2H)-one 1510 (520 mg, 1.99 mmol) in MeOH (10 mL) was added N-methyl-5-(piperazin-l-yl)picolinamide 1004 (658 mg, 2.99 mmol), AcOH (2 drops) and NaBHsCN (250 mg, 3.98 mmol). The reaction mixture was stirred at 50 °C for 2 h. The reaction mixture was quenched with water and the aqueous layer was extracted with EtOAc (30 mL x 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 95:5) to afford 5-(4-(5-(7-fluoro-l-methoxyisoquinolin-3- yl)tetrahydrofuran-3-yl)piperazin-l-yl)-N-methylpicolinamide 1511 (480 mg, 90 % purity, 46 % yield) as a white solid.

[0526] LCMS (ESI) calcd for C25H28FN5O3 [M + H]+m / z 466.22, found 466.11.

[0527] Preparation of 5-(4-(5-(7-fluoro-l-oxo-l,2-dihydroisoquinolin-3-yl)tetrahydrofuran-3- yl)piperazin-l-yl)-N-methylpicolinamide (compound 31)

[0528] To a solution of 5-(4-(5-(7-fluoro-l-methoxyisoquinolin-3-yl)tetrahydrofuran-3-yl)piperazin- l-yl)-N-methylpicolinamide 1511 (480 mg, 1.03 mmol) in ACN (15 mL) was added TMSI (619 mg, 3.09 mmol). The reaction mixture was stirred at 50 °C for 2 h. The reaction solution was cooled to rt and concentrated under reduced pressure. The residue was purified by flashcolumn chromatography (eluting with DCM / MeOH = 100:0 to 95:5) to give compound 31(mixture of cis- and trans-isomers). The mixture was separated by prep-HPLC (column : YMC-Actus Triar - C18150 × 21.2 mm, 5 µm; mobile phase : ACN - H2O (0.05% NH3); gradient : 30 -70) to give 31trans-rac (the first fraction, 5.01 mg, 99 % purity) as a white solid and 31cis-rac(the second fraction, 38 mg, 95 % purity) as a white solid.The 31cis-rac was then separated by SFC (Column: Chiralpak-OD-H SFC 30 mm I.D. × 250 mmL,10 μm; Mobile phase: CO2 / MeOH [0.1 % NH3 (7 M Solution in MeOH)] = 70 / 30) andconcentrated under reduced pressure to afford the first fraction as 31cis-a (9.2 mg, 99 %purity, ee%: 100, white solid) and the second fraction as 31cis-b (10.6 mg, 95 % purity, ee%:100, white solid). 31trans-rac1H NMR (400 MHz, DMSO-d6,, ppm) δ: 11.35 (s, 1H), 8.45-8.33 (m, 1 H), 8.27 (d, J = 2.8 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1 H), 7.81-7.72 (m, 2 H), 7.64-7.51 (m, 1 H), 7.40 (dd, J = 8.8, 2.8 Hz, 1H), 6.58 (s, 1 H), 4.86 (t, J = 7.0 Hz, 1 H), 4.26-4.15 (m, 1 H), 3.81-3.71 (m, 1 H), 3.37-3.32 (m,4 H), 3.15-3.02 (m, 1 H), 2.78 (d, J = 4.8 Hz, 3 H), 2.66-2.51 (m, 4 H), 2.37-2.29 (m, 1 H), 2.09-1.99 (m, 1 H).Trans stereochemistry assigned based on NOE experiments. LCMS (ESI) calcd for C24H26FN5O3[M + H]+m / z 452.20, found 452.35. 31cis-a1H NMR (400 MHz, DMSO-d6,, ppm) δ: 12.12 (s, 1 H), 8.46-8.36 (m, 1 H), 8.31 (d, J = 2.8 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1 H), 7.79-7.68 (m, 2 H), 7.67-7.51 (m, 1 H), 7.43 (dd, J = 8.8, 2.8 Hz, 1H), 6.64 (s, 1 H), 4.86-4.79 (m, 1 H), 4.27-4.17 (m, 1 H), 3.79-3.71 (m, 1 H), 3.57-3.37 (m, 4 H),3.07-2.94 (m, 1 H), 2.79 (d, J = 4.8 Hz, 3 H), 2.76-2.65 (m, 4 H), 2.47-2.44 (m, 1 H), 2.18-2.09(m, 1 H).Cis stereochemistry assigned based on NOE experiments. LCMS (ESI) calcd for C24H26FN5O3 [M + H] + m / z 452.20, found 452.35. 31cis-b1H NMR (400 MHz, DMSO-d6, ppm) δ: 12.13 (s, 1 H), 8.47-8.38 (m, 1 H), 8.31 (d, J = 2.8 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1 H), 7.80-7.70 (m, 2 H), 7.62-7.55 (m, 1 H), 7.44 (dd, J = 8.8, 2.8 Hz, 1H), 6.64 (s, 1 H), 4.89-4.77 (m, 1 H), 4.29-4.13 (m, 1 H), 3.82-3.69 (m, 1 H), 3.57-3.39 (m, 4 H),3.06-2.97 (m, 1 H), 2.79 (d, J = 4.8 Hz, 3 H), 2.76-2.66 (m, 4 H), 2.48-2.46 (m, 1 H), 2.20-2.07(m, 1 H).Cis stereochemistry assigned based on NOE experiments.LCMS (ESI) calcd for C24H26FN5O3[M + H]+m / z 452.20, found 452.35.

[0529] Example 7: synthesis of48cis-a, 48cis-b, 48trans-a, 48trans-b

[0530] SCHEME 7

[0531] Preparation of 5-(7-fluoro-l-methoxyisoquinolin-3-yl)-2H-pyran-3(6H)-one (1603)

[0532] To a solution of 3-chloro-7-fluoro-l-methoxyisoquinoline 1602 (4.7 g, 22.30 mmol) in dioxane / H2O (50 mL, 10:1) was added 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2H- pyran-3(6H)-one 1601 (5 g, 22.30 mmol), RuPhos Pd G3 (1.9 g, 2.23 mmol) and Na2CO3 (7.1 g, 66.90 mmol). The reaction mixture was stirred at 80 °C for 6 h under N2 atmosphere. The reaction solution was cooled to rt and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with PE / EtOAc = 100:0 to 60:40) to afford 5-(7-fluoro-l-methoxyisoquinolin-3-yl)-2H-pyran-3(6H)-one 1603 (580 mg, 90 % purity, 8 % yield) as a white solid. LCMS (ESI) calcd for C15H12FNO3 [M + H]+m / z 274.08, found 274.00.

[0533] Preparation of 5-(4-(5-( 7-fluoro-l -methoxyisoquinolin-3-yl)-3, 6-dihydro-2H-pyran-3- yl)piperazin-l-yl)-N-methylpicolinamide (1604)

[0534] To a solution of 5-(7-fluoro-l-methoxyisoquinolin-3-yl)-2H-pyran-3(6H)-one 1603 (580 mg, 2.12 mmol) in EtOH (25 mL) was added N-methyl-5-(piperazin-l-yl)picolinamide 1004 (701 mg, 3.18 mmol), NaBH(OAc)s (900 mg, 4.25 mmol) and NaBHsCN (133 mg, 2.12 mmol) successively at rt. The reaction mixture was stirred at 90 °C for 16 h. The reaction mixture was cooled to rt and quenched with water, concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with DCM / MeOH = 100:0 to 90:10) to afford a mixture of 5-(4-(5-(7-fluoro-l-methoxyisoquinolin-3-yl)-3,6-dihydro-2H-pyran-3- yl)piperazin-l-yl)-N-methylpicolinamide 1604 (750 mg, 90 % purity, 66 % yield) and 5-(4-(5- (7-fluoro-l-methoxyisoquinolin-3-yl)tetrahydro-2H-pyran-3-yl)piperazin-l-yl)-N- methylpicolinamide 1605 as a white solid.

[0535] LCMS (ESI) calcd for C26H28FN5O3 [M + H]+m / z 478.22, found 478.40.

[0536] Preparation of 5-(4-(5-(7-fluoro-l-methoxyisoquinolin-3-yl)tetrahydro-2H-pyran-3- yl)piperazin-l-yl)-N-methylpicolinamide (1605)

[0537] 5-(4-(5-(7-fluoro-l-methoxyisoquinolin-3-yl)-3,6-dihydro-2H-pyran-3-yl)piperazin-l-yl)-N- methylpicolinamide 1604 (750 mg, 1.57 mmol ) and Pd(OH)2 / C (110 mg, 0.79 mmol) in MeOH (25 mL) was stirred under balloon pressure of H2 at 50 °C for 16 h. The mixture was filtered through a Celite pad and the filtrate was concentrated to give 5-(4-(5-(7-fluoro-l- methoxyisoquinolin-3-yl)tetrahydro-2H-pyran-3-yl)piperazin-l-yl)-N-methylpicolinamide 1605 (700 mg, 80 % purity, 74 % yield) as a colourless oil.

[0538] LCMS (ESI) calcd for C26H30FN5O3 [M + H]+m / z 480.23, found 480.40.

[0539] Preparation of 5-(4-(5-(7-fluoro-l-oxo-l,2-dihydroisoquinolin-3-yl)tetrahydro-2H-pyran-3- yl)piperazin-l-yl)-N-methylpicolinamide (compound 48)

[0540] To a solution of 5-(4-(5-(7-fluoro-l-methoxyisoquinolin-3-yl)tetrahydro-2H-pyran-3- yl)piperazin-l-yl)-N-methylpicolinamide 1605 (700 mg, 1.46 mmol) in ACN (25 mL) was added TMSI (876 mg, 4.38 mmol). The reaction mixture was stirred at 50 °C for 2 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 60:40) and prep-HPLC(column : Gemini - C18150 × 21.2 mm, 5 µm; mobile phase : ACN - H2O (0.1 % FA); gradient :5 - 50) to give 5-(4-(5-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)tetrahydro-2H-pyran-3-yl)piperazin-1-yl)-N-methylpicolinamide compound 48 (mixture of cis- and trans-isomers).The mixture was separated by SFC (Column: DAICEL OJ-H SFC 30 mm I.D. × 250 mm, 10 μm;Mobile phase: CO2 / MeOH [0.1 % NH3 (7 M Solution in MeOH)] = 60 / 40) and concentratedunder reduced pressure to afford the first fraction as 48trans-a (17.6 mg, 96 % purity, ee%:100, white solid), the second fraction as 48cis-a(35.4 mg, 99 % purity, ee%: 100, white solid),the third fraction as 48cis-b (40.7 mg, 99 % purity, ee%: 100, white solid) and the fourthfraction as 48trans-b (16.4 mg , 99 % purity, ee%: 100, white solid).48trans-a1H NMR (400 MHz, DMSO-d6, ppm) δ: 11.37 (s, 1 H), 8.43-8.36 (m, 1 H), 8.27 (d, J = 2.8 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1 H), 7.78 (dd, J = 9.6, 2.8 Hz, 1 H), 7.75-7.69 (m, 1 H), 7.63-7.53 (m, 1H), 7.40 (dd, J = 8.8, 3.2 Hz, 1 H), 6.55 (s, 1 H), 3.95-3.78 (m, 2 H), 3.75-3.60 (m, 2 H), 3.37-3.32(m, 4 H), 3.17-3.04 (m, 1 H), 2.78 (d, J = 4.8 Hz, 3 H), 2.73-2.63 (m, 4 H), 2.43-2.35 (m, 1 H),2.21-2.11 (m, 1 H), 2.09-1.96 (m, 1 H).Trans stereochemistry assigned based on NOE experiments. LCMS (ESI) calcd for C25H28FN5O3[M + H]+m / z 466.22, found 466.35. 48trans-b1H NMR (400 MHz, DMSO-d6, ppm) δ: 11.38 (s, 1 H), 8.46-8.36 (m, 1 H), 8.27 (d, J = 2.8 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1 H), 7.78 (dd, J = 9.6, 2.8 Hz, 1 H), 7.75-7.67 (m, 1 H), 7.61-7.53 (m, 1H), 7.40 (dd, J = 8.8, 2.8 Hz, 1 H), 6.55 (s, 1 H), 3.94-3.78 (m, 2 H), 3.75-3.62 (m, 2 H), 3.36-3.33(m, 4 H), 3.15-3.05 (m, 1 H), 2.78 (d, J = 4.8 Hz, 3 H), 2.74-2.62 (m, 4 H), 2.42-2.34 (m, 1H),2.22-2.08 (m, 1 H), 2.08-1.95 (m, 1 H).Trans stereochemistry assigned based on NOE experiments.LCMS (ESI) calcd for C25H28FN5O3 [M + H] + m / z 466.22, found 466.30.48cis-a1H NMR (400 MHz, DMSO-d6, ppm) δ: 11.47 (s, 1 H), 8.43-8.34 (m, 1 H), 8.27 (d, J = 2.8 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1 H), 7.78 (dd, J = 9.6, 2.8 Hz, 1 H), 7.73-7.65 (m, 1 H), 7.63-7.53 (m, 1H), 7.40 (dd, J = 8.8, 2.8 Hz, 1 H), 6.52 (s, 1 H), 4.06-3.94 (m, 2 H), 3.32-3.25 (m, 6 H), 2.87-2.80(m, 1 H), 2.78 (d, J = 4.8 Hz, 3 H), 2.76-2.66 (m, 4 H), 2.63-2.54 (m, 1 H), 2.29-2.16 (m, 1 H),1.86-1.70 (m, 1 H).Cis stereochemistry assigned based on NOE experiments.LCMS (ESI) calcd for C25H28FN5O3 [M + H] + m / z 466.22, found 466.35.48cis-b1H NMR (400 MHz, DMSO-d6, ppm) δ: 11.48 (s, 1 H), 8.44-8.35 (m, 1 H), 8.27 (d, J = 2.8 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1 H), 7.78 (dd, J = 9.2, 2.8 Hz, 1 H), 7.73-7.66 (m, 1 H), 7.63-7.51 (m, 1H), 7.40 (dd, J = 8.8, 2.8 Hz, 1 H), 6.52 (s, 1 H), 4.06-3.94 (m, 2 H), 3.33-3.24 (m, 6 H), 2.87-2.80(m, 1 H), 2.78 (d, J = 4.8 Hz, 3 H), 2.76-2.65 (m, 4 H), 2.62-2.54 (m, 1 H), 2.29-2.18 (m, 1 H),1.85-1.71 (m, 1 H).Cis stereochemistry assigned based on NOE experiments.LCMS (ESI) calcd for C25H28FN5O3 [M + H] + m / z 466.22, found 466.35.Example 8: 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 8A. 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 / mlsolution, using a Na2CO3 / HCO3 coating buffer at pH 9.6, overnight at 4 °C, in order to achievea final immobilisation per well of 0.3 ^g. Wells were then washed 3 x 5 min in coating wash buffer (PBS / 0.05 % Tween (v / v)), and blocked with 2 % BSA (w / v) in coating wash bufferovernight at 4 °C. Prior to assay, wells were washed 3 x 5 min in coating wash buffer. For theassay 20 ^l of 2.5 nM recombinant full length human N-terminally FLAG-tagged PARP1 wasadded to each well of the 384-well plate for 30 min at room temperature followed by additionof 50 nL of compound solution in DMSO using pintool technology. Following incubation for30 min at room temperature, 5 ^l of 10 ^M biotin-NAD+ and 10 nM activation DNA (sequenceshown 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 temperatureprior to the addition of 5 ^l of 12 mM NAD+quenching solution. After 30 min at roomtemperature, assay solution was removed and following washing 5 times for 3 min, 100 ^l ofa 1:1000 dilution of DELFIA Eu-N1 Streptavidin reagent was added. Plates were thenincubated for 30 min at room temperature. The reaction mixture was removed and the plateswashed 5 times for 3 min prior to the addition of 25 ^l DELFIA enhancement solution.Following incubation for 30 min at room temperature, fluorescence was measured on aPherastar FS (Ex337 nm, Em620 nm; integration start 60 ^s; integration time 400 ^s).Typically compounds were tested from 20 ^M at 3-fold dilution intervals in 12-pointconcentration-response curves to determine IC50 values. Data was analysed usingActivityBase software and replicate values for the low (without enzyme, 0.2 % DMSO) andhigh (0.2 % DMSO) % controls were averaged and the data obtained from the test compoundsexpressed 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 IC50 values for a variety of test compounds are shown in Table 1. Activation DNA sequence: Duplex Sequences 5’-ACCCTGCTGTGGGC / ideoxyU / GGAGAACAAGGTGAT-3’ (SEQ ID NO:1) 5’-ATCACCTTGTTCTCCAHGCCCACAGCAGGGT-3’ (SEQ ID NO:2) 5’-ACCCTGCTGTGGGCGGAGAACAAGGTGAT-3’ (SEQ ID NO:3)| || | |||||||||||||||3’-TGGGACGACACCCGHACCTCTTGTTCCACTA-5’ Example 8B. 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 shownbelow and described in Papeo, G. et al. J. Biomol. Screen. 2014; 19:1212-1219. 6 ^l of thisreaction mixture was then transferred to each well of a black non-binding surface 384-wellplate 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 PherastarFS (Ex 337 nm, Em620 nm, em665 nm; integration start 60 µs; integration time 400 µs) usingthe HTRF module.Typically compounds were tested from 58.5 ^M at factor 3 dilution intervals in 12-pointconcentration-response curves to determine IC50values. Data was analysed usingActivityBase software and replicate values for the low (without enzyme but with probe andTb-cryptate antibody, 0.6 % DMSO) and high (0.6 % DMSO) % controls were averaged and thedata obtained from the test compounds expressed as a % of 100 % using the below formulae: %activity = 100*(value – low control) / (high control – low control)%activity data was fitted to a non-linear regression equation to obtain IC50 values. Kd values were calculated using Cheng-Prussoff formula: IC50 = (1+ ([probe concentration] / [Kmprobe]))*Kd Therefore Kd = IC50 / (l+[[probe concentration] / [Kmprobe])); using probe at 10 x Km, this equated to Kd = IC50 / H

[0541] Example 8C. PARP2 probe displacement homogeneous time-resolved fluorescence assay (HTRF assay)

[0542] 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.

[0543] Cy5 probe structure:

[0544] NanoBRET cellular target occupancy assay

[0545] NanoBRET assays were employed to demonstrate cellular target engagement and selectivity at PARP1 and PARP2. These assays are based on bioluminescence resonance energy transfer (BRET) between a Nano-luc-tagged protein (eg PARP1 or PARP2) and a fluorescent group on a high affinity NAD+competitive binding probe. Such cellular probe displacement assays can be utilised to measure inhibitor affinities and selectivity ratios at PARP1 and 2.

[0546] Frozen HEK293 cells transiently transfected with either PARPl-NanoLuc® fusion or PARP2- NanoLuc® fusion constructs (Promega) were thawed and dispensed as a suspension in 384- well microplates each at a density of 1750 cells per well. NanoBRET™ TE PARP Tracer-01 was then added to final concentrations of 11 and 2 nM for PARP1 and PARP2 assays, respectively. Compounds were added from 25 pM at factor 3 dilution intervals in 12-point concentrationresponse curves and plates were incubated for 2 hours at 37 °C. BRET ratios were then measured using a NanoBRET module (LUM 61O-LP 450-80) and PHERAstar FS or FSX reader following addition of NanoBRET™ Nano-Gio® Substrate and Extracellular NanoLuc® Inhibitor according to manufacturer's instructions. Kd values were calculated using Cheng-Prussoff formula:

[0547] IC50 = (1+ ([tracer concentration] / [Km tracer ])) * Kd

[0548] 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.

[0549] TABLE 1 Results ofParp 1 / 2 assays for selected compounds (DELFIA and Probe Displacement HTRF)

[0550] TABLE 2

[0551] Results ofParp 1 / 2 assays for selected compounds (NanoBRET) Key DELFIA, Probe Displacement HTRF and NanoBRET assay categories: -indicates IC50 or Kd value above 10 µM+ indicates IC50 or Kd value above 1 µM up to 10 µM++ indicates IC50 or Kd value above 100 nM up to 1 µM+++ indicates IC50 or Kd value above 10 nM up to 100 nM++++ indicates IC50 or Kd value of 10 nM or lessSelectivity 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

[0552] NT: not tested The selectivity values relate to the selectivity preference of PARP1 over PARP2. They are calculated from the ratio of Kd values for PARP1 and PARP2 inhibition as Kd (PARP2) / Kd (PARP1). It will be appreciated that the above embodiments have been described by way of example only.

[0553] 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

Claims1. A PARP1 inhibitor compound having a structure of:wherein: a dotted line represents a bond selected from a single bond and a double bond; y is 0, 1, or 2; ring D is aromatic or non-aromatic; each XDis independently selected from C, O, and N; with the provisos that: no more than one XDis O; and when an XDis O or N, ring D is non-aromatic; each R1is independently absent, or present and selected from H and a substituted or unsubstituted organic group; each R4is independently absent or selected from:H; a halogen;C(R9)i, wherein i is an integer in the range 1 to 3;OR9; andS(R9)j, where j is an integer in the range 1 to 5; wherein each R9is independently selected from H and a substituted or unsubstituted organic group;R2and R3are each independently selected from H and a substituted or unsubstituted organic group; andL is a group having a structure of:wherein:X1, X3, X4and X5are each independently selected from C and N; each X2is independently selected from C, N, O, and S; n is 0, 1, 2, 3, 4, or 5; m is 0, 1, 2, 3, 4, or 5, with the proviso that n + m is in the range 1 to 5; p is 1, 2 or 3; q is 1, 2 or 3, with the proviso that p + q is in the range 2 to 5; r is 0, 1, 2, 3, 4, or 5; s is 0, 1, 2, 3, 4, or 5, with the proviso that r + s is in the range 2 to 5; each R5A, R5B, and R5Cis independently absent or selected from H and a substituted or unsubstituted organic group;R6is absent or selected from H and a substituted or unsubstituted organic group; andQ1and Q2are each independently a bond or a linking group having a structure selected from:wherein: t is 0, 1, 2, 3, 4 or 5; u is 0, 1, 2, 3, 4 and 5, with the proviso that t + u is in the range 0 to 6; and each R7and R8is independently selected from H and a substituted or unsubstituted organic group.

2. The PARP1 inhibitor compound according to claim 1, wherein each R1and each R4is independently absent or selected from:H; a halogen; a nitrile group; a Cl to C6 alkyl group, such as a C3 to C6 cycloalkyl group; a Cl to C6 alkoxy group; a Cl to C6 haloalkoxy group, such as -OCF3 or OCHF2; a haloalkyl group; andR22being selected from H, a halogen, a Cl to C6 alkyl group, a C3 to C6 cycloalkyl group, a Cl to C6 alkoxy group, a Cl to C6 haloalkyl group, and each R23being independently selected from H, a halogen, a Cl to C6 linear or branched alkyl group, a Cl to C6 linear or branched aminoalkyl group, a Cl to C6 alkoxy group, a Cl to C6 haloalkoxy group, such as -OCF3 or OCHF2; and a Cl to C6 haloalkyl group.

3. The PARP1 inhibitor compound according to claim 2, wherein each R1and each R4is independently absent or selected from H; a halogen, optionally Cl or F; a Cl to C3 alkyl group, optionally a methyl group; a Cl to C3 haloalkyl group, optionally a halomethyl group such as -CH2F, -CHF2, or -CF3; a haloethyl group, such as -CH2CF3; and a nitrile group.

4. The PARP1 inhibitor compound according to claim 3, wherein each R1and each R4is independently absent or selected from: H; Cl; F; a halomethyl group, such as CF3; and a nitrile group.

5. The PARP1 inhibitor compound according to claim 4, wherein each R1and each R4is independently absent or selected from H and F; optionally wherein each R4is H.

6. The PARP1 inhibitor compound according to claim 5, wherein exactly one R1or exactly one R4is F.

7. The PARP1 inhibitor compound according to any preceding claim, wherein y is 1.

8. The PARP1 inhibitor compound according to any preceding claim, wherein each XDis C.

9. The PARP1 inhibitor compound according to claim 8, having a structure of:

10. The PARP1 inhibitor compound according to claim 9, having a structure of:

11. The PARP1 inhibitor compound according to claim 9, having a structure selected from:

12. The PARP1 inhibitor compound according to any of claims 1 to 8, wherein ring D is non-aromatic.

13. The PARP1 inhibitor compound according to claim 12, having a structure selected from:each R1and each R4being present; optionally wherein the compound has a structure of:

14. The PARP1 inhibitor compound according to claim 12, having a structure selected from:

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

16. The PARP1 inhibitor compound according to claim 12, having a structure selectedand preferably having a structure of:

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

18. The PARP1 inhibitor compound according to any preceding claim, wherein R2is selected from H; a halogen, optionally F or Cl; a Cl to C3 alkyl group, optionally an isopropyl group or a cyclopropyl group; a Cl to C3 haloalkyl group, optionally -CH2F, -CHF2, -CF3, - CH2CF3, or -CH2CH2F; a Cl to C3 alcohol group, optionally -CH2CH2OH; a Cl to C3 alkoxy group, optionally a methoxy group, a methoxymethyl group, or methoxyethyl group; and a Cl to C3 aminoalkyl group.

19. The PARP1 inhibitor compound according to claim 18, wherein R2is H.

20. The PARP1 inhibitor compound according to any preceding claim, wherein R3is selected from H, a Cl to C3 alkyl group, and a Cl to C3 haloalkyl group.

21. The PARP1 inhibitor compound according to claim 20, wherein R3is H.

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

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

24. The PARP1 inhibitor compound according to claim 23, wherein ring A is a saturated ring.

25. The PARP1 inhibitor compound according to any preceding claim, wherein when present each R5Ais independently selected from H; a halogen, optionally F; a hydroxyl group; a carbonyl group; and a Cl to C3 alkyl group, optionally wherein a pair of R5Agroups form a ring, further optionally wherein the ring bridges ring A; preferably wherein each R5Ais H.

26. The PARP1 inhibitor compound according to any preceding claim, wherein n + m is in the range 2 to 5, optionally 2 to 4; and / or wherein both n and m are at least 1.

27. The PARP1 inhibitor compound according to claim 26, wherein: i) ring A is a 7-membered ring, 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; or ii) ring A is a 6-membered non-aromatic ring, optionally a cyclohexane, cyclohexene, or tetra hydro pyran 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 5-membered non-aromatic ring, 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 4-membered ring having a structure of:each R5Aand R5A3being independently selected from H and a substituted or unsubstituted organic group, wherein R5A3is most preferably H; or v) ring A is a bridged ring, 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.

28. The PARP1 inhibitor compound for use according to any preceding claim, wherein ringA 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 provisos that:R5A1is absent when X1is N; andR5A2is absent when the corresponding X2is O.

29. The PARP1 inhibitor compound according to claim 28, wherein ring A has a structure of:wherein: m is 1 or 2; n is 1 or 2; and preferably wherein R5A3is H.

30. The PARP1 inhibitor compound according to claim 28 or claim 29, wherein:R5A1is absent, H, or forms a -CH2- or -CH2CH2- group together with an R5A2group or R5A3; each R5A2is independently absent, H, an oxo group, or forms a -CH2- or -CH2CH2- group together with R5A1, R5A3, or another R5A2;R5A3is H or forms a -CH2- or -CH2CH2- group together with R5A1or an R5A2group.

31. The PARP1 inhibitor compound according to claim 28 or claim 29, wherein: exactly two groups selected from the R5A1, R5A2, and R5A3groups together represent a phenyl group fused to ring A; andeach other group of the R5A1, R5A2, and R5A3groups is independently absent, H, or an oxo group.

32. The PARP1 inhibitor compound according to claim 28 or claim 29, wherein each R5A2independently is absent or H.

33. The PARP1 inhibitor compound according to claim 28, wherein ring A is a tetra hydrofuran or a tetra hydro pyran.

34. The PARP1 inhibitor compound according to any preceding claim, wherein ring A hasA20A17 A18 A19A53 A54 optionally wherein ring A has a structure selected from: Al, A3 to A8, and A15 to A42.

35. The PARP1 inhibitor compound according to claim 34, wherein ring A has a structure selected from:A1636. The PARP1 inhibitor compound according to claim 35, wherein:Q1is a bond and ring A has a structure selected from: Al, A3, A4, A5, A6, A12, A13, and A14; or ring A is selected from Al, A2, A3, A5, A7, A8, A10, All, A15, and A16.

37. The PARP1 inhibitor compound according to claim 36, wherein ring A has a structure of:

38. The PARP1 inhibitor compound according to any preceding claim, wherein ring A is a three- or four-membered ring, and wherein Q1is -CH2-; optionally wherein ring A is:

39. The PARP1 inhibitor compound according to any of claims 1 to 36, wherein Q1is a bond.

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

41. The PARP1 inhibitor compound according to any preceding claim, wherein ring B has a structure of:

42. The PARP1 inhibitor compound according to any preceding claim, wherein X3is N.

43. The PARP1 inhibitor compound according to claim 41 or claim 42, wherein ring B has a structure selected from:

44. The PARP1 inhibitor compound according to any preceding claim, wherein each R5Bis independently absent or H.

45. The PARP1 inhibitor compound according to claim 43, wherein ring B has a structure selected from:

46. The PARP1 inhibitor compound according to claim 45, wherein ring B has a structure of:

47. The PARP1 inhibitor compound according to claim 45, wherein ring B has a structure of:and wherein Q2is -O-.

48. The PARP1 inhibitor compound for use according to claim 41, wherein: i) ring B is an azepane, optionally having a structure of:a substituted or unsubstituted organic group, optionally wherein each R5Bis H; or ii) ring B is a piperidine, optionally having a structure of: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 claim 41, wherein ring B has a structureeach R5Bbeing independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5Bis H.

50. The PARP1 inhibitor compound according to any preceding claim, wherein at least one of Q1and Q2is a linking group selected from:wherein t + u is at least 1; and wherein R7is selected from H; a halogen, such as -F, -Cl, -Br, and -I, and preferably - F; an -OH group; a Cl to C6 alkyl group; a Cl to C6 haloalkyl group, preferably CF3; an -NH2 group; a Cl to C6 amino group; a Cl to C6 alcohol group; and a Cl to C6 alkoxy group.

51. The PARP1 inhibitor compound according to claim 50, wherein R7is selected from: H; a halogen, optionally F; a Cl to C6 alkyl group; and a Cl to C6 haloalkyl group.

52. The PARP1 inhibitor compound according to any preceding claim, wherein at least one of Q1and Q2has a structure of:and wherein R8is selected from:H; a substituted or unsubstituted linear or branched Ci-Ce alkyl group (such as Me, Et, Pr, i-Pr, n-Bu, i-Bu, t-Bu, pentyl and hexyl); a substituted or unsubstituted linear or branched Ci-Ce a Ikyl-a ryl group(such as -CH2Ph, -CH2(2,3 or 4)F-Ph, -CH2(2,3 or 4)CI-Ph, -CH2(2,3 or 4)Br-Ph, -CH2(2,3 or 4)l-Ph, -CH2CH2Ph, -CH2CH2CH2Ph,-CH2CH2CH2CH2Ph, -CH2CH2CH2CH2CH2Ph, and -CH2CH2CH2CH2CH2CH2Ph); a substituted or unsubstituted linear or branched Ci-Ce halogenated alkyl group (such as -CH2F, -CF3, -CH2CH2F and -CH2CF3); a substituted or unsubstituted cyclic amine or amido group(such as pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, 2-keto-pyrrolidinyl,3-keto-pyrrolidinyl, 2-keto-piperidinyl, 3-keto-piperidinyl, and4-keto-piperidinyl); a substituted or unsubstituted cyclic C3-Cs alkyl group(such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl); a substituted or unsubstituted linear or branched C2-Ce alcohol group (such as -CH2CH2OH, -CH(CH3)CH2OH, -C(CH3)2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, -CH(CH3)CH2CH2OH, -CH(CH3)CH(CH3)OH, -CH(CH2CH3)CH2OH, -C(CH3)2CH2OH, -CH2CH2CH2CH2CH2OH, and -CH2CH2CH2CH2CH2CH2OH); a substituted or unsubstituted linear or branched C2-Ce carboxylic 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)-l,3-epoxypropan-2-y I; -(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 Ci-Ce 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 Ci-Ce amide group(such as -CO-NH2, -CO-NMeH, -CO-NMe2, -CO-NEtH, -CO-NEtMe, -CO-NEt2, -CO-NPrH, -CO-NPrMe, and -CO-NPrEt); a substituted or unsubstituted sulfonyl group(such as -SO2Me, -SO2Et, -SO2Pr, -SO2iPr, -SO2Ph, -SO2-(2,3 or 4)-F-Ph, -SO2-cyclopropyl, -SO2CH2CH2OCH3, -SO2NH2, -SO2NHMe, -SO2NMe2, -SO2NHEt, -SO2NEt2, -SO2-pyrrolidine-N-yl,-SO2-morpholine-N-yl, -SO2NHCH2OMe, and -SO2NHCH2CH2OMe); a substituted or unsubstituted aromatic group(such as Ph-, 2-F-Ph-, 3-F-Ph-, 4-F-Ph-, 2-CI-Ph-, 3-CI-Ph-, 4-CI-Ph-, 2-Br-Ph-, 3-Br-Ph-, 4-Br-Ph-, 2-l-Ph-, 3-l-Ph, 4-l-Ph-, 2, (3, 4, 5 or 6)-F2-Ph-,2, (3,4,5 or 6)-CI2-Ph-, 2, (3,4,5 or 6)-Br2-Ph-, 2, (3,4,5 or 6)-l2-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)-CI2-Ph-, 3,(4 or 5)-Br2-Ph-, 3,(4 or 5)-l2-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, l,2,3-triazole-4-yl, l,2,3-triazole-5-yl, l,2,4-triazole-3-yl, l,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, (l,3,4-oxadiazol)-2-yl, (l,3,4-oxadiazol)-5-yl, (l,2,4-oxadiazol)-3-yl, (l,2,4-oxadiazol)-5-yl; and tetrazole-5-yl).

53. The PARP1 inhibitor compound according to claim 52, wherein R8is selected from H, a substituted or unsubstituted linear or branched Ci-Ce alkyl group, and a substituted or unsubstituted linear or branched Ci-Ce halogenated alkyl group.

54. The PARP1 inhibitor compound according to any preceding claim, wherein Q2is a bond or -CH2-, preferably wherein Q2is a bond.

55. The PARP1 inhibitor compound according to any preceding claim, wherein X3is C and X4is C.

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

57. The PARP1 inhibitor compound according to claim 56, wherein: i) ring C is a 6-membered aliphatic ring, optionally a 6-membered aliphatic ring having structure of:each R5Cand R5C1being independently selected from H and a substituted or unsubstituted organic group, preferably wherein R5C1is H, more preferably wherein R5C1and each R5Cis H; ii) ring C is a 6-membered aromatic ring, optionally selected from: iia) a phenyl group, optionally having a structure of:each R5Cbeing independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5Cis H; iib) a pyridine group, optionally having a structure selected from:each R5Cbeing independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5Cis H;iic) a diazine group, optionally having a structure selected from:each R5Cbeing independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5Cis H; or iii) ring C is a 5-membered aromatic ring, optionally selected from: iiia) an imidazole group, optionally an imidazole group having a structure selected from:each R5Cbeing independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5Cis H; iiib) a thiophene group, optionally having a structure selected from:each R5Cbeing independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5Cis H; iiic) a thiazole group, optionally having a structure selected from:each R5Cbeing independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5Cis H; iiid) a triazole, optionally a triazole having a structure of:R5Cbeing selected from H and a substituted or unsubstituted organic group, optionally wherein R5Cis H.

58. The PARP1 inhibitor compound according to any preceding claim, wherein when present each R5Cis H or an organic group selected from a halogen, preferably F; a Cl to C3 alkyl group, optionally a cyclopropyl group; a Cl to C3 haloalkyl group, optionally a fluoromethyl group such as CF2H or CF3; a Cl to C3 alkoxy group; and a nitrile group; optionally wherein when present each R5Cis H or an organic group selected from a halogen, preferably F; a Cl to C3 alkyl group; a Cl to C3 haloalkyl group, optionally a fluoromethyl group such as CF2H or CF3; and a nitrile group.

59. The PARP1 inhibitor compound according to claim 58, wherein exactly one R5Cis an organic group.

60. The PARP1 inhibitor compound according to claim 59, wherein the organic group is F.

61. The PARP1 inhibitor compound according to any preceding claim, wherein ring C has a structure of:wherein: each Xcatom is selected from C and N, with the proviso that at least two Xcatoms are C; when an Xcis N, the corresponding R5Cis absent; when an Xcis C, the corresponding R5Cis H, or a substituent selected from a halogen, such as F or Cl; -CN; a methyl group; and a halomethyl group, such as -CHF2; optionally wherein no more than one R5Cis a substituent.

62. The PARP1 inhibitor compound according to claim 61, wherein ring C has a structurewherein:XCoand XCmare each selected from C and N; when XCois C, RCois H or a halogen, F being the preferred halogen; when XCois N, RCois absent; when XCmis C, RCmis H or a halogen, F being the preferred halogen; and when XCmis N, RCmis absent; optionally wherein at least one of XCoand XCmis N.

63. The PARP1 inhibitor compound according to claim 62, wherein exactly one of XCoandXCmis N.

64. The PARP1 inhibitor compound according to any preceding claim, wherein ring C hasC23 C24C37C3865. The PARP1 inhibitor compound according to claim 64, wherein: ring C has a structure selected from Cl to C36; or ring C has a structure selected from C3, C8, CIO, Cll, C13, C14, C15, C18, C19, C21, C25, C28, C36, C37, and C38.

66. The PARP1 inhibitor compound according to claim 64 or claim 65, wherein ring C has a structure selected from:T3T1T20T3367. The PARP1 inhibitor compound 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:unsubstituted organic group, optionally wherein R51and R52are each independently selected from H, a halogen, optionally-deuterated Cl to C3 alkyl, and Cl to C3 haloalkyl.

68. The PARP1 inhibitor compound according to claim 67, wherein R6is selected from -F,-Cl, -CN, -CONH2, -CONHMe (optionally -CONHCD3), -CONHEt, -CONMe2,-CONHCOMe, -CONHCH2-CH2OMe, -CONH-CH2-CH2F, -CONH-CH2-CF3, -CONH-CH2-CHF2,69. The PARP1 inhibitor compound according to claim 68, wherein R6is F.

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

71. The PARP1 inhibitor compound according to claim 68, wherein R6is CN.

72. The PARP1 inhibitor compound according to claim 67, wherein R6has a structure of:wherein R51is selected from: a Cl to C6 alkyl group, optionally a C3 to C6 cycloalkyl group, a Cl to C3 alkyl group, or a Cl to C3 deuterated alkyl group; a Cl to C3 haloalkyl group, optionally a Cl 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.

73. The PARP1 inhibitor compound according to claim 72, wherein R6is selected from:

74. The PARP1 inhibitor compound according to claim 73, wherein R6is -CONHMe.

75. The PARP1 inhibitor compound according to claim 73, wherein76. The PARP1 inhibitor compound according to claim 73, wherein R6 is -C(O)NHEt.

77. The PARP1 inhibitor compound according to claim 73, wherein78. The PARP1 inhibitor compound according to claim 73, wherein R6is 079. The PARP1 inhibitor compound according to claim 73, wherein R6is -C(O)NHCH2CF3.

80. The PARP1 inhibitor compound according to claim 73, wherein R6is C(O)NHCH2CH2F.

81. The PARP1 inhibitor compound according to claim 73, wherein R51is a tetrahydropyranyl group, optionally wherein R6is:

82. The PARP1 inhibitor compound for use according to any of claims 1 to 66, 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 Cl to C3 alkyl group; a Cl to C3 haloalkyl group, optionally a Cl to C3 fluoroalkyl group; and -NHR63, wherein R63is H or a Cl to C3 alkyl group.

83. The PARP1 inhibitor compound for use according to claim 82, wherein R6is selected from:

84. The PARP1 inhibitor compound according to any preceding claim, wherein L has a structure selected from:

85. The PARP1 inhibitor compound according to claim 84, wherein L has a structure selected from:

86. The PARP1 inhibitor compound according to any preceding claim, wherein rings D andB are in a cis configuration with respect to ring A, optionally wherein group L is selected from:

87. The PARP1 inhibitor compound according to any of claims 1 to 85, wherein rings D and B are in a trans configuration with respect to ring A, optionally wherein group L is selected from:

88. The PARP1 inhibitor compound according to claim 1, having a structure of:each Z independently represents -CH2- or a heteroatom-containing fragment selected from -O- and -N(RD)-, with the proviso that no more than one Z is a heteroatomcontaining fragment; wherein RDis H or a Cl to C3 alkyl group, preferably a methyl group;XC1and XC2are each independently selected from C and N; when XC1is N, R5C1is absent; when XC1is C, R5C1is selected from H and a halogen; when XC2is N, RC2is absent; when XC2is C, R5C2is selected from H and a halogen;R6is selected from -CONHMe, -Cl, and -CN.

89. The PARP1 inhibitor compound according to claim 88, wherein: when XC1is C, R5C1is selected from H and F; and when XC2is C, R5C2is selected from H and F.

90. The PARP1 inhibitor compound according to claim 88 or claim 89, wherein exactly one of XC1and XC2is N, and preferably wherein XC1is C and XC2is N.

91. The PARP1 inhibitor compound according to any of claims 88 to 90, wherein R6isCONHMe, optionally -CONHCD3.

92. The PARP1 inhibitor compound according to claim 1, having a structure of:wherein:RD1and RD2are each independently selected from H and F; two R5Agroups together represent a -CH2- group bridging ring A, and each other R5Agroup is H; or each R5Ais H; each Xcatom is selected from C and N, with the proviso that at least two Xcatoms are when an Xcis N, the corresponding R5Cis absent; when an Xcis C, the corresponding R5Cis H, or a substituent selected from a halogen, such as F or Cl; -CN; a methyl group; and a halomethyl group, such as-CHF2;R6is selected from a halogen, -CN, andwherein R51is selected from a Cl to C3 alkyl group; a Cl to C3 deuterated alkyl group; a Cl to C3 fluoroalkyl group; a tetrahydrofuranyl group; and a tetrahydropyranyl group.

93. The PARP1 inhibitor compound according to claim 92, having a structure of:RD1and RD2are each independently selected from H and F;XC1and XC2are each independently selected from C and N; when XC1is N, R5C1is absent; when XC1is C, R5C1is selected from H and a halogen, preferably F; when XC2is N, RC2is absent; when XC2is C, R5C2is selected from H and a halogen, preferably F;R6is selected from -CONHMe, -Cl, and -CN.

94. The PARP1 inhibitor compound according to claim 92 or claim 93, wherein exactly one of XC1and XC2is N.

95. The PARP1 inhibitor compound according to claim 94, wherein XC2is C and XC1is N, and optionally wherein R5C2is H.

96. The PARP1 inhibitor compound according to claim 94, wherein XC1is C and XC2is N.

97. The PARP1 inhibitor compound according to any of claims 92 to 96, wherein exactly one of RD1and RD2is F.

98. The PARP1 inhibitor compound according to claim 1, which is selected from:ĵtranslOtransıijtrans99. The PARP1 inhibitor compound according to any of claims 1 to 87, wherein when one or more of R1, R2, R3, R5A(e.g. R5A1, R5A2, R5A3), R5B, R5C(e.g. R5C1) , R6, R7, R9, 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 Ci-Ce alkyl group (such as Me, Et, Pr, i-Pr, n-Bu, i-Bu, t-Bu, pentyl and hexyl); a substituted or unsubstituted linear or branched Ci-Ce a Ikyl-a ryl group(such as -CH2Ph, -CH2(2,3 or 4)F-Ph, -CH2(2,3 or 4)CI-Ph, -CH2(2,3 or 4)Br-Ph, -CH2(2,3 or 4)l-Ph, -CH2CH2Ph, -CH2CH2CH2Ph,-CH2CH2CH2CH2Ph, -CH2CH2CH2CH2CH2Ph, and -CH2CH2CH2CH2CH2CH2Ph); a substituted or unsubstituted linear or branched Ci-Ce halogenated alkyl group (such as -CH2F, -CH2CI, -CH2Br, -CH2I, -CHF2, -CF3, -CCI3-CBr3, -CCI3,-CH2CH2F, -CH2CF3, -CH2CCl3, -CH2CBr3, and -CH2CH2CCI3); NH2 or a substituted or unsubstituted linear or branched primary secondary or tertiary C1-C6 amine group (such as -NMeH, -NMe2, -NEtH, -NEtMe, -NEt2, -NPrH, -NPrMe, -NPrEt, -NPr2, - NBuH, -NBuMe, -NBuEt, –CH2-NH2, -CH2-NMeH, -CH2-NMe2, -CH2-NEtH, - CH2-NEtMe, -CH2-NEt2, -CH2-NPrH, -CH2-NPrMe, and –CH2-NPrEt); a substituted or unsubstituted amino-aryl group (such as -NH-Ph, -NH-(2,3 or 4)F-Ph, -NH-(2,3 or 4)Cl-Ph, -NH-(2,3 or 4)Br-Ph, -NH-(2,3 or 4)I-Ph, -NH-(2,3 or 4)Me-Ph, -NH-(2,3 or 4)Et-Ph, -NH-(2,3 or 4)Pr-Ph, -NH-(2,3 or 4)Bu-Ph, NH-(2,3 or 4)OMe-Ph, -NH-(2,3 or 4)OEt-Ph, -NH-(2,3 or 4)OPr-Ph, -NH-(2,3 or 4)OBu-Ph, -NH-2,(3,4,5 or 6)F2-Ph, -NH-2,(3,4,5 or 6)Cl2-Ph, -NH-2,(3,4,5 or 6)Br2-Ph, -NH-2,(3,4,5 or 6)I2-Ph, -NH-2,(3,4,5 or 6)Me2-Ph, -NH-2,(3,4,5 or 6)Et2-Ph, -NH-2,(3,4,5, or 6)Pr2-Ph, -NH-2,(3,4,5 or 6)Bu2-Ph), a substituted or unsubstituted cyclic amine or amido group (such as pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl,piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, 2-keto-pyrrolidinyl, 3-keto-pyrrolidinyl, 2-keto-piperidinyl, 3-keto-piperidinyl, and 4-keto-piperidinyl); a substituted or unsubstituted cyclic C3-C8alkyl group (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl); an -OH group; a substituted or unsubstituted linear or branched C1-C6 alcohol group (such as –CH2OH, -CH2CH2OH, -CH(CH3)CH2OH, -C(CH3)2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, -CH(CH3)CH2CH2OH, -CH(CH3)CH(CH3)OH, -CH(CH2CH3)CH2OH, -C(CH3)2CH2OH, -CH2CH2CH2CH2CH2OH, and -CH2CH2CH2CH2CH2CH2OH); a substituted or unsubstituted linear or branched C1-C6 carboxylic acid group (such as -COOH, -CH2COOH, -CH2CH2COOH, -CH2CH2CH2COOH, -CH2CH2CH2CH2COOH, and -CH2CH2CH2CH2CH2COOH);a substituted or unsubstituted linear or branched carbonyl group(such as -(CO)Me, -(CO)Et, -(CO)Pr, -(CO)iPr, -(CO)nBu, -(CO)iBu, -(CO)tBu, -(CO)Ph, -(CO)CH2Ph, -(CO)CH2OH, -(CO)CH2OCH3, -(CO)CH2NH2, -(CO)CH2NHMe, -(CO)CH2NMe2, -(CO)-cyclopropyl, -(CO)-l,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 Ci-Ce 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 Ci-Ce amide group(such as -CO-NH2, -CO-NMeH, -CO-NMe2, -CO-NEtH, -CO-NEtMe, -CO-NEt2, -CO-NPrH, -CO-NPrMe, and -CO-NPrEt); a substituted or unsubstituted linear or branched C1-C7 amino 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-C7 alkoxy 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, -OCH2CI, -OCHCI2, -OCCI3, -O-Ph, -O-CH2-Ph, -O-CH2-(2,3 or 4)-F-Ph, -O-CH2-(2,3 or 4)-CI-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, -SChNHEt, -SO2NEt2, -SO2-pyrrolidine-N-yl,-SO2-morpholine-N-yl, -SO2NHCH2OMe, and -SO2NHCH2CH2OI\ / le); 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-CI-Ph-, 3-CI-Ph-, 4-CI-Ph-, 2-Br-Ph-,3-Br-Ph-, 4-Br-Ph-, 2-l-Ph-, 3-l-Ph, 4-l-Ph-, 2, (3, 4, 5 or 6)-F2-Ph-,2, (3,4,5 or 6)-CI2-Ph-, 2, (3,4,5 or 6)-Br2-Ph-, 2, (3,4,5 or 6)-l2-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)-CI2-Ph-, 3,(4 or 5)-Br2-Ph-, 3,(4 or 5)-l2-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-l-yl, pyrrole-2-yl, pyrrole-3-yl, pyrazole-l-yl, pyrazole-3-yl, pyrazole-4-yl, pyrazole-5-yl, imidazole-l-yl, imidazole-2-yl, imidazole-4-yl, imidazole-5-yl, 1,2,3-triazole-l-yl, l,2,3-triazole-4-yl, l,2,3-triazole-5-yl, 1,2,4-triazole-l-yl, l,2,4-triazole-3-yl, l,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-l-yl, pyrrolidine-2-yl, pyrrolidine-3-yl, piperidine-l-yl, piperidine-2-yl, piperidine-3-yl, piperidine-4-yl, 2-azapiperidine-l-yl, 2-azapiperidine-3-yl,2-azapiperidine-4-yl, 3-azapiperidine-l-yl, 3-azapiperidine-2-yl,3-azapiperidine-4-yl, 3-azapiperidine-5-yl, piperazine-l-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, (l,3,4-oxadiazol)-2-yl, (l,3,4-oxadiazol)-5-yl, (l,2,4-oxadiazol)-3-yl, (l,2,4-oxadiazol)-5-yl; and tetrazole-l-yl, tetrazole-2-yl, tetrazole-5-yl); wherein: a pair of R5Agroups attached to different atoms may together form a ring with ring A atoms; and / ora pair of R5Bgroups attached to different atoms may together form a ring with ring B atoms, and / or a pair of R5Cgroups attached to different atoms may together form a ring with ring C atoms; and / or an R5Cgroup and an R6group attached to different atoms may together form a ring with ring C atoms.

100. The PARP1 inhibitor compound according to claim 99, wherein each of R5A (e.g., R5A1,R5A2, R5A3), R5B, and R5C(e.g., R5C1) is independently absent or selected from: H, deuterium, a halogen, such as –F, -Cl, -Br, and –I; preferably F or Cl; a nitrile group; a C1-C6 alkyl group; a C1-C6 halogenated alkyl group, preferably CF3 or CHF2; a cyclopropyl group; an -OH group; a C1-C6 alcohol group; a C1-C7 amino carbonyl group, such as -NH-CO-Me; an -NH2 group; a C1-C6 amino group; and a C1-C6 alkoxy group; wherein, when a pair of R5Agroups attached to different atoms together forms a ring with ring A atoms and / or a pair of R5Bgroups attached to different atoms together forms a ring with ring B atoms and / or a pair R5Cgroups attached to different atoms together forms a ringwith ring C atoms, each of the pair of R5A, R5B or R5C groups independently comprises -CH2- or-CH2CH2-, or the pair of groups together comprise -CH=CH-CH=CH- or -NH-CO-NH-.

101. The PARP1 inhibitor compound according to any preceding claim, which is in the formof: an isolated enantiomer, or a mixture of two or more enantiomers, ora mixture of two or more diastereomers, and / or epimers, or a racemic mixture, or a tautomer of the compound.

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

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

104. The PARP1 inhibitor compound for use according to claim 103, which is for use in treating a cancer.

105. The PARP1 inhibitor compound for use according to claim 104, 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, 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, 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.

106. The PARP1 inhibitor compound for use according to claim 104 or claim 105, wherein the cancer is deficient in a DNA damage response repair pathway, such as Homologous Recombination dependent DNA Double Strand Break DNA repair activity.

107. The PARP1 inhibitor compound for use according to any of claims 104 to 106, wherein the cancer is deficient in BRCA1 and / or BRCA2 function.

108. The PARP1 inhibitor compound for use according to any of claims 104 to 107, 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.

109. The PARP1 inhibitor compound for use according to claim 108, wherein the further agent is an immunotherapeutic agent selected from: an anti-tumour vaccine; an oncolytic virus; an immune stimulatory antibody such as anti-CTLA4, anti-PDl, anti-PDL-1, anti-OX40, anti-41BB, anti-CD27, anti-CD40, anti-LAG3, anti-TIM3, and anti-GITR; a pattern recognition receptor agonist such as a STING, TLR-9 or RIG-1 Helicase agonist; an IDO or TDO inhibitor; a novel adjuvant; a peptide; a cytokine; a chimeric antigen receptor T cell therapy; a small molecule immune modulator; and a tumour microenvironment modulator.

110. A pharmaceutical composition comprising a PARP1 inhibitor compound as defined in any of claims 1 to 102.

111. A pharmaceutical composition according to claim 110, further comprising a pharmaceutically acceptable additive and / or excipient, and / or wherein the compound is inthe form of a pharmaceutically acceptable salt, hydrate, acid, ester, or other alternative form of the compound.

112. The pharmaceutical composition according to claim 110 or claim 111, 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.

113. The pharmaceutical composition according to claim 112, wherein the further agent comprises an immunotherapeutic agent selected from: an anti-tumour vaccine; an oncolytic virus; an immune stimulatory antibody such as anti-CTLA4, anti-PDl, anti-PDL-1, anti-OX40, anti-41BB, anti-CD27, anti-CD40, anti-LAG3, anti-TIM3, and anti-GITR; a pattern recognition receptor agonist such as a STING, TLR-9 or RIG-1 Helicase agonist; an IDO or TDO inhibitor; a novel adjuvant; a peptide; a cytokine; a chimeric antigen receptor T cell therapy; a small molecule immune modulator; and a tumour microenvironment modulator.

114. The pharmaceutical composition according to any of claims 110 to 113, for use in treating a cancer.

115. A pharmaceutical kit for treating a cancer, which pharmaceutical kit comprises: a) a PARP1 inhibitor compound as defined in any of claims 1 to 102; and b) a further agent for treating cancer; wherein the PARP1 inhibitor 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 andhormone analogues, signal transduction pathway inhibitors, other DNA damage repair pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, antibody-drug conjugates, hormone-deprivation therapy, immunotherapeutic agents (such as selected from an anti-tumour vaccine; an oncolytic virus; an immune stimulatory antibody such as anti- CTLA4, anti-PDl, anti-PDL-1, anti-OX40, anti-41BB, anti-CD27, anti-CD40, anti-LAG3, anti- TIM3, and anti-GITR; a pattern recognition receptor agonist such as a STING, TLR-9 or RIG-1 Helicase agonist; an IDO or TDO inhibitor; a novel adjuvant; a peptide; a cytokine; a chimeric antigen receptor T cell therapy; a small molecule immune modulator; a tumour microenvironment modulator), proapoptotic agents, radioligand therapies, anti-angiogenic agents, and cell cycle signalling inhibitors.

116. 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.

117. The method according to claim 116, wherein the patient is an animal, preferably a mammal, optionally a human, canine, equine or feline; and preferably a human.

118. A method of synthesising a PARP1 inhibitor compound as defined in any of claims 1 to 102, which method comprises conducting a reaction between: i) a first reactant comprising rings D and E and bearing a first portion of group L and ii) a second reactant comprising a remainder of group L, to form the PARP1 inhibitor compound.

119. The method according to claim 118, wherein the first reactant comprises rings D, E and ring A, and the second reactant comprises a ring B precursor bearing a reactive group, which method comprises joining ring A to the ring B precursor.

120. The method according to claim 119, wherein the reactive group precursor comprises a carbonyl group, an alkyl halide, or an alkyl sulfonate.

121. The method according to any of claims 118 to 120, wherein the reaction comprises alkylation, reductive amination or amide formation so as to form group L.

122. The method according to claim 118, wherein the first reactant comprises rings D, E, ring A, and ring B, and the second reactant comprises a ring C derivative bearing a leaving group such as a halide or sulfonate.

123. The method according to claim 122, wherein the reaction comprises a nucleophilic substitution reaction, such as a nucleophilic aromatic substitution reaction, so as to form group L.

124. The method according to any of claims 118 to 123, 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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