WO2022111581A1 - 新型苯并氮杂卓螺环衍生物 - Google Patents

新型苯并氮杂卓螺环衍生物 Download PDF

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WO2022111581A1
WO2022111581A1 PCT/CN2021/133158 CN2021133158W WO2022111581A1 WO 2022111581 A1 WO2022111581 A1 WO 2022111581A1 CN 2021133158 W CN2021133158 W CN 2021133158W WO 2022111581 A1 WO2022111581 A1 WO 2022111581A1
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alkyl
mmol
optionally substituted
cycloalkyl
room temperature
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PCT/CN2021/133158
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English (en)
French (fr)
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陆洪福
吕永聪
叶艳
彭建彪
郭海兵
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上海济煜医药科技有限公司
江西济民可信集团有限公司
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Priority to JP2023532393A priority Critical patent/JP2023546527A/ja
Priority to EP21897081.2A priority patent/EP4253367A1/en
Priority to US18/253,935 priority patent/US20240101568A1/en
Priority to CN202180079438.1A priority patent/CN116472271A/zh
Publication of WO2022111581A1 publication Critical patent/WO2022111581A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

  • the present invention relates to novel benzazepine spiro derivatives and salts thereof.
  • the present invention also relates to medicaments comprising benzoazepine spiro derivatives and salts thereof as active ingredients, which can be used for diagnosis, prevention and/or treatment of diseases related to vasopressin receptors.
  • Arginine Vasopressin AVP
  • AVP Arginine Vasopressin
  • Metabolic disturbances of arginine vasopressin (AVP) can cause various diseases such as hyponatremia, abnormal antidiuretic hormone secretion syndrome, congestive heart failure, liver cirrhosis, kidney disease, hypertension, and edema.
  • Arginine vasopressin (AVP) receptor antagonists can inhibit the binding of AVP to the receptor, thereby playing a therapeutic role in the above diseases.
  • Arginine vasopressin V2 receptor antagonists represented by tolvaptan can increase the excretion of free water without affecting the metabolism of electrolytes, thus becoming an ideal drug for the treatment of the above diseases.
  • the marketed AVP V2 receptor antagonists, such as tolvaptan are metabolized by liver metabolizing enzymes, which produce a large number of metabolites in the body and cause severe drug-induced liver toxicity.
  • the FDA gives the drug product label on the label. A black box warning restricts its application. Therefore, it is very important to develop novel V2 receptor antagonists with high efficiency and low side effects.
  • the present invention proposes a compound represented by formula (X), its optical isomer and a pharmacologically acceptable salt thereof,
  • Ring A is selected from heterocycloalkyl and cycloalkyl optionally substituted with 1, 2, 3 or 4 RA ;
  • Ring B is selected from aryl, heteroaryl, heterocycloalkyl and cycloalkyl optionally substituted with 1, 2 or 3 R3 ;
  • Ring C is selected from aryl, heteroaryl, heterocycloalkyl and cycloalkyl optionally substituted with 1, 2 or 3 R4;
  • T 1 , T 2 are independently selected from N and CH;
  • R 1 , R 2 , R 3 , R 4 are each independently selected from H, F, Cl, Br, I, CN, OH, NH 2 , alkyl, heteroalkyl, aryl, heteroaryl, heterocycloalkane and cycloalkyl, the alkyl, heteroalkyl, aryl, heteroaryl, heterocycloalkyl or cycloalkyl optionally substituted with 1, 2, 3 or 4 R;
  • R and RA are each independently selected from H, F, Cl, Br, I, CN, OH, NH2 , alkyl, heteroalkyl, aryl, heteroaryl, heterocycloalkyl and cycloalkyl, whereby said alkyl, heteroalkyl, aryl, heteroaryl, heterocycloalkyl or cycloalkyl is optionally substituted with 1, 2, 3 or 4 R';
  • R' is selected from H, F, Cl, Br, I, CN, OH, NH2 , alkyl and heteroalkyl;
  • n1 and m2 are independently selected from 1, 2, 3 or 4;
  • the present invention provides a compound represented by formula (I), its optical isomer and a pharmacologically acceptable salt thereof,
  • Ring A is selected from 3-6 membered heterocycloalkyl and C 3-6 cycloalkyl, said 3-6 membered heterocycloalkyl and C 3-6 cycloalkyl are optionally substituted with 1 or 2 R A ;
  • Ring B is selected from phenyl and 5-6 membered heteroaryl optionally substituted with 1, 2 or 3 R3 ;
  • Ring C is selected from phenyl and 5-6 membered heteroaryl optionally substituted with 1, 2 or 3 R4;
  • T 1 , T 2 are independently selected from N and CH;
  • R 1 are each independently selected from H, F, Cl, Br, I, CN, OH, NH 2 and C 1-6 alkyl optionally substituted with 1 , 2 or 3 Rs ;
  • R 2 is each independently selected from H, F, Cl, Br, I, CN, OH, NH 2 , C 1-6 alkyl and C 3-6 cycloalkyl, said C 1-6 alkyl or C 3 -6 cycloalkyl optionally substituted with 1, 2 or 3 R;
  • R3 is each independently selected from H, F, Cl, Br, I, CN, OH, NH2 and C1-6 alkyl optionally substituted with 1, 2 or 3 Rs ;
  • R 4 is independently selected from H, F, Cl, Br, I, CN, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-6 Cycloalkyl, phenyl and 5- to 6-membered heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-6 cycloalkyl, phenyl or 5-6 membered heteroaryl is optionally substituted by 1, 2 or 3 R;
  • R and RA are each independently selected from H, F, Cl, Br, I, CN, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy and C 1-6 alkylamino, the C 1-6 alkyl, C 1-6 alkoxy and C 1-6 alkylamino are optionally substituted with 1, 2 or 3 R';
  • R' is selected from H, F, Cl, Br, I, CN, OH, NH 2 and C 1-6 alkyl;
  • n1 and m2 are independently selected from 1, 2 or 3;
  • the present invention provides the compound represented by formula (II), its optical isomers and pharmacologically acceptable salts thereof,
  • X 1 is selected from C( RA ) 2 , NH and O;
  • X 2 is selected from CH and N;
  • T 1 , T 2 are independently selected from N and CH;
  • R 1 are each independently selected from H, F, Cl, Br, I, CN, OH, NH 2 and C 1-6 alkyl optionally substituted with 1 , 2 or 3 Rs ;
  • R 2a and R 2b are each independently selected from H, F, Cl, Br, I, CN, OH, NH 2 , C 1-6 alkyl and C 3-6 cycloalkyl, the C 1-6 alkyl or C 3-6 cycloalkyl optionally substituted with 1, 2 or 3 R;
  • R 3 is selected from H, F, Cl, Br, I, CN, OH, NH 2 and C 1-6 alkyl optionally substituted with 1 , 2 or 3 R;
  • R 4 is independently selected from H, F, Cl, Br, I, CN, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-6 Cycloalkyl, phenyl and 5- to 6-membered heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-6 cycloalkyl, phenyl or 5-6 membered heteroaryl is optionally substituted by 1, 2 or 3 R;
  • R is selected from H, F, Cl, Br, I, CN, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy and C 1-6 alkylamino, the C 1-6 alkyl , C 1-6 alkoxy and C 1-6 alkylamino are optionally substituted by 1, 2 or 3 R';
  • R' is selected from H, F, Cl, Br, I, CN, OH, NH 2 and C 1-6 alkyl;
  • n1 is selected from 0, 1 or 2;
  • n2 is selected from 1, 2 or 3;
  • the present invention also provides the compound represented by formula (III), its optical isomer and its pharmacologically acceptable salt,
  • R 1 are each independently selected from H, F, Cl, Br, I, CN, OH, NH 2 and C 1-6 alkyl optionally substituted with 1 , 2 or 3 Rs ;
  • R 3 is selected from H, F, Cl, Br, I, CN, OH, NH 2 and C 1-6 alkyl optionally substituted with 1 , 2 or 3 R;
  • R 4 is independently selected from H, F, Cl, Br, I, CN, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-6 Cycloalkyl, phenyl and 5- to 6-membered heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-6 cycloalkyl, phenyl or 5-6 membered heteroaryl is optionally substituted by 1, 2 or 3 R;
  • R is selected from H, F, Cl, Br, I, CN, OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy and C 1-6 alkylamino, the C 1-6 alkyl , C 1-6 alkoxy and C 1-6 alkylamino are optionally substituted by 1, 2 or 3 R';
  • R' is selected from H, F, Cl, Br, I, CN, OH, NH 2 and C 1-6 alkyl;
  • X 2 is selected from CH and N.
  • R is selected from H, F, Cl, Br, I, CN, OH, NH2 , CH3 , CF3 , Other variables are as defined in the present invention.
  • RA is selected from H, OH and NH2 , and other variables are as defined herein.
  • R 4 is selected from H, F, Cl, Br, I, CN, OH, NH 2 , CH 3 , CF 3 , Cyclopropyl, cyclobutyl, cyclopentyl, phenyl, pyridyl, pyrimidinyl, thienyl and thiazolyl, and other variables are as defined herein.
  • Ring A is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, aziridine, oxiranyl, azetidinyl, oxetanyl, pyrrolidine cyclopropyl, cyclobutyl, cyclopentyl, aziridinyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl or tetrahydrofuranyl
  • 1 or 2 RAs other variables are as defined herein.
  • Ring A is selected from Other variables are as defined in the present invention.
  • Ring B is selected from phenyl and pyridyl, said phenyl or pyridyl optionally being substituted with 1, 2 or 3 R3 , and other variables are as defined herein.
  • Ring C is selected from Other variables are as defined in the present invention.
  • the present invention also provides a compound of the following formula, its optical isomers and pharmaceutically acceptable salts thereof, which are selected from the group consisting of
  • the present invention also proposes the use of the aforementioned compounds, their optical isomers and their pharmaceutically acceptable salts in the preparation of medicaments for prophylaxis or treatment and spermatogenesis.
  • the arginine vasopressin V1a receptor, arginine vasopressin V1b receptor, arginine vasopressin V2 receptor, sympathetic nervous system, or renin-angiotensin Disorders related to the hormone-aldosterone system including: hypertension, Reye's syndrome, dysmenorrhea, preterm labor, corticotropin-releasing hormone secretion disorder, adrenal hyperplasia, depression, chronic congestive heart failure, liver cirrhosis, antidiuretic hormone secretion Disorder syndrome, hyponatremia due to chronic heart failure/cirrhosis/disordered antidiuretic hormone secretion, or polycystic kidney disease.
  • the phrase "at least one" when referring to a list of one or more elements should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including At least one of each element in the list of elements is specifically listed, and does not exclude any combination of elements in the list of elements.
  • This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase "at least one" refers, whether related or unrelated to those specifically identified elements.
  • the term "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 use without undue toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • salts refers to salts of compounds of the present invention, prepared from compounds discovered by the present invention having specific substituents and relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting the neutral forms of such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting the neutral forms of such compounds with a sufficient amount of acid in solution or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid , hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts including, for example, acetic acid, propionic acid, isobutyric acid, trifluoroacetic acid, maleic acid, malonic acid, benzoic acid, succinic acid , suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid and similar acids; also includes amino acids (such as arginine acid, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base group by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to this within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers and mixtures thereof are included within the scope of the claimed invention.
  • tautomer or “tautomeric form” refers to isomers of different functional groups that are in dynamic equilibrium and are rapidly interconverted at room temperature.
  • a chemical equilibrium of tautomers can be achieved if tautomers are possible (eg, in solution).
  • proton tautomers also called prototropic tautomers
  • prototropic tautomers include interconversions by migration of protons, such as keto-enol isomerization and imine-ene Amine isomerization.
  • Valence tautomers include interconversions by recombination of some bonding electrons.
  • keto-enol tautomerization is the interconversion between two tautomers, pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • deuterated drugs can be formed by replacing hydrogen with deuterium, and the bonds formed by deuterium and carbon are stronger than those formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages.
  • the dotted line indicates the point of attachment of this group to the rest of the molecule.
  • the dotted line represents a single bond or does not exist, which also means represents a single key or double bond
  • substituted or “substituted by” means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, so long as the valence of the specified atom is normal and The substituted compounds are stable.
  • substituent which may include deuterium and hydrogen variants, so long as the valence of the specified atom is normal and The substituted compounds are stable.
  • optionally substituted or “optionally substituted” means that it can be substituted or unsubstituted, and unless otherwise specified, the type and number of substituents can be arbitrary on the basis of chemically achievable of.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with 1 or 2 or 3 R', and in each case R' All have independent options.
  • substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • substituents When the listed substituents do not indicate through which atom it is attached to the substituted group, such substituents may be bonded through any of its atoms, for example, pyridyl as a substituent may be through any one of the pyridine ring The carbon atom is attached to the substituted group.
  • the direction of attachment is arbitrary, for example,
  • the linking group L in the middle is -CH 2 O-, at this time -CH 2 O- can connect phenyl and cyclopentyl in the same direction as the reading order from left to right. It is also possible to link the phenyl and cyclopentyl groups in the opposite direction to the reading order from left to right. Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • the number of atoms in a ring is generally defined as the number of ring members, eg, "3-6 membered ring” refers to a “ring” of 3-6 atoms arranged around it.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably containing An alkyl group of 1 to 6 carbon atoms, more preferably an alkyl group containing 1 to 3 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhe
  • lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-Methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylpropyl butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl base, 2,3-dimethylbutyl, etc.
  • Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from alkanes group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Substituted with one or more substituents of oxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo.
  • C 1-6 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms.
  • the C 1-6 alkyl includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl and the like; it can be is monovalent (eg CH 3 ), bivalent (-CH 2 -) or polyvalent (eg secondary ).
  • Examples of C 1-6 alkyl include, but are not limited to, CH 3 , Wait.
  • C 1-4 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 4 carbon atoms.
  • the C 1-4 alkyl includes C 1-2 , C 1-3 , C 3-4 and C 2-3 alkyl, etc.; it can be monovalent (eg CH 3 ), divalent (-CH 2 - ) or polyvalent (e.g. ).
  • Examples of C 1-4 alkyl groups include, but are not limited to, CH 3 , Wait.
  • C 2-3 alkenyl is used to denote a straight or branched chain hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon double bond, a carbon-carbon double bond can be located anywhere in the group.
  • the C 2-3 alkenyl group includes C 3 and C 2 alkenyl groups; the C 2-3 alkenyl group may be monovalent, divalent or multivalent. Examples of C 2-3 alkenyl groups include, but are not limited to Wait.
  • C 2-3 alkynyl is used to denote a straight or branched chain hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon triple bond, a carbon-carbon triple bond can be located anywhere in the group. It can be monovalent, bivalent or multivalent.
  • the C 2-3 alkynyl groups include C 3 and C 2 alkynyl groups. Examples of C 2-3 alkynyl groups include, but are not limited to Wait.
  • heteroalkyl by itself or in combination with another term means a stable straight or branched chain alkyl radical or a combination thereof consisting of a certain number of carbon atoms and at least one heteroatom or heteroatom thing.
  • the heteroatoms are selected from the group consisting of B, O, N, and S, wherein nitrogen and sulfur atoms are optionally oxidized, and nitrogen heteroatoms are optionally quaternized.
  • the heteroalkyl group is a C 1-6 heteroalkyl group; in other embodiments, the heteroalkyl group is a C 1-3 heteroalkyl group.
  • a heteroatom or group of heteroatoms can be located at any internal position of a heteroalkyl group, including the position at which the alkyl group is attached to the rest of the molecule, but the term "alkoxy" is a customary expression that means attachment to the rest of the molecule through an oxygen atom those alkyl groups.
  • C1-6alkoxy refers to those alkyl groups containing 1 to 6 carbon atoms attached to the remainder of the molecule through an oxygen atom.
  • the C 1-6 alkoxy groups include C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 and C 3 alkoxy groups, etc. .
  • C 1-6 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy) oxy, s-butoxy and t-butoxy), pentyloxy (including n-pentyloxy, isopentyloxy and neopentyloxy), hexyloxy and the like.
  • C1-3alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms attached to the remainder of the molecule through an oxygen atom.
  • the C 1-3 alkoxy group includes C 1-3 , C 1-2 , C 2-3 , C 1 , C 2 and C 3 alkoxy and the like.
  • Examples of C 1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • C 1-6 alkylamino refers to those alkyl groups containing 1 to 6 carbon atoms attached to the remainder of the molecule through an amino group.
  • the C 1-6 alkylamino includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 , C 3 and C 2 alkylamino Wait.
  • C 1-6 alkylamino examples include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -N(CH 2 CH 3 )( CH2CH3 ) , -NHCH2CH2CH3 , -NHCH2 ( CH3 ) 2 , -NHCH2CH2CH2CH3 , etc.
  • C 1-3 alkylamino refers to those alkyl groups containing 1 to 3 carbon atoms attached to the remainder of the molecule through an amino group.
  • the C 1-3 alkylamino group includes C 1-3 , C 1-2 , C 2-3 , C 1 , C 2 and C 3 alkylamino group and the like.
  • Examples of C 1-3 alkylamino include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -NHCH 2 CH 2 CH 3 , - NHCH 2 (CH 3 ) 2 and the like.
  • C1-6 alkylthio refers to those alkyl groups containing 1 to 6 carbon atoms attached to the remainder of the molecule through a sulfur atom.
  • the C 1-6 alkylthio group includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 , C 3 and C 2 alkanes Sulfur, etc.
  • Examples of C1-6 alkylthio groups include, but are not limited to, -SCH3 , -SCH2CH3 , -SCH2CH2CH3 , -SCH2 ( CH3 ) 2 , and the like.
  • C 1-3 alkylthio refers to those alkyl groups containing 1 to 3 carbon atoms attached to the remainder of the molecule through a sulfur atom.
  • the C 1-3 alkylthio group includes C 1-3 , C 1-2 , C 2-3 , C 1 , C 2 and C 3 alkylthio groups and the like.
  • Examples of C1-3 alkylthio groups include, but are not limited to, -SCH3 , -SCH2CH3 , -SCH2CH2CH3 , -SCH2 ( CH3 ) 2 , and the like.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms (may be is a specific point, or an interval composed of two optional points, such as 3, 4, 5, 6 ring atoms, 4 to 11 ring atoms, 6 to 12 ring atoms, etc.), more preferably 3 to 8 carbon atoms, most preferably 3 to 6 (eg 3, 4, 5 or 6) carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene cyclooctyl, cyclooctyl, etc., preferably cycloalkyl; polycyclic cycloalkyl includes spiro, fused and bridged cycloalkyls.
  • spirocycloalkyl refers to a 5- to 20-membered monocyclic polycyclic group sharing one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings are fully conjugated ⁇ electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified into mono-spirocycloalkyl groups, double-spirocycloalkyl groups or poly-spirocycloalkyl groups, preferably mono-spirocycloalkyl groups and double-spirocycloalkyl groups.
  • spirocycloalkyl More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospirocycloalkyl.
  • spirocycloalkyl include: Wait.
  • fused cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more rings. Multiple double bonds, but none of the rings have a fully conjugated pi electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl. Non-limiting examples of fused cycloalkyl groups include: Wait.
  • bridged cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two non-directly connected carbon atoms, which may contain one or more double bonds, but none of the rings have complete Conjugated pi electron system. Preferably it is 5 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • Non-limiting examples of bridged cycloalkyl include: Wait.
  • the cycloalkyl group includes the aforementioned cycloalkyl groups (eg, monocyclic, fused, spiro, and bridged cycloalkyls) fused to an aryl, heteroaryl, or heterocycloalkyl ring, where the parent structure is attached at Rings taken together are cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like; preferably phenylcyclopentyl, tetrahydronaphthyl.
  • Cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , substituted with one or more substituents of heterocycloalkylthio and oxo.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2) heteroatoms, excluding ring moieties of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • It preferably contains 3 to 12 ring atoms (can be a specific point, or an interval consisting of two optional points, such as 3, 4, 5, 6 ring atoms, 4 to 11 ring atoms, 6 to 12 ring atoms atoms, etc.), 1 to 4 of which are heteroatoms; preferably 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; more preferably 3 to 6 ring atoms, of which 1 to 3 are heteroatoms.
  • 3 to 12 ring atoms can be a specific point, or an interval consisting of two optional points, such as 3, 4, 5, 6 ring atoms, 4 to 11 ring atoms, 6 to 12 ring atoms atoms, etc.
  • Non-limiting examples of monocyclic heterocyclyl groups include azetidinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydrofuranyl Hydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc., preferably tetrahydropyranyl, piperidinyl, and pyrrolidinyl.
  • Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.
  • spiroheterocyclyl refers to a 5- to 20-membered monocyclic polycyclic heterocyclic group sharing one atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen or S(O ) m (where m is an integer from 0 to 2) heteroatoms and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings have a fully conjugated pi electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 11 yuan.
  • spiroheterocyclyls are classified into mono-spiroheterocyclyl, bis-spiroheterocyclyl or poly-spiroheterocyclyl, preferably mono-spiroheterocyclyl and bis-spiroheterocyclyl. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclyl group.
  • Non-limiting examples of spiroheterocyclyl include: Wait.
  • fused heterocyclyl refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more of the rings may contain one or more Double bonds, but none of the rings have a fully conjugated pi-electron system, where one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2), the remaining rings Atom is carbon.
  • it is 6 to 14 yuan, more preferably 7 to 11 yuan.
  • the number of constituent rings it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups.
  • fused heterocyclyl groups include: Wait.
  • bridged heterocyclyl refers to a 5- to 14-membered, polycyclic heterocyclyl group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds, but none of the rings have a complete common A pi-electron system of a yoke in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon.
  • m is an integer from 0 to 2
  • it is 6 to 14 yuan, more preferably 7 to 11 yuan.
  • bridged heterocyclyl groups preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged heterocyclyl groups include: Wait.
  • the heterocyclyl groups include the above-mentioned heterocyclyl groups (eg, monocyclic, fused, spirocyclic and bridged heterocyclyls) fused to an aryl, heteroaryl or cycloalkyl ring where it is attached to the parent structure
  • the ring of is heterocyclyl, non-limiting examples of which include: Wait.
  • Heterocyclyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , substituted with one or more substituents of heterocycloalkylthio and oxo.
  • aryl refers to a 6- to 20-membered all-carbon monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, preferably 6 to 10 membered, more preferably 6 elements such as phenyl and naphthyl.
  • the aryl group includes the above-mentioned aryl group fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples of which include:
  • Aryl may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio and heterocycle substituted with one or more substituents in the alkylthio group.
  • heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 20 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl is preferably 5-10-membered, containing 1-3 heteroatoms; more preferably 5- or 6-membered, containing 1-3 heteroatoms; non-limiting examples are pyrazolyl, imidazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl and the like.
  • the heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is a heteroaryl ring, non-limiting examples of which include:
  • Heteroaryl groups can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio and one or more substituents in the heterocycloalkylthio group.
  • C 3-6 cycloalkyl means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which are monocyclic and bicyclic ring systems, said C 3-6 cycloalkyl including C 3-5 , C 4-5 and C 5-6 cycloalkyl and the like; it may be monovalent, divalent or polyvalent.
  • Examples of C3-6 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • 3-6 membered heterocycloalkyl by itself or in combination with other terms denotes a saturated cyclic group consisting of 3 to 6 ring atoms, respectively, of which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, where the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (ie, NO and S(O) p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spiro, paracyclic and bridged rings.
  • a heteroatom may occupy the position of attachment of the heterocycloalkyl to the remainder of the molecule.
  • the 3-6 membered heterocycloalkyl includes 4-6 membered, 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl and the like.
  • Examples of 3-6 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- piperidinyl and 3-piperidyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl
  • the terms “5-6 membered heteroaryl ring” and “5-6 membered heteroaryl” are used interchangeably in the present invention, and the term “5-6 membered heteroaryl” means from 5 to 6 ring atoms It is composed of a monocyclic group with a conjugated ⁇ electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) p , p is 1 or 2).
  • a 5-6 membered heteroaryl group can be attached to the remainder of the molecule through a heteroatom or a carbon atom.
  • the 5-6 membered heteroaryl groups include 5- and 6-membered heteroaryl groups.
  • Examples of the 5-6 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl, etc.) azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4
  • Cn-n+m or Cn - Cn+m includes any particular instance of n to n+ m carbons, eg C1-12 includes C1 , C2 , C3, C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , also including any one range from n to n+m, eg C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 , etc.; in the same way, n yuan to n +m-membered means that the number of atoms in the ring is from n to n+m, for example, 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (eg, affinity substitution reaction).
  • representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters, etc.; acyloxy, such as acetoxy, trifluoroacetoxy, and the like.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to: formyl; acyl groups, such as alkanoyl groups (eg, acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl groups, such as tert-butoxycarbonyl (Boc) ; Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); Arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-Methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-
  • hydroxy protecting group refers to a protecting group suitable for preventing hydroxyl side reactions.
  • Representative hydroxy protecting groups include, but are not limited to: alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl (eg acetyl); arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
  • alkyl groups such as methyl, ethyl and tert-butyl
  • acyl groups such as alkanoyl (eg acetyl)
  • arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenyl
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
  • the solvent used in the present invention is commercially available.
  • FIG. 1 is a graph showing the results of the LLC-PK1 cell proliferation inhibition experiment according to an embodiment of the present invention.
  • the selective fluorine reagent (26.2 g, 74.0 mmol) was added to acetonitrile (200 mL), and Intermediate 1-2 (15.0 g, 37.0 mmol) was added in 5 portions at 40 minute intervals. After the addition was complete, the reaction mixture was stirred at room temperature for 72 hours. Ice water (200 mL) was added, concentrated hydrochloric acid (15.0 mL) was slowly added dropwise under stirring, and after stirring for five minutes, suction filtration was performed, and the obtained solid was dried under reduced pressure to obtain Intermediate I-3.
  • reaction solution was poured into ice water (200 mL), extracted with ethyl acetate (100 mL ⁇ 3), the organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product .
  • the crude product was isolated and purified by silica gel chromatography to obtain intermediate 1-5.
  • 6-aminonicotinic acid methyl ester (1.0 g, 6.57 mmol) was dissolved in pyridine (20 mL), 2-trifluoromethylbenzoyl chloride (1.51 g, 7.25 mmol) was added, and after the addition was completed, the reaction mixture was The reaction was stirred at room temperature for 1 h.
  • the reaction mixture was poured into ice water (100 mL), extracted with ethyl acetate (50 mL ⁇ 3), the combined organic phases were washed with water (50 mL ⁇ 5), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was washed with water.
  • the intermediate I-6 was isolated and purified by silica gel chromatography.
  • the intermediate I-6 (1.35 g, 4.16 mmol) was dissolved in tetrahydrofuran (10 mL), and a solution of sodium hydroxide (499 mg, 12.5 mmol) in water (2 mL) was added. After the addition, the reaction mixture was stirred at 70 °C The reaction was carried out for 1 hour. After the reaction was completed, the pH of the reaction solution was adjusted to 5-6 with 1N hydrochloric acid. Filter and dry the solid to obtain intermediate I-7.
  • intermediate I-7 (244 mg, 0.785 mmol) was dissolved in N,N-dimethylacetamide (6.00 mL), cooled to 0 °C, thionyl chloride (125 mg, 1.05 mmol) was added, After the reaction mixture was stirred at room temperature for 3 hours, a solution of intermediate 1-5 (120 mg, 0.523 mmol) in N,N-dimethylacetamide (3 mL) was added, and the reaction mixture was further stirred at room temperature for 16 hours.
  • reaction solution was added to water (30 mL), extracted with ethyl acetate (20 mL ⁇ 3), the organic phases were combined, washed with saturated aqueous sodium bicarbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate, After filtration, the filtrate was concentrated under reduced pressure to obtain the crude product.
  • the crude product was isolated and purified by silica gel chromatography to give intermediate 1-8.
  • intermediate I-9 (211 mg, 0.785 mmol) was dissolved in N,N-dimethylacetamide (6.00 mL), cooled to 0 °C, and thionyl chloride (125 mg, 1.05 mmol) The reaction mixture was stirred at room temperature for 3 hours, and a solution of Intermediate 1-5 (120 mg, 0.523 mmol) in N,N-dimethylacetamide (3.00 mL) was added. The reaction mixture was continued to stir at room temperature for 16 hours.
  • reaction solution was added to water (30 mL), extracted with ethyl acetate (20 mL ⁇ 3), the organic phases were combined, washed with saturated aqueous sodium bicarbonate solution (50 mL) and saturated brine (50 mL) in turn, dried over anhydrous sodium sulfate, After filtration, the filtrate was concentrated under reduced pressure to obtain the crude product.
  • the crude product was isolated and purified by silica gel chromatography to give intermediate I-10.
  • intermediate I-11 (700 mg, 2.07 mmol) was dissolved in tetrahydrofuran (10 mL), and a solution of sodium hydroxide (414 mg, 10.35 mmol) in water (5 mL) was added. After the addition was completed, the reaction mixture was stirred at 70 °C React for 1 hour. The pH of the reaction solution was adjusted to 5-6 with 1N hydrochloric acid, filtered, and the solid was dried to obtain intermediate I-12.
  • methyltriphenylphosphonium bromide 47.9 g, 0.134 mol was added to a solution of potassium tert-butoxide (18.9 g, 0.168 mol) in tetrahydrofuran (500 mL) at 0 °C, and the reaction solution was heated at 0 °C Stir for 30 minutes.
  • Intermediate I-14 33.0 g, 0.112 mol was added to the reaction system. The reaction solution was stirred at room temperature for 16 hours. The reaction solution was diluted with water (500 mL), and extracted with ethyl acetate (500 mL ⁇ 2).
  • intermediate I-13 150 mg was dissolved in pyridine (10 mL), and intermediate I-16 (60 mg, 0.310 mmol) was added. After the addition, the reaction mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL ⁇ 3), the combined organic phases were washed with water (10 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel chromatography Purification afforded intermediate 1-17.
  • o-Toluoyl chloride (6.11 g, 39.5 mmol) was added to a solution of methyl 6-aminonicotinate (5.00 g, 32.9 mmol) in pyridine (40.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours, poured into water (300 mL), filtered with suction, and the obtained solid was dried to obtain Intermediate I-18.
  • intermediate I-22 (214 mg, 0.65 mmol) was dissolved in pyridine (10 mL), and intermediate I-16 (97 mg, 0.501 mmol) was added. After the addition, the reaction mixture was stirred at room temperature for 16 hours. Diluted with water (10 mL), extracted with ethyl acetate (10 mL ⁇ 3), the combined organic phases were washed with water (10 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel chromatography to obtain Intermediate 1-23.
  • Cuprous cyanide (24.0 g, 0.268 mol) was added to 2-amino-5-bromo-4-methylpyridine (25.0 g, 0.134 mol) in N,N-dimethylacetamide (230 mL) at room temperature ) in the solution.
  • the reaction mixture was stirred at 170°C for 16 hours under argon. After cooling to 0°C, ethylenediamine (50 mL) and water (500 mL) were added to the reaction solution, and the reaction was quenched by stirring for 15 minutes.
  • Extract with ethyl acetate 300 mL ⁇ 3), combine the organic phases, wash the organic phase with water (300 mL ⁇ 3) and saturated brine (500 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to remove the organic solvent to obtain a crude product .
  • the crude product was isolated and purified by silica gel chromatography to give intermediate 1-24.
  • intermediate I-24 (10.2 g, 76.6 mmol) was added to a solution of aqueous sodium hydroxide (90 mL, 10 mol/L) and ethanol (90 mL), and the reaction mixture was refluxed for 16 hours. Cool to room temperature, adjust pH to neutrality with hydrochloric acid (6mol/L), separate out a solid, filter, wash the filter cake with water, and dry to obtain intermediate I-25.
  • N-bromosuccinimide 110 mg, 0.618 mmol was added to a solution of intermediate I-30 (230 mg, 0.516 mmol) in tetrahydrofuran/water (15 mL/3 mL), and the reaction solution was stirred at room temperature 16 hours.
  • Aqueous sodium hydroxide solution (2 mL, 2.5 N) was added thereto, and the reaction solution was stirred at room temperature for 2 hours.
  • the reaction solution was diluted with water (20 mL), and extracted with ethyl acetate (20 mL ⁇ 2).
  • intermediate I-36 (1.00 g, 2.25 mmol) was dissolved in dichloromethane (30.0 mL), m-chloroperoxybenzoic acid (1.95 g, 11.3 mmol) was added, and the reaction system was stirred at room temperature for 10 Hour. The system was concentrated under reduced pressure at room temperature to obtain a crude product, which was separated and purified by C18 reverse-phase chromatography to obtain intermediate I-37.
  • intermediate I-1 (1.00 g, 2.86 mmol) was dissolved in tetrahydrofuran (10 mL), tert-butylsulfinamide (415.74 mg, 3.43 mmol), tetraethyl titanate (1.30 g, 3.43 mmol) were added. 5.72 mmol), microwave at 80°C for 3 hours. Water (10 mL) was added, filtered, the filter cake was washed with ethyl acetate (20 mL), the filtrate was collected, the filtrate was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain the crude product. The crude product was isolated and purified by silica gel chromatography to give intermediate 1-38.
  • Zinc powder (2.01 g, 30.76 mmol) was suspended in tetrahydrofuran (100 mL) at 25°C, and nitrogen was replaced three times.
  • 1,2-Dibromoethane (96.31 mg, 0.51 mmol) and trimethylchlorosilane (278.48 mg, 2.56 mmol) were added, and the mixture was stirred at 65° C. for 1 hour.
  • Tert-butyl bromoacetate (5.00 g, 25.63 mmol) was added dropwise, and after the dropwise addition was completed, the mixture was stirred at 50° C. for 1 hour. Cooling afforded a solution of intermediate 1-39 in tetrahydrofuran (100 mL, 25.63 mmol).
  • intermediate I-40 (350.00 mg, 0.61 mmol) was dissolved in tetrahydrofuran (10 mL), a toluene solution of diisobutylaluminum hydride (2.05 mL, 3.07 mmol, 1.5 M) was added, and the reaction was carried out at room temperature for 16 hours .
  • Water (0.12 mL), 15% aqueous sodium hydroxide solution (0.12 mL), and water (0.3 mL) were sequentially added, and then anhydrous sodium sulfate was added, and the mixture was stirred at room temperature for 0.5 hours. Filtration, concentration of the filtrate, separation and purification by silica gel chromatography to obtain intermediate I-41.
  • intermediate I-41 (170.00 mg, 0.34 mmol) was dissolved in toluene (10 mL), cyanomethylene tri-n-butylphosphine (98.47 mg, 0.41 mmol) was added, and the reaction was stirred at 110 °C 3 Hour. Cool to room temperature, add water (10 mL), and extract with ethyl acetate (10 mL ⁇ 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, separated and purified by silica gel chromatography to obtain intermediate I-42.
  • intermediate I-42 (100.00 mg, 0.21 mmol) was dissolved in concentrated hydrochloric acid (5 mL) and reacted at 100°C for 16 hours. Directly concentrated to dryness, and separated and purified by C18 reverse phase column to obtain intermediate I-43.
  • intermediate I-43 (40.00 mg, 0.18 mmol) was dissolved in tetrahydrofuran (5 mL), 10% aqueous sodium bicarbonate solution (5 mL), di-tert-butyl dicarbonate (47.04 mg, 0.22 mmol) were added, The reaction was carried out at room temperature for 1 hour. Water (10 mL) was added and extracted with ethyl acetate (10 mL ⁇ 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, separated and purified by silica gel chromatography to obtain intermediate I-44.
  • intermediate I-44 50.00 mg, 0.15 mmol was dissolved in dichloromethane (10 mL), triethylamine (47.02 mg, 0.46 mmol), 2-methyl-4-nitrobenzyl were added Acid chloride (46.37 mg, 0.23 mmol), and the reaction was stirred at room temperature for 16 hours. Water (10 mL) was added and extracted with dichloromethane (10 mL ⁇ 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, separated and purified by silica gel chromatography to obtain intermediate I-45.
  • intermediate I-45 50.00 mg, 0.10 mmol was dissolved in ethanol (4 mL), reduced iron powder (28.73 mg, 0.51 mmol) was added, saturated aqueous ammonium chloride solution (2 mL), and the reaction was stirred at 80 °C 5 hours. After filtration, the filter cake was washed with ethyl acetate (10 mL), the filtrate was collected, and water (10 mL) was added to separate the layers. The organic phase was collected, concentrated, and purified by silica gel chromatography to yield intermediate 1-46.
  • intermediate I-46 (30.00 mg, 0.066 mmol) was dissolved in dichloromethane (5 mL), followed by addition of triethylamine (19.97 mg, 0.20 mmol), 2-methylbenzoyl chloride (12.21 mg) , 0.079 mmol), and reacted at room temperature for 1 hour. Water (10 mL) was added and extracted with dichloromethane (10 mL ⁇ 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness, and separated and purified by silica gel chromatography to obtain intermediate I-47.
  • intermediate I-61 (10.0 g, 30.1 mmol) was dissolved in methanol/water (100 mL/20 mL), sodium hydroxide (3.61 g, 90.3 mmol) was added to the system, and the reaction mixture was stirred at room temperature 3 hours.
  • Dilute hydrochloric acid (1.0 mol/L) was used to adjust the pH of the system to 6-7, a large amount of solid was precipitated, filtered, and the solid was collected and dried under reduced pressure to obtain intermediate I-62.
  • intermediate 1-64 500 mg, 1.01 mmol was dissolved in tetrahydrofuran/water (25 mL/5 mL), N-bromosuccinimide (360 mg, 2.02 mmol) was added, and the reaction mixture was at room temperature Stir for 24 hours.
  • the reaction system was poured into water (20 mL), extracted with ethyl acetate (10 mL ⁇ 3), the organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product .
  • the crude product was isolated and purified by silica gel chromatography to give intermediate 1-65.
  • N-methylurea (5.0 g, 67.5 mmol) was dissolved in water (40 mL), and sodium nitrite (5.12 g, 74.2 mmol) was added thereto.
  • concentrated hydrochloric acid (8.9 mL) was slowly added dropwise for about 30 minutes, and the mixture was reacted in an ice-water bath for 30 minutes. The precipitate was filtered, the filter cake was washed with water, and the oil pump was drained to obtain the intermediate I-66, which was directly used in the next reaction without further purification.
  • Trifluoroacetic acid (1 mL) was added to a solution of intermediate 1-68 (90 mg, 0.292 mmol) in dichloromethane (5 mL) at room temperature. The reaction solution was stirred at room temperature for 5 hours. Concentrate to dryness under reduced pressure to obtain the crude intermediate I-69, which is directly used in the next reaction.
  • diethyl malonate (10.0 g, 62.5 mmol) was dissolved in dimethyl sulfoxide (150 mL), sodium hydrogen (2.92 g, 60% wt, 72.9 mmol) was slowly added, and the reaction mixture was stirred at room temperature After 30 minutes, 2,4-dichloronitrobenzene (10.0 g, 52.1 mmol) was added to the reaction solution, and after the addition was completed, the mixture was heated to 80° C. and stirred for 5 hours. Cool to room temperature, add water (300 mL), and extract with ethyl acetate (300 mL ⁇ 3).
  • intermediate I-72 (10.0 g, 31.68 mmol) was dissolved in dimethyl sulfoxide (100 mL) and water (1 mL), lithium chloride (6.65 g, 158.4 mmol) was added, and after the addition was completed, heating Stir to 100°C for 5 hours. It was cooled to room temperature, diluted with water (200 mL), and extracted with ethyl acetate (200 mL ⁇ 3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent to obtain a crude product. The crude product was isolated and purified by silica gel chromatography to give intermediate 1-73.
  • intermediate I-76 800 mg, 3.31 mmol was dissolved in dichloromethane (10 mL), and Dess-Martin oxidant (4.21 g, 9.93 mmol) was added. After the addition, the reaction solution was stirred at room temperature 2 hours. The reaction solution was filtered, the filtrate was diluted with water (20 mL), and extracted with dichloromethane (20 mL ⁇ 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent to obtain a crude product. The crude product was isolated and purified by silica gel chromatography to give intermediate 1-77.
  • aqueous phase was made acidic with 1N hydrochloric acid, extracted with ethyl acetate (50 mL ⁇ 3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent to obtain Intermediate 1-78.
  • intermediate I-85 (670.00 mg, 1.78 mmol) was dissolved in dichloromethane (10 mL), Boc-L-hydroxyproline (493.30 mg, 2.13 mmol), N,N-dichloromethane was added Isopropylethylamine (683.57mg, 5.33mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (809.91mg, 2.13 mmol) and stirred at room temperature for 1 hour. Water (20 mL) was added and extracted with dichloromethane (20 mL ⁇ 3).
  • ABSPR Automatic Back Pressure Regulator
  • intermediate I-87 400.00 mg was dissolved in tetrahydrofuran (4 mL), saturated aqueous sodium bicarbonate solution (2 mL), di-tert-butyl dicarbonate (89.05 mg, 0.41 mmol) were added, and the reaction was carried out at room temperature for 1 Hour. Water (10 mL) was added, extracted with ethyl acetate (10 mL ⁇ 3), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was isolated and purified by silica gel chromatography to give intermediate 1-88.
  • intermediate I-89 (60.00 mg, 0.12 mmol) was dissolved in ethanol (8 mL), reduced iron powder (34.47 mg, 0.62 mmol) was added, saturated aqueous ammonium chloride solution (2 mL), and stirred at 80 °C 5 hours. Filtration, the filter cake was washed with ethyl acetate (20 mL), the filtrate was collected, water (10 mL) was added, and the layers were separated. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was isolated and purified by silica gel chromatography to give intermediate I-90.
  • intermediate I-90 50.00 mg, 0.11 mmol was dissolved in dichloromethane (5 mL), triethylamine (33.29 mg, 0.33 mmol) was added successively, o-toluoyl chloride (25.43 mg) , 0.16 mmol), stirred at room temperature for 1 hour. Water (10 mL) was added and extracted with dichloromethane (10 mL ⁇ 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was isolated and purified by silica gel chromatography to give intermediate I-91.
  • intermediate I-92 (1.40 g) was dissolved in tetrahydrofuran (20 mL), saturated aqueous sodium bicarbonate solution (10 mL), di-tert-butyl dicarbonate (332.61 mg, 1.52 mmol) were added, and the mixture was stirred at room temperature for 1 hour .
  • the crude product was isolated and purified by silica gel chromatography to give intermediate 1-93.
  • intermediate I-93 (70.00 mg, 0.22 mmol) was dissolved in dichloromethane (5 mL), triethylamine (65.77 mg, 0.65 mmol), 2-methyl-4-nitrobenzyl were added Acid chloride (64.92 mg, 0.33 mmol) was stirred at room temperature for 16 hours. Water (10 mL) was added and extracted with dichloromethane (10 mL ⁇ 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was isolated and purified by silica gel chromatography to give intermediate 1-94.
  • intermediate I-94 (90.00 mg, 0.19 mmol) was dissolved in ethanol (8 mL), reduced iron powder (51.71 mg, 0.93 mmol) was added, saturated aqueous ammonium chloride solution (2 mL), and stirred at 80 °C for 5 Hour. Filtration, the filter cake was washed with ethyl acetate (20 mL), the filtrate was collected, water (20 mL) was added, and the layers were separated. The organic phase was collected and concentrated under reduced pressure to give the crude product. The crude product was isolated and purified by silica gel chromatography to give intermediate 1-95.
  • intermediate I-95 (70.00 mg, 0.15 mmol) was dissolved in dichloromethane (5 mL), triethylamine (46.60 mg, 0.46 mmol), o-methylbenzoyl chloride (35.60 mg, 0.46 mmol) were added successively 0.23 mmol) and stirred at room temperature for 1 hour.
  • Water (10 mL) was added and extracted with dichloromethane (10 mL ⁇ 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product.
  • the crude product was isolated and purified by silica gel chromatography to give intermediate 1-96.
  • intermediate I-21 100 mg, 0.232 mmol was dissolved in aqueous ammonia (5.00 mL) solution, and elemental iodine (177 mg, 0.696 mmol), ⁇ -isotridecyl- ⁇ - Hydroxy-poly(oxy-1,2-ethylene) (0.300 mL).
  • reaction mixture was stirred at room temperature for 16 hours, water (20 mL) was added, extracted with ethyl acetate (20 mL ⁇ 3), the organic phases were combined, washed with saturated aqueous sodium thiosulfate solution (30 mL) and saturated brine (50 mL), Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product.
  • the crude product was separated and purified by preparative HPLC (aqueous ammonia system) to obtain compound 4.
  • intermediate I-7 (54.0 mg, 0.174 mmol) was dissolved in N,N-dimethylacetamide (5.00 mL), cooled to 0 °C, and thionyl chloride (20.7 mmol) was added under argon protection. mg, 0.174 mmol), the reaction mixture was stirred at 0 °C for 3 hours, intermediate I-58 (30.0 mg, 0.116 mmol) was added, and the reaction mixture was continued to stir at room temperature for 16 hours.
  • HeLa cell line (HeLa-V2R) stably expressing human vasopressin receptor V2R constructed by Shanghai Jikai Gene Chemical Technology Co., Ltd. using lentiviral infection method, and verified by qPCR to stably express human V2R.
  • DMEM cell culture medium brand: Gibco, product number: 11995065; fetal bovine serum: brand: Gibco, product number: FND500; 0.25% pancreatin: brand: Gibco, product number: 25200072; Puromycin Dihydrochloride: brand: Gibco, product number: A1113803; cAMP-GS HIRANGE KIT: Brand: Cisbio, Item No.: 62AM6PEC; IBMX: Brand: Sigma, Item No.: i5879; Vasopressin AVP: customized by Gill Biochemical (Shanghai) Co., Ltd.
  • HeLa-V2R cells were incubated with DMEM medium supplemented with 10% fetal bovine serum at 37°C and 5% CO 2 , and 2ug/mL puromycin was added to the medium to continuously screen for cells expressing V2R.
  • the cells were digested with trypsin, washed twice with the stimulation buffer in the cAMP-GS HIRANGE kit, resuspended and counted to make 1.6 ⁇ 10 6 cells/ml, and IBMX was added to a final concentration of 0.5 mM.
  • cAMP standard sample (3-fold dilution from 5.6uM, 10 concentration points), and transfer 10uL cAMP standard to the corresponding well of the 384-well plate.
  • lysis buffer in the cAMP-GS HIRANGE kit to dilute the cAMP-d2 fluorescence and anti-cAMP antibody probes provided in the kit by 20 times, add 5uL of each to each well of a 384-well plate, mix well, and briefly centrifuge for 25 minutes. Detection after 2 hours of incubation. The samples were detected by the HTRF method in the Envision microplate reader, and the fluorescence intensity at 615nm and 665nm was detected. Two replicate wells were made for each sample to be tested, and 32 replicate wells were made for Min and Max respectively.
  • Table 1 Evaluation of compounds for inhibition of cAMP increase in human cervical cancer cells (Human V2R Hela-Stable cell line OE2)
  • mice show lower metabolic clearance rate Cl in vivo and higher in vivo exposure AUC 0-inf .
  • Porcine kidney epithelial cells LLC-PK1 purchased from ATCC, Cat#CL ⁇ 101
  • Vasopressin AVP customized by Gill Biochemical (Shanghai) Co., Ltd.
  • the pathogenesis of polycystic kidney disease is related to the low intracellular calcium ion concentration of renal collecting duct epithelial cells, and the cells are in a cAMP-dependent hyperproliferation.
  • the research paper by Tamio Yamaguchi et al. published in The Journal of Biological Chemistry in 2004, we optimized and carried out the LLC-PK1 proliferation assay in renal epithelial cells to evaluate the effect of compounds on vasopressin-induced proliferation after reducing intracellular calcium ion concentration. Inhibitory ability of cell proliferation.
  • LLC-PK1 cells were incubated with M199 medium supplemented with 10% fetal bovine serum at 37 degrees Celsius and 5% CO 2 .
  • M199 medium supplemented with 10% fetal bovine serum at 37 degrees Celsius and 5% CO 2 .
  • 0.01% Poly-D-lysine coat 96-well plate add 100 ul to each well, let stand for 10 min at room temperature, aspirate and air dry at room temperature for 1 hrs, and wash with 200 ul of 1XPBS for use. LLC-PK1 cells were trypsinized, resuspended with serum-free M199 after centrifugation, counted, diluted with serum-free M199 medium to 1 ⁇ 10 5 /ml cell suspension, and FBS was added to a final concentration of 1%. Transfer 200ul of cell suspension/well to a 96-well plate.
  • the supernatant was aspirated, washed with 200 ul PBS, 160 ul M199 medium containing 0.05% FBS and 20 ul 10X Verapamil (final concentration 5 uM) were added successively, and the culture was continued for 24 hrs.
  • 10uL of different concentrations of the test compound final concentration from 3uM, 3-fold dilution, 8 concentration gradients
  • DMSO minimum Min, maximum value Max control
  • the fluorescence intensity of each experimental well sample minus the background well fluorescence intensity average value is the Y value, which represents the number of live cells in the well during detection.
  • the Grouped-Summary data-Separated bar graph in GraphPad Prism 8.0 software was used to make a bar graph to reflect the dose-effect relationship of different compounds on AVP-induced cell proliferation.
  • the inhibitory effect of the compound on proliferation was qualitatively evaluated: the overall performance was better than tolvaptan as "+++”, the performance close to tolvaptan was "++”, weaker than tolvaptan The expression of tolvaptan is "+”, and the expression of no proliferation inhibition is "-".
  • Data quality control Calculate S/B, that is, the average value of Max wells / the average value of Min wells, and ⁇ 2 is regarded as QC passed.

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Abstract

式(I)所示苯并氮杂䓬螺环衍生物及其药效上可接受的盐，以及该化合物可用于诊断、预防和/或治疗与血管加压素受体相关的疾病。

Description

新型苯并氮杂卓螺环衍生物
本发明要求如下优先权：
申请号：CN202011353057.1，申请日：2020年11月26日；
申请号：CN202111322711.7，申请日：2021年11月09日。
技术领域
本发明涉及新型苯并氮杂卓螺环衍生物及其盐。本发明还涉及包含苯并氮杂卓螺环衍生物及其盐作为活性成分的药物，可用于诊断、预防和/或治疗与血管加压素受体相关的疾病。
背景技术
激素在人体内环境稳态的调节过程中发挥了重要作用，其中精氨酸加压素(Arginine Vasopressin，AVP)与人体水钠代谢的调节密切相关。精氨酸加压素(AVP)的代谢紊乱可引起低钠血症、抗利尿激素分泌异常综合征、充血性心力衰竭、肝硬化、肾脏疾病、高血压以及浮肿等多种疾病。精氨酸加压素(AVP)受体拮抗剂可抑制AVP与受体的结合，从而对上述疾病起到治疗作用。以托伐普坦为代表的精氨酸加压素V2受体拮抗剂可以在增加自由水排出的同时不影响电解质的代谢，从而成为治疗上述疾病的理想药物。但上市的AVP V2受体拮抗剂，如托伐普坦通过肝脏代谢酶进行代谢，其在体内产生大量的代谢产物并导致了严重的药物诱导肝毒性，FDA在该药物商品标签上给出了黑框警告，限制了它的应用。因此，开发高效、低副作用的新型V2受体拮抗剂十分重要。
发明内容
本发明的一个目的是提供具有血管加压素V2受体拮抗作用，并有利于代谢稳定性和/或代谢产物具有降低了药物诱导肝毒性性质的一种新颖的苯并氮杂卓螺环化合物或其盐，以及所述化合物的医药用途。
在本发明的一方面，本发明提出了式(X)所示化合物、其光学异构体及其药效上可接受的盐，
Figure PCTCN2021133158-appb-000001
其中，
环A选自杂环烷基和环烷基，所述杂环烷基和环烷基任选被1、2、3或4个R A取代；
环B选自芳基、杂芳基、杂环烷基和环烷基，所述芳基、杂芳基、杂环烷基或环烷基任选被1、2或3个R 3取代；
环C选自芳基、杂芳基、杂环烷基和环烷基，所述芳基、杂芳基、杂环烷基或环烷基任选被1、2或3个R 4取代；
T 1、T 2分别独立地选自N和CH；
R 1、R 2、R 3、R 4分别独立地选自H、F、Cl、Br、I、CN、OH、NH 2、烷基、杂烷基、芳基、杂芳基、杂环烷基和环烷基，所述烷基、杂烷基、芳基、杂芳基、杂环烷基或环烷基任选被1、2、3或4个R取代；
R和R A分别独立地选自H、F、Cl、Br、I、CN、OH、NH 2、烷基、杂烷基、芳基、杂芳基、杂环烷基和环烷基，所述烷基、杂烷基、芳基、杂芳基、杂环烷基或环烷基任选被1、2、3或4个R’取代；
R’选自H、F、Cl、Br、I、CN、OH、NH 2、烷基和杂烷基；
m1和m2分别独立地选自1、2、3或4；
L X选自-NH(C＝O)-、-烷基-NH(C＝O)-、-NH(C＝O)-烷基-、烷基、烯基和炔基，所述-烷基-NH(C＝O)-、-NH(C＝O)-烷基-、烷基、烯基或炔基任选被1、2、3或4个R取代；
且，当环A选自杂环烷基时，式(I)所示化合物不选自
Figure PCTCN2021133158-appb-000002
Figure PCTCN2021133158-appb-000003
所述杂环烷基或杂芳基包含1、2、3或4个独立选自-O-、-NH-、-N＝、-S-、-C(＝O)-、-C(＝O)O-、-S(＝O)-、-S(＝O) 2-和N的杂原子或杂原子团。
在本发明的再一方面，本发明提供了式(I)所示化合物、其光学异构体及其药效上可接受的盐，
Figure PCTCN2021133158-appb-000004
其中，
环A选自3-6元杂环烷基和C 3-6环烷基，所述3-6元杂环烷基和C 3-6环烷基任选被1或2个R A取代；
环B选自苯基和5-6元杂芳基，所述苯基或5-6元杂芳基任选被1、2或3个R 3取代；
环C选自苯基和5-6元杂芳基，所述苯基或5-6元杂芳基任选被1、2或3个R 4取代；
T 1、T 2分别独立地选自N和CH；
R 1分别独立地选自H、F、Cl、Br、I、CN、OH、NH 2和C 1-6烷基，所述C 1-6烷基任选被1、2或3个R取代；
R 2分别独立地选自H、F、Cl、Br、I、CN、OH、NH 2、C 1-6烷基和C 3-6环烷基，所述C 1-6烷基或C 3-6环烷基任选被1、2或3个R取代；
R 3分别独立地选自H、F、Cl、Br、I、CN、OH、NH 2和C 1-6烷基，所述C 1-6烷基任选被1、2或3个R取代；
R 4分别独立地选自H、F、Cl、Br、I、CN、OH、NH 2、C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、C 3-6环烷基、苯基和5～6元杂芳基，所述C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、C 3-6环烷基、苯基或5～6元杂芳基任选被1、2或3个R取代；
R和R A分别独立地选自H、F、Cl、Br、I、CN、OH、NH 2、C 1-6烷基、C 1-6烷氧基和C 1-6烷氨基，所述C 1-6烷基、C 1-6烷氧基和C 1-6烷氨基任选被1、2或3个R’取代；
R’选自H、F、Cl、Br、I、CN、OH、NH 2和C 1-6烷基；
m1和m2分别独立地选自1、2或3；
且，当环A选自3-6元杂环烷基时，式(I)所示化合物不选自
Figure PCTCN2021133158-appb-000005
Figure PCTCN2021133158-appb-000006
所述3-6元杂环烷基或5-6元杂芳基包含1、2或3个独立选自-O-、-NH-、-N＝、-S-、-C(＝O)-、-C(＝O)O-、-S(＝O)-、-S(＝O) 2-和N的杂原子或杂原子团。
在本发明的另一方面，本发明提供了式(II)所示化合物、其光学异构体及其药效上可接受的盐，
Figure PCTCN2021133158-appb-000007
其中，
X 1选自C(R A) 2、NH和O；
X 2选自CH和N；
T 1、T 2分别独立地选自N和CH；
R 1分别独立地选自H、F、Cl、Br、I、CN、OH、NH 2和C 1-6烷基，所述C 1-6烷基任选被1、2或3个R取代；
R 2a和R 2b分别独立地选自H、F、Cl、Br、I、CN、OH、NH 2、C 1-6烷基和C 3-6环烷基，所述C 1-6烷基或C 3-6环烷基任选被1、2或3个R取代；
R 3选自H、F、Cl、Br、I、CN、OH、NH 2和C 1-6烷基，所述C 1-6烷基任选被1、2或3个R取代；
R 4分别独立地选自H、F、Cl、Br、I、CN、OH、NH 2、C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、C 3-6环烷基、苯基和5～6元杂芳基，所述C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、C 3-6环烷基、苯基或5～6元杂芳基任选被1、2或3个R取代；
R选自H、F、Cl、Br、I、CN、OH、NH 2、C 1-6烷基、C 1-6烷氧基和C 1-6烷氨基，所述C 1-6烷基、C 1-6烷氧基和C 1-6烷氨基任选被1、2或3个R’取代；
R’选自H、F、Cl、Br、I、CN、OH、NH 2和C 1-6烷基；
n1选自0、1或2；
n2选自1、2或3；
且，当X 1选自O时，式(II)所示化合物不选自
Figure PCTCN2021133158-appb-000008
Figure PCTCN2021133158-appb-000009
在本发明的再一方面，本发明还提供了式(III)所示化合物、其光学异构体及其药效上可接受的盐，
Figure PCTCN2021133158-appb-000010
其中，
R 1分别独立地选自H、F、Cl、Br、I、CN、OH、NH 2和C 1-6烷基，所述C 1-6烷基任选被1、2或3个R取代；
R 3选自H、F、Cl、Br、I、CN、OH、NH 2和C 1-6烷基，所述C 1-6烷基任选被1、2或3个R取代；
R 4分别独立地选自H、F、Cl、Br、I、CN、OH、NH 2、C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、C 3-6环烷基、苯基和5～6元杂芳基，所述C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、C 3-6环烷基、苯基或5～6元杂芳基任选被1、2或3个R取代；
R选自H、F、Cl、Br、I、CN、OH、NH 2、C 1-6烷基、C 1-6烷氧基和C 1-6烷氨基，所述C 1-6烷基、C 1-6烷氧基和C 1-6烷氨基任选被1、2或3个R’取代；
R’选自H、F、Cl、Br、I、CN、OH、NH 2和C 1-6烷基；
X 2选自CH和N。
本发明的一些方案中，R选自H、F、Cl、Br、I、CN、OH、NH 2、CH 3、CF 3、
Figure PCTCN2021133158-appb-000011
Figure PCTCN2021133158-appb-000012
其他变量如本发明所定义。
本发明的一些方案中，R A选自H、OH和NH 2，其他变量如本发明所定义。
本发明的一些方案中，R 4选自H、F、Cl、Br、I、CN、OH、NH 2、CH 3、CF 3、
Figure PCTCN2021133158-appb-000013
Figure PCTCN2021133158-appb-000014
环丙基、环丁基、环戊基、苯基、吡啶基、嘧啶基、噻吩基和噻唑基，其他变量如本发明所定义。
本发明的一些方案中，环A选自环丙基、环丁基、环戊基、氮丙啶基、环氧乙烷基、氮杂环丁烷基、氧杂环丁烷基、吡咯烷基和四氢呋喃基，所述环丙基、环丁基、环戊基、氮丙啶基、环氧乙烷基、氮杂环丁烷基、氧杂环丁烷基、吡咯烷基或四氢呋喃基任选被1或2个R A取代，其他变量如本发明所定义。
本发明的一些方案中，环A选自
Figure PCTCN2021133158-appb-000015
Figure PCTCN2021133158-appb-000016
其他变量如本发明所定义。
本发明的一些方案中，结构单元
Figure PCTCN2021133158-appb-000017
选自
Figure PCTCN2021133158-appb-000018
Figure PCTCN2021133158-appb-000019
其他变量如本发明所定义。
本发明的一些方案中，环B选自苯基和吡啶基，所述苯基或吡啶基任选被1、2或3个R 3取代，其他变量如本发明所定义。
本发明的一些方案中，环C选自
Figure PCTCN2021133158-appb-000020
其他变量如本发明所定义。
在本发明的再一方面，本发明还提供了下式化合物、其光学异构体及其药效上可接受的盐，其选自
Figure PCTCN2021133158-appb-000021
Figure PCTCN2021133158-appb-000022
在本发明的再一方面，本发明还提出了前面所述的化合物、其光学异构体及其药效上可接受的盐在制备药物中的应用，所述药物用于预防或治疗与精氨酸加压素V1a受体、精氨酸加压素V1b受体、精氨酸加压素V2受体、交感神经系统或肾素-血管紧张素-醛固酮系统相关的疾病。
在本发明的一些方案中，所述与精氨酸加压素V1a受体、精氨酸加压素V1b受体、精氨酸加压素V2受体、交感神经系统或肾素-血管紧张素-醛固酮系统相关的疾病，包括：高血压、雷氏综合征、痛经、早产、促肾上腺皮质激素释放激素分泌紊乱、肾上腺增生、抑郁症、慢性充血性心力衰竭、肝硬化、抗利尿激素分泌紊乱综合征、慢性心力衰竭/肝硬化/抗利尿激素分泌紊乱引起的低钠血症、或多囊肾疾病。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
如本发明中，采用的短语“至少一个”在提及一个或多个要素的列表时应理解为意指至少一个选自所述要素列表中的任一个或多个要素的要素，但不必包括所述要素列表内具体列出的每一个要素中的至少一者，并且不排除所述要素列表中的要素的任何组合。这个定义还允许，可以任选地存在除短语“至少一个”指代的所述要素列表内具体确定的要素以外的要素，不论与那些具体确定的要素相关还是不相关。
这里所采用的术语“药效上可接受的”，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“药效上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药效上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药效上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、三氟乙酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
本发明的药效上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外 消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明要求保护的范围之内。
本发明的化合物可以存在特定的。除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
当基团价键上带有虚线
Figure PCTCN2021133158-appb-000023
时，例如在
Figure PCTCN2021133158-appb-000024
中，该虚线表示该基团与分子其它部分的连接点。当单键上带有
Figure PCTCN2021133158-appb-000025
时，例如在
Figure PCTCN2021133158-appb-000026
中，该虚线代表单键或者不存在，也意味着
Figure PCTCN2021133158-appb-000027
代表了单键
Figure PCTCN2021133158-appb-000028
或者双键
Figure PCTCN2021133158-appb-000029
术语“被取代的”或“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，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。术语“任选被取代的”或“任选被…取代”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被1、2或3个R’所取代，则所述基团可以任选地1个或2个或3个R’所取代，并且每种情况下的R’都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如
Figure PCTCN2021133158-appb-000030
中L 1代表单键时表示该结构实际上是
Figure PCTCN2021133158-appb-000031
当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。
当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，
Figure PCTCN2021133158-appb-000032
中连接基团L为-CH 2O-，此时-CH 2O-既可以按与从左往右的读取顺序相同的方向连接苯基和环戊基构成
Figure PCTCN2021133158-appb-000033
也可以按照与从左往右的读取顺序相反的方向连接苯基和环戊基构成
Figure PCTCN2021133158-appb-000034
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
除非另有规定，环上原子的数目通常被定义为环的元数，例如，“3-6元环”是指环绕排列3-6个原子的“环”。
除非另有规定，术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个碳原子的烷基，更优选含有1至6个碳原子的烷基，更优选含有1至3个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基和氧代基中的一个或多个取代基所取代。
除非另有规定，术语“C 1-6烷基”用于表示直链或支链的由1至6个碳原子组成的饱和碳氢基团。所述C 1-6烷基包括C 1-5、C 1-4、C 1-3、C 1-2、C 2-6、C 2-4、C 6和C 5烷基等；其可以是一价(如CH 3)、二价(-CH 2-)或者多价(如次
Figure PCTCN2021133158-appb-000035
)。C 1-6烷基的实例包括但不限于CH 3、
Figure PCTCN2021133158-appb-000036
Figure PCTCN2021133158-appb-000037
等。
除非另有规定，术语“C 1-4烷基”用于表示直链或支链的由1至4个碳原子组成的饱和碳氢基团。所述C 1-4烷基包括C 1-2、C 1-3、C 3-4和C 2-3烷基等；其可以是一价(如CH 3)、二价(-CH 2-)或者多价(如次
Figure PCTCN2021133158-appb-000038
)。C 1-4烷基的实例包括但不限于CH 3、
Figure PCTCN2021133158-appb-000039
等。
除非另有规定，“C 2-3烯基”用于表示直链或支链的包含至少一个碳-碳双键的由2至3个碳原子组成的碳氢基团，碳-碳双键可以位于该基团的任何位置上。所述C 2-3烯基包括C 3和C 2烯基；所述C 2-3烯基可以是一价、二价或者多价。C 2-3烯基的实例包括但不限于
Figure PCTCN2021133158-appb-000040
等。
除非另有规定，“C 2-3炔基”用于表示直链或支链的包含至少一个碳-碳三键的由2至3个碳原子组成的碳氢基团，碳-碳三键可以位于该基团的任何位置上。其可以是一价、二价或者多价。所述C 2-3炔基包括C 3和C 2炔基。C 2-3炔基的实例包括但不限于
Figure PCTCN2021133158-appb-000041
等。
除非另有规定，术语“杂烷基”本身或者与另一术语联合，表示由一定数目碳原子和至少一个杂原子或杂原子团组成的，稳定的直链或支链的烷基原子团或其组合物。在一些实施方案中，杂原子选自B、O、N和S，其中氮和硫原子任选地被氧化，氮杂原子任选地被季铵化。在另一些实施方案中，杂原子团选自-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O) 2-、-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O) 2N(H)- 和-S(＝O)N(H)-。在一些实施方案中，所述杂烷基为C 1-6杂烷基；在另一些实施方案中，所述杂烷基为C 1-3杂烷基。杂原子或杂原子团可以位于杂烷基的任何内部位置，包括该烷基与分子其余部分的连接位置，但术语“烷氧基”属于惯用表达，是指通过一个氧原子连接到分子的其余部分的那些烷基基团。杂烷基的实例包括但不限于-OCH 3、-OCH 2CH 3、-OCH 2CH 2CH 3、-OCH 2(CH 3) 2、-CH 2-CH 2-O-CH 3、-NHCH 3、-N(CH 3) 2、-NHCH 2CH 3、-N(CH 3)(CH 2CH 3)、-CH 2-CH 2-NH-CH 3、-CH 2-CH 2-N(CH 3)-CH 3、-SCH 3、-SCH 2CH 3、-SCH 2CH 2CH 3、-SCH 2(CH 3) 2、-CH 2-S-CH 2-CH 3、-CH 2-CH 2、-S(＝O)-CH 3、-CH 2-CH 2-S(＝O) 2-CH 3、和至多两个杂原子可以是连续的，例如-CH 2-NH-OCH 3。
除非另有规定，术语“C 1-6烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至6个碳原子的烷基基团。所述C 1-6烷氧基包括C 1-4、C 1-3、C 1-2、C 2-6、C 2-4、C 6、C 5、C 4和C 3烷氧基等。C 1-6烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)、丁氧基(包括n-丁氧基、异丁氧基、s-丁氧基和t-丁氧基)、戊氧基(包括n-戊氧基、异戊氧基和新戊氧基)、己氧基等。
除非另有规定，术语“C 1-3烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C 1-3烷氧基包括C 1-3、C 1-2、C 2-3、C 1、C 2和C 3烷氧基等。C 1-3烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。
除非另有规定，术语“C 1-6烷氨基”表示通过氨基连接到分子的其余部分的那些包含1至6个碳原子的烷基基团。所述C 1-6烷氨基包括C 1-4、C 1-3、C 1-2、C 2-6、C 2-4、C 6、C 5、C 4、C 3和C 2烷氨基等。C 1-6烷氨基的实例包括但不限于-NHCH 3、-N(CH 3) 2、-NHCH 2CH 3、-N(CH 3)CH 2CH 3、-N(CH 2CH 3)(CH 2CH 3)、-NHCH 2CH 2CH 3、-NHCH 2(CH 3) 2、-NHCH 2CH 2CH 2CH 3等。
除非另有规定，术语“C 1-3烷氨基”表示通过氨基连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C 1-3烷氨基包括C 1-3、C 1-2、C 2-3、C 1、C 2和C 3烷氨基等。C 1-3烷氨基的实例包括但不限于-NHCH 3、-N(CH 3) 2、-NHCH 2CH 3、-N(CH 3)CH 2CH 3、-NHCH 2CH 2CH 3、-NHCH 2(CH 3) 2等。
除非另有规定，术语“C 1-6烷硫基”表示通过硫原子连接到分子的其余部分的那些包含1至6个碳原子的烷基基团。所述C 1-6烷硫基包括C 1-4、C 1-3、C 1-2、C 2-6、C 2-4、C 6、C 5、C 4、C 3和C 2烷硫基等。C 1-6烷硫基的实例包括但不限于-SCH 3、-SCH 2CH 3、-SCH 2CH 2CH 3、-SCH 2(CH 3) 2等等。
除非另有规定，术语“C 1-3烷硫基”表示通过硫原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C 1-3烷硫基包括C 1-3、C 1-2、C 2-3、C 1、C 2和C 3烷硫基等。C 1-3烷硫基的实例包括但不限于-SCH 3、-SCH 2CH 3、-SCH 2CH 2CH 3、-SCH 2(CH 3) 2等。
除非另有规定，术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子(可以是具体的点，也可以是任选两点组成的区间，例如3、4、5、6个环原子、4至11个环原子、6至12个环原子等)，更优选包含3至8个碳原子，最优选包含3至6个(例如3、4、5或6)碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等，优选环烷基；多环环烷基包括螺环、稠环和桥环的环烷基。
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括：
Figure PCTCN2021133158-appb-000042
等。
术语“稠环烷基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。稠环烷基的非限制性实例包括：
Figure PCTCN2021133158-appb-000043
Figure PCTCN2021133158-appb-000044
等。
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为5至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更优选为双环或三环。桥环烷基的非限制性实例包括：
Figure PCTCN2021133158-appb-000045
Figure PCTCN2021133158-appb-000046
等。
所述环烷基包括上述环烷基(例如单环、稠环、螺环和桥环环烷基)稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等；优选苯基并环戊基、四氢萘基。
环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基和氧代基中的一个或多个取代基所取代。
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子(可以是具体的点，也可以是任选两点组成的区间，例如3、4、5、6个环原子、4至11个环原子、6至12个环原子等)，其中1～4个是杂原子；优选包含3至8个环原子，其中1～3个是杂原子；更优选包含3至6个环原子，其中1～3个是杂原子。单环杂环基的非限制性实例包括氮杂环丁基、吡咯烷基、咪唑烷基、四氢呋喃基、四氢吡喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等，优选四氢吡喃基、哌啶基、吡咯烷基。多环杂环基包括螺环、稠环和桥环的杂环基。
术语“螺杂环基”指5至20元的单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至11元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。螺杂环基的非限制性实例包括：
Figure PCTCN2021133158-appb-000047
等。
术语“稠杂环基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环 基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至11元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。稠杂环基的非限制性实例包括：
Figure PCTCN2021133158-appb-000048
Figure PCTCN2021133158-appb-000049
等。
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至11元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更有选为双环或三环。桥杂环基的非限制性实例包括：
Figure PCTCN2021133158-appb-000050
等。
所述杂环基包括上述杂环基(例如单环、稠环、螺环和桥环杂环基)稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：
Figure PCTCN2021133158-appb-000051
Figure PCTCN2021133158-appb-000052
等。
杂环基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基和氧代基中的一个或多个取代基所取代。
术语“芳基”指具有共轭的π电子体系的6至20元全碳单环或稠合多环(即共享毗邻碳原子对的环)基团，优选为6至10元，更优选6元，例如苯基和萘基。所述芳基包括上述芳基稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：
Figure PCTCN2021133158-appb-000053
Figure PCTCN2021133158-appb-000054
芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基和杂环烷硫基中的一个或多个取代基所取代。
术语“杂芳基”指包含1至4个杂原子、5至20个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元，含1至3个杂原子；更优选为5元或6元，含1至3个杂原子；非限制性实例如吡唑基、咪唑基、呋喃基、噻吩基、噻唑基、噁唑基、吡咯基、三唑基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：
Figure PCTCN2021133158-appb-000055
Figure PCTCN2021133158-appb-000056
杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基和杂环烷硫基中的一个或多个取代基所取代。
除非另有规定，“C 3-6环烷基”表示由3至6个碳原子组成的饱和环状碳氢基团，其为单环和双环体系，所述C 3-6环烷基包括C 3-5、C 4-5和C 5-6环烷基等；其可以是一价、二价或者多价。C 3-6环烷基的实例包括，但不限于，环丙基、环丁基、环戊基、环己基等。
除非另有规定，术语“3-6元杂环烷基”本身或者与其他术语联合分别表示由3至6个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“3-6元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述3-6元杂环烷基包括4-6元、5-6元、4元、5元和6元杂环烷基等。3-6元杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基或高哌啶基等。
除非另有规定，本发明术语“5-6元杂芳环”和“5-6元杂芳基”可以互换使用，术语“5-6元杂芳基”表示由5至6个环原子组成的具有共轭π电子体系的单环基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子。其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。5-6元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5-6元杂芳基包括5元和6元杂芳基。所述5-6元杂芳基的实例包括但不限于吡咯基(包括N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、三唑基(1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基和4H-1,2,4-三唑基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)、吡啶基(包括2-吡啶基、3-吡啶基和4-吡啶基等)、吡嗪基或嘧啶基(包括2-嘧啶基和4-嘧啶基等)。
除非另有规定，C n-n+m或C n-C n+m包括n至n+m个碳的任何一种具体情况，例如C 1-12包括C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11、和C 12，也包括n至n+m中的任何一个范围，例如C 1-12包括C 1-3、C 1-6、C 1-9、C 3-6、C 3-9、C 3-12、C 6-9、C 6-12、和C 9-12等；同理，n元至n+m元表示环上原子数为n至n+m个，例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环，也包括n至n+m中的任何一个范围，例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、5-10元环、6-7元环、6-8元环、6-9元环和6-10元环等。
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲和取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术 语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明所使用的溶剂可经市售获得。
化合物依据本领域常规命名原则或者使用
Figure PCTCN2021133158-appb-000057
软件命名，市售化合物采用供应商目录名称。
附图说明
图1是根据本发明实施例的LLC-PK1细胞增殖抑制实验结果图。
具体实施方式
下面通过实施例对本申请进行详细描述，但并不意味着存在对本申请而言任何不利的限制。本文已经详细地描述了本申请，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，在不脱离本申请精神和范围的情况下针对本申请具体实施方式进行各种变化和改进将是显而易见的。
以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。
中间体的制备
参考例1：中间体I-1的制备
Figure PCTCN2021133158-appb-000058
在室温下，将对甲苯磺酰氯(21.9g,115mmol)加入到7-氯-1,2,3,4-四氢苯并[B]氮杂卓-5-酮(15g,76.7mmol)的吡啶(150mL)溶液中。反应液于室温反应16小时。减压浓缩，将反应物倒入水(200mL)中，用乙酸乙酯(100mL×3)萃取，合并有机相。有机相经过饱和氯化钠溶液(100mL)洗涤，无水硫酸钠干燥，过滤。滤液减压浓缩除去有机溶剂，残余物经硅胶色谱法分离纯化得中间体I-1。
LC-MS(ESI)[M+H] +349.9。
1H NMR(400MHz,CDCl 3)δ7.66(d,J＝2.4Hz,1H),7.58(d,J＝8.3Hz,2H),7.47(dd,J＝8.6,2.5Hz,1H),7.43(d,J＝8.5Hz,1H),7.28(d,J＝8.0Hz,2H),3.83(t,J＝6.5Hz,2H),2.43(s,3H),2.40–2.35(m,2H),2.00–1.91(m,2H).
参考例2：中间体I-2的制备
Figure PCTCN2021133158-appb-000059
在室温下，将中间体I-1(20.0g,57.2mmol)加入到环己烷(250mL)中，加入正丁胺(8.49mL,85.8mmol)和三氟乙酸(1.00mL)。反应混合物在氩气保护下回流分水48小时，减压浓缩得到残余物，搅拌状态下向残余物加入乙酸乙酯和石油醚的混合溶液(体积比1:15,64mL)，搅拌十分钟后，抽滤，所得固体减压抽干得中间体I-2。
1H NMR(400MHz,CDCl 3)δ7.56–7.51(m,2H),7.45(d,J＝2.2Hz,1H),7.41–7.38(m,1H),7.37–7.34(m,1H),7.22(d,J＝8.0Hz,2H),3.76(t,J＝6.2Hz,2H),2.93(t,J＝7.2Hz,2H),2.40(s,3H),2.10– 2.06(m,2H),1.76–1.69(m,2H),1.65–1.58(m,2H),1.41-1.35(m,2H),0.96(t,J＝7.4Hz,3H).
参考例3：中间体I-3的制备
Figure PCTCN2021133158-appb-000060
在室温下，将选择性氟试剂(26.2g,74.0mmol)加入到乙腈(200mL)中，分5批加入中间体I-2(15.0g,37.0mmol)，每隔40分钟添加一批。添加完毕，反应混合物在室温下搅拌反应72小时。加入冰水(200mL)，搅拌状态下缓慢滴加浓盐酸(15.0mL)，搅拌五分钟后，抽滤，所得固体减压抽干得中间体I-3。
1H NMR(400MHz,DMSO-d 6)δ7.79–7.63(m,4H),7.44(d,J＝8.0Hz,2H),7.37–7.32(m,1H),4.07–3.98(m,2H),2.67–2.53(m,2H),2.41(s,3H).
参考例4：中间体I-4的制备
Figure PCTCN2021133158-appb-000061
在0℃下，将中间体I-3(12.0g,31.1mmol)加入到浓硫酸(15.0mL)中，反应混合物在室温下搅拌反应4小时。倒入冰水中，用50％氢氧化钠水溶液调节pH为11，用乙酸乙酯(100mL×3)萃取，合并有机相，用饱和食盐水(200mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩得粗产品。粗产品经硅胶色谱法分离纯化得到中间体I-4。
LCMS(ESI)[M+H] +232.1。
1H NMR(400MHz,DMSO)δ7.45(dd,J＝8.4,3.6Hz,2H),7.34(dd,J＝8.9,2.6Hz,1H),6.91(d,J＝8.9Hz,1H),3.29–3.21(m,2H),2.70–2.56(m,2H).
参考例5：中间体I-5的制备
Figure PCTCN2021133158-appb-000062
在室温下，将甲基三苯基溴化膦(18.5g,51.8mmol)加入到四氢呋喃(120mL)中，降温至0℃，加入叔丁醇钾(5.81g,51.8mmol)反应混合物在0℃下搅拌反应1小时后于0℃下加入中间体I-4(6.00g,25.9mmol)的四氢呋喃溶液(20mL)。滴加完毕，反应混合物继续在室温下搅拌反应16小时。反应液倒入冰水(200mL)中，用乙酸乙酯(100mL×3)萃取，合并有机相，用饱和食盐水(200mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩得粗产品。粗产品经硅胶色谱法分离纯化得到中间体I-5。
LCMS(ESI)[M+H] +230.1。
参考例6：中间体I-6的制备
Figure PCTCN2021133158-appb-000063
室温下，将6-氨基烟酸甲酯(1.0g,6.57mmol)溶于吡啶(20mL)中，加入2-三氟甲基苯甲酰氯(1.51g,7.25mmol)，加料完毕后，反应混合物室温搅拌反应1h。将反应混合物倒入冰水(100mL) 中，用乙酸乙酯(50mL×3)萃取，合并有机相用水(50mL×5)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物经硅胶色谱法分离纯化得到中间体I-6。
LC-MS(ESI)[M+H] +325.0。
参考例7：中间体I-7的制备
Figure PCTCN2021133158-appb-000064
室温下，将中间体I-6(1.35g,4.16mmol)溶于四氢呋喃(10mL)中，加入氢氧化钠(499mg,12.5mmol)的水(2mL)溶液，加料完毕后，反应混合物70℃搅拌反应1小时，反应完毕后，用1N盐酸调节反应液pH＝5～6。过滤，固体干燥得中间体I-7。
LC-MS(ESI)[M+H] +311.0。
参考例8：中间体I-8的制备
Figure PCTCN2021133158-appb-000065
在室温下，将中间体I-7(244mg,0.785mmol)溶于N,N-二甲基乙酰胺(6.00mL)中，降温至0℃，加入氯化亚砜(125mg,1.05mmol)，反应混合物在室温下搅拌反应3小时后，加入中间体I-5(120mg,0.523mmol)的N,N-二甲基乙酰胺溶液(3mL)，反应混合物继续在室温下搅拌反应16小时。将反应液加入水(30mL)中，用乙酸乙酯(20mL×3)萃取，合并有机相，分别用饱和碳酸氢钠水溶液(50mL)和饱和食盐水(50mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩得粗产品。粗产品经硅胶色谱法分离纯化得到中间体I-8。
LCMS(ESI)[M+H] +522.2。
参考例9：中间体I-9的制备
Figure PCTCN2021133158-appb-000066
在室温下，将邻甲基苯甲酰氯(5.00g,32.3mmol)溶于氯仿(80mL)，加入4-氨基-2-甲基苯甲酸(4.88g,32.3mmol)，三乙胺(9.81g,96.9mmol)。反应混合物在室温下搅拌3小时。将反应体系倒入水(200mL)中，用乙酸乙酯(100mL×3)萃取，合并有机相，用饱和食盐水(100mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品。粗产品经硅胶色谱法分离纯化得到中间体I-9。
1H NMR(400MHz,DMSO-d 6)δ10.53(s,1H),7.87(d,J＝8.4Hz,1H),7.73–7.62(m,2H),7.51–7.45(m,1H),7.44–7.37(m,1H),7.36–7.25(m,2H),2.53(s,3H),2.39(s,3H).
参考例10：中间体I-10的制备
Figure PCTCN2021133158-appb-000067
在室温下，将中间体I-9(211mg,0.785mmol)溶于N,N-二甲基乙酰胺(6.00mL)中，降温至0℃， 氩气保护下加入氯化亚砜(125mg,1.05mmol)反应混合物在室温下搅拌反应3小时后，加入中间体I-5(120mg,0.523mmol)的N,N-二甲基乙酰胺溶液(3.00mL)。反应混合物继续在室温下搅拌反应16小时。将反应液加入水(30mL)中，用乙酸乙酯(20mL×3)萃取，合并有机相，依次用饱和碳酸氢钠水溶液(50mL)和饱和食盐水(50mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩得粗产品。粗产品经硅胶色谱法分离纯化得到中间体I-10。
LCMS(ESI)[M+H] +481.1。
参考例11：中间体I-11的制备
Figure PCTCN2021133158-appb-000068
在室温下，将6-氨基-4-甲基烟酸甲酯(500mg,3.01mmol)溶于吡啶(20mL)中，加入2-三氟甲基苯甲酰氯(628mg,3.01mmol)，加料完毕后，反应混合物室温搅拌反应1小时。将反应混合物倒入冰水(100mL)中，乙酸乙酯(50mL×3)萃取，合并有机相用水(50mL×5)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物经硅胶色谱法分离纯化得到中间体I-11。
LC-MS(ESI)[M+H] +339.1。
参考例12：中间体I-12的制备
Figure PCTCN2021133158-appb-000069
在室温下，将中间体I-11(700mg,2.07mmol)溶于四氢呋喃(10mL)中，加入氢氧化钠(414mg,10.35mmol)的水(5mL)溶液，加料完毕后，反应混合物70℃搅拌反应1小时。用1N盐酸调节反应液pH＝5～6，过滤，固体干燥得到中间体I-12。
参考例13：中间体I-13的制备
Figure PCTCN2021133158-appb-000070
在0℃下，将中间体I-12(200mg,0.617mmol)溶于二氯甲烷(10mL)中，加入草酰氯(165mg,1.30mmol)和N,N-二甲基甲酰胺(1滴)，加料完毕后，反应混合物0℃下搅拌反应1小时。反应液减压浓缩得粗品中间体I-13。粗品未经进一步纯化直接用于下一步反应。
参考例14：中间体I-14的制备
Figure PCTCN2021133158-appb-000071
将7-氯-1,2,3,4-四氢苯并[B]氮杂卓-5-酮(26.0g,0.133mol)和二碳酸二叔丁酯(200g)加热到100℃反应16小时。冷却至室温，用油泵减压除去大部分二碳酸二叔丁酯，残余物经硅胶色谱法分离纯化得到中间体I-14。
LC-MS(ESI)[M+H-56] +239.9。
1H NMR(400MHz,DMSO-d 6)δ7.66–7.58(m,2H),7.48(d,J＝8.4Hz,1H),3.66(s,2H),2.64(t,J＝6.6Hz,2H),2.07–1.96(m,2H),1.40(d,J＝13.8Hz,9H).
参考例15：中间体I-15的制备
Figure PCTCN2021133158-appb-000072
氩气保护下，于0℃将甲基三苯基溴化磷(47.9g,0.134mol)加入到叔丁醇钾(18.9g,0.168mol)的四氢呋喃(500mL)溶液中，反应液于0℃搅拌30分钟。接着将中间体I-14(33.0g,0.112mol)加入到反应体系中。反应液于室温搅拌16小时。将反应液加入水(500mL)中稀释，用乙酸乙酯(500mL×2)萃取。合并有机相，有机相用水(500mL)和饱和食盐水(500mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩除去有机溶剂得到粗品，粗品经硅胶色谱法分离纯化得到中间体I-15。
LC-MS(ESI)[M+H-56] +238.0。
1H NMR(400MHz,DMSO-d 6)δ7.36(s,1H),7.30(dd,J＝8.5,2.5Hz,1H),7.22(d,J＝8.5Hz,1H),5.20(d,J＝11.7Hz,2H),3.51(s,2H),2.37(t,J＝6.1Hz,2H),1.81(s,2H),1.45–1.28(m,9H).
参考例16：中间体I-16的制备
Figure PCTCN2021133158-appb-000073
在室温下，将中间体I-15(6.10g,20.8mmol)溶于三氟乙酸/二氯甲烷(20.0mL/40.0mL)混合溶液中，反应混合物在室温下搅拌3小时。将体系倒入饱和碳酸氢钠溶液(200mL)中，用二氯甲烷(50mL×4)萃取，合并有机相，用饱和食盐水(50mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品，粗产品经硅胶色谱法分离纯化得到中间体I-16。
1H NMR(400MHz,DMSO-d 6)δ7.11(d,J＝2.5Hz,1H),7.00(dd,J＝8.6,2.5Hz,1H),6.69(d,J＝8.6Hz,1H),5.17(d,J＝1.6Hz,1H),4.99–4.93(m,1H),3.18–3.07(m,2H),2.50–2.45(m,2H),1.88–1.76(m,2H).
参考例17：中间体I-17的制备
Figure PCTCN2021133158-appb-000074
在室温下，将中间体I-13(150mg)溶于吡啶(10mL)中，加入中间体I-16(60mg,0.310mmol)，加料完毕后，反应混合物室温搅拌反应16小时。反应液加水(10mL)稀释，用乙酸乙酯(10mL×3)萃取，合并有机相用水(10mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物经硅胶色谱法分离纯化得到中间体I-17。
LC-MS(ESI)[M+H] +500.1。
参考例18：中间体I-18的制备
Figure PCTCN2021133158-appb-000075
在室温下，将邻甲基苯甲酰氯(6.11g,39.5mmol)加入到6-氨基烟酸甲酯(5.00g,32.9mmol)的吡啶(40.0mL)溶液中。反应混合物于室温下搅拌反应2小时后，倒入水(300mL)中，抽滤，所得固体经干燥后得到中间体I-18。
LC-MS(ESI)[M+H] +271.0。
参考例19：中间体I-19的制备
Figure PCTCN2021133158-appb-000076
在室温下，将氢氧化钠(2.66g,66.6mmol)加入到中间体I-18(6.00g,22.2mmol)的甲醇/水(60mL/30mL)溶液中。反应混合物于70℃搅拌30分钟。冷却至室温，冰水浴下用3N稀盐酸调节pH＝5～6，用乙酸乙酯(50mL×6)萃取。合并有机相，用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩除去有机溶剂得到中间体I-19。
LC-MS(ESI)[M+H] +257.1。
参考例20：中间体I-20的制备
Figure PCTCN2021133158-appb-000077
在室温下，将中间体I-19(1.50g,5.85mmol)和N,N-二甲基甲酰胺(0.10mL)加入到二氯甲烷(20.0mL)中，反应体系降温至0℃，加入草酰氯(1.49g,11.7mmol)。反应液于0℃下搅拌反应1小时，浓缩干得粗产品中间体I-20。粗品未经进一步纯化直接用于下一步反应。
参考例21：中间体I-21的制备
Figure PCTCN2021133158-appb-000078
在室温下，将中间体I-16(378mg,1.95mmol)加入到吡啶(5.00mL)中，一次性加入中间体I-20(500mg)。反应液于室温搅拌反应16小时后，倒入水(30mL)中，用乙酸乙酯(20mL×3)萃取，合并有机相，用饱和食盐水(50mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩得粗产品。粗产品经硅胶色谱法分离纯化得到中间体I-21。
LC-MS(ESI)[M+H] +432.1。
参考例22：中间体I-22的制备
Figure PCTCN2021133158-appb-000079
在0℃下，将中间体I-7(200mg,0.65mmol)溶于二氯甲烷(10mL)中，加入草酰氯(165mg,1.30mmol)和N,N-二甲基甲酰胺(1滴)，加料完毕后，反应混合物在0℃下搅拌反应1小时。反应液减压浓缩得粗品中间体I-22。粗品未经进一步纯化直接用于下一步反应。
参考例23：中间体I-23的制备
Figure PCTCN2021133158-appb-000080
在室温下，将中间体I-22(214mg,0.65mmol)溶于吡啶(10mL)中，加入中间体I-16(97mg,0.501mmol)，加料完毕后，反应混合物室温搅拌反应16小时。加水(10mL)稀释，用乙酸乙酯(10mL×3)萃取，合并有机相用水(10mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物经硅胶色谱法分离纯化得到中间体I-23。
LC-MS(ESI)[M+H] +486.2。
参考例24：中间体I-24的制备
Figure PCTCN2021133158-appb-000081
在室温下，将氰化亚铜(24.0g,0.268mol)加入到2-氨基-5-溴-4-甲基吡啶(25.0g,0.134mol)的N,N-二甲基乙酰胺(230mL)溶液中。反应混合物氩气保护下于170℃搅拌反应16小时。冷却至0℃，反应液中加入乙二胺(50mL)和水(500mL)，搅拌15分钟淬灭反应。用乙酸乙酯(300mL×3)萃取，合并有机相，有机相用水(300mL×3)及饱和食盐水(500mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩除去有机溶剂得到粗产品。粗产品经硅胶色谱法分离纯化得到中间体I-24。
LC-MS(ESI)[M+H] +134.1。
1H NMR(400MHz,DMSO-d 6)δ8.23(s,1H),6.89(s,2H),6.35(s,1H),2.25(s,3H).
参考例25：中间体I-25的制备
Figure PCTCN2021133158-appb-000082
在室温下，将中间体I-24(10.2g,76.6mmol)加入氢氧化钠水溶液(90mL,10mol/L)和乙醇(90mL)溶液中，反应混合物回流反应16小时。冷却至室温，用盐酸(6mol/L)调节pH到中性，析出固体，过滤，滤饼用水洗涤，烘干得到中间体I-25。
LC-MS(ESI)[M+H] +153.3。
参考例26：中间体I-26的制备
Figure PCTCN2021133158-appb-000083
在室温下，将氯化亚砜(15mL)加入到中间体I-25(7.8g,51.3mmol)的甲醇(80mL)溶液中。反应混合物回流反应16小时。冷却至室温，减压除去大部分甲醇溶剂，加入水(100mL)稀释，并用氢氧化钠水溶液(2mol/L)调节pH至13，析出固体，抽滤，滤饼用水洗，烘干得到中间体I-26。
LC-MS(ESI)[M+H] +167.1。
参考例27：中间体I-27的制备
Figure PCTCN2021133158-appb-000084
在室温下，将邻甲基苯甲酰氯(5.14g,33.2mmol)加入到中间体I-26(4.6g,27.7mmol)的吡啶(35mL)溶液中，反应混合物于室温搅拌反应3小时。往反应液中加入冰水(70mL)，析出固体，固体过滤，滤饼用大量水和石油醚洗涤，烘干得到中间体I-27。
LC-MS(ESI)[M+H] +285.2。
参考例28：中间体I-28的制备
Figure PCTCN2021133158-appb-000085
在室温下，将5％氢氧化钠水溶液(48mL)加入到中间体I-27(4.1g,14.4mmol)的甲醇(60mL)溶液中，反应混合物于70℃反应30分钟。冷却至室温，加入水(50mL)稀释，并用盐酸(3mol/L)调节pH至弱酸性，析出固体，过滤，滤饼用大量水洗，冻干，得到中间体I-28。
LC-MS(ESI)[M+H] +271.1。
1H NMR(400MHz,DMSO-d 6)δ13.04(s,1H),10.99(s,1H),8.75(s,1H),8.16(s,1H),7.48(d,J＝7.6Hz,1H),7.43–7.35(m,1H),7.32–7.24(m,2H),2.60(s,3H),2.39(s,3H).
参考例29：中间体I-29的制备
Figure PCTCN2021133158-appb-000086
冰水浴下，将草酰氯(2.07g,16.3mmol)和N,N-二甲基甲酰胺(1滴)加入到中间体I-28(2.2g,8.14mmol)的二氯甲烷(30mL)溶液中，反应液于0℃反应30分钟。低温浓缩干溶剂得到粗品中间体I-29，无需纯化直接用于下一步反应。
参考例30：中间体I-30的制备
Figure PCTCN2021133158-appb-000087
在室温下，将中间体I-29(1.75g)加入到中间体I-16(900mg,4.65mmol)的吡啶(30mL)溶液中。反应混合物于室温搅拌反应3小时。加入水(50mL)，用乙酸乙酯(30mL×2)萃取。合并有机相，并用水(30mL×3)和饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩除去有机溶剂得到粗产品。粗品经硅胶色谱法分离纯化得到中间体I-30。
LC-MS(ESI)[M+H] +446.2。
参考例31：中间体I-31的制备
Figure PCTCN2021133158-appb-000088
在室温下，将N-溴代丁二酰亚胺(110mg,0.618mmol)加入到中间体I-30(230mg,0.516mmol)的四氢呋喃/水(15mL/3mL)溶液中，反应液于室温搅拌16小时。再将氢氧化钠水溶液(2mL,2.5N)加入其中，反应液于室温搅拌2小时。反应液加入水(20mL)稀释，用乙酸乙酯(20mL×2)萃取。合并有机相，并用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩除去有机溶剂得到粗产品。粗品经硅胶色谱法分离纯化得到中间体I-31。
LC-MS(ESI)[M+H] +462.0。
1H NMR(400MHz,DMSO-d 6)δ10.97–10.53(m,1H),8.47–7.63(m,2H),7.56–7.10(m,6H),7.03–6.66(m,1H),4.98–4.67(m,1H),3.30–2.62(m,3H),2.48–2.25(m,6H),2.21–1.99(m,2H),1.91–1.52(m,2H).
参考例32：中间体I-32的制备
Figure PCTCN2021133158-appb-000089
室温下，将2-甲基-4-硝基苯甲酰氯(2.06g,10.3mmol)和三乙胺(3.13g,30.9mmol)加入到中间体I-16(2.0g,10.3mmol)的二氯甲烷(40mL)溶液中。反应混合物在室温下搅拌1小时，将体系倒入水(100mL)中，用二氯甲烷(50mL×3)萃取，合并有机相，用饱和食盐水(50mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品。粗品经硅胶色谱法分离纯化得到中间体I-32。
LC-MS(ESI)[M+H] +356.9。
参考例33：中间体I-33的制备
Figure PCTCN2021133158-appb-000090
在室温下，将铁粉(282mg,5.05mmol)和氯化铵(540mg,10.1mmol)加入到中间体I-32(360mg,1.01mmol)的甲醇/水(20mL/5mL)溶液中。氩气保护下，反应液于60℃搅拌3小时。冷却至室温，过滤，滤液浓缩干得到粗产品。粗品经硅胶色谱法分离纯化得到中间体I-33。
LC-MS(ESI)[M+H] +327.0。
参考例34：中间体I-34的制备
Figure PCTCN2021133158-appb-000091
在室温下，将邻氯苯甲酰氯(225mg,1.29mmol)和三乙胺(260mg,2.59mmol)加入到中间体I-33(280mg,0.857mmol)的1,2-二氯乙烷(20mL)溶液中。反应混合物于50℃搅拌2小时。冷却至室温，反应液用二氯甲烷(20mL)稀释，饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩干得粗品。粗品经硅胶色谱法分离纯化得到中间体I-34。
LC-MS(ESI)[M+H] +465.2。
参考例35：中间体I-35的制备
Figure PCTCN2021133158-appb-000092
在室温下，将中间体I-9(2.00g,7.43mmol)加入到氯化亚砜(20.0mL)溶液中，反应混合物于40℃搅拌4小时。将反应体系减压浓缩得粗品中间体I-35，直接用于下一步反应。
参考例36：中间体I-36的制备
Figure PCTCN2021133158-appb-000093
在室温下，将中间体I-16(1.42g,7.31mmol)溶于吡啶(30.0mL)，加入中间体I-35(2.00g)，反应混合物在室温下搅拌8小时。将反应体系倒入水(100mL)中，用乙酸乙酯(50mL×3)萃取，合并有机相，用饱和食盐水(50mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品。粗产品经硅胶色谱法分离纯化得到中间体I-36。
LC-MS(ESI)[M+H] +445.0。
参考例37：中间体I-37的制备
Figure PCTCN2021133158-appb-000094
在室温下，将中间体I-36(1.00g,2.25mmol)溶于二氯甲烷(30.0mL)中，加入间氯过氧苯甲酸(1.95g,11.3mmol)，反应体系在室温下搅拌10小时。将体系室温减压浓缩得到粗产品，粗产品经C18反相色谱法分离纯化得到中间体I-37。
1H NMR(400MHz,DMSO-d 6)δ10.41–10.23(m,1H),7.77–7.10(m,9H),6.83–6.63(m,1H),5.04–3.53(m,1H),3.21–2.68(m,3H),2.37–2.33(m,6H),2.13–1.56(m,4H).
参考例38：中间体I-38的制备
Figure PCTCN2021133158-appb-000095
在25℃下，将中间体I-1(1.00g,2.86mmol)溶于四氢呋喃(10mL)中，加入叔丁基亚磺酰胺(415.74mg,3.43mmol)，钛酸四乙酯(1.30g,5.72mmol)，微波80℃搅拌3小时。加水(10mL)，过滤，滤饼用乙酸乙酯(20mL)洗，收集滤液，滤液用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩干得粗品。粗品经硅胶色谱法分离纯化得到中间体I-38。
LC-MS(ESI)[2M+H] +453.0。
参考例39：中间体I-39的制备
Figure PCTCN2021133158-appb-000096
在25℃下，将锌粉(2.01g,30.76mmol)悬浮于四氢呋喃(100mL)中，置换氮气三次。加入1,2-二溴乙烷(96.31mg,0.51mmol)，三甲基氯硅烷(278.48mg,2.56mmol)，65℃搅拌1小时。滴加溴乙酸叔丁酯(5.00g,25.63mmol)，滴加完毕后，50℃搅拌1小时。冷却得到中间体I-39的四氢呋喃溶液(100mL,25.63mmol)。
参考例40：中间体I-40的制备
Figure PCTCN2021133158-appb-000097
在25℃下，向中间体I-39的四氢呋喃溶液(100mL,25.63mmol)中滴加中间体I-38(850.00mg,1.88mmol)的四氢呋喃(20mL)溶液，50℃搅拌反应16小时。加水(100mL)，用乙酸乙酯(100mL×3)萃取。合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得粗品。粗品经硅胶色谱法分离纯化得到中间体I-40。
LC-MS(ESI)[M+H] +569.2。
参考例41：中间体I-41的制备
Figure PCTCN2021133158-appb-000098
在25℃下，将中间体I-40(350.00mg,0.61mmol)溶于四氢呋喃(10mL)，加入二异丁基氢化铝的甲苯溶液(2.05mL,3.07mmol,1.5M)，室温反应16小时。依次加入水(0.12mL)、15％氢氧化钠水溶液(0.12mL)、水(0.3mL)，再加入无水硫酸钠，室温搅拌0.5小时。过滤，滤液浓缩，经硅胶色谱法分离纯化得到中间体I-41。
LC-MS(ESI)[M+H] +499.2。
参考例42：中间体I-42的制备
Figure PCTCN2021133158-appb-000099
在25℃下，将中间体I-41(170.00mg,0.34mmol)溶于甲苯(10mL)，加入氰基亚甲基三正丁基膦(98.47mg,0.41mmol)，于110℃搅拌反应3小时。冷却到室温，加水(10mL)，用乙酸乙酯(10mL×3)萃取。合并有机相，有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩，经硅胶色谱法分离纯化得到中间体I-42。
LC-MS(ESI)[M+H] +481.2。
参考例43：中间体I-43的制备
Figure PCTCN2021133158-appb-000100
在25℃下，将中间体I-42(100.00mg,0.21mmol)溶于浓盐酸(5mL)，100℃反应16小时。直接浓缩干，经C18反相柱分离纯化得到中间体I-43。
LC-MS(ESI)[M+H] +223.0。
参考例44：中间体I-44的制备
Figure PCTCN2021133158-appb-000101
在25℃下，将中间体I-43(40.00mg,0.18mmol)溶于四氢呋喃(5mL)，加入10％碳酸氢钠水溶液(5mL)，二碳酸二叔丁酯(47.04mg,0.22mmol)，室温反应1小时。加水(10mL)，用乙酸乙酯(10mL×3)萃取。合并有机相，有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩，经硅胶色谱法分离纯化得到中间体I-44。
LC-MS(ESI)[M+H] +323.2。
参考例45：中间体I-45的制备
Figure PCTCN2021133158-appb-000102
在25℃下，将中间体I-44(50.00mg,0.15mmol)溶于二氯甲烷(10mL)，加入三乙胺(47.02mg,0.46mmol)，2-甲基-4-硝基苯甲酰氯(46.37mg,0.23mmol)，室温搅拌反应16小时。加水(10mL)，用二氯甲烷(10mL×3)萃取。合并有机相，有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩，经硅胶色谱法分离纯化得到中间体I-45。
LC-MS(ESI)[M-100+H] +386.2。
参考例46：中间体I-46的制备
Figure PCTCN2021133158-appb-000103
在25℃下，将中间体I-45(50.00mg,0.10mmol)溶于乙醇(4mL)，加入还原铁粉(28.73mg,0.51mmol)，饱和氯化铵水溶液(2mL)，80℃搅拌反应5小时。过滤，滤饼用乙酸乙酯(10mL)洗涤，收集滤液，加水(10mL)分层。收集有机相，浓缩，经硅胶色谱法分离纯化得到中间体I-46。
LC-MS(ESI)[M-100+H] +356.2。
参考例47：中间体I-47的制备
Figure PCTCN2021133158-appb-000104
在25℃下，将中间体I-46(30.00mg,0.066mmol)溶于二氯甲烷(5mL)，依次加入三乙胺(19.97mg,0.20mmol)，2-甲基苯甲酰氯(12.21mg,0.079mmol)，室温反应1小时。加水(10mL)，用二氯甲烷(10mL×3)萃取。合并有机相，有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩干，经硅胶色谱法分离纯化得到中间体I-47。
LC-MS(ESI)[M-100+H] +474.2。
参考例48：中间体I-48的制备
Figure PCTCN2021133158-appb-000105
在室温下，将碳酸铯(82.7g,254mmol)和四三苯基膦钯(2.93g,2.54mmol)加入到2-溴-4-氯-1-硝基苯(20.0g,84.6mmol)和3,6-二氢-2H-吡喃-4-硼酸频哪醇酯(21.3g,101.4mmol)的二氧六环/水(600mL/200mL)溶液中，反应混合物在氩气保护下于100℃搅拌反应5小时。冷却至室温，减压除去大部分溶剂，用乙酸乙酯(100mL×3)萃取，合并有机相，有机相用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩除去有机溶剂得到粗产品。粗产品经硅胶色谱法分离纯化得到中间体I-48。
LC-MS(ESI)[M+H] +240.0。
1H NMR(400MHz,CD 3OD)δ7.92(d,J＝8.7Hz,1H),7.52(dd,J＝8.7,2.3Hz,1H),7.44(d,J＝2.3Hz,1H),5.75–5.71(m,1H),4.26–4.21(m,2H),3.89(t,J＝5.3Hz,2H),2.36–2.31(m,2H).
参考例49：中间体I-49的制备
Figure PCTCN2021133158-appb-000106
在室温下，将间氯过氧苯甲酸(16.2g,93.9mmol)加入到中间体I-48(15.0g,62.6mmol)的二氯甲烷(100mL)溶液中。反应混合物在室温下搅拌反应16小时。反应混合物加二氯甲烷(100mL)稀 释，用饱和硫代硫酸钠水溶液(100mL×3)洗涤，饱和碳酸钠水溶液(100mL×3)以及饱和食盐水(200mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩除去有机溶剂得到粗品。粗产品经硅胶色谱法分离纯化得到中间体I-49。
LC-MS(ESI)[M+H] +256.0。
1H NMR(400MHz,DMSO-d 6)δ8.17(d,J＝8.7Hz,1H),7.77–7.68(m,2H),4.01–3.88(m,2H),3.69–3.61(m,1H),3.53–3.45(m,1H),3.37(s,1H),2.20–2.11(m,1H),2.03–1.95(m,1H).
参考例50：中间体I-50的制备
Figure PCTCN2021133158-appb-000107
在冰水浴下，将三氟化硼乙醚(4.37g,30.8mmol)加入到中间体I-49(7.5g,29.3mmol)的二氯甲烷(70mL)溶液中。反应混合物0℃搅拌30分钟。反应混合物用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩除去有机溶剂得到粗品。粗产品经硅胶色谱法分离纯化得到中间体I-50。
LC-MS(ESI)[M+H] +256.0。
1H NMR(400MHz,DMSO-d 6)δ9.56(s,1H),8.07(d,J＝8.7Hz,1H),7.72(dd,J＝8.7,2.2Hz,1H),7.65(d,J＝3.6Hz,1H),4.31(d,J＝9.8Hz,1H),4.05(d,J＝9.9Hz,1H),4.00–3.86(m,2H),2.69–2.60(m,1H),2.40–2.31(m,1H).
参考例51：中间体I-51的制备
Figure PCTCN2021133158-appb-000108
在冰水浴氩气保护下，将氢化钠(278mg,60％wt,6.95mmol)加入到三乙基膦酰乙酸酯(1.18g,5.26mmol)的四氢呋喃(30mL)中，在冰水浴下搅拌30分钟，然后将中间体I-50(890mg,3.48mmol)加入其中，反应混合物于室温反应2小时。反应混合物加水(30mL)，用乙酸乙酯(20mL×2)萃取。合并有机相，并用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩除去有机溶剂得到粗产品。粗产品经硅胶色谱法分离纯化得到中间体I-51。
LC-MS(ESI)[M+H] +326.1。
1H NMR(400MHz,DMSO-d 6)δ7.91–7.84(m,1H),7.70–7.63(m,2H),7.08(d,J＝15.9Hz,1H),5.68(d,J＝15.9Hz,1H),4.18–4.06(m,3H),3.92–3.81(m,3H),2.48–2.43(m,1H),2.36–2.27(m,1H),1.19(t,J＝7.1Hz,3H).
参考例52：中间体I-52的制备
Figure PCTCN2021133158-appb-000109
在室温下，将二氧化铂(50mg)加入到中间体I-51(720mg,2.21mmol)的四氢呋喃(50mL)溶液中。反应混合物用氢气球室温氢化反应约6小时。过滤，滤液减压浓缩除去有机溶剂得到粗产品。粗产品经硅胶色谱法分离纯化得到中间体I-52。
LC-MS(ESI)[M+H] +298.1。
参考例53：中间体I-53的制备
Figure PCTCN2021133158-appb-000110
在室温下，将氢氧化钠(88.7mg,2.22mmol)加入到中间体I-52(220mg,0.739mmol)的四氢呋喃/水(10mL/3mL)溶液中。反应液于40℃搅拌反应16小时。冷却至室温，反应液用稀盐酸(1N)调节pH至7，减压浓缩除去有机溶剂得到粗品中间体I-53，无需纯化直接用于下一步反应。
LC-MS(ESI)[M+H] +270.1。
参考例54：中间体I-54的制备
Figure PCTCN2021133158-appb-000111
在室温下，将1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(283mg,1.48mmol)和4-二甲氨基吡啶(135mg,1.11mmol)加入到中间体I-53(300mg)的四氢呋喃(60mL)溶液中，反应液于室温反应16小时。反应混合物加水(60mL)，用乙酸乙酯(50mL×3)萃取。合并有机相，并用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩除去有机溶剂得到粗产品。粗产品经硅胶色谱法分离纯化得到中间体I-54。
LC-MS(ESI)[M+H] +252.1。
1H NMR(400MHz,DMSO-d 6)δ9.57(d,J＝30.6Hz,1H),7.40–7.29(m,2H),7.04–6.97(m,1H),3.90–3.78(m,3H),3.73–3.65(m,1H),2.31–2.05(m,6H).
参考例55：中间体I-55的制备
Figure PCTCN2021133158-appb-000112
在室温下，将硼烷-四氢呋喃溶液(2.09mL,1M)加入到中间体I-54(105mg,0.417mmol)的四氢呋喃(20mL)中，反应液于40℃反应2小时。冷却至室温，加入水(20mL)稀释，用乙酸乙酯(20mL×2)萃取。合并有机相，并用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩除去有机溶剂得到粗产品。粗品经硅胶色谱法分离纯化得到中间体I-55。
LC-MS(ESI)[M+H] +238.1。
1H NMR(400MHz,CDCl 3)δ7.21(d,J＝2.3Hz,1H),7.00(dd,J＝8.3,2.4Hz,1H),6.65(d,J＝8.3Hz,1H),4.10(d,J＝8.8Hz,1H),3.97–3.89(m,2H),3.81–3.74(m,1H),3.14–3.05(m,1H),3.00–2.93(m,1H),2.40–2.32(m,1H),2.18–2.09(m,1H),1.89–1.83(m,2H),1.75–1.69(m,2H).
参考例56：中间体I-56的制备
Figure PCTCN2021133158-appb-000113
在室温下，将2-甲基-4-硝基苯甲酰氯(42.4mg,0.212mmol)加入到中间体I-55(42mg,0.177mmol)和吡啶(42.0mg,0.531mmol)的四氢呋喃(5mL)溶液中。反应液于50℃反应5小时。冷却至室温，加入水(15mL)稀释，用乙酸乙酯(10mL×2)萃取。合并有机相，并用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品。粗品经硅胶色谱法分离纯化得到中间体I-56。
LC-MS(ESI)[M+H] +401.0。
参考例57：中间体I-57的制备
Figure PCTCN2021133158-appb-000114
在室温下，将铁粉(31.3mg,0.560mmol)和氯化铵(59.9mg,1.12mmol)加入到中间体I-56(45mg,0.112mmol)的甲醇/水(10mL/3mL)溶液中。氩气保护下，反应液于50℃反应2小时。冷却至室温，过滤，滤液浓缩除去大部分溶剂，加入水(5mL)稀释，用乙酸乙酯(10mL×3)萃取。合并有机相，并用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品。粗品经硅胶色谱法分离纯化得到中间体I-57。
LC-MS(ESI)[M+H] +371.0。
参考例58：中间体I-58的制备
Figure PCTCN2021133158-appb-000115
在室温下，将三甲基碘化亚砜(370mg,1.68mmol)和叔丁醇钾(189mg,1.68mmol)加入到二甲基亚砜(6.00mL)中，氩气保护下搅拌反应30分钟后，于室温下加入中间体I-4(130mg,0.561mmol)，反应混合物继续在室温下搅拌反应3小时。加入水(20mL)，用乙酸乙酯(10mL×3)萃取，合并有机相，用饱和食盐水(50mL)洗，无水硫酸钠干燥，过滤，减压浓缩得粗产品。粗产品经硅胶色谱法分离纯化得到中间体I-58。
LCMS(ESI)[M+H] +260.0。
1HNMR(400MHz,DMSO-d 6)δ7.57(d,J＝2.6Hz,1H),7.17(dd,J＝8.4,2.6Hz,1H),6.86(d,J＝8.4Hz,1H),5.65(d,J＝4.9Hz,1H),4.57–4.40(m,2H),3.22–3.05(m,2H),2.73(t,J＝12.4Hz,1H),2.41–2.32(m,1H),2.20–2.04(m,1H).
参考例59：中间体I-59的制备
Figure PCTCN2021133158-appb-000116
在室温下，将N-溴代丁二酰亚胺(395mg,2.22mmol)加入到中间体I-21(800mg,1.85mmol)的四氢呋喃/水(15mL/3mL)溶液中，反应液于室温搅拌24小时。然后将10％氢氧化钠水溶液(3.70mL,9.25mmol)加入其中。反应液于室温继续搅拌1小时。反应液用乙酸乙酯(15mL×3)萃取。合并有机相，并用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩除去有机溶剂得到粗产品。粗品经C18反相柱分离纯化得到中间体I-59。
LC-MS(ESI)[M+H] +448.1。
1H NMR(400MHz,DMSO-d 6)δ10.87(m,2H),8.20–6.90(m,10H),4.94–4.81(m,1H),3.13–2.78(m,3H),2.35(s,3H),2.15–1.93(m,2H),1.66(m,2H).
参考例60：中间体I-60的制备
Figure PCTCN2021133158-appb-000117
在室温下，将2-苯基苯甲酸(14.0g,70.6mmol)溶于二氯甲烷(200mL)中，向体系中加入氯化亚砜(16.8g,141mmol)，反应混合物在室温下搅拌3小时。将反应液减压浓缩得到粗品中间体I-60，直接用于下一步反应。
参考例61：中间体I-61的制备
Figure PCTCN2021133158-appb-000118
在室温下，将中间体I-60(10.0g)溶于吡啶(80.0mL)，加入6-氨基烟酸甲酯(7.03g,46.2mmol)，反应混合物在室温下搅拌3小时。将反应体系倒入水(500mL)中，用乙酸乙酯(100mL×3)萃取，合并有机相，用饱和食盐水(100mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品。粗产品经C18反相柱分离纯化得到中间体I-61。
LC-MS(ESI)[M+H] +333.0。
参考例62：中间体I-62的制备
Figure PCTCN2021133158-appb-000119
在室温下，将中间体I-61(10.0g,30.1mmol)溶于甲醇/水(100mL/20mL)中，向体系中加入氢氧化钠(3.61g,90.3mmol)，反应混合物在室温下搅拌3小时。用稀盐酸(1.0mol/L)调节体系pH＝6～7，有大量固体析出，过滤，收集固体、减压干燥得到中间体I-62。
LC-MS(ESI)[M+H] +319.0。
参考例63：中间体I-63的制备
Figure PCTCN2021133158-appb-000120
在室温下，将中间体I-62(2.00g,6.28mmol)溶于二氯甲烷(30.0mL)中，加入二氯亚砜(2.24g,18.8mmol)，反应混合物在50℃下搅拌3小时。将反应体系减压浓缩得粗品中间体I-63，直接用于下一步反应。
参考例64：中间体I-64的制备
Figure PCTCN2021133158-appb-000121
在室温下，将中间体I-16(633mg,3.27mmol)溶于吡啶(10.0mL)，加入中间体I-63(1.10g)，反应混合物在室温下搅拌3小时。将体系倒入水(50.0mL)中，用乙酸乙酯(20mL×3)萃取，合并有机相，用饱和食盐水(20mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品。粗产品经硅胶色谱法分离纯化得到中间体I-64。
LC-MS(ESI)[M+H] +494.2。
参考例65：中间体I-65的制备
Figure PCTCN2021133158-appb-000122
在室温下，将中间体I-64(500mg,1.01mmol)溶于四氢呋喃/水(25mL/5mL)中，加入N-溴代丁二酰亚胺(360mg,2.02mmol)，反应混合物在室温下搅拌24小时。向反应体系内加入25％氢氧化钠水溶液(1.00mL)，体系在室温下搅拌1小时。将反应体系倒入水(20mL)中，用乙酸乙酯(10mL×3)萃取，合并有机相，用饱和食盐水(15mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品。粗产品经硅胶色谱法分离纯化得到中间体I-65。
LC-MS(ESI)[M+H] +510.1。
参考例66：中间体I-66的制备
Figure PCTCN2021133158-appb-000123
在冰水浴下，将N-甲基脲(5.0g,67.5mmol)溶于水(40mL)中，然后将亚硝酸钠(5.12g,74.2mmol)加入其中。在冰水浴搅拌下，缓慢滴加浓盐酸(8.9mL)约30分钟，并于冰水浴下反应30分钟。将沉淀过滤，滤饼用水洗，油泵抽干得到中间体I-66，无需继续纯化直接用于下一步反应。
参考例67：中间体I-67的制备
Figure PCTCN2021133158-appb-000124
在冰水浴下，将40％氢氧化钾水溶液(40mL)和乙醚(54mL)加入到光滑的反应瓶中，将中间体I-66(4.2g,40.7mmol)分批次加入上述体系中。轻轻晃动反应瓶数次，反应30分钟后，将上层乙醚液转移到另一放有氢氧化钾固体的光滑瓶中进行干燥。得到中间体I-67的乙醚溶液(0.75M)直接用于下一步反应。
参考例68：中间体I-68的制备
Figure PCTCN2021133158-appb-000125
在冰水浴下，将中间体I-67的乙醚溶液(40mL,0.75M)缓慢加入到中间体I-15(300mg，1.02mmol)和醋酸钯(50mg)的乙醚(10mL)溶液中，在冰水浴下搅拌1小时。反应液加醋酸(1mL)淬灭，并加入水(30mL)稀释，用乙醚(20mL×3)萃取，合并有机相，有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤。滤液减压浓缩除去有机溶剂得到粗产品。粗产品经硅胶色谱法分离纯化得到中间体I-68。
LC-MS(ESI)[M+H-56] +252.1。
参考例69：中间体I-69的制备
Figure PCTCN2021133158-appb-000126
在室温下，将三氟乙酸(1mL)加入到中间体I-68(90mg,0.292mmol)的二氯甲烷(5mL)溶液中。反应液于室温搅拌5小时。减压浓缩干得粗品中间体I-69，直接用于下一步反应。
LC-MS(ESI)[M+H] +208.1。
参考例70：中间体I-70的制备
Figure PCTCN2021133158-appb-000127
在室温下，将2-甲基-4-硝基苯甲酰氯(115mg,0.576mmol)加入到中间体I-69(60mg)和吡啶(68.6mg,0.867mmol)的1,2-二氯乙烷(10mL)溶液中，反应液于50℃搅拌16小时。冷却至室温，加入二氯甲烷(20mL)稀释，用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤。滤液减压浓缩除去有机溶剂得到粗产品。粗产品经硅胶色谱法分离纯化得到中间体I-70。
LC-MS(ESI)[M+H] +371.1。
参考例71：中间体I-71的制备
Figure PCTCN2021133158-appb-000128
在室温下，将铁粉(30.2mg,0.541mmol)和氯化铵(57.8mg,1.08mmol)加入到中间体I-70(40mg,0.108mmol)的甲醇/水(10mL/3mL)溶液中，氩气保护下，反应液于50℃搅拌3小时。冷却至室温，过滤，滤液浓缩干得粗品。粗产品经硅胶色谱法分离纯化得到中间体I-71。
LC-MS(ESI)[M+H] +341.1。
参考例72：中间体I-72的制备
Figure PCTCN2021133158-appb-000129
在室温下，将丙二酸二乙酯(10.0g,62.5mmol)溶于二甲亚砜(150mL)中，缓慢加入钠氢(2.92g,60％wt,72.9mmol)，反应混合物于室温搅拌30分钟后，将2,4-二氯硝基苯(10.0g,52.1mmol)加入到反应液中，加料完毕后，加热至80℃搅拌5小时。冷却至室温，加水(300mL)，用乙酸乙酯(300mL×3)萃取。合并有机相，并用饱和食盐水(300mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩除去有机溶剂得到粗产品。粗产品经硅胶色谱法分离纯化得到中间体I-72。
LC-MS(ESI)[M+H] +316.0。
参考例73：中间体I-73的制备
Figure PCTCN2021133158-appb-000130
在室温下，将中间体I-72(10.0g,31.68mmol)溶于二甲亚砜(100mL)和水(1mL)中，加入氯化锂(6.65g,158.4mmol)，加料完毕后，加热至100℃搅拌5小时。冷却至室温，加水(200mL)稀释，用乙酸乙酯(200mL×3)萃取。合并有机相，并用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩除去有机溶剂得到粗产品。粗产品经硅胶色谱法分离纯化得到中间体I-73。
1H NMR(400MHz,CDCl 3)δ8.08(d,J＝8.8Hz,1H),7.44(dd,J＝8.8,2.3Hz,1H),7.35(d,J＝2.2Hz,1H),4.17(q,J＝7.1Hz,2H),3.99(s,2H),1.25(t,J＝7.1Hz,3H).
参考例74：中间体I-74的制备
Figure PCTCN2021133158-appb-000131
在0℃下，将中间体I-73(3.5g,14.4mmol)溶于N,N-二甲基甲酰胺(100mL)中，缓慢加入到钠氢(860mg,60％wt,21.5mmol)的N,N-二甲基甲酰胺(10mL)溶液中，反应混合物搅拌30分钟后。将1,3二碘丙烷(5.1g,17.2mmol)加入到反应液中，加料完毕后，室温搅拌过夜。加水(200mL)稀释，用乙酸乙酯(200mL×3)萃取。合并有机相，并用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩除去有机溶剂得到粗产品。粗产品经硅胶色谱法分离纯化得到中间体I-74。
1H NMR(400MHz,CDCl 3)δ7.88(d,J＝8.6Hz,1H),7.44(d,J＝2.2Hz,1H),7.37(dd,J＝8.6,2.2Hz,1H),4.20(q,J＝7.1Hz,2H),2.85–2.76(m,2H),2.46–2.31(m,3H),1.92–1.80(m,1H),1.22(t,J＝7.1Hz,3H).
参考例75：中间体I-75的制备
Figure PCTCN2021133158-appb-000132
在室温下，将中间体I-74(1.3g,4.58mmol)溶于甲醇(10mL)和水(10mL)中，加入氢氧化钠 (916mg,22.9mmol)，加热至100℃搅拌3小时。冷却至室温，浓缩反应液除去大部分甲醇，然后用1N盐酸调至反应液呈酸性，用乙酸乙酯(50mL×3)萃取。合并有机相，并用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩除去有机溶剂得到中间体I-75。
1H NMR(400MHz,DMSO-d 6)δ12.52(s,1H),7.97(d,J＝8.6Hz,1H),7.65–7.55(m,2H),2.67–2.58(m,2H),2.39(m,2H),2.17(dt,J＝19.4,8.9Hz,1H),1.85–1.72(m,1H).
参考例76：中间体I-76的制备
Figure PCTCN2021133158-appb-000133
在室温下，将硼烷-四氢呋喃溶液(19.5mL,1M)加入到中间体I-75(1.0g,3.91mmol)的四氢呋喃(50mL)中，反应液于室温下搅拌过夜。加入水(50mL)稀释，用乙酸乙酯(50mL×2)萃取。合并有机相，并用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩除去有机溶剂得到粗产品。粗品经硅胶色谱法分离纯化得到中间体I-76。
参考例77：中间体I-77的制备
Figure PCTCN2021133158-appb-000134
在室温下，将中间体I-76(800mg,3.31mmol)溶于二氯甲烷(10mL)中，加入戴斯-马丁氧化剂(4.21g,9.93mmol)，加料完毕后，反应液在室温下搅拌2小时。将反应液过滤，滤液加水(20mL)稀释，用二氯甲烷(20mL×3)萃取。合并有机相，并用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩除去有机溶剂得到粗产品。粗产品经硅胶色谱法分离纯化得到中间体I-77。
参考例78：中间体I-78的制备
Figure PCTCN2021133158-appb-000135
在0℃下，将氢化钠(157mg,60％wt,3.92mmol)在氩气保护下加入到三乙基膦酰乙酸酯(659mg,2.94mmol)的四氢呋喃(30mL)中，在冰水浴下搅拌30分钟，然后将中间体I-77(470mg,1.96mmol)加入其中。反应混合物于室温反应2小时。浓缩反应液除去大部分四氢呋喃，加水(50mL)，用乙酸乙酯(50mL×3)萃取。水相用1N盐酸调至酸性，再用乙酸乙酯(50mL×3)萃取，合并有机相，并用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩除去有机溶剂得到中间体I-78。
1H NMR(400MHz,DMSO-d 6)δ12.22(s,1H),7.88(d,J＝8.7Hz,1H),7.59(dd,J＝8.7,2.3Hz,1H),7.47(d,J＝2.3Hz,1H),7.30(d,J＝15.7Hz,1H),5.65(d,J＝15.7Hz,1H),2.43–2.33(m,4H),2.05(dd,J＝20.5,10.1Hz,1H),1.79–1.70(m,1H).
参考例79：中间体I-79的制备
Figure PCTCN2021133158-appb-000136
在室温下，将中间体I-78(360mg,1.28mmol)溶于四氢呋喃(20mL)中，加入雷尼镍(300mg)，加料完毕后，反应液在氢气氛围下搅拌16小时。过滤，滤液减压浓缩除去有机溶剂得到粗产品中间体I-79。粗产品直接用于下一步反应。
LC-MS(ESI)[M+H] +254.3。
参考例80：中间体I-80的制备
Figure PCTCN2021133158-appb-000137
在室温下，将1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(331mg,1.73mmol)和4-二甲氨基吡啶(211mg,1.73mmol)加入到中间体I-79(220mg)的四氢呋喃(60mL)溶液中，反应液于室温搅拌16小时。反应混合物加水(50mL)，用乙酸乙酯(50mL×3)萃取。合并有机相，并用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩除去有机溶剂得到粗产品。粗产品经硅胶色谱法分离纯化得到中间体I-80。
LC-MS(ESI)[M+H] +236.2。
参考例81：中间体I-81的制备
Figure PCTCN2021133158-appb-000138
在室温下，将硼烷-四氢呋喃溶液(1.9mL,1M)加入到中间体I-80(90mg,0.382mmol)的四氢呋喃(20mL)中。反应液于40℃反应2小时。冷却至室温，加入水(20mL)稀释，用乙酸乙酯(20mL×2)萃取。合并有机相，并用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩除去有机溶剂得到粗产品。粗品经硅胶色谱法分离纯化得到中间体I-81。
LC-MS(ESI)[M+H] +222.2。
参考例82：中间体I-82的制备
Figure PCTCN2021133158-appb-000139
在室温下，将2-甲基-4-硝基苯甲酰氯(94.8mg,0.475mmol)加入到中间体I-81(70mg,0.316mmol)和吡啶(75.0mg,0.948mmol)的四氢呋喃(5mL)溶液中。反应液于50℃搅拌5小时。冷却至室温，加入水(15mL)稀释，用乙酸乙酯(10mL×2)萃取。合并有机相，并用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品。粗品经硅胶色谱法分离纯化得到中间体I-82。
LC-MS(ESI)[M+H] +385.2。
参考例83：中间体I-83的制备
Figure PCTCN2021133158-appb-000140
在室温下，将铁粉(39.2mg,0.700mmol)和氯化铵(74.9mg,1.40mmol)加入到中间体I-82(54mg,0.140mmol)的甲醇/水(10mL/3mL)溶液中。氩气保护下，反应液于50℃搅拌2小时。冷却至室温，过滤，滤液浓缩除去大部分溶剂，加入水(5mL)稀释，用乙酸乙酯(10mL×3)萃取。合并有机相，并用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品。粗品经硅胶色谱法分离纯化得到中间体I-83。
LC-MS(ESI)[M+H] +355.1。
参考例84：中间体I-84的制备
Figure PCTCN2021133158-appb-000141
在25℃下，将中间体I-42(880.00mg,1.83mmol)溶于浓盐酸(5mL)中，80℃搅拌16小时。直接浓缩干，加入氨的甲醇溶液(1mL,2M)碱化，减压浓缩得到粗产品。粗品经硅胶色谱法分离纯化得到中间体I-84。
LC-MS(ESI)[M+H] +377.2。
参考例85：中间体I-85的制备
Figure PCTCN2021133158-appb-000142
在25℃下，将中间体I-85(670.00mg,1.78mmol)溶于二氯甲烷(10mL)中，加入Boc-L-羟脯氨酸(493.30mg,2.13mmol)，N,N-二异丙基乙胺(683.57mg,5.33mmol)和2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(809.91mg,2.13mmol)，室温搅拌1小时。加入水(20mL)，用二氯甲烷(20mL×3)萃取。合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品。粗产品经硅胶色谱法分离纯化得到中间体I-85。
LC-MS(ESI)[M+H] +590.2。
参考例86：中间体I-86A、86B的制备
Figure PCTCN2021133158-appb-000143
中间体I-85(1.22g)经SFC手性分离柱(ChiralPak AD,250×30mm I.D.,10μm和SS whelk O1, 250×30mm I.D.,10μm)两次制备得到手性中间体I-86A(Rt＝4.726min)和手性中间体I-86B(Rt＝5.077min)。
手性分析方法：色谱柱：Chiralpak AD-3 150×4.6mm I.D.,3μM
流动相：A:超临界二氧化碳B:乙醇(0.05％二乙胺)
洗脱梯度：5％～40％B，5分钟；40％B 2.5分钟；然后5％B 2.5分钟
流动速率：2.5mL/min
色谱柱温度：35℃
自动背压调节器(ABPR)：1500psi
中间体I-86A LC-MS(ESI)[M+H] +590.4；中间体I-86B LC-MS(ESI)[M+H] +590.2。
参考例87：中间体I-87的制备
Figure PCTCN2021133158-appb-000144
在25℃下，将中间体I-86A(200.00mg,0.34mmol)溶于浓盐酸(3mL)中，100℃搅拌16小时。直接浓缩除去有机溶剂得到粗产品手性中间体I-87。粗产品直接用于下一步反应。
LC-MS(ESI)[M+H] +223.0。
参考例88：中间体I-88的制备
Figure PCTCN2021133158-appb-000145
在25℃下，将中间体I-87(400.00mg)溶于四氢呋喃(4mL)中，加入饱和碳酸氢钠水溶液(2mL)，二碳酸二叔丁酯(89.05mg,0.41mmol)，室温反应1小时。加水(10mL)，用乙酸乙酯(10mL×3)萃取，合并有机相，有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品。粗产品经硅胶色谱法分离纯化得到中间体I-88。
LC-MS(ESI)[M+H] +323.0。
参考例89：中间体I-89的制备
Figure PCTCN2021133158-appb-000146
在25℃下，将中间体I-88(60.00mg,0.19mmol)溶于二氯甲烷(5mL)中，加入三乙胺(56.42mg,0.56mmol)，2-甲基-4-硝基苯甲酰氯(55.64mg,0.28mmol)，室温搅拌16小时。加入水(10mL)，用二氯甲烷(10mL×3)萃取。合并有机相，有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品。粗产品经硅胶色谱法分离纯化得到中间体I-89。
LC-MS(ESI)[M-100+H] +386.0。
参考例90：中间体I-90的制备
Figure PCTCN2021133158-appb-000147
在25℃下，将中间体I-89(60.00mg,0.12mmol)溶于乙醇(8mL)中，加入还原铁粉(34.47mg,0.62mmol)，饱和氯化铵水溶液(2mL)，80℃搅拌5小时。过滤，滤饼用乙酸乙酯(20mL)洗涤，收集滤液，加水(10mL)，分层。收集有机相，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品。粗产品经硅胶色谱法分离纯化得到中间体I-90。
LC-MS(ESI)[M-100+H] +356.4。
参考例91：中间体I-91的制备
Figure PCTCN2021133158-appb-000148
在25℃下，将中间体I-90(50.00mg,0.11mmol)溶于二氯甲烷(5mL)中，依次加入三乙胺(33.29mg,0.33mmol)，邻甲基苯甲酰氯(25.43mg,0.16mmol)，室温搅拌1小时。加入水(10mL)，用二氯甲烷(10mL×3)萃取。合并有机相，有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品。粗产品经硅胶色谱法分离纯化得到中间体I-91。
LC-MS(ESI)[M-100+H] +474.0。
参考例92：中间体I-92的制备
Figure PCTCN2021133158-appb-000149
在25℃下，将中间体I-86B(750.00mg,1.27mmol)溶于浓盐酸(8mL)中，100℃搅拌16小时。直接浓缩除去有机溶剂得到粗产品手性中间体I-92。粗产品直接用于下一步反应。
LC-MS(ESI)[M+H] +223.0。
参考例93：中间体I-93的制备
Figure PCTCN2021133158-appb-000150
在25℃下，将中间体I-92(1.40g)溶于四氢呋喃(20mL)，加入饱和碳酸氢钠水溶液(10mL)，二碳酸二叔丁酯(332.61mg,1.52mmol)，室温搅拌1小时。加水(20mL)，用乙酸乙酯(20mL×3)萃取。合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到 粗产品。粗产品经硅胶色谱法分离纯化得到中间体I-93。
LC-MS(ESI)[M+H] +323.2。
参考例94：中间体I-94的制备
Figure PCTCN2021133158-appb-000151
在25℃下，将中间体I-93(70.00mg,0.22mmol)溶于二氯甲烷(5mL)，加入三乙胺(65.77mg,0.65mmol)，2-甲基-4-硝基苯甲酰氯(64.92mg,0.33mmol)，室温搅拌16小时。加水(10mL)，用二氯甲烷(10mL×3)萃取。合并有机相，有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品。粗产品经硅胶色谱法分离纯化得到中间体I-94。
LC-MS(ESI)[M-100+H] +386.0。
参考例95：中间体I-95的制备
Figure PCTCN2021133158-appb-000152
在25℃下，将中间体I-94(90.00mg,0.19mmol)溶于乙醇(8mL)，加入还原铁粉(51.71mg,0.93mmol)，饱和氯化铵水溶液(2mL)，80℃搅拌5小时。过滤，滤饼用乙酸乙酯(20mL)洗涤，收集滤液，加水(20mL)，分层。收集有机相，减压浓缩得到粗产品。粗产品经硅胶色谱法分离纯化得到中间体I-95。
LC-MS(ESI)[M-100+H] +356.2。
参考例96：中间体I-96的制备
Figure PCTCN2021133158-appb-000153
在25℃下，将中间体I-95(70.00mg,0.15mmol)溶于二氯甲烷(5mL)，依次加入三乙胺(46.60mg,0.46mmol)，邻甲基苯甲酰氯(35.60mg,0.23mmol)，室温搅拌1小时。加水(10mL)，用二氯甲烷(10mL×3)萃取。合并有机相，有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品。粗产品经硅胶色谱法分离纯化得到中间体I-96。
LC-MS(ESI)[M-100+H] +474.2。
参考例97：中间体I-97的制备
Figure PCTCN2021133158-appb-000154
在冰水浴下，将氯化亚砜(311mg,2.61mmol)加入到中间体I-19(335mg,1.31mmol)的N,N-二甲基乙酰胺(15mL)中。反应混合物在室温下搅拌3小时，然后加入中间体I-5(150mg,0.653mmol)，反应混合物继续在室温下搅拌反应16小时。加入水(40mL)稀释，用乙酸乙酯(20mL×2)萃取，合并有机相，有机相用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得粗产品。粗产品经硅胶色谱法分离纯化得到中间体I-97。
LCMS(ESI)[M+H] +468.1。
参考例98：中间体I-98的制备
Figure PCTCN2021133158-appb-000155
在室温下，将邻氯苯甲酰氯(1.27g,7.23mmol)加入到6-氨基烟酸甲酯(1.00g,6.57mmol)的吡啶(20.0mL)溶液中。反应混合物于室温下搅拌反应1小时后，倒入水(100mL)中，抽滤，滤饼经干燥后得到中间体I-98。
LC-MS(ESI)[M+H] +290.9。
参考例99：中间体I-99的制备
Figure PCTCN2021133158-appb-000156
在室温下，将氢氧化钠水溶液(2mL,3.5N)加入到中间体I-98(680mg,2.34mmol)的四氢呋喃(10mL)溶液中，反应液于70℃下搅拌1小时。反应液用稀盐酸(1N)调节pH至5，过滤，滤饼抽干得到中间体I-99。
LC-MS(ESI)[M+H] +277.0。
参考例100：中间体I-100的制备
Figure PCTCN2021133158-appb-000157
在冰水浴下，将氯化亚砜(622mg,5.23mmol)加入到中间体I-99(800mg,2.89mmol)的N,N-二甲基乙酰胺(20mL)中。反应混合物在室温下搅拌3小时，然后加入中间体I-5(300mg,1.31mmol)，反应混合物继续在室温下搅拌反应16小时。加入水(40mL)稀释，用乙酸乙酯(20mL×2)萃取，合并有机相，有机相用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得粗产品。粗产品经硅胶色谱法分离纯化得到中间体I-100。
LCMS(ESI)[M+H] +487.9。
实施例的制备：
实施例1：化合物1的制备
Figure PCTCN2021133158-appb-000158
在室温下，将中间体I-8(150mg,0.287mmol)加入到氨水(8.00mL)溶液中，向反应体系中加入单质碘(728mg,2.87mmol)，α-异十三烷基-ω-羟基-聚(氧-1,2-亚乙基)(1.00mL)。反应混合物在室温下搅拌反应24小时，加入饱和硫代硫酸钠水溶液(50mL)，用乙酸乙酯(30mL×3)萃取。合并有机相，用饱和食盐水(50mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品。粗产品经制备HPLC(氨水体系)分离纯化得到化合物1。
LC-MS(ESI)[M+H] +537.0。
1HNMR(400MHz,DMSO-d 6)δ11.25–11.15(m,1H),8.55–8.13(m,1H),8.10–7.48(m,7H),7.27(d,J＝7.4Hz,1H),7.12–6.86(m,1H),5.09–4.71(m,1H),3.19–2.94(m,1H),2.88–2.54(m,2H),2.45–2.16(m,2H).
实施例2：化合物2的制备
Figure PCTCN2021133158-appb-000159
在室温下，将中间体I-10(150mg,0.312mmol)加入到氨水(8.00mL)溶液中，向反应体系中加入单质碘(792mg,3.12mmol)，α-异十三烷基-ω-羟基-聚(氧-1,2-亚乙基)(1.00mL)。反应混合物在室温下搅拌反应24小时，加入饱和硫代硫酸钠水溶液(50mL)，用乙酸乙酯(30mL×3)萃取，合并有机相，用和饱和食盐水(50mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品。粗产品经制备HPLC(氨水体系)分离纯化得到化合物2。
LC-MS(ESI)[M+H] +496.0。
1HNMR(400MHz,DMSO-d 6)δ10.16-10.48(m,1H),7.55-7.80(m,2H),7.04-7.50(m,7H),6.59-6.82(m,1H),4.52-4.98(m,1H),3.54-3.74(m,1H),3.34-3.49(m,1H),2.96-3.12(m,1H),2.72-2.84(m,1H),2.13-2.45(m,8H).
实施例3：化合物3的制备
Figure PCTCN2021133158-appb-000160
在室温下，将中间体I-17(40mg,0.080mmol)加入到氨水(5mL)中，依次加入碘(101.8mg,0.800mmol)和α-异十三烷基-ω-羟基-聚(氧-1,2-亚乙基)(0.1mL)，加料完毕后，反应混合物室温搅拌反应过夜。用饱和亚硫酸钠水溶液(10mL)稀释，乙酸乙酯(10mL×3)萃取，合并有机相用水(10mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物经制备HPLC(氨水体系)分离得到化合物 3。
LC-MS(ESI)[M+H] +515.0。
1H NMR(400MHz,DMSO-d 6)δ11.28-10.84(m,1H),8.64-6.69(m,9H),5.00-4.67(m,1H),2.78(dt,J＝43.7,22.6Hz,1H),2.47(s,3H),2.22-1.74(m,5H),1.54(dd,J＝52.0,31.2Hz,2H).
实施例4：化合物4的制备
Figure PCTCN2021133158-appb-000161
在室温下，将中间体I-21(100mg，0.232mmol)溶于氨水(5.00mL)溶液中，向反应体系中加入单质碘(177mg,0.696mmol)，α-异十三烷基-ω-羟基-聚(氧-1,2-亚乙基)(0.300mL)。反应混合物在室温下搅拌反应16小时，加入水(20mL)，用乙酸乙酯(20mL×3)萃取，合并有机相，用饱和硫代硫酸钠水溶液(30mL)和饱和食盐水(50mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品。粗产品经制备HPLC(氨水体系)分离纯化得到化合物4。
LC-MS(ESI)[M+H] +447.1。
1H NMR(400MHz,DMSO-d 6)δ10.86–10.76(m,1H),8.48–8.01(m,2H),7.61–7.09(m,7H),6.85(dd,J＝43.8,8.3Hz,1H),4.86(d,J＝12.6Hz,1H),2.84–2.71(m,1H),2.35(s,3H),2.13–1.77(m,5H),1.58–1.48(m,1H).
实施例5：化合物5的制备
Figure PCTCN2021133158-appb-000162
在室温下，将中间体I-23(100mg,0.206mmol)加入到氨水(5mL)中，依次加入碘(533mg,2.1mmol)和α-异十三烷基-ω-羟基-聚(氧-1,2-亚乙基)(0.3mL)，加料完毕后，反应混合物室温搅拌反应过夜。用饱和亚硫酸钠水溶液(10mL)稀释，乙酸乙酯(10mL×3)萃取，合并有机相用水(10mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物经制备HPLC(氨水体系)分离得化合物5。
LC-MS(ESI)[M+H] +501.0。
1H NMR(400MHz,DMSO-d 6)δ11.21–11.10(m,1H),8.50–7.93(m,2H),7.84–7.10(m,7H),6.96–6.76(m,1H),4.96–4.71(m,1H),2.86–2.69(m,1H),2.21–1.83(m,5H),1.80–1.44(m,2H).
实施例6：化合物6的制备
Figure PCTCN2021133158-appb-000163
在室温下，将中间体I-30(150mg,0.336mmol)溶于氨水(5.00mL)中，向反应体系中加入单质碘(426mg,1.68mmol)，α-异十三烷基-ω-羟基-聚(氧-1,2-亚乙基)(0.300mL)，反应混合物在室温下搅拌反应16小时。加入水(10mL)，用乙酸乙酯(10mL×3)萃取，合并有机相，用饱和硫代硫酸 钠水溶液(20mL)和饱和食盐水(20mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品。粗产品经制备HPLC(氨水体系)分离纯化得到化合物6。
LC-MS(ESI)[M+H] +461.1。
1H NMR(400MHz,DMSO-d 6)δ10.97–10.44(m,1H),8.59–7.03(m,8H),6.75(dd,J＝41.4,8.3Hz,1H),4.97–4.75(m,1H),2.90–2.63(m,1H),2.48–2.31(m,6H),2.22–1.74(m,5H),1.54(dd,J＝53.9,30.7Hz,2H).
实施例7：化合物7的制备
Figure PCTCN2021133158-appb-000164
在室温下，将叔丁醇钾(85.3mg,0.760mmol)和三甲基碘化亚砜(335mg,1.52mmol)加入到二甲亚砜(1.5mL)中，室温下搅拌10分钟。然后将中间体I-31(70mg,0.152mmol)加入其中，反应液于50℃反应16小时。冷却至室温，反应液加入水(10mL)稀释，用乙酸乙酯(10mL×3)萃取，合并有机相。有机相用饱和食盐水(15mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品。粗品经制备HPLC(碳酸氢铵体系)分离纯化得到化合物7。
LC-MS(ESI)[M+H] +476.1。
1H NMR(400MHz,DMSO-d 6)δ8.43–7.64(m,1H),7.53–6.91(m,7H),6.88–6.51(m,1H),4.94–4.43(m,1H),3.39(d,J＝9.5Hz,1H),3.26(d,J＝12.6Hz,2H),3.18–2.77(m,2H),2.29–1.90(m,8H),1.84–1.46(m,2H).
实施例8：化合物8的制备
Figure PCTCN2021133158-appb-000165
在室温下，将中间体I-34(150mg,0.322mmol)溶于氨水(6mL)中，向反应体系中加入单质碘(817mg,3.22mmol)和α-异十三烷基-ω-羟基-聚(氧-1,2-亚乙基)(0.2mL)。反应混合物在室温下搅拌16小时。反应液用饱和亚硫酸钠(10mL)淬灭反应，用乙酸乙酯(20mL×3)萃取，合并有机相，有机相用饱和食盐水(30mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品。粗产品经制备HPLC分离纯化得到化合物8。
LC-MS(ESI)[M+H] +479.9。
1H NMR(400MHz,DMSO-d 6)δ10.66–10.31(m,1H),7.74–6.99(m,9H),6.78–6.56(m,1H),4.84-3.63(m,1H),3.14–2.65(m,1H),2.39(s,3H),2.19–1.72(m,5H),1.69–1.45(m,2H).
实施例9：化合物9的制备
Figure PCTCN2021133158-appb-000166
在室温下，将化合物I-36(300mg,0.674mmol)溶于氨水(20.0mL)中，向反应体系中加入单质 碘(513mg,2.02mmol)，α-异十三烷基-ω-羟基-聚(氧-1,2-亚乙基)(30mg)，反应混合物在室温下搅拌8小时。将反应体系倒入饱和亚硫酸氢钠溶液(100mL)中，用乙酸乙酯(50mL×3)萃取，合并有机相，用饱和食盐水(50mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品。粗产品经制备HPLC分离纯化得到化合物9。
LC-MS(ESI)[M+H] +460.0。
1H NMR(400MHz,DMSO-d 6)δ10.49–10.10(m,1H),7.92–6.91(m,9H),6.79–6.53(m,1H),4.95–3.61(m,1H),3.10–2.67(m,1H),2.40–2.33(m,6H),2.12–1.75(m,4H),1.69–1.43(m,2H).
实施例10：化合物10A、10B的制备
Figure PCTCN2021133158-appb-000167
在室温下，将中间体I-37(220mg,0.477mmol)溶于叔丁醇(2.20mL)中，依次加入三甲基碘化亚砜(1.05g,4.77mmol)，叔丁醇钾(268mg,2.39mmol)，反应混合物在55℃下搅拌18小时。将反应体系冷却至室温，倒入水(30.0mL)中，用乙酸乙酯(10mL×4)萃取，合并有机相，用饱和食盐水(10mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品。粗产品经制备HPLC分离纯化得到化合物10A和化合物10B。
化合物10A：
LC-MS(ESI)[M+Na] +497.0。
1H NMR(400MHz,DMSO-d 6)δ10.41–10.28(m,1H),7.83–7.54(m,3H),7.48–7.22(m,7H),4.74–4.42(m,2H),3.54(m,1H),3.15–3.01(m,1H),2.96–2.80(m,1H),2.41–2.31(m,8H),1.87–1.52(m,3H).
化合物10B：
LC-MS(ESI)[M+H] +489.1。
1H NMR(400MHz,DMSO-d 6+D 2O)δ7.70–7.56(m,1H),7.41(dd,J＝8.3,2.4Hz,1H),7.33–6.87(m,8H),4.62–4.33(m,2H),3.41–3.30(m,2H),3.28–3.20(m,1H),3.09–2.96(m,1H),2.88–2.72(m,1H),2.30–2.06(m,8H),1.82–1.36(m,3H).
实施例11：化合物11的制备
Figure PCTCN2021133158-appb-000168
在25℃下，将中间体I-47(40.00mg,0.070mmol)溶于氯化氢的二氧六环溶液(5mL,3M)中，室温反应1小时。浓缩干，经制备HPLC(碳酸氢铵体系)分离纯化得到化合物11。
LC-MS(ESI)[M+H] +474.2。
1H NMR(400MHz,Methanol-d 4)δ7.68–7.51(m,1H),7.48–7.08(m,5H),6.92(dd,J＝8.5,2.5Hz,1H),6.73(d,J＝8.5Hz,1H),6.60(d,J＝8.4Hz,1H),6.09(dt,J＝64.2,6.5Hz,1H),4.65–4.55(m,1H),3.71(s,1H),3.46(dt,J＝13.0,5.2Hz,1H),2.89–2.78(m,2H),2.78–2.64(m,1H),2.62–2.51(m,1H),2.51–2.40(m,1H),2.30–2.28(m,6H),2.24–2.06(m,1H),1.97(m,1H).
实施例12：化合物12的制备
Figure PCTCN2021133158-appb-000169
在室温下，将2-甲基苯甲酰氯(21.9mg,0.142mmol)和三乙胺(28.7mg,0.284mmol)加入到中间体I-57(35mg,0.0944mmol)的二氯甲烷(5mL)溶液中，反应液于室温反应3小时。反应液用二氯甲烷(10mL)稀释，用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品。粗品经制备HPLC(碳酸氢铵体系)分离纯化得到化合物12。
LC-MS(ESI)[M+H] +489.1
1H NMR(400MHz,DMSO-d 6)δ10.41–10.26(m,1H),7.77–6.58(m,10H),4.37–4.04(m,1H),3.99–3.47(m,4H),3.06–2.80(m,1H),2.70–2.51(m,1H),2.45–2.16(m,7H),2.04–1.93(m,1H),1.86–1.51(m,3H).
实施例13：化合物13的制备
Figure PCTCN2021133158-appb-000170
在室温下，将中间体I-7(54.0mg,0.174mmol)溶于N,N-二甲基乙酰胺(5.00mL)中，降温至0℃，氩气保护下加入氯化亚砜(20.7mg,0.174mmol)，反应混合物在0℃下搅拌反应3小时后，加入中间体I-58(30.0mg,0.116mmol)，反应混合物继续在室温下搅拌反应16小时。加入水(20mL)中，用乙酸乙酯(10mL×3)萃取，合并有机相，用饱和食盐水(20mL)洗，无水硫酸钠干燥，过滤，减压浓缩得粗产品。粗产品经制备HPLC(氨水体系)分离纯化得到化合物13。
LCMS(ESI)[M+H] +552.0。
1HNMR(400MHz,DMSO-d 6)δ11.29–11.19(m,1H),8.41–7.97(m,2H),7.90–7.63(m,6H),7.45–6.92(m,2H),4.85–4.49(m,3H),3.54–2.63(m,4H),2.38–2.15(m,1H).
实施例14：化合物14的制备
Figure PCTCN2021133158-appb-000171
在室温下，将叔丁醇钾(175mg,1.56mmol)和三甲基碘化亚砜(343mg,1.56mmol)加入到二甲亚砜(1.00mL)中，室温下搅拌5分钟。然后将中间体I-59(100mg,0.223mmol)加入其中，反应液于70℃搅拌20小时。冷却至室温，反应液加入水(10mL)稀释，用乙酸乙酯(5mL×3)萃取，合并有机相。有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品。粗品经制备HPLC(氨水体系)分离纯化得到化合物14。
LC-MS(ESI)[M+H] +462.0。
1H NMR(400MHz,DMSO-d6)δ11.09–10.74(m,1H),8.56–8.00(m,2H),7.87–7.17(m,7H),7.06–6.78(m,1H),4.80–4.33(m,3H),3.11–2.92(m,1H),2.89–2.54(m,2H),2.47–2.15(m,4H),2.12– 1.55(m,3H).
实施例15：化合物15的制备
Figure PCTCN2021133158-appb-000172
在室温下，将中间体I-65(200mg,0.392mmol)溶于二甲基亚砜(5.00mL)溶液中，依次加入三甲基碘化亚砜(863mg,3.92mmol)，叔丁醇钾(220mg,1.96mmol)，反应混合物在50℃下搅拌24小时。将反应体系冷却至室温，倒入水(30mL)中，用乙酸乙酯(20mL×3)萃取，合并有机相，用饱和食盐水(15mL)，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品。粗产品经制备HPLC(碳酸氢铵体系)分离纯化得到化合物15。
LC-MS(ESI)[M+H] +524.0。
1H NMR(400MHz,DMSO-d 6)δ8.12–7.65(m,1H),7.64–7.10(m,10H),7.08–6.01(m,4H),4.88–4.43(m,1H),3.14–2.86(m,4H),2.83–2.66(m,1H),2.17–1.51(m,4H).
实施例16：化合物16的制备
Figure PCTCN2021133158-appb-000173
在室温下，将O-(7-氮杂苯并三唑-1-基)-N,N,N'-四甲基脲六氟磷酸盐(46.8mg,0.123mmol)和N,N-二异丙基乙胺(23.9mg,0.185mmol)加入到中间体I-71(21mg,0.0616mmol)和邻甲基苯甲酸(10.1mg,0.0742mmol)的N,N-二甲基甲酰胺(5mL)溶液中，反应液于50℃搅拌16小时。往反应液中加入水(10mL)，用乙酸乙酯(10mL×3)萃取，合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤。滤液浓缩干，经C18反相色谱法纯化得到化合物16。
LC-MS(ESI)[M+H] +459.2。
1H NMR(400MHz,DMSO-d 6)δ10.40–10.24(m,1H),7.77–7.45(m,2H),7.40–7.02(m,7H),6.76–6.66(m,1H),4.88–2.68(m,1H),2.37(m,6H),2.00–1.87(m,1H),1.82–1.52(m,2H),1.38–1.14(m,2H),1.02–0.85(m,1H),0.82–0.68(m,2H).
实施例17：化合物17的制备
Figure PCTCN2021133158-appb-000174
在室温下，将2-甲基苯甲酸(19.3mg,0.142mmol)，N,N-二异丙基乙胺(43.7mg，0.339mmol)，O-(7-氮杂苯并三唑-1-基)-N,N,N'-四甲基脲六氟磷酸盐(85.9mg,0.226mmol)加入到中间体I-83(40mg，0.113mmol)的N,N-二甲基甲酰胺(3mL)溶液中，反应液于室温反应16小时。反应液经制备HPLC(甲酸体系)分离纯化得到化合物17。
LC-MS(ESI)[M+H] +473.3。
1H NMR(400MHz,DMSO-d 6)δ10.40–10.26(m,1H),7.75–7.17(m,9H),6.86–6.55(m,1H),4.52–3.50(m,1H),2.98–2.83(m,1H),2.77–2.64(m,1H),2.41–2.23(m,7H),2.22–1.35(m,8H).
实施例18：化合物18的制备
Figure PCTCN2021133158-appb-000175
在25℃下，将中间体I-91(50.00mg,0.087mmol)溶于氯化氢的二氧六环溶液(5mL,3M)中，室温搅拌1小时。浓缩干，经制备HPLC(碳酸氢铵体系)分离纯化得到手性化合物18。
LC-MS(ESI)[M+H] +474.2。
1H NMR(400MHz,DMSO-d 6)δ10.31(s,1H),7.58–7.21(m,6H),7.08(dd,J＝8.3,2.5Hz,1H),6.83(d,J＝8.3Hz,1H),6.69(d,J＝8.4Hz,1H),6.32–5.90(m,1H),4.68–4.49(m,1H),3.77–3.64(m,1H),3.59(s,1H),3.49–3.40(m,2H),2.82–2.69(m,2H),2.44(d,J＝6.2Hz,2H),2.39(s,1H),2.34(s,3H),2.29(s,3H),2.22–2.06(m,1H).
实施例19：化合物19的制备
Figure PCTCN2021133158-appb-000176
在25℃下，将中间体I-96(70.00mg,0.12mmol)溶于氯化氢的二氧六环溶液(5mL,3M)中，室温搅拌1小时。浓缩干，经制备HPLC(碳酸氢铵体系)分离纯化得到手性化合物19。
LC-MS(ESI)[M+H] +474.2。
1H NMR(400MHz,DMSO-d 6)δ10.34(s,1H),7.57–7.23(m,6H),7.11(dd,J＝8.5,2.4Hz,1H),6.85(d,J＝8.5Hz,1H),6.66(d,J＝8.4Hz,1H),6.27–5.98(m,1H),4.63–4.48(m,1H),3.85–3.57(m,1H),3.51–3.34(m,1H),2.99–2.78(m,3H),2.64(q,J＝8.6,7.7Hz,1H),2.48(d,J＝18.7Hz,2H),2.39(s,1H),2.34–2.28(m,6H),2.23–1.90(m,1H).
实施例20：化合物20的制备
Figure PCTCN2021133158-appb-000177
在室温下，将α-异十三烷基-ω-羟基-聚(氧-1,2-亚乙基)(1.00mL)和单质碘(1.19g,4.69mmol)加入到中间体I-97(220mg,0.470mmol)的氨水(20mL)中。反应混合物在室温下搅拌反应16小时(LCMS及TLC显示约10％产物生成，大部分原料剩余)。加入饱和亚硫酸钠水溶液(40mL)，用乙酸乙酯(30mL×2)萃取，合并有机相，用和饱和食盐水(30mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品，粗产品经硅胶色谱法纯化回收原料和产品混合物(210mg)，再按照上述操作重新投料，重复两次。反应液加入饱和亚硫酸钠水溶液(30mL)，用乙酸乙酯(30mL×2)萃取，合 并有机相，用和饱和食盐水(30mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品。粗产品依次经过硅胶色谱法及C18反相色谱法分离纯化得到化合物20。
LC-MS(ESI)[M+H] +483.1。
1H NMR(400MHz,DMSO-d 6)δ10.90–10.80(m,1H),8.48–8.07(m,1H),8.08–7.20(m,8H),7.09–6.82(m,1H),5.03–4.76(m,1H),3.19–2.92(m,1H),2.84–2.54(m,2H),2.42–2.13(m,5H).
实施例21：化合物21的制备
Figure PCTCN2021133158-appb-000178
在室温下，将α-异十三烷基-ω-羟基-聚(氧-1,2-亚乙基)(2.00mL)和单质碘(1.56g,6.15mmol)加入到I-100(300mg,0.614mmol)的氨水(20mL)中。反应混合物在室温下搅拌反应16小时(LCMS及TLC显示约10％产物生成，大部分原料剩余)。加入饱和亚硫酸钠水溶液(40mL)，用乙酸乙酯(30mL×2)萃取，合并有机相，用和饱和食盐水(30mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品，粗产品经硅胶色谱法纯化回收原料和产品混合物(295mg)，再按照上述操作重新投料。反应液加入饱和亚硫酸钠水溶液(30mL)，用乙酸乙酯(30mL×2)萃取，合并有机相，用和饱和食盐水(30mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产品。粗产品依次经过硅胶色谱法及C18反相色谱法分离纯化得到化合物21。
LC-MS(ESI)[M+H] +503.0。
1H NMR(400MHz,DMSO-d 6)δ11.16–11.06(m,1H),8.56–6.84(m,10H),5.08–4.57(m,1H),3.18–2.94(m,1H),2.89–2.53(m,2H),2.46–2.16(m,2H).
实验例1：化合物对加压素诱导的血管加压素受体V2R激活的抑制IC 50测试
(1)细胞
稳定表达人加压素受体V2R的HeLa细胞系(HeLa-V2R)：由上海吉凯基因化学技术有限公司利用慢病毒感染方法构建，经qPCR验证稳定表达人V2R。
(2)试剂
DMEM细胞培养基：品牌：Gibco，货号：11995065；胎牛血清：品牌：吉泰，货号：FND500；0.25％胰酶：品牌：Gibco，货号：25200072；Puromycin Dihydrochloride:品牌：Gibco，货号：A1113803；cAMP-GS HIRANGE KIT：品牌：Cisbio，货号：62AM6PEC；IBMX:品牌：Sigma，货号：i5879；加压素AVP：吉尔生化(上海)有限公司定制。
(3)测试方法
HeLa-V2R细胞用添加10％胎牛血清的DMEM培养基在37度、5％CO 2条件下孵育培养，培养基中添加2ug/mL puromycin持续筛选表达V2R的细胞。实验当天用胰酶消化细胞，用cAMP-GS HIRANGE试剂盒中的stimulation buffer洗细胞2次，重悬计数后配制成1.6X10 6个细胞/ml，加入IBMX至终浓度为0.5mM。转移5uL细胞悬液/孔至384孔板，在相应孔中分别加入2.5uL不同浓度的待测化合物(10uM起3倍稀释，10个浓度梯度)或DMSO(最小值Min、最大值Max对照)。室温孵育30分钟后，测试化合物孔及最大值孔中加入2.5uL加压素AVP溶液至终浓度2.25nM，最小值孔中加入2.5uL stimulation buffer，25度孵育60分钟。同时配制cAMP标准品样品(从5.6uM开始3倍稀释，10个浓度点)，转移10uL cAMP标准品至384孔板相应孔。用cAMP-GS HIRANGE试剂盒中的lysis  buffer稀释试剂盒中提供的cAMP-d2荧光和anti-cAMP抗体探针20倍，各取5uL依次加入384孔板中各孔，混匀后简单离心，25度孵育2小时后检测。样品检测用Envision酶标仪中的HTRF方法，检测615nm及665nm处的荧光强度。每个待测样品做两个复孔，Min、Max各做32个复孔。
(4)数据处理
计算各孔样品665nm与615nm波长处的荧光强度比值FI 665/615。以标准品浓度对数为X，FI 665/615X1000为Y值，用Prism 8.0软件中“log(inhibitor)vs response–variable slope(four parameters)“模型拟合获得标准曲线。以测试孔FI 665/615X1000为Y值，在Prism 8.0软件中根据上述标准曲线计算出各个样品对应的cAMP浓度。
％Inhibition(抑制百分率)计算公式如下：
Figure PCTCN2021133158-appb-000179
其中
Figure PCTCN2021133158-appb-000180
为所有最大值孔中cAMP浓度的平均计算值；
Figure PCTCN2021133158-appb-000181
为所有最小值孔中cAMP浓度平均计算值；Ccmpd是待测化合物的cAMP浓度计算值。
以％Inhibition(抑制百分率)为Y值，化合物浓度对数值为X，在Prism 8.0软件中用“log(inhibitor)vs response–variable slope(four parameters)“模型做非线性回归，计算IC50，其中Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*Hill Slope))。
实验结果如表1所示：
表1：化合物对人宫颈癌细胞(Human V2R Hela-Stable cell line OE2)内cAMP增加抑制的评价
化合物编号 IC 50(nM) 化合物编号 IC 50(nM)
1 10.88 2 9.35
4 3.14 5 4.67
8 5.01 9 4.88
16 11.23 17 10.43
20 5.54 21 4.51
实验例2：本发明化合物的体内药代动力学实验
本实验例对小鼠通过静脉注射和口服给药进行了体内药代动力学评价。
实验方法和条件：雄性CD1小鼠，6～8周龄，动物均自由摄食饮水，静脉注射单次给予待测化合物1mg/Kg(溶剂5％DMSO/10％Solutol/85％Saline)，给药后5min,15min,30min,1hr,2hr,4hr,8hr,24hr或口服灌胃给药10mg/kg(溶剂5％DMSO/10％Solutol/85％Saline)，给药后15min,30min,1hr,2hr,4hr,6h,8hr,24hr经眼眶采血，每个样品采集不少于50μL，肝素钠抗凝，采集后放置冰上，并于1小时之内离心分离血浆待测。血浆中血药浓度的检测采用液相串联质谱法(LC/MS/MS)，测得浓度运用Phoenix WinNonlin软件计算药代动力学参数。以托法普坦为对照品1，实验结果如表2和表3所示。
表2：口服给药(10mg/kg)的药代动力学
化合物 T 1/2(hr) C max(ng/mL) AUC 0‐inf(ng*hr/mL) F(％)
化合物1 0.60 1255 4058 56
对照品1 1.58 1307 1613 44
表3：静脉注射给药(1mg/kg)的药代动力学
化合物 T 1/2(hr) AUC 0-inf(ng*hr/mL) Cl(ml/min/kg)
化合物1 0.92 719 23.2
对照品1 0.53 367 45.5
实验数据表明，本发明化合物小鼠静脉和口服给药体内药代动力学结果表现出更低的体内代谢清除率Cl和更高的体内暴露量AUC 0-inf。
实验例3：化合物对LLC-PK1细胞增殖抑制作用测试
(1)细胞
猪肾上皮细胞LLC-PK1：购于ATCC，Cat#CL‐101
(2)试剂：
Medium 199,Gibco(Cat#11150059)
Fetal Bovine Serum(FBS),Australia，吉泰(Cat#FND500)
Trypsin-EDTA(0.25％),phenol red，Gibco(Cat#25200072)
PBS,pH 7.4，Gibco(Cat#10010031)
DMSO(二甲基亚砜)，Sigma(Cat#D8418)
Poly-D-lysine,Gibco(Cat#A3890401)
加压素AVP：吉尔生化(上海)有限公司定制
Verapamil hydrochloride，MCE(Cat#HY-A0064)
AlamarBlue TM HS Cell Viability Reagent，Invitrogen(Cat#A50100)
(3)测试方法：
多囊肾病的发病原理与肾集合管上皮细胞的胞内钙离子浓度低，细胞处于cAMP依赖的过度增殖相关。参考Tamio Yamaguchi等2004年发表于The Journal of Biological Chemistry的研究论文，我们优化并开展了肾上皮细胞LLC-PK1增殖实验，用于评价在降低细胞内钙离子浓度后，化合物对加压素诱导的细胞增殖的抑制能力。
LLC-PK1细胞用添加10％胎牛血清的M199培养基在37摄氏度、5％CO 2条件下孵育培养。实验第一天先用0.01％Poly-D-lysine coat 96孔板，每孔加入100ul，室温静置10min后，吸走并室温风干1hrs，用200ul 1XPBS洗一遍备用。胰酶消化LLC-PK1细胞，离心后用无血清M199重悬、计数，用无血清M199培液稀释为1×10 5/ml的细胞悬液，加入FBS至1％终浓度。转移200ul细胞悬液/孔至96孔板。细胞培养24hr后，吸走配液上清，用200ul PBS洗一遍后，依次加入含0.05％FBS的M199培养液160ul及20ul 10X Verapamil(终浓度5uM)，继续培养24hrs。第三天，在相应孔中分别加入10uL不同浓度的待测化合物(终浓度3uM起，3倍稀释，8个浓度梯度)或DMSO(最小值Min、最大值Max对照)。测试化合物孔及最大值孔中加入10uL加压素AVP溶液至终浓度10nM，最小值孔中加入10uL无血清M199培养液，继续培养48hr。第五天，小心吸走培液，用200ul PBS洗一遍细胞，小心加入90ul M199无血清培液，再加入10ul Alamarblue试剂，300rpm离心1min，37摄氏度培养2小时后检测。样品检测用SpectraMax仪器，激发光560nm，发射光595nm。每个待测样品做3个复孔，Min、Max各做6个复孔。
(4)数据处理
以化合物浓度为X值，各实验孔样品的荧光强度扣除背景孔荧光强度平均值为Y值，代表检测时该孔中的活细胞数量。用GraphPad Prism 8.0软件中Grouped-Summary data-Separated bar graph做条形图，反映不同化合物对AVP诱导的细胞增殖的剂量-效应关系。以托伐普坦为阳性对照，定性评价化合物对增殖的抑制效果：整体表现优于托伐普坦的为“+++”，与托伐普坦表现接近的为“++”，弱于托伐普坦表现的为“+”，无增殖抑制的为“-”。
数据质量控制：计算S/B，即Max孔平均值/Min孔平均值，≥2视为QC通过。
实验结果表明化合物1在LLC-PK1细胞增殖抑制作用强于对照品1(托法普坦)，且在高浓度条 件下没有促增殖作用，如图1所示。

Claims (15)

  1. 式(X)所示化合物、其光学异构体及其药效上可接受的盐，
    Figure PCTCN2021133158-appb-100001
    其中，
    环A选自杂环烷基和环烷基，所述杂环烷基和环烷基任选被1、2、3或4个R A取代；
    环B选自芳基、杂芳基、杂环烷基和环烷基，所述芳基、杂芳基、杂环烷基或环烷基任选被1、2或3个R 3取代；
    环C选自芳基、杂芳基、杂环烷基和环烷基，所述芳基、杂芳基、杂环烷基或环烷基任选被1、2或3个R 4取代；
    T 1、T 2分别独立地选自N和CH；
    R 1、R 2、R 3、R 4分别独立地选自H、F、Cl、Br、I、CN、OH、NH 2、烷基、杂烷基、芳基、杂芳基、杂环烷基和环烷基，所述烷基、杂烷基、芳基、杂芳基、杂环烷基或环烷基任选被1、2、3或4个R取代；
    R和R A分别独立地选自H、F、Cl、Br、I、CN、OH、NH 2、烷基、杂烷基、芳基、杂芳基、杂环烷基和环烷基，所述烷基、杂烷基、芳基、杂芳基、杂环烷基或环烷基任选被1、2、3或4个R’取代；
    R’选自H、F、Cl、Br、I、CN、OH、NH 2、烷基和杂烷基；
    m1和m2分别独立地选自1、2、3或4；
    L X选自-NH(C＝O)-、-烷基-NH(C＝O)-、-NH(C＝O)-烷基-、烷基、烯基和炔基，所述-烷基-NH(C＝O)-、-NH(C＝O)-烷基-、烷基、烯基或炔基任选被1、2、3或4个R取代；
    且，当环A选自杂环烷基时，式(I)所示化合物不选自
    Figure PCTCN2021133158-appb-100002
    Figure PCTCN2021133158-appb-100003
    所述杂环烷基或杂芳基包含1、2、3或4个独立选自-O-、-NH-、-N＝、-S-、-C(＝O)-、-C(＝O)O-、-S(＝O)-、-S(＝O) 2-和N的杂原子或杂原子团。
  2. 式(I)所示化合物、其光学异构体及其药效上可接受的盐，
    Figure PCTCN2021133158-appb-100004
    其中，
    环A选自3-6元杂环烷基和C 3-6环烷基，所述3-6元杂环烷基和C 3-6环烷基任选被1或2个R A取代；
    环B选自苯基和5-6元杂芳基，所述苯基或5-6元杂芳基任选被1、2或3个R 3取代；
    环C选自苯基和5-6元杂芳基，所述苯基或5-6元杂芳基任选被1、2或3个R 4取代；
    T 1、T 2分别独立地选自N和CH；
    R 1分别独立地选自H、F、Cl、Br、I、CN、OH、NH 2和C 1-6烷基，所述C 1-6烷基任选被1、2或3个R取代；
    R 2分别独立地选自H、F、Cl、Br、I、CN、OH、NH 2、C 1-6烷基和C 3-6环烷基，所述C 1-6烷基或C 3-6环烷基任选被1、2或3个R取代；
    R 3分别独立地选自H、F、Cl、Br、I、CN、OH、NH 2和C 1-6烷基，所述C 1-6烷基任选被1、2或3个R取代；
    R 4分别独立地选自H、F、Cl、Br、I、CN、OH、NH 2、C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、C 3-6环烷基、苯基和5～6元杂芳基，所述C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、C 3-6环烷基、苯基或5～6元杂芳基任选被1、2或3个R取代；
    R和R A分别独立地选自H、F、Cl、Br、I、CN、OH、NH 2、C 1-6烷基、C 1-6烷氧基和C 1-6烷氨基，所述C 1-6烷基、C 1-6烷氧基和C 1-6烷氨基任选被1、2或3个R’取代；
    R’选自H、F、Cl、Br、I、CN、OH、NH 2和C 1-6烷基；
    m1和m2分别独立地选自1、2或3；
    且，当环A选自3-6元杂环烷基时，式(I)所示化合物不选自
    Figure PCTCN2021133158-appb-100005
    Figure PCTCN2021133158-appb-100006
    所述3-6元杂环烷基或5-6元杂芳基包含1、2或3个独立选自-O-、-NH-、-N＝、-S-、-C(＝O)-、-C(＝O)O-、-S(＝O)-、-S(＝O) 2-和N的杂原子或杂原子团。
  3. 式(II)所示化合物、其光学异构体及其药效上可接受的盐，
    Figure PCTCN2021133158-appb-100007
    其中，X 1选自C(R A) 2、NH和O；
    X 2选自CH和N；
    T 1、T 2分别独立地选自N和CH；
    R 1分别独立地选自H、F、Cl、Br、I、CN、OH、NH 2和C 1-6烷基，所述C 1-6烷基任选被1、2或3个R取代；
    R 2a和R 2b分别独立地选自H、F、Cl、Br、I、CN、OH、NH 2、C 1-6烷基和C 3-6环烷基，所述C 1-6烷基或C 3-6环烷基任选被1、2或3个R取代；
    R 3选自H、F、Cl、Br、I、CN、OH、NH 2和C 1-6烷基，所述C 1-6烷基任选被1、2或3个R取代；
    R 4分别独立地选自H、F、Cl、Br、I、CN、OH、NH 2、C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、C 3-6环烷基、苯基和5～6元杂芳基，所述C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、C 3-6环烷基、苯基或5～6元杂芳基任选被1、2或3个R取代；
    R和R A分别独立地选自H、F、Cl、Br、I、CN、OH、NH 2、C 1-6烷基、C 1-6烷氧基和C 1-6烷氨基，所述C 1-6烷基、C 1-6烷氧基和C 1-6烷氨基任选被1、2或3个R’取代；
    R’选自H、F、Cl、Br、I、CN、OH、NH 2和C 1-6烷基；
    n1选自0、1或2；
    n2选自1、2或3；
    且，当X 1选自O时，式(II)所示化合物不选自
    Figure PCTCN2021133158-appb-100008
    Figure PCTCN2021133158-appb-100009
  4. 式(III)所示化合物、其光学异构体及其药效上可接受的盐，
    Figure PCTCN2021133158-appb-100010
    其中，
    R 1分别独立地选自H、F、Cl、Br、I、CN、OH、NH 2和C 1-6烷基，所述C 1-6烷基任选被1、2或3个R取代；
    R 3选自H、F、Cl、Br、I、CN、OH、NH 2和C 1-6烷基，所述C 1-6烷基任选被1、2或3个R取代；
    R 4分别独立地选自H、F、Cl、Br、I、CN、OH、NH 2、C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、C 3-6环烷基、苯基和5～6元杂芳基，所述C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、C 3-6环烷基、苯基或5～6元杂芳基任选被1、2或3个R取代；
    R选自H、F、Cl、Br、I、CN、OH、NH 2、C 1-6烷基、C 1-6烷氧基和C 1-6烷氨基，所述C 1-6烷基、C 1-6烷氧基和C 1-6烷氨基任选被1、2或3个R’取代；
    R’选自H、F、Cl、Br、I、CN、OH、NH 2和C 1-6烷基；
    X 2选自CH和N。
  5. 根据权利要求1-4任一项所述化合物、其光学异构体及其药效上可接受的盐，其中，R和R A分别独立地选自H、F、Cl、Br、I、CN、OH、NH 2、CH 3、CF 3、
    Figure PCTCN2021133158-appb-100011
  6. 根据权利要求1-3任一项所述化合物、其光学异构体及其药效上可接受的盐，其中，R A选自H、OH和NH 2。
  7. 根据权利要求1-4任一项所述化合物、其光学异构体及其药效上可接受的盐，其中，R 4选自H、F、Cl、Br、I、CN、OH、NH 2、CH 3、CF 3、
    Figure PCTCN2021133158-appb-100012
    环丙基、环丁基、 环戊基、苯基、吡啶基、嘧啶基、噻吩基和噻唑基。
  8. 根据权利要求1或2所述化合物、其光学异构体及其药效上可接受的盐，其中，环A选自环丙基、环丁基、环戊基、氮丙啶基、环氧乙烷基、氮杂环丁烷基、氧杂环丁烷基、吡咯烷基和四氢呋喃基，所述环丙基、环丁基、环戊基、氮丙啶基、环氧乙烷基、氮杂环丁烷基、氧杂环丁烷基、吡咯烷基或四氢呋喃基任选被1或2个R A取代。
  9. 根据权利要求8所述化合物、其光学异构体及其药效上可接受的盐，其中，环A选自
    Figure PCTCN2021133158-appb-100013
    Figure PCTCN2021133158-appb-100014
  10. 根据权利要求3所述化合物、其光学异构体及其药效上可接受的盐，其中，结构单元
    Figure PCTCN2021133158-appb-100015
    选自
    Figure PCTCN2021133158-appb-100016
  11. 根据权利要求1或2所述化合物、其光学异构体及其药效上可接受的盐，其中，环B选自苯基和吡啶基，所述苯基或吡啶基任选被1、2或3个R 3取代。
  12. 根据权利要求1或2所述化合物、其光学异构体及其药效上可接受的盐，其中，环C选自
    Figure PCTCN2021133158-appb-100017
    Figure PCTCN2021133158-appb-100018
  13. 下式化合物、其光学异构体及其药效上可接受的盐，其选自
    Figure PCTCN2021133158-appb-100019
    Figure PCTCN2021133158-appb-100020
  14. 根据权利要求1-13任一项所述的化合物、其光学异构体及其药效上可接受的盐在制备药物中的应用，所述药物用于预防或治疗与精氨酸加压素V1a受体、精氨酸加压素V1b受体、精氨酸加压素V2受体、交感神经系统或肾素-血管紧张素-醛固酮系统相关的疾病。
  15. 根据权利要求14所述的应用，所述与精氨酸加压素V1a受体、精氨酸加压素V1b受体、精氨酸加压素V2受体、交感神经系统或肾素-血管紧张素-醛固酮系统相关的疾病，包括：高血压、雷氏综合征、痛经、早产、促肾上腺皮质激素释放激素分泌紊乱、肾上腺增生、抑郁症、慢性充血性心力衰竭、肝硬化、抗利尿激素分泌紊乱综合征、慢性心力衰竭/肝硬化/抗利尿激素分泌紊乱引起的低钠血症、或多囊肾疾病。
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