WO2022268176A1 - 甾体类化合物、其药物组合物及其应用 - Google Patents

甾体类化合物、其药物组合物及其应用 Download PDF

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WO2022268176A1
WO2022268176A1 PCT/CN2022/100881 CN2022100881W WO2022268176A1 WO 2022268176 A1 WO2022268176 A1 WO 2022268176A1 CN 2022100881 W CN2022100881 W CN 2022100881W WO 2022268176 A1 WO2022268176 A1 WO 2022268176A1
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alkyl
compound
cycloalkyl
optionally substituted
group
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PCT/CN2022/100881
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English (en)
French (fr)
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刘力锋
李桢
刘小青
赵晓峰
柴晓娟
唐锋
付雅媛
曹卓晓
唐任宏
任晋生
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江苏先声药业有限公司
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Priority to CN202280043886.0A priority Critical patent/CN117580849A/zh
Priority to EP22827668.9A priority patent/EP4365183A1/en
Publication of WO2022268176A1 publication Critical patent/WO2022268176A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A61P5/46—Drugs for disorders of the endocrine system of the suprarenal hormones for decreasing, blocking or antagonising the activity of glucocorticosteroids
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring

Definitions

  • the invention requires submission to the State Intellectual Property Office of China on June 24, 2021.
  • the patent application number is 202110706921.X, and the title of the invention is "Steroidal Compounds and Their Applications", which was submitted to the State Intellectual Property Office of China on January 27, 2022.
  • the patent application number is 202210101639.3
  • the invention name is "steroid compounds and their applications”
  • the entirety of the aforementioned prior application is hereby incorporated by reference in its entirety.
  • the present invention relates to a novel glucocorticoid receptor agonist, its preparation method, a pharmaceutical composition containing the compound, and its use in treating tumors, inflammatory diseases or autoimmune diseases.
  • the glucocorticoid receptor is part of the nuclear receptor family. GR is expressed in nearly every cell in the body and regulates genes that control development, metabolism and immune response. When the glucocorticoid receptor binds glucocorticoids, their primary mechanism of action is regulation of gene transcription. Including the direct route: glucocorticoids enter the cyst through the cell membrane and bind to the GR in the cyst, the latter activates to enter the nucleus, binds to the GR response element (GRE) on the DNA, and initiates or inhibits the mRNA transcription of the corresponding gene.
  • GRE GR response element
  • Glucocorticoid receptor agonists can be divided into two categories: endogenous or synthetic according to their source. Synthetic glucocorticoid receptor agonists are a class of potent small molecule drugs used to treat inflammatory and immune diseases. Glucocorticoids that have been introduced to the market include: prednisone, prednisolone, betamethasone, dexamethasone, fluticasone propionate, budesonide, etc.
  • Glucocorticoid receptor agonists can be used to control inflammatory and allergic diseases such as asthma, rheumatoid arthritis, obstructive airway disease, rhinitis, inflammatory bowel disease, psoriasis, psoriasis and eczema, etc.
  • inflammatory and allergic diseases such as asthma, rheumatoid arthritis, obstructive airway disease, rhinitis, inflammatory bowel disease, psoriasis, psoriasis and eczema, etc.
  • long-term administration of super-physiological doses may cause side effects such as muscle atrophy and osteoporosis, which limits the drug dose and duration of drug use for patients, and its therapeutic potential has not been effectively tapped. Therefore, it is also necessary to develop new glucocorticoid receptor agonists to expand the treatment range of diseases and reduce toxic and side effects.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof:
  • R 1 and R 2 are each independently selected from H, CH 3 or halogen
  • Ring A is selected from phenyl, 5-10 membered heteroaryl or C 3 -C 10 cycloalkyl, and said phenyl, 5-10 membered heteroaryl or C 3 -C 10 cycloalkyl is optionally replaced by R 1a replace;
  • X is selected from O, S, C 1 -C 3 alkylene-O, C 1 -C 3 alkylene-S, NR 6 or C(R 7 )(R 8 );
  • R 6 is selected from H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 4-7 membered heterocyclic group, the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 4-7 membered heterocyclyl is optionally substituted by R b ;
  • R 7 and R 8 are each independently selected from H, halogen, CN, OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 4-7 membered heterocyclic group, or R 7 , R 8 and the atoms they are connected together form a C 3 -C 6 cycloalkyl group or a 4-7 membered heterocyclic group, and the OH, NH 2 , C 1 -C 6 alkyl group, C 3 -C 6 cycloalkyl group or 4-7 membered heterocyclyl is optionally substituted by R b ;
  • Ring B is selected from C 6 -C 10 aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl or 4-14 membered heterocyclic group, the C 6 -C 10 aryl, 5-10 A membered heteroaryl group, a C 3 -C 10 cycloalkyl group or a 4-14 membered heterocyclic group is optionally substituted by R 2a ;
  • R 11 and R 12 are each independently selected from H or C 1 -C 6 alkyl
  • C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 4-7 membered heterocyclyl are optionally substituted by R c ;
  • R 1 , R 2 are each independently selected from H or F.
  • ring A is selected from phenyl or 5-6 membered heteroaryl optionally substituted with R 1a .
  • Ring A is selected from phenyl optionally substituted with R 1a .
  • R 1a is selected from NH 2 .
  • Ring A is selected from
  • Ring A is selected from
  • X is selected from O, S, C 1 -C 3 alkylene-O, C 1 -C 3 alkylene-S, or C(R 7 )(R 8 ).
  • R 7 and R 8 are each independently selected from H, halogen, CN, OH, NH 2 or C 1 -C 3 alkyl, or R 7 and R 8 together with the atoms they are connected to form a C 3 -C 6 cycloalkyl, the OH, NH 2 , C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl is optionally substituted by R b .
  • R 7 and R 8 are each independently selected from H, halogen or C 1 -C 3 alkyl, or R 7 , R 8 together with the atoms they are connected to form a C 3 -C 6 cycloalkyl.
  • R 7 and R 8 are each independently selected from H, F or methyl, or R 7 and R 8 together with the atoms they are connected to form a cyclopropyl group.
  • X is selected from O, S , CH2O, CH2S , CH2 , CF2 , CHCH3 , or
  • X is selected from CH2 .
  • R 11 , R 12 are each independently selected from H, methyl or ethyl.
  • R 10 is selected from OH, SH, OCH 2 F, O(C ⁇ O)CH 3 ,
  • R 10 is selected from OH or
  • ring B is selected from C 6 -C 10 aryl, 5-10 membered heteroaryl or 4-14 membered heterocyclic group, the C 6 -C 10 aryl, 5-10 membered heteroaryl A group or a 4-14 membered heterocyclyl group is optionally substituted by R 2a .
  • ring B is selected from 5-10 membered heteroaryl or 4-14 membered heterocyclyl optionally substituted by R 2a .
  • ring A is substituted with R 1a and/or ring B is substituted with R 2a .
  • R 2a is selected from NH 2 .
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the compound represented by formula (Ia) or a pharmaceutically acceptable salt thereof:
  • R 1 , R 2 , ring A, X and R 10 are as defined above;
  • R 3 is selected from H, OH or NHR 9 , R 4 , R 5 and the atoms they are connected together form a C 5 -C 6 cycloalkenyl, a 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group, said C 5 -C 6 cycloalkenyl, 5-6 membered heterocyclic group or 5-6 membered heteroaryl group is optionally substituted by R 4a ; or, R 5 is selected from H, OH or NHR 9 , R 3 , R 4 and The atoms they connect together form a C 5 -C 6 cycloalkenyl group, a 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group, and the C 5 -C 6 cycloalkenyl group, a 5-6 membered heterocyclic group or 5-6 membered heteroaryl is optionally substituted by R 4a ;
  • R 9 is selected from H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 4-7 membered heterocyclic group, the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or The 4-7 membered heterocyclyl is optionally substituted by R;
  • R 13 and R 14 are each independently selected from H, halogen, CN, OH, NH 2 , O(C 1 -C 3 alkyl) or C 1 -C 6 alkyl;
  • C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 4-7 membered heterocyclyl are optionally substituted by R d ;
  • R 3 is selected from H, OH or NHR 9 , R 4 and R 5 together form a 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group, and the 5-6 A membered heterocyclic group or a 5-6 membered heteroaryl group is optionally substituted by R 4a ; or R 5 is selected from H, OH or NHR 9 , R 3 , R 4 and the atoms they are connected together form a 5-6 membered heterocyclic group Or a 5-6 membered heteroaryl group, the 5-6 membered heterocyclic group or 5-6 membered heteroaryl group is optionally substituted by R 4a .
  • R 9 is selected from H or C 1 -C 6 alkyl.
  • R9 is selected from H.
  • R 3 is selected from H, OH or NH 2 , R 4 , R 5 and the atoms they are connected together form a 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group, and the 5-6 The membered heterocyclyl or 5-6 membered heteroaryl is optionally substituted by R 4a .
  • R 5 is selected from H, OH or NH 2 , and R 3 and R 4 together form a C 5 -C 6 cycloalkenyl, a 5-6 membered heterocyclyl or a 5-6 membered Heteroaryl, the C 5 -C 6 cycloalkenyl, 5-6 membered heterocyclic group or 5-6 membered heteroaryl is optionally substituted by R 4a .
  • R 5 is selected from H, OH or NH 2 , R 3 and R 4 together form a 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group, and the 5-6 The membered heterocyclyl or 5-6 membered heteroaryl is optionally substituted by R 4a .
  • R 3 is selected from H, R 4 , R 5 and the atoms they are connected together form a 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group, and the 5-6 membered heterocyclic group or 5-6 membered heteroaryl is optionally substituted by R 4a .
  • R 5 is selected from H or NH 2 , and R 3 and R 4 together form a C 5 -C 6 cycloalkenyl, a 5-6 membered heterocyclic group or a 5-6 membered heteroaryl
  • the C 5 -C 6 cycloalkenyl, 5-6 membered heterocyclic group or 5-6 membered heteroaryl group is optionally substituted by R 4a .
  • R 5 is selected from H or NH 2 , R 3 and R 4 together form a 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group, and the 5-6 membered heteroaryl Cyclic or 5-6 membered heteroaryl is optionally substituted by R 4a .
  • R 3 is selected from H, OH or NH 2 , R 4 , R 5 and the atoms they are connected to form together said Optionally substituted by R 4a .
  • R 3 is selected from H, R 4 , R 5 and the atoms they are connected together form said Optionally substituted by R 4a .
  • R 5 is selected from H, OH or NH 2 , R 3 , R 4 and the atoms they are connected to form together said Optionally substituted by R 4a .
  • R 5 is selected from H, OH or NH 2 , R 3 , R 4 and the atoms they are connected to form together said Optionally substituted by R 4a .
  • R 5 is selected from H, OH or NH 2 , R 3 , R 4 and the atoms they are connected to form together said Optionally substituted by R 4a .
  • R 5 is selected from H or NH 2 , R 3 , R 4 and the atoms they are connected together form said Optionally substituted by R 4a .
  • R 5 is selected from H or NH 2 , R 3 , R 4 and the atoms they are connected together form said Optionally substituted by R 4a .
  • R 5 is selected from H or NH 2 , R 3 , R 4 and the atoms they are connected together form said Optionally substituted by R 4a .
  • R 5 is selected from H or NH 2 , R 3 , R 4 and the atoms they are connected together form said Optionally substituted by R 4a .
  • R 3 is selected from H, R 4 , R 5 and the atoms they are connected together form
  • R 3 is selected from H, R 4 , R 5 and the atoms they are connected together form
  • R 5 is selected from NH 2 , R 3 , R 4 and the atoms they are connected together form
  • R 5 is selected from NH 2 , R 3 , R 4 and the atoms they are connected together form
  • each of R 13 and R 14 is independently selected from H or NH 2 .
  • R 13 is selected from H.
  • R14 is selected from H or NH2 .
  • R14 is selected from H.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:
  • the present invention provides a pharmaceutical composition, which comprises the compound of formula (I) or a pharmaceutically acceptable salt thereof of the present invention and pharmaceutically acceptable excipients.
  • the present invention provides a method for treating a disease mediated by a glucocorticoid receptor in an individual (such as a mammal), comprising administering a therapeutically effective amount of the formula ( I) A compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the present invention provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for preventing or treating diseases mediated by glucocorticoid receptors.
  • the present invention provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the prevention or treatment of diseases mediated by glucocorticoid receptors.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating diseases mediated by glucocorticoid receptors.
  • the present invention provides a method for treating a tumor, an inflammatory disease or an autoimmune disease in an individual (such as a mammal), comprising administering a therapeutically effective amount of the formula ( I) A compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the present invention provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of medicines for treating tumors, inflammatory diseases or autoimmune diseases.
  • the present invention provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the treatment of tumors, inflammatory diseases or autoimmune diseases.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treating tumors, inflammatory diseases or autoimmune diseases.
  • the glucocorticoid receptor-mediated disease is selected from tumors, inflammatory diseases, or autoimmune diseases.
  • the compounds of the present invention have strong binding activity to glucocorticoid receptors, but have weak or inactive binding activities to other hormone receptors. This strong selectivity of the compounds of the present invention is expected to reduce the effect on other hormone receptors. Receptor side effects.
  • the compounds of the present invention also have good metabolic stability in liver microsomes.
  • the compound of the present invention has less potential risk of drug-drug interaction (DDI) DDI, and the compound of the present invention has no significant inhibition on the hERG potassium ion channel, indicating that the compound of the present invention causes cardiotoxicity due to hERG potassium ion channel inhibition The resulting risk is low.
  • DDI drug-drug interaction
  • tautomer refers to isomers of functional groups resulting from the rapid movement of an atom in a molecule between two positions.
  • the compounds of the present invention may exhibit tautomerism.
  • Tautomeric compounds can exist in two or more interconvertible species. Tautomers generally exist in equilibrium and attempts to isolate a single tautomer usually result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; in phenols, the enol form predominates.
  • the present invention encompasses all tautomeric forms of the compounds.
  • stereoisomer refers to isomers resulting from differences in the arrangement of atoms in a molecule in space, including cis-trans isomers, enantiomers and diastereomers.
  • the compounds of the present invention may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, so the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • Specific geometric or stereoisomeric forms may be cis and trans isomers, E and Z geometric isomers, (-)- and (+)-enantiomers, (R)- and (S )-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic or other mixtures thereof, such as enantiomers or diastereomers Enriched mixtures, all of the above isomers and mixtures thereof are within the definition of the compounds of the present invention.
  • asymmetric carbon atoms there may be additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms in substituents such as alkyl groups, and these isomers and their mixtures involved in all substituents are also included in within the definition of the compounds of the invention.
  • the compounds containing asymmetric atoms of the present invention can be isolated in optically pure form or in racemic form, the optically active form can be resolved from a racemic mixture, or synthesized by using chiral starting materials or chiral reagents .
  • substituted means that any one or more hydrogen atoms on the specified atom are replaced by a substituent, as long as the valence of the specified atom is normal and the substituted compound is stable.
  • ethyl is “optionally” substituted with halogen, meaning that the ethyl group can be unsubstituted ( CH2CH3 ) , monosubstituted ( CH2CH2F , CH2CH2Cl , etc. ) , polysubstituted ( CHFCH2F , CH2CHF2 , CHFCH2Cl , CH2CHCl2 , etc. ) or fully substituted ( CF2CF3 , CF2CCl3 , CCl2CCl3 , etc. ) . It will be appreciated by those skilled in the art that for any group containing one or more substituents, no sterically impossible and/or synthetically impossible substitution or substitution pattern is introduced.
  • any variable eg R a , R b
  • its definition is independent at each occurrence. For example, if a group is substituted by 2 R b , each R b has independent options.
  • linking group When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a bond.
  • linking group mentioned herein does not indicate its linking direction
  • its linking direction is arbitrary.
  • the structural unit When X in is selected from “C 1 -C 3 alkylene-O"
  • X can connect ring A and ring B in the direction from left to right to form “ring AC 1 -C 3 alkylene- O-ring B”
  • ring A and ring B can also be connected from right to left to form “ring AOC 1 -C 3 alkylene-ring B".
  • the substituent When a bond of a substituent cross-links two atoms in a ring, the substituent may be bonded to any atom on the ring.
  • the structural unit Indicates that R 5 can be substituted at any position on the benzene ring.
  • Cm - Cn herein refers to having an integer number of carbon atoms in the range of mn.
  • C 1 -C 10 means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms.
  • alkyl refers to a hydrocarbon group having the general formula C n H 2n+1 , and the alkyl group may be straight or branched.
  • C 1 -C 6 alkyl is understood to mean a straight-chain or branched saturated hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • alkyl group examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl base, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.
  • C 1 -C 3 alkyl is understood to mean a linear or branched saturated alkyl group having 1 to 3 carbon atoms.
  • the "C 1 -C 6 alkyl group” may further include "C 1 -C 3 alkyl group”.
  • alkoxy refers to the group produced by the loss of the hydrogen atom on the hydroxyl group of straight-chain or branched alcohols, which can be understood as “alkyloxy” or “alkyl-O-”.
  • C 1 -C 6 alkoxy can be understood as “C 1 -C 6 alkyloxy” or “C 1 -C 6 alkyl-O-”.
  • the "C 1 -C 6 alkoxy” may further include "C 1 -C 3 alkoxy”.
  • cycloalkyl refers to a fully saturated carbocyclic group that exists in the form of a monocyclic ring, a double ring, a bridged ring, or a spiro ring. Unless otherwise indicated, the carbocycle is typically a 3 to 10 membered ring (eg 3, 4, 5, 6, 7, 8, 9, 10 membered ring).
  • C 3 -C 10 cycloalkyl is understood to mean a saturated monocyclic, fused, spiro or bridged ring having 3 to 10 carbon atoms.
  • cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo[2.2 .1] heptyl), bicyclo [2.2.2] octyl, adamantyl, spiro [4.5] decanyl, etc.
  • C 3 -C 10 cycloalkyl may include “C 3 -C 6 cycloalkyl”, and the term “C 3 -C 6 cycloalkyl” can be understood as representing a saturated monocyclic or bicyclic hydrocarbon ring, which has 3-6 carbon atoms, specific examples include but not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl and the like.
  • cycloalkyloxy can be understood as “cycloalkyl-O-”.
  • cycloalkenyl refers to an incompletely saturated non-aromatic carbocyclic group having at least one carbon-carbon double bond and existing in the form of a single ring, a condensed ring, a bridged ring, or a spiro ring. Unless otherwise indicated, the carbocycle is typically a 5 to 8 membered ring.
  • C 5 -C 6 cycloalkenyl refers to a cycloalkenyl group with 5 or 6 ring carbon atoms, and specific examples include but are not limited to cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexanedi alkenyl etc.
  • N nitrogen atoms
  • O oxygen atoms
  • S sulfur atom
  • P phosphorus atom
  • 4-14 membered heterocyclic group refers to a heterocyclic group with 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, and its ring atoms contain 1-5 independently selected from the heteroatoms or heteroatom groups described above.
  • “4-14 membered heterocyclic group” includes “4-10 membered heterocyclic group” or “4-7 membered heterocyclic group", etc., wherein specific examples of 4-membered heterocyclic group include but are not limited to azetidine Specific examples of 5-membered heterocyclic groups include, but are not limited to, tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4 , 5-dihydrooxazolyl or 2,5-dihydro-1H-pyrrolyl; specific examples of 6-membered heterocyclic groups include, but are not limited to, tetrahydropyranyl, piperidinyl, morpholinyl, dithiane thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridyl, or 4H-[1,3,4]thiadiazinyl; specific examples of 7-
  • the heterocyclic group can also be a bicyclic group, wherein, specific examples of the 5,5-membered bicyclic group include, but are not limited to, hexahydrocyclopenta[c]pyrrol-2(1H)-yl; 5,6-membered bicyclic group Specific examples include, but are not limited to, hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4 ,3-a]pyrazinyl or 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl.
  • the heterocyclic group may be a benzofused cyclic group of the above-mentioned 4-7 membered heterocyclic group, specific examples include but not limited to dihydroisoquinolyl and the like.
  • “4-10 membered heterocyclic group” may include “5-10 membered heterocyclic group”, “4-7 membered heterocyclic group”, “5-6 membered heterocyclic group”, “6-8 membered heterocyclic group” , “4-10 membered heterocycloalkyl”, “5-10 membered heterocycloalkyl”, “4-7 membered heterocycloalkyl”, “5-6 membered heterocycloalkyl”, “6-8 membered "Heterocycloalkyl” and other ranges, "4-7 membered heterocyclyl” may further include "4-6 membered heterocyclyl", “5-6 membered heterocyclyl”, “4-7 membered heterocyclyl” , “4-6 membered heterocycloalkyl", "5-6 membered
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated ⁇ -electron system.
  • C 6 -C 10 aryl is understood to mean an aryl group having 6 to 10 carbon atoms. Especially rings with 6 carbon atoms (“C aryl”), such as phenyl; or rings with 9 carbon atoms (“C aryl”), such as indanyl or indenyl; or rings with 10 carbon atoms (“C 10 aryl”), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl.
  • aryloxy is understood to mean “aryl-O-”.
  • heteroaryl refers to an aromatic monocyclic or fused polycyclic ring system, which contains at least one ring atom selected from N, O, and S, and an aromatic ring group whose ring atoms are C.
  • heteroaryl refers to an aromatic monocyclic or fused polycyclic ring system, which contains at least one ring atom selected from N, O, and S, and an aromatic ring group whose ring atoms are C.
  • 5-10 membered heteroaryl is understood to include monocyclic or bicyclic aromatic ring systems having 5, 6, 7, 8, 9 or 10 ring atoms, in particular 5 or 6 or 9 or 10 ring atoms, and it contains 1-5, preferably 1-3 heteroatoms independently selected from N, O and S.
  • heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiazolyl Diazolyl, etc.
  • benzo derivatives such as benzofuryl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazole base, indazolyl, indolyl or isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl, etc., and their benzo derivatives, such as quinolinyl, quinazole Linyl or isoquinolinyl, etc.; or azocinyl, indolizinyl, purinyl, etc.
  • 5-6 membered heteroaryl refers to an aromatic ring system having 5 or 6 ring atoms, and which contains 1-3, preferably 1-2, heteroatoms independently selected from N, O and S.
  • heteroaryloxy is understood to mean “heteroaryl-O-”.
  • halo or halogen refers to fluorine, chlorine, bromine or iodine.
  • hydroxyl refers to a -OH group.
  • cyano refers to a -CN group.
  • mercapto refers to a -SH group.
  • amino refers to a -NH2 group.
  • terapéuticaally effective amount means (i) treating a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) delaying The amount of a compound of the invention required for the onset of one or more symptoms of a particular disease, condition or disorder.
  • the amount of a compound of the invention that constitutes a “therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art according to its own knowledge and this disclosure.
  • prevention means administering a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease, and includes preventing a disease or disease state from occurring in an individual (eg, a mammal), Especially when such individuals (eg mammals) are susceptible to the disease state, but have not yet been diagnosed as having the disease state.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive Toxicity, irritation, allergic reaction, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to salts of pharmaceutically acceptable acids or bases, including salts formed between compounds and inorganic or organic acids, and salts formed between compounds and inorganic or organic bases.
  • composition refers to a mixture of one or more compounds of the present invention or their salts and pharmaceutically acceptable excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound of the invention to an organism.
  • pharmaceutically acceptable excipients refers to those excipients that have no obvious stimulating effect on the organism and will not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
  • mammals include mammals and non-mammals.
  • mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (such as chimpanzees and other apes and monkeys); livestock such as cattle, horses, sheep, goats, pigs; domesticated animals , such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs.
  • non-human mammals include, but are not limited to, birds, fish, and the like.
  • the mammal is a human.
  • Phosphate compounds described in this application are ester prodrugs, which release biologically active compounds after being hydrolyzed by phosphatases in vivo.
  • the present invention also includes isotopically labeled compounds of the present invention that are identical to those described herein, but with one or more atoms replaced by an atom of an atomic mass or mass number different from that normally found in nature.
  • isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.
  • isotopically labeled compounds of the invention are useful in compound and/or substrate tissue distribution assays. Tritiated (ie3H ) and carbon- 14 (ie14C) isotopes are especially preferred for their ease of preparation and detectability.
  • Positron-emitting isotopes such as 15 O, 13 N, 11 C, and 18 F, can be used in positron emission tomography (PET) studies to determine substrate occupancy.
  • Isotopically labeled compounds of the invention can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • the pharmaceutical composition of the present invention can be prepared by combining the compound of the present invention with suitable pharmaceutically acceptable auxiliary materials, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
  • Typical routes of administration of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, intravenous administration.
  • the pharmaceutical composition of the present invention can be produced by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, emulsifying methods, freeze-drying methods and the like.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical compositions can be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present invention to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to patients.
  • Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. It can be obtained, for example, by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if desired, and processing the mixture into granules to obtain tablets Or the core of the sugar coating.
  • Suitable auxiliary materials include but are not limited to: binders, diluents, disintegrants, lubricants, glidants or flavoring agents, etc.
  • the pharmaceutical composition may also be adapted for parenteral administration as a suitable unit dosage form of sterile solutions, suspensions or lyophilized products.
  • the dose administered per day is 0.001 mg/kg to 200 mg/kg body weight, preferably 0.05 mg/kg to 50 mg/kg body weight, more preferably 0.1 mg/kg to 30 mg/kg body weight, In the form of single or divided doses.
  • Fig. 1 is a COZY diagram of intermediate 1-5 of Example 1 of the present invention.
  • Fig. 2 is a graph showing the results of the drug efficacy test of the test compound in Test Example 6 of the present invention on the CHS mouse model.
  • ratios indicated for mixed solvents are volume mixing ratios.
  • % means wt%.
  • the eluent or mobile phase can be a mixed eluent or mobile phase composed of two or more solvents, and the ratio is the volume ratio of each solvent, such as "0-10% methanol/dichloromethane" means a mixed eluent Or the volume ratio of methanol and dichloromethane in the mobile phase is 0:100-10:100.
  • NMR nuclear magnetic resonance
  • MS mass spectroscopy
  • Example 1 (6aR, 6bS, 7S, 8aS, 8bS, 10R, 11aR, 12aS, 12bS)-10-(4-((7-amino-2,3-dihydrobenzofuran-4-yl)methyl yl)phenyl)-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-6a,6b,7,8,8a,8b,11a,12,12a,12b-decahydro Synthesis of -1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxolan-4(2H)-one (compound 001)
  • the first step the synthesis of 4-bromo-2,3-dihydrobenzofuran-7-amine 1-2
  • the fourth step (6aR, 6bS, 7S, 8aS, 8bS, 10R, 11aR, 12aS, 12bS)-10-(4-(bromomethyl)phenyl)-7-hydroxyl-8b-(2-hydroxyacetyl )-6a,8a-dimethyl-6a,6b,7,8,8a,8b,11a,12,12a,12b-decahydro-1H-naphtho[2',1':4,5]indeno Synthesis of [1,2-d][1,3]dioxolan-4(2H)-one 1-5
  • the fifth step tert-butyl (4-(4-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-7-hydroxy-8b-(2-hydroxyacetyl)-6a, 8a-Dimethyl-4-oxyethylene-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-dodecahydro-1H-naphtho[2',1' :4,5]indeno[1,2-d][1,3]dioxolan-10-yl)benzyl)-2,3-dihydrobenzofuran-7-yl)carbamate 1-6 Synthesis of Esters
  • the sixth step (6aR, 6bS, 7S, 8aS, 8bS, 10R, 11aR, 12aS, 12bS)-10-(4-((7-amino-2,3-dihydrobenzofuran-4-yl)methyl yl)phenyl)-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-6a,6b,7,8,8a,8b,11a,12,12a,12b-decahydro Synthesis of -1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxolan-4(2H)-one 001
  • Example 2 (6aR, 6bS, 7S, 8aS, 8bS, 10R, 11aR, 12aS, 12bS)-10-(4-((1H-benzo[d]imidazol-6-yl)methyl)phenyl) -7-Hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-6a,6b,7,8,8a,8b,11a,12,12a,12b-decahydro-1H-naphtho Synthesis of [2',1':4,5]indeno[1,2-d][1,3]dioxolane-4(2H)-one (compound 002)
  • the second step the synthesis of tert-butyl 6-(4-formylbenzyl)-1H-benzo[d]imidazole-1-carboxylate 2-3
  • the third step (6aR, 6bS, 7S, 8aS, 8bS, 10R, 11aR, 12aS, 12bS)-10-(4-((1H-benzo[d]imidazol-6-yl)methyl)phenyl) -7-Hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-6a,6b,7,8,8a,8b,11a,12,12a,12b-decahydro-1H-naphtho Synthesis of [2',1':4,5]indeno[1,2-d][1,3]dioxolan-4(2H)-one
  • 16 ⁇ -Hydroxyprednisolone F1 (230mg, 0.61mmol) was dissolved in anhydrous acetonitrile (1.5mL), anhydrous magnesium sulfate (279mg, 2.32mmol) was added, and stirred at 25°C for 1 hour. 2-3 (308mg, 0.92mmol) was dissolved in anhydrous acetonitrile (1.5mL) and added to the reaction system, the temperature was lowered to 0°C and trifluoromethanesulfonic acid (431mg, 2.87mmol) was added dropwise, and stirred at 25°C for 2 hours. LCMS detected that the reaction was complete.
  • Example 3 (6aR, 6bS, 7S, 8aS, 8bS, 10R, 11aR, 12aS, 12bS)-10-(4-((1H-indol-6-yl)methyl)phenyl)-7-hydroxy -8b-(2-Hydroxyacetyl)-6a,8a-dimethyl-6a,6b,7,8,8a,8b,11a,12,12a,12b-decahydro-1H-naphtho[2', Synthesis of 1':4,5]indeno[1,2-d][1,3]dioxolan-4(2H)-one (compound 003)
  • Example 4 (6aR, 6bS, 7S, 8aS, 8bS, 10R, 11aR, 12aS, 12bS)-7-hydroxyl-8b-(2-hydroxyacetyl)-10-(4-(indoline-6 -ylmethyl)phenyl)-6a,8a-dimethyl-6a,6b,7,8,8a,8b,11a,12,12a,12b-decahydro-1H-naphtho[2',1' : Synthesis of 4,5]indeno[1,2-d][1,3]dioxolan-4(2H)-one (compound 004)
  • the first step Synthesis of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indoline 4-2
  • the third step the synthesis of tert-butyl 6-(4-formylbenzyl)indoline-1-carboxylate 4-4
  • the second step the synthesis of 4-((3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)methyl)benzaldehyde 5-3
  • the third step (6aR, 6bS, 7S, 8aS, 8bS, 10R, 11aR, 12aS, 12bS)-10-(4-((3,4-dihydro-2H-benzo[b][1,4] Oxazin-7-yl)methyl)phenyl)-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-1,2,6a,6b,7,8,8a, 8b,11a,12,12a,12b-Decahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxolane-4(2H )-Kone (Compound 005) Synthesis
  • 16 ⁇ -Hydroxyprednisolone F1 (350mg, 929 ⁇ mol) was dissolved in acetonitrile (15mL), magnesium sulfate (425mg, 3.53mmol) was added, and after stirring for 1 hour at 25°C, 4-((3,4-dihydro -2H-Benzo[b][1,4]oxazin-7-yl)methyl)benzaldehyde (235mg, 929 ⁇ mol)5-3 was dissolved in acetonitrile (5mL) and added to the reaction system, cooled to 0°C dropwise Add trifluoromethanesulfonic acid (655mg, 4.37mmol) and stir at 25°C for 2 hours.
  • the first step (6S,8S,9R,10S,11S,13S,14S,16R,17S)-6,9-difluoro-11,16,17-trihydroxy-17-(2-hydroxyacetyl)- 10,13-Dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-Dodecahydro-3H-cyclopenta[a]phenanthrene-3- Synthesis of Ketone 6-2
  • Example 7 (6aR, 6bS, 7S, 8aS, 8bS, 10R, 11aR, 12aS, 12bS)-10-(4-((4-aminobenzo[d]oxazol-7-yl)methyl)benzene base)-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-6a,6b,7,8,8a,8b,11a,12,12a,12b-decahydro-1H- Synthesis of naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxolan-4(2H)-one (compound 007)
  • the first step the synthesis of 7-bromobenzo[d]oxazol-4-amine 7-2
  • the third step (6aR, 6bS, 7S, 8aS, 8bS, 10R, 11aR, 12aS, 12bS)-10-(4-((4-aminobenzo[d]oxazol-7-yl)methyl)benzene base)-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-6a,6b,7,8,8a,8b,11a,12,12a,12b-decahydro-1H- Synthesis of naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxolan-4(2H)-one (compound 007)
  • Example 8 (6aR, 6bS, 7S, 8aS, 8bS, 10R, 11aR, 12aS, 12bS)-10-(4-((7-aminobenzo[d][1,3]dioxolane-4 -yl)methyl)phenyl)-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-6a,6b,7,8,8a,8b,11a,12,12a, 12b-Decahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxolan-4(2H)-one (compound 008) synthesis
  • tert-butyl (7-bromobenzo [d] [1,3] dioxolan-4-yl) carbamate 8-3 (820 mg, 2.60 mmol) and bis-anthyl borate ( 1.30g, 5.20mmol) was dissolved in 1,4-dioxane (25mL), potassium acetate (764mg, 7.80mmol) was added, 1,1'-bis(diphenylphosphino)ferrocene]dichloro Palladium chloride (190mg, 0.30mmol), stirred at 80°C for 16 hours under nitrogen atmosphere. LCMS detected that the reaction was complete.
  • the fifth step (6aR, 6bS, 7S, 8aS, 8bS, 10R, 11aR, 12aS, 12bS)-10-(4-((7-aminobenzo[d][1,3]dioxolane-4 -yl)methyl)phenyl)-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-6a,6b,7,8,8a,8b,11a,12,12a, 12b-Decahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxolan-4(2H)-one (compound 008) synthesis
  • Example 9 (6aR, 6bS, 7S, 8aS, 8bS, 10R, 11aR, 12aS, 12bS)-10-(4-((7-amino-2,3-dihydrobenzofuran-5-yl)methyl yl)phenyl)-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-6a,6b,7,8,8a,8b,11a,12,12a,12b-decahydro Synthesis of -1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxolan-4(2H)-one (compound 009)
  • the first step Synthesis of tert-butyl (5-bromo-2,3-dihydrobenzofuran-7-yl) carbamate 9-2
  • tert-Butyl (5-bromo-2,3-dihydrobenzofuran-7-yl) carbamate 9-2 (600mg, 1.91mmol), bis-alcohol borate (533mg, 2.10mmol ), potassium acetate (562mg, 5.73mmol), 1,1-bis(diphenylphosphine)ferrocenepalladium chloride (139mg, 190 ⁇ mol) was dissolved in anhydrous 1,4-dioxane (10mL), React at 80° C. for 16 hours under nitrogen atmosphere. LCMS detected that the reaction was complete.
  • reaction solution was concentrated by filtration, and the residue was separated and purified by column chromatography (0-10% tetrahydrofuran/petroleum ether) to obtain the intermediate tert-butyl (5-(4,4,5,5-tetramethyl-1,3 ,2-Dioxaborolan-2-yl)-2,3-dihydrobenzofuran-7-yl)carbamate 9-3 (990 mg, 71.8%).
  • the first step (2S, 6aS, 6bR, 7S, 8aS, 8bS, 10R, 11aR, 12aS, 12bS)-10-(4-(bromomethyl)phenyl)-2,6b-difluoro-7-hydroxy -8b-(2-Hydroxyacetyl)-6a,8a-dimethyl-6a,6b,7,8,8a,8b,11a,12,12a,12b-decahydro-1H-naphtho[2', Synthesis of 1':4,5]indeno[1,2-d][1,3]dioxolan-4(2H)-one 010-3
  • the third step (2S, 6aS, 6bR, 7S, 8aS, 8bS, 10R, 11aR, 12aS, 12bS)-10-(4-((7-amino-2,3-dihydrobenzofuran-4-yl )methyl)phenyl)-2,6b-difluoro-7-hydroxyl-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-6a,6b,7,8,8a,8b,11a ,12,12a,12b-Decahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxolane-4(2H)-one Synthesis of 010
  • Example 11 (6aR, 6bS, 7S, 8aS, 8bS, 10R, 11aR, 12aS, 12bS)-10-(4-((7-amino-2,3-dihydro-1H-inden-4-yl) Methyl)phenyl)-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-6a,6b,7,8,8a,8b,11a,12,12a,12b-deca Synthesis of Hydrogen-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxolan-4(2H)-one (Compound 011)
  • the first step Synthesis of 7-bromo-2,3-dihydro-1H-inden-4-amine 11-2
  • reaction solution was filtered and concentrated, and the obtained residue was separated and purified by column chromatography (0-60% ethyl acetate/petroleum ether) to obtain the intermediate 7-(4,4,5,5-tetramethyl-1,3 ,2-Dioxaborolan-2-yl)-2,3-dihydro-1H-inden-4-amine 11-3 (77.0 mg, 63.0%).
  • the third step (6aR, 6bS, 7S, 8aS, 8bS, 10R, 11aR, 12aS, 12bS)-10-(4-((7-amino-2,3-dihydro-1H-inden-4-yl) Methyl)phenyl)-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-6a,6b,7,8,8a,8b,11a,12,12a,12b-deca Synthesis of Hydrogen-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxolane-4(2H)-one 011
  • Example 12 (6aR, 6bS, 7S, 8aS, 8bS, 10R, 11aR, 12aS, 12bS)-10-(4-((6-amino-2,3-dihydrobenzofuran-4-yl)methyl yl)phenyl)-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-6a,6b,7,8,8a,8b,11a,12,12a,12b-decahydro Synthesis of -1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxolan-4(2H)-one (compound 012)
  • Example 13 (6aR, 6bS, 7S, 8aS, 8bS, 10R, 11aR, 12aS, 12bS)-10-(4-((5-aminobenzo[d]oxazol-7-yl)methyl)benzene base)-7-hydroxy-8b-(2-hydroxyacetyl)-6a,8a-dimethyl-6a,6b,7,8,8a,8b,11a,12,12a,12b-decahydro-1H- Synthesis of naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxolan-4(2H)-one (compound 013)
  • Example 14 2-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-((7-amino-2,3-dihydrobenzofuran-5- base)methyl)phenyl)-7-hydroxyl-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b -Dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxolan-8b-yl)-2-oxoethyl Synthesis of dihydrogen phosphate (compound 009-p)
  • the second step 2-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-((7-amino-2,3-dihydrobenzofuran-5- base)methyl)phenyl)-7-hydroxyl-6a,8a-dimethyl-4-oxo-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b -Dodecahydro-1H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxolan-8b-yl)-2-oxoethyl Synthesis of Dihydrogen Phosphate 009-p
  • Example 15 Phosphate compounds 001-p, 002-p, 003-p, 004-p, 005-p, 006-p, 007-p, 008-p, 010-p, 011-p, 012- Synthesis of p and 013-p
  • phosphate ester compounds 001-p, 002-p, 003-p, 004-p, 005-p, 006-p, 007-p, 008-p, 010 were prepared -p, 011-p, 012-p, and 013-p.
  • Test example 1.K562-GRE reporter gene detects the activity of compound of the present invention
  • K562 cells were seeded at 5 ⁇ 10 cells/well into 6-well culture dishes (brand Costar, Product No. 3516), cultured at 37°C, 5% CO 2 for 24 hours. The next day, dilute 3 ⁇ g of pNL2.2[NLucP/MMTV/Hygro-NANO] (Promega) and 3 ⁇ l of PLUS reagent (brand Invitrogen, Cat. No. 11514-015) into 150 ⁇ L of Opti-MEM (Brand Gibco, Cat. No. 11058021) and incubate at room temperature for 5 minutes.
  • the pNL2.2[NLucP/MMTV/Hygro-NANO] vector contains the MMTV LTR (murine mammary tumor virus long terminal repeat), which responds to the activation of several nuclear receptors such as the glucocorticoid receptor and the androgen receptor and drives Transcription of the luciferase reporter gene NanoLuc.
  • the diluted DNA solution was mixed with Lipofectamine LTX solution (brand Invitrogen, Cat. No. 15338-100) (6 ⁇ l Lipofectamine LTX+144 ⁇ l Opti-MEM) at a ratio of 1:1 and pre-incubated, and incubated at room temperature for 15 minutes to form DNA-Lipofectamine LTX complex.
  • K562 cells were transfected for 24 hours at 37 °C, 5% CO2 . After transfection, cells were washed with 3 mL of PBS and grown for two weeks with selection in complete growth medium containing 125 ⁇ g/mL hygromycin B (brand Invitrogen, cat. no. 10687010). "K562-GRE(pNL2.2[NLucP/MMTV/Hygro-NANO])" cells were generated.
  • K562-GRE pNL2.2[NLucP/MMTV/Hygro-NANO) cells in 50 ⁇ l of assay medium (RPMI 1640 medium, 1% FBS, 1% sodium pyruvate, 1% MEM non-essential amino acids and 1% penicillin -streptomycin) inoculate 50000 cells per well in a 96-well tissue culture-treated white plate (brand Costar, product number 3917), add 50 ⁇ L (2 ⁇ ) of 5-fold serial dilutions of the assay medium to treat the cells, and There are 8 concentrations of each compound, and the final concentration of the compound in the system is 0.0000128 ⁇ M-1 ⁇ M. After mixing, place in a 37°C incubator for 24 hours.
  • assay medium RPMI 1640 medium, 1% FBS, 1% sodium pyruvate, 1% MEM non-essential amino acids and 1% penicillin -streptomycin
  • Test example 2 The binding activity determination of compound of the present invention and glucocorticoid receptor GR
  • the binding activity of the compound to GR was determined using the Polarscreen Glucocorticoid Receptor Assay Kit, Red (brand Thermo, Cat. No. A15898).
  • the compound to be tested was diluted 10-fold with DMSO in a 96-well V-bottom plate (brand Nunc, product number 249944), with a maximum concentration of 100 ⁇ M, and a total of 8 concentrations.
  • the detection buffer solution Complete GR Screening buffer provided in the kit to further dilute the compound 50 times, and transfer 10 ⁇ l of the diluted compound to a 384 microwell plate (brand Corning, product number 4514), and 5 ⁇ l Fluormone GS Red (4 ⁇ concentration) Add it to the compound to be tested, and then add 5 ⁇ l of GR Full length mixture (4 ⁇ concentration), and make duplicate holes in the experiment.
  • the 384-well plate was incubated at room temperature in the dark for 2 hours, and the fluorescence polarization (mP) was detected with an EnVision multifunctional microplate reader (manufacturer: Perkinelmer). Taking the log value of the final concentration of the compound on the X axis and the mP value on the Y axis, the data was entered into the processing software Graphpad Prism 9 for four-parameter fitting and EC 50 was calculated.
  • Test example 3 The determination of the binding activity of the compound of the present invention and estrogen receptor ER
  • TR-FRET ER Alpha Coactivator Assay kit brand Thermo, catalog number A15885 was used to determine the binding activity of the compound to ER.
  • the ER receptor agonist Estradiol brand name Sigma, product number E8875-25 was diluted 10-fold in DMSO in a 96-well V-bottom plate, with a maximum concentration of 100 ⁇ M, a total of 8 concentrations.
  • the compound to be tested was serially diluted 10 times with DMSO, the highest concentration was 3000 ⁇ M, and there were 8 concentrations in total.
  • Test example 4 Determination of the binding activity of the compound to the androgen receptor AR
  • the TR-FRET Androgen Receptor Coactivator Assay kit (brand Thermo, catalog number A15878) was used to determine the binding activity of the compound to AR.
  • the AR receptor agonist dihydrotestosterone (DHT) (brand Sigma, product number D-073) was diluted 10-fold in DMSO in a 96-well V-bottom plate, with a maximum concentration of 100 ⁇ M, a total of 8 concentrations.
  • DHT dihydrotestosterone
  • the compound to be tested was serially diluted 10 times with DMSO, the highest concentration was 3000 ⁇ M, and there were 8 concentrations in total.
  • Test example 5 Determination of the binding activity of the compound to the progesterone receptor PR
  • TR-FRET Progesterone Receptor Coactivator Assay kit brand Thermo, catalog number A15903 was used to determine the binding activity of the compound to PR.
  • the PR receptor agonist Progesterone brand Sigma, product number P0130 was serially diluted 10 times with DMSO in a 96-well V-bottom plate, with a maximum concentration of 100 ⁇ M, a total of 8 concentrations.
  • the compound to be tested was diluted tenfold with DMSO, the highest concentration was 3000 ⁇ M, a total of 8 concentrations, and then the compound was further diluted 50 times with the detection buffer Nuclear Receptor Buffer F (containing 5 mM DTT) provided in the kit, and 10 ⁇ l of the diluted compound was transferred A good compound was added to a 96-well half-area microplate, 5 ⁇ l of PR-LBD protein (4 ⁇ concentration) was added to the detection compound, and then 5 ⁇ l of a mixture of fluorescein coactivator peptide and Tb-labeled anti-GST antibody ( 4 ⁇ concentration), the experiment was done in duplicate.
  • the detection buffer Nuclear Receptor Buffer F containing 5 mM DTT
  • N/A means not tested.
  • test results show that the test compound has strong binding activity to GR, weak binding activity to PR, does not bind ER and AR, and is expected to reduce the side effects caused by acting on other hormone receptors.
  • CHS mouse model 6-8 week-old C57BL/6N female mice (Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.) were selected, and the abdominal hair of each mouse was removed with small animal electric clippers. Use a micropipette to draw 400 ⁇ l of the sensitizer, and spread it evenly on the abdomen of the mouse for epidermal sensitization. Hold the mouse for 3-5 seconds after application and allow the solvent to evaporate as much as possible from the skin.
  • the specific preparation method of the sensitizer is: Weigh 0.5g of FITC (fluorescein isothiocyanate; sigma-Aldrich) powder, mix 50mL acetone (acetone; Sinopharm Reagent) and 50mL DBP (dibutyl phthalate; sigma -Aldrich) are fully dissolved in the solvent mixed in equal proportions to obtain a sensitizer with a FITC content of 0.5%. On the 6th day after sensitization, measure the thickness of the right ear of the mouse with a dial-type thickness gauge as the baseline value, and then use a micropipette to absorb the freshly prepared sensitizer and apply it evenly on the inner and outer sides of the right ear of the mouse.
  • FITC fluorescein isothiocyanate
  • acetone acetone
  • DBP dibutyl phthalate
  • ⁇ ear thickness (thickness of the right ear 24 hours after stimulation) - (baseline value of the thickness of the right ear).
  • Treatment scheme for CHS model mice Divide mice into blank group, negative control group, positive control group and experimental group. Among them, the dosage of compound 001 and compound 009 in the experimental group was 3 ⁇ g/only, the positive control group was 3 ⁇ g/compound a (synthesized according to the method reported in patent WO2017210471 compound 41), and the negative control group was blank vehicle (0.5% DMSO/ PBS). One hour before the stimulation of the epidermis of the right ear, it was administered once by intraperitoneal injection.
  • Test Example 7 Determination of Metabolic Stability of Compounds of the present invention in Liver Microsomes
  • the metabolic stability of the compounds of the present invention in liver microsomes was determined by the following test method.
  • KH 2 PO 4 (Tianjin Guangfu Fine Chemical Research Institute 20180920)
  • Intrinsic clearance in vitro (unit: ⁇ L/min/mg protein) was calculated with the following formula:
  • CL int is the intrinsic clearance rate
  • k is the elimination rate constant
  • volume of incubation is the incubation volume ( ⁇ L)
  • amount of proteins is the protein amount (mg)
  • the corresponding liver microsome stability of the compound of the present invention is shown in Table 2.
  • membrane permeability and transport properties of the compounds of the present invention were determined using the following test methods.
  • HEPES Solarbio 804D049
  • penicillin/streptomycin Solarbio 20200109
  • PBS PBS
  • Fetal bovine serum (FBS) (Sigma WXBD0055V), fluorescent yellow (Sigma MKCJ3738) and NaHCO 3 (Sigma SLBZ4647)
  • HBSS Hank’s balanced salt solution
  • NEAA non-essential amino acids
  • Trpsin/EDTA Trypsin/EDTA
  • Cell culture medium was added to resuspend the cells to adjust the cell suspension to a density of 6.86 ⁇ 10 5 cells/mL.
  • TEER value measured TEER value ( ⁇ ) ⁇ membrane area (cm 2 )
  • the resistance of the monolayer cell membrane is less than 230 ⁇ cm 2 , indicating that the monolayer cell membrane is poorly compacted and cannot be used for the test.
  • Fluorescence value was measured after the transfer experiment, and a 10 mM lucifer yellow stock solution was prepared with water, and then diluted to 100 ⁇ M with a transfer buffer solution.
  • I acceptor (I receiving end ) refers to the fluorescence density of the receiving side (0.3mL)
  • I donor (I donor ) refers to the fluorescence density of the administration side (0.1mL).
  • LY > 1.0% indicates poor monolayer membrane compactness and corresponding results will be excluded from the evaluation.
  • V A is the volume of the receiving end solution (A ⁇ B is 0.3mL, B ⁇ A is 0.1mL), Area (membrane area) is the membrane area of Transwell-96 well plate (0.143cm 2 ); incubation time is the incubation time (unit : s); [drug] acceptor ([drug] receiving end ) is the drug concentration at the receiving end; [drug] initial donor ([drug] initial, donor ) is the initial drug concentration at the administration side.
  • P app(BA) is the apparent permeability coefficient from the base to the top
  • P app(AB) is the apparent permeability from the top to the base.
  • Test example 9 the determination of the plasma protein binding rate of the compound of the present invention
  • the protein binding rate of the compound of the present invention in plasma of 5 species was determined by the following test method.
  • BioIVT Human plasma
  • monkey plasma ADME-plasma-pooled monkey-05212020
  • beagle dog plasma BioIVT
  • SD rat plasma BioIVT
  • CD-1 mouse plasma BioIVT
  • Concentration is the preparation of the buffer solution of 100mM sodium phosphate and 150mM NaCl: prepare the alkaline solution that concentration is 14.2g/L Na HPO 4 and 8.77g /L NaCl with ultrapure water, prepare concentration with ultrapure water 12.0g/L NaH 2 PO 4 and 8.77g/L NaCl acidic solution, then titrate the alkaline solution with acidic solution to pH 7.4 to prepare a buffer solution with a concentration of 100mM sodium phosphate and 150mM NaCl.
  • Preparation of the dialysis membrane Soak the dialysis membrane in ultrapure water for 60 minutes to separate the membrane into two pieces, then soak in 20% ethanol for 20 minutes, and finally soak in dialysis buffer for 20 minutes.
  • Plasma preparation Thaw the frozen plasma quickly at room temperature, then centrifuge at 4°C, 3,220g for 10 minutes to remove clots, and collect the supernatant into a new centrifuge tube. The pH of the plasma was measured and recorded, using plasma with a pH of 7-8.
  • Equilibrium dialysis step assemble the dialysis device according to the operating instructions. 120 ⁇ L of plasma samples containing 1 ⁇ M compound were added to one side of the dialysis membrane, and an equal volume of dialysate (phosphate buffered saline) was added to the other side. The experiment has two samples. The dialysis plate was sealed, placed in an incubation device, and incubated at 37° C., 5% CO 2 and about 100 rpm for 6 hours. After incubation, remove the sealant and pipette 50 ⁇ L of samples from the buffer side and plasma side of each well into different wells of a new plate.
  • dialysate phosphate buffered saline
  • the peak areas of the compounds on the buffer side and the plasma side were determined.
  • the formula for calculating the plasma protein binding rate of a compound is as follows:
  • % free rate (the ratio of the compound peak area to the internal standard peak area on the buffer side /the ratio of the compound peak area to the internal standard peak area on the plasma side ) ⁇ 100%
  • Test example 10 the inhibitory effect of the compound of the present invention on CYP2C9, CYP2D6 enzyme activity
  • the inhibition of CYP2C9 and CYP2D6 enzyme activity by the compound of the present invention is determined by the following test method.
  • the reduction of metabolite production in the drug-dosed group compared with the control group was compared by the ratio of the peak area of the sample to the internal standard, and the IC 50 value was calculated with Excel XLfit 5.3.1.3.
  • Remaining activity percentage ratio of metabolite peak area to internal standard peak area test substance /metabolite peak area to internal standard peak area ratio blank solvent ⁇ 100%.
  • Drug-drug interaction refers to the physical or chemical changes produced by two or more drugs, and the changes in drug efficacy caused by these changes. Understanding drug interactions can provide patients with better pharmaceutical services, promote rational drug use, and maximize the avoidance of adverse reactions. Drug interactions are mainly metabolic interactions, which are mainly related to CYP450 enzymes involved in drug metabolism. The experimental results in Table 5 show that the compound of the present invention has weak inhibitory ability to CYP450, indicating that the compound of the present invention has a low potential risk of DDI.
  • the inhibition of hERG activity by the compounds of the present invention was determined by the following test method.
  • HEK293 cell line stably expressing hERG ion channel (product number: K1236) was purchased from Invitrogen.
  • the cell line was cultured in 85% DMEM, 10% dialyzed fetal bovine serum, 0.1mM non-essential amino acid solution, 100U/mL penicillin-streptomycin solution, 25mM HEPES, 5 ⁇ g/mL blasticidin and 400 ⁇ g/mL genetic in the culture medium of mycomycin.
  • trypsin is used for digestion and passage, and the passage is carried out three times a week.
  • the cells were cultured in a 6 cm dish at a density of 5 ⁇ 10 5 , induced by adding 1 ⁇ g/mL doxycycline for 48 hours, and then the cells were digested and seeded on glass slides for subsequent manual patch clamp experiments.
  • Extracellular fluid in mM: 132 sodium chloride, 4 potassium chloride, 3 calcium chloride, 0.5 magnesium chloride, 11.1 glucose and 10 HEPES (adjust pH to 7.35 with sodium hydroxide).
  • Intracellular fluid 140 potassium chloride, 2 magnesium chloride, 10 EGTA, 5 ATP-magnesium salt and 10 HEPES (adjust pH to 7.35 with potassium hydroxide).
  • the osmotic pressure of the solution is controlled between 280 and 300mOsmol/kg.
  • the solution needs to be filtered and stored at 4°C before use.
  • ATP-magnesium salt was prepared into 100mM stock solution first, and stored in -20°C refrigerator in aliquots. On the day of the experiment, take a certain amount and add it to the intracellular fluid, and prepare it for immediate use.
  • the hERG current test method is as follows: apply a depolarization command voltage for 4.8 seconds to depolarize the membrane potential from -80mV to +30mV, and then apply a repolarization voltage for 5.2 seconds to reduce the membrane potential to -50mV to remove channel loss. live, so that the hERG tail current can be observed.
  • the peak value of the tail current is the magnitude of the hERG current.
  • the hERG current used to detect the test compound was continuously recorded for 120 seconds before administration to evaluate the stability of the hERG current produced by the test cells. Only stable cells within the acceptance range of the evaluation criteria can enter the subsequent compound detection.
  • the hERG current measured in the extracellular fluid containing 0.1% DMSO was used as the detection baseline. After the hERG current remained stable for at least 5 minutes, the solutions containing the compound to be tested were perfused sequentially around the cells from low to high concentrations. Wait about 5 minutes after each perfusion to allow the compound to fully act on the cells and simultaneously record the hERG current. After the recorded current tends to be stable, record the last 5 hERG current values, and take the average value as the final current value at a specific concentration. After testing the compound, add 150nM dofferin to the same cell to completely inhibit the current, which is used as the positive control of the cell. At the same time, the positive compound Duofilide was detected synchronously with the same patch clamp system before and after the end of the test compound experiment to ensure the reliability and sensitivity of the entire detection system.
  • the data is output by PatchMaster software and analyzed according to the following steps:.

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Abstract

一种式(I)所示化合物或其药学上可接受的盐、药物组合物及其制备方法，以及其在治疗肿瘤、炎性疾病或自身免疫性疾病中的用途。

Description

甾体类化合物、其药物组合物及其应用
本发明要求2021年6月24日向中国国家知识产权局提交的，专利申请号为202110706921.X，发明名称为“甾体类化合物及其应用”、2022年1月27日向中国国家知识产权局提交的，专利申请号为202210101639.3，发明名称为“甾体类化合物及其应用”以及2022年4月1日向中国国家知识产权局提交的，专利申请号为202210340109.4，发明名称为“甾体类化合物及其应用”的中国专利申请的优先权。上述在先申请的全文通过援引整体并入本文中。
技术领域
本发明涉及一种新颖的糖皮质激素受体激动剂、其制备方法、含有该化合物的药物组合物、以及其在治疗肿瘤、炎性疾病或自身免疫性疾病中的用途。
背景技术
糖皮质激素受体(GR)是核受体家族的一部分。GR几乎在人体的每个细胞中表达，并调节控制发育、新陈代谢和免疫反应的基因。当糖皮质激素受体与糖皮质激素结合时，其主要作用机制是调节基因转录。包括直接途径：糖皮质激素通过细胞膜进入包浆并与包浆内的GR结合，后者活化进入细胞核，与DNA上的GR反应原件(GRE)结合，启动或者抑制响应基因的mRNA转录。如抑制TNFα、IL-1β、IL-2、IL-6等mRNA转录，启动IκB(能抑制NF-κB的活化)的mRNA转录。间接途径：与其他转录因子等的相互作用，发挥抗炎和免疫作用。
糖皮质激素受体激动剂按照来源可以分为内源性或者人工合成的两类。合成的糖皮质激素受体激动剂是一类强效的用于治疗炎性疾病和免疫疾病的小分子药物。已经推向市场的糖皮质激素包括：泼尼松、泼尼松龙、倍它米松、地塞米松、丙酸氟替卡松、布地奈德等。糖皮质激素受体激动剂可以用于控制炎症和过敏性疾病如哮喘、类风湿性关节炎、阻赛性气道疾病、鼻炎、炎肠性疾病、牛皮癣、银屑病和湿疹等。但是长期超生理剂量的服用，可出现肌肉萎缩、骨质疏松等副作用，限制了可用于患者的药物剂量和持续用药时间，其治疗潜力尚未有效挖掘。因此还需要开发出新的糖皮质激素受体激动剂，扩大疾病的治疗范围和减少毒副作用。
发明内容
本发明提供一种式(I)所示化合物或其药学上可接受的盐：
Figure PCTCN2022100881-appb-000001
其中，
R 1、R 2各自独立地选自H、CH 3或卤素；
环A选自苯基、5-10元杂芳基或C 3-C 10环烷基，所述苯基、5-10元杂芳基或C 3-C 10环烷基任选被R 1a取代；
X选自O、S、C 1-C 3亚烷基-O、C 1-C 3亚烷基-S、NR 6或C(R 7)(R 8)；
R 6选自H、C 1-C 6烷基、C 3-C 6环烷基或4-7元杂环基，所述C 1-C 6烷基、C 3-C 6环烷基或4-7元杂环基任选被R b取代；
R 7、R 8各自独立地选自H、卤素、CN、OH、NH 2、C 1-C 6烷基、C 3-C 6环烷基或4-7元杂环基，或者R 7、R 8与它们连接的原子共同形成C 3-C 6环烷基或4-7元杂环基，所述OH、NH 2、C 1-C 6烷基、C 3-C 6环烷基或4-7元杂环基任选被R b取代；
环B选自C 6-C 10芳基、5-10元杂芳基、C 3-C 10环烷基或4-14元杂环基，所述C 6-C 10芳基、5-10元杂芳基、C 3-C 10环烷基或4-14元杂环基任选被R 2a取代；
R 10选自OH、SH、O(C 1-C 6烷基)、S(C 1-C 6烷基)、O-C(＝O)-(C 1-C 6烷基)或
Figure PCTCN2022100881-appb-000002
所述O(C 1-C 6烷基)、S(C 1-C 6烷基)、O-C(＝O)-(C 1-C 6烷基)任选被卤素或CN取代；
R 11、R 12各自独立地选自H或C 1-C 6烷基；
每一个R 1a、R 2a独立地选自卤素、CN、＝O、OH、NH 2、C 1-C 6烷基、C 3-C 6环烷基或4-7元杂环基，所述OH、NH 2、C 1-C 6烷基、C 3-C 6环烷基或4-7元杂环基任选被R b取代；
每一个R b独立地选自卤素、CN、＝O、OH、NH 2、C 1-C 6烷基、C 3-C 6环烷基或4-7元杂环基，所述OH、NH 2、C 1-C 6烷基、C 3-C 6环烷基或4-7元杂环基任选被R c取代；
每一个R c独立地选自卤素、CN、＝O、C 1-C 3烷基、OH、O(C 1-C 3烷基)、NH 2、NH(C 1-C 3烷基)或N(C 1-C 3烷基) 2。
在一些实施方案中，R 1、R 2各自独立地选自H或F。
在一些实施方案中，环A选自苯基或5-6元杂芳基，所述苯基或5-6元杂芳基任选被R 1a 取代。
在一些实施方案中，环A选自苯基，所述苯基任选被R 1a取代。
在一些实施方案中，R 1a选自卤素、CN、＝O、OH、NH 2或C 1-C 6烷基。
在一些实施方案中，R 1a选自NH 2。
在一些实施方案中，环A选自
Figure PCTCN2022100881-appb-000003
在一些实施方案中，环A选自
Figure PCTCN2022100881-appb-000004
在一些实施方案中，X选自O、S、C 1-C 3亚烷基-O、C 1-C 3亚烷基-S或C(R 7)(R 8)。
在一些实施方案中，R 7、R 8各自独立地选自H、卤素、CN、OH、NH 2或C 1-C 3烷基，或者R 7、R 8与它们连接的原子共同形成C 3-C 6环烷基，所述OH、NH 2、C 1-C 3烷基或C 3-C 6环烷基任选被R b取代。
在一些实施方案中，R 7、R 8各自独立地选自H、卤素或C 1-C 3烷基，或者R 7、R 8与它们连接的原子共同形成C 3-C 6环烷基。
在一些实施方案中，R 7、R 8各自独立地选自H、F或甲基，或者R 7、R 8与它们连接的原子共同形成环丙基。
在一些实施方案中，X选自O、S、CH 2O、CH 2S、CH 2、CF 2、CHCH 3或
Figure PCTCN2022100881-appb-000005
在一些实施方案中，X选自CH 2。
在一些实施方案中，R 10选自OH、SH、O(C 1-C 3烷基)、O-C(＝O)-(C 1-C 3烷基)或
Figure PCTCN2022100881-appb-000006
所述O(C 1-C 3烷基)或O-C(＝O)-(C 1-C 3烷基)任选被卤素取代。在一些实施方案中，所述O(C 1-C 3烷基)任选被卤素取代。
在一些实施方案中，R 11、R 12各自独立地选自H、甲基或乙基。
在一些实施方案中，R 10选自OH、SH、OCH 2F、O(C＝O)CH 3、
Figure PCTCN2022100881-appb-000007
Figure PCTCN2022100881-appb-000008
在一些实施方案中，R 10选自OH或
Figure PCTCN2022100881-appb-000009
在一些实施方案中，环B选自C 6-C 10芳基、5-10元杂芳基或4-14元杂环基，所述C 6-C 10芳基、5-10元杂芳基或4-14元杂环基任选被R 2a取代。
在一些实施方案中，环B选自5-10元杂芳基或4-14元杂环基，所述5-10元杂芳基或4-14元杂环基任选被R 2a取代。
在一些实施方案中，其中环A被R 1a取代和/或环B被R 2a取代。
在一些实施方案中，其中环A被R 1a取代或环B被R 2a取代。在一些实施方案中，R 2a选自卤素、CN、＝O、OH、NH 2、C 1-C 6烷基、C 3-C 6环烷基或4-7元杂环基。
在一些实施方案中，R 2a选自NH 2或＝O。
在一些实施方案中，R 2a选自NH 2。在一些实施方案中，式(I)所示化合物或其药学上可接受的盐选自式(Ia)所示化合物或其药学上可接受的盐：
Figure PCTCN2022100881-appb-000010
其中，R 1、R 2、环A、X和R 10如上文定义；
R 3选自H、OH或NHR 9，R 4、R 5与它们连接的原子共同形成C 5-C 6环烯基、5-6元杂环基或5-6元杂芳基，所述C 5-C 6环烯基、5-6元杂环基或5-6元杂芳基任选被R 4a取代；或者，R 5选自H、OH或NHR 9，R 3、R 4与它们连接的原子共同形成C 5-C 6环烯基、5-6元杂环基或5-6元杂芳基，所述C 5-C 6环烯基、5-6元杂环基或5-6元杂芳基任选被R 4a取代；
R 9选自H、C 1-C 6烷基、C 3-C 6环烷基或4-7元杂环基，所述C 1-C 6烷基、C 3-C 6环烷基或4-7元杂环基任选被R d取代；
R 13、R 14各自独立地选自H、卤素、CN、OH、NH 2、O(C 1-C 3烷基)或C 1-C 6烷基；
每一个R 4a独立地选自卤素、CN、＝O、OH、NH 2、C 1-C 6烷基、C 3-C 6环烷基或4-7元杂环基，所述OH、NH 2、C 1-C 6烷基、C 3-C 6环烷基或4-7元杂环基任选被R d取代；
每一个R d独立地选自卤素、CN、＝O、C 1-C 3烷基、OH、O(C 1-C 3烷基)、NH 2、NH(C 1-C 3烷基)或N(C 1-C 3烷基) 2。
在一些实施方案中，R 3选自H、OH或NHR 9，R 4、R 5与它们连接的原子共同形成5-6元杂环基或5-6元杂芳基，所述5-6元杂环基或5-6元杂芳基任选被R 4a取代；或者R 5选自H、OH或NHR 9，R 3、R 4与它们连接的原子共同形成5-6元杂环基或5-6元杂芳基，所述5-6元杂环基或5-6元杂芳基任选被R 4a取代。
在一些实施方案中，R 9选自H或C 1-C 6烷基。
在一些实施方案中，R 9选自H。
在一些实施方案中，R 3选自H、OH或NH 2，R 4、R 5与它们连接的原子共同形成5-6元杂环基或5-6元杂芳基，所述5-6元杂环基或5-6元杂芳基任选被R 4a取代。
在一些实施方案中，R 5选自H、OH或NH 2，R 3、R 4与它们连接的原子共同形成C 5-C 6环烯基、5-6元杂环基或5-6元杂芳基，所述C 5-C 6环烯基、5-6元杂环基或5-6元杂芳基任选被R 4a取代。
在一些实施方案中，R 5选自H、OH或NH 2，R 3、R 4与它们连接的原子共同形成5-6元杂环基或5-6元杂芳基，所述5-6元杂环基或5-6元杂芳基任选被R 4a取代。
在一些实施方案中，R 3选自H，R 4、R 5与它们连接的原子共同形成5-6元杂环基或5-6元杂芳基，所述5-6元杂环基或5-6元杂芳基任选被R 4a取代。
在一些实施方案中，R 5选自H或NH 2，R 3、R 4与它们连接的原子共同形成C 5-C 6环烯基、5-6元杂环基或5-6元杂芳基，所述C 5-C 6环烯基、5-6元杂环基或5-6元杂芳基任选被R 4a取代。
在一些实施方案中，R 5选自H或NH 2，R 3、R 4与它们连接的原子共同形成5-6元杂环基或5-6元杂芳基，所述5-6元杂环基或5-6元杂芳基任选被R 4a取代。
在一些实施方案中，R 3选自H、OH或NH 2，R 4、R 5与它们连接的原子共同形成
Figure PCTCN2022100881-appb-000011
Figure PCTCN2022100881-appb-000012
所述
Figure PCTCN2022100881-appb-000013
任选被R 4a取代。
在一些实施方案中，R 3选自H，R 4、R 5与它们连接的原子共同形成
Figure PCTCN2022100881-appb-000014
Figure PCTCN2022100881-appb-000015
所述
Figure PCTCN2022100881-appb-000016
任选被R 4a取代。
在一些实施方案中，R 5选自H、OH或NH 2，R 3、R 4与它们连接的原子共同形成
Figure PCTCN2022100881-appb-000017
Figure PCTCN2022100881-appb-000018
所述
Figure PCTCN2022100881-appb-000019
Figure PCTCN2022100881-appb-000020
任选被R 4a取代。
在一些实施方案中，R 5选自H、OH或NH 2，R 3、R 4与它们连接的原子共同形成
Figure PCTCN2022100881-appb-000021
Figure PCTCN2022100881-appb-000022
所述
Figure PCTCN2022100881-appb-000023
任选被R 4a取代。
在一些实施方案中，R 5选自H、OH或NH 2，R 3、R 4与它们连接的原子共同形成
Figure PCTCN2022100881-appb-000024
Figure PCTCN2022100881-appb-000025
所述
Figure PCTCN2022100881-appb-000026
Figure PCTCN2022100881-appb-000027
任选被R 4a取代。
在一些实施方案中，R 5选自H或NH 2，R 3、R 4与它们连接的原子共同形成
Figure PCTCN2022100881-appb-000028
Figure PCTCN2022100881-appb-000029
所述
Figure PCTCN2022100881-appb-000030
Figure PCTCN2022100881-appb-000031
任选被R 4a取代。
在一些实施方案中，R 5选自H或NH 2，R 3、R 4与它们连接的原子共同形成
Figure PCTCN2022100881-appb-000032
Figure PCTCN2022100881-appb-000033
所述
Figure PCTCN2022100881-appb-000034
Figure PCTCN2022100881-appb-000035
任选被R 4a取代。
在一些实施方案中，R 5选自H或NH 2，R 3、R 4与它们连接的原子共同形成
Figure PCTCN2022100881-appb-000036
Figure PCTCN2022100881-appb-000037
所述
Figure PCTCN2022100881-appb-000038
任选被R 4a取代。
在一些实施方案中，R 5选自H或NH 2，R 3、R 4与它们连接的原子共同形成
Figure PCTCN2022100881-appb-000039
Figure PCTCN2022100881-appb-000040
所述
Figure PCTCN2022100881-appb-000041
Figure PCTCN2022100881-appb-000042
任选被R 4a取代。
在一些实施方案中，R 4a选自卤素、CN、＝O、OH、NH 2、C 1-C 6烷基或C 3-C 6环烷基。在一些实施方案中，R 4a选自卤素、CN、＝O、OH、NH 2或C 1-C 3烷基。
在一些实施方案中，R 4a选自＝O或NH 2。
在一些实施方案中，R 3选自H，R 4、R 5与它们连接的原子共同形成
Figure PCTCN2022100881-appb-000043
Figure PCTCN2022100881-appb-000044
在一些实施方案中，R 3选自H，R 4、R 5与它们连接的原子共同形成
Figure PCTCN2022100881-appb-000045
Figure PCTCN2022100881-appb-000046
在一些实施方案中，R 5选自NH 2，R 3、R 4与它们连接的原子共同形成
Figure PCTCN2022100881-appb-000047
Figure PCTCN2022100881-appb-000048
在一些实施方案中，R 5选自NH 2，R 3、R 4与它们连接的原子共同形成
Figure PCTCN2022100881-appb-000049
在一些实施方案中，R 13、R 14各自独立地选自H或NH 2。
在一些实施方案中，R 13选自H。
在一些实施方案中，R 14选自H或NH 2。
在一些实施方案中，R 14选自H。
在一些实施方案中，
Figure PCTCN2022100881-appb-000050
选自
Figure PCTCN2022100881-appb-000051
Figure PCTCN2022100881-appb-000052
在一些实施方案中，
Figure PCTCN2022100881-appb-000053
选自
Figure PCTCN2022100881-appb-000054
Figure PCTCN2022100881-appb-000055
在一些实施方案中，
Figure PCTCN2022100881-appb-000056
选自
Figure PCTCN2022100881-appb-000057
Figure PCTCN2022100881-appb-000058
在一些实施方案中，
Figure PCTCN2022100881-appb-000059
选自
Figure PCTCN2022100881-appb-000060
Figure PCTCN2022100881-appb-000061
在一些实施方案中，
Figure PCTCN2022100881-appb-000062
选自
Figure PCTCN2022100881-appb-000063
Figure PCTCN2022100881-appb-000064
在一些实施方案中，
Figure PCTCN2022100881-appb-000065
选自
Figure PCTCN2022100881-appb-000066
Figure PCTCN2022100881-appb-000067
在不冲突的情况下，应理解上述实施方案可以任意组合，形成包括所组合的实施方案的特征的技术方案。这样的组合的技术方案在本发明的范围内。
在一些实施方案中，式(I)所示化合物或其药学上可接受的盐选自以下所示化合物或其药学上可接受的盐：
Figure PCTCN2022100881-appb-000068
Figure PCTCN2022100881-appb-000069
Figure PCTCN2022100881-appb-000070
Figure PCTCN2022100881-appb-000071
Figure PCTCN2022100881-appb-000072
另一方面，本发明提供药物组合物，其包含本发明的式(I)化合物或其药学上可接受的盐和药学上可接受的辅料。
另一方面，本发明提供治疗个体(例如哺乳动物)由糖皮质激素受体介导的疾病的方法，包括对需要该治疗的个体(例如哺乳动物，优选人类)，给予治疗有效量的式(I)化合物或其药学上可接受的盐、或其药物组合物。
另一方面，本发明提供式(Ⅰ)化合物或其药学上可接受的盐、或其药物组合物在制备用于预防或者治疗糖皮质激素受体介导的疾病的药物中的用途。
另一方面，本发明提供式(Ⅰ)化合物或其药学上可接受的盐、或其药物组合物在预防或者治疗糖皮质激素受体介导的疾病中的用途。
另一方面，本发明提供用于预防或者治疗糖皮质激素受体介导的疾病的式(Ⅰ)化合物或其药学上可接受的盐、或其药物组合物。
另一方面，本发明提供治疗个体(例如哺乳动物)肿瘤、炎性疾病或自身免疫性疾病的方法，包括对需要该治疗的个体(例如哺乳动物，优选人类)，给予治疗有效量的式(I)化合物或其药学上可接受的盐、或其药物组合物。
另一方面，本发明提供式(Ⅰ)化合物或其药学上可接受的盐、或其药物组合物在制备用于治疗肿瘤、炎性疾病或自身免疫性疾病的药物中的用途。
另一方面，本发明提供式(Ⅰ)化合物或其药学上可接受的盐、或其药物组合物在治疗肿瘤、炎性疾病或自身免疫性疾病中的用途。
另一方面，本发明提供用于治疗肿瘤、炎性疾病或自身免疫性疾病的式(Ⅰ)化合物或其药学上可接受的盐、或其药物组合物。
在一些实施方案中，糖皮质激素受体介导的疾病选自肿瘤、炎性疾病或自身免疫性疾病。
本发明的有益效果
本发明的化合物对于糖皮质激素受体具有较强的结合活性，而对于其它激素受体的结合活性较弱或无活性，本发明的化合物的这种较强的选择性有望减少作用于其它激素受体带来的副作用。本发明的化合物还具有良好的肝微粒体代谢稳定性。另外，本发明化合物发生药物相互作用(drug-druginteraction，DDI)DDI的潜在风险较小，并且本发明化合物对hERG钾离子通道无明显抑制，表明本发明的化合物因hERG钾离子通道抑制导致心脏毒性产生的风险低。
术语定义和说明
除非另有说明，本发明中所用的术语具有下列含义，本发明中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。一个特定的术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，而应该按照本领域普通的含义去理解。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。
本文中
Figure PCTCN2022100881-appb-000073
表示连接位点。
本文中消旋体或者对映体纯的化合物的图示法来自Maehr，J.Chem.Ed.1985，62:114-120。除非另有说明，用楔形键和虚楔键
Figure PCTCN2022100881-appb-000074
表示一个立体中心的绝对构型，用黑实键和虚键
Figure PCTCN2022100881-appb-000075
表示一个立体中心的相对构型(如脂环化合物的顺反构型)。
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本发明化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。互变异构体一般以平衡形式存在，尝试分离单一互变异构体时通常产生一种混合物，其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如，在很多脂族醛和酮如乙醛中，酮型占优势；而在酚中，烯醇型占优势。本发明包含化合物的所有互变异构形式。
术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体和非对映异构体。
本发明的化合物可以具有不对称原子如碳原子、硫原子、氮原子、磷原子或不对称双键，因此本发明的化合物可以存在特定的几何或立体异构体形式。特定的几何或立体异构体形式可以是顺式和反式异构体、E型和Z型几何异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，以及其外消旋混合物或其它混合物，例如对映异构体或非对映体富集的混合物，以上所有这些异构体以及它们的混合物都属于本发明化合物的定义范围之内。烷基等取代基中可存在另外的不对称碳原子、不对称硫原子、不对称氮原子或不对称磷原子，所有取代基中涉及到的这些异构体以及它们的混合物，也均包括在本发明化合物的定义范围之内。本发明的含有不对称原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来，光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。
术语“被取代”是指特定原子上的任意一个或多个氢原子被取代基取代，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。当取代基为氧代(即＝O)时，意味着两个氢原子被取代，氧代不会发生在芳香基上。
术语“任选”或“任选地”是指随后描述的事件或情况可以发生或不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，乙基“任选”被卤素取代，是指乙基可以是未被取代的(CH 2CH 3)、单取代的(CH 2CH 2F、CH 2CH 2Cl等)、多取代的(CHFCH 2F、CH 2CHF 2、CHFCH 2Cl、CH 2CHCl 2等)或完全被取代的(CF 2CF 3、CF 2CCl 3、CCl 2CCl 3等)。本领域技术人员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。
当任何变量(例如R a、R b)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。例如，如果一个基团被2个R b所取代，则每个R b都有独立的选项。
当一个连接基团的数量为0时，比如-(CH 2) 0-，表示该连接基团为键。
当其中一个变量选自化学键或不存在时，表示其连接的两个基团直接相连，比如A-L-Z中L代表键时表示该结构实际上是A-Z。
当本文中涉及到的连接基团若没有指明其连接方向，则其连接方向是任意的。例如当结构单元
Figure PCTCN2022100881-appb-000076
中的X选自“C 1-C 3亚烷基-O”时，此时X既可以按照与从左到右的方向连接环A和环B构成“环A-C 1-C 3亚烷基-O-环B”，也可以按照从右到左的方向连接环A和环B构成“环A-O-C 1-C 3亚烷基-环B”。
当一个取代基的键交叉连接到一个环上的两个原子时，这种取代基可以与这个环上的任 意原子相键合。例如，结构单元
Figure PCTCN2022100881-appb-000077
表示R 5可在苯环上的任意一个位置发生取代。
本文中的C m-C n是指具有m-n范围中的整数个碳原子。例如“C 1-C 10”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子、6个碳原子、7个碳原子、8个碳原子、9个碳原子或10个碳原子。
术语“烷基”是指通式为C nH 2n+1的烃基，该烷基可以是直链或支链的。术语“C 1-C 6烷基”可理解为表示具有1、2、3、4、5或6个碳原子的直链或支链饱和烃基。所述烷基的具体实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、新戊基、己基、2-甲基戊基等。术语“C 1-C 3烷基”可理解为表示具有1至3个碳原子的直链或支链饱和烷基。所述“C 1-C 6烷基”可以进一步包含“C 1-C 3烷基”。
术语“烷氧基”是指直链或支链醇类失去羟基上的氢原子产生的基团，可理解为“烷基氧基”或“烷基-O-”。术语“C 1-C 6烷氧基”可理解为“C 1-C 6烷基氧基”或“C 1-C 6烷基-O-”。所述“C 1-C 6烷氧基”可以进一步包含“C 1-C 3烷氧基”。
术语“环烷基”是指完全饱和的且以单环、并环、桥环或螺环等形式存在的碳环基。除非另有指示，该碳环通常为3至10元环(例如3、4、5、6、7、8、9、10元环)。术语“C 3-C 10环烷基”可理解为表示饱和的单环、并环、螺环或桥环，其具有3～10个碳原子。所述环烷基的具体实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基、环癸基，降冰片基(双环[2.2.1]庚基)、双环[2.2.2]辛基、金刚烷基、螺[4.5]癸烷基等。术语“C 3-C 10环烷基”可以包含“C 3-C 6环烷基”，术语“C 3-C 6环烷基”可理解为表示饱和的单环或双环烃环，其具有3～6个碳原子，具体实例包括但不限于环丙基、环丁基、环戊基或环己基等。
术语“环烷基氧基”可理解为“环烷基-O-”。
术语“环烯基”是指不完全饱和的具有至少一个碳-碳双键且以单环、稠环、桥环或螺环等形式存在的非芳香族碳环基。除非另有指示，该碳环通常为5至8元环。术语“C 5-C 6环烯基”是指环碳原子数为5或6的环烯基，具体实例包括但不限于环戊烯基、环戊二烯基、环己烯基、环己二烯基等。
术语“杂环基”是指完全饱和的或部分饱和的(整体上不是具有芳香性的杂芳族)单环、并环、螺环或桥环基团，其环原子中含有1-5个(例如1-3个或1-2个)杂原子或杂原子团(即含有杂原子的原子团)，所述“杂原子或杂原子团”包括但不限于氮原子(N)、氧原子(O)、硫原子(S)、磷原子(P)、硼原子(B)、-S(＝O) 2-、-S(＝O)-、-P(＝O) 2-、-P(＝O)-、-NH-、-S(＝O)(＝NH)-、 -C(＝O)NH-或-NHC(＝O)NH-等。术语“4-14元杂环基”是指环原子数目为4、5、6、7、8、9、10、11、12、13或14的杂环基，且其环原子中含有1-5个独立选自上文所述的杂原子或杂原子团。“4-14元杂环基”包括“4-10元杂环基”或“4-7元杂环基”等，其中，4元杂环基的具体实例包括但不限于氮杂环丁烷基或氧杂环丁烷基；5元杂环基的具体实例包括但不限于四氢呋喃基、二氧杂环戊烯基、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基、4,5-二氢噁唑基或2,5-二氢-1H-吡咯基；6元杂环基的具体实例包括但不限于四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、哌嗪基、三噻烷基、四氢吡啶基或4H-[1,3,4]噻二嗪基；7元杂环基的具体实例包括但不限于二氮杂环庚烷基。所述杂环基还可以是双环基，其中，5,5元双环基的具体实例包括但不限于六氢环戊并[c]吡咯-2(1H)-基；5,6元双环基的具体实例包括但不限于六氢吡咯并[1,2-a]吡嗪-2(1H)-基、5,6,7,8-四氢-[1,2,4]三唑并[4,3-a]吡嗪基或5,6,7,8-四氢咪唑并[1,5-a]吡嗪基。任选地，所述杂环基可以是上述4-7元杂环基的苯并稠合环基，具体实例包括但不限于二氢异喹啉基等。“4-10元杂环基”可以包含“5-10元杂环基”、“4-7元杂环基”、“5-6元杂环基”、“6-8元杂环基”、“4-10元杂环烷基”、“5-10元杂环烷基”、“4-7元杂环烷基”、“5-6元杂环烷基”、“6-8元杂环烷基”等范围，“4-7元杂环基”进一步可以包含“4-6元杂环基”、“5-6元杂环基”、“4-7元杂环烷基”、“4-6元杂环烷基”、“5-6元杂环烷基”等范围。本发明中尽管有些双环类杂环基部分地含有一个苯环或一个杂芳环，但所述杂环基整体上仍是无芳香性的。
术语“芳基”是指具有共轭的π电子体系的全碳单环或稠合多环的芳香环基团。术语“C 6-C 10芳基”可理解为具有6～10个碳原子的芳基。特别是具有6个碳原子的环(“C 6芳基”)，例如苯基；或者具有9个碳原子的环(“C 9芳基”)，例如茚满基或茚基；或者具有10个碳原子的环(“C 10芳基”)，例如四氢化萘基、二氢萘基或萘基。
术语“芳基氧基”可理解为“芳基-O-”。
术语“杂芳基”是指具有芳香性的单环或稠合多环体系，其中含有至少一个选自N、O、S的环原子，其余环原子为C的芳香环基。术语“5-10元杂芳基”可理解为包括这样的单环或双环芳族环系：其具有5、6、7、8、9或10个环原子，特别是5或6或9或10个环原子，且其包含1-5个，优选1-3个独立选自N、O和S的杂原子。特别地，杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基或噻二唑基等以及它们的苯并衍生物，例如苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并噁唑基、苯并异噁唑基、苯并咪唑基、苯并三唑基、吲唑基、吲哚基或异吲哚基等；或吡啶基、哒嗪基、嘧啶基、吡嗪基或三嗪基等以及它们的苯并衍生物，例如喹啉基、喹唑啉基或异喹啉基等；或吖辛因基、吲嗪基、嘌呤基等以及它们的苯并衍生物；或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基或吩噁嗪基等。 术语“5-6元杂芳基”指具有5或6个环原子的芳族环系，且其包含1-3个，优选1-2个独立选自N、O和S的杂原子。
术语“杂芳基氧基”可理解为“杂芳基-O-”。
术语“卤”或“卤素”是指氟、氯、溴或碘。
术语“羟基”是指-OH基团。
术语“氰基”是指-CN基团。
术语“巯基”是指-SH基团。
术语“氨基”是指-NH 2基团。
术语“治疗有效量”意指(i)治疗特定疾病、病况或障碍，(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状，或(iii)延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本发明化合物的用量。构成“治疗有效量”的本发明化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。
术语“预防”意为将本申请所述化合物或制剂进行给药以预防疾病或与所述疾病相关的一个或多个症状，且包括预防疾病或疾病状态在个体(例如哺乳动物)中出现，特别是当这类个体(例如哺乳动物)易患有该疾病状态，但尚未被诊断为已患有该疾病状态时。
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。
术语“药学上可接受的盐”是指药学上可接受的酸或碱的盐，包括化合物与无机酸或有机酸形成的盐，以及化合物与无机碱或有机碱形成的盐。
术语“药物组合物”是指一种或多种本发明的化合物或其盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对有机体给予本发明的化合物。
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。
术语“个体”包括哺乳动物和非哺乳动物。哺乳动物的实例包括但不限于哺乳动物纲的任何成员：人，非人的灵长类动物(例如黑猩猩和其它猿类和猴)；家畜，例如牛、马、绵羊、山羊、猪；家养动物，例如兔、狗和猫；实验室动物，包括啮齿类动物，例如大鼠、小鼠和豚鼠等。非人哺乳动物的实例包括但不限于鸟类和鱼类等。在本文提供的一个有关方法和组合物的实施方案中，所述哺乳动物为人。
词语“包括(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising可理解为开放的、非排他性的意义，即“包括但不限于”。
本申请中记载的磷酸酯类化合物(如R 10选自
Figure PCTCN2022100881-appb-000078
的化合物)为酯类前药，其经生物体内的磷酸酯酶水解后释放出具有生物活性的化合物。例如，磷酸酯类化合物
Figure PCTCN2022100881-appb-000079
经生物体内的磷酸酯酶水解后释放得到糖皮质激素受体激动剂
Figure PCTCN2022100881-appb-000080
因此，本领域技术人员可以理解或可以预期，若化合物009具备某种生物学活性(如糖皮质激素受体激动活性)，则对应的酯类化合物009-p在生物体内也具备相同或相似的生物学活性。
本发明还包括与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本发明化合物。可结合到本发明化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为 2H、 3H、 11C、 13C、 14C、 13N、 15N、 15O、 17O、 18O、 31P、 32P、 35S、 18F、 123I、 125I和 36Cl等。
某些同位素标记的本发明化合物(例如用 3H及 14C标记)可用于化合物和/或底物组织分布分析中。氚化(即 3H)和碳-14(即 14C)同位素对于由于它们易于制备和可检测性是尤其优选的。正电子发射同位素，诸如 15O、 13N、 11C和 18F可用于正电子发射断层扫描(PET)研究以测定底物占有率。通常可以通过与公开于下文的方案和/或实施例中的那些类似的下列程序，通过同位素标记试剂取代未经同位素标记的试剂来制备同位素标记的本发明化合物。
本发明的药物组合物可通过将本发明的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。
给予本发明化合物或其药学上可接受的盐或其药物组合物的典型途径包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。
本发明的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、 制粒法、乳化法、冷冻干燥法等。
在一些实施方案中，药物组合物是口服形式。对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的辅料混合，来配制该药物组合物。这些辅料能使本发明的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体辅料混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂或矫味剂等。
药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。
本文所述化合物的所有施用方法中，每天给药的剂量为0.001mg/kg到200mg/kg体重，优选为0.05mg/kg到50mg/kg体重，更优选0.1mg/kg到30mg/kg体重，以单独或分开剂量的形式。
本发明采用下述缩略词：
Figure PCTCN2022100881-appb-000081
附图说明
图1为本发明实施例1中间体1-5的COSY图。
图2为本发明测试例6中测试化合物在CHS小鼠模型上的药效试验结果图。
具体实施方式
下面通过实施例对发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种改变将是显而易见的。本发明所使用的所有试剂是市售的，无需进一步纯化即可使用。
除非另作说明，混合溶剂表示的比例是体积混合比例。
除非另作说明，否则，％是指wt％。
洗脱剂或流动相可由两种或两种以上溶剂组成的混合洗脱剂或流动相，其比值为各溶剂的体积比，如“0～10％甲醇/二氯甲烷”表示混合洗脱剂或流动相中的甲醇与二氯甲烷的体积用量比为0:100～10:100。
化合物经手工或
Figure PCTCN2022100881-appb-000082
软件命名，市售化合物采用供应商目录名称。
化合物的结构是通过核磁共振(NMR)和/或质谱(MS)来确定的。NMR位移的单位为10 -6(ppm)。NMR测定的溶剂为氘代二甲基亚砜、氘代氯仿、氘代甲醇等，内标为四甲基硅烷(TMS)；“IC 50”指半数抑制浓度，指达到最大抑制效果一半时的浓度,“EC 50”指能半数最大效应浓度，引起50％最大效应的浓度。
实施例1：(6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-((7-氨基-2,3-二氢苯并呋喃-4-基)甲基)苯基)-7-羟基-8b-(2-羟基乙酰基)-6a,8a-二甲基-6a,6b,7,8,8a,8b,11a,12,12a,12b-十氢-1H-萘并[2',1':4,5]茚并[1,2-d][1,3]二噁戊环-4(2H)-酮(化合物001)的合成
Figure PCTCN2022100881-appb-000083
合成路线和具体合成步骤：
Figure PCTCN2022100881-appb-000084
第一步：4-溴-2,3-二氢苯并呋喃-7-胺1-2的合成
按照文献报道的方法(WO2016169504A1)，将2,3-二氢苯并呋喃-7-胺(1.0g,7.40mmol)溶于二甲基甲酰胺(20mL)，加入N-溴代丁二酰亚胺(1.48g,8.33mmol)，25℃搅拌3小时。LCMS显示反应完毕，加水(20mL)稀释，使用乙酸乙酯(100mL x 2)进行萃取，有机相用饱和氯化钠水(30mL x2)溶液洗涤，有机相干燥过滤减压浓缩，粗产物经柱层析(四氢呋喃/石油醚＝1/4)分离纯化，得到4-溴-2,3-二氢苯并呋喃-7-胺1-2(1.0g)。
LC-MS:Rt:0.444min；MS m/z(ESI):213.9[M+H] +；
第二步：(4-溴-2,3-二氢苯并呋喃-7-基)氨基甲酸叔丁酯的合成
将4-溴-2,3-二氢苯并呋喃-7-胺1-2(1.0g,4.67mmol)溶于二氯甲烷(20mL)，加入二碳酸二叔丁酯(1.41g,6.46mmol)和4-二甲氨基吡啶(571mg,4.67mmol)，25℃搅拌16小时。LCMS显示反应完毕，加水(20mL)稀释，使用乙酸乙酯(100mL x 2)进行萃取，有机相用饱和氯化钠水溶液(30mL)洗涤，有机相干燥过滤减压浓缩，粗产物经柱层析(四氢呋喃/石油醚＝1/5)分离纯化，得到(4-溴-2,3-二氢苯并呋喃-7-基)氨基甲酸叔丁酯1-3(600mg,38.8％)。
LC-MS:Rt:1.756min；MS m/z(ESI):258.1[M-56+H] +；
1H NMR(400MHz,CHLOROFORM-d)δ＝7.71-7.54(m,1H),6.87(d,J＝8.6Hz,1H),6.44(s,1H),4.55(t,J＝8.8Hz,2H),3.15(t,J＝8.8Hz,2H),1.43(s,9H)。
第三步：(4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-2,3-二氢苯并呋喃-7-基)氨基甲酸叔丁酯1-4的合成
将(4-溴-2,3-二氢苯并呋喃-7-基)氨基甲酸叔丁酯1-3(450mg,1.43mmol)溶于二氧六环(10mL)，加入双联频哪醇硼酸酯(909mg,3.58mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(105mg,0.14mmol)和乙酸钾(422mg,4.30mmol)，氮气氛围下80℃搅拌16小时。LCMS显示反应完毕，反应液过滤浓缩，残留物经柱层析(四氢呋喃/石油醚＝1/6)分离纯化，得到化合物1-4(410mg,79.2％)。
LC-MS:Rt:1.937min；MS m/z(ESI):306.2[M-56+H] +。
第四步：(6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(溴甲基)苯基)-7-羟基-8b-(2-羟基乙酰基)-6a,8a-二甲基-6a,6b,7,8,8a,8b,11a,12,12a,12b-十氢-1H-萘并[2',1':4,5]茚并[1,2-d][1,3]二噁戊环-4(2H)-酮1-5的合成
将反应物16α-羟基泼尼松龙F1(1g,2.66mmol)和无水硫酸镁(1.22g,10.1mmol)溶于乙腈(20mL)中，25℃搅拌1小时，再将4-(溴甲基)苯甲醛(529mg,2.66mmol)溶于乙腈(2mL)并加入到反应液中，冷却至0℃滴加三氟甲磺酸(1.88g,12.5mmol)，25℃搅拌2小时。LCMS显示反应完毕，反应液用碳酸氢钠水溶液(20mL)淬灭，使用乙酸乙酯(100mL x 2)进行萃取，有机相用饱和氯化钠水溶液(50mL)洗涤，有机相干燥过滤减压浓缩，粗产物经柱层析(四氢呋喃/石油醚＝1/2)分离纯化，得到的粗产品经SFC[柱子:DAICEL CHIRALCEL OD(250mm*50mm,10μm)；流动相:A:0.1％氨甲醇溶液；B:CO 2,50％]分离纯化，得到中间体1-5(1.2g,80.9％)。
LC-MS:Rt:1.551min；MS m/z(ESI):557.1[M+H] +；
1H NMR(400MHz,DMSO-d6)δ＝7.45(s,3H),7.31(d,J＝10.1Hz,1H),6.16(dd,J＝1.8,10.1Hz,1H),5.93(s,1H),5.75(s,1H),5.45(s,1H),5.16-5.03(m,1H),4.94(d,J＝4.9Hz,1H),4.79(d,J＝3.0Hz,1H),4.68(s,2H),4.53(d,J＝19.5Hz,1H),4.30(s,1H),4.19(d,J＝19.4Hz,1H),2.61-2.53(m,1H),2.31-2.25(m,1H),2.17-2.07(m,1H),2.06-1.98(m,1H),1.81-1.61(m,5H),1.39(s,3H),1.10-0.99(m,2H),0.87(s,3H)。
中间体1-5的绝对构型经二维核磁验证(见图1)。
第五步：叔丁基(4-(4-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-7-羟基-8b-(2-羟基乙酰基)-6a,8a-二甲基-4-氧亚基-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氢-1H-萘并[2',1':4,5]茚并[1,2-d][1,3]二噁戊环-10-基)苯甲基)-2,3-二氢苯并呋喃-7-基)氨基甲酸酯的1-6合成
将化合物1-5(300mg,0.54mmol)溶于四氢呋喃(6mL)和水(0.6mL)，加入叔丁基(4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-2,3-二氢苯并呋喃-7-基)氨基甲酸酯(194mg,0.54 mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(78.8mg,0.11mmol)和碳酸钾(223mg,1.61mmol)，氮气氛围下80℃搅拌16小时。LCMS显示反应完毕，反应液过滤浓缩，残留物经柱层析(四氢呋喃/石油醚＝1/1)分离纯化，得到化合物1-6(300mg,54.8％)。
LC-MS:Rt:0.584min；MS m/z(ESI):712.4[M+H] +；
第六步：(6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-((7-氨基-2,3-二氢苯并呋喃-4-基)甲基)苯基)-7-羟基-8b-(2-羟基乙酰基)-6a,8a-二甲基-6a,6b,7,8,8a,8b,11a,12,12a,12b-十氢-1H-萘并[2',1':4,5]茚并[1,2-d][1,3]二噁戊环-4(2H)-酮001的合成
将1-6(280mg,0.39mmol)溶于二氯甲烷(6mL)，加入三氟乙酸(2mL)，25℃搅拌1小时。LCMS显示反应完毕，反应液浓缩，粗产品经制备-HPLC[柱子:Phenomenex luna 30*30mm*10μm；YMC AQ 100*30*10μm；流动相:A:水(HCl)；B:ACN,B％，30％-60％,15min]分离纯化，得到化合物001(10mg,19.0％)。
LC-MS:Rt:1.511min；MS m/z(ESI):612.5[M+H] +；
1H NMR(400MHz,DMSO-d 6)δ＝9.52-8.19(m,2H),7.38(d,J＝8.1Hz,2H),7.32(d,J＝10.1Hz,1H),7.20(d,J＝8.0Hz,2H),6.89(d,J＝8.0Hz,1H),6.65(d,J＝8.0Hz,1H),6.17(dd,J＝1.8,10.1Hz,1H),5.93(s,1H),5.41(s,1H),4.92(d,J＝5.0Hz,1H),4.81(br s,1H),4.60(t,J＝8.8Hz,2H),4.50(d,J＝19.4Hz,1H),4.29(br s,1H),4.18(d,J＝19.4Hz,1H),3.86(s,2H),3.16-3.08(m,2H),2.62-2.54(m,1H),2.30(m,1H),2.19-2.08(m,1H),2.07-1.97(m,1H),1.81-1.59(m,5H),1.40(s,3H),1.12-0.96(m,2H),0.87(s,3H)。
实施例2：(6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-((1H-苯并[d]咪唑-6-基)甲基)苯基)-7-羟基-8b-(2-羟基乙酰基)-6a,8a-二甲基-6a,6b,7,8,8a,8b,11a,12,12a,12b-十氢-1H-萘并[2',1':4,5]茚并[1,2-d][1,3]二噁戊环-4(2H)-酮(化合物002)的合成
Figure PCTCN2022100881-appb-000085
合成路线和具体合成步骤：
Figure PCTCN2022100881-appb-000086
第一步：6-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1H-苯并[d]咪唑-1-甲酸叔丁酯2-2的合成
将6-(4,4,5-三甲基-1,3,2-二噁硼戊环-2-基)-1H-苯并[d]咪唑(1.00g,4.10mmol)，N,N-二异丙基乙胺(1.06g,8.19mmol)，4-二甲氨基吡啶(50mg,0.41mmol)和二碳酸二叔丁酯(894mg,4.10mmol)溶于无水二氯甲烷(20mL)中，25℃反应6小时。LCMS检测反应完毕。加入水(20mL)淬灭反应，使用二氯甲烷(50mL x 2)萃取，有机相用饱和氯化钠水溶液(30mL)洗涤，有机相干燥过滤减压浓缩，粗产物经柱层析(乙酸乙酯/石油醚＝1/5)分离纯化，得到2-2(1.0g,69.5％)。
LC-MS:Rt:1.793min；MS m/z(ESI):345.3[M+H] +；
1H NMR(400MHz,DMSO-d 6)δ＝8.50–8.24(m,2H),8.00-7.75(m,2H),1.70(d,J＝3.5Hz,9H),1.36(d,J＝5.1Hz,12H)。
第二步：6-(4-甲酰基苯甲基)-1H-苯并[d]咪唑-1-甲酸叔丁酯2-3的合成
将2-2(500mg,1.45mmol)，4-(溴甲基)苯甲醛(376mg,1.89mmol)，碳酸钾(602mg,4.36mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(106mg,0.14mmol)溶于无水四氢呋喃(10mL)中，氮气氛围下80℃反应16小时。LCMS检测反应完毕。将反应液过滤浓缩，残留物经柱层析(乙酸乙酯/石油醚＝1/5)分离纯化，得到2-3(380mg,crude)。
LC-MS:Rt:1.563min和1.593；MS m/z(ESI):337.3[M+H] +；
第三步：(6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-((1H-苯并[d]咪唑-6-基)甲基)苯基)-7-羟基-8b-(2-羟基乙酰基)-6a,8a-二甲基-6a,6b,7,8,8a,8b,11a,12,12a,12b-十氢-1H-萘并[2',1':4,5]茚并[1,2-d][1,3]二噁戊环-4(2H)-酮的合成
将16α-羟基泼尼松龙F1(230mg,0.61mmol)溶于无水乙腈(1.5mL)，加入无水硫酸镁(279mg,2.32mmol)，25℃下搅拌1小时。将2-3(308mg,0.92mmol)溶于无水乙腈(1.5mL)中加入反应体系，降温至0℃滴加三氟甲磺酸(431mg,2.87mmol)，25℃搅拌2小时。LCMS检测反应完毕。加入饱和碳酸氢钠溶液(5mL)淬灭反应，用乙酸乙酯(30mL x 2)萃取，有机相用饱和氯化钠水溶液(20mL)洗涤，有机相干燥过滤减压浓缩，粗产物经Prep-HPLC[柱子:Phenomenex Luna 30*30mm*10μm；YMC AQ 100*30*10μm；流动相:A:水(含0.225％的甲酸)；B:MeCN,B％,15％-45％,20mins]，得到化合物002(35.8mg,9.75％)。
LC-MS:Rt:1.390min；MS m/z(ESI):595.5[M+H]；Chiral(手性)-HPLC:Rt:2.211min，手性纯度＝97.56％；
1H NMR(400MHz,DMSO-d 6)δ＝8.39(br s,1H),7.52(d,J＝8.3Hz,1H),7.44(s,1H),7.40-7.35(m,2H),7.33-7.26(m,3H),7.12(d,J＝8.4Hz,1H),6.16(dd,J＝1.6,10.1Hz,1H),5.93(s,1H),5.40(s,1H),5.08(br s,1H),4.92(d,J＝4.9Hz,1H),4.78(d,J＝3.0Hz,1H),4.50(br d,J＝ 16.0Hz,1H),4.28(s,1H),4.17(d,J＝19.5Hz,1H),4.05(s,2H),2.30(s,1H),2.15-1.98(m,2H),1.81-1.60(m,5H),1.39(s,3H),1.10-0.97(m,2H),0.86(s,3H)。
实施例3:(6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-((1H-吲哚-6-基)甲基)苯基)-7-羟基-8b-(2-羟基乙酰基)-6a,8a-二甲基-6a,6b,7,8,8a,8b,11a,12,12a,12b-十氢-1H-萘并[2',1':4,5]茚并[1,2-d][1,3]二噁戊环-4(2H)-酮(化合物003)的合成
Figure PCTCN2022100881-appb-000087
合成路线和具体合成步骤：
Figure PCTCN2022100881-appb-000088
将化合物1-5(500mg,0.89mmol)溶于四氢呋喃(5mL)和水(0.5mL)，加入6-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1H-吲哚3-1(262mg,1.08mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(66mg,0.09mmol)和碳酸钾(372mg,2.69mmol)，氮气氛围下80℃下搅拌16小时。LCMS显示反应完毕，用乙酸乙酯(100mL)稀释，有机相用饱和氯化钠水溶液(30mL)洗涤，有机相干燥过滤减压浓缩，粗产物经柱层析(四氢呋喃/石油醚＝1/1)分离纯化，得到的粗产品经Prep-HPLC[柱子:Phenomenex luna 30*30mm*10μm+YMC AQ 100*30*10μm；流动相:A:水(0.225％FA)；B:MeCN,B％,50％-80％,20min]分离纯化，得到化合物003(60mg 11.2％)。
LC-MS:Rt:2.098min；MS m/z(ESI):594.3[M+H] +；Chiral-HPLC:Rt:1.204min,手性纯度＝100％；
1H NMR(400MHz,DMSO-d 6)δ＝10.92(s,1H),7.41(d,J＝8.1Hz,1H),7.37(d,J＝8.0Hz,2H),7.30(d,J＝10.1Hz,1H),7.28-7.23(m,3H),7.18(s,1H),6.85(dd,J＝1.3,8.1Hz,1H),6.34(s,1H),6.16(dd,J＝1.8,10.1Hz,1H),5.93(s,1H),5.40(s,1H),5.08(t,J＝5.9Hz,1H),4.92(d,J＝5.0Hz,1H),4.78(d,J＝3.1Hz,1H),4.50(dd,J＝6.3,19.4Hz,1H),4.29(s,1H), 4.17(dd,J＝5.4,19.4Hz,1H),4.00(s,2H),2.59-2.53(m,1H),2.36-2.26(m,1H),2.18-2.06(m,1H),2.05-1.96(m,1H),1.80-1.54(m,5H),1.39(s,3H),1.11-0.97(m,2H),0.86(s,3H)。
实施例4：(6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-7-羟基-8b-(2-羟基乙酰基)-10-(4-(二氢吲哚-6-基甲基)苯基)-6a,8a-二甲基-6a,6b,7,8,8a,8b,11a,12,12a,12b-十氢-1H-萘并[2',1':4,5]茚并[1,2-d][1,3]二噁戊环-4(2H)-酮(化合物004)的合成
Figure PCTCN2022100881-appb-000089
合成路线和具体合成步骤：
Figure PCTCN2022100881-appb-000090
第一步：6-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)二氢吲哚4-2的合成
将6-溴二氢吲哚(1.0g,5.05mmol)溶于二氧六环(20mL)中，加入双联频哪醇硼酸酯(2.56g,10.1mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(369mg,504μmol)和乙酸钾(1.49g,15.2mmol)，氮气氛围下80℃反应12小时。LCMS检测反应完毕。反应液过滤浓缩，残留物经柱层析(四氢呋喃/石油醚＝1/3)分离纯化，得到6-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)二氢吲哚4-2(1.2g,96.9％)。
LC-MS:Rt:1.509min；MS m/z(ESI):246.3[M+H] +；
第二步：6-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)二氢吲哚-1-甲酸叔丁酯4-3的合成
将4-2(500mg,2.04mmol)溶于二氯甲烷(8mL)中，加入二碳酸二叔丁酯(891mg,4.08mmol)，二异丙基乙胺(528mg,4.08mmol)和4-二甲氨基吡啶(49.8mg,408μmol)，25℃搅拌6小时。LCMS显示反应完毕。加入二氯甲烷稀释(50mL)，有机相用饱和氯化钠水溶 液(15mL)洗涤，有机相干燥过滤减压浓缩，残留物经柱层析(四氢呋喃/石油醚＝1/5)分离纯化，得到4-3(260mg,36.9％)。
LC-MS:Rt:2.340min；MS m/z(ESI):290.3[M-56+H]；
第三步：6-(4-甲酰基苯甲基)二氢吲哚-1-甲酸叔丁酯4-4的合成
将6-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)二氢吲哚-1-甲酸叔丁酯(260mg,753μmol)溶于四氢呋喃(5mL)中，加入4-(溴甲基)苯甲醛(299mg,1.51mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(165mg,226μmol)和碳酸钾(520mg,3.77mmol)，氮气氛围下80℃搅拌12小时。LCMS显示反应完毕。反应液过滤浓缩，残留物经柱层析(四氢呋喃/石油醚为1/5)分离纯化，得到4-4(190mg,74.8％)。
LC-MS:Rt:1.810min；MS m/z(ESI):282.2[M-56+H] +；
第四步：(6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-7-羟基-8b-(2-羟基乙酰基)-10-(4-(二氢吲哚-6-基甲基)苯基)-6a,8a-二甲基-6a,6b,7,8,8a,8b,11a,12,12a,12b-十氢-1H-萘并[2',1':4,5]茚并[1,2-d][1,3]二噁戊环-4(2H)-酮004的合成
将16α-羟基泼尼松龙F1(165mg,438μmol)溶于乙腈(3mL)中，加入无水硫酸镁(258mg,2.15mmol)，25℃搅拌1小时，将6-(4-甲酰基苯甲基)二氢吲哚-1-甲酸叔丁酯(178mg,526μmol)溶于乙腈(1mL)后加入反应液，降温至0℃后滴加三氟甲磺酸(322mg,2.15mmol)，25℃搅拌2小时。LCMS显示反应完毕。加入饱和碳酸氢钠水溶液(10mL)淬灭反应，使用乙酸乙酯(30mL x 3)进行萃取，有机相用饱和氯化钠水溶液(20mL)洗涤，有机相干燥过滤减压浓缩，粗产物经Prep-HPLC[柱子:Phenomenex luna 30*30mm*10μm+YMC AQ 100*30*10μm；流动相:A:水(0.225％FA)；B:MeCN,B％,18％-48％,20min]分离纯化，得到化合物004(42.9mg,6.45％)。
LC-MS:Rt:1.532min；MS m/z(ESI):596.3[M+H] +；Chiral-HPLC:Rt:2.502min,手性纯度＝100％；
1H NMR(400MHz,DMSO-d 6)δ＝7.37-7.33(m,2H),7.30(d,J＝10.1Hz,1H),7.20(d,J＝8.0Hz,2H),6.88(d,J＝7.3Hz,1H),6.37(d,J＝7.4Hz,1H),6.28(s,1H),6.18-6.13(m,1H),5.95-5.91(m,1H),5.39(s,2H),5.12-5.06(m,1H),4.91(d,J＝5.0Hz,1H),4.80-4.75(m,1H),4.54-4.45(m,1H),4.32-4.25(m,1H),4.21-4.12(m,1H),3.75(s,2H),3.38-3.34(m,2H),2.84-2.77(m,2H),2.55-2.47(m 1H),2.34-2.27(m,1H),2.16-2.07(m,1H),2.06-1.97(m,1H),1.79-1.59(m,5H),1.39(s,3H),1.12-0.97(m,2H),0.89-0.82(m,3H)。
实施例5：(6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-((3,4-二氢-2H-苯并[b][1,4]噁嗪-7-基)甲基)苯基)-7-羟基-8b-(2-羟基乙酰基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十氢 -1H-萘并[2',1':4,5]茚并[1,2-d][1,3]二噁戊环-4(2H)-酮(化合物005)的合成
Figure PCTCN2022100881-appb-000091
合成路线和具体合成步骤：
Figure PCTCN2022100881-appb-000092
第一步：7-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-3,4-二氢-2H-苯并[b][1,4]噁嗪5-2的合成
将7-溴-3,4-二氢-2H-苯并[b][1,4]噁嗪(1.00g,4.67mmol)5-1溶于四氢呋喃(20mL)中，加入双联频哪醇硼酸酯(1.30g,5.14mmol)，乙酸钾(1.38g,14.0mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(341mg,467μmol)，氮气氛围下80℃反应16小时。LCMS检测反应完毕。反应液过滤浓缩，残留物经柱层析(乙酸乙酯/石油醚＝1/5)纯化，得到7-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-3,4-二氢-2H-苯并[b][1,4]噁嗪5-2(950mg,77.9％)。
LC-MS:Rt:1.454min；MS m/z(ESI):262.3[M+H] +；
第二步：4-((3,4-二氢-2H-苯并[b][1,4]噁嗪-7-基)甲基)苯(甲)醛5-3的合成
将5-2(900mg,3.45mmol)溶于四氢呋喃(20mL)中，加入4-(溴甲基)苯甲醛(1.03g,5.17mmol)，碳酸钾(1.43g,10.3mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(252mg,345μmol)，氮气氛围下80℃反应16小时。LCMS检测反应完毕。反应液过滤浓缩，残留物经柱层析(乙酸乙酯/石油醚＝1/3)纯化，得到4-((3,4-二氢-2H-苯并[b][1,4]噁嗪-7-基)甲基)苯甲醛5-3(397mg)。
LC-MS:Rt:1.202min；MS m/z(ESI):254.1[M+H] +；
第三步：(6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-((3,4-二氢-2H-苯并[b][1,4]噁嗪-7-基) 甲基)苯基)-7-羟基-8b-(2-羟基乙酰基)-6a,8a-二甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十氢-1H-萘并[2',1':4,5]茚并[1,2-d][1,3]二噁戊环-4(2H)-酮(化合物005)的合成
将16α-羟基泼尼松龙F1(350mg,929μmol)溶于乙腈(15mL)中，加入硫酸镁(425mg,3.53mmol)，25℃搅拌1小时后，将4-((3,4-二氢-2H-苯并[b][1,4]噁嗪-7-基)甲基)苯甲醛(235mg,929μmol)5-3溶于乙腈(5mL)后加入至反应体系，降温至0℃滴加三氟甲磺酸(655mg,4.37mmol)，25℃搅拌2小时。LCMS检测反应完毕。加入饱和碳酸氢钠水溶液(15mL)淬灭反应，使用乙酸乙酯(50mL x 3)进行萃取，有机相用饱和氯化钠水溶液(20mL)洗涤，有机相干燥过滤减压浓缩，粗产物经prep-HPLC[柱子:Xtimate C18 150*40mm*10μm；流动相:A:水(10mM NH 4HCO 3)；B:MeCN,B％,40％-70％,10min]分离纯化，得到化合物005(20mg,21.1％)。
LC-MS:Rt:1.874min；MS m/z(ESI):612.3[M+H] +；
1H NMR(400MHz,DMSO-d 6)δ＝7.41-7.27(m,3H),7.19(br d,J＝7.9Hz,2H),6.56-6.38(m,3H),6.16(dd,J＝1.1,10.0Hz,1H),5.93(s,1H),5.52(br s,1H),5.39(s,1H),5.05(t,J＝5.9Hz,1H),4.92(br d,J＝5.0Hz,1H),4.76(br d,J＝2.6Hz,1H),4.49(br dd,J＝6.3,19.4Hz,1H),4.29(br s,1H),4.17(br dd,J＝5.6,19.4Hz,1H),4.10-4.01(m,2H),3.70(s,2H),3.29-3.25(m,1H),3.21(br s,2H),2.37-2.25(m,1H),2.18-1.96(m,2H),1.84-1.56(m,5H),1.39(s,3H),1.14-0.97(m,2H),0.86(s,3H)。
实施例6：(2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-((3,4-二氢-2H-苯并[b][1,4]噁嗪-7-基)甲基)苯基)-2,6b-二氟-7-羟基-8b-(2-羟基乙酰基)-6a,8a-二甲基-6a,6b,7,8,8a,8b,11a,12,12a,12b-十氢-1H-萘并[2',1':4,5]茚并[1,2-d][1,3]二噁戊环-4(2H)-酮(化合物006)的合成
Figure PCTCN2022100881-appb-000093
合成路线和具体合成步骤：
Figure PCTCN2022100881-appb-000094
第一步：(6S,8S,9R,10S,11S,13S,14S,16R,17S)-6,9-二氟-11,16,17-三羟基-17-(2-羟基乙酰基)-10,13-二甲基-6,7,8,9,10,11,12,13,14,15,16,17-十二氢-3H-环戊二烯并[a]菲-3-酮6-2的合成
将化合物(2S,6aS,6bR,7S,8aS,8bS,11aR,12aS,12bS)-2,6b-二氟-7-羟基-8b-(2-羟基乙酰基)-6a,8a,10,10-四甲基-6a,6b,7,8,8a,8b,11a,12,12a,12b-十氢-1H-萘并[2',1':4,5]茚并[1,2-d][1,3]二噁戊环-4(2H)-酮6-1(1.0g,2.21mmol)溶于30％氟硼酸水溶液(20mL)中，室温搅拌48小时。LCMS检测反应完毕。加入40mL水搅拌5分钟，过滤得到的用水(10mL x 3)和乙醇(10mL x 3)依次洗涤滤渣，得到粗产品(6S,8S,9R,10S,11S,13S,14S,16R,17S))-6,9-二氟-11,16,17-三羟基-17-(2-羟基乙酰基)-10,13-二甲基-6,7,8,9,10,11,12,13,14,15,16,17-十二氢-3H-环戊二烯并[a]菲-3-酮6-2(0.7g)。
LC-MS:Rt:0.426min；MS m/z(ESI):413.1[M+H] +；
第二步：(2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-((3,4-二氢-2H-苯并[b][1,4]噁嗪-7-基)甲基)苯基)-2,6b-二氟-7-羟基-8b-(2-羟基乙酰基)-6a,8a-二甲基-6a,6b,7,8,8a,8b,11a,12,12a,12b-十氢-1H-萘并[2',1':4,5]茚并[1,2-d][1,3]二噁戊环-4(2H)-酮006的合成
将6-2(150mg,0.36mmol)溶于无水乙腈(1.5mL)中，加入硫酸镁(166mg,1.38mmol)，25℃下搅拌1小时后，将4-((3,4-二氢-2H-苯并[b][1,4]噁嗪-7-基)甲基)苯甲醛(138mg,0.55mmol)溶于无水乙腈(1.5mL)后加入至反应体系中，降温至0℃滴加三氟甲磺酸(257mg,1.71mmol)，25℃反应2小时。LCMS检测反应完毕。加入饱和碳酸氢钠水溶液(10mL)淬灭反应，使用乙酸乙酯(50mL x 2)进行萃取，有机相用饱和氯化钠水溶液(20mL)洗涤，有机相干燥过滤减压浓缩，粗产物经Prep-HPLC[柱子:Phenomenex Luna C18 100*30mm*3μm；流动相:A:水(0.225％FA)；B:MeCN,B％:40％-70％,8min]分离纯化，得到化合物006(82.7mg,34.6％)。
LC-MS:Rt:1.553min；MS m/z(ESI):648.2[M+H] +；Chiral-HPLC:Rt:3.241min,手性纯度＝100％；
1H NMR(400MHz,DMSO-d 6)δ＝7.32(d,J＝8.1Hz,2H),7.26(d,J＝10.1Hz,1H),7.20(d,J＝8.1Hz,2H),6.53-6.48(m,1H),6.47-6.43(m,2H),6.33-6.27(m,1H),6.13(s,1H),5.72-5.57 (m,1H),5.50(d,J＝3.0Hz,1H),5.43(s,1H),4.94(d,J＝4.9Hz,1H),4.51(d,J＝19.5Hz,1H),4.19-4.04(m,2H),4.07-4.03(m,2H),3.69(s,2H),3.22-3.19(m,2H),2.65-2.56(m,1H),2.28-2.07(m,2H),2.05-1.98(m,1H),1.75-1.65(m,3H),1.51-1.49(m,1H),1.50(s,3H),0.86(s,3H)。
实施例7：(6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-((4-氨基苯并[d]噁唑-7-基)甲基)苯基)-7-羟基-8b-(2-羟基乙酰基)-6a,8a-二甲基-6a,6b,7,8,8a,8b,11a,12,12a,12b-十氢-1H-萘并[2',1':4,5]茚并[1,2-d][1,3]二噁戊环-4(2H)-酮(化合物007)的合成
Figure PCTCN2022100881-appb-000095
合成路线和具体合成步骤：
Figure PCTCN2022100881-appb-000096
第一步：7-溴苯并[d]噁唑-4-胺7-2的合成
按照文献报道的方法(CN110903258)，将苯并[d]噁唑-4-胺(1.0g,7.5mmol)溶于二甲基甲酰胺(20mL)中，加入NBS(1.3g,7.1mmol)，25℃搅拌1小时。LCMS检测反应完毕。反应液加入水(20mL)稀释，使用乙酸乙酯(100mL x 2)萃取，有机相用饱和氯化钠水溶液(30mL x2)洗涤，有机相干燥过滤减压浓缩，粗产物经柱层析(四氢呋喃/石油醚＝1/2)分离纯化，得到7-溴苯并[d]噁唑-4-胺7-2(1.3g,64.5％)。
LC-MS:Rt:1.181min；MS m/z(ESI):214.9[M+H] +；
1H NMR(400MHz,DMSO-d 6)δ＝8.59(s,1H),7.24(d,J＝8.5Hz,1H),6.52(d,J＝8.6Hz,1H),5.86(s,2H)。
第二步：7-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)苯并[d]噁唑-4-胺7-3的合成
将7-溴苯并[d]噁唑-4-胺7-2(1.3g,6.1mmol)和双联频哪醇硼酸酯(3.1g,12.2mmol)溶于无水二氧六环(26mL)中，加入乙酸钾(1.8g,18.3mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(447mg,0.6mmol)，80℃氮气保护下搅拌16小时。LCMS检测反应完毕。反应液过滤浓缩，残留物经柱层析(四氢呋喃/石油醚＝1/2)纯化，得到7-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)苯并[d]噁唑-4-胺7-3(1.4g,64.3％)。
LC-MS:Rt:1.368min；MS m/z(ESI):261.2[M+H]；
第三步：(6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-((4-氨基苯并[d]噁唑-7-基)甲基)苯基)-7-羟基-8b-(2-羟基乙酰基)-6a,8a-二甲基-6a,6b,7,8,8a,8b,11a,12,12a,12b-十氢-1H-萘并[2',1':4,5]茚并[1,2-d][1,3]二噁戊环-4(2H)-酮(化合物007)的合成
将化合物7-3(112mg,0.4mmol)和化合物1-5(200mg,0.4mmol)溶于四氢呋喃(4mL)和水(0.4mL)中，加入碳酸钾(149mg,1.1mmol)和四(三苯基膦)钯(124mg,0.1mmol)，氮气氛围下80℃搅拌16小时。LCMS检测反应完毕。反应液过滤，残留物经柱层析(四氢呋喃/石油醚＝1/2)分离纯化，得到的粗产物再经制备HPLC[柱子:Phenomenex C18 75*30mm*3μm；流动相:A:水(NH 4HCO 3)；B：乙腈，B％,34％-58％,10min]分离纯化，得到化合物007(37.7mg,20.52％)。
LC-MS:Rt:1.832min；MS m/z(ESI):611.5[M+H] +；
1H NMR(400MHz,DMSO-d 6)δ＝8.45(s,1H),7.36(d,J＝8.1Hz,2H),7.31(d,J＝10.1Hz,1H),7.25(d,J＝8.1Hz,2H),6.93(d,J＝8.0Hz,1H),6.48(d,J＝8.0Hz,1H),6.17(dd,J＝1.8,10.1Hz,1H),5.94(s,1H),5.48(s,2H),5.39(s,1H),5.08(s,1H),4.92(d,J＝5.0Hz,1H),4.78(d,J＝2.9Hz,1H),4.50(dd,J＝3.0,19.3Hz,1H),4.29(s,1H),4.17(d,J＝18.4Hz,1H),4.03(s,2H),2.61-2.53(m,1H),2.37-2.29(m,1H),2.16-1.97(m,2H),1.82-1.59(m,5H),1.40(s,3H),1.13-1.00(m,2H),0.86(s,3H)。
实施例8：(6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-((7-氨基苯并[d][1,3]二噁戊环-4-基)甲基)苯基)-7-羟基-8b-(2-羟基乙酰基)-6a,8a-二甲基-6a,6b,7,8,8a,8b,11a,12,12a,12b-十氢-1H-萘并[2',1':4,5]茚并[1,2-d][1,3]二噁戊环-4(2H)-酮(化合物008)的合成
Figure PCTCN2022100881-appb-000097
合成路线和具体合成步骤：
Figure PCTCN2022100881-appb-000098
第一步：7-溴苯并[d][1,3]二噁戊环-4-胺8-2的合成
将起始物料苯并[d][1,3]二噁戊环-4-胺8-1(2.00g,14.6mmol)溶于N,N-二甲基甲酰胺(50mL)中，0℃加入N-溴代丁二酰亚胺(2.50g,13.9mmol)，0℃搅拌1小时。LCMS检测反应完毕。反应液加乙酸乙酯(200mL)稀释，用水(100mL*2)和饱和食盐水(50mL)洗涤，有机相干燥过滤浓缩，残留物经柱层析(石油醚/四氢呋喃＝2/1)纯化，得到7-溴苯并[d][1,3]二噁戊环-4-胺8-2(1.30g,94.8％)。
LC-MS:Rt:1.311min；MS m/z(ESI):218.1[M+H] +；
第二步：叔丁基(7-溴苯并[d][1,3]二噁戊环-4-基)氨基甲酸酯8-3的合成
将7-溴苯并[d][1,3]二噁戊环-4-胺8-2(1.00g,4.6mmol)和二碳酸二叔丁酯(3.0g,13.9mmol)溶于1,4-二氧六环(20mL)中，100℃搅拌16小时。LCMS检测反应完毕。反应液浓缩，残留物经柱层析(石油醚/乙酸乙酯＝6/1)纯化，得到叔丁基(7-溴苯并[d][1,3]二噁戊环-4-基)氨基甲酸酯8-3(820mg,43.5％)。
LC-MS:Rt:1.707min；MS m/z(ESI):262.1[M+H-56] +；
1H NMR(400MHz,DMSO-d 6)δ＝8.95(s,1H),6.98-6.89(m,2H),6.10(s,2H),1.44(s,9H)。
第三步：叔丁基(7-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)苯并[d][1,3]二噁戊环-4-基)氨基甲酸酯8-4的合成
将叔丁基(7-溴苯并[d][1,3]二噁戊环-4-基)氨基甲酸酯8-3(820mg,2.60mmol)和双联嚬哪醇硼酸酯(1.30g,5.20mmol)溶于1,4-二氧六环(25mL)中，加入乙酸钾(764mg,7.80mmol)，1,1’-双(二苯基膦基)二茂铁]二氯化钯(190mg,0.30mmol)，在氮气氛围下80℃搅拌16小时。LCMS检测反应完毕。反应液过滤浓缩，残留物经柱层析(石油醚/四氢呋喃＝6/1)纯化，得到叔丁基(7-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)苯并[d][1,3]二噁戊环-4-基)氨基甲酸酯8-4(1.00g,83.8％)。
LC-MS:Rt:1.782min；MS m/z(ESI):308.3[M+H-56] +；
第四步：叔丁基(7-(4-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-7-羟基-8b-(2-羟基乙酰基)-6a,8a-二甲基-4-氧亚基-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氢-1H-萘并[2',1':4,5]茚并[1,2-d][1,3]二噁戊环-10-基)苯甲基)苯并[d][1,3]二噁戊环-4-基)氨基甲酸酯8-5的合成
将叔丁基(7-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)苯并[d][1,3]二噁戊环-4-基)氨基甲酸酯8-4(489mg,1.35mmol)和(6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(溴甲基)苯基)-7-羟基-8b-(2-羟基乙酰基)-6a,8a-二甲基-6a,6b,7,8,8a,8b,11a,12,12a,12b-十氢-1H-萘并[2',1':4,5]茚并[1,2-d][1,3]二噁戊环-4(2H)-酮1-5(500mg,0.9mmol)溶于四氢呋喃(20mL)和水(2mL)混合溶剂中，加入碳酸钾(372mg,2.70mmol)和四三苯基膦钯(311mg,0.3mmol)，氮气氛围下80℃搅拌16小时。LCMS检测反应完毕。反应液加入水稀释，使用乙酸乙酯(100mL)萃取，有机相用饱和食盐水(30mL)洗涤，干燥过滤浓缩，残留物经柱层析(石油醚/四氢呋喃＝1/1)纯化，再经高效制备液相[柱子：Gemini NX C18 5μm*10*150mm；流动相:A:0.1％甲酸水溶液；B:乙腈,49％-79％,10min]分离纯化，得到中间体叔丁基(7-(4-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-7-羟基-8b-(2-羟基乙酰基)-6a,8a-二甲基-4-氧亚基-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氢-1H-萘并[2',1':4,5]茚并[1,2-d][1,3]二噁戊环-10-基)苯甲基)苯并[d][1,3]二噁戊环-4-基)氨基甲酸酯8-5(20mg,2.8％)。
LC-MS:Rt:1.742min；MS m/z(ESI):714.4[M+H] +；
第五步：(6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-((7-氨基苯并[d][1,3]二噁戊环-4-基)甲基)苯基)-7-羟基-8b-(2-羟基乙酰基)-6a,8a-二甲基-6a,6b,7,8,8a,8b,11a,12,12a,12b-十氢-1H-萘并[2',1':4,5]茚并[1,2-d][1,3]二噁戊环-4(2H)-酮(化合物008)的合成
将叔丁基(7-(4-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-7-羟基-8b-(2-羟基乙酰基)-6a,8a-二甲基-4-氧亚基-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氢-1H-萘并[2',1':4,5]茚并[1,2-d][1,3]二噁戊环-10-基)苯甲基)苯并[d][1,3]二噁戊环-4-基)氨基甲酸酯8-5(20mg,0.03mmol)溶于二氯甲烷(4mL)中，加入三氟乙酸(1mL)，25℃搅拌0.5小时。LCMS检测反应完毕。反应液浓缩，残留物经高效制备液相[柱子：Xtimate C18 100*30mm*10μm；流动相: A:0.1％氨水溶液；B:乙腈,B％,20％-70％,35min]分离纯化，得到(6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-((7-氨基苯并[d][1,3]二噁戊环-4-基)甲基)苯基)-7-羟基-8b-(2-羟基乙酰基)-6a,8a-二甲基-6a,6b,7,8,8a,8b,11a,12,12a,12b-十氢-1H-萘并[2',1':4,5]茚并[1,2-d][1,3]二噁戊环-4(2H)-酮(化合物008)(3.1mg,17.3％)。
LC-MS:Rt:1.681min；MS m/z(ESI):614.5[M+H] +；
1H NMR(400MHz,DMSO-d 6)δ＝7.36(d,J＝8.0Hz,2H),7.32(d,J＝10.1Hz,1H),7.20(d,J＝7.9Hz,2H),6.42(d,J＝8.3Hz,1H),6.22-6.15(m,2H),5.94(s,1H),5.88(s,2H),5.40(s,1H),5.11(t,J＝5.9Hz,1H),4.92(d,J＝5.0Hz,1H),4.83-4.75(m,3H),4.51(dd,J＝6.3,19.4Hz,1H),4.30(s,1H),4.18(dd,J＝5.6,19.4Hz,1H),3.73(s,2H),2.31(d,J＝2.3Hz,1H),2.15-2.00(m,2H),1.81-1.61(m,5H),1.40(s,3H),1.25(s,1H),1.13-1.01(m,2H),0.87(s,3H)。
实施例9：(6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-((7-氨基-2,3-二氢苯并呋喃-5-基)甲基)苯基)-7-羟基-8b-(2-羟基乙酰基)-6a,8a-二甲基-6a,6b,7,8,8a,8b,11a,12,12a,12b-十氢-1H-萘并[2',1':4,5]茚并[1,2-d][1,3]二噁戊环-4(2H)-酮(化合物009)的合成
Figure PCTCN2022100881-appb-000099
合成路线和具体合成步骤：
Figure PCTCN2022100881-appb-000100
第一步：叔丁基(5-溴-2,3-二氢苯并呋喃-7-基)氨基甲酸酯9-2的合成
将5-溴-2,3-二氢苯并呋喃-7-羧酸9-1(1.00g,4.11mmol)溶于甲苯(10mL)和叔丁醇(10mL)的中，室温加入
Figure PCTCN2022100881-appb-000101
分子筛(200mg)和三乙胺(1.25g,12.3mmol)，110℃搅拌半小时后，冷却至室温，滴加叠氮磷酸二苯酯(1.70g,6.17mmol)，升温至110℃搅拌10小时。LCMS 检测反应完毕。将反应液过滤，用乙酸乙酯(150mL)稀释，有机相用饱和食盐水(30mL)洗涤，干燥过滤浓缩，残留物经柱层析(0～40％乙酸乙酯/石油醚)分离纯化，得到中间体叔丁基(5-溴-2,3-二氢苯并呋喃-7-基)氨基甲酸酯9-2(1.03g,79.7％)。
LC-MS:Rt:1.065min；MS m/z(ESI):259.7[M+H-56] +；
1H NMR(400MHz,DMSO-d 6)δ＝8.59(s,1H),7.50(br s,1H),7.13-7.11(m,1H),4.61-4.50(m,2H),3.24-3.17(m,2H),1.48-1.41(m,9H)。
第二步：叔丁基(5-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-2,3-二氢苯并呋喃-7-基)氨基甲酸酯9-3的合成
将叔丁基(5-溴-2,3-二氢苯并呋喃-7-基)氨基甲酸酯9-2(600mg,1.91mmol)，双联嚬哪醇硼酸酯(533mg,2.10mmol)，醋酸钾(562mg,5.73mmol)，1,1-双(二苯基膦)二茂铁氯化钯(139mg,190μmol)溶于无水1,4-二氧六环(10mL)中，氮气氛围下80℃反应16小时。LCMS检测反应完毕。将反应液过滤浓缩，残留物经柱层析(0～10％四氢呋喃/石油醚)分离纯化，得到中间体叔丁基(5-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-2,3-二氢苯并呋喃-7-基)氨基甲酸酯9-3(990mg,71.8％)。
LC-MS:Rt:4.417min；MS m/z(ESI):306.2[M+H-56] +；
1H NMR(400MHz,CHLOROFORM-d)δ＝8.17-8.27(m,1H)7.38(s,1H)7.25-7.31(m,1H)4.59-4.66(m,2H)3.20-3.29(m,2H)1.33(s,12H)1.31(s,9H)
第三步：叔丁基(5-(4-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-7-羟基-8b-(2-羟基乙酰基)-6a,8a-二甲基-4-氧亚基-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氢-1H-萘并[2',1':4,5]茚并[1,2-d][1,3]二噁戊环-10-基)苯甲基)-2,3-二氢苯并呋喃-7-基)氨基甲酸酯9-4的合成
将(6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(溴甲基)苯基)-7-羟基-8b-(2-羟基乙酰基)-6a,8a-二甲基-6a,6b,7,8,8a,8b,11a,12,12a,12b-十氢-1H-萘并[2',1':4,5]茚并[1,2-d][1,3]二噁戊环-4(2H)-酮1-5(300mg,538μmol)，叔丁基(5-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-2,3-二氢苯并呋喃-7-基)氨基甲酸酯9-3(300mg,830μmol)，四三苯基膦钯(62.2mg,53.8μmol)和碳酸钾(148mg,1.08mmol)溶于无水四氢呋喃(5mL)和水(1mL)中，氮气氛围下80℃搅拌2小时。LCMS检测反应完毕。反应液用乙酸乙酯(50mL)萃取，有机相用饱和食盐水(10mL)洗涤，干燥过滤浓缩，残留物经柱层析(0～50％四氢呋喃/石油醚)分离纯化，得到中间体(5-(4-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-7-羟基-8b-(2-羟基乙酰基)-6a,8a-二甲基-4-氧亚基-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氢-1H-萘并[2',1':4,5]茚并[1,2-d][1,3]二噁戊环-10-基)苯甲基)-2,3-二氢苯并呋喃-7-基)氨基甲酸酯9-4(300mg,78.3％)。
LC-MS:Rt:2.156min；MS m/z(ESI):712.3[M+H] +；
第四步：(6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-((7-氨基-2,3-二氢苯并呋喃-5-基)甲基)苯基)-7-羟基-8b-(2-羟基乙酰基)-6a,8a-二甲基-6a,6b,7,8,8a,8b,11a,12,12a,12b-十氢-1H-萘并[2',1':4,5]茚并[1,2-d][1,3]二噁戊环-4(2H)-酮(化合物009)的合成
将中间体叔丁基(5-(4-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-7-羟基-8b-(2-羟基乙酰基)-6a,8a-二甲基-4-氧亚基-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氢-1H-萘并[2',1':4,5]茚并[1,2-d][1,3]二噁戊环-10-基)苯甲基)-2,3-二氢苯并呋喃-7-基)氨基甲酸酯9-4(220mg,309μmol)溶于无水二氯甲烷(4mL)中，加入三氟乙酸(1mL)，25℃搅拌40分钟。LCMS检测反应完毕。将反应液用氮气吹干，得到的残留物经高效制备液相[柱子:YMC-Pack CN 150*30mm*5μm；流动相:A,0.1％甲酸水溶液；B:乙腈,B％,40％-60％,12min]分离纯化，得到化合物(6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-((7-氨基-2,3-二氢苯并呋喃-5-基)甲基)苯基)-7-羟基-8b-(2-羟基乙酰基)-6a,8a-二甲基-6a,6b,7,8,8a,8b,11a,12,12a,12b-十氢-1H-萘并[2',1':4,5]茚并[1,2-d][1,3]二噁戊环-4(2H)-酮009(2.00mg,1.06％)。
LC-MS:Rt:2.576min；MS m/z(ESI):612.3[M+H] +；
1H NMR(400MHz,DMSO-d 6)δ＝7.33-7.38(m,2H)7.31(d,J＝10.13Hz,1H)7.19(d,J＝8.13Hz,2H)6.29(d,J＝17.26Hz,2H)6.17(dd,J＝10.13,1.88Hz,1H)5.94(s,1H)5.39(s,1H)5.08(s,1H)4.90-4.94(m,1H)4.77-4.81(m,1H)4.45-4.73(m,3H)4.42(t,J＝8.63Hz,2H)4.29(d,J＝2.88Hz,1H)4.13-4.23(m,1H)3.71(s,2H)3.04(t,J＝8.69Hz,2H)2.30(s,1H)2.09-2.17(m,1H)1.98-2.06(m,1H)1.56-1.84(m,6H)1.40(s,3H)0.97-1.11(m,2H)0.86(s,3H)。
实施例10：(2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-((7-氨基-2,3-二氢苯并呋喃-4-基)甲基)苯基)-2,6b-二氟-7-羟基-8b-(2-羟基乙酰基)-6a,8a-二甲基-6a,6b,7,8,8a,8b,11a,12,12a,12b-十氢-1H-萘并[2',1':4,5]茚并[1,2-d][1,3]二噁戊环-4(2H)-酮(化合物010)的合成
Figure PCTCN2022100881-appb-000102
合成路线和具体合成步骤：
Figure PCTCN2022100881-appb-000103
第一步：(2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(溴甲基)苯基)-2,6b-二氟-7-羟基-8b-(2-羟基乙酰基)-6a,8a-二甲基-6a,6b,7,8,8a,8b,11a,12,12a,12b-十氢-1H-萘并[2',1':4,5]茚并[1,2-d][1,3]二噁戊环-4(2H)-酮010-3的合成
将原料双羟氟轻松SM-1(1.00g,2.42mmol)溶于无水乙腈(10mL)中，加入无水硫酸镁(1.46g,12.1mmol)，25℃搅拌1小时后，0℃加入4-溴甲基苯甲醛(579mg,2.91mmol)的乙腈(2mL)溶液，再缓慢滴加三氟甲磺酸(1.82g,12.12mmol)的乙腈(2mL)溶液，0℃搅拌五分钟。LCMS检测反应完毕。用饱和碳酸氢钠水溶液(20mL)淬灭反应，用乙酸乙酯(50mL*2)萃取，有机相用饱和氯化钠水溶液(20mL)洗涤，干燥过滤浓缩，残留物经Prep-HPLC[柱子:YMC-Pack CN 150*30mm*5μm；流动相:A,0.1％甲酸水溶液；B,乙腈,B％，53％-63％,12min]分离纯化，得到中间体(2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(溴甲基)苯基)-2,6b-二氟-7-羟基-8b-(2-羟基乙酰基)-6a,8a-二甲基-6a,6b,7,8,8a,8b,11a,12,12a,12b-十氢-1H-萘并[2',1':4,5]茚并[1,2-d][1,3]二噁戊环-4(2H)-酮010-3(640mg,42％)。
LC-MS:Rt:2.845min；MS m/z(ESI):595.1[M+H] +；
1H NMR(400MHz,DMSO-d 6)δ＝7.62-7.39(m,4H),7.27(d,J＝10.3Hz,1H),6.30(dd,J＝1.8,10.0Hz,1H),6.13(s,1H),5.77-5.45(m,3H),5.01-4.95(m,1H),4.68(s,2H),4.55(br d,J＝19.3Hz,1H),4.22(br d,J＝19.3Hz,2H),2.74-2.56(m,1H),2.37-2.12(m,3H),2.09-1.95(m,1H),1.77-1.64(m,3H),1.56-1.42(m,4H),0.87(s,3H)；
19F NMR(376MHz,DMSO-d 6)δ＝-164.99(s,1F),-186.39(s,1F)。
第二步：4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-2,3-二氢苯并呋喃-7-胺010-2的合成
4-溴-2,3-二氢苯并呋喃-7-胺1-3(7.30g,34.1mmol)溶于1,4-二氧六环(150mL)，加入双联嚬哪醇硼酸酯(20.0g,78.8mmol)，1,1-双(二苯基膦)二茂铁氯化钯(2.50g,3.4mmol)和乙酸钾(10.0g,102.3mmol)，氮气氛围下80℃搅拌16小时。LCMS显示反应完毕，反应液过滤浓缩，残留物经柱层析(四氢呋喃/石油醚＝1/6)分离纯化，得到中间体4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-2,3-二氢苯并呋喃-7-胺010-2(9.50g,96.0％)。
LC-MS:Rt:1.470min；MS m/z(ESI):262.0[M+H]；
第三步：(2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-((7-氨基-2,3-二氢苯并呋喃-4-基)甲基)苯基)-2,6b-二氟-7-羟基-8b-(2-羟基乙酰基)-6a,8a-二甲基-6a,6b,7,8,8a,8b,11a,12,12a,12b-十氢-1H-萘并[2',1':4,5]茚并[1,2-d][1,3]二噁戊环-4(2H)-酮010的合成
将(2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(溴甲基)苯基)-2,6b-二氟-7-羟基-8b-(2-羟基乙酰基)-6a,8a-二甲基-6a,6b,7,8,8a,8b,11a,12,12a,12b-十氢-1H-萘并[2',1':4,5]茚并[1,2-d][1,3]二噁戊环-4(2H)-酮010-3(150mg,253μmol)溶于四氢呋喃(2mL)和水(0.5mL)中，依次加入4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-2,3-二氢苯并呋喃-7-胺(79mg,303μmol)，碳酸钾(79mg,303μmol)，四三苯基膦钯(29mg,25.3μmol)，氮气氛围下80℃反应两个小时。LCMS检测反应完全。反应液用乙酸乙酯(10mL*3)萃取，有机相用饱和氯化钠水溶液(5mL)洗涤，干燥过滤浓缩，残留物经药效制备液相[柱子:Phenomenex C18 75*30mm*3μm；流动相:A,0.1％氨水溶液；B:乙腈,B％,30％-70％,9min]分离纯化，得到化合物(2S,6aS,6bR,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-((7-氨基-2,3-二氢苯并呋喃-4-基)甲基)苯基)-2,6b-二氟-7-羟基-8b-(2-羟基乙酰基)-6a,8a-二甲基-6a,6b,7,8,8a,8b,11a,12,12a,12b-十氢-1H-萘并[2',1':4,5]茚并[1,2-d][1,3]二噁戊环-4(2H)-酮010(20.0mg)。
LC-MS:Rt:2.092min；MS m/z(ESI):648.3[M+H] +；
1H NMR(400MHz,DMSO-d 6)δ＝7.33(d,J＝8.0Hz,2H),7.27(d,J＝9.8Hz,1H),7.18(d,J＝8.0Hz,2H),6.42-6.37(m,2H),6.30(dd,J＝1.8,10.3Hz,1H),6.13(s,1H),5.75-5.56(m,1H),5.52(d,J＝2.8Hz,1H),5.45(s,1H),5.11(t,J＝6.0Hz,1H),4.95(d,J＝4.8Hz,1H),4.56-4.38(m,5H),4.25-4.15(m,2H),3.73(s,2H),2.97(t,J＝8.7Hz,2H),2.44(br s,1H),2.32-2.19(m,2H),2.10-2.00(m,1H),1.78-1.64(m,3H),1.50(s,4H),0.86(s,3H)；
19F NMR(376MHz,DMSO-d 6)δ＝-164.96(s,1F),-186.39(s,1F)。
实施例11：(6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-((7-氨基-2,3-二氢-1H-茚-4-基)甲基)苯基)-7-羟基-8b-(2-羟基乙酰基)-6a,8a-二甲基-6a,6b,7,8,8a,8b,11a,12,12a,12b-十氢-1H-萘并[2',1':4,5]茚并[1,2-d][1,3]二噁戊环-4(2H)-酮(化合物011)的合成
Figure PCTCN2022100881-appb-000104
合成路线和具体合成步骤：
Figure PCTCN2022100881-appb-000105
第一步：7-溴-2,3-二氢-1H-茚-4-胺11-2的合成
将2,3-二氢-1H-茚-4-胺(2.00g,15.0mmol)溶于N,N-二甲基甲酰胺(20mL)中，0℃下加入N-溴代丁二酰亚胺(NBS)(2.67g,15.0mmol)，0℃搅拌1小时。LCMS检测反应完毕。0℃加入饱和碳酸氢钠溶液(50mL)进行淬火，用乙酸乙酯(100mL*2)萃取，有机相用水(50mL*3)和饱和食盐水(50mL)洗涤，干燥过滤浓缩，得到的残留物经柱层析(0～15％乙酸乙酯/石油醚)分离纯化，得到7-溴-2,3-二氢-1H-茚-4-胺11-2(1.70g,53.4％)。
LC-MS:Rt:0.800min；MS m/z(ESI):213.8[M+H] +；
第二步：7-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-2,3-二氢-1H-茚-4-胺11-3的合成
将7-溴-2,3-二氢-1H-茚-4-胺11-2(100mg,471μmol)和双联嚬哪醇硼酸酯(239mg,943μmol)溶于1,4-二氧六环(5mL)中，加入1,1-双(二苯基膦)二茂铁氯化钯(34.5mg,47.2μmol)和醋酸钾(92.5mg,943μmol)，氮气氛围下80℃搅拌12小时。LCMS检测反应完毕。将反应液过滤浓缩，得到的残留物经柱层析(0～60％乙酸乙酯/石油醚)分离纯化，得到中间体7-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-2,3-二氢-1H-茚-4-胺11-3(77.0mg,63.0％)。
LC-MS:Rt:0.914min；MS m/z(ESI):260.3[M+H] +；
第三步：(6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-((7-氨基-2,3-二氢-1H-茚-4-基)甲基)苯基)-7-羟基-8b-(2-羟基乙酰基)-6a,8a-二甲基-6a,6b,7,8,8a,8b,11a,12,12a,12b-十氢-1H-萘并[2',1':4,5]茚并[1,2-d][1,3]二噁戊环-4(2H)-酮011的合成
将7-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-2,3-二氢-1H-茚-4-胺11-3(77mg,295.98μmol)和(6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-(溴甲基)苯基)-7-羟基-8b-(2-羟基乙酰基)-6a,8a-二甲基-6a,6b,7,8,8a,8b,11a,12,12a,12b-十氢-1H-萘并[2',1':4,5]茚并[1,2-d][1,3]二噁戊 环-4(2H)-酮1-5(110mg,197μmol)溶于四氢呋喃(5mL)和水(1mL)中，加入1,1-双(二苯基膦)二茂铁氯化钯(14.4mg,19.7μmol)和碳酸钾(54.5mg,394μmol)，氮气氛围下80℃搅拌反应2小时。LCMS检测反应完毕。加水(20mL)稀释，然后用乙酸乙酯(50mL*2)萃取，有机相用饱和食盐水(20mL)洗涤，干燥过滤浓缩，得到的残留物经高效制备液相[柱子：Boston Prime C18 150*30mm*5μm；流动相:A,0.1％甲酸水溶液；B,ACN,29％-49％,12min)分离纯化，得到(6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-((7-氨基-2,3-二氢-1H-茚-4-基)甲基)苯基)-7-羟基-8b-(2-羟基乙酰基)-6a,8a-二甲基-6a,6b,7,8,8a,8b,11a,12,12a,12b-十氢-1H-萘并[2',1':4,5]茚并[1,2-d][1,3]二噁戊环-4(2H)-酮(55.0mg,45.7％)。
LC-MS:Rt:0.856min；MS m/z(ESI):610.4[M+H] +；
1H NMR(400MHz,DMSO-d 6)δ＝7.37-7.28(m,3H),7.16-7.11(m,1H),7.14(d,J＝7.8Hz,1H),6.66(d,J＝7.8Hz,1H),6.33(d,J＝8.0Hz,1H),6.16(dd,J＝1.6,10.2Hz,1H),5.93(s,1H),5.39(s,1H),5.08(s,1H),4.91(d,J＝5.3Hz,1H),4.80-4.75(m,1H),4.75-4.55(m,2H),4.50(d,J＝17.8Hz,1H),4.29(s,1H),4.17(d,J＝18.1Hz,1H),3.73(s,2H),2.66(t,J＝7.5Hz,2H),2.63-2.57(m,2H),2.57-2.53(m,1H),2.30(s,1H),2.16-1.98(m,2H),1.91(quin,J＝7.4Hz,2H),1.81-1.60(m,5H),1.40(s,3H),1.11-0.97(m,2H),0.90-0.81(m,3H)。
实施例12：(6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-((6-氨基-2,3-二氢苯并呋喃-4-基)甲基)苯基)-7-羟基-8b-(2-羟基乙酰基)-6a,8a-二甲基-6a,6b,7,8,8a,8b,11a,12,12a,12b-十氢-1H-萘并[2',1':4,5]茚并[1,2-d][1,3]二噁戊环-4(2H)-酮(化合物012)的合成
Figure PCTCN2022100881-appb-000106
以化合物12-1(CAS 1677706-25-0)为起始原料，参考实施例5和实施例9制备得到化合物012。
LC-MS:MS m/z(ESI):612.3[M+H] +。
实施例13：(6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-((5-氨基苯并[d]噁唑-7-基)甲基)苯基)-7-羟基-8b-(2-羟基乙酰基)-6a,8a-二甲基-6a,6b,7,8,8a,8b,11a,12,12a,12b-十氢-1H-萘并 [2',1':4,5]茚并[1,2-d][1,3]二噁戊环-4(2H)-酮(化合物013)的合成
Figure PCTCN2022100881-appb-000107
以化合物
Figure PCTCN2022100881-appb-000108
(CAS 1267216-18-1)为起始原料，参考实施例7制备得到化合物013。
LC-MS:MS m/z(ESI):611.5[M+H] +。
实施例14：2-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-((7-氨基-2,3-二氢苯并呋喃-5-基)甲基)苯基)-7-羟基-6a,8a-二甲基-4-氧亚基-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氢-1H-萘并[2',1':4,5]茚并[1,2-d][1,3]二噁戊环-8b-基)-2-氧代乙基磷酸二氢酯(化合物009-p)的合成
Figure PCTCN2022100881-appb-000109
合成路线和具体合成步骤：
Figure PCTCN2022100881-appb-000110
第一步：叔丁基(5-(4-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-8b-(2-((二-叔丁氧基膦酰爪基)氧代)乙酰基)-7-羟基-6a,8a-二甲基-4-氧亚基-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氢-1H-萘并[2',1':4,5]茚并[1,2-d][1,3]二噁戊环-10-基)苯甲基)-2,3-二氢苯并呋喃-7-基)氨基甲酸酯(009-p-1)的合成
将中间体9-4(80.0mg,112μmol)溶于N,N-二甲基甲酰胺(4mL)中，加入N,N-二乙基亚磷酰胺二叔丁酯(336mg,1.35mmol)和四氮唑(78.7mg,1.12mmol)，室温下搅拌30分钟。TLC 监测反应完全，冷却至0℃，向反应液加入过氧化氢(580mg,5.12mmol)，恢复至室温下搅拌1小时。LCMS检测反应完毕。在0℃加入亚硫酸钠水溶液(10mL)淬灭反应，用乙酸乙酯(30mL)萃取，有机相用饱和食盐水(10mL)洗涤，干燥过滤浓缩，得到的残留物经柱层析(0～60％乙酸乙酯/石油醚)分离纯化，得到中间体009-p-1(50.0mg,49.2％)。
LC-MS:Rt:1.216min；MS m/z(ESI):904.6[M+H] +；
第二步：2-((6aR,6bS,7S,8aS,8bS,10R,11aR,12aS,12bS)-10-(4-((7-氨基-2,3-二氢苯并呋喃-5-基)甲基)苯基)-7-羟基-6a,8a-二甲基-4-氧亚基-2,4,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氢-1H-萘并[2',1':4,5]茚并[1,2-d][1,3]二噁戊环-8b-基)-2-氧代乙基磷酸二氢酯009-p的合成
将中间体009-p-1(50.0mg,55.3μmol)溶于二氯甲烷(3mL)中，加入三氟乙酸(630mg,5.53mmol)，室温下搅拌反应30分钟。LCMS检测反应完毕。将反应液用氮气吹干，得到的残留物经制备高效液相[柱子:Boston Prime C18 150*30mm*5μm；流动相:A,0.1％甲酸水溶液；B,乙腈,B％,38％-58％,12min)分离纯化，得到化合物009-p(10.0mg,26.1％)。
LC-MS:Rt:2.752min；MS m/z(ESI):692.3[M+H]；
1H NMR(400MHz,DMSO-d 6)δ＝7.37-7.24(m,3H),7.14(d,J＝6.8Hz,2H),6.27(s,2H),6.16(dd,J＝1.6,10.0Hz,1H),5.93(s,1H),5.47(s,1H),4.94-4.84(m,2H),4.66-4.56(m,1H),4.40(t,J＝8.6Hz,2H),4.28(s,1H),3.68(s,2H),3.00(t,J＝8.7Hz,2H),2.29(d,J＝2.9Hz,1H),2.16-1.94(m,3H),1.83-1.60(m,5H),1.39(s,3H),1.04-0.83(m,5H)。
实施例15：磷酸酯类化合物001-p、002-p、003-p、004-p、005-p、006-p、007-p、008-p、010-p、011-p、012-p和013-p的合成
以化合物001、002、003、004、005、006、007、008、010、011、012、013或上述化合物的N-Boc中间体(如实施例1中间体1-6)为起始原料，参考实施例14所述的磷酸化步骤，制备得到磷酸酯类化合物001-p、002-p、003-p、004-p、005-p、006-p、007-p、008-p、010-p、011-p、012-p和013-p。
除了在实施例1-15中合成的化合物之外的其它化合物通过参考实施例1-15中的合成路径和源材料合成得到。
生物学活性及相关性质测试例
以下测试例中的化合物均根据本发明上述实施例的方法制备获得。
测试例1.K562-GRE报告基因检测本发明化合物的活性
为了产生亲本K562-GRE细胞系，将K562细胞以5×10 5个细胞/孔接种到含2mL完全培养基(RPM1640、10％FBS、青霉素-链霉素)的6孔培养皿(品牌Costar，货号3516)上，在37℃、5％CO 2下培养24小时。第二天，将3μg的pNL2.2[NLucP/MMTV/Hygro-NANO](Promega) 和3μl的PLUS试剂(品牌Invitrogen，货号11514-015)稀释到150μL Opti-MEM(品牌Gibco，货号11058021)中并在室温下孵育5分钟。pNL2.2[NLucP/MMTV/Hygro-NANO]载体含有MMTV LTR(鼠乳腺肿瘤病毒长末端重复)，其响应于若干种核受体(如糖皮质激素受体和雄激素受体)的激活并驱动荧光素酶报告基因NanoLuc的转录。孵育之后，将稀释的DNA溶液与Lipofectamine LTX溶液(品牌Invitrogen，货号15338-100)(6μl Lipofectamine LTX+144μl Opti-MEM)以1:1比例混合并预孵育，并且在室温下孵育15分钟以形成DNA-Lipofectamine LTX复合物。孵育之后，将300μl的DNA-Lipofectamine复合物直接添加到细胞孔中。将K562细胞在37℃、5％CO 2下转染24小时。转染之后，将细胞用3mL的PBS洗涤，并且用含有125μg/mL潮霉素B(品牌Invitrogen，货号10687010)的完全生长培养基选择生长两周。产生“K562-GRE(pNL2.2[NLucP/MMTV/Hygro-NANO])”细胞。
将K562-GRE(pNL2.2[NLucP/MMTV/Hygro-NANO)细胞在50μl的测定培养基(RPMI 1640培养基，1％FBS，1％丙酮酸钠，1％MEM非必须氨基酸和1％青霉素-链霉素)中以每孔50000个细胞接种于96孔组织培养处理的白板(品牌Costar，货号3917)中，加入50μL(2×)用测定培养基5倍系列稀释的化合物处理细胞，每个化合物共8个浓度，化合物在体系中的终浓度为0.0000128μM-1μM。混匀后，放于37℃培养箱中培养24小时。在孵育24小时后，向细胞中加入等体积100μL的Nano-Glo荧光素酶测定系统(品牌Promega，货号N1120)，放于摇床500g反应10分钟，并用PHERAstar仪器进行读取化学发光。以抗体浓度的对数值为横坐标，对应的化学发光读值为纵坐标绘制抗体的结合曲线，四参数拟合(GraphPad Prism9)，计算EC 50值，结果见表1。
测试例2.本发明化合物与糖皮质激素受体GR的结合活性测定
使用Polarscreen Glucocorticoid Receptor Assay Kit,Red(品牌Thermo,货号A15898)试剂盒测定化合物与GR的结合活性。将待测化合物在96孔V底板(品牌Nunc，货号249944)中用DMSO进行10倍梯度稀释，最高浓度为100μM，共8个浓度。然后用试剂盒中提供的检测缓冲液Complete GR Screening buffer进一步50倍稀释化合物，并转移10μl稀释好的化合物至384微孔板(品牌Corning，货号4514)，将5μl Fluormone GS Red(4×浓度)添加到待测化合物中，然后加入5μl GR Full length的混合物(4×浓度)，实验做复孔。将384孔板室温避光孵育2个小时，用EnVision多功能酶标仪(厂家：Perkinelmer)检测荧光偏振(mP)。以化合物终浓度的log值为X轴，mP值为Y轴，将数据录入处理软件Graphpad Prism 9进行四参数拟合并计算EC 50。
测试例3.本发明化合物与雌激素受体ER的结合活性测定
使用
Figure PCTCN2022100881-appb-000111
TR-FRET ER Alpha Coactivator Assay kit(品牌Thermo,货号A15885)试剂盒测定化合物与ER的结合活性。将ER受体激动剂Estradiol(品牌Sigma，货号E8875-25)在96孔V底板中用DMSO进行10倍梯度稀释，最高浓度为100μM，共8个浓度。待测化合物用DMSO进行10倍梯度稀释，最高浓度为3000μM，共8个浓度。然后用试剂盒中提供的检测缓冲液Nuclear Receptor Buffer E(含5mM DTT)进一步50倍稀释化合物，并转移10μl稀释好的化合物加至96孔半区微孔板(品牌Corning，货号3694)，将5μl ER-LBD蛋白(4×浓度)添加到待测化合物中，然后加入5μl荧光素辅激活物肽和Tb标记的anti-GST抗体的混合物(4×浓度)，实验做复孔。将板室温孵育2个小时，用PHERAstar仪器读取荧光值(Excitation 337,Emission 520/495nm)，计算520:495比值。以化合物终浓度的log值为X轴，520/495比值为Y轴，将数据录入软件Graphpad Prism 9进行四参数拟合并计算EC 50。结果见表1，待测化合物对雌激素受体结合活性较弱。
测试例4.化合物与雄激素受体AR的结合活性测定
使用
Figure PCTCN2022100881-appb-000112
TR-FRET Androgen Receptor Coactivator Assay kit(品牌Thermo,货号A15878)试剂盒测定化合物与AR的结合活性。将AR受体激动剂dihydrotestosterone(DHT)(品牌Sigma，货号D-073)在96孔V底板中用DMSO进行10倍梯度稀释，最高浓度为100μM，共8个浓度。待测化合物用DMSO进行10倍梯度稀释，最高浓度为3000μM，共8个浓度。用试剂盒中提供的检测缓冲液Nuclear Receptor Buffer A(含5mM DTT)进一步50倍稀释化合物，并转移10μl稀释好的化合物加至96孔半区微孔板，将5μl AR-LBD蛋白(4×浓度)添加到待测化合物中，然后加入5μl荧光素辅激活物肽和Tb标记的anti-GST抗体的混合物(4×浓度)，实验做复孔。将板室温孵育2个小时，用PHERAstar仪器读取荧光值(Excitation 337,Emission 520/495nm)，计算520:495比值。以化合物终浓度的log值为X轴，520/495比值为Y轴，将数据录入处理软件Graphpad Prism 9进行四参数拟合并计算EC 50。结果表1，待测化合物对雄激素受体结合活性较弱。
测试例5.化合物与孕激素受体PR的结合活性测定
使用
Figure PCTCN2022100881-appb-000113
TR-FRET Progesterone Receptor Coactivator Assay kit(品牌Thermo,货号A15903)试剂盒测定化合物与PR的结合活性。将PR受体激动剂Progesterone(品牌Sigma，货号P0130)在96孔V底板中用DMSO进行10倍梯度稀释，最高浓度为100μM，共8个浓度。待测化合物用DMSO进行十倍梯度稀释，最高浓度为3000μM，共8个浓度，然后用试剂盒中提供的检测缓冲液Nuclear Receptor Buffer F(含5mM DTT)进一步50倍稀释化合物，并转移10μl稀释好的化合物加至96孔半区微孔板，将5μl PR-LBD蛋白(4×浓 度)添加到检测化合物中，然后加入5μl荧光素辅激活物肽和Tb标记的anti-GST抗体的混合物(4×浓度)，实验做复孔。将板室温孵育2个小时，用PHERAstar仪器读取荧光值(Excitation 337,Emission 520/495nm)，计算520:495比值。以化合物终浓度的log值为X轴，520/495比值为Y轴，将数据录入处理软件Graphpad Prism 9进行四参数拟合并计算EC 50。结果表1，待测化合物与孕激素受体有一定的结合活性。
表1体外活性汇总表
Figure PCTCN2022100881-appb-000114
N/A表示未测试。
测试结果表明，测试化合物对于GR结合活性较强，对于PR结合活性弱，不结合ER和AR，有望减少作用于其它激素受体带来的副作用。
测试例6：CHS小鼠模型药效试验
CHS小鼠模型构建：选择6-8周龄C57BL/6N雌性小鼠(北京维通利华实验动物技术有限公司)，将每只小鼠腹部的毛发用小动物电推剪剔除干净。用微量移液器吸取400μl致敏剂，将其均匀涂抹在小鼠腹部进行表皮致敏。涂抹后控制住小鼠3-5秒，并让溶剂从皮肤上尽量蒸发干净。致敏剂的具体配制方法为：称取FITC(异硫氰酸荧光素；sigma-Aldrich)粉末0.5g，用50mL丙酮(acetone；国药试剂)与50mL DBP(邻苯二甲酸二丁酯；sigma-Aldrich)等比例混合后的溶剂充分溶解，得到FITC含量为0.5％的致敏剂。致敏后第6天，先用刻度盘式测厚仪测量小鼠右耳厚度作为基线值，然后用微量移液器吸取新鲜配制的致敏剂分别均匀涂抹在小鼠右耳的内外两侧进行表皮刺激，每侧涂抹10μL。刺激后24h，用刻度盘式测厚仪再次测量小鼠右耳厚度，得到小鼠右耳厚度变化值Δ耳朵厚度＝(刺激后24h右耳厚度)-(右耳厚度基线值)。
CHS模型小鼠治疗方案：将小鼠分组为空白组、阴性对照组、阳性对照组及实验组。其 中实验组化合物001和化合物009置给药剂量为3μg/只，阳性对照组为3μg/只的化合物a(根据专利WO2017210471化合物41报道的方法合成)，阴性对照组为空白溶媒(0.5％DMSO/PBS)。在右耳表皮刺激前1h，通过腹腔注射一次性给药。
试验结果见图2。经化合物001和009给药后，与阴性对照组相比，CHS小鼠的右耳厚度有显著降低；化合物001和009的药效均优于同等剂量的阳性参照化合物a。(*表示各实验组与阴性对照组相比统计学差异的显著性，统计方法为one-way ANOVA，**表示P值<0.01，****表示P值<0.0001)。
测试例7、本发明化合物在肝微粒体中的代谢稳定性测定
本发明化合物在肝微粒体中的代谢稳定性采用如下试验方法测定。
一、试验材料及仪器
1.人肝微粒体(Corning 452117)，比格犬肝微粒体(XENOTECH D1000)，SD大鼠肝微粒体(XENOTECH R1000)和CD-1小鼠肝微粒体(XENOTECH M1000)
2.Na 2HPO 4(天津市光复精细化工研究所20180130)
3.KH 2PO 4(天津市光复精细化工研究所20180920)
4.MgCl 2(天津市光复精细化工研究所20191216)
5.NADPH(Solarbio 1216C022)
6.阳性对照化合物维拉帕米(Sigma MKBV4993V)
7.AB Sciex API4000液质联用仪
二、试验步骤
1. 100mM磷酸缓冲液(PBS)的配制：称取7.098g Na 2HPO 4，加入500mL纯水超声溶解，作为溶液A。称取3.400g KH 2PO 4，加入250mL纯水超声溶解，作为溶液B。将A溶液放置在搅拌器上缓慢加入B溶液直至pH值达到7.4即配制成100mM的PBS缓冲液。
2.反应体系的配制
按下表配制反应体系：
Figure PCTCN2022100881-appb-000115
3.将反应体系置于37℃水浴中预孵育10分钟。向反应体系中加入40μL 10mM NADPH溶液(NADPH由100mM的磷酸缓冲液溶解)，NADPH的最终浓度为1mM。用40μL磷酸缓冲液代替NADPH溶液作为阴性对照。阴性对照的作用是排除化合物自身化学稳定性的影 响。
4.在反应体系中加入4μL 100μM的本发明化合物和阳性对照化合物维拉帕米启动反应，化合物的最终浓度为1μM。
5.涡旋振荡器上充分混匀后，在0.5、15、30、45和60分钟分别取出50μL孵育样品，用200μL含有内标的冰乙腈终止反应。样品在3220g转速下离心45分钟。离心结束后转移90μL上清液到进样板，加入90μL超纯水混匀，用于LC-MS/MS分析。
所有的数据均通过Microsoft Excel软件进行计算。提取离子图谱检测峰面积，通过对化合物消除百分比的自然对数与时间进行线性拟合，测定化合物的体外半衰期(t 1/2)。
体外(in vitro)半衰期(t 1/2)通过斜率k计算：
in vitro t 1/2＝0.693/k
体外固有清除率(单位：μL/min/mg蛋白质(protein))用下列公式计算：
in vitro CL int＝k×volume of incubation(μL)/amount of proteins(mg)
CL int为固有清除率；k为消除速率常数；volume of incubation为孵育体积(μL)；amount of proteins为蛋白量(mg)
本发明化合物相应的肝微粒体稳定性具体见表2。
表2
Figure PCTCN2022100881-appb-000116
测试例8、本发明化合物的膜渗透性及转运特性测定
本发明化合物的膜渗透性及转运特性采用如下试验方法测定。
一、试验材料及仪器
1.Caco-2细胞(ATCC)
2.HEPES(Solarbio 804D049)、青霉素/链霉素(Solarbio 20200109)和PBS(Solarbio 20200620)
3.胎牛血清(FBS)(Sigma WXBD0055V)、荧光黄(Sigma MKCJ3738)和NaHCO 3(Sigma SLBZ4647)
4.Hank’s平衡盐溶液(HBSS)(Gibco 2085528)、非必需氨基酸(NEAA)(Gibco 2211548)和Trypsin/EDTA(Gibco 2120732)
5.高糖DMEM(Corning 20319014)
6.HTS Transwell-96Well Permeable(Corning,3391)
7.电阻检测仪(Millipore，
Figure PCTCN2022100881-appb-000117
ERS-2)
8.
Figure PCTCN2022100881-appb-000118
Vision(Nexcelom Bioscience)
9.Infinite 200 PRO酶标仪(Tecan，Infinite M200PRO)
10.阳性对照化合物美托洛尔(Sinopharm 100084-201403)、红霉素(MCE 84550)和西咪替丁(Sinopharm 100158-201406)
11.ABI QTrap 5500液质联用仪
二、试验步骤
1.Caco-2细胞培养
1)转运缓冲液(含25mM HEPES的HBSS，pH 7.4)的配制：精确称量5.958g HEPES和0.35g NaHCO 3，加900mL纯水让其溶解，然后加100mL 10×HBSS搅拌均匀，调pH至7.4，过滤。
2)Caco-2细胞培养基的配制：高糖DMEM(含有L-谷氨酰胺)培养基中加入FBS、青霉素/链霉素、卡那霉素和NEAA配制成含10％FBS、100单位青霉素/0.1mg/mL链霉素、0.6μg/mL卡那霉素和1×NEAA的细胞培养基。
3)在37℃、5％CO 2的培养箱中用T-75培养瓶培养细胞，细胞生长达到80-90％密度时弃去培养基。用5mL PBS冲洗细胞，加入1.5mL Trypsin/EDTA，然后在37℃培养箱中孵育5-10分钟直至细胞呈流沙状脱落，最后用含FBS的培养基中和Trypsin/EDTA。
4)细胞混悬液在120g下离心10分钟，弃去上清液。
5)加细胞培养基重悬细胞，调至密度为6.86×10 5cells/mL的细胞悬浮液。
2.Caco-2细胞接种
1)Transwell小室每孔加入50μL培养基，下层加入25mL培养基，置于37℃，5％CO 2培养箱中预热1小时。
2)预热的Transwell小室每孔加入50μL细胞悬浮液，最终接种密度为2.4×10 5cells/cm 2(个细胞/mL)。
3)培养14-18天，隔一天换一次培养基，在最初种板以后的48小时之内更换培养基。实验前一天培养基必须更换。
3.评估单层细胞膜完整性
1)细胞培养14天后融合并且分化，准备进行转运实验。
2)用电阻仪测量单层膜电阻，记录每孔电阻。
3)测量完毕后，将Transwell培养板重新孵育。
4)计算TEER值：
TEER值＝TEER测量值(Ω)×膜面积(cm 2)
单层细胞膜的电阻<230Ω·cm 2，表明单层细胞膜致密性差，不能用于试验。
4.转运实验
1)用DMSO稀释10mM的本发明化合物或阳性对照化合物的储备液得到2mM的储备液，然后用转运缓冲液稀释2mM的储备液得到10μM的本发明化合物或阳性对照化合物的工作液。
2)从培养箱中取出Caco-2细胞板，然后用预热的转运缓冲液清洗Transwell培养板两次，再置于37℃培养箱孵育30分钟。
3)为测定化合物从顶端到基底端(A→B)的转运速率，加108μL化合物的工作液到Transwell小室(顶端)，同时立即从顶端取出8μL样品至72μL转运缓冲液中，加入240μL含内标的终止液终止转运以作为初始顶端样品。同时，接收端(基底端)加入300μL转运缓冲液。试验设双样本。
4)为测定化合物从基底端到顶端(B→A)的转运速率，加308μL化合物的工作液到基底端，同时立即从基底端取出8μL样品至72μL转运缓冲液中，加入240μL含内标的终止液终止转运以作为初始基底端样品。同时，Transwell小室(顶端)加入100μL转运缓冲液。试验设双样本。
5)将细胞培养板置于37℃ CO 2培养箱中孵育2小时。
6)转运实验结束后，从给药端(即A→B方向的顶端和B→A方向的基底端)取8μL样品至72μL转运缓冲液中，然后加入240μL含内标的终止液终止转运。从接收端(即A→B方向的基底端和B→A方向的顶端)取80μL样品至240μL含内标的终止液中，1000rpm下涡旋10分钟，3220g下离心30分钟。取100μL上清液至进样板，加入100μL超纯水混匀，用于LC-MS/MS分析。
7)转运实验结束后测量荧光值，用水配制10mM荧光黄储备液，然后用转运缓冲溶液稀释至100μM。往Transwell小室(顶端)中加入100μL荧光黄溶液，基底端加入300μL转运缓冲溶液，置于37℃的CO 2培养箱中孵育30分钟。从顶端和基底端取80μL溶液至96孔板中，在激发波长为485nm及发射波长为530nm下用酶标仪测量细胞荧光值(检测膜完整性)。
用以下公式计算渗漏率(Percentage leakage(％)或LY(％))：
Percentage Leakage＝{I acceptor×0.3/(I acceptor×0.3+I donor×0.1)}×100％
I acceptor(I 接收端)指接收侧(0.3mL)的荧光密度，I donor(I 供体)指给药侧(0.1mL)的荧光密度。LY>1.0％表明单层细胞膜致密性差，相应的结果将从评估中排除。
测定化合物在给药侧和接收侧的峰面积，计算化合物的表观渗透系数(P app，单位：cm/s) 和外排比(Efflux ratio)：
P app＝{V A×[drug] acceptor/(Area×incubation time×[drug] initial donor}
V A为接收端溶液的体积(A→B是0.3mL，B→A是0.1mL)，Area(膜面积)为Transwell-96孔板膜面积(0.143cm 2)；incubation time为孵育时间(单位：s)；[drug] acceptor([药物] 接收端)为接收端药物浓度；[drug] initial donor([药物] 初始，供体)为给药侧药物初始浓度。
Figure PCTCN2022100881-appb-000119
P app(B-A)为由基底端到顶端的表观渗透系数；P app(A-B)为由顶端到基底端的表观渗透系数。
表3
化合物 P app(A-B)(10 -6cm/s) P app(B-A)(10 -6cm/s) Efflux Ratio
化合物009 0.73 3.86 5.26
测试例9、本发明化合物的血浆蛋白结合率测定
本发明化合物在5个种属(人、猴、犬、大鼠和小鼠)血浆中的蛋白结合率采用如下试验方法测定。
一、试验材料及仪器
1.人血浆(BioIVT)、猴血浆(ADME-plasma-pooled monkey-05212020)、比格犬血浆(BioIVT)、SD大鼠血浆(BioIVT)、CD-1小鼠血浆(BioIVT)
2.Na 2HPO 4(Sigma S5136-500G)
3.NaH 2PO 4(Sigma S3139-500G)
4.NaCl(Sigma S5886-IKG)
5. 96孔平衡透析板(HTDialysis LLC,Gales Ferry,CT,HTD96B)和平衡透析膜(MWCO 12-14K,1101)
6.阳性对照化合物华法林
7.ABI QTrap 5500液质联用仪
二、试验步骤
1.浓度为100mM磷酸钠盐和150mM NaCl的缓冲液的配制：用超纯水配制浓度为14.2g/L Na 2HPO 4和8.77g/L NaCl的碱性溶液，用超纯水配制浓度为12.0g/L NaH 2PO 4和8.77g/L NaCl的酸性溶液，然后用酸性溶液滴定碱性溶液至pH值为7.4配制成浓度为100mM磷酸钠盐和150mM NaCl的缓冲液。
2.透析膜的准备：将透析膜浸泡在超纯水中60分钟以便将膜分离成两片，然后用20％乙醇浸泡20分钟，最后用透析用缓冲液浸泡20分钟。
3.血浆的准备：将冷冻的血浆迅速在室温下解冻，然后在4℃、3,220g下离心10分钟去除凝块，并将上清收集到新的离心管中。测定和记录血浆的pH值，使用pH值为7-8的血浆。
4.含化合物的血浆样品的配制：用DMSO稀释10mM的本发明化合物或阳性对照化合物的储备液得到200μM的工作液。597μL人、猴、犬、大鼠或小鼠血浆中加入3μL 200μM的化合物工作液得到终浓度为1μM的血浆样品。
5.平衡透析步骤：按照操作说明将透析装置组装起来。在透析膜的一侧加入120μL含1μM化合物的血浆样品，另一侧加入等体积的透析液(磷酸盐缓冲液)。试验设双样本。透析板封膜，置于孵育装置，在37℃、5％CO 2及约100rpm转速下孵育6小时。孵育结束后，去除封膜，从每个孔的缓冲液侧和血浆侧吸取50μL样品到新板的不同孔中。在磷酸盐缓冲液样品中加入50μL空白血浆，在血浆样品中加入等体积的空白磷酸盐缓冲液，然后加入300μL含内标的乙腈沉淀蛋白。涡旋5分钟，在4℃、3220g下离心30分钟。取100μL上清液至进样板，加入100μL超纯水混匀，用于LC-MS/MS分析。
测定化合物在缓冲液侧和血浆侧的峰面积。计算化合物的血浆蛋白结合率公式如下：
％游离率＝(化合物峰面积与内标峰面积比值 缓冲液侧/化合物峰面积与内标峰面积比值 血浆侧)×100％
％结合率＝100％-％游离率
表4
化合物 人血浆蛋白结合率％ 小鼠血浆蛋白结合率％
化合物009 99.8 99.8
测试例10、本发明化合物对CYP2C9、CYP2D6酶活性的抑制作用
本发明化合物对CYP2C9、CYP2D6酶活性的抑制采用如下试验方法测定。
一、试验材料及仪器
1.人肝微粒体(Corning 452117)
2.NADPH(Solarbio 705Y021)
3.阳性底物双氯芬酸(Sigma SLBV3438)、右美沙芬(TRC 3-EDO-175-1)
4.阳性抑制剂磺胺苯吡唑(D.Ehrenstorfer GmbH 109012)、奎尼丁(TCI WEODL-RE)
5.AB Sciex Triple Quad 5500液质联用仪
二、试验步骤
1. 100mM磷酸缓冲液(PBS)的配制：称取7.098g Na 2HPO 4，加入500mL纯水超声溶解，作为溶液A。称取3.400g KH 2PO 4，加入250mL纯水超声溶解，作为溶液B。将A溶液放置在搅拌器上缓慢加入B溶液直至pH值达到7.4即配制成100mM的PBS缓冲液。
2.用100mM的PBS缓冲液配制10mM的NADPH溶液。用DMSO稀释10mM的本发明化合物储备液得到200×浓度的化合物工作液(6000、2000、600、200、60、20、0μM)。用DMSO稀释阳性抑制剂储备液得到200×浓度的阳性抑制剂工作液(磺胺苯吡唑，1000、300、100、30、10、3、0μM；奎尼丁，100、30、10、3、1、0.3、0μM)。用水、乙腈或乙腈/甲醇配制200×浓度的底物工作液(120μM双氯芬酸、400μM右美沙芬)。
3.取2μL 20mg/ml的肝微粒体溶液、1μL底物工作液、1μL化合物工作液和176μL PBS缓冲液，混合均匀，置于37℃水浴中预孵育15分钟。阳性对照组加入1μL磺胺苯吡唑或奎尼丁工作液代替化合物工作液。同时将10mM的NADPH溶液一起置于37℃水浴中预孵育15分钟。15分钟后，取20μL NADPH加入到各个孔中，启动反应，37℃下孵育5分钟(CYP2C9)、20分钟(CYP2D6)。所有孵育样品设双样本。孵育相应时间后向所有样本中加入400μL含内标的冰甲醇终止反应。涡旋混匀，3220g、4℃下离心40分钟。离心结束后转移100μL上清液到进样板，加入100μL超纯水混匀，用于LC-MS/MS分析。
通过样品与内标峰面积比值来比较加药组比对照组代谢物生成的减少，并用Excel XLfit 5.3.1.3计算IC 50值。
用下列公式计算剩余活性百分比：
剩余活性百分比＝代谢产物峰面积与内标峰面积比值 测试物/代谢产物峰面积与内标峰面积比值 空白溶剂×100％。
药物相互作用(drug-druginteraction，DDI)是指2种或2种以上的药物所产生的物理或者化学变化，以及由于这些变化所造成的药效改变。了解药物相互作用，可为患者提供更好的药学服务及促进合理用药，最大化地避免不良反应的发生。药物的相互作用以代谢性相互作用为主，代谢性相互作用主要与参与药物代谢的CYP450酶有关。表5的实验结果表明，本发明化合物对CYP450的抑制能力弱，预示本发明化合物发生DDI的潜在风险较小。
表5
Figure PCTCN2022100881-appb-000120
测试例11、本发明化合物的hERG抑制活性测定
本发明化合物对hERG活性的抑制采用如下试验方法测定。
一、试验材料及仪器
1.透析胎牛血清 上海博晗生物科技有限公司(BS-0005-500)
2.DMEM培养基 赛默飞世尔科技(中国)有限公司(10569)
3.HEPES 赛默飞世尔科技(中国)有限公司(15630080)
4.胰蛋白酶 赛默飞世尔科技(中国)有限公司(2192509)
5.青霉素-链霉素溶液 赛默飞世尔科技(中国)有限公司(15140-122)
6.MEM非必需氨基酸溶液 赛默飞世尔科技(中国)有限公司(11140)
7.遗传霉素(G418) 赛默飞世尔科技(中国)有限公司(11811031)
8.杀稻瘟菌素 赛默飞世尔科技(中国)有限公司(R21001)
9.多聚赖氨酸 赛默飞世尔科技(中国)有限公司(P4832)
10.多菲莱德 北京伊普瑞斯技术开发有限公司(D525700)
11.强力霉素 西格玛奥德里奇(上海)贸易有限公(D9891)
12.二氧化碳培养箱 赛默飞世尔科技(中国)有限公司(371)
13.拉制仪 美国Sutter公司(P-97)
14.微操纵器 美国Siskiyou公司(MC1000e)
15.微操纵器 美国Sutter公司(ROE-200；MP285)
16.放大器 德国HEKA公司(EPC10)
17.显微镜 奥林巴斯中国有限公司(IX51/71/73)
18.灌流系统 美国ALA公司(VM8型重力给药系统)
二、细胞系与细胞培养
稳定表达hERG离子通道的HEK293细胞株(货号：K1236)购自Invitrogen公司。该细胞株培养于含85％DMEM、10％透析胎牛血清、0.1mM非必需氨基酸溶液、100U/mL青霉素-链霉素溶液、25mM HEPES、5μg/mL杀稻瘟菌素和400μg/mL遗传霉素的培养基中。待细胞密度增长至培养皿底面积的40％～80％时，采用胰蛋白酶进行消化传代，每周传代三次。在实验前，细胞按照5×10 5的密度培养在6cm培养皿中，加入1μg/mL强力霉素诱导48小时，然后将细胞消化并接种在玻片上以备后续的手动膜片钳的实验。
三、溶液配制
1)细胞外液(以mM为单位)：132氯化钠，4氯化钾，3氯化钙，0.5氯化镁，11.1葡萄糖和10HEPES(用氢氧化钠调节pH至7.35)。
2)细胞内液(以mM为单位)：140氯化钾，2氯化镁，10 EGTA，5 ATP-镁盐和10 HEPES(用氢氧化钾调节pH至7.35)。
注：溶液渗透压控制在280～300mOsmol/kg之间。溶液在使用前需要过滤并放在4℃保存。ATP-镁盐先配成100mM储备液，分装保存于-20℃冰箱。在实验当天，取一定量加入到细胞内液中，现配现用。
四、实验步骤
1)将培养皿中载有HEK293细胞的小玻片放置于显微操作台的灌流槽中。
2)在Olympus IX51，IX71或IX73倒置显微镜下将合适的细胞调置于视野中央，使用×10倍物镜找到玻璃电极的尖端，并置于视野的中央。然后使用微操纵器下移电极，同时调整粗准焦螺旋，使电极慢慢接近细胞。
3)当快接近细胞时，转换为×40倍物镜进行观察，通过微操纵器微调档，使电极逐渐接近细胞的表面。
4)给予负压，使电极尖与细胞膜之间形成电阻高于1GΩ的封接。
5)在电压钳模式下对瞬时电容电流Cfast进行补偿。然后重复给予短促的负压进行破膜，最终形成全细胞记录模式。
6)在膜电位钳制于-60mV的条件下，对缓慢电容电流Cslow、细胞膜电容(Cm)和输入膜电阻(Ra)分别进行补偿。
7)细胞稳定后，将钳制电压改为-90mV，采样频率设置为20kHz，过滤频率为10kHz。漏电流的检测条件为钳制电压转为-80mV，时程500ms。
8)hERG电流测试方法如下：施加4.8秒去极化命令电压将膜电位从-80mV去极化至+30mV，然后瞬间施加5.2秒的复极化电压使膜电位降至-50mV以去除通道失活，从而得以观察到hERG尾电流。尾电流的峰值为hERG电流的大小。
9)用于检测待测化合物的hERG电流在给药前均被持续记录120秒以评估受试细胞产生hERG电流的稳定性。只有在评价标准接受范围以内的稳定细胞才能进入后续化合物检测。
测定待测化合物对hERG电流的抑制作用：首先将在含0.1％DMSO的细胞外液中测定得到的hERG电流作为检测基线。在hERG电流保持稳定至少5分钟后将含有待测化合物的溶液从低浓度到高浓度依次灌注于细胞周围。每次灌流结束后等待约5分钟以使化合物充分作用于细胞并同步记录hERG电流。待记录电流趋于稳定后记录最后5个hERG电流值，并取其平均值作为其最终在特定浓度下的电流值。在测试完化合物后，加入150nM多菲莱德至同一个细胞上，将其电流完全抑制，作为该细胞的阳性对照。同时，阳性化合物多菲莱德在测试化合物实验结束前后用同一膜片钳系统进行同步检测，以确保整个检测系统的可靠性和灵敏性。
五、数据分析
数据由PatchMaster软件输出，按以下步骤进行分析：。
1)灌注空白溶剂或化合物梯度溶液后，稳定得到的5个连续电
Figure PCTCN2022100881-appb-000121
值，求取平均值，分别 作为“尾电流大小 空白”和“尾电流大小 化合物”。
2)电流抑制百分率通过以下公式进行计算。
Figure PCTCN2022100881-appb-000122
3)量效曲线通过Graphpad Prism 8.0软件进行拟合并计算IC 50值。
本发明化合物均对hERG钾离子通道无明显抑制，表明化合物因hERG钾离子通道抑制导致心脏毒性产生的风险低。待测化合物相应的hERG钾离子通道抑制活性具体见表6。
表6
化合物 IC 50
化合物009 >30μM

Claims (18)

  1. 式(I)所示化合物或其药学上可接受的盐：
    Figure PCTCN2022100881-appb-100001
    其中，
    R 1、R 2各自独立地选自H、CH 3或卤素；
    环A选自苯基、5-10元杂芳基或C 3-C 10环烷基，所述苯基、5-10元杂芳基或C 3-C 10环烷基任选被R 1a取代；
    X选自O、S、C 1-C 3亚烷基-O、C 1-C 3亚烷基-S、NR 6或C(R 7)(R 8)；
    R 6选自H、C 1-C 6烷基、C 3-C 6环烷基或4-7元杂环基，所述C 1-C 6烷基、C 3-C 6环烷基或4-7元杂环基任选被R b取代；
    R 7、R 8各自独立地选自H、卤素、CN、OH、NH 2、C 1-C 6烷基、C 3-C 6环烷基或4-7元杂环基，或者R 7、R 8与它们连接的原子共同形成C 3-C 6环烷基或4-7元杂环基，所述OH、NH 2、C 1-C 6烷基、C 3-C 6环烷基或4-7元杂环基任选被R b取代；
    环B选自C 6-C 10芳基、5-10元杂芳基、C 3-C 10环烷基或4-14元杂环基，所述C 6-C 10芳基、5-10元杂芳基、C 3-C 10环烷基或4-14元杂环基任选被R 2a取代；
    R 10选自OH、SH、O(C 1-C 6烷基)、S(C 1-C 6烷基)、O-C(＝O)-(C 1-C 6烷基)或
    Figure PCTCN2022100881-appb-100002
    所述O(C 1-C 6烷基)、S(C 1-C 6烷基)、O-C(＝O)-(C 1-C 6烷基)任选被卤素或CN取代；
    R 11、R 12各自独立地选自H或C 1-C 6烷基；
    每一个R 1a、R 2a独立地选自卤素、CN、＝O、OH、NH 2、C 1-C 6烷基、C 3-C 6环烷基或4-7元杂环基，所述OH、NH 2、C 1-C 6烷基、C 3-C 6环烷基或4-7元杂环基任选被R b取代；
    每一个R b独立地选自卤素、CN、＝O、OH、NH 2、C 1-C 6烷基、C 3-C 6环烷基或4-7元杂环基，所述OH、NH 2、C 1-C 6烷基、C 3-C 6环烷基或4-7元杂环基任选被R c取代；
    每一个R c独立地选自卤素、CN、＝O、C 1-C 3烷基、OH、O(C 1-C 3烷基)、NH 2、NH(C 1-C 3烷基)或N(C 1-C 3烷基) 2。
  2. 根据权利要求1所述的式(I)所示化合物或其药学上可接受的盐，其中，R 1、R 2各自独立地选自H或F。
  3. 根据权利要求1或2所述的式(I)所示化合物或其药学上可接受的盐，其中：
    环A选自苯基或5-6元杂芳基，所述苯基或5-6元杂芳基任选被R 1a取代；或者
    环A选自苯基，所述苯基任选被R 1a取代。
  4. 根据权利要求1至3中任一项所述的式(I)所示化合物或其药学上可接受的盐，其中：
    R 7、R 8各自独立地选自H、卤素、CN、OH、NH 2或C 1-C 3烷基，或者R 7、R 8与它们连接的原子共同形成C 3-C 6环烷基，所述OH、NH 2、C 1-C 3烷基或C 3-C 6环烷基任选被R b取代；或者
    R 7、R 8各自独立地选自H、卤素或C 1-C 3烷基，或者R 7、R 8与它们连接的原子共同形成C 3-C 6环烷基。
  5. 根据权利要求1至4中任一项所述的式(I)所示化合物或其药学上可接受的盐，其中，R 10选自OH、SH、O(C 1-C 3烷基)、O-C(＝O)-(C 1-C 3烷基)或
    Figure PCTCN2022100881-appb-100003
    所述O(C 1-C 3烷基)或O-C(＝O)-(C 1-C 3烷基)任选被卤素取代。
  6. 根据权利要求1至5中任一项所述的式(I)所示化合物或其药学上可接受的盐，其中，R 11、R 12各自独立地选自H、甲基或乙基。
  7. 根据权利要求1至6中任一项所述的式(I)所示化合物或其药学上可接受的盐，其中，环B选自C 6-C 10芳基、5-10元杂芳基或4-14元杂环基，所述C 6-C 10芳基、5-10元杂芳基或4-14元杂环基任选被R 2a取代。
  8. 根据权利要求1至7中任一项所述的式(I)所示化合物或其药学上可接受的盐，其中：
    R 2a选自卤素、CN、＝O、OH、NH 2、C 1-C 6烷基、C 3-C 6环烷基或4-7元杂环基；或者
    R 2a选自NH 2或＝O；或者
    R 2a选自NH 2。
  9. 根据权利要求1所述的式(I)所示化合物或其药学上可接受的盐，其中，所述式(I)所示化合物或其药学上可接受的盐选自式(Ia)所示化合物或其药学上可接受的盐：
    Figure PCTCN2022100881-appb-100004
    其中，R 1、R 2、环A、X和R 10如权利要求1定义；
    R 3选自H、OH或NHR 9，R 4、R 5与它们连接的原子共同形成C 5-C 6环烯基、5-6元杂环基或5-6元杂芳基，所述C 5-C 6环烯基、5-6元杂环基或5-6元杂芳基任选被R 4a取代；或者，R 5选自H、OH或NHR 9，R 3、R 4与它们连接的原子共同形成C 5-C 6环烯基、5-6元杂环基或5-6元杂芳基，所述C 5-C 6环烯基、5-6元杂环基或5-6元杂芳基任选被R 4a取代；
    R 9选自H、C 1-C 6烷基、C 3-C 6环烷基或4-7元杂环基，所述C 1-C 6烷基、C 3-C 6环烷基或4-7元杂环基任选被R d取代；
    R 13、R 14各自独立地选自H、卤素、CN、OH、NH 2、O(C 1-C 3烷基)或C 1-C 6烷基；
    每一个R 4a独立地选自卤素、CN、＝O、OH、NH 2、C 1-C 6烷基、C 3-C 6环烷基或4-7元杂环基，所述OH、NH 2、C 1-C 6烷基、C 3-C 6环烷基或4-7元杂环基任选被R d取代；
    每一个R d独立地选自卤素、CN、＝O、C 1-C 3烷基、OH、O(C 1-C 3烷基)、NH 2、NH(C 1-C 3烷基)或N(C 1-C 3烷基) 2。
  10. 根据权利要求9所述的式(Ia)化合物或其药学上可接受的盐，其中：
    所述R 3选自H、OH或NH 2，R 4、R 5与它们连接的原子共同形成5-6元杂环基或5-6元杂芳基，所述5-6元杂环基或5-6元杂芳基任选被R 4a取代；或者
    所述R 3选自H，R 4、R 5与它们连接的原子共同形成5-6元杂环基或5-6元杂芳基，所述5-6元杂环基或5-6元杂芳基任选被R 4a取代；或者
    所述R 3选自H、OH或NH 2，R 4、R 5与它们连接的原子共同形成
    Figure PCTCN2022100881-appb-100005
    Figure PCTCN2022100881-appb-100006
    所述
    Figure PCTCN2022100881-appb-100007
    任选被R 4a取代；或者
    R 3选自H，R 4、R 5与它们连接的原子共同形成
    Figure PCTCN2022100881-appb-100008
    Figure PCTCN2022100881-appb-100009
    所述
    Figure PCTCN2022100881-appb-100010
    任选被R 4a取代。
  11. 根据权利要求9或10所述的式(Ia)化合物或其药学上可接受的盐，其中：
    R 5选自H、OH或NH 2，R 3、R 4与它们连接的原子共同形成C 5-C 6环烯基、5-6元杂环基或5-6元杂芳基，所述C 5-C 6环烯基、5-6元杂环基或5-6元杂芳基任选被R 4a取代；或者
    R 5选自H或NH 2，R 3、R 4与它们连接的原子共同形成C 5-C 6环烯基、5-6元杂环基或5-6元杂芳基，所述C 5-C 6环烯基、5-6元杂环基或5-6元杂芳基任选被R 4a取代；或者
    R 5选自H、OH或NH 2，R 3、R 4与它们连接的原子共同形成
    Figure PCTCN2022100881-appb-100011
    Figure PCTCN2022100881-appb-100012
    所述
    Figure PCTCN2022100881-appb-100013
    Figure PCTCN2022100881-appb-100014
    任选被R 4a取代；或者
    R 5选自H或NH 2，R 3、R 4与它们连接的原子共同形成
    Figure PCTCN2022100881-appb-100015
    Figure PCTCN2022100881-appb-100016
    所述
    Figure PCTCN2022100881-appb-100017
    Figure PCTCN2022100881-appb-100018
    任选被R 4a取代。
  12. 根据权利要求9至11中任一项所述的式(Ia)化合物或其药学上可接受的盐，其中，X选自O、S、C 1-C 3亚烷基-O、C 1-C 3亚烷基-S或C(R 7)(R 8)，所述R 7、R 8各自独立地选自H、卤素、CN、OH、NH 2或C 1-C 3烷基，或者R 7、R 8与它们连接的原子共同形成C 3-C 6环烷基，所述OH、NH 2、C 1-C 3烷基或C 3-C 6环烷基任选被R b取代；或者
    所述R 7、R 8各自独立地选自H、卤素或C 1-C 3烷基，或者R 7、R 8与它们连接的原子共同形成C 3-C 6环烷基。
  13. 根据权利要求9至12中任一项所述的式(Ia)化合物或其药学上可接受的盐，其中：
    R 4a选自卤素、CN、＝O、OH、NH 2、C 1-C 6烷基或C 3-C 6环烷基；或者
    R 4a选自＝O或NH 2。
  14. 根据权利要求9至13中任一项所述的式(Ia)化合物或其药学上可接受的盐，其中，R 13、R 14各自独立地选自H或NH 2。
  15. 根据权利要求9至14中任一项所述的式(Ia)化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2022100881-appb-100019
    选自
    Figure PCTCN2022100881-appb-100020
    Figure PCTCN2022100881-appb-100021
  16. 化合物或其药学上可接受的盐，其中，所述化合物选自以下结构之一：
    Figure PCTCN2022100881-appb-100022
    Figure PCTCN2022100881-appb-100023
    Figure PCTCN2022100881-appb-100024
    Figure PCTCN2022100881-appb-100025
    Figure PCTCN2022100881-appb-100026
  17. 一种药物组合物，所述组合物包含权利要求1至16中任一项所述的化合物或其药学 上可接受的盐和药学上可接受的辅料。
  18. 权利要求1至16中任一项所述的化合物或其药学上可接受的盐、或权利要求17所述的药物组合物在制备用于预防或者治疗糖皮质激素受体介导的疾病的药物中的用途。
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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101227912A (zh) * 2005-06-14 2008-07-23 基利得科学公司 用于治疗肺炎和支气管收缩的作为类固醇和β-激动剂的协同前药的取代苯基磷酸酯
CN101878221A (zh) * 2007-11-30 2010-11-03 辉瑞有限公司 新颖的糖皮质激素受体激动剂
WO2016169504A1 (zh) 2015-04-24 2016-10-27 广州再极医药科技有限公司 稠环嘧啶氨基衍生物﹑其制备方法、中间体、药物组合物及应用
WO2017210471A1 (en) 2016-06-02 2017-12-07 Abbvie Inc. Glucocorticoid receptor agonist and immunoconjugates thereof
CN110903258A (zh) 2018-09-18 2020-03-24 江苏三月光电科技有限公司 一种芳香胺化合物及其应用
CN111417410A (zh) * 2017-12-01 2020-07-14 艾伯维公司 糖皮质激素受体激动剂及其免疫缀合物
CN111465399A (zh) * 2017-12-01 2020-07-28 艾伯维公司 抗cd40抗体药物结合物
WO2021216913A1 (en) * 2020-04-22 2021-10-28 Immunext, Inc. Anti-human vista antibodies and use thereof

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101227912A (zh) * 2005-06-14 2008-07-23 基利得科学公司 用于治疗肺炎和支气管收缩的作为类固醇和β-激动剂的协同前药的取代苯基磷酸酯
CN101878221A (zh) * 2007-11-30 2010-11-03 辉瑞有限公司 新颖的糖皮质激素受体激动剂
WO2016169504A1 (zh) 2015-04-24 2016-10-27 广州再极医药科技有限公司 稠环嘧啶氨基衍生物﹑其制备方法、中间体、药物组合物及应用
WO2017210471A1 (en) 2016-06-02 2017-12-07 Abbvie Inc. Glucocorticoid receptor agonist and immunoconjugates thereof
CN109476699A (zh) * 2016-06-02 2019-03-15 艾伯维公司 糖皮质激素受体激动剂及其免疫偶联物
CN111417410A (zh) * 2017-12-01 2020-07-14 艾伯维公司 糖皮质激素受体激动剂及其免疫缀合物
CN111465399A (zh) * 2017-12-01 2020-07-28 艾伯维公司 抗cd40抗体药物结合物
CN110903258A (zh) 2018-09-18 2020-03-24 江苏三月光电科技有限公司 一种芳香胺化合物及其应用
WO2021216913A1 (en) * 2020-04-22 2021-10-28 Immunext, Inc. Anti-human vista antibodies and use thereof

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DAVID S. MILLAN; STEPHEN A. BALLARD; SARA CHUNN; JOSEPH A. DYBOWSKI; CRAIG K. FULTON; PAUL A. GLOSSOP; EDOUARD GUILLABERT; CHRISTO: "Design and synthesis of long acting inhaled corticosteroids for the treatment of asthma", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, ELSEVIER, AMSTERDAM NL, vol. 21, no. 19, 27 July 2011 (2011-07-27), Amsterdam NL , pages 5826 - 5830, XP028286375, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2011.07.106 *
KNIGHT CRAIG J., MILLAN DAVID S., MOSES IAN B., ROBIN AURELIE A., SELBY MATTHEW D.: "Kilogram-Scale Synthesis of an Inhaled Corticosteroid", ORGANIC PROCESS RESEARCH & DEVELOPMENT, AMERICAN CHEMICAL SOCIETY, US, vol. 16, no. 4, 20 April 2012 (2012-04-20), US , pages 697 - 703, XP093016809, ISSN: 1083-6160, DOI: 10.1021/op200257g *
MAEHR, JCHEM, vol. 62, 1985, pages 114 - 120

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