WO2022247785A1 - Utilisation d'un inhibiteur de la kinase 9 cycline-dépendante - Google Patents

Utilisation d'un inhibiteur de la kinase 9 cycline-dépendante Download PDF

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WO2022247785A1
WO2022247785A1 PCT/CN2022/094454 CN2022094454W WO2022247785A1 WO 2022247785 A1 WO2022247785 A1 WO 2022247785A1 CN 2022094454 W CN2022094454 W CN 2022094454W WO 2022247785 A1 WO2022247785 A1 WO 2022247785A1
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substituted
unsubstituted
independently selected
dichloromethane
mmol
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PCT/CN2022/094454
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English (en)
Chinese (zh)
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郭谦
魏冰
王振玉
李冰
史慧静
刘喜宝
曹泽峰
道硕
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石药集团中奇制药技术（石家庄）有限公司
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Publication of WO2022247785A1 publication Critical patent/WO2022247785A1/fr

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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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • 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
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
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    • 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
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present application relates to the field of medicine, in particular, to a cyclin-dependent kinase 9 (CDK9) inhibitor or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotope derivative or a prodrug thereof, and a pharmaceutical composition comprising the same , or the use of a medicament containing it, particularly the inhibitor or its pharmaceutically acceptable salt, its stereoisomer, isotopic derivative or prodrug, a pharmaceutical composition containing it, or a medicament containing it in the preparation of a therapeutic entity Neoplastic diseases, especially in the medicine of malignant solid tumors.
  • CDK9 cyclin-dependent kinase 9
  • CDKs Cyclin-dependent kinases
  • CDKs are a class of serine/threonine protein kinases that play key roles in regulating the cell cycle and transcription.
  • CDKs can be activated by cell cycle proteins and play different biological functions.
  • CDKs are classified according to The functions can be divided into two types, one controls the cell cycle and the other regulates cell transcription.
  • CDK1, 2, 3, 4, and 6 directly intervene in the cell cycle; CDK5 does not regulate the cell cycle, but plays a key role in the complex migration of neurons after mitosis; CDK7 acts indirectly as an activator of these CDKs; CDK9 acts only in the cell transcription play a role in the regulation of the cell cycle.
  • CDK9 is an important member of the transcriptional CDKs subfamily, a group of kinases whose function is to control the main steps in the synthesis and processing of mRNA by eukaryotic RNA polymerase II (Pol II).
  • CDK9 exists in all mammalian cells, and the activation of CDK9 in vivo depends on its combination with the corresponding cell cycle protein (Cyclin T/K), forming a heterodimer, that is, positive transcription elongation factor b (P-TEFb ).
  • NELF negative transcription elongation factor
  • NELFs negative transcription elongation factors
  • P-TEFb Phosphorylation of the CTD domain
  • CDK9 cyclin-dependent kinase inhibitors
  • CDK9 inhibitors for cancer treatment, for example, AZD4573 of AstraZeneca and BAY-1251152 of Bayer, both of which are in clinical I
  • AZD4573 of AstraZeneca and BAY-1251152 of Bayer both of which are in clinical I
  • BAY-1251152 of Bayer both of which are in clinical I
  • no CDK9 inhibitor has been approved for marketing.
  • CDK9 inhibitors Although some small molecules of CDK9 inhibitors have been disclosed (for example, WO2009047359, WO2014076091, etc.), it is still necessary to develop new compounds with good efficacy and safety, so as to benefit more patients clinically.
  • the present application provides a compound as shown in formula (I) or its pharmaceutically acceptable salt, its stereoisomer, isotopic derivative or prodrug for the preparation of solid tumors, especially malignant solid tumors Uses in medicine.
  • the present application provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotope derivative or a prodrug thereof for use in the preparation and treatment of liver cancer, breast cancer or prostate cancer, In particular, the use in the medicine of CDK9-related liver cancer, breast cancer or prostate cancer.
  • the present application provides a compound 45 or its pharmaceutically acceptable salt, stereoisomer, isotopic derivative or prodrug as a CDK9 inhibitor in the preparation of a drug for treating solid tumors, especially malignant solid tumors. Uses in medicine.
  • the present application provides a compound 45 or its pharmaceutically acceptable salt, stereoisomer, isotope derivative or prodrug as a CDK9 inhibitor for the preparation of treatment of liver cancer, breast cancer or prostate cancer, especially
  • the invention is used in the medicine of CDK9-related liver cancer, breast cancer or prostate cancer.
  • the present application provides a pharmaceutical composition for treating solid tumors, which comprises a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, its stereoisomer, isotope derivative or pro medicine.
  • the present application provides a pharmaceutical composition for treating liver cancer, breast cancer or prostate cancer, which comprises a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a stereoisomer, Isotopic derivatives or prodrugs.
  • the present application provides a pharmaceutical composition for treating solid tumors, which comprises compound 45 or a pharmaceutically acceptable salt thereof, stereoisomers, isotope derivatives or prodrugs thereof.
  • the present application provides a pharmaceutical composition for treating liver cancer, breast cancer or prostate cancer, which comprises compound 45 or a pharmaceutically acceptable salt, stereoisomer, isotope derivative or prodrug thereof.
  • X is selected from Cl, F, wherein F is preferred;
  • R 1 is selected from substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; the "substituted" in R 1 means that it is independently replaced by 1, 2, 3, 4 or 5 selected from -F, -Cl, -Br, -NH 2 , -OH, -SH, -CN, -NO 2 , -N 3 , -C ⁇ CH, -COOH, -R 3 , -(CH 2 ) w O(CH 2 ) n R 3 , -(CH 2 ) w NH(CH 2 ) n R 3 , -(CH 2 ) w NR 3 (CH 2 ) n R 4 , -(CH 2 ) w S(CH 2 ) n R 3 , -(CH 2 ) w C(O)(CH 2 ) n R 3 , -(CH 2 ) w C(O)O(CH 2 ) n R 3
  • the A ring is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; the "substituted" in the A ring refers to being replaced by 1, 2, 3, 4 or 5 independently selected from -F, -Cl, -Br, OH, NH 2 , SH, CN, NO 2 , -N 3 , -C ⁇ CH, COOH, R 5 , OR 5 , -NHR 5 , -NR 5 R 6 , -SR 5 , -NHCOR 5 , -CONHR 5 , -NHS(O) 2 R 5 , -S(O) 2 NHR 5 , -NR 5 S(O) 2 R 6 , -S(O) 2 NR 5 R 6 is replaced by a group, or one, two or more -CH 2 - groups in the A ring structure can be optionally replaced by a -C(O)- group; wherein, R 5
  • R 2 is selected from H, R 7 , -(CH 2 ) x R 7 , -(CH 2 ) x NH(CH 2 ) y R 7 , -(CH 2 ) x O(CH 2 ) y R 7 , -( CH 2 ) x NR 7 (CH 2 ) y R 8 , -(CH 2 ) x C(O)(CH 2 ) y H, -(CH 2 ) x C(O)(CH 2 ) y R 7 , - (CH 2 ) x S(O) 2 (CH 2 ) y R 7 , -(CH 2 ) x C(O)C(O)(CH 2 ) y R 7 , -(CH 2 ) x S(O) 2 NH 2 , -(CH 2 ) x NHS(O) 2 H, -(CH 2 ) x S(O) 2 NH(CH 2 ) y R 7 , -(
  • R 7 and R 8 are independently selected from substituted or unsubstituted R 9 , OR 9 , -R 10 -OR 9 , -R 10 -NH-R 9 , -R 10 -C(O)-R 9 , -R 10 -NHC(O)-R 9 , -R 10 -C(O)NH-R 9 , -R 10 -SR 9 , -R 10 -S(O)-R 9 , -R 10 -SC(O) -R 9 , cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -R 10 -aryl, -R 10 -heteroaryl, -OR 10 -aryl, -OR 10 -heteroaryl, -R 10 -O-aryl, -R 10 -O-heteroaryl, -cycloalkyl-aryl, -cycloalkyl-aryl-heteroaryl,
  • -C ⁇ CH -COOH, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy , -NHCN, -NHCONH 2 , NHC(O ) CH 3 , N(CH 3 ) 2 , N(C 2 H 5 ) 2 , -SC(O)CH 3 , -OC(O)-C 1-6 alkyl, etc.;
  • said isotopic derivatives are deuterated forms of derivatives.
  • aryl preferably contains 6-10 carbon atoms
  • cycloalkyl preferably contains 3-6 carbon atoms
  • heteroaryl is preferably 5-10 membered heteroaryl
  • heterocycloalkyl is preferably 3 ⁇ 8-membered heterocyclyl
  • heteroaryl or heterocycloalkyl preferably contains 1, 2 or 3 heteroatoms each independently selected from N, O or S, the remainder being carbon atoms.
  • the compound represented by formula (I) or its pharmaceutically acceptable salt, its stereoisomer, isotopic derivative or prodrug wherein, the A ring is selected from substituted or unsubstituted 4-6 membered Cycloalkyl, substituted or unsubstituted 4-6 membered heterocycloalkyl, or substituted or unsubstituted 5-6 cycloalkyl, or substituted or unsubstituted 5-6 membered heterocycloalkyl; more preferably, A The ring is selected from substituted or unsubstituted 5-6 cycloalkyl, or substituted or unsubstituted 5-6 membered heterocycloalkyl; more preferably, ring A is selected from substituted or unsubstituted 5-6 cycloalkyl.
  • ring A is selected from cyclohexane, tetrahydropyrrolyl, piperidinyl, piperazinyl, cyclopentyl or morpholinyl, further preferably, ring A is selected from cyclohexane, Cyclopentyl or tetrahydropyrrolyl.
  • the compound represented by the formula (I) or its pharmaceutically acceptable salt, its stereoisomer, isotopic derivative or prodrug wherein the "substitution" in the A ring refers to being replaced by 1 , 2, 3, 4 or 5 groups independently selected from -F, -Cl, -Br, OH, NH 2 , SH, CN, R 5 , OR 5 are substituted, wherein, R 5 is C 1-6 alkyl or C 1-6 alkoxy, and R 5 can be further selected from C 1-4 alkyl or C 1-4 alkoxy.
  • the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotopic derivative or a prodrug thereof has a structure represented by the formula (II):
  • R 1 , R 2 and X are as shown in formula (I).
  • the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotopic derivative or a prodrug thereof has a structure represented by the formula (IIa):
  • R 1 , R 2 and X are as shown in formula (I).
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotopic derivative or a prodrug thereof has a structure represented by formula (III):
  • R 1 , R 2 and X are as shown in formula (I).
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotopic derivative or a prodrug thereof has a structure represented by formula (IIIa):
  • R 1 , R 2 and X are as shown in formula (I).
  • the compound represented by formula (I) or its pharmaceutically acceptable salt, its stereoisomer, isotopic derivative or prodrug wherein, R is selected from substituted or unsubstituted 6-10 membered Aryl, or a substituted or unsubstituted 5-10 membered heteroaryl; the heteroaryl contains 1 or 2 heteroatoms independently selected from N or O; the number of the substituents is selected from 1, 2 or 3.
  • the compound represented by the formula (I) or its pharmaceutically acceptable salt, its stereoisomer, isotopic derivative or prodrug wherein, R is selected from substituted or unsubstituted benzene ring, pyridine ring, indole ring, indazole ring, benzofuran ring, pyrrolopyridine ring; more preferably substituted or unsubstituted benzene ring, pyridine ring, indole ring, benzofuran ring, pyrrolopyridine ring; more preferably substituted The benzene ring, pyridine ring and unsubstituted indole ring, benzofuran ring, pyrrolopyridine ring; more preferably substituted benzene ring.
  • the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotopic derivative or a prodrug thereof wherein the substituents on the R1 are independently selected from -F, -Cl, -OH, -NH 2 , -R 3 , -(CH 2 ) w O(CH 2 ) n R 3 or -(CH 2 ) w OC(O)(CH 2 ) n R 3 ;
  • Each occurrence of w and n is independently selected from 0, 1 or 2, wherein R 3 is as defined in formula (I).
  • the substituents on R 1 are independently selected from -F-, -Cl, -OH, -R 3 , -(CH 2 ) w O(CH 2 ) n R 3 ; further preferably, the The substituents on R 1 are independently selected from -F-, -OH, -R 3 , -(CH 2 ) w O(CH 2 ) n R 3 .
  • R is a substituted benzene ring
  • the substituents are selected from -F, -OH or alkoxy, preferably 1 or 2 fluorine atoms and 1 -OH or alkoxy, preferably 1 or 2 Fluorine atom substitution and 1 alkoxyl substitution.
  • the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotopic derivative or a prodrug thereof has a structure represented by the formula (II):
  • R is a substituted benzene ring, and the substituent is selected from -F, -OH or alkoxy; preferably 1 or 2 fluorine atoms are substituted and 1 -OH or alkoxy is substituted, preferably 1 or 2 fluorine atoms substituted and 1 alkoxy substituted;
  • R 2 and X are shown in formula (I).
  • the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotopic derivative or a prodrug thereof has a structure represented by the formula (IIa):
  • R 1 is a substituted benzene ring, and the substituent is selected from -F, -OH or alkoxy; preferably 1 or 2 fluorine atoms are substituted and 1 -OH or alkoxy are substituted, preferably 1 or 2 Fluorine atom substitution and 1 alkoxy substitution;
  • R 2 and X are shown in formula (I).
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotopic derivative or a prodrug thereof wherein R and R are independently selected from substituted or unsubstituted Substituted 6-membered aryl, substituted or unsubstituted 5-6-membered heteroaryl, substituted or unsubstituted C 1-3 alkyl, substituted or unsubstituted C 1-3 alkoxy, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 3-6 heterocycloalkyl, or when R 3 and R 4 are jointly linked to the same nitrogen atom, R 3 , R 4 and the nitrogen atom to which they are jointly linked 3-7 membered substituted or unsubstituted heterocycloalkyl; said heterocycloalkyl contains 1 or 2 heteroatoms independently selected from N, O or S; the "substitution" described in R3 and R4 refers to 1,
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotopic derivative or a prodrug thereof wherein R and R are independently selected from substituted or unsubstituted Substituted benzene ring, pyridine ring, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl or Cyclohexyl, "substituted" in R 3 and R 4 refers to being 1, 2 or 3 independently selected from -F, -Cl, -Br, -OH, -CH 3 , -C 2 Substituents of H 5 , -OCH 3 , -OC 2 H 5 .
  • R and R are independently selected from substituted or unsubstituted methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, pyridine rings; more preferably, R 3 and R 4 are independently selected from substituted or unsubstituted methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy; more preferably, R 3 and R 4 are independently selected from substituted or unsubstituted methyl and methoxy groups.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotopic derivative or a prodrug thereof wherein R 2 is selected from R 7 , -(CH 2 ) x R 7 , -(CH 2 ) x NH(CH 2 ) y R 7 , -(CH 2 ) x C(O)(CH 2 ) y R 7 , -(CH 2 ) x S(O) 2 (CH 2 ) y R 7 , -(CH 2 ) x C(O)C(O)(CH 2 ) y R 7 , -(CH 2 ) x C(O)O(CH 2 ) y R 7 , -(CH 2 ) x C(O)NH(CH 2 ) y R 7 , -(CH 2 ) x C(O)NR 7 (CH 2 ) y R 8 or -(CH 2 ) x NR 7 C(O)
  • R 2 is selected from R 7 , -(CH 2 ) x R 7 , -(CH 2 ) x C(O)(CH 2 ) y R 7 , -(CH 2 ) x S(O) 2 ( CH 2 ) y R 7 , -(CH 2 ) x C(O)C(O)(CH 2 ) y R 7 , -(CH 2 ) x C(O)O(CH 2 ) y R 7 , -( CH 2 ) x C(O)NH(CH 2 ) y R 7 ; more preferably, R 2 is selected from R 7 , -(CH 2 ) x R 7 , -(CH 2 ) x C(O)(CH 2 ) y R 7 ; more preferably, R 2 is selected from -(CH 2 ) x C(O)(CH 2 ) y R 7 .
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotopic derivative or a prodrug thereof wherein R 7 and R 8 are each independently selected from substituted or unsubstituted Substituted R 9 , OR 9 , -R 10 -OR 9 , -R 10 -NH-R 9 , -R 10 -C(O)-R 9 , -R 10 -NHC(O)-R 9 , -R 10 -C(O)NH-R 9 , -R 10 -SR 9 , -R 10 -SC(O)-R 9 , C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6- 10 aryl, 5-10 membered heteroaryl, -R 10 -C 6-10 aryl, -R 10 -5-10 membered heteroaryl, -OR 10 -C 6-10 aryl, -OR 10 - 5-10
  • R 7 and R 8 form a substituted or unsubstituted 3-6 membered heterocycloalkyl group with the jointly connected nitrogen atom; further preferably, R 7 is independently selected from the group consisting of substituted Or unsubstituted R 9 , OR 9 , -R 10 -OR 9 , C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl; further Preferably, R 7 is independently selected from substituted or unsubstituted R 9 , OR 9 , -R 10 -OR 9 , C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl; more preferably, R 7 independently
  • the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotopic derivative or a prodrug thereof wherein each of the R 7 and R 8 is independently selected from the substituent or unsubstituted methyl, ethyl, propyl, isopropyl, butyl, pentyl, methoxy, ethoxy, propoxy, isopropoxy, -CH 2 OCH 3 , -CH 2 OCH 2 CH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridyl, azetidinyl, nitrogen Heterocyclopentyl, azacyclohexyl, oxirane, oxetanyl, oxolyl, oxanyl, phenyl, pyridyl,
  • R is independently selected from substituted or unsubstituted methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, azetidinyl, azacyclohexyl, oxetane Butyl, oxanyl, phenyl, pyridyl, pyrazolyl, isoxazolyl, thienyl, thiazolyl, benzyl, vinyl, propenyl or ethynyl; further preferably, R independently selected from substituted or unsubstituted methyl, ethyl, methoxy, cyclopropyl, cyclobutyl, azacyclohexyl, oxetanyl, oxetyl, pyridyl, pyrazolyl, isoxane Azolyl, vinyl, propenyl or ethynyl; Further preferably, R is
  • R 7 and R 8 refers to being 1, 2 or 3 independently selected from -F, -Cl, -Br, -OH, -NH 2 , -SH, -CN, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, -NHCN, -NHCONH 2 , NHC(O ) CH 3 , N(CH 3 ) 2 , N(C 2 H 5 ) 2 , -SC(O)CH 3 , -OC(O)-C 1-6 alkyl, etc.; preferably , the ""Substituted” refers to being 1, 2 or 3 independently selected from -F, -OH, -SH, -CN, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkane Oxygen, NHC(O)CH 3 , N(CH 3 ) 2 , N(C 2 H 5 ) 2
  • substitution in R7 and R8 refers to being substituted by 1, 2 or 3 groups independently selected from -F, -OH, -CN, etc.; Further preferably, the "substitution" in R 7 and R 8 refers to being substituted by 1, 2 or 3 groups independently selected from -OH, -CN, etc.; further preferably, R 7 and the "substituted” in R 8 means to be substituted by one group independently selected from -OH, -CN, etc.; further preferably, the "substituted" in R 7 and R 8 means Substituted by 1 group each independently selected from -OH.
  • the compound represented by the formula (I) or its pharmaceutically acceptable salt, its stereoisomer, isotopic derivative or prodrug wherein, R 9 is C 1-4 alkyl, R 10 is C 1-4 alkylene.
  • the solid tumor is a malignant solid tumor; preferably an advanced malignant solid tumor; more preferably liver cancer, breast cancer or prostate cancer.
  • the liver cancer, breast cancer or prostate cancer is CDK9-related liver cancer, breast cancer or prostate cancer.
  • the liver cancer, breast cancer or prostate cancer is liver cancer, breast cancer or prostate cancer caused by overexpression of CDK9.
  • the liver cancer is hepatocellular carcinoma; preferably advanced hepatocellular carcinoma; more preferably CDK9-related advanced hepatocellular carcinoma; further preferably advanced hepatocellular carcinoma caused by overexpression of CDK9.
  • the breast cancer is triple negative breast cancer.
  • the triple-negative breast cancer is a CDK9-associated triple-negative breast cancer; preferably, it is a triple-negative breast cancer caused by overexpression of CDK9.
  • said CDK9 association refers to CDK9 overexpression.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt, stereoisomer, isotopic derivative or prodrug thereof is the only active ingredient in the drug.
  • the compound represented by the formula (I) or its pharmaceutically acceptable salt, its stereoisomer, isotopic derivative or prodrug is used in combination with one or more other targeted drugs or chemotherapeutic drugs
  • the drug is prepared.
  • the medicament is formulated into a clinically acceptable formulation.
  • the formulation is an oral formulation or an injectable formulation.
  • the compound represented by formula (I) or its pharmaceutically acceptable salt, its stereoisomer, isotopic derivative or prodrug is administered at a daily dose of from about 0.001 mg/kg to about 1000 mg/kg
  • the dosage range is administered; preferably 0.01 mg/kg to about 100 mg/kg, more preferably 0.02 mg/kg to about 10 mg/kg.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotopic derivative or a prodrug thereof is administered in a daily dosage range from about 0.001 mg to about 1000 mg ; preferably 0.01 mg to about 100 mg, more preferably 0.1 mg to about 80 mg, further preferably 1 mg to about 70 mg, further preferably 1.5 mg to about 60 mg, further preferably 2 mg to about 50 mg.
  • the dosing frequency is single dose or multiple doses.
  • the dosing frequency is once a day, twice a day, three times a day, once every two days, once every three days, once every four days, once every five days 1. Dosing once every six days or once every seven days.
  • the medicament contains a therapeutically effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt, stereoisomer, isotope derivative or prodrug thereof.
  • the therapeutically effective amount is 0.001-1000 mg.
  • the therapeutically effective amount is 0.01-100 mg.
  • the therapeutically effective amount is 0.1-50 mg. More preferably 2mg, 3mg, 4mg, 5mg, 6mg, 8mg, 10mg, 12mg, 16mg, 18mg, 20mg, 24mg, 25mg, 30mg, 32mg, 36mg, 40mg, 42mg, 45mg, 50mg.
  • the single dosage form of the drug contains 0.01-100 mg of the compound represented by formula (I) or its pharmaceutically acceptable salt, stereoisomer, isotopic derivative or prodrug; preferably 0.1- 80mg; more preferably 1-60mg; further preferably 1-50mg; further preferably 2-20mg; further preferably 2-15mg; further preferably 2-10mg; further preferably 2-8mg; ; More preferably 2-5mg; More preferably 2-4mg; More preferably 2-3mg.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt, stereoisomer, isotopic derivative or prodrug thereof is administered in a single dose or in divided doses.
  • the medicament is administered orally or by injection. In a preferred embodiment, the medicament is administered orally.
  • a pharmaceutical composition for treating solid tumors which comprises the compound represented by formula (I) or its pharmaceutically acceptable salt, its stereoisomer, Isotopic derivatives or prodrugs, optionally comprising a pharmaceutically acceptable carrier.
  • a method for treating a solid tumor in an individual comprising administering to the individual a therapeutically effective amount of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof as described in the first aspect , a stereoisomer, an isotope derivative or a prodrug thereof, or administering a therapeutically effective amount of the pharmaceutical composition for treating solid tumors described in the second aspect to the individual.
  • the solid tumor is a malignant solid tumor; preferably an advanced malignant solid tumor; more preferably liver cancer, breast cancer or prostate cancer.
  • the liver cancer, breast cancer or prostate cancer is CDK9-related liver cancer, breast cancer or prostate cancer.
  • the liver cancer, breast cancer or prostate cancer is liver cancer, breast cancer or prostate cancer caused by overexpression of CDK9.
  • the liver cancer is hepatocellular carcinoma; preferably advanced hepatocellular carcinoma; more preferably CDK9-related advanced hepatocellular carcinoma; further preferably advanced hepatocellular carcinoma caused by overexpression of CDK9.
  • the breast cancer is triple negative breast cancer.
  • the triple-negative breast cancer is a CDK9-associated triple-negative breast cancer; preferably, it is a triple-negative breast cancer caused by overexpression of CDK9.
  • said CDK9 association refers to CDK9 overexpression.
  • the compound 45 or a pharmaceutically acceptable salt, stereoisomer, isotopic derivative or prodrug thereof, is the sole active ingredient in the medicament.
  • the compound 45 or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotopic derivative or a prodrug thereof is used in combination with one or more other targeted drugs or chemotherapeutic drugs for the preparation of the drug.
  • the medicament is formulated into a clinically acceptable formulation.
  • the formulation is an oral formulation or an injectable formulation.
  • said Compound 45 or a pharmaceutically acceptable salt thereof, stereoisomer, isotopic derivative or prodrug thereof, is administered at a daily administered dosage ranging from about 0.001 mg/kg to about 1000 mg/kg; Preferably 0.01 mg/kg to about 100 mg/kg, more preferably 0.02 mg/kg to about 10 mg/kg.
  • the compound 45, or a pharmaceutically acceptable salt thereof, stereoisomer, isotopic derivative or prodrug thereof is administered at a daily dose ranging from about 0.001 mg to about 1000 mg; preferably 0.01 mg to About 100 mg, more preferably 0.1 mg to about 80 mg, more preferably 1 mg to about 70 mg, further preferably 1.5 mg to about 60 mg, further preferably 2 mg to about 50 mg. More preferably 2mg, 3mg, 4mg, 5mg, 6mg, 8mg, 10mg, 12mg, 16mg, 18mg, 20mg, 24mg, 25mg, 30mg, 32mg, 36mg, 40mg, 42mg, 45mg, 50mg.
  • the dosing frequency is single dose or multiple doses.
  • the dosing frequency is once a day, twice a day, three times a day, once every two days, once every three days, once every four days, once every five days 1. Dosing once every six days or once every seven days.
  • the medicament contains a therapeutically effective amount of Compound 45, or a pharmaceutically acceptable salt, stereoisomer, isotopic derivative, or prodrug thereof.
  • the therapeutically effective amount is 0.001-1000 mg.
  • the therapeutically effective amount is 0.01-100 mg.
  • the therapeutically effective amount is 0.1-50 mg. More preferably 2mg, 3mg, 4mg, 5mg, 6mg, 8mg, 10mg, 12mg, 16mg, 18mg, 20mg, 24mg, 25mg, 30mg, 32mg, 36mg, 40mg, 42mg, 45mg, 50mg.
  • the single dosage form of the drug contains 0.01-100 mg of compound 45 or its pharmaceutically acceptable salt, stereoisomer, isotope derivative or prodrug; preferably 0.1-80 mg; more preferably 1-60mg; more preferably 1-50mg; further preferably 2-20mg; further preferably 2-15mg; further preferably 2-10mg; further preferably 2-8mg; further preferably 2-6mg; -5 mg; more preferably 2-4 mg; more preferably 2-3 mg.
  • the compound 45 or a pharmaceutically acceptable salt, stereoisomer, isotopic derivative or prodrug thereof, is administered in a single dose or in divided doses.
  • the medicament is administered orally or by injection. In a preferred embodiment, the medicament is administered orally.
  • a pharmaceutical composition for the treatment of solid tumors which comprises Compound 45 of the present application or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotope derivative or a prodrug thereof, and optionally Optionally, a pharmaceutically acceptable carrier is included.
  • a method for treating a solid tumor in an individual comprising administering to the individual a therapeutically effective amount of Compound 45 of the present application or a pharmaceutically acceptable salt thereof, a stereoisomer, an isotopically derived substance or prodrug, or administering a therapeutically effective amount of the pharmaceutical composition for treating solid tumors according to the fifth aspect to the individual.
  • the compound of the present application has optical activity, and the compound of the present application can be a racemate, or an optical isomer or a mixture thereof, and the synthesis of the optical isomer in the compound of the present application can be achieved by the formation of the optical isomer It can also be prepared from the starting material, and can also be prepared by separation of the racemate.
  • ethyl is “optionally” substituted with halogen , meaning that the ethyl group can be unsubstituted ( CH2CH3 ), monosubstituted (eg CH2CH2F ), polysubstituted (eg CHFCH2F , CH 2 CHF 2 etc.) or fully substituted (CF 2 CF 3 ). It will be appreciated by those skilled in the art that for any group containing one or more substituents, no sterically impossible and/or synthetically impossible substitution or substitution pattern is introduced.
  • C mn herein, is that the moiety has an integer number of carbon atoms in the given range.
  • C 1-6 means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.
  • variable e.g, R
  • R any variable
  • its definition is independent at each occurrence. So, for example, if a group is substituted by 2 R's, each R has independent options.
  • alkyl refers to a monovalent saturated aliphatic hydrocarbon group, a linear or branched group containing 1-20 carbon atoms, preferably containing 1-10 carbon atoms (i.e. C 1-10 alkyl), more preferably Contains 1-8 carbon atoms (C 1-8 alkyl), more preferably contains 1-6 carbon atoms (ie C 1-6 alkyl), for example "C 1-6 alkyl” refers to the group is an alkyl group, and the number of carbon atoms in the carbon chain is between 1 and 6 (specifically 1, 2, 3, 4, 5 or 6).
  • Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethyl Propyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl , N-octyl, etc.
  • cycloalkyl refers to a monocyclic saturated aliphatic hydrocarbon group having a specific number of carbon atoms, preferably containing 3-12 carbon atoms (i.e. C 3-12 cycloalkyl), more preferably containing 3-10 carbon atoms (C 3-10 cycloalkyl), more preferably 3-6 carbon atoms (C 3-6 cycloalkyl), 4-6 carbon atoms (C 4-6 cycloalkyl), 5-6 carbon atoms (C 5-6 cycloalkyl).
  • Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, and the like.
  • alkoxy refers to an -O-alkyl group as defined above, that is, containing 1-20 carbon atoms, preferably containing 1-10 carbon atoms, preferably 1-8 carbon atoms , more preferably 1 to 6 carbon atoms (specifically 1, 2, 3, 4, 5 or 6).
  • Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentyloxy, Oxygen, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2 , 2-dimethylpropoxy, 1-ethylpropoxy, etc.
  • halogen refers to F, Cl, Br, I.
  • haloalkyl refers to an alkyl group as defined above in which one, two or more hydrogen atoms or all hydrogen atoms are replaced by halogen.
  • Representative examples of haloalkyl include CCl3 , CF3 , CHCl2, CH2Cl , CH2Br , CH2I , CH2CF3 , CF2CF3 , and the like .
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic cyclic hydrocarbon substituent, which is a non-aromatic structure, containing 3-20 ring atoms, of which 1, 2, 3 or more One ring atom is selected from N, O or S, and the remaining ring atoms are C.
  • It preferably contains 3-12 ring atoms (C 3-12 heterocyclyl), further preferably contains 3-10 ring atoms (C 3-10 heterocyclyl), or 3-8 ring atoms (C 3-8 heterocyclyl) ring group), or 3 to 6 ring atoms (C 3-6 heterocyclyl), or 4 to 6 ring atoms (C 4-6 heterocyclyl), or 5 to 6 ring atoms (C 5-6 heterocyclyl).
  • the number of heteroatoms is preferably 1-4, more preferably 1-3 (ie 1, 2 or 3).
  • Examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyranyl, and the like.
  • Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.
  • heterocycloalkyl means a saturated “heterocyclyl” as defined above, containing 3 to 20 ring atoms, of which 1, 2, 3 or more ring atoms are selected from N, O or S , and the remaining ring atoms are C.
  • It preferably contains 3-12 ring atoms (C 3-12 heterocycloalkyl), further preferably contains 3-10 ring atoms (C 3-10 heterocycloalkyl), or 3-8 ring atoms (C 3- 8 heterocycloalkyl), or 3-7 ring atoms (C 3-7 heterocycloalkyl), or 3-6 ring atoms (C 3-6 heterocycloalkyl), or 4-6 ring atoms (C 4-6 heterocycloalkyl), or 5-6 ring atoms (C 5-6 heterocycloalkyl).
  • the number of heteroatoms is preferably 1-4, more preferably 1-3 (ie 1, 2 or 3).
  • Examples include aziridinyl, oxiranyl, thietidinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, oxa Cyclohexane, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolidinyl Wait.
  • aryl denotes monocyclic, bicyclic and tricyclic aromatic carbocyclic ring systems containing 6-16 carbon atoms, or 6-14 carbon atoms, or 6-12 carbon atoms, or 6-10 carbon atoms , preferably 6-10 carbon atoms, the term “aryl” may be used interchangeably with the term “aromatic ring”.
  • aryl groups may include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, or pyrenyl, and the like.
  • heteroaryl means an aromatic monocyclic or polycyclic ring system containing a 5-12-membered structure, or preferably a 5-10-membered structure, a 5-8-membered structure, and more preferably a 5-6-membered structure, wherein one, 2, 3 or more ring atoms are heteroatoms and the remaining atoms are carbon, the heteroatoms are independently selected from O, N or S, and the number of heteroatoms is preferably 1, 2 or 3.
  • heteroaryl examples include, but are not limited to, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl , tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolinyl, isoquinolinyl, pteridyl, purinyl, indyl Indolyl, Isoindolyl, Indazolyl, Benzofuryl, Benzothienyl, Benzopyridyl, Benzopyrimidinyl, Benzopyrazinyl, Benzimidazolyl, Benzophthalazinyl, Pyrrole A[2,3
  • pharmaceutically acceptable salt or “pharmaceutically acceptable salt” means, within the scope of sound medical judgment, suitable for use in contact with the tissues of mammals, especially humans, without undue toxicity, irritation, allergic reaction, etc. and with reasonable benefits. /risk ratio with a grain of salt.
  • salt includes salts prepared from inorganic acids. If the compound of the present application is acidic, the pharmaceutically acceptable non-toxic bases include salts prepared with inorganic bases and organic bases.
  • stereoisomer refers to isomers produced by different arrangements of atoms in space, including configuration isomers and conformational isomers, wherein configuration isomers include geometric isomers isomers (or cis-trans isomers) and optical isomers (including enantiomers and diastereomers).
  • Geometric isomers may exist in the present compounds.
  • the compounds of the present application may contain a carbon-carbon double bond or a carbon-nitrogen double bond of E or Z configuration, wherein the term “E” represents a higher order substituent on the opposite side of the carbon-carbon or carbon-nitrogen double bond, and the term “Z” represents a higher order substituent on the same side of a carbon-carbon or carbon-nitrogen double bond (determined using the Cahn-Ingold Prelog priority rule).
  • the compounds of the present application may also exist as a mixture of "E” and "Z” isomers. Substituents around a cycloalkyl or heterocycloalkyl group are referred to as cis or trans configurations.
  • Optical isomers refer to substances with exactly the same molecular structure, similar physical and chemical properties, but different optical activity.
  • the compounds of the present application may contain asymmetrically substituted carbon atoms in the R or S configuration, wherein the terms "R” and "S” are as in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl.Chem. (1976) 45, 13-10 as defined.
  • Compounds with asymmetrically substituted carbon atoms are racemic at those carbon atoms. Atoms having an excess of one configuration (relative to the other) such that that configuration is present in a higher amount, preferably an excess of about 85% to 90%, more preferably an excess of about 95% to 99%, and still more preferably an excess of greater than about 99% .
  • the present application includes racemic mixtures, relative and absolute stereoisomers and mixtures of relative and absolute stereoisomers.
  • isotopic derivatives may also be referred to as “isotopic forms", which means that the compounds of the present application may exist in isotope-labeled or enriched forms, containing one or more atoms whose atomic weight or mass number is different from that in nature The atomic mass or mass number of the most abundant atom found in .
  • Isotopes can be radioactive or non-radioactive isotopes.
  • Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine, and iodine include, but are not limited to: 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 32 P, 35 S, 18 F, 36 Cl and 125 I.
  • Compounds containing other isotopes of these and/or other atoms are within the scope of this application; deuterated forms are preferred.
  • the isotopically labeled compound contains a deuterium ( 2 H), tritium ( 3 H) or 14 C isotope.
  • the isotope-labeled compounds of the present application can be prepared using general methods well known to those of ordinary skill in the art.
  • relevant literature includes: Lizondo, J et al, Drugs Fut, 21(11), 1116(1996); Brickner, S J et al, J Med Chem, 39(3), 673(1996); Mallesham, B et al, Org Lett, 5(7), 963 (2003).
  • drugs containing non-radioactive isotopes such as deuterated drugs known as "heavy drugs" can be used to treat related diseases and conditions.
  • Increasing the amount of an isotope present in the above compounds above its natural abundance is called enrichment.
  • Examples of enriched amounts include about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71, 75, 79, 84, 88, 92, 96 to about 100 mol%.
  • any possible position in the molecular structure can be replaced by an isotope to obtain an isotope derivative.
  • deuterium ( 2 H) can be substituted at any possible site in the molecule to give a deuterated form of the derivative.
  • Drugs labeled with stable isotopes can alter the physicochemical properties of the drug, such as pKa and lipid solubility. If isotopic substitutions affect regions involved in ligand-receptor interactions, these effects and changes can affect the pharmacodynamic response of drug molecules. Although some physical properties of stable isotope-labeled molecules differ from those of unlabeled molecules, the chemical and biological properties are the same, with one important difference being that due to the increased mass of the heavy isotope, Any bond to another atom is stronger than the same bond between the light isotope and that atom. Accordingly, incorporation of isotopes at sites of metabolic or enzymatic transformations can potentially slow down said reactions, and can alter pharmacokinetic properties or effects relative to non-isotopic compounds.
  • prodrug or “prodrug” is a designed derivative of an active drug that improves some identified, undesirable physical or biological property. Physical properties are usually related to solubility (too high or insufficient lipid or water solubility) or stability, while problematic biological properties include too fast metabolism or poor bioavailability, which may themselves be related to physicochemical properties.
  • Prodrugs are usually prepared by a) forming esters, half-esters, carbonates, nitrates, amides, hydroxamic acids, carbamates, imines, Mannich bases, phosphates, phosphate esters and Enamines, b) functionalization of drugs with azo, glycoside, peptide and ether functional groups, c) use of aminals, hemiaminals, polymers, salts, complexes, phosphoramides, acetals, hemiaminals of drugs Acetal and ketal forms.
  • Esters can be prepared from substrates containing hydroxyl or carboxyl groups using general methods known to those skilled in the art. A typical reaction in these compounds is the substitution of one heteroatom with another.
  • Amides can be prepared in a similar manner from substrates containing amino or carboxyl groups. Esters can also react with amines or ammonia to form amides. Another way to prepare amides is to heat carboxylic acids and amines together.
  • liver cancer means any proliferative lesion or proliferative abnormality of the liver, for example, malignant tumors arising from the liver cells that make up the majority of the liver, including all types of malignant tumors that start within the liver and spread to the liver from elsewhere of metastatic liver cancer.
  • breast cancer or “breast neoplasm” refers to any proliferative lesion or proliferative abnormality of the breast, which includes, for example, benign lesions, premalignant and malignant lesions, solid tumors, and metastatic disease (local metastases, such as stage III , and more extensive metastases, such as stage IV), including but not limited to triple-negative breast cancer.
  • prostate cancer or “prostate neoplasm” means any proliferative lesion or proliferative abnormality of the prostate which develops in the prostate and is histologically or cytologically confirmed as prostate cancer or prostate neoplasm, including but not limited to primary Prostate tumors and metastases of said primary prostate tumors (which may be located anywhere in the body).
  • treating means administering a compound or formulation described herein to ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes: (i) inhibiting a disease or disease state, i.e. curbing its development; (ii) remission of a disease or disease state, even if the disease or disease state regresses.
  • terapéuticaally effective amount means that amount of a compound of the present application that (i) treats a particular disease, condition or disorder, or (ii) alleviates, ameliorates or eliminates one or more symptoms of a particular disease, condition or disorder.
  • the amount of a compound of the present application that constitutes a “therapeutically effective amount” varies depending on the compound, the disease state and its severity, the mode of administration, and the individual characteristics (e.g., sensitivity, body weight, age, etc.) of the individual to be treated, However, it can be routinely determined by those skilled in the art based on their own knowledge and the present disclosure.
  • pharmaceutical composition refers to a mixture of one or more compounds of the present application or pharmaceutically acceptable salts, stereoisomers or prodrugs thereof and pharmaceutically acceptable auxiliary materials.
  • the purpose of the pharmaceutical composition is to facilitate administration of a compound of the present application, or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, to an organism.
  • the pharmaceutical composition of the present invention can be prepared by conventional methods in the art.
  • the term "pharmaceutically acceptable carrier” or “excipient” or “pharmaceutically acceptable adjuvant” or “pharmaceutically acceptable adjuvant” means no significant irritation to the organism, and Those excipients that do not impair the biological activity and performance of the active compound.
  • pharmaceutically acceptable excipients includes: solvents, propellants, solubilizers, co-solvents, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, Stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adherents, antioxidants, chelating agents, penetration enhancers, pH regulators, buffers, plasticizers Agents, surfactants, foaming agents, defoamers, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants and deflocculants, filter aids, release retardants, etc.
  • the compounds of the present application can be prepared by other synthetic methods, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those known to those skilled in the art
  • preferred implementations include but are not limited to the examples of the present application.
  • the term "individual” or “subject” refers to a cell or a mammal, such as a human being, but can also be other mammals, such as livestock or laboratory animals and the like.
  • the application evaluates the compound shown in the formula (I) for different subtypes of CDK In vitro kinase inhibitory activity and proliferation inhibitory activity with various liver cancer, breast cancer and prostate cancer cell lines, and further evaluated the inhibition of tumor growth by the compound represented by formula (I) (especially compound 45) for liver cancer tumor xenograft model Effect.
  • results of in vitro kinase activity test and cell test show that the compound of the present application has good in vitro kinase inhibitory activity against CDK9 and good selectivity to other CDK subtypes; have a strong inhibitory effect.
  • results of the in vivo test show that, compared with the reference compound, the compound of the present application has better anti-tumor effect in vivo, is better tolerated, and has a higher possibility of becoming a drug, which provides a better choice for inhibiting CDK9 target drugs.
  • Embodiment 6 is a diagrammatic representation of Embodiment 6
  • 6b (250mg, 0.52mmol) was dissolved in dichloromethane (10mL), then trifluoroacetic acid (1mL) was added, and reacted at room temperature for 1.5 hours. TLC followed and monitored that no raw material remained. Add saturated sodium bicarbonate (30mL) to the reaction solution, extract with dichloromethane (20mL ⁇ 3), combine the organic phases, wash with saturated sodium chloride (20mL ⁇ 2), dry over anhydrous sodium sulfate, and remove the solvent under reduced pressure to obtain 6c (130 mg, 65% yield).
  • Embodiment 7 is a diagrammatic representation of Embodiment 7:
  • Embodiment 8 is a diagrammatic representation of Embodiment 8
  • Embodiment 9 is a diagrammatic representation of Embodiment 9:
  • 2-Methoxyphenylboronic acid (0.42 g, 2.77 mmol) was dissolved in diethylene glycol dimethyl ether (30 mL) and water (6 mL), followed by the addition of the compound 5-fluoro-4-iodopyridin-2-amine ( 0.60 g, 2.52 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (95 mg, 0.13 mmol) and potassium carbonate (1.04 g, 7.56 mmol). The system was protected with nitrogen, stirred at 100° C., and reacted for 4 hours. TLC monitored that there was no residue in the raw material reaction.
  • 2,6-Difluoropyridine-3-boronic acid 550 mg, 3.14 mmol
  • compound 5-fluoro-4-iodopyridin-2-amine 898 mg, 3.77 mmol
  • 1,4-dioxane 15 mL
  • sequentially added [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (219mg, 0.30mmol)
  • potassium carbonate (1.30g, 9.42mmol
  • 23a (806mg, 1.74mmol) was dissolved in dichloromethane (10mL), then 5mL of trifluoroacetic acid was added in an ice-water bath, and the whole system was stirred at room temperature for 2 hours, and no raw material was detected by TLC.
  • Dissolve 24a 400mg, 0.86mmol
  • dichloromethane 25mL
  • trifluoroacetic acid 3mL
  • TLC monitors that there is no remaining raw material
  • the aqueous phase was extracted with dichloromethane (30 mL ⁇ 3), and the organic phases were combined and dried over anhydrous sodium sulfate.
  • 26a (0.30 g, 1.18 mmol) was dissolved in N,N-dimethylformamide (30 mL), followed by the addition of (1S,3R)-3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid (0.35 g, 1.42mmol), 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.54g, 1.42mmol) and N,N-di Methylethylamine (0.30 g, 2.36 mmol), the whole system was stirred overnight at room temperature, and no raw material was found by TLC.
  • 26b (0.20g, 0.42mmol) was dissolved in dichloromethane (30mL), then trifluoroacetic acid (2mL) was added under an ice-water bath, the whole system was stirred overnight at room temperature, and TLC was detected until no raw material remained.
  • 26c (0.11 g, 0.29 mmol) was dissolved in dichloromethane (35 mL), followed by the addition of methanesulfonyl chloride (0.40 g, 0.35 mmol) and triethylamine (44 mg, 0.46 mmol). The system was stirred at room temperature, followed by TLC monitoring until no raw material remained.
  • 2,2'-Dibromodiethyl ether (12.85 g, 55.60 mmol) was dissolved in N,N-dimethylformamide (10 mL), followed by the addition of methyl cyanoacetate (5.00 g, 50.45 mmol) and 1,8 - Diazabicyclo[5.4.0]undec-7-ene (11.50 g, 75.68 mmol), replaced with nitrogen three times, and kept the whole system under nitrogen atmosphere. The system was stirred at 85° C. and reacted for 4 hours. TLC monitored that there was no remaining raw material.
  • 35a (2.37g, 14.00mmol) was dissolved in ethanol (36mL) and water (5mL), then sodium hydroxide (2.24g, 56.00mmol) was added, and the whole system was stirred at room temperature for 4 hours, and no raw material was detected by TLC.
  • 35b (123 mg, 0.79 mmol) was dissolved in N,N-dimethylformamide (5 mL), followed by the addition of (1S,3R)-3-amino-N-(5-fluoro-4-(4-fluoro- 2-methoxyphenyl)pyridin-2-yl)cyclohexylamide (260mg, 0.72mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyl Urea hexafluorophosphate (548mg, 1.44mmol) and N,N-diisopropylethylamine (357 ⁇ L, 2.16mmol), the whole system was stirred at room temperature, and reacted for 10 hours.
  • Triphosgene (33 mg, 0.11 mmol) was dissolved in dichloromethane (2 mL), followed by dropwise addition of a solution of 5b (61 mg, 0.17 mmol) and triethylamine (22 mg, 0.22 mmol) dissolved in dichloromethane (2 mL), The whole system was stirred at room temperature and reacted for 2 hours, then methanol solution (2 mL) was added, and the reaction was continued for 3 hours, monitored by TLC until no raw material remained.
  • 60a (623mg, 1.09mmol) was dissolved in dichloromethane (20mL), then trifluoroacetic acid (5mL) was added, and the whole system was stirred at room temperature for 2 hours, and no raw material was detected by TLC.
  • Dissolve 5b (0.07g, 0.19mmol) in N,N-dimethylformamide (10mL), add cyclopropylacetic acid (0.02g, 0.21mmol), 2-(7-azobenzotriazole )-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.09g, 0.23mmol) and N,N-diisopropylethylamine (0.05g, 0.38mmol), react at room temperature for 8 hours , TLC monitors that there is no remaining raw material.
  • 26c (99 mg, 0.26 mmol) was dissolved in N,N-dimethylformamide (5 mL), followed by the addition of 1-cyano-1-cyclopropanecarboxylic acid (44 mg, 0.40 mmol), 2-(7- Nitrobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (152 mg, 0.40 mmol) and N,N-diisopropylethylamine (131 ⁇ L, 0.79 mmol), The whole system was stirred overnight at room temperature, and no raw material was found by TLC.
  • 1-cyano-1-cyclopropanecarboxylic acid 44 mg, 0.40 mmol
  • 2-(7- Nitrobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate 152 mg, 0.40 mmol
  • N,N-diisopropylethylamine 131 ⁇ L,
  • 26c (99 mg, 0.26 mmol) was dissolved in N,N-dimethylformamide (5 mL), followed by the addition of glycolic acid (20 mg, 0.26 mmol), 2-(7-azobenzotriazole)-N , N,N',N'-tetramethyluronium hexafluorophosphate (152mg, 0.40mmol) and N,N-diisopropylethylamine (131 ⁇ L, 0.79mmol), the whole system was stirred overnight at room temperature, TLC Check that there are no remaining raw materials.
  • Dissolve 69a (0.03g, 0.07mmol) in absolute ethanol (10mL), add 2.0M ammonia ethanol solution (0.004g, 0.28mmol), heat to 90°C, seal the tube for 4 hours, TLC monitors that there is no remaining raw material .
  • the solvent was evaporated under reduced pressure, the residue was dissolved in absolute ethanol (10 mL), and 40% dichloroacetaldehyde aqueous solution (0.005 g, 0.07 mmol) was added, heated to 90° C. for 8 hours, and there was no remaining raw material as monitored by TLC.
  • 70b (1.17g, 4.83mmol) was dissolved in dichloromethane (30mL), then 10mL of trifluoroacetic acid was added under an ice-water bath, and the whole system was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure to afford 70c (1.50 g) which was used directly in the next step.
  • 71a (0.45g, 0.94mmol) was dissolved in dichloromethane (30mL), then 2mL of trifluoroacetic acid was added in an ice-water bath, and the whole system was stirred at room temperature overnight, and no raw materials were detected by TLC.
  • 71b (0.31g, 0.82mmol) was dissolved in dichloromethane (35mL), then acetic anhydride (0.25g, 2.47mmol) and triethylamine (0.25g, 2.47mmol) were added, and the system was stirred at room temperature, monitored by TLC There are no raw materials left.
  • Add water (50mL) to the reaction solution, extract with dichloromethane (50mL ⁇ 3), combine the organic phases, wash with saturated sodium chloride (50mL ⁇ 2), dry over anhydrous sodium sulfate, remove the solvent under reduced pressure, and perform column chromatography Separation and purification (dichloromethane:methanol 50:1-10:1) gave the final product 71 (0.18g, yield 52%).
  • 6-Bromo-1-methyl-1H-indazole (211mg, 1.00mmol), bis-pinacol diborane (508mg, 2.00mmol), potassium acetate (294mg, 3.00mmol) and [1,1' - Bis(diphenylphosphino)ferrocene]palladium dichloride (73 mg, 0.10 mmol) was dissolved in 1,4-dioxane (20 mL). The reaction system was protected with nitrogen and reacted at 100° C. for 4 hours. TLC detected that there was no remaining raw material, and the heating was stopped.
  • 74b (0.12g, 0.25mmol) was dissolved in dichloromethane (20ml), 4mL of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 4 hours, and there was no remaining raw material as monitored by TLC. Wash the reaction solution with water (30mL ⁇ 3), combine the aqueous phase, adjust the pH of the aqueous phase to 8-9 with sodium carbonate, extract with dichloromethane (30mL ⁇ 3), combine the organic phase, wash with saturated sodium chloride (50mL ⁇ 2 ), dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure to give 74c (0.08 g, 84% yield).
  • Test Example 1 The inhibitory effect test of the compound of the present application on CDK9, CDK1, CDK2, CDK4, CDK5, CDK6 and CDK7
  • the compound was diluted with DMSO to 11 concentrations, 3-fold dilution, and the highest concentration of the compound to be tested was 10 ⁇ M.
  • Test Example 2 In vitro Inhibitory Effect of CDK9 Inhibitors on the Proliferation of Human Hepatoma Cells
  • MTT is thiazolium blue, which is a tetrazolium salt of a dye that can accept hydrogen atoms.
  • Amber dehydrogenase in the mitochondria of living cells can reduce exogenous MTT to insoluble blue-purple crystals and deposit them in cells, while dead cells have no such function.
  • Dimethyl sulfoxide can dissolve the blue-purple complex in the cells, and its light absorption value is measured at a wavelength of 490-550nm with an enzyme-linked immunosorbent detector, which can indirectly reflect the number of cells. Within a certain cell number range, the amount of MTT crystal formation is proportional to the cell number.
  • the OD value can reflect the number of living cells, and its IC 50 value is calculated with SPSS19.0.
  • the cell culture environment is 37°C, 5% CO 2 .
  • MTT working solution Weigh 0.5g of MTT and dissolve in 100mL PBS, filter and sterilize with a 0.22 ⁇ m microporous membrane, and store in a 4°C refrigerator (use within two weeks) or -20°C for long-term storage.
  • Inhibition rate (%) (well with normal OD value-well with drug-treated OD value)/(well with normal OD value-blank well with OD value) ⁇ 100%
  • the half inhibitory concentration IC 50 of the drug was calculated by SPSS19.0. See Table 3-1 and Table 3-2 for the cell proliferation inhibition results of the compounds:
  • the compound of the present application has a strong inhibitory effect on a variety of liver cancer cells, and the IC 50 of the in vitro cell inhibitory activity is basically below 1000nM, and the best can reach tens of nM .
  • Test Example 3 In vitro inhibitory effect of compounds on the proliferation of prostate cancer and breast cancer cells
  • the cell culture environment is 37°C, 5% CO 2 .
  • Inhibition rate (%) (well with normal OD value- well with drug-treated OD value)/(well with normal OD value- blank well with OD value) ⁇ 100%
  • the half inhibitory concentration IC 50 of the drug was calculated by SPSS19.0.
  • DU145 human prostate cancer cells
  • MDA-MB-231 human triple-negative breast cancer cells.
  • Test Example 4 In vivo investigation of anti-tumor activity of drugs - in vivo pharmacodynamics of the compound of the present application in the subcutaneous xenograft tumor model of human liver cancer Huh7 cells
  • Cell culture high glucose DMEM medium containing 10% fetal bovine serum (FBS), 37°C, 5% CO 2 .
  • FBS fetal bovine serum
  • mice Female, weighing about 18-22 grams, were inoculated with 0.1 mL (5 ⁇ 10 6 ) of Huh7 cells in the subcutaneous tissue of the armpit of each mouse.
  • 0.1 mL 5 ⁇ 10 6
  • administration began, and the dosage and method of administration were shown in the table below.
  • the tumor volume was measured twice a week, and the volume was measured in cubic millimeters.
  • the administration was terminated to compare the difference in average tumor volume between the test compound group and the solvent group.
  • the antitumor efficacy of compounds was evaluated by TGI (%).
  • TGI (%) reflects tumor growth inhibition rate.
  • the solvent composition of the solvent group and the administration group DMSO: HP- ⁇ -CD (0.5g/mL): water ratio is 2%: 20%: 78% (v/v/v)
  • TGI (%) [1-(average tumor volume at the end of certain treatment group administration-average tumor volume at the beginning of this treatment group)/(average tumor volume at the end of solvent control group administration-solvent The average tumor volume at the beginning of the control group)] ⁇ 100%.
  • the compound of the present application showed good drug efficacy and tolerance in vivo in the subcutaneous xenograft tumor model of human liver cancer Huh7 cells, which was comparable to that of BAY1251152 (at a dose of 5 mg/kg, 2 animals died and the tolerance was poor). Compared with, it has significant antitumor effect and better tolerance.
  • Test Example 5 In vivo investigation of anti-tumor activity of drugs - in vivo pharmacodynamics of the compound of the present application in the subcutaneous xenograft tumor model of human liver cancer SMMC-7721 cells
  • Cell culture RPMI-1640 medium containing 10% fetal bovine serum (FBS), 37°C, 5% CO 2 .
  • mice Female, 6-8 weeks old, weighing about 18-22 grams, were inoculated with 0.1 mL (1 ⁇ 10 8 ) of SMMC-7721 cells in the subcutaneous tissue of each mouse's forelimb armpit.
  • 0.1 mL (1 ⁇ 10 8 ) of SMMC-7721 cells in the subcutaneous tissue of each mouse's forelimb armpit.
  • administration began, and the dosage and method of administration were shown in the table below.
  • the tumor volume was measured twice a week, and the volume was measured in cubic millimeters.
  • the administration was terminated to compare the difference in average tumor volume between the test compound group and the solvent group.
  • the antitumor efficacy of compounds was evaluated by TGI (%).
  • TGI (%) reflects tumor growth inhibition rate.
  • the solvent composition of the solvent group and the administration group DMSO: HP- ⁇ -CD (0.5g/mL): water ratio is 2%: 20%: 78% (v/v/v)
  • TGI (%) [1-(average tumor volume at the end of certain treatment group administration-average tumor volume at the beginning of this treatment group)/(average tumor volume at the end of solvent control group administration-solvent The average tumor volume at the beginning of the control group)] ⁇ 100%.
  • the compound of the present application showed good drug efficacy and tolerance in vivo in the subcutaneous xenograft tumor model of human liver cancer SMMC-7721 cells, and the tolerance of mice was significantly better than that of the control drug.
  • Test Example 6 Investigation of anti-tumor activity of drugs in vivo - the in vivo drug efficacy of the compound of the present application in the subcutaneous xenograft tumor model of human liver cancer HepG2-Luc cells.
  • mice BALB/c Nude mice, weighing about 17-20 grams.
  • TGI tumor growth inhibition
  • TGI (%) [1-(average tumor volume at the end of certain treatment group administration-average tumor volume at the beginning of this treatment group)/(average tumor volume at the end of solvent control group administration-solvent The average tumor volume at the beginning of the control group)] ⁇ 100%.
  • Solvent 2% DMSO and 20% aqueous solution of 0.5g/mL concentration HP- ⁇ -CD (DMSO: HP- ⁇ -CD (0.5g/mL): water ratio is 2%: 20%: 78%, v/v/v).
  • Lenvatinib preparation Weigh an appropriate amount of Lenvatinib (approved by the FDA for the first-line treatment of patients with unresectable hepatocellular carcinoma), add it to the mixture of castor oil and absolute ethanol (1:1 by volume), and vortex Sonicate to a homogeneous solution, then add ultrapure water, vortex and sonicate to a homogeneous solution. (castor oil: absolute ethanol: ultrapure water volume ratio is 1:1:6).
  • the compounds of the present application show good drug efficacy and tolerance in vivo in the subcutaneous xenograft tumor model of human liver cancer HepG2-Luc cells; : 10mg/kg); at the dose of 7.5mg/kg, the degree of tumor inhibition of compound 45 was significantly better than that of Lenvatinib; during the test, the mice tolerated it well.
  • Test Example 7 Investigation of anti-tumor activity of the drug in vivo - the in vivo drug effect of the compound of the present application in the subcutaneous xenograft tumor model of human liver cancer Hep3B cells.
  • mice BALB/c Nude mice, weighing about 17-20 grams.
  • TGI tumor growth inhibition
  • TGI (%) [1-(average tumor volume at the end of certain treatment group administration-average tumor volume at the beginning of this treatment group)/(average tumor volume at the end of solvent control group administration-solvent The average tumor volume at the beginning of the control group)] ⁇ 100%.
  • Solvent 2% DMSO and 20% aqueous solution of 0.5g/mL concentration HP- ⁇ -CD (DMSO: HP- ⁇ -CD (0.5g/mL): water ratio is 2%: 20%: 78%, v/v/v).
  • Lenvatinib preparation Weigh an appropriate amount of Lenvatinib, add it to the mixture of castor oil and absolute ethanol (1:1 volume ratio), vortex and sonicate to a uniform solution, then add ultrapure water, vortex and sonicate to a uniform solution. (castor oil: absolute ethanol: ultrapure water volume ratio is 1:1:6).
  • the compounds of the present application show good drug efficacy and tolerance in vivo in the subcutaneous xenograft tumor model of human liver cancer Hep3B cells; at a dosage of 7.5 mg/kg, the degree of tumor inhibition of compound 45 is comparable to that of Lenvatinib (dosage: 10 mg/kg); during the test, the mice tolerated it well.
  • Test Example 8 Investigation of hERG Inhibitory Activity in Vitro
  • This test includes the following aspects:
  • hERG currents were recorded using the whole-cell patch clamp technique. Take the cell suspension and add it to the cell tank, and place it on the stage of the upright microscope. After the cells adhered to the wall, they were perfused with extracellular fluid at a flow rate of 1–2 mL/min. The glass microelectrode is drawn in two steps by a microelectrode pulling instrument, and its water resistance value is 2-5M ⁇ . After establishing whole-cell recordings, the clamping potential was maintained at -80mV. Depolarization to +60mV and repolarization to -50mV elicited hERG tail currents when voltage stimulation was given. All recordings were performed after the current was stabilized.
  • the administration of extracellular perfusion starts at a low concentration, and each concentration lasts for 5-10 minutes until the current is stable, and then the next concentration is given.
  • the half maximal inhibitory concentration (IC50 ) of the test compound was obtained by the best fit of the Logistic equation.
  • Amitripyline is one of the most widely used drugs to block hERG current, so it was used as a positive control drug in this study.
  • the IC 50 result of the active control drug Amitriptyline on the inhibition of hERG current is consistent with the historical results of the test party, and also consistent with the results reported in the literature, indicating that the results of this test are credible.
  • the above test results show that the tested compound cannot achieve half inhibition of hERG current at the highest test concentration, so the IC50 cannot be measured, indicating that the compound of the present application has no obvious inhibitory effect on the hERG channel within the detection concentration range of this test. To a certain extent, it can reflect that the compound of the application has low or no cardiotoxicity, which has positive significance for drug safety evaluation.
  • mice ICR mice (5 weeks), male and female
  • Test method ICR mice were divided into 7 groups according to weight balance, with 5 males and 5 mice in each group.
  • the method of administration is intragastric administration, once a day, for 7 consecutive days, and the dosage and results are shown in the table below.

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Abstract

L'invention concerne une application d'un composé représenté par la formule (I) ou un sel pharmaceutiquement acceptable, un stéréoisomère, un dérivé isotopique ou un promédicament de celui-ci dans le traitement de tumeurs solides, en particulier dans le traitement du cancer du foie, du cancer du sein ou du cancer de la prostate, comprenant une utilisation pharmaceutique associée, une composition pharmaceutique ou un procédé de traitement, etc.
PCT/CN2022/094454 2021-05-24 2022-05-23 Utilisation d'un inhibiteur de la kinase 9 cycline-dépendante WO2022247785A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102471310A (zh) * 2009-09-04 2012-05-23 诺瓦提斯公司 用于治疗增生性疾病的联吡啶化合物
CN102482265A (zh) * 2009-09-04 2012-05-30 诺瓦提斯公司 用于治疗增殖性疾病的吡嗪基吡啶化合物
CN102498107A (zh) * 2009-09-04 2012-06-13 诺瓦提斯公司 作为激酶抑制剂的杂芳基化合物
CN105189481A (zh) * 2013-03-13 2015-12-23 艾伯维公司 吡啶cdk9激酶抑制剂
CN107873028A (zh) * 2015-06-29 2018-04-03 阿斯利康(瑞典)有限公司 用作cdk9抑制剂的多环酰胺衍生物
WO2021050824A1 (fr) * 2019-09-11 2021-03-18 Prelude Therapeutics Incorporated Inhibiteurs de cdk et leur utilisation en tant que produits pharmaceutiques
WO2021115335A1 (fr) * 2019-12-09 2021-06-17 石药集团中奇制药技术（石家庄）有限公司 Composé utile en tant qu'inhibiteur de la kinase 9 dépendante de la cycline et son utilisation

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102471310A (zh) * 2009-09-04 2012-05-23 诺瓦提斯公司 用于治疗增生性疾病的联吡啶化合物
CN102482265A (zh) * 2009-09-04 2012-05-30 诺瓦提斯公司 用于治疗增殖性疾病的吡嗪基吡啶化合物
CN102498107A (zh) * 2009-09-04 2012-06-13 诺瓦提斯公司 作为激酶抑制剂的杂芳基化合物
CN105189481A (zh) * 2013-03-13 2015-12-23 艾伯维公司 吡啶cdk9激酶抑制剂
CN107873028A (zh) * 2015-06-29 2018-04-03 阿斯利康(瑞典)有限公司 用作cdk9抑制剂的多环酰胺衍生物
WO2021050824A1 (fr) * 2019-09-11 2021-03-18 Prelude Therapeutics Incorporated Inhibiteurs de cdk et leur utilisation en tant que produits pharmaceutiques
WO2021115335A1 (fr) * 2019-12-09 2021-06-17 石药集团中奇制药技术（石家庄）有限公司 Composé utile en tant qu'inhibiteur de la kinase 9 dépendante de la cycline et son utilisation

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