WO2022184172A1 - 新型苯并氮杂卓并环衍生物 - Google Patents

新型苯并氮杂卓并环衍生物 Download PDF

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WO2022184172A1
WO2022184172A1 PCT/CN2022/079350 CN2022079350W WO2022184172A1 WO 2022184172 A1 WO2022184172 A1 WO 2022184172A1 CN 2022079350 W CN2022079350 W CN 2022079350W WO 2022184172 A1 WO2022184172 A1 WO 2022184172A1
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alkyl
independently selected
mmol
alkylamino
alkoxy
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PCT/CN2022/079350
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English (en)
French (fr)
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陆洪福
裘德智
彭建彪
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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 KR1020237033116A priority Critical patent/KR20230152111A/ko
Priority to BR112023017755A priority patent/BR112023017755A2/pt
Priority to CN202280003642.XA priority patent/CN115427048A/zh
Priority to CA3210848A priority patent/CA3210848A1/en
Priority to IL305652A priority patent/IL305652A/en
Priority to EP22762633.0A priority patent/EP4302762A1/en
Priority to AU2022230013A priority patent/AU2022230013A1/en
Priority to JP2023553451A priority patent/JP2024509437A/ja
Publication of WO2022184172A1 publication Critical patent/WO2022184172A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • 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
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered

Definitions

  • the present invention relates to novel benzazepine derivatives and salts thereof.
  • the present invention also relates to medicaments comprising benzoazepine derivatives and salts thereof as active ingredients, which can be used for diagnosis, prevention and/or treatment of vasopressin receptor-related diseases.
  • 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 (I), an optical isomer or a pharmacologically acceptable salt thereof,
  • Ring A is selected from 4-6 membered heterocyclyl and C3-6 membered cycloalkyl, said 4-6 membered heterocyclyl or C3-6 membered cycloalkyl optionally surrounded by 1, 2 or 3 R A Substituted;
  • Ring B is selected from phenyl and 5-6 membered heteroaryl, the phenyl or 5-6 membered heteroaryl is 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 C(R T );
  • R 1 , R 2 , R 3 , RA , R T are each independently selected from H, F, Cl, Br, I, CN, OH, NH 2 , C 1-6 alkyl and C 1-6 heteroalkyl , the C 1-6 alkyl or C 1-6 heteroalkyl is optionally substituted by 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 4a ;
  • R and R 4a are 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;
  • n 1, 2 are independently selected from 0, 1 or 2;
  • the present invention also provides the compound represented by formula (II), its optical isomer or its pharmacologically acceptable salt,
  • X 1 , X 2 , and X 3 are independently selected from O, C( RA ) 2 and NRA ;
  • 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 C(R T );
  • R 1 , R 2 , R 3 , RA , R T are each independently selected from H, F, Cl, Br, I, CN, OH, NH 2 , C 1-6 alkyl and C 1-6 heteroalkyl , the C 1-6 alkyl or C 1-6 heteroalkyl is optionally substituted by 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 4a ;
  • R and R 4a are 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;
  • n are independently selected from 0, 1 or 2;
  • the present invention also provides compounds represented by formula (II-1), (II-2), (II-3), (II-4), their optical isomers or their pharmacological effects on acceptable salt,
  • Ring B, Ring C, X 1 , X 2 , X 3 , T 1 , T 2 , R 1 , R 2 , m1 , m2 , and n are as defined above.
  • the present invention also provides the compound represented by formula (III), its optical isomer or its pharmacologically acceptable salt,
  • X 1 , X 2 , and X 3 are independently selected from O, C( RA ) 2 and NRA ;
  • T 1 , T 2 are independently selected from N and C(R T );
  • Y 1 , Y 2 are each independently selected from N and C(R Y );
  • R 1 , R 2 , R 3 , RA , RT , R Y are each independently selected from H, F, Cl, Br, I, CN, OH, NH 2 , C 1-6 alkyl and C 1-6 Heteroalkyl, the C 1-6 alkyl or C 1-6 heteroalkyl is 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 4a ;
  • R and R 4a are 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;
  • n are independently selected from 0, 1 or 2;
  • the present invention also provides compounds represented by formula (III-1), (III-2), (III-3), (III-4), their optical isomers or their pharmacological effects on acceptable salt,
  • X 1 , X 2 , X 3 , T 1 , T 2 , Y 1 , Y 2 , R 1 , R 2 , R 3 , R 4 , m1 , m2 , m3 , m4 , and n are as defined above.
  • the present invention also proposes a compound represented by formula (IV), an optical isomer or a pharmacologically acceptable salt thereof,
  • T 1 and T 2 are independently selected from O, N and C(R T );
  • Y 1 , Y 2 are each independently selected from N and C(R Y );
  • R 1 , R 2 , R 3 , RA , RT , R Y are each independently selected from H, F, Cl, Br, I, CN, OH, NH 2 , C 1-6 alkyl and C 1-6 Heteroalkyl, the C 1-6 alkyl or C 1-6 heteroalkyl is 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 4a ;
  • R and R 4a are 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;
  • n are independently selected from 0, 1 or 2;
  • the present invention also provides compounds represented by formulas (V-1), (V-2), (V-3), (V-4), their optical isomers or their pharmacological effects on acceptable salt,
  • T 1 , T 2 , Y 1 , Y 2 , R 1 , R 2 , R 3 , R 4 , R A , m2 , m3 and n are as defined above.
  • 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, the remaining variables are as defined herein.
  • the above-mentioned ring A is selected from azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, cyclobutanyl, cyclopentyl and cyclohexyl, so Said azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, cyclobutanyl, cyclopentyl or cyclohexyl is optionally substituted with 1 or 2 R A , and the remaining variables are as as defined in the present invention.
  • the above-mentioned ring A is selected from The remaining variables are as defined in the present invention.
  • the above-mentioned ring B is selected from phenyl and pyridyl, said phenyl or pyridyl optionally being substituted with 1, 2 or 3 R3 , and the remaining variables are as defined herein.
  • the above-mentioned ring B is selected from The remaining variables are as defined in the present invention.
  • the above-mentioned ring C is selected from The remaining variables are as defined in the present invention.
  • the present invention also provides a compound of the following formula, an optical isomer or a pharmacologically acceptable salt thereof, which is selected from the group consisting of
  • the present invention also provides a compound of the following formula, an optical isomer or a pharmacologically acceptable salt thereof, which is selected from the group consisting of
  • the present invention also proposes the use of the aforementioned compound, its optical isomer or its pharmaceutically acceptable salt in the preparation of a medicament 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 compound of the present invention has lower liver toxicity, and the specific manifestations include but are not limited to: the compound of the present invention can reduce the inhibition of bile excretion to the bile duct, and does not trap GSH (glutathione) and/or no production of DM4103-like metabolites;
  • GSH glutathione
  • the proportional dose-effect of the compound of the present invention has no hook effect in the proliferation of LLC-PK1 cells induced by AVP, so the compound of the present invention has a better curative effect;
  • the compound of the present invention does not inhibit CYP;
  • the compounds of the present invention have high selectivity for V2 receptors.
  • 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.
  • 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.
  • 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.
  • C 4-6 cycloalkyl means a saturated cyclic hydrocarbon group consisting of 4 to 6 carbon atoms, which are monocyclic and bicyclic ring systems, said C 4-6 cycloalkyl group includes C 4-5 , C 5-6 , C 4 and C 5 cycloalkyl, etc.; it may be monovalent, divalent or polyvalent.
  • Examples of C4-6 cycloalkyl include, but are not limited to, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • 4-6 membered heterocyclyl by itself or in combination with other terms denotes a saturated cyclic group consisting of 4 to 6 ring atoms, respectively, of which 1, 2, 3 or 4 ring atoms are Heteroatoms independently selected from O, S, and N, the remainder being 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 4-6 membered heterocycloalkyl includes 4-5 membered, 4 membered, 5 membered, 5-6 membered and 6 membered heterocycloalkyl and the like.
  • 4-6 membered heterocyclyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including Tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidyl) pyridyl and 3-piperidyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), di- oxanyl, dithianyl, isoxazolidinyl, isothiazolid
  • 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 group 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,
  • 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. 2 is a second diagram of repeated experiments according to an embodiment of the present invention.
  • intermediate I-1 (37.00 g, 106.00 mmol) was dissolved in anhydrous tetrahydrofuran (350 mL), and under argon protection and ice-water bath cooling, sodium hydride (6.36 g, 60% wt, 159.00 mmol). After cooling in an ice-water bath and stirring for 1 hour, dimethyl carbonate (19.08 g, 212.00 mmol) was added, and the temperature was raised to 50° C. and stirred for 24 hours. After cooling, the reaction solution was slowly poured into cold saturated aqueous ammonium chloride solution (500 mL), concentrated to remove most of the tetrahydrofuran, and filtered. The filter cake is washed with clean water, then slurried with petroleum ether, filtered, and the filter cake is sucked dry to obtain Intermediate I-2.
  • intermediate I-2 (19.00 g, 46.68 mmol) was dissolved in anhydrous N,N-dimethylformamide (187 mL), and sodium carbonate (14.84 g, 140.00 mmol) and 2- (2-Bromoethyl)isoindoline-1,3-dione (23.71 g, 93.36 mmol) was stirred at 90°C overnight under argon.
  • reaction solution was cooled, diluted with ethyl acetate (500 mL), washed with water (150 mL ⁇ 3), washed with saturated brine (100 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 I-3.
  • intermediate I-4 200 mg, 0.38 mmol was dissolved in ethanol (7 mL), 85% hydrazine hydrate (0.35 mL) was added, and the reaction solution was stirred at 35°C for 4 hours. It was concentrated under reduced pressure to remove most of the ethanol, diluted with ethyl acetate (50 mL), washed with water (20 mL ⁇ 3) and saturated brine (20 mL) successively, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude intermediate I -5. The crude product was used directly in the next reaction.
  • intermediate I-5 (170 mg, 0.45 mmol) was dissolved in methanol (10 mL), and sodium borohydride (190 mg, 5.00 mmol) was slowly added under ice-water bath cooling.
  • the reaction solution was stirred at room temperature for 1 hour, concentrated under reduced pressure to remove most of the methanol, diluted with ethyl acetate (50 mL), washed with water (20 mL ⁇ 3) and saturated brine (20 mL) successively, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude intermediate I-6.
  • the crude product was used directly in the next reaction.
  • intermediate I-7 (85 mg, 0.38 mmol) was dissolved in dichloromethane (3 mL), followed by the addition of triethylamine (121 mg, 1.20 mmol) and di-tert-butyl dicarbonate (124 mg, 0.57 mmol) , and stirred at room temperature overnight.
  • the reaction was concentrated to dryness, dissolved in ethyl acetate (50 mL), washed with dimethylethylenediamine aqueous solution (1M, 10 mL ⁇ 2), then washed with water (20 mL ⁇ 2), washed with saturated brine (20 mL), and anhydrous Dry over sodium sulfate and filter.
  • the filtrate was concentrated under reduced pressure to obtain the crude intermediate I-8.
  • the crude product was used directly in the next reaction.
  • intermediate I-10 33 mg, 0.073 mmol was dissolved in dichloromethane (2 mL), followed by the addition of triethylamine (50 mg, 0.50 mmol) and o-toluoyl chloride (23.00 mg, 0.15 mmol) ). After stirring at room temperature for 1 hour, methanol (0.5 mL) was added to quench, and the crude product was obtained by concentration under reduced pressure. The crude product was isolated and purified by silica gel chromatography to give intermediate I-11.
  • 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 Stir 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-12 was isolated and purified by silica gel chromatography.
  • intermediate I-12 (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 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-13.
  • intermediate I-8 50 mg, 0.16 mmol was dissolved in tetrahydrofuran (1 mL), followed by pyridine (0.79 mL, 10.00 mmol), 1-propylphosphonic anhydride (50% wt ethyl acetate solution) , 0.79 mL) and Intermediate 1-13 (53 mg, 0.17 mmol) were stirred in a sealed microwave tube at 65°C overnight.
  • intermediate I-6 (115 mg, 0.31 mmol) was dissolved in anhydrous dichloromethane (2 mL), and paraformaldehyde (56 mg, 0.62 mmol) and sodium borohydride acetate (20 mg, 0.93 mmol) were added sequentially ), stirred at 90°C overnight under argon protection.
  • reaction solution was quenched with saturated aqueous ammonium chloride solution (2 mL), concentrated under reduced pressure to remove dichloromethane, diluted with ethyl acetate (50 mL), washed with water (30 mL ⁇ 2) and saturated brine (20 mL) in turn, Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product.
  • the crude product was isolated and purified by silica gel chromatography to give intermediate 1-15.
  • intermediate I-19 (5.00 g, 11.87 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL), cooled in an ice-water bath under argon protection, and 60% sodium hydride (0.95 g, 23.74 mmol) was slowly added .
  • the ice-water bath was maintained, and after stirring for 0.5 hours, methyl bromoacetate (3.63 g, 23.74 mmol) was added, and the mixture was stirred at room temperature overnight.
  • reaction solution was poured into ice-cold saturated aqueous ammonium chloride solution (100 mL), concentrated under reduced pressure to remove most of the tetrahydrofuran, and extracted with ethyl acetate (150 mL ⁇ 2).
  • the combined organic phases were washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered.
  • the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel chromatography to obtain intermediate I-20.
  • Mobile phase A: water (0.01% trifluoroacetic acid)
  • B acetonitrile (0.01% trifluoroacetic acid)
  • the acid chloride was dissolved in anhydrous dichloromethane, and the intermediate I-27 (50 mg, 0.22 mmol), triethylamine (310 mg, 3.10 mmol) and p-dimethylaminopyridine were slowly added under argon protection and ice-water bath cooling. (1.83 mg, 0.15 mmol) in dichloromethane (2 mL) and stirred at 40°C overnight after the addition was complete.
  • intermediate I-19 (5.0 g, 11.85 mmol) was dissolved in tetrahydrofuran (50 mL), and under nitrogen protection, sodium borohydride (8.78 g, 232.09 mmol) was added to the reaction system, and the reaction solution was at room temperature. under stirring for 24 hours.
  • the crude product was isolated and purified by silica gel chromatography to give intermediate I-30.
  • intermediate I-30 (3.54 g, 9.29 mmol) was dissolved in dichloromethane (10 mL), followed by methanesulfonyl chloride (1.16 g, 10.22 mmol), triethylamine (1.41 g, 13.93 mmol) ) was added, and the reaction solution was stirred at 0 °C for 1 hour under the protection of argon.
  • the crude product was used directly in the next reaction without purification.
  • intermediate I-31 (3.71 g, 8.08 mmol) was dissolved in tetrahydrofuran (10 mL), 60% sodium hydride (808 mg, 20.20 mmol) was added to the reaction solution under argon protection, and stirred at room temperature for 16 hours .
  • Water (50 mL) was added to quench, extracted with ethyl acetate (30 mL ⁇ 2), the organic phases were combined, washed with saturated brine (30 mL ⁇ 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent to obtain the crude product.
  • the crude product was isolated and purified by silica gel chromatography to give intermediate 1-32.
  • intermediate I-33 400 mg, 1.91 mmol was dissolved in dichloromethane (20 mL), N,N-diisopropylethylamine (740 mg, 5.74 mmol) was added at room temperature, and under nitrogen protection, 2-Methyl-4-nitrobenzoyl chloride (455 mg, 2.29 mmol) was added to the above reaction solution, and the reaction solution was stirred at room temperature for 16 hours.
  • the crude product was isolated and purified by silica gel chromatography to give intermediate 1-34.
  • intermediate I-34 (100 mg, 0.27 mmol) was dissolved in tetrahydrofuran (10 mL), zinc powder (349 mg, 5.37 mmol) and ammonium chloride (284 mg, 5.37 mmol) were added under nitrogen protection, and the reaction solution was Stir at 80°C for 1 hour. The reaction solution was filtered and concentrated to dryness under reduced pressure to obtain the crude product Intermediate I-35. The crude product was used directly in the next reaction without purification.
  • intermediate I-37 (2.50 g) was dissolved in dichloromethane (20 mL), followed by addition of triethylamine (1.48 g, 14.70 mmol), di-tert-butyl dicarbonate (2.20 g, 10.09 mmol) ) and stirred at 25°C overnight.
  • the reaction solution was concentrated, dissolved in ethyl acetate (100 mL), washed with aqueous dimethylethylenediamine (1M, 30 mL ⁇ 2), washed with water (30 mL), washed with saturated aqueous sodium chloride (30 mL), and washed with anhydrous sulfuric acid Dry over sodium and filter.
  • the filtrate was concentrated under reduced pressure to remove the organic solvent to obtain the crude product Intermediate I-38.
  • the crude product was used directly in the next reaction without purification.
  • intermediate I-38 (2.50 g) was dissolved in anhydrous dichloromethane (20 mL), triethylamine (1.00 g, 9.90 mmol) was added, and formazan was added dropwise under argon protection and ice-water bath. Sulfonyl chloride (0.82 g, 7.13 mmol). The reaction solution was stirred at 25°C for 1 hour, quenched by dropwise addition of methanol (1 mL), concentrated under reduced pressure, dissolved in ethyl acetate (100 mL), washed with saturated aqueous sodium bicarbonate solution (30 mL ⁇ 2), and washed with water (30 mL).
  • intermediate I-39 (2.00 g, 3.58 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), 60% sodium hydride (2.90 g, 72.5 mmol) was added, and argon was replaced for three times and then stirred at 70 °C overnight.
  • the reaction solution was cooled, poured into ice-cold saturated aqueous ammonium chloride solution (20 mL), concentrated under reduced pressure to remove most of tetrahydrofuran, and extracted with ethyl acetate (50 mL ⁇ 2).
  • intermediate I-40 (0.45 g, 0.97 mmol) was dissolved in a dichloromethane solution of trifluoroacetic acid (1/10, 5 mL), stirred for 1 hour, and poured into ice-cold saturated aqueous sodium bicarbonate solution (50 mL), concentrated at room temperature to remove most of the dichloromethane and extracted with ethyl acetate (30 mL ⁇ 2). The organic phases were combined, washed with water (20 mL ⁇ 2), washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent to obtain the crude product Intermediate I-41. The crude product was used directly in the next reaction without purification.
  • the intermediate I-41 (0.31 g, 0.86 mmol) was dissolved in anhydrous methanol (20 mL), magnesium turnings (1.20 g, 50.00 mmol) were added, and argon was replaced three times. Under the protection of argon, 70 Stir overnight at °C. After cooling the reaction solution, it was filtered through a pad of celite, the filtrate was concentrated, diluted with dichloromethane/methanol (10/1, 100 mL), washed with saturated aqueous ammonium chloride solution (30 mL ⁇ 2), washed with water (30 mL ⁇ 2), Washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent to obtain the crude product Intermediate I-42. The crude product was used directly in the next reaction without purification.
  • intermediate I-42 (0.15 g) was dissolved in dichloromethane (3 mL), triethylamine (0.22 g, 2.16 mmol), di-tert-butyl dicarbonate (0.31 g, 1.44 mmol) were added successively ). After stirring at 25°C for 3 hours, the mixture was concentrated under reduced pressure, and the residue was separated and purified by silica gel chromatography to obtain intermediate I-43.
  • 2-methyl-4-nitrobenzoic acid (0.58 g, 3.20 mmol) was dissolved in anhydrous dichloromethane (5 mL), and after adding a drop of N,N-dimethylformamide, argon Cool in an ice-water bath under air, slowly add oxalyl chloride (1.63 g, 12.8 mmol) dropwise, keep cooling in an ice-water bath and stir for 1 hour, and then concentrate to dryness at room temperature to obtain an acid chloride intermediate.
  • reaction solution was stirred at 40 °C overnight, cooled to room temperature, quenched by dropwise addition of methanol (2 mL), concentrated under reduced pressure, diluted with ethyl acetate (50 mL), washed with saturated aqueous sodium bicarbonate solution (20 mL ⁇ 2), water (20 mL) ), washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent to obtain the crude product. The crude product was isolated and purified by silica gel chromatography to give intermediate 1-44.
  • intermediate I-44 (63 mg, 0.13 mmol) was dissolved in tetrahydrofuran (5 mL), zinc powder (87 mg, 1.30 mmol), ammonium chloride (35 mg, 0.65 mmol) were added in sequence, and under argon protection Stir at 70°C for 5 hours.
  • the reaction solution was cooled, filtered through celite, concentrated under reduced pressure, dissolved in ethyl acetate (50 mL), washed with water (20 mL ⁇ 2), washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and filtered .
  • the filtrate was concentrated under reduced pressure to remove the organic solvent to obtain the crude product Intermediate I-45.
  • the crude product was used directly in the next reaction without purification.
  • intermediate I-45 (50 mg) was dissolved in dichloromethane (2 mL), triethylamine (33 mg, 0.33 mmol), o-chlorobenzoyl chloride (50% wt ethyl acetate solution, 0.79mL).
  • dichloromethane (2 mL)
  • triethylamine 33 mg, 0.33 mmol
  • o-chlorobenzoyl chloride 50% wt ethyl acetate solution, 0.79mL.
  • 4-aminobutanol 0.5mL
  • dichloromethane (30mL) to dilute, wash with water (20mL ⁇ 2), saturated aqueous sodium chloride solution (20 mL) washed, dried over anhydrous sodium sulfate, and filtered.
  • the filtrate was concentrated under reduced pressure to remove the organic solvent to obtain the crude product Intermediate I-46.
  • the crude product was used directly in the next reaction without purification.
  • intermediate I-47 (4.70 g, 10.58 mmol) was dissolved in anhydrous tetrahydrofuran (35 mL), pyridine (8.37 g, 106.00 mmol), intermediate I-13 (4.92 g, 15.87 mmol) were sequentially added ) and 1-propylphosphoric anhydride (50% wt ethyl acetate solution, 20.00 g, 31.74 mmol), stirred at 65° C. overnight under argon protection. The reaction solution was cooled, concentrated to remove most of the tetrahydrofuran, and diluted with ethyl acetate (150 mL).
  • Mobile phase A: water (0.01% trifluoroacetic acid)
  • B acetonitrile (0.01% trifluoroacetic acid)
  • potassium tert-butoxide 17.81 g, 158.68 mmol was added to a solution of p-chloronitrobenzene (10.00 g, 63.47 mmol) in N,N-dimethylformamide (300 mL), and stirred for 30 min and then additional ethyl chloroacetate (8.56 g, 69.82 mmol) was added. The reaction solution was stirred at -5°C for 1 hour under nitrogen protection.
  • reaction solution was poured into water (1000 mL), extracted with ethyl acetate (200 mL ⁇ 4), the organic phases were combined, washed with saturated brine (800 mL ⁇ 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent to obtain the crude product.
  • the crude product was isolated and purified by silica gel chromatography to give intermediate 1-49.
  • Methoxyformylmethylenetriphenylphosphine (12.06 g, 32.07 mmol) was added to a solution of Intermediate 1-50 (7.20 g, 36.07 mmol) in toluene (200 mL) at 25 °C. The reaction mixture was stirred at 110°C for 3 hours under nitrogen protection. The reaction solution was cooled to room temperature, 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 I-51.
  • Trifluoroacetic acid (10 mL) was added to a solution of Intermediate 1-51 (7.70 g, 30.12 mmol) in dichloromethane (150 mL) at 25°C, followed by dropwise addition of N-(methoxymethyl)-N- (Trimethylsilylmethyl)benzylamine (20.34 g, 85.66 mmol) and the reaction mixture was stirred at 25°C for 12 hours. The organic solvent was removed by concentration under reduced pressure to obtain a crude product. The crude product was isolated and purified by silica gel chromatography to give intermediate 1-52.
  • Zinc powder (2.35 g, 36.00 mmol) was added to Intermediate 1-52 (2.8 g, 7.20 mmol) and ammonium chloride (3.08 g, 57.61 mmol) in methanol (60 mL)/water (20 mL) at 25°C in the mixture.
  • the reaction mixture was stirred at 70°C for 12 hours under nitrogen protection.
  • the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure, and separated and purified by silica gel chromatography to obtain intermediate I-53.
  • N,N-diisopropylethylamine (2.25 g, 17.40 mmol) was added to a solution of intermediate 1-54 (2.00 g, 5.80 mmol) in dichloromethane (60 mL) followed by O - Benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate (3.72 g, 11.6 mmol).
  • the reaction mixture was stirred at 25°C for 12 hours under nitrogen protection.
  • the organic solvent was removed by concentration under reduced pressure to obtain the crude product.
  • the crude product was isolated and purified by silica gel chromatography to give intermediate 1-55.
  • lithium tetrahydroaluminum (27.23 mL, 27.23 mmol, 1 M in THF) was added to a solution of intermediate 1-55 (1.78 g, 5.45 mmol) in tetrahydrofuran (30 mL), and the reaction mixture was Stir at 0°C for 1 hour.
  • intermediate I-13 (38.5 mg, 0.124 mmol) was dissolved in N,N-dimethylacetamide (2 mL), cooled to 0 °C, and thionyl chloride (14.8 mg) was added under argon protection. , 0.124 mmol), after the reaction mixture was stirred at room temperature for 1 hour, Intermediate I-59 (20.0 mg, 0.062 mmol) was added, and the reaction mixture was continued to stir at room temperature for 16 hours.
  • reaction mixture was poured into saturated aqueous sodium bicarbonate solution (20 mL), extracted with ethyl acetate (5 mL ⁇ 3), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent to obtain the crude product.
  • the crude product was isolated and purified by silica gel chromatography to give intermediate 1-60.
  • intermediate I-14 (30 mg, 0.049 mmol) was dissolved in a methanol solution of hydrogen chloride (3 M, 3 mL), stirred at room temperature for 1 hour, concentrated to dryness, and separated and purified by preparative HPLC (formic acid system) to obtain compound 2 .
  • Mobile phase A: water (0.01% trifluoroacetic acid)
  • B acetonitrile (0.01% trifluoroacetic acid)
  • intermediate I-26 38 mg, 0.11 mmol was dissolved in dichloromethane (2 mL), followed by triethylamine (55 mg, 0.55 mmol), o-toluoyl chloride (34 mg, 0.22 mmol) . After stirring at room temperature for 1 hour, quenched by adding methanol (1 mL), concentrated to dryness under reduced pressure, and separated and purified by preparative HPLC (formic acid system) to obtain compound 4.
  • intermediate I-29 (26 mg, 0.073 mmol) was dissolved in dichloromethane (2 mL), triethylamine (55 mg, 0.55 mmol), and o-toluoyl chloride (34 mg, 0.22 mmol) were added successively. . After stirring at room temperature for 1 hour, quenched by adding methanol (1 mL), concentrated to dryness under reduced pressure, and separated and purified by preparative HPLC (formic acid system) to obtain compound 5.
  • intermediate I-46 (40 mg, 0.069 mmol) was dissolved in a dichloromethane solution of trifluoroacetic acid (1/10, 3 mL), stirred at room temperature for 1 hour, and poured into ice-cold saturated aqueous sodium bicarbonate ( 20mL), extracted with dichloromethane/methanol (10/1, 20mL ⁇ 2), combined the organic phases, washed with water (20mL), concentrated under reduced pressure, the residue was separated and purified by preparative HPLC (ammonium bicarbonate system) to obtain compound 7 .
  • Chromatographic column ChiralPak AD, 250 ⁇ 30mm I.D., 10 ⁇ m
  • Chromatographic column ChiralPak AD, 150 ⁇ 4.6mm I.D., 3 ⁇ m
  • HeLa cell line stably expressing human vasopressin receptor V2R (HeLa-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 intensities at 615 nm and 665 nm were 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 Male CD1 mice, 6-8 weeks old, all animals had free access to food and water, orally administered 10 mg/kg (solvent 5% DMSO/10% Solutol/85% Saline), 15 minutes after administration, 30min, 1hr, 2hr, 4hr, 8hr, 10hr, 24hr blood collection, 150 ⁇ L of each sample was collected, anticoagulated with heparin sodium, placed on ice after collection, and centrifuged within 1 hour to separate plasma for testing. The plasma concentration of the drug was detected by liquid tandem mass spectrometry (LC/MS/MS), and the pharmacokinetic parameters were calculated by Phoenix WinNonlin software. Taking tofatriptan as reference substance 1, the experimental results are shown in Table 2.
  • mice show longer half-life T 1/2 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 later use. LLC-PK1 cells were trypsinized, resuspended with serum-free M199 after centrifugation, counted, diluted with serum-free M199 medium to a cell suspension of 1 ⁇ 10 5 /ml, and FBS was added to a final concentration of 1%.
  • 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 living cells in the well at the time of 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 "++”, and the performance was weaker than that of 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.
  • Amplify cells with high expression of human V1a receptor collect cells, wash twice with PBS, resuspend cells with PBS containing protease inhibitors, and homogenize cells with a homogenizer at 15000 r/min, 3000 r/min at 4°C Centrifuge for 15 minutes, collect the supernatant, centrifuge at 20,000 r/min at 4°C for 45 minutes, discard the supernatant, and obtain cell membrane pellets. Add buffer to resuspend to measure the protein concentration, and store in aliquots at -80°C. Cell membranes with high expression of human V1b and V2 receptors were purchased from Perkinelmer, USA.
  • the positive control Vasopressin was formulated as a 10 mM stock solution.
  • test compound and positive control were diluted to 1 mM (10-fold dilution) and 0.1 mM (100-fold dilution) with DMSO, respectively, and then successively diluted four-fold with DMSO to the 10th point.
  • Cell membranes overexpressing human receptors were prepared at 5 mg/mL with assay buffer.
  • Y Bottom+(Top-Bottom)/(1+10 ⁇ ((X-LogIC50))), where: Y is the reading value of the liquid scintillation instrument, and X is the logarithmic value of the compound concentration.
  • Ki IC50/(1+([L]/Kd)), where [L] is the concentration of isotope-labeled Vasopressin in the test, and Kd is the concentration of isotope-labeled Vasopressin with the receptor.
  • the dissociation constant of the body is the concentration of isotope-labeled Vasopressin with the receptor.

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Abstract

式(I)所示苯并氮杂卓并环衍生物或其药效上可接受的盐，以及该化合物作可用于诊断、预防和/或治疗与血管加压素受体相关的疾病。

Description

新型苯并氮杂卓并环衍生物
本发明要求如下优先权：
CN202110264947.3，申请日：2021年03月05日；
CN202110559685.3，申请日：2021年05月21日；
CN202210198716.1，申请日：2022年03月02日。
技术领域
本发明涉及新型苯并氮杂卓并环衍生物及其盐。本发明还涉及包含苯并氮杂卓并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
在本发明的第一方面，本发明提出了式(I)所示化合物、其光学异构体或其药效上可接受的盐，
Figure PCTCN2022079350-appb-000001
其中，
环A选自4-6元杂环基和C 3-6元环烷基，所述4-6元杂环基或C 3-6元环烷基任选被1、2或3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C(R T)；
R 1、R 2、R 3、R A、R T分别独立地选自H、F、Cl、Br、I、CN、OH、NH 2、C 1-6烷基和C 1-6杂烷基，所述C 1-6烷基或C 1-6杂烷基任选被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 4a取代；
R、R 4a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、m2分别独立地选自0、1或2；
且，当环A选自4-6元杂环基时，式(I)所示化合物不选自
Figure PCTCN2022079350-appb-000002
Figure PCTCN2022079350-appb-000003
所述4-6元杂环基、C 1-6杂烷基或5-6元杂芳基包含1、2、3或4个独立选自-O-、-NH-、-S-、-C(＝O)-、-C(＝O)O-、-S(＝O)-、-S(＝O) 2-和N的杂原子或杂原子团。
在本发明的第二方面，本发明还提出了式(II)所示化合物、其光学异构体或其药效上可接受的盐，
Figure PCTCN2022079350-appb-000004
其中，X 1、X 2、X 3分别独立地选自O、C(R A) 2和NR A；
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C(R T)；
R 1、R 2、R 3、R A、R T分别独立地选自H、F、Cl、Br、I、CN、OH、NH 2、C 1-6烷基和C 1-6杂烷基，所述C 1-6烷基或C 1-6杂烷基任选被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 4a取代；
R、R 4a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、m2、n分别独立地选自0、1或2；
且，当X 1、X 3同时选自O时，式(II)所示化合物不选自
Figure PCTCN2022079350-appb-000005
所述C 1-6杂烷基或5-6元杂芳基包含1、2、3或4个独立选自-O-、-NH-、-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，本发明还提出了式(II-1)、(II-2)、(II-3)、(II-4)所示化合物、其光学异构体或其药效上可接受的盐，
Figure PCTCN2022079350-appb-000006
Figure PCTCN2022079350-appb-000007
其中，环B、环C、X 1、X 2、X 3、T 1、T 2、R 1、R 2、m1、m2、n如前面所定义。
在本发明的另一方面，本发明还提出了式(III)所示化合物、其光学异构体或其药效上可接受的盐，
Figure PCTCN2022079350-appb-000008
其中，X 1、X 2、X 3分别独立地选自O、C(R A) 2和NR A；
T 1、T 2分别独立地选自N和C(R T)；
Y 1、Y 2分别独立地选自N和C(R Y)；
R 1、R 2、R 3、R A、R T、R Y分别独立地选自H、F、Cl、Br、I、CN、OH、NH 2、C 1-6烷基和C 1-6杂烷基，所述C 1-6烷基或C 1-6杂烷基任选被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 4a取代；
R、R 4a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、m2、m3、m4、n分别独立地选自0、1或2；
且，当X 1、X 3同时选自O时，式(III)所示化合物不选自
Figure PCTCN2022079350-appb-000009
所述C 1-6杂烷基或5-6元杂芳基包含1、2、3或4个独立选自-O-、-NH-、-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，本发明还提出了式(III-1)、(III-2)、(III-3)、(III-4)所示化合物、其光学异构体或其药效上可接受的盐，
Figure PCTCN2022079350-appb-000010
Figure PCTCN2022079350-appb-000011
其中，X 1、X 2、X 3、T 1、T 2、Y 1、Y 2、R 1、R 2、R 3、R 4、m1、m2、m3、m4、n如前面所定义。
在本发明的另一方面，本发明还提出了式(IV)所示化合物、其光学异构体或其药效上可接受的盐，
Figure PCTCN2022079350-appb-000012
其中，T 1、T 2分别独立地选自O、N和C(R T)；
Y 1、Y 2分别独立地选自N和C(R Y)；
R 1、R 2、R 3、R A、R T、R Y分别独立地选自H、F、Cl、Br、I、CN、OH、NH 2、C 1-6烷基和C 1-6杂烷基，所述C 1-6烷基或C 1-6杂烷基任选被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 4a取代；
R、R 4a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；
m2、m3、n分别独立地选自0、1或2；
所述C 1-6杂烷基或5-6元杂芳基包含1、2、3或4个独立选自-O-、-NH-、-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，本发明还提出了式(V-1)、(V-2)、(V-3)、(V-4)所示化合物、其光学异构体或其药效上可接受的盐，
Figure PCTCN2022079350-appb-000013
Figure PCTCN2022079350-appb-000014
其中，T 1、T 2、Y 1、Y 2、R 1、R 2、R 3、R 4、R A、m2、m3、n如前面所定义。
在本发明的一些方案中，上述R 4选自H、F、Cl、Br、I、CN、OH、NH 2、CH 3、CF 3、
Figure PCTCN2022079350-appb-000015
Figure PCTCN2022079350-appb-000016
环丙基、环丁基、环戊基、苯基、吡啶基、嘧啶基、噻吩基和噻唑基，其余变量如本发明所定义。
在本发明的一些方案中，上述环A选自氮杂环丁烷基、氧杂环丁烷基、吡咯烷基、四氢呋喃基、环丁烷基、环戊烷基和环己烷基，所述氮杂环丁烷基、氧杂环丁烷基、吡咯烷基、四氢呋喃基、环丁烷基、环戊烷基或环己烷基任选被1或2个R A取代，其余变量如本发明所定义。
在本发明的一些方案中，上述环A选自
Figure PCTCN2022079350-appb-000017
其余变量如本发明所定义。
在本发明的一些方案中，上述环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，其余变量如本发明所定义。
在本发明的一些方案中，上述环B选自
Figure PCTCN2022079350-appb-000018
其余变量如本发明所定义。
在本发明的一些方案中，上述环C选自
Figure PCTCN2022079350-appb-000019
其余变量如本发明所定义。
在本发明的再一方面，本发明还提出了下式化合物、其光学异构体或其药效上可接受的盐，其选自
Figure PCTCN2022079350-appb-000020
Figure PCTCN2022079350-appb-000021
在本发明的再一方面，本发明还提出了下式化合物、其光学异构体或其药效上可接受的盐，其选自
Figure PCTCN2022079350-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、其光学异构体或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。
本发明具有如下技术效果至少之一：
1)与现有技术(例如阳性药物托伐普坦等)相比，本发明化合物具有更低的肝毒性，具体表现包括但不限于：本发明化合物可降低胆汁排泄到胆管的抑制、不捕获GSH(谷胱甘肽)和/或不产生DM4103样代谢物；
2)与现有技术相比，本发明化合物的比例剂量效应(Proportional dose-effect)在AVP诱导的LLC-PK1细胞增殖中没有钩子效应(hook effect)，因而本发明化合物具有更优的疗效；
3)与现有技术(例如阳性药物Lixivaptan等)相比，本发明化合物不抑制CYP；
4)与现有技术相比，本发明化合物的半衰期较长，因而能延长药效；
5)与现有技术相比，本发明化合物对V2受体具有高选择性。
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。
除非另有说明，用楔形实线键
Figure PCTCN2022079350-appb-000023
和楔形虚线键
Figure PCTCN2022079350-appb-000024
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2022079350-appb-000025
和直形虚线键
Figure PCTCN2022079350-appb-000026
表示立体中心的相对构型，如
Figure PCTCN2022079350-appb-000027
中C1和C2原子处的直形实线键和直形虚线键表示了与C1和C2相连的两个键分别朝里和朝外，即代表了
Figure PCTCN2022079350-appb-000028
两个反式构型的化合物，而如果化合物为顺式结构，则可用两个直形实线键
Figure PCTCN2022079350-appb-000029
或两个直形虚线键
Figure PCTCN2022079350-appb-000030
表示，即
Figure PCTCN2022079350-appb-000031
与
Figure PCTCN2022079350-appb-000032
其均代表
Figure PCTCN2022079350-appb-000033
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 PCTCN2022079350-appb-000034
时，例如在
Figure PCTCN2022079350-appb-000035
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 PCTCN2022079350-appb-000036
时，例如在
Figure PCTCN2022079350-appb-000037
中，该虚线代表单键或者不存在，也意味着
Figure PCTCN2022079350-appb-000038
代表了单键
Figure PCTCN2022079350-appb-000039
或者双键
Figure PCTCN2022079350-appb-000040
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 PCTCN2022079350-appb-000041
中L 1代表单键时表示该结构实际上是
Figure PCTCN2022079350-appb-000042
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 PCTCN2022079350-appb-000043
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 PCTCN2022079350-appb-000044
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 PCTCN2022079350-appb-000045
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“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 PCTCN2022079350-appb-000046
)。C 1-6烷基的实例包括但不限于CH 3、
Figure PCTCN2022079350-appb-000047
Figure PCTCN2022079350-appb-000048
Figure PCTCN2022079350-appb-000049
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 PCTCN2022079350-appb-000050
)。C 1-4烷基的实例包括但不限于CH 3、
Figure PCTCN2022079350-appb-000051
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 PCTCN2022079350-appb-000052
Figure PCTCN2022079350-appb-000053
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 PCTCN2022079350-appb-000054
等。
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，“C 4-6环烷基”表示由4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 4-6环烷基包括C 4-5、C 5-6、C 4和C 5环烷基等；其可以是一价、二价或者多价。C 4-6环烷基的实例包括，但不限于，环丁基、环戊基、环己基等。
除非另有规定，术语“4-6元杂环基”本身或者与其他术语联合分别表示由4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“4-6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4-6元杂环烷基包括4-5元、4元、5元、5-6元和6元杂环烷基等。4-6元杂环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 PCTCN2022079350-appb-000055
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重复实验一图；
图2是根据本发明实施例的重复实验二图。
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 PCTCN2022079350-appb-000056
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 PCTCN2022079350-appb-000057
在25℃下，将中间体I-1(37.00g,106.00mmol)溶于无水四氢呋喃(350mL)中，氩气保护及冰水浴冷却下，分批加入氢化钠(6.36g,60％wt,159.00mmol)。保持冰水浴冷却搅拌1小时后，加入碳酸二甲酯(19.08g,212.00mmol)，升温到50℃搅拌24小时。冷却后将反应液缓慢倒入冷的饱和氯化铵水溶液(500mL)中，浓缩除去大部分四氢呋喃，过滤。滤饼用清水洗涤，再用石油醚打浆，过滤，滤饼抽干，得到中间体I-2。
LC-MS(ESI)[M+H] +408.0。
参考例3：中间体I-3的制备
Figure PCTCN2022079350-appb-000058
在25℃下，将中间体I-2(19.00g,46.68mmol)溶于无水N,N-二甲基甲酰胺(187mL)中，依次加入碳酸钠(14.84g,140.00mmol)和2-(2-溴乙基)异吲哚啉-1,3-二酮(23.71g,93.36mmol)，氩气保护下90℃搅拌过夜。反应液冷却后加乙酸乙酯(500mL)稀释，水洗(150mL×3)，饱和食盐水(100mL)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-3。
LC-MS(ESI)[M+H] +581.2。
参考例4：中间体I-4的制备
Figure PCTCN2022079350-appb-000059
在25℃下，将中间体I-3(20.00g,34.48mmol)溶于二甲基亚砜/水(130mL/13mL)中，加入氯化钠(16.70g,28.60mmol)。体系氩气置换三次后，氩气保护下150℃搅拌10小时。反应液冷却后加乙酸乙酯(400mL)稀释，水洗(150mL×3)，饱和食盐水(100mL)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。
LC-MS(ESI)[M+H] +523.2。
参考例5：中间体I-5的制备
Figure PCTCN2022079350-appb-000060
在25℃下，将中间体I-4(200mg,0.38mmol)溶于乙醇(7mL)，加入85％水合肼(0.35mL)，反应液于35℃搅拌4小时。减压浓缩除去大部分乙醇，加入乙酸乙酯(50mL)稀释，依次用水(20mL×3)和饱和食盐水(20mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩得粗品中间体I-5。粗产品直接用于下一步反应。
LC-MS(ESI)[M+H] +375.2。
参考例6：中间体I-6的制备
Figure PCTCN2022079350-appb-000061
在25℃下，将中间体I-5(170mg,0.45mmol)溶于甲醇(10mL)，冰水浴冷却下缓慢加入硼氢化钠(190mg,5.00mmol)。反应液室温搅拌1小时后，减压浓缩除掉大部分甲醇，加乙酸乙酯(50mL)稀释，依次用水(20mL×3)和饱和食盐水(20mL)洗，无水硫酸钠干燥，过滤。滤液减压浓缩得粗品中间体I-6。粗产品直接用于下一步反应。
LC-MS(ESI)[M+H] +377.2。
参考例7：中间体I-7的制备
Figure PCTCN2022079350-appb-000062
在25℃下，将中间体I-6(150mg,0.40mmol)溶于无水甲醇(20mL)，加入镁屑(2.00g,83.33mmol)。置换氮气三次，氮气氛围(气球)下70℃搅拌过夜。冷却后，垫硅藻土过滤，滤液浓缩干，加二氯甲烷/甲醇混合液(10/1,50mL)溶解，用饱和氯化铵水溶液(20mL×3)洗涤，水(20mL×2)洗，无水硫酸钠干燥，过滤。滤液减压浓缩得粗品中间体I-7。粗产品直接用于下一步反应。
LC-MS(ESI)[M+H] +223.0。
参考例8：中间体I-8的制备
Figure PCTCN2022079350-appb-000063
在25℃下，将中间体I-7(85mg,0.38mmol)溶于二氯甲烷(3mL)，依次加入三乙胺(121mg,1.20mmol)和二碳酸二叔丁酯(124mg,0.57mmol)，室温搅拌过夜。将反应浓缩干，加乙酸乙酯(50mL)溶解，用二甲基乙二胺水溶液(1M,10mL×2)洗涤，再用水洗(20mL×2)，饱和食盐水(20mL)洗，无水硫酸钠干燥，过滤。滤液减压浓缩得粗品中间体I-8。粗产品直接用于下一步反应。
LC-MS(ESI)[M+H-56] +267.0。
参考例9：中间体I-9的制备
Figure PCTCN2022079350-appb-000064
在25℃下，将2-甲基-4-硝基苯甲酸(181mg,1.00mmol)溶于无水二氯甲烷(5mL)，在冰水浴及氩气保护下，依次加入N,N-二甲基甲酰胺(20mg)和草酰氯(591mg,4.65mmol)。继续在冰水浴下搅拌1小时后，室温浓缩干，得到酰氯中间体。将该酰氯溶于无水二氯甲烷，在冰水浴及氩气保护下缓慢加入中间体I-8(110mg,0.34mmol)，三乙胺(343mg,3.4mmol)和对二甲胺基吡啶(1.83mg,0.15mmol)的二氯甲烷(2.5mL)溶液，加料完毕后40℃搅拌过夜。加入甲醇(0.5mL)淬灭，减压浓缩干，加乙酸乙酯(50mL)溶解，依次用水(30mL×2)和饱和食盐水(20mL)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-9。
LC-MS(ESI)[M+H] +486.2。
参考例10：中间体I-10的制备
Figure PCTCN2022079350-appb-000065
在25℃下，将中间体I-9(37.00mg,0.076mmol)溶于乙醇(5mL)，加入锌粉(130mg,2.00mmol)。置换氮气三次，氮气氛围(气球)下70℃搅拌3小时。冷却后，垫硅藻土过滤，滤液减压浓缩干得粗品中间体I-10。粗产品直接用于下一步反应。
LC-MS(ESI)[M+H] +456.4。
参考例11：中间体I-11的制备
Figure PCTCN2022079350-appb-000066
在25℃下，将中间体I-10(33mg,0.073mmol)溶于二氯甲烷(2mL)，依次加入三乙胺(50mg,0.50mmol)和邻甲基苯甲酰氯(23.00mg,0.15mmol)。室温搅拌1小时后加甲醇(0.5mL)淬灭，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-11。
LC-MS(ESI)[M+H] +574.3。
参考例12：中间体I-12的制备
Figure PCTCN2022079350-appb-000067
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-12。
LC-MS(ESI)[M+H] +325.0。
参考例13：中间体I-13的制备
Figure PCTCN2022079350-appb-000068
室温下，将中间体I-12(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-13。
LC-MS(ESI)[M+H] +311.0。
参考例14：中间体I-14的制备
Figure PCTCN2022079350-appb-000069
在25℃下，将中间体I-8(50mg,0.16mmol)溶于四氢呋喃(1mL)中，依次加入吡啶(0.79mL,10.00mmol)，1-丙基膦酸酐(50％wt乙酸乙酯溶液，0.79mL)和中间体I-13(53mg,0.17mmol)，于密封微波管中65℃搅拌过夜。冷却后减压浓缩干，加乙酸乙酯溶解(50mL)，用饱和碳酸氢钠水溶液(30mL×2)洗涤，水(20mL×2)洗，饱和食盐水(20mL)洗，无水硫酸钠干燥，过滤。滤液减压浓缩得粗品中间体I-14。粗产品直接用于下一步反应。
LC-MS(ESI)[M+H] +615.3。
参考例15：中间体I-15的制备
Figure PCTCN2022079350-appb-000070
在25℃下，将中间体I-6(115mg,0.31mmol)溶于无水二氯甲烷(2mL)中，依次加入多聚甲醛(56mg,0.62mmol)和醋酸硼氢化钠(20mg,0.93mmol)，氩气保护下90℃搅拌过夜。反应液冷却后，加饱和氯化铵水溶液(2mL)淬灭，减压浓缩除去二氯甲烷，加乙酸乙酯(50mL)稀释，依次用水(30mL×2)和饱和食盐水(20mL)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-15。
LC-MS(ESI)[M+H] +391.2。
参考例16：中间体I-16的制备
Figure PCTCN2022079350-appb-000071
在25℃下，将中间体I-15(100mg,0.26mmol)溶于无水甲醇(20mL)，加入镁屑(2.00g,83.33mmol)。置换氮气三次，氮气氛围下70℃搅拌过夜。冷却后，垫硅藻土过滤，滤液浓缩干，加二氯甲烷/甲醇混合液(10/1,50mL)溶解，用饱和氯化铵水溶液(20mL×3)洗涤，水(20mL×2)洗，无水硫酸钠干燥，过滤。滤液减压浓缩得粗品中间体I-16。粗产品直接用于下一步反应。
LC-MS(ESI)[M+H] +237.2。
参考例17：中间体I-17的制备
Figure PCTCN2022079350-appb-000072
在室温下，将4-甲苯磺酰氯(247g,1.30mol)加入到2-氨基-5-氯苯甲酸甲酯(200g,1.08mol)的吡啶(1000mL)中。反应混合物于室温下搅拌反应16小时。将反应液倒入冰水(1500mL)中，用乙酸乙酯(1000mL×3)萃取。合并有机相，有机相依次用水(1500mL)和饱和食盐水(1500mL)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。粗产品经乙酸乙酯/石油醚(5:95)打浆纯化得到中间体I-17。
LC-MS(ESI)[M+H] +340.0。
1H NMR(400MHz,DMSO-d 6)δ10.29(s,1H),7.78(d,J＝2.6Hz,1H),7.67(d,J＝8.3Hz,2H),7.63(dd,J＝8.9,2.6Hz,1H),7.46(d,J＝8.9Hz,1H),7.36(d,J＝8.1Hz,2H),3.80(s,3H),2.34(s,3H).
参考例18：中间体I-18的制备
Figure PCTCN2022079350-appb-000073
在室温下，将碳酸铯(384g,1.18mol)加入到中间体I-17(200g,0.589mol)和4-溴丁酸乙酯(121g,0.620mol)的N,N-二甲基甲酰胺(1000mL)溶液中，反应混合物在120℃下搅拌2小时。将反应液冷却至室温，倒入冰水(2L)中，用乙酸乙酯(1000mL×3)萃取。合并有机相，有机相依次用水(1000mL×3)和饱和食盐水(1000mL)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。粗产品经乙酸乙酯/石油醚(5:95)打浆纯化得到中间体I-18。
LC-MS(ESI)[M+H] +454.1。
1H NMR(400MHz,DMSO-d 6)δ7.79(d,J＝2.6Hz,1H),7.61(dd,J＝8.6,2.6Hz,1H),7.39(s,4H),6.97(d,J＝8.6Hz,1H),4.01(q,J＝7.1Hz,2H),3.76(s,3H),3.70(m,1H),3.45(m,1H),2.45–2.32(m,5H),1.71–1.60(m,2H),1.14(t,J＝7.1Hz,3H).
参考例19：中间体I-19的制备
Figure PCTCN2022079350-appb-000074
在室温下，将叔丁醇钾(69.0g,0.615mol)加入到甲苯(1.6L)中，升温至70℃搅拌30分钟。然后将中间体I-18(186g,0.410mol)加入其中，反应混合物在100℃下搅拌1小时。将反应液冷却至室温，加入水(1L)，用乙酸乙酯(1L×2)萃取。合并有机相，有机相用饱和食盐水(1L)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中间体I-19。粗产品未经纯化直接用于下一步反应。
参考例20：中间体I-20的制备
Figure PCTCN2022079350-appb-000075
在25℃下，将中间体I-19(5.00g,11.87mmol)溶于无水四氢呋喃(60mL)中，在氩气保护下冰水浴冷却，缓慢加入60％氢化钠(0.95g,23.74mmol)。保持冰水浴，搅拌0.5小时后加入溴乙酸甲酯(3.63g,23.74mmol)，室温搅拌过夜。将反应液倒入冰冷的饱和氯化铵水溶液(100mL)中，减压浓缩除掉大部分四氢呋喃，用乙酸乙酯(150mL×2)萃取。合并有机相用水(50mL)洗，饱和食盐水(50mL)洗，无水硫酸钠干燥，过滤。滤液减压浓缩，残留物经硅胶色谱法分离纯化得到中间体I-20。
LC-MS(ESI)[M+H] +494.2。
参考例21：中间体I-21的制备
Figure PCTCN2022079350-appb-000076
在25℃下，将中间体I-20(5.50g,11.16mmol)溶于二甲基亚砜/水(55mL/5mL)中，加入氯化钠(0.71g,12.00mmol)。体系氩气置换三次后，氩气保护下150℃搅拌10小时。反应液冷却后加乙酸乙酯(200mL)稀释，水(50mL×3)洗，饱和食盐水(50mL)洗，无水硫酸钠干燥，过滤。滤液减压浓缩，残留物经硅胶色谱法分离纯化得到中间体I-21。
LC-MS(ESI)[M+H] +422.0。
参考例22：中间体I-22的制备
Figure PCTCN2022079350-appb-000077
在25℃下，将中间体I-21(1.00g,2.38mmol)溶于无水四氢呋喃(15mL)。体系氩气保护下用冰水浴冷却，搅拌下缓慢加入硼氢化锂的四氢呋喃溶液(1M,7.14mL,7.14mmol)，加料完毕后回到室温搅拌3小时左右。将反应液倒入冰冷的饱和氯化铵水溶液(100mL)，减压浓缩除掉大部分四氢呋喃，用二氯甲烷/甲醇混合溶剂(10/1,50mL×2)萃取。合并有机相，水洗(30mL)，饱和食盐水(20mL)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中间体I-22。粗产品未经纯化直接用于下一步反应。
LC-MS(ESI)[M-H 2O+H] +378.2。
参考例23：中间体I-23A和I-23B的制备
Figure PCTCN2022079350-appb-000078
在25℃下，将中间体I-22(900mg,2.27mmol)溶于无水二氯甲烷(30mL)，加入三氟化硼乙醚(1.26mL,10mmol)。置换氩气三次，氩气保护下40℃搅拌16小时。将反应液减压浓缩，残留物经硅胶色谱法分离纯化得到中间体I-23A(Rt＝1.342min)和中间体I-23B(Rt＝1.321min)。
LCMS分析方法：色谱柱：Infinitylab Poroshell 120EC-C18 3.0×30mm,1.9μm
流动相：A:水(0.01％三氟乙酸)B:乙腈(0.01％三氟乙酸)
洗脱梯度：5％-95％B，0.7分钟；95％B 0.8分钟；然后5％B 0.5分钟
流动速率：1.2mL/min
色谱柱温度：40℃
质谱扫描范围：100-1000
中间体I-23A(Rt＝1.342min)LC-MS(ESI)[M+H] +378.0。
中间体I-23B(Rt＝1.321min)LC-MS(ESI)[M+H] +378.0。
参考例24：中间体I-24的制备
Figure PCTCN2022079350-appb-000079
在25℃下，将中间体I-23A(280.00mg,0.74mmol)溶于无水甲醇(20mL)，加入镁屑(2.00g,83.33mmol)。置换氮气三次，氮气氛围下70℃搅拌过夜。将反应液冷却后，垫硅藻土过滤，滤液减压浓缩干，加乙酸乙酯(100mL)溶解，用饱和氯化铵水溶液(30mL×3)洗涤，水(30mL×2)洗，饱和食盐水(20mL)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中间体I-24。粗产品未经纯化直接用于下一步反应。
LC-MS(ESI)[M+H] +224.0。
参考例25：中间体I-25的制备
Figure PCTCN2022079350-appb-000080
在25℃下，将2-甲基-4-硝基苯甲酸(168mg,0.93mmol)溶于无水二氯甲烷(5mL)，氩气保护、冰水浴冷却下，依次加入二甲基甲酰胺(20mg)和草酰氯(591mg,4.65mmol)。保持冰水浴冷却，继续搅拌1小时后，室温浓缩干得到酰氯中间体。将该酰氯溶于无水二氯甲烷，在氩气保护、冰水浴冷却下缓慢加入中间体I-24(70mg,0.31mmol)，三乙胺(310mg,3.10mmol)和对二甲胺基吡啶(1.83mg,0.15mmol)的二氯甲烷(2mL)溶液，加料完毕后于40℃搅拌过夜。反应完全后，加甲醇(0.5mL)淬灭，减压浓缩干，加乙酸乙酯(50mL)溶解，水(30mL×2)洗，饱和食盐水(20mL)洗，无水硫酸钠干燥，过滤。滤液减压浓缩，残留物经硅胶色谱法分离纯化得到中间体I-25。
LC-MS(ESI)[M+H] +387.2。
参考例26：中间体I-26的制备
Figure PCTCN2022079350-appb-000081
在25℃下，将中间体I-25(40mg,0.10mmol)溶于乙醇(5mL)，加入锌粉(130mg,2.00mmol)。置换氮气三次，氮气氛围下70℃搅拌3小时。将反应液冷却后，垫硅藻土过滤，滤液减压浓缩除去有机溶剂得到粗产品中间体I-26。粗产品未经纯化直接用于下一步反应。
LC-MS(ESI)[M+H] +357.2。
参考例27：中间体I-27的制备
Figure PCTCN2022079350-appb-000082
在25℃下，将中间体I-23B(280mg,0.74mmol)溶于无水甲醇(20mL)，加入镁屑(2.00g,83.33mmol)。置换氮气三次，氮气氛围下70℃搅拌过夜。将反应液冷却后，垫硅藻土过滤，滤液减压浓缩干，加乙酸乙酯(100mL)溶解，用饱和氯化铵水溶液(30mL×3)洗涤，水(30mL×2)洗，饱和食盐水(20mL)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中间体I-27。粗产品未经纯化直接用于下一步反应。
LC-MS(ESI)[M+H] +224.0。
参考例28：中间体I-28的制备
Figure PCTCN2022079350-appb-000083
在25℃下，将2-甲基-4-硝基苯甲酸(168mg,0.93mmol)溶于无水二氯甲烷(5mL)，氩气保护、冰水浴冷却下，依次加入二甲基甲酰胺(20mg)和草酰氯(591mg,4.65mmol)。保持冰水浴冷却，继续搅拌1小时后，室温浓缩干得到酰氯中间体。将该酰氯溶于无水二氯甲烷，在氩气保护、冰水浴冷却下缓慢加入中间体I-27(50mg,0.22mmol)，三乙胺(310mg,3.10mmol)和对二甲胺基吡啶(1.83mg,0.15mmol)的二氯甲烷(2mL)溶液，加料完毕后于40℃搅拌过夜。反应完全后，加甲醇(0.5mL)淬灭，减压浓缩干，加乙酸乙酯(50mL)溶解，水(30mL×2)洗，饱和食盐水(20mL)洗，无水硫酸钠干燥，过滤。滤液减压浓缩，残留物经硅胶色谱法分离纯化得到中间体I-28。
LC-MS(ESI)[M+H] +387.2。
参考例29：中间体I-29的制备
Figure PCTCN2022079350-appb-000084
在25℃下，将中间体I-28(30mg,0.078mmol)溶于乙醇(5mL)，加入锌粉(130mg,2.00mmol)。置换氮气三次，氮气氛围下70℃搅拌3小时。将反应液冷却后，垫硅藻土过滤，滤液减压浓缩除去有机溶剂得到粗产品中间体I-29。粗产品未经纯化直接用于下一步反应。
LC-MS(ESI)[M+H] +357.2。
参考例30：中间体I-30的制备
Figure PCTCN2022079350-appb-000085
在室温下，将中间体I-19(5.0g,11.85mmol)溶于四氢呋喃(50mL)中，氮气保护下，将硼氢化钠(8.78g,232.09mmol)加到反应体系中，反应液在室温下搅拌24小时。加水(50mL)稀释，用乙酸乙酯(50mL×2)萃取，合并有机相，用饱和食盐水(30mL×2)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-30。
LC-MS(ESI)[M+H] +382.2。
参考例31：中间体I-31的制备
Figure PCTCN2022079350-appb-000086
在室温下，将中间体I-30(3.54g,9.29mmol)溶于二氯甲烷(10mL)中，依次将甲基磺酰氯(1.16g,10.22mmol)，三乙胺(1.41g,13.93mmol)加入其中，反应液在氩气保护下0℃搅拌1小时。加水(50mL)稀释，用二氯甲烷(30mL×2)萃取，合并有机相，用饱和食盐水(30mL×2)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中间体I-31。粗产品未经纯化直接用于下一步反应。
参考例32：中间体I-32的制备
Figure PCTCN2022079350-appb-000087
在室温下，将中间体I-31(3.71g,8.08mmol)溶于四氢呋喃(10mL)中，在氩气保护下往反应液中加入60％氢化钠(808mg,20.20mmol)，室温搅拌16小时。加水(50mL)淬灭，用乙酸乙酯(30mL×2)萃取，合并有机相，饱和食盐水(30mL×2)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-32。
LC-MS(ESI)[M+Na] +386.0。
参考例33：中间体I-33的制备
Figure PCTCN2022079350-appb-000088
在室温下，将中间体I-32(2.34g,6.43mmol)溶于甲醇(50mL)中，在氮气保护下加入镁屑(1.54g,64.40mmol)，反应液在70℃搅拌1小时。将反应体系冷却至室温，加饱和氯化铵溶液(50mL)稀释，用乙酸乙酯(30mL×2)萃取，合并有机相，用饱和氯化铵水溶液(30mL×2)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-33。
LC-MS(ESI)[M+H] +210.0。
参考例34：中间体I-34的制备
Figure PCTCN2022079350-appb-000089
在室温下，将中间体I-33(400mg,1.91mmol)溶于二氯甲烷(20mL)中，室温下加入N,N-二异丙基乙胺(740mg,5.74mmol)，氮气保护下，将2-甲基-4-硝基苯甲酰氯(455mg,2.29mmol)加入到上述反应液中，反应液在室温下搅拌16小时。加水(20mL)稀释，用二氯甲烷(30mL×2)萃取，合并有机相，用饱和氯化钠水溶液(30mL×2)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-34。
LC-MS(ESI)[M+H] +373.2。
参考例35：中间体I-35的制备
Figure PCTCN2022079350-appb-000090
在室温下，将中间体I-34(100mg,0.27mmol)溶于四氢呋喃(10mL)中，氮气保护下加入锌粉(349mg,5.37mmol)和氯化铵(284mg,5.37mmol)，反应液在80℃下搅拌1小时。将反应液过滤，减压浓缩干，得到粗产品中间体I-35。粗产品未经纯化直接用于下一步反应。
LC-MS(ESI)[M+H] +343.2。
参考例36：中间体I-36的制备
Figure PCTCN2022079350-appb-000091
在25℃下，将中间体I-19(2.00g,4.75mmol)溶于吡啶(10mL)中，加入甲氧胺盐酸盐(0.79g,9.50mmol)。于密封微波管中80℃搅拌10小时后浓缩，加乙酸乙酯稀释(100mL)，用饱和氯化铵水溶液(50mL×2)洗涤，水(50mL×2)洗，饱和氯化钠水溶液(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中间体I-36。粗产品未经纯化直接用于下一步反应。
LC-MS(ESI)[M+H] +451.2。
参考例37：中间体I-37的制备
Figure PCTCN2022079350-appb-000092
在25℃下，将中间体I-36(2.20g)溶于硼烷四氢呋喃(24.50mL,22.05mmol)中，氩气置换三次，氩气保护下50℃搅拌过夜。在冰水浴冷却下滴加甲醇到不冒泡为止，减压浓缩得到粗产品中间体I-37。粗产品未经纯化直接用于下一步反应。
LC-MS(ESI)[M+H] +381.2。
参考例38：中间体I-38的制备
Figure PCTCN2022079350-appb-000093
在25℃下，将中间体I-37(2.50g)溶于二氯甲烷(20mL)中，依次加入三乙胺(1.48g,14.70mmol)，二碳酸二叔丁酯(2.20g,10.09mmol)，25℃搅拌过夜。将反应液浓缩，加乙酸乙酯(100mL)溶解，用二甲基乙二胺水溶液(1M,30mL×2)洗涤，水(30mL)洗，饱和氯化钠水溶液(30mL)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产品中间体I-38。粗产品未经纯化直接用于下一步反应。
LC-MS(ESI)[M+H-56] +425.3。
参考例39：中间体I-39的制备
Figure PCTCN2022079350-appb-000094
在25℃下，将中间体I-38(2.50g)溶于无水二氯甲烷(20mL)中，加入三乙胺(1.00g,9.90mmol)，在氩气保护、冰水浴下滴加甲磺酰氯(0.82g,7.13mmol)。反应液于25℃搅拌1小时后，滴加甲醇(1mL)淬灭，减压浓缩，加乙酸乙酯(100mL)溶解，用饱和碳酸氢钠水溶液(30mL×2)洗涤，水(30mL)洗，饱和氯化钠水溶液(30mL)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产品。粗产品经硅胶色谱法分离纯化得到中间体I-39。
LC-MS(ESI)[M+H-100] +459.0。
参考例40：中间体I-40的制备
Figure PCTCN2022079350-appb-000095
在25℃下，将中间体I-39(2.00g,3.58mmol)溶于无水四氢呋喃(10mL)中，加入60％氢化钠(2.90g,72.5mmol)，氩气置换三次后于70℃搅拌过夜。将反应液冷却后，倒入冰冷的饱和氯化铵水溶液(20mL)，减压浓缩除去大部分四氢呋喃，用乙酸乙酯萃取(50mL×2)。合并有机相，水(30mL×2)洗，饱和氯化钠水溶液(30mL)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产品。粗产品经硅胶色谱法分离纯化得到中间体I-40。
LC-MS(ESI)[M+H-56] +406.90。
参考例41：中间体I-41的制备
Figure PCTCN2022079350-appb-000096
在25℃下，将中间体I-40(0.45g,0.97mmol)溶于三氟乙酸的二氯甲烷溶液(1/10,5mL)中，搅拌1小时后倒入冰冷的饱和碳酸氢钠水溶液(50mL)，室温浓缩除去大部分二氯甲烷后用乙酸乙酯萃取(30mL×2)。合并有机相，水(20mL×2)洗，饱和氯化钠水溶液(20mL)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产品中间体I-41。粗产品未经纯化直接用于下一步反应。
参考例42：中间体I-42的制备
Figure PCTCN2022079350-appb-000097
在25℃下，将中间体I-41(0.31g,0.86mmol)溶于无水甲醇(20mL)中，加入镁屑(1.20g,50.00mmol)后，氩气置换三次，氩气保护下70℃搅拌过夜。将反应液冷却后，垫硅藻土过滤，滤液浓缩，加二氯甲烷/甲醇(10/1,100mL)稀释，用饱和氯化铵水溶液(30mL×2)洗涤，水(30mL×2)洗，饱和氯化钠水溶液(20mL)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产品中间体I-42。粗产品未经纯化直接用于下一步反应。
LC-MS(ESI)[M+H] +208.8。
参考例43：中间体I-43的制备
Figure PCTCN2022079350-appb-000098
在25℃下，将中间体I-42(0.15g)溶于二氯甲烷(3mL)中，依次加入三乙胺(0.22g,2.16mmol)，二碳酸二叔丁酯(0.31g,1.44mmol)。25℃搅拌3小时后减压浓缩，残留物经硅胶色谱法分离纯化得到中间体I-43。
LC-MS(ESI)[M+H] +309.2。
参考例44：中间体I-44的制备
Figure PCTCN2022079350-appb-000099
在25℃下，将2-甲基-4-硝基苯甲酸(0.58g,3.20mmol)溶于无水二氯甲烷(5mL)中，加入一滴N,N-二甲基甲酰胺后，氩气下冰水浴冷却，缓慢滴加草酰氯(1.63g,12.8mmol)，保持冰水浴冷却搅拌1小时后室温浓缩干得酰氯中间体。将该酰氯中间体溶于无水二氯甲烷(5mL)，在冰水浴及氩气保护下加入三乙胺(2.56g,25.60mmol)，4-二甲氨基吡啶(2.44mg,0.02mmol)和中间体I-43(100mg,0.32mmol)。反应液于40℃搅拌过夜后冷却到室温，滴加甲醇(2mL)淬灭，减压浓缩，加乙酸乙酯(50mL)稀释，用饱和碳酸氢钠水溶液(20mL×2)洗涤，水(20mL)洗，饱和氯化钠水溶液(20mL)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产品。粗产品经硅胶色谱法分离纯化得到中间体I-44。
LC-MS(ESI)[M+H] +471.8。
参考例45：中间体I-45的制备
Figure PCTCN2022079350-appb-000100
在25℃下，将中间体I-44(63mg,0.13mmol)溶于四氢呋喃(5mL)中，依次加入锌粉(87mg,1.30mmol)，氯化铵(35mg,0.65mmol)，氩气保护下70℃搅拌5小时。将反应液冷却后，垫硅藻土过滤，减压浓缩，加乙酸乙酯(50mL)溶解，水(20mL×2)洗，饱和氯化钠水溶液(20mL)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产品中间体I-45。粗产品未经纯化直接用于下一步反应。
LC-MS(ESI)[M+H] +441.8。
参考例46：中间体I-46的制备
Figure PCTCN2022079350-appb-000101
在25℃下，将中间体I-45(50mg)溶于二氯甲烷(2mL)中，依次加入三乙胺(33mg,0.33mmol)，邻氯苯甲酰氯(50％wt乙酸乙酯溶液,0.79mL)。氩气保护下25℃搅拌1小时，加入4-氨基丁醇(0.5mL)，25℃继续搅拌15分钟，加二氯甲烷(30mL)稀释，水(20mL×2)洗，饱和氯化钠水溶液(20mL)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产品中间体I-46。粗产品未经纯化直接用于下一步反应。
LC-MS(ESI)[M+H] +580.2。
参考例47：中间体I-47的制备
Figure PCTCN2022079350-appb-000102
在25℃下，将中间体I-7(7.30g,32.89mmol)和三乙胺(10.10g,100.00mmol)溶于无水二氯甲烷(100mL)中。在氩气保护及冰水浴冷却下，缓慢加入氯甲酸-9-芴基甲酯(12.73g,49.33mmol)，于25℃搅拌16小时。室温减压浓缩，用石油醚打浆，过滤，滤饼用水(20mL)洗，抽干得到中间体I-47。
LC-MS(ESI)[M+H] +444.8。
参考例48：中间体I-48A和I-48B的制备
Figure PCTCN2022079350-appb-000103
在25℃下，将中间体I-47(4.70g,10.58mmol)溶于无水四氢呋喃(35mL)中，依次加入吡啶(8.37g,106.00mmol)，中间体I-13(4.92g,15.87mmol)和1-丙基磷酸酐(50％wt乙酸乙酯溶液,20.00g,31.74mmol)，氩气保护下65℃搅拌过夜。将反应液冷却后，浓缩除去大部分四氢呋喃，加乙酸乙酯(150mL)稀释。依次用1N盐酸(100mL×2)洗涤，饱和碳酸氢钠水溶液(100mL×3)洗涤，水(100mL)洗，饱和氯化钠水溶液(100mL)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产品。粗产品经硅胶色谱法分离纯化得到中间体I-48A(Rt＝1.541min)和中间体I-48B(Rt＝1.508min)。
LCMS分析方法：色谱柱：Waters acquity UPLC CSH 2.1×50mm,1.7μm
流动相：A:水(0.01％三氟乙酸)B:乙腈(0.01％三氟乙酸)
洗脱梯度：5％-95％B，0.7分钟；95％B 0.8分钟；然后5％B 0.5分钟
流动速率：1.0mL/min
色谱柱温度：60℃
质谱扫描范围：100-1000
中间体I-48A(Rt＝1.541min)LC-MS(ESI)[M+H] +737.3。
中间体I-48B(Rt＝1.508min)LC-MS(ESI)[M+H] +737.3。
参考例49：中间体I-49的制备
Figure PCTCN2022079350-appb-000104
在-5℃下，将叔丁醇钾(17.81g,158.68mmol)加入到对氯硝基苯(10.00g,63.47mmol)的N,N-二甲基甲酰胺(300mL)溶液中，搅拌30分钟然后再加入氯乙酸乙酯(8.56g,69.82mmol)。反应液在氮气保护下，于-5℃搅拌1小时。将反应液倒入水(1000mL)中，用乙酸乙酯(200mL×4)萃取，合并有机相，并用饱和食盐水(800mL×3)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产品。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] +244.0。
参考例50：中间体I-50的制备
Figure PCTCN2022079350-appb-000105
在氮气保护及-78℃冷却下，将二异丁基氢化铝(1.5M in THF,65.67mL,98.50mmol)加入到中间体I-49(12.00g,49.25mmol)的乙醚(200mL)溶液中，反应混合物在-78℃下搅拌1小时。将反应液升温至0℃，搅拌下滴入水(4mL)，然后加入15％氢氧化钠水溶液(4mL)，最后加入水(10mL)，升温至室温搅拌15分钟。加入适量无水硫酸钠，搅拌15分钟后过滤。滤液减压浓缩除去有机溶剂得到中间体I-50。
LC-MS(ESI)[M+H] +200.0。
参考例51：中间体I-51的制备
Figure PCTCN2022079350-appb-000106
在25℃下，将甲氧甲酰基亚甲基三苯基膦(12.06g,32.07mmol)加入到中间体I-50(7.20g,36.07mmol)的甲苯(200mL)溶液中。反应混合物在氮气保护下，于110℃搅拌3小时。将反应液冷却至室温，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。
参考例52：中间体I-52的制备
Figure PCTCN2022079350-appb-000107
在25℃下，将三氟乙酸(10mL)加入到中间体I-51(7.70g,30.12mmol)的二氯甲烷(150mL)溶液中，然后滴加N-(甲氧甲基)-N-(三甲基硅甲基)苄胺(20.34g,85.66mmol)，反应混合物在25℃下搅拌12小时。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] +389.2。
参考例53：中间体I-53的制备
Figure PCTCN2022079350-appb-000108
在25℃下，将锌粉(2.35g,36.00mmol)加入到中间体I-52(2.8g,7.20mmol)和氯化铵(3.08g,57.61mmol)在甲醇(60mL)/水(20mL)的混合物中。反应混合物在氮气保护下，于70℃搅拌12小时。将反应液冷却至室温，过滤，滤液减压浓缩，经硅胶色谱法分离纯化得到中间体I-53。
LC-MS(ESI)[M+H] +359.2。
参考例54：中间体I-54的制备
Figure PCTCN2022079350-appb-000109
在25℃下，将氢氧化钾(1.08g,19.29mmol)加入到中间体I-53(2.30g,6.41mmol)的四氢呋喃(10mL)/甲醇(10mL)/水(10mL)的混合溶液中。反应混合物在氮气保护下，于25℃搅拌12小时。用1N盐酸将反应液调至酸性(pH＝5～6)，用乙酸乙酯(30mL×4)萃取。合并有机相，并用饱和食盐水(100mL)洗，无水硫酸钠干燥，过滤。减压浓缩除去有机溶剂得到中间体I-54。
LC-MS(ESI)[M+H] +345.2。
参考例55：中间体I-55的制备
Figure PCTCN2022079350-appb-000110
在25℃下，将N,N-二异丙基乙胺(2.25g,17.40mmol)加入到中间体I-54(2.00g,5.80mmol)的二氯甲烷(60mL)溶液中，然后加入O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯(3.72g,11.6mmol)。反应混合物在氮气保护下，于25℃搅拌12小时。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-55。
LC-MS(ESI)[M+H] +327.2。
参考例56：中间体I-56的制备
Figure PCTCN2022079350-appb-000111
在氮气保护及冰水浴冷却下，将四氢铝锂(27.23mL,27.23mmol,1M in THF)加入到中间体I-55(1.78g,5.45mmol)的四氢呋喃(30mL)溶液中，反应混合物在0℃下搅拌1小时。搅拌下往反应液中依次加入水(4mL)，15％氢氧化钠溶液(4mL)，水(10mL)。搅拌15分钟后，过滤，滤液用乙酸乙酯(30mL×4)萃取。合并有机相，并用饱和食盐水(100mL)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产品。粗产品经硅胶色谱法分离纯化得到中间体I-56。
参考例57：中间体I-57的制备
Figure PCTCN2022079350-appb-000112
往100mL的高压釜中加入中间体I-56(250mg,0.799mmol)，钯碳(10％,含水50％,200mg)和甲醇(20mL)，置换氢气2次后，反应混合物在氢气氛围(1MPa)中室温搅拌过夜。将混合物过滤，滤液减压浓缩得到中间体I-57。
LC-MS(ESI)[M+H] +189.1。
参考例58：中间体I-58的制备
Figure PCTCN2022079350-appb-000113
将中间体I-57(110mg,0.584mmol)和三乙胺(295mg,2.92mmol)混合于二氯甲烷(5mL)中，室温搅拌下加入二碳酸二叔丁酯(153mg,0.701mmol)，反应混合物室温搅拌2小时。将混合物浓缩后经硅胶色谱法分离纯化得到中间体I-58。
LC-MS(ESI)[M+H] +289.2。
参考例59：中间体I-59的制备
Figure PCTCN2022079350-appb-000114
在室温下，将中间体I-58(120mg,0.416mmol)，二水合氯化铜(213mg,1.25mmol)和氯化锂(53mg,1.25mmol)溶于乙醇(5mL)中，反应混合物加热至80℃搅拌6小时。将混合物冷却至室温后，减压除去溶剂，残留物用乙酸乙酯(10mL)稀释后倒入水(50mL)中，加氨水(2mL)后用乙酸乙酯(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-59。
LCMS(ESI)[M+H+MeCN] +364.3。
参考例60：中间体I-60的制备
Figure PCTCN2022079350-appb-000115
在室温下，将中间体I-13(38.5mg,0.124mmol)溶于N,N-二甲基乙酰胺(2mL)中，降温至0℃，氩气保护下加入氯化亚砜(14.8mg,0.124mmol)，反应混合物在室温下搅拌1小时后，加入中间体I-59(20.0mg,0.062mmol)，反应混合物继续在室温下搅拌16小时。将反应混合物倒入饱和碳酸氢钠水溶液(20mL)中，用乙酸乙酯(5mL×3)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-60。
LC-MS(ESI)[M+H] +615.1。
实施例的制备：
实施例1：化合物1的制备
Figure PCTCN2022079350-appb-000116
在25℃下，将中间体I-11(38mg,0.066mmol)溶于氯化氢的甲醇溶液(3M,2mL)。室温搅拌1小时后，浓缩干，经制备HPLC(甲酸体系)分离纯化得到化合物1。
LC-MS(ESI)[M+H] +474.2。
1H NMR(400MHz,DMSO-d 6)δ10.42–10.23(m,1H),7.82–7.18(m,7H),7.09(dd,J＝8.3,2.5Hz,1H),6.90–6.43(m,2H),4.94–4.72(m,1H),4.30(s,1H),3.15(m,3H),2.73–2.62(m,1H),2.43–2.27(m,6H),2.27–1.98(m,2H),1.75(m,3H).
实施例2：化合物2的制备
Figure PCTCN2022079350-appb-000117
在25℃下，将中间体I-14(30mg,0.049mmol)溶于氯化氢的甲醇溶液(3M,3mL)，室温搅拌1小时后，浓缩干，经制备HPLC(甲酸体系)分离纯化得到化合物2。
LC-MS(ESI)[M+H] +515.2。
1H NMR(400MHz,DMSO-d 6)δ11.18(s,1H),8.10–7.95(m,2H),7.88–7.54(m,6H),7.25–7.06(m,1H),6.95(d,J＝8.4Hz,1H),4.89(d,J＝13.5Hz,1H),4.39(s,1H),3.17(s,2H),2.73–2.67(m,1H),2.54(m,1H),2.27–2.01(m,2H),1.85(m,2H),1.67(m,1H).
实施例3：化合物3A和3B的制备
Figure PCTCN2022079350-appb-000118
在25℃下，将中间体I-16(70mg,0.30mmol)溶于四氢呋喃(1mL)，加入吡啶(0.79mL,10mmol)，1-丙基磷酸酐(50％wt乙酸乙酯溶液,0.79mL)和中间体I-7(101mg,0.33mmol)，于微波管中密封，65℃搅拌过夜。冷却后，减压浓缩干，用乙酸乙酯(50mL)溶解，水(20mL×2)洗，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(甲酸体系)分离纯化得到化合物3A(Rt＝1.023min)和化合物3B(Rt＝1.039min)。
LCMS分析方法：色谱柱：Infinitylab Poroshell 120EC-C18 3.0×30mm,1.9μm
流动相：A:水(0.01％三氟乙酸)B:乙腈(0.01％三氟乙酸)
洗脱梯度：5％-95％B，0.7分钟；95％B 0.8分钟；然后5％B 0.5分钟
流动速率：1.2mL/min
色谱柱温度：40℃
质谱扫描范围：100-1000
化合物3A(Rt＝1.023min)：
LC-MS(ESI)[M+H] +529.2。
1H NMR(400MHz,DMSO-d 6)δ8.15–7.95(m,2H),7.92–7.34(m,6H),7.15–6.95(m,1H),6.87–6.60(m,1H),5.01(m,1H),3.55–3.35(m,2H),2.80–2.32(m,5H),2.28–1.83(m,4H),1.63(m,1H).
化合物3B(Rt＝1.039min)：
LC-MS(ESI)[M+H] +529.2。
1H NMR(400MHz,DMSO-d 6)δ8.17–7.90(m,2H),7.85–7.54(m,6H),7.20–7.00(m,1H),6.90–6.60(m,1H),4.70–4.50(m,1H),4.15(m,1H),3.98(d,J＝10.6Hz,1H),2.80–2.45(m,5H),2.35–2.20(m,1H),2.10–1.73(m,3H),1.59–1.37(m,1H).
实施例4：化合物4的制备
Figure PCTCN2022079350-appb-000119
在25℃下，将中间体I-26(38mg,0.11mmol)溶于二氯甲烷(2mL)，依次加入三乙胺(55mg,0.55mmol)，邻甲基苯甲酰氯(34mg,0.22mmol)。室温搅拌1小时后，加甲醇(1mL)淬灭，减压浓缩干，经制备HPLC(甲酸体系)分离纯化得到化合物4。
LC-MS(ESI)[M+H] +475.2。
1H NMR(400MHz,DMSO-d 6)δ10.41–10.23(m,1H),7.80–7.58(m,1H),7.56–7.17(m,6H),7.08(dd,J＝8.4,2.6Hz,1H),6.78(m,2H),4.96–4.80(m,1H),4.75(d,J＝7.8Hz,1H),4.14–3.88(m,2H),2.73–2.61(m,1H),2.45–2.30(m,6H),2.30–2.03(m,2H),1.84(m,3H).
实施例5：化合物5的制备
Figure PCTCN2022079350-appb-000120
在25℃下，将中间体I-29(26mg,0.073mmol)溶于二氯甲烷(2mL)，依次加入三乙胺(55mg,0.55mmol)，邻甲基苯甲酰氯(34mg,0.22mmol)。室温搅拌1小时后，加甲醇(1mL)淬灭，减压浓缩干，经制备HPLC(甲酸体系)分离纯化得到化合物5。
LC-MS(ESI)[M+H] +475.2。
1H NMR(400MHz,DMSO-d 6)δ10.24(s,1H),7.81–7.55(m,1H),7.55–6.99(m,7H),6.76(dd,J＝33.3,8.3Hz,2H),5.37(d,J＝9.1Hz,1H),4.25–3.90(m,2H),3.79(m,1H),2.70–2.58(m,1H),2.35(m,7H),2.14–1.95(m,2H),1.28(m,1H),1.00–0.77(m,1H).
实施例6：化合物6的制备
Figure PCTCN2022079350-appb-000121
在室温下，将中间体I-35(90mg,0.26mmol)溶于二氯甲烷(10mL)中，依次加入邻甲基苯甲酰氯(60.7mg,0.39mmol)和三乙胺(79.6mg,0.79mmol)。反应液在室温下搅拌1小时，加水(10mL)稀释，用二氯甲烷(20mL×2)萃取，合并有机相，用饱和氯化钠水溶液(30mL×2)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。粗产品依次经过硅胶色谱法及制备HPLC(甲酸体系)分离纯化得到化合物6。
LC-MS(ESI)[M+H] +461.2。
1H NMR(400MHz,DMSO-d 6)δ10.41-10.22(s,1H),7.75-7.66(m,1H),7.53-7.17(m,6H),7.09-6.79(m,3H),5.87-5.65(m,1H),4.90-4.87(m,1H),4.72-4.68(m,1H),4.42-4.39(m,1H),2.89-2.76(m,1H),2.67-2.55(m,1H),2.39-2.33(m,6H),2.20-2.09(m,1H),1.82-1.80(m,1H).
实施例7：化合物7的制备
Figure PCTCN2022079350-appb-000122
在25℃下，将中间体I-46(40mg,0.069mmol)溶于三氟乙酸的二氯甲烷溶液(1/10,3mL)，室温搅拌1小时后倒入冰冷的饱和碳酸氢钠水溶液(20mL)，用二氯甲烷/甲醇(10/1,20mL×2)萃取，合并有机相，水(20mL)洗，减压浓缩，残留物经制备HPLC(碳酸氢铵体系)分离纯化得到化合物7。
LC-MS(ESI)[M-H] -477.80。
1H NMR(400MHz,DMSO-d 6)δ10.67–10.35(m,1H),7.74–7.24(m,7H),7.22–6.95(m,2H),6.82–6.76(m,1H),4.95–4.50(m,2H),3.47(m,1H),3.18(t,J＝6.3Hz,1H),2.99–2.70(m,1H),2.42–2.30(m,3H),2.04–1.54(m,2H),1.15(t,J＝7.0Hz,1H),1.04–0.95(m,1H).
实施例8：化合物8的制备
Figure PCTCN2022079350-appb-000123
在25℃下，将中间体I-48A(14mg,0.019mmol)溶于N,N-二甲基甲酰胺(3mL)，加入吡咯烷(35.50mg,0.50mmol)，25℃搅拌1小时。加乙酸乙酯(20mL)稀释，水(10mL×3)洗，无水硫酸钠干燥，过滤。滤液减压浓缩，经C18反相色谱法(甲酸体系)分离纯化得到化合物8。
LC-MS(ESI)[M+H] +515.2。
1H NMR(400MHz,DMSO-d 6)δ11.18(s,1H),8.13–7.90(m,2H),7.88–7.52(m,6H),7.09(dd,J＝8.3,2.7Hz,1H),6.89(d,J＝8.3Hz,1H),4.90(dt,J＝13.7,3.3Hz,1H),4.14(d,J＝9.2Hz,1H),3.80–3.35(m,1H),3.15–3.03(m,1H),3.03–2.92(m,1H),2.66(t,J＝12.7Hz,1H),2.09(dd,J＝12.1,4.1Hz,2H),1.86–1.64(m,2H),1.64–1.51(m,1H).
实施例9：化合物9的制备
Figure PCTCN2022079350-appb-000124
在25℃下，将中间体I-48B(4.00mg,0.0054mmol)溶于N,N-二甲基甲酰胺(3mL)，加入吡咯烷(35.50mg,0.50mmol)，25℃搅拌1小时。加乙酸乙酯(20mL)稀释，水(10mL×3)洗，无水硫酸钠干燥，过滤。滤液减压浓缩，经C18反相色谱法(甲酸体系)分离纯化得到化合物9。
LC-MS(ESI)[M+H] +515.2。
1H NMR(400MHz,DMSO-d 6)δ11.19(s,1H),8.13–7.90(m,2H),7.86–7.58(m,6H),7.12(dd,J＝8.2,2.6Hz,1H),6.93–6.74(m,1H),4.70(d,J＝9.4Hz,1H),3.99(td,J＝13.4,3.5Hz,1H),3.37(m,1H),3.11–2.90(m,2H),2.47–2.28(m,1H),2.06–1.85(m,2H),1.20–0.78(m,3H).
实施例10：化合物10A和化合物10B的制备
Figure PCTCN2022079350-appb-000125
化合物8经SFC手性拆分得到化合物10A(Rt＝1.424min)和化合物10B(Rt＝1.993min)。
手性拆分方法：
仪器：MG Ⅱ preparative SFC(SFC-14)
色谱柱：ChiralPak AD,250×30mm I.D.,10μm
流动相：A:二氧化碳B:乙醇(0.1％氨水)
洗脱梯度：35％B
流动速率：80mL/min
背压：100bar
柱温：38℃
检测波长：220nm
循环时间：～8min
手性分析方法：
仪器：Waters UPC2 analytical SFC(SFC-H)
色谱柱：ChiralPak AD,150×4.6mm I.D.,3μm
流动相：A:二氧化碳B:乙醇(0.05％二乙胺)
洗脱梯度：40％B
流动速率：2.5mL/min
背压：1500psi
柱温：35℃
检测波长：220nm
化合物10A：
Rt＝1.424min
LC-MS(ESI)[M+H] +515.2。
1H NMR(400MHz,DMSO-d 6)δ11.18(s,1H),8.30–7.88(m,2H),7.88–7.55(m,6H),7.10(dd,J＝8.4,2.7Hz,1H),6.89(d,J＝8.3Hz,1H),4.90(dt,J＝13.5,3.2Hz,1H),4.14(d,J＝9.2Hz,1H),3.40–3.39(m,1H),3.13–2.90(m,2H),2.66(t,J＝12.3Hz,1H),2.16–2.05(m,2H),1.87–1.49(m,3H).
化合物10B：
Rt＝1.993min
LC-MS(ESI)[M+H] +515.0。
1H NMR(400MHz,DMSO-d 6)δ11.18(s,1H),8.12–7.89(m,2H),7.87–7.59(m,6H),7.18–7.03(m,1H),6.90(d,J＝8.4Hz,1H),4.98–4.83(m,1H),4.17(m,1H),3.11–2.92(m,2H),2.73–2.60(m,1H),2.15–2.02(m,2H),1.86–1.66(m,2H),1.64–1.52(m,1H).
实施例11：化合物11的制备
Figure PCTCN2022079350-appb-000126
在室温下，将中间体I-60(15.0mg,0.0244mmol)溶于二氯甲烷(0.5mL)中，室温搅拌下滴加三氟乙酸(0.5mL)，反应混合物在室温下搅拌2小时。混合物浓缩后经制备HPLC(氨水体系)分离纯化得到化合物11。
LC-MS(ESI)[M+H] +515.2。
1H NMR(400MHz,DMSO-d 6)δ11.17(s,1H),8.10–7.94(m,2H),7.81(d,J＝7.6Hz,1H),7.78–7.58(m,4H),7.23(d,J＝2.4Hz,1H),7.12(dd,J＝8.6,2.4Hz,1H),6.94(d,J＝8.3Hz,1H),4.90(d,J＝13.9Hz,1H),3.77–3.64(m,1H),3.59–3.50(m,1H),3.21–3.07(m,3H),2.74–2.61(m,2H),2.10–2.01(m,1H),1.84–1.66(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 PCTCN2022079350-appb-000127
其中
Figure PCTCN2022079350-appb-000128
为所有最大值孔中cAMP浓度的平均计算值；
Figure PCTCN2022079350-appb-000129
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IC 50，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 14.65 2 32.62
3A 84.73 4 7.45
5 61.55 6 3.85
7 92.68 8 69.52
10A 30.97    
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，口服灌胃给药10mg/kg(溶 剂5％DMSO/10％Solutol/85％Saline)，给药后15min,30min,1hr,2hr,4hr,8hr,10hr,24hr采血，每个样品采集150μL，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10A 4.44 833.03 2026.32 73.34
对照品1 1.58 1307 1613 44
实验数据表明，本发明化合物小鼠口服给药体内药代动力学结果表现出更长的半衰期T 1/2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 TMHS 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(见图1、图2和下表3)在AVP诱导的LLC-PK1细胞增殖实验中，作为阳性参照物的Tolvaptan表现出高浓度促增殖的hook效应，而化合物1则无hook效应，表现出优于Tolvaptan的剂量效应。
表3：化合物对LLC-PK1细胞增殖抑制作用
Figure PCTCN2022079350-appb-000130
实验例4：化合物与V1a，V1b，V2受体结合测试
本实验用竞争性同位素配体结合实验测试化合物1和对照品1与人V1aR，V1bR，V2R的亲和力Ki。
(1)细胞膜
扩增高表达人源V1a受体的细胞，收集细胞，用PBS洗涤2次，再用含有蛋白酶抑制剂的PBS重悬细胞，用匀浆机15000r/min匀浆破碎细胞，4℃3000r/min离心15分钟，收集上清，4℃20000r/min离心45分钟，弃上清，得到细胞膜沉淀。加入缓冲液重悬测蛋白浓度，分装-80℃保存。高表达人员V1b，V2受体的细胞膜购买自美国Perkinelmer公司。
(2)分析缓冲液
50mM Tris-HCl，pH 7.4
10mM MgCl2
0.1％BSA
蛋白酶抑制剂混合物(一片/50ml)
(3)冲洗缓冲液
50mM Tris-HCl，pH 7.4
(4)化合物配置
1.化合物母液的配制
受试化合物分别取1.59mg,1.24mg,1.38mg，用100％二甲基亚砜溶解各待测化合物至终浓度为10mM。阳性对照Vasopressin配制成10mM母液。
2.100X化合物的配制
用DMSO将受试化合物和阳性对照的母液分别稀释至1mM(10倍稀释)及0.1mM(100倍稀释)，然后分别依次用DMSO四倍梯度稀释至第10个点。
3.细胞膜母液配制
过表达人源受体的细胞膜用分析缓冲液制备成5mg/mL。
(5)操作步骤
1.从稀释板中吸入1μl的化合物到96孔测试板的每个孔(测试化合物在反应中的浓度将稀释100倍)。对照孔加入1uL DMSO。
2.配置10mL含有5μg/μL的膜溶液。
3.用移液器把步骤2的膜溶液加入到化合物测试板，每孔加入89μL。
4.把50μCi/mL的同位素标记Vasopressin母液用分析缓冲液稀释至10倍终浓度，用移液器加入10μL/孔至反应板。V1a，V1b，V2受体实验中同位素标记Vasopressin的终浓度是分别是1.5nM，0.75nM及1nM。
5.把配置好的测试板置30℃孵育60mins。
6.用Cell Harvester将膜复合物收集至0.5％PEI预包被的GF/B板中，使用4℃预冷的洗脱缓冲液2ml冲洗3次。
7.37℃烘干2小时。用液体闪烁/发光计数仪测量结合在受体上的同位素标记Vasopressin含量。
8.将读取的数据用prism 5处理，用下述方程拟合得到化合物的剂量效应曲线，以及化合物竞争性抑制同位素标记Vasopressin与受体结合的IC50值。
Y＝Bottom+(Top-Bottom)/(1+10^((X-LogIC50)))，其中：Y为液闪仪读值，X为化合物浓度的对数值。用IC50值计算化合物竞争性结合受体的亲和力Ki：Ki＝IC50/(1+([L]/Kd))，其中[L]为试验中同位素标记Vasopressin的浓度，Kd为同位素标记Vasopressin与受体的解离常数。
两次重复试验结果如表4所示，Vasopressin与三个受体的结合Ki与文献报道接近，化合物10A与对照品1均不结合V1b受体(IC50>10uM)；对V2R的结合亲和力均高于对V1a的结合，具有不同程度的V1a/V2选择性。
表4：受试化合物与V1a，V1b，V2受体的结合亲和力
Figure PCTCN2022079350-appb-000131

Claims (14)

  1. 式(I)所示化合物、其光学异构体或其药效上可接受的盐，
    Figure PCTCN2022079350-appb-100001
    其中，
    环A选自4-6元杂环基和C 3-6元环烷基，所述4-6元杂环基或C 3-6元环烷基任选被1、2或3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C(R T)；
    R 1、R 2、R 3、R A、R T分别独立地选自H、F、Cl、Br、I、CN、OH、NH 2、C 1-6烷基和C 1-6杂烷基，所述C 1-6烷基或C 1-6杂烷基任选被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 4a取代；
    R、R 4a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、m2分别独立地选自0、1或2；
    且，当环A选自4-6元杂环基时，式(I)所示化合物不选自
    Figure PCTCN2022079350-appb-100002
    Figure PCTCN2022079350-appb-100003
    所述4-6元杂环基、C 1-6杂烷基或5-6元杂芳基包含1、2、3或4个独立选自-O-、-NH-、-S-、-C(＝O)-、-C(＝O)O-、-S(＝O)-、-S(＝O) 2-和N的杂原子或杂原子团。
  2. 式(II)所示化合物、其光学异构体或其药效上可接受的盐，
    Figure PCTCN2022079350-appb-100004
    其中，X 1、X 2、X 3分别独立地选自O、C(R A) 2和NR A；
    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C(R T)；
    R 1、R 2、R 3、R A、R T分别独立地选自H、F、Cl、Br、I、CN、OH、NH 2、C 1-6烷基和C 1-6杂烷基，所述C 1-6烷基或C 1-6杂烷基任选被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 4a取代；
    R、R 4a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、m2、n分别独立地选自0、1或2；
    且，当X 1、X 3同时选自O时，式(II)所示化合物不选自
    Figure PCTCN2022079350-appb-100005
    所述C 1-6杂烷基或5-6元杂芳基包含1、2、3或4个独立选自-O-、-NH-、-S-、-C(＝O)-、-C(＝O)O-、-S(＝O)-、-S(＝O) 2-和N的杂原子或杂原子团。
  3. 式(III)所示化合物、其光学异构体或其药效上可接受的盐，
    Figure PCTCN2022079350-appb-100006
    其中，X 1、X 2、X 3分别独立地选自O、C(R A) 2和NR A；
    T 1、T 2分别独立地选自N和C(R T)；
    Y 1、Y 2分别独立地选自N和C(R Y)；
    R 1、R 2、R 3、R A、R T、R Y分别独立地选自H、F、Cl、Br、I、CN、OH、NH 2、C 1-6烷基和C 1-6杂烷基， 所述C 1-6烷基或C 1-6杂烷基任选被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 4a取代；
    R、R 4a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、m2、m3、m4、n分别独立地选自0、1或2；
    且，当X 1、X 3同时选自O时，式(III)所示化合物不选自
    Figure PCTCN2022079350-appb-100007
    所述C 1-6杂烷基或5-6元杂芳基包含1、2、3或4个独立选自-O-、-NH-、-S-、-C(＝O)-、-C(＝O)O-、-S(＝O)-、-S(＝O) 2-和N的杂原子或杂原子团。
  4. 式(IV)所示化合物、其光学异构体或其药效上可接受的盐，
    Figure PCTCN2022079350-appb-100008
    其中，T 1、T 2分别独立地选自O、N和C(R T)；
    Y 1、Y 2分别独立地选自N和C(R Y)；
    R 1、R 2、R 3、R A、R T、R Y分别独立地选自H、F、Cl、Br、I、CN、OH、NH 2、C 1-6烷基和C 1-6杂烷基，所述C 1-6烷基或C 1-6杂烷基任选被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 4a取代；
    R、R 4a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；
    m2、m3、n分别独立地选自0、1或2；
    所述C 1-6杂烷基或5-6元杂芳基包含1、2、3或4个独立选自-O-、-NH-、-S-、-C(＝O)-、-C(＝O)O-、-S(＝O)-、-S(＝O) 2-和N的杂原子或杂原子团。
  5. 式(V-1)、(V-2)、(V-3)、(V-4)所示化合物、其光学异构体或其药效上可接受的盐，
    Figure PCTCN2022079350-appb-100009
    其中，T 1、T 2、Y 1、Y 2、R 1、R 2、R 3、R 4、R A、m2、m3、n如权利要求4所定义。
  6. 根据权利要求1-5任一项所述化合物、其光学异构体或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 PCTCN2022079350-appb-100010
    环丙基、环丁基、环戊基、苯基、吡啶基、嘧啶基、噻吩基和噻唑基。
  7. 根据权利要求1所述化合物、其光学异构体或其药效上可接受的盐，其中，环A选自氮杂环丁烷基、氧杂环丁烷基、吡咯烷基、四氢呋喃基、环丁烷基、环戊烷基和环己烷基，所述氮杂环丁烷基、氧杂环丁烷基、吡咯烷基、四氢呋喃基、环丁烷基、环戊烷基或环己烷基任选被1或2个R A取代。
  8. 根据权利要求7所述化合物、其光学异构体或其药效上可接受的盐，其中，环A选自
    Figure PCTCN2022079350-appb-100011
    Figure PCTCN2022079350-appb-100012
  9. 根据权利要求1或2所述化合物、其光学异构体或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。
  10. 根据权利要求9所述化合物、其光学异构体或其药效上可接受的盐，其中，环B选自
    Figure PCTCN2022079350-appb-100013
    Figure PCTCN2022079350-appb-100014
  11. 根据权利要求1或2所述化合物、其光学异构体或其药效上可接受的盐，其中，环C选自
    Figure PCTCN2022079350-appb-100015
    Figure PCTCN2022079350-appb-100016
  12. 下式化合物、其光学异构体或其药效上可接受的盐，其选自
    Figure PCTCN2022079350-appb-100017
  13. 根据权利要求1-11任一项所述的化合物、其光学异构体或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。
  14. 根据权利要求13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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