WO2024061554A1 - Pharmaceutical compound - Google Patents

Abstract

A PARP7 inhibitor compound comprises formula (I), X1 is selected from C, and N. R1, R2, and R3, are each independently H or an organic group. R9 is H or an organic group, or is absent when X1 is N. L is (II). Each R4 is independently selected from H or an organic group. t is selected from 1, 2, or 3. Y is (III) or (IV). Z is (V). X2 and X3 are independently selected from C and N. Each R6 is H or an organic group, or absent when attached to an N. p + q equals 1, 2, 3 or 4 and r + s equals 1, 2, 3, or 4. R5 is (VI), (VII), (VIII) or (IX). Each X4 is C or N. Each R7 is H or an organic group, or absent when attached to an N. R8 is H or an organic group.

Description

PHARMACEUTICAL COMPOUND

Technical Field

The present invention relates to PARP7 inhibitor compounds, and in particular to PARP7 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, an infectious disease, a central nervous system disease or disorder, a pain condition and other diseases, conditions and disorders. The invention also relates to methods of manufacture of such inhibitors, and methods of treatment using such inhibitors.

Background to the Invention

Monoclonal antibody-based therapeutics targeting immune checkpoints, most notably the PDL1-PD1 axis, are transforming approaches to the treatment of cancer. These agents have been demonstrated to elicit complete and durable regressions of metastatic disease, most notably in the setting of malignant melanoma. PDL1 expressed by tumour (and other) cells delivers an inhibitory signal via ligation of PD1 on T-cells. Blocking this interaction with antibodies targeting PD1 or PDL1 results in T-cell reactivation, recognition of tumour cell neoantigens and CD8+ve T-cell-mediated tumour cell killing (Hashem O. et al. PD-1 and PD- L1 Checkpoint Signalling Inhibition for Cancer Immunotherapy: Mechanism, Combinations, and Clinical Outcome. Front Pharmacol. 8: 561, (2017)). Despite these developments the fact remains that tumour responses are only observed in a minority of cancer patients. Furthermore, in many patients that do respond responses are not durable. There is an urgent need to identify and develop complementary therapies that will broaden the population for whom immunomodulatory therapy delivers benefit.

Immune checkpoint inhibitors (ICIs) such as anti-PDl and anti-PDLl act by relieving checkpoint restraints on anti-tumour T cell responses. They work best against immunogenic, T-cell inflamed or hot tumours. In contrast, ICIs are poorly efficient in cold tumour microenvironments (TMEs) that are largely devoid of T cells and infiltrated by immunosuppressive cells. In hot TMEs, increased expression of type I interferons (IFN-I) and IFN-stimulated genes (ISGs), such as T-cell attracting chemokines, contribute to potent antitumour responses. One emerging therapeutic strategy to transform cold tumours into hot exploits the use of pattern recognition receptor (PRR) agonists. Indeed, combinations of ICIs with agonists of RIG-I Helicase, Toll-like receptor 9 (TLR9) or stimulator of interferon genes (STING) have now reached clinical evaluation.

The innate immune system provides a first line of host defence and plays a crucial role in initiating and driving the development of adaptive immune responses. The cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) can be activated by double stranded DNA arising from the genomes of invading pathogens and also by aberrant cytosolic levels of host DNA that are generated in tumour cells (Chen Q et al. Regulation and function of the cGAS-STING pathway of cytosolic DNA sensing. Nat Immunol. 17: 1142-9, (2016)). Activation of cGAS leads to the generation of cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) which induces 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 generation of immunity (Zhu Y et al. STING: a master regulator in the cancer-immunity cycle. Mol Cancer 18: 152 (2019)). As such, activation of the STING pathway has become of increasing interest to the cancer drug discovery community as a potential strategy to boost the development of adaptive immune responses to tumour cell neoantigens (Sivick K.E. et al. Magnitude of Therapeutic STING Activation Determines CD8+ T Cell-Mediated Anti -tumor Immunity. Cell Reports. 25: 3074, (2018)). Cytoplasmic DNA sensing has also been linked to inactivation of cellular proliferation providing an additional potential mechanistic axis that may contribute to control of tumorigenesis (Paludan S.R. et al. DNA-stimulated cell death: implications for host defence, inflammatory diseases and cancer. Nat Rev Immunol . 19: 141- 153, (2019)).

Cancer cells can exhibit a chronic Interferon-stimulate gene (ISG) signature triggered by a STING-dependent pathway, which results in a unique primed cancer cell state that is sensitized to respond to aberrant nucleic acid accumulation (Liu H et al. Tumor-derived IFN triggers chronic pathway agonism and sensitivity to ADAR loss. Nat Medicine. 25: 95-102, 2019). It has recently been shown that genomic instability, in the form of unrepaired DNA double-strand breaks or micronuclei disruption can trigger STING-dependent anti-tumour responses. For example, use of chemotherapeutics can lead to higher levels of aberrant DNA in the cytosol which in turn can trigger cancer cell intrinsic STING signalling leading to anti-tumour immunity. Indeed the efficacy of the commonly used chemotherapeutic drug 5 -fluorouracil (5- FU) was recently shown to depend on anti-tumor immunity triggered by the activation of cancer-cell intrinsic STING (Tian J etal. 5 -Fluorouracil efficacy requires anti-tumor immunity triggered by cancer-cell-intrinsic STING. EMBO J 40: el06065 (2021)). In addition, PARP inhibitor-induced STING pathway activation and anti-tumor immune responses have been demonstrated in multiple tumour models, providing rationale for exploiting combinations of PARP inhibitors with immunotherapies for improved therapeutic efficacy. 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. STING agonism enhances anti-tumor immune responses and therapeutic efficacy of PARP inhibition in BRCA-associated breast cancer. bioRxiv (2021)). The authors hypothesize that STING agonism can enhance the therapeutic efficacy of PARP inhibitors in BRCA-associated triplenegative breast cancer (TNBC).

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.

Poly-ADP -ribose polymerase 7 (PARP7, TIP ARP, ARTD14), a member of the wider PARP enzyme family, modulates protein function by using nicotinamide adenine dinucleotide (NAD+) as a substrate to transfer an ADP -ribose monomer onto specific amino acid acceptor residues of target proteins (Gomez A et al. Characterisation of TCDD-inducible poly-ADP- ribose polymerase (TIPARP/ARTD14) catalytic activity. Biochemical Journal. 475: 3827- 3846, (2018)). PARP7 catalyses mono-ADP ribosylation (MARylation) of its target substrates and as such is a member of the mono(ADP -ribosyl) transferase (MART) enzymes, a subclass of the PARP family of enzymes (reviewed in Challa L. et al. MARTs and MARylation in the Cytosol: Biological Functions, Mechanisms of Action, and Therapeutic Potential. Cells 10, 313 (2021)). PARP7 is a target gene of the Aryl Hydrocarbon Receptor (AHR) which is a ligand- activated transcription factor and member of the basic helix-loop-helix/Per-AHR nuclear translocator (ARNT)-Sim (PAS) protein family which plays a central role in controlling immune responses. Therefore, PARP7 has emerged as a critical regulator of the innate immune response. The PARP7 gene is amplified in a number of cancers, notably those of the upper aerodigestive tract (Vasbinder, M.M. et al. RBN-2397: A First-in-class PARP7 inhibitor targeting a newly discovered cancer vulnerability in stress-signalling pathways. Cancer Res. 80: 16 suppl DDT02-01, (2020)). PARP7 has been reported to ADP ribosylate and inactivate the kinase domain of TBK1 resulting in suppression of a central pathway for interferon production (Yamada T et al. Constitutive aryl hydrocarbon receptor signalling constrains type I interferon-mediated antiviral innate defence. Nature Immunol. 17: 687-694, (2016)). The possibility of using PARP7 inhibitors in cancer therapy, especially in the treatment of lung squamous cell carcinoma, has been described in WO 2016/116602 Al. The discovery of a potent and selective inhibitor of PARP7, RBN-2397 has been recently reported (Vasbinder, M.M. et al. RBN-2397: A First-in-class PAPR7 inhibitor targeting a newly discovered cancer vulnerability in stress-signalling pathways. Cancer Res. 80: 16 suppl DDT02-01, (2020); Gozgit J et al. PARP7 negatively regulates the type I interferon response in cancer cells and its inhibition leads to tumour regression. Cancer Res. 80: 16 suppl 3405, (2020); Gozgit J et al. PARP7 negatively regulates the type I interferon response in cancer cells and its inhibition triggers antitumor immunity. Cancer Cell 39: 1-13, 2021). RBN-2397 potently inhibited proliferation in cancer cell lines with high baseline expression of interferon stimulated genes and restored type I interferon responses both in vitro and in vivo resulting in tumour regression and establishment of specific anti-tumour immunity in animal models. WO 2019/212937 Al describes pyridazinone compounds as inhibitors of PARP7 for use in the treatment of cancer. The monocyclic pyridazinone ring is claimed as an essential feature in the interaction with the PARP7 target. These observations provide a rational basis for generating novel agents to inhibit PARP7 and induce therapeutic anti-tumour responses.

There is also an established and growing literature highlighting key roles of PARP7 in other diseases: Infectious diseases

The inactive PARP family member, PARP13, which plays a key role in regulating the antiviral innate immune response, is a major substrate of PARP7 (Rodriguez, K etal. Chemical genetics and proteome-wide site mapping reveal cysteine MARylation by PARP-7 on immune-relevant protein targets. Elife. 10:e60480, (2021)). PARP13 is preferentially MARylated on cysteine residues in its RNA binding zinc finger domain. PARP 13 stimulates the interferon response in response to influenza A viral infection via direct activation of the cytosolic nucleic acid sensor RNA helicase RIG-I. This interaction is dependent on the finger domains of PARP13. Hence Cys MARylation of PARP 13 by PARP7 could potentially disrupt the interaction between PARP 13 and RIG-I thus regulating its antiviral and immune regulatory roles.

In addition, PARP7 promotes influenza A virus infection by ADP-ribosylating TBK1, which inhibits type I IFN (IFN-I) production (Yamada T. et al. Constitutive aryl hydrocarbon receptor signaling constrains type-I-interferon-mediated antiviral innate defense. Nat. Immunol. 17: 687-694, (2016)). The same study found that constitutive AHR signalling negatively regulated the type I interferon (IFN-I) response during infection with various types of virus; therefore revealing the physiological importance of endogenous activation of AHR signalling in shaping the IFN-I-mediated innate response and, further, suggesting that the AHR-PARP7 axis is a potential therapeutic target for controlling antiviral responses.

More recently (Heer C. et al. Coronavirus infection and PARP expression dysregulate the NAD Metabolome: an actionable component of innate immunity. J Biol Chem. 195, 17986-17996 (2020)) it has been shown that SARS-CoV-2 infection strikingly upregulates MARylating PARPs including PARP7. and induces the expression of genes encoding enzymes for salvage NAD synthesis from nicotinamide (NAM) and nicotinamide riboside (NR), while downregulating other NAD biosynthetic pathways. Furthermore, infection of mice with mouse hepatitis virus (MHV), a coronavirus (CoV), stimulated upregulation of downstream effector PARP7 via activation of the AHR. Knockdown of PARP7 reduced viral replication and increased interferon expression, suggesting that PARP7 functions in a proviral manner during MHV infection (Grunewald M.E. et al. Murine Coronavirus Infection Activates the Aryl Hydrocarbon Receptor in an Indoleamine 2,3 -Dioxygenase-Independent Manner, Contributing to Cytokine Modulation and Proviral TCDD-Inducible-PARP Expression. J. Virology 94: e01743-19 (2020)). The AhR is also overexpressed following coronavirus infection, including SARS-CoV-2 and, as it regulates PARP gene expression, the latter is likely to be activated in COVID-19 (Badawy A. Immunotherapy of COVID-19 with poly (ADP -ribose) polymerase inhibitors: starting with nicotinamide. Bioscience Reports. 40: BSR20202856 (2020)). Therefore, given its key role in the innate immune system, PARP7 inhibition could be used to improve the outcome of patients with a wide variety of infectious diseases including those driven by viral infection.

Central Nervous System Diseases

PARP7 affects neural progenitor cell proliferation and migration, and its loss leads to aberrant organization of the mouse cortex during development (Grimaldi G et al. Loss of Tiparp Results in Aberrant Layering of the Cerebral Cortex. ENeuro 6(6) 0239-19.2019). PARP7 is highly expressed in the brain with increased expression reported in a range of neurological diseases. PARP7 was identified as a highly upregulated protein following trace fear conditioning and in neurologic disorders, such as epilepsy (Dachet et al. Predicting novel histopathological microlesions in human epileptic brain through transcriptional clustering. Brain 138:356-370, (2015)). In an integrated multi-cohort transcriptional meta-analysis of neurodegenerative diseases including Alzheimers Disease, Amyotrophic Lateral Sclerosis, Parkinsons Disease and Huntingdons Disease, PARP7 was shown to be strongly upregulated (Li et al. Integrated multi-cohort transcriptional meta-analysis of neurodegenerative diseases. Acta Neuropathol Commun 2:93 (2014)). The phenotype of the PARP7-/- mice and expression pattern suggests that alterations in PARP7 expression or function could increase susceptibility to a wide range of both developmental and degenerative neurologic diseases and that inhibitors may potentially show beneficial effects in these conditions.

Nociception

It has recently been reported that STING is a critical regulator of nociception mediated through induction of type I interferon production and subsequent activation of type I interferon receptors on sensory neurons (Donnelly CR et al. STING controls nociception via type I interferon signalling in sensory neurons. Nature. 591 : 275-280 (2021)). Mice lacking STING exhibit hypersensitivity to nociceptive stimuli whereas STING activation elicits marked antinociception in mice and non-human primates. PARP7 is a negative regulator of the STING pathway and inhibitors of PARP7 have been shown to activate this pathway. Such inhibitors may have utility as antinociceptive agents and the treatment of chronic pain conditions including cancer-associated pain and peripheral neuropathy.

In addition, there is therapeutic potential for use of a PARP7 inhibitor in canine cancer as notably recent data showed that intratumoral delivery of a STING agonist resulted in clinical responses in canine glioblastoma (Boudreau CE et al. Delivery of STING Agonist Results in Clinical Responses in Canine Glioblastoma. Clin Cancer Res (2021)).

Having regard to the above, it is an aim of the present invention to provide PARP7 inhibitors, and in particular PARP7 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, an infectious disease, a central nervous system disease or disorder and other diseases, conditions and disorders. It is also an aim to provide methods of synthesis of the compounds.

Summary of the Invention

Accordingly, the present invention provides a PARP7 inhibitor compound, which compound comprises the following formula:

wherein, is independently selected from C and N; R1 is independently selected from H or a substituted or unsubstituted organic group; R^ is independently selected from H or a substituted or unsubstituted organic group; is independently selected from H or a substituted or unsubstituted organic group; and R^ is independently selected from H or a substituted or unsubstituted organic group, and when

is N, R^ is absent; and wherein L is a group having the following formula:

wherein each R^ is independently selected from H or a substituted or unsubstituted organic group; t is selected from 1, 2, or 3, preferably 1 or 2; wherein Y comprises a group selected from one of the following formulae:

and wherein Z comprises a group having the following formula:

wherein X² and X³ are each independently selected from C and N; each R⁶ is independently selected from H or a substituted or unsubstituted organic group, and when an R⁶ is attached to an X² or an X³ that is an N, it is absent; each of p, q, r and s are independently selected from 0, 1, 2, 3, and 4, provided that p + q equals 1, 2, 3 or 4 and r + s equals 1, 2, 3, or 4; the bonds between all of the atoms in ring A may independently be single bonds or double bonds provided that when X² is N the bonds to X² are single bonds; the bonds between all of the atoms in ring B may independently be single bonds or double bonds provided that when X³ is N the bonds to X³ are single bonds; and wherein R⁵ comprises a group selected from one of the following formulae:

wherein each X⁴ is independently selected from C and N; each R⁷ is independently selected from H or a substituted or unsubstituted organic group, and when an X⁴ is N, the R⁷ attached to it is absent; and R⁸ is independently selected from H or a substituted or unsubstituted organic group. Preferably, each of p, q, r and s are independently selected from 0, 1, 2 and 3, provided that p + q equals 1, 2, or 3 and r + s equals 1, 2, or 3. Optionally, Z comprises a group having the following formula:

In these compounds, and elsewhere herein, in some embodiments any R group may form a ring with any other R group on an adjacent and/or proximal atom, although in most embodiments this is not preferred, except where explicitly stated. Thus, in some embodiments the following substituents may together form a ring: R¹ with R⁹; R³ with R⁴; R⁴ with another R⁴; R⁴ with R⁶; R⁴ with R⁹; R⁵ with R⁶; R⁶ with another R⁶; R⁶ with R⁷; R⁷ with another R⁷; and R⁷ with R⁸. In the context of the present invention, 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 R groups attached to the same atom do not together form a ring, although this is not excluded.

In the present context the invention includes compounds in which a single R group on an atom, or two R groups on the same atom, form a group which is double bonded to that atom. Accordingly, an R group, or two R groups attached to the same atom, may together form a =0 group, or a =C(R’)2 group (wherein each R’ group is the same or different and is H or an organic group, preferably H or a straight or branched Ci-Ce alkyl group). This is more typical in cases where the R groups are attached to a C atom, such that together they form a C=0 group or a C=C(R’)2 group. Thus, in some cases a C ring atom in a ring may comprise a =0 group, as may any X, and/or and one or more of R⁴ and R⁶.

In the present context, part of any structure present in brackets may be repeated the number of times given by the numbers next to the brackets (whether regular brackets or square brackets). For example, in the case of (C(R))O,I,2 or [C(R)]O,I,2 the C-R group may be absent, present once i.e. -C(R)-; or present twice i.e. -C(R)-C(R)-.

Further in the present context, where a structural component is depicted with a wavy line on a bond, that bond is the bond that attaches to another structural component of the compound.

In the context of the present invention, a compound is considered to be a PARP7 inhibitor if its presence is capable of preventing or reducing the ability of immobilised PARP7 to undergo auto-mono-ADP ribosylation (AutoMARylation) following incubation with biotinylated- NAD+ as compared to the same process in its absence. Typically, the compound is considered to be a PARP7 inhibitor if it has an IC50 < lOpM in a suitable assay. A suitable assay may be conducted using 10-30nM PARP7 (amino acids 456-657), 2 pM biotin-NAD⁺ assay solution in 20 mM HEPES (pH 7.5), 100 mM NaCl, 2 mM DTT, 0.1 % BSA (w/v), 0.02 % Tween (v/v) assay buffer. MARylation may take place for 2-3 h at room temperature and may be detected using a dissociation-enhanced lanthanide fluorescence immunoassay (DELFIA) readout. This assay format has been recently utilised for screening for modulators of PARP7 and other MonoP ARP enzymes (Wigle T. etal. Forced Self-Modification Assays as a Strategy to Screen MonoP ARP Enzymes. SLAS Discovery. 25; 241-252, (2020)). A particularly suitable assay is described in the Examples below.

In all of the embodiments of this invention (both above and below herein), the substituents (each of the R groups) are not especially limited, provided that they do not prevent the PARP7 inhibitory function from occurring. In all of the embodiments mentioned in connection with this invention, both above and in the following, the substituents are selected from H and an 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. Thus, ‘substituent’ and ‘organic group’ may have any of the following meanings.

The organic group may comprise any one or more atoms from any of groups IIIA, IVA, VA, VIA or VIIA of the Periodic Table, such as a B, Si, N, P, O, or S atom (e.g. OH, OR, NH2, NHR, NR2, SH, SR, SO2R, SO3H, PO4H2) or a halogen atom (e g. F, Cl, Br or I) where R is a linear or branched lower hydrocarbon (1-6 C atoms) or a linear or branched higher hydrocarbon (7 C atoms or more, e.g. 7-40 C atoms).

The organic group preferably comprises a hydrocarbon group. The hydrocarbon group may comprise a straight chain, a branched chain or a cyclic group. Independently, the hydrocarbon group may comprise an aliphatic or an aromatic group. Also independently, the hydrocarbon group may comprise a saturated or unsaturated group.

When the hydrocarbon comprises an unsaturated group, it may comprise one or more alkene functionalities and/or one or more alkyne functionalities. When the hydrocarbon comprises a straight or branched chain group, it may comprise one or more primary, secondary and/or tertiary alkyl groups.

When the hydrocarbon comprises a cyclic group, it may comprise an aromatic ring, a nonaromatic ring, an aliphatic ring, a heterocyclic group, and/or fused ring derivatives of these groups. The ring may be fully saturated, partially saturated, or fully unsaturated. The cyclic group may thus comprise a benzene, naphthalene, anthracene, phenanthrene, phenalene, biphenylene, pentalene, indene, as-indacene, s-indacene, acenaphthylene, fluorene, fluoranthene, acephenanthrylene, azulene, heptal ene, pyrrole, pyrazole, imidazole, 1,2,3- triazole, 1,2,4-triazole, tetrazole, pyrrolidine, furan, tetrahydrofuran, 2-aza-tetrahydrofuran, 3- aza-tetrahydrofuran, oxazole, isoxazole, furazan, 1,2,4-oxadiazol, 1,3,4-oxadiazole, thiophene, isothiazole, thiazole, thiolane, pyridine, pyridazine, pyrimidine, pyrazine, piperidine, 2- azapiperidine, 3 -azapiperidine, piperazine, pyran, oxetan-2-yl, oxetan-3-yl, tetrahydropyran, 2- azapyran, 3 -azapyran, 4-azapyran, 2-aza-tetrahydropyran, 3-aza-tetrahydropyran, morpholine, thiopyran, 2-azathiopyran, 3 -azathiopyran, 4-azathiopyran, thiane, indole, indazole, benzimidazole, 4-azaindole, 5-azaindole, 6-azaindole, 7-azaindole, isoindole, 4-azaisoindole, 5-azaisoindole, 6-azaisoindole, 7-azaisoindole, indolizine, 1-azaindolizine, 2-azaindolizine, 3- azaindolizine, 5-azaindolizine, 6-azaindolizine, 7-azaindolizine, 8-azaindolizine, 9- azaindolizine, purine, carbazole, carboline, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, quinoline, cinnoline, quinazoline, quinoxaline, 5 -azaquinoline, 6- azaquinoline, 7-azaquinoline, isoquinoline, phthalazine, 6-azaisoquinoline, 7-azaisoquinoline, pteridine, chromene, isochromene, acridine, phenanthridine, perimidine, phenanthroline, phenoxazine, xanthene, phenoxanthiin, and/or thianthrene, as well as regioisomers of the above groups. These groups may generally be attached at any point in the group, and also may be attached at a hetero-atom or at a carbon atom. In some instances particular attachment points are preferred, such as at 1-yl, 2-yl and the like, and these are specified explicitly where appropriate. All tautomeric ring forms are included in these definitions. For example pyrrole is intended to include I //-pyrrole, 2//-pyrrole and 3 //-pyrrole.

The number of carbon atoms in the hydrocarbon group is not especially limited, but preferably the hydrocarbon group comprises from 1-40 C atoms. The hydrocarbon group may thus be a lower hydrocarbon (1-6 C atoms) or a higher hydrocarbon (7 C atoms or more, e.g. 7-40 C atoms). The lower hydrocarbon group may be a methyl, ethyl, propyl, butyl, pentyl or hexyl group or regioisomers of these, such as isopropyl, isobutyl, tert-butyl, etc. The number of atoms in the ring of the cyclic group is not especially limited, but preferably the ring of the cyclic group comprises from 3-10 atoms, such as 3, 4, 5, 6, 7, 8, 9 or 10 atoms.

The groups comprising heteroatoms described above, as well as any of the other groups defined above, may comprise one or more heteroatoms from any of groups IIIA, IVA, VA, VIA or VIIA of the Periodic Table, such as a B, Si, N, P, O, or S atom or a halogen atom (e.g. F, Cl, Br or I). Thus the substituent may comprise one or more of any of the common functional groups in organic chemistry, such as hydroxy groups, carboxylic acid groups, ester groups, ether groups, aldehyde groups, ketone groups, amine groups, amide groups, imine groups, thiol groups, thioether groups, sulphate groups, sulphonic acid groups, sulphonyl 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 above.

The R groups referred to in the compounds and structures herein will now be described in more detail. As has been mentioned, in all of the embodiments of this invention (both above and below herein), the substituent is not especially limited, provided that it does not prevent the PARP7 inhibitory function from occurring. However, in typical embodiments, the substituents may be selected independently as follows.

Rl, R.3, R4, R6, R7 R8 _ANC| R9 _are typically each independently selected from H and a group selected from the following groups:

-deuterium

- a halogen (such as -F, -Cl, -Br and -I);

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

- a substituted or unsubstituted linear or branched Ci-Ce alkyl-aryl group (such as -CH₂Ph, - CH₂(2,3 or 4)F-Ph, -CH₂(2,3 or 4)C1-Ph, -CH₂(2,3 or 4)Br-Ph, -CH₂(2,3 or 4)I-Ph, - CH₂CH₂Ph, -CH₂CH₂CH₂Ph, -CH₂CH₂CH₂CH₂Ph, -CH₂CH₂CH₂CH₂CH₂Ph, and -CH₂CH₂CH₂CH₂CH₂CH₂Ph);

- a substituted or unsubstituted linear or branched Ci-Ce halogenated alkyl group (such as -CH₂F, -CHF₂, - CH₂CH₂F, -CH₂C1, -CH₂Br, -CH₂I, -CF₃, -CCh -CBr₃, -CI3, -CH₂CF₃, -C H₂CC1₃, -CH₂CBr₃, and -CH₂CI₃);

- -NH₂ or a substituted or unsubstituted linear or branched primary secondary or tertiary Ci-Ce amine group (such as -NMeH, -NMe₂, -NEtH, -NEtme, -NEt₂, -NPrH, -NPrme, -NPrEt, -NPr₂, -NBuH, -NBume, -NBuEt, -CH₂-NH₂, -CH₂-NMeH, -CH₂-NMe₂, -CH₂-NEtH, -CH₂-NEtMe, -CH₂-NEt₂, -CH₂-NPrH, -CH₂-NPrMe, and -CH₂-NPrEt);

- a substituted or unsubstituted amino-aryl group (such as -NH-Ph, -NH-(2,3 or 4)F-Ph, -NH- (2,3 or 4)C1-Ph, -NH-(2,3 or 4)Br-Ph, -NH-(2,3 or 4)I-Ph, -NH-(2,3 or 4)Me-Ph, -NH-(2,3 or 4)Et-Ph, -NH-(2,3 or 4)Pr-Ph, -NH-(2,3 or 4)Bu-Ph, NH-(2,3 or 4)OMe-Ph, -NH-(2,3 or 4)OEt-Ph, -NH-(2,3 or 4)OPr-Ph, -NH-(2,3 or 4)OBu-Ph, -NH-2,(3,4,5 or 6)F₂-Ph, -NH- 2, (3 ,4, 5 or 6)Cl₂-Ph, -NH-2,(3,4,5 or 6)Br₂-Ph, -NH-2,(3,4,5 or 6)I₂-Ph, -NH-2,(3,4,5 or 6)Me₂- Ph, -NH-2,(3,4,5 or 6)Et₂-Ph, -NH-2,(3,4,5, or 6)Pr₂-Ph, -NH-2,(3,4,5 or 6)Bu₂-Ph,

- a substituted or unsubstituted cyclic amine or amido group (such as pyrrolidin-l-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-l-yl, piperi din-2 -yl, piperi din-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 or a substituted or unsubstituted linear or branched C1-C6 alcohol group (such as –CH₂OH, -CH₂CH₂OH, -CH(CH₃)CH₂OH, -C(CH₃)₂OH, -CH₂CH₂CH₂OH, - CH₂CH₂CH₂CH₂OH, -CH(CH₃)CH₂CH₂OH, -CH(CH₃)CH(CH₃)OH, -CH(CH₂CH₃)CH₂OH, -C(CH3)2CH2OH, -CH2CH2CH2CH2CH2OH, and -CH2CH2CH2CH2CH2CH2OH); - a substituted or unsubstituted linear or branched C₁-C₆ carboxylic acid group (such as - COOH, -CH2COOH, -CH2CH2COOH, -CH2CH2CH2COOH, -CH2CH2CH2CH2COOH, and -CH2CH2CH2CH2CH2COOH); - a substituted or unsubstituted linear or branched carbonyl group (such as -(CO)Me, -(CO)Et, -(CO)Pr, -(CO)iPr, -(CO)nBu, -(CO)iBu, -(CO)tBu, -(CO)Ph, -(CO)CH2Ph, -(CO)CH2OH, -(CO)CH2OCH3, -(CO)CH2NH2, -(CO)CH2NHMe, -(CO)CH2NMe2, -(CO)-cyclopropyl, -(CO)-1,3-epoxypropan-2-yl; -(CO)NH₂, -(CO)NHMe, -(CO)NMe₂, -(CO)NHEt, -(CO)NEt₂, -(CO)-pyrrolidine-N-yl, -(CO)-morpholine-N-yl, -(CO)-piperazine-N-yl, -(CO)-N-methyl-piperazine-N-yl, -(CO)NHCH2CH2OH, -(CO)NHCH2CH2OMe, -(CO)NHCH2CH2NH2, -(CO)NHCH₂CH₂NHMe, and -(CO)NHCH₂CH₂NMe₂; - a substituted or unsubstituted linear or branched C₁-C₆ carboxylic acid ester group (such as - COOMe, -COOEt, -COOPr, -COO-i-Pr, -COO-n-Bu, -COO-i-Bu, -COO-t-Bu, -CH2COOMe, -CH₂CH₂COOMe, -CH₂CH₂CH₂COOMe, and -CH₂CH₂CH₂CH₂COOMe); - a substituted or unsubstituted linear or branched C₁-C₆ amide group (such as -CO-NH₂, - CO-NMeH, -CO-NMe2, -CO-NEtH, -CO-NEtMe, -CO-NEt2, -CO-NPrH, -CO-NPrMe, and - CO-NPrEt); - a substituted or unsubstituted linear or branched C₁-C₇ amino carbonyl group (such as -NH- CO-Me, -NH-CO-Et, -NH-CO-Pr, -NH-CO-Bu, -NH-CO-pentyl, -NH-CO-hexyl, -NH- CO-Ph, -NMe-CO-Me, -NMe-CO-Et, -NMe-CO-Pr, -NMe-CO-Bu, -NMe-CO-pentyl, -NMe- CO-hexyl, -NMe-CO-Ph; - a substituted or unsubstituted linear or branched C1-C7 alkoxy or aryloxy group (such as – Ome, -Oet, -OPr, -O-i-Pr, -O-n-Bu, -O-i-Bu, -O-t-Bu, -O-pentyl, -O-hexyl, -OCH2F, -OCHF2, -OCF3, -OCH2Cl, -OCHCl2, -OCCl3, -O-Ph, -O-CH2-Ph, -O-CH2-(2,3 or 4)-F-Ph, -O-CH2-(2,3 or 4)-Cl-Ph, –CH2OMe, –CH2OEt, –CH2OPr, –CH2OBu, -CH2CH2OMe, -CH2CH2CH2OMe, -CH₂CH₂CH₂CH₂OMe, and -CH₂CH₂CH₂CH₂CH₂OMe); - a substituted or unsubstituted linear or branched aminoalkoxy group (such as – OCH2NH2, -OCH2NHMe, -OCH2NMe2, -OCH2NHEt, -OCH2NEt2, -OCH2CH2NH2, -OCH2C H2NHMe, -OCH2CH2NMe2, -OCH2CH2NHEt, and -OCH2CH2NEt2; - a substituted or unsubstituted sulphonyl group (such as -SO₂Me, -SO₂Et, -SO₂Pr, -SO₂iPr, - SO₂Ph, -SO₂-(2,3 or 4)-F-Ph, -SO₂- cyclopropyl, -SO2CH2CH2OCH3), -SO2NH2, -SO2NHMe, -SO2NMe2, -SO₂NHEt, -SO₂NEt₂, -SO2-pyrrolidine-N-yl, -SO₂-morpholine-N-yl, -SO₂NHCH₂OMe, and -SO2NHCH2CH2OMe; - a substituted or unsubstituted aminosulphonyl group (such as –NHSO2Me, - NHSO2Et, - NHSO2Pr, - NHSO2iPr, - NHSO2Ph, - NHSO2-(2,3 or 4)-F-Ph, - NHSO2- cyclopropyl, - NHSO₂CH₂CH₂OCH₃); - a substituted or unsubstituted aromatic group (such as Ph-, 2-F-Ph-, 3-F-Ph-, 4-F-Ph-, 2-Cl- Ph-, 3-Cl-Ph-, 4-Cl-Ph-, 2-Br-Ph-, 3-Br-Ph-, 4-Br-Ph-, 2-I-Ph-, 3-I-Ph, 4-I-Ph-, 2,(3,4,5 or 6)- F₂-Ph-, 2,(3,4,5 or 6)-Cl₂-Ph-, 2,(3,4,5 or 6)-Br₂-Ph-, 2,(3,4,5 or 6)-I₂-Ph-, 2,(3,4,5 or 6)-Me₂- Ph-, 2,(3,4,5 or 6)-Et2-Ph-, 2,(3,4,5 or 6)-Pr2-Ph-, 2,(3,4,5 or 6)-Bu2-Ph-, 2,(3,4,5 or 6)-(CN)2- Ph-, 2,(3,4,5 or 6)-(NO2)2-Ph-, 2,(3,4,5 or 6)-(NH2)2-Ph-, 2,(3,4,5 or 6)-(MeO)2-Ph-, 2,(3,4,5 or 6)-(CF₃)₂-Ph-, 3,(4 or 5)-F₂-Ph-, 3,(4 or 5)-Cl₂-Ph-, 3,(4 or 5)-Br₂-Ph-, 3,(4 or 5)-I₂-Ph-, 3,(4 or 5)-Me₂-Ph-, 3,(4 or 5)-Et₂-Ph-, 3,(4 or 5)-Pr₂-Ph-, 3,(4 or 5)-Bu₂-Ph-, 3,(4 or 5)-(CN)₂-Ph-, 3,(4 or 5)-(NO2)2-Ph-, 3,(4 or 5)-(NH2)2-Ph-, 3,(4 or 5)-(MeO)2-Ph-, 3,(4 or 5)-(CF3)2-Ph-, 2- Me-Ph-, 3-Me-Ph-, 4-Me-Ph-, 2-Et-Ph-, 3-Et-Ph-, 4-Et-Ph-, 2-Pr-Ph-, 3-Pr-Ph-, 4-Pr-Ph-, 2- Bu-Ph-, 3-Bu-Ph-, 4-Bu-Ph-, 2-(CN)-Ph-, 3-(CN)-Ph-, 4-(CN)-Ph-, 2-(NO₂)-Ph-, 3-(NO₂)-Ph- , 4-(NO2)-Ph-, 2-(NH2)-Ph-, 3-(NH2)-Ph-, 4-(NH2)-Ph-, 2-MeO-Ph-, 3-MeO-Ph-, 4-MeO-Ph-, 2-(NH2-CO)-Ph-, 3-(NH2-CO)-Ph-, 4-(NH2-CO)-Ph-, 2-CF3-Ph-, 3-CF3-Ph-, 4-CF3-Ph-, 2- CF₃O-Ph-, 3-CF₃O-Ph-, and 4-CF₃O-Ph-); - a saturated or unsaturated, substituted or unsubstituted, heterocyclic group including an aromatic heterocyclic group and/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-l-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, thi ophen-3 -yl, isothiazole-3-yl, isothiazole-4-yl, isothiazole-5-yl, thiazole-2-yl, thi azol e-4-yl, thiazole-5-yl, thiopyran-2-yl, thiopyran-3-yl, thiopyran-4-yl, 2-azathiopyran-2-yl, 2-azathiopyran-3-yl, 2-azathiopyran-4-yl, 2-azathiopyran-5-yl, 2-azathiopyran-6-yl, 3-azathiopyran-2-yl, 3-azathiopyran-4-yl, 3- azathiopyran-5-yl, 3-azathiopyran-6-yl, 4-azathiopyran-2-yl, 4-azathiopyran-3-yl, 4- azathiopyran-4-yl, 4-azathiopyran-5-yl, 4-azathiopyran-6-yl, thiolane-2-yl, thiolane-3 -yl, thiane-2-yl, thiane-3-yl, thiane-4-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, furazan-3-yl, (l,3,4-oxadiazol)-2-yl, (l,3,4-oxadiazol)-5-yl,

(l,2,4-oxadiazol)-3-yl, (l,2,4-oxadiazol)-5-yl; and tetrazole-l-yl, tetrazole-2-yl, tetrazole-5- yl); and

- where there are two R groups attached to the same atom, they may together form a group which is double bonded to that atom, (such as a carbonyl group (=0) or an alkene group (=C(R’)₂) wherein each R’ group is the same or different and is H or an organic group, preferably H or a straight or branched Ci-Ce alkyl group).

R¹, R³, R⁷, R⁸, and R⁹ may also be independently selected from a nitrile group. More typically, R1, R3, R7, and R8 are each independently selected from H, deuterium, a halogen (such as –F, -Cl, -Br, and –I), a substituted or unsubstituted C₁-C₆ alkyl or cycloalkyl group, a substituted or unsubstituted linear or branched C₁-C₆ halogenated alkyl group, an -OH group or a substituted or unsubstituted linear or branched C1-C6 alcohol group, an -NH2 group or a substituted or unsubstituted C1-C6 amino group, a substituted or unsubstituted C1-C6 alkoxy group, and a nitrile group. In particular, R1, R3, and R7 may each be independently selected from H, deuterium, a halogen (such as –F, -Cl, -Br, and –I), a substituted or unsubstituted C₁-C₆ alkyl or cycloalkyl group, a substituted or unsubstituted linear or branched C1-C6 halogenated alkyl group, an -OH group or a substituted or unsubstituted linear or branched C1-C6 alcohol group, an -NH2 group or a substituted or unsubstituted C1-C6 amino group, a substituted or unsubstituted C1-C6 alkoxy group, and a nitrile group. R1 is preferably a fluoromethyl group such as CF2H or CF3, with CF3 being particularly preferred. R3 is preferably H. Each R7 may be H. Preferably, R² is selected from H, a C₁-C₃ alkyl group and a C₁-C₃ halogenated alkyl group. More preferably, R² is H. More typically R⁴ is selected from H, deuterium, a halogen (such as –F, -Cl, -Br, and –I, preferably -F), a substituted or unsubstituted C₁-C₆ alkyl group, a substituted or unsubstituted linear or branched C1-C6 halogenated alkyl group (preferably CF3), an -NH2 group or a substituted or unsubstituted C1-C6 amino group, an -OH group or a substituted or unsubstituted linear or branched C₁-C₆ alcohol group and a substituted or unsubstituted C₁-C₆ alkoxy group. In particular, each R4 may be H or a methyl group. Optionally, at most one R4 is a methyl group. Preferably, each R4 is H. More typically, R

is independently selected from H, deuterium, a halogen (such as –F, -Cl, - Br, and –I, preferably F), a substituted or unsubstituted C₁-C₆ alkyl group, a substituted or unsubstituted linear or branched C1-C6 halogenated alkyl group, an -OH group or a substituted or unsubstituted linear or branched C1-C6 alcohol group, an -NH2 group or a substituted or unsubstituted C₁-C₆ amino group and a substituted or unsubstituted C₁-C₆ alkoxy group. Preferably, each R6 is H. More typically, R⁸ is selected from a halogenated C1 to C3 alkyl group, a halogenated methoxy group, -H, -CH₃, -CN, -OMe, a halogen group (-F, -Cl, -Br, -I), -SO₂Me, -CONHMe, t-Bu, cyclopropyl and

. Preferably, R⁸ is selected from a halogen group, -CF₃, -CHF₂, - CH₂F, -OCF₃, -CH₂CF₃, -CF₂CH₃, -OCHF₂, -OCH₂F, and a -CN group. In accordance with another possibility, R8 may be selected from a halogenated C1 to C3 alkyl group, a halogen group, and a -CN group, and is preferably a -CF₃, -F, -Cl, or a -CN group. R8 is most preferably a -CF₃, -F, -Cl, or a -CN group. More typically, R⁹ is selected from H, a substituted or unsubstituted C₁-C₆ alkyl group or a substituted or unsubstituted linear or branched C₁-C₆ halogenated alkyl group, more preferably a substituted or unsubstituted C1-C3 alkyl group or a substituted or unsubstituted linear or branched C -C ha 9 1 3 logenated alkyl group. R is most preferably H. t is preferably 1 or 2, most preferably 2. The invention will now be described in more detail with reference to some of the preferred embodiments. The compound may have a structure selected from:

In preferred embodiments, and independently from the ring to which it is attached, L may comprise a group having one of the following formulae:

. . Z may comprise a group having one of the following formulae:

In preferred embodiments, Z may comprise a group having one of the following formulae:

wherein R^ are each as defined herein.

More preferably, Z comprises a group having one of the following formulae:

wherein the stereochemistry depicted is relative stereochemistry. Thus, in the above Z groups, where two H substituents are shown with solid wedged bonds in a cis relationship to one another, this does not depict the absolute configuration of the group, only that the two H substituents are cis, not trans H substituents.

In accordance with another possibility, Z may have a structure of:

An example Z group in the above class is:

where the stereochemistry depicted is relative stereochemistry. In preferred embodiments,

comprises a group having one of the following formulae:

wherein R& is as defined herein.

More preferably, R^ comprises a group having one of the following formulae:

In accordance with another possibility, R⁵ may have a structure of:

such as:

In some embodiments, group L is selected from:

wherein the stereochemistry depicted is relative stereochemistry. Further examples of L groups include:

the depicted stereochemistry being relative stereochemistry.

In some embodiments, the present invention provides a PARP7 inhibitor compound which comprises a formula selected from one of the following, wherein the stereochemistry depicted is relative stereochemistry:

24 25

Further embodiments of PARP7 inhibitor compounds include:

the depicted stereochemistry being relative stereochemistry. In some embodiments, the present invention provides a PARP7 inhibitor compound which comprises a formula selected from one of the following:

The compounds of the present invention have been described in detail above in terms of their structures. For the avoidance of doubt, any compounds for use in the invention may comprise compounds or compositions in accordance with their structure as follows:

- 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

- one or more tautomers; of each structure.

For the above numbered compounds, compounds 1 and 11 are achiral. Compounds 1, 10, 12,13, 17 and 20 to 22 are shown with absolute stereochemistry. The remaining compounds represent more than one enantiomeric structure which may have PARP7 inhibitory activity as a racemic mixture and/or as a separated enantiomer(s). In the examples below, a compound with a suffix “a” (eg 2a) represents an enantiomer eluted as a first fraction when a racemic mixture of the two enantiomers is applied to a Daicel CHIRALPAK chiral chromatography column. In the examples below, a compound with a suffix “b” (eg 2b) represents an enantiomer eluted as a second fraction when a racemic mixture of the two enantiomers is applied to a Daicel CHIRALPAK chiral chromatography column. For diastereomeric compounds, the suffix “a” denotes a compound eluted as a first fraction, and “b”, “c” and “d” denote compounds eluted as second, third, and fourth fractions respectively. In the examples below, a compound with no suffix represents either an achiral compound or a compound with assigned absolute stereochemistry. In the examples below, a compound which bears a suffix “rac” represents a racemic mixture of the enantiomers. The compounds described herein may be provided 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 PARP7 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 PARP7 inhibitor. Typically, this comprises a disease condition and/or a disorder selected from: a cancer, an infectious disease, a central nervous system disease or disorder, and a pain condition.

When the disease, condition or disorder is a cancer, it is not especially limited, provided that the cancer is one which may be treated, prevented or ameliorated by using a PARP7 inhibitor. Thus the cancer may be a cancer selected from: a solid or liquid tumour including cancer of the eye, brain (such as gliomas, glioblastomas, medullablastomas, 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 leukemia (T-PLL), large granular lymphocytic leukemia, adult T-cell leukemia, juvenile myelomonocytic leukaemia, Hodgkin lymphoma, non-Hodgkin lymphoma, mantle lymphoma, follicular lymphoma, primary effusion lymphoma, AIDS-related lymphoma, Hodgkin lymphoma, diffuse B cell lymphoma, Burkitt lymphoma, and cutaneous T-cell lymphoma), preferably wherein the cancer is a cancer selected from oesaphageal, head and neck, non-small cell lung cancer, squamous cell cancer of the lung, breast, acute myeloid leukemia (AML), a small-cell lung cancer, a melanoma, an ovarian cancer, a colorectal cancer, a pancreatic cancer, an endometrial cancer, and a skin papilloma. When the disease is an infectious disease, it is not especially limited, provided that the disease is one which may be treated, prevented or ameliorated by using a PARP7 inhibitor. However, typically the infectious disease is selected from a bacterial infection and a viral infection, preferably a respiratory infection, immune system infection, gut infection and sepsis. Such viral respiratory infections include influenza and coronavirus infections, particularly influenza A and SARS- CoV-2 infections.

When the disease, condition or disorder is a central nervous system disease, condition or disorder, it is not especially limited, provided that the disease, condition or disorder is one which may be treated, prevented or ameliorated by using a PARP7 inhibitor. However, the central nervous system disease, condition or disorder is typically selected from amyotrophic lateral sclerosis (AML), Huntington’s disease, Alzheimer’s disease, pain, a psychiatric disorder, multiple sclerosis, Parkinson’s disease, and HIV related neurocognitive decline.

When the disease, condition or disorder is a pain condition it is not especially limited, provided that the condition is one which may be treated, prevented or ameliorated by using a PARP7 inhibitor. Typically, the pain condition is nociceptive pain or neuropathic pain and may be a chronic pain condition such as cancer-associated pain and peripheral neuropathy.

The present invention also provides a pharmaceutical composition comprising a compound as defined above. Whilst the pharmaceutical composition is not especially limited, typically the composition further comprises a pharmaceutically acceptable additive and/or excipient. In the pharmaceutical composition, the 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 treating a disease, condition or disorder as defined above. In some instances, the compound may be present in the composition as a pharmaceutically acceptable salt, or other alternative form of the compound, in order to ameliorate pharmaceutical formulation. In some embodiments the pharmaceutical composition is a composition for treating a cancer, further comprising 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. However, typically the further agent for treating cancer is selected from anti -microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, senolytic agents, hormones and hormone analogues, signal transduction pathway inhibitors, DNA damage repair pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents (such as an anti-tumour vaccine, an oncolytic virus, an immune stimulatory antibody such as anti-CTLA4, anti-PDl, anti-PDL-1, anti-OX40, anti-41BB, anti-CD27, anti-CD40, anti-LAG3, anti-TIM3, and anti-GITR, a novel adjuvant, a peptide, a cytokine, a chimeric antigen receptor T cell therapy (CAR-T), a small molecule immune modulator such as an IDO or TDO inhibitor or a pattern recognition receptor agonist such as a STING, TLR-9 or RIG-I Helicase agonist, and tumour microenvironment modulators), anti -angiogenic agents, receptor tyrosine kinase inhibitors, cell growth inhibitors such as Ras and Raf inhibitors, proapoptotic agents and cell cycle signalling inhibitors.

In still further embodiments the invention provides a pharmaceutical kit for treating a cancer, which pharmaceutical kit comprises:

(a) a compound as defined above; and

(b) a further agent for treating cancer; preferably wherein the further agent for treating cancer is selected from anti -microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, senolytic agents, hormones and hormone analogues, signal transduction pathway inhibitors, DNA damage repair pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents (such as an anti-tumour vaccine, an oncolytic virus, an immune stimulatory antibody such as anti-CTLA4, anti-PDl, anti-PDL-1, anti-OX40, anti- 41BB, anti-CD27, anti-CD40, anti-LAG3, anti-TIM3, and anti-GITR, a novel adjuvant, a peptide, a cytokine, a chimeric antigen receptor T cell therapy (CAR-T), a small molecule immune modulator such as a pattern recognition receptor agonist such as a STING, TLR-9 or RIG-I Helicase agonist, and tumour microenvironment modulators), anti -angiogenic agents, receptor tyrosine kinase inhibitors, cell growth inhibitors such as Ras and Raf inhibitors, proapoptotic agents and cell cycle signalling inhibitors; wherein the compound and the further agent are suitable for administration simultaneously, sequentially or separately.

Further provided by the invention is a method of treating a disease and/or a condition and/or a disorder, which method comprises administering to a patient (or subject) a compound, or a composition, or a kit as defined above. 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. Preferably such a method comprises administering to a 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 type of cancer indicated.

Typically, in all embodiments of the invention, both above and below, the patient (or subject) is an animal, typically a mammal, including canines and felines, and more typically a human.

Further provided by the invention is a method of synthesis of a compound as defined above, which method comprises conducting a reaction between a first reactant and a second reactant so as to form the PARP7 inhibitor compound. The first reactant comprises a compound of general formula:

and the second reactant comprises a compound of general formula:

wherein R¹⁰ and R¹¹ are each independently substituent groups which are removed during the reaction; and wherein X¹, X², X³, Y, R¹, R², R⁴, R⁵, R⁶, R⁹, p, q, r, s and t are as defined herein.

Optionally, the second reactant may comprise a compound of general formula:

In typical embodiments, this method of synthesis is carried out by reacting under conditions suitable for an amide formation reaction. The skilled person may select the reaction conditions, with reference to known synthesis techniques depending on the appropriate starting materials. In some embodiments, the method comprises one or more additional substitution steps. In some embodiments, the method comprises use of a protecting group as R² during an amide formation step. Exemplary syntheses are shown in the Examples herein.

For the avoidance of doubt, throughout the present disclosure a single formula is 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, the above formulae (and all formulae herein) are intended to represent all tautomeric forms equivalent to the corresponding formula.

The term “comprises” as used throughout the description and claims herein means “includes or consists of’. The term denotes the inclusion of at least the features following the term and does not exclude the inclusion of other features which have not been explicitly mentioned. The term may also denote an entity which consists only of the features following the term.

Detailed description of the invention

The invention will now be described in more detail, by way of example only, with reference to the following examples.

EXAMPLES

Exemplary syntheses of compounds of the invention

The compounds of the invention may be synthesised using readily available starting materials and known reactions.

Exemplary syntheses of various compounds are shown below:

1. Synthesis of 5-(4-methoxybenzyl)-3-(trifluoromethyl)-l,5-dihydro-4H-pyrazolo[3,4- d]pyridazin-4-one (INT-1) (a reference example)

5-(4-methoxybenzyl)-3-(trifluoromethyl)-l,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one

INT-1:

INT-1 an intermediate product useful in the preparation of various compounds of the invention, was prepared in accordance with the following scheme:

Preparation of 4,5-dichloro-2-(4-methoxybenzyl) pyridazin-3(2H)-one (2)

To a solution of 4,5-dichloropyridazin-3(2J7)-one 1 (8 g, 48.5 mmol) in DMF (100 mL) were added PMBC1 (19 g, 121.3 mmol) and DIPEA (31.4 g, 242.5 mmol) at room temperature. The resulting mixture was stirred at 50 °C for 6 h. After cooling to room temperature, water (400 mL) was added, and the mixture was extracted EtOAc (3 x 150 mL). The combined organic layers were dried (Na2SO4), concentrated in vacuo. The residue was purified by flash chromatography (silica gel, eluting with PE / EtOAc = 100: 0 to 80: 20) to obtain 4,5-dichloro- 2-(4-m ethoxybenzyl) pyridazin-3(2J7)-one 2 (8 g, 90 % purity, 52 % yield) as white solid. LCMS (ESI) calcd for C12H10CI2N2O2 [M + H] ⁺m/z 285.02, found 285. Preparation of 4-chloro-5-(dimethylamino)-2-(4-methoxybenzyl) pyridazin-3(2H)-one (3) To a solution of 4,5-dichloro-2-(4-methoxybenzyl) pyridazin-3(2J7)-one 2 (8 g, 28.1 mmol) in EtOH (100 mL) and H2O (50 mL) was added dimethylamine in MeOH (2 M, 70.5 mL) at room temperature. The reaction mixture was stirred at 50 °C for 4 h. After cooling to room temperature, the mixture was concentrated in vacuo. Water (100 mL) was added, and the mixture was extracted EtOAc (3 x 150 mL). The combined organic layers were dried (Na2SO4), concentrated in vacuo, and purified by flash chromatography (silica gel, eluting with PE / EtOAc = 100: 0 to 20: 80) to obtain 4-chloro-5-(dimethylamino)-2-(4-methoxybenzyl) pyridazin-3(2J7)-one 3 (8 g, 85 % purity, 82 % yield) as white solid.

LCMS (ESI) calcd for C14H16CIN3O2 [M + H] ⁺ m/z 294.1, found 294.

Preparation of 5-(dimethylamino)-2-(4-methoxybenzyl)-4-vinylpyridazin-3(2H)-one (4)

To a solution of 4-chloro-5-(dimethylamino)-2-(4-methoxybenzyl) pyridazin-3(2J7)-one 3 (8 g, 27.2 mmol) in ACN (100 mL) were added tributyl(vinyl) stannane (17.3 g, 54.4 mmol) and Pd(AMPHOS)C12 (1.93 g, 2.72 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 10 h. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was purified by flash chromatography (silica gel, eluting with PE / EtOAc = 100: 0 to 10 : 90) to obtain 5-(dimethylamino)-2-(4-methoxybenzyl)-4-vinylpyridazin-3(2J7)-one 4 (6 g, 90 % purity, 69 % yield) as white solid.

LCMS (ESI) calcd for C16H19N3O2 [M + H] ⁺ m/z 286.16, found 286.

Preparation of 5-(dimetbylamino)-2-(4-methoxybenzyl)-3-oxo-2,3-dibydropyridazine-4- carbaldehyde (5)

To a solution of 5-(dimethylamino)-2-(4-methoxybenzyl)-4-vinylpyridazin-3(2J7)-one 4 (3 g, 0.01 mol) in MeOH/H₂O (2: 1, 30 mL) were added K₂OsO₄ 2H₂O (0.39 g, 0.001 mol), NaIO₄ (8.9 g, 0.04 mol) at rt. The reaction mixture was stirred at rt for 1 h. The resulting mixture was quenched with water and extracted with DCM (50 mL x 3). The combined organic layer was washed with brine and concentrated under reduced pressure. The residue was purified by silica gel column (eluting with PEZEtOAc = 100 : 0 to 50 : 50) to give 5-(dimethylamino)-2-(4- methoxybenzyl)-3-oxo-2,3-dihydropyridazine-4-carbaldehyde 5 (1.8 g, 90% purity, 53% yield) as yellow oil.

LCMS (ESI) calcd for C15H17N3O3 [M + H] ⁺ m/z 288.13, found 288.10.

Preparation of 5-(dimethylamino)-2-(4-methoxybenzyl)-4-(2,2,2-trifluoro-l- hydroxyethyl)pyridazin-3(2H)-one (6)

To a solution of 5-(dimethylamino)-2-(4-methoxybenzyl)-3-oxo-2,3-dihydropyridazine-4- carbaldehyde 5 (1.8 g, 0.006 mol), trimethyl(trifluoromethyl)silane (0.9 g, 0.006 mol) in THF (20 mL) was added TBAF in THF (1 M, 0.6 mL) at rt. The reaction mixture was stirred at rt for 1 h. The resulting mixture was quenched with water and extracted with DCM (50 mL x 3). The combined organic layer was washed with brine and concentrated under reduced pressure. The residue was purified by silica gel column (eluting with PEZEtOAc = 100: 0 to 30: 70) to obtain 5-(dimethylamino)-2-(4-methoxybenzyl)-4-(2, 2, 2-trifluoro-l -hydroxy ethyl)pyridazin- 3(2J7)-one 6 (1.6 g, 90 % purity, 63 % yield) as yellow oil.

LCMS (ESI) calcd for CieHi^^Ch [M + H] ⁺ m/z 358.13, found 358.10.

Preparation of 5-(dimethylamino)-2-(4-methoxybenzyl)-4-(2,2,2-trifluoroacetyl)pyridazin- 3(2H)-one (7)

To a solution of 5-(dimethylamino)-2-(4-methoxybenzyl)-4-(2,2,2-trifluoro-l- hydroxyethyl)pyridazin-3(2J7)-one 6 (1.6 g, 0.004 mol) in DCM (30 mL) was added Dess- Martin periodinane (3.8 g, 0.009 mol) at rt. The reaction mixture was stirred at rt for 1 h. The resulting mixture was quenched with water and extracted with DCM (50 mL x 3). The combined organic layer was washed with brine and concentrated under reduced pressure. The residue was purified by silica gel column (eluting with PEZEtOAc = 100: 0 to 50: 50) to obtain 5-(dimethylamino)-2-(4-methoxybenzyl)-4-(2,2,2-trifluoroacetyl)pyridazin-3(2J7)-one 7 (1.5 g, 90 % purity, 84 % yield) as yellow oil.

LCMS (ESI) calcd for C16H16F3N3O3 [M + H] ⁺ m/z 356.11, found 356.10. Preparation of 5-(4-methoxybenzyl)-3-(trifluoromethyl)-l, 5-dibydro-4H-pyrazolo[3,4- d]pyridazin-4-one (INT-1)

To a solution of 5-(dimethylamino)-2-(4-methoxybenzyl)-4-(2,2,2-trifluoroacetyl)pyridazin- 3(2J7)-one 7 (1.6 g, 0.004 mol) in EtOH (30 mL) was added H₂NNH₂ H₂O (80 % wt, 1.0 g, 0.020 mol) at rt. The reaction mixture was stirred at 80 °C for 3 h. The resulting light brown solution was concentrated under reduced pressure to remove most EtOH to get crude. The crude was purified by C18 column (Agela 40 g, mobile phase: ACN - H₂O (0.1 % FA), gradient: 30

60) to give 5-(4-methoxybenzyl)-3-(trifluoromethyl)-l,5-dihydro-4J/-pyrazolo[3,4- d]pyridazin-4-one INT-1 (0.9 g, 90 % purity, 55 % yield) as white solid.

LCMS (ESI) calcd for C14H11F3N4O2 [M + H] ⁺ m/z 325.08, found 325.05.

2 Synthesis of 3-(2-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro-lH- pyrrolo[2,3-d]pyridazin-l-yl)ethoxy)propanoic acid (INT-2) (a reference example) 3-(2-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro-lH-pyrrolo[2,3- d]pyridazin-l-yl)ethoxy)propanoic acid INT-2:

INT-2 an intermediate product useful in the synthesis of various compounds according to the invention, was prepared in accordance with the following scheme:

Preparation of ethyl l-(2-ethoxy-2-oxoethyl)-2-methyl-lH-pyrrole-3-carboxylate (13)

To a solution of ethyl 2-methyl - I //-pyrrol e-3 -carboxylate 11 (45 g, 0.2938 mol) in THF (500 mL) were added ethyl 2-bromoacetate 12 (122 g, 0.7345 mol) and NaH (60 % wt, 23.5 g, 0.5876 mol) at 0 °C. After completion of addition, the reaction solution was warmed to rt and kept stirring at rt for an additional 16 h. Water was added to quench the reaction. The obtained solution was extracted with EtOAc (300 mL x 4). The combined organic phase 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 l-(2- ethoxy-2-oxoethyl)-2-methyl-l//-pyrrole-3-carboxylate 13 (55 g, 90 % purity, 70 % yield) as yellow solid.

LCMS (ESI) calcd for C12H17NO4 [M + H] ⁺ m/z 240.12, found 240.05.

Preparation of ethyl l-(2-ethoxy-2-oxoethyl)-2-formyl-lH-pyrrole-3-carboxylate (14)

To a stirred solution of ethyl l-(2-ethoxy-2-oxoethyl)-2-m ethyl- lJ7-pyrrole-3 -carboxylate 13 (55 g, 0.230 mol) in THF: AcOH: H₂O (1 : 1 : 1, 1100 mb) was added CAN (504 g, 0.920 mol) at rt. The reaction mixture was stirred at room temperature for 6 h. The reaction mixture was poured carefully into an ice bath-cooled solution, and then extracted with EtOAc (3 x 500 mL). The combined extracts were washed with NaHCOs solution (1000 mL). The organic layer dried over sodium sulfate and concentrated under reduced pressure to give crude. The crude was purified by flash column chromatography (eluting with PE/EtOAc = 80: 20 to 50: 50) to afford ethyl l-(2-ethoxy-2-oxoethyl)-2-formyl-177-pyrrole-3 -carboxylate 14 (33 g, 90 % purity, 51 % yield) as a yellow oil.

LCMS (ESI) calcd for CI₂HI₅NO₅ [M + H] ⁺ m/z 254.10, found 254.15.

Preparation of ethyl 4-bromo-l-(2-ethoxy-2-oxoethyl)-2-formyl-lH-pyrrole-3-carboxylate (15)

To the solution of ethyl l-(2-ethoxy-2-oxoethyl)-2-formyl-l//-pyrrole-3 -carboxylate 14 (30 g, 0.119 mol) in MeCN (500 mL) was added NBS (21 g, 0.118 mmol) at rt. The mixture was kept stirring at room temperature for 1 h. The resulting mixture was diluted with water and extracted with DCM (300 mL x 3). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE/EtOAc = 100 : 0 to 70 : 30) to give ethyl 4-bromo-l-(2-ethoxy-2-oxoethyl)-2 -formyl- 1/7- pyrrole-3 -carb oxy late 15 (20 g, 90 % purity, 45 % yield) as yellow oil.

LCMS (ESI) calcd for Ci₂Hi₄BrNO₅ [M + H] ⁺ m/z 332.01, found 331.85. Preparation of ethyl 2-(3-bromo-5-(4-methoxybenzyl)-4-oxo-4,5-dihydro-lH-pyrrolo[2,3- d]pyridazin-l-yl)acetate (16)

To a solution of ethyl 4-bromo- l -(2-ethoxy-2-oxoethyl )-2-formyl - I //-pyrrol e-3 -carboxylate 15 (22 g, 66.2 mmol) in EtOH/AcOH (10: 1, 440 mL) was added PMBNHNH₂ (20 g, 0.1324 mmol) in one portion. The reaction mixture was heated with stirring at 80 °C for 2 h. After the reaction mixture was cooled to room temperature. The precipitate was collected by filtration, washed with EtOH to provide ethyl 2-(3-bromo-5-(4-methoxybenzyl)-4-oxo-4,5-dihydro-lH- pyrrolo[2,3-d]pyridazin-l-yl)acetate 16 (15 g, 90 % purity, 48 % yield) as a white solid.

LCMS (ESI) calcd for CisHisBrNsCU [M + H] ⁺ m/z 420.05, found 420.03.

Preparation of ethyl 2-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro-lH- pyrrolo[2,3-d]pyridazin-l-yl)acetate (18)

To a solution of ethyl 2-(3-bromo-5-(4-methoxybenzyl)-4-oxo-4,5-dihydro-lH-pyrrolo[2,3- d]pyridazin-l-yl)acetate 16 (10 g, 23.8 mmol) was added Cui (9 g, 47.6 mmol) and HMPA (21.3 g, 115 mmol) in NMP (300 mL) at rt. To this solution, Methyl 2,2-difluoro-2- (fluorosulfonyl)acetate (17, 22.8 g, 115 mmol) in NMP (50 mL) was added dropwise via an addition funnel for 2 h at 150 °C. After cooling to ambient temperature, the mixture was filtered through celite, and the filtrate was concentrated under vacuum. The residue was diluted with water (2000 mL) and extracted withEtOAc (1000 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, 20% to 40%) to give ethyl 2-(5-(4-methoxybenzyl)- 4-oxo-3-(trifluoromethyl)-4,5-dihydro-lH-pyrrolo[2,3-d]pyridazin-l-yl)acetate 18 (12 g, 50 % purity, 61 % yield) as a yellow oil.

LCMS (ESI) calcd for Ci9Hi₈F₃N3O₄ [M + H] ⁺ m/z 410.13, found 410.00.

Preparation of l-(2-hydroxyethyl)-5-(4-methoxybenzyl)-3-(trifluoroniethyl)-l,5-dihydro- 4H-pyrrolo[2,3-d]pyridazin-4-one (19)

To a solution of ethyl 2-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro-lZ7- pyrrolo[2,3-d]pyridazin-l-yl)acetate 18 (8.5 g, 20.7 mmol) in MeOH (1000 mL) were added LiCl (3.5 g, 82.9 mmol), NaBEL (3.1 g, 82.9 mmol) at rt successively. The reaction mixture was stirred at rt for 1 h. The resulting mixture was quenched with water and extracted with EtOAc (100 mL x 3). The combined organic layer was washed with brine and concentrated under reduced pressure. The residue was purified by silica gel column (eluting with PE/EtOAc = 100: 0 to 50: 50) to obtain l-(2-hydroxyethyl)-5-(4-methoxybenzyl)-3-(trifluoromethyl)-l,5- dihydro-4J/-pyrrolo[2,3-J]pyridazin-4-one 19 (5 g, 85 % purity, 40 % yield) as a colorless oil.

LCMS (ESI) calcd for C17H16F3N3O3 [M + H] ⁺ m/z 368.11, found 368.25.

Preparation of tert-butyl (E)-3-(2-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5- dihydro-lH-pyrrolo[2,3-d]pyridazin-l-yl)ethoxy)acrylate (21 )

To a solution of l-(2-hydroxyethyl)-5-(4-methoxybenzyl)-3-(trifluoromethyl)-l,5-dihydro- 4J/-pyrrolo[2,3-t/]pyridazin-4-one 19 (1.5 g, 4.07 mmol) and tert-butyl propiolate 20 (0.6 g, 4.9 mmol) in DCM (50 mL) was added P(n-Bu)3 (82 mg, 0.41 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was quenched with water and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine and concentrated under reduced pressure. The residue was purified by silica gel column (eluting with PE/EtOAc = 100 : 0 to 0 : 100) to obtain tert-butyl (E)-3-(2-(5-(4- methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro-U/-pyrrolo[2,3-J]pyridazin-l- yl)ethoxy)acrylate 21 (1.5 g, 90 % purity, 55 % yield) as colorless oil.

LCMS (ESI) calcd for C24H26F3N3O5 [M + H] ⁺ m/z 494.18, found 494.10.

Preparation of tert-butyl 3-(2-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro- lH-pyrrolo[2,3-d]pyridazin-l-yl)ethoxy)propanoate (22)

A solution of tert-butyl (E)-3-(2-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5- dihydro-U/-pyrrolo[2,3-J]pyridazin-l-yl)ethoxy)acrylate 21 (1.5 g, 3.0 mmol) and Pd/C (150 mg) in EtOAc (35 mL) was stirred at room temperature for 1 h under EE atmosphere. The resulting solution was filtered through celite, and the filter cake was washed with DCM (20 mL x 4). The filtrate was concentrated under reduced pressure to give tert-butyl 3-(2-(5-(4- methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro-U/-pyrrolo[2,3-J]pyridazin-l- yl)ethoxy)propanoate 22 (1.2 g, 90 % purity, 75 % yield) as a colorless oil. LCMS (ESI) calcd for C24H28F3N3O5 [M + H] ⁺ m/z 496.20, found 496.22.

Preparation of 3-(2-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro-lH- pyrrolo[2,3-d]pyridazin-l-yl)ethoxy)propanoic acid (INT-2)

A solution of tert-butyl 3-(2-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro- l/Z-pyrrolo[2,3-J]pyridazin-l-yl)ethoxy)propanoate 22 (1.2 g, 2.6 mmol) in HC1 dioxane solution (4- M, 10 mL) was stirred at rt for 2 hours. The mixture was concentrated under reduced pressure. The residue was triturated with DCM, filtered, and dried under vacuum to 3- (2-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro-lH-pyrrolo[2,3-d]pyridazin- l-yl)ethoxy)propanoic acid INT-2 (1 g, 90 % purity, 68 % yield) as a white solid.

LCMS (ESI) calcd for C20H20F3N3O5 [M + H] ⁺ m/z 440.14, found 440.12.

3 Synthesis of l-(2-(3-oxo-3-(cis-4-(5-(trifluoromethyl)pyrimidin-2- yl)hexahydropyrrolo[3,2-b]pyrrol-l(2H)-yl)propoxy)ethyl)-3-(trifluoromethyl)-l,5-dihydro- 4H-pyrazolo[3,4-d]pyridazin-4-one (Compounds 2a and 2b)

Compounds 2a and 2b were prepared in accordance with the following scheme:

Compounds 2a + 2b

1005

Preparation of tert-butyl cis-4-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyrrolo[3,2- b]pyrrole-l (2H)-carboxylate (1003)

To a solution of 2-chloro-5-(trifluoromethyl)pyrimidine 1001 (150 mg, 0.81 mmol) in NMP (25 mL) were added tert-butyl cis-hexahydropyrrolo[3,2-b]pyrrole-l(2H)-carboxylate 1002 (174 mg, 0.81 mmol) and K2CO3 (225 mg, 1.63 mmol) at rt. After completion of addition, the reaction solution was stirred at 80 °C for 1 h. After cooling to rt, the reaction mixture was added into cold water and then extracted with EtOAc (50 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 silica chromatography (eluting with PE/EtOAc = 100 : 0 to 50 : 50) to give tert-butyl cis-4-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyrrolo[3,2-b]pyrrole- l(2H)-carboxylate 1003 (250 mg, 90 % purity, 76 % yield) as yellow oil.

LCMS (ESI) calcd for C16H21F3N4O2 [M + H] ⁺ m/z 359.16, found 359.10.

Preparation of (cis)-l-(5-(trifluoromethyl)pyrimidin-2-yl)octahydropyrrolo[3,2-b]pyrrole hydrochloride (1004)

A solution of tert-butyl cis-4-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyrrolo[3,2- b]pyrrole-l(2H)-carboxylate 1003 (200 mg, 0.55 mmol) in HCl-Dioxane (4 M, 20 mL) was stirred at rt for 1 h. The resulting solution was concentrated under reduced pressure to give cis- l-(5-(trifluoromethyl)pyrimidin-2-yl)octahydropyrrolo[3,2-b]pyrrole hydrochloride 1004 (150 mg, 90 % purity, 93 % yield) as white solid.

LCMS (ESI) calcd for C11H13F3N4 [M + H] ⁺ m/z 259.11, found 259.00.

Synthesis of 3-(2-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro-lH-

Preparation of ethyl 2-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro-lH- pyrazolo[3,4-d]pyridazin-l-yl)acetate (1007)

To a solution of 5-(4-rnethoxybenzyl)-3-(trifluoromethyl)-l,5-dihydro-4H-pyrazolo[3,4- d]pyridazin-4-one INT-1 (2.5 g, 0.0077 mol) in DMF (50 mL) were added t-BuOK (1.30 g, 0.011 mol) and ethyl 2-bromoacetate 1006 (1.93 g, 0.011 mol) at rt. After completion of addition, the reaction was kept stirring for an additional 1 h. The resulting reaction mixture was poured into cold saturated aqueous NH4CI and sitrred for 5 min. Then the solution was extracted with EtOAc (50 mL x 3). The combined organic layer was washed with brine (30 mL x 3), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash silica chromatography (eluting with PE/EtOAc = 100 : 0 to 55 : 45) to give ethyl 2-(5- (4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro-lH-pyrazolo[3,4-d]pyridazin-l- yl)acetate 1007 (2.5 g, 90 % purity, 71 % yield) as yellow oil.

LCMS (ESI) calcd for CisHnFs^CU [M + H] ⁺ m/z 411.12, found 411.00.

Preparation of l-(2-hydroxyethyl)-5-(4-methoxybenzyl)-3-(trifluoromethyl)-l,5-dihydro- 4H-pyrazolo[3,4-d]pyridazin-4-one (1008)

To a solution of ethyl 2-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro-lH- pyrazolo[3,4-d]pyridazin-l-yl)acetate 1007 (2.5 g, 0.006 mol) in EtOH (20 mL) were added LiCl (1.03 g, 0.024 mol) and NaBEL (0.92 g, 0.024 mol) at rt. After completion of addition, the reaction solution was stirred at rt for 1 h. The resulting solution was extracted with EtOAc (30 mL x 4). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash silica chromatography (eluting with PE/EtOAc = 50 : 50 to 0 : 100) to give 1 -(2 -hydroxy ethyl)-5-(4-methoxybenzyl)- 3-(trifluoromethyl)-l,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one 1008 (2.2 g, 90 % purity, 88 % yield) as yellow oil.

LCMS (ESI) calcd for Ci6Hi₅F₃N₄O3 [M + H] ⁺ m/z 369.11, found 369.00. Preparation of ethyl (E)-3-(2-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro- 1H-pyrazolo[3,4-d]pyridazin-1-yl)ethoxy)acrylate (1010) To a solution of 1-(2-hydroxyethyl)-5-(4-methoxybenzyl)-3-(trifluoromethyl)-1,5-dihydro- 4H-pyrazolo[3,4-d]pyridazin-4-one 1008 (2.2 g, 0.006 mol) in DCM (30 mL) were added ethyl propiolate 1009 (1.18 g, 0.012 mol) and P(n-Bu)3 (0.12 g, 0.0006 mol) at rt. After completion of addition, the reaction solution was stirred at rt for 1 h. The resulting solution was evaporated under reduced pressure to get deep brown solid crude which was purified by flash silica chromatography (eluting with PE/EtOAc = 50 : 50 to 0 : 100) to give ethyl (E)-3-(2-(5-(4- methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1- yl)ethoxy)acrylate 1010 (2 g, 90 % purity, 65 % yield) as yellow oil. LCMS (ESI) calcd for C + 21H21F3N4O5 [M + Na] m/z 489.15, found 489.10. Preparation of ethyl 3-(2-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H- pyrazolo[3,4-d]pyridazin-1-yl)ethoxy)propanoate (1011) To a solution of ethyl (E)-3-(2-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro- 1H-pyrazolo[3,4-d]pyridazin-1-yl)ethoxy)acrylate 1010 (2.2 g, 0.0047 mol) in MeOH (50 mL) was added Pd/C (2.5 g) at rt. After completion of addition, the reaction solution was stirred at rt for 1 h under H₂. The resulting solution was filtered through diatomaceous earth and the filter cake was washed with DCM (5 mL × 4). The filtrate was concentrated under reduced pressure to give ethyl 3-(2-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H- pyrazolo[3,4-d]pyridazin-1-yl)ethoxy)propanoate 1011 (2 g, 90 % purity, 80 % yield) as yellow oil. LCMS (ESI) calcd for C + 21H23F3N4O5 [M + H] m/z 469.16, found 469.24. Preparation of 3-(2-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H- pyrazolo[3,4-d]pyridazin-1-yl)ethoxy)propanoic acid (1012) To a solution of ethyl 3-(2-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H- pyrazolo[3,4-d]pyridazin-1-yl)ethoxy)propanoate 1011 (2 g, 0.0043 mol) in THF:H2O (1:1, 40 mL) was added NaOH (0.34 g, 0.0086 mol) at rt. After completion of addition, the reaction solution was stirred at rt for 1 h. The resulting solution was evaporated under reduced pressure and then adjusted to pH 6 with saturated aqueous HCl at 0 ℃. The solution was extracted with DCM (10 mL × 3). The combined organic layer was washed with brine, dried over Na₂SO₄ and concentrated under reduced pressure to give 3-(2-(5-(4-methoxybenzyl)-4-oxo-3- (trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)ethoxy)propanoic acid 1012 (1.3 g, 90 % purity, 62 % yield) as yellow oil. LCMS (ESI) calcd for C₁₉H₁₉F₃N₄O₅ [M + H] + m/z 441.13, found 441.05. Preparation of 5-(4-methoxybenzyl)-1-(2-(3-oxo-3-(cis-4-(5-(trifluoromethyl)pyrimidin-2- yl)hexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl)propoxy)ethyl)-3-(trifluoromethyl)-1,5-dihydro- 4H-pyrazolo[3,4-d]pyridazin-4-one (1005) To a solution of cis-1-(5-(trifluoromethyl)pyrimidin-2-yl)octahydropyrrolo[3,2-b]pyrrole hydrochloride 1004 (150 mg, 0.58 mmol), 3-(2-(5-(4-methoxybenzyl)-4-oxo-3- (trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazin-1-yl)ethoxy)propanoic acid 1012 (255 mg, 0.58 mmol) in DCM (20 mL) were added DIPEA (150 mg, 1.16 mmol) and T3P (50% wt in EtOAc, 458 mg, 0.72 mmol) at room temperature successively. The mixture was kept stirring at room temperature for 1 h. The resulting mixture was diluted with water and extracted with DCM (20 mL x 3). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash silica chromatography (eluting with DCM/MeOH = 100 : 0 to 90 : 10) to give 5-(4-methoxybenzyl)-1-(2-(3-oxo-3- (cis-4-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyrrolo[3,2-b]pyrrol-1(2H)- yl)propoxy)ethyl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one 1005 (200 mg, 90 % purity, 45 % yield) as a white solid. LCMS (ESI) calcd for C + 30H30F6N8O4 [M + H] m/z 681.23, found 681.15. Preparation of 1-(2-(3-oxo-3-(cis-4-(5-(trifluoromethyl)pyrimidin-2- yl)hexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl)propoxy)ethyl)-3-(trifluoromethyl)-1,5-dihydro- 4H-pyrazolo[3,4-d]pyridazin-4-one (Compounds 2a and 2b) To a solution of 5-(4-methoxybenzyl)-1-(2-(3-oxo-3-(cis-4-(5-(trifluoromethyl)pyrimidin-2- yl)hexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl)propoxy)ethyl)-3-(trifluoromethyl)-1,5-dihydro- 4H-pyrazolo[3,4-d]pyridazin-4-one 1005 (200 mg, 0.29 mmol) in TFA (3 mL) was added TfOH (0.5 mL) at rt. After completion of addition, the reaction solution was stirred at rt for 1 h. The residue was diluted with DCM (50 mL) and then adjusted to pH 8 with saturated aqueous NaHCO₃ at 0 ℃. The basified solution was extracted with DCM (10 mL × 3). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by C18 column (Agela 40 g, mobile phase: ACN - H₂O (0.1% FA), gradient: 30 - 60) to give racemic 1-(2-(3-oxo-3-(cis-4-(5- (trifluoromethyl)pyrimidin-2-yl)hexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl)propoxy)ethyl)-3- (trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (Compounds 2a and 2b) (80 mg, 90 % purity, 43 % yield) as a white solid. Chiral resolution of 1-(2-(3-oxo-3-((cis-4-(5-(trifluoromethyl)pyrimidin-2- yl)hexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl)propoxy)ethyl)-3-(trifluoromethyl)-1,5-dihydro- 4H-pyrazolo[3,4-d]pyridazin-4-one (Compounds 2a and 2b) Compounds 2a and 2b were separated by SFC (Column: DAICEL OJ-H 250 mm × 20 mm I.D., 5 μmm; Mobile phase: CO2/IPA [0.1% NH3] = 75/25) and concentrated under reduced pressure to afford the first fraction as Compound 2a (35.1 mg, 99 % purity, 100 %ee, white solid) and the second fraction as Compound 2b (32.2 mg, 98 % purity, 99 %ee, white solid). Compound 2a 1H NMR (400 MHz, DMSO-d₆, ppm) δ: 12.87 (s, 1 H), 8.73 (d, J = 4.4 Hz, 2 H), 8.59 (s, 1 H), 4.75-4.39 (m, 4 H), 3.97-3.75 (m, 3 H), 3.71- 3.52 (m, 3 H), 3.32- 3.00 (m, 2 H), 2.47-2.30 (m, 2 H), 2.15-1.89 (m, 4 H). LCMS (ESI) calcd for C22H22F6N8O3 [M + H] + m/z 561.17, found 561.10. Compound 2b 1H NMR (400 MHz, DMSO-d6, ppm) δ: 12.87 (s, 1 H), 8.73 (d, J = 4.0 Hz, 2 H), 8.59 (s, 1 H), 4.75-4.39 (m, 4 H), 3.96-3.77 (m, 3 H), 3.71-3.52 (m, 3 H), 3.32-3.01 (m, 2 H), 2.48-2.29 (m, 2 H), 2.15-1.90 (m, 4 H). LCMS (ESI) calcd for C + 22H22F6N8O3 [M + H] m/z 561.17, found 561.05. 4 Synthesis of l-(2-(3-oxo-3-(cis-4-(5-(trifluoromethyl)pyrimidin-2- yl)hexahydropyrrolo[3,2-b]pyrrol-l(2H)-yl)propoxy)ethyl)-3-(trifluoromethyl)-l,5-dihydro- 4H-pyrrolo[2,3-d]pyridazin-4-one (Compounds 3a and 3b)

Compounds 3a and 3b were synthesised as follows:

Compounds 3a and 3b

Preparation of 5-(4-methoxybenzyl)-l-(2-(3-oxo-3-(cis-4-(5-(trifluoromethyl)pyrimidin-2- yl)hexahydropyrrolo[3,2-b]pyrrol-l(2H)-yl)propoxy)ethyl)-3-(trifluoromethyl)-l,5-dihydro- 4H-pyrrolo[2,3-d]pyridazin-4-one (1101)

To a solution of cis-l-(5-(trifluoromethyl)pyrimidin-2-yl)octahydropyrrolo[3,2-b]pyrrole hydrochloride 1004 (100 mg, 0.33 mmol) and 3-(2-(5-(4-methoxybenzyl)-4-oxo-3- (trifluoromethyl)-4,5-dihydro-lH-pyrrolo[2,3-d]pyridazin-l-yl)ethoxy)propanoic acid INT-2 (149 mg, 0.33 mmol) in DCM (20 mL) were added DIPEA (87 mg, 0.67 mmol) and T3P (50 % wt in EtOAc, 458 mg, 0.72 mmol) at room temperature successively. The mixture was kept stirring at room temperature for 1 h. The resulting mixture was diluted with water and extracted with DCM (20 mL x 3). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash silica chromatography (eluting with DCM/MeOH = 100 : 0 to 90 : 10) to give 5-(4-methoxybenzyl)-l-(2-(3-oxo-3-(cis-4-(5- (trifluoromethyl)pyrimidin-2-yl)hexahydropyrrolo[3,2-b]pyrrol-l(2H)-yl)propoxy)ethyl)-3- (trifluoromethyl)-l,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one 1101 (150 mg, 90 % purity, 60 % yield) as yellow oil.

LCMS (ESI) calcd for C31H31F6N7O4 [M + H] ⁺ m/z 680.23, found 680.32.

Preparation of l-(2-(3-oxo-3-(cis-4-(5-(trifluoromethyl)pyrimidin-2- yl)hexahydropyrrolo[3,2-b]pyrrol-l(2H)-yl)propoxy)ethyl)-3-(trifluoromethyl)-l,5-dihydro- 4H-pyrrolo[2,3-d]pyridazin-4-one (Compounds 3a and 3b)

To a solution of 5-(4-methoxybenzyl)-l-(2-(3-oxo-3-(cis-4-(5-(trifluoromethyl)pyrimidin-2- yl)hexahydropyrrolo[3,2-b]pyrrol-l(2H)-yl)propoxy)ethyl)-3-(trifluoromethyl)-l,5-dihydro- 4H-pyrrolo[2,3-d]pyridazin-4-one 1101 (150 mg, 0.21 mmol) in TFA (5 mL) was added TfOH (0.5 mL) at rt. After completion of addition, the reaction solution was stirred at rt for 1 h. The resulting light brown solution was concentrated under reduced pressure to remove most TFA. The residue was diluted with DCM (50 mL) and then adjusted pH to 8 with saturated aqueous NaHCCh at 0 °C. The basified solution was extracted with DCM (10 mL x 3). The combined organic layer was washed with brine, dried over Na2SC>4 and concentrated under reduced pressure. The crude product was purified by flash silica chromatography (eluting with DCM/MeOH = 100 : 0 to 90 : 10) and Ci8 column (Agela 40 g, mobile phase: ACN - H2O (0.1% FA), gradient: 30 - 60) to give racemic l-(2-(3-oxo-3-(cis-4-(5-

(trifluoromethyl)pyrimidin-2-yl)hexahydropyrrolo[3,2-b]pyrrol-l(2H)-yl)propoxy)ethyl)-3- (trifluoromethyl)-l,5-dihydro-4H-pyrrolo[2,3-d]pyridazin-4-one (Compounds 3a and 3b, 80 mg, 90 % purity, 70 % yield) as a white solid.

Chiral resolution of l-(2-(3-oxo-3-(cis-4-(5-(trifluoromethyl)pyrimidin-2- yl)hexahydropyrrolo[3,2-b]pyrrol-l(2H)-yl)propoxy)ethyl)-3-(trifluoromethyl)-l,5-dihydro- 4H-pyrrolo[2,3-d]pyridazin-4-one (Compounds 3a and 3b)

Compounds 3a and 3b were separated by SFC (Column: DAICEL OJ-H 250 mm x 20 mm I.D., 5 pmm; Mobile phase: CO2/IPA [0.1% NH3] = 75/25) and concentrated under reduced pressure to afford the first fraction as Compound 3a (34.6 mg, 99 % purity, 100%ee, white solid) and the second fraction as Compound 3b (36.0 mg, 99 % purity, 98 %ee, white solid). Compound 3a 1H NMR (400 MHz, DMSO-d₆, ppm) δ: 12.59-12.53 (m, 1 H), 8.80-8.71 (m, 2 H), 8.42 (s, 1 H), 8.01 (s, 1 H), 4.72-4.39 (m, 4 H), 3.98-3.85 (m, 1 H), 3.80-3.58 (m,5 H), 3.31-3.04 (m, 2 H), 2.48-2.31 (m, 2 H), 2.20-1.93 (m, 4 H). LCMS (ESI) calcd for C₂₃H₂₃F₆N₇O₃ [M + H] + m/z 560.18, found 560.10. Compound 3b 1H NMR (400 MHz, DMSO-d6, ppm) δ: 12.63-12.51 (m, 1 H), 8.79-8.68 (m, 2 H), 8.42 (s, 1 H), 8.01 (s, 1 H), 4.73-4.39 (m, 4 H), 3.97-3.85 (m, 1 H), 3.80-3.54 (m,5 H), 3.31-3.01 (m, 2 H), 2.48-2.31 (m, 2 H), 2.18-1.90 (m, 4 H). LCMS (ESI) calcd for C H F N O [M + + 23 23 6 7 3 H] m/z 560.18, found 560.10.

5 Synthesis of 1-(1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2- yl)hexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl)propoxy)propan-2-yl)-3-(trifluoromethyl)-1,5- dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (compounds 28a, 28b, 28c and 28d) Compound 28 was synthesised in accordance with the following scheme:

Preparation of 5-(4-methoxybenzyl)-1-(1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2- yl)hexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl)propoxy)propan-2-yl)-3-(trifluoromethyl)-1,5- dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (1202 racemate) To a solution of 3-(2-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H- pyrazolo[3,4-d]pyridazin-1-yl)propoxy)propanoic acid 1201 racemate (320 mg, 0.704 mmol) in DCM (20 mL) were added racemic cis-1-(5-(trifluoromethyl)pyrimidin-2- yl)octahydropyrrolo[3,2-b]pyrrole hydrochloride 1004 (207 mg, 0.704 mmol), DIPEA (545 mg, 4.225 mmol) and T3P (1793 mg, 2.817 mmol, 50 wt.% in EtOAc). The reaction mixture was stirred at rt for 1 h. The resulting mixture was concentrated and purified by flash silica chromatography (eluting with MeOH/DCM, 0 to 5 %) to obtain 5-(4-methoxybenzyl)-1-(1-(3- oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyrrolo[3,2-b]pyrrol-1(2H)- yl)propoxy)propan-2-yl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one 1202 racemate (340 mg, 90 % purity, 62 % yield) as a colorless oil. LCMS (ESI) calcd for C₃₁H₃₂F₆N₈O₄ [M + Na] + m/z 717.25, found 717.20. Preparation of 1-(1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyrrolo[3,2- b]pyrrol-1(2H)-yl)propoxy)propan-2-yl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4- d]pyridazin-4-one (28a/28b/28c/28d diastereomeric mixture) TfOH (0.5 mL) was added to a solution of 5-(4-methoxybenzyl)-1-(1-(3-oxo-3-(4-(5- (trifluoromethyl)pyrimidin-2-yl)hexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl)propoxy)propan-2- yl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one 1202 racemate (340 mg, 0.158 mmol) in TFA (5 mL). The mixture was stirred at rt for 30 min, adjusted to pH 8.0 with saturated NaHCO₃ solution and extracted with DCM (100 mL × 3). The combined organic layer was washed with brine, dried over Na2SO4, concentrated and purified with prep-HPLC (Column: Gemini 5 μm C18150 × 21.2 mm, mobile phase: ACN - H2O (0.1% FA), gradient: 40 - 60) to obtain 1-(1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyrrolo[3,2- b]pyrrol-1(2H)-yl)propoxy)propan-2-yl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4- d]pyridazin-4-one 28a/28b/28c/28d diastereomeric mixture (250 mg, 99 % purity, 88 % yield) as a white solid. Chiral resolution of 1-(1-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2- yl)hexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl)propoxy)propan-2-yl)-3-(trifluoromethyl)-1,5- dihydro-4H-pyrazolo[3,4-d]pyridazin-4-one (28a/28b/28c/28d diastereomeric mixture) The 28a/28b/28c/28d diastereomeric mixture was separated by SFC (Column: Daicel AD-H 250 mm × 20 mm I.D., 5 μm; Mobile phase: CO2/MeOH (0.1 % NH3) = 70/30) and concentrated under reduced pressure to afford the first fraction as 28a (50.7 mg, 99 % purity, 100 %ee, white solid), the second fraction as 28b (55.3 mg, 99 % purity, 100 %ee, white solid), the third fraction as 28c (48.0 mg, 99 % purity, 100 %ee, white solid) and the fourth fraction as 28d (43.9 mg, 99 % purity, 100 %ee, white solid). 28a 1H NMR (400 MHz, DMSO-d₆, ppm) δ: 12.88 (d, J = 5.6 Hz, 1 H), 8.73 (d, J = 3.6 Hz, 2 H), 8.66 (s, 1 H), 5.26-5.10 (m, 1 H), 4.69-4.53 (m, 1 H), 4.50-4.37 (m, 1 H), 3.96-3.82 (m, 1 H), 3.75-3.63 (m, 3 H), 3.57-3.39 (m, 2 H), 3.30-3.24 (m, 1 H), 3.18-2.99 (m, 1 H), 2.41-2.28 (m, 2 H), 2.14-1.89 (m, 4 H), 1.50 (d, J = 6.8 Hz, 3 H). LCMS (ESI) calcd for C + 23H24F6N8O3 [M + H] m/z 575.19, found 575.45. 28b 1H NMR (400 MHz, DMSO-d6, ppm) δ: 12.86 (s, 1 H), 8.73 (d, J = 3.6 Hz, 2 H), 8.65 (s, 1 H), 5.24-5.09 (m, 1 H), 4.70-4.51 (m, 1 H), 4.48-4.34 (m, 1 H), 3.97-3.83 (m, 1 H), 3.77-3.64 (m, 3 H), 3.55-3.39 (m, 2 H), 3.31-3.27 (m, 1 H), 3.23-3.01 (m, 1 H), 2.42-2.29 (m, 2 H), 2.11-1.85 (m, 4 H), 1.50 (d, J = 6.8 Hz, 3 H). LCMS (ESI) calcd for C₂₃H₂₄F₆N₈O₃ [M + H] + m/z 575.19, found 575.50. 28c 1H NMR (400 MHz, DMSO-d₆, ppm) δ: 12.86 (s, 1 H), 8.73 (d, J = 3.6 Hz, 2 H), 8.65 (s, 1 H), 5.27-5.09 (m, 1 H), 4.68-4.54 (m, 1 H), 4.48-4.37 (m, 1 H), 3.98-3.85 (m, 1 H), 3.75-3.64 (m, 3 H), 3.56-3.41 (m, 2 H), 3.31-3.28 (m, 1 H), 3.21-3.00 (m, 1 H), 2.41-2.29 (m, 2 H), 2.12-1.91 (m, 4 H), 1.50 (d, J = 6.8 Hz, 3 H). LCMS (ESI) calcd for C H F N + 23 24 6 8O3 [M + H] m/z 575.19, found 575.50. 28d 1H NMR (400 MHz, DMSO-d6, ppm) δ: 12.88 (d, J = 5.6 Hz, 1 H), 8.73 (d, J = 3.6 Hz, 2 H), 8.66 (s, 1 H), 5.27-5.09 (m, 1 H), 4.70-4.51 (m, 1 H), 4.49-4.37 (m, 1 H), 3.98-3.80 (m, 1 H), 3.75-3.63 (m, 3 H), 3.55-3.37 (m, 2 H), 3.30-3.25 (m, 1 H), 3.19-3.00 (m, 1 H), 2.40-2.30 (m, 2 H), 2.11-1.87 (m, 4 H), 1.50 (d, J = 6.8 Hz, 3 H). LCMS (ESI) calcd for C + 23H24F6N8O3 [M + H] m/z 575.19, found 575.50. 6 Assays Exemplary compounds of the invention were prepared and tested to determine their effect as PARP7 inhibitors. A typical assay is described below. 6A PARP7 biochemical dissociation-enhanced lanthanide fluorescence immunoassay (DELFIA assay) Optiplate HB 384-well plates were coated with anti-FLAG antibody, supplied as a 4 mg/ml solution, using a Na₂CO₃/HCO₃ coating buffer at pH 9.6, overnight at 4 °C, in order to achieve a final immobilisation per well of 0.3 ^g. Wells were then washed 3 x in coating wash buffer (PBS/0.05 % Tween (v/v)), blocked with 2 % BSA (w/v) in coating wash buffer and washed 3 further times prior to assay. For the assay 20 ^l of 12.5-37.5 nM recombinant human Flag- tagged PARP7 (amino acids 456-657) was added to each well of the 384-well plate for 30 min at room temperature. 50 nl of test compound in DMSO was added using pintool technology and plates were incubated for a further 30 min at room temperature. 5 ^l of 15 ^M biotin- NAD+ assay solution in 20 mM HEPES (pH 7.5), 100 mM NaCl, 2 mM DTT, 0.1 % BSA (w/v), 0.02 % Tween (v/v) assay buffer was then added and MARylation proceeded for 2-3 h at room temperature prior to the addition of 5 ^l of 12 mM NAD+ quenching solution. After 30 min at room temperature, assay solution was removed and following washing 5 times, 100 ^l of a 1:1000 dilution of DELFIA Eu-N1 Streptavidin reagent was added. Plates were then incubated for 30 min at room temperature. Reaction mixture was removed and plates washed 5 times prior to the addition of 25 ^l DELFIA enhancement solution. Following incubation for 30 min at room temperature, fluorescence was read on either an Envision or Pherastar FS (Ex337 nm, Em620 nm). Typically compounds were tested from 10-20 ^M at 0.5 log intervals in 10-12-point concentration-response curves to determine IC₅₀ values. Data was analysed using ActivityBase software and replicate values for the low (without enzyme, 0.2% DMSO) and high (0.2 % DMSO) % controls were averaged and the data obtained from the test compounds expressed as a % of 100 % using the below formula: %activity = 100*(value – low control) / (high control – low control) %activity data was fitted with 4-parameter non-linear regression equation to obtain IC50 values.

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

TABLE 1

Results of Parp 7 assay for selected compounds

Key: ++++ indicates IC50 ≤ 10 nM +++ indicates IC₅₀ > 10 nM and ≤ 100 nM ++ indicates IC50 > 100 nM and ≤ 1 ^M + indicates IC50 > 1 ^M and ≤ 10 ^M

Claims

CLAIMS: 1. A PARP7 inhibitor compound, which compound comprises the following formula:

wherein: X¹ is independently selected from C and N; R¹ is independently selected from H or a substituted or unsubstituted organic group; is independently selected from H or a substituted or unsubstituted organic group; is independently selected from H or a substituted or unsubstituted organic group; R⁹ is independently selected from H or a substituted or unsubstituted organic group, and when

absent; L is a group having the following formula:

wherein: each R⁴ is independently selected from H or a substituted or unsubstituted organic group; t is selected from 1, 2, or 3; Y comprises a group selected from one of the following formulae:

Z comprises a group having the following formula:

pendently selected from C and N; each R⁶ is independently selected from H or a substituted or unsubstituted organic group, and when an

⁶ is attached to an X² or an X³ that is an N, it is absent; each of p, q, r and s are independently selected from 0, 1, 2, 3, and 4, provided that p + q equals 1, 2, 3 or 4 and r + s equals 1, 2, 3, or 4; the bonds between all of the atoms in ring A may independently be single bonds or double bonds provided that when X² is N the bonds to X² are single bonds; the bonds between all of the atoms in ring B may independently be single bonds or double bonds provided that when X³ is N the bonds to X³ are single bonds; and R⁵ comprises a group selected from one of the following formulae:

wherein: each ⁴ is independently selected from C and N; each R⁷ is independently selected from H or a substituted or unsubstituted organic group, and when an

⁴ is N, the R⁷ attached to it is absent; and R⁸ is independently selected from H or a substituted or unsubstituted organic group.

2. A compound according to claim 1, wherein Z comprises a group having the following formula:

.

3. A compound according to claim 1 or claim 2, wherein R¹, R³ and R⁷ are each independently selected from H, deuterium, a halogen (such as –F, -Cl, -Br, and –I), a substituted or unsubstituted C1-C6 alkyl or cycloalkyl group, a substituted or unsubstituted linear or branched C1-C6 halogenated alkyl group, an -OH group or a substituted or unsubstituted linear or branched C1-C6 alcohol group, an -NH2 group or a substituted or unsubstituted C1-C6 amino group, a substituted or unsubstituted C₁-C₆ alkoxy group, and a nitrile group.

4. A compound according to claim 3, wherein R1 is a fluoromethyl group, preferably CF₂H or CF₃, more preferably CF₃.

5. A compound according to claim 3 or claim 4, wherein R3 is H.

6. A compound according to any of claims 3 to 5, wherein each R7 is H.

7. A compound according to any preceding claim, wherein R² is selected from H, a C₁- C₃ alkyl group and a C₁-C₃ halogenated alkyl group, preferably wherein R2 is H.

8. A compound according to any preceding claim, wherein each R⁴ is independently selected from H, deuterium, a halogen (such as –F, -Cl, -Br, and –I, preferably -F), a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted linear or branched C1-C6 halogenated alkyl group (preferably CF₃), an -NH₂ group or a substituted or unsubstituted C₁- C₆ amino group, an -OH group or a substituted or unsubstituted linear or branched C₁-C₆ alcohol group and a substituted or unsubstituted C1-C6 alkoxy group.

9. A compound according to claim 8, wherein each R4 is H or a methyl group; optionally wherein at most one R4 is a methyl group; further optionally wherein each R4 is H.

10. A compound according to any preceding claim, wherein each R⁶ is independently selected from H, deuterium, a halogen (such as –F, -Cl, -Br, and –I, preferably F), a substituted or unsubstituted C₁-C₆ alkyl group, a substituted or unsubstituted linear or branched C₁-C₆ halogenated alkyl group, an -OH group or a substituted or unsubstituted linear or branched C1-C6 alcohol group, an -NH2 group or a substituted or unsubstituted C1-C6 amino group and a substituted or unsubstituted C₁-C₆ alkoxy group; or wherein there are two R⁶ groups on the same atom which together form a carbonyl group.

11. A compound according to claim 10, wherein each R6 is H.

12. A compound according to any preceding claim, wherein R⁸ is selected from a halogenated C1 to C3 alkyl group, a halogenated methoxy group, -H, -CH₃, -CN, -OMe, a halogen group (-F, -Cl, -Br, -I), -SO₂Me, -CONHMe, t-Bu, cyclopropyl and

.

13. A compound according to claim 12, wherein R⁸ is selected from a halogenated C₁ to C₃ alkyl group, a halogen group, and a -CN group, and is preferably a -CF₃, -F, -Cl, or a -CN group.

14. A compound according to any preceding claim, wherein

is selected from H, a substituted or unsubstituted C1-C3 alkyl group or a substituted or unsubstituted linear or branched C1-C3 halogenated alkyl group.

15. A compound according to claim 14, wherein R⁹ is H.

16. A compound according to any preceding claim, wherein t is 1 or 2, optionally wherein t is 2.

17. A compound according to any preceding claim, having a structure selected from:

.

18. A compound according to any preceding claim, wherein L comprises a group having one of the following formulae:

.

19. A compound according to any preceding claim, wherein Z comprises a group having one of the following formulae:

20. A compound according to claim 19, wherein Z comprises a group having one of the following formulae:

21. A compound according to claim 20, wherein Z comprises a group having one of the following formulae:

wherein the stereochemistry depicted is relative stereochemistry.

22. A compound according to any preceding claim, wherein

comprises a group having one of the following formulae:

23. A compound according to claim 22, wherein comprises a group having one of the following formulae:

24. A compound according to any preceding claim, wherein group L is selected from:

wherein the stereochemistry depicted is relative stereochemistry.

25. A compound according to any preceding claim, which is selected from:

wherein the stereochemistry depicted is relative stereochemistry.

26. A compound according to any of claims 1 to 24, which is selected from:

27. A compound 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.

28. A compound as defined in any preceding claim for use in medicine.

29. A compound for use according to claim 28, which is for use in treating a disease, condition and/or a disorder selected from: a cancer, an infectious disease, a central nervous system disease or disorder, and a pain condition.

30. A compound for use according to claim 29, wherein the disease, condition and/or a disorder is a cancer selected from: a solid or liquid tumour including cancer of the eye, brain (such as gliomas, glioblastomas, medullablastomas, 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 leukemia (T-PLL), large granular lymphocytic leukemia, adult T-cell leukemia, juvenile myelomonocytic leukaemia, Hodgkin lymphoma, non-Hodgkin lymphoma, mantle lymphoma, follicular lymphoma, primary effusion lymphoma, AIDS-related lymphoma, Hodgkin lymphoma, diffuse B cell lymphoma, Burkitt lymphoma, and cutaneous T-cell lymphoma), preferably wherein the cancer is a cancer selected from oesaphageal, head and neck, non-small cell lung cancer, squamous cell cancer of the lung, breast, acute myeloid leukemia (AML), a small-cell lung cancer, a melanoma, an ovarian cancer, a colorectal cancer, a pancreatic cancer, an endometrial cancer, and a skin papilloma.

31. A compound for use according to claim 29, wherein the disease, condition and/or a disorder is an infectious disease selected from a bacterial infection and a viral infection, preferably a respiratory infection, immune system infection, gut infection or sepsis; optionally wherein the respiratory infection is a coronavirus infection, further optionally wherein the coronavirus is SARS-CoV-2.

32. A compound for use according to claim 29, wherein the disease, condition and/or a disorder is a central nervous system disease or disorder selected from amyotrophic lateral sclerosis (AML), Huntington’s disease, Alzheimer’s disease, pain, a psychiatric disorder, multiple sclerosis, Parkinson’s disease, and HIV related neurocognitive decline.

33. A pharmaceutical composition comprising a compound as defined in any of claims 1 to 27.

34. A pharmaceutical composition according to claim 33, 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.

35. A pharmaceutical composition according to claim 33 or claim 34, which composition is for use in treating a disease, condition or disorder as defined in any of claims 29 to 31.

36. A pharmaceutical composition for use according to claim 35, which is for use in treating a cancer, further comprising a further agent for treating cancer; preferably wherein the further agent for treating cancer is selected from anti -microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, senolytic agents, hormones and hormone analogues, signal transduction pathway inhibitors, DNA damage repair pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents (such as an anti-tumour vaccine, an oncolytic virus, an immune stimulatory antibody such as anti-CTLA4, anti-PDl, anti-PDL-1, anti-OX40, anti-41BB, anti-CD27, anti-CD40, anti-LAG3, anti-TIM3, and anti-GITR, a novel adjuvant, a peptide, a cytokine, a chimeric antigen receptor T cell therapy (CAR-T), a small molecule immune modulator such as an IDO or TDO inhibitor or a pattern recognition receptor agonist such as a STING, TLR-9 or RIG-I Helicase agonist, and tumour microenvironment modulators) anti -angiogenic agents, receptor tyrosine kinase inhibitors, cell growth inhibitors such as Ras and Raf inhibitors, proapoptotic agents and cell cycle signalling inhibitors.

37. A pharmaceutical composition for use according to claim 36, further comprising an agent selected from: an anti -turn our vaccine; a cancer immunotherapy treatment (such as an immune checkpoint modulator such as an anti-CTLA4, anti-PDl, anti PDL-1, anti-LAG3, or anti-TIM3 agent, and CD40, 0X40, 4 IBB or GITR agonists, IDO or TDO inhibitors); an immunomodulator such as a pattern recognition receptor agonist such as a STING, TLR-9 or RIG-I Helicase; an immunosuppressant; a cytokine therapy; a tyrosine kinase inhibitor; and a chimeric antigen receptor T cell therapy (CAR-T).

38. A pharmaceutical kit for treating a cancer, which pharmaceutical kit comprises:

(a) a compound as defined in any of claims 1 to 27; and

(b) a further agent for treating cancer; wherein the compound and the further agent are suitable for administration simultaneously, sequentially or separately; and preferably wherein the further agent for treating cancer is selected from anti -microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, senolytic agents, hormones and hormone analogues, signal transduction pathway inhibitors, DNA damage repair pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents (such as an anti-tumour vaccine, an oncolytic virus, an immune stimulatory antibody such as anti-CTLA4, anti-PDl, anti-PDL-1, anti-OX40, anti-41BB, anti-CD27, anti-CD40, anti- LAG3, anti-TIM3, and anti-GITR, a novel adjuvant, a peptide, a cytokine, a chimeric antigen receptor T cell therapy (CAR-T), a small molecule immune modulator such as a pattern recognition receptor agonist such as a STING, TLR-9 or RIG-I Helicase agonist, or a tumour microenvironment modulator), anti -angiogenic agents, receptor tyrosine kinase inhibitors, cell growth inhibitors such as Ras and Raf inhibitors, proapoptotic agents and cell cycle signalling inhibitors.

39. A method of treating a disease and/or a condition and/or a disorder, which method comprises administering to a patient a compound or a composition or a kit as defined in any preceding claim.

40. A method according to claim 39, wherein the disease or condition or disorder is a disease, condition or disorder as defined in any of claims 29 to 31.

41. A method according to claim 40 for treating a cancer, which method comprises administering to a patient a compound or a composition as defined in any of claims 1 to 37 and a further agent for treating a cancer as defined in any of claims 36 or 37; preferably wherein the compound or composition and the further agent are administered simultaneously, sequentially or separately.

42. A method according to any of claims 36 to 38, wherein the patient is an animal, preferably a mammal, such as a human, canine or feline.

43. A method according to claim 42, wherein the patient is a human.

44. A method of synthesis of a compound as defined in any of claims 1 to 27, which method comprises conducting a reaction between a first reactant and a second reactant so as to form the PARP7 inhibitor compound, wherein the first reactant comprises a compound of general formula:

and the second reactant comprises a compound of general formula:

wherein R¹⁰ and R¹¹ are each independently substituent groups which are removed during the reaction; and wherein X¹, X², X³, Y, R¹, R², R⁴, R⁵, R⁶, R⁹, p, q, r, s and t are as defined in any of claims 1 to 27.

45. A method according to claim 44, wherein the second reactant comprises a compound of general formula:

46. A method according to claim 44 or claim 45, wherein the reaction is carried out under conditions suitable for an amide formation reaction, optionally with one or more additional substitution steps and optionally with use of a protecting group for R² during an amide formation step.