WO2024066984A1 - Tricyclic derivative, pharmaceutical composition and use - Google Patents

Tricyclic derivative, pharmaceutical composition and use Download PDF

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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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French (fr)
Chinese (zh)
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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/en

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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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Abstract

Provided in the present invention is a tricyclic derivative, and the structure thereof is as shown in formula (I). In addition, further disclosed in the present invention are a pharmaceutically acceptable salt of the derivative, a stereoisomer, and a pharmaceutical composition thereof, and the use thereof. The compound of the present invention has a significant CDK12 inhibitory activity and has great practical value.

Description

三并环类衍生物、药物组合物以及应用Tricyclic derivatives, pharmaceutical compositions and applications 技术领域Technical Field
本发明涉及医药技术领域，特别是涉及一种三并环类衍生物、其药学上可接受的盐、立体异构体、药物组合物以及应用。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.
背景技术Background technique
细胞周期依赖性激酶(CDK)属于丝氨酸/苏氨酸激酶家族。它们参与细胞的增殖、转录等生理过程。根据CDK功能的不同，可以将其分为两大类：一类CDK参与细胞周期调控，主要包括CDK1、CDK2、CDK4、CDK6等；另一类CDK参与转录调节，主要包括CDK7、CDK8、CDK9、CDK12、CDK13等。Cyclin-dependent kinases (CDKs) belong to the serine/threonine kinase family. They are involved in physiological processes such as cell proliferation and transcription. According to the different functions of CDKs, they can be divided into two categories: one type of CDKs participates in cell cycle regulation, mainly including CDK1, CDK2, CDK4, CDK6, etc.; the other type of CDKs participates in transcriptional regulation, mainly including CDK7, CDK8, CDK9, CDK12, CDK13, etc.
CDK12通过与细胞周期素K结合成为活性物质，并向下游传递信号。将DNA的遗传信息复制到信使RNA(mRNA)的过程称为“转录”。CDK12通过在RNA聚合酶II的C端区域使第二个丝氨酸(Ser2)磷酸化来扩展mRNA的转录反应，CDK12被认为参与具有长基因长度的基因的转录延伸反应，并且影响BRCA1、ATM、FANCD2基因等的表达。所有这些基因都是涉及DNA损伤响应(DDR)的一组基因，并且主要通过DNA修复机制参与维持基因组DNA的稳定性。抑制CDK12降低DDR相关基因的表达，从而抑制DNA修复反应。DNA中所涉及的PARP和CDK12的抑制都通过合成致死作用完全抑制了DNA修复反应并诱导了癌细胞的细胞死亡。所以，抑制CDK12的作用对于预防和治疗癌症非常有用。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. 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 treatment of cancer.
为了更好地开发出治疗癌症等相关疾病的新药，以及鉴于市场上对于CDK介导的疾病药物的大量需求，迫切需要开发新颖的、安全有效的、能够治疗多种癌症的CDK12抑制剂，特别是选择性靶向CDK12的小分子抑制剂，其可能会具有更高的安全性。In order to better develop new drugs for the treatment of cancer and other related diseases, and in view of the huge demand for CDK-mediated disease drugs in the market, there is an urgent need to develop novel, safe and effective CDK12 inhibitors that can treat a variety of cancers, especially small molecule inhibitors that selectively target CDK12, which may have higher safety.
发明内容Summary of the invention
基于此，本发明提供了一种对CDK12抑制剂活性高的三并环类衍生物、其药学上可接受的盐或立体异构体。Based on this, the present invention provides a tricyclic derivative with high CDK12 inhibitor activity, and a pharmaceutically acceptable salt or stereoisomer thereof.
本发明通过如下技术方案实现。The present invention is achieved through the following technical solutions.
一种式(I)所示的化合物、或其药学上可接受的盐、或其立体异构体：
A compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
其中：in:
R1、R2分别独立地选自氰基、-CF3、-OCF3、-Cl、-Br、-F、羟基、硝基、取代或未被取代的咪唑基、取代或未被取代的吡唑基、具有1至20个C原子的直链烷基、具有1至20个C原子的烷氧基、具有3至20个C原子的支链烷基、取代或未被取代的具有3至20个C原子的环状的烷基、取代或未被取代的具有3至20个C原子的环状烷氧基、取代或未被取代的具有3至20个环原子的杂环基、-OR、-NH-R，或这些体系的组合；R每次出现，分别独立地选自取代或未被取代的具有3至20个C原子的环状烷氧基、取代或未被取代的具有3至20个环原子的杂环基；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 having 3 to 20 ring atoms;
R3、R4分别独立地选自-H、-D、具有1至20个C原子的直链烷基、具有3至20个C原子的支链或环状的烷基、取代或未取代的具有6至60个环原子的芳香基团，或这些基团的组合； 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;
Ar1选自如下结构中的任一种：
Ar 1 is selected from any one of the following structures:
X1每次出现，独立地选自CR5或N；Each occurrence of X 1 is independently selected from CR 5 or N;
Y1每次出现，独立地选自NR6、CR6R7、C＝O、O、S或S＝O；Each occurrence of Y 1 is independently selected from NR 6 , CR 6 R 7 , C═O, O, S or S═O;
R5、R6、R7每次出现，分别独立地选自-H、-D、具有1至20个C原子的直链烷基、具有1至20个C原子的烷氧基、具有3至20个C原子的支链烷基、具有3至20个C原子的环状的烷基、具有3至20个C原子的支链烷氧基、具有3至20个C原子的环状烷氧基，或这些体系的组合。 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.
在其中一个实施例中，式(I)化合物为式(II)所示结构：
In one embodiment, the compound of formula (I) is a compound of formula (II):
在其中一个实施例中，R3、R4分别独立地选自-H、-D、取代或未取代的具有6至30个环原子的芳香基团。In one embodiment, R 3 and R 4 are independently selected from -H, -D, and a substituted or unsubstituted aromatic group having 6 to 30 ring atoms.
在其中一个实施例中，式(I)化合物为式(Ⅲ)所示结构：
In one embodiment, the compound of formula (I) is a compound of formula (III):
在其中一个实施例中，Ar1选自如下结构中的任一种：
In one embodiment, Ar 1 is selected from any one of the following structures:
在其中一个实施例中，Ar1选自如下结构中的任一种：
In one embodiment, Ar 1 is selected from any one of the following structures:
在其中一个实施例中，R1、R2分别独立地选自氰基、-CF3、-Cl、-Br、-F或如下结构中的任一种：
In one embodiment, R 1 and R 2 are independently selected from cyano, -CF 3 , -Cl, -Br, -F or any one of the following structures:
在其中一个实施例中，式(I)化合物为下列化合物中的任一种：
In one embodiment, the compound of formula (I) is any one of the following compounds:
本发明还提供一种如上所述的化合物、或其药学上可接受的盐、或其立体异构体在制备治疗和/或预防与CDK12活性相关的或由CDK12活性介导的疾病的药物中的应用。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.
在其中一个实施例中，所述与CDK12活性相关的或由CDK12活性介导的疾病为癌症。In one embodiment, the disease associated with CDK12 activity or mediated by CDK12 activity is cancer.
本发明还提供一种药物组合物，包括如上所述的化合物、或其药学上可接受的盐、或其立体异构体，以及药学上可接受的载体。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.
与现有技术相比较，本发明的化合物、或其药学上可接受的盐、或其立体异构体具有如下有益效果：Compared with the prior art, the compound of the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof has the following beneficial effects:
本发明提供了一系列结构新颖的杂环取代的三并环类衍生物，其对CDK12具有较高的抑制活性，对CDK12激酶的抑制活性IC50值为42nM至367nM，因此可用作治疗和/或预防与 CDK12活性相关的或由CDK12活性介导的疾病的药物，对于CDK12活性介导的疾病具有潜在的优异治疗效果。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.
具体实施方式Detailed ways
为了便于理解本发明，下面将参照相关实施例对本发明进行更全面的描述。实施例中给出了本发明的较佳实施方式。但是，本发明可以以许多不同的形式来实现，并不限于本文所描述的实施方式。相反地，提供这些实施方式的目的是使对本发明的公开内容的理解更加透彻全面。For ease of understanding of the present invention, the present invention will be described more fully below with reference to relevant embodiments. Preferred embodiments of the present invention are provided in the embodiments. However, the present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosure of the present invention more thorough and comprehensive.
此外，术语“第一”、“第二”仅用于描述目的，而不能理解为指示或暗示相对重要性或者隐含指明所指示的技术特征的数量。由此，限定有“第一”、“第二”的特征可以明示或者隐含地包括至少一个该特征。在发明的描述中，“多个”的含义是至少两个，例如两个，三个等，除非另有明确具体的限定。在本发明的描述中，“若干”的含义是至少一个，例如一个，两个等，除非另有明确具体的限定。In addition, the terms "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. In the description of the invention, the meaning of "multiple" is at least two, such as two, three, etc., unless otherwise clearly and specifically defined. In the description of the present invention, the meaning of "several" is at least one, such as one, two, etc., unless otherwise clearly and specifically defined.
本发明中的词语“优选地”、“更优选地”等是指，在某些情况下可提供某些有益效果的本发明实施方案。然而，在相同的情况下或其他情况下，其他实施方案也可能是优选的。此外，对一个或多个优选实施方案的表述并不暗示其他实施方案不可用，也并非旨在将其他实施方案排除在本发明的范围之外。The words "preferably", "more preferably", etc. in the present invention refer to embodiments of the present invention that may provide certain beneficial effects in certain circumstances. However, other embodiments may also be preferred under the same circumstances or other circumstances. In addition, the description of one or more preferred embodiments does not imply that other embodiments are not applicable, nor is it intended to exclude other embodiments from the scope of the present invention.
当本文中公开一个数值范围时，上述范围视为连续，且包括该范围的最小值及最大值，以及这种最小值与最大值之间的每一个值。进一步地，当范围是指整数时，包括该范围的最小值与最大值之间的每一个整数。此外，当提供多个范围描述特征或特性时，可以合并该范围。换言之，除非另有指明，否则本文中所公开之所有范围应理解为包括其中所归入的任何及所有的子范围。When a numerical range is disclosed herein, the above range is considered to be continuous and includes the minimum and maximum values of the range, as well as every value between such minimum and maximum values. Further, when a range refers to an integer, every integer between the minimum and maximum values of the range is included. In addition, when multiple ranges are provided to describe features or characteristics, the ranges can be combined. In other words, unless otherwise indicated, all ranges disclosed herein should be understood to include any and all subranges included therein.
除非另外指明，所有百分比、分数和比率都是按本发明组合物的总质量计算的。除非另外指明，有关所列成分的所有质量均给予活性物质的含量，因此它们不包括在可商购获得的材料中可能包含的溶剂或副产物。本文术语“质量百分比含量”可用符号“％”表示。除非另外指明，在本文中所有的分子量都是以道尔顿为单位表示的重均分子量。除非另外指明，在本文中所有配制和测试发生在25℃的环境。本文中“包括”、“包含”、“含”、“含有”、“具有”或其它变体意在涵盖非封闭式包括，这些术语之间不作区分。术语“包含”是指可加入不影响最终结果的其它步骤和成分。本发明的组合物和方法/工艺包含、由其组成和基本上由本文描述的必要元素和限制项以及本文描述的任一的附加的或任选的成分、组份、步骤或限制项组成。本文中术语“效能”、“性能”、“效果”、“功效”之间不作区分。Unless otherwise specified, all percentages, fractions and ratios are calculated by the total mass of the composition of the present invention. Unless otherwise specified, all masses of the listed ingredients are given to the content of active substances, so they do not include solvents or by-products that may be contained in commercially available materials. The term "mass percentage content" herein can be represented by the symbol "%". Unless otherwise specified, all molecular weights in this article are weight average molecular weights expressed in Daltons. Unless otherwise specified, all formulations and tests in this article occur in an environment of 25°C. "Including", "including", "containing", "containing", "having" or other variants herein are intended to cover non-closed inclusions, and these terms are not distinguished. The term "comprising" means that other steps and ingredients that do not affect the final result can be added. The 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. The terms "efficacy", "performance", "effect" and "efficacy" are not distinguished between herein.
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commercial product or its active ingredient.
术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。The term "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.
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如甲酸、乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯 磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。The term "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. When the compounds of the invention contain relatively acidic functional groups, 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. When the compounds of the invention contain relatively basic functional groups, 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.
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。Pharmaceutically acceptable 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.
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。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.
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of one another.
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。Unless otherwise indicated, the term "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.
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。Unless otherwise indicated, the term "diastereomer" refers to stereoisomers that have two or more chiral centers and that are not mirror images of each other.
除非另有说明，“(+)”表示右旋，“(-)”表示左旋，“(±)”表示外消旋。Unless otherwise indicated, "(+)" indicates dextrorotatory, "(-)" indicates levorotatory, and "(±)" indicates racemic.
除非另有说明，用楔形实线键和楔形虚线键表示一个立体中心的绝对构型，用直形实线键和直形虚线键表示立体中心的相对构型，用波浪线表示楔形实线键或楔形虚线键或用波浪线表示直形实线键和直形虚线键 Unless otherwise specified, 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
除非另有说明，当化合物中存在双键结构，如碳碳双键、碳氮双键和氮氮双键，且双键上的各个原子均连接有两个不同的取代基时(包含氮原子的双键中，氮原子上的一对孤对电子视为其连接的一个取代基)，如果该化合物中双键上的原子与其取代基之间用波浪线连接，则表示该化合物的(Z)型异构体、(E)型异构体或两种异构体的混合物。例如下式(A)表示该化合物以式(A-1)或式(A-2)的单一异构体形式存在或以式(A-1)和式(A-2)两种异构体的混合物形式存在；下式(B)表示该化合物以式(B-1)或式(B-2)的单一异构体形式存在或以式(B-1)和式(B-2)两种异构体的混合物形式存在。下式(C)表示该化合物以式(C-1)或式(C-2)的单一异构体形式存在或以式(C-1)和式(C-2)两种异构体的混合物形式存在。
Unless otherwise specified, when 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. For example, the following 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); the following 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). The following 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).
除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构 体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。Unless otherwise indicated, the term "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. For example, proton tautomers (also called prototropic tautomers) include interconversions through proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions through the reorganization of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between the two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。Unless otherwise indicated, 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%.
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。Unless otherwise indicated, 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%.
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。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. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), 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. In addition, 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).
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚(3H)，碘-125(125I)或C-14(14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more atoms constituting the compound. For example, the compound may be labeled with a radioactive isotope, such as tritium ( 3H ), iodine-125 ( 125I ) or C-14 ( 14C ). For another example, 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.
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
术语“取代”是指特定原子上的任意一个或多个氢原子被取代基取代，取代基可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。取代基的种类和数目在化学上可以实现的基础上可以是任意的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。The term "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. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups.
当任何变量(例如R1)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R1所取代，则所述基团可以任选地至多被两个R1所取代，并且每种情况下的R1都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。When any variable (e.g., R 1 ) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 R 1 s, the group may be optionally substituted with up to two R 1 s , and each occurrence of R 1 is an independent choice. In addition, combinations of substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
当一个连接基团的数量为0时，比如-(CRR)0-，表示该连接基团为单键。When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected. For example, when L in A-L-Z represents a single bond, it means that the structure is actually A-Z.
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。 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.
当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。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.
除非另有规定，当某一基团具有一个或多个可连接位点时，该基团的任意一个或多个位点可以通过化学键与其他基团相连。当该化学键的连接方式是不定位的，且可连接位点存在H原子时，则连接化学键时，该位点的H原子的个数会随所连接化学键的个数而对应减少变成相应价数的基团。所述位点与其他基团连接的化学键可以用直形实线键直形虚线键或波浪线表示。例如-OCH3中的直形实线键表示通过该基团中的氧原子与其他基团相连；中的直形虚线键表示通过该基团中的氮原子的两端与其他基团相连；中的波浪线表示通过该苯基基团中的1和2位碳原子与其他基团相连；表示该哌啶基上的任意可连接位点可以通过1个化学键与其他基团相连，至少包括 这4种连接方式，即使-N-上画出了H原子，但是仍包括这种连接方式的基团，只是在连接1个化学键时，该位点的的H会对应减少1个变成相应的一价哌啶基。Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When 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. Straight dotted key or wavy line For example, 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.
除非另有规定，环上原子的数目通常被定义为环的元数，例如，“3-7元环”是指环绕排列3-7个原子的“环”。Unless otherwise specified, 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.
除非另有规定，术语“C1-6烷基”用于表示直链或支链的由1至6个碳原子组成的饱和碳氢基团。优选为C1-4烷基，其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C1-3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)、丁基(包括正丁基、异丁基、叔丁基和仲丁基)。Unless otherwise specified, the term "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).
除非另有规定，术语“C1-6烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至6个碳原子的烷基基团。优选为C1-3烷氧基。C1-3烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。Unless otherwise specified, the term "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.
除非另有规定，术语“C1-6烷氨基”表示通过氨基连接到分子的其余部分的那些包含1至6 个碳原子的烷基基团。优选为C1-3烷氨基。C1-3烷氨基的实例包括但不限于-NHCH3、-N(CH3)2、-NHCH2CH3、-N(CH3)CH2CH3、-NHCH2CH2CH3、-NHCH2(CH3)2等。Unless otherwise specified, the term "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.
除非另有规定，术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。[0043] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
除非另有规定，本发明术语“5杂芳环”和“5元杂芳基”可以互换使用，术语“5元杂芳基”表示由5环原子组成的具有共轭π电子体系的单环基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子。其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。5元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5元杂芳基的实例包括但不限于吡咯基(包括N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、三唑基(1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基和4H-1,2,4-三唑基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)。Unless otherwise specified, the terms "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 π 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-thiazolyl and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.).
除非另有规定，Cn-n+m或Cn-Cn+m包括n至n+m个碳的任何一种具体情况，例如C1-12包括C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、和C12，也包括n至n+m中的任何一个范围，例如C1-12包括C1-3、C1-6、C1-9、C3-6、C3-9、C3-12、C6-9、C6-12、和C9-12等；同理，n元至n+m元表示环上原子数为n至n+m个，例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环，也包括n至n+m中的任何一个范围，例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环、和6-10元环等。Unless otherwise specified, 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 . 9-12 , etc.; similarly, n-membered to n+m-membered means that the number of atoms in the ring is n to n+m, for example, 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.
除非另有规定，“C3-7环烷基”表示由3至7个碳原子组成的饱和环状碳氢基团，其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。所述C3-7环烷基包括C3-6、C4-6、C4-5、C5-7或C5-6环烷基等；其可以是一价、二价或者多价。C3-7环烷基的实例包括，但不限于，环丙基、环丁基、环戊基、环己基、环庚基等。Unless otherwise specified, "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.
除非另有规定，术语“3-7元杂环烷基”本身或者与其他术语联合分别表示由3至7个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“3-7元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述3-7元杂环烷基包括5-7元、3元、4元、5元、6元和7元杂环烷基等。3-7元杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基或六氢哒嗪基等。Unless otherwise specified, 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. In addition, with respect to the "3-7 membered heterocycloalkyl", 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. Examples of 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, 1,2-oxazinyl, 1,2-thiazinyl or hexahydropyridazinyl, etc.
除非另有规定，术语“3-7元含氮杂环烷基”表示为至少含有一个N原子的3-7元杂环烷基。Unless otherwise specified, the term "3-7 membered nitrogen-containing heterocycloalkyl" refers to a 3-7 membered heterocycloalkyl group containing at least one nitrogen atom.
脂环基是指饱和或部分不饱和的全碳环系统。其中“部分不饱和”是指包括至少一个双键或三键的环部分，“部分不饱和”意图涵盖具有多个不饱和位点的环，但并不意图包括如本文所定义的芳基或杂芳基部分。非限制性实施例包括环丙基环、环丁基环、环戊基环、环戊烯基环、环己基环、环己烯基环、环己二烯基环、环庚基环、环庚三烯基环、环戊酮环、环戊烷-1,3-二酮环等。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.
脂杂环基是指饱和或部分不饱和脂环基中的1、2或3个环碳原子被选自氮、氧或S(O)t(其中t是整数0至2)的杂原子所取代，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。非限制性实施例包括环氧丙烷环、氮杂环丁烷环、氧杂环丁烷环、四氢呋喃环、四氢噻吩环、四氢吡咯环、哌啶环、吡咯啉环、噁唑烷环、哌嗪环、二氧戊环、二氧六环、吗啉环、 硫代吗啉环、硫代吗啉-1,1-二氧化物、四氢吡喃环、氮杂环丁烷-2-酮环、氧杂环丁烷-2-酮环、吡咯烷-2-酮环、吡咯烷-2,5-二酮环、哌啶-2-酮环、二氢呋喃-2(3H)-酮环、二氢呋喃-2,5-二酮环、四氢-2H-吡喃-2-酮环、哌嗪-2-酮环、吗啉-3-酮环。部分不饱和单杂环的非限制性实施例包括1,2-二氢氮杂环丁二烯环、1,2-二氢氧杂环丁二烯环、2,5-二氢-1H-吡咯环、2,5-二氢呋喃环、2,3-二氢呋喃环、2,3-二氢-1H-吡咯环、3,4-二氢-2H-吡喃环、1,2,3,4-四氢吡啶环、3,6-二氢-2H-吡喃环、1,2,3,6-四氢吡啶环、4,5-二氢-1H-咪唑环、1,4,5,6-四氢嘧啶环、3,4,7,8-四氢-2H-1,4,6-噁二唑嗪环、1,6-二氢嘧啶环、4,5,6,7-四氢-1H-1,3-二氮杂环、2,5,6,7-四氢-1,3,5-噁二氮杂环等。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, piperazin-2-one ring, morpholine-3-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-diazapine ring. Cyclic, 2,5,6,7-tetrahydro-1,3,5-oxadiazepine Ring, etc.
“芳基”和“芳环”可互换使用，均指具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，该基团可以与环烷基环、杂环烷基环、环烯基环、杂环烯基环或杂芳基稠合。“C6-10芳基”指具有6至10个碳原子的单环或双环芳基，芳基的非限制性实施例包括苯基、萘基等。"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 π 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.
“杂芳基”和“杂芳基环”可互换使用，均指具有环碳原子和环杂原子的单环、双环或多环的4n+2芳族环体系(例如，具有以环状排列共享的6或10个π电子)的基团，其中每个杂原子独立地选自氮、氧和硫。本发明中，杂芳基还包括其中上述杂芳基环与一个或多个环烷基环、杂环烷基环、环烯基环、杂环烯基环或芳环稠合的环系统。杂芳基环可以任选地被取代。“5至10元杂芳基”是指具有5至10个环原子，其中1、2、3或4个环原子为杂原子的单环或双环杂芳基。“5至6元杂芳基”是指具有5至6个环原子，其中1、2、3或4个环原子为杂原子的单环杂芳基，非限制性实施例包括噻吩基、呋喃基、噻唑基、异噻唑基、咪唑基、噁唑基、吡咯基、吡唑基、三唑基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基、四唑基、异噁唑基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-恶二唑基、噻二唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、四嗪基。“8至10元杂芳基”是指具有8至10个环原子，其中1、2、3或4个环原子为杂原子的双环杂芳基，非限制性实施例包括吲哚基、异吲哚基、吲唑基、苯并三唑基、苯并噻吩基、异苯并噻吩基、苯并呋喃基、苯并异呋喃基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噁二唑基、苯并噻唑基、苯并异噻唑基、苯并噻二唑基、茚嗪基、嘌呤基、吡啶并[3,2-d]嘧啶基、吡啶并[2,3-d]嘧啶基、吡啶并[3,4-d]嘧啶基、吡啶并[4,3-d]嘧啶基、1,8-萘啶基、1,7-萘啶基、1,6-萘啶基、1,5-萘啶基、喋啶基、喹啉基、异喹啉基、噌琳基、喹喔啉基、酞嗪基和喹唑啉基。“杂原子”是指氮、氧或硫。在含有一个或多个氮原子的杂芳基中，只要化合价允许，连接点可以是碳或氮原子。杂芳基双环系统在一个或两个环中可以包括一个或多个杂原子。"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 π electrons shared in a cyclic arrangement) having ring carbon atoms and ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur. In the present invention, 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-oxadiazolyl, 1,3,4-oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl. "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, The term "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.
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲核取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等。The term "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). For example, 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.
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxy protecting group" or "thiol protecting group". The term "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-butyldimethylsilyl (TBS), etc. The term "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.
除非另有定义，本发明所述“各自独立地选自……的取代基”是指当基团上的一个以上的氢被取代基取代时，所述的取代基种类可以相同或不同，所选自的取代基为各自独立的种类。 Unless otherwise defined, the "substituents independently selected from..." mentioned in the present invention 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.
通常本发明化合物或其药学可接受的盐、或其立体异构体可以与一种或多种药用载体形成适合的剂型施用。这些剂型适用于口服、直肠给药、局部给药、口内给药以及其他非胃肠道施用(例如，皮下、肌肉、静脉等)。例如，适合口服给药的剂型包括胶囊、片剂、颗粒剂以及糖浆等。这些制剂中包含的本发明的化合物可以是固体粉末或颗粒；水性或非水性液体中的溶液或是混悬液；油包水或水包油的乳剂等。上述剂型可由活性化合物与一种或多种载体或辅料经由通用的药剂学方法制成。上述的载体需要与活性化合物或其他辅料兼容。对于固体制剂，常用的无毒载体包括但不限于甘露醇、乳糖、淀粉、硬脂酸镁、纤维素、葡萄糖、蔗糖等。用于液体制剂的载体包括水、生理盐水、葡萄糖水溶液、乙二醇和聚乙二醇等。活性化合物可与上述载体形成溶液或是混悬液。Generally, 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. These dosage forms are suitable for oral, rectal, topical, oral and other parenteral administration (e.g., subcutaneous, intramuscular, intravenous, etc.). For example, 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. The above carriers need to be compatible with the active compounds or other excipients. For solid preparations, commonly used 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.
本发明的组合物以符合医学实践规范的方式配制，定量和给药。给予化合物的“治疗有效量”由要治疗的具体病症、治疗的个体、病症的起因、药物的靶点以及给药方式等因素决定。The 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.
“治疗有效量”是指将引起个体的生物学或医学响应，例如降低或抑制酶或蛋白质活性或改善症状、缓解病症、减缓或延迟疾病进程或预防疾病等的本发明化合物的量。"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.
本发明的所述药物组合物或所述药用组合物中含有的本发明化合物或其药学上可接受的盐、或其立体异构体的治疗有效量优选为0.1mg-5g/kg(体重)。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).
“患者”是指一种动物，最好为哺乳动物，更好的为人。术语“哺乳动物”是指温血脊椎类哺乳动物，包括如猫、狗、兔、熊、狐狸、狼、猴子、鹿、鼠、猪和人类。"Patient" refers to an animal, preferably a mammal, more preferably a human. The term "mammal" refers to warm-blooded vertebrate mammals, including, for example, cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, mice, pigs and humans.
“治疗”是指减轻、延缓进展、衰减、预防，或维持现有疾病或病症(例如癌症)。治疗还包括将疾病或病症的一个或多个症状治愈、预防其发展或减轻到某种程度。"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.
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。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.
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：φ扫描，收集相关数据后，进一步采用直接法(Shelxs97)解析晶体结构，便可以确证绝对构型。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. For example, single crystal X-ray diffraction (SXRD) is used to collect diffraction intensity data of the cultured single crystal using a Bruker D8 venture diffractometer, the light source is CuKα radiation, and the scanning mode is φ scanning. After collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure, and the absolute configuration can be confirmed.
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词：Pd/C代表钯碳；H2代表氢气；N2代表氮气；mL代表毫升；H2O代表水；AcOH代表醋酸；B2Pin2代表双联频哪醇硼酸酯；Pd(dppf)Cl2代表1,1'-双二苯基膦二茂铁二氯化钯；KOAc代表醋酸钾；EtOAc代表乙酸乙酯；K2CO3代表碳酸钾；MeCN代表乙腈；DIEA代表N,N-二异丙基乙胺；MeOH代表甲醇；THF代表四氢呋喃；DMAP代表4-二甲氨基吡啶；Pd(Amphos)2Cl2代表二氯二叔丁基-(4-二甲基氨基苯基)磷钯(II)；SO2Cl2代表二氯化砜；NaHCO3代表碳酸氢钠；BrCN代表溴化氰；NaOH代表氢氧化钠；TEA代表三乙胺；DMF代表N,N-二甲基甲酰胺；H2O代表水；Na2SO4代表硫酸钠；FA代表甲酸；Cs2CO3代表碳酸铯；NaCl代表氯化钠；CuI代表碘化亚铜；K3PO4代表磷酸钾；NaH代表钠氢；MeI代表碘甲烷；DMSO代表二甲基亚砜；POCl3代表三氯氧磷；Xphos代表2-二环己基膦-2',4',6'-三异丙基联苯；BH3-Me2S代表硼烷甲基硫醚；DPPA代表叠氮磷酸二苯酯；XPhosPdG3代表甲烷磺酸(2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)；The solvent used in the present invention is commercially available. The present invention adopts the following abbreviations: Pd/C represents palladium on carbon; H 2 represents hydrogen; N 2 represents nitrogen; mL represents milliliter; H 2 O represents 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); SO 2 Cl 2 represents dichlorosulfone; NaHCO 3 represents sodium bicarbonate; BrCN represents cyanogen bromide; NaOH represents sodium hydroxide; TEA represents triethylamine; DMF represents N,N-dimethylformamide; H 2 O represents water; Na 2 SO 4 represents sodium sulfate; FA represents formic acid; Cs 2 CO 3 represents cesium carbonate; NaCl represents sodium chloride; CuI represents cuprous iodide; K 3 PO 4 represents potassium phosphate; NaH represents sodium hydrogen; MeI represents methyl iodide; DMSO represents dimethyl sulfoxide; POCl 3 represents phosphorus oxychloride; Xphos represents 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl; BH 3 -Me 2 S represents borane methyl sulfide; DPPA represents diphenylphosphoryl azide; XPhosPdG3 represents methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II);
化合物依据本领域常规命名原则或者使用软件命名，市售化合物采用供应商目录名称。Compounds are named according to the conventional nomenclature in the art or using The software names were used, and commercially available compounds were named using the supplier's catalog names.
除非另有定义，本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在本发明的说明书中所使用的术语只是为了描述具体的实施方式的目的，不是旨在于限制本发明。本文所使用的术语“和/或”包括一个或多个相关的所列项目的任意的和所有的组合。Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used herein in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention. The term "and/or" used herein includes any and all combinations of one or more related listed items.
本发明提供了一种式(I)所示的化合物、或其药学上可接受的盐、或其立体异构体：
The present invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
其中：in:
R1、R2分别独立地选自氰基、-CF3、-OCF3、-Cl、-Br、-F、羟基、硝基、取代或未被取代的咪唑基、取代或未被取代的吡唑基、具有1至20个C原子的直链烷基、具有1至20个C原子的烷氧基、具有3至20个C原子的支链烷基、取代或未被取代的具有3至20个C原子的环状的烷基、取代或未被取代的具有3至20个C原子的环状烷氧基、取代或未被取代的具有3至20个环原子的杂环基、-OR、-NH-R，或这些体系的组合；R每次出现，分别独立地选自取代或未被取代的具有3至20个C原子的环状烷氧基、取代或未被取代的具有3至20个环原子的杂环基；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 having 3 to 20 ring atoms;
R3、R4分别独立地选自-H、-D、具有1至20个C原子的直链烷基、具有3至20个C原子的支链或环状的烷基、取代或未取代的具有6至60个环原子的芳香基团，或这些基团的组合；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;
Ar1选自如下结构中的任一种：
Ar 1 is selected from any one of the following structures:
X1每次出现，独立地选自CR5或N；Each occurrence of X 1 is independently selected from CR 5 or N;
Y1每次出现，独立地选自NR6、CR6R7、C＝O、O、S或S＝O；Each occurrence of Y 1 is independently selected from NR 6 , CR 6 R 7 , C═O, O, S or S═O;
R5、R6、R7每次出现，分别独立地选自-H、-D、具有1至20个C原子的直链烷基、具有1至20个C原子的烷氧基、具有3至20个C原子的支链烷基、具有3至20个C原子的环状的烷基、具有3至20个C原子的支链烷氧基、具有3至20个C原子的环状烷氧基，或这些体系的组合。 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.
在一个具体的示例中，式(I)化合物为式(II)所示结构：
In a specific example, the compound of formula (I) is a structure shown in formula (II):
在一个具体的示例中，R3、R4分别独立地选自-H、-D、取代或未取代的具有6至30个环原子的芳香基团。In a specific example, R 3 and R 4 are independently selected from -H, -D, and a substituted or unsubstituted aromatic group having 6 to 30 ring atoms.
在一个具体的示例中，R3、R4分别独立地选自-H、-D、取代或未取代的具有6至15个环原子的芳香基团。In a specific example, R 3 and R 4 are independently selected from -H, -D, and a substituted or unsubstituted aromatic group having 6 to 15 ring atoms.
在一个具体的示例中，R3、R4分别独立地选自-H、-D、取代或未取代的苯基。In a specific example, R 3 and R 4 are independently selected from -H, -D, and substituted or unsubstituted phenyl.
在一个具体的示例中，式(I)化合物为式(Ⅲ)所示结构：
In a specific example, the compound of formula (I) is a structure shown in formula (III):
在一个具体的示例中，Ar1选自如下结构中的任一种：
In a specific example, Ar 1 is selected from any one of the following structures:
在一个具体的示例中，R5、R6、R7每次出现，分别独立地选自-H、-D、具有1至10个C原子的直链烷基、具有1至10个C原子的烷氧基、具有3至10个C原子的支链烷基、具有3至10个C原子的环状的烷基、具有3至10个C原子的支链烷氧基、具有3至10个C原子的环状烷氧基，或这些体系的组合。In a specific example, 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.
在一个具体的示例中，R5、R6、R7每次出现，分别独立地选自-H、-D、具有1至5个C原子的直链烷基、具有1至5个C原子的烷氧基、具有3至5个C原子的支链烷基、具有3至5个C原子的环状的烷基、具有3至5个C原子的支链烷氧基、具有3至5个C原子的环状烷氧基，或这些体系的组合。In a specific example, 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.
在一个具体的示例中，Ar1选自如下结构中的任一种：
In a specific example, Ar 1 is selected from any one of the following structures:
在一个具体的示例中，R1、R2分别独立地选自氰基、-CF3、-OCF3、-Cl、-Br、-F、羟基、硝基、未被取代的咪唑基、被烷基、Cl或F取代的咪唑基、未被取代的吡唑基、被烷基、Cl或F取代的吡唑基、未被取代的具有3至20个环原子的杂环基、被烷基、羟基、Cl、F或上述组合形式取代的具有3至20个环原子的杂环基、-OR、-NH-R。In a specific example, 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.
在一个具体的示例中，R1、R2分别独立地选自氰基、-CF3、-OCF3、-Cl、-Br、-F、羟基、硝基、未被取代的咪唑基、被烷基、Cl或F取代的咪唑基、未被取代的吡唑基、被烷基、Cl或F取代的吡唑基、未被取代的具有3至10个环原子的杂环基、被烷基、羟基、Cl、F或上述组合形式取代的具有3至10个环原子的杂环基、-OR、-NH-R。In a specific example, 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.
在一个具体的示例中，R1、R2分别独立地选自氰基、-CF3、-OCF3、-Cl、-Br、-F、羟基、硝基、未被取代的咪唑基、被烷基、Cl或F取代的咪唑基、未被取代的吡唑基、被烷基、Cl或F取代的吡唑基、未被取代的具有3至5个环原子的杂环基、被烷基、羟基、Cl、F或上述组合形式取代的具有3至5个环原子的杂环基、-OR、-NH-R。In a specific example, 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.
更具体地，杂环基为含氮的环烷基。More specifically, the heterocyclyl group is a nitrogen-containing cycloalkyl group.
在一个具体的示例中，R每次出现，分别独立地选自取代或未被取代的具有3至10个C原子的环状烷氧基、取代或未被取代的具有3至10个环原子的杂环基。 In a specific example, 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.
在一个具体的示例中，R每次出现，分别独立地选自取代或未被取代的具有3至5个C原子的环状烷氧基、取代或未被取代的具有3至5个环原子的杂环基。In a specific example, 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.
更具体地，杂环基为含氮的环烷基。More specifically, the heterocyclyl group is a nitrogen-containing cycloalkyl group.
在一个具体的示例中，R1、R2分别独立地选自氰基、-CF3、-Cl、-Br、-F或如下结构中的任一种：
In a specific example, R 1 and R 2 are independently selected from cyano, -CF 3 , -Cl, -Br, -F or any one of the following structures:
在一个具体的示例中，式(I)化合物为下列化合物中的任一种：
In a specific example, the compound of formula (I) is any one of the following compounds:
在一个具体的示例中，药学上可接受的盐为烷基酸盐。进一步地，药学上可接受的盐为甲酸盐。In a specific example, the pharmaceutically acceptable salt is an alkyl acid salt. Further, the pharmaceutically acceptable salt is a formate salt.
本发明还提供一种上述化合物、或其药学上可接受的盐、或其立体异构体在制备治疗和/或预防与CDK12活性相关的或由CDK12活性介导的疾病的药物中的应用。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.
在一个具体的示例中，与CDK12活性相关的或由CDK12活性介导的疾病为癌症。In a specific example, the disease associated with or mediated by CDK12 activity is cancer.
本发明还提供一种药物组合物，包括上述化合物、或其药学上可接受的盐、或其立体异 构体，以及药学上可接受的载体。The present invention also provides a pharmaceutical composition comprising the above compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. construct, and a pharmaceutically acceptable carrier.
可以理解地，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。It is understandable that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here.
以下结合具体实施例对本发明的三并环类衍生物及其制备方法做进一步详细的说明。以下实施例中所用的原料，如无特别说明，均为市售产品。The tricyclic derivatives and the preparation method of the present invention are further described in detail below in conjunction with specific examples. The raw materials used in the following examples are all commercially available products unless otherwise specified.
实施例1Example 1
本实施例提供化合物1，其结构式如下：
This embodiment provides compound 1, whose structural formula is as follows:
反应路线如下所示：
The reaction route is as follows:
制备过程具体如下：The preparation process is as follows:
第1步：step 1:
在25mL三颈烧瓶中，将化合物1-1(5.00g,26.7mmol,1.0eq)、BrCN(3.87g,36.5mmol,2.69mL,1.37eq)加入到乙醇(25.0mL)和水(25.0mL)的混合溶液中，在70℃下搅拌12小时。将反应混合物减压浓缩以除去乙醇(25.0mL)。然后将产物溶于NaOH(2mol/L)溶液中调至pH＝9.0，过滤去除可溶性物质。得到粗产物化合物1-2。LCMS:MS(ESI)m/z＝213.9[M+H]+。1H NMR:DMSO-d6,400MHzδ＝7.22(d,J＝2.0Hz,1H),7.05-7.00(m,1H),6.99-6.94(m, 1H),6.36(s,2H)。In a 25mL three-necked flask, compound 1-1 (5.00g, 26.7mmol, 1.0eq) and BrCN (3.87g, 36.5mmol, 2.69mL, 1.37eq) were added to a mixed solution of ethanol (25.0mL) and water (25.0mL) and stirred at 70°C for 12 hours. The reaction mixture was concentrated under reduced pressure to remove ethanol (25.0mL). The product was then dissolved in NaOH (2mol/L) solution and adjusted to pH=9.0, and the soluble material was removed by filtration. The crude product compound 1-2 was obtained. LCMS: MS (ESI) m/z=213.9[M+H]+. 1 H NMR: DMSO-d6, 400MHzδ=7.22(d, J=2.0Hz, 1H), 7.05-7.00(m, 1H), 6.99-6.94(m, 1H),6.36(s,2H).
第2步：Step 2:
在室温下，将化合物1-2(3.00g,14.1mmol,1.00eq)，化合物1-3(1.54g,14.1mmol,1.00eq),，TEA(14.1g,14.1mmol,1.8mL,1.00eq)分别加入到甲苯(10.0mL)中在100℃下搅拌2小时。反应完成后，加入30.0mL水搅拌30min，待固体析出完全后，将混合物过滤，获得不溶性粗产物化合物1-4和1-4a。LCMS:MS(ESI)m/z＝365.8[M+H]+。At room temperature, 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] +.
第3步：Step 3:
在室温下，将化合物1-4和1-4a(5.70g,15.6mmol,1.00eq)与NaOH(1.25g,31.2mmol,2.00eq)在MeCN(10.0mL)中进行脱气，N2氛围下置换3次，然后在70℃，N2气氛下搅拌1小时。反应完成后，加入30.0mL水搅拌30min，待固体析出完全后，将混合物过滤，获得不溶性粗产物化合物1-5和1-5a。LCMS:MS(ESI)m/z＝366.8[M+H]+。1H NMR:DMSO-d6,400MHzδ＝8.77(t,J＝8.0Hz,1H),8.23(d,J＝1.6Hz,1H),7.88(d,J＝8.0Hz,1H),7.72(br d,J＝1.6Hz,1H),7.64(br d,J＝2.0Hz,1H),7.41(brdd,J＝1.6,8.4Hz,1H),6.17-6.11(m,1H)。At room temperature, compounds 1-4 and 1-4a (5.70 g, 15.6 mmol, 1.00 eq) and NaOH (1.25 g, 31.2 mmol, 2.00 eq) were degassed in MeCN (10.0 mL), replaced 3 times under N 2 atmosphere, and then stirred at 70 ° C, N 2 atmosphere for 1 hour. 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 1-5 and 1-5a. LCMS: MS (ESI) m/z = 366.8 [M + H] +. 1 H NMR: DMSO-d6, 400 MHz δ＝8.77 (t, J＝8.0 Hz, 1H), 8.23 (d, J＝1.6 Hz, 1H), 7.88 (d, J＝8.0 Hz, 1H), 7.72 (br d, J＝1.6 Hz, 1H), 7.64 (br d, J＝2.0 Hz, 1H), 7.41 (brdd, J＝1.6, 8.4 Hz, 1H), 6.17-6.11 (m, 1H).
第4步：Step 4:
在室温下，将化合物1-5和1-5a(4.00g,15.1mmol,1.00eq)、CH3I(2.58g,18.1mmol,1.13mL,1.20eq)、K2CO3(4.19g,30.2mmol,2.00eq)分别加入到DMF(20.0mL)中在95℃下搅拌12小时。用H2O 50.0mL稀释后，然后用EtOAc 45.0mL(15.0mL×3)萃取三次，然后用NaCl(15.0mL×3)水洗三次，无水Na2SO4干燥，过滤，减压浓缩得到粗品。采用制备-高效液相色谱法(FA条件)对其进行纯化，得到化合物1-6和化合物1-6a。LCMS:MS(ESI)m/z＝279.9[M+H]+。1H NMR:DMSO-d6,400MHzδ＝8.84(t,J＝8.0Hz,1H),8.28(d,J＝1.6Hz,1H),7.92(d,J＝8.0Hz,1H),7.82(d,J＝1.6Hz,1H),7.57(d,J＝8.0Hz,1H),7.50-7.41(m,1H),6.31-6.25(m,1H)。At room temperature, compounds 1-5 and 1-5a (4.00 g, 15.1 mmol, 1.00 eq), CH 3 I (2.58 g, 18.1 mmol, 1.13 mL, 1.20 eq), and K 2 CO 3 (4.19 g, 30.2 mmol, 2.00 eq) were added to DMF (20.0 mL) and stirred at 95°C for 12 hours. After dilution with H 2 O 50.0 mL, the mixture was extracted three times with EtOAc 45.0 mL (15.0 mL×3), then washed three times with NaCl (15.0 mL×3), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative high performance liquid chromatography (FA conditions) to obtain compounds 1-6 and 1-6a. LCMS: MS (ESI) m/z=279.9 [M+H]+. 1 H NMR: DMSO-d6, 400 MHz δ＝8.84(t, J＝8.0 Hz, 1H), 8.28(d, J＝1.6 Hz, 1H), 7.92(d, J＝8.0 Hz, 1H), 7.82(d, J＝1.6 Hz, 1H), 7.57(d, J＝8.0 Hz, 1H), 7.50-7.41(m, 1H), 6.31-6.25(m, 1H).
第5步：Step 5:
在室温下，将化合物1-6(100mg,359.μmol,1.00eq)、化合物1-7(154mg,719μmol,2.0eq)、Xphos(32.6mg,35.9μmol,0.10eq)、BrettPhosPd G3(34.2mg,71.9μmol,0.20eq)，Cs2CO3(351mg,1.08mmol,3.00eq)分别加入到DMSO(1.00mL)中，在微波90℃下搅拌12小时。反应完成后，在反应混合物中加入10.0mL水，并用EtOAc 15.0mL(5.00mL×3)萃取三次，然后用NaCl(5.00mL×3)水洗三次，无水Na2SO4干燥，过滤，减压浓缩得到粗品化合物1-8。LCMS:MS(ESI)m/z＝412.1[M+H]+。1H NMR:DMSO-d6,400MHzδ＝8.77(d,J＝8.0Hz,1H),8.44-8.40(m,1H),7.59(d,J＝8.4Hz,1H),7.29(d,J＝8.4Hz,1H),7.08-7.05(m,1H),6.71(d,J＝2.0Hz,1H),6.66-6.53(m,1H),6.14-6.08(m,1H),5.42-5.31(m,1H),3.53-3.50(m,4H),3.19-3.11(m,2H),2.36-2.31(m,1H),2.07-1.98(m,2H),1.87-1.75(m,3H),1.39(d,J＝1.6Hz,9H)。At room temperature, compound 1-6 (100 mg, 359.μmol, 1.00 eq), compound 1-7 (154 mg, 719μmol, 2.0 eq), Xphos (32.6 mg, 35.9μmol, 0.10 eq), BrettPhosPd G3 (34.2 mg, 71.9μmol, 0.20 eq), and Cs 2 CO 3 (351 mg, 1.08 mmol, 3.00 eq) were added to DMSO (1.00 mL) and stirred at 90°C for 12 hours in a microwave. After the reaction was completed, 10.0 mL of water was added to the reaction mixture, and the mixture was extracted three times with EtOAc 15.0 mL (5.00 mL×3), then washed three times with NaCl (5.00 mL×3), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to obtain a crude compound 1-8. LCMS: MS (ESI) m/z=412.1 [M+H]+. 1 H NMR: DMSO-d6, 400 MHz δ = 8.77 (d, J = 8.0 Hz, 1H), 8.44-8.40 (m, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.08-7.05 (m, 1H), 6.71 (d, J = 2.0 Hz, 1H), 6.66-6.53 (m, 1H), 6.14-6.08 (m, 1H), 5.42-5.31 (m, 1H), 3.53-3.50 (m, 4H), 3.19-3.11 (m, 2H), 2.36-2.31 (m, 1H), 2.07-1.98 (m, 2H), 1.87-1.75 (m, 3H), 1.39 (d, J = 1.6 Hz, 9H).
第6步：Step 6:
室温下，在THF(4.00mL)中加入化合物1-8(400mg,969μmol,1.00eq)，苄基异氰酸酯(258mg,1.94mmol,236μL,2.00eq),TEA(TEA(294mg,2.91mmol,404μL,3.00eq)。混合物在25℃下搅拌2小时。在反应混合物中加入10.0mL水，并用EtOAc(5.00mL×3)萃取三次，然后用NaCl(5.00mL×3)水洗三次，无水Na2SO4干燥，过滤，减压浓缩得到粗品。粗产物化合物1-9。LCMS:MS(ESI)m/z＝545.0[M+H]+。Compound 1-8 (400 mg, 969 μmol, 1.00 eq), benzyl isocyanate (258 mg, 1.94 mmol, 236 μL, 2.00 eq), and TEA (294 mg, 2.91 mmol, 404 μL, 3.00 eq) were added to THF (4.00 mL) at room temperature. The mixture was stirred at 25°C for 2 hours. 10.0 mL of water was added to the reaction mixture, and it was extracted three times with EtOAc (5.00 mL×3), then washed three times with NaCl (5.00 mL×3), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to obtain a crude product. Crude product Compound 1-9. LCMS: MS (ESI) m/z=545.0 [M+H]+.
第7步：Step 7:
在室温下，将化合物1-9(500mg,918.03μmol,1.00eq)、HCl/乙酸乙酯(4.0M,229μL,1.00eq)加入到乙酸乙酯(5.00mL)中，在25℃下搅拌1hr。减压浓缩得到的粗产物化合物1-10的盐酸盐。LCMS:MS(ESI)m/z＝411.1[M+H]+。At room temperature, compound 1-9 (500 mg, 918.03 μmol, 1.00 eq) and HCl/ethyl acetate (4.0 M, 229 μL, 1.00 eq) were added to ethyl acetate (5.00 mL) and stirred at 25° C. for 1 hr. The crude product, compound 1-10 hydrochloride, was concentrated under reduced pressure. LCMS: MS (ESI) m/z=411.1 [M+H]+.
第8步：Step 8:
室温下，将化合物1-10(100mg,224μmol,1.00eq)、化合物1-11(68.7mg,269μmol,1.20eq)、DIEA(87.2mg,674μmol,117μL,3.00eq)分别加入到DMF(0.50mL)中，在25℃搅拌10hrs。然后将混合物过滤，去除不溶性物质。采用制备-高效液相色谱法(柱:Phenomenexluna C18  150×25.0mm×10.0μm；mobile phase:[water(FA)-ACN]；B％:39.0％-69.0％,9.0min)分离纯化，得到化合物1的甲酸盐。LCMS:MS(ESI)m/z＝663.0[M+H]+。1H NMR:DMSO-d6,400MHzδ＝8.93-8.87(m,1H),8.32-8.26(m,1H),8.05-7.92(m,2H),7.47-7.39(m,1H),7.33-7.22(m,3H),7.20-7.08(m,4H),6.30-6.26(m,1H),5.72-5.50(m,2H),4.90-4.83(m,1H),4.72-4.65(m,1H),4.56-4.50(m,2H),4.37-4.26(m,1H),4.20-4.13(m,2H),3.57(s,3H),1.58-0.96(m,8H)。At room temperature, compound 1-10 (100 mg, 224 μmol, 1.00 eq), compound 1-11 (68.7 mg, 269 μmol, 1.20 eq), and DIEA (87.2 mg, 674 μmol, 117 μL, 3.00 eq) were added to DMF (0.50 mL) and stirred at 25 °C for 10 hrs. The mixture was then filtered to remove insoluble matter. The product was purified by preparative high performance liquid chromatography (column: Phenomenexluna C18 150×25.0mm×10.0μm; mobile phase: [water(FA)-ACN]; B%: 39.0%-69.0%, 9.0min) was separated and purified to obtain the formate salt of compound 1. LCMS: MS (ESI) m/z=663.0[M+H]+. 1 H NMR: DMSO-d6, 400 MHz δ＝8.93-8.87 (m, 1H), 8.32-8.26 (m, 1H), 8.05-7.92 (m, 2H), 7.47-7.39 (m, 1H), 7.33-7.22 (m, 3H), 7.20-7.08 (m, 4H), 6.30-6.26 (m, 1H), 5.72-5.50 (m, 2H), 4.90-4.83 (m, 1H), 4.72-4.65 (m, 1H), 4.56-4.50 (m, 2H), 4.37-4.26 (m, 1H), 4.20-4.13 (m, 2H), 3.57 (s, 3H), 1.58-0.96 (m, 8H).
实施例2Example 2
本实施例提供化合物2，其结构式如下：
This embodiment provides compound 2, whose structural formula is as follows:
反应路线如下所示：
The reaction route is as follows:
制备过程具体如下：The preparation process is as follows:
第1步：step 1:
在25mL三颈烧瓶中，将化合物2-1(10.0g,53.1mmol,1.00eq)、BrCN(7.79g,73.5mmol,5.41mL,1.38eq)加入到乙醇(25.0mL)和水(25.0mL)的混合溶液中，在70℃下搅拌12小时。将反应混合物减压浓缩以除去乙醇。然后将产物溶于NaOH(2.0mol/L)溶液中调至pH＝9.0，过滤去除可溶性物质。粗产物化合物2-2。LCMS:MS(ESI)m/z＝215.0[M+H]+。1H NMR:DMSO-d6,400MHzδ＝7.29(d,J＝8.0Hz,1H),6.97-6.90(m,1H),6.86(br s,2H),3.30(s,1H)。In a 25 mL three-necked flask, compound 2-1 (10.0 g, 53.1 mmol, 1.00 eq) and BrCN (7.79 g, 73.5 mmol, 5.41 mL, 1.38 eq) were added to a mixed solution of ethanol (25.0 mL) and water (25.0 mL) and stirred at 70 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure to remove ethanol. The product was then dissolved in a NaOH (2.0 mol/L) solution and adjusted to pH = 9.0, and the soluble material was removed by filtration. Crude product compound 2-2. LCMS: MS (ESI) m/z = 215.0 [M + H] +. 1 H NMR: DMSO-d6, 400 MHz δ = 7.29 (d, J = 8.0 Hz, 1H), 6.97-6.90 (m, 1H), 6.86 (br s, 2H), 3.30 (s, 1H).
第2步：Step 2:
在室温下，将化合物2-2(8.00g,37.5mmol,1.00eq)，化合物1-3(8.17g,37.5mmol,1.00eq)，TEA(3.80g,37.5mmol,5.23mL,1.00eq)分别加入到DMSO(80.0mL)中在120℃下搅拌4小时。反应完成后，加入30.0mL水搅拌30.0min，待固体析出完全后，将混合物过滤，获得不溶性粗产物化合物2-4和2-4a。LCMS:MS(ESI)m/z＝267.0[M+H]+。At room temperature, compound 2-2 (8.00 g, 37.5 mmol, 1.00 eq), compound 1-3 (8.17 g, 37.5 mmol, 1.00 eq), TEA (3.80 g, 37.5 mmol, 5.23 mL, 1.00 eq) were added to DMSO (80.0 mL) and stirred at 120 ° C for 4 hours. After the reaction was completed, 30.0 mL of water was added and stirred for 30.0 min. After the solid was completely precipitated, the mixture was filtered to obtain insoluble crude products of compounds 2-4 and 2-4a. LCMS: MS (ESI) m/z = 267.0 [M + H] +.
第3步： Step 3:
在室温下，将化合物2-4和2-4a(19.0g,71.6mmol,1.00eq)、CH3I(10.1g,71.6mmol,4.46mL,1.00eq)、K2CO3(9.91g,71.6mmol,1.00eq)分别加入到DMF(190mL)中在95℃下搅拌12小时。用H2O 200mL稀释后，然后用EtOAc(200mL×3)萃取三次，然后用NaCl(200mL×3)水洗三次，无水Na2SO4干燥，过滤，减压浓缩得到粗品。采用制备-高效液相色谱法(FA条件)对其进行纯化，得到化合物2-5和化合物2-5a。LCMS:MS(ESI)m/z＝280.9[M+H]+。At room temperature, compounds 2-4 and 2-4a (19.0 g, 71.6 mmol, 1.00 eq), CH 3 I (10.1 g, 71.6 mmol, 4.46 mL, 1.00 eq), and K 2 CO 3 (9.91 g, 71.6 mmol, 1.00 eq) were added to DMF (190 mL) and stirred at 95°C for 12 hours. After dilution with H 2 O 200 mL, the mixture was extracted three times with EtOAc (200 mL×3), washed three times with NaCl (200 mL×3), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative high performance liquid chromatography (FA conditions) to obtain compounds 2-5 and 2-5a. LCMS: MS (ESI) m/z=280.9[M+H]+.
第4步：Step 4:
在室温下，将化合物2-5(100mg,358μmol,1.00eq)、化合物1-7(153mg,716μmol,2.00eq)、CuI(68.2mg,358μmol,1.00eq)、K3PO4(228mg,1.07mmol,3.00eq)分别加入到DMSO(1.00ml)中，在90℃下搅拌3小时。反应完成后，在反应混合物中加入10.0mL水，并用EtOAc1(5.00mL×3)萃取三次，然后用NaCl(5.00mL×3)水洗三次，无水Na2SO4干燥，过滤，减压浓缩得到粗品。采用制备-高效液相色谱法(FA条件:柱:Phenomenexluna C18 150×25.0mm×10.0μm；流动相:[水(FA)-ACN]；B％:17.0％-47.0％，9.0min)纯化得到化合物2-6。LCMS:MS(ESI)m/z＝413.0[M+H]+。1H NMR:DMSO-d6,400MHzδ＝8.68-8.63(m,1H),7.89(d,J＝8.8Hz,1H),6.82-6.75(m,1H),6.47-6.40(m,1H),6.36-6.31(m,1H),6.21-6.14(m,1H),3.73-3.63(m,1H),3.54(s,3H),3.24-3.14(m,1H),2.08-1.95(m,2H),1.88-1.73(m,4H),1.42-1.32(m,15H)。At room temperature, compound 2-5 (100 mg, 358 μmol, 1.00 eq), compound 1-7 (153 mg, 716 μmol, 2.00 eq), CuI (68.2 mg, 358 μmol, 1.00 eq), K 3 PO 4 (228 mg, 1.07 mmol, 3.00 eq) were added to DMSO (1.00 ml) and stirred at 90°C for 3 hours. After the reaction was completed, 10.0 mL of water was added to the reaction mixture, and it was extracted three times with EtOAc1 (5.00 mL×3), then washed three times with NaCl (5.00 mL×3), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to obtain a crude product. Compound 2-6 was purified by preparative high performance liquid chromatography (FA conditions: column: Phenomenexluna C18 150×25.0 mm×10.0 μm; mobile phase: [water (FA)-ACN]; B%: 17.0%-47.0%, 9.0 min). LCMS: MS (ESI) m/z=413.0 [M+H]+. 1 H NMR: DMSO-d6, 400 MHz δ＝8.68-8.63 (m, 1H), 7.89 (d, J＝8.8 Hz, 1H), 6.82-6.75 (m, 1H), 6.47-6.40 (m, 1H), 6.36-6.31 (m, 1H), 6.21-6.14 (m, 1H), 3.73-3.63 (m, 1H), 3.54 (s, 3H), 3.24-3.14 (m, 1H), 2.08-1.95 (m, 2H), 1.88-1.73 (m, 4H), 1.42-1.32 (m, 15H).
第5步：Step 5:
室温下，在THF(1.00mL)中加入化合物2-6(100mg,242μmol,1.00eq)和DIEA(94.0mg,727μmol,126μL,3.00eq)溶液中，加入双(三氯甲基)碳酸酯(359mg,1.21mmol,5.00eq)。混合物在60℃下搅拌1小时。再加入化合物2-7(51.9mg,484μmol,52.8μL,2.00eq)和DMAP(29.6mg,242μmol,1.00eq)。反应完成后，在反应混合物中加入10.0mL水，并用EtOAc(5.00mL×3)萃取三次，然后用NaCl(5.00mL×3)水洗三次，无水Na2SO4干燥，过滤，减压浓缩得到粗品。粗产物化合物2-8。LCMS:MS(ESI)m/z＝546.2[M+H]+。At room temperature, compound 2-6 (100 mg, 242 μmol, 1.00 eq) and DIEA (94.0 mg, 727 μmol, 126 μL, 3.00 eq) were added to a solution of THF (1.00 mL), and bis(trichloromethyl) carbonate (359 mg, 1.21 mmol, 5.00 eq) was added. The mixture was stirred at 60 °C for 1 hour. Compound 2-7 (51.9 mg, 484 μmol, 52.8 μL, 2.00 eq) and DMAP (29.6 mg, 242 μmol, 1.00 eq) were then added. After the reaction was completed, 10.0 mL of water was added to the reaction mixture, and the mixture was extracted three times with EtOAc (5.00 mL × 3), then washed three times with NaCl (5.00 mL × 3), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to obtain a crude product. The crude product compound 2-8. LCMS: MS (ESI) m/z = 546.2 [M+H] +.
第6步：Step 6:
在室温下，将化合物2-8(30.0mg,55.0μmol,1.00eq)、HCl/乙酸乙酯(4.00M,12.5μL,1.00eq)加入到乙酸乙酯(5.00mL)中，在25℃下搅拌0.5hr。减压浓缩得到的粗产物化合物2-9的盐酸盐。LCMS:MS(ESI)m/z＝446.1[M+H]+。At room temperature, compound 2-8 (30.0 mg, 55.0 μmol, 1.00 eq) and HCl/ethyl acetate (4.00 M, 12.5 μL, 1.00 eq) were added to ethyl acetate (5.00 mL) and stirred at 25° C. for 0.5 hr. The crude product, compound 2-9 hydrochloride, was concentrated under reduced pressure. LCMS: MS (ESI) m/z=446.1 [M+H]+.
第7步：Step 7:
室温下，将化合物2-9(30.0mg,67.4μmol,1.00eq)、化合物1-11(20.6mg,80.9μmol,1.20eq)、DIEA(26.1mg,202μmol,35.2μL,3.00eq)分别加入到DMF(0.50mL)中，在25℃搅拌10hrs。然后将混合物过滤，去除不溶性物质。采用制备-高效液相色谱法(柱:Phenomenexluna C18 150×25.0mm×10μm；流动相:[水(FA)-ACN]；B％:36.0％-66.0％,9.0min)分离纯化，得到化合物2。LCMS:MS(ESI)m/z＝663.9[M+H]+。1H NMR:DMSO-d6,400MHzδ＝9.23-8.76(m,2H),8.42-8.36(m,1H),8.33-8.26(m,1H),7.34-7.19(m,7H),6.37(d,J＝8.0Hz,1H),5.85-5.52(m,2H),4.89-4.84(m,1H),4.76-4.70(m,1H),4.63(dd,J＝4.8,8.0Hz,2H),4.55(br d,J＝6.4Hz,1H),4.18(br d,J＝4.8Hz,2H),3.60(s,3H),1.92-1.83(m,4H),1.43-1.36(m,4H)。At room temperature, compound 2-9 (30.0 mg, 67.4 μmol, 1.00 eq), compound 1-11 (20.6 mg, 80.9 μmol, 1.20 eq), and DIEA (26.1 mg, 202 μmol, 35.2 μL, 3.00 eq) were added to DMF (0.50 mL) and stirred at 25 ° C for 10 hrs. The mixture was then filtered to remove insoluble matter. Preparative-HPLC (column: Phenomenexluna C18 150×25.0 mm×10 μm; mobile phase: [water (FA)-ACN]; B%: 36.0%-66.0%, 9.0 min) was used for separation and purification to obtain compound 2. LCMS: MS (ESI) m/z=663.9[M+H]+. 1 H NMR: DMSO-d6, 400 MHz δ＝9.23-8.76 (m, 2H), 8.42-8.36 (m, 1H), 8.33-8.26 (m, 1H), 7.34-7.19 (m, 7H), 6.37 (d, J＝8.0 Hz, 1H), 5.85-5.52 (m, 2H), 4.89-4.84 (m, 1H), 4.76-4.70 (m, 1H), 4.63 (dd, J＝4.8, 8.0 Hz, 2H), 4.55 (br d, J＝6.4 Hz, 1H), 4.18 (br d, J＝4.8 Hz, 2H), 3.60 (s, 3H), 1.92-1.83 (m, 4H), 1.43-1.36 (m, 4H).
实施例3Example 3
本实施例提供化合物3，其结构式如下：
This embodiment provides compound 3, whose structural formula is as follows:
反应路线如下所示：
The reaction route is as follows:
制备过程具体如下：The preparation process is as follows:
第1步：step 1:
在0℃的温度下，将化合物3-1(6.00g,23.9mmol,1.00eq)溶于四氢呋喃(50.0mL)中，加入甲醇(4.75g,148mmol,6.00mL,6.19eq)，叔丁醇钾(4.03g,35.9mmol,1.5eq)后，升温至20℃，反应3小时。在25℃下向反应体系加入氯化铵(50.0mL)淬灭反应，再用乙酸乙酯(100mL×3)萃取3次。合并有机相，用饱和氯化钠水溶液(150mL×3)洗涤3次，无水硫酸钠干燥，过滤，浓缩滤液得到化合物3-2。LCMS:MS(ESI)m/z＝246.0[M+H]+。1HNMR:(400MHz,CDCl3)δ7.75(d,J＝8.8Hz,1H),6.73(d,J＝8.8Hz,1H),3.97(s,3H),3.94(s,3H)。At 0°C, 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. The organic phases were combined, washed 3 times with saturated sodium chloride aqueous solution (150 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 3-2. LCMS: MS (ESI) m/z = 246.0 [M + H] +. 1 H NMR: (400 MHz, CDCl3) δ7.75 (d, J＝8.8 Hz, 1H), 6.73 (d, J＝8.8 Hz, 1H), 3.97 (s, 3H), 3.94 (s, 3H).
第2步：Step 2:
室温下，将化合物3-2(4.00g,16.2mmol,1.00eq)，Pin2B2(8.26g,32.5mmol,2.00eq),KOAc(3.19g,32.5mmol,2.00eq),Pd(dppf)Cl2(356mg,487μmol,0.03eq)溶于二氧六环(40.0mL)中，氮气置换3次。在90℃的氮气氛围下反应3小时。用乙酸乙酯(100mL)萃取3次。合并有机相，用饱和氯化钠水溶液(150mL)洗涤3次，无水硫酸钠干燥，过滤，浓缩滤液得到化合物3-3。LCMS:MS(ESI)m/z＝293.9[M+H]+。At room temperature, 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 μmol, 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). The organic phases were combined, washed three times with a saturated sodium chloride aqueous solution (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 3-3. LCMS: MS (ESI) m/z=293.9 [M+H]+.
第3步：Step 3:
室温下，将化合物3-3(4.77g,16.2mmol,1.00eq)，化合物3-4(7.34g,24.4mmol,1.50eq),Cs2CO3(10.6g,32.5mmol,2.00eq),Pd(dppf)Cl2(398mg,488μmol,0.0300eq)溶于二氧六环(40.0mL)和水(4.00mL)中，氮气置换3次。在90℃的氮气氛围下反应3小时。用乙酸乙酯(100mL)萃取3次。合并有机相，用饱和氯化钠水溶液(150mL)洗涤3次，无水硫酸钠干燥，过滤，浓缩滤液得到粗产品。粗产品经柱层析(SiO2,石油醚/乙酸乙酯＝1/0to 5/1)纯化后得到化合物3-5。LCMS:MS(ESI)m/z＝339.9[M+H]+。1HNMR:(400MHz,CDCl3)δ7.56(d,J＝8.4Hz,1H),7.36-7.33(m,1H),7.30(dd,J＝1.6,9.2Hz,1H),7.13(t,J＝8.0Hz,1H),6.97-6.92(m,1H),4.03(s,3H),3.78(s,3H)。At room temperature, compound 3-3 (4.77 g, 16.2 mmol, 1.00 eq), compound 3-4 (7.34 g, 24.4 mmol, 1.50 eq), Cs 2 CO 3 (10.6 g, 32.5 mmol, 2.00 eq), Pd(dppf)Cl 2 (398 mg, 488 μmol, 0.0300 eq) were dissolved in dioxane (40.0 mL) and water (4.00 mL), and the atmosphere was 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). The organic phases were combined, washed three times with a saturated sodium chloride aqueous solution (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by column chromatography (SiO 2 , petroleum ether/ethyl acetate = 1/0 to 5/1) to obtain compound 3-5. LCMS: MS (ESI) m/z = 339.9 [M+H] +. 1 H NMR: (400 MHz, CDCl 3 ) δ 7.56 (d, J = 8.4 Hz, 1H), 7.36-7.33 (m, 1H), 7.30 (dd, J = 1.6, 9.2 Hz, 1H), 7.13 (t, J = 8.0 Hz, 1H), 6.97-6.92 (m, 1H), 4.03 (s, 3H), 3.78 (s, 3H).
第4步：Step 4:
在25℃的温度下，化合物3-5(2.70g,7.94mmol,1.00eq)，氢氧化钾(2.23g,39.7mmol,5.00eq)加入水(25.0mL)中，100℃下搅拌3小时。然后用1M盐酸溶液将水层酸化至pH等 于1.0。反应用乙酸乙酯(20.0mL)萃取3次。合并有机相，饱和氯化钠水溶液(50.0mL)洗涤3次，无水硫酸钠干燥，过滤，浓缩滤液得到化合物3-6。LCMS:m/z＝325.8(M+H)+。1HNMR:(400MHz,CDCl3)δ7.63(d,J＝8.4Hz,1H),7.35(dd,J＝1.6,8.4Hz,1H),7.31(dd,J＝1.6,9.2Hz,1H),7.12-7.08(m,2H),4.05(s,3H)。At 25°C, 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. LCMS: m/z=325.8 (M+H)+. 1 HNMR: (400 MHz, CDCl 3 )δ7.63 (d, J=8.4 Hz, 1H), 7.35 (dd, J=1.6, 8.4 Hz, 1H), 7.31 (dd, J=1.6, 9.2 Hz, 1H), 7.12-7.08 (m, 2H), 4.05 (s, 3H).
第5步：Step 5:
在0℃的温度下，化合物3-6(1.57g,4.81mmol,1.00eq)溶于THF(15.0mL)中，缓慢滴加BH3-Me2S(10M,1.20mL,2.50eq)，50℃下搅拌6小时，将反应体系缓慢加入水(30mL×3)中，用乙酸乙酯(30.0mL)萃取3次。合并有机相，饱和氯化钠水溶液(50.0mL)洗涤3次，无水硫酸钠干燥，过滤，浓缩滤液得到化合物3-7。LCMS:m/z＝311.9(M+H)+。At 0°C, compound 3-6 (1.57 g, 4.81 mmol, 1.00 eq) was dissolved in THF (15.0 mL), BH 3 -Me 2 S (10 M, 1.20 mL, 2.50 eq) was slowly added dropwise, and stirred at 50°C for 6 hours. The reaction system was slowly added into water (30 mL×3), and extracted 3 times with ethyl acetate (30.0 mL). The organic phases were combined, washed 3 times with saturated sodium chloride aqueous solution (50.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 3-7. LCMS: m/z=311.9 (M+H)+.
第6步：Step 6:
在0℃的温度下，化合物3-7(1.28g,4.10mmol,1.00eq)溶于THF(10.0mL)中，缓慢加入NaH(410mg,10.2mmol,60％purity,2.50eq)，50℃下搅拌12小时。在0℃下，将反应体系缓慢加入氯化铵(5.00mL)中，用乙酸乙酯(20.0mL)萃取3次。合并有机相，饱和氯化钠水溶液(30.0mL)洗涤3次，无水硫酸钠干燥，过滤，浓缩滤液得到粗产品，粗产品经prep-HPLC(FA condition)纯化后得到化合物3-8。LCMS:m/z＝291.9(M+H)+。1HNMR:(400MHz,CDCl3)δ7.83(d,J＝8.4Hz,1H),7.42-7.38(m,1H),7.18-7.15(m,2H),6.75(d,J＝8.4Hz,1H),5.15(s,2H),3.95(s,3H)。At 0°C, compound 3-7 (1.28 g, 4.10 mmol, 1.00 eq) was dissolved in THF (10.0 mL), and NaH (410 mg, 10.2 mmol, 60% purity, 2.50 eq) was slowly added, and stirred at 50°C for 12 hours. At 0°C, the reaction system was slowly added to ammonium chloride (5.00 mL) and extracted 3 times with ethyl acetate (20.0 mL). The organic phases were combined, washed 3 times with saturated sodium chloride aqueous solution (30.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by prep-HPLC (FA condition) to obtain compound 3-8. LCMS: m/z=291.9 (M+H)+. 1 H NMR: (400 MHz, CDCl3) δ7.83 (d, J＝8.4 Hz, 1H), 7.42-7.38 (m, 1H), 7.18-7.15 (m, 2H), 6.75 (d, J＝8.4 Hz, 1H), 5.15 (s, 2H), 3.95 (s, 3H).
第7步：Step 7:
室温下，将化合物3-8(100mg×2,342μmol,1.00eq)，化合物1-7(110mg,513μmol,1.50eq)，RuPhosPdG3(28.6mg,34.2μmol,0.100eq)和Cs2CO3(334mg,1.03mmol,3.00eq)溶于DMSO(1.00mL)中，N2置换3次，在100℃的氮气氛围下反应12小时。将反应体系用水(5.00mL)稀释，用乙酸乙酯(10.0mL×3)萃取3次。合并有机相，饱和氯化钠水溶液(15.0mL×3)洗涤3次，无水硫酸钠干燥，过滤，浓缩滤液得到粗产品，粗产品经prep-HPLC(FA condition)纯化后得到化合物3-9。LCMS:m/z＝426.1(M+H)+。1HNMR:(400MHz,CDCl3)δ7.72(d,J＝8.4Hz,1H),7.34(d,J＝8.4Hz,1H),6.69(d,J＝8.4Hz,1H),6.44-6.11(m,2H),5.09(s,2H),4.40(br s,1H),3.93(s,3H),3.48(br s,1H),3.23(br s,1H),2.23-2.13(m,2H),2.13-2.04(m,2H),1.46(s,9H),1.32-1.21(m,4H)。At room temperature, compound 3-8 (100 mg×2, 342 μmol, 1.00 eq), compound 1-7 (110 mg, 513 μmol, 1.50 eq), RuPhosPdG 3 (28.6 mg, 34.2 μmol, 0.100 eq) and Cs 2 CO 3 (334 mg, 1.03 mmol, 3.00 eq) were dissolved in DMSO (1.00 mL), replaced with N 2 three times, and reacted for 12 hours under a nitrogen atmosphere at 100°C. The reaction system was diluted with water (5.00 mL) and extracted three times with ethyl acetate (10.0 mL×3). The organic phases were combined, washed three times with saturated sodium chloride aqueous solution (15.0 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by prep-HPLC (FA condition) to obtain compound 3-9. LCMS: m/z=426.1 (M+H)+. 1 H NMR: (400 MHz, CDCl 3 ) δ 7.72 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 6.69 (d, J = 8.4 Hz, 1H), 6.44-6.11 (m, 2H), 5.09 (s, 2H), 4.40 (br s, 1H), 3.93 (s, 3H), 3.48 (br s, 1H), 3.23 (br s, 1H), 2.23-2.13 (m, 2H), 2.13-2.04 (m, 2H), 1.46 (s, 9H), 1.32-1.21 (m, 4H).
第8步：Step 8:
室温下，将化合物3-9(110mg,258μmol,1.00eq)，BnNCO(68.8mg,517μmol,63.1μL,2.00eq)，和DMAP(3.16mg,25.8μmol,0.100eq)溶于四氢呋喃(0.50mL)中，N2置换3次，在50℃的氮气氛围下反应12小时。将反应体系浓缩除去溶剂后得到化合物3-10。LCMS:m/z＝559.0(M+H)+。At room temperature, compound 3-9 (110 mg, 258 μmol, 1.00 eq), BnNCO (68.8 mg, 517 μmol, 63.1 μL, 2.00 eq), and DMAP (3.16 mg, 25.8 μmol, 0.100 eq) were dissolved in tetrahydrofuran (0.50 mL), replaced with N 2 three times, and reacted for 12 hours under a nitrogen atmosphere at 50 ° C. The reaction system was concentrated to remove the solvent to obtain compound 3-10. LCMS: m/z=559.0 (M+H)+.
第9步：Step 9:
室温下，将化合物3-10(114mg,204μmol,1.00eq)溶于HCl/EtOAc(2.00mL)中，在20℃下反应2小时。将反应体系浓缩除去溶剂后得到化合物3-11。LCMS:m/z＝459.0(M+H)+。At room temperature, compound 3-10 (114 mg, 204 μmol, 1.00 eq) was dissolved in HCl/EtOAc (2.00 mL) and reacted at 20° C. for 2 hours. The reaction system was concentrated to remove the solvent to obtain compound 3-11. LCMS: m/z=459.0 (M+H)+.
第10步：Step 10:
室温下，将化合物3-11(93.0mg,202μmol,1.00eq)，化合物1-11(51.6mg,202μmol,1.00eq)溶于DMF(1.00mL)，再加入DIEA(78.6mg,608μmol,105μL,3.00eq)，在20℃反应12小时。将反应体系用水(3.00mL)稀释，用乙酸乙酯(5.00mL×3)萃取3次。合并有机相，饱和氯化钠水溶液(8.00mL×3)洗涤3次，无水硫酸钠干燥，过滤，浓缩滤液得到粗产品，粗产品经prep-HPLC(FA condition)纯化后得到化合物3的甲酸盐。LCMS:m/z＝676.9[M+H]+。1HNMR:(400MHz,DMSO-d6)δ8.30(d,J＝6.0Hz,1H),8.23(dd,J＝6.0,8.8Hz,1H),7.98-7.72(m,2H),7.31-7.25(m,2H),7.21-7.15(m,3H),6.90(s,1H),6.79(dd,J＝2.0,11.2Hz,1H),6.03-5.95(m,1H),5.57(quin,J＝5.7Hz,1H),5.17(s,2H),4.85(t,J＝7.2Hz,1H),4.74(t,J＝7.2Hz,1H),4.60-4.50(m,2H),4.30-4.20(m,1H),4.16(br d,J＝5.6Hz,2H),3.89(s,3H),1.94-1.79(m,4H),1.43-1.33(m,2H),1.27-1.16(m,2H)。 At room temperature, compound 3-11 (93.0 mg, 202 μmol, 1.00 eq) and compound 1-11 (51.6 mg, 202 μmol, 1.00 eq) were dissolved in DMF (1.00 mL), and DIEA (78.6 mg, 608 μmol, 105 μL, 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. The organic phases were combined, washed three times with saturated sodium chloride aqueous solution (8.00 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by prep-HPLC (FA condition) to obtain the formate salt of compound 3. LCMS: m/z = 676.9 [M + H] +. 1 H NMR: (400 MHz, DMSO-d6) δ8.30 (d, J = 6.0 Hz, 1H), 8.23 (dd, J = 6.0, 8.8 Hz, 1H), 7.98-7.72 (m, 2H), 7.31-7.25 (m, 2H), 7.21-7.15 (m, 3H), 6.90 (s, 1H), 6.79 (dd, J = 2.0, 11.2 Hz, 1H), 6.03-5.95 (m, 1H), 5.57 (quin, J = 5.7 Hz, 1H), 5.17 (s, 2H), 4.85 (t, J = 7.2 Hz, 1H), 4.74 (t, J = 7.2 Hz, 1H), 4.60-4.50 (m, 2H), 4.30-4.20 (m, 1H), 4.16 (br d, J = 5.6 Hz, 2H), 3.89 (s, 3H), 1.94-1.79 (m, 4H), 1.43-1.33 (m, 2H), 1.27-1.16 (m, 2H).
实施例4Example 4
本实施例提供化合物4，其结构式如下：
This embodiment provides compound 4, whose structural formula is as follows:
反应路线如下所示：
The reaction route is as follows:
制备过程具体如下：The preparation process is as follows:
第1步：step 1:
室温下，将化合物4-1(6.00g,23.9mmol,1.00eq)，氢氧化钾(6.21g,110mmol,5.00eq)溶于H2O(60.0mL)中，100℃，反应3小时。反应体系用盐酸调至pH等于1，再用二氯甲烷(100mL×3)萃取3次。合并有机相，用饱和氯化钠水溶液(150mL×3)洗涤3次，无水硫酸钠干燥，过滤，浓缩滤液得到化合物4-2。LCMS:MS(ESI)m/z＝256.9[M+H]+。1HNMR:(400MHz,CDCl3)δ8.11(s,1H),8.06(d,J＝0.8Hz,1H),7.78(d,J＝8.4Hz,1H),7.55(dd,J＝1.6,8.4Hz,1H)。At room temperature, compound 4-1 (6.00 g, 23.9 mmol, 1.00 eq) and potassium hydroxide (6.21 g, 110 mmol, 5.00 eq) were dissolved in H 2 O (60.0 mL) and reacted at 100°C for 3 hours. The reaction system was adjusted to pH 1 with hydrochloric acid and then extracted with dichloromethane (100 mL×3) for 3 times. The organic phases were combined, washed 3 times with saturated sodium chloride aqueous solution (150 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 4-2. LCMS: MS (ESI) m/z＝256.9[M+H]+. 1 H NMR: (400 MHz, CDCl 3 ) δ 8.11 (s, 1H), 8.06 (d, J=0.8 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.55 (dd, J=1.6, 8.4 Hz, 1H).
第2步：Step 2:
室温下，将化合物4-2(5.60g,21.7mmol,1.00eq)，TEA(2.42g,23.9mmol,3.33mL,1.10eq)和DPPA(6.59g,23.9mmol,5.19mL,1.10eq)溶于叔丁醇(60.0mL)中，在20℃温度下反应0.5小时后升温到80℃反应8小时，用NaHCO3(aq,40.0mL)稀释，乙酸乙酯(80.0mL×3)萃取3次。合并有机相，无水硫酸钠干燥，过滤，浓缩滤液得到粗产品，粗产品用柱层析(SiO2,石油醚/乙酸乙酯＝5/1)纯化，得到化合物4-3。LCMS:MS(ESI)m/z＝271.9[M+H]+。At room temperature, 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. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by column chromatography (SiO 2 , petroleum ether/ethyl acetate=5/1) to obtain compound 4-3. LCMS: MS (ESI) m/z=271.9[M+H]+.
第3步：Step 3:
在0℃下，将DMF(1.34g,18.2mmol,1.41mL,2.00eq)溶于四氢呋喃(15.0mL)，滴加POCl3(4.20g,27.4mmol,2.55mL,3.00eq)，在0℃下反应0.5小时，然后将化合物4-3(3.00g,9.14mmol,1.00eq)溶于四氢呋喃(15.0mL)后，滴加到反应体系。在20℃下反应1.5小时。反应体系用氢氧化钠(2.0M，10.0mL)淬灭，用乙酸乙酯(30.0mL×3)萃取3次。合并有机相，用饱和氯化钠水溶液(40.0mL×3)洗涤3次，无水硫酸钠干燥，过滤，浓缩滤液得到化合物4-4。LCMS:MS(ESI)m/z＝299.8[M+H]+。1HNMR:(400MHz,CDCl3)δ11.11-10.99(m,1H),10.11(s,1H),7.78(d,J＝1.6Hz,1H),7.68(d,J＝8.8Hz,1H),7.45(dd,J＝1.6,8.4Hz,1H),1.51(s, 9H)。At 0°C, DMF (1.34 g, 18.2 mmol, 1.41 mL, 2.00 eq) was dissolved in tetrahydrofuran (15.0 mL), POCl 3 (4.20 g, 27.4 mmol, 2.55 mL, 3.00 eq) was added dropwise, and the mixture was reacted at 0°C for 0.5 hours. Then, compound 4-3 (3.00 g, 9.14 mmol, 1.00 eq) was dissolved in tetrahydrofuran (15.0 mL) and added dropwise to the reaction system. The mixture was reacted at 20°C for 1.5 hours. The reaction system was quenched with sodium hydroxide (2.0 M, 10.0 mL) and extracted three times with ethyl acetate (30.0 mL×3). The organic phases were combined, washed three times with saturated sodium chloride aqueous solution (40.0 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 4-4. LCMS: MS (ESI) m/z=299.8[M+H]+. 1 HNMR: (400MHz,CDCl 3 )δ11.11-10.99(m,1H),10.11(s,1H),7.78(d,J＝1.6Hz,1H),7.68(d,J＝8.8Hz,1H),7.45(dd,J＝1.6,8.4Hz,1H),1.51(s, 9H).
第4步：Step 4:
在0℃的温度下，化合物4-5(7.55g,33.7mmol,6.68mL,4.00eq加入四氢呋喃(18.0mL)中，缓慢加入NaH(1.35g,33.7mmol,60％purity,4.0eq)，在0℃下反应0.5小时，然后将化合物4-4(3.00g,8.42mmol,1.00eq)溶于四氢呋喃(18.0mL)后，滴加到反应体系。60℃下反应12小时。室温下，将反应体系加入氯化铵溶液(40.0mL)淬灭，乙酸乙酯(100mL×3)萃取3次。合并有机相，饱和氯化钠水溶液(150×3mL)洗涤3次，无水硫酸钠干燥，过滤，浓缩滤液得到化合物4-6。LCMS:m/z＝327.8(M+H)+。At 0°C, 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. At room temperature, the reaction system was quenched by adding ammonium chloride solution (40.0 mL) and extracted 3 times with ethyl acetate (100 mL×3). The organic phases were combined, washed 3 times with saturated sodium chloride aqueous solution (150×3 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 4-6. LCMS: m/z=327.8 (M+H)+.
第5步：Step 5:
室温下，化合物4-6(3.56g,8.35mmol,1.00eq)溶于HCl/MeOH(30.0mL)中，20℃下搅拌4小时。用碳酸氢钠溶液调节pH到9，过滤得到化合物4-7。LCMS:m/z＝281.8(M+H)+1HNMR:(400MHz,DMSO-d6)δ12.19-11.71(m,1H),8.46(br d,J＝8.8Hz,1H),8.26(d,J＝1.6Hz,1H),8.09(d,J＝8.4Hz,1H),7.63(dd,J＝1.6,8.4Hz,1H),6.68(br d,J＝8.8Hz,1H)。At room temperature, 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. LCMS: m/z=281.8 (M+H)+ 1 HNMR: (400 MHz, DMSO-d6) δ12.19-11.71 (m, 1H), 8.46 (br d, J=8.8 Hz, 1H), 8.26 (d, J=1.6 Hz, 1H), 8.09 (d, J=8.4 Hz, 1H), 7.63 (dd, J=1.6, 8.4 Hz, 1H), 6.68 (br d, J=8.8 Hz, 1H).
第6步：Step 6:
在0℃的温度下，化合物4-7(1.30g,4.64mmol,1.00eq)溶于DMF(15.0mL)中，加入MeI(988mg,6.96mmol,433μL,1.50eq)和K2CO3(1.28g,9.28mmol,2.00eq)，50℃下搅拌3小时。将反应体系用水(20.0mL)稀释，用乙酸乙酯(40.0×3mL)萃取3次。合并有机相，饱和氯化钠水溶液(30.0mL×3)洗涤3次，无水硫酸钠干燥，过滤，浓缩滤液得到粗产品，粗产品经柱层析(SiO2,石油醚/乙酸乙酯＝2/1to 0/1)纯化后得到化合物4-8。LCMS:m/z＝293.8(M+H)+。1HNMR:(400MHz,CDCl3)δ8.34(d,J＝1.6Hz,1H),8.30(d,J＝9.6Hz,1H),8.03(d,J＝8.4Hz,1H),7.64(dd,J＝1.6,8.4Hz,1H),6.53(d,J＝9.6Hz,1H),3.62(s,3H)。At 0°C, 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 μL, 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. The organic phases were combined, washed with saturated sodium chloride aqueous solution (30.0 mL×3) for 3 times, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by column chromatography (SiO 2 , petroleum ether/ethyl acetate=2/1 to 0/1) to obtain compound 4-8. LCMS: m/z=293.8 (M+H)+. 1 H NMR: (400 MHz, CDCl 3 ) δ 8.34 (d, J = 1.6 Hz, 1H), 8.30 (d, J = 9.6 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.64 (dd, J = 1.6, 8.4 Hz, 1H), 6.53 (d, J = 9.6 Hz, 1H), 3.62 (s, 3H).
第7步：Step 7:
室温下，将化合物4-8(200mg，2.67μmol,1.00eq)，化合物1-7(218mg,1.02mmol,1.50eq)，XPhosPdG3(57.5mg,67.9μmol,0.100eq)和Cs2CO3(664mg,2.04mmol,3.00eq)溶于DMSO(2.00mL)中，N2置换3次，在100℃的氮气氛围下反应12小时。将反应体系用水(10.0mL)稀释，用乙酸乙酯(15.0mL×3)萃取3次。合并有机相，饱和氯化钠水溶液(20.0mL×3)洗涤3次，无水硫酸钠干燥，过滤，浓缩滤液得到粗产品，粗产品经prep-HPLC(FA condition)纯化后得到化合物4-9。LCMS:m/z＝428.0(M+H)+。At room temperature, compound 4-8 (200 mg, 2.67 μmol, 1.00 eq), compound 1-7 (218 mg, 1.02 mmol, 1.50 eq), XPhosPdG 3 (57.5 mg, 67.9 μmol, 0.100 eq) and Cs 2 CO 3 (664 mg, 2.04 mmol, 3.00 eq) were dissolved in DMSO (2.00 mL), replaced with N 2 three times, and reacted for 12 hours under a nitrogen atmosphere at 100°C. The reaction system was diluted with water (10.0 mL) and extracted three times with ethyl acetate (15.0 mL×3). The organic phases were combined, washed three times with saturated sodium chloride aqueous solution (20.0 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by prep-HPLC (FA condition) to obtain compound 4-9. LCMS: m/z=428.0 (M+H)+.
第8步：Step 8:
室温下，将化合物4-9(60.0mg,140μmol,1.00eq)，BnNCO(37.3mg,280μmol,34.2μL,2.00eq)，和DMAP(1.71mg,14.0μmol,0.100eq)溶于四氢呋喃(1.00mL)中，在50℃下反应12小时。将反应体系浓缩除去溶剂后得到化合物4-10。LCMS:m/z＝561.0(M+H)+。At room temperature, compound 4-9 (60.0 mg, 140 μmol, 1.00 eq), BnNCO (37.3 mg, 280 μmol, 34.2 μL, 2.00 eq), and DMAP (1.71 mg, 14.0 μmol, 0.100 eq) were dissolved in tetrahydrofuran (1.00 mL) and reacted at 50° C. for 12 hours. The reaction system was concentrated to remove the solvent to obtain compound 4-10. LCMS: m/z=561.0 (M+H)+.
第9步：Step 9:
室温下，将化合物4-10(78.0mg,139μmol,1.00eq)溶于HCl/EtOAc(2.00mL)中，在20℃下反应2小时。将反应体系浓缩除去溶剂后得到化合物4-11。LCMS:m/z＝460.9(M+H)+。At room temperature, compound 4-10 (78.0 mg, 139 μmol, 1.00 eq) was dissolved in HCl/EtOAc (2.00 mL) and reacted at 20° C. for 2 hours. The reaction system was concentrated to remove the solvent to obtain compound 4-11. LCMS: m/z=460.9 (M+H)+.
第10步：Step 10:
室温下，将化合物4-11(64.0mg,138μmol,1.00eq)，化合物1-11(35.3mg,138μmol,1.00eq)溶于DMF(1.00mL)，再加入DIEA(53.8mg,416μmol,72.6μL,3.00eq)，在20℃反应12小时。将反应体系用水(3.00mL)稀释，用乙酸乙酯(5.00mL×3)萃取3次。合并有机相，饱和氯化钠水溶液(8.00mL×3)洗涤3次，无水硫酸钠干燥，过滤，浓缩滤液得到粗产品，粗产品经prep-HPLC(FA condition)纯化后得到化合物4的甲酸盐。LCMS:m/z＝678.9[M+H]+。1HNMR:(400MHz,DMSO)δ8.35(dd,J＝2.4,9.6Hz,1H),8.31-8.26(m,1H),8.16(dd,J＝8.4,10.8Hz,1H),8.00-7.68(m,2H),7.33-7.25(m,3H),7.20-7.14(m,3H),6.54(d,J＝9.4Hz,1H),5.95(td,J＝6.0,16.4Hz,1H),5.66-5.45(m,1H),4.85(t,J＝6.8Hz,1H),4.69(t,J＝7.2Hz,1H),4.62-4.47(m,2H),4.37-4.24(m,1H),4.14(br d,J＝6.0Hz,2H),3.64(s,3H),3.48(br s,1H),1.93-1.79(m,4H),1.49-1.32(m,2H),1.24-1.08(m,2H)。 At room temperature, compound 4-11 (64.0 mg, 138 μmol, 1.00 eq) and compound 1-11 (35.3 mg, 138 μmol, 1.00 eq) were dissolved in DMF (1.00 mL), and DIEA (53.8 mg, 416 μmol, 72.6 μL, 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. The organic phases were combined, washed 3 times with saturated sodium chloride aqueous solution (8.00 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by prep-HPLC (FA condition) to obtain the formate salt of compound 4. LCMS: m/z = 678.9 [M + H] +. 1 H NMR: (400 MHz, DMSO) δ8.35 (dd, J = 2.4, 9.6 Hz, 1H), 8.31-8.26 (m, 1H), 8.16 (dd, J = 8.4, 10.8 Hz, 1H), 8.00-7.68 (m, 2H), 7.33-7.25 (m, 3H), 7.20-7.14 (m, 3H), 6.54 (d, J = 9.4 Hz, 1H), 5.95 (td, J = 6.0, 16.4 Hz, 1H), 5.66-5.45 (m, 1H), 4.85 (t, J = 6.8 Hz, 1H), 4.69 (t, J = 7.2 Hz, 1H), 4.62-4.47 (m, 2H), 4.37-4.24 (m, 1H), 4.14 (br d, J = 6.0 Hz, 2H), 3.64 (s, 3H), 3.48 (br s, 1H), 1.93-1.79 (m, 4H), 1.49-1.32 (m, 2H), 1.24-1.08 (m, 2H).
实施例5Example 5
本实施例提供化合物5，其结构式如下：
This embodiment provides compound 5, whose structural formula is as follows:
反应路线如下所示：
The reaction route is as follows:
制备过程具体如下：The preparation process is as follows:
第1步：step 1:
在室温下，在THF(10.0mL)中分别加入化合物5-1(1.00g,4.61mmol,1.00eq)，DIEA(1.19g,9.22mmol,1.61mL,2.00eq)和化合物5-2(404mg,5.53mmol,1.20eq)，将混合物在0℃下搅拌7小时。向反应体系中加入50.0mL H2O稀释，用EtOAc(15.0mL×3)萃取三次，然后用饱和氯化钠溶液(15.0mL×3)水洗三次，无水硫酸钠干燥，过滤，减压浓缩得到粗产物。采用制备-高效液相色谱法(FA条件)对其进行纯化获得的化合物5-3。LCMS:MS(ESI)m/z＝253.9[M+H]+。1H NMR:CDCl3,400MHzδ＝8.40-8.31(m,1H),5.95-5.79(m,1H),5.32-5.21(m,1H),5.04(t,J＝7.2Hz,2H),4.59(t,J＝6.4Hz,2H)。At room temperature, compound 5-1 (1.00 g, 4.61 mmol, 1.00 eq), DIEA (1.19 g, 9.22 mmol, 1.61 mL, 2.00 eq) and compound 5-2 (404 mg, 5.53 mmol, 1.20 eq) were added to THF (10.0 mL) and the mixture was stirred at 0°C for 7 hours. 50.0 mL of H 2 O was added to the reaction system for dilution, extracted three times with EtOAc (15.0 mL×3), then washed three times with saturated sodium chloride solution (15.0 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. Compound 5-3 was obtained by purification using preparative high performance liquid chromatography (FA conditions). LCMS: MS (ESI) m/z=253.9[M+H]+. 1 H NMR: CDCl3, 400 MHz δ＝8.40-8.31 (m, 1H), 5.95-5.79 (m, 1H), 5.32-5.21 (m, 1H), 5.04 (t, J＝7.2 Hz, 2H), 4.59 (t, J＝6.4 Hz, 2H).
第2步：Step 2:
室温下，将化合物1-10(100mg,224μmol,1.00eq)、化合物5-3(68.4mg,269μmol,1.20eq)、DIEA(87.2mg,674μmol,117μL,3.00eq)分别加入到DMF(1.00mL)中，在25℃下搅拌10小时。将反应液过滤以去除不溶物，采用制备-高效液相色谱法(FA条件:柱:Phenomenexluna C18 150×25mm×10μm；流动相:[水(FA)-ACN]；B％:15％-45％，9min)对混合物进行纯化，获得的5。LCMS:MS(ESI)m/z＝622.3[M+H]+。1H NMR:DMSO-d6,400MHzδ＝8.93-8.86(m,1H),8.50-8.21(m,1H),8.01(q,J＝8.0Hz,2H),7.48-7.41(m,1H),7.29-7.07(m,9H),6.31-6.25(m,1H),5.77-5.62(m,1H),4.78-4.64(m,1H),4.59-4.47(m,2H),4.39-4.26(m,1H),4.14(br d,J＝6.3Hz,2H),3.57(s,3H),1.91-1.82(m,4H),1.46-1.32(m,2H),1.15-1.06(m,2H)。At room temperature, compound 1-10 (100 mg, 224 μmol, 1.00 eq), compound 5-3 (68.4 mg, 269 μmol, 1.20 eq), and DIEA (87.2 mg, 674 μmol, 117 μL, 3.00 eq) were added to DMF (1.00 mL) and stirred at 25°C for 10 hours. The reaction solution was filtered to remove insoluble matter, and the mixture was purified by preparative-HPLC (FA conditions: column: Phenomenexluna C18 150×25 mm×10 μm; mobile phase: [water (FA)-ACN]; B%: 15%-45%, 9 min) to obtain 5. LCMS: MS (ESI) m/z=622.3[M+H]+. 1 H NMR: DMSO-d6, 400 MHz δ＝8.93-8.86 (m, 1H), 8.50-8.21 (m, 1H), 8.01 (q, J＝8.0 Hz, 2H), 7.48-7.41 (m, 1H), 7.29-7.07 (m, 9H), 6.31-6.25 (m, 1H), 5.77-5.62 (m, 1H), 4.78-4.64 (m, 1H), 4.59-4.47 (m, 2H), 4.39-4.26 (m, 1H), 4.14 (br d, J＝6.3 Hz, 2H), 3.57 (s, 3H), 1.91-1.82 (m, 4H), 1.46-1.32 (m, 2H), 1.15-1.06 (m, 2H).
实施例6Example 6
本实施例提供化合物6，其结构式如下：
This embodiment provides compound 6, whose structural formula is as follows:
反应路线如下所示：
The reaction route is as follows:
制备过程具体如下：The preparation process is as follows:
第1步：step 1:
室温下，将化合物6-1(1.00g,5.39mmol,1.00eq)，化合物6-2(3.00g,10.7mmol,2.00eq)，Pd(Amphos)2Cl2(114mg,161μmol,114μL,0.03eq)和K2CO3(1.49g,10.7mmol,2.00eq)溶于二氧六环(10.0mL)和水(2.00mL)中，N2置换3次，在90.0℃的氮气氛围下反应12小时后监测。将反应体系用水(10.0mL)稀释，用乙酸乙酯(50.0mL×3)萃取3次。合并有机相，饱和氯化钠水溶液(80.0mL×3)洗涤3次，无水硫酸钠干燥，过滤，浓缩滤液得到化合物6-3。LCMS:m/z＝218.0(M+H)+。1H NMR:(400MHz,CDCl3)δ8.80(s,1H),7.70(d,J＝2.0Hz,1H),7.22(d,J＝2.0Hz,1H),6.22(dd,J＝2.4,9.2Hz,1H),2.66(s,3H)。At room temperature, compound 6-1 (1.00 g, 5.39 mmol, 1.00 eq), compound 6-2 (3.00 g, 10.7 mmol, 2.00 eq), Pd(Amphos) 2 Cl 2 (114 mg, 161 μmol, 114 μL, 0.03 eq) and K 2 CO 3 (1.49 g, 10.7 mmol, 2.00 eq) were dissolved in dioxane (10.0 mL) and water (2.00 mL), replaced with N 2 three times, and monitored after reacting for 12 hours under a nitrogen atmosphere at 90.0°C. The reaction system was diluted with water (10.0 mL) and extracted three times with ethyl acetate (50.0 mL×3). The organic phases were combined, washed three times with a saturated sodium chloride aqueous solution (80.0 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 6-3. LCMS: m/z＝218.0(M+H)+. 1 H NMR: (400 MHz, CDCl3) δ 8.80 (s, 1H), 7.70 (d, J = 2.0 Hz, 1H), 7.22 (d, J = 2.0 Hz, 1H), 6.22 (dd, J = 2.4, 9.2 Hz, 1H), 2.66 (s, 3H).
第2步：Step 2:
在0℃下，将化合物6-3(300mg,1.38mmol,1.00eq)溶于乙腈(5.00mL)中，向体系中滴加SO2Cl2(559mg,4.14mmol,414μL,3.00eq)，在20℃下反应12小时。将反应体系用水(5.00mL)稀释，用乙酸乙酯(10.0mL×3)萃取3次。合并有机相，饱和氯化钠水溶液(15.0mL×3)洗涤3次，无水硫酸钠干燥，过滤，浓缩滤液得到化合物6-4。LCMS:m/z＝240.0(M+H)+1H NMR:(400MHz,CDCl3)δ8.97(s,1H),7.80(s,1H)。At 0°C, compound 6-3 (300 mg, 1.38 mmol, 1.00 eq) was dissolved in acetonitrile (5.00 mL), and SO 2 Cl 2 (559 mg, 4.14 mmol, 414 μL, 3.00 eq) was added dropwise to the system, and the mixture was reacted at 20°C for 12 hours. The reaction system was diluted with water (5.00 mL) and extracted three times with ethyl acetate (10.0 mL×3). The organic phases were combined, washed three times with saturated sodium chloride aqueous solution (15.0 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 6-4. LCMS: m/z＝240.0(M+H)+ 1 H NMR:(400MHz,CDCl 3 )δ8.97(s,1H),7.80(s,1H).
第3步：Step 3:
室温下，将化合物1-10(10.0mg,22.5μmol,1.00eq)，化合物6-4(5.40mg,22.5μmol,1.00eq)溶于DMF(1.00mL)，再加入K2CO3(9.33mg,67.5μmol,3.00eq)，在60℃反应12小时。将反应体系用水(3.00mL)稀释，用乙酸乙酯(5.00mL×3)萃取3次。合并有机相，饱和氯化钠水溶液(8.00mL×3)洗涤3次，无水硫酸钠干燥，过滤，浓缩滤液得到粗产品，粗产品经prep-HPLC(FA condition)纯化后得到化合物6。LCMS:m/z＝648.3[M+H]+。1H NMR:(400MHz,DMSO)δ13.84-13.62(m,1H),8.96-8.84(m,1H),8.68-8.60(m,1H),8.32-8.19(m,1H),8.12-8.06(m,1H),8.01(d,J＝8.4Hz,1H),7.48-7.41(m,1H),7.33-7.22(m,2H),7.20-7.14(m,3H),7.12-7.07(m,1H),6.40-6.21(m,1H),5.79-5.63(m,1H),4.47-4.24(m,1H),4.14(br d,J＝5.6Hz,2H),3.56(s,3H),2.02-1.95(m,2H),1.89(br d,J＝9.2Hz,2H),1.51-1.40(m,2H),1.23(br s,1H),1.16-1.04(m,2H)。At room temperature, compound 1-10 (10.0 mg, 22.5 μmol, 1.00 eq) and compound 6-4 (5.40 mg, 22.5 μmol, 1.00 eq) were dissolved in DMF (1.00 mL), and K 2 CO 3 (9.33 mg, 67.5 μmol, 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 organic phases were combined, washed with saturated sodium chloride aqueous solution (8.00 mL×3) for 3 times, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by prep-HPLC (FA condition) to obtain compound 6. LCMS: m/z=648.3[M+H]+. 1 H NMR: (400 MHz, DMSO) δ 13.84-13.62 (m, 1H), 8.96-8.84 (m, 1H), 8.68-8.60 (m, 1H), 8.32-8.19 (m, 1H), 8.12-8.06 (m, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.48-7.41 (m, 1H), 7.33-7.22 (m, 2H), 7.20-7.14 (m, 3H), 7.12-7.07 (m, 1H), 6.40-6.21 (m, 1H), 5.79-5.63 (m, 1H), 4.47-4.24 (m, 1H), 4.14 (br d, J = 5.6 Hz, 2H), 3.56 (s, 3H), 2.02-1.95 (m, 2H), 1.89 (br d, J = 9.2 Hz, 2H), 1.51-1.40 (m, 2H), 1.23 (br s, 1H), 1.16-1.04 (m, 2H).
实施例7Example 7
本实施例提供化合物7，其结构式如下：
This example provides compound 7, whose structural formula is as follows:
反应路线如下所示：
The reaction route is as follows:
制备过程具体如下：The preparation process is as follows:
第1步：step 1:
室温下，依次将化合物7-1(500mg,2.69mmol,1.00eq)，化合物7-2(1.24g,4.04mmol,1.50eq)，碳酸钠(2.0M,2.69mL,2.00eq)溶于二甲醚(10.0mL)，N2保护下加入二氯双[二叔丁基-(4-二甲基氨基苯基)膦]钯(II)(190mg,269μmol,190μL,0.10eq)，80℃下搅拌10小时。将混合液倒入水(10mL)中，用乙酸乙酯(10.0mL x3)萃取3次。合并有机相，饱和食盐水(10.0mL x 2)洗涤两次，无水硫酸钠干燥，过滤，浓缩滤液得到粗产品。粗产品用反相高效液相色谱法(0.1％，甲酸条件)纯化得到化合物7-3。LCMS:MS(ESI)m/z＝231.7[M+H]+。At room temperature, 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) were dissolved in dimethyl ether (10.0 mL) in turn, and dichlorobis[di-tert-butyl-(4-dimethylaminophenyl)phosphine]palladium (II) (190 mg, 269 μmol, 190 μL, 0.10 eq) was added under N 2 protection, and stirred at 80°C for 10 hours. The mixture was poured into water (10 mL) and extracted 3 times with ethyl acetate (10.0 mL x 3). The organic phases were combined, washed twice with saturated brine (10.0 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by reverse phase high performance liquid chromatography (0.1%, formic acid conditions) to obtain compound 7-3. LCMS: MS (ESI) m/z = 231.7 [M+H] +.
第2步：Step 2:
将化合物7-3(20.0mg,86.5μmol,1.00eq)溶于乙腈(2.00mL)，使用氮气置换空气3次，氮气环境下缓慢加入磺酰氯(46.7mg,346μmol,34.6μL,4.00eq)。25℃反应10小时。将混合液浓缩得到粗产品。粗产品用反相高效液相色谱法(0.1％，甲酸条件)纯化得到化合物7-4。LCMS:MS(ESI)m/z＝219.7[M+H]+。1HNMR:CDCl3,400MHzδ9.15(s,1H),8.41(s,1H),2.55(s,3H)。Compound 7-3 (20.0 mg, 86.5 μmol, 1.00 eq) was dissolved in acetonitrile (2.00 mL), and the air was replaced with nitrogen three times. Sulfuryl chloride (46.7 mg, 346 μmol, 34.6 μL, 4.00 eq) was slowly added under nitrogen. The mixture was reacted at 25°C for 10 hours. The mixture was concentrated to obtain a crude product. The crude product was purified by reverse phase high performance liquid chromatography (0.1%, formic acid conditions) to obtain compound 7-4. LCMS: MS (ESI) m/z = 219.7 [M+H] +. 1 HNMR: CDCl3, 400 MHz δ 9.15 (s, 1H), 8.41 (s, 1H), 2.55 (s, 3H).
第3步：Step 3:
将化合物1-10(30.0mg,67.5μmol,1.00eq)和化合物7-4(14.8mg,67.5μmol,1.00eq)溶于N,N-二甲基甲酰胺(0.50mL)，氮气环境下，向反应液加入N,N-二异丙基乙胺(26.2mg,202μmol,35.3μL,3.00eq)，20℃反应12小时。将反应液缓慢倒入水(5.00mL)，乙酸乙酯(3.00mL x 3)萃取三次。合并有机相，用饱和食盐水(2.00mL)洗涤一次，用无水硫酸钠干燥，过滤，浓缩滤液得到产品。粗产品用反相高效液相色谱法(0.1％，甲酸条件)纯化得到化合物7。LCMS:MS(ESI)m/z＝628.3[M+H]+。1H NMR:DMSO-d6,400MHzδ12.91-13.26(m,1H),8.84-8.89(m,1H),8.52-8.55(m,1H),7.95-8.08(m,2H),7.38(s,1H),7.23-7.30(m,2H),7.15–7.17(m,3H),7.07-7.10(m,1H),6.26(d,J＝8.0Hz,1H),5.70-5.83(m,1H),4.33(s,1H),4.16(br d,J＝5.2Hz,2H),3.54(s,3H),2.54(s,3H),2.33(s,2H),1.88(s,4H),1.44(d,J＝12.0Hz,2H),1.23(s,1H),1.00-1.18(m,2H)。Compound 1-10 (30.0 mg, 67.5 μmol, 1.00 eq) and compound 7-4 (14.8 mg, 67.5 μmol, 1.00 eq) were dissolved in N, N-dimethylformamide (0.50 mL). N, N-diisopropylethylamine (26.2 mg, 202 μmol, 35.3 μL, 3.00 eq) was added to the reaction solution under nitrogen atmosphere, and the reaction was carried out at 20°C for 12 hours. The reaction solution was slowly poured into water (5.00 mL) and extracted three times with ethyl acetate (3.00 mL x 3). The organic phases were combined, washed once with saturated brine (2.00 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the product. The crude product was purified by reverse phase high performance liquid chromatography (0.1%, formic acid conditions) to obtain compound 7. LCMS: MS (ESI) m/z = 628.3 [M + H] +. 1 H NMR: DMSO-d6, 400 MHz δ 12.91-13.26 (m, 1H), 8.84-8.89 (m, 1H), 8.52-8.55 (m, 1H), 7.95-8.08 (m, 2H), 7.38 (s, 1H), 7.23-7.30 (m, 2H), 7.15–7.17 (m, 3H), 7.07-7.10 (m, 1H), 6.26 (d, J = 8.0 Hz, 1H), 5.70-5.83 (m, 1H), 4.33 (s, 1H), 4.16 (br d, J = 5.2 Hz, 2H), 3.54 (s, 3H), 2.54 (s, 3H), 2.33 (s, 2H), 1.88 (s, 4H), 1.44 (d, J = 12.0 Hz, 2H), 1.23 (s, 1H), 1.00-1.18 (m, 2H).
实施例8Example 8
本实施例提供化合物8，其结构式如下：
This example provides compound 8, whose structural formula is as follows:
反应路线如下所示：
The reaction route is as follows:
制备过程具体如下：The preparation process is as follows:
第1步：step 1:
室温下，将化合物8-1(500mg,2.30mmol,1.00eq)，化合物8-2(242mg,2.30mmol,1.00eq)溶于四氢呋喃(10.0mL)和乙腈(10.0mL)中，25℃反应10小时。将反应减压浓缩得到粗产品，粗产品经prep-HPLC(FA condition)纯化后得到化合物8-3。LCMS:MS(ESI)m/z＝285.9[M+H]+。At room temperature, compound 8-1 (500 mg, 2.30 mmol, 1.00 eq) and compound 8-2 (242 mg, 2.30 mmol, 1.00 eq) were dissolved in tetrahydrofuran (10.0 mL) and acetonitrile (10.0 mL) and reacted at 25°C for 10 hours. The reaction was concentrated under reduced pressure to obtain a crude product, which was purified by prep-HPLC (FA condition) to obtain compound 8-3. LCMS: MS (ESI) m/z = 285.9 [M + H] +.
第2步：Step 2:
室温下，将化合物8-3(12.9mg,45.2μmol,1.00eq)，化合物1-10(20.0mg,45.1μmol,1.00eq)溶于DMF(1.00mL)，再加入DIEA(17.5mg,135μmol,23.6μL,3.00eq)，在25℃反应12小时。将反应体系用水(3.00mL)稀释，用乙酸乙酯(5.00mL×3)萃取3次。合并有机相，饱和氯化钠水溶液(8.00mL×3)洗涤3次，无水硫酸钠干燥，过滤，浓缩滤液得到粗产品，粗产品经prep-HPLC(FA condition)纯化后得到化合物8。LCMS:m/z＝694.3[M+H]+。1HNMR:(400MHz,DMSO-d6)δ9.91(s,1H),7.95(s,1H),7.01(s,1H),6.02(s,1H),4.99(br s,1H),4.37(s,2H),3.62-3.53(m,1H),2.89(s,3H),2.73(s,3H),2.43-2.32(m,1H),1.81-1.61(m,6H),1.51(s,9H),1.03(br d,J＝6.4Hz,6H)。At room temperature, compound 8-3 (12.9 mg, 45.2 μmol, 1.00 eq) and compound 1-10 (20.0 mg, 45.1 μmol, 1.00 eq) were dissolved in DMF (1.00 mL), and DIEA (17.5 mg, 135 μmol, 23.6 μL, 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. The organic phases were combined, washed three times with saturated sodium chloride aqueous solution (8.00 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by prep-HPLC (FA condition) to obtain compound 8. LCMS: m/z = 694.3 [M + H] +. 1 H NMR: (400 MHz, DMSO-d6) δ9.91 (s, 1H), 7.95 (s, 1H), 7.01 (s, 1H), 6.02 (s, 1H), 4.99 (br s, 1H), 4.37 (s, 2H), 3.62-3.53 (m, 1H), 2.89 (s, 3H), 2.73 (s, 3H), 2.43-2.32 (m, 1H), 1.81-1.61 (m, 6H), 1.51 (s, 9H), 1.03 (br d, J=6.4 Hz, 6H).
体外活性测试In vitro activity test
实验例一：体外CDK2/CyclinE 1酶活性测试Experimental Example 1: In vitro CDK2/CyclinE 1 enzyme activity test
实验材料：Experimental Materials:
CDK2/CyclinE 1购自新格诺康。ΜLight-4E-BP1多肽，Eu-anti-phospho-tyrosine抗体，1X检测缓冲液购自PerkinElmer公司。高纯度ATP购自Promega公司。EDTA购自Sigma。Nivo多标记分析仪(PerkinElmer)。CDK2/CyclinE 1 was purchased from Syngenecon. ΜLight-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).
实验方法：experimental method:
激酶缓冲液配制：激酶缓冲液包含50mM HEPES，1mM EDTA，10mM MgCl2，0.01％Brij-35，pH7.4 200ml缓冲液中加入2.38g HEPES，58mg EDTA，406mg MgCl2，20mg Brij-35，调整pH到7.4。Preparation of kinase buffer: 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.
终止液配制：Stop solution preparation:
使用100μL1MEDTA原液加上0.625μL的1X检测缓冲液与1725μL蒸馏水混合配置成终止液。使用激酶缓冲液稀释酶，ΜLight-4E-BP1多肽，ATP和抑制剂。使用检测缓冲液稀释Eu-anti-phospho-tyrosine抗体稀释至8nM/L浓度。将待测化合物用排枪进行5倍稀释至第8 个浓度，即从40μM稀释至0.512nM，DMSO终浓度为4％，设置双复孔实验。向微孔板中加入2.5μL抑制剂各浓度梯度，5μLCDK2/CyclinE 1酶(10ng)，2.5μL底物和ATP的混合物(4mMATP，100nM ΜLight-4E-BP1多肽)，此时化合物终浓度梯度为10μM稀释至0.128nM,ATP和底物终浓度为1mM和25nM。反应体系置于25度反应120分钟。反应结束后，每孔加入5μL终止液，25度继续反应5分钟，结束反应后每孔加入5μL的Eu-anti-phospho-tyrosine抗体稀释液，25度反应60分钟后采用PerkinElmerNivo多标记分析仪TR-FRET模式进行数据采集(激发波长为320nm发射波长为615nm和665nm)。Use 100 μL 1M EDTA stock solution plus 0.625 μL 1X detection buffer and 1725 μL distilled water to prepare the stop solution. Use kinase buffer to dilute the enzyme, ΜLight-4E-BP1 peptide, ATP and inhibitor. Use detection buffer to dilute Eu-anti-phospho-tyrosine antibody to 8nM/L concentration. Use a pipette to dilute the test compound 5 times to 8 Concentrations, that is, diluted from 40μM to 0.512nM, the final DMSO concentration is 4%, and a double-well experiment is set up. 2.5μL of inhibitor concentration gradients, 5μLDK2/CyclinE 1 enzyme (10ng), 2.5μL of a mixture of substrate and ATP (4mMATP, 100nM ΜLight-4E-BP1 polypeptide) were added to the microplate. At this time, the final concentration gradient of the compound was diluted from 10μM to 0.128nM, and the final concentrations of ATP and substrate were 1mM and 25nM. The reaction system was placed at 25 degrees for 120 minutes. After the reaction was completed, 5μL of stop solution was added to each well, and the reaction was continued at 25 degrees for 5 minutes. After the reaction was completed, 5μL of Eu-anti-phospho-tyrosine antibody dilution was added to each well. After 60 minutes of reaction at 25 degrees, the data was collected using the PerkinElmerNivo multi-label analyzer TR-FRET mode (excitation wavelength is 320nm and emission wavelength is 615nm and 665nm).
数据分析：data analysis:
利用方程式(Sample-Min)/(Max-Min)×100％将原始数据换算成抑制率，IC50的值即可通过四参数进行曲线拟合得出(GraphPad Prism中log(inhibitor)vs.response--Variable slope模式得出)。表1提供了本发明的化合物对CDK2/CyclinE 1酶学抑制活性。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.
实验例二：体外CDK12/CyclinK酶活性测试Experimental Example 2: In vitro CDK12/CyclinK enzyme activity test
实验材料：Experimental Materials:
CDK12/CyclinK购自BIORTUS。ΜLight-4E-BP1多肽，Eu-anti-phospho-tyrosine抗体，1X检测缓冲液购自PerkinElmer公司。高纯度ATP购自Promega公司。EDTA购自Sigma。Nivo多标记分析仪(PerkinElmer)。CDK12/CyclinK was purchased from BIORTUS. ΜLight-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).
实验方法：experimental method:
激酶缓冲液配制：激酶缓冲液包含50mM HEPES，1mM EDTA，10mM MgCl2，0.01％Brij-35，pH7.4 200ml缓冲液中加入2.38g HEPES，58mg EDTA，406mg MgCl2，20mg Brij-35，调整pH到7.4。Preparation of kinase buffer: 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.
终止液配制：Stop solution preparation:
使用100μL1MEDTA原液加上0.625μL的1X检测缓冲液与1725μL蒸馏水混合配置成终止液。使用激酶缓冲液稀释酶，ΜLight-4E-BP1多肽，ATP和抑制剂。使用检测缓冲液稀释Eu-anti-phospho-tyrosine抗体稀释至8nM/L浓度。将待测化合物用排枪进行5倍稀释至第8个浓度，即从40μM稀释至0.512nM，DMSO终浓度为4％，设置双复孔实验。向微孔板中加入2.5μL抑制剂各浓度梯度，5μLCDK12/CyclinK酶(50ng)，2.5μL底物和ATP的混合物(800μMATP，100nMΜLight-4E-BP1多肽)，此时化合物终浓度梯度为10μM稀释至0.128nM，ATP和底物终浓度为200μM和25nM。反应体系置于25度反应180分钟。反应结束后，每孔加入5μL终止液，25度继续反应5分钟，结束反应后每孔加入5μL的Eu-anti-phospho-tyrosine抗体稀释液，25度反应60分钟后采用PerkinElmerNivo多标记分析仪TR-FRET模式进行数据采集(激发波长为320nM发射波长为665nM)。Use 100 μL 1M EDTA stock solution plus 0.625 μL 1X detection buffer and 1725 μL distilled water to mix and prepare the stop solution. Use kinase buffer to dilute the enzyme, ΜLight-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 40μM to 0.512nM, the final DMSO concentration is 4%, and a double-well experiment is set up. Add 2.5μL of each inhibitor concentration gradient, 5μLDK12/CyclinK enzyme (50ng), 2.5μL of a mixture of substrate and ATP (800μM ATP, 100nM ΜLight-4E-BP1 peptide) to the microplate. At this time, the final concentration gradient of the compound is 10μM diluted to 0.128nM, and the final concentrations of ATP and substrate are 200μM and 25nM. The reaction system was placed at 25 degrees for 180 minutes. After the reaction was completed, 5 μL of stop solution was added to each well, and the reaction was continued at 25 degrees for 5 minutes. After the reaction was completed, 5 μL of Eu-anti-phospho-tyrosine antibody dilution was added to each well. After 60 minutes of reaction at 25 degrees, data were collected using the PerkinElmerNivo multi-label analyzer TR-FRET mode (excitation wavelength of 320nM emission wavelength of 665nM).
数据分析：data analysis:
利用方程式(Sample-Min)/(Max-Min)×100％将原始数据换算成抑制率，IC50的值即可通过四参数进行曲线拟合得出(GraphPad Prism中log(inhibitor)vs.response--Variable slope模式得出)。表1提供了本发明的化合物对CDK12/CyclinK酶学抑制活性。The raw data were converted into inhibition rate using the equation (Sample-Min)/(Max-Min)×100%, and the IC 50 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 CDK12/CyclinK enzymes.
实验例三：体外A2780细胞活性测试Experimental Example 3: In vitro A2780 cell activity test
实验材料：Experimental Materials:
1640培养基自Vivacell，胎牛血清自Biosera，盘尼西林/链霉素抗生素购自源培。CellTiter-Glo(细胞活率化学发光检测试剂)试剂购自Promega。A2780细胞系购自科佰。Envision多标记分析仪(PerkinElmer)。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).
实验方法：experimental method:
将A2780细胞种于白色96孔板中，80μL细胞悬液每孔，其中包含3000个A2780细胞。细胞板置于二氧化碳培养箱中过夜培养。将待测化合物用排枪进行5倍稀释至第8个浓度，即从2000μM稀释至0.0256nM，设置双复孔实验。向中间板中加入78μL培养基，再按照对应位置，转移2μL每孔的梯度稀释化合物至中间板，混匀后转移20μL每孔到细胞板中。转移到细胞板中的化合物浓度范围是10μM至0.128nM。细胞板置于二氧化碳培养箱中培养3 天。另准备一块细胞板，在加药当天读取信号值作为最大值(下面方程式中Max值)参与数据分析。向此细胞板每孔加入25μL细胞活率化学发光检测试剂，室温孵育10分钟使发光信号稳定。采用多标记分析仪读数。向细胞板中加入每孔25μL的细胞活率化学发光检测试剂，室温孵育10分钟使发光信号稳定。采用多标记分析仪读数。A2780 cells were seeded in a white 96-well plate, with 80 μL 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 μM to 0.0256 nM, using a dispenser, and a double-well experiment was set up. 78 μL of culture medium was added to the middle plate, and then 2 μL of the gradient diluted compound per well was transferred to the middle plate according to the corresponding position, and 20 μL of each well was transferred to the cell plate after mixing. The concentration range of the compound transferred to the cell plate was 10 μM 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. Add 25 μL of cell viability chemiluminescent detection reagent to each well of this cell plate and incubate at room temperature for 10 minutes to stabilize the luminescent signal. Read the data using a multi-label analyzer. Add 25 μL of cell viability chemiluminescent detection reagent to each well of the cell plate and incubate at room temperature for 10 minutes to stabilize the luminescent signal. Read the data using a multi-label analyzer.
数据分析：data analysis:
利用方程式(Sample-Min)/(Max-Min)×100％将原始数据换算成抑制率，IC50的值即可通过四参数进行曲线拟合得出(GraphPad Prism中"log(inhibitor)vs.response--Variable slope"模式得出)。表1提供了本发明的化合物对A2780细胞增殖的抑制活性。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 A2780 cell proliferation.
表1
Table 1
以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.
以上所述实施例仅表达了本发明的几种实施方式，便于具体和详细地理解本发明的技术方案，但并不能因此而理解为对发明专利保护范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。应当理解，本领域技术人员在本发明提供的技术方案的基础上，通过合乎逻辑的分析、推理或者有限的试验得到的技术方案，均在本发明所附权利要求的保护范围内。因此，本发明专利的保护范围应以所附权利要求的内容为准，说明书可以用于解释权利要求的内容。 The above-described embodiments only express several implementation methods of the present invention, which are convenient for understanding the technical solutions of the present invention in detail, but they cannot be understood as limiting the scope of protection of the invention patent. It should be pointed out that for ordinary technicians in this field, without departing from the concept of the present invention, several modifications and improvements can be made, which all belong to the protection scope of the present invention. It should be understood that the technical solutions obtained by those skilled in the art through logical analysis, reasoning or limited experiments on the basis of the technical solutions provided by the present invention are all within the protection scope of the claims attached to the present invention. Therefore, the protection scope of the patent of the present invention shall be based on the contents of the attached claims, and the description can be used to interpret the contents of the claims.

Claims (11)

  1. 一种式(I)所示的化合物、或其药学上可接受的盐、或其立体异构体：
    A compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
    其中：in:
    R1、R2分别独立地选自氰基、-CF3、-OCF3、-Cl、-Br、-F、羟基、硝基、取代或未被取代的咪唑基、取代或未被取代的吡唑基、具有1至20个C原子的直链烷基、具有1至20个C原子的烷氧基、具有3至20个C原子的支链烷基、取代或未被取代的具有3至20个C原子的环状的烷基、取代或未被取代的具有3至20个C原子的环状烷氧基、取代或未被取代的具有3至20个环原子的杂环基、-OR、-NH-R，或这些体系的组合；R每次出现，分别独立地选自取代或未被取代的具有3至20个C原子的环状烷氧基、取代或未被取代的具有3至20个环原子的杂环基；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 having 3 to 20 ring atoms;
    R3、R4分别独立地选自-H、-D、具有1至20个C原子的直链烷基、具有3至20个C原子的支链或环状的烷基、取代或未取代的具有6至60个环原子的芳香基团，或这些基团的组合；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;
    Ar1选自如下结构中的任一种：
    Ar 1 is selected from any one of the following structures:
    X1每次出现，独立地选自CR5或N；Each occurrence of X 1 is independently selected from CR 5 or N;
    Y1每次出现，独立地选自NR6、CR6R7、C＝O、O、S或S＝O；Each occurrence of Y 1 is independently selected from NR 6 , CR 6 R 7 , C═O, O, S or S═O;
    R5、R6、R7每次出现，分别独立地选自-H、-D、具有1至20个C原子的直链烷基、具有1至20个C原子的烷氧基、具有3至20个C原子的支链烷基、具有3至20个C原子的环状的烷基、具有3至20个C原子的支链烷氧基、具有3至20个C原子的环状烷氧基，或这些体系的组合。 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.
  2. 根据权利要求1所述的化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，式(I)化合物为式(II)所示结构：
    The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that the compound of formula (I) is a structure represented by formula (II):
  3. 根据权利要求1所述的化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，R3、R4分别独立地选自-H、-D、取代或未取代的具有6至30个环原子的芳香基团。The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that R 3 and R 4 are independently selected from -H, -D, a substituted or unsubstituted aromatic group having 6 to 30 ring atoms.
  4. 根据权利要求1所述的化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，式(I)化合物为式(Ⅲ)所示结构：
    The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that the compound of formula (I) is a structure represented by formula (III):
  5. 根据权利要求1所述的化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，Ar1选自如下结构中的任一种：
    The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that Ar 1 is selected from any one of the following structures:
  6. 根据权利要求5所述的化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，Ar1选自如下结构中的任一种：
    The compound according to claim 5, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that Ar 1 is selected from any one of the following structures:
  7. 根据权利要求1所述的化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，R1、R2分别独立地选自氰基、-CF3、-Cl、-Br、-F或如下结构中的任一种：
    The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that R 1 and R 2 are independently selected from cyano, -CF 3 , -Cl, -Br, -F or any one of the following structures:
  8. 根据权利要求1所述的化合物、或其药学上可接受的盐、或其立体异构体，其特征在于，式(I)化合物为下列化合物中的任一种：
    The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that the compound of formula (I) is any one of the following compounds:
  9. 权利要求1～8任一项所述的化合物、或其药学上可接受的盐、或其立体异构体在制备治疗和/或预防与CDK12活性相关的或由CDK12活性介导的疾病的药物中的应用。Use of the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof in the preparation of a medicament for treating and/or preventing a disease associated with CDK12 activity or mediated by CDK12 activity.
  10. 根据权利要求9所述的应用，其特征在于，所述与CDK12活性相关的或由CDK12活性介导的疾病为癌症。 The use according to claim 9, characterized in that the disease associated with CDK12 activity or mediated by CDK12 activity is cancer.
  11. 一种药物组合物，其特征在于，包括权利要求1～8任一项所述的化合物、或其药学上可接受的盐、或其立体异构体，以及药学上可接受的载体。 A pharmaceutical composition, characterized in that it comprises the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and a pharmaceutically acceptable carrier.
PCT/CN2023/117257 2022-09-30 2023-09-06 Tricyclic derivative, pharmaceutical composition and use WO2024066984A1 (en)

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Citations (4)

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CN105849099A (en) * 2013-10-18 2016-08-10 达纳-法伯癌症研究所股份有限公司 Polycyclic inhibitors of cyclin-dependent kinase 7 (CDK7)
CN107530329A (en) * 2015-03-09 2018-01-02 奥瑞基尼探索技术有限公司 Pyrazolo [1,5 a] [1,3,5] triazine and pyrazolo [1,5 a] pyrimidine derivatives as CDK inhibitor
CN108024970A (en) * 2015-06-04 2018-05-11 奥瑞基尼探索技术有限公司 The Hete rocyclic derivatives by substitution as CDK inhibitor
CN111918863A (en) * 2018-03-29 2020-11-10 武田药品工业株式会社 Heterocyclic compounds

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105849099A (en) * 2013-10-18 2016-08-10 达纳-法伯癌症研究所股份有限公司 Polycyclic inhibitors of cyclin-dependent kinase 7 (CDK7)
CN107530329A (en) * 2015-03-09 2018-01-02 奥瑞基尼探索技术有限公司 Pyrazolo [1,5 a] [1,3,5] triazine and pyrazolo [1,5 a] pyrimidine derivatives as CDK inhibitor
CN108024970A (en) * 2015-06-04 2018-05-11 奥瑞基尼探索技术有限公司 The Hete rocyclic derivatives by substitution as CDK inhibitor
CN111918863A (en) * 2018-03-29 2020-11-10 武田药品工业株式会社 Heterocyclic compounds

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