WO2021068952A1 - Composé de benzodihydropyrane ciblant l'aldo-céto réductase 1c3 - Google Patents

Composé de benzodihydropyrane ciblant l'aldo-céto réductase 1c3 Download PDF

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WO2021068952A1
WO2021068952A1 PCT/CN2020/120281 CN2020120281W WO2021068952A1 WO 2021068952 A1 WO2021068952 A1 WO 2021068952A1 CN 2020120281 W CN2020120281 W CN 2020120281W WO 2021068952 A1 WO2021068952 A1 WO 2021068952A1
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compound
pharmaceutically acceptable
acceptable salt
isomer
compound according
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PCT/CN2020/120281
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English (en)
Chinese (zh)
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蔡哲
孙飞
丁照中
陈曙辉
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南京明德新药研发有限公司
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Priority to CN202080071652.8A priority Critical patent/CN114555574B/zh
Publication of WO2021068952A1 publication Critical patent/WO2021068952A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/04—Nitro compounds
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A61K31/06—Phenols the aromatic ring being substituted by nitro groups
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/664—Amides of phosphorus acids
    • 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
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/74—Benzo[b]pyrans, hydrogenated in the carbocyclic ring

Definitions

  • the present invention relates to a novel structurally novel chroman compound targeting AKR1C3 enzyme (aldehyde ketone reductase 1C3), and specifically relates to a compound represented by formula (II), a pharmaceutically acceptable salt or isomer thereof, and The pharmaceutical composition containing them, and the application of the compound represented by formula (II), its pharmaceutically acceptable salt, its isomers and the pharmaceutical composition containing them in the treatment of malignant tumors.
  • Cancer tumor is a major disease that seriously threatens human life and health.
  • the current treatment methods mainly include surgical treatment, chemotherapy, and targeted therapy.
  • Chemotherapy is a treatment that uses chemical drugs to kill tumor cells and inhibit the growth of tumor cells. It is a systemic treatment method. Due to the heterogeneity of malignant tumors, chemotherapy is still an important method to treat tumors. However, it is this systemic treatment that causes chemotherapy to have great side effects. There is a huge unmet clinical need to develop targeted chemotherapeutics.
  • Aldone reductase 1C3 is a member of the aldone reductase family, which is mainly involved in the synthesis of hormones and the removal of toxins.
  • AKR1C3 can be overexpressed by factors such as smoking, alcohol, hepatitis B or hepatitis C infection.
  • AKR1C3 is overexpressed in a variety of refractory cancers, such as liver cancer, lung cancer, gastric cancer, esophageal cancer, colorectal cancer, previous adenocarcinoma, acute lymphoblastic leukemia, especially liver cancer, with a high proportion of more than 60%.
  • AKR1C3 inhibitor drugs have been developed clinically, but no good progress has been made.
  • Threshold Pharmaceuticals reported a compound TH3424 that targets the AKR1C3 enzyme.
  • TH3424 is a selective prodrug that releases a potent DNA alkylating agent in tumor cells with high expression of AKR1C3 enzyme, and selectively kills tumor cells with high expression of AKR1C3, making chemical drugs have obvious targeting effects.
  • HCC hepatocellular carcinoma
  • CRPC castrated prostate cancer
  • the present invention provides a compound represented by formula (II), a pharmaceutically acceptable salt or isomer thereof,
  • R 1 is H, C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl or phenyl, wherein said C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, aryl, 5-6 membered heteroaryl and phenyl are optionally substituted with 1, 2, or 3 R a;
  • Each R a is independently H, F, Cl, Br, I, -CN, -OH, C 1-3 alkoxy, or C 1-3 alkyl;
  • R 2 is H or C 1-6 alkyl
  • R 1 and R 2 are joined together to form a 4-6 membered heterocycloalkyl group together with the N atom to which they are connected, wherein the 4-6 membered heterocycloalkyl group is optionally substituted by 1, 2 or 3 R b ;
  • Each R b is independently H, F, Cl, Br, I, -CN, -OH, -NH 2 , -OCH 3 , -OCH 2 CH 3 , -CH 3 or -CH 2 CH 3 ;
  • R 3 is H, F, Cl, Br, I, -OH, -NH 2 , C 1-3 alkoxy or C 1-3 alkyl;
  • R 2 and R 3 are connected together to make the structural unit for
  • T 1 is -(CR c R d ) m -or -(CR c R d ) n -O-;
  • n 1, 2 or 3;
  • n 1 or 2;
  • T 2 is N or CH
  • R c and R d are each independently H, F, C 1-3 alkyl or C 1-3 alkoxy;
  • R 4 , R 5 and R 6 are each independently H, F, Cl, Br, I, C 1-3 alkyl or C 1-3 alkoxy;
  • T is N or CH
  • R 7 and R 8 are each independently H, F, Cl, Br or I;
  • R 9 and R 10 are each independently H, F, Cl, Br, I, -CN or
  • the 4-6 membered heterocycloalkyl group and the 5-6 membered heteroaryl group each contain 1, 2, 3, or 4 heteroatoms independently selected from N, -O- and -S-.
  • the present invention provides a compound represented by formula (I), a pharmaceutically acceptable salt or isomer thereof,
  • R 1 is H, C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl or phenyl, wherein the C 1-6 alkane group, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, aryl, 5-6 membered heteroaryl and phenyl are optionally substituted with 1, 2, or 3 R a;
  • Each R a is independently H, F, Cl, Br, I, -CN, -OH, C 1-3 alkoxy, or C 1-3 alkyl;
  • R 2 is H or C 1-6 alkyl
  • R 1 and R 2 are joined together to form a 4-6 membered heterocycloalkyl group together with the N atom to which they are connected, wherein the 4-6 membered heterocycloalkyl group is optionally substituted by 1, 2 or 3 R b ;
  • Each R b is independently H, F, Cl, Br, I, -CN, -OH, -NH 2 , -OCH 3 , -OCH 2 CH 3 , -CH 3 or -CH 2 CH 3 ;
  • R 3 is H, F, Cl, Br, I, -OH, -NH 2 , C 1-3 alkoxy or C 1-3 alkyl;
  • R 2 and R 3 are connected together to make the structural unit for
  • T 1 is -(CR c R d ) m -or -(CR c R d ) n -O-;
  • n 1, 2 or 3;
  • n 1 or 2;
  • T 2 is N or CH
  • R c and R d are each independently H, F, C 1-3 alkyl or C 1-3 alkoxy;
  • R 4 , R 5 and R 6 are each independently H, F, Cl, Br, I, C 1-3 alkyl or C 1-3 alkoxy;
  • the 4-6 membered heterocycloalkyl group and the 5-6 membered heteroaryl group each contain 1, 2, 3, or 4 heteroatoms independently selected from N, -O- and -S-.
  • the above-mentioned compound has a structure represented by formula (II-1) or formula (II-2):
  • the carbon atom with "*" is a chiral carbon atom, which exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer; R 7 , R 8 , R 9 and R 10 As defined in the present invention.
  • the above-mentioned compound has a structure represented by formula (I-1):
  • the carbon atom with "*" is a chiral carbon atom, which exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer; R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined in the present invention.
  • the above-mentioned compound has a structure represented by formula (II-3) or formula (II-4):
  • the carbon atom with "*" is a chiral carbon atom, which exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer; R 7 , R 8 , R 9 and R 10 As defined in the present invention.
  • R 2 is H or -CH 3 , and other variables are as defined in the present invention.
  • R 1 and R 2 are connected together to form the N atom to which they are connected which said Optionally substituted by 1, 2 or 3 R b , R b and other variables are as defined in the present invention.
  • R 1 and R 2 are connected together to form the N atom to which they are connected R b and other variables are as defined in the present invention.
  • R 1 and R 2 are connected together to form the N atom to which they are connected
  • Other variables are as defined in the present invention.
  • R 2 and R 3 are connected together so that the structural unit for R 1 , R 4 , R 5 and R 6 and other variables are as defined in the present invention.
  • R 2 and R 3 are connected together so that the structural unit for Other variables are as defined in the present invention.
  • R c and Rd are each independently H, F or -CH 3 , and other variables are as defined in the present invention.
  • T 1 is -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, -CH 2 -O-, -O-CH 2 -or -CH 2 -CH 2 -O-, other variables are as defined in the present invention.
  • the above-mentioned compound has a structure represented by any one of formulas (I-2) to (I-7):
  • T 2 , R 1 , R 3 , R 4 , R 5 and R 6 are as defined in the present invention.
  • the above-mentioned compound has a structure represented by any one of formulas (I-8) to (I-13):
  • the carbon atom with "*" is a chiral carbon atom, which exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer; T 2 , R 1 , R 3 , R 4 , R 5 and R 6 are as defined in the present invention.
  • each of the above Ra is independently H, F, Cl, Br, I, -CN, -OH, -OCH 3 or -CH 3 , and other variables are as defined in the present invention.
  • the above-mentioned R 1 is H, -CH 3 , -CH 2 CH 3 , cyclopropyl, cyclopentyl, cyclohexyl, oxetanyl, pyrrolidinyl, piperidinyl, pyridine Azolyl, pyridyl or phenyl, wherein the -CH 3 , -CH 2 CH 3 , cyclopropyl, cyclopentyl, cyclohexyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl , pyridyl, and phenyl is optionally substituted with 1, 2 or 3 R a, R a, and the other variables are as defined in the present invention.
  • R 1 is H, -CH 3 , -CH 2 CH 3 , Wherein the -CH 3 , -CH 2 CH 3 , Optionally substituted with 1, 2 or 3 R a, R a, and the other variables are as defined in the present invention.
  • R 1 is H, -CH 3 , -CH 2 CH 3 , R a and the other variables are as defined in the present invention.
  • R 1 is H, -CH 3 , -CH 2 CH 3 , Other variables are as defined in the present invention.
  • R 3 is H, F, Cl, Br, I, -OH, -NH 2 , -OCH 3 or -CH 3 , and other variables are as defined in the present invention.
  • R 4 , R 5 and R 6 are each independently H, F, Cl, Br, I or -CH 3 , and other variables are as defined in the present invention.
  • the above-mentioned compound is:
  • the above-mentioned compound is:
  • the present invention also provides a pharmaceutical composition, which contains a therapeutically effective amount of the above-mentioned compound, a pharmaceutically acceptable salt or isomer thereof, and a pharmaceutically acceptable carrier.
  • the present invention also provides the application of the above-mentioned compound, its pharmaceutically acceptable salt or its isomer and the above-mentioned pharmaceutical composition in the preparation of a medicine targeting AKR1C3 enzyme.
  • the present invention provides a compound targeting AKR1C3 with a novel structure.
  • the compound of the present invention has excellent anti-proliferative activity against tumor cells with high AKR1C3 expression, and has weak activity against tumor cells with low AKR1C3 expression, and exhibits excellent selectivity.
  • pharmaceutically acceptable salt refers to a salt of the compound of the present invention, which is prepared from the compound with specific substituents discovered in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting the neutral form of the compound 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 salt or similar salts.
  • the acid addition salt can be obtained by contacting the neutral form of the compound 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 including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, the organic acid includes, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid; also include 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
  • the pharmaceutically acceptable salt of the present invention can be synthesized from the parent compound containing acid or base by conventional chemical methods. In general, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of appropriate base or acid in water or organic solvent or a mixture of both.
  • the term "effective amount” or “therapeutically effective amount” refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect.
  • the "effective amount” of one active substance in the composition refers to the amount required to achieve the desired effect when combined with another active substance in the composition.
  • the determination of the effective amount varies from person to person, and depends on the age and general conditions of the recipient, as well as the specific active substance. The appropriate effective amount in a case can be determined by those skilled in the art according to routine experiments.
  • the compounds provided by the present invention also exist in prodrug forms.
  • the prodrugs of the compounds described herein easily undergo chemical changes under physiological conditions to transform into the compounds of the invention.
  • prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in the in vivo environment.
  • Certain compounds of the present invention may exist in unsolvated or solvated forms, including hydrated forms.
  • the solvated form is equivalent to the unsolvated form, and both are included in the scope of the present invention.
  • 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 Conformers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomer-enriched mixtures, all of these mixtures belong to Within the scope of the present invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All these isomers and their mixtures are included in the scope of the present invention.
  • enantiomer or “optical isomer” refers to stereoisomers that are mirror images of each other.
  • cis-trans isomer or “geometric isomer” is caused by the inability to freely rotate the double bond or the single bond of the ring-forming carbon atom.
  • diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the relationship between the molecules is non-mirror mirror image.
  • wedge-shaped solid line keys And wedge-shaped dashed key Represents the absolute configuration of a solid center, with a straight solid line key And straight dashed key Indicates the relative configuration of the three-dimensional center, using wavy lines Represents a wedge-shaped solid line key Or wedge-shaped dashed key Or use wavy lines Represents a straight solid line key And straight dashed key
  • the compound of the present invention may be specific.
  • tautomer or “tautomeric form” means that at room temperature, the isomers of different functional groups are in dynamic equilibrium and can be transformed into each other quickly. If tautomers are possible (such as in solution), the chemical equilibrium of tautomers can be reached.
  • proton tautomer also called prototropic tautomer
  • proton migration such as keto-enol isomerization and imine-ene Amine isomerization.
  • Valence isomers include some recombination of bonding electrons to carry out mutual transformation.
  • keto-enol tautomerization is the tautomerization between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms “enriched in one isomer”, “enriched in isomers”, “enriched in one enantiomer” or “enriched in enantiomers” refer to one of the isomers or pairs of
  • the content of the 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 96% or greater, or 97% or greater, or 98% or greater, or 99% or greater, or 99.5% or greater, or 99.6% or greater, or 99.7% or greater, or 99.8% or greater, or greater than or equal 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 enantiomer 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 you want to obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure The desired enantiomer.
  • the molecule when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), it forms a diastereomeric salt with an appropriate optically active acid or base, and then passes through a conventional method known in the art The diastereoisomers are resolved, and then the pure enantiomers are recovered.
  • the separation of enantiomers and diastereomers is usually accomplished through the use of chromatography, which uses a chiral stationary phase and is optionally combined with chemical derivatization (for example, the formation of amino groups from amines). Formate).
  • the compound of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
  • deuterium can be substituted for hydrogen to form deuterated drugs.
  • the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
  • deuterated drugs can reduce toxic side effects and increase drug stability. , Enhance the efficacy, prolong the biological half-life of drugs and other advantages. All changes in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
  • “Optional” or “optionally” means that the event or condition described later may but not necessarily occur, and the description includes a situation in which the event or condition occurs and a situation in which the event or condition does not occur.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by substituents, and may include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable of.
  • oxygen it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it can be substituted or unsubstituted. Unless otherwise specified, the type and number of substituents can be arbitrary on the basis that they can be chemically realized.
  • any variable such as R
  • its definition in each case is independent.
  • the group can optionally be substituted with up to two Rs, and R has independent options in each case.
  • combinations of substituents and/or variants thereof are only permitted 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.
  • substituents When a substituent is vacant, it means that the substituent is absent. For example, when X in A-X is vacant, it means that the structure is actually A.
  • substituents do not indicate which atom is connected to the substituted group, such substituents can be bonded via any atom.
  • a pyridyl group can pass through any one of the pyridine ring as a substituent. The carbon atom is attached to the substituted group.
  • the middle linking group L is -MW-, at this time -MW- can be formed by connecting ring A and ring B in the same direction as the reading order from left to right It can also be formed by connecting ring A and ring B in the direction opposite to the reading order from left to right Combinations of the linking groups, substituents, and/or variants thereof are only permitted 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 between the site and other groups can be a straight solid bond Straight dashed key Or wavy line Said.
  • the straight solid bond in -OCH 3 means that it is connected to other groups through the oxygen atom in the group;
  • the straight dashed bond in indicates that the two ends of the nitrogen atom in the group are connected to other groups;
  • the wavy line in indicates that the phenyl group is connected to other groups through the 1 and 2 carbon atoms.
  • the number of atoms in a ring is generally defined as the number of ring members.
  • “5-7 membered ring” refers to a “ring” in which 5-7 atoms are arranged around.
  • C 1-6 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 6 carbon atoms.
  • the C 1-6 alkyl group includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl groups, etc.; it may Is monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine).
  • C 1-6 alkyl examples include but are not limited to methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl) , S-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.
  • C 1-3 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) .
  • Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • C 1-3 alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule through an oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups and the like.
  • Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy) and the like.
  • C 3-6 cycloalkyl means a saturated cyclic hydrocarbon group composed of 3 to 6 carbon atoms, which is a monocyclic and bicyclic ring system, and the C 3-6 cycloalkyl includes C 3-5 , C 4-5 and C 5-6 cycloalkyl, etc.; it can be monovalent, divalent or multivalent.
  • Examples of C 3-6 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • 4-6 membered heterocycloalkyl by itself or in combination with other terms means a saturated cyclic group consisting of 4 to 6 ring atoms, with 1, 2, 3 or 4 ring atoms.
  • heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein nitrogen atoms are optionally quaternized, and nitrogen and sulfur heteroatoms can be optionally oxidized (ie, NO and S(O) p , p Is 1 or 2). It includes monocyclic and bicyclic ring systems, where the bicyclic ring system includes spiro, fused, and bridged rings.
  • a heteroatom may occupy the connection position of the heterocycloalkyl group with the rest of the molecule.
  • the 4-6 membered heterocycloalkyl group includes 5-6 membered, 4-membered, 5-membered and 6-membered heterocycloalkyl groups and the like.
  • 4-6 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( 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, dithiazinyl, isoxazolidinyl, isothiazolidin
  • 5-6 membered heteroaryl ring and “5-6 membered heteroaryl group” can be used interchangeably in the present invention.
  • the term “5-6 membered heteroaryl group” means a ring consisting of 5 to 6 ring atoms. It is composed of a monocyclic group with a conjugated ⁇ -electron system, in which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may optionally be oxidized (ie NO and S(O) p , p is 1 or 2).
  • the 5-6 membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or a carbon atom.
  • the 5-6 membered heteroaryl group includes 5-membered and 6-membered heteroaryl groups.
  • Examples of the 5-6 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl, etc.) Azolyl, 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, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,
  • C 6-10 aromatic ring and “C 6-10 aryl” can be used interchangeably in the present invention.
  • C 6-10 aromatic ring or “C 6-10 aryl” means that A cyclic hydrocarbon group with a conjugated ⁇ -electron system composed of 6 to 10 carbon atoms, which can be a monocyclic, fused bicyclic or fused tricyclic system, in which each ring is aromatic. It may be monovalent, divalent or multivalent, and C 6-10 aryl groups include C 6-9 , C 9 , C 10 and C 6 aryl groups and the like. Examples of C 6-10 aryl groups include, but are not limited to, phenyl, naphthyl (including 1-naphthyl, 2-naphthyl, etc.).
  • C n-n+m or C n -C n+m includes any specific case of n to n+m carbons, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , including any range from n to n+m, for example, C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12, etc.; similarly, from n to n +m member means that the number of atoms in the ring is from 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
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (for example, a nucleophilic substitution reaction).
  • representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups, such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters, etc.; acyloxy groups, such as acetoxy, trifluoroacetoxy and the like.
  • 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-butoxycarbonyl (Boc) ; Arylmethyloxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-Methoxyphenyl)methyl; silyl group, such as trimethylsilyl (TMS) and tert-butyldi
  • hydroxyl 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 groups (such as acetyl); arylmethyl groups, such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and so on.
  • alkyl groups such as methyl, ethyl, and tert-butyl
  • acyl groups such as alkanoyl groups (such as acetyl)
  • arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (
  • 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, the embodiments formed by combining them with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
  • Pd/C Pd/C catalyst palladium content 10w% DCM Dichloromethane THF Tetrahydrofuran EtOAc Ethyl acetate TBME Tert-butyl methyl ether DMF N,N-Dimethylformamide IV Intravenous injection QW once a week TFA Trifluoroacetate PE Petroleum ether DMSO Dimethyl sulfoxide EtOH Ethanol MeOH Methanol HOAc Acetic acid DIPEA Diisopropylethylamine EDTA Ethylenediaminetetraacetic acid SiO 2 100-200 mesh silica gel powder for column chromatography psi Pound force/square inch, pressure unit p-HPLC Preparative high performance liquid chromatography for compound purification
  • the compounds of the present invention are used according to conventional naming principles in the field or The software is named, and the commercially available compounds use the supplier catalog name.
  • the solvent used in the present invention is commercially available and does not require further purification.
  • the reaction is generally carried out in an anhydrous solvent under inert nitrogen.
  • the proton nuclear magnetic resonance data was recorded on a Bruker Avance III 400 (400MHz) spectrometer, and the chemical shift was expressed in ppm at the high field of tetramethylsilane.
  • LC/MS or Shimadzu MS includes a DAD: SPD-M20A (LC) and Shimadzu Micromass 2020 detector.
  • the mass spectrometer is equipped with an electrospray ion source (ESI) that operates in positive or negative mode.
  • the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art.
  • the single crystal X-ray diffraction method uses the Bruker D8 venture diffractometer to collect the diffraction intensity data of the cultured single crystal.
  • the light source is CuK ⁇ radiation
  • the scanning method After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure to confirm the absolute configuration.
  • the Shimadzu LC20AB system equipped with Shimadzu SIL-20A autosampler and Shimadzu DAD: SPD-M20A detector was used for high performance liquid chromatography analysis, using Xtimate C18 (3 ⁇ m packing, 2.1 ⁇ 300mm) chromatographic column.
  • 0-60AB_6 minutes method apply a linear gradient, start elution with 100% A (A is 0.0675% TFA in water), and end elution with 60% B (B is 0.0625% TFA in MeCN solution), the whole process is 4.2 minutes, then eluted with 60% B for 1 minute.
  • the column was re-equilibrated for 0.8 minutes to reach 100:0, and the total running time was 6 minutes.
  • 10-80AB_6 minutes method apply a linear gradient, start elution with 90% A (A is 0.0675% TFA in water), and end with 80% B (B is 0.0625% TFA in acetonitrile), the whole process is 4.2 minutes, then eluted with 80% B for 1 minute.
  • the column was re-equilibrated for 0.8 minutes to reach 90:10, and the total running time was 6 minutes.
  • the column temperature is 50°C, and the flow rate is 0.8 mL/min.
  • the scanning wavelength of the diode array detector is 200-400nm.
  • Thin layer chromatography was performed on Sanpont-group’s silica gel GF254. Spots are usually detected by ultraviolet light. In some cases, other methods are used to detect spots.
  • iodine (10g silica gel is added About 1g of iodine and thoroughly mixed), vanillin (prepared by dissolving about 1g of vanillin in 100mL 10% H 2 SO 4 ), ninhydrin (purchased from Aldrich) or special color developer (thoroughly mixed 25g ( NH 4 )6Mo 7 O 24 ⁇ 4H 2 O, 5g (NH 4 )2Ce(IV)(NO 3 )6, 450 mL H 2 O and 50 mL concentrated H 2 SO 4 ) The thin layer plate was developed and the compound was inspected.
  • the preparative chromatographic analysis was performed on the Gilson-281Prep LC 322 system using the Gilson UV/VIS-156 detector.
  • the column used was Agella Venusil ASB Prep C18 (5 ⁇ m packing, 150 ⁇ 21.2mm), Phenomenex Gemini C18( 5 ⁇ m packing, specification of 150 ⁇ 30mm), Boston Symmetrix C18 (5 ⁇ m packing, specification of 150 ⁇ 30mm) or Phenomenex Synergi C18 (4 ⁇ m packing, specification of 150 ⁇ 30mm).
  • the compound was eluted with a low gradient of acetonitrile/water (water containing 10 mM ammonium bicarbonate), and the total running time was 8-15 minutes.
  • Figure 1 shows the tumor growth curve of HepG2 orthotopic xenograft tumor model tumor-bearing mice after administration of sorafenib, compound 4A and compound 8.
  • Figure 2 shows the body weight changes of HepG2 xenograft tumor model tumor-bearing mice during the administration of sorafenib, compound 4A and compound 8.
  • Step A Sodium hydrogen (8.43 g, 210.87 mmol, 60% purity) was dissolved in DMF (260 mL), and compound 1-1 (13 g, 84.35 mmol) was added. Under the protection of nitrogen, the mixture was stirred at 25°C for 1 hour. Then benzyl bromide (14.43 g, 84.35 mmol) was added, the mixture was stirred at 25 degrees Celsius for 5 hours, and benzyl bromide (2.89 g, 16.87 mmol) was added, and the mixture was stirred at 25 degrees Celsius for 2 hours. Add water (1000 ml) and hydrochloric acid (250 ml, 1 mole per liter) to the reaction solution to adjust the pH to 1-3.
  • Step B Dissolve compound 1-2 (18.8 g, 55.42 mmol) in a mixture of pyridine (35 mL) and anhydrous DCM (150 mL), and cool to 0-5 degrees Celsius.
  • Triphosgene 11.02 g, 37.13 mmol was dissolved in anhydrous DCM (80 mL) and slowly added dropwise to the mixed solution containing compound 1-2. After the addition is complete, the reaction solution is continuously stirred at 25-30 degrees Celsius for 14 hours. Then, methylamine hydrochloride (19.10 g, 277.16 mmol), triethylamine (28.62 g, 277.16 mmol), and anhydrous DCM (150 mL) were added to the reaction solution.
  • Step C Dissolve compound 1-3 (4.6 g, 17.88 mmol) in chloroform (30 mL), add paraformaldehyde (6.44 g, 71.52 mmol), and then add concentrated sulfuric acid (175.36 mg, 1.79 mmol) ). Under the protection of nitrogen, the mixture was stirred at 70 degrees Celsius for 12 hours. The reaction solution was added with water (50 mL) and extracted with DCM (50 mL ⁇ 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 1-4.
  • Step D Compound 1-4 (4.81 g, 17.86 mmol) was dissolved in dry MeOH (400 mL), and Pd/C (10% purity, 100 mg, 17.86 mmol) was added. Under a hydrogen atmosphere, the mixture was stirred at 25 degrees Celsius for 3 hours. After filtration, the filtrate was concentrated under reduced pressure to obtain intermediate compound 1-5.
  • Step A To a mixture of compound 2-1 (25 g, 137.23 mmol) and cesium carbonate (49.18 g, 150.96 mmol) in DMF (250 mL), add 2-2 (33.83 g, 150.96 mmol). The mixture was stirred at 15-28 degrees Celsius for 12 hours. The reaction solution was poured into water (1000 ml) and TBME (800 ml) for separation. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 2-3.
  • Step B Compound 2-3 (44 g, 135.24 mmol) was dissolved in dioxane (250 mL), and dioxane hydrochloride solution (4M, 220 mL) was added. The mixture was stirred at 30 degrees Celsius for 2 hours. The reaction solution was concentrated under reduced pressure to obtain compound 2-4.
  • Step C Compound 2-4 (35.91 g, 137.22 mmol) was added to toluene (600 mL), and sodium methoxide (16.31 g, 301.88 mmol) was added. The mixture was stirred at 120 degrees Celsius for 12 hours. The reaction solution was concentrated under reduced pressure to remove the solvent. The residue was added with aqueous ammonium chloride solution (60 mL), and extracted with DCM/isopropanol (3:1, 200 mL ⁇ 3). The combined organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 2-5.
  • Step D To DMF (100 mL) of compound 2-5 (18 g, 93.17 mmol) at 0 degrees Celsius, sodium hydrogen (4.84 g, 121.12 mmol, purity 60%) was added. The mixture was stirred at 0 degrees Celsius for 10 minutes. Then methyl iodide (19.84 g, 139.75 mmol) was added. The mixture was stirred at 10 degrees Celsius for 2 hours. The reaction solution was added to water at 0 degrees Celsius, and then extracted with DCM/isopropanol (3:1, 200 ml ⁇ 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 2-6.
  • Step E Compound 2-6 (9 g, 43.43 mmol) was dissolved in DCM (100 mL), and boron tribromide (21.76 g, 86.86 mmol) was added at 0 degrees Celsius. The reaction solution was stirred at 0 degrees Celsius for 2 hours. The reaction solution was slowly added to water (50 mL) to quench at 0 degrees Celsius, and then extracted with DCM/isopropanol (3:1, 30 mL ⁇ 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 2-7.
  • Step A Compound 3-1 (100 g, 657.26 mmol) was dissolved in THF (300 mL), and triethylamine (106.69 g, 1.05 mol) was added. Triphosgene (29.53 g, 99.50 mmol) was dissolved in DCM (200 mL), and added dropwise to the above reaction solution at zero degrees Celsius. The mixture was stirred at zero degrees Celsius for 20 minutes and at 25 degrees Celsius for 16 hours.
  • Step C Compound 3-4 (30.29 g, 91.97 mmol) was dissolved in DCM (460 mL), and trifluoromethanesulfonic acid (138.03 g, 919.70 mmol) was added dropwise at zero degrees Celsius. The mixture was stirred at 20 degrees Celsius for 1.5 hours. The reaction solution was quenched by adding ice water (500 mL) with stirring, and extracted with DCM (300 mL ⁇ 2). The combined organic phases were washed with 1 mol/L sodium hydroxide aqueous solution (500 mL ⁇ 2) and saturated brine (200 mL) successively, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Step D Compound 3-5 (3.3 g, 18.62 mmol) was dissolved in DMF (33 mL), and sodium hydrogen (1.49 g, 37.25 mmol) was added in portions at zero degrees Celsius. The mixture was stirred at zero degrees Celsius for 15 minutes, and methyl iodide (5.82 g, 40.97 mmol) was added. The mixture was stirred at 25 degrees Celsius for 1 hour. The reaction solution was quenched by adding ice water (60 mL) with stirring, and extracted with DCM (60 mL ⁇ 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. EtOAc (60 mL) and saturated brine (20 mL) were added, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 3-6.
  • Step A Compound 5-1 (25 g, 149.56 mmol) was dissolved in DMF (500 mL), and carbonyldiimidazole (23.76 g, 146.53 mmol) was added. The reaction solution was stirred at 70 degrees Celsius for 1 hour under the protection of nitrogen. Then ammonia water (3.36 mol, 518.16 ml, purity 25%) was added to the reaction solution. The reaction solution was stirred at 70 degrees Celsius for 16 hours under the protection of nitrogen. The reaction solution was separated by adding water (2.5 liters) and EtOAc (2 liters).
  • Step B Compound 5-2 (22.5 g, 135.40 mmol) and N,N-dimethylformal (48.40 g, 406.19 mmol) were added to DMF (500 mL). The reaction solution was stirred at 140 degrees Celsius for 16 hours. The reaction solution was concentrated under reduced pressure. The crude product was added to EtOAc/TBME (100 mL) and stirred for 1 hour, and filtered to obtain compound 5-3.
  • Step C Compound 5-3 (7 g, 36.80 mmol) was dissolved in DCM (100 mL), and boron tribromide (18.44 g, 73.61 mmol) was added at 0°C. The reaction solution was stirred at 0°C for 2 hours. The reaction solution was quenched by slowly adding MeOH (20 mL) at 0-10 degrees Celsius, and concentrated under reduced pressure. The crude product was added to MeOH (50 mL) and stirred for 1 hour, and filtered to obtain compound 5-4.
  • Step A Dissolve compound 6-1 (4.00 g, 18.60 mmol) in DMSO (36 mL), add magnesium sulfate (2.24 g, 18.60 mmol), 1,1'-bis(diphenylphosphine) two Ferrocene (206.24 mg, 372.02 micromole), palladium acetate (83.52 mg, 372.02 micromole), hydrazine methyl sulfate (2.68 g, 18.60 mmol) and 1,8-diazabicycloundec-7- Ene (8.50 g, 55.80 mmol). The suspension was replaced with carbon monoxide three times, and stirred at 100 degrees Celsius for 16 hours in a carbon monoxide (45Psi) atmosphere.
  • reaction solution was added to water (30 mL), extracted with EtOAc (30 mL), the organic phase was washed with water (30 mL) and saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Step B Compound 6-2 (390 mg, 2.05 mmol) was dissolved in DCM (5 mL), and boron tribromide (1.03 g, 4.10 mmol) was added dropwise at zero degrees Celsius. The mixture was stirred at 25 degrees Celsius for 16 hours. The reaction solution was quenched by adding MeOH (20 mL) dropwise at zero degrees Celsius with stirring, and concentrated under reduced pressure to obtain compound 6-3.
  • Step D Compound 7-3 (0.9 g, 2.91 mmol) was dissolved in MeOH (10 mL), and Pd/C (0.1 g) was added under the protection of nitrogen. The mixture was replaced with hydrogen three times, and stirred at 25 degrees Celsius for 16 hours under a hydrogen atmosphere (15 psi). Filter and concentrate under reduced pressure to obtain compound 7-4.
  • Step A Dissolve compound 1-6 (40.0 g, 169.49 mmol) in dioxane (600 mL), add bis(triphenylphosphine) palladium dichloride (4.0 g, 5.7 mmol) and three Butyl(1-ethoxyethylene)tin (57.3 mL, 169.49 mmol). Under the protection of nitrogen, the mixture was stirred at 60 degrees Celsius for 16 hours. The reaction solution was poured into saturated potassium fluoride aqueous solution (200 mL) and EtOAc (200 mL), stirred for 1 hour, filtered, and the filter cake was washed with EtOAc, and the organic phase was separated and dried over anhydrous sodium sulfate. Concentrate under reduced pressure to obtain compound 1-7.
  • Step C To a solution of compound 1-8 (10.1 g, 50.72 mmol) in ethyl formate (151.5 ml, 1.88 mol) at 0-5 degrees Celsius, sodium hydrogen (12.17 g, 304.32 mmol) was added in batches. Purity 60%). The reaction solution was stirred at 0-5 degrees Celsius for 20 minutes, and then heated to 20-30 degrees Celsius and stirred for 2 hours. MeOH (21 mL) and concentrated hydrochloric acid (63 mL) were sequentially added at 10 degrees Celsius, and the reaction solution was stirred at 20-30 degrees Celsius for another 2 hours.
  • Step D A solution of compound 1-9 (500 mg, 2.39 mmol), compound 1-5 (449.79 mg, 2.51 mmol), potassium carbonate (991.29 mg, 7.17 mmol) in DMF (10 mL) at 40 degrees Celsius Stir for 14 hours.
  • the reaction solution was poured into water (50 mL) and stirred for 0.5 hour, filtered, the filter cake was rinsed with TBME (5 mL ⁇ 2), and dried under reduced pressure to obtain compound 1-10.
  • Step F Dissolve compound 1-11 (70 mg, 188.01 ⁇ mol) in THF (5 mL), add LiHMDS (1 mol/L, 282.01 ⁇ l) at minus 60 degrees Celsius, and stir the mixture at minus 60 degrees Celsius for 15 minute. A mixture of phosphorus oxychloride (57.65 mg, 376.01 micromole) in THF (0.2 mL) was added. The reaction solution was stirred at minus 60 degrees Celsius for 10 minutes. Add 2-bromoethylamine hydrobromide (308.17 mg, 1.5 mmol) and DIPEA (194.38 mg, 1.5 mmol) successively, stir vigorously and raise the temperature to 0 degrees Celsius and stir for 30 minutes.
  • Step G Compound 1-12 (80 mg, 120.44 ⁇ mol) was dissolved in THF (6 mL), and silver oxide (279.11 mg, 1.2 mmol) was added. The mixture was stirred at 60 degrees Celsius for 14 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by HPLC (Separation column: Waters Xbridge (specification: C18 150 ⁇ 50mm, particle size: 10 ⁇ m); mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; elution gradient: 17 %-47%, 10 minutes) to obtain compound 1.
  • Step A A solution of compound 8-1 (1 g, 8.84 mmol), compound 1-9 (1.85 g, 8.84 mmol), potassium carbonate (3.67 g, 26.53 mmol) in acetonitrile (15 mL) at 50 degrees Celsius Stir for 12 hours.
  • Step C Dissolve compound 8-3 (650 mg, 2.12 mmol) in THF (20 mL), add lithium bis(trimethylsilyl)amide (1 mol/L, 3.18 mL) at minus 60 degrees Celsius , The mixture was stirred at minus 60 degrees Celsius for 15 minutes. A mixture of phosphorus oxychloride (650.13 mg, 394.02 micromole) in THF (3 mL) was added all at once. The reaction solution was stirred at minus 60 degrees Celsius for 15 minutes. 2-Bromoethylamine hydrobromide (2.10 g, 16.96 mmol) and DIPEA (2.19 g, 16.96 mmol) were sequentially added, and the reaction solution was stirred at minus 60 degrees Celsius for 30 minutes.
  • Step B Compound 9-1 (4.00 g, 9.38 mmol) was dissolved in tetrahydrofuran (60 mL), and lithium bis(trimethylsilyl)amide (1 mol/L, 14.07 mL) was added dropwise at minus 60 degrees Celsius , 14.07 mmol), and then stir the reaction at minus 60 degrees Celsius for 15 minutes.
  • Phosphorus oxychloride (2.16 g, 14.07 mmol) was added to the reaction solution at one time. After stirring the reaction for 15 minutes at minus 60 degrees Celsius, 2-bromoethylamine hydrobromide (9.61 g, 46.90 mmol) was added successively.
  • Step C Compound 9-2 (3.00 g, 5.94 mmol) was dissolved in tetrahydrofuran (54 mL), silver oxide (3 g, 178.19 mmol) was added, and the reaction solution was heated to 70 degrees Celsius and stirred for 12 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 9-3.
  • Step D Dissolve compound 9-3 (100 mg, 291.34 micromoles) in acetonitrile (3 mL), add potassium carbonate (80.53 mg, 582.67 micromoles) and 4-fluorophenol (35.93 mg, 320.47 micromoles), The reaction solution was heated to 55 degrees Celsius and stirred for 12 hours. The reaction solution was filtered and concentrated under reduced pressure to obtain a crude product.
  • the synthesis of compound 10 refers to the method of compound 9.
  • the intermediate 4-fluorophenol can be replaced with the intermediate 3-hydroxypyridine.
  • the synthesis of compound 11 refers to the method of compound 9.
  • the intermediate 4-fluorophenol can be replaced with the intermediate 3-hydroxy-6-fluoropyridine.
  • the synthesis of compound 12 refers to the method of compound 9.
  • the intermediate 4-fluorophenol can be replaced with the intermediate 3-hydroxy-5-fluoropyridine.
  • RPMI-1640 medium penicillin/streptomycin antibiotics were purchased from Vicente, and fetal bovine serum was purchased from Biosera.
  • CellTiter-Glo (cell viability chemiluminescence detection reagent) reagent was purchased from Promega.
  • the NCI-H460 cell line was purchased from Nanjing Kebai Biotechnology Co., Ltd. Nivo multi-label analyzer (PerkinElmer).
  • Plant NCI-H460 cells in a white 96-well plate 80 ⁇ L of cell suspension per well, which contains 4000 NCI-H460 cells.
  • the cell plate was placed in a carbon dioxide incubator for overnight culture.
  • the compound to be tested was diluted 3-fold to the 8th concentration with a discharge gun, that is, diluted from 200 ⁇ M to 92 nM, and a double-well experiment was set up.
  • the concentration of the compound transferred to the cell plate ranges from 1 ⁇ M to 0.46 nM.
  • the cell plate was cultured in a carbon dioxide incubator for 2 hours, after which the drug-containing medium was removed, the cell plate was rinsed with fresh medium, and 100 ⁇ L of drug-free fresh medium was added to each well to continue culturing for 70 hours. Another cell plate is prepared, and the signal value is read as the maximum value (Max value in the following equation) on the day of drug addition to participate in data analysis.
  • Using multi-marker analyzer readings Add 25 ⁇ L of cell viability chemiluminescence detection reagent per well to the cell plate, and incubate for 10 minutes at room temperature to stabilize the luminescence signal. Using multi-marker analyzer readings.
  • the IC 50 value can be obtained by four-parameter curve fitting ("log(inhibitor) vs. GraphPad Prism" response--Variable slope” mode).
  • Table 1 provides the inhibitory activity of the compounds of the present invention on the proliferation of NCI-H460 cells.
  • the compound of the present invention has excellent anti-proliferative activity against NCI-H460 which highly expresses AKR1C3 enzyme.
  • EMEM Eagle's Minimum Essential Medium
  • penicillin/streptomycin antibiotics were purchased from Vicente
  • fetal bovine serum was purchased from Biosera.
  • CellTiter-Glo cell viability chemiluminescence detection reagent
  • the Hep3B cell line was purchased from the Cell Bank of the Chinese Academy of Sciences. Nivo multi-label analyzer (PerkinElmer).
  • Plant Hep3B cells in a white 96-well plate 80 ⁇ L of cell suspension per well, which contains 3000 Hep3B 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 9th concentration with a discharge gun, that is, diluted from 2mM to 5.12nM, and a double-well experiment was set up.
  • the concentration of the compound transferred to the cell plate ranges from 10 ⁇ M to 0.0256 nM.
  • the cell plate was placed in a carbon dioxide incubator for 3 days. In addition, prepare a cell plate, and read the signal value as the maximum value (Max value in the following equation) on the day of dosing to participate in data analysis. Add 25 ⁇ L of cell viability chemiluminescence detection reagent to each well of this cell plate, and incubate for 10 minutes at room temperature to stabilize the luminescence signal. Using multi-marker analyzer readings. Add 25 ⁇ L of cell viability chemiluminescence detection reagent per well to the cell plate, and incubate for 10 minutes at room temperature to stabilize the luminescence signal. Using multi-marker analyzer readings.
  • the IC 50 value can be obtained by four-parameter curve fitting ("log(inhibitor) vs. GraphPad Prism" response--Variable slope” mode).
  • Table 2 provides the inhibitory activity of the compounds of the invention on Hep3B cell proliferation.
  • the compound of the present invention has no anti-proliferative activity against Hep3B with low expression of AKR1C3, and shows high selectivity.
  • DMEM medium penicillin/streptomycin antibiotics were purchased from Vicente, and fetal bovine serum was purchased from Biosera.
  • CellTiter-Glo (cell viability chemiluminescence detection reagent) reagent was purchased from Promega.
  • the HepG2 cell line was purchased from the Cell Bank of the Chinese Academy of Sciences. Nivo multi-label analyzer (PerkinElmer).
  • HepG2 cells were planted in a white 384-well plate, 25 ⁇ M cell suspension per well, which contained 1000 HepG2 cells.
  • the cell plate was placed in a carbon dioxide incubator for overnight culture.
  • the compound to be tested was diluted 3-fold to the 9th concentration with a discharge gun, that is, diluted from 200 ⁇ M to 30 nM, and a double-well experiment was set up.
  • the concentration of the compound transferred to the cell plate ranges from 1 ⁇ M to 0.15 nM.
  • the cell plate was placed in a carbon dioxide incubator for 5 days.
  • Another cell plate is prepared, and the signal value is read as the maximum value (Max value in the following equation) on the day of drug addition to participate in data analysis.
  • Using multi-marker analyzer readings. Add 20 ⁇ M cell viability chemiluminescence detection reagent per well to the cell plate, and incubate for 10 minutes at room temperature to stabilize the luminescence signal. Using multi-marker analyzer readings.
  • the IC 50 value can be obtained by four-parameter curve fitting ("log(inhibitor) vs. GraphPad Prism" response--Variable slope” mode).
  • Table 3 provides the inhibitory activity of the compounds of the present invention on the proliferation of HepG2 cells.
  • the compound of the present invention has excellent anti-proliferative activity against HepG2 that highly expresses AKR1C3.
  • the HepG2 orthotopic xenograft tumor nude mouse model was used to evaluate the anti-tumor effect of the compound.
  • mice Female Balb/C nude mice, 6-8 weeks old, weighing 18-22 grams, fetal bovine serum (PBS), medium EMEM (Cat. No. 30-2003), phosphate buffer, double antibody (Cat. No. 15240-062), Matrigel, pancreatin.
  • PBS fetal bovine serum
  • EMEM medium EMEM
  • phosphate buffer Cat. No. 15240-062
  • Matrigel pancreatin.
  • the experimental index is whether the tumor growth can be delayed or the tumor can be cured.
  • T is the administration group and C is the average bioluminescence intensity value of the blank control group at a set time.
  • Tumor inhibition rate TGI calculation formula: TGI(%) [1-(T i -T 0 )/(V i -V 0 )] ⁇ 100, where T i is the average bioluminescence intensity of the treatment group at the set time; T 0 is the average intensity of bioluminescence at the starting point of administration. V i is the average bioluminescence intensity of the blank control group at the set time; V 0 is the average bioluminescence intensity of the administration starting point.
  • the p value is obtained by analyzing the relative tumor volume value (RTV) using one-way ANOVA.
  • the body weight of the animals in the sorafenib treatment group fluctuates to a large extent, and the average weight of the whole animal decreases by more than 5%.
  • the animal weights in the compound 4A and compound 8 groups are better, and no significant decrease is found, and the animals have good tolerance. See Figure 2 for details.

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Abstract

L'invention concerne un composé de benzodihydropyrane structuralement inédit ciblant l'enzyme AKR1C3 (aldo-céto réductase 1C3). En particulier, l'invention concerne un composé représenté par la formule (II) ou un sel ou isomère pharmaceutiquement acceptable de celui-ci.
PCT/CN2020/120281 2019-10-12 2020-10-12 Composé de benzodihydropyrane ciblant l'aldo-céto réductase 1c3 WO2021068952A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202080071652.8A CN114555574B (zh) 2019-10-12 2020-10-12 靶向醛酮还原酶1c3的苯并二氢吡喃类化合物

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CN201910969224 2019-10-12
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WO2022048492A1 (fr) 2020-09-02 2022-03-10 深圳艾欣达伟医药科技有限公司 Procédé de détection d'akr1c3 et kit de diagnostic pour la détection d'akr1c3 et son utilisation
WO2022057838A1 (fr) * 2020-09-18 2022-03-24 南京明德新药研发有限公司 Composé d'isochromane
CN116249698A (zh) * 2020-09-18 2023-06-09 深圳扬厉医药技术有限公司 异色满类化合物
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WO2023174319A1 (fr) * 2022-03-15 2023-09-21 深圳艾欣达伟医药科技有限公司 Méthode de traitement d'un patient atteint d'un cancer à mutation de brca
WO2024078392A1 (fr) * 2022-10-09 2024-04-18 Anrui Biomedical Technology (Guangzhou) Co., Ltd. Composés de phosphoramidate et leurs utilisations

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