WO2022171160A1 - 苯并氮杂䓬类化合物及其制备方法和医药用途 - Google Patents

苯并氮杂䓬类化合物及其制备方法和医药用途 Download PDF

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WO2022171160A1
WO2022171160A1 PCT/CN2022/075793 CN2022075793W WO2022171160A1 WO 2022171160 A1 WO2022171160 A1 WO 2022171160A1 CN 2022075793 W CN2022075793 W CN 2022075793W WO 2022171160 A1 WO2022171160 A1 WO 2022171160A1
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alkyl
alkoxy
pharmaceutically acceptable
cycloalkyl
compound
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PCT/CN2022/075793
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English (en)
French (fr)
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祝令建
石健宇
姬长进
董邦杰
黄建
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上海森辉医药有限公司
上海盛迪医药有限公司
江苏恒瑞医药股份有限公司
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Application filed by 上海森辉医药有限公司, 上海盛迪医药有限公司, 江苏恒瑞医药股份有限公司 filed Critical 上海森辉医药有限公司
Priority to JP2023548794A priority Critical patent/JP2024506365A/ja
Priority to KR1020237030236A priority patent/KR20230143165A/ko
Priority to CA3207957A priority patent/CA3207957A1/en
Priority to MX2023009161A priority patent/MX2023009161A/es
Priority to AU2022219348A priority patent/AU2022219348A1/en
Priority to CN202280008547.9A priority patent/CN116744935A/zh
Priority to EP22752320.6A priority patent/EP4293032A1/en
Publication of WO2022171160A1 publication Critical patent/WO2022171160A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/5532—Seven-(or more) membered rings
    • C07F9/5535—Seven-(or more) membered rings condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • 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
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the present disclosure belongs to the field of medicine, and relates to a benzazepine Compounds and preparation methods, compositions and medical uses.
  • Vasopressin is a nonapeptide hormone secreted primarily by the posterior pituitary gland, which acts via the vascular V1 receptor and renal V2 receptor subtypes. The presence of V2 receptors in the kidney can stimulate adenylate cyclase to produce urine. Vasopressin receptor antagonists are widely used in the treatment of hypertension, congestive heart failure, liver cirrhosis, renal failure, cerebral edema and other diseases. benzazepine The class is a class of small molecule vasopressin V2 receptor antagonists, and Tolvaptan was the first such compound to be marketed.
  • Tolvaptan blocks the binding of vasopressin to the V2 receptor of the collecting duct, so that aquaporin-2 cannot move to the surface of the cell membrane, inhibits the concentration of urine, increases the excretion of free water without excreting sodium, and achieves a diuretic effect (J Clin Med, 2014, 3(4):1276-1290).
  • tolvaptan has a diuretic effect on rats and dogs, and can significantly increase the clearance of electrolytes and water, and increase the concentration of sodium ions compared with furanosine (Circulation, 2003, 107, 690-2696).
  • hyponatremia due to congestive heart failure (CHF) and cirrhosis showed that the compound was well tolerated and rapidly and effectively increased serum sodium concentrations without oral Dryness, thirst and other side effects, and do not have to limit water intake.
  • CHF congestive heart failure
  • SIADH antidiuretic hormone
  • Tolvaptan is a known compound that has been disclosed in U.S. Patent No. 5,258,510 and has the following structure:
  • WO2009001968A discloses benzazepines useful as vasopressin antagonists Derivatives of tolvaptan were studied.
  • CN101346390A discloses a new phosphate derivative of tolvaptan, which can be used to improve its water solubility.
  • One aspect of the present disclosure provides a compound represented by formula I-1 or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from C 1-6 alkyl, C 3-8 cycloalkyl, 3-12-membered heterocycle; the C 1-6 alkyl, C 3-8 cycloalkyl, 3-12-membered heterocycle group is optionally substituted with A;
  • R 2 is selected from C 1-6 alkyl, C 3-8 cycloalkyl, 3-12-membered heterocycle; the C 1-6 alkyl, C 3-8 cycloalkyl, 3-12-membered heterocycle group is optionally substituted with A;
  • R 1 and R 2 together with the N atom to which they are attached form a 3-12-membered heterocyclyl group containing 1-3 heteroatoms; the 3-12-membered heterocyclyl group is optionally further substituted with A;
  • A is selected from H, -COOH, -NH 2 , -OH, halogen, cyano, nitro, oxo, C 1-6 alkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclyl; the The -NH 2 , C 1-6 alkyl, C 3-8 cycloalkyl, 3-12-membered heterocyclic group are optionally substituted by R 4 ;
  • R 4 is selected from halogen, -NH 2 , -OH, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl.
  • the present disclosure provides a compound represented by formula I-1 or a pharmaceutically acceptable salt thereof, wherein, is an amino acid residue; the amino acid is selected from alanine, arginine, aspartic acid, cysteine, glutamine, glutamic acid, histidine, isoleucine, glycine, leucine , lysine, methionine, phenylalanine, serine, threonine, tyrosine, valine.
  • the present disclosure provides a compound represented by formula I-1 or a pharmaceutically acceptable salt thereof, wherein, is an amino acid residue; the amino acid residue is glutamic acid.
  • the present disclosure provides a compound represented by formula I-1 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 together with the N atom to which they are attached form a compound containing 1-3 heteroatoms.
  • 3-8 membered heterocyclyl the 3-8 membered heterocyclyl is optionally substituted by A;
  • A is selected from H, -COOH, -NH 2 , -OH, halogen, cyano, nitro, oxo, C 1-6 alkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclyl; the -NH 2 , C 1-6 alkyl, C 3-8 cycloalkyl, 3-12 membered heterocyclyl
  • R 4 is selected from halogen, -NH 2 , -OH, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl.
  • the present disclosure provides a compound represented by formula I-1 or a pharmaceutically
  • the present disclosure provides a compound represented by formula I-1 or a pharmaceutically acceptable salt thereof, wherein A is selected from C 1-6 alkyl, C 3-8 cycloalkyl, 3- 12-membered heterocyclic group; the C 1-6 alkyl group, C 3-8 cycloalkyl group, and 3-12-membered heterocyclic group are optionally substituted by R 4 ; R 4 is selected from halogen, -NH 2 , -OH, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl.
  • the present disclosure provides a compound represented by formula I-1 or a pharmaceutically acceptable salt thereof, wherein, A is selected from a 3-12-membered heterocyclic group, the 3-12-membered heterocyclic group Optionally substituted with R 4 ; R 4 is selected from halogen, -NH 2 , -OH, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl.
  • the present disclosure provides a compound represented by formula I-1 or a pharmaceutically acceptable salt thereof, wherein, A is selected from a 3-8 membered heterocyclic group, the 3-8 membered heterocyclic group Optionally substituted with R 4 ; R 4 is selected from halogen, -NH 2 , -OH, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl.
  • the present disclosure provides a compound represented by formula I-1 or a pharmaceutically acceptable salt thereof, wherein A is selected from a 5-6 membered heterocyclic group, wherein the connecting atom of A is a heteroatom, The heteroatom is selected from N; the 5-6 membered heterocyclic group is optionally substituted by R 4 , and R 4 is selected from halogen, -OH, C 1-6 alkyl, and C 1-6 alkoxy.
  • the present disclosure provides a compound represented by formula I-1 or a pharmaceutically acceptable salt thereof, wherein A is selected from a 5-6 membered heterocyclic group, wherein the connecting atom of A is a heteroatom, The heteroatom is selected from N.
  • the present disclosure provides a compound represented by formula I-1 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from C 1-6 alkyl, and the C 1-6 alkyl is any Selected to be substituted by A; R 2 is selected from C 1-6 alkyl, C 3-8 cycloalkyl, 3-12-membered heterocyclyl; the C 1-6 alkyl, C 3-8 cycloalkyl, 3 -12-membered heterocyclyl optionally substituted by A; A is selected from H, -COOH, -NH 2 , -OH, halogen, cyano, nitro, oxo, C 1-6 alkyl, C 3-8 ring Alkyl, 3-12-membered heterocyclyl; the -NH 2 , C 1-6 alkyl, C 3-8 cycloalkyl, 3-12-membered heterocyclyl are optionally substituted by R 4 ; R 4 is selected from Halogen, -NH 2 , -OH, C
  • the present disclosure provides a compound represented by formula I-1 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from C 1-6 alkyl, and the C 1-6 alkyl is any is selected to be substituted by A; R 2 is selected from C 1-6 alkyl, said C 1-6 alkyl is optionally substituted by A; A is selected from H, -COOH, -NH 2 , -OH, halogen, cyano, Nitro, oxo, C 1-6 alkyl, C 3-8 cycloalkyl, 3-12-membered heterocyclic group; the -NH 2 , C 1-6 alkyl, C 3-8 cycloalkyl, The 3-12 membered heterocyclic group is optionally substituted by R 4 ; R 4 is selected from halogen, -NH 2 , -OH, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl.
  • the present disclosure provides a compound represented by formula I-1 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from C 1-6 alkyl, and the C 1-6 alkyl is any is substituted by A; R 2 is selected from C 1-6 alkyl, the C 1-6 alkyl is optionally substituted by A; A is selected from H, -COOH, -NH 2 , -OH, halogen, C 1- 6 alkyl, C 3-8 cycloalkyl, 3-12-membered heterocyclyl; the -NH 2 , C 1-6 alkyl, C 3-8 cycloalkyl, 3-12-membered heterocyclyl are optional Substituted by R 4 ; R 4 is selected from halogen, -NH 2 , -OH, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl.
  • the present disclosure provides a compound represented by formula I-1 or a pharmaceutically acceptable salt thereof, wherein, wherein, R 1 is selected from C 1-6 alkyl, the C 1-6 alkane
  • the base is optionally substituted by A;
  • R 2 is selected from C 1-6 alkyl, and the C 1-6 alkyl is optionally substituted by A;
  • A is selected from H, C 1-6 alkyl, C 3-8 cycloalkane base, 3-12-membered heterocyclyl; the C 1-6 alkyl, C 3-8 cycloalkyl, 3-12-membered heterocyclyl are optionally substituted by R 4 ;
  • R 4 is selected from halogen, -NH 2 , -OH, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl.
  • the present disclosure provides a compound represented by formula I-1 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from C 1-6 alkyl, and the C 1-6 alkyl is any is substituted by A; R 2 is selected from C 1-6 alkyl, the C 1-6 alkyl is optionally substituted by A, and A is selected from H, 3-12-membered heterocyclic group, preferably, A is 3-8 membered heterocyclyl, more preferably, A is a 5-7 membered heterocyclyl.
  • the present disclosure provides a compound represented by formula I-1 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from C 1-6 alkyl; R 2 is selected from C 1-6 alkyl base, the C 1-6 alkyl group is substituted by A, and the A is selected from H, a 3-12-membered heterocyclic group, preferably, A is a 3-8-membered heterocyclic group, more preferably, A is a 5- 7-membered heterocyclyl.
  • the present disclosure provides a compound represented by formula I-1 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from C 1-3 alkyl; R 2 is selected from C 1-3 alkyl base, the C 1-3 alkyl group is substituted by A; the A is selected from H, a 3-12-membered heterocyclic group, preferably, A is a 3-8-membered heterocyclic group, more preferably, A is a 5- 7-membered heterocycloalkane.
  • the present disclosure provides a compound represented by formula I-1 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from C 1-3 alkyl; R 2 is selected from C 1-3 alkyl group, the C 1-3 alkyl group is substituted by A; the A is selected from H, 5-7 membered heterocycloalkane.
  • the present disclosure provides a compound represented by formula I-1 or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula I-1 is selected from:
  • Another aspect of the present disclosure provides a compound represented by formula II-1 or a pharmaceutically acceptable salt thereof,
  • L 1 is -(CH 2 ) m -, the -(CH 2 )- is optionally replaced by a heteroatom selected from O, S, N;
  • L 2 is -(CH 2 ) n -, the -(CH 2 )- is optionally replaced by a heteroatom selected from O, S, N;
  • n is selected from 0, 1, 2, 3, 4, 5, 6;
  • n is selected from 1, 2, 3, 4, 5, 6;
  • X is selected from O and S;
  • R 1 is selected from C 1-6 alkyl, C 3-8 cycloalkyl, 3-12-membered heterocycle; the C 1-6 alkyl, C 3-8 cycloalkyl, 3-12-membered heterocycle group is optionally substituted with group B;
  • R 2 is selected from C 1-6 alkyl, C 3-8 cycloalkyl, 3-12-membered heterocycle; the C 1-6 alkyl, C 3-8 cycloalkyl, 3-12-membered heterocycle group is optionally substituted with group B;
  • R 3 is selected from C 1-6 alkyl, C 3-8 cycloalkyl, 3-12-membered heterocycle; the C 1-6 alkyl, C 3-8 cycloalkyl, 3-12-membered heterocycle group is optionally substituted with group B;
  • R 1 and R 2 or R 2 and R 3 together with the N atom to which they are attached, form a 3-12-membered heterocyclic group containing 1-3 heteroatoms; the 3-12-membered heterocyclic group is optionally Group B replaced;
  • A is selected from H, -COOH, -NH 2 , -OH, halogen, cyano, nitro, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3 -12-membered heterocyclyl, -COR 4 , -NHCOR 4 , -OCOR 4 ; the -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3- 12 -membered heterocyclyl optionally substituted by R4;
  • R 4 is selected from halogen, -NH 2 , -OH, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-12 membered heterocyclyl; the C 1-6 Alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-12 membered heterocyclyl optionally selected from -COOH, -NH 2 , -OH, halogen, cyano, nitro, oxygen One or more groups of substitution, C 1-6 alkyl, C 1-6 alkoxy;
  • the group B is selected from H, -COOH, -NH2 , -OH, halogen, cyano, nitro, oxo.
  • the present disclosure provides a compound represented by formula II-1 or a pharmaceutically acceptable salt thereof, wherein X is O.
  • the present disclosure provides a compound represented by formula II-1 or a pharmaceutically acceptable salt thereof, wherein m is selected from 0, 1, 2, 3, 4, and 5.
  • the present disclosure provides a compound represented by formula II-1 or a pharmaceutically acceptable salt thereof, wherein m is selected from 0, 1, 2, and 3.
  • the present disclosure provides a compound represented by formula II-1 or a pharmaceutically acceptable salt thereof, wherein n is selected from 2, 3, 4, and 5.
  • the present disclosure provides a compound represented by formula II-1 or a pharmaceutically acceptable salt thereof, wherein n is selected from 2 and 3.
  • the present disclosure provides a compound represented by formula II-1 or a pharmaceutically acceptable salt thereof, wherein A is selected from H, -COOH, -NH 2 , -OH, halogen, cyano, Nitro, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-12-membered heterocyclic group; the C 1-6 alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, 3-12 membered heterocyclyl are optionally substituted by R 4 ;
  • R 4 is selected from halogen, -NH 2 , -OH, C 1-6 alkyl.
  • the present disclosure provides a compound represented by formula II-1 or a pharmaceutically acceptable salt thereof, wherein A is selected from H, -COOH, -NH 2 , -OH, halogen, cyano, nitro base.
  • the present disclosure provides a compound represented by formula II-1 or a pharmaceutically acceptable salt thereof, wherein the -(CH 2 )- is unsubstituted.
  • the present disclosure provides a compound represented by formula II-1 or a pharmaceutically acceptable salt thereof, wherein L 1 is -CH 2 -O-.
  • the present disclosure provides a compound represented by formula II-1 or a pharmaceutically acceptable salt thereof, wherein L 1 is -(CH 2 ) m -, and m is 0.
  • the present disclosure provides a compound represented by formula II-1 or a pharmaceutically acceptable salt thereof, wherein L 2 is -(CH 2 ) 2 -.
  • the present disclosure provides a compound represented by formula II-1 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from C 1-6 alkyl.
  • the present disclosure provides a compound represented by formula II-1 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from C 1-3 alkyl.
  • the present disclosure provides a compound represented by formula II-1 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from C 1-6 alkyl.
  • the present disclosure provides a compound represented by formula II-1 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from C 1-3 alkyl.
  • the present disclosure provides a compound represented by formula II-1 or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from C 1-6 alkyl.
  • the present disclosure provides a compound represented by formula II-1 or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from C 1-3 alkyl.
  • the present disclosure provides a compound represented by formula II-1 or a pharmaceutically acceptable salt thereof, wherein,
  • R 1 is selected from C 1-6 alkyl
  • R 2 is selected from C 1-6 alkyl
  • R 3 is selected from C 1-6 alkyl
  • the C 1-6 alkyl group is optionally substituted with a group B; the group B is selected from H, -COOH, -NH 2 , -OH, halogen, cyano, nitro, oxo.
  • the present disclosure provides a compound represented by formula II-1 or a pharmaceutically acceptable salt thereof, wherein,
  • X is O
  • L 1 is -(CH 2 ) m -, m is 0; or L 1 is -CH 2 -O-;
  • L 2 is -(CH 2 ) n -; n is selected from 2 and 3;
  • R 1 is selected from methyl, ethyl, n-propyl, isopropyl
  • R 2 is selected from methyl, ethyl, n-propyl, isopropyl
  • R3 is selected from methyl, ethyl, n-propyl, isopropyl.
  • the present disclosure provides a compound represented by formula II-1 or a pharmaceutically acceptable salt thereof, wherein,
  • X is O
  • L 1 is -(CH 2 ) m -, m is 0; or L 1 is -CH 2 -O-;
  • L 2 is -(CH 2 ) n -; n is selected from 2 and 3;
  • the present disclosure provides a compound represented by formula II-1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
  • Another aspect of the present disclosure provides a compound represented by formula III-1 or a pharmaceutically acceptable salt thereof,
  • T is an amino acid residue in which the carboxyl group of the amino acid is attached to O; the amino acid is not glycine or valine.
  • the present disclosure provides the compound of formula III-1 or a pharmaceutically acceptable salt thereof, wherein the amino acid is selected from alanine, arginine, aspartic acid, cysteine, glutamine, glutamine acid, histidine, isoleucine, glycine, leucine, lysine, methionine, phenylalanine, serine, threonine, tyrosine, valine.
  • the amino acid is selected from alanine, arginine, aspartic acid, cysteine, glutamine, glutamine acid, histidine, isoleucine, glycine, leucine, lysine, methionine, phenylalanine, serine, threonine, tyrosine, valine.
  • the present disclosure provides a compound of formula III-1 or a pharmaceutically acceptable salt thereof, wherein T is an amino acid residue, wherein the carboxyl group of the amino acid is connected to O, and the amino acid is glutamine acid, proline, lysine.
  • the present disclosure provides a compound of formula III-1 or a pharmaceutically acceptable salt thereof, wherein the compound of formula III-1 is selected from the group consisting of
  • Another aspect of the present disclosure provides a compound of formula IV-1 or a pharmaceutically acceptable salt thereof,
  • W is -C(O)-L-NR 1 R 2 R 3 , where:
  • L is -(CH 2 ) n -, n is selected from 1, 2, 3, 4, 5, 6; the -(CH 2 )- is optionally substituted by A;
  • R 1 is selected from C 1-6 alkyl, C 3-8 cycloalkyl, 3-12-membered heterocycle; the C 1-6 alkyl, C 3-8 cycloalkyl, 3-12-membered heterocycle group is optionally further substituted with group B;
  • R 2 is selected from C 1-6 alkyl, C 3-8 cycloalkyl, 3-12-membered heterocycle; the C 1-6 alkyl, C 3-8 cycloalkyl, 3-12-membered heterocycle group is optionally further substituted with group B;
  • R 3 is selected from C 1-6 alkyl, C 3-8 cycloalkyl, 3-12-membered heterocycle; the C 1-6 alkyl, C 3-8 cycloalkyl, 3-12-membered heterocycle group is optionally further substituted with group B;
  • R 1 and R 2 or R 2 and R 3 together with the N atom to which they are attached, form a 3-12-membered heterocyclic group containing 1-3 heteroatoms; the 3-12-membered heterocyclic group is optionally further group B substituted;
  • A is selected from H, -COOH, -NH 2 , -OH, halogen, cyano, nitro, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3 -12-membered heterocyclyl, -COR 4 , -NHCOR 4 , -OCOR 4 ; the -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3- 12 -membered heterocyclyl optionally substituted by R4;
  • R 4 is selected from halogen, -NH 2 , -OH, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-12 membered heterocyclyl; the C 1-6 Alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-12 membered heterocyclyl are optionally further selected from -COOH, -NH 2 , -OH, halogen, cyano, nitro, One or more groups of oxo, C 1-6 alkyl, and C 1-6 alkoxy are substituted;
  • the group B is selected from H, -COOH, -NH2 , -OH, halogen, cyano, nitro, oxo.
  • the present disclosure provides a compound represented by formula IV-1 or a pharmaceutically acceptable salt thereof, wherein n is selected from 2, 3, 4, and 5.
  • the present disclosure provides a compound represented by formula IV-1 or a pharmaceutically acceptable salt thereof, wherein n is selected from 2 and 3.
  • the present disclosure provides a compound represented by formula IV-1 or a pharmaceutically acceptable salt thereof, wherein A is selected from H, -COOH, -NH 2 , -OH, halogen, cyano, nitro base, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-12-membered heterocyclic group; the C 1-6 alkyl, C 1-6 alkane Oxygen, C 3-8 cycloalkyl, 3-12 membered heterocyclyl are optionally substituted by R 4 ;
  • R 4 is selected from halogen, -NH 2 , -OH, C 1-6 alkyl.
  • the present disclosure provides a compound represented by formula IV-1 or a pharmaceutically acceptable salt thereof, wherein A is selected from H, -COOH, -NH 2 , -OH, halogen, cyano, nitro base.
  • the present disclosure provides a compound represented by formula IV-1 or a pharmaceutically acceptable salt thereof, wherein the -(CH 2 )- is unsubstituted.
  • the present disclosure provides a compound represented by formula IV-1 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from C 1-6 alkyl.
  • the present disclosure provides a compound represented by formula IV-1 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from C 1-3 alkyl.
  • the present disclosure provides a compound represented by formula IV-1 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from C 1-6 alkyl.
  • the present disclosure provides a compound represented by formula IV-1 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from C 1-3 alkyl.
  • the present disclosure provides a compound represented by formula IV-1 or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from C 1-6 alkyl.
  • the present disclosure provides a compound represented by formula IV-1 or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from C 1-3 alkyl.
  • the present disclosure provides a compound represented by formula IV-1 or a pharmaceutically acceptable salt thereof, wherein,
  • R 1 is selected from C 1-6 alkyl
  • R 2 is selected from C 1-6 alkyl
  • R 3 is selected from C 1-6 alkyl
  • the C 1-6 alkyl is optionally further substituted with a group B;
  • the group B is selected from H, -COOH, -NH2 , -OH, halogen, cyano, nitro, oxo.
  • the present disclosure provides a compound represented by formula IV-1 or a pharmaceutically acceptable salt thereof, wherein,
  • L is -(CH 2 ) n -;
  • n is selected from 2, 3;
  • R 1 is selected from methyl, ethyl, n-propyl, isopropyl
  • R 2 is selected from methyl, ethyl, n-propyl, isopropyl
  • R3 is selected from methyl, ethyl, n-propyl, isopropyl.
  • the present disclosure provides a compound represented by formula IV-1 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from methyl; R 2 is selected from methyl; R 3 is selected from methyl .
  • Another aspect of the present disclosure provides a compound represented by formula V-1 or a pharmaceutically acceptable salt thereof,
  • n is selected from an integer between 1-10;
  • X is selected from O and S;
  • R 1 is selected from H or a hydroxyl protecting group
  • R 2 is selected from hydroxyl, hydroxyl optionally protected by a protecting group, thiol optionally protected by a protecting group, amino optionally protected by a protecting group;
  • the "hydroxyl protecting group” or “protecting group” is selected from C 1-6 alkyl; the C 1-6 alkyl is optionally selected from OH, CN, halogen, -C(O)OC 1- One or more group substitutions of 6 -alkyl, 6-12-membered aryl, and 6-12-membered heteroaryl.
  • the present disclosure provides a compound represented by formula V-1 or a pharmaceutically acceptable salt thereof, wherein n is selected from an integer between 2-8.
  • the present disclosure provides a compound represented by formula V-1 or a pharmaceutically acceptable salt thereof, wherein n is selected from an integer between 2-5.
  • the present disclosure provides a compound represented by formula V-1 or a pharmaceutically acceptable salt thereof, wherein X is selected from O.
  • the present disclosure provides a compound represented by formula V-1 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from H.
  • the present disclosure provides a compound represented by formula V-1 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from a hydroxyl group, a hydroxyl group optionally protected by a protecting group, and the protecting group
  • R 2 is selected from a hydroxyl group, a hydroxyl group optionally protected by a protecting group, and the protecting group
  • the group is selected from C 1-6 alkyl; the C 1-6 alkyl is optionally substituted with one or more groups selected from OH, CN, halogen, -C(O)OC 1-6 alkyl.
  • the present disclosure provides a compound represented by formula V-1 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from a hydroxyl group, a hydroxyl group optionally protected by a protecting group, and the protecting group
  • R 2 is selected from a hydroxyl group, a hydroxyl group optionally protected by a protecting group, and the protecting group
  • the group is selected from C 1-6 alkyl; the C 1-6 alkyl is optionally substituted with one or more groups selected from CN, -C(O)OC 1-6 alkyl.
  • the present disclosure provides a compound represented by formula V-1 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from hydroxyl, hydroxyl optionally protected by a protecting group, and the protecting group is selected from From C 1-3 alkyl; the C 1-3 alkyl is optionally substituted with CN, -C(O)OC 1-3 alkyl.
  • the present disclosure provides a compound represented by formula V-1 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from hydroxyl.
  • the present disclosure provides a compound represented by formula V-1 or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula V-1 is selected from:
  • Another aspect of the present disclosure provides a compound represented by formula VI-1 or a pharmaceutically acceptable salt thereof,
  • n is selected from 0 and 1;
  • R 1 and R 2 are each independently selected from H or A;
  • R 3 is selected from mPEG, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-12 membered heterocyclyl; the C 1-6 Alkyl, C 2-6 alkenyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-12-membered heterocyclyl are optionally substituted by A;
  • A is selected from H, -COOH, -NH 2 , -OH, halogen, cyano, nitro, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3 -12-membered heterocyclyl, -COR 4 , -NHCOR 4 , -OCOR 4 ; the -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3- 12 -membered heterocyclyl optionally substituted by R4;
  • R 4 is selected from halogen, -COOH, -NH 2 , -OH, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-12 membered heterocyclyl; the C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-12 membered heterocyclyl optionally selected from -COOH, -NH 2 , -OH, halogen, cyano, nitro substituted with one or more groups of radical, oxo, C 1-6 alkyl, and C 1-6 alkoxy.
  • the present disclosure provides a compound represented by formula VI-1 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each independently selected from H.
  • the present disclosure provides a compound represented by formula VI-1 or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from mPEG, C 1-6 alkyl, and C 2-6 alkenyl; The C 1-6 alkyl group and the C 2-6 alkenyl group are optionally substituted by A.
  • the present disclosure provides a compound represented by formula VI-1 or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from mPEG, C 1-6 alkyl; the C 1-6 alkyl; group is optionally substituted with A.
  • the present disclosure provides a compound represented by formula VI-1 or a pharmaceutically acceptable salt thereof, wherein A is selected from H, -COOH, -NH 2 , -OH, halogen, cyano, Nitro, C 1-6 alkyl, C 1-6 alkoxy; the C 1-6 alkyl, C 1-6 alkoxy are optionally substituted by R 4 .
  • the present disclosure provides a compound represented by formula VI-1 or a pharmaceutically acceptable salt thereof, wherein A is selected from H, -COOH, -NH 2 , -OH, C 1-6 alkane group, C 1-6 alkoxy; the C 1-6 alkyl, C 1-6 alkoxy is optionally substituted by R 4 .
  • the present disclosure provides a compound represented by formula VI-1 or a pharmaceutically acceptable salt thereof, wherein A is selected from H, -COOH, -NH 2 , -OH, C 1-6 alkane group, C 1-6 alkoxy; the C 1-6 alkyl, C 1-6 alkoxy is optionally substituted by R 4 .
  • the present disclosure provides a compound represented by formula VI-1 or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from halogen, -COOH, -NH 2 , -OH, C 1-6 Alkyl, C 1-6 alkoxy; the C 1-6 alkyl, C 1-6 alkoxy are optionally selected from -COOH, -NH 2 , -OH, halogen, cyano, nitro, One or more groups of oxo, C 1-6 alkyl, and C 1-6 alkoxy are substituted.
  • the present disclosure provides a compound represented by formula VI-1 or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from halogen, -COOH, -NH 2 , -OH, C 1-6 Alkyl, C 1-6 alkoxy.
  • the present disclosure provides a compound represented by formula VI-1 or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from -COOH, -NH 2 , and -OH.
  • the present disclosure provides a compound represented by formula VI-1 or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula VI-1 is selected from:
  • Another aspect of the present disclosure provides a compound of formula VII-1 or a pharmaceutically acceptable salt thereof,
  • n is selected from 0, 1, 2, 3 and 4;
  • R 1 is selected from C 1-6 alkyl group, C 2-6 alkenyl group, C 1-6 alkoxy group, C 3-8 cycloalkyl group, 3-12 membered heterocyclic group; the C 1-6 alkyl group , C 2-6 alkenyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-12-membered heterocyclyl optionally substituted by A;
  • A is selected from H, -COOH, -NH 2 , -OH, halogen, cyano, nitro, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3 -12-membered heterocyclyl, -COR 4 , -NHCOR 4 , -OCOR 4 ; the -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3- 12 -membered heterocyclyl optionally substituted by R4;
  • R 4 is selected from halogen, -NH 2 , -OH, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-12 membered heterocyclyl; the C 1-6 Alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-12 membered heterocyclyl optionally selected from -COOH, -NH 2 , -OH, halogen, cyano, nitro, oxygen Substituted with one or more groups of substituted, C 1-6 alkyl, C 1-6 alkoxy.
  • the present disclosure provides a compound represented by formula VII-1 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from C 1-6 alkyl, C 2-6 alkenyl; the C 1-6 alkyl, C 2-6 alkenyl optionally substituted by A; A is selected from H, -COOH, -NH 2 , -OH, halogen, cyano, nitro, oxo, C 1-6 alkane base, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-12-membered heterocyclic group, -COR 4 , -NHCOR 4 , -OCOR 4 ; the -NH 2 , C 1-6 alkyl , C 1-6 alkoxy, C 3-8 cycloalkyl, 3-12-membered heterocyclic group optionally substituted by R 4 ;
  • R 4 is selected from halogen, -NH 2 , -OH, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-12 membered heterocyclyl; the C 1-6 Alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-12 membered heterocyclyl optionally selected from -COOH, -NH 2 , -OH, halogen, cyano, nitro, oxygen Substituted with one or more groups of substituted, C 1-6 alkyl, C 1-6 alkoxy.
  • the present disclosure provides a compound represented by formula VII-1 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from C 1-6 alkyl, C 2-6 alkenyl; the C 1-6 alkyl, C 2-6 alkenyl optionally substituted by A; A is selected from H, -COOH, -NH 2 , -OH, halogen, cyano, nitro, oxo, C 1-6 alkane base, C 1-6 alkoxy.
  • the present disclosure provides a compound represented by formula VII-1 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from C 1-6 alkyl; the C 1-6 alkyl is any is optionally substituted with A; A is selected from H, -COOH, -NH 2 , -OH, halogen, cyano, nitro, oxo, C 1-6 alkyl, C 1-6 alkoxy.
  • the present disclosure provides a compound represented by formula VII-1 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from C 1-6 alkyl; the C 1-6 alkyl is any Optionally substituted with A; A is selected from H, -COOH, -NH2 , -OH, halogen.
  • the present disclosure provides a compound represented by formula VII-1 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from C 1-3 alkyl; the C 1-3 alkyl is any Optionally substituted with A; A is selected from H, -COOH, -NH2 , -OH, halogen.
  • the present disclosure provides a compound represented by formula VII-1 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from C 1-3 alkyl.
  • the present disclosure provides a compound represented by formula VII-1 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from methyl, ethyl, n-propyl, and isopropyl.
  • the present disclosure provides a compound shown in VII-1 or a pharmaceutically acceptable salt thereof, wherein the compound shown in VII-1 is selected from:
  • Another aspect of the present disclosure provides a compound represented by formula VIII-1 or a pharmaceutically acceptable salt thereof,
  • n is selected from 0, 1, 2, 3, 4;
  • R 1 and R 2 are each independently selected from H or A;
  • R 3 is selected from mPEG, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-12 membered heterocyclyl; the C 1-6 Alkyl, C 2-6 alkenyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-12 membered heterocyclyl are optionally substituted by A; and when R is selected from methyl, by A replaces;
  • A is selected from -COOH, -NH 2 , -OH, halogen, cyano, nitro, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-12 Member heterocyclic group, -COR 4 , -NHCOR 4 , -OCOR 4 ; the -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-12 membered Heterocyclyl is optionally substituted by R4 ;
  • R 4 is selected from halogen, -COOH, -NH 2 , -OH, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-12 membered heterocyclyl; the C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-12 membered heterocyclyl optionally selected from -COOH, -NH 2 , -OH, halogen, cyano, nitro substituted with one or more groups of radical, oxo, C 1-6 alkyl, and C 1-6 alkoxy.
  • the present disclosure provides a compound represented by formula VIII-1 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each independently selected from H.
  • the present disclosure provides a compound represented by formula VIII-1 or a pharmaceutically acceptable salt thereof, wherein,
  • R 3 is selected from mPEG, C 1-6 alkyl, and C 2-6 alkenyl; the C 1-6 alkyl and C 2-6 alkenyl are optionally substituted by A;
  • A is selected from -COOH, -NH 2 , -OH, halogen, cyano, nitro, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-12 Member heterocyclic group, -COR 4 , -NHCOR 4 , -OCOR 4 ; the -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-12 membered Heterocyclyl is optionally substituted by R4 ;
  • R 4 is selected from halogen, -COOH, -NH 2 , -OH, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-12 membered heterocyclyl; the C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-12 membered heterocyclyl optionally selected from -COOH, -NH 2 , -OH, halogen, cyano, nitro substituted with one or more groups of radical, oxo, C 1-6 alkyl, and C 1-6 alkoxy.
  • the present disclosure provides a compound represented by formula VIII-1 or a pharmaceutically acceptable salt thereof, wherein,
  • R 3 is selected from mPEG, C 1-6 alkyl; the C 1-6 alkyl is optionally substituted by A;
  • A is selected from -COOH, -NH 2 , -OH, halogen, cyano, nitro, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-12 A membered heterocyclic group, -COR 4 , -NHCOR 4 , -OCOR 4 ;
  • the -NH 2 , C 1-6 alkyl group, C 1-6 alkoxy group, C 3-8 cycloalkyl group, and 3-12-membered heterocyclic group are optionally substituted by R 4 ;
  • R 4 is selected from halogen, -COOH, -NH 2 , -OH, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-12 membered heterocyclyl; the C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-12 membered heterocyclyl optionally selected from -COOH, -NH 2 , -OH, halogen, cyano, nitro substituted with one or more groups of radical, oxo, C 1-6 alkyl, and C 1-6 alkoxy.
  • the present disclosure provides a compound represented by formula VIII-1 or a pharmaceutically acceptable salt thereof, wherein A is selected from -COOH, -NH 2 , -OH, halogen, cyano, nitro , C 1-6 alkyl, C 1-6 alkoxy; the C 1-6 alkyl, C 1-6 alkoxy are optionally substituted by R 4 ; R 4 is selected from halogen, -COOH, -NH 2 , -OH, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-12-membered heterocyclic group; the C 1-6 alkyl, C 1-6 alkane Oxy, C 3-8 cycloalkyl, 3-12 membered heterocyclyl optionally selected from -COOH, -NH 2 , -OH, halogen, cyano, nitro, oxo, C 1-6 alkyl , C 1-6 alkoxy group substituted with one or more groups.
  • the present disclosure provides a compound represented by formula VIII-1 or a pharmaceutically acceptable salt thereof, wherein A is selected from -COOH, -NH 2 , -OH, C 1-6 alkyl, C 1-6 alkoxy; the C 1-6 alkyl, C 1-6 alkoxy are optionally substituted by R 4 ; R 4 is selected from halogen, -COOH, -NH 2 , -OH, C 1- 6 alkyl groups, C 1-6 alkoxy groups, C 3-8 cycloalkyl groups, 3-12-membered heterocyclic groups; the C 1-6 alkyl groups, C 1-6 alkoxy groups, C 3-8 ring groups Alkyl, 3-12 membered heterocyclyl optionally selected from -COOH, -NH 2 , -OH, halogen, cyano, nitro, oxo, C 1-6 alkyl, C 1-6 alkoxy substituted with one or more groups.
  • the present disclosure provides a compound represented by formula VIII-1 or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from halogen, -COOH, -NH 2 , -OH, C 1-6 Alkyl, C 1-6 alkoxy; the C 1-6 alkyl, C 1-6 alkoxy are optionally selected from -COOH, -NH 2 , -OH, halogen, cyano, nitro, One or more groups of oxo, C 1-6 alkyl, and C 1-6 alkoxy are substituted.
  • the present disclosure provides a compound represented by formula VIII-1 or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from halogen, -COOH, -NH 2 , -OH, C 1-6 Alkyl, C 1-6 alkoxy.
  • the present disclosure provides a compound represented by formula VIII-1 or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from -COOH, -NH 2 , and -OH.
  • the present disclosure provides a compound represented by formula VIII-1 or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula VIII-1 is selected from:
  • the present disclosure also provides a compound represented by the aforementioned formulas I-1, II-1, III-1, IV-1, V-1, VI-1, VII-1, VIII-1 or pharmaceutically acceptable compounds thereof isotopic substitutions of salts.
  • the isotopic substitution is a deuterium atom substitution.
  • the present disclosure also provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one of the aforementioned formulas I-1, II-1, III-1, IV-1, V-1, VI-1, VII-1, VIII-1
  • the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.
  • the pharmaceutical composition contains 0.01-99.99% of the aforementioned formulas I-1, II-1, III-1, IV-1, V-1, VI- 1.
  • the pharmaceutical composition contains 0.1-99.9% of the aforementioned formulas I-1, II-1, III-1, IV-1, V-1, VI- 1.
  • the pharmaceutical composition contains 0.5%-99.5% of the aforementioned formulas I-1, II-1, III-1, IV-1, V-1, VI based on the total weight of the composition -1.
  • the pharmaceutical composition contains from 1% to 99% of the aforementioned formulas I-1, II-1, III-1, IV-1, V-1, VI based on the total weight of the composition -1.
  • the pharmaceutical composition contains 2%-98% of the aforementioned formulas I-1, II-1, III-1, IV-1, V-1, VI -1.
  • the pharmaceutical composition contains 0.01%-99.99% of a pharmaceutically acceptable excipient based on the total weight of the composition.
  • the pharmaceutical composition contains 0.1% to 99.9% of a pharmaceutically acceptable excipient, based on the total weight of the composition.
  • the pharmaceutical composition contains 0.5% to 99.5% of a pharmaceutically acceptable excipient, based on the total weight of the composition.
  • the pharmaceutical composition contains from 1% to 99% of a pharmaceutically acceptable excipient, based on the total weight of the composition.
  • the pharmaceutical composition contains from 2% to 98% of a pharmaceutically acceptable excipient, based on the total weight of the composition.
  • the compounds provided by the present disclosure have, for example, vasopressin antagonism, vasodilatory activity, hypotensive activity, hepatic carbohydrate release inhibitory activity, mesangial cell growth inhibitory activity, drainage promoting activity, and platelet aggregation inhibitory activity.
  • the compounds provided by the present disclosure are useful as vasodilators, hypotensives, drainage agents, and platelet aggregation inhibitors.
  • the present disclosure also provides a method of preventing and/or treating a patient suffering from a disease associated with the vasopressin receptor, comprising administering to the patient a therapeutically effective amount of formula I-1, II-1, III as previously described -1.
  • the present disclosure also provides a method for preventing and/or treating patients with hypertension, edema (eg, cardiogenic edema, hepatic edema, renal edema, cerebral edema), ascites, heart failure (eg, severe heart failure), renal Approach to patients with dysfunction, vasopressin abnormal secretion syndrome (SIADH), liver cirrhosis, hyponatremia, hypokalemia, diabetes mellitus, circulatory insufficiency, polycystic kidney disease (PKD), cerebral infarction, myocardial infarction , which comprises administering to the patient a therapeutically effective amount of a compound of the aforementioned formulas I-1, II-1, III-1, IV-1, V-1, VI-1, VII-1, VIII-1 or a pharmaceutically acceptable salt or isotopic substitution thereof or the aforementioned pharmaceutical composition.
  • edema eg, cardiogenic edema, hepatic edema, renal edema, cerebral edema
  • the present disclosure also provides compounds represented by the aforementioned formulas I-1, II-1, III-1, IV-1, V-1, VI-1, VII-1, VIII-1 or pharmaceutically acceptable salts thereof Use of its isotopic substitution or the aforementioned pharmaceutical composition in the preparation of a medicament for preventing and/or treating vasopressin receptor-related diseases.
  • the present disclosure also provides compounds represented by the aforementioned formulas I-1, II-1, III-1, IV-1, V-1, VI-1, VII-1, VIII-1 or pharmaceutically acceptable salts thereof Or its isotopic substitution or the aforementioned pharmaceutical composition in the preparation for the prevention and/or treatment of hypertension, edema (such as cardiogenic edema, hepatic edema, renal edema, cerebral edema), ascites disease, heart failure (such as severe heart failure), renal dysfunction, syndrome of abnormal vasopressin secretion (SIADH), cirrhosis, hyponatremia, hypokalemia, diabetes, circulatory insufficiency, polycystic kidney disease (PKD), cerebral infarction , Myocardial infarction drug use.
  • edema such as cardiogenic edema, hepatic edema, renal edema, cerebral edema
  • SIADH abnormal vasopressin secretion
  • cirrhosis hyponatremia, hypo
  • the present disclosure also provides compounds represented by the aforementioned formulas I-1, II-1, III-1, IV-1, V-1, VI-1, VII-1, VIII-1 or pharmaceutically acceptable salts thereof or its isotopic substitution or the aforementioned pharmaceutical composition, which is used for the prevention and/or treatment of vasopressin receptor-related diseases.
  • the present disclosure also provides compounds represented by the aforementioned formulas I-1, II-1, III-1, IV-1, V-1, VI-1, VII-1, VIII-1 or pharmaceutically acceptable salts thereof or its isotopic substitution or the aforementioned pharmaceutical composition for the prevention and/or treatment of hypertension, edema (such as cardiogenic edema, hepatic edema, renal edema, cerebral edema), ascites disease, heart failure (such as severe heart failure), renal dysfunction, syndrome of abnormal vasopressin secretion (SIADH), cirrhosis, hyponatremia, hypokalemia, diabetes, circulatory insufficiency, polycystic kidney disease (PKD), cerebral infarction , myocardial infarction.
  • edema such as cardiogenic edema, hepatic edema, renal edema, cerebral edema
  • SIADH abnormal vasopressin secretion
  • cirrhosis hyponatremia, hypokalemia, diabetes,
  • the pharmaceutically acceptable salts of the compounds described in this disclosure are selected from inorganic and organic salts.
  • Compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. This disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, non- Enantiomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, All such isomers and mixtures thereof are included within the scope of this disclosure.
  • Asymmetric carbon atoms may be present in substituents such as alkyl groups.
  • Compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.
  • Optically active (R)- and (S)-enantiomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide the pure desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, followed by conventional methods known in the art
  • the diastereoisomers were resolved and the pure enantiomers recovered.
  • separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (eg, from amines to amino groups) formate).
  • Bonds in the chemical structures of the compounds described in the present disclosure Indicates an unspecified configuration, i.e. if a chiral isomer exists in the chemical structure, the bond can be or or both and Two configurations.
  • key Indicates unspecified configuration, including cis (E) or trans (Z) configuration.
  • tautomer or "tautomeric form” refers to structural isomers of different energies that are interconvertible via a low energy barrier.
  • proton tautomers also known as proton tautomers
  • proton transfer such as keto-enol and imine-enamine, lactam-lactam isomerizations .
  • An example of a lactam-lactam equilibrium is between A and B as shown below.
  • the present disclosure also includes certain isotopically-labeled compounds of the present disclosure which are identical to those described herein, except that one or more atoms have been replaced by an atom having an atomic weight or mass number different from that normally found in nature.
  • isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2H, 3H , 11C , 13C , 14C , 13 , respectively N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl and the like.
  • deuterium when a position is specifically designated as deuterium (D), the position is understood to have an abundance of deuterium (ie, at least 1000 times greater than the natural abundance of deuterium (which is 0.015%)) % of deuterium incorporated).
  • Exemplary compounds having natural abundance greater than deuterium may be at least 1000 times more abundant deuterium, at least 2000 times more abundant deuterium, at least 3000 times more abundant deuterium, at least 4000 times more abundant deuterium, at least 4000 times more abundant 5000 times more abundant deuterium, at least 6000 times more abundant deuterium or more abundant deuterium.
  • the present disclosure also includes compounds in various deuterated forms. Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom.
  • deuterated starting materials can be used in the preparation of deuterated forms of compounds of formula (I), or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated borane, trideuterated Borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane and deuterated iodomethane, etc.
  • Alkyl refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 20 carbon atoms. An alkyl group containing 1 to 12 carbon atoms is preferred, and an alkyl group containing 1 to 6 carbon atoms is more preferred.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, and various branched chain isomers, etc. .
  • Alkyl may be substituted or unsubstituted, when substituted, the substituent may be substituted at any available point of attachment, preferably one or more substituents are independently selected from halogen, hydroxy, oxo, nitro , cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-12-membered heterocyclic group.
  • alkenyl refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above and has 2 to 12 (eg 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (ie C 2-12 alkenyl).
  • alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbut-2-enyl, 3-methylbut-1-enyl, 1-pentenyl, 3-pentenyl and 4-hexenyl.
  • Alkenyl can be substituted or unsubstituted, when substituted, the substituent can be substituted at any available point of attachment, preferably one or more substituents are independently selected from halogen, hydroxy, oxo, nitro , cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-12-membered heterocyclic group.
  • alkynyl refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above and has 2 to 12 (eg 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 ) carbon atoms (ie C2-12 alkynyl). Examples are ethynyl, propynyl (eg 1-propynyl, 2-propynyl), 3-butynyl, pentynyl, hexynyl and 1-methylpent-2-ynyl.
  • Alkynyl can be substituted or unsubstituted, when substituted, the substituent can be substituted at any available point of attachment, preferably one or more substituents are independently selected from halogen, hydroxy, oxo, nitro , cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-12-membered heterocyclic group.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl group contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms atom, more preferably contains 3 to 6 carbon atoms.
  • monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene base, cyclooctyl, etc.
  • Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
  • the cycloalkyl group can be fused to an aryl, heteroaryl or heterocyclyl group, wherein the ring attached to the parent structure is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthyl, benzene And cycloheptyl and so on.
  • Cycloalkyl can be optionally substituted or unsubstituted, when substituted, the substituents are preferably one or more independently selected from halogen, hydroxyl, oxo, nitro, cyano, C 1-6 alkyl , C 1-6 alkoxy, C 3-8 cycloalkyl, 3-12-membered heterocyclic group.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2) heteroatoms, excluding ring moieties of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • ring atoms excluding ring moieties of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably 3 to 8 ring atoms.
  • Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc.
  • Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.
  • Non-limiting examples of polycyclic heterocyclyls include:
  • the heterocyclyl group may be fused to an aryl, heteroaryl or cycloalkyl group, wherein the ring attached to the parent structure is a heterocyclyl group, non-limiting examples of which include:
  • Heterocyclyl can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more independently selected from halogen, hydroxyl, oxo, nitro, cyano, C 1-6 alkyl , C 1-6 alkoxy, C 3-8 cycloalkyl, 3-12-membered heterocyclic group.
  • aryl refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, preferably 6 to 12 membered, such as benzene base and naphthyl.
  • the aryl ring can be fused to a heteroaryl, heterocyclyl, or cycloalkyl, wherein the ring attached to the parent structure is an aryl, non-limiting examples of which include:
  • Aryl can be substituted or unsubstituted, and when substituted, the substituents are preferably one or more independently selected from halogen, hydroxyl, oxo, nitro, cyano, C 1-6 alkyl, C 1 -6 alkoxy, C 3-8 cycloalkyl, 3-12 membered heterocyclic group.
  • heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • the heteroaryl group is preferably 6- to 12-membered, more preferably 5- or 6-membered.
  • Non-limiting examples thereof include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazine, Wait.
  • the heteroaryl group can be fused to an aryl group, a heterocyclyl group, or a cycloalkyl group, wherein the ring attached to the parent structure is a heteroaryl group, non-limiting examples of which include:
  • Heteroaryl can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more independently selected from halogen, hydroxy, oxo, nitro, cyano, C 1-6 alkyl , C 1-6 alkoxy, C 3-8 cycloalkyl, 3-12-membered heterocyclic group.
  • alkoxy refers to -O-(alkyl), wherein alkyl is as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • Alkoxy can be optionally substituted or unsubstituted, when substituted, the substituents are preferably one or more independently selected from halogen, hydroxyl, oxo, nitro, cyano, C 1-6 alkyl , C 1-6 alkoxy, C 3-8 cycloalkyl, 3-12-membered heterocyclic group.
  • a “hydroxyl protecting group” of the present disclosure is a group known in the art that can be used to protect a hydroxyl group, see the literature ("Protective Groups in Organic Synthesis", 5 Th Ed. TW Greene & P. GMWuts) for hydroxyl protecting groups.
  • the hydroxyl protecting group can be (C 1-10 alkyl or aryl) 3 silyl group, for example: triethylsilyl, triisopropylsilyl , tert-butyldimethylsilyl, tert-butyldiphenylsilyl, etc.; can be C 1-10 alkyl or substituted alkyl, such as: methyl, tert-butyl, allyl, benzyl, methyl Oxymethyl, ethoxyethyl, 2-tetrahydropyranyl (THP), etc.; can be (C 1-10 alkyl or aryl) acyl, such as: formyl, acetyl, benzoyl, etc.
  • ; can be (C 1-6 alkyl or C 6-10 aryl) sulfonyl; can also be (C 1-6 alkoxy or C 6-10 aryloxy) carbonyl, can be acetyl (Ac ), 2-methoxyethoxymethyl ether (MEM), methoxymethyl ether (MOM), p-methoxybenzyl ether (PMB), methylthiomethyl ether (MTM).
  • MEM 2-methoxyethoxymethyl ether
  • MOM methoxymethyl ether
  • PMB p-methoxybenzyl ether
  • MTM methylthiomethyl ether
  • hydroxy refers to the -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • heterocyclyl optionally substituted with an alkyl group means that an alkyl group may, but need not, be present, and the description includes instances where the heterocyclyl group is substituted with an alkyl group and instances where the heterocyclyl group is not substituted with an alkyl group.
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of one another, are substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as pharmaceutically acceptable carriers and excipients agent.
  • the purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • Fig. 1 is the serum sodium curve of the compounds of the present invention in beagle dogs.
  • Figure 2 is the PK curve in beagle dog plasma after oral administration of compound 5 capsules and tolvaptan tablets.
  • Figure 3 shows the 0-6h urine output of beagle dogs after oral administration of compound 5 capsules and tolvaptan tablets.
  • experimental methods without specific conditions are generally based on conventional conditions or conditions suggested by raw material or commodity manufacturers.
  • Reagents with no specific source indicated are conventional reagents purchased in the market.
  • the structures of the compounds were determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • NMR shifts ([delta]) are given in units of 10<" 6 > (ppm). NMR was measured by Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was four Methylsilane (TMS).
  • DMSO-d 6 dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS Methylsilane
  • MS The determination of MS was performed with Agilent 1200/1290 DAD-6110/6120 Quadrupole MS LC/MS (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), Waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS Model: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).
  • HPLC High performance liquid chromatography
  • Chiral HPLC analysis was determined using an Agilent 1260 DAD high performance liquid chromatograph.
  • the CombiFlash rapid preparative chromatograph used a Combiflash Rf200 (TELEDYNE ISCO).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm, and the size of the TLC separation and purification products is 0.4mm ⁇ 0.5mm.
  • Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the known starting materials of the present disclosure can be synthesized using or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui chemical companies.
  • reaction can be carried out in an argon atmosphere or a nitrogen atmosphere.
  • Argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.
  • the pressure hydrogenation reaction uses Parr 3916EKX hydrogenation apparatus and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation apparatus.
  • the hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.
  • the microwave reaction used a CEM Discover-S 908860 microwave reactor.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, preferably 20°C to 30°C.
  • reaction solution was suction filtered with celite, washed with ethyl acetate (100 mL), the filtrate was washed with water (25 mL x 3), and washed with saturated brine (25 mL).
  • the organic phase was dried, filtered, and concentrated under reduced pressure to obtain 650 mg of crude product, which was separated and purified by silica gel column chromatography to obtain compound 11-b, 270 mg, yield: 100%.
  • Test Example 1 In vivo pharmacokinetic test in dogs
  • tolvaptan and compound 5 Accurately weigh an appropriate amount of tolvaptan and compound 5, add an appropriate volume of 1% hydroxypropyl methylcellulose, vortex or sonicate to mix well, and obtain 0.5 mg/mL tolvaptan administration solution and 2.15 mg of tolvaptan. /mL of Compound 5 dosing solution for gavage.
  • Tolvaptan and compound 5 were administered by gavage.
  • the blood collection points were before administration and 10min, 30min, 1h, 2h, 4h, 6h, 8h, and 24h after administration.
  • EDTA-K2 was anticoagulated, and esterase was added.
  • Inhibitor DDVP manufactured by Sigma
  • separated plasma samples frozen at -70°C, and detected the levels of compound 5 and tolvaptan by LC-MS/MS.
  • Tmax is the time when the drug concentration reaches the peak
  • Cmax is the peak drug concentration
  • AUC 0-t and AUC 0- ⁇ are the area under the curve of the drug
  • t 1/2 is the half-life of the drug in the body.
  • Test Example 2 Inhibitory activity of the compounds of the present invention on arginine vasopressin receptor 2 (AVPR2)
  • AVPR2 Arginine vasopressin receptor 2
  • test compound was diluted with experimental buffer (Hank's balanced salt solution+20mM HEPES+0.1%BSA+500 ⁇ M IBMX (manufacturer: Sigma)), the highest initial concentration of the test compound was 10 ⁇ M, and the dilution factor was 5 times.
  • Flpin-CHO-AVPR2 (this cell line was constructed by the experimental institution Kanglong Chemical (Beijing) New Drug Technology Co., Ltd.; AVPR2 is of human origin)
  • Tolvaptan and compound 5 were administered by gavage.
  • the blood collection points were before administration and 10min, 0.5h, 1h, 2h, 4h, 6h, 8h, and 24h after administration.
  • EDTA-K2 was anticoagulated, and ester was added.
  • enzyme inhibitor DDVP plasma samples were separated and frozen at -70°C, and the levels of compound 5 and tolvaptan were detected by LC-MS/MS.
  • the compounds in the intravenous administration group were administered by intravenous drip for 1 h, respectively, and the compounds in the intragastric administration group were administered by intragastric administration respectively.
  • Blood collection points were before administration and 30min, 1h, 1.5h, 2h, 4h, 6h, 12h, 24h after the end of administration.
  • About 1 mL of blood was collected through the jugular vein or other suitable methods, EDTA-K2 was anticoagulated, and the esterase inhibitor DDVP was added, and the plasma samples were separated and stored at -70 °C.
  • Fig. 1 is the serum sodium curve of the compounds of the present invention in beagle dogs.
  • intravenous infusion of Compound 5 can achieve a considerable degree of sodium elevation at doses lower than Compound 1b disodium salt (0.5 mg/kg vs 1 mg/kg), indicating that Compound 5 The prototype molecule is active.
  • the conversion of tolvaptan by gavage of compound 5 at a lower molar dose resulted in a higher AUC 0-t and increased serum sodium.
  • Tolvaptan tablets are commercially available tablets (trade name: rebactam; manufacturer: Jiangsu Hengrui Pharmaceutical Co., Ltd.), and compound 5 enteric-coated capsules are obtained by directly filling an appropriate amount of compound 5 into enteric-coated capsules ( Enteric-coated capsules manufacturer: Qingdao Yiqing Biotechnology Co., Ltd.).
  • Figure 2 and Figure 3 are respectively the PK curve in the plasma of Beagle dogs and the urine output of 0-6h after oral administration of compound 5 enteric-coated capsules and tolvaptan tablets.
  • Table 6 and Figure 2 compared with tolvaptan tablets, the AUC 0-t converted to tolvaptan in vivo was higher after compound 5 enteric-coated capsules were administered to beagle dogs at equivalent molar doses. The maintenance time of high and effective concentration can be extended by about 2h.
  • Fig. 3 that the gavage administration of compound 5 enteric-coated capsules and tolvaptan tablets can significantly increase the urine output of beagle dogs from 0 to 6 hours after administration.

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Abstract

苯并氮杂䓬类化合物及其制备方法和医药用途。具体地，涉及式II-1或式VIII-1所示的化合物及含有其的药物组合物，以及其医药用途。所述的苯并氮杂䓬类化合物可以用于治疗与血管加压素受体相关的疾病，特别是高血压、心脏病等。

Description

苯并氮杂䓬类化合物及其制备方法和医药用途 技术领域
本公开属于医药领域，涉及一种苯并氮杂
Figure PCTCN2022075793-appb-000002
类化合物及制备方法、组合物和医药用途。
背景技术
加压素是主要由垂体后叶腺体分泌的九肽激素，该激素经由血管V l受体和肾V 2受体亚型实施作用。肾脏中存在的V 2受体可以刺激腺苷酸环化酶达到制尿的作用。加压素受体拮抗剂应用非常广泛，可以用于治疗高血压、充血性心衰、肝硬化、肾衰竭、脑水肿等疾病。苯并氮杂
Figure PCTCN2022075793-appb-000003
类是一类小分子加压素V 2受体拮抗剂，托伐普坦(Tolvaptan)是第一个上市的此类化合物。托伐普坦通过阻滞血管加压素与集合管V 2受体结合，使水通道蛋白-2不能移动到细胞膜表面，抑制尿液浓缩，不排钠而增加自由水的排出，达到利尿效果(J Clin Med,2014,3(4):1276-1290)。动物实验中，托伐普坦对大鼠和狗都有利尿作用，与呋喃苯氨酸相比，能显著增加电解质和水的清除，提高钠离子的浓度(Circulation,2003,107,690-2696)。另外两项在充血性心力衰竭(CHF)和肝硬化所致低钠血症病人中进行的临床试验表明，该化合物的耐受性好，能快速有效地升高血清中钠离子浓度，没有口干、渴感等副作用，且不必限制水的摄入。适用于临床明显的高容量性和正常容量性低钠血症，包括伴心力衰竭、肝硬化及抗利尿激素分泌异常综合征(SIADH)(中国新药杂志,2010,19(10):819-822)。
托伐普坦是已知化合物，已在美国专利US 5,258,510中公开，结构如下所示：
Figure PCTCN2022075793-appb-000004
然而由于其低水溶性、肠道吸收不充分等原因，给药受到了限制。WO2009001968A公开了可用作血管加压素拮抗剂的苯并氮杂
Figure PCTCN2022075793-appb-000005
类衍生物，对托伐普坦的衍生物做了研究。另外，CN101346390A公开了一种新的托伐普坦的磷酸酯衍生物，可用于改善其水溶性。
发明内容
本公开一方面提供一种式I-1所示的化合物或其药学上可接受的盐，
Figure PCTCN2022075793-appb-000006
其中：
Figure PCTCN2022075793-appb-000007
为氨基酸残基；或者
R 1选自C 1-6烷基、C 3-8环烷基、3-12元杂环基；所述C 1-6烷基、C 3-8环烷基、3-12元杂环基任选被A取代；
R 2选自C 1-6烷基、C 3-8环烷基、3-12元杂环基；所述C 1-6烷基、C 3-8环烷基、3-12元杂环基任选被A取代；
或者R 1和R 2与其连接的N原子一起形成含有1-3个杂原子的3-12元杂环基；所述3-12元杂环基任选进一步被A取代；
A选自H、-COOH、-NH 2、-OH、卤素、氰基、硝基、氧代、C 1-6烷基、C 3-8环烷基、3-12元杂环基；所述-NH 2、C 1-6烷基、C 3-8环烷基、3-12元杂环基任选被R 4取代；
R 4选自卤素、-NH 2、-OH、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基。
可选的实施方案中，本公开提供的式I-1所示的化合物或其药学上可接受的盐，其中，
Figure PCTCN2022075793-appb-000008
为氨基酸残基；所述氨基酸选自丙氨酸、精氨酸、天冬氨酸、半胱氨酸、谷氨酰胺、谷氨酸、组氨酸、异亮氨酸、甘氨酸、亮氨酸、赖氨酸、甲硫氨酸、苯丙氨酸、丝氨酸、苏氨酸、酪氨酸、缬氨酸。
可选的实施方案中，本公开提供的式I-1所示的化合物或其药学上可接受的盐，其中，
Figure PCTCN2022075793-appb-000009
为氨基酸残基；所述氨基酸残基为谷氨酸。
可选的实施方案中，本公开提供的式I-1所示的化合物或其药学上可接受的盐，其中，R 1和R 2与其连接的N原子一起形成含有1-3个杂原子的3-8元杂环基；所述3-8元杂环基任选被A取代；A选自H、-COOH、-NH 2、-OH、卤素、氰基、硝基、氧代、C 1-6烷基、C 3-8环烷基、3-12元杂环基；所述-NH 2、C 1-6烷基、C 3-8环烷基、3-12元杂环基任选被R 4取代；R 4选自卤素、-NH 2、-OH、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基。可选的实施方案中，本公开提供的式I-1所示的化合物或其药学上可接受的盐，其中，R 1和R 2与其连接的N原子一起形成含有1个杂原子的3-8元杂环基。
可选的实施方案中，本公开提供的式I-1所示的化合物或其药学上可接受的盐， 其中，A选自C 1-6烷基、C 3-8环烷基、3-12元杂环基；所述C 1-6烷基、C 3-8环烷基、3-12元杂环基任选被R 4取代；R 4选自卤素、-NH 2、-OH、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基。
可选的实施方案中，本公开提供的式I-1所示的化合物或其药学上可接受的盐，其中，A选自3-12元杂环基，所述3-12元杂环基任选被R 4取代；R 4选自卤素、-NH 2、-OH、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基。
可选的实施方案中，本公开提供的式I-1所示的化合物或其药学上可接受的盐，其中，A选自3-8元杂环基，所述3-8元杂环基任选被R 4取代；R 4选自卤素、-NH 2、-OH、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基。
可选的实施方案中，本公开提供的式I-1所示的化合物或其药学上可接受的盐，其中，A选自5-6元杂环基，其中A的连接原子是杂原子，所述杂原子选自N；所述5-6元杂环基任选被R 4取代，R 4选自卤素、-OH、C 1-6烷基、C 1-6烷氧基。
可选的实施方案中，本公开提供的式I-1所示的化合物或其药学上可接受的盐，其中，A选自5-6元杂环基，其中A的连接原子是杂原子，所述杂原子选自N。
可选的实施方案中，本公开提供的式I-1所示的化合物或其药学上可接受的盐，其中，R 1选自C 1-6烷基，所述C 1-6烷基任选被A取代；R 2选自C 1-6烷基、C 3-8环烷基、3-12元杂环基；所述C 1-6烷基、C 3-8环烷基、3-12元杂环基任选被A取代；A选自H、-COOH、-NH 2、-OH、卤素、氰基、硝基、氧代、C 1-6烷基、C 3-8环烷基、3-12元杂环基；所述-NH 2、C 1-6烷基、C 3-8环烷基、3-12元杂环基任选被R 4取代；R 4选自卤素、-NH 2、-OH、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基。
可选的实施方案中，本公开提供的式I-1所示的化合物或其药学上可接受的盐，其中，R 1选自C 1-6烷基，所述C 1-6烷基任选被A取代；R 2选自C 1-6烷基、所述C 1-6烷基任选被A取代；A选自H、-COOH、-NH 2、-OH、卤素、氰基、硝基、氧代、C 1-6烷基、C 3-8环烷基、3-12元杂环基；所述-NH 2、C 1-6烷基、C 3-8环烷基、3-12元杂环基任选被R 4取代；R 4选自卤素、-NH 2、-OH、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基。
可选的实施方案中，本公开提供的式I-1所示的化合物或其药学上可接受的盐，其中，R 1选自C 1-6烷基，所述C 1-6烷基任选被A取代；R 2选自C 1-6烷基、所述C 1-6烷基任选被A取代；A选自H、-COOH、-NH 2、-OH、卤素、C 1-6烷基、C 3-8环烷基、3-12元杂环基；所述-NH 2、C 1-6烷基、C 3-8环烷基、3-12元杂环基任选被R 4取代；R 4选自卤素、-NH 2、-OH、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基。
可选的实施方案中，本公开提供的式I-1所示的化合物或其药学上可接受的盐，其中，其中，R 1选自C 1-6烷基，所述C 1-6烷基任选被A取代；R 2选自C 1-6烷基、所述C 1-6烷基任选被A取代；A选自H、C 1-6烷基、C 3-8环烷基、3-12元杂环基；所述C 1-6烷基、C 3-8环烷基、3-12元杂环基任选被R 4取代；R 4选自卤素、-NH 2、-OH、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基。
可选的实施方案中，本公开提供的式I-1所示的化合物或其药学上可接受的盐，其中，R 1选自C 1-6烷基，所述C 1-6烷基任选被A取代；R 2选自C 1-6烷基、所述C 1-6烷基任选被A取代，所述A选自H、3-12元杂环基，优选地，A为3-8元杂环基，更优选地，A为5-7元杂环基。
可选的实施方案中，本公开提供的式I-1所示的化合物或其药学上可接受的盐，其中，R 1选自C 1-6烷基；R 2选自C 1-6烷基，所述C 1-6烷基被A取代，所述A选自H、3-12元杂环基，优选地，A为3-8元杂环基，更优选地，A为5-7元杂环基。
可选的实施方案中，本公开提供的式I-1所示的化合物或其药学上可接受的盐，其中，R 1选自C 1-3烷基；R 2选自C 1-3烷基，所述C 1-3烷基被A取代；所述A选自H、3-12元杂环基，优选地，A为3-8元杂环基，更优选地，A为5-7元杂环烷。
可选的实施方案中，本公开提供的式I-1所示的化合物或其药学上可接受的盐，其中，R 1选自C 1-3烷基；R 2选自C 1-3烷基，所述C 1-3烷基被A取代；所述A选自H、5-7元杂环烷。
可选的实施方案中，本公开提供的式I-1所示的化合物或其药学上可接受的盐，其中式I-1所示的化合物选自：
Figure PCTCN2022075793-appb-000010
本公开另一方面提供一种式II-1所示的化合物或其药学上可接受的盐，
Figure PCTCN2022075793-appb-000011
其中，
Q为
Figure PCTCN2022075793-appb-000012
其中：
L 1为-(CH 2) m-，所述-(CH 2)-任选被选自O、S、N的杂原子替换；
L 2为-(CH 2) n-，所述-(CH 2)-任选被选自O、S、N的杂原子替换；
m选自0、1、2、3、4、5、6；
n选自1、2、3、4、5、6；
所述L 2的-(CH 2)-任选被A取代；
X选自O和S；
R 1选自C 1-6烷基、C 3-8环烷基、3-12元杂环基；所述C 1-6烷基、C 3-8环烷基、3-12元杂环基任选被基团B取代；
R 2选自C 1-6烷基、C 3-8环烷基、3-12元杂环基；所述C 1-6烷基、C 3-8环烷基、3-12元杂环基任选被基团B取代；
R 3选自C 1-6烷基、C 3-8环烷基、3-12元杂环基；所述C 1-6烷基、C 3-8环烷基、3-12元杂环基任选被基团B取代；
或者，R 1与R 2或R 2与R 3，与其连接的N原子一起形成含有1-3个杂原子的3-12元杂环基；所述3-12元杂环基任选被基团B取代；
A选自H、-COOH、-NH 2、-OH、卤素、氰基、硝基、氧代、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基、-COR 4、-NHCOR 4、-OCOR 4；所述-NH 2、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基任选被R 4取代；
R 4选自卤素、-NH 2、-OH、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基；所述C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基任选被选自-COOH、-NH 2、-OH、卤素、氰基、硝基、氧代、C 1-6烷基、C 1-6烷氧基的一个或多个基团取代；
基团B选自H、-COOH、-NH 2、-OH、卤素、氰基、硝基、氧代。
可选的实施方案中，本公开提供的式II-1所示的化合物或其药学上可接受的盐，其中，X为O。
可选的实施方案中，本公开提供的式II-1所示的化合物或其药学上可接受的盐，其中m选自0、1、2、3、4、5。
可选的实施方案中，本公开提供的式II-1所示的化合物或其药学上可接受的盐，其中m选自0、1、2、3。
可选的实施方案中，本公开提供的式II-1所示的化合物或其药学上可接受的盐，其中n选自2、3、4、5。
可选的实施方案中，本公开提供的式II-1所示的化合物或其药学上可接受的盐，其中n选自2、3。
可选的实施方案中，本公开提供的式II-1所示的化合物或其药学上可接受的盐，其中，A选自H、-COOH、-NH 2、-OH、卤素、氰基、硝基、氧代、C 1-6烷基、 C 1-6烷氧基、C 3-8环烷基、3-12元杂环基；所述C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基任选被R 4取代；
R 4选自卤素、-NH 2、-OH、C 1-6烷基。
可选的实施方案中，本公开提供的式II-1所示的化合物或其药学上可接受的盐，其中A选自H、-COOH、-NH 2、-OH、卤素、氰基、硝基。
可选的实施方案中，本公开提供的式II-1所示的化合物或其药学上可接受的盐，其中所述-(CH 2)-无取代。
可选的实施方案中，本公开提供的式II-1所示的化合物或其药学上可接受的盐，其中，L 1为-CH 2-O-。
可选的实施方案中，本公开提供的式II-1所示的化合物或其药学上可接受的盐，其中，L 1为-(CH 2) m-，m为0。
可选的实施方案中，本公开提供的式II-1所示的化合物或其药学上可接受的盐，其中L 2为-(CH 2) 2-。
可选的实施方案中，本公开提供的式II-1所示的化合物或其药学上可接受的盐，其中，R 1选自C 1-6烷基。
可选的实施方案中，本公开提供的式II-1所示的化合物或其药学上可接受的盐，其中，R 1选自C 1-3烷基。
可选的实施方案中，本公开提供的式II-1所示的化合物或其药学上可接受的盐，其中，R 2选自C 1-6烷基。
可选的实施方案中，本公开提供的式II-1所示的化合物或其药学上可接受的盐，其中，R 2选自C 1-3烷基。
可选的实施方案中，本公开提供的式II-1所示的化合物或其药学上可接受的盐，其中，R 3选自C 1-6烷基。
可选的实施方案中，本公开提供的式II-1所示的化合物或其药学上可接受的盐，其中，R 3选自C 1-3烷基。
可选的实施方案中，本公开提供的式II-1所示的化合物或其药学上可接受的盐，其中，
R 1选自C 1-6烷基；
R 2选自C 1-6烷基；
R 3选自C 1-6烷基；
所述C 1-6烷基任选被基团B取代；基团B选自H、-COOH、-NH 2、-OH、卤素、氰基、硝基、氧代。
可选的实施方案中，本公开提供的式II-1所示的化合物或其药学上可接受的盐，其中，
X为O；
L 1为-(CH 2) m-，m为0；或L 1为-CH 2-O-；
L 2为-(CH 2) n-；n选自2和3；
R 1选自甲基、乙基、正丙基、异丙基；
R 2选自甲基、乙基、正丙基、异丙基；
R 3选自甲基、乙基、正丙基、异丙基。
可选的实施方案中，本公开提供的式II-1所示的化合物或其药学上可接受的盐，其中，
X为O；
L 1为-(CH 2) m-，m为0；或L 1为-CH 2-O-；
L 2为-(CH 2) n-；n选自2和3；
R 1选自甲基；R 2选自甲基；R 3选自甲基。
可选的实施方案中，本公开提供的式II-1所示的化合物或其药学上可接受的盐，其中所述化合物选自：
Figure PCTCN2022075793-appb-000013
本公开另一方面提供一种式III-1所示的化合物或其药学上可接受的盐，
Figure PCTCN2022075793-appb-000014
其中，
T为氨基酸残基，其中氨基酸的羧基与O连接；所述氨基酸不为甘氨酸或缬氨酸。
本公开提供的式III-1所述的化合物或其药学上可接受的盐，所述氨基酸选自丙氨酸、精氨酸、天冬氨酸、半胱氨酸、谷氨酰胺、谷氨酸、组氨酸、异亮氨酸、甘氨酸、亮氨酸、赖氨酸、甲硫氨酸、苯丙氨酸、丝氨酸、苏氨酸、酪氨酸、缬氨酸。
可选的实施方案中，本公开提供的式III-1所示的化合物或其药学上可接受的盐，其中T为-氨基酸残基，其中氨基酸的羧基与O连接，所述氨基酸为谷氨酸、脯氨酸、赖氨酸。
可选的实施方案中，本公开提供的式III-1所示的化合物或其药学上可接受的盐，其中式III-1所述的化合物选自
Figure PCTCN2022075793-appb-000015
本公开另一方面提供一种式IV-1所示的化合物或其药学上可接受的盐，
Figure PCTCN2022075793-appb-000016
其中，
W为-C(O)-L-NR 1R 2R 3，其中：
L为-(CH 2) n-，n选自1、2、3、4、5、6；所述-(CH 2)-任选被A取代；
R 1选自C 1-6烷基、C 3-8环烷基、3-12元杂环基；所述C 1-6烷基、C 3-8环烷基、3-12元杂环基任选进一步被基团B取代；
R 2选自C 1-6烷基、C 3-8环烷基、3-12元杂环基；所述C 1-6烷基、C 3-8环烷基、3-12元杂环基任选进一步被基团B取代；
R 3选自C 1-6烷基、C 3-8环烷基、3-12元杂环基；所述C 1-6烷基、C 3-8环烷基、3-12元杂环基任选进一步被基团B取代；
或者，R 1与R 2或R 2与R 3，与其连接的N原子一起形成含有1-3个杂原子的3-12元杂环基；所述3-12元杂环基任选进一步被基团B取代；
A选自H、-COOH、-NH 2、-OH、卤素、氰基、硝基、氧代、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基、-COR 4、-NHCOR 4、-OCOR 4；所述-NH 2、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基任选被R 4取代；
R 4选自卤素、-NH 2、-OH、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基；所述C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基任选进一步被选自-COOH、-NH 2、-OH、卤素、氰基、硝基、氧代、C 1-6烷基、C 1-6烷氧基的一个或多个基团取代；
基团B选自H、-COOH、-NH 2、-OH、卤素、氰基、硝基、氧代。
可选的实施方案中，本公开提供的式IV-1所示的化合物或其药学上可接受的盐，其中n选自2、3、4、5。
可选的实施方案中，本公开提供的式IV-1所示的化合物或其药学上可接受的盐，其中n选自2、3。
可选的实施方案中，本公开提供的式IV-1所示的化合物或其药学上可接受的盐，其中A选自H、-COOH、-NH 2、-OH、卤素、氰基、硝基、氧代、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基；所述C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基任选被R 4取代；
R 4选自卤素、-NH 2、-OH、C 1-6烷基。
可选的实施方案中，本公开提供的式IV-1所示的化合物或其药学上可接受的盐，其中A选自H、-COOH、-NH 2、-OH、卤素、氰基、硝基。
可选的实施方案中，本公开提供的式IV-1所示的化合物或其药学上可接受的盐，其中，所述-(CH 2)-无取代。
可选的实施方案中，本公开提供的式IV-1所示的化合物或其药学上可接受的盐，其中，R 1选自C 1-6烷基。
可选的实施方案中，本公开提供的式IV-1所示的化合物或其药学上可接受的盐，其中，R 1选自C 1-3烷基。
可选的实施方案中，本公开提供的式IV-1所示的化合物或其药学上可接受的盐，其中，R 2选自C 1-6烷基。
可选的实施方案中，本公开提供的式IV-1所示的化合物或其药学上可接受的盐，其中，R 2选自C 1-3烷基。
可选的实施方案中，本公开提供的式IV-1所示的化合物或其药学上可接受的盐，其中，R 3选自C 1-6烷基。
可选的实施方案中，本公开提供的式IV-1所示的化合物或其药学上可接受的盐，其中，R 3选自C 1-3烷基。
可选的实施方案中，本公开提供的式IV-1所示的化合物或其药学上可接受的盐，其中，
R 1选自C 1-6烷基；
R 2选自C 1-6烷基；
R 3选自C 1-6烷基；
所述C 1-6烷基任选进一步被基团B取代；
基团B选自H、-COOH、-NH 2、-OH、卤素、氰基、硝基、氧代。
可选的实施方案中，本公开提供的式IV-1所示的化合物或其药学上可接受的盐，其中，
L为-(CH 2) n-；
n选自2、3；
R 1选自甲基、乙基、正丙基、异丙基；
R 2选自甲基、乙基、正丙基、异丙基；
R 3选自甲基、乙基、正丙基、异丙基。
可选的实施方案中，本公开提供的式IV-1所示的化合物或其药学上可接受的盐，其中，R 1选自甲基；R 2选自甲基；R 3选自甲基。
本公开另一方面提供一种式V-1所示的化合物或其药学上可接受的盐，
Figure PCTCN2022075793-appb-000017
其中，
n选自1-10之间的整数；
X选自O和S；
R 1选自H或羟基保护基团；
R 2选自羟基、任选由保护基团保护的羟基、任选由保护基团保护的巯基、任选由保护基团保护的氨基；
所述“羟基保护基团”或“保护基团”选自C 1-6烷基；所述C 1-6烷基任选被选自OH、CN、卤素、-C(O)OC 1-6烷基、6-12元芳基和6-12元的杂芳基的一个或多个基团取代。
可选的实施方案中，本公开提供的式V-1所示的化合物或其药学上可接受的盐，其中，n选自2-8之间的整数。
可选的实施方案中，本公开提供的式V-1所示的化合物或其药学上可接受的盐，其中，n选自2-5之间的整数。
可选的实施方案中，本公开提供的式V-1所示的化合物或其药学上可接受的盐，其中，X选自O。
可选的实施方案中，本公开提供的式V-1所示的化合物或其药学上可接受的盐，其中，R 1选自H。
可选的实施方案中，本公开提供的式V-1所示的化合物或其药学上可接受的盐，其中，R 2选自羟基、任选由保护基团保护的羟基，所述保护基团选自C 1-6烷基；所述C 1-6烷基任选被选自OH、CN、卤素、-C(O)OC 1-6烷基的一个或多个基团取代。
可选的实施方案中，本公开提供的式V-1所示的化合物或其药学上可接受的盐，其中，R 2选自羟基、任选由保护基团保护的羟基，所述保护基团选自C 1-6烷基；所述C 1-6烷基任选被选自CN、-C(O)OC 1-6烷基的一个或多个基团取代。
可选的实施方案中，本公开提供的式V-1所示的化合物或其药学上可接受的盐，其中，R 2选自羟基、任选由保护基团保护的羟基，保护基团选自C 1-3烷基； 所述C 1-3烷基任选被CN、-C(O)OC 1-3烷基取代。
可选的实施方案中，本公开提供的式V-1所示的化合物或其药学上可接受的盐，其中，R 2选自羟基。
可选的实施方案中，本公开提供的式V-1所示的化合物或其药学上可接受的盐，其中式V-1所示的化合物选自：
Figure PCTCN2022075793-appb-000018
本公开另一方面，提供一种式VI-1所示的化合物或其药学上可接受的盐，
Figure PCTCN2022075793-appb-000019
其中，
n选自0和1；
R 1和R 2各自独立地选自H或A；
R 3选自mPEG、C 1-6烷基、C 2-6烯基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基；所述C 1-6烷基、C 2-6烯基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基任选被A取代；
A选自H、-COOH、-NH 2、-OH、卤素、氰基、硝基、氧代、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基、-COR 4、-NHCOR 4、-OCOR 4；所述-NH 2、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基任选被R 4取代；
R 4选自卤素、-COOH、-NH 2、-OH、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基；所述C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基任选被选自-COOH、-NH 2、-OH、卤素、氰基、硝基、氧代、C 1-6烷基、C 1-6烷氧基的一个或多个基团取代。
可选的实施方案中，本公开提供的式VI-1所示的化合物或其药学上可接受的盐，其中，R 1和R 2各自独立地选自H。
可选的实施方案中，本公开提供的式VI-1所示的化合物或其药学上可接受的盐，其中，R 3选自mPEG、C 1-6烷基、C 2-6烯基；所述C 1-6烷基、C 2-6烯基任选被A取代。
可选的实施方案中，本公开提供的式VI-1所示的化合物或其药学上可接受的盐，其中，R 3选自mPEG、C 1-6烷基；所述C 1-6烷基任选被A取代。
可选的实施方案中，本公开提供的式VI-1所示的化合物或其药学上可接受的盐，其中，A选自H、-COOH、-NH 2、-OH、卤素、氰基、硝基、C 1-6烷基、C 1-6烷氧基；所述C 1-6烷基、C 1-6烷氧基任选被R 4取代。
可选的实施方案中，本公开提供的式VI-1所示的化合物或其药学上可接受的盐，其中，A选自H、-COOH、-NH 2、-OH、C 1-6烷基、C 1-6烷氧基；所述C 1-6烷基、C 1-6烷氧基任选被R 4取代。
可选的实施方案中，本公开提供的式VI-1所示的化合物或其药学上可接受的盐，其中，A选自H、-COOH、-NH 2、-OH、C 1-6烷基、C 1-6烷氧基；所述C 1-6烷基、C 1-6烷氧基任选被R 4取代。
可选的实施方案中，本公开提供的式VI-1所示的化合物或其药学上可接受的盐，其中，R 4选自卤素、-COOH、-NH 2、-OH、C 1-6烷基、C 1-6烷氧基；所述C 1-6烷基、C 1-6烷氧基任选被选自-COOH、-NH 2、-OH、卤素、氰基、硝基、氧代、C 1-6烷基、C 1-6烷氧基的一个或多个基团取代。
可选的实施方案中，本公开提供的式VI-1所示的化合物或其药学上可接受的盐，其中，R 4选自卤素、-COOH、-NH 2、-OH、C 1-6烷基、C 1-6烷氧基。
可选的实施方案中，本公开提供的式VI-1所示的化合物或其药学上可接受的盐，其中，R 4选自-COOH、-NH 2、-OH。
可选的实施方案中，本公开提供的式VI-1所示的化合物或其药学上可接受的盐，其中，式VI-1所示的化合物选自：
Figure PCTCN2022075793-appb-000020
Figure PCTCN2022075793-appb-000021
本公开另一方面，提供一种式VII-1所示的化合物或其药学上可接受的盐，
Figure PCTCN2022075793-appb-000022
其中，
n选自0，1，2，3和4；
R 1选自C 1-6烷基、C 2-6烯基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基；所述C 1-6烷基、C 2-6烯基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基任选被A取代；
A选自H、-COOH、-NH 2、-OH、卤素、氰基、硝基、氧代、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基、-COR 4、-NHCOR 4、-OCOR 4；所述-NH 2、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基任选被R 4取代；
R 4选自卤素、-NH 2、-OH、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基；所述C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基任选被选自-COOH、-NH 2、-OH、卤素、氰基、硝基、氧代、C 1-6烷基、C 1-6烷氧基的一个或多个基团取代。
可选的实施方案中，本公开提供的式VII-1所示的化合物或其药学上可接受的盐，其中，R 1选自C 1-6烷基、C 2-6烯基；所述C 1-6烷基、C 2-6烯基任选被A取代；A选自H、-COOH、-NH 2、-OH、卤素、氰基、硝基、氧代、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基、-COR 4、-NHCOR 4、-OCOR 4；所述-NH 2、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基任选被R 4取代；
R 4选自卤素、-NH 2、-OH、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基；所述C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基任选被选自-COOH、-NH 2、-OH、卤素、氰基、硝基、氧代、C 1-6烷基、C 1-6烷氧基的一个或多个基团取代。
可选的实施方案中，本公开提供的式VII-1所示的化合物或其药学上可接受的 盐，其中，R 1选自C 1-6烷基、C 2-6烯基；所述C 1-6烷基、C 2-6烯基任选被A取代；A选自H、-COOH、-NH 2、-OH、卤素、氰基、硝基、氧代、C 1-6烷基、C 1-6烷氧基。
可选的实施方案中，本公开提供的式VII-1所示的化合物或其药学上可接受的盐，其中，R 1选自C 1-6烷基；所述C 1-6烷基任选被A取代；A选自H、-COOH、-NH 2、-OH、卤素、氰基、硝基、氧代、C 1-6烷基、C 1-6烷氧基。
可选的实施方案中，本公开提供的式VII-1所示的化合物或其药学上可接受的盐，其中，R 1选自C 1-6烷基；所述C 1-6烷基任选被A取代；A选自H、-COOH、-NH 2、-OH、卤素。
可选的实施方案中，本公开提供的式VII-1所示的化合物或其药学上可接受的盐，其中，R 1选自C 1-3烷基；所述C 1-3烷基任选被A取代；A选自H、-COOH、-NH 2、-OH、卤素。
可选的实施方案中，本公开提供的式VII-1所示的化合物或其药学上可接受的盐，其中，R 1选自C 1-3烷基。
可选的实施方案中，本公开提供的式VII-1所示的化合物或其药学上可接受的盐，其中，R 1选自甲基、乙基、正丙基、异丙基。
可选的实施方案中，本公开提供的VII-1所示的化合物或其药学上可接受的盐，其中VII-1所示的化合物选自：
Figure PCTCN2022075793-appb-000023
本公开另一方面，提供一种式VIII-1所示的化合物或其药学上可接受的盐，
Figure PCTCN2022075793-appb-000024
其中，
n选自0、1、2、3、4；
R 1和R 2各自独立地选自H或A；
R 3选自mPEG、C 1-6烷基、C 2-6烯基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基；所述C 1-6烷基、C 2-6烯基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基任选被A取代；且当R 3选自甲基时，被A取代；
A选自-COOH、-NH 2、-OH、卤素、氰基、硝基、氧代、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基、-COR 4、-NHCOR 4、-OCOR 4；所述-NH 2、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基任选被R 4取代；
R 4选自卤素、-COOH、-NH 2、-OH、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基；所述C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基任选被选自-COOH、-NH 2、-OH、卤素、氰基、硝基、氧代、C 1-6烷基、C 1-6烷氧基的一个或多个基团取代。
可选的实施方案中，本公开提供的式VIII-1所示的化合物或其药学上可接受的盐，其中，R 1和R 2各自独立地选自H。
可选的实施方案中，本公开提供的式VIII-1所示的化合物或其药学上可接受的盐，其中，
R 3选自mPEG、C 1-6烷基、C 2-6烯基；所述C 1-6烷基、C 2-6烯基任选被A取代；
A选自-COOH、-NH 2、-OH、卤素、氰基、硝基、氧代、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基、-COR 4、-NHCOR 4、-OCOR 4；所述-NH 2、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基任选被R 4取代；
R 4选自卤素、-COOH、-NH 2、-OH、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基；所述C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基任选被选自-COOH、-NH 2、-OH、卤素、氰基、硝基、氧代、C 1-6烷基、C 1-6烷氧基的一个或多个基团取代。
可选的实施方案中，本公开提供的式VIII-1所示的化合物或其药学上可接受的盐，其中，
R 3选自mPEG、C 1-6烷基；所述C 1-6烷基任选被A取代；
A选自-COOH、-NH 2、-OH、卤素、氰基、硝基、氧代、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基、-COR 4、-NHCOR 4、-OCOR 4；
所述-NH 2、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基任选被R 4取代；
R 4选自卤素、-COOH、-NH 2、-OH、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基；所述C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基任选被选自-COOH、-NH 2、-OH、卤素、氰基、硝基、氧代、C 1-6烷基、C 1-6烷氧基的一个或多个基团取代。
可选的实施方案中，本公开提供的式VIII-1所示的化合物或其药学上可接受的盐，其中，A选自-COOH、-NH 2、-OH、卤素、氰基、硝基、C 1-6烷基、C 1-6烷氧基；所述C 1-6烷基、C 1-6烷氧基任选被R 4取代；R 4选自卤素、-COOH、-NH 2、 -OH、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基；所述C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基任选被选自-COOH、-NH 2、-OH、卤素、氰基、硝基、氧代、C 1-6烷基、C 1-6烷氧基的一个或多个基团取代。
可选的实施方案中，本公开提供的式VIII-1所示的化合物或其药学上可接受的盐，其中，A选自-COOH、-NH 2、-OH、C 1-6烷基、C 1-6烷氧基；所述C 1-6烷基、C 1-6烷氧基任选被R 4取代；R 4选自卤素、-COOH、-NH 2、-OH、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基；所述C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基任选被选自-COOH、-NH 2、-OH、卤素、氰基、硝基、氧代、C 1-6烷基、C 1-6烷氧基的一个或多个基团取代。
可选的实施方案中，本公开提供的式VIII-1所示的化合物或其药学上可接受的盐，其中，R 4选自卤素、-COOH、-NH 2、-OH、C 1-6烷基、C 1-6烷氧基；所述C 1-6烷基、C 1-6烷氧基任选被选自-COOH、-NH 2、-OH、卤素、氰基、硝基、氧代、C 1-6烷基、C 1-6烷氧基的一个或多个基团取代。
可选的实施方案中，本公开提供的式VIII-1所示的化合物或其药学上可接受的盐，其中，R 4选自卤素、-COOH、-NH 2、-OH、C 1-6烷基、C 1-6烷氧基。
可选的实施方案中，本公开提供的式VIII-1所示的化合物或其药学上可接受的盐，其中，R 4选自-COOH、-NH 2、-OH。
可选的实施方案中，本公开提供的式VIII-1所示的化合物或其药学上可接受的盐，其中式VIII-1所示的化合物选自：
Figure PCTCN2022075793-appb-000025
本公开中还提供一种前述式I-1、II-1、III-1、IV-1、V-1、VI-1、VII-1、VIII-1所示的化合物或其药学上可接受的盐的同位素取代物。
在一些实施方案中，所述的同位素取代为氘原子取代。
本公开中还提供一种药物组合物，其包含至少一种前述式I-1、II-1、III-1、IV-1、V-1、VI-1、VII-1、VIII-1所示的化合物或其药学上可接受的盐或其同位素取代物以及药学上可接受的赋形剂。
在一些实施方案中，所述的药物组合物的单位剂量为0.001mg-1000mg。
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01-99.99％的前述式I-1、II-1、III-1、IV-1、V-1、VI-1、VII-1、VIII-1所示的化合物或其药学上可接受的盐或其同位素取代物。
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.1-99.9％的前述式I-1、II-1、III-1、IV-1、V-1、VI-1、VII-1、VIII-1所示的化合物或其药学上可接受的盐或其同位素取代物。
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.5％-99.5％的前述式I-1、II-1、III-1、IV-1、V-1、VI-1、VII-1、VIII-1所示的化合物或其药学上可接受的盐或其同位素取代物。
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有1％-99％的前述式I-1、II-1、III-1、IV-1、V-1、VI-1、VII-1、VIII-1所示的化合物或其药学上可接受的盐或其同位素取代物。
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有2％-98％的前述式I-1、II-1、III-1、IV-1、V-1、VI-1、VII-1、VIII-1所示的化合物或其药学上可接受的盐或其同位素取代物。
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01％-99.99％的药学上可接受的赋形剂。
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.1％-99.9％的药学上可接受的赋形剂。
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.5％-99.5％的药学上可接受的赋形剂。
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有1％-99％的药学上可接受的赋形剂。
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有2％-98％的药学上可接受的赋形剂。
本公开提供的化合物具有例如血管加压素拮抗作用、血管舒张活性、降血压活性、抑制肝脏糖类释放活性、系膜细胞生长抑制活性、促排水活性和血小板聚集抑制活性。
本公开提供的化合物可用作血管扩张剂、降压剂、促排水剂和血小板聚集抑制剂。
本公开还提供一种预防和/或治疗患有与血管加压素受体相关疾病的患者的方法，其包括向所述患者施用治疗有效量的如前述式I-1、II-1、III-1、IV-1、V-1、VI-1、VII-1、VIII-1所示的化合物或其药学上可接受的盐或其同位素取代物或前述药物组合物。
本公开还提供一种预防和/或治疗患有高血压、水肿(例如心源性水肿、肝病性水肿、肾性水肿、脑水肿)、腹水病、心力衰竭(例如严重的心力衰竭)、肾功能障碍、血管加压素分泌异常综合征(SIADH)、肝硬化、低钠血症、低钾血症、糖尿病、循环功能不全、多囊肾疾病(PKD)、脑梗死、心肌梗死患者的方法，其包括向所述患者施用治疗有效量的如前述式I-1、II-1、III-1、IV-1、V-1、VI-1、VII-1、VIII-1 所示的化合物或其药学上可接受的盐或其同位素取代物或前述药物组合物。
本公开还提供如前述式I-1、II-1、III-1、IV-1、V-1、VI-1、VII-1、VIII-1所示的化合物或其药学上可接受的盐或其同位素取代物或前述药物组合物在制备用于预防和/或治疗与血管加压素受体相关疾病的药物中的用途。
本公开还提供如前述式I-1、II-1、III-1、IV-1、V-1、VI-1、VII-1、VIII-1所示的化合物或其药学上可接受的盐或其同位素取代物或前述药物组合物在制备用于预防和/或治疗高血压、水肿(例如心源性水肿、肝病性水肿、肾性水肿、脑水肿)、腹水病、心力衰竭(例如严重的心力衰竭)、肾功能障碍、血管加压素分泌异常综合征(SIADH)、肝硬化、低钠血症、低钾血症、糖尿病、循环功能不全、多囊肾疾病(PKD)、脑梗死、心肌梗死的药物中的用途。
本公开还提供如前述式I-1、II-1、III-1、IV-1、V-1、VI-1、VII-1、VIII-1所示的化合物或其药学上可接受的盐或其同位素取代物或前述药物组合物，其用于预防和/或治疗患有与血管加压素受体相关疾病。
本公开还提供如前述式I-1、II-1、III-1、IV-1、V-1、VI-1、VII-1、VIII-1所示的化合物或其药学上可接受的盐或其同位素取代物或前述药物组合物，其用于预防和/或治疗高血压、水肿(例如心源性水肿、肝病性水肿、肾性水肿、脑水肿)、腹水病、心力衰竭(例如严重的心力衰竭)、肾功能障碍、血管加压素分泌异常综合征(SIADH)、肝硬化、低钠血症、低钾血症、糖尿病、循环功能不全、多囊肾疾病(PKD)、脑梗死、心肌梗死。
另一方面，本公开中所述化合物的药学上可接受的盐选自无机盐和有机盐。
本公开化合物可以存在特定的几何或立体异构体形式。本公开设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映异构体、(R)-和(S)-对映异构体、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异构体富集的混合物，所有这些异构体以及它们的混合物均包括在本公开的范围之内。烷基等取代基中可存在不对称碳原子。本公开的含有不对称碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。
可以通过手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-对映异构体以及(D)-和(L)-异构体。如果想得到本公开某化合物的一种对映异构体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映异构体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映异构体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本公开所述化合物的化学结构中键
Figure PCTCN2022075793-appb-000026
表示未指定构型，即如果化学结构中存在手性异构体，键
Figure PCTCN2022075793-appb-000027
可以为
Figure PCTCN2022075793-appb-000028
或
Figure PCTCN2022075793-appb-000029
或者同时包含
Figure PCTCN2022075793-appb-000030
和
Figure PCTCN2022075793-appb-000031
两种构型。键
Figure PCTCN2022075793-appb-000032
表示未指定构型，包括顺式(E)或反式(Z)构型。
本公开的化合物和中间体还可以以不同的互变异构体形式存在，并且所有这样的形式包含于本公开的范围内。术语“互变异构体”或“互变异构体形式”是指可经由低能垒互变的不同能量的结构异构体。例如，质子互变异构体(也称为质子转移互变异构体)包括经由质子迁移的互变，如酮-烯醇及亚胺-烯胺、内酰胺-内酰亚胺异构化。内酰胺-内酰亚胺平衡实例是在如下所示的A和B之间。
Figure PCTCN2022075793-appb-000033
所有的互变异构形式在本公开的范围内。化合物的命名不排除任何互变异构体。
本公开还包括一些与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本公开化合物。可结合到本公开化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为 2H、 3H、 11C、 13C、 14C、 13N、 15N、 15O、 17O、 18O、 31P、 32P、 35S、 18F、 123I、 125I和 36Cl等。
除另有说明，当一个位置被特别地指定为氘(D)时，该位置应理解为具有大于氘的天然丰度(其为0.015％)至少1000倍的丰度的氘(即，至少10％的氘掺入)。示例中化合物的具有大于氘的天然丰度可以是至少1000倍的丰度的氘、至少2000倍的丰度的氘、至少3000倍的丰度的氘、至少4000倍的丰度的氘、至少5000倍的丰度的氘、至少6000倍的丰度的氘或更高丰度的氘。本公开还包括各种氘化形式的化合物。与碳原子连接的各个可用的氢原子可独立地被氘原子替换。本领域技术人员能够参考相关文献合成氘化形式的式(I)化合物。在制备氘代形式的式(I)化合物时可使用市售的氘代起始物质，或它们可使用常规技术采用氘代试剂合成，氘代试剂包括但不限于氘代硼烷、三氘代硼烷四氢呋喃溶液、氘代氢化锂铝、氘代碘乙烷和氘代碘甲烷等。
术语解释：
“烷基”指饱和的脂族烃基团，包括1至20个碳原子的直链和支链基团。优选含有1至12个碳原子的烷基，更优选含有1至6个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基，及其各种支链异构体等。烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，取代基优选一个或多个独立地选自 卤素、羟基、氧代、硝基、氰基、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基的基团。
术语“烯基”指分子中含有至少一个碳碳双键的烷基，其中烷基的定义如上所述，其具有2至12个(例如2、3、4、5、6、7、8、9、10、11和12个)碳原子的烯基(即C 2-12烯基)。烯基的实例包括但不限于，乙烯基、烯丙基、1-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、2-甲基丁-2-烯基、3-甲基丁-1-烯基、1-戊烯基、3-戊烯基及4-己烯基。烯基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，取代基优选一个或多个独立地选自卤素、羟基、氧代、硝基、氰基、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基的基团。
术语“炔基”指分子中含有至少一个碳碳三键的烷基，其中烷基的定义如上所述，其具有2至12个(例如2、3、4、5、6、7、8、9、10、11和12个)碳原子(即C 2- 12炔基)。例如乙炔基、丙炔基(例如1-丙炔基、2-丙炔基)、3-丁炔基、戊炔基、己炔基及1-甲基戊-2-炔基。炔基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，取代基优选一个或多个独立地选自卤素、羟基、氧代、硝基、氰基、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基的基团。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基包含3至20个碳原子，优选包含3至12个碳原子，进一步优选3至8个碳原子，更优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等。多环环烷基包括螺环、稠环和桥环的环烷基。
所述环烷基可以稠合于芳基、杂芳基或杂环基上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个独立地选自卤素、羟基、氧代、硝基、氰基、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基的基团。
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；更优选包含3至8个环原子。单环杂环基的非限制性实例包括吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。多环杂环基包括螺环、稠环和桥环的杂环基。多环杂环基的非限制性实例包括：
Figure PCTCN2022075793-appb-000034
Figure PCTCN2022075793-appb-000035
Figure PCTCN2022075793-appb-000036
等。
所述杂环基可以稠合于芳基、杂芳基或环烷基上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：
Figure PCTCN2022075793-appb-000037
等。
杂环基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个独立地选自卤素、羟基、氧代、硝基、氰基、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基的基团。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至12元，例如苯基和萘基。所述芳基环可以稠合于杂芳基、杂环基或环烷基上，其中与母体结构连接在一起的环为芳基，其非限制性实例包括：
Figure PCTCN2022075793-appb-000038
芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个独立地选自卤素、羟基、氧代、硝基、氰基、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基的基团。
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为6至12元，更优选为5元或6元。其非限制性实例包括：咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪，
Figure PCTCN2022075793-appb-000039
等。
所述杂芳基可以稠合于芳基、杂环基或环烷基上，其中与母体结构连接在一起的环为杂芳基，其非限制性实例包括：
Figure PCTCN2022075793-appb-000040
杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个独立地选自卤素、羟基、氧代、硝基、氰基、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基的基团。
术语“烷氧基”指-O-(烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个独立地选自卤素、羟基、氧代、硝基、氰基、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基的基团。
本公开“羟基保护基”是本领域已知的、能用于保护羟基的基团，参见文献(《Protective Groups in Organic Synthesis》，5 Th Ed.T.W.Greene&P.G.M.Wuts)中的羟基保护基团。作为示例，包括但不限于作为示例，优选地，所述的羟基保护基可以是(C 1-10烷基或芳基) 3硅烷基，例如：三乙基硅基、三异丙基硅基、叔丁基二甲基硅基、叔丁基二苯基硅基等；可以是C 1-10烷基或取代烷基，例如：甲基、叔丁基、烯丙基、苄基、甲氧基甲基、乙氧基乙基、2-四氢吡喃基(THP)等；可以是(C 1-10烷基或芳香基)酰基，例如：甲酰基、乙酰基、苯甲酰基等；可以是(C 1-6烷基或C 6-10芳基)磺酰基；也可以是(C 1-6烷氧基或C 6-10芳基氧基)羰基，可以是乙酰基(Ac)、2-甲氧基乙氧甲基醚(MEM)、甲氧甲基醚(MOM)、对甲氧基苄基醚(PMB)、甲硫甲基醚(MTM)。
术语“羟基”指-OH基团。
术语“卤素”指氟、氯、溴或碘。
术语“氨基”指-NH 2。
术语“氰基”指-CN。
术语“硝基”指-NO 2。
术语“氧代”指＝O取代基。
“任选”或“任选地”意味着随后所描述的事件或情况可以但不必发生，该说明包括该事件或情况发生或不发生地场合。例如，“任选被烷基取代的杂环基”意味着烷基可以但不必须存在，该说明包括杂环基被烷基取代的情形和杂环基不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的 可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。
“药物组合物”表示含有一种或多种本文所述化合物或其药学上可接受的盐或前体药物与其他化学组分的混合物，以及其他组分例如药学上可接受的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
附图说明
图1为本发明化合物在比格犬体内的血钠曲线。
图2为口服化合物5胶囊与托伐普坦片后，比格犬血浆中的PK曲线。
图3为口服化合物5胶囊与托伐普坦片后，比格犬的0-6h尿量。
具体实施方式
以下结合实施例进一步描述本公开，但这些实施例并非限制本公开的范围。
本公开实施例中未注明具体条件的实验方法，通常按照常规条件，或按照原料或商品制造厂商所建议的条件。未注明具体来源的试剂，为市场购买的常规试剂。
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。
NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。
MS的测定用Agilent 1200/1290 DAD-6110/6120 Quadrupole MS液质联用仪(生产商：Agilent，MS型号：6110/6120 Quadrupole MS)，Waters ACQuity UPLC-QD/SQD(生产商：waters，MS型号：waters ACQuity Qda Detector/waters SQ Detector)、THERMO Ultimate 3000-Q Exactive(生产商：THERMO，MS型号：THERMO Q Exactive)。
高效液相色谱法(HPLC)分析使用Agilent HPLC 1200DAD、Agilent HPLC 1200VWD和Waters HPLC e2695-2489高压液相色谱仪。
手性HPLC分析测定使用Agilent 1260 DAD高效液相色谱仪。
高效液相制备色谱法使用Waters 2545-2767、Waters 2767-SQ Detecor2、Shimadzu LC-20AP和Gilson GX-281制备型色谱仪。
手性制备色谱法使用Shimadzu LC-20AP制备型色谱仪。
CombiFlash快速制备色谱仪使用Combiflash Rf200(TELEDYNE ISCO)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
硅胶柱层析色谱法一般使用烟台黄海硅胶200～300目硅胶为载体。
本公开的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG、Acros Organics、Aldrich Chemical Company、韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。
实施例中无特殊说明，反应均能够在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。
氢化反应通常抽真空，充入氢气，反复操作3次。
微波反应使用CEM Discover-S 908860型微波反应器。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，优选为20℃～30℃。
实施例1
(7-氯-1-(2-甲基-4-(2-甲基苯甲酰氨基)苯甲酰基)-2,3,4,5-四氢-苯并[b]氮杂
Figure PCTCN2022075793-appb-000041
-5-氧羰基)-L-谷氨酸二钠盐(化合物1)的制备
Figure PCTCN2022075793-appb-000042
步骤1：化合物1-d的制备
氮气氛下，将市售托伐普坦1-a(300mg，0.67mmol)、化合物1-b(204mg，0.67mmol)和二异丙基乙胺(432mg，3.35mmol)溶N,N-二甲基甲酰胺(10mL)中，室温搅拌3小时。加入化合物1-c(297mg，1.005mmol)，室温搅拌过夜。加水稀释，用乙酸乙酯萃取，浓缩后通过柱层析色谱法分离纯化，得到化合物1-d 494mg，收率：93.92％。
1H NMR(400MHz,DMSO-d 6)δ10.45-10.15(m,1H),7.86-7.65(m,1H),7.60-7.51(m,1H),7.46-7.33(m,3H),7.33-7.24(m,3H),7.18-7.08(m,1H),7.01-6.58(m,2H),5.96-5.60(m,1H),5.00-4.52(m,1H),4.08-3.92(m,1H),2.84-2.72(m,1H), 2.43-2.31(m,6H),2.30-2.21(m,3H),2.21-2.11(m,1H),2.07-1.92(m,1H),1.89-1.67(m,2H),1.59-1.47(m,1H),1.41(s,9H),1.40(s,9H)。
步骤2：化合物1-e的制备
将化合物1-d(394mg，0.88mmol)溶于二氯甲烷(5mL)中，加入三氟乙酸(1mL)，室温搅拌24小时。加入饱和碳酸钠溶液调pH至9～10，用二氯甲烷洗涤。水相用1mol/L盐酸溶液调pH至1～2，用乙酸乙酯萃取，浓缩后用制备HPLC纯化，得化合物1-e 163mg，收率：48.82％。
1H NMR(400MHz,DMSO-d 6)δ12.65(br,2H),10.44-10.10(m,1H),7.99-7.72(m,1H),7.67-7.53(m,1H),7.48-7.35(m,3H),7.33-7.19(m,3H),7.17-7.03(m,1H),7.00-6.60(m,2H),5.87-5.60(m,1H),4.97-4.53(m,1H),4.13-3.98(m,1H),2.85-2.65(m,1H),2.43-2.26(m,8H),2.23-2.10(m,1H),2.10-1.91(m,2H),1.90-1.45(m,3H)。
步骤3：化合物1的制备
将氢氧化钠(12.9mg，0.32mmol)溶于水(15mL)中，冷却至0℃，边搅拌边滴加化合物1-e(100mg，0.16mmol)的乙腈溶液(5mL)，滴完后继续搅拌5分钟。真空冷冻干燥除去溶剂得到化合物1，101mg，收率：94.39％。
1H NMR(400MHz,DMSO-d 6)δ10.45-10.12(m,1H),7.85-7.60(m,1H),7.59-7.15(m,7H),7.15-7.02(m,1H),7.01-6.57(m,2H),5.96-5.57(m,1H),5.00-4.55(m,1H),3.90-3.75(m,1H),2.83-2.70(m,1H),2.43-2.31(m,6H),2.27-2.03(m,3H),2.03-1.83(m,2H),1.83-1.47(m,3H)。
MS:m/z[M+H] +：622.2。
实施例2
7-氯-1-(2-甲基-4-(2-甲基苯甲酰氨基)苯甲酰基)-2,3,4,5-四氢-1H-苯并[b]氮杂
Figure PCTCN2022075793-appb-000043
-5-基甲基((S)-吡咯烷-2-基)甲基)氨基甲酸酯(化合物3)盐酸盐的制备
Figure PCTCN2022075793-appb-000044
步骤1：化合物3-b的制备
称取市售托伐普坦1-a(225mg，0.500mmol)、二(对硝基苯)碳酸酯(175mg，0.580mmol)和二异丙基乙胺(323mg，2.50mmol)于反应瓶中，加入干燥的N,N-二甲基甲酰胺(10mL)。氮气氛下，于室温搅拌3小时。然后，加入(S)-2-((甲基氨基)甲基)吡咯烷-1-羧酸叔丁酯(161mg，0.75mmol)，继续于室温搅拌过夜。加入乙酸乙酯和水稀释反应液，水相用乙酸乙酯萃取，合并有机相，依次用水、饱和氯化钠溶液洗涤，有机相加入无水硫酸钠干燥，过滤，滤液减压浓缩，残余物经反相柱层析色谱法得到化合物3-b，280mg，收率：81％。
1H NMR(400MHz,DMSO-d 6)δ10.23(s,1H),7.81-6.55(m,10H),6.02-5.66(m,1H),4.92-4.52(m,1H),4.23-3.80(m,1H),3.63-3.21(m,1H),3.28-2.71(m,7H),2.36(s,6H),2.25-1.62(m,8H),1.40(s,9H)。
步骤2：化合物3的制备
称取化合物3-b(100mg，0.145mmol)，用氮气置换三次，在冰水浴下加入氯化氢乙酸乙酯溶液(5.0mL，2.0M)，室温搅拌4小时。将反应液减压浓缩，加入乙酸乙酯(4.0mL)，室温搅拌打浆1小时，过滤，并用乙酸乙酯(1mL)洗涤，减压抽干，得到化合物3的盐酸盐，75mg，收率：82％。
1H NMR(400MHz,DMSO-d 6)δ7.82-6.38(m,10H),5.97-5.68(m,1H),4.95-4.48(m,1H),4.08-3.74(m,2H),3.36-2.71(m,7H),2.33(s,6H),2.22-1.46(m,8H)。
实施例3
7-氯-1-(2-甲基-4-(2-甲基苯甲酰氨基)苯甲酰基)-2,3,4,5-四氢-苯并[b]氮杂
Figure PCTCN2022075793-appb-000045
-5-(2-(三甲基铵基)乙基)磷酸酯(化合物4)的制备
Figure PCTCN2022075793-appb-000046
步骤1：化合物4-b的制备
氮气氛下，将市售托伐普坦1-a(224mg，0.5mmol)溶于四氢呋喃(5mL)中，冷却至-60℃。缓慢滴加双(三甲基硅基)胺基锂(1.5mL，1.5mmol，1M在THF中)，滴完后于-60℃搅拌0.5小时。随后滴加化合物4-a(538mg，1.0mmol)的 THF(2mL)溶液，滴完后升至室温反应过夜。用饱和氯化铵溶液淬灭反应，用乙酸乙酯萃取，有机相减压浓缩，残余物通过柱层析色谱法分离纯化，得到化合物4-b，323mg，收率：91.11％。
1H NMR(400MHz,DMSO-d 6)δ10.44-10.14(m,1H),7.81-7.45(m,3H),7.45-7.21(m,15H),7.20-7.00(m,1H),6.87-6.62(m,1H),5.72-5.45(m,1H),5.17-4.96(m,3H),4.94-4.46(m,1H),3.52-3.37(m,1H),2.85-2.69(m,1H),2.45-2.25(m,6H),2.25-2.08(m,1H),1.95-1.45(m,3H)。
步骤2：化合物4-c的制备
将化合物4-b(323mg，0.46mmol)溶于二氯甲烷(3mL)和三氟乙酸(6mL)中，室温搅拌24小时。浓缩后用乙酸乙酯稀释，用1mol/L氢氧化钠溶液调pH至9～10，有机相用水萃取两次。合并水相，用1mol/L HCl溶液调pH至1～2，用乙酸乙酯萃取，有机相减压浓缩，得到化合物4-c，190mg，收率：78.84％。
1H NMR(400MHz,DMSO-d 6)δ10.44-10.18(m,1H),7.80-7.52(m,1H),7.49-7.35(m,3H),7.34-7.24(m,3H),7.22-7.12(m,1H),6.90-6.61(m,2H),5.54-5.25(m,2H),4.94-4.55(m,1H),2.84-2.64(m,1H),2.43-2.19(m,8H),2.04-1.48(m,3H)。
步骤3：化合物4的制备
将化合物4-c(300mg，0.57mmol)、化合物4-d(700mg，2.84mmol)和碳酸钾(391mg，2.84mmol)溶于N,N-二甲基甲酰胺(20mL)中，加热至90℃反应24小时。反应液减压浓缩，残余物用制备HPLC纯化，得到化合物4，154mg，收率：44.25％。
1H NMR(400MHz,DMSO-d 6)δ10.44-10.16(m,1H),7.80-7.49(m,2H),7.49-7.22(m,5H),7.21-7.04(m,1H),6.99-6.89(m,1H),6.85-6.59(m,1H),5.45-5.07(m,1H),4.92-4.50(m,1H),4.17-3.87(m,2H),3.63-3.47(m,2H),3.25-2.87(m,9H),2.79-2.65(m,1H),2.43-2.30(m,6H),2.29-2.17(m,1H),2.05-1.85(m,1H),1.77-1.65(m,1H),1.62-1.44(m,1H)。
MS:m/z[M+H] +：614.2。
实施例4
((7-氯-1-(2-甲基-4-(2-甲基苯甲酰氨基)苯甲酰基)-2,3,4,5-四氢-1H-苯并[b]氮杂
Figure PCTCN2022075793-appb-000047
-5-基)氧基)甲基(2-(三甲基铵基)乙基)磷酸酯(化合物5)的制备
Figure PCTCN2022075793-appb-000048
Figure PCTCN2022075793-appb-000049
称取化合物5-a(参考文献WO2009/1968公开的方法制备)(368mg，0.660mmol)于反应瓶中，依次加入N,N-二甲基甲酰胺(10mL)、碳酸钾(910mg，6.60mmol)和(2-溴乙基)三甲基溴化铵(1.63g，6.60mmol)，加热至65℃，反应16小时。反应液过滤，滤液经制备HPLC纯化，得到化合物5，75mg，收率：17.68％。
1H NMR(400MHz,DMSO-d 6)δ10.41-10.24(m,1H),7.54-6.74(m,10H),5.22-4.94(m,2H),4.86-4.58(m,1H),4.06-3.99(m,2H),3.51-3.44(m,2H),3.13-3.08(m,9H),2.78-2.67(m,1H),2.40-2.34(m,6H),2.23-1.47(m,5H)。
实施例5
((7-氯-1-(2-甲基-4-(2-甲基苯甲酰氨基)苯甲酰基)-2,3,4,5-四氢-1H-苯并[b]氮杂
Figure PCTCN2022075793-appb-000050
-5-基)氧基)甲基L-缬氨酸酯(化合物11)盐酸盐的制备
Figure PCTCN2022075793-appb-000051
步骤1：化合物11-b的制备
称取化合物11-a(200mg，0.393mmol)(参考文献US2011/71084公开的方法制备)、N-Boc-L-缬氨酸(85mg，0.393mmol)、溴化铜(263mg，1.18mmol)、TBAB(380mg，1.18mmol)、分子筛(560mg)，用氮气置换三次，在冰水浴下加入DMF(7.5mL)，室温搅拌10min，撤去冰水浴，室温搅拌过夜。反应液用硅藻土抽滤，并用乙酸乙酯(100mL)洗涤，滤液用水洗(25mL x 3)，饱和食盐水洗(25mL)。将有机相干燥，过滤，减压浓缩，得到650mg粗品，通过硅胶柱层析色谱法分离纯化，得到化合物11-b，270mg，收率：100％。
1H NMR(400MHz,CDCl 3)δ8.07-6.45(m,10H),5.68-5.31(m,2H),5.20-4.65(m,3H),4.32-4.12(m,1H),2.60-2.35(m,6H),2.28-2.11(m,1H),1.86-1.60(m,4H), 1.52-1.19(m,9H),1.05-0.77(m,6H)。
步骤2：化合物11的制备
称取化合物11-b(270mg，0.398mmol)，加入二氯甲烷(24mL)，搅拌溶清，氮气氛下，冰水浴降温至5℃，加入TFA(3.0mL)，加毕，保温搅拌2小时。将反应液减压浓缩，残余物经制备HPLC纯化，得到化合物11，77mg，收率：29％。,
1H NMR(400MHz,DMSO-d 6)δ10.44-10.17(m,1H),8.38(s,3H),7.82-7.19(m,8H),7.19-6.91(m,1H),6.87-6.61(m,1H),5.83-5.43(m,2H),5.38-5.06(m,1H),5.01-4.80(m,1H),4.58(s,1H),4.02(s,1H),2.44-2.28(m,6H),2.26-2.07(m,2H),2.07-1.87(m,1H),1.85-1.66(m,1H),1.65-1.43(m,1H),1.10-0.70(m,6H)。
实施例6
((((7-氯-1-(2-甲基-4-(2-甲基苯甲酰氨基)苯甲酰基)-2,3,4,5-四氢-1H-苯并[b]氮杂
Figure PCTCN2022075793-appb-000052
-5-基)氧基)甲酰氧基)甲基L-缬氨酸酯(化合物16)盐酸盐的制备
Figure PCTCN2022075793-appb-000053
步骤1：化合物16-b的制备
称取化合物16-a(参考文献US2011/71084公开的方法制备)(350mg，0.67mmol)于反应瓶中，加入N,N-二甲基甲酰胺(4mL)，室温下搅拌使溶清。氩气置换三次后，依次加入碘化钠(150mg，1.00mmol)、N-Boc-L-缬氨酸(220mg，1.50mmol)和二异丙基乙基胺(432mg，3.30mmol)。升温至50-55℃，反应16小时。向反应液中加入20mL纯化水，乙酸乙酯萃取(30mL×2)。收集有机相，饱和氯化铵水溶液洗涤，无水硫酸钠干燥，减压浓缩得到粗品化合物16-b，470mg，收率：97.01％。
MS：m/z[M+H] +：722.3。
步骤2：(16)的制备
称取化合物16-b(470mg，0.650mmol)于反应瓶中，加入1,4-二氧六环(8mL)， 降温至0-5℃，加入4mol/L氯化氢的二氧六环溶液(8mL)，室温搅拌1小时。减压浓缩除去溶剂，粗品经制备HPLC纯化得到化合物16的盐酸盐，175mg，收率：41.95％。
1H NMR(400MHz,DMSO-d 6)δ10.43-10.27(m,1H),8.55(s,3H),7.74-6.69(m,10H),6.08-5.80(m,3H),4.86-4.60(m,1H),4.08-4.02(m,1H),2.83-2.67(m,1H),2.39-2.34(m,6H),2.21-1.76(m,5H),1.01-0.88(m,6H)。
实施例7
2-(2-((7-氯-1-(2-甲基-4-(2-甲基苯甲酰氨基)苯甲酰基)-2,3,4,5-四氢-1H-苯并[b]氮杂
Figure PCTCN2022075793-appb-000054
-5-基)氧基甲氧基)-2-氧代乙氧基)乙酸(化合物14)的制备
Figure PCTCN2022075793-appb-000055
称取化合物14-a(250mg，0.491mmol)(参考文献US2011/71084公开的方法制备)、二甘醇酸(99mg，0.737mmol)、溴化铜(329mg，1.47mmol)、TBAB(475mg，1.47mmol)、分子筛(700mg)，用氮气置换三次。在冰水浴下加入DMF(10mL)，保温搅拌10min，撤去冰水浴，室温搅拌2h。反应液用硅藻土抽滤，并用乙酸乙酯(100mL)洗涤，滤液用水洗涤(40mL x 2)，饱和食盐水洗涤(40mL)。有机相干燥，过滤，减压浓缩，得到700mg粗品。制备HPLC纯化，得到化合物14，190mg，收率：65％。
1H NMR(400MHz,DMSO-d 6+D 2O)δ7.77-6.61(m,10H),5.60-4.45(m,4H),4.20-3.95(m,2H),3.92-3.78(m,3H),2.41-2.28(m,6H),2.25-1.35(m,4H)。
实施例8
化合物M的制备
Figure PCTCN2022075793-appb-000056
步骤1：化合物M-1的制备
称取市售托伐普坦1-a(500mg，1.11mmol)溶于二氯甲烷中，加入N-(叔丁氧羰基)-L-缬氨酸(291mg，1.34mmol)、DMAP(13mg，0.11mmol)，冰浴下加入DCC(276mg，1.34mmol)，室温反应过夜。将反应液过滤，滤液减压浓缩，得到浅黄色胶状物890mg(化合物M-1)，不经纯化直接用于下一步反应。
MS：计算值647.3，实测值648.3[M+H]。
步骤2：化合物M的制备
称取化合物M-1(1.11mmol)，用氮气置换三次，在冰水浴下加入氯化氢/二氧六环溶液(5.0mL，4.0M)，室温搅拌2小时。将反应液减压浓缩，得到浅黄色固体，700mg粗品。经反相柱层析色谱法分离纯化，冻干，得到白色固体状的化合物M，450mg，收率：69％。
MS：计算值547.2，实测值548.2[M+H]。
1H NMR(400MHz,CDCl 3)δ8.99-8.41(m,3H),8.11-5.87(m,11H),4.88-.396(m,1H),2.81-0.87(m,20H)。
生物学试验
试验例1：犬体内药代动力学测试
1、犬PK实验
1.1试验方案
1.1.1实验动物：比格犬，
Figure PCTCN2022075793-appb-000057
级别，来源为美迪西普亚储备动物库：999M-004。
1.1.2给药方案：
Figure PCTCN2022075793-appb-000058
*：所有动物给药前禁食过夜(10-18小时)，给药4小时后恢复给食。
1.1.3样品配制方法
准确称取适量托伐普坦和化合物5，加入适宜体积1％羟丙基甲基纤维素，涡旋或超声使充分混匀，得到0.5mg/mL的托伐普坦给药溶液和2.15mg/mL的化合物5给药溶液，用于灌胃给药。
1.1.4试验方法
托伐普坦和化合物5通过灌胃给药，采血点为给药前及给药结束后10min、30min、1h、2h、4h、6h、8h、24h，EDTA-K2抗凝，并加入酯酶抑制剂DDVP(厂家：Sigma)，分离血浆样品，-70℃冻存，LC-MS/MS检测化合物5及托伐普坦水平。
1.2实验结果
表1
Figure PCTCN2022075793-appb-000059
注：T max为药物浓度达峰时间，C max为药物达峰浓度，AUC 0-t和AUC 0-∞为药时曲线下面积，t 1/2是药物在体内的半衰期。
比格犬灌胃给药后，与托伐普坦组相比，化合物5在体内转化为托伐普坦后的暴露量更高，且半衰期更长。
试验例2：本发明化合物对精氨酸加压素受体2(AVPR2)的抑制活性
1、精氨酸加压素受体2(AVPR2)受体cAMP实验
1.1样品制备方法
以实验缓冲液(Hank's平衡盐溶液+20mM HEPES+0.1％BSA+500μM IBMX(厂家：Sigma))稀释待测化合物，待测化合物的试验最高起始浓度为10μM，稀释倍数为5倍。
1.2细胞株
Flpin-CHO-AVPR2(该细胞株由实验机构康龙化成(北京)新药技术有限公司构建；AVPR2为人源)
1.3试验方法
1)将细胞消化，重悬到实验缓冲液中，接种到384孔细胞培养板中，接种密度为每孔8000个细胞，接种体积为每孔15μL。
2)将化合物用实验缓冲液稀释。
3)每孔加入2.5μL的化合物，37℃孵育10分钟。
4)用实验缓冲液稀释精氨酸加压素(厂家：MedChemExpress)至浓度为16pM。
5)加入2.5μL浓度为16pM的精氨酸加压素溶液，37℃孵育30分钟。
6)冻融Eu-cAMP示踪剂和Ulight-抗-cAMP，用裂解缓冲液将其稀释(Eu-cAMP示踪剂、Ulight-抗-cAMP及裂解缓冲液均取用自cAMP检测试剂盒(厂家：Perkin Elmer)。
7)加入10μL Eu-cAMP示踪剂至实验孔，然后加入10μL Ulight-抗-cAMP至实验孔中。
8)将反应板于室温200g离心30s，25℃静置1h后，酶标仪收集数据。
1.4实验结果
表2
Figure PCTCN2022075793-appb-000060
*以下简称化合物1b二钠盐
结果表明，化合物5的AVPR2受体抑制活性明显高于化合物1b二钠盐的活性。
试验例3：大鼠药代动力学测试
1、大鼠PK实验
1.1试验方案
1.1.1实验动物：SD大鼠，雄性及雌性，体重约220g。饲养环境：SPF级。动物转移自实验机构动物储备库(999M-017)，上海市计划生育科学研究所实验动物经营部。
1.1.2给药方案：
Figure PCTCN2022075793-appb-000061
1.1.3样品配制方法
准确称取适量的化合物，加入适宜体积10％DMSO+35％PEG400+55％生理盐水，涡旋或超声使充分混匀，得到澄清的给药溶液，用于静脉注射给药。
1.1.4试验方法
静脉注射给药后于不同时间点取血(给药前及给药后0.0833、0.25、0.5、1、2、4、8、24h)，EDTA-K2抗凝，并加入酯酶抑制剂DDVP，分离血浆样品，-70℃冻存，LC-MS/MS检测化合物及托伐普坦水平。
1.2实验结果
表3
Figure PCTCN2022075793-appb-000062
注：“-”表示未计算。
与化合物M相比，化合物16的盐酸盐在体内转化为托伐普坦的暴露量更高，且转化速度更快。
试验例4：大鼠药代动力学测试
1、大鼠PK实验
1.1试验方案
1.1.1实验动物：SD大鼠，雄性及雌性，体重约180-220g。饲养环境：SPF级。动物转移自实验机构动物储备库(999M-017)，上海市计划生育科学研究所实验动物经营部。
1.1.2给药方案：
Figure PCTCN2022075793-appb-000063
*：所有动物给药前禁食过夜(10-18小时)，给药4小时后恢复给食。
1.1.3样品配制方法
准确称取适量托伐普坦和化合物5，加入适宜体积1％羟丙基甲基纤维素，涡旋或超声使充分混匀，得到0.9mg/mL的托伐普坦给药溶液及1.29mg/mL的化合物5给药溶液，用于灌胃给药。
1.1.4试验方法
托伐普坦和化合物5通过灌胃给药，采血点为给药前及给药结束后10min、0.5h、1h、2h、4h、6h、8h、24h，EDTA-K2抗凝，并加入酯酶抑制剂DDVP，分离血浆样品，-70℃冻存，LC-MS/MS检测化合物5及托伐普坦水平。
1.2实验结果
表4
Figure PCTCN2022075793-appb-000064
相比于托伐普坦，相当摩尔剂量下化合物5转化形成的托伐普坦AUC 0-t更高。
试验例5：比格犬药代动力学测试
1、比格犬PK实验
1.1试验方案
1.1.1实验动物：比格犬，
Figure PCTCN2022075793-appb-000065
级别，来源为美迪西普亚储备动物库：999M-004。
1.1.2给药方案：
Figure PCTCN2022075793-appb-000066
Figure PCTCN2022075793-appb-000067
*：所有动物给药前禁食过夜(10-18小时)，给药4小时后恢复给食。
1.1.3样品配制方法
准确称取适量化合物1b二钠盐、化合物5，加入适宜体积生理盐水，涡旋或超声使充分混匀，得到0.5mg/mL的化合物1b二钠盐、0.25mg/mL的化合物5及1.35mg/mL的化合物5澄清给药溶液，用于静脉滴注给药。
准确称取适量托伐普坦和化合物5，加入适宜体积1％羟丙基甲基纤维素，涡旋或超声使充分混匀，得到5mg/mL的托伐普坦给药溶液及1.35mg/mL的化合物5给药溶液，用于灌胃给药。
1.1.4试验方法
静脉给药组化合物分别通过静脉滴注1h给药，灌胃给药组化合物分别通过灌胃给药。采血点为给药前及给药结束后30min、1h、1.5h、2h、4h、6h、12h、24h。经颈静脉或其它合适方式采血约1mL，EDTA-K2抗凝，并加入酯酶抑制剂DDVP，分离血浆样品，-70℃冻存，LC-MS/MS检测体内相关化合物水平；经颈静脉或其它合适方式采血约0.5mL，置于分离胶采血管(无抗凝剂)离心分离血清(室温3500转/分钟离心10分钟)，离子选择电极法检测血清Na +浓度。
1.2实验结果
表5
Figure PCTCN2022075793-appb-000068
图1为本发明化合物在比格犬体内的血钠曲线。如表5和图1所示，静脉滴 注给药化合物5可在低于化合物1b二钠盐的剂量下(0.5mg/kg vs 1mg/kg)达到相当程度的升血钠作用，表明化合物5原型分子具有活性。相比于灌胃托伐普坦，较低摩尔剂量下的灌胃化合物5转化形成的托伐普坦AUC 0-t更高，且具有升血钠作用。
试验例6：比格犬药代动力学测试
1、比格犬PK实验
1.1试验方案
1.1.1实验动物：比格犬(11±1.5kg)，
Figure PCTCN2022075793-appb-000069
级别，来源为四川格林泰科储备动物库。
1.1.2样品配制
托伐普坦片为市售片剂(商品名：瑞贝坦；生产厂家：江苏恒瑞医药股份有限公司)，化合物5肠溶胶囊通过将适量的化合物5直接灌装至肠溶胶囊得到(肠溶胶囊生产厂家：青岛益青生物科技股份有限公司)。
1.1.3给药方案：
Figure PCTCN2022075793-appb-000070
1.1.4试验方法
雄性比格犬3只/组，托伐普坦片(2片/只)及化合物5肠溶胶囊(2粒/只)分别通过灌胃给药(给药为完整片剂或胶囊)。采血点为给药前及给药开始后30min、1h、、2h、4h、6h、8h、12h、24h。EDTA-K2抗凝，并加入酯酶抑制剂DDVP，分离血浆样品，-70℃冻存，LC-MS/MS检测化合物5及托伐普坦水平，并记录给药0-6h后的尿量情况。
1.2实验结果
表6
Figure PCTCN2022075793-appb-000071
图2和图3分别为口服化合物5肠溶胶囊与托伐普坦片后，比格犬血浆中的PK曲线和0-6h的尿量情况。如表6及图2可知，相比于托伐普坦片剂，相当摩尔 剂量下化合物5肠溶胶囊灌胃给药至比格犬后，体内转化为托伐普坦的AUC 0-t更高且有效浓度维持时间可延长约2h。由图3可知，灌胃给药化合物5肠溶胶囊及托伐普坦片均可显著增加比格犬给药后0-6h尿量。

Claims (24)

  1. 一种式II-1所示的化合物或其药学上可接受的盐，
    Figure PCTCN2022075793-appb-100001
    其中，
    Q为
    Figure PCTCN2022075793-appb-100002
    其中：
    L 1为-(CH 2) m-，所述-(CH 2)-任选被选自O、S、N的杂原子替换；
    L 2为-(CH 2) n-，所述-(CH 2)-任选被选自O、S、N的杂原子替换；
    m选自0、1、2、3、4、5、6；
    n选自1、2、3、4、5、6；
    所述L 2的-(CH 2)-任选被A取代；
    X选自O和S；
    R 1选自C 1-6烷基、C 3-8环烷基、3-12元杂环基；所述C 1-6烷基、C 3-8环烷基、3-12元杂环基任选被基团B取代；
    R 2选自C 1-6烷基、C 3-8环烷基、3-12元杂环基；所述C 1-6烷基、C 3-8环烷基、3-12元杂环基任选被基团B取代；
    R 3选自C 1-6烷基、C 3-8环烷基、3-12元杂环基；所述C 1-6烷基、C 3-8环烷基、3-12元杂环基任选被基团B取代；
    或者，R 1与R 2或R 2与R 3，与其连接的N原子一起形成含有1-3个杂原子的3-12元杂环基；所述3-12元杂环基任选被基团B取代；
    A选自H、-COOH、-NH 2、-OH、卤素、氰基、硝基、氧代、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基、-COR 4、-NHCOR 4、-OCOR 4；所述-NH 2、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基任选被R 4取代；
    R 4选自卤素、-NH 2、-OH、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基；所述C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基任选被选自-COOH、-NH 2、-OH、卤素、氰基、硝基、氧代、C 1-6烷基、C 1-6烷氧基的一个或多个基团取代；
    基团B选自H、-COOH、-NH 2、-OH、卤素、氰基、硝基、氧代。
  2. 根据权利要求1所述的式II-1所示的化合物或其药学上可接受的盐，其中， X为O。
  3. 根据权利要求2所述的式II-1所示的化合物或其药学上可接受的盐，其中，n选自2、3、4、5，优选地，n选自2和3。
  4. 根据权利要求2所述的式II-1所示的化合物或其药学上可接受的盐，其中，m选自0、1、2、3、4、5，优选地，m选自0、1、2、3。
  5. 根据权利要求3或4所述的式II-1所示的化合物或其药学上可接受的盐，其中，A选自H、-COOH、-NH 2、-OH、卤素、氰基、硝基、氧代、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基；所述C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基任选被R 4取代；
    R 4选自卤素、-NH 2、-OH、C 1-6烷基；
    优选地，A选自H、-COOH、-NH 2、-OH、卤素、氰基、硝基。
  6. 根据权利要求5所述的式II-1所示的化合物或其药学上可接受的盐，其中，L 1为-CH 2-O-。
  7. 根据权利要求5所述的式II-1所示的化合物或其药学上可接受的盐，其中，L 1为-(CH 2) m-，m为0。
  8. 根据权利要求6或7所述的式II-1所示的化合物或其药学上可接受的盐，其中，L 2为-(CH 2) 2-。
  9. 根据权利要求8所述的式II-1所示的化合物或其药学上可接受的盐，其中，R 1选自C 1-6烷基，优选C 1-3烷基。
  10. 根据权利要求9所述的式II-1所示的化合物或其药学上可接受的盐，其中，R 2选自C 1-6烷基，优选C 1-3烷基。
  11. 根据权利要求9或10所述的式II-1所示的化合物或其药学上可接受的盐，其中，R 3选自C 1-6烷基，优选C 1-3烷基。
  12. 根据权利要求1所述的式II-1所示的化合物或其药学上可接受的盐，
    其中，
    X为O；
    L 1为-(CH 2) m-，m为0；或L 1为-CH 2-O-；
    L 2为-(CH 2) n-，n选自2和3；
    R 1选自甲基、乙基、正丙基、异丙基；
    R 2选自甲基、乙基、正丙基、异丙基；
    R 3选自甲基、乙基、正丙基、异丙基；
    优选地，R 1选自甲基，R 2选自甲基，R 3选自甲基。
  13. 根据权利要求1-12中任一项所述的式II-1所示的化合物或其药学上可接受的盐，其中所述化合物选自：
    Figure PCTCN2022075793-appb-100003
  14. 一种式VIII-1所示的化合物或其药学上可接受的盐，
    Figure PCTCN2022075793-appb-100004
    其中，
    n选自0、1、2、3和4；
    R 1和R 2各自独立地选自H或A；
    R 3选自mPEG、C 1-6烷基、C 2-6烯基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基；所述C 1-6烷基、C 2-6烯基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基任选被A取代；且当R 3选自甲基时，R 3被A取代；
    A选自-COOH、-NH 2、-OH、卤素、氰基、硝基、氧代、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基、-COR 4、-NHCOR 4、-OCOR 4；所述-NH 2、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基任选被R 4取代；
    R 4选自卤素、-COOH、-NH 2、-OH、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基；所述C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基任选被选自-COOH、-NH 2、-OH、卤素、氰基、硝基、氧代、C 1-6烷基、C 1-6烷氧基的一个或多个基团取代。
  15. 根据权利要求14所述的式VIII-1所示的化合物或其药学上可接受的盐，其中，R 1和R 2各自独立地选自H。
  16. 根据权利要求14所述的式VIII-1所示的化合物或其药学上可接受的盐，
    其中，
    R 3选自mPEG、C 1-6烷基、C 2-6烯基；所述C 1-6烷基、C 2-6烯基任选被A取代；
    A选自-COOH、-NH 2、-OH、卤素、氰基、硝基、氧代、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基、-COR 4、-NHCOR 4、-OCOR 4；所述-NH 2、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基任选被R 4取代；
    R 4选自卤素、-COOH、-NH 2、-OH、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基；所述C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基任选被选自-COOH、-NH 2、-OH、卤素、氰基、硝基、氧代、C 1-6烷基、C 1-6烷氧基的一个或多个基团取代。
  17. 根据权利要求16所述的式VIII-1所示的化合物或其药学上可接受的盐，
    其中，
    R 3选自mPEG、C 1-6烷基；所述C 1-6烷基任选被A取代；
    A选自-COOH、-NH 2、-OH、卤素、氰基、硝基、氧代、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基、-COR 4、-NHCOR 4、-OCOR 4；所述-NH 2、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基任选被R 4取代；
    R 4选自卤素、-COOH、-NH 2、-OH、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基；所述C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基任选被选自-COOH、-NH 2、-OH、卤素、氰基、硝基、氧代、C 1-6烷基、C 1-6烷氧基的一个或多个基团取代。
  18. 根据权利要求14-17中任一项所述的式VIII-1所示的化合物或其药学上可接受的盐，其中，A选自-COOH、-NH 2、-OH、卤素、氰基、硝基、C 1-6烷基、C 1-6烷氧基；所述C 1-6烷基、C 1-6烷氧基任选被R 4取代；
    优选地，A选自-COOH、-NH 2、-OH、C 1-6烷基、C 1-6烷氧基；所述C 1-6烷基、C 1-6烷氧基任选被R 4取代；
    R 4选自卤素、-COOH、-NH 2、-OH、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基；所述C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-12元杂环基任选被选自-COOH、-NH 2、-OH、卤素、氰基、硝基、氧代、C 1-6烷基、C 1-6烷氧基的一个或多个基团取代。
  19. 根据权利要求14所述的式VIII-1所示的化合物或其药学上可接受的盐， 其中，R 4选自卤素、-COOH、-NH 2、-OH、C 1-6烷基、C 1-6烷氧基；所述C 1-6烷基、C 1-6烷氧基任选被选自-COOH、-NH 2、-OH、卤素、氰基、硝基、氧代、C 1-6烷基、C 1-6烷氧基的一个或多个基团取代；
    优选地，R 4选自卤素、-COOH、-NH 2、-OH、C 1-6烷基、C 1-6烷氧基；
    更优选地，R 4选自-COOH、-NH 2、-OH。
  20. 根据权利要求14-19中任一项所述的式VIII-1所示的化合物或其药学上可接受的盐，其中所述化合物选自：
    Figure PCTCN2022075793-appb-100005
  21. 一种根据权利要求1-20中任一项所述的化合物或其药学上可接受的盐的同位素取代物，优选所述同位素取代为氘原子取代。
  22. 一种药物组合物，其包含至少一种根据权利要求1-13中任一项所述的式II-1所示的化合物或其药学上可接受的盐，或者根据权利要求14-20中任一项所述的式VIII-1所示的化合物或其药学上可接受的盐，或者根据权利要求21所述的同位素取代物，以及药学上可接受的赋形剂。
  23. 根据权利要求1-13中任一项所述的式II-1所示的化合物或其药学上可接受的盐，或者根据权利要求14-20中任一项所述的式VIII-1所示的化合物或其药学上可接受的盐，或者根据权利要求21所述的同位素取代物，或者根据权利要求22所述的药物组合物在制备用于预防和/或治疗血管加压素受体相关疾病的药物中的用途。
  24. 根据权利要求1-13中任一项所述的式II-1所示的化合物或其药学上可接受的盐，或者根据权利要求14-20中任一项所述的式VIII-1所示的化合物或其药学上可接受的盐，或者根据权利要求21所述的同位素取代物，或者根据权利要求22所述的药物组合物在制备用于预防和/或治疗高血压、水肿、腹水病、心力衰竭、肾功能障碍、血管加压素分泌异常综合征、肝硬化、低钠血症、低钾血症、糖尿病、循环功能不全、多囊肾疾病、脑梗死、心肌梗死的药物中的用途。
PCT/CN2022/075793 2021-02-10 2022-02-10 苯并氮杂䓬类化合物及其制备方法和医药用途 WO2022171160A1 (zh)

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KR1020237030236A KR20230143165A (ko) 2021-02-10 2022-02-10 벤즈아제핀 화합물, 이의 제조 방법 및 이의 약학적 용도
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