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WO2024066984A1 - Dérivé tricyclique, composition pharmaceutique et utilisation - Google Patents

Dérivé tricyclique, composition pharmaceutique et utilisation Download PDF

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Publication number
WO2024066984A1
WO2024066984A1 PCT/CN2023/117257 CN2023117257W WO2024066984A1 WO 2024066984 A1 WO2024066984 A1 WO 2024066984A1 CN 2023117257 W CN2023117257 W CN 2023117257W WO 2024066984 A1 WO2024066984 A1 WO 2024066984A1
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atoms
compound
ring
substituted
pharmaceutically acceptable
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PCT/CN2023/117257
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English (en)
Chinese (zh)
Inventor
胡璞
陆居权
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楚浦创制（武汉）医药科技有限公司
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Publication of WO2024066984A1 publication Critical patent/WO2024066984A1/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
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to the field of medical technology, and in particular to a tricyclic derivative, a pharmaceutically acceptable salt, a stereoisomer, a pharmaceutical composition and application thereof.
  • CDKs Cyclin-dependent kinases
  • CDK12 becomes an active substance by binding to cyclin K and transmits signals downstream.
  • the process of copying the genetic information of DNA to messenger RNA (mRNA) is called "transcription".
  • CDK12 extends the transcription reaction of mRNA by phosphorylating the second serine (Ser2) in the C-terminal region of RNA polymerase II.
  • CDK12 is believed to be involved in the transcription extension reaction of genes with long gene lengths and affects the expression of BRCA1, ATM, FANCD2 genes, etc. All of these genes are a group of genes involved in the DNA damage response (DDR) and are mainly involved in maintaining the stability of genomic DNA through DNA repair mechanisms.
  • DDR DNA damage response
  • Inhibition of CDK12 reduces the expression of DDR-related genes, thereby inhibiting the DNA repair response.
  • the inhibition of PARP and CDK12 involved in DNA completely inhibits the DNA repair response and induces cell death of cancer cells through synthetic lethality. Therefore, inhibiting the action of CDK12 is very useful for the prevention and
  • CDK12 inhibitors that can treat a variety of cancers, especially small molecule inhibitors that selectively target CDK12, which may have higher safety.
  • the present invention provides a tricyclic derivative with high CDK12 inhibitor activity, and a pharmaceutically acceptable salt or stereoisomer thereof.
  • the present invention is achieved through the following technical solutions.
  • R 1 and R 2 are independently selected from cyano, -CF 3 , -OCF 3 , -Cl, -Br, -F, hydroxyl, nitro, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, straight-chain alkyl having 1 to 20 C atoms, alkoxy having 1 to 20 C atoms, branched alkyl having 3 to 20 C atoms, substituted or unsubstituted cyclic alkyl having 3 to 20 C atoms, substituted or unsubstituted cyclic alkoxy having 3 to 20 C atoms, substituted or unsubstituted heterocyclyl having 3 to 20 ring atoms, -OR, -NH-R, or a combination of these systems; each occurrence of R is independently selected from substituted or unsubstituted cyclic alkoxy having 3 to 20 C atoms, substituted or unsubstituted heterocyclyl
  • R 3 and R 4 are independently selected from -H, -D, a linear alkyl group having 1 to 20 C atoms, a branched or cyclic alkyl group having 3 to 20 C atoms, a substituted or unsubstituted aromatic group having 6 to 60 ring atoms, or a combination of these groups;
  • Ar 1 is selected from any one of the following structures:
  • Each occurrence of X 1 is independently selected from CR 5 or N;
  • Each occurrence of Y 1 is independently selected from NR 6 , CR 6 R 7 , C ⁇ O, O, S or S ⁇ O;
  • R5 , R6 , and R7 are each independently selected from -H, -D, linear alkyl having 1 to 20 C atoms, alkoxy having 1 to 20 C atoms, branched alkyl having 3 to 20 C atoms, cyclic alkyl having 3 to 20 C atoms, branched alkoxy having 3 to 20 C atoms, cyclic alkoxy having 3 to 20 C atoms, or a combination of these systems.
  • the compound of formula (I) is a compound of formula (II):
  • R 3 and R 4 are independently selected from -H, -D, and a substituted or unsubstituted aromatic group having 6 to 30 ring atoms.
  • the compound of formula (I) is a compound of formula (III):
  • Ar 1 is selected from any one of the following structures:
  • Ar 1 is selected from any one of the following structures:
  • R 1 and R 2 are independently selected from cyano, -CF 3 , -Cl, -Br, -F or any one of the following structures:
  • the compound of formula (I) is any one of the following compounds:
  • the present invention also provides a use of the compound as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof in the preparation of a drug for treating and/or preventing a disease associated with CDK12 activity or mediated by CDK12 activity.
  • the disease associated with CDK12 activity or mediated by CDK12 activity is cancer.
  • the present invention also provides a pharmaceutical composition, comprising the compound as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and a pharmaceutically acceptable carrier.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof has the following beneficial effects:
  • the present invention provides a series of novel heterocyclic substituted tricyclic derivatives, which have high inhibitory activity against CDK12, and the inhibitory activity IC50 value against CDK12 kinase is 42nM to 367nM, so they can be used for treating and/or preventing diseases related to Drugs for diseases related to or mediated by CDK12 activity have potentially excellent therapeutic effects on diseases mediated by CDK12 activity.
  • first and second are used for descriptive purposes only and should not be understood as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Therefore, a feature defined as “first” or “second” may explicitly or implicitly include at least one of the features.
  • the meaning of “multiple” is at least two, such as two, three, etc., unless otherwise clearly and specifically defined.
  • severeal is at least one, such as one, two, etc., unless otherwise clearly and specifically defined.
  • composition and method/process of the present invention include, consist of and are essentially composed of the necessary elements and restrictions described herein and any additional or optional ingredients, components, steps or restrictions described herein.
  • effcacy “performance”, “effect” and “efficacy” are not distinguished between herein.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to salts of compounds of the invention, prepared from compounds of the invention having specific substituents with relatively nontoxic acids or bases.
  • base addition salts can be obtained by contacting such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like; and organic acid salts such as formic acid, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzene
  • the invention also includes salts of amino acids (such as arginine, etc.) and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic functional groups, and thus can be converted into any base or acid addition salt.
  • salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, the preparation method of such salts is: in water or an organic solvent or a mixture of the two, these compounds in free acid or base form are reacted with a stoichiometric amount of an appropriate base or acid to prepare.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present invention.
  • enantiomer or “optical isomer” refers to stereoisomers that are mirror images of one another.
  • cis-trans isomers or “geometric isomers” arises from the inability of a double bond or single bond forming a ring carbon atom to rotate freely.
  • diastereomer refers to stereoisomers that have two or more chiral centers and that are not mirror images of each other.
  • the key is a solid wedge. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond. and straight dashed key To indicate the relative configuration of a stereocenter, use a wavy line Denotes a solid wedge bond or dotted wedge key Or use a wavy line Represents a straight solid bond and straight dashed key
  • a compound contains a double bond structure, such as a carbon-carbon double bond, a carbon-nitrogen double bond, and a nitrogen-nitrogen double bond, and each atom on the double bond is connected to two different substituents (in a double bond containing a nitrogen atom, a lone pair of electrons on the nitrogen atom is regarded as a substituent connected to it), if a wavy line is used between the atom on the double bond and its substituent in the compound, If connected, it means the (Z) isomer, (E) isomer or a mixture of the two isomers of the compound.
  • formula (A) means that the compound exists in the form of a single isomer of formula (A-1) or formula (A-2) or in the form of a mixture of two isomers of formula (A-1) and formula (A-2);
  • formula (B) means that the compound exists in the form of a single isomer of formula (B-1) or formula (B-2) or in the form of a mixture of two isomers of formula (B-1) and formula (B-2).
  • formula (C) means that the compound exists in the form of a single isomer of formula (C-1) or formula (C-2) or in the form of a mixture of two isomers of formula (C-1) and formula (C-2).
  • tautomer or “tautomeric form” refers to isomers that differ in their functional groups at room temperature.
  • the isomers are in dynamic equilibrium and can be converted into each other very quickly. If tautomers are possible (such as in solution), chemical equilibrium of tautomers can be achieved.
  • proton tautomers also called prototropic tautomers
  • Valence tautomers include interconversions through the reorganization of some bonding electrons.
  • keto-enol tautomerization is the interconversion between the two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms “enriched in one isomer”, “isomerically enriched”, “enriched in one enantiomer” or “enantiomerically enriched” mean that the content of one isomer or enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
  • the term “isomer excess” or “enantiomeric excess” refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80%.
  • Optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is usually accomplished by using chromatography, which uses a chiral stationary phase and is optionally combined with a chemical derivatization method (for example, a carbamate is generated from an amine).
  • the compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more atoms constituting the compound.
  • the compound may be labeled with a radioactive isotope, such as tritium ( 3H ), iodine-125 ( 125I ) or C-14 ( 14C ).
  • deuterated drugs may be formed by replacing hydrogen with heavy hydrogen. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending the biological half-life of drugs. All isotopic composition changes of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable.
  • the type and number of substituents can be any on the basis of chemical achievable.
  • any variable e.g., R 1
  • its definition at each occurrence is independent.
  • the group may be optionally substituted with up to two R 1 s , and each occurrence of R 1 is an independent choice.
  • substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • substituent When a substituent is vacant, it means that the substituent does not exist. For example, when X in AX is vacant, it means that the structure is actually A. When the listed substituent does not specify which atom it is connected to the substituted group through, the substituent can be bonded through any atom of it. For example, pyridyl as a substituent can be connected to the substituted group through any carbon atom on the pyridine ring.
  • linking group L When the linking group is listed without specifying its linking direction, its linking direction is arbitrary, for example,
  • the connecting group L is -MW-, in which case -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form You can also connect ring A and ring B in the opposite direction of the reading order from left to right to form Combinations of linkers, substituents, and/or variations thereof are permissible only if such combinations result in stable compounds.
  • any one or more sites of the group can be connected to other groups through chemical bonds.
  • the chemical bond connection mode is non-positional and there are H atoms at the connectable sites, when the chemical bonds are connected, the number of H atoms at the site will decrease accordingly with the number of connected chemical bonds to become a group with a corresponding valence.
  • the chemical bond connecting the site to other groups can be a straight solid bond.
  • the straight solid bond in -OCH 3 indicates that it is connected to other groups through the oxygen atom in the group;
  • the straight dashed bond in the group indicates that the two ends of the nitrogen atom in the group are connected to other groups;
  • the wavy line in the phenyl group indicates that it is connected to other groups through the carbon atoms at positions 1 and 2 in the phenyl group; It means that any connectable site on the piperidine group can be connected to other groups through one chemical bond, including at least These four connection methods, even if the H atom is drawn on -N-, Still includes For groups connected in this way, when one chemical bond is connected, the H at that site will be reduced by one and become the corresponding monovalent piperidine group.
  • the number of atoms in a ring is generally defined as the ring member number, for example, "3-7 membered ring” refers to a “ring” having 3-7 atoms arranged around it.
  • C 1-6 alkyl is used to represent a straight or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. Preferably, it is a C 1-4 alkyl group, which may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine).
  • Examples of C 1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, tert-butyl and sec-butyl).
  • C 1-6 alkoxy refers to those alkyl groups containing 1 to 6 carbon atoms connected to the rest of the molecule through an oxygen atom. Preferably, it is C 1-3 alkoxy. Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • C 1-6 alkylamino refers to those containing 1 to 6
  • the alkyl group is preferably a C 1-3 alkylamino group.
  • Examples of C 1-3 alkylamino groups include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -NHCH 2 CH 2 CH 3 , -NHCH 2 (CH 3 ) 2 and the like.
  • halo or halogen, by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
  • 5-membered heteroaromatic ring and “5-membered heteroaryl” are used interchangeably in the present invention.
  • the term “5-membered heteroaryl” refers to a monocyclic group with a conjugated ⁇ electron system consisting of 5 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms.
  • the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2).
  • the 5-membered heteroaryl can be connected to the rest of the molecule through a heteroatom or a carbon atom.
  • Examples of the 5-membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2 H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazo
  • Cn-n+m or Cn - Cn+m includes any specific case of n to n+m carbon atoms, for example, C1-12 includes C1 , C2 , C3 , C4 , C5 , C6 , C7 , C8 , C9 , C10 , C11 , and C12 , and also includes any range from n to n+m, for example, C1-12 includes C1-3 , C1-6 , C1-9, C3-6 , C3-9 , C3-12 , C6-9 , C6-12 , and C13 .
  • n-membered to n+m-membered means that the number of atoms in the ring is n to n+m
  • 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, and 12-membered ring, and also includes any range from n to n+m, for example, 3-12-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring, 5-7-membered ring, 6-7-membered ring, 6-8-membered ring, and 6-10-membered ring, etc.
  • C 3-7 cycloalkyl means a saturated cyclic hydrocarbon group consisting of 3 to 7 carbon atoms, including monocyclic and bicyclic systems, wherein the bicyclic system includes spirocyclic, fused and bridged rings.
  • the C 3-7 cycloalkyl includes C 3-6 , C 4-6 , C 4-5 , C 5-7 or C 5-6 cycloalkyl, etc.; it can be monovalent, divalent or polyvalent.
  • Examples of C 3-7 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.
  • the term "3-7 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 3 to 7 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spirocyclic, paracyclic and bridged rings.
  • heteroatoms may occupy the position where the heterocycloalkyl is connected to the rest of the molecule.
  • the 3-7 membered heterocycloalkyl includes 5-7 membered, 3 membered, 4 membered, 5 membered, 6 membered and 7 membered heterocycloalkyl, etc.
  • 3-7 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl
  • 3-7 membered nitrogen-containing heterocycloalkyl refers to a 3-7 membered heterocycloalkyl group containing at least one nitrogen atom.
  • Alicyclic refers to a saturated or partially unsaturated all-carbon ring system. Wherein “partially unsaturated” refers to a ring portion including at least one double bond or triple bond, and “partially unsaturated” is intended to cover rings with multiple unsaturated sites, but is not intended to include aryl or heteroaryl moieties as defined herein.
  • Non-limiting examples include cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, cyclopentenyl ring, cyclohexyl ring, cyclohexenyl ring, cyclohexadienyl ring, cycloheptyl ring, cycloheptatrienyl ring, cyclopentanone ring, cyclopentane-1,3-dione ring, etc.
  • Alicyclic group refers to a saturated or partially unsaturated alicyclic group in which 1, 2 or 3 ring carbon atoms are replaced by heteroatoms selected from nitrogen, oxygen or S(O) t (wherein t is an integer from 0 to 2), but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon.
  • Non-limiting examples include propylene oxide ring, azetidine ring, oxetane ring, tetrahydrofuran ring, tetrahydrothiophene ring, tetrahydropyrrole ring, piperidine ring, pyrroline ring, oxazolidine ring, piperazine ring, dioxolane ring, dioxane ring, morpholine ring, Thiomorpholine ring, thiomorpholine-1,1-dioxide, tetrahydropyran ring, azetidine-2-one ring, oxetane-2-one ring, pyrrolidine-2-one ring, pyrrolidine-2,5-dione ring, piperidine-2-one ring, dihydrofuran-2(3H)-one ring, dihydrofuran-2,5-dione ring, tetrahydro-2H-pyran-2-one ring
  • Non-limiting examples of partially unsaturated monocyclic heterocycles include 1,2-dihydroazetidine ring, 1,2-dihydrooxetadiene ring, 2,5-dihydro-1H-pyrrole ring, 2,5-dihydrofuran ring, 2,3-dihydrofuran ring, 2,3-dihydro-1H-pyrrole ring, 3,4-dihydro-2H-pyran ring, 1,2,3,4-tetrahydropyridine ring, 3,6-dihydro-2H-pyran ring, 1,2,3,6-tetrahydropyridine ring, 4,5-dihydro-1H-imidazole ring, 1,4,5,6-tetrahydropyrimidine ring, 3,4,7,8-tetrahydro-2H-1,4,6-oxadiazolidine ring, 1,6-dihydropyrimidine ring, 4,5,6,7-tetrahydro-1H-1,3-diazapin
  • Aryl and “aromatic ring” are used interchangeably, and both refer to an all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group with a conjugated ⁇ electron system, which group may be fused with a cycloalkyl ring, a heterocycloalkyl ring, a cycloalkenyl ring, a heterocycloalkenyl ring, or a heteroaryl group.
  • C6-10 aryl refers to a monocyclic or bicyclic aromatic group having 6 to 10 carbon atoms, and non-limiting examples of aryl include phenyl, naphthyl, and the like.
  • Heteroaryl and “heteroaryl ring” are used interchangeably and refer to a monocyclic, bicyclic or polycyclic 4n+2 aromatic ring system (e.g., having 6 or 10 ⁇ electrons shared in a cyclic arrangement) having ring carbon atoms and ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur.
  • heteroaryl also includes a ring system in which the above-mentioned heteroaryl ring is fused with one or more cycloalkyl rings, heterocycloalkyl rings, cycloalkenyl rings, heterocycloalkenyl rings or aromatic rings.
  • the heteroaryl ring may be optionally substituted.
  • “5 to 10 membered heteroaryl” refers to a monocyclic or bicyclic heteroaryl having 5 to 10 ring atoms, wherein 1, 2, 3 or 4 ring atoms are heteroatoms.
  • “5- to 6-membered heteroaryl” refers to a monocyclic heteroaryl group having 5 to 6 ring atoms, wherein 1, 2, 3 or 4 of the ring atoms are heteroatoms, non-limiting examples of which include thienyl, furanyl, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-o
  • 8- to 10-membered heteroaryl refers to a bicyclic heteroaryl group having 8 to 10 ring atoms, wherein 1, 2, 3 or 4 of the ring atoms are heteroatoms, non-limiting examples of which include indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl,
  • heteroatom refers to nitrogen, oxygen or sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valence permits. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings.
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (e.g., a nucleophilic substitution reaction).
  • a substitution reaction e.g., a nucleophilic substitution reaction.
  • representative leaving groups include trifluoromethanesulfonate; chlorine, bromine, iodine; sulfonate groups, such as mesylate, tosylate, p-brosylate, p-toluenesulfonate, etc.; acyloxy groups, such as acetoxy, trifluoroacetoxy, etc.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butyloxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-bis-(4'-methoxyphenyl)methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldi
  • hydroxy protecting group refers to a protecting group suitable for preventing side reactions of the hydroxyl group.
  • Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl (e.g., acetyl); arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like.
  • alkyl groups such as methyl, ethyl and tert-butyl
  • acyl groups such as alkanoyl (e.g., acetyl)
  • arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (
  • substituted independently selected from
  • substituents independently selected from means that when more than one hydrogen on a group is replaced by a substituent, the substituents may be the same or different, and the substituents selected are independently of each other.
  • the compound of the present invention or its pharmaceutically acceptable salt, or its stereoisomer can be used in a suitable dosage form with one or more pharmaceutical carriers.
  • dosage forms are suitable for oral, rectal, topical, oral and other parenteral administration (e.g., subcutaneous, intramuscular, intravenous, etc.).
  • dosage forms suitable for oral administration include capsules, tablets, granules and syrups.
  • the compounds of the present invention contained in these preparations can be solid powders or particles; solutions or suspensions in aqueous or non-aqueous liquids; water-in-oil or water-in-oil emulsions, etc.
  • the above dosage forms can be made from active compounds and one or more carriers or excipients via a common pharmaceutical method.
  • non-toxic carriers include but are not limited to mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose, etc.
  • Carriers for liquid preparations include water, saline, aqueous glucose solution, ethylene glycol and polyethylene glycol, etc.
  • the active compound can form a solution or suspension with the above carriers.
  • compositions of the present invention are formulated, dosed and administered in a manner consistent with medical practice.
  • the "therapeutically effective amount" of the compound administered is determined by factors such as the specific condition to be treated, the individual being treated, the cause of the condition, the target of the drug, and the mode of administration.
  • “Therapeutically effective amount” refers to the amount of the compound of the present invention that will elicit a biological or medical response in a subject, such as reducing or inhibiting enzyme or protein activity or improving symptoms, alleviating symptoms, slowing or delaying disease progression, or preventing disease.
  • the therapeutically effective amount of the compound of the present invention or its pharmaceutically acceptable salt, or its stereoisomer contained in the pharmaceutical composition or the pharmaceutical composition of the present invention is preferably 0.1 mg-5 g/kg (body weight).
  • Patient refers to an animal, preferably a mammal, more preferably a human.
  • mammal refers to warm-blooded vertebrate mammals, including, for example, cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, mice, pigs and humans.
  • Treatment means to lessen, slow the progression, attenuate, prevent, or maintain an existing disease or condition (eg, cancer). Treatment also includes curing, preventing the development of, or alleviating to some extent, one or more symptoms of a disease or condition.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.
  • the structure of the compounds of the present invention can be confirmed by conventional methods known to those skilled in the art. If the present invention relates to the absolute configuration of the compounds, the absolute configuration can be confirmed by conventional technical means in the art.
  • single crystal X-ray diffraction SXRD
  • the light source is CuK ⁇ radiation
  • the scanning mode is ⁇ scanning.
  • the direct method Shelxs97 is further used to analyze the crystal structure, and the absolute configuration can be confirmed.
  • Pd/C represents palladium on carbon
  • H 2 represents hydrogen
  • N 2 represents nitrogen
  • mL represents milliliter
  • H 2 O water
  • AcOH represents acetic acid
  • B 2 Pin 2 represents bis-pinacol borate
  • Pd(dppf)Cl 2 represents 1,1'-bisdiphenylphosphinoferrocene palladium dichloride
  • KOAc represents potassium acetate
  • EtOAc represents ethyl acetate
  • K 2 CO 3 represents potassium carbonate
  • MeCN represents acetonitrile
  • DIEA represents N,N-diisopropylethylamine
  • MeOH represents methanol
  • THF represents tetrahydrofuran
  • DMAP represents 4-dimethylaminopyridine
  • Pd(Amphos) 2 Cl 2 represents dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium(II
  • the present invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
  • R 1 and R 2 are independently selected from cyano, -CF 3 , -OCF 3 , -Cl, -Br, -F, hydroxyl, nitro, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, straight-chain alkyl having 1 to 20 C atoms, alkoxy having 1 to 20 C atoms, branched alkyl having 3 to 20 C atoms, substituted or unsubstituted cyclic alkyl having 3 to 20 C atoms, substituted or unsubstituted cyclic alkoxy having 3 to 20 C atoms, substituted or unsubstituted heterocyclyl having 3 to 20 ring atoms, -OR, -NH-R, or a combination of these systems; each occurrence of R is independently selected from substituted or unsubstituted cyclic alkoxy having 3 to 20 C atoms, substituted or unsubstituted heterocyclyl
  • R 3 and R 4 are independently selected from -H, -D, a linear alkyl group having 1 to 20 C atoms, a branched or cyclic alkyl group having 3 to 20 C atoms, a substituted or unsubstituted aromatic group having 6 to 60 ring atoms, or a combination of these groups;
  • Ar 1 is selected from any one of the following structures:
  • Each occurrence of X 1 is independently selected from CR 5 or N;
  • Each occurrence of Y 1 is independently selected from NR 6 , CR 6 R 7 , C ⁇ O, O, S or S ⁇ O;
  • R5 , R6 , and R7 are each independently selected from -H, -D, linear alkyl having 1 to 20 C atoms, alkoxy having 1 to 20 C atoms, branched alkyl having 3 to 20 C atoms, cyclic alkyl having 3 to 20 C atoms, branched alkoxy having 3 to 20 C atoms, cyclic alkoxy having 3 to 20 C atoms, or a combination of these systems.
  • the compound of formula (I) is a structure shown in formula (II):
  • R 3 and R 4 are independently selected from -H, -D, and a substituted or unsubstituted aromatic group having 6 to 30 ring atoms.
  • R 3 and R 4 are independently selected from -H, -D, and a substituted or unsubstituted aromatic group having 6 to 15 ring atoms.
  • R 3 and R 4 are independently selected from -H, -D, and substituted or unsubstituted phenyl.
  • the compound of formula (I) is a structure shown in formula (III):
  • Ar 1 is selected from any one of the following structures:
  • each occurrence of R 5 , R 6 , and R 7 is independently selected from -H, -D, a straight-chain alkyl group having 1 to 10 C atoms, an alkoxy group having 1 to 10 C atoms, a branched-chain alkyl group having 3 to 10 C atoms, a cyclic alkyl group having 3 to 10 C atoms, a branched-chain alkoxy group having 3 to 10 C atoms, a cyclic alkoxy group having 3 to 10 C atoms, or a combination of these systems.
  • each occurrence of R 5 , R 6 , and R 7 is independently selected from -H, -D, a straight-chain alkyl group having 1 to 5 C atoms, an alkoxy group having 1 to 5 C atoms, a branched-chain alkyl group having 3 to 5 C atoms, a cyclic alkyl group having 3 to 5 C atoms, a branched-chain alkoxy group having 3 to 5 C atoms, a cyclic alkoxy group having 3 to 5 C atoms, or a combination of these systems.
  • Ar 1 is selected from any one of the following structures:
  • R 1 and R 2 are independently selected from cyano, -CF 3 , -OCF 3 , -Cl, -Br, -F, hydroxyl, nitro, unsubstituted imidazolyl, imidazolyl substituted by alkyl, Cl or F, unsubstituted pyrazolyl, pyrazolyl substituted by alkyl, Cl or F, unsubstituted heterocyclyl having 3 to 20 ring atoms, heterocyclyl having 3 to 20 ring atoms substituted by alkyl, hydroxyl, Cl, F or a combination thereof, -OR, -NH-R.
  • R 1 and R 2 are independently selected from cyano, -CF 3 , -OCF 3 , -Cl, -Br, -F, hydroxyl, nitro, unsubstituted imidazolyl, imidazolyl substituted by alkyl, Cl or F, unsubstituted pyrazolyl, pyrazolyl substituted by alkyl, Cl or F, unsubstituted heterocyclyl having 3 to 10 ring atoms, heterocyclyl having 3 to 10 ring atoms substituted by alkyl, hydroxyl, Cl, F or a combination thereof, -OR, -NH-R.
  • R 1 and R 2 are independently selected from cyano, -CF 3 , -OCF 3 , -Cl, -Br, -F, hydroxyl, nitro, unsubstituted imidazolyl, imidazolyl substituted by alkyl, Cl or F, unsubstituted pyrazolyl, pyrazolyl substituted by alkyl, Cl or F, unsubstituted heterocyclyl having 3 to 5 ring atoms, heterocyclyl having 3 to 5 ring atoms substituted by alkyl, hydroxyl, Cl, F or a combination thereof, -OR, -NH-R.
  • the heterocyclyl group is a nitrogen-containing cycloalkyl group.
  • each occurrence of R is independently selected from a substituted or unsubstituted cyclic alkoxy group having 3 to 10 C atoms, or a substituted or unsubstituted heterocyclyl group having 3 to 10 ring atoms.
  • each occurrence of R is independently selected from a substituted or unsubstituted cyclic alkoxy group having 3 to 5 C atoms, or a substituted or unsubstituted heterocyclyl group having 3 to 5 ring atoms.
  • the heterocyclyl group is a nitrogen-containing cycloalkyl group.
  • R 1 and R 2 are independently selected from cyano, -CF 3 , -Cl, -Br, -F or any one of the following structures:
  • the compound of formula (I) is any one of the following compounds:
  • the pharmaceutically acceptable salt is an alkyl acid salt.
  • the pharmaceutically acceptable salt is a formate salt.
  • the present invention also provides a use of the above-mentioned compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof in the preparation of a drug for treating and/or preventing a disease related to CDK12 activity or mediated by CDK12 activity.
  • the disease associated with or mediated by CDK12 activity is cancer.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. construct, and a pharmaceutically acceptable carrier.
  • This embodiment provides compound 1, whose structural formula is as follows:
  • the reaction route is as follows:
  • the preparation process is as follows:
  • step 1
  • compound 1-2 (3.00 g, 14.1 mmol, 1.00 eq), compound 1-3 (1.54 g, 14.1 mmol, 1.00 eq), TEA (14.1 g, 14.1 mmol, 1.8 mL, 1.00 eq) were added to toluene (10.0 mL) and stirred at 100 ° C for 2 hours. After the reaction was completed, 30.0 mL of water was added and stirred for 30 min. After the solid was completely precipitated, the mixture was filtered to obtain insoluble crude products of compounds 1-4 and 1-4a.
  • LCMS: MS (ESI) m/z 365.8 [M+H] +.
  • compound 1-6 100 mg, 359. ⁇ mol, 1.00 eq
  • compound 1-7 154 mg, 719 ⁇ mol, 2.0 eq
  • Xphos 32.6 mg, 35.9 ⁇ mol, 0.10 eq
  • BrettPhosPd G3 34.2 mg, 71.9 ⁇ mol, 0.20 eq
  • Cs 2 CO 3 351 mg, 1.08 mmol, 3.00 eq
  • compound 1-10 100 mg, 224 ⁇ mol, 1.00 eq
  • compound 1-11 68.7 mg, 269 ⁇ mol, 1.20 eq
  • DIEA 87.2 mg, 674 ⁇ mol, 117 ⁇ L, 3.00 eq
  • the product was purified by preparative high performance liquid chromatography (column: Phenomenexluna C18 150 ⁇ 25.0mm ⁇ 10.0 ⁇ m; mobile phase: [water(FA)-ACN]; B%: 39.0%-69.0%, 9.0min) was separated and purified to obtain the formate salt of compound 1.
  • This embodiment provides compound 2, whose structural formula is as follows:
  • the reaction route is as follows:
  • the preparation process is as follows:
  • step 1
  • Compound 2-6 was purified by preparative high performance liquid chromatography (FA conditions: column: Phenomenexluna C18 150 ⁇ 25.0 mm ⁇ 10.0 ⁇ m; mobile phase: [water (FA)-ACN]; B%: 17.0%-47.0%, 9.0 min).
  • compound 2-6 100 mg, 242 ⁇ mol, 1.00 eq
  • DIEA 94.0 mg, 727 ⁇ mol, 126 ⁇ L, 3.00 eq
  • THF 1.00 mL
  • bis(trichloromethyl) carbonate 359 mg, 1.21 mmol, 5.00 eq
  • the mixture was stirred at 60 °C for 1 hour.
  • Compound 2-7 (51.9 mg, 484 ⁇ mol, 52.8 ⁇ L, 2.00 eq) and DMAP (29.6 mg, 242 ⁇ mol, 1.00 eq) were then added.
  • This embodiment provides compound 3, whose structural formula is as follows:
  • the reaction route is as follows:
  • the preparation process is as follows:
  • step 1
  • compound 3-1 (6.00 g, 23.9 mmol, 1.00 eq) was dissolved in tetrahydrofuran (50.0 mL), methanol (4.75 g, 148 mmol, 6.00 mL, 6.19 eq) and potassium tert-butoxide (4.03 g, 35.9 mmol, 1.5 eq) were added, and the temperature was raised to 20°C for 3 hours.
  • Ammonium chloride (50.0 mL) was added to the reaction system at 25°C to quench the reaction, and then extracted with ethyl acetate (100 mL ⁇ 3) 3 times.
  • compound 3-2 (4.00 g, 16.2 mmol, 1.00 eq), Pin 2 B 2 (8.26 g, 32.5 mmol, 2.00 eq), KOAc (3.19 g, 32.5 mmol, 2.00 eq), Pd(dppf)Cl 2 (356 mg, 487 ⁇ mol, 0.03 eq) were dissolved in dioxane (40.0 mL) and replaced with nitrogen three times. The mixture was reacted at 90° C. under a nitrogen atmosphere for 3 hours. The mixture was extracted three times with ethyl acetate (100 mL).
  • compound 3-5 (2.70 g, 7.94 mmol, 1.00 eq) and potassium hydroxide (2.23 g, 39.7 mmol, 5.00 eq) were added to water (25.0 mL) and stirred at 100°C for 3 hours.
  • the aqueous layer was then acidified to pH 5 with 1 M hydrochloric acid solution.
  • the reaction mixture was extracted with ethyl acetate (20.0 mL) for 3 times.
  • the organic phases were combined, washed with saturated sodium chloride aqueous solution (50.0 mL) for 3 times, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 3-6.
  • compound 3-8 100 mg ⁇ 2, 342 ⁇ mol, 1.00 eq
  • compound 1-7 110 mg, 513 ⁇ mol, 1.50 eq
  • RuPhosPdG 3 28.6 mg, 34.2 ⁇ mol, 0.100 eq
  • Cs 2 CO 3 334 mg, 1.03 mmol, 3.00 eq
  • the reaction system was diluted with water (5.00 mL) and extracted three times with ethyl acetate (10.0 mL ⁇ 3).
  • compound 3-11 (93.0 mg, 202 ⁇ mol, 1.00 eq) and compound 1-11 (51.6 mg, 202 ⁇ mol, 1.00 eq) were dissolved in DMF (1.00 mL), and DIEA (78.6 mg, 608 ⁇ mol, 105 ⁇ L, 3.00 eq) was added, and the mixture was reacted at 20 °C for 12 hours.
  • the reaction system was diluted with water (3.00 mL) and extracted with ethyl acetate (5.00 mL ⁇ 3) three times.
  • This embodiment provides compound 4, whose structural formula is as follows:
  • the reaction route is as follows:
  • the preparation process is as follows:
  • step 1
  • compound 4-2 (5.60 g, 21.7 mmol, 1.00 eq), TEA (2.42 g, 23.9 mmol, 3.33 mL, 1.10 eq) and DPPA (6.59 g, 23.9 mmol, 5.19 mL, 1.10 eq) were dissolved in tert-butyl alcohol (60.0 mL), reacted at 20 ° C for 0.5 hours, then heated to 80 ° C for 8 hours, diluted with NaHCO 3 (aq, 40.0 mL), and extracted with ethyl acetate (80.0 mL ⁇ 3) for 3 times.
  • compound 4-5 (7.55 g, 33.7 mmol, 6.68 mL, 4.00 eq) was added to tetrahydrofuran (18.0 mL), and NaH (1.35 g, 33.7 mmol, 60% purity, 4.0 eq) was slowly added. The mixture was reacted at 0°C for 0.5 hours, and then compound 4-4 (3.00 g, 8.42 mmol, 1.00 eq) was dissolved in tetrahydrofuran (18.0 mL) and added dropwise to the reaction system. The mixture was reacted at 60°C for 12 hours.
  • compound 4-6 (3.56 g, 8.35 mmol, 1.00 eq) was dissolved in HCl/MeOH (30.0 mL) and stirred at 20°C for 4 hours. The pH was adjusted to 9 with sodium bicarbonate solution and filtered to obtain compound 4-7.
  • compound 4-7 (1.30 g, 4.64 mmol, 1.00 eq) was dissolved in DMF (15.0 mL), and MeI (988 mg, 6.96 mmol, 433 ⁇ L, 1.50 eq) and K 2 CO 3 (1.28 g, 9.28 mmol, 2.00 eq) were added, and stirred at 50°C for 3 hours.
  • the reaction system was diluted with water (20.0 mL) and extracted with ethyl acetate (40.0 ⁇ 3 mL) for 3 times.
  • compound 4-8 200 mg, 2.67 ⁇ mol, 1.00 eq
  • compound 1-7 (218 mg, 1.02 mmol, 1.50 eq)
  • XPhosPdG 3 57.5 mg, 67.9 ⁇ mol, 0.100 eq
  • Cs 2 CO 3 664 mg, 2.04 mmol, 3.00 eq
  • the reaction system was diluted with water (10.0 mL) and extracted three times with ethyl acetate (15.0 mL ⁇ 3).
  • compound 4-11 (64.0 mg, 138 ⁇ mol, 1.00 eq) and compound 1-11 (35.3 mg, 138 ⁇ mol, 1.00 eq) were dissolved in DMF (1.00 mL), and DIEA (53.8 mg, 416 ⁇ mol, 72.6 ⁇ L, 3.00 eq) was added, and the mixture was reacted at 20 °C for 12 hours.
  • the reaction system was diluted with water (3.00 mL) and extracted with ethyl acetate (5.00 mL ⁇ 3) for 3 times.
  • This embodiment provides compound 5, whose structural formula is as follows:
  • the reaction route is as follows:
  • the preparation process is as follows:
  • step 1
  • This embodiment provides compound 6, whose structural formula is as follows:
  • the reaction route is as follows:
  • the preparation process is as follows:
  • step 1
  • compound 1-10 (10.0 mg, 22.5 ⁇ mol, 1.00 eq) and compound 6-4 (5.40 mg, 22.5 ⁇ mol, 1.00 eq) were dissolved in DMF (1.00 mL), and K 2 CO 3 (9.33 mg, 67.5 ⁇ mol, 3.00 eq) was added, and the mixture was reacted at 60°C for 12 hours.
  • the reaction system was diluted with water (3.00 mL) and extracted with ethyl acetate (5.00 mL ⁇ 3) for 3 times.
  • the reaction route is as follows:
  • the preparation process is as follows:
  • step 1
  • compound 7-1 500 mg, 2.69 mmol, 1.00 eq
  • compound 7-2 (1.24 g, 4.04 mmol, 1.50 eq)
  • sodium carbonate 2.0 M, 2.69 mL, 2.00 eq
  • dimethyl ether 10.0 mL
  • dichlorobis[di-tert-butyl-(4-dimethylaminophenyl)phosphine]palladium (II) 190 mg, 269 ⁇ mol, 190 ⁇ L, 0.10 eq
  • II dichlorobis[di-tert-butyl-(4-dimethylaminophenyl)phosphine]palladium
  • the reaction route is as follows:
  • the preparation process is as follows:
  • step 1
  • compound 8-3 (12.9 mg, 45.2 ⁇ mol, 1.00 eq) and compound 1-10 (20.0 mg, 45.1 ⁇ mol, 1.00 eq) were dissolved in DMF (1.00 mL), and DIEA (17.5 mg, 135 ⁇ mol, 23.6 ⁇ L, 3.00 eq) was added, and the mixture was reacted at 25 °C for 12 hours.
  • the reaction system was diluted with water (3.00 mL) and extracted with ethyl acetate (5.00 mL ⁇ 3) three times.
  • CDK2/CyclinE 1 was purchased from Syngenecon. ⁇ Light-4E-BP1 peptide, Eu-anti-phospho-tyrosine antibody, and 1X detection buffer were purchased from PerkinElmer. High-purity ATP was purchased from Promega. EDTA was purchased from Sigma. Nivo multi-label analyzer (PerkinElmer).
  • Kinase buffer contains 50 mM HEPES, 1 mM EDTA, 10 mM MgCl 2 , 0.01% Brij-35, pH 7.4. Add 2.38 g HEPES, 58 mg EDTA, 406 mg MgCl 2 , 20 mg Brij-35 to 200 ml buffer and adjust the pH to 7.4.
  • Example-Min The raw data were converted into inhibition rate using the equation (Sample-Min)/(Max-Min) ⁇ 100%, and the IC50 value was obtained by four-parameter curve fitting (obtained by log(inhibitor) vs.response--Variable slope mode in GraphPad Prism).
  • Table 1 provides the inhibitory activity of the compounds of the present invention on CDK2/CyclinE 1 enzyme.
  • CDK12/CyclinK was purchased from BIORTUS. ⁇ Light-4E-BP1 peptide, Eu-anti-phospho-tyrosine antibody, and 1X detection buffer were purchased from PerkinElmer. High-purity ATP was purchased from Promega. EDTA was purchased from Sigma. Nivo multi-label analyzer (PerkinElmer).
  • Kinase buffer contains 50 mM HEPES, 1 mM EDTA, 10 mM MgCl 2 , 0.01% Brij-35, pH 7.4. Add 2.38 g HEPES, 58 mg EDTA, 406 mg MgCl 2 , 20 mg Brij-35 to 200 ml buffer and adjust the pH to 7.4.
  • Use kinase buffer to dilute the enzyme, ⁇ Light-4E-BP1 peptide, ATP and inhibitor.
  • Use detection buffer to dilute Eu-anti-phospho-tyrosine antibody to a concentration of 8nM/L. Dilute the test compound 5 times to the 8th concentration with a gun, that is, from 40 ⁇ M to 0.512nM, the final DMSO concentration is 4%, and a double-well experiment is set up.
  • Table 1 provides the inhibitory activity of the compounds of the present invention on CDK12/CyclinK enzymes.
  • 1640 culture medium was from Vivacell, fetal bovine serum was from Biosera, penicillin/streptomycin antibiotics were purchased from Yuanpei, CellTiter-Glo (cell viability chemiluminescence detection reagent) reagent was purchased from Promega, A2780 cell line was purchased from Cobright, Envision multi-label analyzer (PerkinElmer).
  • A2780 cells were seeded in a white 96-well plate, with 80 ⁇ L of cell suspension per well, containing 3000 A2780 cells.
  • the cell plate was placed in a carbon dioxide incubator for overnight culture.
  • the compound to be tested was diluted 5-fold to the 8th concentration, from 2000 ⁇ M to 0.0256 nM, using a dispenser, and a double-well experiment was set up.
  • 78 ⁇ L of culture medium was added to the middle plate, and then 2 ⁇ L of the gradient diluted compound per well was transferred to the middle plate according to the corresponding position, and 20 ⁇ L of each well was transferred to the cell plate after mixing.
  • the concentration range of the compound transferred to the cell plate was 10 ⁇ M to 0.128 nM.
  • the cell plate was placed in a carbon dioxide incubator for 3 day. Prepare another cell plate and read the signal value on the day of drug addition as the maximum value (Max value in the equation below) for data analysis.
  • Table 1 provides the inhibitory activity of the compounds of the present invention on A2780 cell proliferation.

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  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un dérivé tricyclique, et sa structure est telle que représentée dans la formule (I). En outre, la présente invention concerne en outre un sel pharmaceutiquement acceptable du dérivé, un stéréoisomère, et une composition pharmaceutique de celui-ci, et son utilisation. Le composé de la présente invention a une activité inhibitrice de CDK12 significative et a une grande valeur pratique.
PCT/CN2023/117257 2022-09-30 2023-09-06 Dérivé tricyclique, composition pharmaceutique et utilisation WO2024066984A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105849099A (zh) * 2013-10-18 2016-08-10 达纳-法伯癌症研究所股份有限公司 周期蛋白依赖性激酶7(cdk7)的多环抑制剂
CN107530329A (zh) * 2015-03-09 2018-01-02 奥瑞基尼探索技术有限公司 用作CDK抑制剂的吡唑并[1,5‑a][1,3,5]三嗪和吡唑并[1,5‑a]嘧啶衍生物
CN108024970A (zh) * 2015-06-04 2018-05-11 奥瑞基尼探索技术有限公司 用作cdk抑制剂的经过取代的杂环衍生物
CN111918863A (zh) * 2018-03-29 2020-11-10 武田药品工业株式会社 杂环化合物

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105849099A (zh) * 2013-10-18 2016-08-10 达纳-法伯癌症研究所股份有限公司 周期蛋白依赖性激酶7(cdk7)的多环抑制剂
CN107530329A (zh) * 2015-03-09 2018-01-02 奥瑞基尼探索技术有限公司 用作CDK抑制剂的吡唑并[1,5‑a][1,3,5]三嗪和吡唑并[1,5‑a]嘧啶衍生物
CN108024970A (zh) * 2015-06-04 2018-05-11 奥瑞基尼探索技术有限公司 用作cdk抑制剂的经过取代的杂环衍生物
CN111918863A (zh) * 2018-03-29 2020-11-10 武田药品工业株式会社 杂环化合物

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