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WO2025098445A1 - Inhibiteur de parg, son procédé de préparation et son utilisation - Google Patents

Inhibiteur de parg, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2025098445A1
WO2025098445A1 PCT/CN2024/130553 CN2024130553W WO2025098445A1 WO 2025098445 A1 WO2025098445 A1 WO 2025098445A1 CN 2024130553 W CN2024130553 W CN 2024130553W WO 2025098445 A1 WO2025098445 A1 WO 2025098445A1
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Prior art keywords
alkyl
group
compound
mmol
pharmaceutically acceptable
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Chinese (zh)
Inventor
樊后兴
姜强强
王天才
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Nanjing Synnocare Pharmaceutical Technology Co Ltd
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Nanjing Synnocare Pharmaceutical Technology Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • 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
    • 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
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D421/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms
    • C07D421/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the present invention relates to the field of pharmaceutical chemistry, and more specifically, to a class of PARG inhibitors having a structure as shown in formula (1), and a preparation method thereof and the use of such compounds in preparing a pharmaceutical composition for treating, regulating and/or preventing diseases mediated by PARG
  • Poly(ADP-ribosyl)ation [PAR] is a process in which poly(ADP-ribose) polymers in eukaryotic cells are covalently linked to glutamic acid and aspartic acid residues of receptor proteins under the catalysis of poly(ADP-ribose) polymerase, which is used to achieve post-translational modification of proteins.
  • PARP poly(ADP-ribose) polymerase
  • PARG poly(ADP-ribose) glycohyfrolase
  • PARP DNA breaks activate PARP, which recognizes and binds to DNA chain gaps, activating PARP and catalyzing the synthesis of PAR, causing itself and related nuclear proteins to be PARylated; PARylated nuclear proteins transmit DNA break signals and activate the DNA repair system, while self-modified PARP loses its affinity for DNA and falls off from DNA, allowing DNA repair enzymes to approach the damaged site, cut off and repair DNA chain gaps; finally, PARG degrades PAR on PARP nuclear protein, restoring it to its unmodified form, completing the entire repair process.
  • PARG has many biological functions, such as participating in cell cycle regulation, spindle concentration in mitosis, development, differentiation, cell death and DNA repair. Existing studies have found that PARG is closely related to clinical diseases such as tumors, inflammation and autoimmune diseases.
  • PARG gene silencing can reduce cell proliferation and enhance cell sensitivity to chemotherapeutic drugs, so the research and development of PARG inhibitors for tumors has attracted everyone's attention.
  • PARG inhibitors cause synthetic lethality by inhibiting DNA replication factors [Cancer Cell, 2019, 35: 519-533].
  • PARG can act as an oncogene in hepatocellular carcinoma (HCC) by regulating PARG/DDB1/c-Myc signaling, and can be used as a biomarker to identify HCC patients who may benefit from anti-PD-1 treatment.
  • HCC hepatocellular carcinoma
  • PDAC pancreatic ductal adenocarcinoma
  • PARG inhibitors are mainly compounds such as tannic acid and gallic tannic acid, which have drugability defects such as poor specificity and low oral bioavailability.
  • Patent WO2021055744 discloses the following class of PARG inhibitors with new structures, which have good inhibitory effects on the enzyme activity of PARG in vivo, and representative compounds such as Ref-01 (Example 38 in the patent, used as a control compound below).
  • the purpose of the present invention is to provide a novel PARG inhibitor with high activity and excellent oral absorption, and a preparation method and application thereof.
  • the dotted line is a chemical bond or does not exist, and the same ring atom in ring B does not form two double bond structures at the same time, and both ring A and ring B are aromatic;
  • U and V are each independently N or C, and U and V are not N at the same time;
  • W and X are each independently N, NR 7 or CR 7 ;
  • n 0, 1, 2, 3 or 4;
  • L is selected from the group consisting of none, a chemical bond, or -C(O)-;
  • R1 and R2 are independently C1-3 alkyl, or R1 and R2 and the C atom to which they are connected together form a 3-6 membered cyclic structure, the cyclic structure optionally containing 0, 1 or 2 heteroatoms independently selected from N, O, S; and the cyclic structure is a saturated ring;
  • R 3 is H, CN, C 1-3 alkyl or halogenated C 1-3 alkyl
  • R 4 is independently C 1-3 alkyl, the alkyl is optionally substituted by one or more groups selected from the group consisting of OH, halogen, CN, C 1-3 alkoxy or C 3-6 cycloalkyl, or two R 4 on the same C atom form a 3-6 membered spirocyclic structure with the C atom to which they are connected, the spirocyclic structure optionally containing 0, 1 or 2 heteroatoms selected from N, O, S; and the spirocyclic structure is a saturated ring;
  • R is selected from the group consisting of H, C1-6 alkyl, -C(O) -C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 4-7 membered heterocycloalkyl, NR a R b or -C1-3 alkylene-NR a R b , wherein the alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more groups selected from the group consisting of -OH, halogen, CN, C1-3 alkyl, C1-3 alkoxy, C2-6 alkenyl, C2-6 alkynyl, halo-substituted C1-3 alkyl, hydroxy-substituted C1-3 alkyl, cyano-substituted C1-3 alkyl, C1-3 alkoxy-substituted C1-3 alkyl, C3-6 cycloalkyl or 4-7 member
  • Ra and Rb are independently selected from the following group: H, C1-6 alkyl, C3-6 cycloalkyl or 4-7 membered heterocycloalkyl, or Ra and Rb are connected to the N atom to which they are commonly connected to form a 4-6 membered heterocycloalkyl; the alkyl, cycloalkyl or heterocycloalkyl is optionally substituted by one or more groups selected from the following group: OH, halogen, CN, C1-3 alkyl, C1-3 alkoxy, halogenated C1-3 alkyl, hydroxy substituted C1-3 alkyl, cyano substituted C1-3 alkyl, C1-3 alkoxy substituted C1-3 alkyl, C3-6 cycloalkyl or 4-7 membered heterocycloalkyl;
  • R6 is selected from the group consisting of H, C1-3 alkyl, halogenated C1-3 alkyl, C3-6 cycloalkyl or C2-4 alkenyl;
  • R 7 When R 7 is connected to a C atom, R 7 is selected from the group consisting of H, halogen, C 1-3 alkyl, halogenated C 1-3 alkyl or C 3-6 cycloalkyl; or when R 7 is connected to a N atom, R 7 is selected from the group consisting of H, C 1-3 alkyl, halogenated C 1-3 alkyl or C 3-6 cycloalkyl.
  • the compound of formula (1) has the structure shown in (2-1), (2-2) or (2-3):
  • L and R5 are as defined in the first aspect of the present invention.
  • L is selected from the following group: none, chemical bond or -CO-;
  • R 5 is selected from the following group:
  • R 3 is defined as described in the first aspect of the present invention.
  • R 6 is selected from the following group: H, Me, Et, CH 2 F, CHF 2 , CF 3 , cyclopropyl or vinyl.
  • R 7 is selected from the following group: H, F, Cl, Me, Et, CH 2 F, CHF 2 , CF 3 , CH 2 CF 3 or cyclopropyl.
  • the compound has a structure selected from the following group:
  • a pharmaceutical composition for treating, regulating and/or preventing diseases mediated by PARG comprising a pharmaceutically acceptable excipient or carrier, and a compound as described in the first aspect of the present invention, or its isomer, polymorph, pharmaceutically acceptable salt, hydrate or solvate as an active ingredient.
  • the PARG-mediated related disease is cancer, and the cancer is selected from solid tumors or blood tumors.
  • the solid tumor is selected from the group consisting of breast cancer, liver cancer, pancreatic ductal adenocarcinoma, ovarian cancer, cervical cancer, endometrial cancer, colorectal cancer, gastric cancer, lung cancer, kidney cancer, or a combination thereof.
  • the blood tumor is selected from the following group: leukemia, lymphoma, or a combination thereof.
  • the compound as described in the first aspect of the present invention or its isomers, polymorphs, pharmaceutically acceptable salts, hydrates or solvates, for preparing drugs for treating, regulating and/or preventing diseases mediated by PARG.
  • a method for treating, regulating and/or preventing diseases mediated by PARG comprises the steps of: administering the compound described in the first aspect of the present invention, or its isomer, polymorph, pharmaceutically acceptable salt, hydrate or solvate to an individual in need thereof.
  • the individual includes humans and non-human mammals.
  • the compounds of the present invention have good inhibitory activity on PARG enzymes and good cell proliferation inhibitory activity on ZR-75-1 cell lines.
  • the compounds have good pharmacokinetic properties, and it is expected that the compounds have significant tumor inhibition effects and drugability. On this basis, the present invention was completed.
  • the present invention also provides a method for preparing the compound of formula (1) of the present invention.
  • the following specifically describes the method for preparing the compound of general formula (1) of the present invention, but these specific methods do not constitute any limitation to the present invention.
  • the compounds described herein are based on methods known in the art. However, the conditions of the method, such as reactants, solvents, bases, the amount of compounds used, reaction temperature, reaction time required, etc. are not limited to the following explanation.
  • the compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such a combination can be easily performed by a technician in the field to which the present invention belongs.
  • the present invention also provides a method for preparing the compound represented by the general formula (1), which is prepared using the following general reaction scheme 1, reaction scheme 2 or reaction scheme 3:
  • Embodiments of compounds of formula (1) can be prepared according to General Reaction Scheme 1, wherein Y1 , Y2 , Y3 are independently halogen, and R1 , R2 , R3 , R4 , R5 , R6 , U, W, X, A, B, Y, L and n are as defined above.
  • Embodiments of compounds of formula (1) can be prepared according to General Reaction Scheme 2, wherein Y1 , Y2 , Y3 are independently halogen, and R1 , R2 , R3 , R4 , R5 , R6 , R7 , Y, L and n are as defined above.
  • Embodiments of compounds of formula (1) can be prepared according to General Reaction Scheme 3, wherein Y1 , Y2 , Y3 , are independently halogen, and R1 , R2 , R3 , R4 , R5 , R6 , R7, Y, L and n are as defined above.
  • pharmaceutically acceptable refers to those 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 human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to salts of compounds of the invention, prepared from compounds of the invention having specific substituents with relatively nontoxic acids or bases.
  • base addition salts can be obtained by contacting such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, oxalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid, and salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid.
  • Certain specific compounds of the present invention contain basic and acidic functional groups, and thus
  • salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, the preparation method of such salts is: in water or an organic solvent or a mixture of the two, these compounds in free acid or base form are reacted with a stoichiometric amount of an appropriate base or acid to prepare.
  • the isomer is selected from the following group: enantiomers, cis-trans isomers, diastereomers, stereoisomers, or a combination thereof.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically enriched mixtures, all of which are within the scope of the present invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present invention.
  • enantiomer or “optical isomer” refers to stereoisomers that are mirror images of one another.
  • cis-trans isomers or “geometric isomers” arises from the inability of a ring to rotate freely about double bonds or single bonds of ring carbon atoms.
  • diastereomer refers to stereoisomers that have two or more chiral centers and that are not mirror images of each other.
  • the key is a solid wedge. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond. and straight dashed key To indicate the relative configuration of a stereocenter, use a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Represents a straight solid bond and straight dashed key
  • the term “isomer excess” or “enantiomeric excess” refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80%.
  • Optically active (R)- and (S)-isomers as well as D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, followed by diastereoisomer resolution by conventional methods known in the art, and then the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is usually accomplished by using chromatography, which uses a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate formation from an amine).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more atoms constituting the compound.
  • the compound may be labeled with a radioactive isotope, such as tritium ( 3H ), iodine-125 ( 125I ) or C-14 ( 14C ).
  • a radioactive isotope such as tritium ( 3H ), iodine-125 ( 125I ) or C-14 ( 14C ).
  • deuterated compounds may be formed by replacing hydrogen atoms with heavy hydrogen. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
  • deuterated drugs Compared with non-deuterated drugs, deuterated drugs generally have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending the half-life of drugs in vivo. All isotopic composition changes of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include a variant of deuterium and hydrogen, as long as the valence state of the particular atom is normal and the substituted compound is stable.
  • oxygen it means that two hydrogen atoms are replaced.
  • Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it may be substituted or not substituted, and unless otherwise specified, the type and number of the substituents may be arbitrary on the basis of chemical achievable.
  • any variable e.g., R
  • its definition at each occurrence is independent.
  • the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice.
  • substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a single bond.
  • Cn -n+m or Cn - Cn+m includes any specific situation of n to n+m carbon atoms
  • C1-12 includes C1 , C2 , C3, C4 , C5 , C6 , C7, C8, C9, C10 , C11 and C12 , and also includes any range from n to n+m, for example, C1-12 includes C1-3 , C1-6, C1-9, C3-6, C3-9, C3-12, C6-9, C6-12 and C9-12 , etc .
  • n-membered to n+m-membered means that the number of atoms in the ring is n to n+m
  • a 3-12 membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6- membered ring, a 7-membered ring, an 8-membered ring,
  • C 1-6 alkyl is used to refer to a straight or branched saturated aliphatic hydrocarbon group consisting of 1 to 6 carbon atoms.
  • the C 1-6 alkyl group includes C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 2-4 , C 2-6 , C 3-5 , C 5 and C 6 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine).
  • Ci -6 alkyl groups include methyl, ethyl, propyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, and various branched chain isomers thereof, and the like.
  • C 1-3 alkyl is used to refer to a straight or branched saturated aliphatic hydrocarbon group consisting of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine).
  • Non-limiting examples of C 1-3 alkyl groups include methyl, ethyl, propyl, n-propyl, isopropyl, etc.
  • C 3-6 cycloalkyl means a saturated cyclic aliphatic hydrocarbon group consisting of 3 to 6 carbon atoms, including monocyclic and bicyclic ring systems.
  • the C 3-6 cycloalkyl group includes C 3-5 , C 4-5 and C 5-6 cycloalkyl groups, etc.; they can be monovalent, divalent or polyvalent.
  • Non-limiting examples of C 3-6 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • C 1-3 alkoxy refers to an alkyl group containing 1 to 3 carbon atoms that is attached to the rest of the molecule through an oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2 and C 3 alkoxy groups, etc.; non-limiting examples of C 1-3 alkoxy groups include methoxy, ethoxy, propoxy, n-propoxy, isopropoxy, etc.
  • C 2-6 alkenyl is used to represent a linear or branched unsaturated aliphatic hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon double bond, and the carbon-carbon double bond can be located at any position of the group.
  • the C 2-6 alkenyl includes C 2-3 , C 2-4 , C 2-6 , C 3-5 , C 4-6 , C 5 and C 6 alkenyl, etc.; the C 2-6 alkenyl can be monovalent, divalent or polyvalent.
  • Non-limiting examples of C 2-6 alkenyl include vinyl, 1-propenyl, 1-butenyl, 1-pentenyl, 1-hexenyl, 2-methylpropenyl, 2-methylbutenyl, etc.
  • C 2-6 alkynyl is used to represent a linear or branched unsaturated aliphatic hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon triple bond, and the carbon-carbon triple bond can be located at any position of the group.
  • the C 2-6 alkynyl includes C 2-3 , C 2-4 , C 2-6 , C 3-5 , C 4-6 , C 5 and C 6 alkynyl, etc.; the C 2-6 alkynyl can be monovalent, divalent or polyvalent.
  • C 2-6 alkynyl include ethynyl, 1-propynyl, 1-butynyl, 1-pentynyl, 1-hexynyl, 2-methylpropynyl, 2-methylbutynyl, etc.
  • a heteroatom may occupy the position at which the heterocycloalkyl is connected to the rest of the molecule.
  • the 4-14 membered heterocycloalkyl includes 5-7 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl, etc.
  • Non-limiting examples of 4-14 membered heterocycloalkyl include azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophene (including tetrahydrothiophene-2-yl) 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, etc.
  • Halogen or halo refers to fluorine, chlorine, bromine or iodine.
  • Cyano refers to -CN.
  • acceptable means that a formulation component or active ingredient has no undue deleterious effect on health and well-being for the general purpose of treatment.
  • treat include alleviating, inhibiting or improving symptoms or conditions of a disease; inhibiting the occurrence of complications; improving or preventing potential metabolic syndrome; inhibiting the occurrence of a disease or symptom, such as controlling the development of a disease or condition; alleviating a disease or symptom; reducing a disease or symptom; alleviating complications caused by a disease or symptom, or preventing or treating signs caused by a disease or symptom.
  • a compound or pharmaceutical composition after administration, can improve a disease, symptom or condition, especially improve its severity, delay the onset, slow the progression of the disease, or reduce the duration of the disease. Whether fixed or temporary administration, continuous administration or intermittent administration, can be attributed to or related to the administration.
  • Active ingredient refers to the compound shown in the general formula (1), and the pharmaceutically acceptable inorganic or organic salt of the compound of formula (1).
  • the compounds of the present invention may contain one or more asymmetric centers (axial chirality) and therefore appear in the form of racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers.
  • the asymmetric centers that may exist depend on the properties of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures as well as pure or partially pure compounds are included within the scope of the present invention.
  • the present invention is meant to include all such isomeric forms of these compounds.
  • composition refers to a compound or composition that, when administered to a subject (human or animal), is capable of inducing a desired pharmaceutical and/or physiological response through local and/or systemic action.
  • administered refers to directly administering the compound or composition, or administering a prodrug, derivative, or analog of the active compound.
  • the compounds of the present invention and their pharmaceutically acceptable salts can be prepared into various preparations, which contain the compounds of the present invention or their pharmaceutically acceptable salts within the safe and effective amount range and pharmacologically acceptable excipients or carriers.
  • the "safe and effective amount” means that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the safe and effective amount of the compound is determined according to the specific circumstances such as the age, condition, and course of treatment of the subject.
  • “Pharmaceutically acceptable excipients or carriers” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility” here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • pharmacologically acceptable excipients or carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate,
  • the compounds of the present invention may be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), or topically.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or solubilizers, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting
  • Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottons
  • composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.
  • suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.
  • compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • Dosage forms for topical administration of the compounds of the invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.
  • the compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of the compound of the present invention is administered to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 50 to 1000 mg.
  • the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill of a skilled physician.
  • the main advantages of the present invention include:
  • the compounds of the present invention show strong anti-proliferative activity against ZR-75-1 cells and HCC1806 XRCC1 KO cells, and are more suitable for development as drugs.
  • the structure of the compound of the present invention can be confirmed by conventional methods known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art.
  • single crystal X-ray diffraction SXRD
  • the light source being CuK ⁇ phase radiation
  • the scanning mode being: After scanning and collecting relevant data, the crystal structure is further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.
  • 1 H-NMR was recorded using a Varian Mercury 400 nuclear magnetic resonance instrument, and chemical shifts were expressed in ⁇ (ppm);
  • the silica gel used for separation was 200-300 mesh unless otherwise specified, and the ratios of the eluents were all by volume.
  • ACN represents acetonitrile
  • AcOH represents acetic acid
  • DIBAL-H represents diisobutylaluminum hydride
  • °C degrees Celsius
  • CuBr 2 represents cupric bromide
  • Cs 2 CO 3 represents cesium carbonate
  • DCM represents dichloromethane
  • DIEA DIPEA
  • NMM represents N-methylmorpholine
  • Dioxane represents 1,4-dioxane
  • DMF represents N,N-dimethylformamide
  • DMSO represents dimethyl sulfoxide
  • EA (EtOAc) represents ethyl acetate
  • EtOH represents ethanol
  • h represents hour
  • HATU represents 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • KOAc represents potassium acetate
  • K 3 PO 4 represents potassium phosphate
  • LC-MS represents liquid
  • 6-Bromo-4-fluoro-1H-indazole (5 g, 23.26 mmol) and benzyl mercaptan (2.89 g, 23.26 mmol) were dissolved in Dioxane (50 mL), and then Pd 2 (dba) 3 (2.10 g, 2.33 mmol), Xantphos (2.70 g, 4.65 mmol) and DIEA (6 g, 46.52 mmol) were added. The mixture was protected by nitrogen and reacted at 100 °C. LC-MS monitoring showed that the reaction of the raw materials was complete.
  • Example 2-60 Synthesis of Compounds 2-36, B1-B8, B13-B20, B25-B32
  • Intermediates 1 to 5 are used for substitution reaction with nitrogen atoms of differently substituted indazoles, corresponding amines are used as raw materials for substitution reaction with sulfonyl chlorides, intermediates 6 to 9 and other corresponding amines are used as raw materials for substitution or coupling reaction with the parent core skeleton, and target compounds 2-36, B1-B8, B13-B20, and B25-B32 are obtained according to a similar synthesis method as in Example 1.
  • 6-Bromo-4-chloro-1H-indazole (2g, 8.64mmol) and benzyl mercaptan (1.07g, 8.64mmol) were dissolved in Dioxane (50mL), and then Pd 2 (dba) 3 (791mg, 0.86mmol), Xantphos (1.00g, 1.73mmol) and DIEA (2.23g, 17.28mmol) were added. The mixture was protected by nitrogen and reacted at 100°C. LC-MS monitoring showed that the reaction of the raw materials was complete.
  • the target compound 38 was obtained according to a similar synthesis method in Example 61.
  • the target compound 40 was obtained according to a similar synthesis method as in Example 63.
  • the target compounds 42-50, B9-B12, B21-B24 were obtained according to a similar synthesis method in Example 65.
  • Example 65 Using 1-(fluoromethyl)cyclopropylamine hydrochloride as a raw material, compound B33-3 was obtained according to a similar synthesis method in Example 1. Subsequently, using B33-3 and the corresponding carboxylic acid as raw materials, target compounds B33-B34, B36-B39 were obtained according to a similar synthesis method in Example 65.
  • the target compounds 52-56 and B35 were obtained according to a similar synthesis method in Example 89.
  • Methoxy(cyclooctadiene)iridium dimer (2.44 g, 3.68 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (1.98 g, 7.36 mmol) and biboric acid pinacol ester (18.68 g, 73.59 mmol) were added to MTBE (100 mL), replaced with argon, stirred at room temperature for 10 minutes, and then 57-2 (8.78 g, 24.53 mmol) in MTBE (50 mL) was added, replaced with argon, reacted at 80 ° C, monitored by LC-MS, and the raw material reaction was completed.
  • the target compound 58-76 was obtained according to a similar synthesis method in Example 96.
  • 77-1 (6.10 g, 27.73 mmol) was dissolved in DCM (100 mL), TEA (5.6 g, 55.45 mmol) and ethyl oxalyl chloride (4.54 g, 33.28 mmol) were added, and the reaction was carried out at room temperature.
  • the reaction of the raw materials was completed by LC-MS monitoring.
  • 77-4 (4.74 g, 13.70 mmol) was dissolved in EtOH (80 mL), hydrazine hydrate (8.06 g, 137.0 mmol) was added, and the reaction was carried out at 80°C. LC-MS monitoring showed that the reaction of the raw material was complete. The reaction was cooled to 0°C, and a large amount of solid was precipitated. The yellow solid compound 77-5 (4.02 g, yield 88%) was obtained by suction filtration. ESI-MS m/z: 333.0 [M+H] + .
  • 77-13 (80 mg, 0.10 mmol) was dissolved in DCM (5 mL), TFA (2 mL) was added, and the reaction was carried out at room temperature. The reaction was monitored by LC-MS. The raw material reaction was completed. The mixture was directly spin-dried, saturated NaHCO 3 was added for neutralization, EA was extracted (20 mL*3), the organic phases were combined, dried, concentrated, and Pre-HPLC was used to obtain a light yellow solid compound 77 (33 mg, yield 59%).
  • the target compounds 78-84, B40-B48, B57-B66, B75-B83, B92-B100 and B109-B117 were obtained according to a similar synthesis method in Example 116.
  • Examples 170-204 Synthesis of Compounds B49-B50, B52-B56, B67-68, B70-B74, B84-B85, B87-B91, B101-B102, B104-B108, B118-B119, and B121-B125
  • Compound B84-5 can be obtained by using 1-amino-1-cyclopropylcyanide hydrochloride instead of 1-methylcyclopropylamine hydrochloride in the synthetic route of compound B49-2.
  • B49-2, B67-9, B84-5, B101-5, B118-5 and the corresponding carboxylic acids were used as raw materials, and the target compounds B49-B50, B52-B56, B67-68, B70-B74, B84-B85, B87-B91, B101-B102, B104-B108, B118-B119 and B121-B125.
  • the target compounds B51, B69, B86, B103, and B120 were obtained according to a similar synthesis method in Example 89.
  • 0.1 ⁇ L of the diluted compound solution was transferred to a 384 assay plate (Cornning) using an ECHO acoustic pipetting device (LABCYTE), 2.5 ⁇ L of PARylation working solution was added to the 384-well assay plate, centrifuged at 1000 prm for 1 min, incubated at 25 °C for 60 min, and then 5 ⁇ L of a mixture of His-Tb (Cisbio) and SA-XL665 (Cisbio) was added to react and incubated at 25 °C for 50 min. The HTRF signal was then read using an HTS high-throughput drug screening multifunctional microplate reader (BMG).
  • BMG HTS high-throughput drug screening multifunctional microplate reader
  • the IC 50 curve of the compound was fitted according to the nonlinear regression equation using the software Graphpad 8.0. Table 1 provides the inhibitory activity of the compounds of the present invention on PARG protein.
  • Table 1 Compounds' inhibitory activity on PARG enzyme (IC 50 ) A means: IC 50 ⁇ 50nM; B means: 50nM ⁇ IC 50 ⁇ 500nM; C means IC 50 ⁇ 500nM
  • the compounds of the present invention have strong inhibitory activity on PARG enzyme, and the IC 50 values of the inhibitory activity of most compounds on PARG are less than 50 nM.
  • Example 211 Screening of antiproliferative activity of compounds on ZR-75-1 cells
  • a cell proliferation assay was used to analyze the cytotoxicity of ZR-75-1 breast cancer cells after four days of PARG inhibitor action.
  • the ZR-75-1 cell line was purchased from Wuhan Pronocell Life Science Co., Ltd. and cultured in a cell culture incubator (Thermo) at 37 degrees Celsius and 5% carbon dioxide using 1640 medium (Viva cell).
  • PARG inhibitors were dissolved in DMSO to an initial concentration of 30 ⁇ M and diluted threefold in DMSO for a total of eight data points. The final concentration of DMSO was 0.5%.
  • ZR-75-1 cells were seeded in a white 96-well plate, with 80 ⁇ L of cell suspension per well, containing 5000 ZR-75-1 cells.
  • the cell plate was placed in a carbon dioxide incubator for overnight culture, and then 20 ⁇ L of PARG inhibitor solution of different concentrations was added to the well plate, and the 96-well plate was placed in the incubator for four days.
  • the raw data was converted into inhibition rate using the equation (Sample-Min)/(Max-Min)*100%, and the IC 50 value was obtained by The curve was fitted by four parameters (obtained by "log (inhibitor) vs. response--Variable slope" mode in GraphPad Prism).
  • Min 0.5% DMSO treated cell wells; Max: Day 0 wells.
  • Table 2 provides the inhibitory activity of the compounds of the present invention on the proliferation of ZR-75-1 cells.
  • Example 212 Screening of antiproliferative activity of compounds on HCC1806 (XRCC1 KO) cells
  • HCC1806 XRCC1 KO breast cancer cells were constructed by Beijing Aisi Yipu Biotechnology Co., Ltd., and the parent cell line HCC1806 was purchased from ATCC (American type culture collection).
  • HCC1806 XRCC1 KO used RPMI medium (30-2001, ATCC) and was cultured in a cell culture incubator (CLM-240B-8-TC, ESCO) at 37 degrees Celsius and 5% carbon dioxide.
  • PARG inhibitors were dissolved in DMSO to have an initial concentration of 3 ⁇ M and three-fold dilutions were performed in DMSO for a total of ten data points. The final concentration of DMSO was 0.3%.
  • HCC1806 XRCC1 KO cells were seeded in a black 384-well plate (3764, Corning), with 40 ⁇ L of cell suspension per well, containing 250 HCC1806 XRCC1 KO cells.
  • the cell plate was placed in a carbon dioxide incubator for overnight culture, and then 120 nL of PARG inhibitor solution of different concentrations was added to the well plate, and the 384-well plate was placed in the incubator for seven days.
  • the raw data were converted into inhibition rate using the equation (Sample-Min)/(Max-Min)*100%, and the IC50 value was obtained by four-parameter curve fitting (obtained in the "log (inhibitor) vs. response--Variable slope" mode in GraphPad Prism).
  • Min 0.5% DMSO-treated cell wells; Max: Day0 wells.
  • Table 2 provides the inhibitory activity of the compounds of the present invention on the proliferation of HCC1806 XRCC1 KO cells.
  • the compounds of the present invention have strong antiproliferative activity against ZR-75-1 cells and HCC1806 XRCC1 KO cells. Compared with the control drug Ref-01, most of the compounds of the present invention have stronger antiproliferative activity against ZR-75-1 cells and HCC1806 XRCC1 KO cells.

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Abstract

L'invention concerne un inhibiteur de PARG, son procédé de préparation et son utilisation. Plus particulièrement, la présente invention concerne un composé représenté par la formule (1) et son procédé de préparation, et une composition contenant le composé représenté par la formule (1) et/ou un sel pharmaceutiquement acceptable de la composition, un procédé de préparation de la composition et une utilisation de celui-ci en tant qu'inhibiteur de PARG dans la préparation d'un médicament antitumoral.
PCT/CN2024/130553 2023-11-07 2024-11-07 Inhibiteur de parg, son procédé de préparation et son utilisation Pending WO2025098445A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004018419A2 (fr) * 2002-08-23 2004-03-04 Chiron Corporation Quinolinones de benzimidazole et leurs utilisations
CN107295799A (zh) * 2014-12-19 2017-10-24 癌症研究科技有限公司 Parg抑制化合物
CN114555593A (zh) * 2019-09-20 2022-05-27 伊迪亚生物科学有限公司 作为parg抑制剂的4-取代的吲哚和吲唑磺酰胺衍生物
WO2023057389A1 (fr) * 2021-10-04 2023-04-13 Forx Therapeutics Ag Composés inhibiteurs de parg
CN116693519A (zh) * 2022-03-04 2023-09-05 上海璎黎药业有限公司 一种含五元杂芳环结构化合物、其药物组合物及应用
CN117304183A (zh) * 2022-06-29 2023-12-29 杭州圣域生物医药科技有限公司 五元并六元含氮化合物、其中间体、制备方法和应用

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004018419A2 (fr) * 2002-08-23 2004-03-04 Chiron Corporation Quinolinones de benzimidazole et leurs utilisations
CN107295799A (zh) * 2014-12-19 2017-10-24 癌症研究科技有限公司 Parg抑制化合物
CN114555593A (zh) * 2019-09-20 2022-05-27 伊迪亚生物科学有限公司 作为parg抑制剂的4-取代的吲哚和吲唑磺酰胺衍生物
WO2023057389A1 (fr) * 2021-10-04 2023-04-13 Forx Therapeutics Ag Composés inhibiteurs de parg
CN116693519A (zh) * 2022-03-04 2023-09-05 上海璎黎药业有限公司 一种含五元杂芳环结构化合物、其药物组合物及应用
CN117304183A (zh) * 2022-06-29 2023-12-29 杭州圣域生物医药科技有限公司 五元并六元含氮化合物、其中间体、制备方法和应用

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