WO2023067356A1 - Heterocyclic compounds for use in the treatment of cancer - Google Patents

Heterocyclic compounds for use in the treatment of cancer Download PDF

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Publication number
WO2023067356A1
WO2023067356A1 PCT/GB2022/052690 GB2022052690W WO2023067356A1 WO 2023067356 A1 WO2023067356 A1 WO 2023067356A1 GB 2022052690 W GB2022052690 W GB 2022052690W WO 2023067356 A1 WO2023067356 A1 WO 2023067356A1
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Prior art keywords
compound
compounds
agents
formula
inhibitors
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PCT/GB2022/052690
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English (en)
French (fr)
Inventor
Owen Davis
Robert Heald
Martin Stockley
Harry Finch
Sam MANN
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Artios Pharma Ltd
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Artios Pharma Ltd
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Priority to KR1020247015701A priority Critical patent/KR20240099274A/ko
Priority to DK22797829.3T priority patent/DK4419526T3/da
Priority to US18/699,286 priority patent/US20240425511A1/en
Priority to RS20250272A priority patent/RS66620B1/sr
Priority to CA3233255A priority patent/CA3233255A1/en
Priority to SI202230104T priority patent/SI4419526T1/sl
Priority to HRP20250334TT priority patent/HRP20250334T1/hr
Priority to EP22797829.3A priority patent/EP4419526B1/en
Priority to LTEPPCT/GB2022/052690T priority patent/LT4419526T/lt
Priority to CN202280070670.3A priority patent/CN118234728A/zh
Priority to ES22797829T priority patent/ES3008687T3/es
Priority to AU2022374050A priority patent/AU2022374050A1/en
Priority to IL311922A priority patent/IL311922A/en
Priority to JP2024523445A priority patent/JP2024542949A/ja
Priority to SM20250123T priority patent/SMT202500123T1/it
Priority to FIEP22797829.3T priority patent/FI4419526T3/fi
Priority to PL22797829.3T priority patent/PL4419526T3/pl
Priority to MX2024004874A priority patent/MX2024004874A/es
Publication of WO2023067356A1 publication Critical patent/WO2023067356A1/en
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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

  • DDR DNA damage response
  • An aberrant DDR can also sensitise cancer cells to specific types of DNA damage, thus, defective DDR can be exploited to develop targeted cancer therapies.
  • cancer cells with impairment or inactivation of HR and NHEJ become hyper-dependent on MMEJ-mediated DNA repair. Genetic, cell biological and biochemical data have identified PolQ (UniProtKB - 075417 (DPOLQ_HUMAN) as the key protein in MMEJ (Kent et al.
  • the salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods such as methods described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used.
  • N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Commun. 1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.
  • mCPBA m-chloroperoxybenzoic acid
  • the compounds of the present invention may be useful for the treatment of the adult population.
  • the compounds of the present invention may be useful for the treatment of the pediatric population.
  • the PolQ inhibitors of the present invention suitably show synthetic sickness and/or synthetic lethality in a variety of tumours with loss of ATM activity (ATM' /_ ) particularly in the context of WT p53.
  • Tumour types will include around 10% of all solid tumours including gastric, lung, breast, and CRC, along with CLL.
  • Co-medicating with another DDR modifier, such as a DNA-PK inhibitor, PARP inhibitor or ATR inhibitor may further enhance such activity.
  • PolQ inhibitors will resensitise CLL to classical chemotherapy and chemo-immunotherapy where drug resistance has emerged.
  • the pharmaceutical composition of the present invention additionally comprises a DNA-PK inhibitor, PARP inhibitor, or ATR inhibitor.
  • the PolQ inhibitors of the present invention suitably suppress TLS polymerase activity, sensitising primary and secondary solid tumours (e.g. breast, lung, ovarian, CRC) to drugs (e.g. cisplatin, mitomycin and cyclophosphamide) as well as reducing the acquisition of drug-induced mutations implicated in tumour resistance leading to prolongation of remission and increased TTR.
  • primary and secondary solid tumours e.g. breast, lung, ovarian, CRC
  • drugs e.g. cisplatin, mitomycin and cyclophosphamide
  • cancers include hepatocellular carcinoma, melanoma, oesophageal, renal, colon, colorectal, lung e.g. mesothelioma or lung adenocarcinoma, breast, bladder, gastrointestinal, ovarian and prostate cancers.
  • PolQ inhibitory compounds are likely to be useful in enhancing the efficiency of CRISPR based editing methodologies and/or CRISPR based editing therapeutics.
  • compound mediated PolQ inhibition is likely to reduce the frequency of random integration events and thus provide a route to ameliorate any safety concerns of CRISPR mediated technology.
  • a compound of formula (I) as defined herein in a CRISPR based editing methodology and/or CRISPR based editing therapeutics such as the enhancement of efficiency of CRISPR based editing methodology and/or CRISPR based editing therapeutics.
  • pharmaceutically acceptable refers to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (e.g. human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • a subject e.g. human
  • Each carrier, excipient, etc. must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.
  • a chewable tablet can contain the solid solution blended with a bulking agent, a lubricant, and if desired an additional sweetening agent (such as an artificial sweetener), and suitable flavours.
  • Solid solutions may also be formed by spraying solutions of drug and a suitable polymer onto the surface of inert carriers such as sugar beads (‘non-pareils’). These beads can subsequently be filled into capsules or compressed into tablets.
  • the compounds of the formula (I) and sub-groups as defined herein may be useful in the prophylaxis or treatment of a range of disease states or conditions mediated by PolQ.
  • a method of treating a disease state or condition mediated by PolQ e.g. cancer
  • a disease state or condition mediated by PolQ e.g. cancer
  • diseases states and conditions are set out above, and in particular include cancer.
  • a patient is given the compound orally once a week.
  • Alkylating agents such as nitrogen mustards or nitrosourea, for example cyclophosphamide, chlorambucil, carmustine (BCNll), bendamustine, thiotepa, melphalan, treosulfan, lomustine (CCNll), altretamine, busulfan, dacarbazine, estramustine, fotemustine, ifosfamide (optionally in combination with mesna), pipobroman, procarbazine, streptozocin, temozolomide, uracil, mechlorethamine, methylcyclohexylchloroethylnitrosurea, or nimustine (ACNll);
  • nitrogen mustards or nitrosourea for example cyclophosphamide, chlorambucil, carmustine (BCNll), bendamustine, thiotepa, melphalan, treosulfan, lomustine (CCNll
  • Therapeutic Vaccines such as sipuleucel-T (Provenge) or OncoVex;
  • the anti-tumour nucleoside derivative is advantageously administered in a dosage of 200 to 2500 mg per square meter (mg/m 2 ) of body surface area, for example 700 to 1500 mg/m 2 , particularly for 5-Fll in a dosage of 200 to 500mg/m 2 , for gemcitabine in a dosage of about 800 to 1200 mg/m 2 and for capecitabine in about 1000 to 2500 mg/m 2 per course of treatment.
  • radiosensitizer is defined as a molecule administered to patients in therapeutically effective amounts to increase the sensitivity of the cells to ionizing radiation and/or to promote the treatment of diseases which are treatable with ionizing radiation.
  • Step xiv To a mixture of (3aR,11aS)-6-chloro-10-methyl-1-(6-methyl-4- (trifluoromethyl)pyridin-2-yl)-1 ,3a,4,5,10,11a-hexahydro-2/7-benzo[b]pyrrolo[2,3- f][1 ,4]diazocine-2,11 (3/7)-dione (11.3 g, 25.7 mmol), Na2COs (8.19 g, 77.2 mmol) and TBAB (830 mg, 2.58 mmol) in DMF (110 mL) was added allyl bromide (15.5 g, 128 mmol). The reaction mixture was stirred at 100 °C for 12 h.

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  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
PCT/GB2022/052690 2021-10-21 2022-10-21 Heterocyclic compounds for use in the treatment of cancer Ceased WO2023067356A1 (en)

Priority Applications (18)

Application Number Priority Date Filing Date Title
KR1020247015701A KR20240099274A (ko) 2021-10-21 2022-10-21 암의 치료에의 사용을 위한 헤테로사이클릭 화합물
DK22797829.3T DK4419526T3 (da) 2021-10-21 2022-10-21 Heterocykliske forbindelser til anvendelse i behandlingen af cancer
US18/699,286 US20240425511A1 (en) 2021-10-21 2022-10-21 Heterocyclic compounds for use in the treatment of cancer
RS20250272A RS66620B1 (sr) 2021-10-21 2022-10-21 Heterociklična jedinjenja za upotrebu u lečenju kancera
CA3233255A CA3233255A1 (en) 2021-10-21 2022-10-21 Heterocyclic compounds for use in the treatment of cancer
SI202230104T SI4419526T1 (sl) 2021-10-21 2022-10-21 Heterociklične spojine za uporabo pri zdravljenju raka
HRP20250334TT HRP20250334T1 (hr) 2021-10-21 2022-10-21 Heterociklički spojevi za uporabu u liječenju raka
EP22797829.3A EP4419526B1 (en) 2021-10-21 2022-10-21 Heterocyclic compounds for use in the treatment of cancer
LTEPPCT/GB2022/052690T LT4419526T (lt) 2021-10-21 2022-10-21 Heterocikliniai junginiai, skirti vėžiui gydyti
CN202280070670.3A CN118234728A (zh) 2021-10-21 2022-10-21 用于治疗癌症的杂环化合物
ES22797829T ES3008687T3 (en) 2021-10-21 2022-10-21 Heterocyclic compounds for use in the treatment of cancer
AU2022374050A AU2022374050A1 (en) 2021-10-21 2022-10-21 Heterocyclic compounds for use in the treatment of cancer
IL311922A IL311922A (en) 2021-10-21 2022-10-21 Heterocyclic compounds for use in cancer treatment
JP2024523445A JP2024542949A (ja) 2021-10-21 2022-10-21 がん治療での使用のためのヘテロ環式化合物
SM20250123T SMT202500123T1 (it) 2021-10-21 2022-10-21 Composti eterociclici per uso nel trattamento del cancro
FIEP22797829.3T FI4419526T3 (fi) 2021-10-21 2022-10-21 Heterosyklisiä yhdisteitä käytettäväksi syövän hoidossa
PL22797829.3T PL4419526T3 (pl) 2021-10-21 2022-10-21 Związki heterocykliczne do stosowania w leczeniu nowotworu
MX2024004874A MX2024004874A (es) 2021-10-21 2022-10-21 Compuestos heterociclicos para uso en el tratamiento de cancer.

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GB2115156.8 2021-10-21
GBGB2115156.8A GB202115156D0 (en) 2021-10-21 2021-10-21 Novel compounds

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JP (2) JP2024539132A (enExample)
KR (1) KR20240099274A (enExample)
CN (2) CN119053600A (enExample)
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AU (1) AU2022374050A1 (enExample)
CA (1) CA3233255A1 (enExample)
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MX (1) MX2024004874A (enExample)
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PT (1) PT4419526T (enExample)
RS (1) RS66620B1 (enExample)
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WO2025077896A1 (zh) * 2023-10-12 2025-04-17 上海湃隆生物科技有限公司 一种DNA聚合酶theta抑制剂及其应用

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CN118084767B (zh) * 2024-04-02 2025-06-17 康龙化成手性医药技术(宁波)有限公司 一种外型-6-氟甲基-3-氮杂双环[3,1,0]己烷盐酸盐及其衍生物的合成方法
WO2025214463A1 (zh) * 2024-04-13 2025-10-16 正大天晴药业集团股份有限公司 含有三并环结构的化合物

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WO2017062754A1 (en) 2015-10-07 2017-04-13 New York University Compositions and methods for enhancing crispr activity by polq inhibition
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WO2025077896A1 (zh) * 2023-10-12 2025-04-17 上海湃隆生物科技有限公司 一种DNA聚合酶theta抑制剂及其应用

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