Parp1 inhibitor compounds

Abstract

A PARP1 inhibitor compound has a structure: (I) y is 0, 1, or 2. Each XD is selected from C, N, O or S. XET and XEB are selected from C and N. Each R1 and each R4 is independently absent, H, or an organic group. The R4 groups are not fused to form a ring. R3 is H or an organic group. L is: (II) Ring C is aromatic. XA1 and XB3 are selected from C and N. Each XA2, XB2 and XC is selected from C, N, O and S. Ring C is a heterocycle. Each R5A, R5B, and R5C is absent, H, or an organic group. R6 is H or an organic group. n, m, p, q, r and s are integers, with n+m being 1 to 5, p p+q being 2 to 6, and r+s being 3 or 4. Q1 and Q2 are each independently a bond or a 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 a / . 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 2021.01.26.428337vl).

[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; each XDis independently selected from C, N, O and S;

[0019] XETand XEBare each independently selected from C and N; each R1is independently absent or selected from H and a substituted or unsubstituted organic group; each R4is independently absent or selected from H and a substituted or unsubstituted organic group, with the proviso that the R4groups are not fused to form a ring;

[0020] R3is H or a substituted or unsubstituted organic group;

[0021] L is a group having a structure of: wherein: ring C is an aromatic ring;

[0022] XA1is C or N; each XA2is independently selected from C, N, O and S; each XB2is independently selected from C, N, O and S; XB3is selected from C and N; each Xcis independently selected from C, N, O, and S, with the proviso that ring C is a heterocycle; each R5Aand R5Cis independently absent or selected from H and a substituted or unsubstituted organic group; each R5Bis independently absent, H, a substituted or unsubstituted organic group, or together with another R5Brepresents a bond bridging ring B;

[0023] R6is selected from H and a substituted or unsubstituted organic group; 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; r is 0, 1, 2, 3, or 4; and s is 0, 1, 2, 3, or 4, with the proviso that r + s is 3 or 4;

[0024] 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; each R5Bis independently absent or selected from H and a substituted or unsubstituted organic group; n + m is in the range 2 to 5; and p + q 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. Another aspect of the invention provides a pharmaceutical composition comprising a PARP1 inhibitor compound as defined herein.

[0027] 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.

[0028] 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.

[0035] 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.

[0036] A compound is considered to be a selective PARP1 inhibitor if its presence is capable of displacing or reducing the ability of a high affinity Cy5 fluorescent dye-labelled chemical probe to bind to PARP1 whilst displacing the same chemical probe at PARP2 with at least 10-fold weaker activity. Typically, the compound is considered to be a selective PARP1 inhibitor if it has an IC50 < 10 pM in this assay at PARP1 with at least 10-fold selectivity preference over PARP2. A suitable such assay may be conducted for 1 h at room temperature using 10 nM PARP1 or PARP2, Tb-cryptate antibody and PARP1 / 2 binding probe in 20 mM HEPES (pH 7.5), 100 mM NaCI, 2 mM DTT, 0.1 % BSA (w / v), 0.02 % Tween (v / v) assay buffer. Probe binding displacement may be detected using homogeneous time-resolved fluorescence. A particularly suitable assay is described in the Examples below. Preferably the selectivity preference of PARP1 over PARP2 is at least 50-fold, more preferably at least 100-fold. A compound is also considered to be a selective PARP1 inhibitor if it has an IC50 < 10 pM at PARP1 with at least 10-fold selectivity preference over PARP2 in NanoBRET assays demonstrating cellular target engagement. These assays are based on bioluminescence resonance energy transfer (BRET) between a Nano-luc-tagged protein (e.g. PARP1 or PARP2) and a fluorescent group on a high affinity NAD+ competitive binding probe. Such cellular probe displacement assays can be utilised to measure inhibitor affinities and selectivity ratios at PARP1 and 2. A particularly suitable assay is described in the Examples below. Preferably the selectivity preference of PARP1 over PARP2 is at least 50-fold, more preferably at least 100-fold.

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

[0041] Where a general formula depicts an element in the format (X)i, where X is variable element and i is a number, the parentheses are expanded before assigning each X. For example, if variable X may be C or N, then (X)z encompasses C-C, C-N, and N-N.

[0042] Where stereochemistry is depicted, the stereochemistry shown is relative stereochemistry rather than absolute stereochemistry.

[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 refer to pairs of diastereomers having the indicated configuration of the A ring. Nuclear Overhauser Effect nuclear magnetic resonance spectroscopy ("NOE NMR") may be used to determine the stereochemistry of compounds as described herein.

[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. The suffix 'b' in a compound number denotes an enantiomer eluted as a second fraction when a mixture of two enantiomers is separated by supercritical fluid chromatography ("SFC") using a chiral column. Discussion

[0048] 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; each XDis independently selected from C, N, O and S;

[0049] XETand XEBare each independently selected from C and N; each R1is independently absent or selected from H and a substituted or unsubstituted organic group; each R4is independently absent or selected from H and a substituted or unsubstituted organic group, with the proviso that the R4groups are not fused to form a ring;

[0050] R3is H or a substituted or unsubstituted organic group; ring C is an aromatic ring;

[0051] XA1is C or N; each XA2is independently selected from C, N, O and S; each XB2is independently selected from C, N, O and S;

[0052] XB3is selected from C and N; each Xcis independently selected from C, N, O, and S, with the proviso that ring C is a heterocycle; each R5Aand R5Cis independently absent or selected from H and a substituted or unsubstituted organic group; each R5Bis independently absent, H, a substituted or unsubstituted organic group, or together with another R5Brepresents a bond bridging ring B;

[0053] R6is selected from H and a substituted or unsubstituted organic group; 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; r is 0, 1, 2, 3, or 4; s is 0, 1, 2, 3, or 4, with the proviso that r + s is 3 or 4; and

[0054] Q1and Q2are each independently a bond or a linking group having a structure selected from: where: 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.

[0055] Optionally, Q1is a bond; each R5Bis independently absent or selected from H and a substituted or unsubstituted organic group; n +m is in the range 2 to 5; and p + q is in the range 2 to 5.

[0056] Various aspects of the above general structure will now be discussed in more detail.

[0057] Stereochemistry

[0058] 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.

[0059] Some PARP1 inhibitor compounds may be capable of tautomerism. Such compounds may be provided in the form of any possible tautomer.

[0060] 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:

[0061] And a "trans" compound has a trans configuration across ring A:

[0062] Substituents - general

[0063] 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, XET, XEB, XA1, XA2, XB2,

[0064] XB3, Xc).

[0065] In the compounds provided herein, various ones of the R1, R4, and R5groups may be absent.

[0066] 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).

[0067] 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.

[0068] Each R1, R4and R5group may independently be absent or present, and may be the same or different. For the avoidance of doubt, where the number of R groups attached to an atom may vary according to the choice of corresponding X group, the following provisos typically apply: i) When an X atom is O, its corresponding R groups are both absent. ii) When an X atom is S, its corresponding R groups are both absent or are both selected from =0 and =NR10, where R10is H or a substituted or unsubstituted organic group, preferably a Cl to C3 alkyl group. iii) When an X is N and is double bonded to an adjacent ring atom, its corresponding R groups are absent. iv) When an X is N and is not double bonded to an adjacent ring atom, exactly one corresponding R group is present. v) When an X is C and is double bonded to an adjacent ring atom, exactly one corresponding R group is present. vi) When an X is C and is not double bonded to an adjacent ring atom, both corresponding R5groups or both the corresponding R5and R6groups are present.

[0069] Atom XA1of ring A is a special case, since this atom connects rings E and A. XA1bears an R5substituent only if XA1is C and does not form a double bond to another ring atom.

[0070] The substituents (i.e. R groups; R1, R3, R4, R5, R6, R7, and R8) are not especially limited, provided that they do not prevent the PARP1 inhibitory function from occurring. The substituents are selected from H and a substituted or unsubstituted organic group. Thus, both above and in the following, the terms 'substituent' and 'organic group' are not especially limited and may be any functional group or any atom, especially any functional group or atom common in organic chemistry.

[0071] Any R5or R6group may form a ring with any other R5or R6group on an adjacent and / or proximal atom, although in most embodiments this is not preferred, except where explicitly stated. Thus, the following substituents may together form a ring: an R5Awith another R5A; an R5Bwith another R5B; an R5Cwith another R5C; or an R5Cwith R6. In the present context, an adjacent and / or proximal atom may mean another atom directly bonded to an atom (adjacent) or may be two atoms with only a single atom in between (proximal), or may mean two atoms close enough sterically to be capable of forming a ring (proximal). Preferably R5 / R6groups attached to the same atom do not together form a ring, although this is not excluded.

[0072] 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')2 group (wherein each R' group is the same or different and is H or an organic group, preferably H or a linear 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 XD, XA2or XB2atom which is C may bear a =0 group.

[0073] 'Substituent' and 'organic group' may have any of the following meanings.

[0074] The organic group may comprise any one or more atoms from any of groups 11 IA, 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).

[0075] 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.

[0076] 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.

[0077] 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-tetrahydropyran, morpholine, thiopyran, 2-azathiopyran, 3-azathiopyran, 4-azathiopyran, thiane, indole, indazole, benzimidazole, 4-azaindole, 5-azaindole, 6-azaindole, 7-azaindole, isoindole, 4- azaisoindole, 5-azaisoindole, 6-azaisoindole, 7-azaisoindole, indolizine, 1-azaindolizine, 2- azaindolizine, 3-azaindolizine, 5-azaindolizine, 6-azaindolizine, 7-azaindolizine, 8- azaindolizine, 9-azaindolizine, purine, carbazole, carboline, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, quinoline, cinnoline, quinazoline, quinoxaline, 5- azaquinoline, 6-azaquinoline, 7-azaquinoline, isoquinoline, phthalazine, 6-azaisoquinoline, 7- azaisoquinoline, pteridine, chromene, isochromene, acridine, phenanthridine, perimidine, phenanthroline, phenoxazine, xanthene, phenoxanthiin, and / or thianthrene, as well as regioisomers of the above groups. These groups may generally be attached at any point in the group, and also may be attached at a hetero-atom or at a carbon atom. In some instances particular attachment points are preferred, such as at 1-yl, 2-yl and the like, and these are specified explicitly where appropriate. All tautomeric ring forms are included in these definitions. For example pyrrole is intended to include 1 / 7-pyrrole, 2 / 7-pyrrole and 3 / 7-pyrrole.

[0078] 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.

[0079] 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.

[0080] In addition, any substituent may comprise a combination of two or more of the substituents and / or functional groups defined herein.

[0081] Where it is said that a substituent (R1, R3, R4, R5A(e.g. R5A1, R5A2, R5A3), R5B, R5C, 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

[0082] (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

[0083] (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,

[0084] -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 -CH2CH2CI3);

[0085] NH2or a substituted or unsubstituted linear or branched primary secondary or tertiary Ci-Ce amine group

[0086] (such as -NMeH, -NMe2, -NEtH, -NEtMe, -NEt2, -NPrH, -NPrMe, -NPrEt, -NPr2, - NBuH, -NBuMe, -NBuEt, -CH2-NH2, -CH2-NMeH, -CH2-NMe2, -CH2-NEtH, - CH2-NEtMe,

[0087] -CH2-NEt2, -CH2-NPrH, -CH2-NPrMe, and -CH2-NPrEt); a substituted or unsubstituted amino-aryl group

[0088] (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, -NH-(2,3 or 4)I-Ph, -NH-(2,3 or 4)Me-Ph, -NH-(2,3 or 4)Et-Ph,

[0089] -NH-(2,3 or 4)Pr-Ph, -NH-(2,3 or 4)Bu-Ph, NH-(2,3 or 4)OMe-Ph,

[0090] -NH-(2,3 or 4)0Et-Ph, -NH-(2,3 or 4)0Pr-Ph, -NH-(2,3 or 4)OBu-Ph,

[0091] -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,

[0092] -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,

[0093] -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

[0094] (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

[0095] (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl); an -OH group; a substituted or unsubstituted linear or branched Ci-Ce alcohol group

[0096] (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,

[0097] -CH2CH2CH2COOH, -CH2CH2CH2CH2COOH, and -CH2CH2CH2CH2CH2COOH); a substituted or unsubstituted linear or branched carbonyl group

[0098] (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,

[0099] -(CO)-l,3-epoxypropan-2-yl; -(CO)NH2, -(CO)NHMe, -(CO)NMe2,

[0100] -(CO)NHEt, -(CO)NEt2,

[0101] -(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, -CH2CH2CH2COOI\ / le, and -CH2CH2CH2CH2COOMe); a substituted or unsubstituted linear or branched Ci-Ce amide group

[0102] (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, -CH2CH2CH2OI\ / le, -CH2CH2CH2CH2OMe, and -CH2CH2CH2CH2CH2OMe); a substituted or unsubstituted linear or branched aminoalkoxy group

[0103] (such as -OCH2NH2, -OCH2NHMe, -OCH2NMe2, -OCH2NHEt, -OCH2NEt2, -OCH2CH2NH2, -OCH2CH2NHMe, -OCH2CH2NMe2, -OCH2CH2NHEt, and -OCH2CH2NEt2); a substituted or unsubstituted sulfonyl group

[0104] (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,

[0105] -SO2-morpholine-N-yl, -SO2NHCH2OMe, and -SO2NHCH2CH2OMe); a substituted or unsubstituted aminosulfonyl group

[0106] (such as -NHSO2Me, -NHSO2Et, - NHSO2Pr, -NHSO2iPr, -NHSO2Ph, -NHSO2-(2,3 or 4)-F-Ph, -NHSO2-cyclopropyl, -NHSO2CH2CH2OCH3); a substituted or unsubstituted aromatic group

[0107] (such as Ph-, 2-F-Ph-, 3-F-Ph-, 4-F-Ph-, 2-CI-Ph-, 3-CI-Ph-, 4-CI-Ph-, 2-Br-Ph-,

[0108] 3-Br-Ph-, 4-Br-Ph-, 2-l-Ph-, 3-l-Ph, 4-l-Ph-, 2, (3, 4, 5 or 6)-F2-Ph-,

[0109] 2, (3, 4, 5 or 6)-CI2-Ph-, 2, (3, 4, 5 or 6)-Br2-Ph-, 2, (3, 4, 5 or 6)-l2-Ph-,

[0110] 2, (3, 4, 5 or 6)-Me2-Ph-, 2, (3, 4, 5 or 6)-Et2-Ph-, 2, (3, 4, 5 or 6)-Pr2-Ph-,

[0111] 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-,

[0112] 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-,

[0113] 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-,

[0114] 3,(4 or 5)-(MeO)2-Ph-, 3,(4 or 5)-(CF3)2-Ph-, 2-Me-Ph-, 3-Me-Ph-, 4-Me-Ph-,

[0115] 2-Et-Ph-, 3-Et-Ph-, 4-Et-Ph-, 2-Pr-Ph-, 3-Pr-Ph-, 4-Pr-Ph-, 2-Bu-Ph-, 3-Bu-Ph-,

[0116] 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-,

[0117] 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

[0118] (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,

[0119] 2-azapiperidine-4-yl, 3-azapiperidine-l-yl, 3-azapiperidine-2-yl,

[0120] 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,

[0121] 2-azapyran-3-yl, 2-azapyran-4-yl, 2-azapyran-5-yl, 2-azapyran-6-yl,

[0122] 3-azapyran-2-yl, 3-azapyran-4-yl, 3-azapyran-5-yl, 3-azapyran-6-yl,

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

[0124] 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,

[0125] 2-aza-tetrahydrofuran-4-yl, 2-aza-tetrahydrofuran-5-yl,

[0126] 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,

[0127] 2-aza-tetrahydropyran-5-yl, 2-aza-tetrahydropyran-6-yl,

[0128] 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,

[0129] 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).

[0130] With the exception of R4, pairs of substituent groups with matching identifiers may together form a single group.

[0131] For example, a pair of R5Agroups attached to the same atom may together represent a carbonyl group.

[0132] Alternatively or additionally, 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.

[0133] It is also contemplated that an R5Cgroup and an R6group attached to different atoms may together form a ring with ring C atoms.

[0134] The R4groups are not fused to form a ring. In particular, the R4groups are not fused into a spirocyclopropyl group.

[0135] Preferably, each R5group (R5A, R5B, R5C) is independently absent or selected from:

[0136] H, deuterium, a halogen (such as -F, -Cl, -Br, and -I; preferably F or Cl), a nitrile group, a Ci-Ce alkyl group, a C1-C6halogenated alkyl group (preferably CF3, CHF2, or CH2CF3), a cyclopropyl group, an -OH group, a C1-C6alcohol group, a C1-C7amino carbonyl group (such as -NH-CO-Me), an -NH2group, a C1-C6amino group, and a C1-C6alkoxy group. 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-. 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: R8is bonded to a nitrogen. In some instances, an R1, R4, or R5Aor R5Bgroup may be attached to a ring atom which is N. The preferred substituents for N atoms are: H; a substituted or unsubstituted linear or branched C1-C6alkyl group (such as Me, Et, Pr, i-Pr, n-Bu, i-Bu, t-Bu, pentyl and hexyl); a substituted or unsubstituted linear or branched C1-C6alkyl-aryl group (such as –CH2Ph, -CH2(2,3 or 4)F-Ph, -CH2(2,3 or 4)Cl-Ph, -CH2(2,3 or 4)Br-Ph, -CH2(2,3 or 4)I-Ph, -CH2CH2Ph, -CH2CH2CH2Ph, -CH2CH2CH2CH2Ph, -CH2CH2CH2CH2CH2Ph, and -CH2CH2CH2CH2CH2CH2Ph); a substituted or unsubstituted linear or branched Ci-Ce halogenated alkyl group

[0137] (such as -CH2F, -CF3, -CH2CH2F and -CH2CF3); a substituted or unsubstituted cyclic amine or amido group

[0138] (such as pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, 2-keto-pyrrolidinyl,

[0139] 3-keto-pyrrolidinyl, 2-keto-piperidinyl, 3-keto-piperidinyl, and

[0140] 4-keto-piperidinyl); a substituted or unsubstituted cyclic C3-Cs alkyl group

[0141] (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl); a substituted or unsubstituted linear or branched C2-Ce alcohol group

[0142] (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

[0143] (such as -CH2COOH, -CH2CH2COOH, -CH2CH2CH2COOH, -CH2CH2CH2CH2COOH, and -CH2CH2CH2CH2CH2COOH); a substituted or unsubstituted linear or branched carbonyl group

[0144] (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

[0145] (such as -CO-NH2, -CO-NMeH, -CO-NMe2, -CO-NEtH, -CO-NEtMe, -CO-NEt2, -CO-NPrH, -CO-NPrMe, and -CO-NPrEt); a substituted or unsubstituted sulfonyl group (such as -SO2Me, -SO2Et, -SO2Pr, -SO2iPr, -SO2Ph, -SO2-(2,3 or 4)-F-Ph, -SO2-cyclopropyl, -SO2CH2CH2OCH3, -SO2NH2, -SO2NHMe, -SO2NMe2, -SO2NHEt, -SO2NEt2, -SO2-pyrrolidine-N-yl, -SO2-morpholine-N-yl, -SO2NHCH2OMe, and -SO2NHCH2CH2OMe); a substituted or unsubstituted aromatic group (such as Ph-, 2-F-Ph-, 3-F-Ph-, 4-F-Ph-, 2-Cl-Ph-, 3-Cl-Ph-, 4-Cl-Ph-, 2-Br-Ph-, 3-Br-Ph-, 4-Br-Ph-, 2-I-Ph-, 3-I-Ph, 4-I-Ph-, 2,(3,4,5 or 6)-F2-Ph-, 2,(3,4,5 or 6)-Cl2-Ph-, 2,(3,4,5 or 6)-Br2-Ph-, 2,(3,4,5 or 6)-I2-Ph-, 2,(3,4,5 or 6)-Me2-Ph-, 2,(3,4,5 or 6)-Et2-Ph-, 2,(3,4,5 or 6)-Pr2-Ph-, 2,(3,4,5 or 6)-Bu2-Ph-, 2,(3,4,5 or 6)-(CN)2-Ph-, 2,(3,4,5 or 6)-(NO2)2-Ph-, 2,(3,4,5 or 6)-(NH2)2-Ph-, 2,(3,4,5 or 6)-(MeO)2-Ph-, 2,(3,4,5 or 6)-(CF3)2-Ph-, 3,(4 or 5)-F2-Ph-, 3,(4 or 5)-Cl2-Ph-, 3,(4 or 5)-Br2-Ph-, 3,(4 or 5)-I2-Ph-, 3,(4 or 5)-Me2-Ph-, 3,(4 or 5)-Et2-Ph-, 3,(4 or 5)-Pr2-Ph-, 3,(4 or 5)-Bu2-Ph-, 3,(4 or 5)-(CN)2-Ph-, 3,(4 or 5)-(NO2)2-Ph-, 3,(4 or 5)-(NH2)2-Ph-, 3,(4 or 5)-(MeO)2-Ph-, 3,(4 or 5)-(CF3)2-Ph-, 2-Me-Ph-, 3-Me-Ph-, 4-Me-Ph-, 2-Et-Ph-, 3-Et-Ph-, 4-Et-Ph-, 2-Pr-Ph-, 3-Pr-Ph-, 4-Pr-Ph-, 2-Bu-Ph-, 3-Bu-Ph-, 4-Bu-Ph-, 2-(CN)-Ph-, 3-(CN)-Ph-, 4-(CN)-Ph-, 2-(NO2)-Ph-, 3-(NO2)-Ph-, 4-(NO2)-Ph-, 2-(NH2)-Ph-, 3-(NH2)-Ph-, 4-(NH2)-Ph-, 2-MeO-Ph-, 3-MeO-Ph-, 4-MeO-Ph-, 2-(NH2-CO)-Ph-, 3-(NH2-CO)-Ph-, 4-(NH2-CO)-Ph-, 2-CF3-Ph-, 3-CF3-Ph-, 4-CF3-Ph-, 2-CF3O-Ph-, 3-CF3O-Ph-, and 4-CF3O-Ph-); and a substituted or unsubstituted heterocyclic group (such as pyrrole-2-yl, pyrrole-3-yl, pyrazole-3-yl, pyrazole-4-yl, pyrazole-5-yl, imidazole-2-yl, imidazole-4-yl, imidazole-5-yl, 1,2,3-triazole-4-yl, 1,2,3-triazole-5-yl, 1,2,4-triazole-3-yl, 1,2,4-triazole-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazine-3-yl, pyridazine-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, pyrazine-2-yl, pyrrolidine-2-yl, pyrrolidine-3-yl, piperidine-2-yl, piperidine-3-yl, piperidine-4-yl, 2-azapiperidine-3-yl, 2-azapiperidine-4-yl, 3-azapiperidine-2-yl, 3-azapiperidine-4-yl, 3-azapiperidine-5-yl, piperazine-2-yl, furan-2-yl, furan-3- yl, pyran-2-yl, pyran-3-yl, pyran-4-yl, 2-azapyran-3-yl, 2-azapyran-4-yl, 2-azapyran-5-yl, 2-azapyran-6-yl, 3-azapyran-2-yl, 3-azapyran-4-yl, 3-azapyran-5-yl, 3-azapyran-6-yl, 4-azapyran-2-yl, 4-azapyran-3-yl, 4-azapyran-5-yl, 4-azapyran-6-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-4-yl, 2-aza-tetrahydrofuran-5-yl, 3-aza-tetrahydrofuran-2-yl, 3-aza-tetrahydrofuran-4-yl, 3-aza-tetrahydrofuran-5-yl, tetrahydropyran-2-yl, oxetan-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, 2-aza-tetrahydropyran-3-yl, 2-aza-tetrahydropyran-4-yl, 2-aza-tetrahydropyran-5-yl, 2-aza-tetrahydropyran-6-yl, 3-aza-tetrahydropyran-2-yl, 3-aza-tetrahydropyran-4-yl, 3-aza-tetrahydropyran-5-yl, 3-aza-tetrahydropyran-6-yl, morpholine-2-yl, morpholine-3-yl, thiophen-2-yl, thiophen-3-yl, isothiazole-3-yl, isothiazole-4-yl, isothiazole-5-yl, thiazole-2-yl, thiazole-4-yl, thiazole-5-yl, thiopyran-2-yl, thiopyran-3-yl, thiopyran-4-yl, 2-azathiopyran-3-yl, 2-azathiopyran-4-yl, 2-azathiopyran-5-yl, 2-azathiopyran-6-yl, 3-azathiopyran-2-yl, 3-azathiopyran-4-yl, 3-azathiopyran-5-yl, 3-azathiopyran-6-yl, 4-azathiopyran-2-yl, 4-azathiopyran-3-yl, 4-azathiopyran-5-yl, 4-azathiopyran-6-yl, thiolane-2-yl, thiolane-3-yl, thiane-2-yl, thiane-3-yl, thiane-4-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, furazan-3-yl, (1,3,4-oxadiazol)-2-yl, (1,3,4-oxadiazol)-5-yl, (1,2,4-oxadiazol)-3-yl, (1,2,4-oxadiazol)-5-yl; and tetrazole-5-yl). Optionally, R8, or any R1, R4, or R5Aor R5Bthat is attached to a ring nitrogen, may preferablybe selected from H, a substituted or unsubstituted linear or branched C1-C6 alkyl group, anda substituted or unsubstituted linear or branched C1-C6halogenated alkyl group. An R1or R4attached to a N is preferably selected from H, a C1 to C3 alkyl group, and a C1 to C3 fluoroalkyl group, such as -CH2CF3. Head group - general

[0146] The head group of the PARP1 inhibitor compound comprises rings D and E, as shown in the general formula below:

[0147] 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 are particularly preferred.

[0148] Each XDrepresents an atom independently selected from C, N, O, and S. The XDatoms are typically selected such that ring D is free of any 0-0 bonds. Usually, at least one XDis C.

[0149] Optionally, each XDis independently selected from C and N. Further optionally, each XDis C.

[0150] Rings D and E are connected via atoms XETand XEB. These atoms may be referred to herein as the "bridgehead atoms". XETand XEBare each individually selected from C and N. Typically, at least one of XETand XEBis C. Preferably, XETis C and XEBis either C or N, and most preferably XETand XEBare each C.

[0151] Ring D may bear optional substituents R1and R4. In the above general formula, each R1is independently absent or selected from H and a substituted or unsubstituted organic group; and each R4is independently absent or selected from H and a substituted or unsubstituted organic group, with the proviso that the R4groups are not fused to form a ring.

[0152] For any given ring D atom XD, the number of substituents (R1or R4groups), and the nature of the bonds to adjacent atoms of ring D are selected as appropriate depending upon the identity of the XDatom, to satisfy the normal valency of that atom.

[0153] When an XDatom is O: the atom lacks any substituent (R1or R4); the atom is bonded to adjacent ring atoms via single bonds; and neither adjacent ring atom is O.

[0154] When an XDatom is N: the atom bears up to one substituent (R1or R4); if the atom bears a substituent, then the atom is bonded to adjacent ring atoms via single bonds; or if the atom does not bear a substituent, then the atom forms a double bond with one adjacent ring atom, and a single bond with the other adjacent ring atom.

[0155] When an XDatom is C: the atom bears one or two substituents (R1or R4); if the atom bears two substituents, then the atom is bonded to adjacent ring atoms via single bonds; or if the atom bears one substituent, then the atom forms a double bond with one adjacent ring atom, and a single bond with the other adjacent ring atom.

[0156] Each R1and each R4may be independently absent or selected from H and a substituted or unsubstituted organic group. The organic group may be selected from any of the various groups already discussed, subject to the proviso that the R4groups are not fused to form a ring. In particular, the R4groups do not represent a spirocyclopropyl group. For example, each R1and each R4may independently be absent or selected from:

[0157] H; a halogen; a nitrile group; a Cl to C6 acyclic alkyl group; a Cl to C6 acyclic alkoxy group; a Cl to C6 acyclic haloalkyl group; a Cl to C6 acyclic haloalkoxy group, such as -OCF3 or OCHF2; a Cl to C6 acyclic aminoalkyl group; and

[0158] 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 alkyl group; a Cl to C6 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.

[0159] Optionally, each R1and each R4is independently absent or selected from H; a halogen, optionally Cl or F; a Cl to C3 acyclic 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.

[0160] Preferably, each R1and each R4is independently absent or selected from: H; Cl; F; a halomethyl group, such as CF3; and a nitrile group.

[0161] Most preferably, each R1and each R4is independently absent or selected from H and F.

[0162] For instance, exactly one R1may be F, or alternatively exactly one R4may be F.

[0163] Alternatively, each R1and each R4is absent or H. Typically, ring D bears no more than two organic groups in total, with all other R1and R4groups being either absent or H. As shown in the general formula, ring E bears a substituent R3, which may be H or a substituted or unsubstituted organic group.

[0164] R3is preferably selected from H, a Cl to C3 alkyl group, and a Cl to C3 haloalkyl group. Most preferably, R3is H.

[0165] Example head groups - N-bridged variants

[0166] When XEBis N, the PARP1 inhibitor compound may have a structure selected from: with R1, R4, and R3each being as defined above.

[0167] The preferred head group in this class is: Head group - general structural formulae for C-bridged variants

[0168] In examples where XEBand XETare each C, the PARP1 inhibitor compound may have a structure selected from:

[0169] with R1, R3and R4each being as previously discussed.

[0170] In accordance with further possibilities, the PARP1 inhibitor compound may have a structure selected from: with R1, R3and R4each being as previously discussed.

[0171] Head groups - aromatic examples Ring D of the PARP1 inhibitor compound may be an aromatic ring.

[0172] For instance, ring D may be a 6-membered carbocyclic ring:

[0173] R4and each R1being present.

[0174] In such examples, the head group of the PARP1 inhibitor compound may have a substitution pattern as shown below: and optionally:

[0175] Preferred PARP1 inhibitor compounds in this class include:

[0176] Other preferred examples of PARP1 inhibitor compounds with aromatic D rings include:

[0177] R4and each R1being present.

[0178] Particularly preferred PARP1 inhibitors in this class may be selected from: Additional examples of PARP1 inhibitor compounds having aromatic D rings include those having a structure selected from:

[0179]

[0180] R4and each R1being present.

[0181] Preferred structures for PARP1 inhibitor compounds with aromatic D rings include: Additional preferred structures for PARP1 inhibitor compounds with aromatic D rings are:

[0182] Additional examples of PARP1 inhibitor compounds include those having a structure selected from:

[0183]

[0184] Head groups - non-aromatic examples

[0185] Alternatively, ring D may be a non-aromatic ring. Ring D may be a non-aromatic carbocyclic ring. For example, the PARP1 inhibitor compound may have a structure selected from:

[0186] As will be appreciated, in these examples, each R1and each R4is present.

[0187] Preferred PARP1 inhibitor compounds in the above class have a structure of: Ring D may alternatively be a cyclic ether, having a structure selected from: each R1and each R4being present.

[0188] Further examples of compounds in which ring D is a cyclic ether are: each R1and each R4being present. In accordance with a still further possibility, ring D may be a cyclic amine. Examples of such

[0189] PARP1 inhibitor compounds include: where each R1and each R4is present. Other examples of PARP 1 inhibitor compounds in which ring D is a cyclic amine are: where each R1and each R4is present. An R1or R4which is bonded to an N is preferably selected from H, a Cl to C3 alkyl group, and a Cl to C3 fluoroalkyl group. Preferred structures for PARP1 inhibitor compounds with non-aromatic D rings include:

[0190] Additional examples of structures for PARP1 inhibitor compounds include: L group - general

[0191] Group L of the PARP1 inhibitor compounds provided herein has a structure according to general formula: where: ring C is an aromatic ring;

[0192] XA1is C or N; each XA2is independently selected from C, N, O and S; each XB2is independently selected from C, N, O and S;

[0193] XB3is selected from C and N; each Xcis independently selected from C, N, O, and S, with the proviso that ring C is a heterocycle; each R5A, and R5Cis independently absent or selected from H and a substituted or unsubstituted organic group; each R5Bis independently absent, H, a substituted or unsubstituted organic group, or together with another R5Brepresents a bond bridging ring B;

[0194] R6is selected from H and a substituted or unsubstituted organic group; 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, or 4; and s is 0, 1, 2, 3, or 4, with the proviso that r + s is 3 or 4; and

[0195] Q1and Q2are each independently a bond or a linking group having a structure selected from: where: 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.

[0196] Each XA2, each XB2, and each Xcis independently selected from C, N, O and S, with the proviso that at least one Xcis O, N or S (preferably N) such that ring C is a heterocycle.

[0197] Optionally, Q1is a bond.

[0198] Optionally, n + m is in the range 2 to 5.

[0199] Optionally, p + q is in the range 2 to 5. Optionally, each RBis independently absent or selected from H and a substituted or unsubstituted organic group.

[0200] Typically, Q1is a bond; n + m is in the range 2 to 5; p + q is in the range 2 to 5; and each RBis independently absent or selected from H and a substituted or unsubstituted organic group.

[0201] 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 is a 3-membered ring, ring A is typically a carbocycle. 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 0-0, S-S, and S-0 bonds.

[0202] Each portion of group L is discussed in more detail below.

[0203] Ring A

[0204] 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. In other words, ring A may be a 3, 4, 5, 6, or 7-membered ring. Optionally, n + m is in the range 2 to 5, such that ring A is a 4, 5, 6, or 7-membered ring. Preferably, ring A is a 5- or 6-membered ring (n + m = 3 or 4), with 5-membered rings (n + m = 3) being particularly preferred.

[0205] 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.

[0206] XA1is bonded to ring E, and is selected from C and N. When XA1is N, R5A1is absent. When XA1is C, R5A1may be present or absent, and is preferably present.

[0207] Each XA2is independently selected from C, N, O, and S. Preferably, each XA2is independently selected from C and N. Most preferably, each XA2is C.

[0208] 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. Preferably, ring A is saturated.

[0209] 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.

[0210] Generally, when an R5Agroup is present, that R5Agroup is preferably H.

[0211] Ring A may be a bicyclic ring, in which two R5Agroups are fused together. The bicyclic ring may be a bridged bicyclic ring.

[0212] R5A3is most typically H.

[0213] It is preferable that, when present, each R5Ais independently selected from H; a halogen, optionally F; a hydroxyl group; an oxo group (in other words, a carbonyl group: =0); and a Cl to C3 alkyl group, optionally wherein a pair of R5Agroups form a ring, further optionally wherein the ring bridges ring A. In accordance with another possibility, two R5Agroups on adjacent atoms may together represent a ring fused to ring A, optionally a phenyl group fused to ring A.

[0214] Particularly preferably: i) one pair of R5Agroups forms -CH2- group bridging ring A, with each other R5Abeing

[0215] H; or ii) each R5Ais H.

[0216] Ring A may be a 7-membered ring. For example, ring A may be a cycloheptane having a structure selected from: each R5Abeing present.

[0217] 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:

[0218] each R5Abeing present. 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.

[0219] In accordance with a further possibility, ring A may be a 5-membered aromatic ring, optionally an oxazole or isoxazole, optionally having a structure selected from: each R5Abeing independently selected from H and a substituted or unsubstituted organic group. In other examples, ring A may be a 4-membered ring having a structure of: each R5Aand R5A3being present. Alternatively, ring A may be a 3-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. In accordance with still another possibility, ring A may be a bridged ring. Examples of suitable bridged ring structures include: each R5Abeing present. Further examples of bridged ring A structures include:

[0220] Ring A typically includes no more than one bridging group. In the example bridged rings shown above, no R5Agroups are fused to form a further ring, and each R5Agroup is preferably H.

[0221] Examples of suitable structures for ring A include:

[0222] A37

[0223] Additional examples of suitable structures for ring A include:

[0224] A41

[0225] 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) XA1is C and R5A1is selected from H and a substituted or unsubstituted organic group; or ii) XA1is N and R5A1is absent.

[0226] Each R5A1, R5A2and R5A3may independently be absent or selected from H; a halogen, optionally F; a hydroxyl group; an oxo group (also referred to as a carbonyl group; =0); and a

[0227] Cl to C3 alkyl group, optionally wherein a pair of R5Agroups form a Cl to C3 alkyl group bridging ring A. Preferably, each R5A1, R5A2and R5A3is absent or H. Preferred A ring structures include:

[0228] Particularly preferred A ring structures include: Other particularly preferred ring A structures are:

[0229] The most preferred ring A structure is: Q1is typically a bond. When ring A is a 3- or 4-membered ring, Q1is optionally a linking group such as -CH2- or -CHfCHs)-. In particular, when ring A is:

[0230] Q1may be a linking group selected from -CH2- or -CHfCHs)-. Ring B

[0231] Ring B of group L has a general structure of: Each XB2is independently selected from C, N, O and S. XB3is selected from C and N. p is 1, 2 or 3; and q is 1, 2 or 3. Typically, p + q is in the range 2 to 5: in other words, ring B is typically 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. Typically, each R5Bis independently absent or selected from H and a substituted or unsubstituted organic group. Preferably, each R5Bis independently absent or H. In certain examples, particularly those in which p + q is 6, two R5Bgroups may together represent a bond bridging ring B. In other words, ring B may be a fused ring system comprising two rings.

[0232] Depending upon the number of R5Bgroups present, ring B may be saturated or unsaturated. Preferably, ring B is a saturated ring.

[0233] Preferably, each XB2is C, and ring B has a structure of: XB3is preferably N. In such examples, Ring B may have a structure of:

[0234]

[0235] XB3may be C. For example, 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.

[0236] 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.

[0237] More specific examples of suitable ring B structures include:

[0238]

[0239] Most preferably, ring B has a structure of: In accordance with another possibility, ring B may have a structure of:

[0240] Q2is typically a bond. When ring B is a 4-membered ring, such as the azetidine illustrated immediately above, Q2may be a linking group, such as -O-.

[0241] In accordance with still a further possibility, p + q may be 6 and ring B may comprise two fused rings. For example, ring B may have a structure of: optionally wherein each R5Bis absent or H. Optionally, ring B may have a structure of: More specific examples of B ring structures comprising fused rings include:

[0242] Linkers - Q1and Q2group

[0243] Ring A is coupled to ring B via a linker Q1, and ring B is coupled to ring C via a linker Q2:

[0244] Typically, Q1is a bond, such that rings A and B are directly connected to one another:

[0245] Q2may be a bond. In other words, atom XB3may be directly connected to ring C.

[0246] Alternatively, Q1and / or Q2may be a 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.

[0247] R7may be selected from H; a halogen; such as -F, -Cl, -Br, or -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.

[0248] Preferably, each R7is independently selected from H; a halogen, optionally F; a Cl to C6 alkyl group; and a Cl to C6 haloalkyl group.

[0249] When XB3of ring typically at least one.

[0250] When Q1and / or Q2is:

[0251] R8may be selected from:

[0252] 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

[0253] (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,

[0254] -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

[0255] (such as pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, 2-keto-pyrrolidinyl,

[0256] 3-keto-pyrrolidinyl, 2-keto-piperidinyl, 3-keto-piperidinyl, and

[0257] 4-keto-piperidinyl); a substituted or unsubstituted cyclic C3-C8 alkyl group

[0258] (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl); a substituted or unsubstituted linear or branched C2-C6 alcohol group

[0259] (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

[0260] (such as -CH2COOH, -CH2CH2COOH, -CH2CH2CH2COOH, -CH2CH2CH2CH2COOH, and -CH2CH2CH2CH2CH2COOH); a substituted or unsubstituted linear or branched carbonyl group

[0261] (such as -(CO)Me, -(CO)Et, -(CO)Pr, -(CO)-i_Pr, -(CO)-n-Bu, -(CO)-i-Bu, -(CO)-t-Bu,

[0262] -(CO)Ph, -(CO)CH2Ph, -(CO)CH2OH, -(CO)CH2OCH3, -(CO)CH2NH2,-(CO)CH2NH Me, -(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)-m orpholine-N-yl, -(CO)-piperazine-N-yl, -(CO)-N-methyl-piperazine-N-yl, -(CO)N HCH2CH2OH,

[0263] -(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

[0264] (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

[0265] (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,

[0266] -SO2-morpholine-N-yl, -SO2NHCH2OMe, and -SO2NHCH2CH2OMe); a substituted or unsubstituted aromatic group

[0267] (such as Ph-, 2-F-Ph-, 3-F-Ph-, 4-F-Ph-, 2-CI-Ph-, 3-CI-Ph-, 4-CI-Ph-, 2-Br-Ph-,

[0268] 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-,

[0269] 2, (3, 4, 5 or 6)-Me2-Ph-, 2, (3, 4, 5 or 6)-Et2-Ph-, 2, (3, 4, 5 or 6)-Pr2-Ph-,

[0270] 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-,

[0271] 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-,

[0272] 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-,

[0273] 3,(4 or 5)-(MeO)2-Ph-, 3,(4 or 5)-(CF3)2-Ph-, 2-Me-Ph-, 3-Me-Ph-, 4-Me-Ph-,

[0274] 2-Et-Ph-, 3-Et-Ph-, 4-Et-Ph-, 2-Pr-Ph-, 3-Pr-Ph-, 4-Pr-Ph-, 2-Bu-Ph-, 3-Bu-Ph-,

[0275] 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-,

[0276] 3-CF3-Ph-, 4-CF3-Ph-, 2-CF3O-Ph-, 3-CF3O-Ph-, and 4-CF3O-Ph-); and a substituted or unsubstituted heterocyclic group

[0277] (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,

[0278] 2-azapiperidine-3-yl, 2-azapiperidine-4-yl, 3-azapiperidine-2-yl,

[0279] 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,

[0280] 4-azapyran-5-yl, 4-azapyran-6-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl,

[0281] 2-aza-tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-4-yl,

[0282] 2-aza-tetrahydrofuran-5-yl, 3-aza-tetrahydrofuran-2-yl,

[0283] 3-aza-tetrahydrofuran-4-yl, 3-aza-tetrahydrofuran-5-yl, tetrahydropyran-2-yl, oxetan-3-yl, tetra hydropyran-3-yl, tetrahydropyran-4-yl, 2-aza-tetrahydropyran-3-yl, 2-aza-tetrahydropyran-4-yl,

[0284] 2-aza-tetrahydropyran-5-yl, 2-aza-tetrahydropyran-6-yl,

[0285] 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,

[0286] 2-azathiopyran-4-yl, 2-azathiopyran-5-yl, 2-azathiopyran-6-yl,

[0287] 3-azathiopyran-2-yl, 3-azathiopyran-4-yl, 3-azathiopyran-5-yl,

[0288] 3-azathiopyran-6-yl, 4-azathiopyran-2-yl, 4-azathiopyran-3-yl,

[0289] 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).

[0290] 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.

[0291] Preferably, Q2is a bond, -O- or -CH2-; optionally a bond or -CH2-. Most preferably, Q2is a bond. Ring C of the PARP1 inhibitor compound is a heteroaromatic ring having a general structure r is 0, 1, 2, 3, or 4; and s is 0, 1, 2, 3, or 4, with the proviso that r + s is 3 or 4. In other words, ring C may be a 5-membered ring or a 6-membered ring.

[0292] Each R5Cis independently absent or selected from H and a substituted or unsubstituted organic group.

[0293] Each R5Cmay be independently 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.

[0294] Preferably, each R5Cis 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. Optionally, the organic group may be selected from F, Cl, a nitrile group, a methyl group, and a fluoromethyl group such as -CF2H. F is the preferred organic group.

[0295] Optionally, exactly one R5Cis an organic group. Further optionally, exactly one R5Cis F, with each other R5Cbeing either absent or H.

[0296] Alternatively, each R5Cmay be absent or H. At least one Xcis a heteroatom.

[0297] When ring C is a 5-membered ring, each Xcis independently selected from C, N, O, and S, with at least one Xcbeing C, N, or O. Optionally, each Xcis independently selected from C and N. Further optionally, exactly one Xcatom is N or exactly two Xcatoms are N.

[0298] When ring C is a 6-membered ring, each Xcis independently selected from C and N, with at least one Xcbeing N.

[0299] Preferably, the carbon atom which is connected to linker Q2and the carbon atom which bears terminal substituent R6are non-adjacent. In other words, it is preferable that r is at least 1 and s is at least 1.

[0300] Ring C may be a 6-membered ring (r + s = 4). Preferably, in such examples, Q2is para to terminal substituent R6(r = 2, s = 2).

[0301] Ring C preferably has a general structure of: wherein:

[0302] XCoand XCmare each selected from C and N, with the proviso that at least one of XCoand XCmis 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; when XCmis N, RCmis absent. Optionally, exactly one of XCoand XCmis N.

[0303] Ring C may be a pyridine group, optionally having a structure selected from: Preferably, ring C is a pyridine group having a structure of:

[0304] More preferably, ring C has a structure of:

[0305] Most preferably, ring C has a structure of: Alternatively, ring C may be a diazine group, optionally having a structure selected from:

[0306] In particular, ring C may have a structure selected from:

[0307] In accordance with another possibility, ring C may be a 5-membered ring (r+s=3).

[0308] For example, ring C may be an imidazole group, optionally Alternatively, ring C may be a thiophene group, optionally having a structure selected from:

[0309] In accordance with another possibility, ring C may be a thiazole group. For instance, ring C may have a structure selected from:

[0310] The preferred thiazole structure for ring C is: , optionally wherein R5Cis H.

[0311] Alternatively, ring C may be a triazole, optionally having a structure selected from:

[0312] More specific examples of suitable ring C structures include:

[0313] C2 C4

[0314] C25 C26 C28

[0315] In accordance with another possibility, ring C may have a structure of:

[0316] C29. Specific examples of ring C structures include:

[0317] T19

[0318] Terminal substituent R6

[0319] Ring C bears a substituent R6, which is selected from H and a substituted or unsubstituted organic group.

[0320] 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:

[0321]

[0322] 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.

[0323] Optionally, R6is selected from -F, -Cl, -CN, -CONH2, -CONHMe (optionally -CONHCD3), -

[0324] CONHEt, -CONMe2, -CONHCOMe, -CONHCH2-CH2OMe, -CONH-CH2-CH2F, -CONH-CH2-CF3, -

[0325] CONH-CH2-CHF2,

[0326] R6may alternatively be H.

[0327] Particularly preferably, R6is selected from: i) CONHMe; ia) CONHCD3; iii) F; iv) Cl; and v) CN.

[0328] Where a compound is depicted with an R6group selected from i) to v) as defined immediately above, replacement of the R6group with any other one of groups i) to v) is explicitly contemplated. 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.

[0329] Examples of R6groups according to the above general formula include:

[0330] R6may be selected from the following list:

[0331] -CONHMe;

[0332] Alternatively, R6may have a structure of: wherein: each X6is independently selected from C, N, and O;

[0333] 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. Examples of cyclic R6groups according to the above formula include:

[0334] The preferred cyclic R6group is: Example L groups

[0335] Group L of the PARP1 inhibitor compound may in particular be selected from: Alternatively, group L may be selected from:

[0336]

[0337] Group L may have a cis configuration with respect to ring A. For example, group L may have a structure selected from: Further examples of L groups with a cis configuration are:

[0338] Alternatively, group L may have a trans configuration with respect to ring A. For example, group L may have a structure selected from:

[0339] Further examples of L groups having a trans configuration are:

[0340] Example Compounds

[0341] Provided are PARP1 inhibitor compounds having a structure of: wherein:

[0342] XDis selected from C and N; when XDis N:

[0343] RD1is selected from H, a Cl to C3 alkyl group, and a Cl to C3 haloalkyl group; preferably a methyl group; and

[0344] RD2is absent; when XDis C:

[0345] RD1and RD2are each H; n is 1 or 2;

[0346] RA1and RA3are each H, or RA1and RA3together represent a -CH2- group bridging ring A, with the proviso that when n is 1, RA1and RA3are each H;

[0347] XCoand XCmare each selected from C and N, with the proviso that at least one of XCoand XCmis N; when XCois C, RCois H or a halogen, preferably F; when XCois N, RCois absent; when XCmis C, RCmis H or a halogen, preferably F; when XCmis N, RCmis absent;

[0348] R6is selected from -C(O)NHMe; -CN; and a halogen, optionally F or Cl.

[0349] XDis preferably C. n is preferably 2.

[0350] RA1and RA3are preferably each H

[0351] XCmis preferably N, and RCois preferably H or F.

[0352] R6is preferably -C(O)NHMe, e.g. C(O)NHCD3.

[0353] When RA1and RA3are each H, the compound may have a cis configuration across ring A: or a trans configuration across ring A:

[0354] Specific examples of compounds in this class are:

[0355] ıĶtrans

[0356] ıĸtrans

[0357] Also provided are PARP1 inhibitor compounds having a general structure of: wherein:

[0358] XDis C or N; when XDis C, RD4is selected from H and a halogen, and is preferably H; when XDis N, RD4is absent;

[0359] RD1and RD2are each independently selected from H and a halogen; n is 1 or 2;

[0360] XAis C or N; when XAis C:

[0361] RA1and RA3are each H, or RA1and RA3together represent a -CH2- group bridging ring A, with the proviso that when n is 1, RA1and RA3are each when XAis N:

[0362] RA1is absent, and RA3is H;

[0363] XCoand XCmare each selected from C and N, with the proviso that at least one of XCoand XCmis N; when XCois C, RCois H or a halogen, preferably H or F; when XCois N, RCois absent; when XCmis C, RCmis H or a halogen, preferably H or F; when XCmis N, RCmis absent;

[0364] R6is selected from -C(O)NHMe; -CN; and a halogen, optionally F or Cl. Preferably, XDis C and RD4is H.

[0365] RD1and RD2are preferably selected from H and F. In such examples, exactly one of RD1and RD2may be F. n is preferably 2.

[0366] When R6is C(O)NHMe, XCmis preferably N.

[0367] When XAis C and RA1and RA3are each H, the compound may have a cis configuration across ring A:

[0368] or a trans configuration across ring A:

[0369] Examples of compounds in this class include:

[0370]

[0371] 

[0372]

[0373] 

[0374]

[0375] 

[0376] lOtrans

[0377]

[0378] 

[0379] ıĵtrans

[0380] Further provided are PARP1 inhibitor compounds having a general structure of: wherein: a dotted line represents a single bond or a double bond;

[0381] XEBis C or N;

[0382] XD1and XD2are each independently selected from C and N, with the proviso that when

[0383] XEBis N, XD1is C;

[0384] RD1and RD2are each independently absent or present and selected from H, a halogen, a methyl group, and a halomethyl group, such as CF3;

[0385] RD3is selected from H, a halogen, a methyl group, and a halomethyl group, such as CF3; n is 1 or 2;

[0386] RA1and RA3are each H, or RA1and RA3together represent a -CH2- group bridging ring

[0387] A, with the proviso that when n is 1, RA1and RA3are each H;

[0388] XCoand XCmare each selected from C and N, with the proviso that at least one of XCoand XCmis N; when XCois C RCois H or a halogen, and is optionally H or F; when XCois N, RCois absent; when XCmis C, RCmis H or a halogen, and is optionally H or F; when XCmis N, RCmis absent;

[0389] R6is selected from -C(O)NHMe; -CN; and a halogen, optionally F or Cl. In particular: a) XEBmay be C, XD1may be N, and XD2may be C, with RD1and RD2each being present; or b) XEBmay be C, XD1may be N, and XD2may be N, with RD1being present and RD2being absent; or c) XEBmay be N, XD1and XD2may each be C, with RD1and RD2each being present

[0390] RD3is preferably CF3. n is preferably 2.

[0391] RA1and RA3are preferably each H.

[0392] R6is preferably C(O)NHMe (e.g., C(O)NHCD3).

[0393] XCmis preferably N. RCois preferably H.

[0394] Examples of compounds in this class include:

[0395] 13cis

[0396]

[0397]

[0398] Further example compounds provided herein are: cis Ill trans

[0399]

[0400]

[0401] 15

[0402]

[0403]

[0404]

[0405]

[0406]

[0407]

[0408] Medical Uses

[0409] 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.

[0410] 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.

[0411] 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.

[0412] 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.

[0413] 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.

[0414] 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. Othercomponents 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.

[0415] 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).

[0416] The compounds provided herein may be administered to a patient who is undergoing radiotherapy and / or chemotherapy using a further agent for treating cancer.

[0417] For example, the PARP1 inhibitor compound may be administered in conjunction with a further agent for treating cancer.

[0418] 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.

[0419] 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. Pharmaceutical Compositions

[0420] Another aspect provides a pharmaceutical composition comprising a PARP1 inhibitor compound as defined herein.

[0421] Typically, the composition includes a pharmaceutically acceptable additive and / or excipient.

[0422] 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.

[0423] Typically, the composition is for use in medicine, e.g. for use in treating a disease, condition or disorder as defined above.

[0424] 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.

[0425] 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.

[0426] In particular, the further agent for treating cancer may comprise an immunotherapeutic agent selected from: an anti-tumour vaccine; an oncolytic virus; an immune stimulatory antibody such as anti-CTLA4, anti-PDl, anti-PDL-1, anti-OX40, anti-41BB, anti-CD27, anti-CD40, anti- LAG3, anti-TIM3, and anti-GITR; a pattern recognition receptor agonist such as a STING, TLR- 9 or RIG-1 Helicase agonist; an IDO or TDO inhibitor; a novel adjuvant; a peptide; a cytokine; a chimeric antigen receptor T cell therapy (CAR-T); a small molecule immune modulator; and a tumour microenvironment modulator.

[0427] Kits

[0428] 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.

[0429] 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.

[0430] In particular, the further agent for treating cancer may comprise one or more chemotherapeutic agents selected from: anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase I inhibitors, topoisomerase II inhibitors, antimetabolites, senolytic agents, hormones and hormone analogues, signal transduction pathway inhibitors, other DNA damage repair pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, antibody-drug conjugates, hormone-deprivation therapies, radioligand therapies, antiangiogenic agents, immunotherapeutic agents (such as selected from an anti-tumour vaccine, an oncolytic virus, an immune stimulatory antibody such as anti-CTLA4, anti-PDl, anti-PDL-1, anti-OX40, anti-41BB, anti-CD27, anti-CD40, anti- LAG3, anti-TIM3, and anti-GITR, a pattern recognition receptor agonist such as a STING, TLR- 9 or RIG-1 Helicase agonist, an IDO or TDO inhibitor, a novel adjuvant, a peptide, a cytokine, a chimeric antigen receptor T cell therapy (CAR-T), a small molecule immune modulator, tumour microenvironment modulators), proapoptotic agents and cell cycle signalling inhibitors. Methods of Treatment

[0431] 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.

[0432] 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.

[0433] 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).

[0434] The patient may be undergoing treatment using ionising radiation.

[0435] Methods of synthesising PARP1 inhibitor compounds

[0436] Also provided are methods for synthesising the PARP1 inhibitor compounds as defined herein. In general, the method comprises conducting a reaction between: (i) a first reactant comprising ring E bearing a first portion of group L, and (ii) a second reactant comprising a remainder of group L, to form the PARP1 inhibitor compound. The skilled person may select reaction conditions with reference to known synthesis techniques depending on the appropriate starting materials. The method may comprise one or more additional steps. Exemplary synthesis methodology is shown in the Examples hereinbelow.

[0437] 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.

[0438] In another example method, the first reactant comprises rings D, E, ring A, Q1, 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.

[0439] The PARP1 inhibitor compound may be obtained in the form of a mixture of two or more structural isomers. The method may further comprise separating the structural isomers. For example, the method may further comprise comprising separating structural isomers of the PARP1 inhibitor compound using chiral supercritical fluid chromatography ("SFC") and / or chiral high-performance liquid chromatography ("HPLC"). When the PARP1 inhibitor compound is diastereomeric, separation may proceed in two stages. In a first stage, two pairs of stereoisomers may be isolated by HPLC. In a second stage, individual stereoisomers may be isolated from the pairs of stereoisomers by SFC.

[0440] Examples

[0441] Example 1: synthesis of 4a and 4b

[0442] Preparation of tert-butyl 3-(4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-l-yl)pyrrolidine- 1-carboxylate (1003) To a solution of tert-butyl 3-oxopyrrolidine-l-carboxylate 1001 (170 mg, 0.92 mmol) in MeOH (5 mL) was added N-methyl-5-(piperazin-l-yl)picolinamide 1002 (202 mg, 0.92 mmol). Then acetic acid (2 drops) and NaBHsCN (115 mg, 1.84 mmol) were added. The mixture was stirred for 2 h at 50 °C. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with DCM / MeOH = 100 : 0 to 93 : 7) to give tert-butyl 3-(4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-l-yl)pyrrolidine-l-carboxylate 1003 (195 mg, 49 % yield) as a white solid.

[0443] LCMS (ESI) calcd for C20H31N5O3 [M + H]+m / z 390.24, found 390.10.

[0444] Preparation of N-methyl-5-(4-(pyrrolidin-3-yl)piperazin-l-yl)picolinamide (1004)

[0445] Tert-butyl 3-(4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-l-yl)pyrrolidine-l-carboxylate

[0446] 1003 (195 mg, 0.50 mmol) was added to HCI in dioxane (4 M, 10 mL), stirred for lh at room temperature, concentrated to give N-methyl-5-(4-(pyrrolidin-3-yl)piperazin-l-yl)picolinamide

[0447] 1004 (160 mg, 99 % yield) as a yellow solid.

[0448] LCMS (ESI) calcd for C15H17N3O [M + H]+m / z 290.19, found 290.20.

[0449] Preparation of 5-(4-(l-(4-methoxyquinazolin-2-yl)pyrrolidin-3-yl)piperazin-l-yl)-N- methylpicolinamide (1006)

[0450] To a solution of N-methyl-5-(4-(pyrrolidin-3-yl)piperazin-l-yl)picolinamide 1004 (160 mg, 0.56 mmol) and 2-chloro-4-methoxyquinazoline 1005 (215 mg, 1.11 mmol) in dioxane (10 mL) was added DIEA (143 mg, 1.1 mmol). The reaction mixture was irradiated in a microwave reactor at 100 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with DCM / MeOH = 100 : 0 to 95 : 5) to give 5-(4-(l-(4-methoxyquinazolin-2-yl)pyrrolidin-3-yl)piperazin-l-yl)-N- methylpicolinamide 1006 (120 mg, 44 % yield) as a white solid.

[0451] LCMS (ESI) calcd for C24H29N7O2 [M + H]+m / z 448.24, found 448.15.

[0452] Preparation of tert-butyl N-methyl-5-(4-(l-(4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidin-3- yl)piperazin-l-yl)picolinamide (4a and 4b)

[0453] 5-(4-(l-(4-methoxyquinazolin-2-yl)pyrrolidin-3-yl)piperazin-l-yl)-N-methylpicolinamide 1006 (120 mg, 0.27 mmol) was added to pyridine chlorhydrate (62 mg, 0.54 mmol), heated to 130 °C stirred for lh, then cooled to room temperature, separated with EtOAc (30 mL*3) and brine, the organic phase concentrated and purified by flash chromatography (eluting with DCM / MeOH = 100 : 0 to 90 : 10) to give crude product, which was separated by SFC (Column: Daicel Chiralpak OJ-H 250 mm × 20 mm I.D., 5 μmm; Mobile phase: CO2 / MeOH[0.1 %(NH3)] = 65 / 35) and concentrated under reduced pressure to afford the first fraction as 4a (28.05 mg, 100 % purity, ee%: 100, white solid) and the second fraction as 4b (37.9 mg, 100 % purity, ee%: 100, white solid). 4a1H NMR (400 MHz, DMSO) δ 11.04 (s, 1H), 8.40 (dd, J = 4.0 Hz, 1H), 8.29 (d, J = 2.4 Hz, 1H), 7.93-7.81 (m, 2H), 7.60-7.51 (m, 1H), 7.44-7.39 (m, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.14-6.98 (m, 1H), 3.90-3.83 (m, 1H), 3.78-3.71 (m, 1H), 3.49-3.43 (m, 1H), 3.39-3.34 (m, 4H), 3.28 (s, 1H), 3.00-2.89 (m, 1H), 2.78 (d, J = 4.8 Hz, 3H), 2.69-2.56 (m, 4H), 2.24-2.15 (m, 1H), 1.90-1.77 (m, 1H). LCMS (ESI) calcd for C23H27N7O2[M + H]+m / z 434.22, found 434.40. 4b1H NMR (400 MHz, DMSO) δ 10.88 (s, 1H), 8.40 (q, J = 4.4 Hz, 1H), 8.29 (d, J = 2.8 Hz, 1H), 7.91- 7.81 (m, 2H), 7.59-7.51 (m, 1H), 7.41 (dd, J = 8.8, 2.8 Hz, 1H), 7.30-7.16 (m, 1H), 7.15-7.00 (m, 1H), 3.91-3.82 (m, 1H), 3.79-3.70 (m, 1H), 3.49-3.42 (m, 1H), 3.38-3.34 (m, 4H), 3.28 (s, 1H), 3.01-2.89 (m, 1H), 2.78 (d, J = 4.8 Hz, 3H), 2.71-2.63 (m, 2H), 2.61-2.55 (m, 2H), 2.25-2.15 (m, 1H), 1.90-1.77 (m, 1H). LCMS (ESI) calcd for C23H27N7O2[M + H]+m / z 434.22, found 434.35.

[0454] Example 2: synthesis of 5cis and 5trans

[0455] SCHEME 2

[0456] Preparation of methyl 3-(4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-l-yl)cyclobutane-l- carboxylate (1102)

[0457] To a solution of methyl 3-oxocyclobutane-l-carboxylate 1101 (230 mg, 1.80 mmol) in MeOH (50 mL) was added N-methyl-5-(piperazin-l-yl) picolinamide 1002 (395 mg, 1.80 mmol), then two drops of acetic acid and NaBH(OAc)3 (950 mg, 4.49 mmol) were added at room temperature. After 1 h, NaBHsCN (135 mg, 2.15 mmol) was added. The reaction mixture was stirred at 50 °C for 5 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with DCM / MeOH = 100 : 0 to 90 : 10) to give 3-(4-(6-(methylcarbamoyl)pyridin-3- yl)piperazin-l-yl)cyclobutane-l-carboxylate 1102 (600 mg, 90 % yield) as a white solid.

[0458] LCMS (ESI) calcd for C17H24N4O3 [M + H]+m / z 333.18, found 333.00.

[0459] Preparation of 3-(4-( 6-(methylcarbamoyl)pyridin-3-yl)piperazin-l -yl)cyclobutane-l - carboxylic acid (1103)

[0460] To a solution of methyl 3-(4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-l-yl)cyclobutane-l- carboxylate 1102 (400 mg, 1.20 mmol) in MeOH:H2O=l:l (20 mL) was added LiOH (43 mg, 1.80 mmol). The reaction mixture stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give 3-(4-(6-(methylcarbamoyl)pyridin-3- yl)piperazin-l-yl)cyclobutane-l-carboxylic acid 1103 (260 mg, 61 % yield ) as a white solid.

[0461] LCMS (ESI) calcd for C16H22N4O3 [M + H]+m / z 319.17, found 319.00.

[0462] Preparation of 5-(4-(3-((2-carbamoylphenyl)carbamoyl)cyclobutyl)piperazin-l-yl)-N- methylpicolinamide (1105)

[0463] To a solution of 3-(4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-l-yl)cyclobutane-l- carboxylic acid 1103 (260 mg, 0.86 mmol) in DMF (10 mL) was added 2-aminobenzamide 1104 (222 mg, 1.63 mmol), HATU (621 mg, 1.63 mmol) and DIEA (528 mg, 4.08 mmol), stirred for lh at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with DCM / MeOH = 100: 0 to 97: 3) to give 5-(4-(3-((2-carbamoylphenyl)carbamoyl)cyclobutyl)piperazin-l-yl)-N- methylpicolinamide 1105 (150 mg, 53 % yield) as a white solid.

[0464] LCMS (ESI) calcd for C23H28N6O3 [M + H]+m / z 437.22, found 437.10. Preparation of N-methyl-5-(4-(3-(4-oxo-3,4-dihydroquinazolin-2-yl)cyclobutyl)piperazin-1- yl)picolinamide (5) To a solution of 5-(4-(3-((2-carbamoylphenyl)carbamoyl)cyclobutyl)piperazin-1-yl)-N- methylpicolinamide 1105 (150 mg, 0.34 mmol) in DME (15 mL) was added KOH (81 mg, 1.03 mmol). The reaction mixture stirred at 60 °C for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with DCM / MeOH = 100: 0 to 95: 5) to give N-methyl-5-(4-(3-(4-oxo- 3,4-dihydroquinazolin-2-yl)cyclobutyl)piperazin-1-yl)picolinamide 5 (30 mg, 19 % yield) as a white solid. LCMS (ESI) calcd for C23H26N6O2[M + H]+m / z 419.21, found 419.00. Preparation of N-methyl-5-(4-(3-(4-oxo-3,4-dihydroquinazolin-2-yl)cyclobutyl)piperazin-1- yl)picolinamide (5cis and 5trans) N-methyl-5-(4-(3-(4-oxo-3,4-dihydroquinazolin-2-yl)cyclobutyl)piperazin-1-yl)picolinamide cis / trans mixture 5 was separated by prep-HPLC (Column Gemini 5um C18 150*21.2mm; Mobile phase: ACN--H2O(0.1 %FA) and concentrated under reduced pressure to afford the first fraction as 5cis (14 mg, 97 % purity, white solid) and the second fraction as 5trans (1.8 mg, 97 % purity, white solid). 5cis1H NMR (400 MHz, DMSO) δ 12.21 (s, 1 H), 8.41 (d, J = 4.8 Hz, 1 H), 8.27 (s, 1 H), 8.07 (d, J = 8.0 Hz, 1 H), 7.87-7.74 (m, 2 H), 7.65 (d, J = 8.0 Hz, 1 H), 7.50-7.36 (m, 2 H), 3.20-3.13 (m, 1 H), 2.78 (d, J = 4.8 Hz, 4 H), 2.50-2.49 (m, 4 H), 2.44 (s, 6 H), 2.23 (d, J = 9.6 Hz, 2 H). NOE experiments suggested cis stereochemistry for this compound. LCMS (ESI) calcd for C23H26N6O2 [M + H]+m / z 419.21, found 419.00. 5trans1H NMR (400 MHz, DMSO) δ 12.11 (s, 1 H), 8.41 (d, J = 4.8 Hz, 1 H), 8.28 (s, 1 H), 8.08 (d, J = 7.6 Hz, 1 H), 7.89-7.73 (m, 2 H), 7.66 (d, J = 8.0 Hz, 1 H), 7.43 (dd, J = 23.3, 8.0 Hz, 2 H), 3.04- 2.89 (m, 2 H), 2.78 (d, J = 3.6 Hz, 3 H), 2.49-2.48 (m, 3 H), 2.45 (s, 7 H), 2.28 (d, J = 7.6 Hz, 2 H). NOE experiments suggested trans stereochemistry for this compound. LCMS (ESI) calcd for C23H26N6O2[M + H]+m / z 419.21, found 419.00. Example 3: synthesis of 6 6 SCHEME 3 Preparation of tert-butyl (4-((2-carbamoylphenyl)carbamoyl)bicyclo[2.1.1]hexan-l- yl)carbamate (1202)

[0465] To a solution of 4-((tert-butoxycarbonyl)amino)bicyclo[2.1.1]hexane-l-carboxylic acid 1201 (350 mg, 1.45 mmol) and 2-aminobenzamide 1104 (217 mg, 1.59 mmol) in pyridine (20 mL) was added EDCI (305 mg, 1.59 mmol), then the mixture was stirred for 12 h at room temperature. The reaction mixture was quenched with water, the aqueous layer was extracted with EtOAc (150 mL x 3). The combined organic layers were washed by IM HCI solution and brine, dried over NazSCU, concentrated under reduced pressure to give product of tert-butyl (4-((2-carbamoylphenyl)carbamoyl)bicyclo[2.1.1]hexan-l-yl)carbamate 1202 (500 mg, 86 % yield) as a white solid.

[0466] LCMS (ESI) calcd for C19H25N3O4 [M + H]+m / z 360.18, found 360.10.

[0467] Preparation of tert-butyl (4-(4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[2.1.1]hexan-l- yl)carbamate (1203)

[0468] To the solution of tert-butyl (4-((2-carbamoylphenyl)carbamoyl)bicyclo[2.1.1]hexan-l- yl)carbamate 1202 (500 mg, 1.39 mmol) in DME (50 mL) was added KOH (234 mg, 4.17 mmol), stirred at 60 °C for 2 h, cooled to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with DCM / MeOH = 100 : 0 to 90 : 10) to give tert-butyl (4-(4-oxo-3,4-dihydroquinazolin-2- yl)bicyclo[2.1.1]hexan-l-yl)carbamate 1203 (400 mg, 76 % yield) as a white solid.

[0469] LCMS (ESI) calcd for C19H23N3O3 [M + H]+m / z 342.17, found 342.15.

[0470] Preparation of 2-(4-aminobicyclo[2.1.1 ]hexan-l-yl)quinazolin-4(3H)-one (1204)

[0471] To a solution of tert-butyl (4-(4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[2.1.1]hexan-l- yl)carbamate 1203 (400 mg, 1.17 mmol) in DCM (20 mL) was added HCI in dioxane (4M, 10 mL). The mixture was stirred for lh at room temperature. The reaction mixture was concentrated under reduced pressure to give product of 2-(4-aminobicyclo[2.1.1]hexan-l- yl)quinazolin-4(3H)-one 1204 (250 mg, 80 % yield) as a white solid.

[0472] LCMS (ESI) calcd for C14H15N3O [M + H]+m / z 242.12, found 242.10. Preparation of 2-(4-(4-benzylpiperazin-l-yl)bicyclo[2.1.1]hexan-l-yl)quinazolin-4(3H)-one (1206)

[0473] To a solution of 2-(4-aminobicyclo[2.1.1]hexan-l-yl)quinazolin-4(3H)-one 1204 (250 mg, 1.04 mmol) in DIPEA (40 mL) was added N-benzyl-2-chloro-N-(2-chloroethyl)ethan-l-amine 1205 (483 mg, 2.07 mmol).The reaction mixture was stirred at 120 °C for 5 h, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with DCM / MeOH = 100 : 0 to 90 : 10) to give N-benzyl-2-chloro-N-(2- chloroethyl)ethan-l-amine 1206 (150 mg, 29 % yield ) as a brown solid.

[0474] LCMS (ESI) calcd for C25H28N4O [M + H]+m / z 401.23, found 401.15.

[0475] Preparation of 2-(4-(piperazin-l -yl)bicyclo[2.1.1 ]hexan-l-yl)quinazolin-4(3H)-one (1207)

[0476] To a solution of N-benzyl-2-chloro-N-(2-chloroethyl)ethan-l-amine 1206 (150 mg, 0.37 mmol) in IPA (30 mL) was added Pd / C (39 mg). The mixture was evacuated and backfilled with hydrogen three times and then charged with hydrogen. The resulting mixture was stirred at 70 °C for 5 h. Then, the mixture was filtered through celite and concentrated under vacuum to give 2-(4-(piperazin-l-yl)bicyclo[2.1.1]hexan-l-yl)quinazolin-4(3H)-one 1207 (90 mg, 62 % yield) as a white solid.

[0477] LCMS (ESI) calcd for C18H22N4O [M + H]+m / z 311.18, found 311.10.

[0478] Preparation of N-methyl-5-(4-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[2.1.1]hexan-l- yl)piperazin-l -yl)picolinamide (6)

[0479] To a solution 2-(4-(piperazin-l-yl)bicyclo[2.1.1]hexan-l-yl)quinazolin-4(3H)-one 1207 (30 mg, 0.09 mmol) in DMF (5 mL) was added CS2CO3 (63 mg, 0.19 mmol) and 5-fluoro-N- methylpicolinamide 1208 (22 mg, 0.14 mmol). The mixture was stirred for 5 h at 150 °C using a microwave. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with DCM / MeOH = 100 : 0 to 92 : 8) to give crude N-methyl-5-(4-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[2.1.1]hexan-l- yl)piperazin-l-yl)picolinamide (10 mg, 70 % purity) as a yellow solid. The crude product was purified by prep-HPLC (Gemini 5 pm Cis 150 x 21.2 mm, mobile phase: ACN - H2O (0.1 % TFA), gradient: 20 - 80) to give N-methyl-5-(4-(4-(4-oxo-3,4-dihydroquinazolin-2- yl)bicyclo[2.1.1]hexan-1-yl)piperazin-1-yl)picolinamide 6 (1.8 mg, 91 % purity, 4 % yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6, ppm) δ: 12.28 (s, 1 H), 11.79-11.33 (m, 1 H), 8.46 (d, J = 4.6 Hz, 1 H), 8.37-8.44 (m, 1 H), 8.11 (dd, J = 6.8 Hz, 1.6 Hz, 1 H), 7.91 (d, J = 8.8 Hz, 1 H), 7.83-7.79 (m, 1 H), 7.63 (d, J = 8.0 Hz, 1 H), 7.56-7.49 (m, 2 H), 4.16-4.13 (m, 2 H), 3.92 (s, 2 H), 3.27 (s, 4 H), 2.80 (d, J = 4.8 Hz, 3 H), 2.43 (s, 2 H), 2.13-2.12 (m, 4 H), 2.04 (s, 2 H). LCMS (ESI) calcd for C25H28N6O2[M + H]+m / z 445.23, found 445.20. Example 4: synthesis of 3cis-a, 3cis-b, 3trans-a, 3trans-b SCHEME 4 Preparation of 2-fluoro-6-(3-oxocyclopentane-1-carboxamido)benzamide (1303) To a solution of 3-oxocyclopentane-1-carboxylic acid 1302 (2.08 g, 16.2 mmol) in pyridine (30 mL) were added 2-amino-6-fluorobenzamide 1301 (2.5 g, 16.2 mmol) and EDCI (6.2 g, 32.4 mmol) at room temperature successively. The mixture was kept stirring at room temperature for 2 h. The resulting mixture was diluted with water (200 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with MeOH / DCM, 2 % to 5 %) to give 2-fluoro-6-(3-oxocyclopentane-l-carboxamido)benzamide 1303 (3 g, 90 % purity, 62 % yield) as a yellow solid.

[0480] LCMS (ESI) calcd for C13H13FN2O3 [M + H]+m / z 265.09, found 265.05.

[0481] Preparation of 5-fluoro-2-(3-oxocyclopentyl)quinazolin-4(3H)-one (1304)

[0482] To a solution of 2-fluoro-6-(3-oxocyclopentane-l-carboxamido)benzamide 1303 (3 g, 11.4 mmol) in DIVIE (200 mL) was added KOH (1.92 g, 34.2 mmol). The mixture was heated at 50 °C for 2 hours. The final mixture was quenched with saturated aqueous NH4CI solution and extracted with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated to give 5-fluoro-2-(3-oxocyclopentyl)quinazolin-4(3H)-one 1304 (2 g, 90 % purity, 64 % yield) as a yellow solid.

[0483] LCMS (ESI) calcd for C13H11FN2O2 [M + H]+m / z 247.08, found 247.05.

[0484] Preparation of 6-fluoro-5-(4-(3-(5-fluoro-4-oxo-3,4-dihydroquinazolin-2- yl)cyclopentyl)piperazin-l-yl)-N-methylpicolinamide (3cis-a / 3cis-b racemic mixture and 3trans-a / 3trans-b racemic mixture)

[0485] To a solution of 5-fluoro-2-(3-oxocyclopentyl)quinazolin-4(3H)-one 1304 (300 mg, 1.22 mmol) in MeOH (30 mL) were added 6-fluoro-N-methyl-5-(piperazin-l-yl)picolinamide 1305 (435 mg, 1.83 mmol), NaBHsCN (77 mg, 1.22 mmol) and NaBH(OAc)3 (516 mg, 2.44 mmol) at room temperature. The reaction mixture was stirred at 50 °C for 1 h. The resulting solution was quenched with water and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with DCM / MeOH = 100 : 0 to 90 : 10) to afford the first fraction as 6-fluoro-5-(4-(3-(5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)cyclopentyl)piperazin-l-yl)-N- methylpicolinamide 3cis-a / 3cis-b racemic mixture (50 mg, 90 % purity, 8 % yield, racemic mixture of cis enantiomers) and the second fraction as 6-fluoro-5-(4-(3-(5-fluoro-4-oxo-3,4- dihydroquinazolin-2-yl)cyclopentyl)piperazin-l-yl)-N-methylpicolinamide 3trans-a / 3trans-b racemic mixture (25 mg, 90 % purity, 4 % yield, racemic mixture of trans enantiomers) as a white solid. Preparation of 6-fluoro-5-(4-(3-(5-fluoro-4-oxo-3,4-dihydroquinazolin-2- yl)cyclopentyl)piperazin-1-yl)-N-methylpicolinamide (3cis-a and 3cis-b) 3cis-a / 3cis-b racemic mixture was separated by SFC (Column: Daicel Chiralpak-AD-H 20 mm I.D. × 250 mm, 5 μm; Mobile phase: CO2 / MeOH [0.1 % (NH3)] = 60 / 40) and concentrated under reduced pressure to afford the first fraction as 3cis-a (13.6 mg, 99.94 % purity, 100% ee, white solid) and the second fraction as 3cis-b (16.6 mg, 99.37 % purity, 100% ee, white solid). 3cis-a1H NMR (400 MHz, DMSO-d6, ppm) δ: 12.49 (s, 1 H), 8.44-8.37 (m, 1.4 H), 7.86 (d, J = 8.0 Hz, 1 H), 7.78-7.68 (m, 1 H), 7.60-7.51 (m, 1 H), 7.42 (d, J = 8.0 Hz, 1 H), 7.26-7.10 (m, 1 H), 3.24- 3.19 (m, 4 H), 3.15-3.08 (m, 1 H), 2.78-2.70 (m, 4 H), 2.68-2.63 (m, 4 H), 2.23-2.16 (m, 1 H), 2.09-2.00 (m, 1 H), 1.98-1.86 (m, 2 H), 1.86-1.72 (m, 2 H). NOE experiments suggested cis stereochemistry. LCMS (ESI) calcd for C24H26F2N6O2[M + H]+m / z 469.21, found 469.25. 3cis-b1H NMR (400 MHz, DMSO-d6, ppm) δ: 12.50 (s, 1 H), 8.45-8.34 (m, 1.5 H), 7.86 (d, J = 8.0 Hz, 1 H), 7.79-7.68 (m, 1 H), 7.62-7.53 (m, 1 H), 7.42 (d, J = 8.0 Hz, 1 H), 7.24-7.13 (m, 1 H), 3.24- 3.18 (m, 4 H), 3.15-3.09 (m, 1 H), 2.80-2.70 (m, 4 H), 2.69-2.63 (m, 4 H), 2.27-2.16 (m, 1 H), 2.12-2.01 (m, 1 H), 1.97-1.87 (m, 2 H), 1.85-1.65 (m, 2 H). NOE experiments suggested cis stereochemistry. LCMS (ESI) calcd for C24H26F2N6O2[M + H]+m / z 469.21, found 469.20. Preparation of 6-fluoro-5-(4-(3-(5-fluoro-4-oxo-3,4-dihydroquinazolin-2- yl)cyclopentyl)piperazin-1-yl)-N-methylpicolinamide (3trans-a and 3trans-b) 3trans-a / 3trans-b racemic mixture was separated by SFC (Column: Daicel IJ 20 mmI.D. × 250 mmL, 5 μmm; Mobile phase: CO2 / MeOH[0.1 %(NH3)] = 75 / 25) and concentrated under reduced pressure to afford the first fraction as 3trans-a (9.3 mg, 99.54 % purity, 100% ee, white solid) and the second fraction as 3trans-b (7.0 mg, 99.79 % purity, 100% ee, white solid). 3trans-a1H NMR (400 MHz, DMSO-d6, ppm) δ: 12.56-11.47 (m, 1 H), 8.42-8.35 (m, 2 H), 7.90-7.82 (m, 1 H), 7.76-7.69 (m, 1 H), 7.61-7.51 (m, 1 H), 7.42 (d, J = 8.4 Hz, 1 H), 7.25-7.13 (m, 1 H), 3.19- 3.14 (m, 5 H), 2.86-2.80 (m, 1 H), 2.77 (d, J = 4.8 Hz, 3 H), 2.62-2.56 (m, 4 H), 2.22-2.06 (m, 2 H), 2.01-1.88 (m, 3 H), 1.57-1.47 (m, 1 H). NOE experiments suggested trans stereochemistry. LCMS (ESI) calcd for C24H26F2N6O2[M + H]+m / z 469.21, found 469.10. 3trans-b1H NMR (400 MHz, DMSO-d6, ppm) δ: 12.17 (s, 1 H), 8.43-8.36 (m, 1.6 H), 7.85 (d, J = 8.0 Hz, 1 H), 7.76-7.66 (m, 1 H), 7.61-7.51 (m, 1 H), 7.41 (d, J = 8.4 Hz, 1 H), 7.22-7.14 (m, 1 H), 3.20- 3.11 (m, 5 H), 2.87-2.80 (m, 1 H), 2.77 (d, J = 4.8 Hz, 3 H), 2.64-2.56 (m, 4 H), 2.21-2.02 (m, 2 H), 2.03-1.85 (m, 3 H), 1.59-1.47 (m, 1 H). NOE experiments suggested trans stereochemistry. LCMS (ESI) calcd for C24H26F2N6O2[M + H]+m / z 469.21, found 469.10. Example 5: Synthesis of 14cis-a, 14cis-b, 14trans-rac SCHEME 5 Preparation of 3-(4-methoxy-1-methyl-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-6- yl)cyclopent-2-en-1-one (1403) To a solution of 6-chloro-4-methoxy-1-methyl-3-(trifluoromethyl)-1H-pyrazolo[3,4- d]pyrimidine 1401 (1.10 g, 4.14 mmol) in dioxane:H2O=5:1 (24 mL) was added 3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-2-en-1-one 1402 (2 g, 9.61 mmol), RuPhos- Pd-G3(110 mg, 0.13 mmol) and Na2CO3(1.50 g, 14.15 mmol). The reaction mixture was stirred under N2at 100 °C for 5 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE / EtOAc = 100: 0 to 75: 25) to give 3-(4-methoxy-1-methyl-3-(trifluoromethyl)- 1H-pyrazolo[3,4-d]pyrimidin-6-yl)cyclopent-2-en-1-one 1403 (210 mg, 16 % yield ) as a white solid. LCMS (ESI) calcd for C13H11F3N4O2[M + H]+m / z 313.08, found 313.00. Preparation of 5-(4-(3-(4-methoxy-1-methyl-3-(trifluoromethyl)-1H-pyrazolo[3,4- d]pyrimidin-6-yl)cyclopent-2-en-1-yl)piperazin-1-yl)-N-methylpicolinamide (1404) To a solution of 3-(4-methoxy-1-methyl-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-6- yl)cyclopent-2-en-1-one 1403 (210 mg, 0.67 mmol) in EtOH (10 mL) was added N-methyl-5- (piperazin-1-yl)picolinamide 1002 (210 mg, 0.95 mmol) and 3 drops of HOAc. 10 mins later, NaBH3CN (400 mg, 6.45 mmol) was added. The reaction mixture stirred at 90 °C for 15 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with DCM / MeOH = 100: 0 to 93: 7) to give 5-(4-(3-(4-methoxy-1-methyl-3-(trifluoromethyl)-1H-pyrazolo[3,4- d]pyrimidin-6-yl)cyclopent-2-en-1-yl)piperazin-1-yl)-N-methylpicolinamide 1404 (250 mg, mixture with compound 1405, 72 % yield) as a yellow solid. LCMS (ESI) calcd for C24H27F3N8O2[M + H]+m / z 517.22, found 517.10. Preparation of 5-(4-(3-(4-methoxy-1-methyl-3-(trifluoromethyl)-1H-pyrazolo[3,4- d]pyrimidin-6-yl)cyclopentyl)piperazin-1-yl)-N-methylpicolinamide (1405) To a solution of 5-(4-(3-(4-methoxy-1-methyl-3-(trifluoromethyl)-1H-pyrazolo[3,4- d]pyrimidin-6-yl)cyclopent-2-en-1-yl)piperazin-1-yl)-N-methylpicolinamide 1404 (250 mg (mixture with compound 1405), 0.48 mmol) in MeOH (20 mL) was added Pd / C (100 mg, 0.94 mmol). The reaction mixture was stirred under H2at room temperature for 3 h. The mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to give 5-(4-(3-(4-methoxy-1-methyl-3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-6- yl)cyclopentyl)piperazin-1-yl)-N-methylpicolinamide 1405 (160 mg, 64 % yield) as a yellow solid. LCMS (ESI) calcd for C24H29F3N8O2[M + H]+m / z 519.24, found 519.2. Preparation of N-methyl-5-(4-(3-(1-methyl-4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H- pyrazolo[3,4-d]pyrimidin-6-yl)cyclopentyl)piperazin-1-yl)picolinamide (14, mixture of 4 isomers) To a solution of 5-(4-(3-(4-methoxy-1-methyl-3-(trifluoromethyl)-1H-pyrazolo[3,4- d]pyrimidin-6-yl)cyclopentyl)piperazin-1-yl)-N-methylpicolinamide 1405 (160 mg, 0.31 mmol) in ACN (10 mL) was added TMSI (200 mg, 1.00 mmol). The reaction mixture stirred at 50 °C for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (columns: Gemini 5 µm C18150 × 21.2 mm, mobile phase: ACN - H2O (0.1% FA), gradient: 10 - 25) to give N-methyl-5-(4-(3-(1-methyl-4-oxo-3-(trifluoromethyl)-4,5-dihydro- 1H-pyrazolo[3,4-d]pyrimidin-6-yl)cyclopentyl)piperazin-1-yl)picolinamide 14, as a mixture of 4 isomers (50 mg, 93 % purity, 32 % yield) as a white solid. LCMS (ESI) calcd for C23H27F3N8O2[M + H]+m / z 505.22, found 505.19. Preparation of N-methyl-5-(4-(3-(1-methyl-4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H- pyrazolo[3,4-d]pyrimidin-6-yl)cyclopentyl)piperazin-1-yl)picolinamide (14trans-rac / 14cis- a / 14cis-b) N-methyl-5-(4-(3-(1-methyl-4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4- d]pyrimidin-6-yl)cyclopentyl)piperazin-1-yl)picolinamide Compound 14, mixture of 4 isomers (50 mg, 0.10 mmol) was separated by SFC (Column: (R,R)-Whelk-O14.6mm *250 mmL 5μm; Mobile phase: CO2 / MeOH[0.1 % NH3(7 M Solution in MeOH)]=60 / 40) and concentrated under reduced pressure to afford the first fraction as 14trans-rac (10 mg, 97 % purity, ee%: 100, white solid), the second fraction as 14cis-a (5 mg, 99 % purity, ee%: 100, white solid) and the third fraction as 14cis-b (0.8 mg, 98 % purity, ee%: 100, white solid). 14trans-rac1H NMR (400 MHz, DMSO) δ 12.39 (s, 1 H), 8.39 (q, J = 5.2 Hz, 1 H), 8.27 (d, J = 2.8 Hz, 1 H), 7.83 (d, J = 8.8 Hz, 1 H), 7.39 (dd, J = 8.8, 2.8 Hz, 1 H), 3.95 (s, 3 H), 3.38-3.32 (m, 4 H), 3.28- 3.22 (m, 1 H), 2.93-2.80 (m, 1 H), 2.78 (d, J = 4.8 Hz, 3 H), 2.62-2.55 (m, 4 H), 2.19-2.05 (m, 2 H), 2.05-1.85 (m, 3 H), 1.63-1.47 (m, 1 H). Trans stereochemistry was assigned based on NOE experiments. LCMS (ESI) calcd for C23H27F3N8O2[M + H]+m / z 505.22, found 505.20. 14cis-a1H NMR (400 MHz, DMSO) δ 12.79 (s, 1 H), 8.40 (q, J = 5.2 Hz, 1 H), 8.28 (d, J = 2.8 Hz, 1 H), 7.84 (d, J = 8.8 Hz, 1 H), 7.41 (dd, J = 8.8, 2.8 Hz, 1 H), 3.95 (s, 3 H), 3.48-3.35 (m, 4 H), 3.27- 3.17 (m, 1 H), 2.78 (d, J = 4.8 Hz, 3 H), 2.76-2.69 (m, 1 H), 2.68-2.61 (m, 4 H), 2.25-2.16 (m, 1 H), 2.14-2.03 (m, 1 H), 2.00-1.90 (m, 2 H), 1.87-1.75 (m, 2 H). Cis stereochemistry was assigned based on NOE experiments. LCMS (ESI) calcd for C23H27F3N8O2[M + H]+m / z 505.22, found 505.25. 14cis-b1H NMR (400 MHz, MeOD) δ 8.30 (d, J = 2.8 Hz, 1 H), 7.91 (d, J = 8.8 Hz, 1 H), 7.39 (dd, J = 8.8, 2.9 Hz, 1 H), 4.00 (s, 3 H), 3.59-3.43 (m, 5 H), 2.93 (s, 3 H), 2.88-2.78 (m, 5 H), 2.37-2.28 (m, 1 H), 2.26-2.18 (m, 1 H), 2.17-2.04 (m, 2 H), 2.03-1.96 (m, 2 H). Cis stereochemistry was assigned based on NOE experiments. LCMS (ESI) calcd for C23H27F3N8O2[M + H]+m / z 505.22, found 505.15.

[0486] Example 6: synthesis ofl6cis-a, 16cis-b, 16trans-a, and 16trans-b

[0487] Preparation of 2-chloro-4-methoxypyrido[2,3-d]pyrimidine (1502)

[0488] To a solution of 2,4-dichloropyrido[2,3-d]pyrimidine 1501 (2.5 g, 0.0125 mol) in MeOH (50 mL) was added MeONa (0.88 g, 0.0162 mol). The reaction mixture was stirred at rt for 2 h. The reaction solution was concentrated under reduced pressure and the residue was purified by flash column chromatography (eluting with PE / EtOAc = 100:0 to 80:20) to afford 2-chloro- 4-methoxypyrido[2,3-d]pyrimidine 1502 (2.1 g, 90 % purity, 77 % yield) as a white solid.

[0489] LCMS (ESI) calcd for C8H6CIN3O [M + H]+m / z 196.02, found 196.10. Preparation of 2-chloro-4-methoxy-5, 6, 7,8-tetrahydropyrido[2,3-d]pyrimidine ( 1503)

[0490] A solution of 2-chloro-4-methoxypyrido[2,3-d]pyrimidine 1502 (2.1 g, 0.0107 mol ) and PtCh (2.4 g, 0.0107 mol) in THF / H2O (50 mL, 5:1) was stirred under balloon pressure of H2 at rt for 6 h. The mixture was filtered through a Celite pad, and the filtrate was washed with EtOAc (50 mL x 2). The combined organic layers were concentrated to give 2-chloro-4-methoxy- 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine 1503 (2.1 g, 90 % purity, 88 % yield) as a white solid.

[0491] LCMS (ESI) calcd for C8HI0CIN3O [M + H]+m / z 200.05, found 200.15.

[0492] Preparation of 2-chloro-4-methoxy-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine (1504)

[0493] To a solution of 2-chloro-4-methoxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine 1503 (2.1 g, 0.0105 mol) in DMF (30 mL) was added NaH (633 mg, 0.0157 mol, 60% wt) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. Mel (2.2 g, 0.0157 mol) was added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched with water, and the aqueous layer was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL x 3) and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with PE / EtOAc = 100:0 to 80:20) to afford 2-chloro-4-methoxy-8-methyl-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidine 1504 (1.6 g, 95 % purity, 67 % yield) as a white solid.

[0494] LCMS (ESI) calcd for C9H12CIN3O [M + H]+m / z 214.07, found 213.89.

[0495] Preparation of 3-(4-methoxy-8-methyl-5,6, 7,8-tetrahydropyrido[2,3-d]pyrimidin-2- yl)cyclopent-2-en-l-one (1505)

[0496] To a solution of 2-chloro-4-methoxy-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine 1504 (400 mg, 1.8721 mmol) in dioxane / FhO (25 mL, 5:1) was added 3-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)cyclopent-2-en-l-one 1402 (506 mg, 2.4337 mmol), Pd(dppf)Cl2 (137 mg, 0.1872 mmol) and Na2CC>3 (584 mg, 5.6163 mmol) successively. The reaction mixture was stirred at 80 °C for 4 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 50:50) to afford 3-(4-methoxy-8-methyl- 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)cyclopent-2-en-l-one 1505 (400 mg, 90 % purity, 74 % yield) as a white solid.

[0497] LCMS (ESI) calcd for C14H17N3O2 [M + H]+m / z 260.13, found 260.20.

[0498] Preparation of 5-(4-(3-(4-methoxy-8-methyl-5,6, 7,8-tetrahydropyrido[2,3-d]pyrimidin-2- yl)cyclopen t-2-en-l-yl)piperazin-l -yl)-N-methylpicolin amide (1506)

[0499] To a solution of 3-(4-methoxy-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2- yl)cyclopent-2-en-l-one 1505 (400 mg, 1.5426 mmol) in EtOH (15 mL) was added N-methyl- 5-(piperazin-l-yl)picolinamide 1002 (510 mg, 2.3139 mmol), NaBH(OAc)3 (981 mg, 4.6278 mmol) and NaBHsCN (97 mg, 1.5426 mmol) successively at rt. The reaction mixture was stirred at 90 °C for 16 h. The reaction solution was cooled to rt, quenched with water (10 mL) and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with DCM / MeOH = 100:0 to 93:7) to afford 5-(4-(3-(4-methoxy-8- methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)cyclopent-2-en-l-yl)piperazin-l-yl)-N- methylpicolinamide 1506 (obtained as a mixture with compound 1507, 420 mg, 90 % purity, 52 % yield)

[0500] LCMS (ESI) calcd for C25H33N7O2 [M + H]+m / z 464.27, found 464.20.

[0501] Preparation of 5-(4-(3-(4-methoxy-8-methyl-5,6, 7,8-tetrahydropyrido[2,3-d]pyrimidin-2- yl)cyclopentyl)piperazin-l-yl)-N-methylpicolinamide (1507)

[0502] A solution of 5-(4-(3-(4-methoxy-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2- yl)cyclopent-2-en-l-yl)piperazin-l-yl)-N-methylpicolinamide 1506 (400 mg, 0.8629 mmol, mixture with compound 1507) and Pd(OH)2 / C (121 mg) in MeOH (15 mL) was stirred under balloon pressure of H2 at rt for 16 h. The mixture was filtered through a Celite pad, and the filtrate was concentrated to give 5-(4-(3-(4-methoxy-8-methyl-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidin-2-yl)cyclopentyl)piperazin-l-yl)-N-methylpicolinamide 1507 (400 mg, 80 % yield, 79 % yield) as a colourless oil.

[0503] LCMS (ESI) calcd for C25H35N7O2 [M + H]+m / z 466.29, found 466.14. Preparation of N-methyl-5-(4-(3-(8-methyl-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3- d]pyrimidin-2-yl)cyclopentyl)piperazin-1-yl)picolinamide (16) A solution of 5-(4-(3-(4-methoxy-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2- yl)cyclopentyl)piperazin-1-yl)-N-methylpicolinamide 1507 (400 mg, 0.8591 mmol) in HBr (10 mL, 48 % in H2O) was stirred at 80 °C for 2 h. The reaction solution was cooled to rt and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with DCM / MeOH = 100:0 to 95:5) and prep-HPLC (column : Gemini - C18150 × 21.2 mm, 5 µm; mobile phase : ACN - H2O (0.1 % TFA); gradient : 15 - 45) to obtain N-methyl-5-(4-(3-(8-methyl-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-2- yl)cyclopentyl)piperazin-1-yl)picolinamide 16 as a mixture of 4 isomers. The mixture of isomers was separated by SFC (Column: IH, SFC 30 mm I.D. × 250 mmL, 10 μm; mobile phase: CO2 / MeOH [0.1 % NH3(7 M Solution in MeOH)] = 60 / 40) to afford 16cis-rac and 16trans-rac. 16cis-rac was separated by SFC (Column: Chiralpak IB N-5, SFC 30 mm I.D. × 250 mmL, 10 μm; Mobile phase: CO2 / MeOH [0.1% NH3(7 M Solution in MeOH)] = 60 / 40) to afford the first fraction as 16cis-a (9.8 mg, 93 % purity, ee%: 100, white solid) and the second fraction as 16cis-b (9.6 mg, 97 % purity, ee%: 100, white solid). 16trans-rac was separated by SFC (Column: Chiralpak-IB N-5, SFC 30 mm I.D. × 250 mmL, 10 μm; Mobile phase: CO2 / MeOH [0.1 % NH3(7 M Solution in MeOH)] = 60 / 40) to afford the first fraction as 16trans-a (16.1 mg, 97 % purity, ee%: 100, white solid) and the second fraction as 16trans-b (15.9 mg, 99 % purity, ee%: 100, white solid). 16cis-a1H NMR (400 MHz, DMSO-d6, ppm) δ: 11.57 (s, 1 H), 8.50-8.32 (m, 1 H), 8.26 (d, J = 2.8 Hz, 1 H), 7.83 (d, J = 8.8 Hz, 1 H), 7.39 (dd, J = 8.8, 2.8 Hz, 1 H), 3.40-3.34 (m, 2 H), 3.32-3.27 (m, 2 H), 3.25-3.19 (m, 2 H), 3.04 (s, 3 H), 2.98-2.85 (m, 1 H), 2.78 (d, J = 4.8 Hz, 3 H), 2.71-2.63 (m, 1 H), 2.62-2.54 (m, 4 H), 2.35-2.29 (m, 2 H), 2.18-2.08 (m, 1 H), 1.97-1.84 (m, 2 H), 1.83-1.65 (m, 5 H) Cis stereochemistry was assigned based on NOE experiments. LCMS (ESI) calcd for C24H33N7O2[M + H]+m / z 452.27, found 452.45. 16cis-b1H NMR (400 MHz, DMSO-d6, ppm) δ: 11.57 (s, 1 H), 8.46-8.37 (m, 1 H), 8.26 (d, J = 2.4 Hz, 1 H), 7.83 (d, J = 8.8 Hz, 1 H), 7.39 (dd, J = 8.8, 2.8 Hz, 1 H), 3.39-3.34 (m, 2 H), 3.33-3.29 (m, 2 H), 3.26-3.18 (m, 2 H), 3.04 (s, 3 H), 2.98-2.86 (m, 1 H), 2.78 (d, J = 4.8 Hz, 3 H), 2.71-2.62 (m, 1 H), 2.61-2.56 (m, 4 H), 2.35-2.28 (m, 2 H), 2.18-2.05 (m, 1 H), 1.94-1.64 (m, 7 H). Cis stereochemistry was assigned based on NOE experiments. LCMS (ESI) calcd for C24H33N7O2[M + H]+m / z 452.27, found 452.45. 16trans-a1H NMR (400 MHz, DMSO-d6, ppm) δ: 11.39 (s, 1 H), 8.44-8.34 (m, 1 H), 8.26 (d, J = 2.8 Hz, 1 H), 7.84 (d, J = 8.8 Hz, 1 H), 7.38 (dd, J = 8.8, 2.8 Hz, 1 H), 3.31-3.28 (m, 4 H), 3.25-3.19 (m, 2 H), 3.04 (s, 3 H), 3.01-2.94 (m, 1 H), 2.84-2.73 (m, 4 H), 2.60-2.53 (m, 4 H), 2.35-2.29 (m, 2 H), 2.09-1.90 (m, 3 H), 1.86-1.67 (m, 4 H), 1.57-1.39 (m, 1H). Trans stereochemistry was assigned based on NOE experiments. LCMS (ESI) calcd for C24H33N7O2[M + H]+m / z 452.27, found 452.45. 16trans-b1H NMR (400 MHz, DMSO-d6, ppm) δ: 11.40 (s, 1 H), 8.45-8.35 (m, 1 H), 8.26 (d, J = 2.8 Hz, 1 H), 7.83 (d, J = 8.8 Hz, 1 H), 7.38 (dd, J = 8.8, 2.4 Hz, 1 H), 3.32-3.26 (m, 4 H), 3.25-3.18 (m, 2 H), 3.04 (s, 3 H), 3.03-2.94 (m, 1 H), 2.84-2.73 (m, 4 H), 2.61-2.53 (m, 4 H), 2.36-2.28 (m, 2 H), 2.11-1.89 (m, 3 H), 1.87-1.70 (m, 4 H), 1.56-1.39 (m, 1 H). Trans stereochemistry was assigned based on NOE experiments. LCMS (ESI) calcd for C24H33N7O2 [M + H]+m / z 452.27, found 452.45.

[0504] Example 7: synthesis of 17cis-a, 17cis-b, and 17trans-rac

[0505] SCHEME 7A

[0506] Preparation of methyl 3-bromo-1-(phenylsulfonyl)-1H-pyrrole-2-carboxylate (1603) To a solution of methyl 3-bromo-1H-pyrrole-2-carboxylate 1601 (10 g, 0.049 mol) in DMF (100 mL) was added NaH (2.94 g, 0.073 mol, 60 % wt) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. Then benzenesulfonyl chloride 1602 (9.52 g, 0.054 mol) was added and the mixture was stirred at rt for 2 h. The mixture was quenched with water slowly, then extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (3 times), dried over Na2SO4, filtered and concentrated to obtain methyl 3-bromo-1-(phenylsulfonyl)-1H-pyrrole- 2-carboxylate 1603 (12.9 g, 85 % purity, 65 % yield) as a yellow gum. LCMS (ESI) calcd for C12H10BrNO4S [M + H]+m / z 343.95, found 343.95. Preparation of methyl 1-(phenylsulfonyl)-3-(trifluoromethyl)-1H-pyrrole-2-carboxylate (1605) A mixture of methyl 3-bromo-1-(phenylsulfonyl)-1H-pyrrole-2-carboxylate 1603 (12.9 g, 0.037 mol), CuI (7.14 g, 0.037 mol) and HMPA (33.60 g, 0.19 mol) in NMP (100 mL) was heated to 130 °C under N2, then methyl 2,2-difluoro-2-(fluorosulfonyl)acetate 1604 (36.02 g, 0.19 mol) was added dropwise. The mixture was stirred at 130 °C for 2 h under an atmosphere of N2. The mixture was cooled, quenched with water slowly, then extracted with EtOAc (400 mL x 3). The combined organic layers were washed with brine (3 times), dried over Na2SO4, filtered, concentrated and purified by flash silica chromatography (eluting with EtOAc / PE, 0 to 13 %) to obtain methyl 1-(phenylsulfonyl)-3-(trifluoromethyl)-1H-pyrrole-2-carboxylate 1605 (6.2 g, 90 % purity, 44 % yield) as a yellow solid. LCMS (ESI) calcd for C13H10F3NO4S [M + H]+m / z 334.03, found 333.55. Preparation of methyl 3-(trifluoromethyl)-1H-pyrrole-2-carboxylate (1606) To a solution of methyl 1-(phenylsulfonyl)-3-(trifluoromethyl)-1H-pyrrole-2-carboxylate 1605 (6.2 g, 0.019 mol) in MeOH (60 mL) was added MeONa (5.00 g, 0.093 mol), the reaction mixture was stirred at rt for 2 h. The mixture was quenched with NH4Cl aqueous solution, extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (3 times), dried over Na2SO4, filtered, concentrated and purified by flash chromatography (eluting with DCM / MeOH = 100 : 0 to 90 : 10) to obtain methyl 3-(trifluoromethyl)-1H-pyrrole- 2-carboxylate 1606 (4.2 g, 80 % purity, 93 % yield) as a yellow solid. LCMS (ESI) calcd for C7H6F3NO2[M + H]+m / z 194.04, no MS signal.1H NMR (400 MHz, DMSO-d6, ppm) δ: 9.87-9.33 (m, 1 H), 6.92 (t, J = 2.8 Hz, 1 H), 6.55 (t, J = 2.8 Hz, 1 H), 3.92 (s, 3 H).19F NMR (376.69 MHz, DMSO-d6, ppm) δ: 62.21. Preparation of methyl l-amino-3-(trifluoromethyl)-lH-pyrrole-2-carboxylate (1608)

[0507] To a solution of methyl 3-(trifluoromethyl)-lH-pyrrole-2-carboxylate 1606 (800 mg, 0.0041 mol) in DMF (10 mL) was added NaH (0.16 g, 0.0041 mol, 60 % wt) at 0 °C and the mixture was stirred at 0 °C for 40 min. Then O-(2,4-dinitrophenyl)hydroxylamine 1607 (0.98 g, 0.0049 mol) was added at 0 °C and the mixture was stirred at rt for 4 h. The mixture was quenched with water slowly, then extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (3 times), dried over NazSCU, filtered and concentrated to obtain methyl l-amino-3-(trifluoromethyl)-lH-pyrrole-2-carboxylate 1608 (810 mg, 80 % purity, 75 % yield) as a brown oil.

[0508] LCMS (ESI) calcd for C7H7F3N2O2 [M + H]+m / z 209.05, found 208.95.

[0509] Preparation of 3-(4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-l-yl)cyclopentane-l- car boxy lie acid (1610)

[0510] To a solution of 3-oxocyclopentane-l-carboxylic acid 1609 (1 g, 0.0078 mol) in MeOH (10 mL) and AcOH (0.05 mL) was added N-methyl-5-(piperazin-l-yl)picolinamide 1002 (1.37 g, 0.0062 mol) and the mixture was stirred at 50 °C for 30 min. Then NaBHsCN (0.49 g, 0.0078 mol) was added, the reaction mixture was stirred at 50 °C for 2 h. The mixture was concentrated and purified by flash silica chromatography (DCM / MeOH = 100:0 to 90:10) to obtain 3-(4-(6- (methylcarbamoyl)pyridin-3-yl)piperazin-l-yl)cyclopentane-l-carboxylic acid 1610 (800 mg, 85 % purity, 26 % yield) as a yellow gum.

[0511] LCMS (ESI) calcd for C17H24N4O3 [M + H]+m / z 333.18, found 333.00.

[0512] Preparation of methyl l-(3-(4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-l- yl)cyclopentane-l-carboxamido)-3-(trifluoromethyl)-lH-pyrrole-2-carboxylate (1611)

[0513] To a solution of 3-(4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-l-yl)cyclopentane-l- carboxylic acid 1610 (720 mg, 2.17 mmol) in pyridine (7 mL) was added methyl l-amino-3- (trifluoromethyl)-lH-pyrrole-2-carboxylate 1608 (677 mg, 3.25 mmol) and EDCI (833 mg, 4.34 mmol). The mixture was stirred at rt for 18 h. The mixture was quenched with water slowly, then extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (3 times), dried over Na2SO4, filtered, concentrated and purified by flash silica chromatography (DCM / MeOH = 100:0 to 85:15) to obtain methyl l-(3-(4-(6- (methylcarbamoyl)pyridin-3-yl)piperazin-l-yl)cyclopentane-l-carboxamido)-3- (trifluoromethyl)-lH-pyrrole-2-carboxylate 1611 (181 mg, 80 % purity, 12 % yield) as a yellow solid.

[0514] LCMS (ESI) calcd for C24H29F3N6O4 [M + Na]+m / z 545.22, found 545.25.

[0515] Preparation of 1 -(3-(4-( 6-(methylcarbamoyl)pyridin-3-yl)piperazin-l -yl)cyclopentane-l- carboxamido)-3-( trifluoromethyl)-l H-pyrrole-2-carboxylic acid (1612)

[0516] To a solution of methyl l-(3-(4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-l- yl)cyclopentane-l-carboxamido)-3-(trifluoromethyl)-lH-pyrrole-2-carboxylate 1611 (181 mg, 0.35 mmol) in DME (8 mL) was added SnfCHshOH (188 mg, 1.04 mmol). The resulting mixture was stirred for 48 h at 80 °C. The mixture was concentrated and purified by flash silica chromatography (DCM / MeOH = 100:0 to 40:60) to obtain l-(3-(4-(6-

[0517] (methylcarbamoyl)pyridin-3-yl)piperazin-l-yl)cyclopentane-l-carboxamido)-3- (trifluoromethyl)-lH-pyrrole-2-carboxylic acid 1612 (135 mg, 80 % purity, 61 % yield) as a yellow gum.

[0518] LCMS (ESI) calcd for C23H27F3N6O4 [M + H]+m / z 509.20, found 509.05.

[0519] Preparation of 5-(4-(3-((2-carbamoyl-3-(trifluoromethyl)-lH-pyrrol-l- yl)carbamoyl)cyclopentyl)piperazin-l-yl)-N-methylpicolinamide (1613)

[0520] To a solution of l-(3-(4-(6-(methylcarbamoyl)pyridin-3-yl)piperazin-l-yl)cyclopentane-l- carboxamido)-3-(trifluoromethyl)-lH-pyrrole-2-carboxylic acid 1612 (135 mg, 0.27 mmol) in THF (8 mL) were added (NH4hCO3 (102 mg, 1.06 mmol), EDCI (76 mg, 0.40 mmol) and HOBT (18 mg, 0.13 mmol). The reaction mixture was stirred at rt for 3 h. The mixture was concentrated and purified by flash silica chromatography (DCM / MeOH = 100:0 to 90:10) to obtain 5-(4-(3-((2-carbamoyl-3-(trifluoromethyl)-lH-pyrrol-l- yl)carbamoyl)cyclopentyl)piperazin-l-yl)-N-methylpicolinamide 1613 (90 mg, 85 % purity, 56 % yield) as a yellow gum.

[0521] LCMS (ESI) calcd for C23H28F3N7O3 [M + H]+m / z 508.22, found 508.45. Preparation of N-methyl-5-(4-(3-(4-oxo-5-(trifluoromethyl)-3,4-dihydropyrrolo[2,1- f][1,2,4]triazin-2-yl)cyclopentyl)piperazin-1-yl)picolinamide (17) To a solution of 5-(4-(3-((2-carbamoyl-3-(trifluoromethyl)-1H-pyrrol-1- yl)carbamoyl)cyclopentyl)piperazin-1-yl)-N-methylpicolinamide 1613 (90 mg, 0.18 mmol) in MeOH (6 mL) was added MeONa (19 mg, 0.35 mmol). The reaction mixture was stirred at 60 °C for 8 h. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with DCM / MeOH = 100 : 0 to 90 : 10) and prep-HPLC (Gemini 5 um C18 column, 150 × 21.2 mm, eluting with 0 to 35 % MeCN / H2O containing 0.1 % NH3) to obtain N-methyl-5-(4-(3-(4-oxo-5-(trifluoromethyl)-3,4-dihydropyrrolo[2,1- f][1,2,4]triazin-2-yl)cyclopentyl)piperazin-1-yl)picolinamide 17 (30 mg, 95% purity, 32% yield, mixture of 4 isomers) as a yellow solid. Chiral resolution of N-methyl-5-(4-(3-(4-oxo-5-(trifluoromethyl)-3,4-dihydropyrrolo[2,1- f][1,2,4]triazin-2-yl)cyclopentyl)piperazin-1-yl)picolinamide (17) Compound 17 (mixture of 4 isomers) was separated by SFC (Column: DAICEL OJ-H 20 mm I.D × 250 mmL 5 μm; Mobile phase: CO2 / MeOH (0.1 % NH3) = 65 / 35) and concentrated under reduced pressure to afford the first fraction as 17cis-a (8.0 mg, 99 % purity, 100 %ee, white solid), the second fraction as 17cis-b (7.2 mg, 98 % purity, 95 %ee, white solid) and the third fraction as 17trans-rac (12.0 mg, 98 % purity, white solid). 17cis-a1H NMR (400 MHz, DMSO-d6, ppm) δ: 12.68 (s, 1 H), 8.46-8.37 (m, 1 H), 8.29 (d, J = 2.8 Hz, 1 H), 7.84 (d, J = 8.8 Hz, 1 H), 7.66 (d, J = 2.8 Hz, 1 H), 7.42 (dd, J = 8.8, 2.8 Hz, 1 H), 6.88 (d, J = 2.8 Hz, 1 H), 3.48-3.36 (m, 4 H), 3.16-3.07 (m, 1 H), 2.78 (d, J = 5.2 Hz, 3 H), 2.75-2.61 (m, 5 H), 2.22-2.05 (m, 2 H), 2.03-1.94 (m, 1 H), 1.91-1.75 (m, 3 H). Assigned cis stereochemistry based on NOE experiments. LCMS (ESI) calcd for C23H26F3N7O2[M + H]+m / z 490.21, found 490.10. 17cis-b1H NMR (400 MHz, DMSO-d6, ppm) δ: 12.67 (s, 1 H), 8.44-8.37 (m, 1 H), 8.29 (d, J = 2.8 Hz, 1 H), 7.84 (d, J = 8.8 Hz, 1 H), 7.66 (d, J = 2.8 Hz, 1 H), 7.42 (dd, J = 8.8, 2.8 Hz, 1 H), 6.88 (d, J = 2.8 Hz, 1 H), 3.48-3.36 (m, 4 H), 3.17-3.07 (m, 1 H), 2.78 (d, J = 4.8 Hz, 3 H), 2.75-2.63 (m, 5 H), 2.23-2.05 (m, 2 H), 2.03-1.94 (m, 1 H), 1.91-1.74 (m, 3 H). Assigned cis stereochemistry based on NOE experiments. LCMS (ESI) calcd for C23H26F3N7O2[M + H]+m / z 490.21, found 490.10. 17trans-rac1H NMR (400 MHz, DMSO-d6, ppm) δ: 12.06 (s, 1 H), 8.45-8.37 (m, 1 H), 8.27 (d, J = 2.8 Hz, 1 H), 7.83 (d, J = 8.8 Hz, 1 H), 7.67 (d, J = 2.8 Hz, 1 H), 7.41 (dd, J = 8.8, 2.8 Hz, 1 H), 6.88 (d, J = 2.8 Hz, 1 H), 3.33-3.28 (m, 4 H), 3.19-3.08 (m, 1 H), 2.85-2.72 (m, 4 H), 2.62-2.54 (m, 4 H), 2.16- 2.04 (m, 2 H), 2.03-1.92 (m, 2 H), 1.91-1.80 (m, 1 H), 1.59-1.46 (m, 1 H). Assigned trans stereochemistry based on NOE experiments. LCMS (ESI) calcd for C23H26F3N7O2[M + H]+m / z 490.21, found 490.10.

[0522] Example 8: Synthesis ofl8cis-a, 18cis-b, 18trans-a, and 18trans-b

[0523] SCHEME S

[0524] Preparation of ethyl 2-(3-oxocyclopentane-l-carboxamido)cyclohex-l-ene-l-carboxylate (1702)

[0525] To a solution of ethyl 2-aminocyclohex-l-ene-l-carboxylate 1701 (2.0 g, 0.0118 mol) in pyridine (20 mL) was added 3-oxocyclopentane-l-carboxylic acid 1609 (1.5 g, 0.0118 mol) and POCI3 (2.7 g, 0.0177 mol) successively. The reaction mixture was stirred at rt for 6 h. The reaction solution was concentrated under reduced pressure and the residue was purified by flash column chromatography (eluting with PE / EtOAc = 100:0 to 50:50) to afford ethyl 2-(3- oxocyclopentane-l-carboxamido)cyclohex-l-ene-l-carboxylate 1702 (1.55 g, 90 % purity, 42 % yield) as a colourless oil.

[0526] LCMS (ESI) calcd for C15H21NO4 [M + H]+m / z 280.15, found 280.10. Preparation of ethyl 2-(3-(4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-l- yl)cyclopentane-l-carboxamido)cyclohex-l-ene-l-carboxylate (1703)

[0527] To a solution of ethyl 2-(3-oxocyclopentane-l-carboxamido)cyclohex-l-ene-l-carboxylate 1702 (410 mg, 1.4678 mmol) in MeOH (15 mL) was added 6-fluoro-N-methyl-5-(piperazin-l- yl)picolinamide 1305 (420 mg, 1.7613 mmol), AcOH (3 drops) and NaBHsCN (185 mg, 2.9356 mmol) successively. The reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was quenched with water (5 mL) and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with DCM / MeOH = 100:0 to 95:5) to afford ethyl 2-(3-(4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-l-yl)cyclopentane- lcarboxamido)cyclohex-l-ene-l-carboxylate 1703 (305 mg, 85 % purity, 38 % yield) as a colourless oil.

[0528] LCMS (ESI) calcd for C26H36FN5O4 [M + H]+m / z 502.28, found 502.25.

[0529] Preparation of 2-(3-(4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-l- yl)cyclopentane-l-carboxamido)cyclohex-l-ene-l-carboxylic acid (1704)

[0530] To a solution of ethyl 2-(3-(4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-l- yl)cyclopentane-lcarboxamido)cyclohex-l-ene-l-carboxylate 1703 (305 mg, 0.6081 mmol) in MeOH / HzO (10 mL, 3:1) was added LiOH (29 mg, 1.2162 mmol). The reaction mixture was stirred at 50 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give 2-(3-(4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-l-yl)cyclopentane-l- carboxamido)cyclohex-l-ene-l-carboxylic acid 1704 (250 mg, 90 % purity, 78 % yield) as a white solid.

[0531] LCMS (ESI) calcd for C24H32FN5O4 [M + H]+m / z 474.24, found 474.16.

[0532] Preparation of 6-fluoro-N-methyl-5-(4-(3-(4-oxo-3,4,5,6,7,8-hexahydroquinazolin-2- yl)cyclopentyl)piperazin-l-yl)picolinamide (compound 18)

[0533] To a solution of 2-(3-(4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-l- yl)cyclopentane-l-carboxamido)cyclohex-l-ene-l-carboxylic acid 1704 (250 mg, 0.5279 mmol) in ACN (5 mL) was added NMI (130 mg, 1.5837 mmol) and TCFH (296 mg, 1.0558 mmol) successively at rt. The reaction mixture was heated to 50 °C and NHs-MeOH (15 mL, 7 M) was added at 50 °C. The reaction solution was stirred at 50 °C for 1 h. The reaction mixture was cooled to rt and concentrated under reduced pressure, the residue was purified by flash column chromatography (eluting with DCM / MeOH = 100:0 to 95:5) and prep-HPLC (column : Gemini - C18150 × 21.2 mm, 5 µm; mobile phase : ACN - H2O (0.05 % NH3); gradient : 35 - 75) to give 6-fluoro-N-methyl-5-(4-(3-(4-oxo-3,4,5,6,7,8-hexahydroquinazolin-2- yl)cyclopentyl)piperazin-1-yl)picolinamide 18cis-rac (35 mg, 95 % purity, 13 % yield ) and 18trans-rac (30 mg, 95 % purity, 11 % yield) as white solids. Chiral resolution of 6-fluoro-N-methyl-5-(4-(3-(4-oxo-3,4,5,6,7,8-hexahydroquinazolin-2- yl)cyclopentyl)piperazin-1-yl)picolinamide (18cis-rac) Compound 18cis-rac was separated by SFC (Column: Daicel Chiralpak IH SFC; 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 first fraction as 18cis-a (7.3 mg, 97.27 % purity, 100% ee, white solid) and the second fraction as 18cis-b (9.6 mg, 95.19 % purity, 100 % ee, white solid). 18cis-a1H NMR (400 MHz, DMSO-d6, ppm) δ: 12.33 (s, 1 H), 8.47-8.35 (m, 1 H), 7.88-7.81 (m, 1 H), 7.63-7.51 (m, 1 H), 3.25-3.14 (m, 4 H), 3.05-2.94 (m, 1 H), 2.76 (d, J = 4.8 Hz, 3 H), 2.70-2.66 (m, 1 H), 2.64-2.57 (m, 4 H), 2.47-2.44 (m, 2 H), 2.32-2.24 (m, 2 H), 2.17-2.06 (m, 1 H), 2.03- 1.91 (m, 1 H), 1.85-1.75 (m, 3 H), 1.72-1.59 (m, 5 H). Cis stereochemistry assigned based on NOE experiments. LCMS (ESI) calcd for C24H31FN6O2[M + H]+m / z 455.25, found 455.40. 18cis-b1H NMR (400 MHz, DMSO-d6, ppm) δ: 12.33 (s, 1 H), 8.47-8.32 (m, 1 H), 7.95-7.77 (m, 1 H), 7.65-7.49 (m, 1 H), 3.26-3.12 (m, 4 H), 3.06-2.93 (m, 1 H), 2.76 (d, J = 4.8 Hz, 3 H), 2.69-2.65 (m, 1 H), 2.65-2.57 (m, 4 H), 2.48-2.44 (m, 2 H), 2.32-2.24 (m, 2 H), 2.18-2.06 (m, 1 H), 2.04- 1.91 (m, 1 H), 1.87-1.75 (m, 3 H), 1.75-1.58 (m, 5 H). Cis stereochemistry assigned based on NOE experiments. LCMS (ESI) calcd for C24H31FN6O2[M + H]+m / z 455.25, found 455.45. Chiral resolution of 6-fluoro-N-methyl-5-(4-(3-(4-oxo-3,4,5,6,7,8-hexahydroquinazolin-2- yl)cyclopentyl)piperazin-1-yl)picolinamide (18trans-rac) Compound 18trans-rac was separated by SFC (Column: Daicel Chiralpak IH SFC; 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 first fraction as 18trans-a (4.3 mg, 98.29 % purity, 100 %ee, white solid) and the second fraction as 18trans-b (5.5 mg, 99.96 % purity, 100 %ee, white solid). 18trans-a1H NMR (400 MHz, DMSO-d6, ppm) δ: 12.07 (s, 1 H), 8.49-8.32 (m, 1 H), 7.94-7.77 (m, 1 H), 7.61-7.49 (m, 1 H), 3.20-3.11 (m, 4 H), 3.09-2.98 (m, 1 H), 2.83-2.72 (m, 4 H), 2.61-2.54 (m, 4 H), 2.47-2.43 (m, 2 H), 2.31-2.25 (m, 2 H), 2.07-1.91 (m, 3 H), 1.89-1.73 (m, 2 H), 1.72-1.59 (m, 4 H), 1.53-1.41 (m, 1 H). Trans stereochemistry assigned based on NOE experiments. LCMS (ESI) calcd for C24H31FN6O2[M + H]+m / z 455.25, found 455.40. 18trans-b1H NMR (400 MHz, DMSO-d6, ppm) δ: 12.07 (s, 1 H), 8.47-8.36 (m, 1 H), 7.90-7.80 (m, 1 H), 7.62-7.48 (m, 1 H), 3.19-3.10 (m, 4 H), 3.09-2.99 (m, 1 H), 2.82-2.73 (m, 4 H), 2.61-2.55 (m, 4 H), 2.47-2.45 (m, 2 H), 2.32-2.25 (m, 2 H), 2.07-1.92 (m, 3 H), 1.89-1.73 (m, 2 H), 1.73-1.59 (m, 4 H), 1.53-1.42 (m, 1 H). Trans stereochemistry assigned based on NOE experiments. LCMS (ESI) calcd for C24H31FN6O2[M + H]+m / z 455.25, found 455.40. Example 9: synthesis of21cis-a, 21cis-b, 21trans-a, 21trans-b

[0534] SCHEME 9

[0535] Preparation of methyl 5-((l-(tert-butoxycarbonyl)azetidin-3-yl)oxy)picolinate (1803)

[0536] To a solution of tert-butyl 3-hydroxyazetidine-l-carboxylate 1801 (1 g, 5 mmol) in THF (30 mL) were added methyl 5-hydroxypicolinate 1802 (0.87 g, 5 mmol), PPhs (2.99 g, 11 mmol) and DIAD (2.31 g, 11 mmol) at rt. The mixture was stirred at rt for 4 h. Then the solvent was removed under reduced pressure. The residue was purified by flash column chromatography (PE / EtOAc = 100:0 to 46:54) to afford methyl 5-((l-(tert-butoxycarbonyl)azetidin-3- yl)oxy)picolinate 1803 (1.5 g, 90 % purity, 77 % yield) as a yellow oil.

[0537] LCMS (ESI) calcd for C15H20N2O5 [M + H] +m / z 309.14, found 309.15. Preparation of 5-((l-(tert-butoxycarbonyl)azetidin-3-yl)oxy)picolinic acid (1804)

[0538] To a solution of methyl 5-((l-(tert-butoxycarbonyl)azetidin-3-yl)oxy)picolinate 1803 (1.5 g, 4 mmol) in THF (10 mL) and H2O (10 mL) was added sodium hydroxide (0.38 g, 9 mmol) at rt. The mixture was stirred at rt for 1 h. Then the organic solvent was removed under reduced pressure. The reaction mixture was diluted with water (15 mL) and adjusted to pH 6 with 1 M aq. HCI and extracted with EtOAc. The combined organic phases were washed with water and brine, dried with sodium sulfate, concentrated to afford 5-((l-(tert-butoxycarbonyl)azetidin- 3-yl)oxy)picoli nic acid 1804 (1.4 g, 90 % purity, 89 % yield) as a yellow oil.

[0539] LCMS (ESI) calcd for C14H18N2O5 [M + H]+m / z 295.12, found 295.15.

[0540] Preparation of tert-butyl 3-((6-(methylcarbamoyl)pyridin-3-yl)oxy)azetidine-l-carboxylate (1805)

[0541] To a solution of 5-((l-(tert-butoxycarbonyl)azetidin-3-yl)oxy)picolinic acid 1804 (1.4 g, 4 mmol) and MeNH2-HCI (0.95 g, 14 mmol) in DCM (20 mL) were added DIPEA (1.82 g, 14 mmol) and T4P (50% in EtOAc, 3.39 g, 9 mmol) at rt. The mixture was stirred at rt for 4 hours. The reaction mixture was quenched with water (15 mL) and extracted with DCM (15 mL x 3). The combined organic layers were washed with water and brine, dried over Na2SO4, concentrated and purified by column chromatography on silica gel (eluting with EtOAc / PE, 0 to 20 %) to afford tert-butyl 3-((6-(methylcarbamoyl)pyridin-3-yl)oxy)azetidine-l-carboxylate 1805 (1.2 g, 90 % purity, 74 % yield) as a yellow oil.

[0542] LCMS (ESI) calcd for C15H21N3O4 [M + H]+m / z 308.15, found 308.15.

[0543] Preparation of 5-(azetidin-3-yloxy)-N-methylpicolinamide 2,2,2-trifluoroacetate (1806)

[0544] To a solution of tert-butyl 3-((6-(methylcarbamoyl)pyridin-3-yl)oxy)azetidine-l-carboxylate 1805 (500 mg, 1.6 mmol) in DCM (5 mL) was added TFA (5 mL) at rt. The solution was then kept stirring at rt for 1 h. The reaction mixture was concentrated to afford 5-(azetidin-3-yloxy)- N-methylpicolinamide 2,2,2-trifluoroacetate 1806 (350 mg, 90 % purity, 93 % yield) as a yellow oil.

[0545] LCMS (ESI) calcd for C10H13N3O2 [M + H]+m / z 208.10, found 208.15. Preparation of 5-((1-(3-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)cyclopentyl)azetidin-3- yl)oxy)-N-methylpicolinamide (21) To a solution of 5-(azetidin-3-yloxy)-N-methylpicolinamide 2,2,2-trifluoroacetate 1806 (200 mg, 0.9 mmol) in MeOH (30 mL) was added 6-fluoro-2-(3-oxocyclopentyl)quinazolin-4(3H)- one 1807 (237 mg, 0.9 mmol, prepared in a similar manner to compound 1304), then two drops of acetic acid and NaBH3CN (60 mg, 0.9 mmol) were added at room temperature. The reaction mixture stirred at 50 ℃ for 4 h. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (eluting with DCM / MeOH = 100 : 0 to 92 : 8) and C18column (Gemini 5 µm C18150 × 21.2 mm, mobile phase: ACN - H2O (0.05 % NH3·H2O), gradient: 25 - 60) to afford 5-((1-(3-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)cyclopentyl)azetidin-3-yl)oxy)-N- methylpicolinamide 21trans-rac (60 mg, 95 % purity) and 21cis-rac (90 mg, 95 % purity). 21trans-rac was then separated by SFC (Column: DAICEL IH SFC 30 mm I.D. × 250 mmL, 10 μm; Mobile phase: CO2 / MeOH [0.1 % NH3(7 M Solution in MeOH)] = 70 / 30) and concentrated under reduced pressure to afford the first fraction as 21trans-a (14.4 mg, 99 % purity, ee%: 100, white solid) and the second fraction as 21trans-b (20.9 mg, 99 % purity, ee%: 100, white solid). 21cis-rac was then separated by SFC (Column: DAICEL OJ-H SFC 30 mm I.D. × 250 mmL, 10 μm; Mobile phase: CO2 / MeOH [0.1 % NH3(7 M Solution in MeOH)] = 65 / 35) and concentrated under reduced pressure to afford the first fraction as 21cis-a (38.2 mg, 99 % purity, ee%: 100, white solid) and the second fraction as 21cis-b (37.4 mg, 99 % purity, ee%: 100, white solid). 21trans-a LCMS (ESI) calcd for C23H24FN5O3[M + H]+m / z 438.19, found 438.15.1H NMR (400 MHz, DMSO-d6, ppm) δ: 12.26 (s, 1 H), 8.60-8.54 (m, 1 H), 8.23 (d, J = 2.8 Hz, 1 H), 7.96 (d, J = 8.4 Hz, 1 H), 7.77-7.71 (m, 1 H), 7.65 (d, 2 H), 7.42 (dd, J = 8.8, 2.8 Hz, 1 H), 5.00- 4.90 (m, 1 H), 3.77-3.68 (m, 2 H), 3.28-3.19 (m, 1 H), 3.07-2.99 (m, 2 H), 2.99-2.92 (m, 1 H), 2.79 (d, J = 4.8 Hz, 3 H), 2.13-2.01 (m, 1 H), 1.96-1.84 (m, 3 H), 1.83-1.73 (m, 1 H), 1.50-1.41 (m, 1 H). Trans stereochemistry assigned based on NOE experiments. 21trans-b LCMS (ESI) calcd for C23H24FN5O3[M + H]+m / z 438.19, found 438.20.1H NMR (400 MHz, DMSO-d6, ppm) δ: 12.27 (s, 1 H), 8.61-8.55 (m, 1 H), 8.24 (d, J = 2.8 Hz, 1 H), 7.96 (d, J = 8.8Hz, 1 H), 7.77-7.72 (m, 1 H), 7.68-7.63 (m, 2 H), 7.42 (dd, J = 8.8, 2.8 Hz, 1 H), 4.99-4.92 (m, 1 H), 3.76-3.69 (m, 2 H), 3.27-3.19 (m, 1 H), 3.07-2.99 (m, 2 H), 2.99-2.92 (m, 1 H), 2.79 (d, J = 4.8 Hz, 3 H), 2.12-2.03 (m, 1 H), 1.94-1.83 (m, 3 H), 1.83-1.75 (m, 1 H), 1.50- 1.41 (m, 1 H). Trans stereochemistry assigned based on NOE experiments. 21cis-a LCMS (ESI) calcd for C23H24FN5O3[M + H]+m / z 438.19, found 438.10.1H NMR (400 MHz, DMSO-d6, ppm) δ: 12.86 (s, 1 H), 8.63-8.55 (m, 1 H), 8.26 (d, J = 2.8 Hz, 1 H), 7.97 (d, J = 8.4 Hz, 1 H), 7.78-7.71 (m, 1 H), 7.70-7.63 (m, 2 H), 7.42 (dd, J = 8.6, 2.6 Hz, 1 H), 5.02-4.94 (m, 1 H), 3.86-3.76 (m, 2 H), 3.22-3.12 (m, 3 H), 3.03-2.96 (m, 1 H), 2.79 (d, J = 4.8 Hz, 3 H), 2.14-1.99 (m, 2 H), 1.94-1.84 (m, 1 H), 1.82-1.74 (m, 1 H), 1.71-1.60 (m, 2 H). Cis stereochemistry assigned based on NOE experiments. 21cis-b LCMS (ESI) calcd for C23H24FN5O3[M + H]+m / z 438.19, found 438.10.1H NMR (400 MHz, DMSO-d6, ppm) δ: 12.86 (s, 1 H), 8.61-8.54 (m, 1 H), 8.25 (d, J = 2.8 Hz, 1 H), 7.97 (d, J = 8.8 Hz, 1 H), 7.77-7.71 (m, 1 H), 7.69-7.63 (m, 2 H), 7.42 (dd, J = 8.6, 3.0 Hz, 1 H), 5.05-4.94 (m, 1 H), 3.86-3.76 (m, 2 H), 3.22-3.12 (m, 3 H), 3.03-2.95 (m, 1 H), 2.79 (d, J = 4.8 Hz, 3 H), 2.12-1.99 (m, 2 H), 1.94-1.83 (m, 1 H), 1.81-1.74 (m, 1 H), 1.69-1.61 (m, 2 H). Cis stereochemistry assigned based on NOE experiments. Example 10: Synthesis of 23cis-rac, 23trans-rac SCHEME 10 Preparation of 5-fluoro-2-(3-oxocyclohexane-1-carboxamido)benzamide (1903) To a solution of 2-amino-5-fluorobenzamide 1901 (1.5 g, 0.0097 mol) in pyridine (10 mL) was added 3-oxocyclohexane-1-carboxylic acid 1902 (1.52 g, 0.011 mol) and EDCI (0.91 g, 0.014 mol), the reaction mixture was stirred at rt for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with DCM / MeOH = 100 : 0 to 97 : 3) to obtain 5-fluoro-2-(3-oxocyclohexane-1- carboxamido)benzamide 1903 (2.1 g, 85 % purity, 65 % yield) as a yellow solid. LCMS (ESI) calcd for C14H15FN2O3[M + H]+m / z 279.11, found 279.10. Preparation of 6-fluoro-2-(3-oxocyclohexyl)quinazolin-4(3H)-one (1904)

[0546] To a solution of 5-fluoro-2-(3-oxocyclohexane-l-carboxamido)benzamide 1903 (2.1 g, 0.0075 mol) in MeOH (20 mL) was added MeONa (0.81 g, 0.015 mol). The reaction mixture was stirred at 50 °C for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with DCM / MeOH = 100 : 0 to 97 : 3) to obtain 6- fluoro-2-(3-oxocyclohexyl)quinazolin-4(3H)-one 1904 (1.5 g, 90 % purity, 69 % yield) as a brown gum.

[0547] LCMS (ESI) calcd for C14H13FN2O2 [M + H]+m / z 261.10, found 261.10.

[0548] Preparation of 5-(4-(3-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)cyclohexyl)piperazin-l- yl)-N-methylpicolinamide (23)

[0549] To a solution of 6-fluoro-2-(3-oxocyclohexyl)quinazolin-4(3H)-one 1904 (600 mg, 2.30 mmol) in DMF (10 mL) was added N-methyl-5-(piperazin-l-yl)picolinamide 1002 (406 mg, 1.84 mmol) and two drops of AcOH. After stirring at 50 °C for 30 min, NaBHsCN (145 mg, 2.30 mmol) was added, the reaction mixture was stirred at 50 °C for a further 2 h. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with DCM / MeOH = 100 : 0 to 97 : 3) and prep-HPLC (Gemini 5 pm C18 column, 150 x 21.2 mm, eluting with 20 % to 65 % MeCN / H2O containing 0.05 % NH3) to obtain 5-(4-(3-(6- fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)cyclohexyl)piperazin-l-yl)-N-methylpicolinamide 23 (mixture of 4 isomers) (30 mg, 98 % purity, 2 % yield) as a white solid.

[0550] Chiral resolution of5-(4-(3-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)cyclohexyl)piperazin- l-yl)-N-methylpicolinamide (Compound 23)

[0551] Compound 23 (mixture of 4 isomers) was separated by SFC (Column: IB N-5 30 mm x 250 mmL, 5 pm; Mobile phase: CO2 / MeOH (0.1 % NH3) = 60 / 40) and concentrated under reduced pressure to afford the first fraction as 23cis-rac (13.0 mg, 99 % purity, racemate, white solid) and the second fraction as 23trans-rac (8.9 mg, 99 % purity, racemate, white solid). 23cis-rac1H NMR (400 MHz, DMSO-d6, ppm) δ: 12.24 (s, 1 H), 8.70-8.65 (m, 1 H), 8.19 (dd, J = 8.8, 2.4 Hz, 1 H), 7.76-7.71 (m, 1 H), 7.69-7.61 (m, 2 H), 7.08-7.02 (m, 1 H), 5.28-5.10 (m, 1 H), 3.72- 3.62 (m, 2 H), 3.28-3.18 (m, 1 H), 3.07-2.99 (m, 2 H), 2.97-2.91 (m, 1 H), 2.12-2.01 (m, 1 H), 1.93-1.74 (m, 4 H), 1.48-1.39 (m, 1 H). Cis stereochemistry assigned based on NOE experiments. LCMS (ESI) calcd for C25H29FN6O2[M + H]+m / z 465.23, found 465.15. 23trans-rac1H NMR (400 MHz, DMSO-d6, ppm) δ: 12.21 (s, 1 H), 8.44-8.36 (m, 1 H), 8.28 (d, J = 2.8 Hz, 1 H), 7.84 (d, J = 8.8 Hz, 1 H), 7.74 (dd, J = 8.4, 2.4 Hz, 1 H), 7.71-7.62 (m, 2 H), 7.41 (dd, J = 8.8, 2.8 Hz, 1 H), 3.41-3.33 (m, 4 H), 3.12-3.01 (m, 1 H), 2.78 (d, J = 4.8 Hz, 3 H), 2.70-2.56 (m, 4 H), 2.48-2.47 (m, 1 H), 2.15-2.05 (m, 1 H), 1.93-1.64 (m, 5 H), 1.59-1.41 (m, 2 H). Trans stereochemistry assigned based on NOE experiments. LCMS (ESI) calcd for C25H29FN6O2[M + H]+m / z 465.23, found 465.10.

[0552] Example 11: synthesis of 38cis-rac, 38trans-rac

[0553] Preparation of tert-butyl 4-(6-cyanopyridin-3-yl)piperazine-l-carboxylate (2003)

[0554] To a solution of 5-fluoropicolinonitrile 2001 (2 g, 0.016 mol) in NMP (25 mL) was added tertbutyl piperazine-l-carboxylate 2002 (4.61 g, 0.025 mol) and K2CO3 (5.66 g, 0.041 mol). The reaction mixture was stirred at 100 °C for 3 h. The mixture was cooled to rt, quenched with water slowly, then extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (3 times), dried over Na2SO4, filtered, concentrated and purified by flash silica chromatography (PE / EtOAc = 100:0 to 70:30) to obtain tert-butyl 4-(6-cyanopyridin-3- yl)piperazine-l-carboxylate 2003 (3.2 g, 85 % purity, 57 % yield) as a yellow solid. LCMS (ESI) calcd for C15H20N4O2 [M + H]+m / z 289.16, found 288.85. Preparation of tert-butyl 4-(6-(5-ethyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)piperazine-1- carboxylate (2005) To a solution of tert-butyl 4-(6-cyanopyridin-3-yl)piperazine-1-carboxylate 2003 (2 g, 0.0069 mol) in MeOH (20 mL) was added propanehydrazide 2004 (3.04 g, 0.034 mol) and MeONa (0.75 g, 0.014 mol). The reaction mixture was stirred at 70 °C for 4 h. Then AcOH was added (1.66 g, 0.028 mol) and the mixture was stirred at 70 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography (eluting with DCM / MeOH = 100 : 0 to 92 : 10) to obtain tert-butyl 4-(6-(5-ethyl-4H-1,2,4-triazol-3- yl)pyridin-3-yl)piperazine-1-carboxylate 2005 (1 g, 85 % purity, 34 % yield) as a yellow gum. LCMS (ESI) calcd for C18H26N6O2[M + H]+m / z 359.21, found 359.20. Preparation of 1-(6-(5-ethyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)piperazine hydrochloride (2006) A solution of tert-butyl 4-(6-(5-ethyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)piperazine-1- carboxylate 2005 (1 g, 0.0028 mol) in HCl in dioxane (4.0 M, 10 mL) was stirred for 2 h at rt. The mixture was concentrated under reduced pressure to obtain 1-(6-(5-ethyl-4H-1,2,4- triazol-3-yl)pyridin-3-yl)piperazine hydrochloride 2006 (800 mg, 85 % purity, 92 % yield) as a yellow solid. LCMS (ESI) calcd for C13H18N6[M + H]+m / z 259.16, found 259.20. Preparation of 2-(3-(4-(6-(5-ethyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)piperazin-1- yl)cyclopentyl)-6-fluoroquinazolin-4(3H)-one (38) To a solution of 1-(6-(5-ethyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)piperazine hydrochloride 2006 (220 mg, 0.85 mmol) in MeOH (8 mL) was added 6-fluoro-2-(3-oxocyclopentyl)quinazolin- 4(3H)-one 1807 (315 mg, 1.28 mmol) and two drops of AcOH and the mixture was stirred at 50 °C for 30 min. Then NaBH3CN (107 mg, 1.70 mmol) was added, the reaction mixture was stirred at 50 °C for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with DCM / MeOH = 100 : 0 to 97 : 3) and prep- TLC (MeOH / DCM, 1 / 30) to obtain 2-(3-(4-(6-(5-ethyl-4H-1,2,4-triazol-3-yl)pyridin-3- yl)piperazin-1-yl)cyclopentyl)-6-fluoroquinazolin-4(3H)-one 38 (40 mg, 98 % purity, 9 % yield) as a white solid. Chiral resolution of 2-(3-(4-(6-(5-ethyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)piperazin-1- yl)cyclopentyl)-6-fluoroquinazolin-4(3H)-one (38) Compound 38 (mixture of 4 isomers) was separated by SFC (Column: DAICEL IH 20 mm I.D × 250 mmL 5 μm; Mobile phase: CO2 / MeOH (0.1 % NH3) = 80 / 20) and concentrated under reduced pressure to afford the first fraction as 38cis-rac (18.6 mg, 93 % purity, yellow solid) and the second fraction as 38trans-rac (8.9 mg, 94 % purity, yellow solid). 38cis-rac1H NMR (400 MHz, DMSO-d6, ppm) δ: 13.94 (s, 1 H), 12.64 (s, 1 H), 8.40-8.30 (m, 1 H), 8.21 (s, 0.50 H), 7.86 (d, J = 8.8 Hz, 1 H), 7.77-7.62 (m, 3 H), 7.49-7.37 (m, 1 H), 3.32-3.26 (m, 4 H), 3.19-3.13 (m, 1 H), 2.77-2.56 (m, 7 H), 2.27-2.16 (m, 1 H), 2.12-2.03 (m, 1 H), 2.01-1.90 (m, 2 H), 1.88-1.72 (m, 2 H), 1.25 (t, J = 7.4 Hz, 3 H). Cis stereochemistry was assigned based on NOE experiments. LCMS (ESI) calcd for C26H29FN8O [M + H]+m / z 489.24, found 489.15. 38trans-rac1H NMR (400 MHz, DMSO-d6, ppm) δ: 13.95 (s, 1 H), 12.28 (s, 1 H), 8.39-8.31 (m, 1 H), 8.15 (s, 0.70 H), 7.85 (d, J = 8.8 Hz, 1 H), 7.75 (dd, J = 8.4, 2.4 Hz, 1 H), 7.72-7.63 (m, 2 H), 7.48-7.36 (m, 1 H), 3.31-3.24 (m, 4 H), 3.23-3.17 (m, 1 H), 2.87-2.78 (m, 1 H), 2.73-2.57 (m, 6 H), 2.24- 2.06 (m, 2 H), 2.05-1.87 (m, 3 H), 1.61-1.47 (m, 1 H), 1.25 (t, J = 7.6 Hz, 3 H). Trans stereochemistry was assigned based on NOE experiments. LCMS (ESI) calcd for C26H29FN8O [M + H]+m / z 489.24, found 489.25. Example 12: synthesis of 40a and 40b

[0555] 40

[0556] SCHEME 12

[0557] Preparation of N-(2-carbamoyl-4-fluorophenyl)-3-oxobicyclo[2.1.1 ]hexane-l -carboxamide (2103)

[0558] To a solution of 2-amino-5-fluorobenzamide 2101 (150 mg, 0.9 mmol) in pyridine (10 mL) were added 3-oxobicyclo[2.1.1]hexane-l-carboxylic acid 2102 (136 mg, 0.9 mmol) and EDCI (373 mg, 1.9 mmol) at rt. The mixture was stirred at 50 °C for 1 h. The mixture was concentrated and purified by column chromatography on silica gel (eluting with DCM / MeOH, 0 to 10 %) to afford N-(2-carbamoyl-4-fluorophenyl)-3-oxobicyclo[2.1.1]hexane-l- carboxamide 2103 (150 mg, 90 % purity, 50 % yield) as a yellow solid. LCMS (ESI) calcd for C14H13FN2O3 [M + H]+m / z 277.09, found 277.05.

[0559] Preparation of6-fluoro-2-(3-oxobicyclo[2.1.1]hexan-l-yl)quinazolin-4(3H)-one (2104)

[0560] To a solution of N-(2-carbamoyl-4-fluorophenyl)-3-oxobicyclo[2.1.1]hexane-l-carboxamide

[0561] 2103 (150 mg, 0.5 mmol) in MeOH (30 mL) was added MeONa (117 mg, 2.1 mmol) at rt. The mixture was stirred at 50 °C for 4 h. The mixture was concentrated and purified by column chromatography on silica gel (eluting with DCM / MeOH, 0 to 10 %) to afford 6-fluoro-2-(3- oxobicyclo[2.1.1]hexan-1-yl)quinazolin-4(3H)-one 2104 (150 mg, 90 % purity, 96 % yield) as a yellow oil. LCMS (ESI) calcd for C14H11FN2O2[M + H]+m / z 259.08, found 259.10. Preparation of 6-fluoro-5-(4-(4-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2- yl)bicyclo[2.1.1]hexan-2-yl)piperazin-1-yl)-N-methylpicolinamide (40) To a solution of 6-fluoro-2-(3-oxobicyclo[2.1.1]hexan-1-yl)quinazolin-4(3H)-one 2104 (75 mg, 0.2 mmol) in MeOH (10 mL) was added 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide 1305 (69 mg, 0.2 mmol), then two drops of acetic acid was added at room temperature. The reaction mixture was stirred at 50 °C for 1 h. Then NaBH3CN (1 mg, 0.01 mmol) and NaBH(OAc)3(85 mg, 0.4 mmol) were added. The reaction mixture was stirred at 50 °C for 4 h. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure. The residue was purified with flash silica chromatography (eluting with MeOH / DCM, 0 to 10 %) and C18column (Gemini 5 µm C18150 × 21.2 mm, mobile phase: ACN - H2O (0.1 % FA), gradient: 10 - 50) to afford 6-fluoro-5-(4-(4-(6-fluoro-4-oxo-3,4- dihydroquinazolin-2-yl)bicyclo[2.1.1]hexan-2-yl)piperazin-1-yl)-N-methylpicolinamide 40rac (80 mg, 95 % purity, 40 % yield) as a white solid. The product 40rac was then separated by SFC (Column: IB N-5 SFC 30 mm I.D. × 250 mmL, 10 μm; 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 40a (38.7 mg, 98 % purity, ee%: 100, white solid) and the second fraction as 40b (24.2 mg, 99 % purity, ee%: 100, white solid). 40a LCMS (ESI) calcd for C25H26F2N6O2[M + H]+m / z 481.21, found 481.10.1H NMR (400 MHz, DMSO-d6, ppm) δ: 12.19 (s, 1 H), 8.46-8.39 (m, 1 H), 7.85 (d, J = 8.0 Hz, 1 H), 7.79-7.73 (m, 1 H), 7.72-7.64 (m, 2 H), 7.58 (dd, J = 10.4, 8.2 Hz, 1 H), 3.18 (s, 4 H), 2.77 (d, J = 4.8 Hz, 3 H), 2.71-2.67 (m, 1 H), 2.65-2.57 (m, 5 H), 2.19-2.12 (m, 1 H), 2.11-2.05 (m, 1 H), 1.99-1.90 (m, 2 H), 1.87-1.80 (m, 1 H), 1.58-1.52 (m, 1 H). 40b LCMS (ESI) calcd for C25H26F2N6O2[M + H]+m / z 481.21, found 481.15.1H NMR (400 MHz, DMSO-d6, ppm) δ: 12.19 (s, 1 H), 8.46-8.39 (m, 1 H), 7.85 (d, J = 8.0 Hz, 1 H), 7.76 (dd, J = 8.0, 2.0 Hz, 1 H), 7.71-7.64 (m, 2 H), 7.58 (dd, J = 10.4, 8.4 Hz, 1 H), 3.18 (s, 4 H), 2.77 (d, J = 4.8 Hz, 3 H), 2.71-2.67 (m, 1 H), 2.65-2.57 (m, 5 H), 2.19-2.13 (m, 1 H), 2.10- 2.05 (m, 1 H), 1.99-1.90 (m, 2 H), 1.88-1.81 (m, 1 H), 1.58-1.51 (m, 1 H).

[0562] Example 13: synthesis of 54 542210 SCHEME 13 Preparation of 2-chloro-6-fluoro-4-methoxyquinazoline (2202) To a solution of 2,4-dichloro-6-fluoroquinazoline 2201 (30.0 g, 0.139 mol) in MeOH (100 mL) was added MeONa (9.00 g, 0.167 mol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with PE / EtOAc = 100:0 to 80:20) to afford 2-chloro-6-fluoro-4-methoxyquinazoline 2202 (25.9 g, 88 % yield) as a white solid. LCMS (ESI) calcd for C9H6ClFN2O [M + H]+m / z 213.02, found 213.10. Preparation of6-fluoro-4-methoxy-2-vinylquinazoline (2204)

[0563] To a solution of 2-chloro-6-fluoro-4-methoxyquinazoline 2202 (25.9 g, 0.122 mol) in ACN (500 mL) were added tributyl(vinyl)stannane 2203 (116 g, 0.366 mol) and Pd(amphos)Cl2 (2.59 g, 3.65 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 6 h under N2. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was purified by flash chromatography (eluting with PE / EtOAc = 100: 0 to 60 : 40) to obtain 6-fluoro-4-methoxy-2-vinylquinazoline 2204 (8.10 g, 33 % yield) as a white solid.

[0564] LCMS (ESI) calcd for C11H9FN2O [M + H]+m / z 205.07, found 205.15.

[0565] Preparation of 6-fluoro-4-methoxyquinazoline-2-carbaldehyde (2205)

[0566] To a solution of 6-fluoro-4-methoxy-2-vinylquinazoline 2204 (8.10 g, 39.2 mmol) in 1,4- dioxane / FhO (2:1, 150 mL) were added K2OsO4-2H2O (730 mg, 1.98 mmol) and NaICU (16.98 g, 79.3 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 h. The resulting mixture was diluted with water (500 mL) and extracted with EtOAc (500 mL x 3). The combined organic layer was washed with brine and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE / EtOAc = 100: 0 to 40 : 60) to give 6-fluoro-4-methoxyquinazoline-2-carbaldehyde 2205 (6.10 g, 75 % yield) as a white solid.

[0567] LCMS (ESI) calcd for C10H7FN2O2 [M + H]+m / z 207.05, found 207.15.

[0568] Preparation of l-(6-fluoro-4-methoxyquinazolin-2-yl)but-3-en-l-ol (2206)

[0569] To a solution of 6-fluoro-4-methoxyquinazoline-2-carbaldehyde 2205 (6.10 g, 30 mmol) in THF (120 mL) was added allylmagnesium bromide (IM, 33 mL) slowly at room temperature. The reaction mixture was stirred at 0 °C for 2 h under N2. The mixture was diluted with water (500 mL) and extracted with EtOAc (500 mL x 3). The combined organic layer was washed with brine (500 mLx 2), dried over Na2SO4, filtered and concentrated in vacuo to get crude product, which was purified by flash column chromatography (PE / EtOAc = 100: 0 to 20: 80) to afford l-(6-fluoro-4-methoxyquinazolin-2-yl)but-3-en-l-ol 2206 (900 mg, 12 % yield) as a yellow oil.

[0570] LCMS (ESI) calcd for C13H13FN2O2 [M + H]+m / z 249.10, found 249.15. Preparation of 4-(6-fluoro-4-methoxyquinazolin-2-yl)butane-l,2,4-triol (2207)

[0571] To a solution of l-(6-fluoro-4-methoxyquinazolin-2-yl)but-3-en-l-ol 2206 (900 mg, 3.63 mmol) in THF / H2O (5:1, 50 mL) were added KzOsCU- 2H2O (67 mg, 0.182 mmol) and NMO (4.24 g, 36.24 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 h. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL x 3). The combined organic layer was washed with brine and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with DCM / MeOH = 100: 0 to 90 : 10) to give 4-(6-fluoro-4-methoxyquinazolin-2-yl)butane-l,2,4-triol 2207 (1.0 g, 98 % yield) as a yellow oil.

[0572] LCMS (ESI) calcd for C13H15FN2O4 [M + H]+m / z 283.10, found 283.20.

[0573] Preparation of 5-(6-fluoro-4-methoxyquinazolin-2-yl)tetrahydrofuran-3-ol (2208)

[0574] To a solution of 4-(6-fluoro-4-methoxyquinazolin-2-yl)butane-l,2,4-triol 2207 (1 g, 3.54 mmol) in toluene (25 mL) was added CMBP (10 mL). The reaction mixture was stirred at 100 °C for 3 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE / EtOAc = 100:0 to 0:100) to give 5-(6-fluoro-4-methoxyquinazolin-2-yl)oxolan-3-ol 2208 (700 mg, 75 % yield) as a yellow oil.

[0575] LCMS (ESI) calcd for C13H15FN2O4 [M + H]+m / z 265.09, found 265.15.

[0576] Preparation of 5-(6-fluoro-4-methoxyquinazolin-2-yl)dihydrofuran-3(2H)-one (2209)

[0577] To a solution of 5-(6-fluoro-4-methoxyquinazolin-2-yl)oxolan-3-ol 2208 (700 mg, 2.65 mmol) in DCM (3 mL) was added Dess-Martin reagent (2.25 g, 5.30 mmol). The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with water and extracted with DCM (50 mL x 3). The combined organic layers were washed by brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE / EtOAc = 100:0 to 0:100) to give 5-(6-fluoro-4-methoxyquinazolin-2- yl)dihydrofuran-3(2H)-one 2209 (170 mg, 24 % yield) as a yellow oil. LCMS (ESI) calcd for C13H11FN2O3 [M + H]+m / z 263.08, found 263.15.

[0578] Preparation of 5-(4-(5-(6-fluoro-4-methoxyquinazolin-2-yl)tetrahydrofuran-3-yl)piperazin- 1 -yl)-N-methylpicolinamide (2210)

[0579] To a solution of 5-(6-fluoro-4-methoxyquinazolin-2-yl)dihydrofuran-3(2H)-one 2209 (170 mg, 0.648 mmol) and N-methyl-5-(piperazin-l-yl)picolinamide 1002 (214 mg, 0.971 mmol) in EtOH (3 mL) was added NaBH(OAc)3 (206 mg, 0.972 mmol) and two drops of HOAc, the mixture was stirred at 90 °C for 10 min. Then NaBHsCN (122 mg, 1.941 mmol) was added. The reaction mixture was stirred at 90 °C for 3 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with DCM / MeOH = 100: 0 to 90:10) to give 5-(4-(5-(6-fluoro-4- methoxyquinazolin-2-yl)tetrahydrofuran-3-yl)piperazin-l-yl)-N-methylpicolinamide 2210 (200 mg, 66 % yield) as a yellow oil.

[0580] LCMS (ESI) calcd for C24H27FN6O3 [M + H]+m / z 467.21, found 467.10.

[0581] Preparation of 5-(4-(5-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)tetrahydrofuran-3- yl)piperazin-l-yl)-N-methylpicolinamide (54)

[0582] To a solution of 5-(4-(5-(6-fluoro-4-methoxyquinazolin-2-yl)tetrahydrofuran-3-yl)piperazin-l- yl)-N-methylpicolinamide 2210 (500 mg, 1.07 mmol) in ACN (5 mL) was added TMSI (300 mg, 2.14 mmol). The reaction mixture was stirred at 50 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (Gemini 5um C18 150*21.2mm, mobile phase: ACN - H2O (0.1% FA), gradient: 30% - 95%) to afford 5-(4-(5- (6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)tetrahydrofuran-3-yl)piperazin-l-yl)-N- methylpicolinamide 54 fraction 1 (8.8 mg, 97 % purity) and 54 fraction 2(2.2 mg, 89 % purity) as white solids.

[0583] One of fractions 1 and 2 was a racemic mixture of cis isomers, and the other of fractions 1 and 2 was a racemic mixture of trans isomers. 54 fraction 11H NMR (400 MHz, MeOD-d4, ppm) δ: 8.29 (d, J = 2.4 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.79 (dd, J = 8.4, 2.8 Hz, 1H), 7.75-7.71 (m, 1H), 7.62-7.57 (m, 1H), 7.38 (dd, J = 8.8, 2.8 Hz, 1H), 4.95- 4.90 (m, 1H), 4.36 (dd, J = 9.6, 2.4 Hz, 1H), 3.95-3.89 (m, 1H), 3.51-3.45 (m, 4H), 3.13-3.10 (m, 1H), 2.93 (s, 3H), 2.81 (t, J = 4.8 Hz, 4H), 2.65-2.57 (m, 1H), 2.48-2.41 (m, 1H). LCMS (ESI) calcd for C23H25FN6O3[M + H]+m / z 453.20, found 453.30. 54 fraction 2 1H NMR (400 MHz, MeOD-d4, ppm) δ: 8.29 (d, J = 2.8 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.83 (dd, J = 8.4, 2.8 Hz, 1H), 7.77-7.70 (m, 1H), 7.64-7.57 (m, 1H), 7.37 (dd, J = 8.8, 2.8 Hz, 1H), 5.08-5.00 (m, 1H), 4.32-4.26 (m, 1H), 3.93-3.89 (m, 1H), 3.40 (t, J = 4.8 Hz, 4H), 3.21-3.19 (m, 1H), 2.93 (s, 3H), 2.80-2.74 (m, 2H), 2.68-2.63 (m, 2H), 2.56-2.46 (m, 2H). LCMS (ESI) calcd for C23H25FN6O3[M + H]+m / z 453.20, found 453.30.

[0584] Example 14: synthesis of 59

[0585] SCHEME 14

[0586] Preparation of methyl 3-(methoxymethylene)cyclobutane-l-carboxylate (2303)

[0587] To a solution of (methoxymethyl)triphenylphosphonium chloride 2302 (5.35 g, 0.015 mol) in THF (20 mL) was added ‘BuOK (1.75 g, 0.016 mol) at 0 °C under N2. The mixture was stirred at rt for 30 min. Then methyl 3-oxocyclobutane-l-carboxylate 2301 (1 g, 0.0078 mol) was added to the mixture. The mixture was heated at 70 °C for 2 h. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography (eluting with EtOAc / PE, 0 to 50 %) to give methyl 3- (methoxymethylene)cyclobutane-l-carboxylate 2303 (200 mg, 90 % purity, 15 % yield) as a white solid.

[0588] LCMS (ESI) calcd for C8H12O3 [M + H]+m / z 157.08, no MS signal found.

[0589] Preparation of methyl 3-formylcyclobutane-l-carboxylate (2304)

[0590] To a solution of methyl 3-(methoxymethylene)cyclobutane-l-carboxylate 2303 (200 mg, 1.28 mmol) in DCM / H2O = 10:1 (11 mL) was added TFA (292 mg, 2.56 mol). The mixture was stirred at rt for 2 hours. The resulting mixture was diluted with water (50 mL) and extracted with DCM (50 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give methyl 3-formylcyclobutane-l- carboxylate 2304 (100 mg, 90 % purity, 49 % yield) as a white solid.

[0591] LCMS (ESI) calcd for C7H10O3 [M + H]+m / z 143.06, no MS signal found.

[0592] Preparation of methyl 3-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-l- yl)methyl)cyclobutane-l-carboxylate (2305)

[0593] To a solution of methyl 3-formylcyclobutane-l-carboxylate 2304 (100 mg, 0.70 mmol) and 6- fluoro-N-methyl-5-(piperazin-l-yl)picolinamide 1305 (168 mg, 0.70 mmol) in MeOH (10 mL) was added AcOH (0.1 mL). The mixture was heated at 50 °C for 10 min. Then NaBHsCN (89 mg, 1.4 mmol) was added to the mixture. The mixture was stirred at 50 °C for 1 hour. The resulting mixture was quenched with water (1 mL) and concentrated under reduced pressure then purified by silica gel column chromatography (eluting with MeOH / DCM, 0 to 10 %) to give methyl 3-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-l- yl)methyl)cyclobutane-l-carboxylate 2305 (120 mg, 90 % purity, 42 % yield) as a white solid.

[0594] LCMS (ESI) calcd for C18H25FN4O3 [M + H]+m / z 365.19, found 365.15 Preparation of 3-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-l- yl)methyl)cyclobutane-l-carboxylic acid (2306)

[0595] To a solution of methyl 3-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-l- yl)methyl)cyclobutane-l-carboxylate 2305 (100 mg, 0.27 mmol) in THF / H2O (3 / 1, 10 mL) was added LiOH (14 mg, 0.55 mmol). The mixture was stirred at room temperature for 1 h. Then the organic solvent was removed under reduced pressure. The aqueous solution was adjusted to pH 2-3 with 1 M aq. HCI. The resulting solution was purified by prep-HPLC (Gemini 5 urn C18 150 x 21.2 mm, eluting with 5 % to 40 % MeCN / HzO containing 0.1% HCOOH) to provide crude 3-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-l-yl)methyl)cyclobutane-l- carboxylic acid 2306 (60 mg, 90 % purity, 56 % yield) as an orange solid.

[0596] LCMS (ESI) calcd for C17H23FN4O3 [M + H]+m / z 351.18, found 351.10.

[0597] Preparation of 5-(4-((3-((2-carbamoyl-4- fluorophenyl)carbamoyl)cyclobutyl)methyl)piperazin-l-yl)-6-fluoro-N-methylpicolinamide (2308)

[0598] To a solution of 3-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-l- yl)methyl)cyclobutane-l-carboxylic acid 2306 (60 mg, 0.17 mmol) in pyridine (5 mL) was added 2-amino-5-fluorobenzamide 2307 (40 mg, 0.26 mmol) and EDCI (66 mg, 0.34 mmol). The mixture was stirred at rt for 2 hours. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography (eluting with MeOH / DCM, 0 to 10 %) to give 5-(4-((3-((2- carbamoyl-4-fluorophenyl)carbamoyl)cyclobutyl)methyl)piperazin-l-yl)-6-fluoro-N- methylpicolinamide 2308 (50 mg, 90 % purity, 54 % yield) as a white solid.

[0599] LCMS (ESI) calcd for C24H28F2N6O3 [M + H]+m / z 487.22, found 487.15.

[0600] Preparation of 6-fluoro-5-(4-((3-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2- yl)cyclobutyl)methyl)piperazin-l-yl)-N-methylpicolinamide (59)

[0601] To a solution of 5-(4-((3-((2-carbamoyl-4- fluorophenyl)carbamoyl)cyclobutyl)methyl)piperazin-l-yl)-6-fluoro-N-methylpicolinamide 2308 (50 mg, 0.10 mmol) in DME (10 mL) was added KOH (17 mg, 0.21 mmol). The mixture was heated at 50 °C for 2 hours. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluting with MeOH / DCM, 0 to 10%) to give 6-fluoro-5-(4-((3-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2- yl)cyclobutyl)methyl)piperazin-1-yl)-N-methylpicolinamide 59 (40 mg, 99 % purity, 74 % yield, cis / trans mixture) as a white solid. Separation of isomers of 6-fluoro-5-(4-((3-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2- yl)cyclobutyl)methyl)piperazin-1-yl)-N-methylpicolinamide (59) Compound 59 (cis / trans mixture) was separated by SFC (Column: Daicel Chiralpak IH SFC, 20 mm I.D. × 250 mmL, 20 μm; 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 59a (2.0 mg, 99.8 % purity, ee%: 100, white solid), the second fraction as 59b (1.2 mg, 97.0 % purity, ee%: 95, white solid). NOE experiments were not successful in determining cis or trans stereochemistry to the two samples. 59a1H NMR (400 MHz, DMSO-d6, ppm) δ: 12.23 (s, 1 H), 8.44-8.39 (m, 1 H), 7.86-7.83 (m, 1 H), 7.76-7.64 (m, 3 H), 7.59-7.52 (m, 1 H), 3.41-3.36 (m, 1 H), 3.17-3.12 (m, 4 H), 2.76 (d, J = 4.8 Hz, 3 H), 2.55-2.51 (m, 5 H), 2.45-2.36 (m, 4 H), 2.12-2.00 (m, 2 H). LCMS (ESI) calcd for C24H26F2N6O2[M + H]+m / z 469.21, found 469.15. 59b1H NMR (400 MHz, DMSO-d6, ppm) δ: 12.19 (s, 1 H), 8.44-8.38 (m, 1 H), 7.87-7.82 (m, 1 H), 7.78-7.71 (m, 2 H), 7.70-7.64 (m, 1 H), 7.60-7.53 (m, 1 H), 3.54-3.46 (m, 1 H), 3.20-3.11 (m, 4 H), 2.76 (d, J = 4.8 Hz, 3 H), 2.57-2.51 (m, 9 H), 2.10-2.02 (m, 2 H). LCMS (ESI) calcd for C24H26F2N6O2[M + H]+m / z 469.21, found 469.15. Example 15: synthesis of 62

[0602] SCHEME 15

[0603] Preparation of methyl 3-formylbicyclo[l.l.l]pentane-l-carboxylate (2402)

[0604] To a solution of methyl 3-(hydroxymethyl)bicyclo[l.l.l]pentane-l-carboxylate 2401 (3 g, 19 mmol) in DCM (50 mL) was added PCC (8.28 g, 38 mmol) at rt. The reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated and purified by flash column chromatography (eluting with PE / EtOAc = 100:0 to 0:100) to afford methyl 3- formylbicyclofl. l.l]pentane-l-carboxylate 2402 (2.5 g, 90 % purity, 76 % yield) as a yellow

[0605] No MS signal. Preparation of methyl 3-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-l- yl)methyl)bicyclo[l.l.l]pentane-l-carboxylate (2403)

[0606] To a solution of methyl 3-formylbicyclo[l.l.l]pentane-l-carboxylate 2402 (600 mg, 3.8 mmol), 6-fluoro-N-methyl-5-(piperazin-l-yl)picolinamide 1305 (927 mg, 3.8 mmol), and NaBH(OAc)3 (1649 mg, 7.7 mmol) in MeOH (30 mL) was added 2 drops of AcOH at room temperature, the mixture was stirred for 10 min. Then NaBHsCN (244 mg, 3.8 mmol) was added. The reaction mixture was stirred at 50 °C for 1 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with DCM / MeOH = 100 : 0 to 90 : 10) to afford methyl 3-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-l- yl)methyl)bicyclo[l.l.l]pentane-l-carboxylate 2403 (600 mg, 90 % purity, 36 % yield) as a yellow oil.

[0607] LCMS (ESI) calcd for C19H25FN4O3 [M + H]+m / z 377.19, found 377.15.

[0608] Preparation of 3-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-l- yl)methyl)bicyclo[l.l.l]pentane-l-carboxylic acid (2404)

[0609] To a solution of methyl 3-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-l- yl)methyl)bicyclo[l.l.l]pentane-l-carboxylate 2403 (600 mg, 1.5 mmol) in THF / H2O = 1 / 1 (30 mL) was added LiOH (153 mg, 6.3 mmol) at rt. The reaction mixture was stirred at room temperature for 2 h. The mixture was acidified to pH 6 with 1 M aq. HCI. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layer was washed with brine (100 mL x 3), dried over Na2SO4, filtered and concentrated in vacuo to get 3-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-l- yl)methyl)bicyclo[l.l.l]pentane-l-carboxylic acid 2404 (500 mg, 90 % purity, 77 % yield) as a yellow oil.

[0610] LCMS (ESI) calcd for C18H23FN4O3 [M + H]+m / z 363.18, found 363.10. Preparation of 5-(4-((3-((2-carbamoyl-4-fluorophenyl)carbamoyl)bicyclo[1.1.1]pentan-1- yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide (2406) To a solution of 3-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-1- yl)methyl)bicyclo[1.1.1]pentane-1-carboxylic acid 2404 (500 mg, 1.3 mmol) and 2-amino-5- fluorobenzamide 2405 (425 mg, 2.7 mmol) in pyridine (30 mL) was added EDCI (528 mg, 2.7 mmol) at rt. The reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo to get crude product, which was purified by flash column chromatography (DCM / MeOH = 100:0 to 90:10) to afford 5-(4-((3-((2-carbamoyl-4- fluorophenyl)carbamoyl)bicyclo[1.1.1]pentan-1-yl)methyl)piperazin-1-yl)-6-fluoro-N- methylpicolinamide 2406 (500 mg, 90 % purity, 65 % yield) as a yellow oil. LCMS (ESI) calcd for C25H28F2N6O3[M + H]+m / z 499.22, found 499.10. Preparation of 6-fluoro-5-(4-((3-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2- yl)bicyclo[1.1.1]pentan-1-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (62) To a solution of 5-(4-((3-((2-carbamoyl-4-fluorophenyl)carbamoyl)bicyclo[1.1.1]pentan-1- yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide 2406 (250 mg, 0.5 mmol) in EtOH (30 mL) was added sodium ethoxide (68 mg, 1.0 mmol) at rt. The reaction mixture was stirred at room temperature for 16 h. The mixture was concentrated in vacuo to obtain the crude product, which was purified by flash column chromatography (DCM / MeOH = 100:0 to 90:10) to afford 6-fluoro-5-(4-((3-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)bicyclo[1.1.1]pentan-1- yl)methyl)piperazin-1-yl)-N-methylpicolinamide 62 (117.5 mg, 96 % purity, 43 % yield) as a white solid. LCMS (ESI) calcd for C25H26F2N6O2[M + H]+m / z 481.21, found 481.10.1H NMR (400 MHz, DMSO-d6, ppm) δ: 12.29 (s, 1 H), 8.43-8.37 (m, 1 H), 7.89-7.82 (m, 1 H), 7.79-7.73 (m, 1 H), 7.72-7.64 (m, 2 H), 7.60-7.52 (m, 1 H), 3.22-3.13 (m, 4 H), 2.77 (d, J = 4.8 Hz, 3 H), 2.65-2.58 (m, 4 H), 2.53-2.51 (m, 2 H), 2.14 (s, 6 H). Example 16: Assays

[0611] Exemplary compounds of the invention were prepared and tested to determine their effect as PARP1 and PARP2 inhibitors. Typical assays are described below.

[0612] Example 16A. PARP1 biochemical dissociation-enhanced lanthanide fluorescence immunoassay (DELFIA assay)

[0613] Optiplate HB 384-well plates were coated with anti-FLAG antibody, supplied as a 4 mg / ml solution, using a NazCOs / HCOs coating buffer at pH 9.6, overnight at 4 °C, in order to achieve a final immobilisation per well of 0.3 pg. Wells were then washed 3 x 5 min in coating wash buffer (PBS / 0.05 % Tween (v / v)), and blocked with 2 % BSA (w / v) in coating wash buffer overnight at 4 °C. Prior to assay, wells were washed 3 x 5 min in coating wash buffer. For the assay 20 pl of 2.5 nM recombinant full length human N-terminally FLAG-tagged PARP1 was added to each well of the 384-well plate for 30 min at room temperature followed by addition of 50 nL of compound solution in DMSO using pintool technology. Following incubation for 30 min at room temperature, 5 pl of 10 pM biotin-NAD+and 10 nM activation DNA (sequence shown below) in solution in 20 mM HEPES (pH 7.5), 100 mM NaCI, 2 mM DTT, 0.1 % BSA (w / v), 0.02 % Tween (v / v) assay buffer. Auto-PARylation proceeded for 2 h at room temperature prior to the addition of 5 pl of 12 mM NAD+quenching solution. After 30 min at room temperature, assay solution was removed and following washing 5 times for 3 min, 100 pl of a 1:1000 dilution of DELFIA Eu-Nl Streptavidin reagent was added. Plates were then incubated for 30 min at room temperature. The reaction mixture was removed and the plates washed 5 times for 3 min prior to the addition of 25 pl DELFIA enhancement solution. Following incubation for 30 min at room temperature, fluorescence was measured on a Pherastar FS (Ex337 nm, Em620 nm; integration start 60 ps; integration time 400 ps).

[0614] Typically compounds were tested from 20 pM at 3-fold dilution intervals in 12-point concentration-response curves to determine IC50 values. Data was analysed using ActivityBase software and replicate values for the low (without enzyme, 0.2 % DMSO) and high (0.2 % DMSO) % controls were averaged and the data obtained from the test compounds expressed as a % of 100 % using the below formulae:

[0615] % value = 100-(100*((high control - unknown) / (high control - low control))

[0616] % data was fitted to a non-linear regression equation (log inhibitor vs response-variable slope 4-parameters) to obtain IC50 values.

[0617] The IC50 values for a variety of test compounds are shown in Table 1.

[0618] Activation DNA sequence:

[0619] Duplex Sequences

[0620] 5'-ACCCTGCTGTGGGC / ideoxyU / GGAGAACAAGGTGAT-3' (SEQ ID NO:1) 5'-ATCACCTTGTTCTCCAHGCCCACAGCAGGGT-3' (SEQ ID NO:2)

[0621] 5 ' -ACCCTGCTGTGGGCGGAGAACAAGGTGAT-3 ' (SEQ ID NO:3) I I I I I I I I I I I I I I I I I I I

[0622] 3 ' -TGGGACGACACCCGHACCTCTTGTTCCACTA-5 '

[0623] Example 16B. PARP1 probe displacement homogeneous time-resolved fluorescence assay (HTRF assay)

[0624] 10 nM full length N-terminally FLAG-tagged PARP1 was incubated with 2 nM Anti-FLAG Tb- cryptate antibody and PARP1 / 2 Cy5 fluorescent dye-labelled binding probe (10-fold probe Kd = 270 nM) in 20 mM HEPES (pH 7.5), 100 mM NaCI, 2 mM DTT, 0.1 % BSA (w / v), 0.02 % Tween (v / v) assay buffer for 40 min at room temperature. A Cy5-labelled binding probe is shown below and described in Papeo, G. et al. J. Biomol. Screen. 2014; 19:1212-1219. 6 pl of this reaction mixture was then transferred to each well of a black non-binding surface 384-well plate and 35 nl of compound solution in DMSO was then added using pintool technology. Following incubation for 1 h at room temperature, fluorescence was measured on a Pherastar FS (Ex 337 nm, Em620 nm, em665 nm; integration start 60 ps; integration time 400 ps) using the HTRF module.

[0625] Typically compounds were tested from 58.5 pM at factor 3 dilution intervals in 12-point concentration-response curves to determine IC50 values. Data was analysed using ActivityBase software and replicate values for the low (without enzyme but with probe and Tb-cryptate antibody, 0.6 % DMSO) and high (0.6 % DMSO) % controls were averaged and the data obtained from the test compounds expressed as a % of 100 % using the below formulae:

[0626] %activity = 100*(value - low control) / (high control - low control)

[0627] %activity data was fitted to a non-linear regression equation to obtain IC50 values

[0628] Kd values were calculated using Cheng-Prussoff formula:

[0629] IC50 = (1+ ([probe concentration] / [KmProbe]))*Kd

[0630] Therefore Kd = IC50 / (l+[[probe concentration] / [Kmprobe])); using probe at 10 x Km, this equated to Kd = IC50 / H

[0631] Example 16C. PARP2 probe displacement homogeneous time-resolved fluorescence assay (HTRF assay)

[0632] 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.

[0633] Cy5 probe structure: NanoBRET cellular target occupancy assay

[0634] 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.

[0635] Frozen HEK293 cells transiently transfected with either PARPl-NanoLuc® fusion or PARP2- NanoLuc® fusion constructs (Promega) were thawed and dispensed as a suspension in 384- well microplates each at a density of 1750 cells per well. NanoBRET™ TE PARP Tracer-01 was then added to final concentrations of 11 and 2 nM for PARP1 and PARP2 assays, respectively. Compounds were added from 25 pM at factor 3 dilution intervals in 12-point concentrationresponse curves and plates were incubated for 2 hours at 37 °C. BRET ratios were then measured using a NanoBRET module (LUM 610-LP 450-80) and PHERAstar FS or FSX reader following addition of NanoBRET™ Nano-Gio® Substrate and Extracellular NanoLuc® Inhibitor according to manufacturer's instructions. Kd values were calculated using Cheng-Prussoff formula:

[0636] IC50 = (1+ ([tracer concentration] / [Kmtracer])) * Kd

[0637] 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.

[0638] TABLE 1

[0639] Results ofParp 1 / 2 assays for selected compounds (DELFIA and Probe Displacement HTRF)

[0640] *The stereochemistry of this compound was not definitively established. One of fractions 1 and 2 was a cis isomer, and the other of fractions 1 and 2 was a trans isomer. TABLE 2

[0641] Results ofParp 1 / 2 assays for selected compounds (NanoBRET)

[0642] DELFI A, Probe Displacement HTRF and NanoBRET assay categories: - indicates IC50 or Kd value above 10 pM

[0643] + indicates IC50 or Kd value above 1 pM up to 10 pM

[0644] ++ indicates IC50 or Kd value above 100 nM up to 1 pM

[0645] +++ indicates IC50 or Kd value above 10 nM up to 100 nM

[0646] ++++ indicates IC50 or Kd value of 10 nM or less NT: not tested

[0647] Selectivity categories:

[0648] - indicates a value of less than 10

[0649] + indicates a value of 10 to less than 50 ++ indicates a value of 50 to less than 100

[0650] +++ indicate a value of at least 100 The selectivity values relate to the selectivity preference of PARP1 over PARP2. They are calculated from the ratio of Kd values for PARP1 and PARP2 inhibition as Kd (PARP2) / Kd (PARP1).

[0651] It will be appreciated that the above embodiments have been described by way of example only.

[0652] 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; each XDis independently selected from C, N, O and S;XETand XEBare each independently selected from C and N; each R1is independently absent or selected from H and a substituted or unsubstituted organic group; each R4is independently absent or selected from H and a substituted or unsubstituted organic group, with the proviso that the R4groups are not fused to form a ring;R3is H or a substituted or unsubstituted organic group;L is a group having a structure of:wherein: ring C is an aromatic ring;XA1is C or N; each XA2is independently selected from C, N, O and S; each XB2is independently selected from C, N, O and S;XB3is selected from C and N; each Xcis independently selected from C, N, O, and S, with the proviso that ring C is a heterocycle; each R5Aand R5Cis independently absent or selected from H and a substituted or unsubstituted organic group; each R5Bis independently absent, H, a substituted or unsubstituted organic group, or together with another R5Brepresents a bond bridging ring B;R6is selected from H and a substituted or unsubstituted organic group; 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;r is 0, 1, 2, 3, or 4; and s is 0, 1, 2, 3, or 4, with the proviso that r + s is 3 or 4;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.

2. The PARP1 inhibitor compound according to any preceding claim, wherein each R1and each R4is independently absent or selected from:H; a halogen; a nitrile group; a Cl to C6 acyclic alkyl group; a Cl to C6 acyclic alkoxy group; a Cl to C6 acyclic haloalkyl group; a Cl to C6 acyclic haloalkoxy group, such as -OCF3 or OCHF2; a Cl to C6 acyclic aminoalkyl 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 alkyl group; a Cl to C6 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 acyclic 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.

6. The PARP1 inhibitor compound according to claim 5, wherein exactly one R1or exactly one R4is F; or wherein each R1and each R4is absent or H.

7. The PARP1 inhibitor compound according to any preceding claim, wherein at least one of XETand XEBis C.

8. The PARP1 inhibitor compound according to claim 7, wherein XEBis N.

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

10. The PARP1 inhibitor compound according to claim 7, wherein XETis C and XEBis C.

11. The PARP1 inhibitor compound according to claim 10, having a structure selected from:

12. The PARP1 inhibitor compound according to any preceding claim, wherein each XDis independently selected from C and N.

13. The PARP1 inhibitor compound according to claim 12, wherein each XDis C.

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

15. The PARP1 inhibitor compound according to any of claims 1 to 13, wherein y is 0.

16. The PARP1 inhibitor compound according to any preceding claim, wherein ring D is an aromatic ring.

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

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

22. The PARP1 inhibitor compound according to any of claims 1 to 15, wherein ring D is a non-aromatic ring.

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

24. The PARP1 inhibitor compound according to claim 23, having a structure of:

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

26. The PARP1 inhibitor compound according to claim 22, having a structure selected from:T1. The PARP1 inhibitor compound according to claim 22, having a structure selected from:

28. 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.

29. The PARP1 inhibitor compound according to claim 28, wherein R3is H.

30. The PARP1 inhibitor compound according to claim 1, having a structure selected from:

31. The PARP1 inhibitor compound according to any preceding claim, wherein n + m is in the range 2 to 5.

32. The PARP1 inhibitor compound according to claim 31, wherein both n and m are at least 1.

33. The PARP1 inhibitor compound according to any preceding claim, wherein XA1is C.

34. The PARP1 inhibitor compound according to claim 33, 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 tetrahydropyran and further optionally having a structure selected from:each R5Aand R5A3being independently selected from H and a substituted or unsubstituted organic group, wherein R5A3is most preferably H; or iii) ring A is a 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 5-membered aromatic ring, optionally an oxazole or isoxazole, optionally having a structure selected from:each R5Abeing independently selected from H and a substituted or unsubstituted organic group, v) 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 vi) ring A is a 3-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; vii) 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.

35. 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; an oxo 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; or two R5Agroups on adjacent atoms may together represent a phenyl group fused to ring A; preferably wherein each R5Ais H.

36. The PARP1 inhibitor compound according to claim 35, wherein a pair of R5Agroups form a ring that is fused to ring A; optionally wherein the ring that is fused to ring A is a phenyl group.

37. The PARP1 inhibitor compound according to claim 34, wherein ring A has a structure selected from:optionally wherein ring A has a structure selected from Al to A37.

38. The PARP1 inhibitor compound according to claim 32, wherein ring A has a structure of:wherein: m is 1 or 2;n is 1 or 2; each R5A2and R5A3independently is absent or selected from H and a substituted or unsubstituted organic group, preferably wherein R5A3is H; and wherein: i) XA1is C and R5A1is absent or selected from H and a substituted or unsubstituted organic group; or ii) XA1is N and R5A1is absent.

39. The PARP1 inhibitor compound according to claim 38, wherein each R5A1, R5A2and R5A3is independently absent or selected from H; a halogen, optionally F; a hydroxyl group; an oxo group; and a Cl to C3 alkyl group, optionally wherein a pair of R5Agroups form a Cl to C3 alkyl group bridging ring A; preferably wherein each R5A1, R5A2and R5A3is absent or H.

40. The PARP1 inhibitor compound according to claim 38 or claim 39, wherein ring A has a structure selected from:

41. The PARP1 inhibitor compound according to any preceding claim, wherein ring A has a structure selected from:

42. The PARP1 inhibitor compound according to any preceding claim, wherein ring A is a5-membered ring.

43. The PARP1 inhibitor compound according to any of claims 1 to 41, wherein ring A is a3- or 4-membered ring, and wherein Q1is -CH2- or -CHfCHs)-; optionally wherein ring A is44. The PARP1 inhibitor compound according to any preceding claim, wherein p + q is in the range 2 to 5.

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

46. The PARP1 inhibitor compound according to any preceding claim, wherein XB3is N.

47. The PARP1 inhibitor compound according to claim 45 or claim 46, wherein ring B has a structure selected from:

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

49. The PARP1 inhibitor compound according to any preceding claim, wherein each R5Bis independently absent, H, a substituted or unsubstituted organic group.

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

51. The PARP1 inhibitor compound according to claim 47, wherein ring B has a structure selected from:

52. The PARP1 inhibitor compound according to claim 51, wherein ring B has a structure of:

53. The PARP1 inhibitor compound according to claim 51, wherein ring B has a structure54. The PARP1 inhibitor compound according to claim 51, wherein ring B has a structure of:optionally wherein Q2is O.

55. The PARP1 inhibitor compound according to any of claims 1 to 43, wherein p + q is 6, and wherein ring B comprises two fused rings.

56. The PARP1 inhibitor compound according to claim 55, wherein ring B has a structureoptionally wherein each R5Bis absent or H.

57. The PARP1 inhibitor compound according to claim 56, wherein ring B has a structure58. The PARP1 inhibitor compound according to claim 57, wherein ring B has a structure of:

59. The PARP1 inhibitor compound according to claim 58, wherein ring B has a structure60. 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.

61. The PARP1 inhibitor compound according to claim 60, wherein R7is selected from: H; a halogen, optionally F; a Cl to C6 alkyl group; and a Cl to C6 haloalkyl group.

62. 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, tetra hydropyran-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).

63. The PARP1 inhibitor compound according to claim 62, 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.

64. The PARP1 inhibitor compound according to any preceding claim, wherein Q1is a bond.

65. The PARP1 inhibitor compound according to any preceding claim, wherein Q2is a bond, -O-, or -CH2-; optionally a bond or -CH2-.

66. The PARP1 inhibitor according to claim 65, wherein Q2is a bond.

67. The PARP1 inhibitor compound according to any preceding claim, wherein r is at least 1 and s is at least 1.

68. The PARP1 inhibitor compound according to any preceding claim, wherein each Xcis independently selected from C and N.

69. The PARP1 inhibitor compound according to claim 68, wherein r+s is 4; optionally wherein r is 2 and s is 2.

70. The PARP1 inhibitor compound according to claim 69, wherein exactly one Xcatom is N, or wherein exactly two Xcatoms are N.

71. The PARP1 inhibitor compound according to claim 69 or claim 70, wherein ring C has a structure of:wherein:XCoand XCmare each selected from C and N, with the proviso that at least one of XCoand XCmis 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 exactly one of XCoand XCmis N.

72. The PARP1 inhibitor compound according to claim 71, wherein ring C is a pyridine group, optionally having a structure selected from:each R5Cbeing independently selected from H and a substituted or unsubstituted organic group.

73. The PARP1 inhibitor compound according to claim 72, wherein ring C is a pyridine group having a structure of:

74. The PARP1 inhibitor compound according to claim 70, wherein ring C is a diazine group, optionally having a structure selected from:each R5Cbeing independently selected from H and a substituted or unsubstituted organic group.

75. The PARP1 inhibitor compound according to claim 74, wherein ring C has a structure selected from:

76. The PARP1 inhibitor compound according to any of claims 1 to 68, wherein r+s is 3 and each Xcis independently selected from C, N, O and S.

77. The PARP1 inhibitor compound according to claim 76, wherein ring C is selected from: i) 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; ii) 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; iii) 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; iv) a triazole, optionally a triazole having a structure of:R5Cbeing selected from H and a substituted or unsubstituted organic group, optionally wherein R5Cis H.

78. The PARP1 inhibitor compound according to claim 77, wherein ring C has a structure of:, optionally wherein R5Cis H.

79. 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.

80. The PARP1 inhibitor compound according to claim 79, wherein the organic group is selected from F, Cl, a nitrile group, a methyl group, and a fluoromethyl group, optionally CF2H.

81. The PARP1 inhibitor compound according to claim 79 or claim 80, wherein exactly one R5Cis an organic group.

82. The PARP1 inhibitor compound according to claim 81, wherein exactly one R5Cis F.

83. The PARP1 inhibitor compound according to claim 79, wherein when present each R5Cis H.

84. The PARP1 inhibitor compound according to any preceding claim, wherein ring C has a structure selected from:C17C2985. The PARP1 inhibitor compound according to claim 84, wherein ring C has a structure selected from:T31T3086. The PARP1 inhibitor compound according to any of claims 1 to 84, 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 independentlyselected from H, a halogen, optionally-deuterated C1 to C3 alkyl, and C1 to C3 haloalkyl.

87. The PARP1 inhibitor compound according to claim 86, wherein R6is H.

88. The PARP1 inhibitor compound according to claim 86, wherein R6is selected from -F, -Cl, -CN, -CONH2, -CONHMe (optionally -CONHCD3), -CONHEt, -CONMe2, -CONHCOMe, -CONHCH2-CH2OMe, -CONH-CH2-CH2F, -CONH-CH2-CF3, -CONH-CH2-CHF2,89. The PARP1 inhibitor compound according to claim 88, wherein R6is F.

90. The PARP1 inhibitor compound according to claim 88, wherein R6is Cl.

91. The PARP1 inhibitor compound according to claim 88, wherein R6is CN.

92. The PARP1 inhibitor compound according to claim 86, 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.

93. The PARP1 inhibitor compound according to claim 92, wherein R6is selected from:

94. The PARP1 inhibitor compound according to claim 93, wherein R6is -CONHMe.

95. The PARP1 inhibitor compound according to claim 93, wherein R6.

96. The PARP1 inhibitor compound according to claim 93, wherein R6is -C(O)NHEt.

97. The PARP1 inhibitor compound according to claim 93, wherein R6.

698. The PARP1 inhibitor compound according to claim 93, wherein R is .

99. The PARP1 inhibitor compound according to claim 93, wherein R6is C(O)NHCH2CH2F.

100. The PARP1 inhibitor compound according to claim 93, wherein R6is C(O)NHCH2CHF2.

101. The PARP1 inhibitor compound according to claim 93, wherein R6is -C(O)NHCH2CF3.

102. The PARP1 inhibitor compound according to claim 93, wherein R51is a tetrahydropyranyl group, optionally wherein R6is:

103. The PARP1 inhibitor compound for use according to any of claims 1 to 84, 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.

104. The PARP1 inhibitor compound for use according to claim 103, wherein R6is selected from:optionally wherein R6 is:

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

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

107. The PARP1 inhibitor compound according to any of claims 1 to 105, wherein rings E and B are in a trans configuration with respect to ring A, optionally wherein group L is selected from:

108. The PARP1 inhibitor compound according to any preceding claim, having a structure of:wherein:XDis selected from C and N; when XDis N:RD1is selected from H, a Cl to C3 alkyl group, and a Cl to C3 haloalkyl group; preferably a methyl group; andRD2is absent; when XDis C:RD1and RD2are each H; n is 1 or 2;RA1and RA3are each H, or RA1and RA3together represent a -CH2- group bridging ring A, with the proviso that when n is 1, RA1and RA3are each H;XCoand XCmare each selected from C and N, with the proviso that at least one of XCoand XCmis N; when XCois C, RCois H or a halogen, and is optionally H or F; when XCois N, RCois absent; when XCmis C, RCmis H or a halogen, and is optionally H or F; when XCmis N, RCmis absent;R6is selected from -C(O)NHMe; -CN; and a halogen, optionally F or Cl.

109. The PARP1 inhibitor compound according to any of claims 1 to 107, having a structure of:wherein:XDis C or N; when XDis C, RD4is selected from H and a halogen, and is preferably H; when XDis N, RD4is absent;RD1and RD2are each independently selected from H and a halogen; n is 1 or 2;XAis C or N; when XAis C:RA1and RA3are each H, or RA1and RA3together represent a -CH2- group bridging ring A, with the proviso that when n is 1, RA1and RA3are each H; when XAis N:RA1is absent, and RA3is H;XCoand XCmare each selected from C and N, with the proviso that at least one of XCoand XCmis N; when XCois C, RCois H or a halogen, and is optionally H or F; when XCois N, RCois absent; when XCmis C, RCmis H or a halogen, and is optionally H or F; when XCmis N, RCmis absent;R6is selected from -C(O)NHMe; -CN; and a halogen, optionally F or Cl.

110. The PARP1 inhibitor compound according to any of claims 1 to 107, having a structurewherein: a dotted line represents a single bond or a double bond;XEBis C or N;XD1and XD2are each independently selected from C and N, with the proviso that whenXEBis N, XD1is C;RD1, and RD2are each independently absent or present and selected from H, a halogen, a methyl group, and a halomethyl group, such as CF3;RD3is selected from H, a halogen, a methyl group, and a halomethyl group, such as CF3; n is 1 or 2;RA1and RA3are each H, or RA1and RA3together represent a -CH2- group bridging ringA, with the proviso that when n is 1, RA1and RA3are each H;XCoand XCmare each selected from C and N, with the proviso that at least one of XCoand XCmis N; when XCois C, RCois H or a halogen, and is optionally H or F; when XCois N, RCois absent; when XCmis C, RCmis H or a halogen, and is optionally H or F; when XCmis N, RCmis absent;R6is selected from -C(O)NHMe; -CN; and a halogen, optionally F or Cl.

111. The PARP1 inhibitor compound according to claim 1, having a structure selected from:ijtransıĵtranszn17cisTIT.T1STil44cisLSL112. The PARP1 inhibitor compound according to any of claims 1 to 107, wherein when one or more of R1, R3, R4, R5A(e.g. R5A1, R5A2, R5A3), R5B, R5C, R6, R7, R8, 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, -CH2CCI3, -CH2CBr3, and -CH2CH2CI3);NH2or a substituted or unsubstituted linear or branched primary secondary or tertiary Ci-Ce 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)CI-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)CI2-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-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(such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl); an -OH group;a substituted or unsubstituted linear or branched C1-C6alcohol group (such as –CH2OH, -CH2CH2OH, -CH(CH3)CH2OH, -C(CH3)2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, -CH(CH3)CH2CH2OH, -CH(CH3)CH(CH3)OH, -CH(CH2CH3)CH2OH, -C(CH3)2CH2OH, -CH2CH2CH2CH2CH2OH, and -CH2CH2CH2CH2CH2CH2OH); a substituted or unsubstituted linear or branched C1-C6carboxylic acid group (such as -COOH, -CH2COOH, -CH2CH2COOH, -CH2CH2CH2COOH, -CH2CH2CH2CH2COOH, and -CH2CH2CH2CH2CH2COOH); a substituted or unsubstituted linear or branched carbonyl group (such as -(CO)Me, -(CO)Et, -(CO)Pr, -(CO)iPr, -(CO)nBu, -(CO)iBu, -(CO)tBu, -(CO)Ph, -(CO)CH2Ph, -(CO)CH2OH, -(CO)CH2OCH3, -(CO)CH2NH2, -(CO)CH2NHMe, -(CO)CH2NMe2, -(CO)-cyclopropyl, -(CO)-1,3-epoxypropan-2-yl; -(CO)NH2, -(CO)NHMe, -(CO)NMe2, -(CO)NHEt, -(CO)NEt2, -(CO)-pyrollidine-N-yl, -(CO)-morpholine-N-yl, -(CO)-piperazine-N-yl, -(CO)-N-methyl-piperazine-N-yl, -(CO)NHCH2CH2OH, -(CO)NHCH2CH2OMe, -(CO)NHCH2CH2NH2, -(CO)NHCH2CH2NHMe, and -(CO)NHCH2CH2NMe2); a substituted or unsubstituted linear or branched C1-C6carboxylic acid ester group (such as -COOMe, -COOEt, -COOPr, -COO-i-Pr, -COO-n-Bu, -COO-i-Bu, -COO-t-Bu, -CH2COOMe, -CH2CH2COOMe, -CH2CH2CH2COOMe, and -CH2CH2CH2CH2COOMe); a substituted or unsubstituted linear or branched C1-C6amide group (such as -CO-NH2, -CO-NMeH, -CO-NMe2, -CO-NEtH, -CO-NEtMe, -CO-NEt2, -CO-NPrH, -CO-NPrMe, and -CO-NPrEt); a substituted or unsubstituted linear or branched C1-C7amino carbonyl group (such as -NH-CO-Me, -NH-CO-Et, -NH-CO-Pr, -NH-CO-Bu, -NH-CO-pentyl, -NH-CO-hexyl, -NH-CO-Ph, -NMe-CO-Me, -NMe-CO-Et, -NMe-CO-Pr, -NMe-CO-Bu, -NMe-CO-pentyl, -NMe-CO-hexyl, -NMe-CO-Ph); a substituted or unsubstituted linear or branched C1-C7alkoxy or aryloxy group (such as –OMe, -OEt, -OPr, -O-i-Pr, -O-n-Bu, -O-i-Bu, -O-t-Bu, -O-pentyl, -O-hexyl, -OCH2F, -OCHF2, -OCF3, -OCH2Cl, -OCHCl2, -OCCl3, -O-Ph, -O-CH2-Ph,-O-CH2-(2,3 or 4)-F-Ph, -O-CH2-(2,3 or 4)-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, -SO2NHEt, -SO2NEt2, -SO2-pyrrolidine-N-yl,-SO2-morpholine-N-yl, -SO2NHCH2OMe,and -SO2NHCH2CH2OMe); a substituted or unsubstituted aminosulfonyl group(such as -NHSO2Me, -NHSO2Et, - NHSO2Pr, -NHSO2iPr, -NHSO2Ph, -NHSO2-(2,3 or 4)-F-Ph, -NHSO2-cyclopropyl, -NHSO2CH2CH2OCH3); a substituted or unsubstituted aromatic group(such as Ph-, 2-F-Ph-, 3-F-Ph-, 4-F-Ph-, 2-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 / or a pair of R5Bgroups attached to different atoms may together form a ring with ring B atoms, and / or a pair of R5Cgroups attached to different atoms may together form a ring with ring C atoms; and / or an R5Cgroup and an R6group attached to different atoms may together form a ring with ring C atoms.

113. The PARP1 inhibitor compound for use according to claim 112, wherein each of R5A(e.g., R5A1, R5A2, R5A3), R5B, and R5Cis independently absent or selected from:H, deuterium, a halogen (such as -F, -Cl, -Br, and -I; preferably F or Cl), a nitrile group, a 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;wherein, when a pair of R5Agroups attached to different atoms together forms a ring with ring A atoms and / or a pair of R5Bgroups attached to different atoms together forms a ring with ring B atoms and / or a pair R5Cgroups attached to different atoms together forms a ring with ring C atoms, the pair of R5A, R5Bor R5Cgroups represents an alkyl group such as -CH2- or -CH2CH2-; or -CH=CH-CH=CH-; or -NH-CO-NH-.

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

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

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

117. The PARP1 inhibitor compound for use according to claim 116, which is for use in treating a cancer.

118. The PARP1 inhibitor compound for use according to claim 117, 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.

119. The PARP1 inhibitor compound for use according to claim 117 or claim 118, wherein the cancer is deficient in a DNA damage response repair pathway, such as Homologous Recombination dependent DNA Double Strand Break DNA repair activity.

120. The PARP1 inhibitor compound for use according to any of claims 117 to 119, wherein the cancer is deficient in BRCA1 and / or BRCA2 function.

121. The PARP1 inhibitor compound for use according to any of claims 117 to 120, 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.

122. The PARP1 inhibitor compound for use according to claim 121, 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 recognitionreceptor 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.

123. A pharmaceutical composition comprising a PARP1 inhibitor compound as defined in any of claims 1 to 115.

124. A pharmaceutical composition according to claim 123, further comprising a pharmaceutically acceptable additive and / or excipient, and / or wherein the compound is in the form of a pharmaceutically acceptable salt, hydrate, acid, ester, or other alternative form of the compound.

125. The pharmaceutical composition according to claim 123 or claim 124, 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.

126. The pharmaceutical composition according to claim 125, 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.

127. The pharmaceutical composition according to any of claims 123 to 126, for use in treating a cancer.

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

129. 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.

130. The method according to claim 129, wherein the patient is an animal, preferably a mammal, optionally a human, canine, equine or feline; and preferably a human.

131. A method of synthesising a PARP1 inhibitor compound as defined in any of claims 1 to 115, 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.

132. A method according to claim 131 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.

133. A method according to claim 121, wherein the reactive group precursor comprises a carbonyl group, an alkyl halide, or an alkyl sulfonate.

134. A method according to any of claims 131 to 133, wherein the reaction comprises alkylation, reductive amination or amide formation so as to form group L.

135. A method according to claim 131, wherein the first reactant comprises rings D, E, ring A, Q1, and ring B, and the second reactant comprises a ring C derivative bearing a leaving group such as a halide or sulfonate.

136. A method according to claim 135, wherein the reaction comprises a nucleophilic substitution reaction, such as a nucleophilic aromatic substitution reaction, so as to form group L.

137. The method according to any of claims 131 to 136, 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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