WO2024061554A1 - Composé pharmaceutique - Google Patents
Composé pharmaceutique Download PDFInfo
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- WO2024061554A1 WO2024061554A1 PCT/EP2023/072871 EP2023072871W WO2024061554A1 WO 2024061554 A1 WO2024061554 A1 WO 2024061554A1 EP 2023072871 W EP2023072871 W EP 2023072871W WO 2024061554 A1 WO2024061554 A1 WO 2024061554A1
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- 208000021722 neuropathic pain Diseases 0.000 description 1
- 235000020956 nicotinamide riboside Nutrition 0.000 description 1
- 239000011618 nicotinamide riboside Substances 0.000 description 1
- 230000003040 nociceptive effect Effects 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- NIHNNTQXNPWCJQ-UHFFFAOYSA-N o-biphenylenemethane Natural products C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 description 1
- FAQDUNYVKQKNLD-UHFFFAOYSA-N olaparib Chemical compound FC1=CC=C(CC2=C3[CH]C=CC=C3C(=O)N=N2)C=C1C(=O)N(CC1)CCN1C(=O)C1CC1 FAQDUNYVKQKNLD-UHFFFAOYSA-N 0.000 description 1
- 229960000572 olaparib Drugs 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 229910000489 osmium tetroxide Inorganic materials 0.000 description 1
- OZQGLZFAWYKKLQ-UHFFFAOYSA-N oxazinane Chemical compound C1CCONC1 OZQGLZFAWYKKLQ-UHFFFAOYSA-N 0.000 description 1
- 125000004287 oxazol-2-yl group Chemical group [H]C1=C([H])N=C(*)O1 0.000 description 1
- 125000003145 oxazol-4-yl group Chemical group O1C=NC(=C1)* 0.000 description 1
- 125000004304 oxazol-5-yl group Chemical group O1C=NC=C1* 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- GUVXZFRDPCKWEM-UHFFFAOYSA-N pentalene Chemical compound C1=CC2=CC=CC2=C1 GUVXZFRDPCKWEM-UHFFFAOYSA-N 0.000 description 1
- 238000003359 percent control normalization Methods 0.000 description 1
- XDJOIMJURHQYDW-UHFFFAOYSA-N phenalene Chemical compound C1=CC(CC=C2)=C3C2=CC=CC3=C1 XDJOIMJURHQYDW-UHFFFAOYSA-N 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 1
- 125000004574 piperidin-2-yl group Chemical group N1C(CCCC1)* 0.000 description 1
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 description 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000004853 protein function Effects 0.000 description 1
- CPNGPNLZQNNVQM-UHFFFAOYSA-N pteridine Chemical compound N1=CN=CC2=NC=CN=C21 CPNGPNLZQNNVQM-UHFFFAOYSA-N 0.000 description 1
- DVUBDHRTVYLIPA-UHFFFAOYSA-N pyrazolo[1,5-a]pyridine Chemical compound C1=CC=CN2N=CC=C21 DVUBDHRTVYLIPA-UHFFFAOYSA-N 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 1
- 125000004943 pyrimidin-6-yl group Chemical group N1=CN=CC=C1* 0.000 description 1
- JBDKAABFESSFMV-UHFFFAOYSA-N pyrrolo[1,2-a]pyrimidine Chemical compound N1=CC=CN2C=CC=C21 JBDKAABFESSFMV-UHFFFAOYSA-N 0.000 description 1
- NISJKLIMPQPAQS-UHFFFAOYSA-N pyrrolo[1,2-b]pyridazine Chemical compound C1=CC=NN2C=CC=C21 NISJKLIMPQPAQS-UHFFFAOYSA-N 0.000 description 1
- RIEKLTCRUGDAPM-UHFFFAOYSA-N pyrrolo[1,2-c]pyrimidine Chemical compound C1=CN=CN2C=CC=C21 RIEKLTCRUGDAPM-UHFFFAOYSA-N 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 230000007420 reactivation Effects 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- WEMQMWWWCBYPOV-UHFFFAOYSA-N s-indacene Chemical compound C=1C2=CC=CC2=CC2=CC=CC2=1 WEMQMWWWCBYPOV-UHFFFAOYSA-N 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate group Chemical group S(=O)(=O)([O-])[O-] QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical group OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- XGTPDIIFEPTULX-UHFFFAOYSA-N tert-butyl prop-2-ynoate Chemical compound CC(C)(C)OC(=O)C#C XGTPDIIFEPTULX-UHFFFAOYSA-N 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- GVIJJXMXTUZIOD-UHFFFAOYSA-N thianthrene Chemical compound C1=CC=C2SC3=CC=CC=C3SC2=C1 GVIJJXMXTUZIOD-UHFFFAOYSA-N 0.000 description 1
- 125000000101 thioether group Chemical group 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- IBBLKSWSCDAPIF-UHFFFAOYSA-N thiopyran Chemical compound S1C=CC=C=C1 IBBLKSWSCDAPIF-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- QIWRFOJWQSSRJZ-UHFFFAOYSA-N tributyl(ethenyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C=C QIWRFOJWQSSRJZ-UHFFFAOYSA-N 0.000 description 1
- MWKJTNBSKNUMFN-UHFFFAOYSA-N trifluoromethyltrimethylsilane Chemical compound C[Si](C)(C)C(F)(F)F MWKJTNBSKNUMFN-UHFFFAOYSA-N 0.000 description 1
- 230000014567 type I interferon production Effects 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Definitions
- 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.
- Monoclonal antibody-based therapeutics targeting immune checkpoints 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.
- Immune checkpoint inhibitors 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.
- IFN-I type I interferons
- ISGs IFN-stimulated genes
- PRR pattern recognition receptor
- 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)).
- cGAS cyclic guanosine monophosphate-adenosine monophosphate
- STING Stimulator of interferon genes
- 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
- IRF3 interferon regulatory transcription factor 3
- 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.
- ISG Interferon-stimulate gene
- 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).
- TNBC BRCA-associated triplenegative breast cancer
- 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, (2016)).
- 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)).
- MART mono(ADP -ribosyl) transferase
- 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.
- AHR Aryl Hydrocarbon Receptor
- ALERT nuclear translocator
- 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.
- 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.
- PARP13 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.
- PARP7 promotes influenza A virus infection by ADP-ribosylating TBK1, which inhibits type I IFN (IFN-I) production
- IFN-I type I IFN
- 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.
- 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)).
- 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.
- 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.
- 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.
- 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 X 2 and X 3 are each independently selected from C and N; each R 6 is independently selected from H or a substituted or unsubstituted organic group, and
- 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.
- Z comprises a group having the following formula:
- 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.
- the following substituents may together form a ring: R 1 with R 9 ; R 3 with R 4 ; R 4 with another R 4 ; R 4 with R 6 ; R 4 with R 9 ; R 5 with R 6 ; R 6 with another R 6 ; R 6 with R 7 ; R 7 with another R 7 ; and R 7 with R 8 .
- 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).
- R groups attached to the same atom do not together form a ring, although this is not excluded.
- 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.
- 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.
- 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).
- the C-R group may be absent, present once i.e. -C(R)-; or present twice i.e. -C(R)-C(R)-.
- That bond is the bond that attaches to another structural component of the compound.
- a compound in the context of the present invention, 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.
- 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.
- DELFIA dissociation-enhanced lanthanide fluorescence immunoassay
- 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
- the substituents are not especially limited, provided that they do not prevent the PARP7 inhibitory function from occurring.
- the substituents are selected from H and an organic group.
- 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.
- ‘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).
- 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
- 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.
- the hydrocarbon 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.
- the hydrocarbon when it 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, pyri
- 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).
- 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).
- 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.
- any substituent may comprise a combination of two or more of the substituents and/or functional groups defined above.
- the substituent is not especially limited, provided that it does not prevent the PARP7 inhibitory function from occurring.
- the substituents may be selected independently as follows.
- R9 are typically each independently selected from H and a group selected from the following groups:
- halogen such as -F, -Cl, -Br and -I
- Ci-Ce alkyl group such as Me, Et, Pr, i-Pr, n-Bu, i-Bu, t-Bu, pentyl and hexyl
- Ci-Ce alkyl-aryl group such as -CH 2 Ph, - CH 2 (2,3 or 4)F-Ph, -CH 2 (2,3 or 4)C1-Ph, -CH 2 (2,3 or 4)Br-Ph, -CH 2 (2,3 or 4)I-Ph, - CH 2 CH 2 Ph, -CH 2 CH 2 CH 2 Ph, -CH 2 CH 2 CH 2 Ph, -CH 2 CH 2 CH 2 CH 2 Ph, -CH 2 CH 2 CH 2 CH 2 Ph, and -CH 2 CH 2 CH 2 CH 2 CH 2 Ph);
- Ci-Ce halogenated alkyl group such as -CH 2 F, -CHF 2 , - CH 2 CH 2 F, -CH 2 C1, -CH 2 Br, -CH 2 I, -CF 3 , -CCh -CBr 3 , -CI3, -CH 2 CF 3 , -C H 2 CC1 3 , -CH 2 CBr 3 , and -CH 2 CI 3 );
- Ci-Ce amine group such as -NMeH, -NMe 2 , -NEtH, -NEtme, -NEt 2 , -NPrH, -NPrme, -NPrEt, -NPr 2 , -NBuH, -NBume, -NBuEt, -CH 2 -NH 2 , -CH 2 -NMeH, -CH 2 -NMe 2 , -CH 2 -NEtH, -CH 2 -NEtMe, -CH 2 -NEt 2 , -CH 2 -NPrH, -CH 2 -NPrMe, and -CH 2 -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)F 2 -Ph, -NH- 2, (3 ,4, 5 or 6)Cl 2 -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 C 3 -C 8 alkyl group (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl); - an -OH group or a substitute
- R 1 , R 3 , R 7 , R 8 , and R 9 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 C 1 -C 6 alkyl or cycloalkyl group, a substituted or unsubstituted linear or branched C 1 -C 6 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.
- a halogen such as –F, -Cl, -Br, and
- 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 C 1 -C 6 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.
- a halogen such as –F, -Cl, -Br, and –I
- a substituted or unsubstituted C 1 -C 6 alkyl or cycloalkyl group such as –F,
- 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.
- R 2 is selected from H, a C 1 -C 3 alkyl group and a C 1 -C 3 halogenated alkyl group. More preferably, R 2 is H.
- R 4 is selected from H, deuterium, a halogen (such as –F, -Cl, -Br, and –I, preferably -F), a substituted or unsubstituted C 1 -C 6 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 C 1 -C 6 alcohol group and a substituted or unsubstituted C 1 -C 6 alkoxy group.
- a halogen such as –F, -Cl, -Br, and –I, preferably -F
- each R4 may be H or a methyl group.
- at most one R4 is a methyl group.
- each R4 is H.
- R is independently selected from H, deuterium, a halogen (such as –F, -Cl, - Br, and –I, preferably F), a substituted or unsubstituted C 1 -C 6 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 C 1 -C 6 amino group and a substituted or unsubstituted C 1 -C 6 alkoxy group.
- a halogen such as –F, -Cl, - Br, and –I, preferably F
- each R6 is H.
- R 8 is selected from a halogenated C1 to C3 alkyl group, a halogenated methoxy group, -H, -CH 3 , -CN, -OMe, a halogen group (-F, -Cl, -Br, -I), -SO 2 Me, -CONHMe, t-Bu, cyclopropyl and .
- R 8 is selected from a halogen group, -CF 3 , -CHF 2 , - CH 2 F, -OCF 3 , -CH 2 CF 3 , -CF 2 CH 3 , -OCHF 2 , -OCH 2 F, and a -CN group.
- R8 may be selected from a halogenated C1 to C3 alkyl group, a halogen group, and a -CN group, and is preferably a -CF 3 , -F, -Cl, or a -CN group.
- R8 is most preferably a -CF 3 , -F, -Cl, or a -CN group.
- R 9 is selected from H, a substituted or unsubstituted C 1 -C 6 alkyl group or a substituted or unsubstituted linear or branched C 1 -C 6 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.
- Z may comprise a group having one of the following formulae:
- R ⁇ are each as defined herein.
- Z comprises a group having one of the following formulae:
- Z may have a structure of:
- An example Z group in the above class is: where the stereochemistry depicted is relative stereochemistry.
- R ⁇ comprises a group having one of the following formulae:
- R 5 may have a structure of: such as:
- group L is selected from:
- stereochemistry depicted is relative stereochemistry.
- L groups include: the depicted stereochemistry being relative stereochemistry.
- 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:
- PARP7 inhibitor compounds include: the depicted stereochemistry being relative stereochemistry.
- the present invention provides a PARP7 inhibitor compound which comprises a formula selected from one of the following:
- any compounds for use in the invention may comprise compounds or compositions in accordance with their structure as follows:
- 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).
- a compound with a suffix “a” eg 2a
- 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.
- the suffix “a” denotes a compound eluted as a first fraction
- “b”, “c” and “d” denote compounds eluted as second, third, and fourth fractions respectively.
- a compound with no suffix represents either an achiral compound or a compound with assigned absolute stereochemistry.
- 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.
- the medicinal use is not especially limited, provided that it is a use which is facilitated by the PARP7 inhibitory effect of the compound.
- 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.
- 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.
- 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, pancrea
- 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.
- the infectious disease is selected from a bacterial infection and a viral infection, preferably a respiratory infection, immune system infection, gut infection and sepsis.
- viral respiratory infections include influenza and coronavirus infections, particularly influenza A and SARS- CoV-2 infections.
- the disease, condition or disorder is a central nervous system disease, condition or disorder
- the disease, condition or disorder is one which may be treated, prevented or ameliorated by using a PARP7 inhibitor.
- 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.
- 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.
- 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
- a pharmaceutical composition comprising a compound as defined above.
- the pharmaceutical composition is not especially limited, typically the composition further comprises a pharmaceutically acceptable additive and/or excipient.
- 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.
- the compound may be in the form of a pharmaceutically acceptable salt, hydrate, acid, ester, or other alternative suitable form.
- the composition is for treating a disease, condition or disorder as defined above.
- 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.
- 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.
- 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
- the invention provides a pharmaceutical kit for treating a cancer, which pharmaceutical kit comprises:
- 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
- a method of treating a disease and/or a condition and/or a disorder 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.
- the method is a method for treating a cancer.
- 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.
- the patient is an animal, typically a mammal, including canines and felines, and more typically a human.
- a method of synthesis of a compound as defined above 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 R 10 and R 11 are each independently substituent groups which are removed during the reaction; and wherein X 1 , X 2 , X 3 , Y, R 1 , R 2 , R 4 , R 5 , R 6 , R 9 , p, q, r, s and t are as defined herein.
- the second reactant may comprise a compound of general formula:
- 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.
- the method comprises one or more additional substitution steps.
- the method comprises use of a protecting group as R 2 during an amide formation step. Exemplary syntheses are shown in the Examples herein.
- 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.
- the above formulae (and all formulae herein) are intended to represent all tautomeric forms equivalent to the corresponding formula.
- the compounds of the invention may be synthesised using readily available starting materials and known reactions.
- 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 NaHCO 3 at 0 °C.
- 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 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.
- %activity 100*(value – low control) / (high control – low control) %activity data was fitted with 4-parameter non-linear regression equation to obtain IC50 values.
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Abstract
L'invention concerne un composé inhibiteur de PARP7 qui comprend la formule (I), X1 est choisi parmi C, et N. R1, R2 et R3, sont chacun indépendamment H ou un groupe organique. R9 est H ou un groupe organique ou est absent lorsque X1 est N. L est (II). Chaque R4 est indépendamment choisi parmi H ou un groupe organique. t est choisi parmi 1, 2 ou 3. Y est (III) ou (IV). Z est (V). X2 et X3 sont indépendamment choisis parmi C et N. Chaque R6 est H ou un groupe organique ou absent lorsqu'il est fixé à un N. p + q égal à 1, 2, 3 ou 4 et r + s est égal à 1, 2, 3 ou 4. R5 est (VI), (VII), (VIII) ou (IX). Chaque X4 est C ou N. Chaque R7 est H ou un groupe organique ou est absent lorsqu'il est fixé à un N. R8 est H ou un groupe organique.
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GBGB2213819.2A GB202213819D0 (en) | 2022-09-22 | 2022-09-22 | Pharmaceutical compound |
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2016116602A1 (fr) | 2015-01-23 | 2016-07-28 | Astrazeneca Ab | Traitement du cancer |
WO2019212937A1 (fr) | 2018-04-30 | 2019-11-07 | Ribon Therapeutics Inc. | Pyridazinones utilisés en tant qu'inhibiteurs de parp7 |
WO2022156708A1 (fr) * | 2021-01-20 | 2022-07-28 | Jacobio Pharmaceuticals Co., Ltd. | Inhibiteur d'enzyme parp7 |
-
2022
- 2022-09-22 GB GBGB2213819.2A patent/GB202213819D0/en not_active Ceased
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- 2023-08-18 WO PCT/EP2023/072871 patent/WO2024061554A1/fr unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2016116602A1 (fr) | 2015-01-23 | 2016-07-28 | Astrazeneca Ab | Traitement du cancer |
WO2019212937A1 (fr) | 2018-04-30 | 2019-11-07 | Ribon Therapeutics Inc. | Pyridazinones utilisés en tant qu'inhibiteurs de parp7 |
WO2022156708A1 (fr) * | 2021-01-20 | 2022-07-28 | Jacobio Pharmaceuticals Co., Ltd. | Inhibiteur d'enzyme parp7 |
Non-Patent Citations (24)
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