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GB2630970A - PARP1 inhibitor compounds - Google Patents

PARP1 inhibitor compounds Download PDF

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Publication number
GB2630970A
GB2630970A GB2308970.9A GB202308970A GB2630970A GB 2630970 A GB2630970 A GB 2630970A GB 202308970 A GB202308970 A GB 202308970A GB 2630970 A GB2630970 A GB 2630970A
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group
substituted
ring
unsubstituted
optionally
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Martin Cowley Phillip
Wise Alan
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Duke Street Bio Ltd
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Duke Street Bio Ltd
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Priority to GB2308970.9A priority Critical patent/GB2630970A/en
Priority to PCT/EP2024/066049 priority patent/WO2024256377A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/08—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing alicyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

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  • Organic Chemistry (AREA)
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  • Animal Behavior & Ethology (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A PARP1 inhibitor compound has a structure of: R1 and R­­­4 are independently selected from H and an organic group. R2 and R3 are independently absent, H, or an organic group. Z1 and Z2 are independently C or N. L has the structure: Each X1 is independently selected from C and N. Each X2 is independently selected from C, N, O and S. Integers n, m, p, q, and s are each in a range of 0-6, provided that m + n, p + q, and r + s are each integers in the range of 2 to 6. Each R5a, R5b, R5c, and R6 is independently absent, H, or an organic group. Qa, Qb, Qc are each independently a bond or an organic linker. The compounds are poly(ADP-ribose) polymerase (PARP) inhibitors and are useful in medicine, e.g., for use in treating cancer. Also provided are composition and kits comprising the compounds, and methods of synthesising the compounds.

Description

PARP1 Inhibitor Compounds
Technical Field
The present invention relates to PARP1 inhibitor compounds, and in particular to PARP1 inhibitor compounds for use in medicine. The inhibitors of the invention may be used in pharmaceutical compositions, and in particular pharmaceutical compositions for treating a cancer. The invention also relates to methods of manufacture of such inhibitors, and methods of treatment using such inhibitors.
Background
The family of poly(ADP-ribose) polymerases (PARPs) consists of 17 PARP proteins that catalyse the transfer of ADP-ribose to target proteins, a posttranslational process termed PARylation.
Target protein modification by PARylation causes significant changes to function and as such PARPs play an important role in many cellular processes such as chromatin remodelling, transcription, replication, recombination, cell cycle progression and DNA damage repair (Kamaletdinova, T. etal. Cell. 2019; 8: 1625).
PARP1 and 2 are the most widely studied PARP enzymes, primarily due to their role in DNA damage repair, in particular in the base excision repair (BER) process of DNA single-strand breaks (Ngoi, YL. et al. Cancer J. 2021; 27: 521-528). PARP1 is activated by DNA damage breaks, and the subsequent PARylation of target proteins leads to recruitment of additional factors that initiate repair of DNA lesions. Auto-PARylation of PARP triggers the release of bound PARP from the DNA allowing other DNA repair proteins access to complete lesion repair. This highlights the critical role PARP plays in enabling a cancer cell to repair DNA damage caused by exogenous agents such as radiation therapy and chemotherapeutic agents.
Inhibition of PARP enzymes has been utilised as a strategy to selectively kill cancer cells that harbour genetic defects in complementary DNA damage repair pathways (Farmer, H. et al. Nature. 2005; 434: 917-921). This synthetic lethality approach has been demonstrated successfully in tumours with epigenetic modifications or deleterious mutations in BRCA1 and BRCA2, two functionally redundant tumour suppressor proteins involved in DNA double-strand break (DSB) repair by homologous recombination (HR) (Lord, O. and Ashworth, A. Science. 2017; 355: 1152-1158). Such tumours with HR deficiency (HRD) are dependent on PARP function for survival -following PARP inhibition in these tumours, DSB breaks will be processed by alternative error-prone repair pathways leading to genomic instability and cancer cell death.
The inhibition of PARP can trap the inactivated PARP at the sites of DNA damage. This leads to replication fork stalling and subsequent collapse in S-phase when the fork reaches the site of the trapped PARP, resulting in the generation of genotoxic DNA double-strand breaks. It is believed that this PARP1-DNA trapping can lead to the selective death of cancer cells harbouring HRD (Farmer, H. et al. Nature. 2005; 434: 917-921).
This strategy has led to the successful approval of several PARP inhibitors for the treatment of cancers with HRD, such as in BRCA1/2-mutated breast, ovarian and prostate cancer, as well as in ovarian and prostate cancer harbouring genomic consequences of HRD, and ovarian cancer in the maintenance setting where platinum sensitivity acts as a surrogate for HRD (Fong, PC. et al. N. EngL J. Med. 2009; 361: 123-134).
It has recently been shown that genomic instability, in the form of unrepaired DNA double-strand breaks or micronuclei disruption can trigger innate immune system activation via the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS), leading to generation of cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) and induction of dimerization of Stimulator of interferon genes (STING). STING subsequently translocates from the endoplasmic reticulum to the Golgi where it recruits and activates TANK-binding kinase 1 (TBK1). TBK1 phosphorylates interferon regulatory transcription factor 3 (IRF3) which drives the production of type I interferons and supports the induction of an adaptive immune response (Zhu, V. et at Mat Cancer. 2019, 18: 152).
For example, PARP inhibitor-induced STING pathway activation and anti-tumour immune responses have been demonstrated in multiple tumour models, providing rationale for exploiting combinations of PARP inhibitors with immunotherapies for improved therapeutic efficacy (Sen, T. et at. Cancer Discov. 2019; 9: 646-661). For example, the PARP inhibitor Olaparib was also recently shown to induce synthetic lethal effects in combination with a synthetic cyclic dinucleotide STING agonist in DNA damage repair deficient cancer cells and a BRCA-deficient breast cancer model (Pantelidou, C. et al. 2021: bioRxiv 2021.01.26.428337v1).
Overall, modulation of nucleic acid sensing pathways via multiple mechanisms has been shown to promote anti-tumour efficacy in a variety of cell and animal models thus demonstrating therapeutic potential for augmenting efficacy of immunotherapies and overcoming resistance to immune checkpoint blockade through use of PARP inhibitors. There are numerous clinical trials ongoing combining PARP inhibitors with immunotherapies (reviewed in Chabanon, RM, et at. Nat. Rev. Cancer. 2021; 21: 701-717).
Recently, PARP1 has also been shown to bind the Epstein Barr Virus (EBV) genome and that PARP1 inhibition can alter EBV chromatin structure and latent gene expression (Morgan, SM.
et at Nat. Commun. 2022; 13: 187). Hence, PARP1 inhibitors may play a role in cancers where EBV plays a contributing role such as Burkitt's lymphoma, Hodgkin's lymphoma, nasopharyngeal and gastrointestinal cancers. Interestingly, EBV has also been shown to be a causative factor in multiple sclerosis (MS) whereby EBV infection greatly increases the risk of subsequent MS (Bjornevik, K. et al. Science (2021); 375: 296-301).
First-generation PARP inhibitors generally demonstrate non-selective activity at PARP1 and 2. Haematological toxicities such as anaemia, neutropenia and thrombocytopenia are associated with clinical use of these molecules which restricts their use in combination with cytotoxic chemotherapies and other targeted agents due to dose-limiting cytopenias (LaFargue, C1. et at Lancet °mot 2019, 20, e15-e28). Evidence from pre-clinical mouse studies strongly suggests that PARP2 inhibition is a major driver of these haematological toxicities, with PARP2 being particularly linked to erythrogenesis in mice (Fart, J. et al. Blood. 2013; 122: 44-54). In addition, PARP2 function has been shown to be dispensable for anti-tumour activity in H RD mouse cancer models (Ronson, G E. et al. Nat. Commun. 2018, 9: 746). Taken together, these data suggest an unmet medical need for the development of inhibitors with improved selectivity for PARP1 over PARP2 and other PARPs, thus providing expanded therapeutic utility (1) as single agents and (2) in combination with other anti-cancer agents.
To date, two PARP1-selective inhibitors, AZD5305 and AZD9574, have entered clinic& development. AZDS305 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 at J. Med, Chem. 2021; 64: 1449S14512). importantly, significantly less haematotoxicity was observed for AZD5305 in rodent models than with first-generation PARP inhibitors, confirming the reported pathogenic role 1.0 of PARP2 in haernatologic toxicity (1111.22:1, G. et of, Ctin. Cancer Res 2022; CCR-22-0301).
Having regard to the above, it is an aim of the present invention to provide PARP1 inhibitors, and in particular PARP1 inhibitors for use in medicine. it is a further aim to provide pharmaceutical compositions comprising such inhibitors, and in particular to provide compounds and pharmaceutical compositions for treating a cancer. It is also an aim to provide methods of synthesis of the compounds.
Summary
In one aspect, there is provided a PARP1 inhibitor compound for use in medicine. The PARP1 inhibitor compound has the following structure: R.1 /R4
N
E
wherein: is selected from H and a substituted or unsubstituted organic group; R2 is absent or selected from H and a substituted or unsubstituted organic group; R' is absent or selected from H and a substituted or unsubstituted organic group; R4 is selected from H and a substituted or unsubstituted organic group; Vi and 72 are each independently selected from C and N; and
S
group having the following structure:
A
2/ R5C )X,N I Oh B (Xi)s N, .X3 ac--X / 5B C y( )f) \ R \R5E1)X)r X2 5C 5Cft R 1 so Ga
X
A
(X2)n----X1 5A7 RfiA R5A
R R5C
wherein: each Xi is independently selected from C and N; each X2 is independently selected from C, N, (l) and 5; n is a number selected from 0, 1, 2, 3, 4, S and 6; and m is a number selected from 0, 1, 2, 3, 4, 5 and 6; with the proviso that m n is a number selected from 2, 3, 4, 5, and 6; p is a number selected from 0, 1, 2, 3, 4, 5 and 6; and q is a number selected from 0, 1, 2, 3, 4, 5 and 6; with the proviso that p q is a number selected from 2, 3, 4, 5, and 6; r is a number independently selected from 0, 1, 2, 3, 4, 5 and 6; s is a number independently selected from 0, 1, 2, 3, 4, 5 and 6; with the proviso that r -f s is a number selected from 2, 3, 4, 5, and 6; each V', R55, and fisc is independently absent or selected from H and a substituted or unsubstituted organic group; and RE is absent or selected from H and a substituted or unsubstituted organic group; the lines forming rings A, B and C each independently represent single or double bonds such that each ring is independently saturated, unsaturated, or aromatic; and each of Qa, Qb, and Qc is independently selected from a bond and a group having a structure independently selected from: wherein: t is a number selected from 0, 1, 2, 3, 4 and 5; and u is independently a number selected from 0, 1, 2, 3, 4 and 5; with the proviso that t+ u is a number selected from 0, 1, 2, 3, 4, 5 and 6; and each R1 and Rs is independently selected from H and a substituted or unsubstituted organic group.
Another aspect provides a pharmaceutical composition comprising a PARP1 inhibitor compound as defined herein.
A further aspect provides a pharmaceutical kit for treating a cancer. The kit comprises a PARP1 inhibitor compound as defined herein, and a further agent for treating cancer. The compound and the further agent are suitable for administration simultaneously, sequentially or separately.
Another aspect provides a method of treating a disease and/or a condition and/or a disorder, which method comprises administering to a patient a compound, a composition or a kit as provided herein.
Still another aspect provides a compound selected from: ° N\ HN Ids / \
N N \ / 2ds
NH \ Ny_40 N\ c
N-4cis N °
Nr-\\_,N0\ / N\ /N \ / HN-N N 7cis 1"--N\-4 "IN N-W-^___./ wails rTh N 7trans rJ
NN
NN Sets
INS
Strans Another aspect provides a method of synthesis of a PARP1 inhibitor compound as provided herein. The method comprises conducting a reaction between a first reactant comprising ring E bearing a first portion of group L and a second reactant comprising a remainder of group L, to form the PARP1 inhibitor compound.
This Summary is provided to introduce a selection of concepts in a simplified form that are further described below in the Detailed Description. This Summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used to limit the scope of the claimed subject matter. Nor is the claimed subject matter limited to implementations that solve any or all of the disadvantages noted herein.
Detailed Description
General Definitions The verb 'to comprise' is used herein as shorthand for 'to include or to consist of'. In other words, although the verb 'to comprise' is intended to be an open term, the replacement of this term with the closed term 'to consist of' is explicitly contemplated, particularly where used in connection with chemical compositions.
It will be appreciated that some compounds disclosed herein may be ionisable, i.e. some compounds may be weak acids, weak bases, or ampholytes. Representations of the free forms of ionisable compounds are intended to encompass the corresponding ionised forms. lonisable compounds may be in free form, or in the form of a pharmaceutically-acceptable salt.
A compound is considered to be a PARP1 inhibitor if its presence is capable of preventing or reducing the ability of immobilised PARP1 to undergo auto-poly-ADP ribosylation (AutoPARylation) following incubation with biotinylated-NAD+ as compared to the same process in its absence. Typically, the compound is considered to be a PARP1 inhibitor if it has an ICSO < 10 p.M in a suitable assay. A suitable assay may be conducted using 2 nM PARP1, 2 p.M 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 ICSO < 1 12M, more preferably < 100 nM and most preferably < 10 nM in the PARP1 inhibitor assay.
A compound is considered to be a selective PARP1 inhibitor if its presence is capable of displacing or reducing the ability of a high affinity Cy5 fluorescent dye-labelled chemical probe to bind to PARP1 whilst displacing the same chemical probe at PARP2 with at least 10-fold weaker activity. Typically, the compound is considered to be a selective PARP1 inhibitor if it has an IC50 < 10 p.M 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.
The expression "substituted or unsubstituted organic group" is used herein as a synonym for "substituent". Example organic groups are discussed in more detail hereinbelow.
Where it is said that an organic group is "substituted", it is meant that an H in the organic group is replaced by a further organic group.
A dotted line in a structural formula represents a covalent bond of any appropriate non-zero order, most typically a single bond or a double bond. As will be appreciated, systems comprising multiple double bonds may be conjugated or aromatic.
Except where the configuration of a particular bond is directly illustrated, all formulae herein are shown in non-stereoisomeric form and are intended to represent all possible stereoisomers of a particular structure, including all possible isolated enantiomers corresponding to the formula, all possible mixtures of enantiomers corresponding to the formula, all possible mixtures of diastereomers corresponding to the formula, all possible mixtures of epimers corresponding to the formula and all possible racemic mixtures corresponding to the formula. In addition to this, all formulae herein are intended to represent all tautomeric forms equivalent to the corresponding formula.
The term "aliphatic ring" is used herein in the broad sense of a ring in which all bonds between ring atoms are single bonds. An aliphatic ring may be carbocylic or heterocyclic, and may be substituted or unsubstituted.
Compound numbering Various ones of the compounds provided herein are enantiomeric or diastereomeric. Where a suffix is applied to a compound number, the suffix indicates stereochemistry. A compound number without a suffix denotes a compound having the indicated structural formula without defining stereochemistry.
The suffix tract in a compound number denotes a racemic mixture.
The suffixes 'cis' and 'trans' denotes compounds which are A ring cis and A ring trans, as explained in the section "stereochemistry" hereinbelow. In the case of diastereomeric compounds, the cis and trans suffixes may refer to pairs of diastereomers having the indicated configuration of the A ring. Nuclear Overhauser Effect nuclear magnetic resonance spectroscopy ("NOE NM R") may be used to determine the stereochemistry of compounds as described herein.
The suffix 'a' in a compound number denotes an enantiomer eluted as a first fraction when a mixture of two enantiomers is separated by supercritical fluid chromatography ("SEC") using a chiral column.
The suffix 'b' in a compound number denotes an enantiomer eluted as a second fraction when a mixture of two enantiomers is separated by supercritical fluid chromatography ("SFC") using a chiral column.
Some structural formulae presented herein illustrate stereochemistry assigned by the applicant. In the event of any discrepancy between order of elution (as represented by compound numbering) and assigned stereochemistry, the order of elution takes precedence.
By way of illustration, Example 3 hereinbelow describes the synthesis of compound 6.
Compound 6 is obtained as a mixture of diastereomers. In a first separation step, the diastereomers are separated into two fractions by prep-HPLC. The first fraction to be eluted comprises a pair of enantiomers 6cis-a and 6cis-b. The second fraction comprises a pair of enantiomers 6trans-a and 6trans-b. In a second separation step, the mixture of 6cis-a and 6cis-b is passed through a Regis (R,R)-Whelk-O chiral chromatography column under the conditions indicated above. The first fraction to be eluted in the second separation step comprises compound 6cis-a, and the second fraction comprises compound 6cis-b. Separately, the mixture of 6trans-a and 6trans-b is passed through a Daicel CHIRALPAK chiral chromatography column under the conditions indicated above to obtain compounds 6trans-a (eluted first) and 6trans-b (eluted second).
Discussion Provided herein are PARP1 inhibitor compounds having monocyclic head groups. Also provided are kits and compositions comprising such compounds, and medical uses of the compounds, compositions, and kits.
e PARR' inhibitor compounds have a structure according to the following general formula: wherein: R' is selected from H and a substituted or unsubstituted organic group; R2 is absent or selected from H and a substituted or unsubstituted organic group; R3 is absent or selected from H and a substituted or unsubstituted organic group; R4 is selected from H and a substituted or unsubstituted organic group; Z1 and 22 are each independently selected from C and N; and i. is a group having the following structure: /R4
N 1 E R 4 L r, SA Qa eiRsA N,X1 Rs
I A (X)
S
RS
1X,,),1 06 N, B \ 513
R \ 58 R58
wherein: each X' is independently selected from C and N; each X2 is independently selected from C, N, 0 and S; n is a number selected from 0, 1, 2, 3, 4, 5 and 6; and rn is a number selected from 0, 1, 2" 3, 4, 5 and 6; with the proviso that m n is a number selected From 2, 3, 4, 5, and 6; p is a number selected from 0, 1, 2, 3, 4, 5 and 6; and q is a number selected from 0, 1, 2, 3, 4, 5 and 6; with the proviso that p+ q is a number selected from 2, 3, 4, 5, and 6; r is a number independently selected from 0, 1, 2, 3, 4, 5 and 5; s is a number independently selected from 0, 1, 2, 3, 4, 5 and 6; with the proviso that r s is a number selected from 2, 3, 4, 5, and 6; Rso each R", and Rbc is independently absent or selected from H and a substituted or unsubstituted organic group; and S6 is absent or selected from H and a substituted or unsubstituted organic group; the lines forming rings A, B and C each independently represent single or double bonds such that each ring is independently saturated, unsaturated, or aromatic; and each of Qa, Qb, and Qc is independently selected from a bond and a group having a structure independently selected from: wherein: t is a number selected from 0, 1, 2, 3, 4 and 5; and u is independently a number selected from 0, 1, 2, 3, 4 and 5; with the proviso that t u is a number selected from 0, 1, 2, 3, 4, 5 and 6; and each R' and PO is independently selected from H and a substituted or unsubstituted organic group.
The PARP1 inhibitor compounds provided herein may be selective for PARP1 over PARP2.
Selective inhibition of PARP1 over PARP2 reduces PARP2 associated side effects including one or more haematological toxicities such as anaemia, neutropenia and thrombocytopenia. This may enable treatment of cancer patients with reduced haematological side effects. Alternatively or additionally, this may enable higher doses of PARP1 inhibitors to be administered to patients and for such inhibitors to be administered in combination with chemotherapeutic agents.
The PARP1 inhibitor compounds provided herein have monocyclic head groups. Comparative compounds have bicyclic head groups, with the groups at positions R1 and R2 being fused to form a ring. Without wishing to be bound by theory, it is believed that the PARP1 inhibitor compounds with monocyclic head groups may have improved physicochemical and pharmacokinetic properties, and potentially central nervous system ("CNS") penetrating activity. Compounds provided herein may therefore be particularly useful for the treatment of a cancer of the brain (such as gliomas, glioblastomas, medulloblastomas, craniopharyngioma, ependymoma, and astrocytoma) or spinal cord.
The improved pharmacokinetics and improved CNS penetration may at least in part be due to improved physicochemical properties of the molecules compared to those having bicyclic head groups, as well as modifying the conformation of the molecule: the head groups of bicyclic head groups tend to be flatter and more lipophilic.
The expression "R5 group" refers generally to groups R5A, R55, and RSC. An "R5A" group is an R5 group which is attached to ring A, and so on. Some of the formulae presented herein use more specific identifiers for R5 groups. For example, "115A1" identifies a subset of R5A groups.
In the compounds provided herein, various ones of the FV, R3, and R5 groups may be absent, with dotted lines in the structural formulae presented herein representing covalent bonds of any non-zero order. As will be appreciated, the number of ring bonds and the number of substituents are selected such that the V-, 22, )(1, and X2 atoms maintain a stable valency. Maintaining a stable valency means ensuring that an atom has its normal (typically most common) valency in organic compounds (i.e. 2 for oxygen; 2 or 6 for sulfur; 3 or 4 for nitrogen; and 4 for carbon).
When an)(1 or X2 atom is N, that atom most preferably has a valency of 3. Compounds in which an X' or X2 atom is tetravalent N are also contemplated. Tetravalent N is positively charged, and such compounds may have a counterion.
Typically, each of rings A, B, and C includes at most a single tetravalent N. Preferably, the PARP1 inhibitor compound includes at most one tetravalent N, and more preferably no tetravalent N. Each R5 group may be absent or present, and may be the same or different. For the avoidance of doubt, where the number of R5 groups may vary according to the choice of corresponding X group, the following provisos typically apply: i) When an X1 is N, its corresponding R5 is absent.
ii) When an X1 is C and is double bonded to an adjacent ring atom, its corresponding R5 is absent.
iii) When an X1 is C and is not double bonded to an adjacent ring atom, its corresponding R5 is present.
iv) When an X2 is 0, its corresponding R5 / R6 groups are both absent.
v) When an X2 is 5, its corresponding R5 /R6groups are both absent or are both selected from =0 and =NV, where R10 is H or a substituted or unsubstituted organic group, preferably a C1 to C3 alkyl group.
vi) When an X2 is N and is doubled bonded to an adjacent ring atom, the or each corresponding R5 / R6 is absent.
vii) When an X2 is N and not doubled bonded to an adjacent ring atom, exactly one corresponding R5 / R6 is present.
viii) When an X2 is C and is double bonded to an adjacent ring atom, exactly one corresponding R5 / R6 is present.
ix) When an X2 is C and is not double bonded to an adjacent ring atom, both corresponding R5 groups or both the corresponding R5 and R6 are present.
The substituents (i.e. R groups; R1, R2, R3, R4, R5, R6, R7, and R8) are not especially limited, provided that they do not prevent the PARP1 inhibitory function from occurring. The substituents are selected from H and a substituted or unsubstituted organic group. Thus, both above and in the following, the terms 'substituent' and 'organic group' are not especially limited and may be any functional group or any atom, especially any functional group or atom common in organic chemistry.
Any R5 or R6 group may form a ring with any other R5 or R6 group 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 R54 with another RSA; an le with another R56; an Rc with another Rsc; or an R5c with 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 / R6 groups attached to the same atom do not together form a ring, although this is not excluded.
The PARP1 inhibitor compounds provided herein have monocyclic head groups. None of R1, R2, R3, and R4 forms a ring with any other R group.
A single R5 or R6 group on an atom, or two R5 / R6 groups on the same atom, may form a group which is double bonded to that atom. Accordingly, an R5 or R6 group, or two R5 / R6 groups attached to the same atom, may together form a =0 group, or a =C(1112 group (wherein each R' group is the same or different and is H or an organic group, preferably H or a straight or branched C1-05 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=0 group or a C=C(R')2 group. Thus in some cases an X2 group which is C may bear a =0 group.
substituents and 'organic group' may have any of the following meanings.
The organic group may comprise any one or more atoms from any of groups IIIA, IVA, VA, VIA or VIIA of the Periodic Table, such as a B, Si, N, P, 0, or S atom (e.g. OH, OR, NH2, NHR, NR2, SH, SR, SO2R, SO3H, P041-12) or a halogen atom (e.g. F, CI, Br or I) where R is a linear or branched lower hydrocarbon (1-6 C atoms) or a linear or branched higher hydrocarbon (7 C atoms or more, e.g. 7-40 C atoms).
The organic group preferably comprises a hydrocarbon group. The hydrocarbon group may comprise a straight chain, a branched chain or a cyclic group. Independently, the hydrocarbon group may comprise an aliphatic or an aromatic group. Also independently, the hydrocarbon group may comprise a saturated or unsaturated group.
When the hydrocarbon comprises an unsaturated group, it may comprise one or more alkene functionalities and/or one or more alkyne functionalities. When the hydrocarbon comprises a straight or branched chain group, it may comprise one or more primary, secondary and/or tertiary alkyl groups.
When the hydrocarbon comprises a cyclic group it may comprise an aromatic ring, a non-aromatic ring, an aliphatic ring, a heterocyclic group, and/or fused ring derivatives of these groups. The ring may be fully saturated, partially saturated, or fully unsaturated. The cyclic group may thus comprise a benzene, naphthalene, anthracene, phenanthrene, phenalene, biphenylene, pentalene, indene, as-indacene, s-indacene, acenaphthylene, fluorene, fluoranthene, acephenanthrylene, azulene, heptalene, pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyrrolidine, furan, oxetane, tetrahydrofuran, 2-azatetrahydrofuran, 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-y1 and the like, and these are specified explicitly where appropriate. All tautomeric ring forms are included in these definitions. For example pyrrole is intended to include 1H-pyrrole, 2H-pyrrole and 3H-pyrrole.
The number of carbon atoms in the hydrocarbon group is not especially limited, but preferably the hydrocarbon group comprises from 1-40 C atoms. The hydrocarbon group may thus be a lower hydrocarbon (1-6 C atoms) or a higher hydrocarbon (7 C atoms or more, e.g. 7-40 C atoms). The lower hydrocarbon group may be a methyl, ethyl, propyl, butyl, pentyl or hexyl group or regioisomers of these, such as isopropyl, isobutyl, tert-butyl, etc. The number of atoms in the ring of the cyclic group is not especially limited, but preferably the ring of the cyclic group comprises from 3-10 atoms, such as 3, 4, 5, 6, 7, 8, 9 or 10 atoms.
The groups comprising heteroatoms described above, as well as any of the other groups defined above, may comprise one or more heteroatoms from any of groups IIIA, IVA, VA, VIA or VIIA of the Periodic Table, such as a B, Si, N, P, 0, or S atom or a halogen atom (e.g. F, CI, Br or I). Thus, the substituent may comprise one or more of any of the common functional groups in organic chemistry, such as hydroxy groups, carboxylic acid groups, ester groups, ether groups, aldehyde groups, ketone groups, amine groups, amide groups, imine groups, thiol groups, thioether groups, sulfate groups, sulfonic acid groups, sulfonyl groups, and phosphate groups etc. The substituent may also comprise derivatives of these groups, such as carboxylic acid anhydrides and carboxylic acid halides.
In addition, any substituent may comprise a combination of two or more of the substituents and/or functional groups defined herein.
Typically, when one or more of R1, R2, R3, R4, RSA (e.g., R5A1, R5A2, R5A3), R5B, RSC (e.g., R50), R6, R7, R51, and R52 is a substituted or unsubstituted organic group, the or each substituted or unsubstituted organic group is independently selected from: deuterium; a halogen (such as -F, -CI, -Br and -I); a nitrile group; a substituted or unsubstituted linear or branched Ci-C6 alkyl group (such as Me, Et, Pr, i-Pr, n-Bu, i-Bu, t-Bu, pentyl and hexyl); a substituted or unsubstituted linear or branched Ci-C6 alkyl-aryl 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)I-Ph, -CH2CH2Ph, -CH2CH2CH2Ph, -CH2CH2CH2CH2Ph, -CH2CH2CH2CH2CH2Ph, and -CH2CH2CH2CH2CH2CH2Ph); a substituted or unsubstituted linear or branched Ci-C6 halogenated alkyl group (such as -CH2F, -CH2CI, -CH2Br, -0121, -CHF2, -CF3, -CCI3 -CBr3, -CI3, -CH2CH2F, -CH2CF3, -CH2CCI3, -CH2CBr3, and -CH2CI3); NH2 or a substituted or unsubstituted linear or branched primary secondary or tertiary Cs-C6 amine group (such as -NMeH, -NMe2, -NEtH, -NEtMe, -NEt2, -NPrH, -NPrMe, -NPrEt, -NPr2, -NBuH, -NBuMe, -NBuEt, -CH2-NH2, -CH2-NMeH, -CH2-NMe2, -CH2-NEtH, -CH2-NEtMe, -CH2-NEt2, -CH2-NPrH, -CH2-NPrMe, and -CH2-NPrEt); a substituted or unsubstituted amino-aryl group (such as -NH-Ph, -NH-(2,3 or 4)F-Ph, -NH-(2,3 or 4)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)C12-Ph, -NH-2,(3,4,5 or 6)Br2-Ph, -NH-2,(3,4,5 or 6)12-Ph, -NH-2,(3,4,5 or 6)Me2-Ph, -NH-2,(3,4,5 or 6)Et2-Ph, -NH-2,(3,4,5, or 6)Pr2-Ph, -NH-2,(3,4,5 or 6)Bu2-Ph), a substituted or unsubstituted cyclic amine or amido group (such as pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, 2-keto-pyrrolidinyl, 3-keto-pyrrolidinyl, 2-keto-piperidinyl, 3-keto-piperidinyl, and 4-keto-piperidinyl); a substituted or unsubstituted cyclic C3-Ca alkyl group (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl); an -OH group; a substituted or unsubstituted linear or branched CI-Cs alcohol group (such as -CH2OH, -CH2CH2OH, -CH(CH3)CH2OH, -C(CH3)20H, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, -CH(CH3)CH2CH2OH, -CH(CH3)CH(CH3)0H, -CH(CH2CH3)CH201-1, -C(CH3)2CH2OH, -CH2CH2CH2CH2CH2OH, and -CH2CH2CH2CH2CH2CH2OH); a substituted or unsubstituted linear or branched Ci-C6 carboxylic acid group (such as -COOH, -CH2COOH, -CH2CH2COOH, -CH2CH2CH2COOH, -CH2CH2CH2CH2COOH, and -CH2CH2CH2CH2CH2COOH); a substituted or unsubstituted linear or branched carbonyl group (such as -(CO)Me, -(CO)Et, -(CO)Pr, -(CO)iPr, -(CO)nBu, -(CO)iBu, -(CO)tBu, -(CO)Ph, -(CO)CH2Ph, -(CO)CH2OH, -(CO)CH2OCH3, -(CO)CH2NH2, -(CO)CH2NHMe, -(CO)CH2NMe2, -(CO)-cyclopropyl, -(CO)-1,3-epoxypropan-2-yl; -(CO)NH2, -(CO)NHMe, -(CO)NMe2, -(CO)NHEt, -(CO)NEt2, -(CO)-pyrollidine-N-yl, -(CO)-morpholine-N-yl, -(CO)-piperazine-N-yl, -(CO)-N-methyl-piperazine-N-yl, -(CO)NHCH2CH2OH, -(CO)NHCH2CH2OMe, -(CO)NHCH2CH2NH2, -(CO)NHCH2CH2NHMe, and -(CO)NHCH2CH2NMe2); a substituted or unsubstituted linear or branched Ci-C6 carboxylic acid ester group (such as -COOMe, -COOEt, -COOPr, -COO-i-Pr, -COO-n-Bu, -COO-i-Bu, -000-t-Bu, -CH2COOMe, -CH2CH2COOMe, -CH2CH2CH2COOMe, and -CH2CH2CH2CH2COOMe); a substituted or unsubstituted linear or branched Ci-C6 amide group (such as -CO-NH2, -CO-NMeH, -CO-NMe2, -CO-NEtH, -CO-NEtMe, -CO-NEt2, -CO-NPrH, -CO-NPrMe, and -CO-NPrEt); a substituted or unsubstituted linear or branched Ci-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 Ci-C7 alkoxy or aryloxy group (such as -0Me, -OEt, -OPr, -0-i-Pr, -0-n-Bu, -0-i-Bu, -O-t-Bu, -0-pentyl, -0-hexyl, -OCH2F, -OCHF2, -OCF3, -OCH2CI, -OCHCl2, -OCCI3, -0-Ph, -0-CH2-Ph, -0-CH2-(2,3 or 4)-F-Ph, -0-CH2-(2,3 or 4)-CI-Ph, -CH20Me, -CH20Et, -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, -502Et, -SO2Pr, -SO2iPr, -SO2Ph, -S02-(2,3 or 4)-F-Ph, -S02-CYCIOPrOPYI, -S020-120-1200-13, -SO2NH2, -SO2NHMe, -SO2NMe2, -SO2N H Et, -SO2N Et2, -502-pyrrolidine-N-yl, -502-morpholine-N-yl, -SO2NHCH2OMe,and -502NHCH2CH20Me); a substituted or unsubstituted aminosulfonyl group (such as -NHSO2Me, -NHSO2Et, -NHSO2Pr, -NHSO2iPr, -NHSO2Ph, -NHS02-(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-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)-12-Ph-, 2,(3,4,5 or 6)-Mee-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)-b-Ph-, 3,(4 or 5)-Me2-Ph-, 3,(4 or 5)-Et2-Ph-, 3,(4 or 5)-PrrPh-, 3,(4 or 5)-Bu2-Ph-, 3,(4 or 5)-(CN)2-Ph-, 3,(4 or 5)-(NO2)2-Ph-, 3,(4 or 5)-(NH2)2-Ph-, 3,(4 or 5)-(MeO)2-Ph-, 3,(4 or 5)-(CF3)2-Ph-, 2-Me-Ph-, 3-Me-Ph-, 4-Me-Ph-, 2-Et-Ph-, 3-Et-Ph-, 4-Et-Ph-, 2-Pr-Ph-, 3-Pr-Ph-, 4-Pr-Ph-, 2-Bu-Ph-, 3-Bu-Ph-, 4-Bu-Ph-, 2-(CN)-Ph-, 3-(CN)-Ph-, 4-(CN)-Ph-, 2-(NO2)-Ph-, 3-(NO2)-Ph-, 4-(NO2)-Ph-, 2-(NH2)-Ph-, 3-(NH2)-Ph-, 4-(NH2)-Ph-, 2-MeO-Ph-, 3-MeO-Ph-, 4-MeO-Ph-, 2-(NH2-CO)-Ph-, 3-(NH2-CO)-Ph-, 4-(NH2-CO)-Ph-, 2-CF3-Ph-, 3-CF3-Ph-, 4-CF3-Ph-, 2-CF3O-Ph-, 3-CF3O-Ph-, and 4-CF3O-Ph-); a saturated or unsaturated, substituted or unsubstituted, heterocyclic group, optionally an aromatic heterocyclic group or a non-aromatic heterocyclic group (such as pyrrole-1-yl, pyrrole-2-yl, pyrrole-3-yl, pyrazole-1-yl, pyrazole-3-yl, pyrazole-4-yl, pyrazole-5-yl, imidazole-1-yl, imidazole-2-yl, imidazole-4-yl, imidazole-5-yl, 1,2,3-triazole-1-yl, 1,2,3-triazole-4-yl, 1,2,3-triazole-5-yl, 1,2,4-triazole-1-yl, 1,2,4-triazole-3-yl, 1,2,4-triazole-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazine-3-yl, pyridazine-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, pyrazine-2-yl, pyrrolidine-1-yl, pyrrolidine-2-yl, pyrrolidine-3-yl, piperidine-1-yl, piperidine-2-yl, piperidine-3-yl, piperidine-4-yl, 2-azapiperidine-1-yl, 2-azapiperidine-3-yl, 2-azapiperidine-4-yl, 3-azapiperidine-1-yl, 3-azapiperidine-2-yl, 3-azapiperidine-4-yl, 3-azapiperidine-5-yl, piperazine-1-yl, piperazine-2-yl, furan-2-yl, furan-3-yl, pyran-2-yl, pyran-3-yl, pyran-4-yl, 2-azapyran-2-yl, 2-azapyran-3-yl, 2-azapyran-4-yl, 2-azapyran-5-yl, 2-azapyran-6-yl, 3-azapyran-2-yl, 3-azapyran-4-yl, 3-azapyran-5-yl, 3-azapyran-6-yl, 4-azapyran-2-yl, 4-azapyran-3-yl, 4-azapyran-4-yl, 4-azapyran-5-yl, 4-azapyran-6-yl, oxetan-2-yl, oxetan-3-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-2-yl, 2-aza-tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-4-yl, 2-aza-tetrahydrofuran-5-yl, 3-aza-tetrahydrofuran-2-yl, 3-aza-tetrahydrofuran-3-yl, 3-aza-tetrahydrofuran-4-yl, 3-aza-tetrahydrofuran-5-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, 2-aza-tetrahydropyran-2-yl, 2-aza-tetrahydropyran-3-yl, 2-aza-tetrahydropyran-4-yl, 2-aza-tetrahydropyran-5-yl, 2-aza-tetrahydropyran-6-yl, 3-aza-tetrahydropyran-2-yl, 3-aza-tetrahydropyran-3-yl, 3-aza-tetrahydropyran-4-yl, 3-aza-tetrahydropyran-5-yl, 3-aza-tetrahydropyran-6-yl, morpholine-2-yl, morpholine-3-yl, morpholine-4-yl, thiophen-2-yl, thiophen-3-yl, isothiazole-3-yl, isothiazole-4-yl, isothiazole-5-yl, thiazole-2-yl, thiazole-4-yl, thiazole-5-yl, thiopyran-2-yl, thiopyran-3-yl, thiopyran-4-yl, 2-azathiopyran-2-yl, 2-azathiopyran-3-yl, 2-azathiopyran-4-yl, 2-azathiopyran-5-yl, 2-azathiopyran-6-yl, 3-azathiopyran-2-yl, 3-azathiopyran-4-yl, 3-azathiopyran-5-yl, 3-azathiopyran-6-yl, 4-azathiopyran-2-yl, 4-azathiopyran-3-yl, 4-azathiopyran-4-yl, 4-azathiopyran-5-yl, 4-azathiopyran-6-yl, thiolane-2-yl, thiolane-3-yl, thiane-2-yl, thiane-3-yl, thiane-4-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, furazan-3-yl, (1,3,4-oxadiazol)-2-y1, (1,3,4-oxadiazol)-5-y1, (1,2,4-oxadiazol)-3-y1, (1,2,4-oxadiazol)-5-y1; and tetrazole-1-yl, tetrazole-2-yl, tetra zol e-5-y1).
A pair of RSA groups attached to different atoms may together form a ring with ring A atoms.
A pair of R56 groups attached to different atoms may together form a ring with ring B atoms.
A pair of RSC groups attached to different atoms may together form a ring with ring C atoms.
An 125c group and an R6 group attached to different atoms may together form a ring with ring C atoms.
R5 groups (RSA, such as R5A1, R5A2, R5A3; R58; or Rsc, such as liscl) may in particular be absent or selected from: H, deuterium, a halogen (such as -F, -CI, -Br, and -I; preferably F or CI), a nitrile group, a substituted or unsubstituted Cl-C6 alkyl group, a substituted or unsubstituted linear or branched Ci-C6 halogenated alkyl group (preferably CF3 or CHF2), a cyclopropyl group, an -OH group, a substituted or unsubstituted linear or branched Ci-C6 alcohol group, a substituted or unsubstituted linear or branched Ci-C7 amino carbonyl group (such as -NH-CO-Me), an -NH2 group, a substituted or unsubstituted CE-05 amino group, and a substituted or unsubstituted alkoxy group.
When a pair of ils4 groups attached to different atoms together forms a ring with ring A atoms and/or a pair of Ra3 groups attached to different atoms together forms a ring with ring B atoms and/or a pair Fe groups attached to different atoms together forms a ring with ring C atoms, each of the pair of R", or Rs' groups independently comprises -CH2-or -CH2CH2-, or the pair of groups together comprise -CH=CH-Cl-lz---CH-or -NH-CO-NH-.
1.0 Ring F Ring E (also referred to as the 'head group") of the compounds provided herein has a structure of: where: 71 and 72 are each independently selected from C and N; R' is selected from H and a substituted or unsubstituted organic group; 11-2 is absent or selected from H and a substituted or unsubstituted organic group; R3 is absent or selected from H and a substituted or unsubstituted organic group; and is selected from H and a substituted or unsubstituted organic group.
Ring E may have a structure of:
N L
R1, R2 and R4 each being independently selected from H and a substituted or Alternatively, ring E may have a structure of: R3 R1, R3 and R4 each being independently selected from H and a substituted or unsubstituted organic group; Preferably, ring E has a structure of: R1, R2, R3 and R4 each being independently selected from H and a substituted or unsubstituted organic group.
Generally, the following provisos apply to the selection of R2 and R3: R2 is absent when Z1 is N. R2 is selected from H and a substituted or unsubstituted organic group when Zi is C. R3 is absent when Z2 is N. R3 is selected from H and a substituted or unsubstituted organic group when Z1 is C. R1 and R2 may each be independently selected from: H; a Cl to C6 alkyl, aminoalkyl, alkoxy or haloalkyl group; a C3 to C6 cycloalkyl group; a halogen group; and wherein R" is selected from H, a Cl to C6 alkyl, cycloalkyl, alkoxy, or haloalkyl group, and a halogen group, and each R' is independently selected from H and a substituted or unsubstituted organic group, and each Rn is preferably selected from H, a C1 to C6 alkyl, a minoalkyl, alkoxy or haloalkyl group, and a halogen group. Usually, at least one R'3 is H. In most implementations, at least one of R= and R' is not H. Preferably, R' is a substituted or unsubstituted organic group and R2 is H. Preferably, at least one of R', R2, R3 and R" is selected from -CH 3, -CH2CH3,-CH2C1-12CH3, -CH2F, -CHF2, CFa, -F, Cl,--CH2CF3, -CH2CH2F, -CH)CH)OH, methoxy, methoxymethyl, methoxyethyl, isopropyl, cyclopropyl or cyclopropylmethyl.
R23 R 23 At least one of H'and R2 may be R22, with each R23 being independently selected from H, F, Cl to C3 alkyl, and C1 to 0 fluoroalkyl.
R' may in particular be selected from H C1 to C3 alkyl, C1 to C3 alkoxy, and Cl.to C3 haloalkyl. Most preferably, R= is an ethyl group.
R2 may in particular be selected from H, CH3, -CH2CH3, -CH2CH2CH:3, -CH2F, -CHF2, -Ch, -F, -Cl, -CH2CF3, -CH2CH2F, -CH2CH2OH, methoxy, methoxymethyl, methoxyethyl, isopropyl, cyclopropyl and cyclopropylmethyl. R2 is most preferably H. 13' may in particular be selected from H, halogen, Cl to C3 alkyl, Cl to C3 haloalkyl, Cl to alcohol, and Cl to C3 aminoalkyl. is most preferably H. IV may in particular be selected from H, Cl to C3 alkyl, and Cl to C3 R4 is most preferably H. In one class of example compounds, V and Z.1 are each C; and 112 and R3 are each independently selected from H, Cl to C3 alkyl, and Cl to C3 haloalkyl. In compounds of this class, and R3 are optionally each H. The E ring may have a structure selected e FaC ?8 and The most preferred E ring has the structure: Rings A, B, and C-general Rings A and C are each independently carbocylie or heterocyclic.
Variable atoms which are part of the skeleton of the A, B and C rings are generically referred to as "X" atoms. Each X1 atom is independently selected from C and N. Each X2 atom is independently selected from C, N, 0, and S; with C and N being particularly preferred.
Each X' and X2 atom is independently selected. One or more, and most preferably all, of the following provisos may apply: Typically, at least one X group per ring is C. When an A, B or C ring is 4-membered, that ring typically includes at most one heteroatorn. When an A, B or C ring is 5 or 6-membered, that ring typically includes at most three heteroatoms, optionally at most two heteroatorns.
Each of rings A, B, and C individually may comprise at most three heteroatoms.
The compound is typically not a quaternary ammonium compound. An X' atom which is N typically does not bear an group. An Xi-atom which is N typically bears at most one R group.
The compound is free of 0-0, S--5, and 5-0 bonds between X? atoms. When an Xis 0 or 5, its adjacent ring atoms are C or N. More generally, the compound may be free of 0-0 bonds and S-5 bonds.
Ring A Ring A of the PARP1 inhibitor compound has the general structure R5A2 R5A3 Xlikt is the Xiatom that is connected to ring E via linker Qa, and X'4 is the X1 atom that is connected to ring B via linker Qb. XM denotes an X2 atom which is part of ring A. X" may be C or N, and is preferably C. When Qa is and ut--0, X' is C, When X" is N, Rs' is typically absent X' may be C or N, and is preferably C. 5A2 t5A2 -.7\v/AE ey\ 2A-2 3A1-;-",' )rn I, A 2A lAS (X)n X Oh R5A2' Rings A and B are most typically not connected via an N-N bond. To thisend, when Qb is a R7 R.7 R7 R7 bond or R8 and Pr:0, Xim is C. When is N, it'^3 is typically absent.
Each X' atom is independently selected from C, N, 0, and S; with C and N being particularly preferred. The X" groups are selected such that ring A is free of 0-0, 0-S, and S-S bonds.
Particularly preferably, all of the X" atoms are C. Ring A is a 4, 5, 6, 7, or 8 membered ring. To this end, n is 0 or an integer in the range 1 to 6; m is 0 or an integer in the range Ito 6, and n and m sum to an integer in the range 2 to 6.
In particular, ring A may be a 4, 5, or 6 membered ring, and is preferably a 5 or 6 membered ring. Put differently, n+m may sum to an integer in the range 2 to 4.
Preferably, both n and m are at least 1. In other words, it is preferable for X'Ar and X'AB to be 1.5 non-adjacent.
The R1' groups (a)m, R5', and Rs") are each independently absent or selected from H and a substituted or unsubstituted organic group. Ring A may be a saturated ring, an unsaturated non-aromatic ring, or an aromatic ring depending upon the number of R" groups present.
In most implementations, no more than one of he R" groups is a substituted or unsubstituted organic group.
When an R5A group is present, that RSA group is most preferably H, Ring A may for example have structure of formula: 5A2 R \ R5A2 R5A1
IA
A.- IT3 -:---\\ Qa< C\:______ 9. ri i:5A3 j R5A2 k 5A2 where: m is 1 or 2; n is 1 or 2, each and R independently is absent or selected from H and a substituted or i) X1 is C and W41 is absent or selected from H and a substituted or unsubstituted organic group; or ii) X1 is N and it'm is absent. In such compounds, ring A is preferably an aliphatic ring (i.e., all bonds between X atoms are single bonds) and R543 is H. Optionally, each R5A2 is H. Particularly preferably, ring A may have a structure selected from: Qb b a ic Qb Qb and In other examples, ring A is a substituted or unsubstituted 7-membered aliphatic carbocycle or heterocycle, optionally a cycloheptane, further optionally a cycloheptane having structure selected from: each RSA and RsA3 being independently selected from H and a substituted or unsubstituted organic group, wherein 0'3 is most preferably H. Alternatively, ring A may be a substituted or unsubstituted 6-membered aliphatic carbocycle or heterocycle, optionally a cyclohexane or tetra hydropyran and further optionally having a structure selected from: b unsubstituted organic group, wherein le'n is most preferably H.
RSA 5A$ asA R5A R5A
5A 'RSA R5A3
REA
RSA R5A
RSA3 being independently each R5A and selected Qa R5A Qb Qa R5A ob Qa Qt.) -R5A3 5A R5A R 5A Qh Qb R5A3 R5A \, 3A R5A and R5A. A Qa RoA R5A R5A3 R5A
RSA R5A Rm. R5A fi 5A
In accordance with another possibility, ring A may be a substituted or unsubstituted 5-membered aliphatic carbocycle or heterocycle, optionally a cyclopentane, cyclopentene, or a tetrahydrofuran, and further optionally having a structure selected from: each RSA and Rs" being independently selected from H and a substituted or unsubstituted organic group, wherein R51-\-3 is most preferably H, In still further examples/ ring A may be a 5-membered aromatic ring, optionally a pyrrole or pyrazole, and further optionally having a structure selected from:
RSA RSA N"c
l\ab \ 0 rs ---c r\i R N--\-,Qb --. Oh 5A each fl'. being independently selected Ffraonmd RHSA 'N/ organic group, b 05A ' Qa 5A3
R
R
R5A 5A Qa b
R --Qb
A
RSA Qa Qa --Qb and R5A A 5Aa 0 R R5A R5A R5A
Other example compounds include those in which ring A is a substituted or unsubstituted cyclobutane, optionally having a structure of: Oa each RSA and RS' being independently selected from H and a substituted or unsubstituted organic group, wherein Rs'' is most preferably H. More specific examples of ring A structures include: -Oh, or Ring B Ring B of the PARP1 inhibitor compound has a structure of: R5B2 Ri3e2 pt., jr C. / B ',. Isc Oh, \ N, to, ..x, 'r Oc J \ ' (X 2i) 5B3 4-)
R /
R R \ * 582 x 5R2 X1 is the X' atom thatis connected to ring C via linker Qc. X' denotes an)(2 atom which is part of ring B. X' may be C or N and is preferably N. When X'" is N, 8663 is typically absent.
Rings 6 and C are most typically not connected via an N-N bond. When Qc is R7 R7 R7 R7 and tr-0, X' is C. When Qc is a bond, no more than one of Xilic and nes is N. Each X23 atom is independently selected from C, N, 0, and 5; with C and N being preferred. The X26 atoms are selected such that ring B is free of 0-0, 0-S, and S-S bonds. Particularly preferably, all of the X26 atoms are C.
S
Ring B may be a 4, 5, 6, 7, or 8 membered ring. To this end, p is 0 or an integer in the range 1 to 6; q is 0 or an integer in the range 1 to 6, and p and q sum to an integer in the range 2 to 6.
In particular, ring B may be a 5 or 6 membered ring, and is particularly preferably a 6 membered ring. Put differently, p and q may sum to 3 or 4, preferably 4.
Preferably, both p and q are at least 1. In other words, X"' is preferably not adjacent to the N atom that connects to linker Qa.
When is a 6-membered ring, it is preferable for p to be 2 and q to be 2.
The R43 groups (R"2, R'') are each independently absent or selected from H and a is independently absent or selected from H and a substituted or unsubstituted organic group. Ring B may be a saturated ring, an unsaturated non-aromatic ring, or an aromatic ring depending upon the number of R55 groups present. Ring B is preferably a saturated heterocycle.
In most implementations, no more than one of the R3 groups is a substituted or unsubstituted organic group.
When an R" group is present, that 1.15 group is most preferably H. Preferably, all R" groups are present and all R" groups are H. Ring B may be a 7-membered saturated heterocyclic ring, optionally a homopiperazine having N Qc R58 R R so 5B each Rss being independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R" is H.
R
a structure: ScR R5 Alternatively, ring B may be a 6-membered saturated heterocyclic ring, optionally a piperazine, further optionally a piperazine having a structure: 58 s R R.5 5E. N R50
R R
each 1,15El being independently selected from H and a substituted or unsubstituted organic group, optionally wherein each fis' is H. In accordance with another possibility, ring B may be a 5-membered saturated heterocyclic ring, optionally an imidazolidine, further optionally an imidazolidine having a structure:
R NSA
Ob4 N QC --N 8515 8 1. R5 / RSb
each RS being independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5' is H. It is particularly preferred for ring B to have a structure of: tic Ring C Ring C of the PARP1 inhibitor compound has a structure of: Qc tr R5C1 8502 XF, (,12011:
C
12C 1 2C ), R5C250.2 1
R b02
X-La denotes the XI atom of ring C which connects ring B via linker Qc. >Cc denotes an Xz atom of ring C. X'" may be C or N, and is preferably C. When Xla is N, R5C1 is typicalIy absent.
When Qc is a bond. X1CC is C. and u=0, Xla' is N. When at XIK of ring B is N and c is Ring C may be a 4, 5, 6, 7, or 8 membered ring. To this end, r is 0 or an integer in the range 1 to 6; s is 0 or an integer in the range 1 to 6, and r and s sum to an integer in the range 2 to 6.
It is preferable for each of r and s to be at least 1.
In particular, ring C may be a 5 or 6 membered ring, and is particularly preferably a 6 membered ring. Put differently, p and q may sum to 3 or 4, preferably 4.
Ring C may be a 6-membered aliphatic ring, optionally membered aliphatic ring having structure: RR5C 5r" -/
R R5C R5C R6
5C 5C
R
each R5 and Rsci being independently selected from H and a substituted or unsubstituted organic group, preferably wherein is H, more preferably wherein R5I-1 and each fist is H. Alternatively, ring C may be a 6-membered aromatic ring, optionally selectedfrom:: iia} a phenyl group, optionally having formula: each being independently selected from H and a substituted or unsubstituted organic group, optionally wherein each Rsc is H; lib) a pyridine group, optionally having a formula selected from: each Rs' being independently selected from H and a substituted or unsubstituted organic group, optionally wherein each W't is H; and iic) a diazine group, optionally having a formula selected from: tic
N Re R5C
N
N 5C
R
N kR s
Qe-IN Qc each RC being independently selected from H and a substituted or unsubstituted organic group, optionally wherein each Rsc is H. In further examples, ring C may be a 5-membered aromatic ring, optionally selected frorn: ilia) an imidazole group, optionally an imidazole group having a structure of: FR R5C 5C;
N
and Rs each Rsc being independently selected from H and a substituted or unsubstituted organic group, optionally wherein each it' is ft iiib) a thiophene group, optionally having a structure selected from: R5C R5C y-r S. C5 and R each RC being independently selected from H and a substituted or unsubstituted organic group, optionally wherein each Rsc is H;.
iiic) a thiazole group, optionally having a structure selected from: R6 Rsc
S R5C and
each RSC being independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R5 is H; and iiid) a triazole, optionally a triazole of or ula: 7R6 \ -N 5C 13' being selected from H and a substituted or unsubstituted organic group, optionally wherein RSC is H. in particular, ring C may have a structure selected from: R$
N
CN 4c
It s preferable for ring C to be a 6-membered aromatic In particular, ring C may have a structure of' R5C2o 75 c2m jecm \z,> R6 where: R5C2° is selected from H and a halogen; and i) )(2' is C and R5c2 is H; or ii) e'm is N and R5c2"4 is absent.
Preferably, R'2" is a halogen, with F being the preferred halogen.
In the PARKinhibitor compounds provided herein, R5 is absent or selected from H and a substituted or unsubstituted organic group. Preferably, R5 is selected from H, -F, -CI, -Br, -I, -CN, -CONR53R51, -NR51COR52, -50-2NR51R53, -NR51502R57, -0-CR521152R52, -CR52R52NR5IR5L and any of the following structures: R52 R51 R51 R52 52 W52
N
N
R52 R52 wherein R5' and R52 are each independently selected from H and a substituted or unsubstituted organic group. RS' and Rs2 are preferably each independently selected from H, a halogen, Cl to C3 alkyl, and Cl to C3 haloalkyL For example, Rst and R52 may each be H. In particular, R6 may be selected from -F, -CI, -CN, -CONH2, -CONHMe, -CONHEt, -CONMe2, -CONHCOMe, -CONHC112-CH2CIMe, -CONH-Chb-CH,,F, -CONH-CH2-CFs, -CONH-CH2-CHF2, -OCHF2, -NHCOMe, -NHSO2Me, -SO2NHMe, -CONR502Nle,
H N y N-0 and
The most preferred R6 groups are CONHMe (i.e. NH}and 0 H Where a compound, L group, or C ring substructure is depicted as having 1:16 CONHMe, replacement of the R6 group vwith is contemplated. Likewise, where a compound, L group, or C ring substructure is depicted as having R6 7--0, replacement of the R6 group with CONHMe is contemplated.
In some examples, Rh and one R5c group together form a ring. For example, ring C may have a structure selected from: NH 0 Typically however, ring Cis not a fused ring system and no R"group forms a ring with another R" or R6 group.
Linkers (Q groups) As shown in the formula below, the E, A, B, and C rings are connected by linkers Qa, Qb, and Qc:
NH R4 ( E
5A2 5A2 Z Oa R "#,R IAC 2A R)(1) A 2A (X),--X1AB Ob N, B,X Q 2B: \ 555 R R5A2 R15A3 95'2 5B2
R
R-R
582 8582 Ft 26 R'5C1 )q 5C2 #.(2C)f--X2 R R 502 \ 5C2 3C2 The linkers may be referred to herein generically as "0 groups". Qa, fib, and Qc and rings A to C may be referred to collectively as group L Each linker is independently selected from a bond and a group having a structure independently selected from: where: t is a number selected from 0, 1, 2, 3, 4 and 5; and Li 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, a, 4, S and 6; and each R' and Ra is independently selected from H and a substituted or unsubstituted organic group.
When a Q group is R, t and u are selected such that the Q group connects to the rings via C-N bonds and not N-N bonds, Typically, t is at least 1 and u is at least 1.
For example, at least one of Qa, Qb, and Qc may be: where t u is at least one; and where R' is selected from H, a halogen (such as -F, -Cl, -Br, and -I, preferably -F), a substituted or unsubstituted CI-Cr, alkyl group, a substituted or unsubstituted linear or branched Ca--Cu halogenated alkyl group (preferably CF3), an -NH2 group or a substituted or unsubstituted Cr-
N
Cs amino group, an -OH group or a substituted or unsubstituted linear or branched Or-C6 alcohol group and a substituted or unsubstituted CI-C6 alkoxy group.
In particular, R7 may be selected from H, a halogen (preferably F), a substituted or unsubstituted CI-C, alkyl group or a substituted or unsubstituted linear or branched Ca-C& halogenated alkyl group.
When at least one of Oa, Ob and Qc has a structure of: le may be selected from H; a substituted or unsubstituted linear or branched C1-C6 alkyl group {such as Me, Et, Pr, i-Pr, n-Bu, 1-Bus t-Bu, pentyl and hexyl); a substituted or unsubstituted linear or branched 0-0 alkyl-aryl group {such as -CH7Ph, -CH2{2,3 or 4)F-Ph, -CH2{2,3 or 4)0-Ph, -017(2,3 or 4)Br-Ph, -CH7(2,3 or 4)I-Ph, -CH2CH2Ph, -CH2CH2CH2Ph, -CH7CH7CH2CH7Ph, -CH2CH7CH7CH7CH7Ph, and -CH2CH7CH7CH2CH7CH7Ph); a substituted or unsubstituted linear or branched Cr-Cr, halogenated alkyl group {such as -CH2F, -CF3, -Cf-I2CH7F and -CH7CF3); a substituted or unsubstituted cyclic amine or amide group (such as pyrroliclin-3-y, piperidin-3-yl, piperidin-4-yl, 2-keto-pyrrolidinyl, 3-keto-pyrroliclinyl, 2-keto-piperidinyl, 3-keto-piperidinyl, and 4-keto-piperidinyl); a substituted or unsubstituted cyclic Cs-Cx alkyl group {such as cyclopropyl, cyclobutyl, cycloheptyl, cyclohexyl, cycloheptyl and cyclooctyl); a substituted or unsubstituted linear or branched C7-0, alcohol group (such as -CH7CHAOH, -CH(C117)CH7OH, -C(CH7)20H, -CH7CH7CH7OH, R7 R7 R7 R7 / -CH2CH2CH2CH2OH, -CH(CH3)CH2CH2OH, -CH(CH3)CH(CH3)0H, -CH(CH2CH3)CH2OH, -C(CH3)2CH2OH, -CH2CH2CH2CH2CH2OH, and -CH2CH2CH2CH2CH2CH2OH); a substituted or unsubstituted linear or branched C2-Cs 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, -(C0)-i_Pr, -(CO)-n-Bu, -(CO)-i-Bu, -(CO)-t-Bu, -(CO)Ph, -(CO)CH2Ph, -(CO)CH2OH, -(CO)CH2OCH3, -(CO)CH2NH2,-(CO)CH2NHMe, -(CO)CH2NMe2, -(CO)-cyclopropyl, -(CO)-1,3-epoxypropan-2-yl; -(CO)NH2, -(CO)NH Me -(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-C6 carboxylic acid ester group (such as -COOMe, -COOEt, -COOPr, -COO-i-Pr, -000-n-Bu, -000-i-Bu, -COO-t-Bu, -CH2COOMe, -CH2CH2COOMe, -CH2CH2CH2COOMe, and -CH2CH2CH2CH2COOMe); a substituted or unsubstituted linear or branched Ci-Cs 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, -5021Pr, -SO2Ph, -502-(2,3 or 4)-F-Ph, -SO2-cyclopropyl, -5020-120-120a13), -SO2NH2, -SO2NHMe, -SO2NMe2, -502NHEt, -SO2NEt2, -502-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-I-Ph-, 3-I-Ph, 4-I-Ph-, 2,(3,4,5 or 6)-F2Ph-, 2,(3,4,5 or 6)-Cl2-Ph-, 2,(3,4,5 or 6)-Br2-Ph-, 2,(3,4,5 or 6)-12-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)-Buz-Ph-, 2,(3,4,5 or 6)-(CN)2-Ph-, 2,(3,4,5 or 6)-(NO2)z-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)-BuzPh-, 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, rnorpholine-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, thlopyran-3-yl, thiopyran-4-yl, 2-azathiopyran-3-yl, 2-azathlopyran-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-azathlopyran-2-yl, 4-azathiopyran-3-yl, 4-azathiopyran-5-yl, 4-azathiopyran-6-yl, thiolarie-2-yl, thiolane-3-yi, thiane-2-yl, thiane-3-yl, thiane-4-yl, oxazoi-2-yl, oxazol-4-yl, oxazol-S-yl, isoxazol-3-yl, isoxazol-S-y, furazan-3-yl. (1,3,4-oxadiazol)-2-yl, (1,3,4-oxadiazol)-S-yl, (1,2,4-oxadiazol)-3-yl, (1,2,4-oxadiazol)-5-y1; and tetrazole-5-y1).
In particular, 13' may be selected from H, a substituted or unsubstituted Cb-Ct: alkyl group or a substituted or unsubstituted linear or branched Cr-C{, halogenated alkyl group.
Optionally, Qa is a bond or -air, and preferably Oa is a bond. Group L may have a structure of: 5A -"/ Oa 5A N 1,7 R5A. (X)rn
A )2 7(
R SA R5A 5B R /Rs° 2 (X)1 N B,X), \ 5B C (X-)D R 2; 2 R5B,R55 X Sc R5C R5C R60
I I 2 5C I
and optionally group L may have a structure of:
SA
Oa R \ 5A R5AfX (X')rn
A R R5B
(X, )q BOc X\ )p R \ 58 R50 R" 2 C * \5C R5C (X2)
H
Optionally, Ob is a bond or -CH2-, and preferably Qb is a bond. Optionally, Qc is a bond or -CH2-, and preferably Qc is a bond.
Preferably, Qa, Qb and Qc are each independently selected from a bond and CH2-. Most preferably, Qa, Qb, and Qc are each bonds.
Group L of the PARPinhibitor compound Stereochemistry Various ones of the PARP1 inhibitor compounds provided herein may include one or more chiral centres.
Without wishing to be bound by theory, it is believed that the configuration of rings E and t3 with respect to the A ring may influence the activity of the PARP1 inhibitor compound.
In the context of the present disclosure, where it is said that a PARP1 inhibitor compound is "A ring cis" or has a cis configuration of the A ring this means that the L group of the compound has a structure of:
RSA
R5A R56 ASS (X2f, X, } (X2),---- B 'x ----- AI,,' 2/ \ sis h) R R5 A / \ R5B,R50 where ring A is a saturated or unsaturated aliphatic carbocycle or heterocycle.
Where it is said that a PARP1 inhibitor compound is "A ring trans" or has a trans configuration of the A ring, this means that the L group of the compound has a structure of: Nh(;)
R A Sc 1 R5 1 F 2
X (X),
X
RSC
RSA
X------(X R5 R5A R58 / SX2,),1 R5C RISC. f SC
-. i R Qb-N. B X: Qc X1 (X2), 2/ \ R bfi X \ )p C \R 2 2 X)r-- R6
SE 5C,
R5.'7; where ring A is a saturated or unsaturated aliphatic carbocycle or heterocycle, In examples where ring A is a saturated &membered ring (n+m = 4, optionally n=m=2), the compound is preferably A ring cis. in such compounds, the A ring cis isomer may display greater PARP1 inhibition activity than the corresponding A ring trans isomer.
In examples where ring. A is a saturated 5-membered ring (n+m = 3), the compound is preferably A ring trans. In such compounds, the A ring trans isomer may display greater PARP1 inhibition activity than the corresponding A ring cis isomer. S4
In some of the compounds provided herein, ring A is an aromatic ring. When ring A is aromatic, the PARP1 inhibitor compound is neither A ring cis nor A ring trans.
The PARP1 inhibitor compounds described herein may be provided in the form of an isolated enantiomer, a mixture of two or more enantiomers, a mixture of two or more diastereomers and/or epimers, or a racemic mixture.
Example L groups
In particular, group L may have a structure of:
R R
5A2 5A2 RSA2 R5A1 (C)n--RSA2 AE 7 R 5C.2M (Cr 6 R5C2o (CH 2)ci \ 2G14 5A3 \ / \ )5 -N-- Br, \ /// N B xl R \ / -R5D3 \ (CH2)0 where: m is 1 or 2; n is 1 or 2; C and Rsm is H, or XI is N and R54 is absent; each R542 is independently absent or H; R543 is absent or H; p is 1 or 2; q is 1 or 2; XI' is C and R5 is H, or KIK is N and 11533 is absent; fisc2° is H or a halogen, optionally F; X2CM is N and Rsum is absent, or X2CM is C and R52CM is H; and
H N
elected from NH and 0 In particular, p may be 2 and q may be 2, such that group L has a structure of:
SS R5C2M
5A2 5A2 \,-R 1 7 -1\--1E \ ) /I R5C2o X AA (Cm /' R5A1 j (0)n -----G-Nil' B \ x 5A2,----R5 \ j \ A2 - 8593 Preferably, X11 is N and 11.3 is absent.
Ring A is preferably selected from: cyclabutyl, cyclopentyl, cyclohexyl, cyclopent nyl, and cyclohexenyl.
When ring A is a saturated 5-membered ring (e.g.; cyclopentyl), the compound is preferably A ring trans.
When ring A is saturated 6-membered g., cyclohexyl), the compound is preferably A ring cis.
M - N 0 \2,".7) N\
N N
11N, optionally N\,/ /N-\\ y) 1211N-* optionally /IN Group L may in particular be selected from: rTh -N 0 N N \..
(o-besciesi HN, optionally N °
N
HN-ii) iii)
N N
C
N
HN
optionally
RN HN-
n\j-C24N °
Example Compounds
Example PARP1 inhibitor compounds provided herein include those having a structure of:
AE R, 1 3
"." -----t. 582 582 R5Al. A R \ 7 R5C2o (611-----a)C)g -' * -----, .,., \\ -N, bi* ex R5A2 RriA2 R5A3 \ z \ (C) \ Ha3 g' R 8532 R 532 \ 582 where: C\N IN N\
H N
optionally viii) vii) 1-N-optionally n
N
R23e 9
NH
R R5C2M
each R." is independently selected from H or a halogen (e.g., F); R22 is selected from H, methyl, and halomethyl (e.g" CH2F, CHF2, CF Z2 is C and 1.12 is H, or Z2 is N and R2 is absent; m is 1 or 2; n is 1 or 2; X" is C and fisAi is absent or H, or XIAE is N and R'" is absen each Rs' is independently absent or H; RS" is absent or H; p is 1 or 2; q is 1 or 2; Xlsc is C and Rs" is H, or Xl6c is N and R583 is absent; 1.0 Rsr-2" is H or a halogen, optionally F; X2" is N and R' is absent, or X2" is C and Rs'is H; and 0
SS A
N
R6 is elected from ' NH and 0 Preferably, each R'' is H and R" is methyl.
Preferably, Z2 is C and R3 is H. Preferably, X' is C and RsAl is H. Ring A is preferably selected from cyclobutyl, c clopentyl, cyclohexyl, cyclopentenyl and cyclohexenyl When ring A is a saturated 5-membered ring (e.g., c clopentyl)" the compound is preferably A ring trans.
When ring A is a saturated 6-membered ring (e.g., cyclohexyl), the compound is preferably A ring cis.
Ring B is preferably a piperazine: The PARP1 inhibitor compound may in particular have a structure selected from:
N
\ -N 0 N \
HN-
NH
kis 2cis
NH N N \ \
\ HN-4th ° r-N N \ f HN-6cis
N N r'i / \ Nc
\ N- HN-NH 0 N \ 6trans oN N 7trans
O tra N \ kis
F rTh
P \ I HN -<1 Reis
NH
IN N
Btrans Medical Uses The compounds described herein may be for use in medicine. In the context of the present invention, the medicinal use is not especially limited, provided that it is a use which is facilitated by the PARP1 inhibitory effect of the compound. Thus, the compounds of the invention may be for use in any disease, condition or disorder that may be prevented, ameliorated or treated using a PARP1 inhibitor.
In particular, the PARP1 inhibitor compound may be for use in treating a cancer. The nature of the cancer is not especially limited, provided that the cancer is one which may be treated, prevented or ameliorated by using a PARP1 inhibitor. The cancer may comprise a solid or liquid tumour.
For example, the cancer selected from: a cancer of the eye, brain (such as gliomas, glioblastomas, medulloblastomas, craniopharyngioma, ependymoma, and astrocytoma), spinal cord, kidney, mouth, lip, throat, oral cavity, nasal cavity, small intestine, colon, parathyroid gland, gall bladder, head and neck, breast, bone, bile duct, cervix, heart, hypopharyngeal gland, lung, bronchus, liver, skin, ureter, urethra, testicles, vagina, anus, laryngeal gland, ovary, thyroid, oesophagus, nasopharyngeal gland, pituitary gland, salivary gland, prostate, pancreas, adrenal glands; an endometrial cancer, oral cancer, melanoma, neuroblastoma, gastric cancer, an angiomatosis, a hemangioblastoma, a pheochromocytoma, a pancreatic cyst, a renal cell carcinoma, Wilms' tumour, squamous cell carcinoma, sarcoma, osteosarcoma, Kaposi sarcoma, rhabdomyosarcoma, hepatocellular carcinoma, PTEN Hamartoma-Tumor Syndromes (PHTS) (such as Lhermitte-Duclos disease, Cowden syndrome, Proteus syndrome, and Proteus-like syndrome), leukaemias and lymphomas (such as acute lymphoblastic leukaemia, chronic lymphocytic leukaemia, acute myelogenous leukaemia, chronic myelogenous leukaemia, hairy cell leukaemia, T-cell prolymphocytic leukaemia (TPLL), large granular lymphocytic leukaemia, adult T-cell leukaemia, juvenile myelomonocytic leukaemia, Hodgkin lymphoma, non-Hodgkin lymphoma, mantle lymphoma, follicular lymphoma, primary effusion lymphoma, AIDS-related lymphoma, diffuse B cell lymphoma, Burkitt lymphoma, cutaneous T-cell lymphoma, nasopharyngeal and gastrointestinal cancers.
In addition, the compounds described herein may be of use in cancers where Epstein Barr Virus, EBV, plays a contributing role such as Burkitt's lymphoma, Hodgkin's lymphoma, nasopharyngeal and gastrointestinal cancers.
The compounds described herein may be provided for use in for treating a cancer which is deficient in DNA damage response repair pathways, in particular in Homologous Recombination ("HR") dependent DNA Double Strand Break ("DSB") DNA repair activity. Components of HR dependent DNA DSB repair pathways and other DNA damage response pathways include but are not limited to the following proteins: ATM, ATR, ERCC1, XRCC1, XRCC2, XRCC3, RAD51, RAD51L1, RAD51C, RAD51D, RAD51L3, DMC1, RAD52, RAD54L, RAD54B, RAD50, MRE11A, NBS1, BRCA1, BRCA2, FANCP (SLX4), FEN1, PALB2, PBRM1, SMARCA4,ARID1A, ARID1B, FANCD2, BLM. Other components involved in HR dependent DNA DSB repair include regulatory factors such as ESMY (Hughes-Davies, L. et at Cell. 2003; 115: 523-535). A cancer which is deficient in HR-dependent DNA DSB repair typically becomes dependent on alternative DSB pathway repair mechanisms. Such cancers include but are not limited to cancers of the ovary, prostate, breast, lung, gastrointestine, blood and pancreas.
The cancer cells may have a BRCA1 and/or BRCA2 deficient phenotype, i.e. the cancer cells may be deficient in BRCA1 and/or 2 function. The deficiency may arise by means of mutation, polymorphism or epigenetic silencing in the encoding nucleic acids or by means of mutation, polymorphism, amplification in a gene encoding a regulatory factor, e.g. the ESMY gene which encodes a BRCA2 regulatory factor (Hughes-Davies, L. et at 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 at Oncogene. 2002; 21: 8981-93) and their detection, as a means of patient selection, is well known in the art (Radice, Pl. et at Exp. Clin. Cancer. Res. 2002; 21: 9-12; Chappnis, PO and Foulkes WO. Cancer Treat Res. 2002; 107: 29-59).
The compounds provided herein may be administered to a patient who is undergoing radiotherapy and/or chemotherapy using a further agent for treating cancer.
For example, the PARP1 inhibitor compound may be administered in conjunction with a further agent for treating cancer.
The further agent for treating cancer may be selected from: anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase I inhibitors, topoisomerase II inhibitors, antimetabolites, senolytic agents, hormones and hormone analogues, signal transduction pathway inhibitors, other DNA damage repair pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, antibody-drug conjugates, immunotherapeutic agents, hormone deprivation therapy, proapoptotic agents, radioligand therapies, anti-angiogenic agents, and cell cycle signalling inhibitors.
In particular, the further agent may comprise an immunotherapeutic agent selected from: an anti-tumour vaccine; an oncolytic virus; an immune stimulatory antibody such as anti-CTLA4, anti-PD1, anti-PDL-1, anti-0X40, anti-41BB, anti-CD27, anti-CD40, anti-LAGS, anti-TI M3, and anti-GITR; a pattern recognition receptor agonist such as a STING, TLR-9 or RIG-I Helicase agonist; an IDO or TDO inhibitor; a novel adjuvant; a peptide; a cytokine; a chimeric antigen receptor T cell therapy (CAR-T); a small molecule immune modulator; and a tumour microenvironment modulator.
Pharmaceutical Compositions Another aspect provides a pharmaceutical composition comprising the PARP1 inhibitor compound as defined above.
Typically, the composition includes a pharmaceutically acceptable additive and/or excipient.
In the pharmaceutical composition, the PARP1 inhibitor compound as defined above may be present in the form described above, but may alternatively be in a form suitable for improving bioavailability, solubility, and/or activity, and/or may be in a form suitable for improving formulation. Thus, the compound may be in the form of a pharmaceutically acceptable salt, hydrate, acid, ester, or other alternative suitable form.
Typically, the composition is for use in medicine, e.g. for use in treating a disease, condition or disorder as defined above.
For example, the pharmaceutical composition may be for use in treating a cancer. The composition may further comprise a further agent for treating cancer. The further agent for treating cancer is not especially limited, provided that it affords some utility for cancer treatment.
The further agent for treating cancer may comprise one or more chemotherapeutic agents such as anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase I inhibitors, topoisomerase II inhibitors, antimetabolites, senolytic agents, hormones and hormone analogues, signal transduction pathway inhibitors, other DNA damage repair pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, antibody-drug conjugates, immunotherapeutic agents, hormone-deprivation therapies, proapoptotic agents, radioligand therapies, anti-angiogenic agents, and cell cycle signalling inhibitors.
In particular, the further agent for treating cancer may comprise an immunotherapeutic agent selected from: an anti-tumour vaccine; an oncolytic virus; an immune stimulatory antibody such as anti-CTLA4, anti-PD1, anti-PDL-1, anti-0X40, anti-41BB, anti-CD27, anti-CD40, antiLAG3, anti-TIM3, and anti-GITR; a pattern recognition receptor agonist such as a STING, TLR9 or RIG-I Helicase agonist; an IDO or TDO inhibitor; a novel adjuvant; a peptide; a cytokine; a chimeric antigen receptor T cell therapy (CAR-T); a small molecule immune modulator; and a tumour microenvironment modulator. Kits
Another aspect provides a pharmaceutical kit for treating a cancer. The pharmaceutical kit comprises a PARP1 inhibitor compound as defined herein, and a further agent for treating cancer. The compound and the further agent are suitable for administration simultaneously, sequentially or separately.
The further agent for treating cancer may be any of the further agents for treating cancer identified above in the discussion of the pharmaceutical composition.
In particular, the further agent for treating cancer may comprise one or more chemotherapeutic agents selected from: anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase I inhibitors, topoisomerase II inhibitors, antimetabolites, senolytic agents, hormones and hormone analogues, signal transduction pathway inhibitors, other DNA damage repair pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, antibody-drug conjugates, hormone-deprivation therapies, radioligand therapies, antiangiogenic agents, immunotherapeutic agents (such as selected from an anti-tumour vaccine, an oncolytic virus, an immune stimulatory antibody such as anti-CTLA4, anti-PD1, anti-PDL-1, anti-OX40, anti-4166, anti-CD27, anti-CD40, antiLAG3, anti-TIM3, and anti-GITR, a pattern recognition receptor agonist such as a STING, TLR- 9 or RIG-I Helicase agonist, an IDO or TDO inhibitor, a novel adjuvant, a peptide, a cytokine, a chimeric antigen receptor T cell therapy (CAR-T), a small molecule immune modulator, tumour microenvironment modulators), proapoptotic agents and cell cycle signalling inhibitors.
Methods of Treatment Another aspect of the invention provides a method of treating a disease and/or a condition and/or a disorder, which method comprises administering to a patient (or subject) a PARP1 inhibitor compound, or a composition, or a kit as defined herein. The method is typically a method for treating any disease condition or disorder mentioned herein. In typical embodiments, the method is a method for treating a cancer.
The patient may be any animal, preferably a mammal. For example, the patient may be a human, canine, equine or feline; and is preferably a human.
The method may comprise administering to the patient (or subject) a compound or a composition as defined above and a further agent for treating cancer as defined above. The compound or composition and the further agent may be administered simultaneously, sequentially or separately, depending upon the agents and patients involved, and the disease to be treated (e.g., the type of cancer to be treated).
The patient may be undergoing treatment using ionising radiation.
Methods of synthesising PARP1 inhibitor compounds Also provided are methods for synthesising the PARP1 inhibitor compounds as defined herein.
In general, the method comprises conducting a reaction between: (i) a first reactant comprising ring E bearing a first portion of group L, and (ii) a second reactant comprising a remainder of group L, to form the PARP1 inhibitor compound. The skilled person may select reaction conditions with reference to known synthesis techniques depending on the appropriate starting materials. The method may comprise one or more additional steps.
Exemplary synthesis methodology is shown in the Examples hereinbelow.
In one example method, the first reactant comprises ring E and ring A, and the second reactant comprises a Qb precursor bearing a reactive group, which method comprises joining ring A to the Qb precursor. In this method, the reactive group of the Qb precursor may comprise a carbonyl group, an alkyl halide, or an alkyl sulfonate. The reaction may comprise alkylation, reductive amination. or amide formation so as to form group L. In another example method, the first reactant comprises ring E, ring A, Qa, and ring B, and the second reactant comprises a ring C derivative bearing a leaving group such as a halide or sulfonate. In this method, the reaction may comprise a nucleophilic substitution reaction, such as a nucleophilic aromatic substitution reaction, so as to form group L. A particularly preferred method is for synthesising PARP1 inhibitor compound where L. is a group having a structure of: sA
R Oa 5A
R 1 2--
-X- (X)rn
A (X2C
R5Ar 5A H R5B Rye N, BOp )X2fp \ R55 B \R5B In the preferred method, the first reactant a structure of: --a R5A 0R Ri.-"0 " .__ / '---'clN R2---72 qa 5A R5A RSA where R9 is a protecting group. R9 is most typically a methyl group. Other examples of protecting groups include acetyl, tert-butyl, benzoyl; benzyl; p-methoxyberszyl; pmethoxyphenyl, methoxyrnethyl, ethoxyethyl, rnethoxyethoxymethyl; methylthiorriethyl, trityl; methoxytrityl; dimethoxytrityl, plyaloyl, tetrahydropyranyl, tetrahydrofuran, and sily1 groups (such as trimethylsilyl, tert-butyldimethyisilyl, tri-iso-propylsilyloxymethyl, and triisopropylsilyI).
The second reactant in the preferred method has a structure of: R5B R58 X2) H----N B' 2" \5B X JD R RSB \ B RwC r.
In the preferred method, conducting the reaction comprises: i) coupling the first reagent and the second reagent using a reducing agent in the presence of an acid to obtain an intermediate product having a structure of: 0 R \ /2 R fr -it 1,x2
R : I E'
2-Z1...;,-..,,_ "...X..., R -22 Qa (5A t 3 RsA ' \ R 11 RSA \R5A R5A R5 5B 5B R (X2), x2 R5C \ i R 5C * 2 V, )q R6 / \ B:X1 -----N,, Oc -X1 2 R58 (X) R R5B/ \ '56 x2)i.
R
58/ Rk 5c, 5C land ii) subsequently deprotecting ring to form the PARP1 inhibitor compound.
The reducing agent and acid used in step i) may be selected as appropriate. Examples of suitable reducing agents include sodium borohydride, sodium cyanoborohydride, and sodium triacetoxyborohydride. The acid may be a weak acid, optionally a weak organic acid such as acetic acid.
The conditions used for deprotection step ii) may be selected as appropriate based on the nature of the protecting group Rs. For example, in implementations where Rs is a methyl group, deprotection may be performed trimethylsilyi iodide ("TM.Si") or boron trihromide in an appropriate solvent (such as dichioromethane. acetonitrile, or chloroform). Other acids or Lewis acids may be used.
In some implementations of the preferred method, rings A, B', and B are all saturated rings, and optionally the X1 of rings B and B' is N. The PARPI 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.
Examples
Example 1: Synthesis of 3rac (1) NaNta), HCI, Rp., 0 'C 1003 117r4NAN 1-"A., -sti i (2) -ffi. H20, 6 'C to 60 t:I I, Pd{cIppftC-1,-DC09. Na2CO, ">#2< 'Br iDNIF,11"0, 65"C 1001 1002 Br Ht.}
LJ cy%
1005 RuPhos Pd G3, '500Na Dionne. 10.0 "C. seated tube r conc. Ha H P&92 "C MOH. rt HC] 1000 1006 HN st'i--..tal 0 1007 14t-NaRH3C11 AcOH tvle0H. 50 'C N Q 1360t rZ =" EXPA, c "C to n 7-is\ f 'k:*-Nj HN 3rac S SCHEME 1 Preparation of 6-bromo-3-iodo-2-methoxypyridine (1002) The following three solutions A-C were prepared: A: a solution of NaNO2 (3.4 g, 0.049 mol) in H2O (100 mL).
B: a solution of 6-bromo-2-methoxypyridin-3-amine 1001 (10 g, 0.049 mol) in conc. HCI: H2O = 1:1 (80 mL).
C: a solution of KI (24.56 g, 0.15 mol) in H2O (450 mL).
A was added to B dropwise at 0 *C. The reaction mixture was stirred at 0 °C for 20 min. Then the reaction mixture was added to C dropwise at 0 *C. The mixture was heated at 60 °C for 2 h. The resulting mixture was diluted with water (200 mL) and extracted with EtOAc (500 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with EtOAc/PE, 0 % to 50 %) to give 6-bromo-3-iodo-2-methoxypyridine 1002 (8.9 g, 90 % purity, 58 % yield) as a white solid.
LCMS (ESI) calcd for C5H5BrINO [M + H] m/z 313.86, no MS signal found.
Preparation of 6-bromo-2-methoxy-3-vinylpyridine (1004) To a solution of 6-bromo-3-iodo-2-methoxypyridine 1002 (1 g, 0.0032 mol) in DMF/H20 = 5:1 (50 mL) was added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane 1003 (0.50 g, 0.0032 mol), Na2CO3 (1.01 g, 0.0096 mol) and Pd(dppf)Cl2*DCM (0.26 g, 0.00032 mol) under N2. The mixture was heated at 65 *C for 2 hours. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with EtOAc/PE, 0% to 100%) to give 6-bromo-2-methoxy-3-vinylpyridine 1004 (600 mg, 90 % purity, 78 % yield) as a white solid.
LCMS (ESI) calcd for C8H8BrNO [M + HI m/z 213.98, no signal found Preparation of 7-(6-methoxy-5-vinylpyridin-2-y1)-1,4-dioxa-7-azaspiro[4.4jnonane (1006) To a solution of 6-bromo-2-methoxy-3-vinylpyridine 1004 (600 mg, 0.0028 mol) and 1,4-dioxa-7-azaspiro[4.4]nonane 1005 (0.41 g, 0.0031 mol) in Dioxane (20 mL) was added tBuONa (0.89 g, 0.0084 mol) and RuPhos Pd G3 (0.24 g, 0.00024 mol) in a sealed tube. The mixture was heated at 100 °C for 2 hours. The resulting mixture was concentrated and purified by silica gel column chromatography (eluting with EtOAc/PE, 0% to 100%) to give 7-(6-methoxy5-vinylpyridin-2-y1)-1,4-dioxa-7-azaspiro[4.4]nonane 1006 (250 mg, 90% purity, 30% yield) as a white solid.
LCMS (ESI) calcd for C141-118N203 [M + H] * m/z 263.13, found 262.92.
Preparation of 7-(5-ethy1-6-methoxypyridin-2-0)-1,4-dioxa-7-azaspiro(4.41nonane (1007) To a solution of 7-(6-methoxy-5-vinylpyridin-2-yI)-1,4-dioxa-7-azaspiro[4.4]nonane 1006 (250 mg, 0.96 mmol) in Me0H (20 mL) was added 10% Pd/C (25 mg). The mixture was evacuated and backfilled with hydrogen three times and then charged with hydrogen. The resulting mixture was stirred at room temperature for 2 hours. Then the mixture was filtered through celite and concentrated under vacuum to give crude 7-(5-ethyl-6-methoxypyridin-2-y1)-1,4-dioxa-7-azaspiro[4.4]nonane 1007 (250 mg, 90 % purity, 90 % yield) which was used directly in next step without further purification.
LCMS (ESI) calcd for C1ahlzoN203 [M + H] m/z 265.15, found 264.95.
Preparation of 1-(5-ethyl-6-methoxypyridin-2-yl)pyrrolidin-3-one (1008) A solution of 7-(5-ethyl-6-methoxypyridin-2-y1)-1,4-dioxa-7-azaspiro[4.4]nonane 1007 (200 mg, 0.76 mmol) in conc. HCI (12 mL) was stirred at 50 °C for 12 h. Then the resulting mixture was adjusted to pH 7-8 with aq. NaHCO3 and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated to give crude 1-(5-ethyl-6-methoxypyridin-2-yl)pyrrolidin-3-one 1008 (130 mg, 90 % purity, 70 % yield) as a white solid.
LCMS (ESI) calcd for C12F136N202 [M + h1]* m/z 221.12, found 221.20.
Preparation of 5-(4-(1-(5-ethyl-6-methoxypyridin-2-yllpyrrolidin-3-yllpiperazin-1-0) -Nmethylpicolinamide (1010) To a solution of 1-(5-ethyl-6-methoxypyridin-2-yl)pyrrolidin-3-one 1008 (120 mg, 0.45 mmol) and N-methyl-5-(piperazin-1-yl)picolinamide 1009 (117 mg, 0.45 mmol) in Me0H (10 mL) was added AcOH (0.1 mL). Then NaBH3CN (29 mg, 0.45 mmol) was added to the mixture. The mixture was heated at 50 °C for 1 hour. The resulting mixture was quenched with water (1 mL), concentrated, and purified by silica gel column chromatography (eluting with Me0H/DCM, 0 % to 10 %) to give 5-(4-(1-(5-ethy1-6-methoxypyridin-2-yl)pyrrolidin-3-yl)piperazin-1-y1) -N-methylpicolinamide 1010 (100 mg, 90 % purity, 38 % yield) as a white solid.
LCMS (ESI) calcd for C23H32N602 [M + H] m/z 425.26, found 425.25.
Preparation of 5-(4-(1-(5-ethyl-6-oxo-1, 6-dihydropyridin-2-Opyrrolidin-3-yllpiperazin-1-15 y1)-N-methylpicolinamide (3rac) To a solution of 5-(4-(1-(5-ethy1-6-methoxypyridin-2-yOpyrrolidin-3-yflpiperazin-1-y1) -Nmethylpicolinamide 1010 (100 mg, 0.24 mmol) in DCM (10 mL) was added BBr3 (118 mg, 0.47 mmol) at 0 °C. The mixture was stirred at rt for 2 hours. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by prep-HPLC (Gemini 5 pm C18 column, 150 x 21.2 mm, eluting with 5 % to 95 % MeCN/H20 containing 0.1% FA) to give 5-(4-(1-(5-ethy1-6-oxo-1,6-dihydropyridin-2-yl)pyrrolidin-3-yl) piperazin-1-y1)-N-methylpicolinamide 3rac (11.9 mg, 99% purity, 13% yield) as a white solid.
1H N MR (400 MHz, DMSO-d5, ppm) 5: 10.20 (s, 1 H), 8.44-8.36 (m, 1 H), 8.28 (d, J = 2.4 Hz, 1 H), 7.83 (d, J = 8.8 Hz, 1 H), 7.44-7.37 (m, 1 H), 7.11 (d, J = 7.6 Hz,1 H), 5.39 (s, 1 H), 3.65-3.57 (m, 1 H), 3.52-3.42 (m, 1 H), 3.37-3.33 (m, 3 H), 3.30-3.22 (m, 2 H), 3.19-3.09 (m, 1 H), 2.94 (d, J = 4.8 Hz, 1 H), 2.78 (d, J = 4.8 Hz, 3 H), 2.68-2.60 (m, 2 H), 2.60-2.53 (m, 2 H), 2.34-2.25 (m, 2 H), 2.23-2.14 (m, 1 H), 1.89-1.77 (m, 1 H), 1.03 (t, J = 7.4 Hz, 3 H).
LCMS (ESI) calcd for C22H3oN602 [M + H] * m/z 411.24, found 411.25.
Example 2: Synthesis of 4cis 1009 FIN, NaBH3CN, HOAc. MeOhl,
N MsCI
TEA, DCM, Et to rt THF, -78 'C Pd/C, H2 Me0H, rt., 2 h Dess-Martin DCM, rt, 2 h 1106 1105 NL. TM&
N
ACN. rt 4cis SCHEME 2 Preparation of 3-(benzyloxy)-15-ethy1-6-methoxypyridin-2-yOcyclabutan-1-of (1103) To a solution of 6-bromo-3-ethyl-2-methoxypyridine 1101 (800 mg, 12.41 mmol) in THE (15 mL) was added n-Buli (2.5 M in hexane, 2.22 mL, 5,55 mmol) dropwise at -78°C under an atmosphere of N2. After addition, the solution was stirred at -78'C for 30 minutes. Then 3- (benzyitaxy)cyclobutan-l-one (1102, 984 mg, 5.55 mmol) was added dropwise. The resulting solution was slowly warmed to room temperature and stirred for 2 hours. The final mixture was quenched with saturated aqueous NH4CI solution and extracted with EtOAc. (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE/EtOAc = 100: 0 to 80: 20) to give 3-(benzyloxy)-1-(5-ethy1-6-methoxypyridin-2-yl)cyclobutan-1-ol 1103 (400 mg, 32 % yield) as a colorless oil.
LCMS (ESI) calcd for C19H24NO3 [M + H] m/z 314.17, found 314.10.
Preparation of 6-(3-(benzyloxy)cydobut-1-en-1-0)-3-ethyl-2-methoxypyridine (1104) To a solution of 3-(benzyloxy)-1-(5-ethyl-6-methoxypyridin-2-yl)cyclobutan-1-ol (1103, 400 mg, 1.27 mmol) and TEA (257 mg, 2.54 mmol) in DCM (10 mL) was added MsCI (292 mg, 2.54 mmol) at 0°C. The resulting solution was slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was added to water and then extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE/EtOAc = 100: 0 to 90: 10) to give 6-(3-(benzyloxy)cyclobut-1-en-1-y1)-3-ethy1-2-methoxypyridine 1104 (120 mg, 30 % yield) as a colorless oil.
LCMS (ESI) calcd for C19l-122NO2 [M + H] m/z 296.16, found 296.05.
Preparation of 3-(5-ethyl-6-methoxypyridin-2-0)cydobutan-1-ol (1105) To a solution of 6-(3-(benzyloxy)cyclobut-1-en-1-yl)-3-ethyl-2-methoxypyridine 1104 (120 mg, 0.40 mmol) in Me0H (10 mL) was added Pd/C (5 mg, 0.04 mmol). The mixture was stirred at room temperature under H2 for 2 h. The reaction mixture was concentrated under reduced pressure to give 3-(5-ethyl-6-methoxypyridin-2-yl)cyclobutan-1-ol 1105 (70 mg, 60 %yield) as a yellow solid.
LCMS (ESI) calcd for C12H18N102 [M + H] m/z 208.13, found 208.05.
Preparation of 3-(5-ethyl-6-methoxypyridin-2-y0cyclobutan-1-one (1106) To a solution of 3-(5-ethyl-6-methoxypyridin-2-yl)cyclobutan-1-ol 1105 (60 mg, 0.29 mmol) in DCM (5 mL) was added Dess-Martin reagent (368 g, 0.87 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was added into sodium hypochlorite solution and then extracted with EtOAc (5 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE/EtOAc = 100: 0 to 80: 20) to give 3-(5-ethyl-6-methoxypyridin-2-yl)cyclobutan-1-one 1106 (35 mg, 37 % yield) as a yellow oil.
LCMS (ESI) calcd for C111-116NO2 [M + H] m/z 206.11, found 205.94.
Preparation of 5-(4-(3-(5-ethyl-6-methoxypyridin-2-yllcyclobutyllpiperazin-1-0) -Nmethylpicolinamide (1107) To a solution of give 3-(5-ethyl-6-methoxypyridin-2-yl)cyclobutan-1-one 1106 (30 mg, 0.15 mmol) and N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide 1009 (32 mg, 0.15 mmol) in Me0H (5 mL) was added sodium triacetoxyborohydride (77 mg, 0.37 mmol). The mixture was stirred at 50 °C for 1 h. Sodium cyanoborohydride (11 mg, 0.18 mmol) was added at 50 °C.
The mixture was stirred at 50 °C for 3 h. Saturated NH4CI aqueous (2 mL) was added. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with DCM/MeOH = 100: 0 to 97: 3) to give 5-(4-(3-(5-ethy1-6-methoxypyridin-2-yl)cyclobutyl)piperazin-1-y1) -N-methylpicolinamide 1107 (40 mg, 7 %yield) as a white solid.
LCMS (ESI) calcd for Cz3H32N502 [M + H] m/z 409.25, found 410.72.
Preparation of 5-(44(1s,3s)-3-(5-ethyl-6-oxo-1,6-dihydropyridin-2-yllcydobutyl) piperazin-1-25 y1)-N-methylpicolinamide (4cis) To a solution of 5-(4-(3-(5-ethy1-6-methoxypyridin-2-yl)cyclobutyl)piperazin-1-y1) -Nmethylpicolinamide 1107 (40 mg, 0.10 mmol) in ACN (5 mL) was added TMSI (58.65 mg, 0.29 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-H PLC (Column: Gemini Sum C18 150*21.2mm; Mobile phase: ACN/H20 [0.1 %(FA)] = 20/80) to give 544-((ls,3s)-3-(5-ethy1-6-oxo-1,6-dihydropyridin-2-yl) cyclobutyppiperazin-1-y1)-N-methylpicolinamide 4cis (5 mg, 13 % yield) as a white solid.
1HNMR(400MHz, DMSO-d6) 6 11.53 (s, 1 H), 8.40 (q, J = 4.4 Hz, 1 H), 8.29 (d, J = 2.4 Hz, 1 H), 7.84 (d, J = 8.8 Hz, 1 H), 7.41 (dd, J = 8.8, 2.4 Hz, 1 H), 7.19 (d, J = 7.2Hz, 1H), 5.98 (d, J = 6.8 Hz, 1 H), 3.49-3.37 (m, 4 H), 3.05-2.97 (m, 1 H), 2.87-2.74 (m, 4 H), 2.59-2.52 (m, 2 H), 2.48- 2.40 (m, 4 H), 2.34 (q,J = 7.2 Hz, 2 H), 2.08-1.84 (m, 2 H), 1.06 (t, J = 7.2 Hz, 3 H).
LCMS (ESI) calcd for C22H30N5O2 [M + H] m/z 396.23, found 396.25.
Example 3: Synthesis of is-a, 6cis-b, 6tr ns-a, 6trans-b :
O
1202 ''''":"<"-"Cl Pd(cIppf)C12, Na2CO3, diy.oaria. H20, 95°C, 6h HN V. \ AcOH, NaBH(C)Ac), NaBH3CN. Me0H, 60 °C
N
PcI(OH)2/C N r \ Me0H, °C \
HN
Preparation of 3-(5-ethyl-6To a solution of 3-14,4,5,5(200 mg, 096 mmol) and 6 dioxane (5 ml) and H2O (0 11ASI, ACN 50 °C, 211 ficis-a, 6trarts-a, etrans-b SCHEME 3 methoxypyridin-2-0cyclopent-2-en-1-one (1203) tetra methyl-1,3,2-dioxa borolan-2-yl)cyclopent-2-en-l-one 1201 -chloro-3-ethyl-2-methoxypyridine 1202 (197 mg, 1.15 mmol) in.5 mt.) was added P4d(dppf)C12 (70 mg, 0.10 mmol) and sodium carbonate (255 mg, 2.40 mmol) at room temperature. The reaction mixture stirred under nitrogen at 95 °C for 6 h. After cooling to ambient temperature, the mixture was filtered through celite and the filtrate was concentrated under vacuum. The residue was diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by flash chromatography (eluting with PE/EtOAc = 100: 0 to 85: 15) to give product of 3-(5-ethy1-6-methoxypyridin-2-yl)cyclopent-2-en-1-one 1203 (90 mg, 43 % yield) as a white solid.
LCMS (ESI) calcd for C23F125NO2 [M + HI m/z 218.12, found 218.00.
Preparation of 5-(4-(3- (5-ethyl-6-methoxypyridin-2-yucydopent-2-en-1-yllpiperazin-1-0-N-methylpic olinamide (1204) To a solution of 3-(5-ethyl-6-methoxypyridin-2-yl)cyclopent-2-en-1-one 1203 (90 mg, 0.42 mmol) and N-methyl-5-(piperazin-1-yl)picolinamide 1009 (110 mg, 0.50 mmol) in Me0H (5 mL) was added two drops of acetic acid at room temperature and stirred for 10 min. NaBH(OAc)3 (220 mg, 1.04 mmol) was added to the reaction mixture and stirred at 60 °C for 1 h. NaBH3CN (261 mg, 4.15 mmol) was added to the reaction mixture and stirred at 60 °C for 15h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with DCM/MeOH = 100: 0 to 95: 5) to give product of 5-(4-(3-(5-ethy1-6-methoxypyridin-2-yl)cyclopent-2-en-1-yl)piperazin-1-y1) -N-methylpicolinamide 1204 (85 mg, 49 % yield) as faint yellow oil.
LCMS (ESI) calcd for C24F132N302 [M + HI m/z 422.26, found 422.25.
Preparation of 5-(4-(3-(5-ethyl-6-methoxypyridin-2-Acydopentyllpiperazin-1-0) -Nmethylpicolinamide (1205) To a solution of 5-(4-(3-(5-ethy1-6-methoxypyridin-2-yl)cyclopent-2-en-1-yflpiperazin-1-y1) -Nmethylpicolinamide 1204 (85 mg, 0.20 mmol) in Me0H (5 mL) was added Pd(OH)2/C (20 mg).
The mixture was evacuated and backfilled with hydrogen three times and then charged with hydrogen, The resulting mixture was stirred at 50 °C for 3 h. Then the mixture was filtered through celite and concentrated under vacuum to give crude 5-(4-(3-(5-ethy1-6-methoxypyridin-2-yl)cyclopentyl)piperazin-1-y1) -N-methylpicolinamide 1205 (80 mg, 93 % yield) as faint yellow oil.
LCMS (ESI) calcd for C24F133N502 [M + HI m/z 424.27, found 424.15.
Preparation of 5-(4-(3-(5-ethyl-6-oxo-1, 6-dihydropyridin-2-yucyclopentyllpiperazin-1-0-Nmethylpicolinamide (6cis-a, 6cis-b, 6trans-a, 6trans-b) To a solution of 5-(4-(3-(5-ethy1-6-methoxypyridin-2-yl)cyclopentyl)piperazin-l-y1) -Nmethylpicolinamide 1205 (80 mg, 0.19 mmol) in ACN (4 mL) was added TMSI (113 mg, 0.57 mmol). The mixture was stirred at 50 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (Gemini 5 11M C18 150*21.2 mm, mobile phase: ACN -H2O (0.1 % FA), gradient: 2 % -95 %) to afford the first fraction as 6cis-a / 6cis-b racemic mixture (cis stereochemistry assumed across cyclopentane based on NOE experiments) (10 mg, 95 % purity, white solid) and the second fraction as 6trans-a / 6trans-b racemic mixture (trans stereochemistry assumed across cyclopentane based on NOE experiments) (3 mg, 95 % purity, white solid).
6cis-a / 6cis-b racemic mixture 1H N MR (400 MHz, CDCI3, ppm) 8.19 (d, J = 2.4 Hz, 1 H), 8.10 (d, J = 8.8 Hz, 1 H), 7.83 (d, = 4.8 Hz, 1 H), 7.69 (d, J = 7.2 Hz, 1 H), 7.29 (d, J = 2.4 Hz, 1 H), 6.82 (d, J= 7.2 Hz, 1 H), 4.20-3.36 (m, 8 H), 3.24 (dt, J = 14.8, 10.8 Hz, 2 H), 3.02 (d, J = 5.2 Hz, 3 H), 2.66-2.54 (m, 3 H), 2.39 (dd, J = 22.0, 11.2 Hz, 2H), 2.31-2.19 (m, 2H), 2.10-2.00 (m, 1H), 1.22 (t, J = 7.4 Hz, 3H).
LCMS (ESI) calcd for C23H32N502 [M + H] m/z 410.26, found 410.20.
6trans-a / 6trans-b racemic mixture 1H NMR (400 MHz, CDC13, PPm) 11.74 (s, 1 H), 8.17 (s, 1 H), 8.06 (dd, = 8.4, 2.4 Hz, 1 H), 7.78 (s, 1 H), 7.25-7.15 (m, 2 H), 6.02 (dd, J = 6.4, 2.0 Hz, 1 H), 3.37 (s, 3 H), 3.22-2.96 (m, 5 H), 2.71 (s, 3 H), 2.57-2.48 (m, 2 H), 2.27-1.98 (m, 4 H), 1.86-1.58 (m, 4 H), 1.18 (td, J = 7.2, 2.4 Hz, 3 H).
LCMS (ESI) calcd for C23H32N502 [M + HI m/z 410.26, found 410.40.
The 6cis-a / 6cis-b racemic mixture was separated by SFC (Column: Regis (R,R)-Whelk-O 1, 250 mm x 20 mm I.D., 5 pmm; Mobile phase: CO2/MeOH [0.1 %(NH3)(7 M solution in Me0H)] = 65/35) and concentrated under reduced pressure to afford the first fraction as 6cis-a (white solid) and the second fraction as 6cis-b (white solid).
The 6trans-a / 6trans-b racemic mixture was separated by SFC (Column: Daicel CHIRALPAK IJ SFC 250 mm x 20 mm I.D., 5 pmm; Mobile phase: COz/Me0H[0.1 %(NH3)(7 M solution in Me0H)] = 60/40) and concentrated under reduced pressure to afford the first fraction as 6trans-a (white solid) and the second fraction as 6trans-b (white solid).
Example 4: Synthesis. of 7cis-a, kis-b, 7trans-a and 7trans-b
SO
1305 ° Pd(dppf)C12. Na2CO2, dixoane, H20. 95%:. 8h ( DIPEA. ACM, rt, 16 h 1301 0 P(p-OMePh)2" Pin282 1.3.54fnmethoxybenzene Pd(0A02,auslone, H20.
1302 0 60QC, is h c.", tr.\
HN
HN--
F 1306 AcON:. Nabh(OAci2, 60 nC NaBH"CN, Me0H, 2 days Chiral SFC 7trans-a t 7trans-b 7trans-a / 7trans-b Chiral SFC 7cis-a cis-b -------7th-a / 7th-b
RN
Pd(OH)2,C, H2 50t. H2 ACN, 50°C, 2 h NO1307 N >-=-0 1308 HN
HN
7trans-a / 7trans-b racemic mixture 7trans-a / 7trans-b racemic mixture SCHEME 4 Preparation of 3-oxocyclopent-1-en-1-y1 pivalate (1302) To a solution of cyclopentane-1,3-dione 1301 (8 g, 81.6 mmol) and DIPEA (21.09 g, 163.2 mmol) in DCM (160 mL) was added pivaloyl chloride (10.77 g, 89.8 mmol) slowly at 0 °C. The reaction mixture stirred at room temperature for 16 h. The mixture was diluted with water (400 mL) and extracted with EtOAc (400 mL x 3). The combined organic layer was washed with brine (100 mL x 2), dried over Na2SO4, filtered and concentrated in vacuo to get crude product, which was purified by flash column chromatography (PE/EtOAc = 100: 0 to 70: 30) to afford product of 3-oxocyclopent-1-en-1-yl pivalate 1302 (12 g, 81 % yield) as faint yellow oil.
LCMS (ESI) calcd for C10111403 [M + H] m/z 183.12, found 183.00.
Preparation of 3-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-Acydopent-2-en-1-one (1303) To a solution of 3-oxocyclopent-1-en-1-yl 2,2-dimethylpropanoate 1302 (8 g, 43.9 mmol), B2Pin2 (22.3 g, 87.9 mmol), palladium diacetate (863 mg, 3.52 mmol) and Tri-o-tolylphosphine (1.2 g, 3.9 mmol) in acetone (80 mL) and H2O (8 mL) was added 1,3,5-trimethoxybenzene (3.7 g, 22.0 mmol). The reaction mixture was stirred at 60 °C for 18 hours. After cooling to room temperature, the reaction mixture was poured into water (800 mL), The aqueous phase was washed with EtOAc (600 mL) 3 times. The water layers were concentrated under reduced pressure to give product of 3-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-yl)cyclopent-2-en-1-one 1303 (2 g, 22 % yield) as a white solid.
LCMS (ESI) calcd for C24H31N502 [M-72 + H] m/z 126, found N/A.
Preparation of 3-(5-ethyl-6-methoxypyridin-2-0)cydopent-2-en-1-one (1305) To a solution of 3-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-yl)cyclopent-2-en-1-one 1303 (2.0 g, 9.6 mmol) and 6-chloro-3-ethyl-2-methoxypyridine 1304 (1.6 g, 9.6 mmol) in dioxane (50 mL) and H2O (5 mL) were added Pd(dppf)Cl2 (351 mg, 0.48 mmol) and sodium carbonate (2.5 g, 24.0 mmol) at room temperature. The reaction mixture stirred under nitrogen at 95 °C for 8 h. After cooling to ambient temperature, the mixture was filtered through celite and the filtrate was concentrated under vacuum. The residue was diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by flash chromatography (eluting with PE/EtOAc = 100: 0 to 85: 15) to give product of 3-(5-ethy1-6-methoxypyridin-2-yl)cyclopent-2-en-1-one 1305 (450 mg, 22 % yield) as a white solid.
LCMS (ESI) calcd for C131-115NO2 [M + H] + m/z 218.12, found 218.00.
Preparation of 5-(4-(3-(5-ethyl-6-methoxypyridin-2-yl)cydopent-2-en-1-yllpiperazin-1-y1) -6-fluoro-N-methylpkolinamide (1307) To a solution of 3-(5-ethyl-6-methoxypyridin-2-yl)cyclopent-2-en-1-one 1305 (186 mg, 0.85 mmol) and 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide 1306 (243 mg, 1.02 mmol) in Me0H (5 mL) was added two drops of acetic acid at room temperature and stirred for 10 min. NaBH (OAc)3 (433 mg, 2.04 mmol) was added to the reaction mixture and stirred at 60 °C for 1 h. NaBH3CN (534 mg, 8.5 mmol) was added to the reaction mixture and stirred at 60 °C for 2 days. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with DCM/MeOH = 100: 0 to 95: 5) to give crude product of 5-(4-(3-(5-ethy1-6-methoxypyridin-2-y0cyclopent-2-en-1-yOpiperazin-1-y1) -6-fluoro-N-methylpicolinamide 1307 (200 mg, 54 % yield) as faint yellow oil.
LCMS (ESI) calcd for C24H3oFN502 [M + H] * m/z 440.25, found 440.20.
Preparation of 5-(4-(3-(5-ethyl-6-methoxypyridin-2-ylkydopentyllpiperazin-1-y1) -6-fluoroN-methylpkolinamide (1308) To a solution of 5-(4-(3-(5-ethy1-6-methempyridin-2-y0cyclopent-2-en-1-yOpiperazin-1-y1) -6-fluoro-N-methylpicolinamide 1307 (200 mg, 0.46 mmol) in Me0H (5 mL) was added Pd(OH)2/C (80 mg). The mixture was evacuated and backfilled with hydrogen three times and then charged with hydrogen. The resulting mixture was stirred at 50 °C for 5 h. Then the mixture was filtered through celite and concentrated under vacuum to give crude product.
The crude product was purified by flash chromatography (eluting with DCM/MeOH = 100: 0 to 95: 5) to give product of 5-(4-(3-(5-ethy1-6-methoxypyridin-2-yl)cyclopentyl)piperazin-1-y1) -6-fluoro-N-methylpicolinamide 1308 (125 mg, 63% yield) as a faint yellow oil.
LCMS (ESI) calcd for C24H32FN502 [M + HI m/z 442.26, found 442.25.
Preparation of 5-(4-(3-(5-ethyl-6-oxo-1,6-dihydropyridin-2-yacydopentyllpiperazin-1-y1) -6-5 fluoro-N-methylpicolinamide (7trans-a/7trans-b/7cis-a/7cisb) To a solution of 5-(4-(3-(5-ethy1-6-methoxypyridin-2-y0cyclopentyl)piperazin-1-y1) -6-fluoroN-methylpicolinamide 1308 (125 mg, 0.283 mmol) in ACN (5 mL) was added TMSI (170 mg, 0.85 mmol). The mixture was stirred at 50 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (Gemini 5 p.m C18 150*21.2mm, mobile phase: ACN -H2O (0.05 % NH3.H20), gradient: 25 %-95 %) to afford the first fraction as a racemic mixture of 7trans-a and 7trans-b (23 mg, white solid) and the second fraction as a racemic mixture of 7cis-a and 7cis-b (33 mg, white solid).
7trans-a / 7trans-b LCMS (ESI) calcd for C231-13FN502 [M + H] m/z 428.25, found 428.20.
7cis-a / 7cis-b LCMS (ESI) calcd for C23H3FN502 [M + H] * m/z 428.25, found 428.20.
Preparation of 5-(4-(3-(5-ethy1-6-oxo-1,6-dihydropyridin-2-Acydopentyl)piperazin-1-y1) -6-fluoro-N-methylpicolinamide (7trans-a, 7trans-b, 7cis-a and 7cis-b) The racemic mixture of 7trans-a and 7trans-b was separated by SFC (Column: Daicel CHIRALPAK IH SFC 250 mm x 20 mm I.D., 5 pmm; Mobile phase: CO2/Me0H[0.1 %(NH3)(7 M solution in Me0H)] = 70/30) and concentrated under reduced pressure to afford the first fraction as 7trans-a (3.85 mg, 99 % purity, ee%: 100, white solid) and the second fraction as 7trans-b (5.43 mg, 99 % purity, ee%: 100, white solid).
7trans-a 1H NMR (400 MHz, Me0D, ppm) 6 7.90 (dd, J = 8.0, 1.2 Hz, 1 H), 7.52 (dd, J = 10.4, 8.4 Hz, 1 H), 7.35 (d, J = 7.2 Hz, 1 H), 6.23 (d, J = 7.2 Hz, 1 H), 3.29-3.24 (m, 4 H), 3.17-3.09 (m, 1 H), 2.96-2.87 (m, 4 H), 2.79-2.68 (m, 4 H), 2.48 (q, J = 7.6 Hz, 2 H), 2.18-2.04 (m, 3 H), 2.00-1.92 (m, 1H), 1.78-1.59 (m, 2 H), 1.16 (t, J = 7.6 Hz, 3 H).
Assigned trans-stereochemistry based on NOE experiments.
LCMS (ESI) calcd for C23H3FN302 [M + H] m/z 428.25, found 428.20.
7trans-b 1H NMR (400 MHz, Me0D, ppm) 6 7.90 (d, J = 8.0 Hz, 1 H), 7.61-7.42 (m, 1 H), 7.35 (d, J = 7.2 Hz, 1 H), 6.22 (d, J = 6.8 Hz, 1 H), 3.29-3.22 (m, 4 H), 3.17-3.08 (m, 1 H), 2.99-2.83 (m, 4 H), 2.80-2.65 (m, 4 H), 2.48 (q, J = 7.6 Hz, 2 H), 2.20-2.04 (m, 3 H), 2.00-1.91 (m, 1 H), 1.78-1.58 (m, 2 H), 1.16 (t, J = 7.6 Hz, 3 H).
Assigned trans-stereochemistry based on NOE experiments.
LCMS (ESI) calcd for C23H3FN302 [M + H] m/z 428.25, found 428.20.
The racemic mixture of 7cis-a and 7cis-b was separated by SFC (Column: Daicel CHIRALPAK IH SFC 250 mm x 20 mm I.D., 5 p.mm; Mobile phase: CO2/Me0H[0.1 %(NH3)(7 M solution in Me0H)] = 70/30) and concentrated under reduced pressure to afford the first fraction as 7cisa (6.20 mg, 98 % purity, ee%: 100, white solid) and the second fraction as 7cis-b (5.34 mg, 98 % purity, ee%: 99, white solid).
7cis-a 1H NMR (400 MHz, Me0D, ppm) 6 7.91 (dd, J = 8.0, 1.2 Hz, 1 H), 7.57 (dd, J = 10.4, 8.2 Hz, 1 H), 7.31 (d, J = 6.8 Hz, 1 H), 6.21 (d, J = 6.8 Hz, 1 H), 3.54-3.42 (m, 2 H), 3.40-3.33 (m, 2 H), 3.19-3.11 (m, 1 H), 2.91 (s, 3 H), 2.84-2.72 (m, 5 H), 2.46 (q, J = 7.6 Hz, 2 H), 2.25-2.14 (m, 2 H), 2.05-1.98 (m, 1 H), 1.90-1.79 (m, 2 H), 1.76-1.65 (m, 1 H), 1.14 (t, J = 7.6 Hz, 3 H).
Assigned cis-stereochemistry based on NOE experiments.
LCMS (ESI) calcd for C23H3FN302 [M + H] m/z 428.25, found 428.20.
7cis-b 1H NMR (400 MHz, Me0D, ppm) 6 7.91 (d, J = 8.0 Hz, 1 H), 7.57 (dd, J = 10.4, 8.2 Hz, 1 H), 7.31 (d, J = 6.8 Hz, 1 H), 6.21 (d, J = 6.8 Hz, 1 H), 3.52-3.42 (m, 2 H), 3.40-3.33 (m, 2 H), 3.19-3.11 (m, 1 H), 2.91 (s, 3 H), 2.84-2.74 (m, 5H), 2.46 (q, J = 7.6 Hz, 2 H), 2.25-2.14 (m, 2 H), 2.05-1.98 (m, 1 H), 1.89-1.79 (m, 2 H), 1.76-1.64 (m, 1 H), 1.14 (t, J = 7.6 Hz, 3 H).
Assigned cis-stereochemistry based on NOE experiments.
LCMS (ESI) calcd for C23H3FN502 [M + HI m/z 428.25, found 428.20.
Example 5 -Assays
Exemplary compounds of the invention were prepared and tested to determine their effect as PARP1 and PARP2 inhibitors. Typical assays are described below.
Example 5A. PARP1 biochemical dissociation-enhanced lanthanide fluorescence immunoassay (DELF1A assay) Optiplate HB 384-well plates were coated with anti-FLAG antibody, supplied as a 4 mg/ml solution, using a Na2CO3/HCO3 coating buffer at pH 9.6, overnight at 4°C, in order to achieve a final immobilisation per well of 0.3 Lig. 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 pi 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, 51.11 of 10 LLM 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 5µl 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 µl of a 1:1000 dilution of DELFIA Eu-N1 Streptavidin reagent was added. Plates were then incubated for 30 min at room temperature. Reaction mixture was removed and plates washed 5 times for 3 min prior to the addition of 25 ul DELFIA enhancement solution. Following incubation for 30 min at room temperature, fluorescence was measured on a Pherastar FS (Ex337 nm, Em620 nm; integration start 60 us; integration time 400 us).
Typically compounds were tested from 20 LtM at 3-fold dilution intervals in 12-point concentration-response curves to determine ICso values. Data was analysed using ActivityBase software and replicate values for the low (without enzyme, 0.2 % DMSO) and high (0.2 % DMSO) % controls were averaged and the data obtained from the test compounds expressed as a % of 100 % using the below formulae: % value = 100-(100*((high control -unknown) / (high control -low control)) % data was fitted to a non-linear regression equation (log inhibitor vs response-variable slope 4-parameters) to obtain ICso values.
The ICsovalues for a variety of test compounds are shown in Table 1.
Activation DNA sequence: Our,,,ex TGAT-3' (SEQ ID NO:1) (SEQ ID N0:2) 5"-ACCGTGCT GIGGGClide on 6GAG4 5',ATCACCTTGTICTCCAHGCCCACAGCAG Example 58. PARP1 probe displacement homogeneous time-resolved fluorescence assay (HTRF assay) 10 nM full length N-terminally FLAG-tagged PARP1 was incubated with 2 nM Anti-FLAG Tb-cryptate antibody and PARP1/2 Cy5 fluorescent dye-labelled binding probe (10-fold probe Kd = 270 nM) in 20 mM HEPES (pH 7.5), 100 mM NaCI, 2 mM DTT, 0.1 % BSA (w/v), 0.02 % Tween (v/v) assay buffer for 40 min at room temperature. A Cy5-labelled binding probe is shown below and described in Papeo, G. et aL J. BiomoL. Screen. 2014; 19:1212-1219. 6 [LI of this -3 '(SEQ ID NO:3) 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 6012s; integration time 40012s) using the HTRF module.
Typically compounds were tested from 58.5 µM at factor 3 dilution intervals in 12-point concentration-response curves to determine ICso values. Data was analysed using ActivityBase software and replicate values for the low (without enzyme but with probe and Tb-cryptate antibody, 0.6% DMSO) and high (0.6 % DMSO) % controls were averaged and the data obtained from the test compounds expressed as a % of 100 % using the below formulae: %activity = 100*(value -low control) / (high control -low control) %activity data was fitted to a non-linear regression equation to obtain 1050 values Kd values were calculated using Cheng-Prussoff formula: ICso = (1+ ([probe concentration]/[Kmprood]))*Ka Therefore Kd = ICso / (1+[[probe concentration]/[Kmprobe])); using 1ng probe at 10 x Km, this equated to Kd = ICso/11 Example SC. PARP2 probe displacement homogeneous time-resolved fluorescence assay (HTRF assay) This assay was performed under identical conditions as for PARP1, except that N-terminally FLAG-tagged PARP2 (amino acids 1-583) was used instead of PARP1, and PARP1/2 binding probe was used at 10-fold probe Kd = 540 nM. Data analysis was performed identical as for PARP1.
Cy5 probe structure: NanoBRET cellular target occupancy assay NanoBRET assays were employed to demonstrate cellular target engagement and selectivity at PARP1 and PARP2. These assays are based on bioluminescence resonance energy transfer (BRET) between a Nano-luc-tagged protein (eg PARP1 or PARP2) and a fluorescent group on a high affinity NAD' competitive binding probe. Such cellular probe displacement assays can be utilised to measure inhibitor affinities and selectivity ratios at PARP1 and 2.
Frozen HEK293 cells transiently transfected with either PARP1-NanoLuc® fusion or PARP2NanoLuc® fusion constructs (Promega) were thawed and dispensed as a suspension in 384-well microplates each at a density of 1750 cells per well. NanoBRETT" 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 µM at factor 3 dilution intervals in 12-point concentration-response curves and plates were incubated for 2 hours at 37°C. BRET ratios were then measured using a NanoBRET module (LUM 610-LP 450-80) and PHERAstar FS or FSX reader following addition of NanoBRETTm Nano-Glo® Substrate and Extracellular NanoLuc® Inhibitor according to manufacturer's instructions. Kd values were calculated using Cheng-Prussoff formula: IC50 = (1+ ([tracer concentrationW[Km-tracer]11 161n, * Binned potency, affinity and selectivity data for a variety of test compounds are shown in Table 1 where DELFIA and Probe Displacement HTRF assays were used. Binned potency, affinity and selectivity data for a subset of test compounds where the NanoBRET assay was used are shown in Table 1.
TABLE 1
Results of Parp 1/2 assays for selected compounds (DELFIA and Probe Displacement HTRF) Compound PARP1 DELFIA PARP1 HTRF PARP2 HTRF Selectivity lcis ++ ++ - + 2cis ++ ++ + 3 ++++ ++++ +++ 4cis +++ +++ - +++ ++ ++ + 6cis-a ++++ ++++ + +++ 6cis-b ++++ ++++ ++ +++ 6trans-a +++ +++ + ++ 6trans-b ++++ ++++ ++ +++ 7cis-a ++++ ++++ + +++ 7cis-b ++++ ++++ ++ +++ 7trans-a +++ +++ - +++ 7trans-b ++++ ++++ ++ +++ 8cis-a ++++ ++++ + +++ 8cis-b ++++ ++++ ++ +++ 8trans-a +++ +++ +++ 8trans-b ++++ ++++ ++ +++
TABLE 2
Results of Parp 1/2 assays for selected compounds (NanoBRET) Compound PARP1 NanoBRET PARP2 NanoBRET Selectivity 6cis-a ++++ + +++ 6cis-b ++++ ++ +++ 6trans-b ++++ ++ +++ 7trans-b ++++ + +++ 8trans-b ++++ ++ +++ Key DELFIA, Probe Displacement HTRF and NanoBRET assay categories: -indicates IC50 or Kd value above 10 pM + indicates IC50 or Kd value above 1 pM up to 10 pM ++ indicates IC50 or Kd value above 100 nM up to 1;AM +++ indicates IC50 or Kd value above 10 nM up to 100 nM ++++ indicates IC50 or Kd value of 10 nM or less Selectivity categories: -indicates a value of less than 10 + indicates a value of 10 to less than 50 ++ indicates a value of 50 to less than 100 +++ indicate a value of at least 100 The selectivity values relate to the selectivity preference of PARP1 over PARP2. They are calculated from the ratio of Kd values for PARP1 and PARP2 inhibition as Kd (PARP2) / Kd (PARP1).
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 (3)

  1. Claims 1. A PARP1 inhibitor compound for use in medicine, which compound comprises a structure of: wherein:.R1 is selected from H and a substituted or unsubstituted organic group; R2 is absent or selected from H and a substituted or unsubstituted organic group; R3 is absent or selected from H and a substituted or unsubstituted organic group; R4 is selected from H and a substituted or unsubstituted organic group; V. and Z2 are each independently selected from C and N; and L is a group having a structure of: 5A 0o RRSA 1 -R55 R&B -X (X SX,)qApan -X Oh N, B R5A R5Fe wherein: each X= is independently selected from C and N; each X' is independently selected from C, N, 0 and S; n is a number selected from 0, 1, 2, 3, 4, 5 and 6; and m is a number selected from 0,1, 2, 3, 4, 5 and 6; with the proviso that m + n is a number selected from 2, 3, 4, 5, and 6; p is a number selected from 0, 1, 2, 3, 4, 5 and 6; and q is a number selected from 0, 1, 2, 3, 4, 5 and 6; with the proviso that p q is a number selected from 2, 3, 4, 5, and 6; R4NER2 ---172 13 R R5C R 50 re R.' ();(4)s.C 2 '2 se Rser is a number independently selected from 0, 1, 2, 3, 4, 5 and 6; s is a number independently selected from 0, 1, 2, 3, 4, 5 and 6; with the proviso that r s is a number selected from 2, 3, 4, 5, and 6; each R';', Rss, and Rs'. is independently absent or selected from H and a substituted or unsubstituted organic group; and Rs is absent or selected from H and a substituted or unsubstituted organic group; the lines forming rings A. B and C each independently represent single or double bonds such that each ring is independently saturated, unsaturated, or aromatic; and each of Qa, Qb, and Qc is independently selected from a bond and a group having a structure independently selected from: wherein: t is a number selected from 0, 1, 2, 3, 4 and 5; and u is independently a number selected from 0, 1, 2, 3, 4 and 5; with the proviso that t + u is a number selected from 0, 1, 2, 3, 4, 5 and 6; and each R7 and IS' is independently selected from H and a substituted or unsubstituted organic group.
  2. 2. The PARP1 inhibitor compound for use according to claim. 1, wherein each X;) is independently selected from C and N.
  3. 3. The PARP1 inhibitor compound for use according to claim 1 or claim 2, wherein the compound has a structure selected from: 0 j) R fs R', R7 and 134 each being independently selected from H and a substituted or unsubstituted organic group; R1, R3 and R4 each being independently selected from H and a substituted or unsubstituted organic group; and preferably' R1, W, R3 and R1 each being independently selected from H and a substituted or unsubstituted organic group, 4. The PARP1 inhibitor compound for use according to any preceding claim, herein Ri and W are each independently selected from H; a Cl to C6 alkyl, aminoalkyl, alkoxy or haloalkyl group; a C3 to C6 cycloalkyl group; a halogen group; and R22 wherein R is elected from H, a Cl to C6 alkyl, cycloalkyl, alkoxy, or haloalkyl group, and a halogen group, and each R73 is independently selected from H and a substituted or unsubstituted organic group, preferably wherein each R7 is independently selected from H, a Cl to C6 alkyl, am inoalkyl, alkoxy or haloalkyi group, and a halogen group, and preferably wherein at least one R2' is H; with the proviso that at least one of IV and R2 is not H, and preferably R2 is H. 5. The PARP I inhibitor compound for use according to claim 4, wherein at least one of R1, R7, and R27 is selected from -CH3, -CH2CH3, -CHZCH2CH3, -CH2F, -CHF,, -CF3, -F, -CI, -CH2CFR, -CH2CH2F, -CH3CH2OH, methoxy, methoxymethyl, methoxyethyi, isopropyl, cyclopropyl or cyclopropylmethyl.6. The PARP inhibitor compound for use according to claim 5, having a structu selected from: F3C F3C Ci !vie° F3C Me° 7. The PARP1 inhibitor compound for use according to any of claims 4 to 6, wherein at 23,e223 least one of R and R2 is R22 and each R" is independently selected from H, F, Cl to C3 alkyl or Cl. to C3 fluoroalkyl.8. The PARP1 inhibitor compound for use according to any of claims 4 to 7, wherein R' is selected from H, C1 to C3 alkyl, Cl to C3 al koxy, and Cl to C3 haloalkyl.9. The PARP1 inhibitor compound s according to claim 8, wherein R' is an ethyl F3C and group.10. The PARP1 inhibitor compound for use according to any preceding claim, wherein fe is selected from H, halogen, Cl to 0 alkyl, Cl to 0 haloalkyl, 01 to C3 alcohol or Cl to 03 a m inoa kyl.11. The PARP1 inhibitor compound for use according to claim 10, wherein: 71 and 72 are each C; and Ft2 and R3 are each independently selected from H, Cl to 03 alkyl, and C1 to C3 haloalkyi; optionally wherein R2 and R3 are each H. 12, The PARP1 inhibitor compound for use according to any preceding claim, wherein R4 is selected from H, Cl to C3 alkyl, and Cl to C3 haloaikyl. preferably wherein R4 is H. 13. The PARP1 inhibitor compound for use according to any preceding claim, wherein ring A is an aromatic ring.14. The PARP1 inhibitor compound for use according to any of claims 1 to 12, wherein L has a structure of: R5A * \ 2 --(X)trt RSAsIAXRSA--No0b------N, B,.X1 Qc Xi --(. 2)5 2/ \ 58 5A X\ )p R C R58 \REa S.> )f ---X Rc R5C Rr / 'IR SC and R5B7 R 5C se wherein ring A is a saturated or unsaturated aliphatic carhacycle or heterocycle.15. The PARP1 inhibitor compound for use according to claim 14, wherein ring A is a 6-membered saturated or unsaturated aliphatic carbocycle or heterocycle.16, The PARP1 inhibitor compound or use ccording to any of ciairns 1 to 12, wherein L has a structure of: 135B RI xC q X2)5C 2 2X)r---X-------\ 5C R5B {X,2,),4 B, )p R50 R5A wherein ring A is a saturated or unsaturated aliphatic carbocycle or heterocycle.17. The PARP1 inhibitor compound for use according to claim 16, wherein ring. A is a 5-membered saturated or unsaturated aliphatic carbocycle or heterocycle.18. The PARP1 inhibitor compound for use according to any preceding claim, wherein Qa is a bond or -CH2-, optionally wherein Qa is a bond, 19, The PARP1 inhibitor compound for use according to any preceding claim, wherein L is a group having a structure of: R5A7 QaRR5A RSA / RSCIw., B Cie X \ \R53 5X,1/4, H58)p R 56 \ R R5C is 20. The PARP1 inhibitor c rnpound for use according to claim 19, wherein L is a group having a structure of:EAR \, 5A 1 2 -R Rae ---> (X)tfi / 0 5C R5A 1,X2,,),4 R5 R5C 1 A i 1 1 -7' N, B ".X Cc 2 (X jr C,X)s \-2 '''.. 6B 6,A 5.X\ )p R CR H\ 5}(2),__ (X.--X / R5C R1 5c 1R SC21. The PARP1 inhibitor compound for use according to claim 20, wherein ring B is a saturated heterocycle.22. The PARP1 inhibitor compound according to any preceding claim, wherein both n and m are at least 1 23. The PARP1 inhibitor compound for use according to claim 22, wherein: i) ring A is a substituted or unsubstituted 7-membered aliphatic carbocycle or heterocycle, optionally a cycloheptane, further optionally a cycloheptane having a structure selected from: and R5A 5A/ \ RA5 5A R5ARSARSARSA R5A3 R5A R5 R5A3 AsRBA bRBAR 5Aeach RSA and 115" being independently selected from H and a substituted or unsubstituted organic group, wherein R'43 is most preferably H; or 1.00 ii) wherein ring A is a substituted or unsubstituted 6-membered aliphatic carbocycle or heterocycle, optionally a cyclohexane or tetrahydropyran and further optionally having a structure selected from: 5A. RSA R5A / RSA5A i RaRR5A 5A R 5A 3 R5A -R5A3 RSA. R5A b/SA \ CA oh R ob R5A R5A Oh R543RSA R5A Ob 5A3RSASA54 RSA R5A 1.01 each R''A and being independently selected from H and a substituted or unsubstituted organic group, wherein RSAZ is most preferably H; or iii) ring A is a substituted or unsubstituted 5-membered aliphatic carbocycle or heterocycle, optionally a cyclopentane, cyclopentene, or a tetrahydrofuran, and further optionally having a structure selected from:RSA andRSAR A R5A b Oa1.0.2.each re4 and Rs" being independently selected from H and a substituted or unsubstituted organic group, wherein Rs" is most preferably H; or iv) ring A is a 5-membered aromatic ring, optionally a pyrrole or pyrazole, and further optionally having a structure selected from: each R''a being independently selected from H and a substituted or unsubstituted organic group; and v) ring A is a substituted or unsubstituted cyclobutane, optionally having a structure of: R 5A ^SA \ R5A Qa N\-QbR and R 5A3 5A Qbeach 115' and feu being independently selected from H and a substituted or unsubstituted organic group, wherein feu is most preferably H. 24. The PARP1 inhibitor compound for se according to claim 23, wherein ring A has a structure selected from: 25. The PARP1. inhibitor compound for use according to claim 22,, wherein ring A has a structure of' REv'2 5A1 A Qa 5A3 \ Oti n R 5A,R 5A2 wherein: m is 1 or 2; n is 1 or 2; each R5"2 and RSaj independently is absent or selected from H and a substituted or unsubstituted organic group, preferably wherein the ring A is an aliphatic ring and Qa Qa., -1-QbHOav, Qb -Qb Qa -Qb Qb, -Qb and b -40b 1.03 1.04 and hereim: i) X1 is C and R4'^ is selected from H and a substituted or unsubstituted organic group; Or ii) X1 is N and Rs"' is absent.26. The PARP1 inhibitor compound for use according to claim 25, wherein each RSA independently is absent or H. 27, The PARP1 inhibitor compound for use according to claim 26, wherein ring A has a structure selected from: 28. The PARP1 inhibitor compound for use according to any preceding claim,wherein Oh is a bond or -CH2-, optionally wherein Qb is a bond.29, The PARP1 inhibitor ompou d for se according to any preceding claim, wherein both p and q are at least 1; optionally wherein p and q sum to 3 or 4, and further optionally wherein p is 2 and q Opt N \ Qb ) . is 2.30. The PARR' inhibitor compound for use according to claim 29, wherein: 0 ring B is a 7-membered saturated heterocyclic ring, optionally a homopiperazine having a structure of: each Rs' being independently selected from H and a substituted or unsubstituted organic group, optionally wherein each R'' is H; ii) ring B is a 6-membered saturated heterocyclic ring, optionally a piperazine, further optionally a piperazine having a structure of:R R58 Sri RSe Oh, IVY RSe R5B_ 5BRR Reach Rs" being independently selected from H and a substituted or unsubstituted organic group, optionally wherein each Rs' is H; or iii) ring B is a 5-membered saturated heterocyclic ring, optionally an irnidazo dine, further optionally an imidazolidine having a structure of: R6B Qb4: 11:N-r is nE1R 113 5 each Rs' being independently selected from H and a substituted or unsubstituted organic group, optionally wherein each Rs' is H. 31. The PARP1 inhibitor compound for use according to claim 3D, wherein ing B has a structure of' 32. The PARP1 inhibitor compound for use according to any preceding claim, wherein Qc is a bond or -CH2-, optionally wherein Qc is a bond.33. The PARPI inhibitor compound for use according to any preceding claim, wherein both r and s are at least 1, optionally wherein r and s sum to 3 or 4.34, The PARP1 inhibitor compound for use according to claim 33, wherein: i) ring C is a 6-membered aliphatic ring, optionally a 6-membered aliphatic ring having structure of.5C, 53 \ R R 5Ci \ R50 R5CRSC R ceRR-R-each ft; andR'crbeing independently selected from H and a substituted or unsubstituted organic group, preferably wherein Rscl is H, more preferably wherein R'e' and each R" is H; ii) ring C is a 6-membered aromatic ring, optionally selected from: ha) a phenyl group, optionally having a structure of: RscPSC Qo 1.07each R" being independently selected from H and a substituted or unsubstituted organic group, optionally wherein each 13' is H; iib) a pyridine group, optionally having a structure selected from: Sc: R \ /7/ Fr. r: C2o--7---\1 ac-4 --------)-(\ R 50 R' 5° 5C and RReach Rx being independently selected from H and a substituted or unsubstituted organic group, optionally wherein each RAis H; iic) a diazine group, optionally having a structure selected from; each Fisc being independently selected from H and a substituted or unsubstituted organic group, optionally wherein each Rsc is It iii) ring C is a 5-membered aromatic ring, optionally selected from: hia) an imidazole group, optionally an imidazole group having a structure selected from:SG Re. Rse R 5CR" and each 135c being independently selected from H and a substituted or unsubstituted organic group, optionally wherein each RX i 5 H; b) a thiophene group, optionally having a structure selected from: * 5C R, and Qc-R5CQ-S \Reeach Rs' being independently selected from H and a substituted or unsubstituted organic group, optionally wherein each Rsc is H; iiic) a thiazole group, optionally having a structure selected from: Qc -Qc each RSC being independently selected from H and a substituted or unsubstituted organic group, optionally wherein each Rs': is H; iiid) a triazole, optionally a triazole having a structure of:R5L being selected from H and a substituted or unsubstituted organic group, optionally wherein R'3c. is H. 35, The PARP1 inhibitor compound for use according to claim 34, wherein ring C has a structure selected from: CF3 CF2H Qc-Rs R5c R c and R5-1.09 R$ CF3 NRe a Ns*-NCFI35. The PARP1 inhibitor corn pounds for use according to claim 34, wherein ring C has a structure of' R5C2N1 R5C2o 12CMXQc \ 'o, R6 wherein.R5c20 is selected from H and a halogen; and X'A is C and rt C 2 " is H; or ii) X2CM is N and R5412m is absent.37. The PARP1 inhibitor compound for use according to claim 33, wherein R5(11 is a halogen, optionally wherein Rscl is F. 38. The RARP1 inhibitor compound for use according to any preceding claim, wherein R6 is selected from H, -F, -Cl, -Br, -I, -CN, -CONR51R5i1, -NRsICOR', -SOMP54151, -NR5150.4R52, -0-CR'Rs2R51, -CR'R52N1354351, and any of the following structures: R51 A52 R 1 R52 R151' R 5 A52 R 5 Fe 2 gal and R52 wherein R51 and R52 are each independently selected from H and a substituted or unsubstituted organic group, optionally wherein R52 and R52 are each independently selected from H, a halogen, Cl to C3 alkyl, and Cl to C3 haloalkyl.39. The PARP1 inhibitor compound for use according to claim 38, wherein R6 is selected from -F, -Cl, -CN, -CONH2, -CONHMe, -CONHEt, -CONMe2, -CONHCOMe, -CONHCH2-CH2ONle, -CONH-CH2-CH2F, -CONH-CH2-CF3, -CONH-CH2-CHF2, -OCHF2, -NHCOMe, -NHSO2Me,H HThsir,N N co _sce..1 H \sick s,,,,,k 502NHMe, -CONHSO2Nle, 0 0 1,1 NJ 1,1-21HN 2-S NI, N --<1 H-tN 1)..HN-N O, and 40. The PARP1 inhibitor compound for use according to claim 39, wherein Ft' is CONHMe.41, The PARP1 inhibitor compound for use according to claim 39, wherein R 42. The PARPI inhibitor compound for use according to any of claims 1 to 37, wherein R5 and one group together form a ring. 112.43. The PARP1 inhibitor compound for use according to any of claims 1 to 12, wherein group I_ is selected from: 4N N MN, optionally \ /F \ /HN, optionally ki(11)-0N1/ \N \HNNiv) - , optionallyN N v)NN \ r <>-Nit411'\ NN-/ H;NN N-Ch( HN-, optionally tr-Th N," " or iiiN N HN'HN-optionally I.NHNviii) , optionally 44. The PARP1 inhibitor compound for use according to claim 43, wherein the compound has a structure selected from. 0 leis 4(15 N 0HN-6cisN -N 0 /NHNHN--N ° rThk,N I-1NN 7(15 aN n 1-1N--(1 kisNHN-k." je7iN-6trans ^IN \L_,N 7 trans use according to any preceding claim, wherein, Wm, R5A2, R5A2), R56, Rsc, R6, R', R52, R52, Rs' is a the or each substituted or unsubstituted organic 45, The PARP1 inhibitor compound for when one or more of R', R2, R5, R4, RSA (e g. substituted or unsubstituted organic group, group is independently selected from: deuterium; a halogen (such as -F, -Cl, -Br nd -I): a nitrile group; a substituted or unsubstituted linear or branched Ci-C6 alkyl group (such as Me, Et, Pr, i-Pr, n-Bu, i-Bu, t-Bu, pentyl and hexyl); a substituted or unsubstituted linear or branched Ci-C6 alkyl-aryl 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)I-Ph, -CH2CH2Ph, -CH2CH2CH2Ph, -CH2CH2CH2CH2Ph, -CH2CH2CH2CH2CH2Ph, and -CH2CH2CH2CH2CH2CH2Ph); a substituted or unsubstituted linear or branched Ci-C6 halogenated alkyl group (such as -CH2F, -CH2CI, -CH2Br, -CH21, -CHF2, -CF3, -CCI3 -CBr3, -CI3, -CH2CH2F, -CH2CF3, -CH2CCI3, -CH2CBr3, and -CH2CI3); NH2 or a substituted or unsubstituted linear or branched primary secondary or tertiary Ci-C6 amine group (such as -NMeH, -NMe2, -NEtH, -NEtMe, -NEt2, -NPrH, -NPrMe, -NPrEt, -NPr2, - NBuH, -NBuMe, -NBuEt, -CH2-NH2, -CH2-NMeH, -CH2-NMe2, -CH2-NEtH, -CH2-NEtMe, -CH2-NEt2, -CH2-NPrH, -CH2-NPrMe, and -CH2-NPrEt); a substituted or unsubstituted amino-aryl group (such as -NH-Ph, -NH-(2,3 or 4)F-Ph, -NH-(2,3 or 4)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)Cl2-Ph, -NH-2,(3,4,5 or 6)Br2-Ph, -NH-2,(3,4,5 or 6)12-Ph, -NH-2,(3,4,5 or 6)Me2-Ph, -NH-2,(3,4,5 or 6)Et2-Ph, -NH-2,(3,4,5, or 6)Pr2-Ph, -NH-2,(3,4,5 or 6)Bu2-Ph), a substituted or unsubstituted cyclic amine or amido group (such as pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, 2-keto-pyrrolidinyl, 3-keto-pyrrolidinyl, 2-keto-piperidinyl, 3-keto-piperidinyl, and 4-keto-piperidinyl); a substituted or unsubstituted cyclic C3-C8 alkyl group (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl); an -OH group; a substituted or unsubstituted linear or branched Ci-C6 alcohol group (such as -CH2OH, -CH2CH2OH, -CH(CH3)CH2OH, -C(CH3)20H, -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-C6 carboxylic acid group (such as -COOH, -CH2COOH, -CH2CH2COOH, -CH2CH2CH2COOH, -CH2CH2CH2CH2COOH, and -CH2CH2CH2CH2CH2COOH); a substituted or unsubstituted linear or branched carbonyl group (such as -(CO)Me, -(CO)Et, -(CO)Pr, -(CO)iPr, -(CO)nBu, -(CO)iBu, -(CO)tBu, -(CO)Ph, -(CO)CH2Ph, -(CO)CH2OH, -(CO)CH2OCH3, -(CO)CH2NH2, -(CO)CH2NHMe, -(CO)CH2NMe2, -(C0)-cyclopropyl, -(CO)-1,3-epoxypropan-2-yl; -(CO)NH2, -(CO)NHMe, -(CO)NMez, -(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)NHCH2CH2NMez); a substituted or unsubstituted linear or branched Ci-C6 carboxylic acid ester group (such as -COOMe, -COOEt, -COOPr, -COO-i-Pr, -000-n-Bu, -000-i-Bu, -000-t-Bu, -CH2COOMe, -CH2CH2COOMe, -CH2CH2CH2COOMe, and -CH2CH2CH2CH2COOMe); a substituted or unsubstituted linear or branched Ci-CE amide group (such as -CO-NH2, -CO-NMeH, -CO-NMe2, -CO-NEtH, -CO-NEtMe, -CO-NEt2, -CO-NPrH, -CO-NPrMe, and -CO-NPrEt); a substituted or unsubstituted linear or branched Ci-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 Ci-C7 alkoxy or aryloxy group (such as -0Me, -OEt, -OPr, -0-i-Pr, -0-n-Bu, -0-i-Bu, -0-t-Bu, -0-pentyl, -0-hexyl, -OCH2F, -OCHF2, -OCF3, -OCH2CI, -OCHCl2, -OCCI3, -0-Ph, -0-CH2-Ph, -0-CH2-(2,3 or 4)-F-Ph, -0-CH2-(2,3 or 4)-CI-Ph, -CH20Me, -CH20Et, -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 -502Me, -502Et, -SO2Pr, -502iPr, -SO2Ph, -S02-(2,3 or 4)-F-Ph, -S02-cyclopropyl, -S020-120-120013, -SO2NH2, -SO2NHMe, -SO2NMe2, -SO2N H Et, -SO2N Et2, -S02-pyrrol idine-N-yl, -S02-morpholine-N-yl, -502NHCH20Me,and -502NHCH2CH20Me); a substituted or unsubstituted aminosulfonyl group (such as -NHSO2Me, -NHS02Et, -NHSO2Pr, -NHS02iPr, -NHSO2Ph, -NHS02-(2,3 or 4)-F-Ph, -NHS02-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-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)-12-Ph-, 2,(3,4,5 or 6)-Mee-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)-(Me0)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)-b-Ph-, 3,(4 or 5)-Me2-Ph-, 3,(4 or 5)-Et2-Ph-, 3,(4 or 5)-PrrPh-, 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)-(Me0)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-Me0-Ph-, 3-Me0-Ph-, 4-Me0-Ph-, 2-(NH2-00)-Ph-, 3-(NH2-CO)-Ph-, 4-(NH2-CO)-Ph-, 2-CF3-Ph-, 3-CF3-Ph-, 4-CF3-Ph-, 2-CF30-Ph-, 3-CF30-Ph-, and 4-CF30-Ph-); a saturated or unsaturated, substituted or unsubstituted, heterocyclic group, optionally an aromatic heterocyclic group or a non-aromatic heterocyclic group (such as pyrrole-1-yl, pyrrole-2-yl, pyrrole-3-yl, pyrazole-1-yl, pyrazole-3-yl, pyrazole-4-yl, pyrazole-5-yl, imidazole-1-yl, imidazole-2-yl, imidazole-4-yl, imidazole-5-yl, 1,2,3-triazole-1-yl, 1,2,3-triazole-4-yl, 1,2,3-triazole-5-yl, 1,2,4-triazole-1-yl, 1,2,4-triazole-3-yl, 1,2,4-triazole-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazine-3-yl, pyridazine-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, pyrazine-2-yl, pyrrolidine-1-yl, pyrrolidine-2-yl, pyrrolidine-3-yl, piperidine-1-yl, piperidine-2-yl, piperidine-3-yl, piperidine-4-yl, 2-azapiperidine-1-yl, 2-azapiperidine-3-yl, 2-azapiperidine-4-yl, 3-azapiperidine-1-yl, 3-azapiperidine-2-yl, 3-azapiperidine-4-yl, 3-azapiperidine-5-yl, piperazine-1-yl, piperazine-2-yl, furan-2-yl, furan-3-yl, pyran-2-yl, pyran-3-yl, pyran-4-yl, 2-azapyran-2-yl, 2-azapyran-3-yl, 2-azapyran-4-yl, 2-azapyran-5-yl, 2-azapyran-6-yl, 3-azapyran-2-yl, 3-azapyran-4-yl, 3-azapyran-5-yl, 3-azapyran-6-yl, 4-azapyran-2-yl, 4-azapyran-3-yl, 4-azapyran-4-yl, 4-azapyran-5-yl, 4-azapyran-6-yl, oxetan-2-yl, oxetan-3-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-2-yl, 2-aza-tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-4-yl, 2-aza-tetrahydrofuran-5-yl, 3-aza-tetrahydrofuran-2-yl, 3-aza-tetrahydrofuran-3-yl, 3-aza-tetrahydrofuran-4-yl, 3-aza-tetrahydrofuran-5-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, 2-aza-tetrahydropyran-2-yl, 2-aza-tetrahydropyran-3-yl, 2-aza-tetrahydropyran-4-yl, 2-aza-tetrahydropyran-5-yl, 2-aza-tetrahydropyran-6-yl, 3-aza-tetrahydropyran-2-yl, 3-aza-tetrahydropyran-3-yl, 3-aza-tetrahydropyran-4-yl, 3-aza-tetrahydropyran-5-yl, 3-aza-tetrahydropyran-6-yl, morpholine-2-yl, morpholine-3-yl, morpholine-4-yl, thiophen-2-yl, thiophen-3-yl, isothiazole-3-yl, isothiazole-4-yl, isothiazole-5-yl, thiazole-2-yl, thiazole-4-yl, thiazole-5-yl, thiopyran-2-yl, thiopyran-3-yl, thiopyran-4-yl, 2-azathiopyran-2-yl, 2-azathiopyran-3-yl, 2-azathiopyran-4-yl, 2-azathiopyran-5-yl, 2-azathiopyran-6-yl, 3-azathiopyran-2-yl, 3-azathiopyran-4-yl, 3-azathiopyran-5-yl, 3-azathiopyran-6-yl, 4-azathiopyran-2-yl, 4-azathiopyran-3-yl, 4-azathiopyran-4-yl, 4-azathiopyran-5-yl, 4-azathiopyran-6-yl, thiolane-2-yl, thiolane-3-yl, thiane-2-yl, thiane-3-yl, thiane-4-yl, oxazol-5-yl, isoxazol-3-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-y1; and tetrazole-1-yl, tetrazole-2-yl, tetra zol e-5-y1); wherein: a pair of RSA groups attached to different atoms may together form a ring with ring A atoms; and/or a pair of R56 groups attached to different atoms may together form a ring with ring B atoms, and/or a pair of RSC groups attached to different atoms may together form a ring with ring C atoms; and/or an RSC group and an R6 group attached to different atoms may together form a ring with ring C atoms.46. The PARP1 inhibitor compound for use according to any preceding claim, wherein each of 115A (e.g., R5A1, R5A2, R5A3), R58, and RSC is independently absent or selected from: H, deuterium, a halogen (such as -CI, -Br, and -I; preferably F or CI), a nitrile group, a substituted or unsubstituted CI-Cs alkyl group, a substituted or unsubstituted linear or branched Ci-C6 halogenated alkyl group (preferably CF3 or CHF2), a cyclopropyl group, an -OH group, a substituted or unsubstituted linear or branched Ci-C6 alcohol group, a substituted or unsubstituted linear or branched Ci-C7 amino carbonyl group (such as -NH-CO-Me), an -NH2 group, a substituted or unsubstituted CE-C6 amino group, and a substituted or unsubstituted alkoxy group; wherein, when a pair of R54 groups attached to different atoms together forms a ring with ring A atoms and/or a pair of 12'4 groups attached to different atoms together forms a ring with ring B atoms and/or a pair R5c groups attached to different atoms together forms a ring with ring C atoms, each of the pair of Rite or Rsc groups independently comprises -CH2-or -CH2CHr, or the pair of groups together comprise -0-1,--CH-ChlirCH-or -NH-CO-NH-.47. The PARP1 inhibitor compound for use according to any preceding claim, wherein at least one of Qa, Qb, and Qc is: wherein t u is at least 1; and wherein R7 is selected from H, a halogen (such as -F, -CI, -Br, and preferably -F), a substituted or unsubstituted Ca-Cv alkyl group, a substituted or unsubstituted linear or branched Ci-C6 halogenated alkyl group (preferably CF,), an -NH2 group or a substituted or unsubstituted Ci-C6 amino group, an -OH group or a substituted or unsubstituted linear or branched C1-C6 alcohol group and a substituted or unsubstituted C1-C6 alkoxy group.48. The PARP1 inhibitor compound for use according to claim 44, wherein R7 is selected from: H; a halogen, optionally F; a substituted or unsubstituted C.E-C6 alkyl group; or a substituted or unsubstituted linear or branched C1-C6 halogenated alkyl group. or 1.2049. The PARR' inhibitor compound for use according to any preceding clairn, wherein at least one of Qa, Qb and Qc has a structure of: R7 R7 and wherein le is selected from: H; a substituted or unsubstituted linear or branched Cr-C6 alkyl group (such as Me, Et, Pr, i-Pr, n-Bu, i-Bu, t-Bu, pentyl and he.xyl); a substituted or unsubstituted linear or branched C1-0 alkyl-aryl group (such as -CH2Ph, -012(2,3 or 4)F-Ph, -CI-12(2,3 or 4)0-Ph, -Ci-12(2,3 or 4)13r-P -CH2(2,3 or 4)I-Ph, -0-12CH2Ph, -CH2CH2C1-12Ph, -CH2CH2CH2CH2Ph, -012012CH2012CH2Ph, and -0-12-012CH2C132012CH2Ph); a substituted or unsubstituted linear or branched Ct-Ca halogenated alkyl group {such as -CH2F, -CF3, -CH2CH2F and -CH2CE-.1); a substituted or unsubstituted cyclic amine or amido group (such as pyrrolidin-3-yl, piperidin-3-yl, 2-keto-pyrrolidinyl, 3-keto-pyrroiidillylp 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); a substituted or unsubstituted linear or branched C2-C6 alcohol group {such as -CH2CH2OH, -CH(CH3}CH2OH, -CfCH020H, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, -CH(CH1)CH2CH2OH, -CH(CF3)CH(CH3)0H, -CH(CH2CH4C)-120H, -C(CH2)2CH2OH, -CH2CH2CH2CH2CH2OH, and -CH2CH2CH2CH2CH2CH2OH); a substituted or unsubstituted linear or branched C2-Co carboxylic acid group (such as -CH2COOH, -CH2CH2COOH, -CH2CH2CH2COOH, -CH2CH2CH2CH2COOH, and -CH2CH2CH2CH2CH2COOH);Na 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, -(C0)-1,3-epoxypropa n-2-y1; -(CO)NH 2, -(CO)NH Me, -(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-C6 carboxylic acid ester group (such as -COOMe, -COOEt, -COOPr, -COO-i-Pr, -COO-n-Bu, -COO-i-Bu, -COO-t-Bu, -CH2COOMe, -CH2CH2COOMe, -CH2CH2CH2COOMe, and -CH2CH2CH2CH2COOMe); a substituted or unsubstituted linear or branched Ci-C6 amide group (such as -CO-NH2, -CO-NMeH, -CO-NMe2, -CO-NEtH, -CO-NEtMe, -CO-NEt2, -CO-NPrH, -CO-NPrMe, and -CO-NPrEt); a substituted or unsubstituted sulfonyl group (such as -502Me, -502Et, -SO2Pr, -S02iPr, -SO2Ph, -S02-(2,3 or 4)-F-Ph, -S02-cyclopropyl, -S02CH2CH2OCH3), -SO2NH2, -SO2NHMe, -SO2NMe2, -SO2NHEt, -SO2NEt2, -502-pyrrolidine-N-yl, -502-morpholine-N-yl, -502NHCH20Me, and -502NHCH2CH20Me); 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-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)-b-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)-BuzPh-, 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)-(Me0)2-Ph-, 2,(3,4,5 or 6)-(CF3)2-Ph-, 3,(4 or 5)-F2-Ph-, 3,(4 or 5)-C12-Ph-, 3,(4 or 5)-Br2-Ph-, 3,(4 or 5)-b-Ph-, 3,(4 or 5)-Me2-Ph-, 3,(4 or 5)-Et2-Ph-, 3,(4 or 5)-Pre-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)-(Me0)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-Me0-Ph-, 3-Me0-Ph-, 4-Me0-Ph-, 2-(NH2-00)-Ph-, 3-(NH2-CO)-Ph-, 4-(NH2-CO)-Ph-, 2-CF3-Ph-, 3-CF3-Ph-, 4-CF3-Ph-, 2-CF30-Ph-, 3-CF30-Ph-, and 4-CF30-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-y1; and tetrazole-5-y1).50. The PARP1 inhibitor compound for use according to claim 49, wherein R8 is selected from H, a substituted or unsubstituted linear or branched Ci-05 alkyl group, and a substituted or unsubstituted linear or branched Cs-C6 halogenated alkyl group.51. The PARP1 inhibitor compound for use according to any preceding claim, which compound comprises: an isolated enantiomer, or a mixture of two or more enantiomers, or a mixture of two or more diastereomers, and/or epimers, or a racemic mixture, or a tautomer of the compound.52. The PARP1 inhibitor compound for use according to any preceding claim, which is selective for PARP1 over PARP2.53. The PARP1 inhibitor compound for use according to any preceding claim, which is for use in treating a cancer.54. The PARP1 inhibitor compound for use according to claim 53, wherein the cancer is selected from: a cancer of the eye, brain (such as gliomas, glioblastomas, medulloblastomas, craniopharyngioma, ependymoma, and astrocytoma), spinal cord, kidney, mouth, lip, throat, oral cavity, nasal cavity, small intestine, colon, parathyroid gland, gall bladder, head and neck, breast, bone, bile duct, cervix, heart, hypopharyngeal gland, lung, bronchus, liver, skin, ureter, urethra, testicles, vagina, anus, laryngeal gland, ovary, thyroid, oesophagus, nasopharyngeal gland, pituitary gland, salivary gland, prostate, pancreas, adrenal glands; an endometrial cancer, oral cancer, melanoma, neuroblastoma, gastric cancer, an angiomatosis, a hemangioblastoma, a pheochromocytoma, a pancreatic cyst, a renal cell carcinoma, Wilms' tumour, squamous cell carcinoma, sarcoma, osteosarcoma, Kaposi sarcoma, rhabdomyosarcoma, hepatocellular carcinoma, PTEN Hamartoma-Tumor Syndromes (PHTS) (such as Lhermitte-Duclos disease, Cowden syndrome, Proteus syndrome, and Proteus-like syndrome), leukaemias and lymphomas (such as acute lymphoblastic leukaemia, chronic lymphocytic leukaemia, acute myelogenous leukaemia, chronic myelogenous leukaemia, hairy cell leukaemia, T-cell prolymphocytic leukaemia (T-PLL), large granular lymphocytic leukaemia, adult T-cell leukaemia, juvenile myelomonocytic leukaemia, Hodgkin lymphoma, non-Hodgkin lymphoma, mantle lymphoma, follicular lymphoma, primary effusion lymphoma, AIDS-related lymphoma, diffuse B cell lymphoma, Burkitt lymphoma, cutaneous T-cell lymphoma, nasopharyngeal and gastrointestinal cancers; optionally wherein the cancer is a cancer of the brain or spinal cord.55. The PARP1 inhibitor compound for use according to claim 53 or claim 54, wherein the cancer is deficient in a DNA damage response repair pathway, such as Homologous Recombination dependent DNA Double Strand Break DNA repair activity.56. The PARP1 inhibitor compound for use according to any of claims 53 to 55, wherein the cancer is deficient in BRCA1 and/or BRCA2 function.57. The PARP1 inhibitor compound for use according to any of claims 53 to 56, 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.58. The PARP1 inhibitor compound for use according to claim 57, wherein the further agent is an immunotherapeutic agent selected from: an anti-tumour vaccine; an oncolytic virus; an immune stimulatory antibody such as a nti-CTLA4, anti-PD1, anti-PDL-1, anti-0X40, anti-41BB, anti-CD27, anti-CD40, anti-LAGS, anti-TIM3, and anti-GITR; a pattern recognition receptor agonist such as a STING, TLR-9 or RIG-I Helicase agonist; an IDO or TDO inhibitor; a novel adjuvant; a peptide; a cytokine; a chimeric antigen receptor T cell therapy (CAR-T); a small molecule immune modulator; and a tumour microenvironment modulator.59. A pharmaceutical composition comprising a PARP1 inhibitor compound as defined in any of claims 1 to 52.60. A pharmaceutical composition according to claim 59, 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.61. The pharmaceutical composition according to claim 59 or claim 60, 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.62. The pharmaceutical composition according to claim 61, wherein the further agent comprises an immunotherapeutic agent selected from: an anti-tumour vaccine; an oncolytic virus; an immune stimulatory antibody such as anti-CTLA4, anti-PD1, anti-PDL-1, anti-0X40, anti-4166, anti-CD27, anti-CD40, anti-LAG3, anti-TIM3, and anti-GITR; a pattern recognition receptor agonist such as a STING, TLR-9 or RIG-I Helicase agonist; an IDO or TDO inhibitor; a novel adjuvant; a peptide; a cytokine; a chimeric antigen receptor T cell therapy (CAR-T); a small molecule immune modulator; and a tumour microenvironment modulator.63. The pharmaceutical composition according to any of claims 59 to 62, for use in treating a cancer.64. A pharmaceutical kit for treating a cancer, which pharmaceutical kit comprises: a) a PARP1 inhibitor compound as defined in any of claims 1 to 51; and b) a further agent for treating cancer; wherein the compound and the further agent are suitable for administration simultaneously, sequentially or separately; and optionally wherein the further agent for treating cancer is selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase I inhibitors, topoisomerase II inhibitors, antimetabolites, senolytic agents, hormones and hormone analogues, signal transduction pathway inhibitors, other DNA damage repair pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, antibody-drug conjugates, hormone-deprivation therapy, immunotherapeutic agents (such as selected from an anti-tumour vaccine; an oncolytic virus; an immune stimulatory antibody such as antiCTLA4, anti-PD1, anti-PDL-1, anti-0X40, anti-41BB, anti-CD27, anti-CD40, anti-LAG3, antiTIM3, and anti-GITR; a pattern recognition receptor agonist such as a STING, TLR-9 or RIG-I Helicase agonist; an IDO or TDO inhibitor; a novel adjuvant; a peptide; a cytokine; a chimeric antigen receptor T cell therapy (CAR-T); a small molecule immune modulator; a tumour microenvironment modulator), proapoptotic agents, radioligand therapies, anti-angiogenic agents, and cell cycle signalling inhibitors.65. 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.66. The method according to claim 65, wherein the patient is an animal, preferably a mammal, optionally a human, canine, equine or feline; and preferably a human.67. A compound selected from: 1.27 ° N\ .1HN irisN.,\2 HN-/ \N N \ / 2ds 4cisNNTTL20--1/ tiN-N 0 "N " / HN-6trans r of \I' \___JN 7transN N 70.5 rJNN N Sets-iiN -&Tarts The compound according to claim 67, which compound comprises: an Isolated enantiomer, or a mixture of two or more enantiomers, or a mixture of two or more diastereomers, and/or epimers, or a racemic mixture, or a tautomer of the compound.69. A method of synthesising a PARP1 inhibitor compound as defined in any of claims 1 to 52, which method comprises conducting a reaction between: i) a first reactant comprising ring E bearing a first portion of group L and ii) a second reactant comprising a remainder of group L, to form the PARP1 inhibitor compound.70. A method according to claim 69, wherein the first reactant comprises ring E and ring A, and the second reactant comprises a Qb precursor bearing a reactive group, which method comprises joining ring A to the Qb precursor.71. A method according to claim 70, wherein the reactive group of the Qb precursor comprises a carbonyl group, an alkyl halide, or an alkyl sulfonate.72. A method according to any of claims 69 to 71, wherein the reaction comprises alkylation, reductive amination or amide formation so as to form group L. 73. A method according to claim 72, wherein the first reactant comprises ring E, ring A, Qa, and ring B, and the second reactant comprises a ring C derivative bearing a leaving group such as a halide or sulfonate.74. A method according to claim 70 or claim 71, wherein the reaction comprises a nucleophilic substitution reaction, such as a nucleophilic aromatic substitution reaction, so as to form group L. 75. The method according to any of claims 9 to 71, which method is to synthesise a PARP1 inhibitor compound wherein Lisa group having a structure of: :NVGAINQa R R5A IRSA H SrR56 &Li (X, NBx1 Qc \cX2); \R55 R561 \R58 5C Rso i X (27R5C ),( Cl 2 '2 6 X)r R F'5e 15C wherein the first reactant has a structure of: R"Th Z1 R 72 R9 being a protectin ou p, optionally a Cl to C6 alkyl group, and preferably a methyl group; wherein the second reactant has a structure of: R5Ei R5B H-N? B' \x" Qc "2" \ 56 (X) R \ P511 R RRSCIX R5C R5C R5C 2:(2() C I 2.9( ); X2 R6 R5C7 6c I 1.30 wherein conducting the reaction comprises: i) coupling the first reagent and the second reagent using a reducing agent in the presence of an acid to obtain an intermediate product having a structure of: 5B 5B Qc -X' (X2), R Sc R \ IR i R 5C * 2)q V / \ ----N, B:xi (x2)0 R58 R9 RSA R50 \ /2 R.1..1 X -': '''-.',4I E2-Z1....,,_ "..-X,.., R -22 Oa (5p 3. R /R \ 11 RSA \R5A \ R R 5B/ n5G/ Rk 5c, -X2 R5 R5C and ii) subsequently deprotecting ring E' to form the PARR' inhibitor compound.76. The method according to claim 75, wherein rings A, B', and B are all saturated rings.77. The method according to claim 76, wherein the X1 of rings B and B' is N. 78. The method according to any of claims 75 to 77, 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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