WO2025237352A1 - Utilisation antitumorale de composé hétérocyclique contenant de l'azote - Google Patents

Utilisation antitumorale de composé hétérocyclique contenant de l'azote

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Publication number
WO2025237352A1
WO2025237352A1 PCT/CN2025/094990 CN2025094990W WO2025237352A1 WO 2025237352 A1 WO2025237352 A1 WO 2025237352A1 CN 2025094990 W CN2025094990 W CN 2025094990W WO 2025237352 A1 WO2025237352 A1 WO 2025237352A1
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Prior art keywords
substituted
unsubstituted
compound
alkyl
another preferred
Prior art date
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Application number
PCT/CN2025/094990
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English (en)
Chinese (zh)
Inventor
施裕丰
马文江
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Shanghai Shijiang Biotechnology Co Ltd
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Shanghai Shijiang Biotechnology Co Ltd
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Publication of WO2025237352A1 publication Critical patent/WO2025237352A1/fr
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Classifications

    • 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
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates to the field of pharmaceuticals, and more specifically to the application of a nitrogen-containing heterocyclic compound in antitumor activity.
  • Cancer is a common disease that seriously endangers human health, and the mortality rate of malignant tumors continues to rise. Due to the heterogeneity of tumors, simply using the same treatment method or the same drug based on their origin or pathological characteristics can easily lead to inappropriate treatment, wasting patients' precious treatment time and opportunities. Therefore, precision medicine tailored to different tumor conditions is essential. With the development of biological technology, tumors are increasingly being subtyped at the molecular level, including genes and proteins. More and more changes in the expression and activity of tumor-related genes and proteins are being discovered. These changes play an important role in the development of malignant tumors. The discovery and application of biomarkers will provide precise guidance for the application of related drugs, making precision medicine for tumors possible. This will enable targeted drug delivery, significantly improve the efficacy of tumor treatment, and reduce drug dosage and toxic side effects.
  • the purpose of this invention is to provide a compound that has significant and excellent precision treatment for tumors with high expression of creatine kinase B.
  • the present invention provides the use of a compound of formula I, or an optical isomer thereof, or a racemic mixture thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, for the preparation of a composition or formulation for the prevention and/or treatment of tumors;
  • R1 , R2 , R3 and R4 are each independently hydrogen, substituted or unsubstituted C1-C10 alkyl
  • R 5 is hydrogen, substituted or unsubstituted C1-C16 alkyl, substituted or unsubstituted C3-C16 cycloalkyl, substituted or unsubstituted 3-16 heterocyclic alkyl, substituted or unsubstituted C6-C16 aryl, or substituted or unsubstituted 5-16 heteroaryl.
  • R6 , R7 and R8 are each independently hydrogen, -OR 15 ; or R6 and R7 , or R7 and R8 are linked to form substituted or unsubstituted 3-12 membered heterocyclic alkane rings;
  • R 9 is hydrogen, substituted or unsubstituted C1-C8 alkyl
  • R 10 is hydrogen, substituted or unsubstituted C1-C16 alkyl, substituted or unsubstituted C6-C16 aryl-substituted or unsubstituted C1-C8 alkyl-, substituted or unsubstituted C1-C10 alkyl-substituted or unsubstituted C6-C16 aryl-C1-C8 alkyl-, substituted or unsubstituted C1-C8 alkoxy-substituted or unsubstituted C6-C16 aryl-substituted or unsubstituted C1-C10 alkyl-, substituted or unsubstituted C1-C8 alkylthio-substituted or unsubstituted C6-C16 aryl-substituted or unsubstituted C1-C10 alkyl-;
  • R11 and R14 are each independently hydrogen, or substituted or unsubstituted C1-C6 alkyl
  • R12 and R13 are linked to form substituted or unsubstituted 3-12 membered heterocyclic alkyl rings;
  • R 15 is hydrogen, substituted or unsubstituted C1-C16 alkyl, substituted or unsubstituted C6-C16 aryl-O-substituted or unsubstituted C1-C10 alkyl-, substituted or unsubstituted C1-C16 haloalkyl, substituted or unsubstituted C2-C12 alkenyl-substituted or unsubstituted C1-C8 alkyl-substituted or unsubstituted C2-C12 alkenyl-substituted or unsubstituted C1-C8 alkyl-, substituted or unsubstituted C2-C12 alkenyl-substituted or unsubstituted C1-C8 alkyl-, substituted or unsubstituted C2-C12 ester-substituted or unsubstituted C1-C10 alkyl-, or
  • R 16 is a substituted or unsubstituted C1-C16 alkyl group
  • R 17 is a substituted or unsubstituted C1-C16 alkylene group.
  • R1 , R2 , R3 and R4 are each independently hydrogen, substituted or unsubstituted C1-C8 alkyl.
  • R1 , R2 , R3 and R4 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl.
  • R1 , R2 , R3 and R4 are each independently hydrogen, substituted or unsubstituted C1-C4 alkyl.
  • R1 , R2 , R3 and R4 are each independently hydrogen.
  • R1 is hydrogen
  • R2 is hydrogen
  • R3 is hydrogen
  • R4 is hydrogen
  • R5 is hydrogen, a substituted or unsubstituted C1-C12 alkyl, a substituted or unsubstituted C3-C12 cycloalkyl, a substituted or unsubstituted 3-12 heterocyclic alkyl, a substituted or unsubstituted C6-C12 aryl, or a substituted or unsubstituted 5-12 heteroaryl.
  • R5 is hydrogen, a substituted or unsubstituted C1-C10 alkyl, a substituted or unsubstituted C3-C10 cycloalkyl, a substituted or unsubstituted 3-10 heterocyclic alkyl, a substituted or unsubstituted C6-C10 aryl, or a substituted or unsubstituted 5-10 heteroaryl.
  • R5 is hydrogen, a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C3-C8 cycloalkyl, a substituted or unsubstituted 3-8 heterocyclic alkyl, a substituted or unsubstituted C6-C8 aryl, or a substituted or unsubstituted 5-8 heteroaryl.
  • R5 is hydrogen, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C3-C8 cycloalkyl, a substituted or unsubstituted 3-8 heterocyclic alkyl, a substituted or unsubstituted C6-C8 aryl, or a substituted or unsubstituted 5-8 heteroaryl.
  • R5 is hydrogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C4-C6 cycloalkyl group, a substituted or unsubstituted 4-7 membered heterocyclic alkyl group, a substituted or unsubstituted C6-C8 aryl group, or a substituted or unsubstituted 5-8 membered heteroaryl group.
  • R5 is hydrogen, ethyl, butyl, hexyl, cyclopentyl, tetrahydropyrrolyl, or piperidinyl.
  • R6 , R7 and R8 are each independently hydrogen, -OR 15 ; or R6 and R7 , or R7 and R8 are connected to form a substituted or unsubstituted 3-10 membered heterocyclic alkane ring.
  • R6 , R7 and R8 are each independently hydrogen, -OR 15 ; or R6 and R7 , or R7 and R8 are connected to form a substituted or unsubstituted 3-8 membered heterocyclic alkane ring.
  • R6 , R7 and R8 are each independently hydrogen, -OR 15 ; or R6 and R7 , or R7 and R8 are connected to form a substituted or unsubstituted 4-6 membered heterocyclic alkane ring.
  • R6 , R7 , and R8 are each independently hydrogen, -OR 15 ; or R6 and R7 , or R7 and R8 , are connected to form substituted or unsubstituted compounds.
  • W1 and W2 are each independently O or S;
  • R 18 is hydrogen, or a substituted or unsubstituted C1-C6 alkyl, or a substituted or unsubstituted C3-C8 cycloalkyl.
  • R6 , R7 , and R8 are each independently hydrogen, -OR 15 ; or R6 and R7 , or R7 and R8 are connected to form a substituted or unsubstituted 3-membered heterocyclic alkyl ring, a substituted or unsubstituted 4-membered heterocyclic alkyl ring, a substituted or unsubstituted 5-membered heterocyclic alkyl ring, a substituted or unsubstituted 6-membered heterocyclic alkyl ring, a substituted or unsubstituted 7-membered heterocyclic alkyl ring, or a substituted or unsubstituted 8-membered heterocyclic alkyl ring.
  • R6 and R7 are linked to form substituted or unsubstituted 3-12-membered heterocyclic rings, substituted or unsubstituted 3-10-membered heterocyclic rings, substituted or unsubstituted 3-8-membered heterocyclic rings, substituted or unsubstituted 4-6-membered heterocyclic rings, substituted or unsubstituted 5-membered heterocyclic rings, or substituted or unsubstituted...
  • W1 and W2 are each independently O or S;
  • R 18 is hydrogen, or a substituted or unsubstituted C1-C6 alkyl, or a substituted or unsubstituted C3-C8 cycloalkyl.
  • R6 and R7 are connected to form substituted or unsubstituted compounds.
  • W1 and W2 are each independently O or S;
  • R 18 is hydrogen, or a substituted or unsubstituted C1-C6 alkyl, or a substituted or unsubstituted C3-C8 cycloalkyl.
  • R7 and R8 are linked to form a substituted or unsubstituted 3-12-membered heterocyclic ring, a substituted or unsubstituted 3-10-membered heterocyclic ring, a substituted or unsubstituted 3-8-membered heterocyclic ring, a substituted or unsubstituted 4-6-membered heterocyclic ring, a substituted or unsubstituted 5-membered heterocyclic ring, or a substituted or unsubstituted ring.
  • W1 and W2 are each independently O or S;
  • R 18 is hydrogen, or a substituted or unsubstituted C1-C6 alkyl, or a substituted or unsubstituted C3-C8 cycloalkyl.
  • R7 and R8 are connected to form substituted or unsubstituted compounds.
  • W1 and W2 are each independently O or S;
  • R 18 is hydrogen, or a substituted or unsubstituted C1-C6 alkyl, or a substituted or unsubstituted C3-C8 cycloalkyl.
  • W1 is O or S.
  • W2 is O or S.
  • R 9 is hydrogen, substituted or unsubstituted C1-C6 alkyl.
  • R 9 is hydrogen, substituted or unsubstituted C1-C4 alkyl.
  • R9 is hydrogen
  • R 10 is hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C6-C12 aryl-substituted or unsubstituted C1-C6 alkyl-, substituted or unsubstituted C1-C8 alkyl-substituted or unsubstituted C6-C12 aryl-C1-C6 alkyl-, substituted or unsubstituted C1-C6 alkoxy-substituted or unsubstituted C6-C12 aryl-substituted or unsubstituted C1-C8 alkyl-, substituted or unsubstituted C1-C6 alkylthio-substituted or unsubstituted C6-C12 aryl-substituted or unsubstituted C1-C8 alkyl-.
  • R 10 is hydrogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C6-C10 aryl-substituted or unsubstituted C1-C4 alkyl-, substituted or unsubstituted C1-C6 alkyl-substituted or unsubstituted C6-C10 aryl-C1-C4 alkyl-, substituted or unsubstituted C1-C4 alkoxy-substituted or unsubstituted C6-C10 aryl-substituted or unsubstituted C1-C6 alkyl-, substituted or unsubstituted C1-C4 alkylthio-substituted or unsubstituted C6-C10 aryl-substituted or unsubstituted C1-C6 alkyl-.
  • R 10 is hydrogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C6-C8 aryl-substituted or unsubstituted C1-C2 alkyl-, substituted or unsubstituted C1-C4 alkyl-substituted or unsubstituted C6-C8 aryl-C1-C2 alkyl-, substituted or unsubstituted C1-C2 alkoxy-substituted or unsubstituted C6-C8 aryl-substituted or unsubstituted C1-C4 alkyl-, substituted or unsubstituted C1-C2 alkylthio-substituted or unsubstituted C6-C8 aryl-substituted or unsubstituted C1-C4 alkyl-.
  • R 10 is hydrogen, methyl, butyl, pentyl, hexyl, dodecyl, phenyl-ethyl-, propyl-phenyl-methyl-, or methoxy-phenyl-propyl-.
  • R11 and R14 are each independently hydrogen, or substituted or unsubstituted C1-C6 alkyl.
  • R11 and R14 are each independently hydrogen, or substituted or unsubstituted C1-C4 alkyl.
  • R11 and R14 are each independently hydrogen.
  • R12 and R13 are linked to form a substituted or unsubstituted 3-10 membered heterocyclic alkyl ring.
  • R12 and R13 are linked to form a substituted or unsubstituted 3-8 membered heterocyclic alkyl ring.
  • R12 and R13 are connected to form a substituted or unsubstituted 3-membered heterocyclic alkyl ring, a substituted or unsubstituted 4-membered heterocyclic alkyl ring, a substituted or unsubstituted 5-membered heterocyclic alkyl ring, a substituted or unsubstituted 6-membered heterocyclic alkyl ring, a substituted or unsubstituted 7-membered heterocyclic alkyl ring, or a substituted or unsubstituted 8-membered heterocyclic alkyl ring.
  • R12 and R13 are linked to form a substituted or unsubstituted 5-membered heterocyclic alkyl ring.
  • R12 and R13 are connected to form substituted or unsubstituted compounds.
  • W3 and W4 are each independently O or S;
  • R 19 is hydrogen, or a substituted or unsubstituted C1-C6 alkyl, or a substituted or unsubstituted C3-C8 cycloalkyl.
  • W3 is O or S.
  • W4 is O or S.
  • R 15 is hydrogen, a substituted or unsubstituted C1-C12 alkyl group, a substituted or unsubstituted C6-C12 aryl-O-substituted or unsubstituted C1-C8 alkyl- group, a substituted or unsubstituted C1-C12 haloalkyl group, a substituted or unsubstituted C2-C10 alkenyl-substituted or unsubstituted C1-C6 alkyl-substituted or unsubstituted C2-C10 alkenyl-substituted or unsubstituted C1-C6 alkyl- group, a substituted or unsubstituted C2-C10 ester-substituted or unsubstituted C1-C8 alkyl- group, or...
  • R 15 is hydrogen, a substituted or unsubstituted C1-C10 alkyl group, a substituted or unsubstituted C6-C10 aryl-O-substituted or unsubstituted C1-C6 alkyl- group, a substituted or unsubstituted C1-C10 haloalkyl group, a substituted or unsubstituted C2-C8 alkenyl-substituted or unsubstituted C1-C4 alkyl-substituted or unsubstituted C2-C8 alkenyl-substituted or unsubstituted C1-C4 alkyl- group, a substituted or unsubstituted C2-C8 esteryl-substituted or unsubstituted C1-C6 alkyl- group, or
  • R 15 is hydrogen, a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C6-C8 aryl-O-substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C1-C8 haloalkyl group, a substituted or unsubstituted C2-C6 alkenyl-substituted or unsubstituted C1-C2 alkyl-substituted or unsubstituted C2-C6 alkenyl-substituted or unsubstituted C1-C2 alkyl group, a substituted or unsubstituted C2-C6 esteryl-substituted or unsubstituted C1-C4 alkyl group, or...
  • R 15 is hydrogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C6-C8 aryl-O-substituted or unsubstituted C2-C6 alkyl group, a substituted or unsubstituted C1-C8 haloalkyl group, a substituted or unsubstituted C2-C6 alkenyl-substituted or unsubstituted C1-C2 alkyl-substituted or unsubstituted C2-C6 alkenyl-substituted or unsubstituted C1-C2 alkyl group, a substituted or unsubstituted C2-C4 alkenyl-substituted or unsubstituted C1-C2 alkyl group, a substituted or unsubstituted C2-C6 esteryl-substituted or unsubstituted C
  • R 15 is hydrogen, methyl, propyl, decyl, phenyl-O-butyl-, halopropyl, halohexyl, butenyl-ethyl-propenyl-methyl-, vinyl-methyl-, pentyl-methyl-,
  • R16 is a substituted or unsubstituted C1-C12 alkyl group.
  • R 16 is a substituted or unsubstituted C1-C10 alkyl group.
  • R 16 is a substituted or unsubstituted C1-C8 alkyl group.
  • R 16 is a substituted or unsubstituted C1-C6 alkyl group.
  • R 16 is a substituted or unsubstituted C2-C6 alkyl group.
  • R16 is butyl
  • R16 is tert-butyl
  • R 17 is a substituted or unsubstituted C1-C12 alkylene group.
  • R 17 is a substituted or unsubstituted C1-C10 alkylene group.
  • R 17 is a substituted or unsubstituted C1-C8 alkylene group.
  • R 17 is a substituted or unsubstituted C2-C10 alkylene group.
  • R 17 is a substituted or unsubstituted C4-C8 alkylene group.
  • R 17 is hexanediol.
  • R 17 is a sub-hexyl group.
  • R 18 is hydrogen, or a substituted or unsubstituted C1-C4 alkyl, or a substituted or unsubstituted C3-C6 cycloalkyl.
  • R 18 is hydrogen
  • R 19 is hydrogen, or a substituted or unsubstituted C1-C4 alkyl, or a substituted or unsubstituted C3-C6 cycloalkyl.
  • R 19 is hydrogen
  • the butyl group is n-butyl.
  • the propyl group is n-propyl or isopropyl.
  • butyl is...
  • the pentyl group is...
  • the hexyl group is a normal hexyl group.
  • the hexyl group is...
  • the decyl group is a normal decyl group.
  • the dodecyl group is n-dodecyl.
  • the structure of the cyclopentyl group is as follows:
  • the structure of the tetrahydropyrrole group is as follows:
  • hexylene is...
  • the halogenated propyl group is a monohalogenated propyl group.
  • the halopropyl group is a monobromopropyl group.
  • the halopropyl group is...
  • the halohexyl group is a monohalohexyl group.
  • the halohexyl group is a monobromohexyl or a monochlorohexyl.
  • the halohexyl group is...
  • propyl ester-propyl- is
  • the pentyl ester-methyl group is...
  • phenyl-ethyl- structure is as follows:
  • the halogen is fluorine, chlorine, bromine, or iodine.
  • the aryl group is phenyl
  • the halogenation is monohalogenated, dihalogenated, trihalogenated, or fully halogenated.
  • the halogenation is fluorination, chlorination, bromination, or iodination.
  • the fluorination is monofluorinated, difluorinated, trifluorinated, or perfluorinated.
  • the chlorination is monochlorination, dichlorination, trichlorination, or perchlorination.
  • the bromination is monobrominated, dibrominated, tribrominated, or perbrominated.
  • the iodination is monoiodinated, diiodinated, triiodinated, or alliodinated.
  • the deuteration is a monodeuteration, a dideuteration, a trideuteration, or a full deuteration.
  • halogenation refers to the independent substitution of one or more (preferably 1, 2 or 3) hydrogen atoms on a group by a halogen.
  • any “substitution” refers to one or more (preferably 1, 2, 3, 4, 5, 6, 7 or 8) hydrogen atoms on a group being independently substituted by a substituent.
  • any “substitution” refers to one or more (preferably 1, 2, 3, 4, 5, 6, 7 or 8) hydrogen atoms on a group being independently substituted by substituents selected from the group consisting of: C1-C8 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C1-C8 haloalkyl, C3-C8 halocycloalkyl, C3-C8 cycloalkoxy, C3-C8 cycloalkylthio, C3-C8 halocycloalkoxy, C3-C8 halocycloalkylthio, halogen, hydroxyl, mercapto, amino, C2-C8 ester, C2-C8 amide, C1-C8 alkoxy, C1-C8 alkylthio, C1-C8 haloalkoxy, C1-C8 haloalkylthio, C6-C12 aryl, and 5-12 heteroaryl groups
  • any “substitution” refers to one or more (preferably 1, 2, 3, 4, 5, 6, 7 or 8) hydrogen atoms on a group being independently substituted by a substituent selected from the group consisting of: C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C3-C8 halocycloalkyl, C3-C8 cycloalkoxy, C3-C8 cycloalkylthio, C3-C8 halocycloalkoxy, C3-C8 halocycloalkylthio, halogen, hydroxyl, mercapto, amino, C2-C6 ester, C2-C6 amide, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkoxy, C1-C6 haloalkylthio, C6-C10 aryl, and 5-10 heteroaryl
  • any “substitution” refers to one or more (preferably 1, 2, 3, 4, 5, 6, 7 or 8) hydrogen atoms on a group being independently substituted by substituents selected from the group consisting of: C1-C4 alkyl, C3-C8 cycloalkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C3-C8 halocycloalkyl, C3-C8 cycloalkoxy, C3-C8 cycloalkylthio, C3-C8 halocycloalkoxy, C3-C8 halocycloalkylthio, halogen, hydroxyl, mercapto, amino, C2-C6 ester, C2-C6 amide, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 haloalkoxy, C1-C4 haloalkylthio, C6-C10 aryl, and 5-10 heteroaryl groups
  • heterocyclic alkyl, heteroaryl, and heterocyclic alkyl rings have 1 to 4 (preferably 1, 2, 3, or 4) heteroatoms, each independently selected from N, O, and S.
  • the heterocyclic alkyl group has 1 to 4 (preferably 1, 2, 3 or 4) heteroatoms, each independently selected from N, O and S.
  • the heterocyclic ring of the heteroaryl group has 1 to 4 (preferably 1, 2, 3 or 4) heteroatoms, each independently selected from N, O and S.
  • the heterocyclic ring has 1 to 4 (preferably 1, 2, 3 or 4) heteroatoms, each independently selected from N, O and S.
  • the compound of formula I has the structure described in formula I-1:
  • R1 , R2 , R3 , R4 , R5 , R6 , R7 , R8 , R9 , R10 , R11 , R14 , R19 , W3 , and W4 are as described above.
  • the compound of formula I has the structure described in formula I-2:
  • R1 , R2 , R3 , R4 , R5 , R8 , R9 , R10 , R11 , R14 , R18 , R19 , W1 , W2 , W3 and W4 are as described above.
  • the compound of formula I has the structure described in formula I-3:
  • R1 , R2 , R3 , R4 , R5 , R6 , R9 , R10 , R11 , R14 , R18 , R19 , W1 , W2 , W3 and W4 are as described above.
  • the compound of formula I, or its optical isomer, racemate, or pharmaceutically acceptable salt thereof has the structure shown in formula I-4:
  • R1 , R2 , R3 and R4 are each independently defined as above;
  • X - is an anionic salt radical.
  • X- is an anionic acid radical.
  • X- is a salt radical formed by the loss of an H + from an acid.
  • the pharmaceutically acceptable salt of the compound of formula I includes a salt formed by the compound of formula I and an acid.
  • the acid includes one or more of hydrochloric acid, viscous 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, benzenesulfonic acid, benzenesulfonic acid, trifluoromethanesulfonic acid, aspartic acid, and glutamic acid.
  • the pharmaceutically acceptable salt of the compound of formula I includes a salt formed by the compound of formula I with one or more of the following: hydrochloric acid, mucoic 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, benzenesulfonic acid, benzenesulfonic acid, trifluoromethanesulfonic acid, aspartic acid, and glutamic acid.
  • the salt radical of the pharmaceutically acceptable salt of the compound of formula I includes F- , Cl- , Br- , I- , HCOO- , CH3COO- , SO 4 2- , NO 3 - or
  • the compound is:
  • the tumor is a human tumor.
  • the tumor is a human tumor.
  • the tumor is an animal tumor.
  • the tumor is a mammalian tumor.
  • the tumor is a non-human mammalian tumor.
  • the tumor includes a tumor that highly expresses creatine kinase B.
  • the tumor with high creatine kinase B expression refers to a tumor from which creatine kinase B can be detected by creatine kinase B antibody detection in 20 ⁇ g of protein extracted from the tumor; more preferably, in 5 ⁇ g of protein extracted from the tumor; more preferably, in 1 ⁇ g of protein extracted from the tumor; more preferably, in 0.2 ⁇ g of protein extracted from the tumor; more preferably, in 0.05 ⁇ g of protein extracted from the tumor; and more preferably, in 0.01 ⁇ g of protein extracted from the tumor.
  • the tumor with high creatine kinase B expression refers to a tumor cell with a higher expression level of creatine kinase B than the same type of cell or normal cells.
  • the tumor with high expression of creatine kinase B refers to a tumor cell with an expression level E1 of creatine kinase B of E1 and an expression level E0 of creatine kinase B of E0 of the same type of cells or normal cells (E1/E0) > 1.0, preferably ⁇ 1.2, more preferably ⁇ 1.5, more preferably ⁇ 2, more preferably ⁇ 3, more preferably ⁇ 5, more preferably ⁇ 8, more preferably ⁇ 10, more preferably ⁇ 15, more preferably ⁇ 20, more preferably ⁇ 30, more preferably ⁇ 50, for example 2-50.
  • the same type of cells includes cells of the same species.
  • the same type of cells includes the same type of tumor cells.
  • the same type of cells includes the same type of tumor cells.
  • creatine kinase B is expressed normally, not expressed, or expressed at low levels in the same type of cells.
  • the same type of cells includes cells that express creatine kinase B normally, do not express it, or express it at low levels (such as the same type of tumor cells or the same kind of tumor cells).
  • the same type of cells includes the same type of tumor cells that express creatine kinase B normally, do not express it, or express it at low levels.
  • the same type of cells includes cells of the same species but which express creatine kinase B normally, not express it, or express it at low levels.
  • the normal cells include normal tissue cells (such as tumor-originating cells, tumor-adjacent cells, or adjacent cancer cells).
  • the normal cells include normal tissue cells that express creatine kinase B normally (such as tumor-originating cells, tumor-adjacent cells, or adjacent cancer cells).
  • E0 represents the expression level of creatine kinase B in cells that express creatine kinase B normally, do not express it, or express it at low levels.
  • the cells that express, do not express, or express low levels of creatine kinase B include cells that are insensitive to the compound of formula I, or its optical isomer, its racemic mixture, its solvate, its pharmaceutically acceptable salt, or its deuterated compound.
  • the tumor is selected from the group consisting of: lung cancer, kidney cancer, breast cancer, colon cancer, lymphoma, leukemia, pancreatic cancer, brain tumor, liver cancer, prostate cancer, or combinations thereof.
  • the lung cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, or a combination thereof.
  • the lung cancer cells comprise NCI-H82 cells.
  • the breast cancer cells comprise MDA-MB-453 cells.
  • the breast cancer includes triple-negative breast cancer.
  • the brain tumor is selected from the group consisting of glioblastoma, glioma, medulloblastoma, neuroblastoma, or combinations thereof.
  • the glioblastoma includes glioblastoma multiforme.
  • the renal cell carcinoma is selected from the group consisting of clear cell adenocarcinoma of the kidney, Wilms' renal cell carcinoma, or a combination thereof.
  • the cancer cells of the renal cell carcinoma include G-401 cells.
  • the pancreatic cancer includes pancreatic ductal carcinoma.
  • the expression includes protein expression and/or mRNA expression.
  • the levels include protein levels and/or mRNA levels.
  • the composition is a pharmaceutical composition.
  • composition or formulation further includes a pharmaceutically acceptable carrier.
  • the dosage form of the composition or preparation is a solid dosage form, a liquid dosage form, or a semi-solid dosage form.
  • the dosage form of the composition or preparation is an oral preparation, a topical preparation, or an injectable preparation.
  • the present invention provides a biomarker for determining whether a cancer patient is suitable for prevention and/or treatment of tumors using a compound of formula I as described in the first aspect of the present invention, or an optical isomer thereof, or a racemic mixture thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, said biomarker including creatine kinase B expression level.
  • the creatine kinase B expression level includes the creatine kinase B expression level in tumor cells.
  • the cancer patient is suitable for prevention and/or treatment with the compound of Formula I as described in the first aspect of the present invention, or its optical isomer, its racemic mixture, its solvate, its pharmaceutically acceptable salt, or its deuterated compound.
  • the cancer patient is not suitable for prevention and/or treatment using the compound of Formula I as described in the first aspect of this invention, or its optical isomer, its racemic mixture, its solvate, its pharmaceutically acceptable salt, or its deuterated compound.
  • the low or no expression of creatine kinase B refers to the ratio (E1/E0) of the expression level E1 of creatine kinase B in tumor cells to the expression level E0 of creatine kinase B in the same type of cells or normal cells ⁇ 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 ⁇ 0.005, more preferably ⁇ 0.001, more preferably ⁇ 0.0001, more preferably ⁇ 0.00001, more preferably ⁇ 0.000001, more preferably ⁇ 0.000001.
  • the present invention provides a detection kit, the detection kit comprising:
  • test sample of the test kit includes tumor cells.
  • the levels include protein levels and/or mRNA levels.
  • the expression includes the expression of mRNA and/or protein.
  • the present invention provides the use of a test kit as described in the third aspect of the invention for preparing a companion diagnostic kit, the companion diagnostic kit being used to determine whether a cancer patient is suitable for prevention and/or treatment with a compound of formula I as described in the first aspect of the invention, or an optical isomer thereof, or a racemic mixture thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof.
  • the companion diagnostic kit also includes instructions or labels.
  • the cancer patient is suitable for prevention and/or treatment with the compound of Formula I as described in the first aspect of the present invention, or its optical isomer, its racemic mixture, its solvate, its pharmaceutically acceptable salt, or its deuterated compound.
  • the cancer patient is not suitable for prevention and/or treatment using the compound of Formula I as described in the first aspect of this invention, or its optical isomer, its racemic mixture, its solvate, its pharmaceutically acceptable salt, or its deuterated compound.
  • the tumor patient is suitable to use a compound of formula I as described in the first aspect of the invention, or an optical isomer thereof, or a racemic mixture thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, which includes tumors of the tumor patient that are sensitive to a compound of formula I as described in the first aspect of the invention, or an optical isomer thereof, or a racemic mixture thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof.
  • the tumor patient is not suitable for use with compounds of formula I as described in the first aspect of the invention, or their optical isomers, racemates, solvates, pharmaceutically acceptable salts, or deuterated compounds, including tumors of the tumor patient that are insensitive to compounds of formula I as described in the first aspect of the invention, or their optical isomers, racemates, solvates, pharmaceutically acceptable salts, or deuterated compounds.
  • the present invention provides a medicine box, the medicine box comprising:
  • the sample being tested includes a tumor.
  • the medicine box also includes instructions or labels.
  • the cancer patient is suitable for prevention and/or treatment with the compound of Formula I as described in the first aspect of the present invention, or its optical isomer, its racemic mixture, its solvate, its pharmaceutically acceptable salt, or its deuterated compound.
  • the cancer patient is not suitable for prevention and/or treatment using the compound of Formula I as described in the first aspect of this invention, or its optical isomer, its racemic mixture, its solvate, its pharmaceutically acceptable salt, or its deuterated compound.
  • the present invention provides the use of a medicine box as described in the fifth aspect of the present invention for preparing a medicine box for the prevention and/or treatment of tumors.
  • the medicine box also includes instructions or labels.
  • the cancer patient is suitable for prevention and/or treatment with the compound of Formula I as described in the first aspect of the present invention, or its optical isomer, its racemic mixture, its solvate, its pharmaceutically acceptable salt, or its deuterated compound.
  • the cancer patient is not suitable for prevention and/or treatment using the compound of Formula I as described in the first aspect of this invention, or its optical isomer, its racemic mixture, its solvate, its pharmaceutically acceptable salt, or its deuterated compound.
  • a seventh aspect of the present invention provides a method for preventing and/or treating tumors, the method comprising: administering to a desired subject a compound of formula I as described in the first aspect of the present invention, or an optical isomer thereof, or a racemic mixture thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, thereby preventing and/or treating tumors.
  • the tumor is as described in the first aspect of the invention.
  • the object is a human or non-human mammal (rodents, rabbits, monkeys, livestock, dogs, cats, etc.).
  • the method includes the steps of:
  • creatine kinase B is highly expressed in the target tumor, and then the tumor is prevented and/or treated by administering the compound of Formula I, or its optical isomer, its racemic mixture, its solvate, its pharmaceutically acceptable salt, or its deuterated compound.
  • the method includes the steps of:
  • the subject is given a creatine kinase B promoter to achieve high expression of creatine kinase B in the subject's tumor.
  • the compound of Formula I, or its optical isomer, its racemic mixture, its solvate, its pharmaceutically acceptable salt, or its deuterated compound is administered to prevent and/or treat the tumor.
  • the promoter includes a specific promoter.
  • the creatine kinase B promoter includes a promoter capable of causing high expression of creatine kinase B in tumors.
  • An eighth aspect of the present invention provides an apparatus or system comprising:
  • a detection module wherein the detection module is used to detect the expression level of creatine kinase B;
  • the cancer patient is suitable for prevention and/or treatment with the compound of Formula I as described in the first aspect of this invention, or its optical isomer, its racemic mixture, its solvate, its pharmaceutically acceptable salt, or its deuterated compound; and/or
  • the cancer patient is not suitable for prevention and/or treatment using the compound of Formula I as described in the first aspect of this invention, or its optical isomer, its racemic mixture, its solvate, its pharmaceutically acceptable salt, or its deuterated compound.
  • the sample being tested includes tumor cells.
  • the device includes a gene analyzer or a protein analyzer.
  • the device or system further includes a sample introduction module.
  • the sample introduction module is used to introduce tumor cell extracts.
  • the device or system further includes a data processing module.
  • the data processing module processes data to determine the level of creatine kinase B expression.
  • the present invention provides the use of a creatine kinase B promoter for preparing a composition or formulation, said composition or formulation for enhancing the antitumor effect of an antitumor drug.
  • the antitumor drug is a compound of Formula I as described in the first aspect of the invention, or an optical isomer thereof, a racemic mixture thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, or a deuterated compound thereof.
  • the creatine kinase B promoter includes a promoter capable of causing high expression of creatine kinase B in tumors.
  • the promoter includes a specific promoter.
  • the tumor is as described in the first aspect of the invention.
  • composition or formulation is a pharmaceutical composition or pharmaceutical formulation.
  • composition or formulation further includes a pharmaceutically acceptable carrier.
  • the dosage form of the composition or preparation is a solid dosage form, a liquid dosage form, or a semi-solid dosage form.
  • the dosage form of the composition or preparation is an oral preparation, a topical preparation, or an injectable preparation.
  • the present invention provides an active ingredient combination comprising the following components:
  • a first active ingredient said first active ingredient including an antitumor drug
  • a second active ingredient wherein the second active ingredient includes a creatine kinase B promoter.
  • the antitumor drug is a compound of Formula I as described in the first aspect of the invention, or an optical isomer thereof, a racemic mixture thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, or a deuterated compound thereof.
  • the creatine kinase B promoter includes a promoter capable of causing high expression of creatine kinase B in tumors.
  • the promoter includes a specific promoter.
  • the molar ratio of the first active ingredient to the second active ingredient is 0.01-600:1, more preferably 0.05-500:1, more preferably 0.1-400:1, more preferably 0.2-200:1, more preferably 0.5-100:1, more preferably 0.5-80:1, and most preferably 1-50:1.
  • At least one of the active ingredients in the combination of active ingredients is independent.
  • the first active ingredient and the second active ingredient in the combination of active ingredients are independent of each other.
  • composition comprising:
  • a first active ingredient said first active ingredient including an antitumor drug
  • a second active ingredient wherein the second active ingredient includes a creatine kinase B promoter.
  • the antitumor drug is a compound of Formula I as described in the first aspect of the invention, or an optical isomer thereof, a racemic mixture thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, or a deuterated compound thereof.
  • the creatine kinase B promoter includes a promoter capable of causing high expression of creatine kinase B in tumors.
  • the promoter includes a specific promoter.
  • the composition is a pharmaceutical composition.
  • the pharmaceutical composition further includes a pharmaceutically acceptable carrier.
  • the dosage form of the composition is a solid dosage form, a liquid dosage form, or a semi-solid dosage form.
  • the dosage form of the composition is an oral preparation, a topical preparation, or an injectable preparation.
  • the content of the first active ingredient is 0.01-99.99 wt%, more preferably 0.1-99.9 wt%, more preferably 1-99 wt%, more preferably 10-99 wt%, and most preferably 20-99 wt%, based on the total weight of the active ingredients in the composition.
  • the content of the second active ingredient is 0.01-99.99 wt%, more preferably 0.1-99.9 wt%, more preferably 1-99 wt%, more preferably 10-99 wt%, and most preferably 20-99 wt%, based on the total weight of the active ingredients in the composition.
  • a medicine box comprising:
  • the antitumor drug is a compound of Formula I as described in the first aspect of the invention, or an optical isomer thereof, a racemic mixture thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, or a deuterated compound thereof.
  • the creatine kinase B promoter includes a promoter capable of causing high expression of creatine kinase B in tumors.
  • the promoter includes a specific promoter.
  • the medicine box also includes an instruction manual.
  • the first and second formulations are independent formulations.
  • first and second formulations are combined formulations.
  • the instructions for use specify that the first formulation and the second formulation are used in combination to enhance the antitumor activity of the antitumor drug.
  • the combined method involves first administering a second formulation containing a creatine kinase B promoter, followed by the administration of an antitumor drug.
  • a method for inhibiting tumor cells comprising the step of contacting tumor cells with a compound of formula I as described in the first aspect of the present invention, or an optical isomer thereof, or a racemic mixture thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, thereby inhibiting tumor cells.
  • the method is an in vitro method or an in vitro method.
  • the method for inhibiting tumor cells includes in vitro, non-therapeutic, and non-diagnostic methods for inhibiting tumor cells.
  • the contact is an in vitro culture contact.
  • the tumor is as described in the first aspect of the invention.
  • Figure 1 shows the expression levels of creatine kinase B in NCI-H82 cells, G-401 cells, MDA-MB-453 cells, 786-O cells, CFPAC-1 cells, and SF126 cells.
  • FIG. 2 shows the expression level of creatine kinase B (CKB) in NCI-H82-shCON cells and NCI-H82-shCKB cells as detected by Western blotting.
  • shCON represents the creatine kinase B expression level in NCI-H82 cells transfected with an empty viral vector that does not carry shRNA specifically knocking down creatine kinase B, serving as a control.
  • shCKB represents the creatine kinase B expression level in NCI-H82 cells transfected with a viral vector carrying shRNA specifically knocking down creatine kinase B.
  • FIG. 3 shows the relative cell viability of NCI-H82-shCON cells and NCI-H82-shCKB cells.
  • shCON represents the cell viability of NCI-H82 cells transfected with an empty viral vector that does not carry shRNA specifically knocking down creatine kinase B, serving as a control.
  • shCKB represents the cell viability of NCI-H82 cells transfected with a viral vector carrying shRNA specifically knocking down creatine kinase B.
  • the inventors unexpectedly discovered for the first time that tumors with high creatine kinase B expression are highly sensitive to the compounds of this invention. That is, the compounds of this invention have superior therapeutic effects on tumors with high creatine kinase B expression. Therefore, the compounds of this invention have excellent precision therapeutic effects on tumors with high creatine kinase B expression, and creatine kinase B can serve as a biomarker for determining whether tumor patients are suitable for precision prevention and/or treatment using the compounds of this invention. Based on this, the inventors completed this invention.
  • the terms “comprising,” “including,” and “containing” are used interchangeably and include not only open-ended definitions but also semi-closed and closed definitions. In other words, the terms include “consisting of” and “substantially consisting of”.
  • anticancer drugs As used in this article, the terms “anticancer drugs” and “antitumor drugs” are used interchangeably.
  • cancer As used in this article, the terms “cancer,” “cancer,” “tumor,” and “tumor” are used interchangeably.
  • a cell refers to a single cell (such as a single cancer cell) or a group of cells containing multiple similar cells (such as a tumor tissue).
  • suitable for use by cancer patients includes cancer patients whose tumors are sensitive to the compounds of the present invention.
  • cancer patients are not suitable for use with the compounds of the present invention
  • IC50 and “IC 50 ” are used interchangeably and refer to the half-inhibiting concentration (50% inhibiting concentration), which is the concentration of the inhibitor at which 50% inhibition is achieved.
  • P/S refers to the addition of penicillin and streptomycin to the relevant culture medium.
  • CKB Creatine kinase B
  • solvent refers to a complex formed by the coordination of a compound with a solvent molecule in a specific ratio.
  • deuterated refers to the substitution of one or more hydrogen atoms in a compound or group by deuterium. Deuteration can be monosubstituted, disubstituted, polysubstituted, or total substituted.
  • MS-ESI electrospray ionization mass spectrometry
  • 1H NMR refers to the hydrogen nuclear magnetic resonance spectrum.
  • substitution refers to a compound in which a hydrogen atom on a group is replaced by a non-hydrogen group, but the substitution must satisfy the valence requirement and the substitution produces a chemically stable compound, i.e., a compound that does not spontaneously undergo transformations such as cyclization or elimination.
  • alkyl refers to a straight-chain (i.e., unbranched) or branched saturated hydrocarbon group containing only carbon and hydrogen atoms, or a combination of straight and branched groups.
  • a carbon number qualifier e.g., C1-C6 alkyl
  • C1-C4 alkyl refers to an alkyl group containing 1-4 carbon atoms.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, or similar groups.
  • alkylene refers to a group formed by removing one hydrogen atom from an alkyl group, as defined above.
  • a carbon number qualifier e.g., C1-C6 alkylene
  • C1-C4 alkylene groups refer to alkylene groups containing 1-4 carbon atoms.
  • Representative examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, tert-butylene, or similar groups.
  • alkenyl refers to a hydrocarbon group formed by removing one hydrogen atom from a straight-chain or branched olefin molecule having one or more double bonds.
  • a carbon number qualifier e.g., C2-C6 alkenyl
  • C2-C4 alkenyl refers to an alkenyl group containing 2-4 carbon atoms.
  • halogen refers to F, Cl, Br, or I.
  • halogenated refers to the substitution of one or more (preferably 1, 2 or 3) hydrogen atoms on a group by a halogen.
  • haloalkyl refers to an alkyl group in which one or more (preferably 1, 2, 3, or 4) hydrogen atoms are substituted with a halogen, wherein the alkyl group and the halogen are as defined above.
  • a number of carbon atoms is specified before the haloalkyl group (e.g., C1-C8 haloalkyl), it refers to the number of carbon atoms contained in the haloalkyl group (e.g., 1-8).
  • C1-C6 haloalkyl refers to a haloalkyl group containing 1-6 carbon atoms.
  • Representative examples of haloalkyl groups include, but are not limited to, -CF3 , -CHF2 , monofluoroisopropyl, difluorobutyl, or similar groups.
  • cycloalkyl refers to a cyclic carbonyl group having a saturated or partially saturated monocyclic, bicyclic, or polycyclic (fused, bridged, or spirocyclic) ring.
  • a carbon number qualifier e.g., C3-C12
  • it refers to the number of ring carbon atoms (e.g., 3-12) of the cycloalkyl group.
  • 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 refers to a bicyclic or polycyclic group in which monocyclic rings share a single carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has a fully conjugated ⁇ -electron system.
  • “Fused cycloalkyl” refers to an all-carbon bicyclic or polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with the other rings in the system, wherein one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated ⁇ -electron system.
  • “Bridged cycloalkyl” refers to a fully carbon polycyclic group in which any two rings share two non-directly bonded carbon atoms. These rings may contain one or more double bonds, but none of them have a fully conjugated ⁇ -electron system.
  • halocycloalkyl refers to a cycloalkyl group in which one or more (preferably 1, 2, 3, or 4) hydrogen atoms are substituted with a halogen, the cycloalkyl group and the halogen being as defined above.
  • a number of carbon atoms is specified before the cycloalkyl group (e.g., C3-C8 cycloalkyl), it refers to the number of ring carbon atoms contained in the cycloalkyl group (e.g., 3-8 ring carbon atoms).
  • C3-C8 cycloalkyl refers to a cycloalkyl group containing 3-8 ring carbon atoms.
  • Representative examples of cycloalkyl groups include, but are not limited to, monofluorocyclopropyl, monochlorocyclobutyl, monofluorocyclopentyl, difluorocycloheptyl, or similar groups.
  • alkoxy refers to an R-O- group, where R is an alkyl group, and the alkyl group is as defined above herein, where the alkoxy group is preceded by a carbon number qualifier, such as C1-C8 alkoxy, which means that the alkyl group in the alkoxy group has 1-8 carbon atoms.
  • Representative examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, or similar groups.
  • alkathio refers to an R-S- group, where R is an alkyl group, and the alkyl group is as defined above.
  • a carbon number qualifier such as C1-C8 alkathio
  • alkathio groups include, but are not limited to: methylthio, ethylthio, n-propylthio, isopropylthio, tert-butylthio, or similar groups.
  • haloalkoxy refers to a haloalkyl group -O-, as defined above, where the haloalkoxy group is preceded by a carbon number definiteness, for example, C1-C6 haloalkoxy refers to a C1-C6 haloalkyl group -O-, i.e., a haloalkoxy group containing 1-6 carbon atoms.
  • Representative examples of haloalkoxy groups include, but are not limited to, monofluoromethoxy, monofluoroethoxy, difluorobutoxy, or similar groups.
  • haloalkylthio refers to a haloalkyl group -S-, as defined above, where the haloalkylthio group is preceded by a carbon number definiteness, for example, C1-C6 haloalkylthio refers to a C1-C6 haloalkyl group -S-, i.e., a haloalkylthio group containing 1-6 carbon atoms.
  • Representative examples of haloalkylthio groups include, but are not limited to: monofluoromethylthio, monofluoroethylthio, difluorobutylthio, or similar groups.
  • cycloalkoxy refers to an R-O- group, where R is a cycloalkyl group, and the cycloalkyl group is as defined above herein.
  • a carbon number qualifier such as C3-C8 cycloalkoxy
  • cycloalkyl group in the cycloalkoxy group has 3-8 cyclic carbon atoms.
  • Representative examples of cycloalkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, or similar groups.
  • cycloalkylthio refers to an R-S-group, where R is a cycloalkyl group, and the cycloalkyl group is as defined above.
  • R is a cycloalkyl group
  • the cycloalkyl group is as defined above.
  • a carbon number qualifier such as C3-C8 cycloalkylthio
  • cycloalkylthio groups include, but are not limited to, cyclopropylthio, cyclobutylthio, or similar groups.
  • halocycloalkoxy refers to a cycloalkoxy group in which one or more (preferably 1, 2, 3, or 4) hydrogen atoms are substituted with a halogen, wherein the cycloalkoxy group and the halogen are as defined above.
  • a number of carbon atoms e.g., C3-C8 cycloalkoxy
  • it refers to the number of ring carbon atoms contained in the cycloalkoxy group (e.g., 3-8).
  • C3-C8 cycloalkoxy refers to a cycloalkoxy group containing 3-8 ring carbon atoms.
  • cycloalkoxy groups include, but are not limited to: monofluorocyclopropyl-O-, monochlorocyclobutyl-O-, monofluorocyclopentyl-O-, difluorocycloheptyl-O-, or similar groups.
  • halocycloalkylthio refers to a cycloalkylthio group in which one or more (preferably 1, 2, 3, or 4) hydrogen atoms are replaced by a halogen, the cycloalkylthio group and the halogen being as defined above.
  • a carbon number limitation e.g., C3-C8 cycloalkylthio
  • C3-C8 cycloalkylthio refers to a cycloalkylthio group containing 3-8 cyclic carbon atoms.
  • Representative examples of cycloalkylthio groups include, but are not limited to: monofluorocyclopropyl-S-, monochlorocyclobutyl-S-, monofluorocyclopentyl-S-, difluorocycloheptyl-S-, or similar groups.
  • heterocyclic alkane refers to a fully saturated or partially unsaturated ring (including, but not limited to, 3-7 membered monocyclic rings, 7-11 membered bicyclic rings, or 8-16 membered tricyclic ring systems), wherein at least one heteroatom is present in a ring with at least one carbon atom.
  • a heterocyclic alkane is preceded by a member number, it refers to the number of ring atoms in the heterocyclic alkane; for example, a 3-16 membered heterocyclic alkane refers to a heterocyclic alkane with 3-16 ring atoms.
  • Each heterocyclic ring containing a heteroatom may have one or more (e.g., 1, 2, 3, or 4) heteroatoms, each independently selected from nitrogen, oxygen, or sulfur atoms, wherein the nitrogen or sulfur atom may be oxidized or quaternized.
  • Typical monocyclic heterocyclic alkane rings include, but are not limited to, azirrobutane rings, oxobutane rings, tetrahydrofuran rings, piperidine rings, piperazine rings, etc.
  • Polycyclic heterocyclic alkane rings include spirocyclic, fused, and bridged rings; the spirocyclic, fused, and bridged heterocyclic alkane rings involved may optionally be connected to other rings by single bonds, or may be further cyclically connected to other cycloalkane rings or heterocyclic alkane rings by any two or more atoms on the ring.
  • heterocyclic alkyl refers to a fully saturated or partially unsaturated cyclic group (including, but not limited to, 3-7 membered monocyclic, 7-11 membered bicyclic, or 8-16 membered tricyclic systems) in which at least one heteroatom is present in a ring with at least one carbon atom, and the group's linking site is located on the ring containing the heteroatom.
  • a heterocyclic alkyl group is preceded by a number, it refers to the number of ring atoms in the heterocyclic alkyl group; for example, 3-16 membered heterocyclic alkyl refers to a heterocyclic alkyl group having 3-16 ring atoms.
  • Each heterocyclic ring containing a heteroatom may have one or more (e.g., 1, 2, 3, or 4) heteroatoms, each independently selected from nitrogen, oxygen, or sulfur atoms, wherein the nitrogen or sulfur atom may be oxidized or quaternized.
  • Typical monocyclic heterocyclic alkyl groups include, but are not limited to, azirrocyclic butyl, oxocyclic butyl, tetrahydrofuranyl, piperidinyl, and piperazineyl.
  • Polycyclic heterocyclic alkyl groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups; wherein the spirocyclic, fused-ring, and bridged-ring heterocyclic alkyl groups involved are optionally connected to other groups by single bonds, or further cyclically linked to other cycloalkane rings or heterocyclic alkyl rings by any two or more atoms on the ring.
  • aryl refers to an all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group with a conjugated ⁇ -electron system. It is an aromatic cyclic hydrocarbon compound group. When the aryl group is preceded by a carbon number limit, it means that the aryl group has a number of ring carbon atoms. For example, C6-C12 aryl means that the aryl group has 6-12 ring carbon atoms, such as phenyl and naphthyl.
  • heteroaryl refers to an aromatic heterocyclic group having one to several (preferably 1, 2, 3, or 4) cyclic heteroatoms, wherein at least one heteroatom is present in a ring containing at least one carbon atom.
  • This heteroatom can be monocyclic (monocyclic) or polycyclic (bicyclic, tricyclic, or polycyclic) groups fused together or covalently linked.
  • Each heterocycle containing a heteroatom may have one or more (e.g., 1, 2, 3, or 4) heteroatoms independently selected from the group consisting of oxygen, sulfur, and nitrogen.
  • heteroaryl refers to the number of ring atoms in the heteroaryl group; for example, a 5-12 member heteroaryl refers to a heteroaryl group having 5-12 ring atoms.
  • Representative examples of heteroaryl groups include, but are not limited to, pyrrole, pyrazolyl, imidazolyl, thiazolyl, furanyl, pyridinyl, and pyrimidinyl.
  • ester group refers to a group having an RC(O)-O- or -C(O)-OR group, where R is an alkyl group, and the alkyl group is as defined above, for example, " C2 - C4 ester group” refers to a group with a C1 - C3 alkyl-C(O)-O- structure or a group with a -C(O) -OC1 - C3 alkyl structure.
  • ester groups include, but are not limited to: CH3C (O)O-, C2H5C (O)O-, ( CH3 ) 2CHC (O) O- , -C(O)OCH3, -C( O ) OC2H5 , or similar groups.
  • amide group refers to a group having an RC(O)-NH- group or a -C(O)-NH-R group, where R is an alkyl group, and the alkyl group is as defined above herein, for example, “ C2 - C4 amide group” refers to a group with a C1 - C3 alkyl-C(O)-NH- structure or a group with a -C(O)-NH- C1 - C3 alkyl structure.
  • amide groups include, but are not limited to: CH3C (O) -NH- , C2H5C (O)-NH-, ( CH3 ) 2CHC (O)-NH-, -C(O)-NH- CH3 , -C(O)-NH- C2H5 , or similar groups.
  • amino is -NH2 , either alone or as part of other substituents.
  • hydroxyl group is -OH, whether used alone or as part of other substituents.
  • thiol is -SH, whether alone or as part of other substituents.
  • substituents should be interpreted as unsubstituted unless explicitly described herein as “substituted”.
  • substituted means that one or more hydrogen atoms on a group are each independently substituted by a substituent. Substituents may be those described accordingly above or those appearing in the various embodiments. Unless otherwise specified, an arbitrary substituted group may be substituted at any substituted site on that group, and the substituents may be the same or different at each position.
  • prevention refers to a method of preventing the onset of a disease and/or its accompanying symptoms or protecting a subject from acquiring a disease.
  • prevention also includes delaying the onset of a disease and/or its accompanying symptoms and reducing the subject's risk of contracting the disease.
  • the term "treatment” includes delaying and halting the progression of a disease, or eliminating the disease, and does not require 100% inhibition, eradication, and reversal.
  • the compounds of this invention reduce, inhibit, and/or reverse the associated disease (such as a tumor) and its complications by, for example, at least about 30%, at least about 50%, or at least about 80%, at least about 90%, or 100%, compared to levels observed in the absence of the compounds described in this invention.
  • the terms "compound of the present invention,” “compound of the present invention,” “compound of formula I of the present invention,” or “compound of formula I” are used interchangeably to refer to a compound having the structure of formula I, or an optical isomer thereof, or a racemic mixture thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof. It should be understood that the term also includes mixtures of the foregoing components.
  • the compound of formula I or its optical isomer, its racemate, its solvate, its pharmaceutically acceptable salt, or its deuterated compound, is as described in the first aspect of the present invention above.
  • the compounds of Formula I described in this invention are specific compounds (including their salt-forming forms or free forms without salt radicals) as described in the embodiments of this invention.
  • the compounds of Formula I described in this invention can be converted into their pharmaceutically acceptable salts by conventional methods.
  • a solution of the corresponding acid can be added to a solution of the above-mentioned compound, and after complete salt formation, the solvent can be removed to obtain the corresponding salt of the compound described in this invention.
  • creatine kinase B is called creatine kinase B, abbreviated as CKB.
  • Tumors with high expression of creatine kinase B are sensitive to the compounds described in this invention. Therefore, the compounds described in this invention have excellent precision therapeutic effects on tumors with high expression of creatine kinase B.
  • the tumor with high expression of creatine kinase B is as described in the first aspect of the present invention.
  • the low or no expression of creatine kinase B refers to the ratio (E1/E0) of the expression level E1 of creatine kinase B in tumor cells to the expression level E0 of creatine kinase B in the same type of cells or normal cells being ⁇ 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 ⁇ 0.005, more preferably ⁇ 0.001, more preferably ⁇ 0.0001, more preferably ⁇ 0.00001, more preferably ⁇ 0.000001, more preferably ⁇ 0.000001.
  • the tumor described herein includes tumors that highly express creatine kinase B.
  • the tumors with high expression of creatine kinase B described in this invention are as described in the first aspect of this invention above.
  • the tumor described in this invention is as described in the first aspect of this invention above.
  • the antitumor drug may be a compound of formula I as described in this invention, or an optical isomer thereof, or a racemic mixture thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof.
  • This invention provides the use of the compound described herein in the prevention and/or treatment of tumors.
  • tumors with high creatine kinase B expression are highly sensitive to the compound of this invention, meaning that the compound of this invention has a superior therapeutic effect on tumors with high creatine kinase B expression. Therefore, the compound of this invention has excellent precision therapeutic effects on tumors with high creatine kinase B expression.
  • the present invention also provides a method for preventing and/or treating tumors by administering the compound described herein to the desired subject.
  • the compound of the present invention has a more significant and superior preventive and therapeutic effect on tumors with high expression of creatine kinase B.
  • a creatine kinase B promoter can be administered to the subject first to make the subject's tumor highly express creatine kinase B, and then the compound of the present invention can be administered to prevent and/or treat the tumor, thereby more significantly preventing and/or treating the tumor.
  • the object is a human or non-human mammal (rodents, rabbits, monkeys, livestock, dogs, cats, etc.).
  • the present invention also provides a biomarker for determining whether a cancer patient is suitable for prevention and/or treatment with the compounds described herein, the biomarker including creatine kinase B expression level.
  • the expression level of creatine kinase B is used as a biomarker to determine whether a cancer patient is suitable for prevention and/or treatment with the compounds described in the present invention, and the methods include, but are not limited to:
  • the cancer patient is suitable for prevention and/or treatment with the compound of Formula I as described in the first aspect of this invention, or its optical isomer, its racemic mixture, its solvate, its pharmaceutically acceptable salt, or its deuterated compound; and/or
  • the cancer patient is not suitable for prevention and/or treatment using the compound of Formula I as described in the first aspect of this invention, or its optical isomer, its racemic mixture, its solvate, its pharmaceutically acceptable salt, or its deuterated compound.
  • the tumors with high expression of creatine kinase B described in this invention are as described in the first aspect of this invention above.
  • compositions or formulations, combinations of active ingredients, and packaging and administration methods are provided.
  • compositions described in this invention are preferably pharmaceutical compositions, and may include pharmaceutically acceptable carriers.
  • pharmaceutically acceptable carrier refers to one or more compatible solid, semi-solid, liquid, or gel fillers that are suitable for human or animal use and must have sufficient purity and sufficiently low toxicity.
  • Cosmetic means that the components and active ingredients in the composition, as well as the interactions between them, do not significantly reduce the efficacy of the drug.
  • pharmaceutically acceptable carriers used; materials commonly used in the art can be selected, or they can be prepared using conventional methods or purchased from the market.
  • pharmaceutically acceptable carriers include cellulose and its derivatives, gelatin, talc, solid lubricants, calcium sulfate, vegetable oils, polyols, emulsifiers, wetting agents, buffers, chelating agents, thickeners, pH adjusters, colorants, flavoring agents, stabilizers, antioxidants, preservatives, antibacterial agents, and pyrogen-free water, etc.
  • the dosage form of the composition or preparation is a solid dosage form, a liquid dosage form, or a semi-solid dosage form.
  • the dosage form of the composition or preparation is an oral preparation, a topical preparation, or an injectable preparation.
  • the dosage form of the composition or preparation is a tablet, injection, infusion, ointment, gel, solution, microsphere or film.
  • the pharmaceutical formulation should be matched with the route of administration.
  • the pharmaceutical formulation of this invention can also be used with other synergistic therapeutic agents (including before, during, or after administration).
  • a safe and effective amount of the drug is administered to the desired subject (such as a human or non-human mammal), said safe and effective amount generally being at least about 10 micrograms per kilogram of body weight, and in most cases not exceeding about 8 milligrams per kilogram of body weight, preferably about 10 micrograms per kilogram of body weight to about 1 milligram per kilogram of body weight.
  • the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are within the scope of the skill of a skilled physician.
  • This invention unexpectedly reveals for the first time that tumors with high creatine kinase B expression are highly sensitive to the compounds of this invention, meaning that the compounds of this invention have superior therapeutic effects on tumors with high creatine kinase B expression. Therefore, the compounds of this invention have excellent precision treatment effects on tumors with high creatine kinase B expression, and creatine kinase B can serve as a biomarker for determining whether tumor patients are suitable for precision prevention and/or treatment using the compounds of this invention. Precision treatment of tumors with high creatine kinase B expression using the compounds of this invention can improve the therapeutic effect on tumors and avoid administering the compounds of this invention to tumor patients who are not sensitive to them.
  • precision treatment of tumors with high creatine kinase B expression using the compounds of this invention has advantages such as superior therapeutic effect on tumors, lower drug dosage, and fewer side effects. While improving the precision treatment effect of the compounds of this invention on tumors, it can reduce side effects and improve patient compliance.
  • the synthesis method is as follows:
  • the synthesis method is as follows:
  • the synthesis method is as follows:
  • the synthesis method is as follows:
  • AB43505 was acquired through commercial purchase.
  • Methylberberine was obtained through commercial purchase.
  • This embodiment examines the sensitivity of cells with different creatine kinase B (CKB) expression levels to the compounds of this invention.
  • CKB creatine kinase B
  • NCI-H82 cells human small cell lung cancer cells
  • G-401 cells human renal cancer Wilms cells
  • MDA-MB-453 cells breast cancer cells
  • 786-O cells renal clear cell adenocarcinoma cells
  • CFPAC-1 cells human pancreatic cancer cells
  • SF126 cells human glioblastoma cells
  • creatine kinase B was highly expressed in NCI-H82, G-401, and MDA-MB-453 cells compared to 786-O, CFPAC-1, and SF126 cells.
  • the Promega CellTiter-Glo cell viability assay kit was used. This kit directly detects cell viability by measuring intracellular ATP content. The IC50 values of the compounds in this invention were used to detect the inhibitory effects of different expression levels of creatine kinase B on the viability of tumor cells.
  • Cell line NCI-H82 (ATCC, HTB-175) was cultured in RPMI 1640 medium (+P/S) containing 10% fetal bovine serum;
  • Cell line G-401 (ATCC, number CRL-1441) was cultured in McCoy’s 5a medium (+P/S) containing 10% fetal bovine serum;
  • the cell line MDA-MB-453 (ATCC, HTB-131) was cultured in Leibovitz's L-15 medium (+P/S) containing 10% fetal bovine serum;
  • Cell line 786-O (ATCC, number CRL-1932) was cultured in RPMI 1640 medium (+P/S) containing 10% fetal bovine serum;
  • the cell line CFPAC-1 (ATCC, number CRL-1918) was cultured in IMDM medium (+P/S) containing 10% fetal bovine serum;
  • Cell line SF126 (JCRB, ID: IFO50286) was cultured in EMEM medium (+P/S) containing 10% fetal bovine serum.
  • IC 50 is the half-inhibiting concentration, which is the concentration of the inhibitory compound required to achieve a 50% inhibitory effect.
  • Creatine kinase B expression in NCI-H82 cells was knocked down by transfecting a viral vector with shRNA specifically designed to knock down creatine kinase B (the nucleotide sequence of the shRNA is CCCTGCTGCTTCCTAACTTAT (SEQ ID No: 1)), resulting in NCI-H82 cells with low creatine kinase B expression (NCI-H82-shCKB cells).
  • NCI-H82 cells transfected with an empty viral vector without shRNA specifically designed to knock down creatine kinase B (NCI-H82-shCON cells) served as a control.
  • NCI-H82-shCON cells and NCI-H82-shCKB cells were detected using the Promega CellTiter-Glo cell viability assay kit (which measures cell viability by detecting intracellular ATP content). The results are shown in Figure 3. As can be seen from Figure 3, the viability of NCI-H82-shCON cells and NCI-H82-shCKB cells was almost identical, and the difference in cell viability was not statistically significant.
  • the Promega CellTiter-Glo cell viability assay kit was used. This kit directly detects cell viability by measuring intracellular ATP content.
  • the IC50 values of the compounds in this embodiment of the invention were used to detect the inhibitory effects of the compounds on the viability of NCI-H82-shCON cells constructed in the above steps and NCI-H82 cells with low creatine kinase B expression (i.e., NCI- H82 -shCKB cells).
  • NCI-H82-shCON cells and NCI-H82 cells with low creatine kinase B expression constructed in the above steps were cultured in RPMI 1640 medium (+P/S) containing 10% fetal bovine serum.
  • the half-inhibitory concentrations ( IC50 ) of each compound in this embodiment of the invention for these two cell types were determined.
  • the experimental results are shown in Table 3.
  • IC50 is the half-inhibiting concentration (50%), which is the concentration of the inhibitory compound required to achieve a 50% inhibitory effect
  • NCI-H82-shCON cells are NCI-H82 cells transfected with an empty viral vector that does not carry shRNA that specifically knocks down creatine kinase B, serving as a control
  • NCI-H82-shCKB cells are NCI-H82 cells transfected with a viral vector that carries shRNA that specifically knocks down creatine kinase B, in which creatine kinase B is expressed at low levels.
  • NCI-H82 cells NCI-H82-shCKB cells
  • NCI-H82-shCKB cells NCI-H82-shCKB cells
  • NCI-H82-shCON cells with high creatine kinase B expression showed strong sensitivity to the compounds of the embodiments of the present invention.
  • the expression level of creatine kinase B in tumor cells is significantly positively correlated with their sensitivity to the compounds of the present invention. Therefore, the compounds of the embodiments of the present invention have excellent precision therapeutic effects on tumor cells with high creatine kinase B expression.

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Abstract

La présente invention concerne l'utilisation antitumorale d'un composé hétérocyclique contenant de l'azote. Plus particulièrement, la présente invention concerne l'utilisation d'un composé de formule (I), d'un isomère optique de celui-ci, d'un racémate de celui-ci, d'un solvate de celui-ci, d'un sel pharmaceutiquement acceptable de celui-ci, ou d'un composé deutéré de celui-ci, pour préparer une composition ou une formulation, la composition ou la formulation étant utilisée pour prévenir et/ou traiter des tumeurs. Le composé décrit dans la présente invention possède un effet thérapeutique précis, notable et excellent sur les tumeurs présentant une expression élevée de créatine kinase B.
PCT/CN2025/094990 2024-05-16 2025-05-15 Utilisation antitumorale de composé hétérocyclique contenant de l'azote Pending WO2025237352A1 (fr)

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