WO2023036285A1 - Composé hétéroaromatique et son utilisation - Google Patents

Composé hétéroaromatique et son utilisation Download PDF

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WO2023036285A1
WO2023036285A1 PCT/CN2022/118064 CN2022118064W WO2023036285A1 WO 2023036285 A1 WO2023036285 A1 WO 2023036285A1 CN 2022118064 W CN2022118064 W CN 2022118064W WO 2023036285 A1 WO2023036285 A1 WO 2023036285A1
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compound
substituted
unsubstituted
ring
alkyl
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PCT/CN2022/118064
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English (en)
Chinese (zh)
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张军波
朱曙灏
齐晓昕
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南京奥利墨斯医药科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • A61K31/4704—2-Quinolinones, e.g. carbostyril
    • 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
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention relates to the fields of medicinal chemistry and pharmacotherapeutics, in particular to a heteroaromatic ring compound and its application.
  • Cancer is one of the major diseases that threaten human health, and there are many new cancer patients every year.
  • the main treatment methods adopted for cancer include surgery, radiotherapy and chemotherapy.
  • the tumor treatment effect of the existing cancer treatment methods such as poor anticancer effect and high toxicity and side effects. Therefore, The curative effect of existing cancer treatment methods is not ideal, which limits the effect of tumor treatment and increases the suffering of patients. Therefore, how to improve the therapeutic effect of tumors and reduce the toxicity and side effects has always been a research hotspot in the medical field.
  • the object of the present invention is to provide a compound with novel structure and its application in anti-tumor.
  • the first aspect of the present invention provides a compound of formula I, or its optical isomer, or its racemate, or its solvate, or its hydrate, or its pharmaceutically acceptable salt, or its precursor medicine;
  • Ring A is a substituted or unsubstituted C6-C14 aromatic ring, a substituted or unsubstituted C3-C14 cycloalkane ring, a substituted or unsubstituted 3-14 membered heterocycloalkane ring, or a substituted or unsubstituted 5-14 membered Heteroaromatic ring;
  • Z 1 is a substituted or unsubstituted C1-C6 alkylene group, -O-, -S-, -N(R 8 )-;
  • Z 2 is a substituted or unsubstituted C3-C14 cycloalkylene, or a substituted or unsubstituted 3-14 membered heterocycloalkylene;
  • R 1 and R 3 are each independently hydrogen or substituted or unsubstituted C1-C8 alkyl
  • R 4 is hydrogen or substituted or unsubstituted C1-C8 alkyl
  • R 5 and R 6 are each independently hydrogen, substituted or unsubstituted C1-C8 alkyl or halogen; or R 5 and R 6 are connected to form a substituted or unsubstituted C6-C12 aromatic ring (such as a benzene ring);
  • R 7 is hydrogen, substituted or unsubstituted C1-C8 alkyl or halogen
  • R 8 is hydrogen or substituted or unsubstituted C1-C8 alkyl
  • R 9 and R 10 are each independently hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C1-C12 haloalkyl, (R 11 R 12 )N-substituted or unsubstituted C1-C8 alkane -, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 cycloalkyl-substituted or unsubstituted C1-C10 alkyl-, or substituted or unsubstituted 3-12 membered hetero Cycloalkyl;
  • R 11 and R 12 are each independently hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, or C3-C8 cycloalkyl.
  • any "substituted” means that one or more (preferably 1, 2, 3, 4, 5, 6, 7 or 8) hydrogen atoms on the ring or group are independently substituted by replace.
  • heterocycloalkyl, heterocycloalkylene, heteroaryl, heterocycloalkane and heteroaromatic rings have 1-4 (preferably 1, 2, 3 or 4 ) are each independently selected from N, O and S heteroatoms.
  • the heterocyclic ring of the heterocycloalkyl has 1-4 (preferably 1, 2, 3 or 4) heteroatoms independently selected from N, O and S.
  • the heterocyclic ring of the heterocycloalkylene has 1-4 (preferably 1, 2, 3 or 4) heteroatoms independently selected from N, O and S.
  • the heterocyclic ring of the heteroaryl group has 1-4 (preferably 1, 2, 3 or 4) heteroatoms independently selected from N, O and S.
  • the heterocyclic ring of the heterocycloalkane ring has 1-4 (preferably 1, 2, 3 or 4) heteroatoms independently selected from N, O and S.
  • the heterocyclic ring of the heteroaromatic ring has 1-4 (preferably 1, 2, 3 or 4) heteroatoms independently selected from N, O and S.
  • ring A is a substituted or unsubstituted C6-C10 aromatic ring, a substituted or unsubstituted C3-C10 cycloalkane ring, a substituted or unsubstituted 3-10 membered heterocycloalkane ring or a substituted or unsubstituted 5- 10-membered heteroaromatic ring.
  • Ring A is a substituted or unsubstituted C6-C8 aromatic ring, a substituted or unsubstituted C3-C8 cycloalkane ring, a substituted or unsubstituted 3-8 membered heterocycloalkane ring or a substituted or unsubstituted 5- 8-membered heteroaromatic ring.
  • Ring A is a substituted or unsubstituted 3-membered heterocycloalkane ring, a substituted or unsubstituted 4-membered heterocycloalkane ring, a substituted or unsubstituted 5-membered heterocycloalkane ring, a substituted or unsubstituted 6-membered heterocycloalkane ring Cycloalkane, substituted or unsubstituted 7-membered heterocycloalkane, substituted or unsubstituted 8-membered heterocycloalkane, substituted or unsubstituted 9-membered heterocycloalkane, or substituted or unsubstituted 10-membered heterocycloalkane ring.
  • Ring A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 13 , R 14 , R 15 , R 16 , R 17 , R 18 or R 19 are each independently hydrogen or C1-C8 alkyl.
  • Ring A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Z1 is a substituted or unsubstituted C1-C4 alkylene, -O-, -S-, NR 8 .
  • Z1 is substituted or unsubstituted methylene, ethylene, propylene, butylene, -O-, -S-, NR 8 .
  • Z 2 is a substituted or unsubstituted C3-C12 cycloalkylene, or a substituted or unsubstituted 3-12 membered heterocycloalkylene.
  • Z 2 is a substituted or unsubstituted C3-C10 cycloalkylene, or a substituted or unsubstituted 3-10 membered heterocycloalkylene.
  • Z is a substituted or unsubstituted 3-membered heterocycloalkylene, a substituted or unsubstituted 4-membered heterocycloalkylene, a substituted or unsubstituted 5-membered heterocycloalkylene, a substituted or unsubstituted 6-membered heterocycloalkylene, substituted or unsubstituted 7-membered heterocycloalkylene, substituted or unsubstituted 8-membered heterocycloalkylene, substituted or unsubstituted 9-membered heterocycloalkylene, substituted or unsubstituted Substituted 10-membered heterocycloalkylene, substituted or unsubstituted 11-membered heterocycloalkylene, substituted or unsubstituted 12-membered heterocycloalkylene, substituted or unsubstituted 13-membered heterocycloalkylene or substituted or an unsubstituted 14
  • Z2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 20 and R 21 are each independently hydrogen or C1-C8 alkyl.
  • n 1 or 2.
  • Z2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 1 and R 3 are each independently hydrogen or substituted or unsubstituted C1-C6 alkyl.
  • R 1 and R 3 are each independently hydrogen or substituted or unsubstituted C1-C4 alkyl.
  • R 1 and R 3 are each independently hydrogen or substituted or unsubstituted C1-C2 alkyl.
  • R 1 is hydrogen
  • R3 is hydrogen
  • R 4 is hydrogen or substituted or unsubstituted C1-C6 alkyl.
  • R 4 is hydrogen or substituted or unsubstituted C1-C4 alkyl.
  • R4 is hydrogen, methyl, ethyl, propyl or butyl.
  • R 5 and R 6 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl or halogen; or R 5 and R 6 are connected to form a C6-C10 aromatic ring (such as a benzene ring).
  • R 5 and R 6 are each independently hydrogen, substituted or unsubstituted C1-C4 alkyl or halogen; or R 5 and R 6 are connected to form a C6-C8 aromatic ring (such as a benzene ring).
  • R 5 and R 6 are each independently hydrogen, methyl, ethyl, propyl, butyl or halogen; or R 5 and R 6 are connected to form a C6-C8 aromatic ring (such as a benzene ring).
  • R5 and R6 are each independently hydrogen, methyl, ethyl, propyl, butyl or halogen; or R5 and R6 are connected to form a benzene ring.
  • R5 and R6 are each independently hydrogen, methyl, ethyl, propyl, butyl, F, Cl, Br or I; or R5 and R6 are connected to form a benzene ring.
  • R 7 is hydrogen, substituted or unsubstituted C1-C6 alkyl or halogen.
  • R 7 is hydrogen, substituted or unsubstituted C1-C4 alkyl or halogen.
  • R 7 is hydrogen, methyl, ethyl, propyl, butyl or or halogen.
  • R7 is hydrogen, methyl, ethyl, propyl, butyl, F, Cl, Br or I.
  • R 8 is hydrogen or substituted or unsubstituted C1-C6 alkyl.
  • R 8 is hydrogen or substituted or unsubstituted C1-C4 alkyl.
  • R8 is hydrogen, methyl, ethyl, propyl or butyl.
  • each of R 9 and R 10 is independently hydrogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 haloalkyl, (R 11 R 12 ) N-substituted or unsubstituted C1 -C8 alkyl-, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 cycloalkyl-substituted or unsubstituted C1-C10 alkyl-, or substituted or unsubstituted 3- 10-membered heterocycloalkyl.
  • each of R 9 and R 10 is independently hydrogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 haloalkyl, (R 11 R 12 ) N-substituted or unsubstituted C1 -C8 alkyl-, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkyl-substituted or unsubstituted C1-C8 alkyl-, or substituted or unsubstituted 3- 8-membered heterocycloalkyl.
  • each of R 9 and R 10 is independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, (R 11 R 12 ) N-substituted or unsubstituted C1 -C6 alkyl-, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkyl-substituted or unsubstituted C1-C6 alkyl-, or substituted or unsubstituted 3- 6-membered heterocycloalkyl.
  • each of R 9 and R 10 is independently hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, (R 11 R 12 ) N-substituted or unsubstituted C1 -C4 alkyl-, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkyl-substituted or unsubstituted C1-C4 alkyl-, or substituted or unsubstituted 3- 6-membered heterocycloalkyl.
  • R9 and R10 are each independently hydrogen, methyl, ethyl, propyl, butyl, oxetanyl, azetidinyl, 1-methylazetidinyl , haloethyl, cyclobutyl-methyl-, dimethylamino-ethyl-, trifluoromethyl.
  • the structure of the oxetanyl group is:
  • the structure of the azetidinyl group is:
  • the structure of 1-methylazetidinyl is:
  • the structure of the haloethyl group is
  • cyclobutyl-methyl- has the structure:
  • the structure of dimethylamino-ethyl- is:
  • said halogen is F, Cl, Br or I.
  • R 11 and R 12 are each independently hydrogen, C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, or substituted or unsubstituted C3-C6 cycloalkyl.
  • R 11 and R 12 are each independently hydrogen, C1-C4 alkyl, substituted or unsubstituted C1-C4 haloalkyl, or substituted or unsubstituted C3-C6 cycloalkyl.
  • R 11 and R 12 are each independently hydrogen, methyl, ethyl, propyl or butyl.
  • R 13 , R 14 , R 15 , R 16 , R 17 , R 18 or R 19 are each independently hydrogen or C1-C6 alkyl.
  • R 13 , R 14 , R 15 , R 16 , R 17 , R 18 or R 19 are each independently hydrogen or C1-C4 alkyl.
  • R 13 , R 14 , R 15 , R 16 , R 17 , R 18 or R 19 are each independently hydrogen, methyl, ethyl, propyl or butyl.
  • R 20 and R 21 are each independently hydrogen or C1-C6 alkyl.
  • R 20 and R 21 are each independently hydrogen or C1-C4 alkyl.
  • R20 and R21 are each independently hydrogen, methyl, ethyl, propyl or butyl.
  • the pharmaceutically acceptable salt of the compound of formula I comprises compound of formula I with hydrochloric acid, mucic acid, D-glucuronic acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid , acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzene methanesulfonic acid, benzene Salts of sulfonic acid, aspartic acid or glutamic acid.
  • the compound of formula I is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the second aspect of the present invention provides a composition, which comprises the compound of formula I as described in the first aspect of the present invention, or its optical isomer, or its racemate, or its solvate , or a hydrate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
  • the compound as described in the first aspect of the present invention or its optical isomer, or its racemate, or its solvate, or its hydrate, or its pharmaceutically acceptable salt
  • the content of the prodrug thereof is 0.001-99wt%, preferably 0.01-70wt%, more preferably 0.05-40wt%, based on the total weight of the composition.
  • the composition is a pharmaceutical composition.
  • the composition further includes a pharmaceutically acceptable carrier.
  • the dosage form of the composition is an injection preparation, an external preparation or an oral preparation.
  • the injection preparation is an intravenous injection preparation, an arterial injection preparation or an intramuscular injection preparation
  • the dosage form of the composition is solid preparation, liquid preparation or semi-solid preparation.
  • the dosage forms of the composition are tablets, capsules, powders, injections, powder injections, emulsions, infusions, oral liquids, aerosols, ointments, gels, microspheres, and creams.
  • the composition further includes other anticancer drugs.
  • the compound of formula I described in the first aspect of the present invention or its optical isomer, or its racemate, or its solvate, or its hydrate, or its pharmaceutical Acceptable salts, or prodrugs thereof, are used as the sole active ingredient.
  • the third aspect of the present invention provides a compound of formula I as described in the first aspect of the present invention, or its optical isomer, or its racemate, or its solvate, or its hydrate, or its pharmaceutical
  • the above acceptable salts or prodrugs thereof are used for preparing compositions, and the compositions are used for preventing and/or treating tumors.
  • the tumor is selected from the group consisting of ovarian cancer, breast cancer, prostate cancer, melanoma, pancreatic cancer, colon cancer, rectal cancer, colorectal cancer, or a combination thereof.
  • said tumors include human tumors or non-human mammalian tumors.
  • the non-human mammals include (but are not limited to): pets (such as dogs, cats), domestic animals (such as cattle, sheep, horses, pigs), various zoo animals (pandas, elephants), etc.
  • said tumor comprises epithelial cell carcinoma.
  • said tumor comprises adenocarcinoma.
  • said tumor comprises colorectal adenocarcinoma.
  • said tumor comprises colorectal adenocarcinoma epithelial cell carcinoma.
  • the tumors include tumors with BRCA, BLM, WRN, NBS1, FANC, CDK12 and/or CHK2 mutations.
  • the tumor is selected from the group consisting of: recurrent ovarian cancer, epithelial recurrent ovarian cancer, platinum-sensitive or partially sensitive fallopian tube cancer, platinum-sensitive or partially sensitive primary peritoneal cancer, 3 Advanced ovarian cancer with gBRCA gene mutation, HER2-negative metastatic breast cancer with BRCA gene mutation, harmful or suspected harmful gBRCA gene who have received neoadjuvant chemotherapy, adjuvant chemotherapy, or metastatic chemotherapy Mutant, HER2-negative metastatic breast cancer, or a combination thereof.
  • the tumor includes a tumor with BRCA2 gene mutation.
  • the BRCA2 gene mutation includes a mutation leading to BRCA2 gene deletion.
  • the BRCA2 gene mutation includes a mutation leading to no or low expression of the BRCA2 gene.
  • said tumors include BRCA2 gene-deleted tumors.
  • said tumors include tumors with no or low expression of BRCA2 gene.
  • the tumor with no or low expression of the BRCA2 gene refers to the ratio (E1/E0) of the expression E1 of the BRCA2 gene in tumor cells to the expression E0 of the BRCA2 gene in the same type of tumor cells (E1/E0) ⁇ 1.0, preferably ⁇ 0.7 , more preferably ⁇ 0.6, more preferably ⁇ 0.5, more preferably ⁇ 0.4, more preferably ⁇ 0.3, more preferably ⁇ 0.2, more preferably ⁇ 0.1, more preferably ⁇ 0.05, more preferably ⁇ 0.01, more preferably Preferably ⁇ 0.005, more preferably ⁇ 0.001, more preferably ⁇ 0.0001, more preferably ⁇ 0.00001, more preferably ⁇ 0.000001, more preferably ⁇ 0.0000001.
  • the tumor cells of the same type refer to cells of the same type but without BRCA2 gene mutation.
  • the tumor cells of the same type refer to cells of the same type but with normal or high expression of BRCA2 gene.
  • the tumor cells include DLD-1 cells or DLD-1 BRCA2(-/-) cells.
  • the composition is a pharmaceutical composition.
  • the composition further includes a pharmaceutically acceptable carrier.
  • the dosage form of the composition is an injection preparation, an external preparation or an oral preparation.
  • the injection preparation is an intravenous injection preparation, an arterial injection preparation or an intramuscular injection preparation.
  • the dosage form of the composition is solid preparation, liquid preparation or semi-solid preparation.
  • the dosage forms of the composition are tablets, capsules, powders, injections, powder injections, emulsions, infusions, oral liquids, aerosols, ointments, gels, microspheres, and creams.
  • the composition further includes other anticancer drugs.
  • the compound of formula I described in the first aspect of the present invention or its optical isomer, or its racemate, or its solvate, or its hydrate, or its pharmaceutical Acceptable salts, or prodrugs thereof, are used as the sole active ingredient.
  • a method for inhibiting tumor cells comprising the steps of: combining tumor cells with the compound of formula I as described in the first aspect of the present invention, or its optical isomer, or its external The racemate, or its solvate, or its hydrate, or its pharmaceutically acceptable salt, or its prodrug can inhibit tumor cells.
  • said method is an in vitro method.
  • the methods are non-therapeutic and non-diagnostic.
  • said contact is in vitro culture contact.
  • the tumor is as described in the third aspect of the present invention.
  • a fifth aspect of the present invention provides a method for preventing and/or treating tumors, the method comprising:
  • said subjects are humans and non-human mammals.
  • the non-human mammals include (but are not limited to): pets (such as dogs, cats), domestic animals (such as cattle, sheep, horses, pigs), various zoo animals (pandas, elephants), etc.
  • the tumor is as described in the third aspect of the present invention.
  • the administration is oral administration, injection administration or topical administration.
  • the injection administration is intravenous injection administration, arterial injection administration or intramuscular injection administration.
  • Fig. 1 is the blood drug concentration-time curve of intravenous administration and oral administration of compound I3, compound I5, compound I15, compound I25, compound I45, compound I57 prepared in the example.
  • the present invention unexpectedly develops a compound for the first time, the compound of the present invention has high selective inhibitory effect on PARP1, and the inhibitory effect on PARP2 is weak, therefore, the compound described in the present invention has excellent selective inhibitory effect, thus It has low side effects while exerting excellent antitumor effect.
  • the compound of the present invention has good druggability, has excellent pharmacokinetics through oral administration and injection administration, shows good bioavailability after oral administration, and is suitable for the development of oral drugs, thereby reducing production costs and improving patient safety. compliance.
  • the terms “comprising”, “including”, and “containing” are used interchangeably to include not only closed definitions, but also semi-closed, and open definitions. In other words, the terms include “consisting of”, “consisting essentially of”.
  • cancer As used herein, the terms “carcinoma”, “cancer”, “tumor” and “neoplastic” are used interchangeably.
  • IC 50 is the half-inhibiting concentration (50% inhibiting concentration), ie the concentration of the inhibitor at which 50% inhibitory effect is achieved.
  • PARP1 refers to polyadenosine diphosphate-ribose polymerase 1, and its English name is PolyADP-ribose polymerase 1.
  • PARP2 refers to polyadenosine diphosphate-ribose polymerase 2, and its English name is PolyADP-ribose polymerase 2.
  • BRCA2 refers to breast cancer gene 2, and its English name is breast cancer gene 2.
  • substituents and substitution patterns on the compounds of the present invention can be selected by one of ordinary skill in the art to produce chemically stable compounds, which can be synthesized by techniques known in the art and methods set forth below. If substituted with more than one substituent group(s), it is understood that the multiple groups may be on the same carbon or on different carbons so long as a stable structure results.
  • substituted or “substituted” means that a hydrogen atom on a group is replaced by a non-hydrogen atom group, but it needs to meet its valence requirements and the substitution results in a chemically stable compound, that is, it will not spontaneously carry out such as ring Compounds that undergo transformations such as chemicalization and elimination.
  • R 1 As used herein, “R 1 ", “R1” and “R 1” have the same meaning and can be replaced with each other, and other similar definitions have the same meaning.
  • alkyl refers to a straight chain (ie, unbranched) or branched chain saturated hydrocarbon group containing only carbon and hydrogen atoms, or a combination of straight chain and branched chain groups.
  • the alkyl group is limited by the number of carbon atoms (such as C1-C6 alkyl group), it refers to the number of carbon atoms contained in the alkyl group (such as 1-6), for example, C1-C4 alkyl group refers to the number of carbon atoms containing 1-4 carbons
  • Atomic alkyl representative examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or the like.
  • alkylene refers to a group formed by removing a hydrogen atom from an alkyl group, and the alkyl group is as defined above, when the alkylene group has a limit on the number of carbon atoms (such as C1-C6 alkylene group) refers to the number of carbon atoms contained in the alkylene group (such as 1-6), for example, C1-C4 alkylene refers to an alkylene group containing 1-4 carbon atoms, representative examples include but are not limited to Methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, tert-butylene, or the like.
  • halogen refers to F, Cl, Br or I.
  • halo means substituted with a halogen
  • haloalkyl means that one or more (preferably 1, 2, 3 or 4) hydrogens of an alkyl group are replaced by a halogen, said alkyl and halogen are as defined above, when the haloalkyl
  • a limited number of carbon atoms such as C1-C8 haloalkyl refers to the number of carbon atoms (such as 1-8) contained in the haloalkyl group, for example, C1-C6 haloalkyl refers to a haloalkyl group containing 1-6 carbon atoms , representative examples include, but are not limited to, -CF3 , -CHF2 , monofluoroisopropyl, difluorobutyl, or similar groups.
  • cycloalkane ring refers to a monocyclic, bicyclic or polycyclic (fused, bridged or spiro) ring system having a saturated or partially saturated ring.
  • a cycloalkane ring has a limited number of carbon atoms (such as C3-C12), it refers to the number of ring carbon atoms (such as 3-12) that the cycloalkane ring has.
  • C3-C8 cycloalkane ring refers to a saturated or partially saturated monocyclic or bicycloalkane ring having 3-8 ring carbon atoms, including cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, cycloheptane ring , or similar rings.
  • Spirocycloalkane means bicyclic or polycyclic rings that share a single carbon atom (called a spiro atom) between the monocyclic rings, these may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system .
  • fused cycloalkane ring means an all-carbon bicyclic or polycyclic ring in which each ring shares an adjacent pair of carbon atoms with other rings in the system, one or more of which may contain one or more double bonds, But none of the rings have a fully conjugated ⁇ -electron system.
  • Bridged cycloalkane ring refers to all carbon polycyclic rings in which any two rings share two carbon atoms that are not directly attached, these may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system.
  • cycloalkyl refers to a monocyclic, bicyclic or polycyclic (fused, bridged or spiro) ring system group having a saturated or partially saturated ring.
  • a certain cycloalkyl group is limited by the number of carbon atoms (such as C3-C12), it refers to the number of ring carbon atoms (such as 3-12) that the cycloalkyl group has.
  • C3-C8 cycloalkyl refers to a saturated or partially saturated monocyclic or bicyclic alkyl group having 3-8 ring carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl , or similar groups.
  • Spirocycloalkyl means a bicyclic or polycyclic group in which the single rings share a single carbon atom (called a spiro atom), these may contain one or more double bonds, but none of the rings has fully conjugated pi electrons system.
  • “Fused cycloalkyl” means an all-carbon bicyclic or polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, one or more of which may contain one or more bicyclic bonds, but none of the rings have a fully conjugated ⁇ -electron system.
  • “Bridged cycloalkyl” refers to an all-carbon polycyclic group in which any two rings share two carbon atoms not directly attached, these may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system .
  • cycloalkylene refers to a group formed by removing a hydrogen atom from a cycloalkyl group as defined above.
  • Representative examples include, but are not limited to: cyclopropylene, cyclopropylene Butyl, cyclopentylene, cycloheptylene, or similar groups.
  • halocycloalkyl means that one or more (preferably 1, 2, 3 or 4) hydrogens of a cycloalkyl group are replaced by halogen, said cycloalkyl group and halogen being as defined above,
  • the cycloalkyl group is limited by the number of carbon atoms (such as C3-C8 halocycloalkyl)
  • the cycloalkyl group contains 3-8 ring carbon atoms
  • C3-C8 halocycloalkyl means that it contains 3 - a halocycloalkyl group of 8 ring carbon atoms
  • representative examples include, but are not limited to, monofluorocyclopropyl, monochlorocyclobutyl, monofluorocyclopentyl, difluorocycloheptyl, or the like group.
  • alkoxy refers to the R-O- group, wherein R is an alkyl group, and the alkyl group is as defined herein above, when the alkoxy group has a limit of carbon atoms, such as C1-C8 alkoxy group refers to The alkyl group in the alkoxy group has 1-8 carbon atoms.
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, or the like.
  • alkylthio refers to an R-S- group, wherein R is an alkyl group, and the alkyl group is as defined herein above, when the alkylthio group is preceded by a limit of carbon atoms, such as the C1-C8 alkylthio group refers to The alkyl group in the above-mentioned alkylthio group has 1-8 carbon atoms.
  • Representative examples of alkylthio include, but are not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, t-butylthio, or the like.
  • haloalkoxy refers to haloalkyl-O-, the haloalkyl is as defined above, for example, C1-C6 haloalkoxy refers to haloalkoxy containing 1-6 carbon atoms, representative examples Including, but not limited to, monofluoromethoxy, monofluoroethoxy, bisfluorobutoxy, or similar groups.
  • haloalkylthio refers to haloalkyl-S-, the haloalkyl is as defined above, for example, C1-C6 haloalkylthio refers to haloalkylthio containing 1-6 carbon atoms, representative examples Including, but not limited to, monofluoromethylthio, monofluoroethylthio, difluorobutylthio, or similar groups.
  • cycloalkoxy refers to the R-O- group, wherein R is cycloalkyl, and cycloalkyl is as defined herein above, when cycloalkoxy is limited by the number of carbon atoms, such as C3-C8 ring Alkoxy means that the cycloalkyl group in the cycloalkoxy group has 3-8 ring carbon atoms.
  • Representative examples of cycloalkoxy include, but are not limited to, cyclopropoxy, cyclobutoxy, or the like.
  • cycloalkylthio refers to an R-S-group, wherein R is a cycloalkyl group, and the cycloalkyl group is as defined herein above, when the cycloalkylthio group has a limit on the number of carbon atoms before it, such as a C3-C8 ring
  • the alkylthio group refers to the cycloalkyl group in the cycloalkylthio group having 3-8 ring carbon atoms.
  • Representative examples of cycloalkylthio include, but are not limited to, cyclopropylthio, cyclobutylthio, or the like.
  • halocycloalkoxy means that one or more (preferably 1, 2, 3 or 4) hydrogens of a cycloalkoxy group are replaced by a halogen, said cycloalkoxy and halogen being as above
  • halocycloalkoxy when there is a limit on the number of carbon atoms in front of the halocycloalkoxy group (such as C3-C8 halocycloalkoxy group), it means that the number of ring carbon atoms contained in the halocycloalkoxy group (such as 3-8 ), for example, C3-C8 halocycloalkoxy refers to halocycloalkoxy containing 3-8 ring carbon atoms, representative examples include but are not limited to monofluorocyclopropyl-O-, monochlorocyclo Butyl-O-, monofluorocyclopentyl-O-, difluorocycloheptyl-O-, or similar groups.
  • halocycloalkylthio means that one or more (preferably 1, 2, 3 or 4) hydrogens of a cycloalkylthio group are replaced by a halogen, said cycloalkylthio and halogen being as above
  • halocycloalkylthio when there is a limit on the number of carbon atoms in front of the halocycloalkylthio group (such as C3-C8 halocycloalkylthio group), it means that the number of ring carbon atoms contained in the halocycloalkylthio group (such as 3-8 ), for example, C3-C8 halocycloalkylthio refers to a halocycloalkylthio group containing 3-8 ring carbon atoms, representative examples include but are not limited to monofluorocyclopropyl-S-, monochlorocyclopropyl Butyl-S-, monofluorocyclopentyl-S-, difluor
  • heterocycloalkane ring refers to a fully saturated or partially unsaturated ring (including but not limited to such as 3-7 membered monocyclic ring, 7-11 membered bicyclic ring, or 8-16 membered tricyclic ring system) , where at least one heteroatom is present in a ring with at least one carbon atom.
  • the heterocycloalkane ring is limited by the number of members, it refers to the number of ring atoms of the heterocycloalkane ring, for example, a 3-16 membered heterocycloalkane ring refers to a heterocycloalkane ring with 3-16 ring atoms.
  • heteroatoms can be carried on each heteroatom-containing heterocycloalkane ring, and these heteroatoms are each independently selected from a nitrogen atom, an oxygen atom or a sulfur atom, wherein Nitrogen or sulfur atoms can be oxidized, and nitrogen atoms can also be quaternized.
  • Typical monocyclic heterocycloalkane rings include, but are not limited to, azetidine rings, oxetane rings, tetrahydrofuran rings, piperidine rings, piperazine rings, and the like.
  • Multicyclic heterocycloalkane rings include spiro rings, fused rings and bridged piperazine rings; the spiro rings, fused rings and bridged rings involved in the heterocycloalkane rings are optionally connected to other rings through single bonds, or through Any two or more atoms on the ring are further linked with other cycloalkane rings and heterocycloalkane rings.
  • heterocycloalkyl refers to a fully saturated or partially unsaturated ring (including but not limited to such as 3-7 membered monocyclic ring, 7-11 membered bicyclic ring, or 8-16 membered tricyclic ring system) groups in which at least one heteroatom is present in a ring having at least one carbon atom.
  • the heterocycloalkyl group is defined by the number of ring atoms, it refers to the number of ring atoms in the heterocycloalkyl group, for example, a 3-16 membered heterocycloalkyl group refers to a heterocycloalkyl group with 3-16 ring atoms.
  • Each heteroatom-containing heterocyclic ring can have one or more (such as 1, 2, 3 or 4) heteroatoms, and these heteroatoms are each independently selected from a nitrogen atom, an oxygen atom or a sulfur atom, wherein the nitrogen atom Or sulfur atoms can be oxidized and nitrogen atoms can also be quaternized.
  • Typical monocyclic heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, tetrahydrofuranyl, piperidinyl, piperazinyl.
  • the polycyclic heterocycloalkyl group includes spiro ring, fused ring and bridged ring heterocyclyl group; wherein the spiro ring, fused ring and bridged ring heterocycloalkyl group are optionally connected with other groups through a single bond, or Further ring connection with other cycloalkane rings and heterocycles through any two or more atoms on the ring.
  • heterocycloalkylene refers to a group formed by removing a hydrogen atom from a heterocycloalkyl group as defined above.
  • Representative examples include, but are not limited to: Nitrogen Heterobutanyl, oxetanylene, tetrahydrofuranylene, piperidinylene, piperazinylene.
  • aromatic ring refers to a full-carbon monocyclic or fused polycyclic ring (that is, a ring sharing adjacent pairs of carbon atoms) with a conjugated ⁇ -electron system, which is an aromatic ring hydrocarbon compound, when The number of carbon atoms in front of the aromatic ring is limited, such as a C6-C12 aromatic ring, which means that the aromatic ring has 6-12 ring carbon atoms, such as benzene ring and naphthalene ring.
  • aryl refers to an all-carbon monocyclic or fused polycyclic (that is, rings that share adjacent pairs of carbon atoms) group with a conjugated ⁇ -electron system, and is an aromatic cyclic hydrocarbon compound Groups, when the aryl group is limited by the number of carbon atoms, such as C6-C12 aryl, it means that the aryl group has 6-12 ring carbon atoms, such as phenyl and naphthyl.
  • heterocyclic ring refers to an aromatic heterocyclic ring system having one to more (preferably 1, 2, 3 or 4) heteroatoms, at least one of which is present on at least one carbon atom In the ring, which may be a single ring (monocyclic) or multiple rings fused together or linked covalently (bicyclic, tricyclic or polycyclic), each heterocycle containing a heteroatom There may be more than one (eg 1, 2, 3, 4) heteroatoms each independently selected from the group consisting of oxygen, sulfur and nitrogen.
  • the heteroaryl ring is limited by the number of members, it refers to the number of ring atoms in the heteroaryl ring.
  • a 5-12 membered heteroaryl ring refers to a heteroaryl ring with 5-12 ring atoms.
  • Representative examples Including but not limited to: pyrrole ring, pyrazole ring, imidazole ring, thiazole ring, furan ring, pyridine ring, pyrimidine ring, etc.
  • heteroaryl refers to an aromatic heterocyclic ring system group having one to more (preferably 1, 2, 3 or 4) heteroatoms, wherein at least one heteroatom is present in at least one In a ring of carbon atoms, which may be a monocyclic (monocyclic) or polycyclic (bicyclic, tricyclic or polycyclic) group fused together or linked covalently, each containing heteroatoms There may be more than one (such as 1, 2, 3, 4) heteroatoms independently selected from the following group on the heterocycle: oxygen, sulfur and nitrogen.
  • the heteroaryl group is limited by the number of ring atoms, it refers to the number of ring atoms of the heteroaryl group.
  • a 5-12 membered heteroaryl group refers to a heteroaryl group with 5-12 ring atoms.
  • Representative examples Including but not limited to: pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furyl, pyridyl, pyrimidinyl, etc.
  • carboxy refers to a -COOH group or -alkyl-COOH group
  • alkyl is as defined herein above, for example "C 2 -C 4 carboxy” refers to -C 1 -C 3 alkyl
  • carboxyl group include (but not limited to): -COOH, -CH 2 COOH, or similar groups.
  • ester group refers to a group with RC(O)-O- or -C(O)-OR, wherein R is an alkyl group, and the alkyl group is as defined herein above, for example, "C 2 - C 4 ester group” refers to a group of C 1 -C 3 alkyl-C(O)-O- structure or a group of -C(O)-OC 1 -C 3 alkyl structure, representative of ester group Examples include, but are not limited to: CH 3 C(O)O-, C 2 H 5 C(O)O-, (CH 3 ) 2 CHC(O)O-, -C(O)OCH 3 , -C(O )OC 2 H 5 , or similar groups.
  • amido refers to a group with RC(O)-N- or -C(O)-NR, wherein R is an alkyl group, and the alkyl group is as defined herein above, such as "C 2 - C 4 amido group” refers to a group of C 1 -C 3 alkyl-C(O)-N-structure or a group of -C(O)-NC 1 -C 3 alkyl structure, representative of amido group Examples include, but are not limited to: CH3C (O)-N-, C2H5C (O)-N-, ( CH3 ) 2CHC (O)-N-, -C(O)-N-CH 3. -C(O)-NC 2 H 5 , or similar groups.
  • amino by itself or as part of another substituent is -NH2 .
  • nitro alone or as part of another substituent, is -NO2 .
  • hydroxy is -OH, alone or as part of another substituent.
  • prevention means a method of preventing the onset of a disease and/or its attendant symptoms or protecting a subject from acquiring a disease.
  • Treatment in the present invention includes delaying and terminating the progression of the disease, or eliminating the disease, and does not require 100% inhibition, eradication and reversal.
  • compounds of the invention reduce, inhibit and/or reverse tumors, e.g., by at least about 10%, at least about 30%, at least About 50%, at least about 80%, or 100%.
  • the compound of formula I, or its optical isomer, or its racemate, or its solvate, or its hydrate, or its pharmaceutically acceptable salt, or its prodrug is as described in the present invention mentioned in the first aspect.
  • pharmaceutically acceptable salt refers to a salt of a compound of the present invention with an acid or a base which is suitable for use as a medicine.
  • Pharmaceutically acceptable salts include inorganic salts and organic salts.
  • One class of preferred salts is the salt formed by the compound of the present invention and an acid.
  • Suitable acids for forming the salt include (but are not limited to): inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid , propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzene methanesulfonic acid, benzenesulfonic acid and other organic acids; And acidic amino acids such as aspartic acid and glutamic acid.
  • a preferred class of salts are metal salts formed from compounds of the present invention and bases.
  • Suitable bases for salt formation include (but are not limited to): sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium phosphate and other inorganic bases, Ammonia, triethylamine, diethylamine and other organic bases.
  • the compounds of the present invention can be converted into their pharmaceutically acceptable salts by conventional methods.
  • the corresponding acid or base solution can be added to the solution of the above compounds.
  • the solvent is removed under reduced pressure to obtain the corresponding salt of the compound.
  • Poly ADP-ribose polymerase can include polyadenosine diphosphate-ribose polymerase 1 (Poly ADP-ribose polymerase 1, PARP1) and poly ADP-ribose polymerase 2 ( Poly ADP-ribose polymerase 2, PARP2).
  • PARP inhibitors PARP1 and PARP2 dual inhibitors
  • PARP2 is not necessary for the curative effect. Therefore, selective inhibition of PARP1 will lead to better curative effect and better safety. Therefore, the development of an anti-tumor drug with a highly selective inhibitory effect on PARP1 can reduce its side effects, thereby improving drug compliance of patients.
  • the compounds of the present invention have excellent therapeutic effects on tumors.
  • the tumor includes, but is not limited to: ovarian cancer, breast cancer, prostate cancer, melanoma, pancreatic cancer, colon cancer, rectal cancer, colorectal cancer, or a combination thereof.
  • the tumor includes a human tumor or a non-human mammalian tumor.
  • the tumor includes epithelial cell carcinoma.
  • the tumor includes adenocarcinoma.
  • said tumor comprises colorectal adenocarcinoma.
  • said tumor comprises colorectal adenocarcinoma epithelial cell carcinoma.
  • the tumor includes but not limited to tumors with mutations in BRCA, BLM, WRN, NBS1, FANC, CDK12 and/or CHK2.
  • the tumors include but are not limited to: recurrent ovarian cancer, epithelial recurrent ovarian cancer, platinum-sensitive or partially sensitive fallopian tube cancer, platinum-sensitive or partially sensitive primary Peritoneal cancer, advanced ovarian cancer with gBRCA gene mutation that still progresses after receiving 3 or more lines of chemotherapy, HER2-negative metastatic breast cancer with BRCA gene mutation, harmful or harmful effects of neoadjuvant chemotherapy, adjuvant chemotherapy, and metastatic chemotherapy Suspected deleterious gBRCA gene mutation, HER2-negative metastatic breast cancer, or a combination thereof.
  • the tumor includes a tumor with BRCA2 gene mutation.
  • the BRCA2 gene mutation includes a mutation leading to BRCA2 gene deletion.
  • the BRCA2 gene mutation includes a mutation leading to no or low expression of the BRCA2 gene.
  • said tumors include BRCA2 gene-deleted tumors.
  • the tumor includes a tumor with no or low expression of BRCA2 gene.
  • the tumor with no or low expression of the BRCA2 gene refers to the ratio (E1/E0) of the expression E1 of the BRCA2 gene in tumor cells to the expression E0 of the BRCA2 gene in the same type of tumor cells (E1/E0) ⁇ 1.0, preferably ⁇ 0.7 , more preferably ⁇ 0.6, more preferably ⁇ 0.5, more preferably ⁇ 0.4, more preferably ⁇ 0.3, more preferably ⁇ 0.2, more preferably ⁇ 0.1, more preferably ⁇ 0.05, more preferably ⁇ 0.01, more preferably Preferably ⁇ 0.005, more preferably ⁇ 0.001, more preferably ⁇ 0.0001, more preferably ⁇ 0.00001, more preferably ⁇ 0.000001, more preferably ⁇ 0.0000001.
  • the tumor cells of the same type refer to cells of the same type but without BRCA2 gene mutation.
  • the tumor cells of the same type refer to cells of the same type but with normal or high expression of BRCA2 gene.
  • the tumor cells include DLD-1 cells or DLD-1 BRCA2(-/-) cells.
  • the compounds of the present invention have excellent preventive and therapeutic effects on tumors.
  • the present invention also provides a method for inhibiting tumor cells, comprising the steps of: mixing tumor cells with the compound described in the present invention, or its optical isomer, or its racemate, or its solvate, or its hydrate, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, thereby inhibiting tumor cells.
  • said method is an in vitro method.
  • the methods are non-therapeutic and non-diagnostic.
  • said contact is in vitro culture contact.
  • the present invention also provides a method for preventing and/or treating tumors, the method comprising: administering the compound of formula I as described in the present invention, or its optical isomer, or its racemate, or a solvate thereof, or a hydrate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a composition according to the present invention, thereby preventing and/or treating tumors.
  • said subjects are humans and non-human mammals.
  • the non-human mammals include (but are not limited to): pets (such as dogs, cats), domestic animals (such as cattle, sheep, horses, pigs), various zoo animals (pandas, elephants), etc.
  • the tumor is as described in the third aspect of the present invention.
  • the administration is oral administration, injection administration or topical administration.
  • the injection administration is intravenous injection administration, arterial injection administration or intramuscular injection administration.
  • the invention provides a composition, which can be used for preventing and treating tumors.
  • the composition is a pharmaceutical composition.
  • composition of the present invention may also include a pharmaceutically acceptable carrier.
  • the dosage forms of the composition include (but not limited to) oral preparations, injections, and external preparations.
  • the injection preparation is an intravenous injection preparation, an arterial injection preparation or an intramuscular injection preparation
  • the dosage form of the composition includes (but not limited to): tablet, capsule, powder, injection, powder injection, emulsion, infusion, oral liquid, aerosol, ointment, gel, microsphere, cream agent.
  • pharmaceutically acceptable carrier refers to: one or more compatible solid, semi-solid, liquid or gel fillers, which are suitable for human or animal use, and must be of sufficient purity and low enough toxicity.
  • Cosmetic means that each component in the pharmaceutical composition and the active ingredients of the medicine and their mutual blending will not significantly reduce the efficacy of the medicine.
  • the carrier is not particularly limited, and it can be made from materials commonly used in the art, or prepared by conventional methods, or purchased from the market.
  • pharmaceutically acceptable carrier parts include cellulose and its derivatives (such as methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, 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, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween), wetting agent (such as sodium lauryl sulfate), buffering agent, chelating agent, thickener, pH regulator, skin penetration enhancer, coloring agent, flavoring agent, stabilizer, antioxidant, preservative , antibacterial agent, pyrogen-free water,
  • cellulose and its derivatives such
  • liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, acetic acid, in addition to the active pharmaceutical ingredient.
  • inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, acetic acid, in addition to the active pharmaceutical ingredient.
  • Ethyl esters, propylene glycol, 1,3-butanediol, dimethylformamide and oils especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.
  • the composition can also contain adjuvants such as wetting agents, emulsifying agents and suspending agents, etc.
  • the pharmaceutical formulation should match the mode of administration. Agents of the invention may also be used together (including before, during or after) other co-therapeutic agents.
  • a safe and effective amount of the drug is administered to a desired subject (such as a human or a non-human mammal), usually at least about 10 micrograms per kilogram of body weight, and in most cases no more than About 8 mg/kg body weight, preferably the dosage is about 10 microgram/kg body weight to about 1 mg/kg body weight.
  • a desired subject such as a human or a non-human mammal
  • the dosage is about 10 microgram/kg body weight to about 1 mg/kg body weight.
  • factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.
  • the compound of the present invention has the advantages of excellent anticancer effect, low toxic and side effects, large safety window, and strong selectivity for specific receptors.
  • the compound of the present invention has good druggability, has excellent pharmacokinetics through oral administration and injection administration, and shows good bioavailability after oral administration, and is suitable for the development of oral drugs, thereby reducing production costs and improving patient efficacy. compliance.
  • HATU (0.43g) was added to a DMF (10mL) solution of compound I5-4 (0.25g), and after stirring at room temperature for 0.5h, DIPEA (0.30g) and MeNH 2 -HCl (0.16g) were added, and the mixture was stirred at room temperature After stirring for 14 h, the reaction mixture was diluted with water and extracted with EA, the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo, the residue was purified by preparative HPLC to give compound 15-5 as a white solid.
  • HATU (0.75g) was added to compound I11-4 (0.42g) DMF solution (5mL), the mixture was stirred at room temperature for 0.5h, DIPEA (0.51g) and MeNH 2 -HCl (0.27g) were added, and the mixture was stirred at room temperature After stirring for 14 h, the reaction mixture was diluted with water and extracted with EA, the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to afford compound I11-5 as a white solid.
  • Example 24 examines the inhibitory effect of the compounds prepared in the examples on PARP1 and PARP2
  • the PARP chemiluminescence kit (BPS Bioscience, PARP1 Catalog#80551, PARP2Catalog#80552) was used to measure the chemiluminescence value according to the instructions, and the average IC50 was calculated by calculating the inhibition percentage and making a logarithmic graph of the compound concentration, and measuring the prepared in the example.
  • the inhibitory effect of the compound on PARP1 Poly ADP-ribose polymerase 1, polyadenosine diphosphate-ribose polymerase 1
  • PARP2 Poly ADP-ribose polymerase2, polyadenosine diphosphate-ribose polymerase 2
  • IC 50 is the half-inhibiting concentration (50% inhibiting concentration), that is, the concentration of the inhibitor when 50% inhibitory effect is achieved.
  • the compound of the present invention has a high selective inhibitory effect on PARP1, and the inhibitory effect on PARP2 is weak, thereby showing that the compound of the present invention has an excellent selective inhibitory effect, thereby in While exerting excellent anti-tumor effect, it has lower side effects.
  • Embodiment 25 investigates the inhibitory effect of the compound prepared by the embodiment on DLD-1 cells and DLD-1 BRCA2 (-/-) cells
  • DLD-1 cells are human colorectal adenocarcinoma epithelial cells.
  • DLD-1 BRCA2 (-/-) cells are DLD-1 cells in which the BRCA2 gene is knocked out, that is, DLD-1 cells in which the BRCA2 gene is deleted.
  • DLD-1 cells and cells were incubated according to ATCC conditions. Transfer 40nL of the compound to a 384-well plate, add 40 ⁇ L of culture medium to each well, and inoculate DLD-1BRCA2(-/-) cells or DLD-1 cells at 600 cells per well, and incubate at 37°C and 5% CO2 for 7 After 30 min at room temperature, 20 ⁇ L of luminescence reagent was added to each well. After incubation at room temperature for 30 min, the luminescence value was recorded and the average IC 50 was calculated. The results are shown in Table 2.
  • IC 50 is the half inhibitory concentration (50% inhibiting concentration), that is, the concentration of the inhibitor when 50% inhibitory effect is achieved.
  • Embodiment 26 investigates the pharmacokinetic research of the compound that embodiment prepares
  • ICR mice were given Compound I3, Compound I5, Compound I15, Compound I25, Compound I45, and Compound I57 prepared in the examples respectively under the conditions of intravenous injection and oral gavage administration, wherein the dose of intravenous administration was 2 mg/kg, orally administered
  • NCA non-compartmental model method
  • iv intravenous administration
  • po oral administration
  • T max is the time to reach the maximum blood concentration
  • C max is the maximum blood concentration
  • AUC 0-t is the drug-time curve area within 0-24h
  • AUC 0- ⁇ is the drug-time curve area within 0- ⁇
  • t 1/2 is the half-life
  • Vss is the steady-state volume of distribution
  • the compounds of the present invention have excellent pharmacokinetics through oral administration and injection administration, show good bioavailability after oral administration, and are suitable for the development of oral drugs, thereby Reduce production costs and improve patient compliance.

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Abstract

L'invention concerne un composé hétéroaromatique et son utilisation. Plus particulièrement, l'invention concerne un composé tel que représenté par la formule I, ou un isomère optique, un composé racémique, un solvate, un hydrate, un sel pharmaceutiquement acceptable, ou un promédicament de celui-ci. Le composé présente d'excellents effets préventifs et thérapeutiques sur les tumeurs.
PCT/CN2022/118064 2021-09-09 2022-09-09 Composé hétéroaromatique et son utilisation WO2023036285A1 (fr)

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Cited By (7)

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Publication number Priority date Publication date Assignee Title
US11802128B2 (en) 2021-10-01 2023-10-31 Xinthera, Inc. Azetidine and pyrrolidine PARP1 inhibitors and uses thereof
US11939329B2 (en) 2022-01-21 2024-03-26 Xinthera, Inc. PARP1 inhibitors and uses thereof
US11795173B1 (en) 2022-04-28 2023-10-24 Xinthera, Inc. Substituted pyridines as PARP1 inhibitors
WO2024067694A1 (fr) * 2022-09-30 2024-04-04 中国医药研究开发中心有限公司 Composé hétérocyclique contenant de l'azote et son utilisation pharmaceutique
WO2024067691A1 (fr) * 2022-09-30 2024-04-04 中国医药研究开发中心有限公司 Composé hétérocyclique contenant de l'azote et son utilisation pharmaceutique
WO2024082654A1 (fr) * 2022-10-20 2024-04-25 上海海和药物研究开发股份有限公司 Composés à activité inhibitrice de parp1 et leurs utilisations
US12006322B2 (en) 2023-09-20 2024-06-11 Xin Thera, Inc. Substituted pyridines as PARP1 inhibitors

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