WO2020253882A1 - 作为rock蛋白激酶抑制剂的异喹啉酮的衍生物及其应用 - Google Patents

作为rock蛋白激酶抑制剂的异喹啉酮的衍生物及其应用 Download PDF

Info

Publication number
WO2020253882A1
WO2020253882A1 PCT/CN2020/097503 CN2020097503W WO2020253882A1 WO 2020253882 A1 WO2020253882 A1 WO 2020253882A1 CN 2020097503 W CN2020097503 W CN 2020097503W WO 2020253882 A1 WO2020253882 A1 WO 2020253882A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
pharmaceutically acceptable
isomers
alkyl
acceptable salts
Prior art date
Application number
PCT/CN2020/097503
Other languages
English (en)
French (fr)
Inventor
刘奕志
王延东
吴凌云
尤旭
肖哲明
陈曙辉
Original Assignee
中山大学中山眼科中心
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 中山大学中山眼科中心 filed Critical 中山大学中山眼科中心
Priority to US17/621,502 priority Critical patent/US20230024516A1/en
Priority to CN202080041488.6A priority patent/CN113906017B/zh
Priority to EP20827811.9A priority patent/EP3988544A4/en
Priority to JP2021576289A priority patent/JP7398137B2/ja
Priority to AU2020296050A priority patent/AU2020296050B2/en
Priority to MX2021016068A priority patent/MX2021016068A/es
Priority to KR1020227002287A priority patent/KR20220024868A/ko
Priority to CA3144211A priority patent/CA3144211A1/en
Publication of WO2020253882A1 publication Critical patent/WO2020253882A1/zh
Priority to ZA2022/00834A priority patent/ZA202200834B/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the invention relates to a series of isoquinolinone derivatives as ROCK protein kinase inhibitors, and their application in preparing drugs for ROCK protein kinase inhibitor-related glaucoma or ocular hypertension diseases. Specifically, it relates to a compound represented by formula (I), its isomers or a pharmaceutically acceptable salt thereof.
  • RHO-associated protein kinase which belongs to serine/threonine protein kinase, is the downstream target effector molecule of RHO, and is widely expressed in the human body.
  • RHO-related protein kinase (ROCK) is involved in the regulation of myosin light chain (MLC) and is suitable for the treatment of vasodilation.
  • MLC myosin light chain
  • ROCK kinase can also act on trabecular outflow tract cells, relax trabecular cells, and reduce the resistance of aqueous humor outflow.
  • ROCK kinase inhibitors can also promote the repair of corneal endothelial cells and prevent fibrosis, which has huge application prospects.
  • Isoquinoline sulfonamide compounds are an important type of ROCK kinase inhibitor. Fasudil and K-115 (patent WO2006057397A1) that have been on the market are both isoquinoline sulfonamide compounds. Fasudil is a new type of drug with extensive pharmacological effects. It is a RHO kinase inhibitor. It expands blood vessels by increasing the activity of myosin light chain phosphatase, reduces the tension of endothelial cells, improves the microcirculation of brain tissue, and does not produce And aggravate the theft of the brain, at the same time can antagonize inflammatory factors, protect nerves against apoptosis, and promote nerve regeneration.
  • K-115 The approved and potential applications of K-115 are very wide, including glaucoma, high intraocular pressure, diabetic retinal injury complications, age-related macular degeneration, corneal injury, recovery after cataract and glaucoma surgery, etc., and may be further expanded to Systemic drugs.
  • Patent WO2007026664A1 reports a series of compounds with ROCK kinase inhibitory effect, such as control compound 1 and control compound 2.
  • the series of compounds have good enzyme activity, but they are in terms of membrane permeability, pharmacokinetics, druggability, etc. Room for improvement.
  • the present invention reports a class of similar compounds through structural modification, which significantly improves the properties in this respect.
  • the present invention provides a compound represented by formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof,
  • T 1 is selected from -(CH 2 ) n -;
  • T 2 is selected from -(CH 2 ) m -and -C(R 7 )(R 8 )-;
  • R 1 is selected from C 1-16 alkyl, phenyl, C 3-7 cycloalkyl, 3-8 membered heterocycloalkyl and 5-10 membered heteroaryl, the C 1-16 alkyl, phenyl , C 3-7 cycloalkyl, 3-8 membered heterocycloalkyl and 5-10 membered heteroaryl each independently optionally substituted with one, two or three R a;
  • R 2 and R 3 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and C 1-3 alkyl;
  • R 4 is selected from H, F, Cl, Br, I, OH, NH 2 , CN and a C 1-3 alkyl group optionally substituted with 1, 2 or 3 R b ;
  • R 5 is selected from NR 9 R 10 ;
  • R 6 is selected from H, F, Cl, Br, I, OH, NH 2 , CN and C 1-3 alkyl;
  • R 7 and R 8 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and C 1-3 alkyl optionally substituted with 1, 2 or 3 R c ; or, R 7.
  • R 9 and R 10 are each independently selected from H and C 1-3 alkyl optionally substituted with 1, 2 or 3 R e ;
  • L is selected from single bond, -O- and -NR 11 -;
  • R 11 is from H and C 1-3 alkyl
  • n is selected from 0, 1 and 2;
  • n 0, 1, 2 and 3;
  • R a is selected from F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy Optionally substituted by 1, 2 or 3 R;
  • R b , R c , Rd and R e are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and C 1-3 alkyl;
  • R is selected from F, Cl, Br, I, OH, NH 2 , CN and CH 3 ;
  • the 3-8 membered heterocycloalkyl group and the 5-10 membered heteroaryl group each independently comprise 1, 2, 3 or 4 heteroatoms independently selected from -NH-, -O-, -S- and N or Heteroatom group.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • T 1 is selected from -(CH 2 ) n -;
  • T 2 is selected from -(CH 2 ) m -and -C(R 7 )(R 8 )-;
  • R 1 is selected from C 1-16 alkyl, phenyl, C 3-7 cycloalkyl, 3-8 membered heterocycloalkyl and 5-10 membered heteroaryl, the C 1-16 alkyl, phenyl , C 3-7 cycloalkyl, 3-8 membered heterocycloalkyl and 5-10 membered heteroaryl each independently optionally substituted with one, two or three R a;
  • R 2 and R 3 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and C 1-3 alkyl;
  • R 4 is selected from H, F, Cl, Br, I, OH, NH 2 , CN and a C 1-3 alkyl group optionally substituted with 1, 2 or 3 R b ;
  • R 5 is selected from NR 9 R 10 ;
  • R 6 is selected from F, Cl, Br, I, OH, NH 2 , CN and C 1-3 alkyl;
  • R 7 and R 8 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and C 1-3 alkyl optionally substituted with 1, 2 or 3 R c ; or, R 7.
  • R 9 and R 10 are each independently selected from H and C 1-3 alkyl optionally substituted with 1, 2 or 3 R e ;
  • L is selected from single bond, -O- and -NR 11 -;
  • R 11 is from H and C 1-3 alkyl
  • n is selected from 0, 1 and 2;
  • n 0, 1, 2 and 3;
  • R a is selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkane
  • the oxy group is optionally substituted with 1, 2 or 3 R;
  • R b , R c , Rd and R e are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and C 1-3 alkyl;
  • R is selected from F, Cl, Br, I, OH, NH 2 , CN and CH 3 ;
  • the 3-8 membered heterocycloalkyl group and the 5-10 membered heteroaryl group each independently comprise 1, 2, 3 or 4 heteroatoms independently selected from -NH-, -O-, -S- and N or Heteroatom group.
  • R a is selected from F, Cl, Br, I, OH, NH 2, CN, CH 3, CF 3, CH 2 F, CHF 2, CH 2 CH 3 and OCH 3, the other variables As defined in the present invention.
  • R a is selected from H, F, Cl, Br, I, OH, NH 2, CN, CH 3, CF 3, CH 2 F, CHF 2, CH 2 CH 3 and OCH 3, Other variables are as defined in the present invention.
  • the above-mentioned R 1 is selected from C 1-12 alkyl, phenyl, cyclobutanyl, cyclopentyl, cyclohexane, tetrahydrofuran, tetrahydropyranyl, piperidinyl, Thienyl, furanyl, pyrrolyl and benzofuranyl, the C 1-12 alkyl, phenyl, cyclobutanyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, piperidyl, thienyl, furyl, pyrrolyl, benzofuranyl, and each independently optionally substituted with 1, 2 or 3 R a, the other variables are as defined in the present invention.
  • the aforementioned R 1 is selected from CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 , (CH 2 ) 3 CH 3 , (CH 2 ) 4 CH 3 , (CH 2 ) 5 CH 3 , (CH 2 ) 6 CH 3 , (CH 2 ) 10 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 ,
  • Other variables are as defined in the present invention.
  • the aforementioned R 1 is selected from CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 , (CH 2 ) 3 CH 3 , (CH 2 ) 4 CH 3 , (CH 2 ) 5 CH 3 , (CH 2 ) 6 CH 3 , (CH 2 ) 10 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 ,
  • Other variables are as defined in the present invention.
  • the aforementioned R 1 is selected from CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 , (CH 2 ) 3 CH 3 , (CH 2 ) 4 CH 3 , (CH 2 ) 5 CH 3 , (CH 2 ) 6 CH 3 , (CH 2 ) 10 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 ,
  • Other variables are as defined in the present invention.
  • the aforementioned R 1 is selected from CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 , (CH 2 ) 3 CH 3 , (CH 2 ) 4 CH 3 , (CH 2 ) 5 CH 3 , (CH 2 ) 6 CH 3 , (CH 2 ) 10 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 ,
  • Other variables are as defined in the present invention.
  • the aforementioned R 1 is selected from CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 , (CH 2 ) 3 CH 3 , (CH 2 ) 4 CH 3 , (CH 2 ) 5 CH 3 , (CH 2 ) 6 CH 3 , (CH 2 ) 10 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 ,
  • Other variables are as defined in the present invention.
  • R 2 and R 3 are independently selected from H, F, Cl, Br, I, OH, and NH 2 , and other variables are as defined in the present invention.
  • R 2 and R 3 are independently selected from H, F, Cl, Br, I, OH, and NH 2 , and other variables are as defined in the present invention.
  • R 4 is selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 and CH 2 CH 3 , and other variables are as defined in the present invention.
  • R 9 and R 10 are independently selected from H, CH 3 and CH 2 CH 3 , and other variables are as defined in the present invention.
  • R 5 is selected from NH 2 , NH(CH 3 ) and N(CH 3 ) 2 , and other variables are as defined in the present invention.
  • R 6 is selected from H, F, Cl, Br, I, OH, NH 2 , CN and CH 3 , and other variables are as defined in the present invention.
  • R 6 is selected from F, Cl, Br, I, OH, NH 2 , CN and CH 3 , and other variables are as defined in the present invention.
  • R 7 and R 8 are independently selected from F, Cl, Br, I, OH, NH 2 , CN, and CH 3 , and other variables are as defined in the present invention.
  • R 7 and R 8 are independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and CH 3 , and other variables are as defined in the present invention.
  • R 7 , R 8 and the atoms connected to them together form a cyclopropyl group optionally substituted with 1, 2, or 3 Rd , and other variables are as defined in the present invention.
  • R 7 , R 8 and the atoms connected to them together form a cyclopropyl group, and other variables are as defined in the present invention.
  • the above L is selected from single bond, -O-, -NH- and -N(CH 3 )-, and other variables are as defined in the present invention.
  • the above-mentioned T 2 is selected from -CH 2 -, -(CH 2 ) 2 -and Other variables are as defined in the present invention.
  • Other variables are as defined in the present invention.
  • Other variables are as defined in the present invention.
  • Other variables are as defined in the present invention.
  • the above-mentioned compound, its isomers or pharmaceutically acceptable salts thereof are selected from
  • R 1 , R 4 , R 5 and L are as defined in the present invention.
  • the above-mentioned compound, its isomers or pharmaceutically acceptable salts thereof are selected from
  • R 1 , R 4 and L are as defined in the present invention.
  • the present invention also provides a compound represented by the following formula, an isomer thereof or a pharmaceutically acceptable salt thereof, and the compound is selected from
  • the above-mentioned compound, its isomer or pharmaceutically acceptable salt thereof is selected from
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned compound, its isomers or pharmaceutically acceptable salts thereof as active ingredients and a pharmaceutically acceptable carrier.
  • the above-mentioned compound, its isomer or pharmaceutically acceptable salt or the above-mentioned composition is used in the preparation of ROCK protein kinase inhibitor related drugs.
  • the aforementioned ROCK protein kinase inhibitor-related drugs are drugs for glaucoma or ocular hypertension.
  • pharmaceutically acceptable salt refers to a salt of the compound of the present invention, which is prepared from a compound with specific substituents discovered in the present invention and a relatively non-toxic acid or base.
  • the base addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of base in a pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
  • the acid addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of acid in a pure solution or a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, the organic acid includes such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid; also include salts of amino acids (such as arginine, etc.) , And salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic
  • the pharmaceutically acceptable salt of the present invention can be synthesized from the parent compound containing acid or base by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of appropriate base or acid in water or an organic solvent or a mixture of both.
  • the compounds provided by the present invention also exist in prodrug forms.
  • the prodrugs of the compounds described herein easily undergo chemical changes under physiological conditions to transform into the compounds of the invention.
  • prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in the in vivo environment.
  • Certain compounds of the present invention may exist in unsolvated or solvated forms, including hydrated forms.
  • the solvated form is equivalent to the unsolvated form, and both are included in the scope of the present invention.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers Conformers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomeric enriched mixtures, all of these mixtures belong to Within the scope of the present invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All these isomers and their mixtures are included in the scope of the present invention.
  • enantiomer or “optical isomer” refers to stereoisomers that are mirror images of each other.
  • cis-trans isomer or “geometric isomer” is caused by the inability to rotate freely because of double bonds or single bonds of ring carbon atoms.
  • diastereomer refers to a stereoisomer in which a molecule has two or more chiral centers and the relationship between the molecules is not mirror images.
  • wedge-shaped solid line keys And wedge-shaped dashed key Represents the absolute configuration of a solid center, with a straight solid line key And straight dashed key Indicates the relative configuration of the three-dimensional center, using wavy lines Represents a wedge-shaped solid line key Or wedge-shaped dotted key Or use wavy lines Represents a straight solid line key And straight dashed key
  • the compound of the present invention may be specific.
  • tautomer or “tautomeric form” means that at room temperature, the isomers of different functional groups are in dynamic equilibrium and can be transformed into each other quickly. If tautomers are possible (such as in solution), the chemical equilibrium of tautomers can be reached.
  • proton tautomers also called prototropic tautomers
  • proton migration such as keto-enol isomerization and imine-ene Amine isomerization.
  • Valence isomers include some recombination of bonding electrons to carry out mutual transformation.
  • keto-enol tautomerization is the tautomerism between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms “enriched in one isomer”, “enriched in isomers”, “enriched in one enantiomer” or “enriched in enantiomers” refer to one of the isomers or pairs of
  • the content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or 96% or greater, or 97% or greater, or 98% or greater, or 99% or greater, or 99.5% or greater, or 99.6% or greater, or 99.7% or greater, or 99.8% or greater, or greater than or equal 99.9%.
  • the term “isomer excess” or “enantiomeric excess” refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90%, and the content of the other isomer or enantiomer is 10%, the isomer or enantiomer excess (ee value) is 80% .
  • optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If you want to obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure The desired enantiomer.
  • the molecule when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), it forms a diastereomeric salt with a suitable optically active acid or base, and then passes through a conventional method known in the art The diastereoisomers are resolved, and then the pure enantiomers are recovered.
  • the separation of enantiomers and diastereomers is usually accomplished through the use of chromatography, which employs a chiral stationary phase and is optionally combined with chemical derivatization (for example, the formation of amino groups from amines). Formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
  • deuterated drugs can be formed by replacing hydrogen with heavy hydrogen. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have reduced toxic side effects and increased drug stability. , Enhance the efficacy, extend the biological half-life of drugs and other advantages. All changes in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by substituents, and can include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable of.
  • oxygen it means that two hydrogen atoms are replaced. Oxygen substitution will not occur on aromatic groups.
  • optionally substituted means that it can be substituted or unsubstituted. Unless otherwise specified, the type and number of substituents can be arbitrary on the basis that they can be chemically realized.
  • any variable such as R
  • its definition in each case is independent.
  • the group may optionally be substituted with up to two Rs, and R has independent options in each case.
  • combinations of substituents and/or variants thereof are only permitted if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • substituents When a substituent is vacant, it means that the substituent is absent. For example, when X in AX is vacant, it means that the structure is actually A.
  • substituents do not indicate which atom is connected to the substituted group, such substituents can be bonded via any atom.
  • a pyridyl group can pass through any one of the pyridine ring as a substituent. The carbon atom is attached to the substituted group.
  • the middle linking group L is -MW-, at this time -MW- can be formed by connecting ring A and ring B in the same direction as the reading order from left to right It can also be formed by connecting ring A and ring B in the direction opposite to the reading order from left to right Combinations of the linking groups, substituents, and/or variants thereof are only permitted if such combinations result in stable compounds.
  • C 1-16 alkyl is used to mean a linear or branched saturated hydrocarbon group composed of 1 to 16 carbon atoms.
  • the C 1-16 alkyl group includes C 1-15 , C 1-14 , C 1-12 , C 1-10 , C 1-9 , C 1-8 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 10 , C 8 , C 7 , C 6 and C 5 alkyl, etc.; it can be monovalent (such as methyl Group), divalent (such as methylene) or multivalent (such as methine).
  • C 1-16 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl) , S-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, heptyl, octyl, etc.
  • C 1-12 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 12 carbon atoms.
  • the C 1-12 alkyl group includes C 1-10 , C 1-9 , C 1-8 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 10 , C 8 , C 7 , C 6 and C 5 alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent ( Such as methine).
  • C 1-12 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl) , S-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, heptyl, octyl, etc.
  • C 1-3 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) .
  • Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • C 1-3 alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms attached to the rest of the molecule through an oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups and the like.
  • Examples of C 1-3 alkoxy include but are not limited to methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy) and the like.
  • C 3-7 cycloalkyl means a saturated cyclic hydrocarbon group composed of 3 to 7 carbon atoms, which is a monocyclic ring system, and the C 3-7 cycloalkyl includes C 5 -7 , C 3-4 and C 4-5 cycloalkyl, etc.; it can be monovalent, divalent or multivalent.
  • Examples of C 3-7 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and the like.
  • C 3-5 cycloalkyl means a saturated cyclic hydrocarbon group composed of 3 to 5 carbon atoms, which is a monocyclic ring system, and the C 3-5 cycloalkyl includes C 3 -4 and C 4-5 cycloalkyl, etc.; it can be monovalent, divalent or multivalent.
  • Examples of C 3-5 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and the like.
  • the term "3-8 membered heterocycloalkyl" by itself or in combination with other terms means a saturated cyclic group consisting of 3 to 8 ring atoms, with 1, 2, 3 or 4 ring atoms Are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein nitrogen atoms are optionally quaternized, and nitrogen and sulfur heteroatoms can be optionally oxidized (ie, NO and S(O) p , p Is 1 or 2). It includes monocyclic and bicyclic ring systems, where the bicyclic ring system includes spiro, fused, and bridged rings.
  • a heteroatom may occupy the connection position of the heterocycloalkyl group with the rest of the molecule.
  • the 3-8 membered heterocycloalkyl group includes 3-6 membered, 3-5 membered, 4-6 membered, 5-6 membered, 4-membered, 5-membered and 6-membered heterocycloalkyl group.
  • 3-8 membered heterocycloalkyl examples include, but are not limited to, azetidinyl, oxetanyl, thietane, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- Piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithiazyl, isoxazolidinyl, isothiazolidiny
  • 5-10 membered heteroaryl ring and “5-10 membered heteroaryl group” can be used interchangeably in the present invention.
  • the term “5-10 membered heteroaryl group” means a ring consisting of 5 to 10 A cyclic group composed of atoms with a conjugated ⁇ -electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. It can be a monocyclic, fused bicyclic or fused tricyclic system, where each ring is aromatic.
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (ie NO and S(O) p , p is 1 or 2).
  • the 5-10 membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or a carbon atom.
  • the 5-10 membered heteroaryl groups include 5-8 membered, 5-7 membered, 5-6 membered, 5 membered and 6 membered heteroaryl groups and the like.
  • Examples of the 5-10 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl, etc.) Azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- Oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thi
  • C n-n+m or C n -C n+m includes any specific case of n to n+m carbons, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4, C 5, C 6, C 7, C 8, C 9, C 10, C 11, and C 12, also including any one of n + m to n ranges, for example C 1- 3 comprises a C 1-12 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12, etc.; in the same way, from n to n +m means the number of atoms in the ring is n to n+m, for example, 3-12 membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring , 10-membered ring, 11-member
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (for example, an affinity substitution reaction).
  • representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups, such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters, etc.; acyloxy groups, such as acetoxy, trifluoroacetoxy and the like.
  • protecting group includes but is not limited to "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; Arylmethyloxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-Methoxyphenyl)methyl; silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethyls
  • hydroxy protecting group refers to a protecting group suitable for preventing side reactions of the hydroxyl group.
  • Representative hydroxy protecting groups include but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, such as alkanoyl groups (such as acetyl); arylmethyl groups, such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and so on.
  • alkyl groups such as methyl, ethyl, and tert-butyl
  • acyl groups such as alkanoyl groups (such as acetyl)
  • arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (P
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
  • the solvent used in the present invention is commercially available.
  • the present invention uses the following abbreviations: aq stands for water; HATU stands for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate ; EDCI stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent amount; CDI stands for Carbonyl diimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for ethyl acetate Esters; EtOH stands for ethanol; MeOH stands for methanol; C
  • the compound of the present invention significantly increases the exposure of the active drug, and the peak blood concentration and the action time are significantly improved; the compound of the present invention exhibits a greater amplitude of lowering intraocular pressure and a longer duration of action for lowering intraocular pressure; In the high intraocular pressure model, the compound of the present invention showed a good blood pressure lowering effect under different test doses, and at the same time, it has a certain dose correlation.
  • the blood pressure lowering amplitude and duration of action are better than K-115; At a high dose of 8 mg/mL, the concentration of metabolites was 0.934 ng/mL after 4 hours of administration; the concentration of metabolites was below the detection limit 8 hours after administration, and the system was highly safe.
  • the combined organic phases were washed with saturated brine (100 mL ⁇ 1), dried over anhydrous sodium sulfate, and the filtrate obtained by filtration was concentrated under reduced pressure to obtain a residue.
  • Water (50 mL) was added to the residue, the pH was adjusted to 10 with an aqueous Na 2 CO 3 solution, and the mixture was extracted with ethyl acetate (50 mL ⁇ 1), and the aqueous phase was collected.
  • the pH of the aqueous phase was adjusted to 4 with 1N aqueous hydrochloric acid solution, and extracted with ethyl acetate (50 mL ⁇ 3).
  • the combined organic phase was washed with saturated brine (100 mL ⁇ 1), dried over anhydrous sodium sulfate, filtered, and the obtained filtrate was concentrated under reduced pressure to obtain compound 5g.
  • the formate of compound 7 can be adjusted to pH 8-9 by adding saturated sodium carbonate aqueous solution to the system, and then extracted with ethyl acetate and concentrated to dryness to obtain compound 7.
  • the formate salt of compound 8 can be adjusted to 8-9 by adding saturated sodium carbonate aqueous solution to the system, and then extracted with ethyl acetate and concentrated to dryness to obtain compound 8.
  • the formate of compound 9 can be adjusted by adding saturated sodium carbonate aqueous solution to the system to adjust the pH of the reaction solution to 8-9, then extracted with ethyl acetate and concentrated to dryness to obtain compound 9.
  • the formate of compound 10 can be added to the system by adding saturated sodium carbonate aqueous solution to adjust the pH of the reaction solution to 8-9, and then extracted with ethyl acetate and concentrated to dryness to obtain compound 10.
  • the formate of compound 11 can be adjusted to 8-9 by adding saturated sodium carbonate aqueous solution to the system, and then extracted with ethyl acetate and concentrated to dryness to obtain compound 11.
  • the formate of compound 13 can be adjusted by adding saturated sodium carbonate aqueous solution to the system to adjust the pH of the reaction solution to 8-9, and then extracted with ethyl acetate and concentrated to dryness to obtain compound 13.
  • the formate of compound 14 can be adjusted by adding saturated sodium carbonate aqueous solution to the system to adjust the pH of the reaction solution to 8-9, and then extracted with ethyl acetate and concentrated to dryness to obtain compound 14.
  • the formate of compound 15 can be adjusted by adding saturated sodium carbonate aqueous solution to the system to adjust the pH of the reaction solution to 8-9, and then extracted with ethyl acetate and concentrated to dryness to obtain compound 15.
  • the formate of compound 16 can be adjusted by adding saturated sodium carbonate aqueous solution to the system to adjust the pH of the reaction solution to 8-9, then extracted with ethyl acetate and concentrated to dryness to obtain compound 16.
  • the formate of compound 17 can be adjusted to 8-9 by adding saturated sodium carbonate aqueous solution to the system, and then extracted with ethyl acetate and concentrated to dryness to obtain compound 17.
  • the formate of compound 18 can be adjusted to 8-9 by adding saturated sodium carbonate aqueous solution to the system, and then extracted with ethyl acetate and concentrated to dryness to obtain compound 18.
  • the formate salt of compound 19 can be adjusted to 8-9 by adding saturated sodium carbonate aqueous solution to the system, and then extracted with ethyl acetate and concentrated to dryness to obtain compound 19.
  • the formate of compound 20 can be adjusted by adding saturated sodium carbonate aqueous solution to the system to adjust the pH of the reaction solution to 8-9, and then extracted with ethyl acetate and concentrated to dryness to obtain compound 20.
  • the formate salt of compound 21 can be adjusted to 8-9 by adding saturated sodium carbonate aqueous solution to the system, and then extracted with ethyl acetate and concentrated to dryness to obtain compound 21.
  • the formate of compound 22 can be adjusted to 8-9 by adding saturated sodium carbonate aqueous solution to the system, and then extracted with ethyl acetate and concentrated to dryness to obtain compound 22.
  • the formate of compound 23 can be adjusted to pH 8-9 by adding saturated sodium carbonate aqueous solution to the system, and then extracted with ethyl acetate and concentrated to dryness to obtain compound 23.
  • the formate of compound 24 can be adjusted by adding saturated sodium carbonate aqueous solution to the system to adjust the pH of the reaction solution to 8-9, then extracted with ethyl acetate and concentrated to dryness to obtain compound 24.
  • the formate of compound 25 can be adjusted to pH 8-9 by adding saturated sodium carbonate aqueous solution to the system, and then extracted with ethyl acetate and concentrated to dryness to obtain compound 25.
  • the formate of compound 26 can be adjusted to pH 8-9 by adding saturated sodium carbonate aqueous solution to the system, and then extracted with ethyl acetate and concentrated to dryness to obtain compound 26.
  • the formate of compound 27 can be adjusted to 8-9 by adding saturated sodium carbonate aqueous solution to the system, and then extracted with ethyl acetate and concentrated to dryness to obtain compound 27.
  • the formate salt of compound 28 can be adjusted to 8-9 by adding saturated sodium carbonate aqueous solution to the system, and then extracted with ethyl acetate and concentrated to dryness to obtain compound 28.
  • the formate salt of compound 29 can be adjusted to 8-9 by adding saturated sodium carbonate aqueous solution to the system, and then extracted with ethyl acetate and concentrated to dryness to obtain compound 29.
  • the formate of compound 30 can be adjusted by adding saturated sodium carbonate aqueous solution to the system to adjust the pH of the reaction solution to 8-9, and then extracted with ethyl acetate and concentrated to dryness to obtain compound 30.
  • Trifluoroacetic acid (1.0 mL) was added to the microwave tube, compound 31a (79 mg, 143 ⁇ mol) was added to the microwave tube, and microwaved at 60 degrees Celsius for 1 hour. The solvent was removed by concentration under reduced pressure, and the crude product was purified by high performance liquid chromatography (acidic, formic acid system) to obtain the formate of compound 31.
  • the formate of compound 31 can be adjusted to 8-9 by adding saturated sodium carbonate aqueous solution to the system, and then extracted with ethyl acetate and concentrated to dryness to obtain compound 31.
  • the formate of compound 32 can be adjusted to pH 8-9 by adding saturated sodium carbonate aqueous solution to the system, and then extracted with ethyl acetate and concentrated to dryness to obtain compound 32.
  • the formate of compound 33 can be adjusted to 8-9 by adding saturated sodium carbonate aqueous solution to the system, and then extracted with ethyl acetate and concentrated to dryness to obtain compound 33.
  • the formate of compound 34 can be adjusted by adding saturated sodium carbonate aqueous solution to the system to adjust the pH of the reaction solution to 8-9, and then extracted with ethyl acetate and concentrated to dryness to obtain compound 34.
  • the formate of compound 35 can be adjusted by adding saturated sodium carbonate aqueous solution to the system to adjust the pH of the reaction solution to 8-9, and then extracted with ethyl acetate and concentrated to dryness to obtain compound 35.
  • the formate of compound 36 can be adjusted by adding saturated sodium carbonate aqueous solution to the system to adjust the pH of the reaction solution to 8-9, and then extracted with ethyl acetate and concentrated to dryness to obtain compound 36.
  • the formate of compound 37 can be adjusted by adding saturated sodium carbonate aqueous solution to the system to adjust the pH of the reaction solution to 8-9, then extracted with ethyl acetate and concentrated to dryness to obtain compound 37.
  • the formate salt of compound 38 can be adjusted to 8-9 by adding saturated sodium carbonate aqueous solution to the system, and then extracted with ethyl acetate and concentrated to dryness to obtain compound 38.
  • the formate of compound 39 can be adjusted to pH 8-9 by adding saturated sodium carbonate aqueous solution to the system, and then extracted with ethyl acetate and concentrated to dryness to obtain compound 39.
  • the formate of compound 40 can be adjusted by adding saturated sodium carbonate aqueous solution to the system to adjust the pH of the reaction solution to 8-9, and then extracted with ethyl acetate and concentrated to dryness to obtain compound 40.
  • the formate of compound 41 can be adjusted by adding saturated sodium carbonate aqueous solution to the system to adjust the pH of the reaction solution to 8-9, and then extracted with ethyl acetate and concentrated to dryness to obtain compound 41.
  • the formate of compound 42 can be adjusted to pH 8-9 by adding saturated sodium carbonate aqueous solution to the system, and then extracted with ethyl acetate and concentrated to dryness to obtain compound 42.
  • the formate of compound 43 can be adjusted by adding saturated sodium carbonate aqueous solution to the system to adjust the pH of the reaction solution to 8-9, and then extracted with ethyl acetate and concentrated to dryness to obtain compound 43.
  • the formate of compound 44 can be adjusted by adding saturated sodium carbonate aqueous solution to the system to adjust the pH of the reaction solution to 8-9, and then extracted with ethyl acetate and concentrated to dryness to obtain compound 44.
  • the formate of compound 45 can be adjusted by adding saturated sodium carbonate aqueous solution to the system to adjust the pH of the reaction solution to 8-9, then extracted with ethyl acetate and concentrated to dryness to obtain compound 45.
  • the formate of compound 46 can be adjusted to pH 8-9 by adding saturated sodium carbonate aqueous solution to the system, and then extracted with ethyl acetate and concentrated to dryness to obtain compound 46.
  • the formate of compound 47 can be adjusted to 8-9 by adding saturated sodium carbonate aqueous solution to the system, and then extracted with ethyl acetate and concentrated to dryness to obtain compound 47.
  • the formate of compound 48 can be adjusted by adding saturated sodium carbonate aqueous solution to the system to adjust the pH of the reaction solution to 8-9, and then extracted with ethyl acetate and concentrated to dryness to obtain compound 48.
  • the formate of compound 49 can be adjusted to pH 8-9 by adding saturated sodium carbonate aqueous solution to the system, and then extracted with ethyl acetate and concentrated to dryness to obtain compound 49.
  • the formate of compound 50 can be adjusted by adding saturated sodium carbonate aqueous solution to the system to adjust the pH of the reaction solution to 8-9, and then extracted with ethyl acetate and concentrated to dryness to obtain compound 50.
  • the formate of compound 51 can be adjusted to pH 8-9 by adding saturated sodium carbonate aqueous solution to the system, and then extracted with ethyl acetate and concentrated to dryness to obtain compound 51.
  • the formate of compound 52 can be added to the system by adding saturated sodium carbonate aqueous solution to adjust the pH of the reaction solution to 8-9, and then extracted with ethyl acetate and concentrated to dryness to obtain compound 52.
  • the formate salt of compound 53 can be adjusted to 8-9 by adding saturated sodium carbonate aqueous solution to the system, and then extracted with ethyl acetate and concentrated to dryness to obtain compound 53.
  • the formate of compound 54 can be adjusted by adding saturated sodium carbonate aqueous solution to the system to adjust the pH of the reaction solution to 8-9, and then extracted with ethyl acetate and concentrated to dryness to obtain compound 54.
  • the hydrochloride salt of compound 56 can be adjusted to 8-9 by adding saturated sodium carbonate aqueous solution to the system, and then extracted with ethyl acetate and concentrated to dryness to obtain compound 56.
  • the formate of compound 57 can be adjusted by adding saturated sodium carbonate aqueous solution to the system to adjust the pH of the reaction solution to 8-9, then extracted with ethyl acetate and concentrated to dryness to obtain compound 57.
  • the formate of compound 59 can be adjusted to pH 8-9 by adding saturated sodium carbonate aqueous solution to the system, and then extracted with ethyl acetate and concentrated to dryness to obtain compound 59.
  • the formate of compound 61 can be adjusted to pH 8-9 by adding saturated sodium carbonate aqueous solution to the system, and then extracted with ethyl acetate and concentrated to dryness to obtain compound 61.
  • the formate of compound 62 can be adjusted by adding saturated sodium carbonate aqueous solution to the system to adjust the pH of the reaction solution to 8-9, then extracted with ethyl acetate and concentrated to dryness to obtain compound 62.
  • control compound 1 can be adjusted to 8-9 by adding saturated sodium carbonate aqueous solution to the system, and then extracted with ethyl acetate and concentrated to dryness to obtain control compound 1.
  • the compound is a prodrug molecule containing an ester functional group, which can be hydrolyzed into an active drug molecule (parent drug) by the action of abundant ester hydrolase in the eye tissue during eye drops administration.
  • This experiment detects the speed of the compound producing active pharmaceutical ingredients in the body and the exposure of active pharmaceutical ingredients.
  • the solvent used was 1.2% hydroxypropyl methylcellulose E5/20.5% poloxamer P407/1.6% poloxamer P188.
  • the dosage of eye drops is 0.5 mg/eye, and both eyes are administered with eye drops.
  • Aqueous humor was collected 0.25h, 0.5h, 2h, 4h, 8h, 24h after administration, and aqueous humor samples were prepared. All samples used liquid chromatography coupled with mass spectrometry to quantitatively detect the content of the administered compound in the aqueous humor of experimental animals.
  • the measured concentration value used WinNonlin non-compartmental model to calculate the half-life based on the aqueous humor concentration-time data. Peak concentration of water medicine, peak time of aqueous medicine, unit exposure and other parameters.
  • test compound prodrug molecule
  • active metabolite parent drug molecule
  • the compound of the present invention is compared with the control compound 1 and the control compound. 2.
  • the exposure of active drugs is significantly increased, and at the same time, the peak blood concentration and action time are significantly increased.
  • Rabbits with normal intraocular pressure were used to screen the potential compounds for lowering intraocular pressure through eye drops.
  • the compound of the present invention exhibits a greater amplitude of lowering intraocular pressure and a longer duration of lowering intraocular pressure.
  • compound 60 at the concentration of 2.5, 5, and 10 mg/mL the intraocular pressure of the animals dropped extremely significantly.
  • Example 3 Test of lowering intraocular pressure in New Zealand rabbits with acute ocular hypertension
  • the anterior chamber injection of viscoelastics was used to induce acute ocular hypertension in rabbits, and the intraocular pressure-lowering effects of compound 60 and compound 63 at different concentrations were investigated through eye drops.
  • the animals in each group were injected with medical sodium hyaluronate gel once in the anterior chamber of the right eye, 100 ⁇ L/eye, to induce the animals to produce high intraocular pressure. 5-15 minutes, 3 and 6 hours after the right eye was modeled, both eyes were given the vehicle, K-115 or the test product (compound 60 at different concentrations), the volume of administration was 50 ⁇ L/eye, before administration, The animal's intraocular pressure was measured 1, 2, 4, 6, 8 and 10 hours after the drug.
  • Table 3 The experimental results are shown in Table 3:
  • the compound of the present invention showed a good blood pressure lowering effect at different test doses, and at the same time, it has a certain dose correlation.
  • the blood pressure reduction amplitude and duration of action are better than K-115.
  • a single administration of compound 63 showed better efficacy (highest antihypertensive effect and duration of action) at all tested doses (0.5-8.0 mg/mL), which was significantly better than K-115.
  • compound 63 can sustain a significant antihypertensive effect at a dose of 0.5 mg/mL, and is still significantly better than K-115 in the evaluation of the peak (Cmax) antihypertensive effect.
  • Evaluation of eye irritation response add the maximum scores of cornea, iris, conjunctiva, edema and secretions to obtain the total score of eye irritation symptoms for each animal eye at each time point.
  • scores of eye irritation symptoms calculate the mean value of points for each observation time point and each group of animals, and determine the degree of eye irritation at each time point and each group of animals according to the following table.
  • Fluorescein sodium check After each eye irritation test, use a hand-held slit lamp to perform a fluorescein sodium check.
  • the scoring standards are as follows:
  • the total score of eye irritation response in each group at each time point is less than 3, and the standard classification is non-irritating.
  • the fluorescein sodium examination scores of the eyes treated with normal saline, vehicle, K-115 and compound 63 of each group of animals were all lower than 1.
  • staining with a corneal fluorescence staining score of 1 appeared at each treatment and individual time point, which was considered as physiological staining.
  • K-115 was instilled in eyes at a concentration of 4 mg/mL for 14 consecutive days, 50 ⁇ l/eye/day, without irritation.
  • Compound 63 was instilled in the eye at a concentration range of 0.25-4 mg/mL for 14 consecutive days, 50 ⁇ l/eye/day, without irritation.
  • BQL means lower than the detection limit.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Ophthalmology & Optometry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

本发明公开了一系列作为ROCK蛋白激酶抑制剂的异喹啉酮衍生物，及其在制备ROCK蛋白激酶抑制剂相关青光眼或高眼压症疾病的药物中的应用。具体公开了式(I)所示化合物、其异构体或其药学上可接受的盐。

Description

作为ROCK蛋白激酶抑制剂的异喹啉酮的衍生物及其应用
本申请主张如下优先权
CN201910544202.5，申请日2019-06-21；
CN201911078066.1，申请日2019-11-06。
技术领域
本发明涉及一系列作为ROCK蛋白激酶抑制剂的异喹啉酮衍生物，及其在制备ROCK蛋白激酶抑制剂相关青光眼或高眼压症疾病的药物中的应用。具体涉及式(I)所示化合物、其异构体或其药学上可接受的盐。
背景技术
RHO相关蛋白激酶(Rho associated kinase，简称ROCK)，属于丝氨酸/苏氨酸蛋白激酶，是RHO的下游靶效应分子，在人体内广泛表达。RHO相关蛋白激酶(ROCK)参与肌球蛋白轻链(MLC)的调节，适用于血管舒张的治疗，ROCK激酶还可以作用于小梁流出道细胞，舒张小梁细胞，降低房水外流阻力。最新的研究显示ROCK激酶抑制剂还可以促进角膜内皮细胞的损伤修复,防止纤维化，有巨大的应用前景。
异喹啉磺酰胺类化合物是一类重要的ROCK激酶抑制剂，目前已经上市的法舒地尔和K-115(专利WO2006057397A1)均是异喹啉磺酰胺类化合物。其中法舒地尔是一种具有广泛药理作用的新型药物，为RHO激酶抑制物，通过增加肌球蛋白轻链磷酸酶的活性扩张血管，降低内皮细胞的张力，改善脑组织微循环，不产生和加重脑的盗血，同时可拮抗炎性因子，保护神经抗凋亡，促进神经再生。而K-115的获批的和潜在的应用非常广泛，包括青光眼，高眼压，糖尿病视网膜损伤并发症，老年黄斑变性，角膜损伤，白内障和青光眼手术后的恢复等等，同时可能进一步拓展至系统性药物。
专利WO2007026664A1报道了一系列具有ROCK激酶抑制作用的化合物，比如对照化合物1和对照化合物2，该系列化合物具有较好的酶活性，但是它们在透膜性、药代动力学、成药性的等方面有待改进。本发明报道了一类通过结构修饰的类似化合物，显著地改善了这方面的性质。
Figure PCTCN2020097503-appb-000001
发明内容
本发明提供了式(I)所示化合物、其异构体或其药学上可接受的盐，
Figure PCTCN2020097503-appb-000002
其中，
T 1选自-(CH 2) n-；
T 2选自-(CH 2) m-和-C(R 7)(R 8)-；
R 1选自C 1-16烷基、苯基、C 3-7环烷基、3-8元杂环烷基和5-10元杂芳基，所述C 1-16烷基、苯基、C 3-7环烷基、3-8元杂环烷基和5-10元杂芳基分别独立地任选被1、2或3个R a取代；
R 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和C 1-3烷基；
R 4选自H、F、Cl、Br、I、OH、NH 2、CN和任选被1、2或3个R b取代C 1-3烷基；
R 5选自NR 9R 10；
R 6选自H、F、Cl、Br、I、OH、NH 2、CN和C 1-3烷基；
R 7和R 8分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和任选被1、2或3个R c取代的C 1-3烷基；或者，R 7、R 8和与它们相连的原子共同构成任选被1、2或3个R d取代的C 3-5环烷基；
R 9和R 10分别独立地选自H和任选被1、2或3个R e取代C 1-3烷基；
L选自单键、-O-和-NR 11-；
R 11自H和C 1-3烷基；
n选自0、1和2；
m选自0、1、2和3；
R a选自F、Cl、Br、I、OH、NH 2、CN、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个R取代；
R b、R c、R d和R e分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和C 1-3烷基；
R选自F、Cl、Br、I、OH、NH 2、CN和CH 3；
所述3-8元杂环烷基和5-10元杂芳基分别独立地包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。
本发明提供了式(I)所示化合物或其药学上可接受的盐，
Figure PCTCN2020097503-appb-000003
其中，
T 1选自-(CH 2) n-；
T 2选自-(CH 2) m-和-C(R 7)(R 8)-；
R 1选自C 1-16烷基、苯基、C 3-7环烷基、3-8元杂环烷基和5-10元杂芳基，所述C 1-16烷基、苯基、C 3-7环烷基、3-8元杂环烷基和5-10元杂芳基分别独立地任选被1、2或3个R a取代；
R 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和C 1-3烷基；
R 4选自H、F、Cl、Br、I、OH、NH 2、CN和任选被1、2或3个R b取代C 1-3烷基；
R 5选自NR 9R 10；
R 6选自F、Cl、Br、I、OH、NH 2、CN和C 1-3烷基；
R 7和R 8分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和任选被1、2或3个R c取代的C 1-3烷基；或者，R 7、R 8和与它们相连的原子共同构成任选被1、2或3个R d取代的C 3-5环烷基；
R 9和R 10分别独立地选自H和任选被1、2或3个R e取代C 1-3烷基；
L选自单键、-O-和-NR 11-；
R 11自H和C 1-3烷基；
n选自0、1和2；
m选自0、1、2和3；
R a选自H、F、Cl、Br、I、OH、NH 2、CN、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个R取代；
R b、R c、R d和R e分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和C 1-3烷基；
R选自F、Cl、Br、I、OH、NH 2、CN和CH 3；
所述3-8元杂环烷基和5-10元杂芳基分别独立地包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。
本发明的一些方案中，上述R a选自F、Cl、Br、I、OH、NH 2、CN、CH 3、CF 3、CH 2F、CHF 2、CH 2CH 3和OCH 3，其他变量如本发明所定义。
本发明的一些方案中，上述R a选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3、CF 3、CH 2F、CHF 2、CH 2CH 3和OCH 3，其他变量如本发明所定义。
本发明的一些方案中，上述R 1选自C 1-12烷基、苯基、环丁烷基、环戊烷基、环己烷基、四氢呋喃基、四氢吡喃基、哌啶基、噻吩基、呋喃基、吡咯基和苯并呋喃基，所述C 1-12烷基、苯基、环丁烷基、环戊烷基、环己烷基、四氢呋喃基、四氢吡喃基、哌啶基、噻吩基、呋喃基、吡咯基、和苯并呋喃基分别独立地任选被1、2或3个R a取代，其他变量如本发明所定义。
本发明的一些方案中，上述R 1选自CH 3、CH 2CH 3、(CH 2) 2CH 3、(CH 2) 3CH 3、(CH 2) 4CH 3、(CH 2) 5CH 3、(CH 2) 6CH 3、(CH 2) 10CH 3、CH(CH 3) 2、C(CH 3) 3、
Figure PCTCN2020097503-appb-000004
Figure PCTCN2020097503-appb-000005
Figure PCTCN2020097503-appb-000006
其他变量如本发明所定义。
本发明的一些方案中，上述R 1选自CH 3、CH 2CH 3、(CH 2) 2CH 3、(CH 2) 3CH 3、(CH 2) 4CH 3、(CH 2) 5CH 3、(CH 2) 6CH 3、(CH 2) 10CH 3、CH(CH 3) 2、C(CH 3) 3、
Figure PCTCN2020097503-appb-000007
Figure PCTCN2020097503-appb-000008
Figure PCTCN2020097503-appb-000009
其他变量如本发明所定义。
本发明的一些方案中，上述R 1选自CH 3、CH 2CH 3、(CH 2) 2CH 3、(CH 2) 3CH 3、(CH 2) 4CH 3、(CH 2) 5CH 3、(CH 2) 6CH 3、(CH 2) 10CH 3、CH(CH 3) 2、C(CH 3) 3、
Figure PCTCN2020097503-appb-000010
Figure PCTCN2020097503-appb-000011
其他变量如本发明所定义。
本发明的一些方案中，上述R 1选自CH 3、CH 2CH 3、(CH 2) 2CH 3、(CH 2) 3CH 3、(CH 2) 4CH 3、(CH 2) 5CH 3、(CH 2) 6CH 3、(CH 2) 10CH 3、CH(CH 3) 2、C(CH 3) 3、
Figure PCTCN2020097503-appb-000012
Figure PCTCN2020097503-appb-000013
其他变量如本发明所定义。
本发明的一些方案中，上述R 1选自CH 3、CH 2CH 3、(CH 2) 2CH 3、(CH 2) 3CH 3、(CH 2) 4CH 3、(CH 2) 5CH 3、(CH 2) 6CH 3、(CH 2) 10CH 3、CH(CH 3) 2、C(CH 3) 3、
Figure PCTCN2020097503-appb-000014
Figure PCTCN2020097503-appb-000015
其他变量如本发明所定义。
本发明的一些方案中，上述R 2和R 3分别独立地选自H、F、Cl、Br、I、OH和NH 2，其他变量如本发明所定义。
本发明的一些方案中，上述R 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2，其他变量如本发明所定义。
本发明的一些方案中，上述R 4选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3和CH 2CH 3，其他变量如本发明所定义。
本发明的一些方案中，上述R 9和R 10分别独立地选自H、CH 3和CH 2CH 3，其他变量如本发明所定义。
本发明的一些方案中，上述R 5选自NH 2、NH(CH 3)和N(CH 3) 2，其他变量如本发明所定义。
本发明的一些方案中，上述R 6选自H、F、Cl、Br、I、OH、NH 2、CN和CH 3，其他变量如本发明所定义。
本发明的一些方案中，上述R 6选自F、Cl、Br、I、OH、NH 2、CN和CH 3，其他变量如本发明所定义。
本发明的一些方案中，上述R 7和R 8分别独立地选自F、Cl、Br、I、OH、NH 2、CN和CH 3，其他变量如本发明所定义。
本发明的一些方案中，上述R 7和R 8分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和CH 3，其他变量如本发明所定义。
本发明的一些方案中，上述R 7、R 8和与它们相连的原子共同构成任选被1、2或3个R d取代的环丙烷基，其他变量如本发明所定义。
本发明的一些方案中，上述R 7、R 8和与它们相连的原子共同构成环丙烷基，其他变量如本发明所定义。
本发明的一些方案中，上述L选自单键、-O-、-NH-和-N(CH 3)-，其他变量如本发明所定义。
本发明的一些方案中，上述T 2选自-CH 2-、-(CH 2) 2-和
Figure PCTCN2020097503-appb-000016
其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2020097503-appb-000017
选自
Figure PCTCN2020097503-appb-000018
Figure PCTCN2020097503-appb-000019
其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2020097503-appb-000020
选自
Figure PCTCN2020097503-appb-000021
Figure PCTCN2020097503-appb-000022
其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2020097503-appb-000023
选自CH 3、CH 2CH 3、(CH 2) 2CH 3、(CH 2) 3CH 3、(CH 2) 4CH 3、(CH 2) 5CH 3、(CH 2) 6CH 3、(CH 2) 10CH 3、CH(CH 3) 2、C(CH 3) 3、OCH 3、OCH 2CH 3、O(CH 2) 2CH 3、O(CH 2) 3CH 3、O(CH 2) 4CH 3、O(CH 2) 5CH 3、O(CH 2) 6CH 3、OCH(CH 3) 2、OC(CH 3) 3、N(CH 3) 2、
Figure PCTCN2020097503-appb-000024
Figure PCTCN2020097503-appb-000025
Figure PCTCN2020097503-appb-000026
其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2020097503-appb-000027
选自CH 3、CH 2CH 3、(CH 2) 2CH 3、(CH 2) 3CH 3、(CH 2) 4CH 3、(CH 2) 5CH 3、(CH 2) 6CH 3、(CH 2) 10CH 3、CH(CH 3) 2、C(CH 3) 3、OCH 3、OCH 2CH 3、O(CH 2) 2CH 3、O(CH 2) 3CH 3、 O(CH 2) 4CH 3、O(CH 2) 5CH 3、O(CH 2) 6CH 3、OCH(CH 3) 2、OC(CH 3) 3、N(CH 3) 2、
Figure PCTCN2020097503-appb-000028
Figure PCTCN2020097503-appb-000029
Figure PCTCN2020097503-appb-000030
其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2020097503-appb-000031
选自CH 3、CH 2CH 3、(CH 2) 2CH 3、(CH 2) 3CH 3、(CH 2) 4CH 3、(CH 2) 5CH 3、(CH 2) 6CH 3、(CH 2) 10CH 3、CH(CH 3) 2、C(CH 3) 3、OCH 3、OCH 2CH 3、O(CH 2) 2CH 3、O(CH 2) 3CH 3、O(CH 2) 4CH 3、O(CH 2) 5CH 3、O(CH 2) 6CH 3、OCH(CH 3) 2、OC(CH 3) 3、N(CH 3) 2、
Figure PCTCN2020097503-appb-000032
Figure PCTCN2020097503-appb-000033
Figure PCTCN2020097503-appb-000034
其他变量如本发明所定义。
本发明还有一些方案是由上述各变量任意组合而来。
本发明的一些方案中，上述化合物、其异构体或其药学上可接受的盐，其选自
Figure PCTCN2020097503-appb-000035
其中，
R 1、R 4、R 5和L如本发明所定义。
本发明的一些方案中，上述化合物、其异构体或其药学上可接受的盐，其选自
Figure PCTCN2020097503-appb-000036
其中，
R 1、R 4和L如本发明所定义。
本发明还提供了下式所示化合物、其异构体或其药学上可接受的盐，所述化合物选自
Figure PCTCN2020097503-appb-000037
Figure PCTCN2020097503-appb-000038
Figure PCTCN2020097503-appb-000039
Figure PCTCN2020097503-appb-000040
本发明的一些方案中，上述的化合物、其异构体或其药学上可接受的盐，其选自
Figure PCTCN2020097503-appb-000041
Figure PCTCN2020097503-appb-000042
Figure PCTCN2020097503-appb-000043
Figure PCTCN2020097503-appb-000044
Figure PCTCN2020097503-appb-000045
本发明还提供了一种药物组合物，包括治疗有效量的根据上述的化合物、其异构体或其药学上可接受的盐作为活性成分以及药学上可接受的载体。
本发明的一些方案中，上述化合物、其异构体或其药学上可接受的盐或者上述的组合物在制备ROCK蛋白激酶抑制剂相关药物上的应用。
本发明的一些方案中，上述的ROCK蛋白激酶抑制剂相关药物是用于青光眼或高眼压症的药物。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发 明的范围之内。
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。
除非另有说明，“(D)”或者“(+)”表示右旋，“(L)”或者“(-)”表示左旋，“(DL)”或者“(±)”表示外消旋。
除非另有说明，用楔形实线键
Figure PCTCN2020097503-appb-000046
和楔形虚线键
Figure PCTCN2020097503-appb-000047
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2020097503-appb-000048
和直形虚线键
Figure PCTCN2020097503-appb-000049
表示立体中心的相对构型，用波浪线
Figure PCTCN2020097503-appb-000050
表示楔形实线键
Figure PCTCN2020097503-appb-000051
或楔形虚线键
Figure PCTCN2020097503-appb-000052
或用波浪线
Figure PCTCN2020097503-appb-000053
表示直形实线键
Figure PCTCN2020097503-appb-000054
和直形虚线键
Figure PCTCN2020097503-appb-000055
本发明的化合物可以存在特定的。除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。
可以通过的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)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，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)。本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，
Figure PCTCN2020097503-appb-000056
中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成
Figure PCTCN2020097503-appb-000057
也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成
Figure PCTCN2020097503-appb-000058
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
除非另有规定，术语“C 1-16烷基”用于表示直链或支链的由1至16个碳原子组成的饱和碳氢基团。所述C 1-16烷基包括C 1-15、C 1-14、C 1-12、C 1-10、C 1-9、C 1-8、C 1-6、C 1-5、C 1-4、C 1-3、C 1-2、C 2-6、C 2-4、C 10、C 8、 C 7、C 6和C 5烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1-16烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)、丁基(包括n-丁基，异丁基，s-丁基和t-丁基)、戊基(包括n-戊基，异戊基和新戊基)、己基、庚基、辛基等。
除非另有规定，术语“C 1-12烷基”用于表示直链或支链的由1至12个碳原子组成的饱和碳氢基团。所述C 1-12烷基包括C 1-10、C 1-9、C 1-8、C 1-6、C 1-5、C 1-4、C 1-3、C 1-2、C 2-6、C 2-4、C 10、C 8、C 7、C 6和C 5烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1-12烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)、丁基(包括n-丁基，异丁基，s-丁基和t-丁基)、戊基(包括n-戊基，异戊基和新戊基)、己基、庚基、辛基等。除非另有规定，术语“C 1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C 1-3烷基包括C 1-2和C 2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1-3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。
除非另有规定，术语“C 1-3烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C 1-3烷氧基包括C 1-2、C 2-3、C 3和C 2烷氧基等。C 1-3烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。
除非另有规定，“C 3-7环烷基”表示由3至7个碳原子组成的饱和环状碳氢基团，其为单环体系，所述C 3-7环烷基包括C 5-7、C 3-4和C 4-5环烷基等；其可以是一价、二价或者多价。C 3-7环烷基的实例包括，但不限于，环丙基、环丁基、环戊基等。
除非另有规定，“C 3-5环烷基”表示由3至5个碳原子组成的饱和环状碳氢基团，其为单环体系，所述C 3-5环烷基包括C 3-4和C 4-5环烷基等；其可以是一价、二价或者多价。C 3-5环烷基的实例包括，但不限于，环丙基、环丁基、环戊基等。
除非另有规定，术语“3-8元杂环烷基”本身或者与其他术语联合分别表示由3至8个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“3-8元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述3-8元杂环烷基包括3-6元、3-5元、4-6元、5-6元、4元、5元和6元杂环烷基等。3-8元杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基、高哌啶基或二氧杂环庚烷基等。
除非另有规定，本发明术语“5-10元杂芳环”和“5-10元杂芳基”可以互换使用，术语“5-10元杂芳基”是 表示由5至10个环原子组成的具有共轭π电子体系的环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子。其可以是单环、稠合双环或稠合三环体系，其中各个环均为芳香性的。其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。5-10元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5-10元杂芳基包括5-8元、5-7元、5-6元、5元和6元杂芳基等。所述5-10元杂芳基的实例包括但不限于吡咯基(包括N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、三唑基(1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基和4H-1,2,4-三唑基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)、吡啶基(包括2-吡啶基、3-吡啶基和4-吡啶基等)、吡嗪基、嘧啶基(包括2-嘧啶基和4-嘧啶基等)、苯并噻唑基(包括5-苯并噻唑基等)、嘌呤基、苯并咪唑基(包括2-苯并咪唑基等)、苯并噁唑基、吲哚基(包括5-吲哚基等)、异喹啉基(包括1-异喹啉基和5-异喹啉基等)、喹喔啉基(包括2-喹喔啉基和5-喹喔啉基等)或喹啉基(包括3-喹啉基和6-喹啉基等)。
除非另有规定，C n-n+m或C n-C n+m包括n至n+m个碳的任何一种具体情况，例如C 1-12包括C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11、和C 12，也包括n至n+m中的任何一个范围，例如C 1-12包括C 1- 3、C 1-6、C 1-9、C 3-6、C 3-9、C 3-12、C 6-9、C 6-12、和C 9-12等；同理，n元至n+m元表示环上原子数为n至n+m个，例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环，也包括n至n+m中的任何一个范围，例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环、和6-10元环等。
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲和取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方 式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词：aq代表水；HATU代表O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐；EDCI代表N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐；m-CPBA代表3-氯过氧苯甲酸；eq代表当量、等量；CDI代表羰基二咪唑；DCM代表二氯甲烷；PE代表石油醚；DIAD代表偶氮二羧酸二异丙酯；DMF代表N,N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；CBz代表苄氧羰基，是一种胺保护基团；BOC代表叔丁氧羰基是一种胺保护基团；HOAc代表乙酸；NaCNBH 3代表氰基硼氢化钠；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc 2O代表二叔丁基二碳酸酯；TFA代表三氟乙酸；SOCl 2代表氯化亚砜；CS 2代表二硫化碳；TsOH代表对甲苯磺酸；NFSI代表N-氟-N-(苯磺酰基)苯磺酰胺；NCS代表1-氯吡咯烷-2,5-二酮；n-Bu 4NF代表氟化四丁基铵；iPrOH代表2-丙醇；mp代表熔点；LDA代表二异丙基胺基锂；LiHMDS代表六甲基二硅基胺基锂；Xantphos代表4,5-双二苯基膦-9,9-二甲基氧杂蒽；LiAlH 4代表四氢铝锂；Pd 2(dba) 3代表三(二亚苄基丙酮)二钯；Pd(dppf)Cl 2代表[1,1'-双(二苯基膦基)二茂铁]二氯化钯；DIEA代表N,N-二异丙基乙胺；Pd(PPh 3) 4代表四三苯基膦钯；IPA代表异丙醇；DEA代表二乙胺。
化合物依据本领域常规命名原则或者使用
Figure PCTCN2020097503-appb-000059
软件命名，市售化合物采用供应商目录名称。
技术效果
本发明化合物相比对照化合物，活性药物的暴露量显著提高，血药峰值浓度和作用时间显著提高；本发明化合物展现了更大的降眼压幅度和更加持久的降眼压作用时间；在急性高眼压模型中，本发明化合物在不同的测试剂量下都展示了良好的降压效果，同时具有一定的剂量相关性，降压幅度和持续作用时间均优于K-115；本发明化合物在8mg/mL的高剂量下，给药4小时后，其代谢产物浓度为0.934ng/mL；给药8小时后，其代谢产物浓度低于检测限，系统安全性高。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
母药片段的合成
中间体1
Figure PCTCN2020097503-appb-000060
第一步
化合物1a(15.0g,71.7mmol)溶于二氯亚砜(164.0g,1.38mol)中，向其加入N,N-二甲基甲酰胺(0.55mL)后，80摄氏度搅拌12小时。待反应完成后，反应混合物减压浓缩得到粗品化合物1b。MS-ESI计算值[M+H] +228，实测值228。
第二步
在0摄氏度条件下，化合物1b(18.9g,62.0mmol)溶于二氯甲烷(150mL)中，在氮气环境中向其中加入化合物1c(12.7g,68.2mmol)和N,N-二异丙基乙胺(124mL)，25摄氏度搅拌0.5小时。待反应完成后，将反应液减压浓缩后用水(100mL)稀释，二氯甲烷萃取(60mL×3)，合并的有机相经饱和氯化钠溶液洗涤、无水硫酸钠干燥、过滤后减压浓缩。残余物经硅胶柱层析法纯化后得到化合物1d。MS-ESI计算值[M+H] +378，实测值378。
第三步
在0摄氏度条件下，将化合物1d(8g,20.3mmol)溶于二氯甲烷(100mL)中，分批加入间氯过氧苯甲酸(6.48g,30.4mmol,纯度：81％)，25摄氏度搅拌2小时。待反应完成后，向其加入饱和碳酸氢钠溶液淬灭(100mL)，二氯甲烷萃取(60mL×3)，有机相经无水硫酸钠干燥过滤后，减压浓缩得到粗品化合物1e。MS-ESI计算值[M+H] +394，实测值394。
第四步
将化合物1e(11.1g,28.2mmol)溶解于乙酸酐(109g,1.07mol)中，130摄氏度搅拌2小时后浓缩除去乙酸酐。向其加入四氢呋喃(100mL)和30％氢氧化钠水溶液(150mL)，25摄氏度搅拌30分钟。减压浓缩掉四氢呋喃后向体系中滴加6M的盐酸溶液将反应液pH调节至7，用乙酸乙酯萃取(50mL×3)，合并后的有机相经无水硫酸钠干燥后过滤并减压浓缩。残余物经硅胶柱层析法纯化得到中间体1。 1H NMR(400MHz,DMSO-d 6)δ＝8.52(d,J＝7.8Hz,1H),8.21(dd,J＝7.8,1.3Hz,1H),7.64(t,J＝7.8Hz,1H),7.37(d,J＝7.8Hz,1H),7.23(d,J＝7.6Hz,1H),3.91(d,J＝5.4Hz,1H),3.20-3.28(m,3H),3.03(dd,J＝9.8,5.0Hz,1H),1.92-2.05(m,1H),1.68-1.77(m,1H),1.34(s,9H)。MS-ESI计算值[M+Na] +416，实测值416。
中间体2
Figure PCTCN2020097503-appb-000061
第一步
将化合物2a(5.0g,36.7mmol)溶于浓盐酸(50mL,12M)中，在-5摄氏度下将亚硝酸钠(2.29g,33.2mmol)溶于水(8mL)得到的溶液缓慢加入到反应中，反应液于-5摄氏度下搅拌1小时。将氯化亚铜(156mg,1.58mmol)和氯化铜(2.34g,17.4mmol)溶于冰醋酸(80mL)，并向溶液中通入二氧化硫直至达到饱和，然后在-5摄氏度将之前的反应液缓慢的滴加入含二氧化硫的溶液中，反应液于20摄氏度下搅拌1小时。反应完成后，向反应液中加入水(150mL)，并用二氯甲烷萃取(150mL×4)。合并所得的有机相用饱和食盐水洗涤(500mL×1)，无水硫酸钠干燥，过滤得到的滤液进行减压浓缩得到剩余物，剩余物粗品2b不经纯化直接用于下一步。MS-ESI计算值[M+H] +242，实测242。
第二步
参照中间体1第二步得到化合物2c。
第三步
参照中间体1第三步得到化合物2d。
第四步
参照中间体1第四步得到中间体2。MS-ESI计算值[M+H] +408，实测值408。
中间体3
Figure PCTCN2020097503-appb-000062
第一步
参照中间体1第二步得到化合物3b。MS-ESI计算值[M+H] +406，实测406。
第二步
参照中间体1第三步得到化合物3c。MS-ESI计算值[M+H] +422，实测422。
第三步
参照中间体1第四步得到中间体3。MS-ESI计算值[M+H] +422，实测422。
中间体4
Figure PCTCN2020097503-appb-000063
第一步
参照中间体1第二步得到化合物4b。MS-ESI计算值[M+H] +364，实测值364。
第二步
参照中间体1第三步得到化合物4c。MS-ESI计算值[M+H] +380，实测值380。
第三步
参照中间体1第四步得到中间体4。MS-ESI计算值[M+Na] +402，实测值402。
中间体5
Figure PCTCN2020097503-appb-000064
第一步
将二异丙胺(36.4g,359mmol)溶于四氢呋喃(1.5mL)中，氮气保护下在-78摄氏度向反应液滴加正丁基锂(2.5M,131.2mL)，反应液在-78摄氏度搅拌1小时后，氮气保护下在-78摄氏度向反应液滴加化合物5b(20.1g,299mmol)，反应液在-78摄氏度搅拌1小时后，氮气保护下在-78摄氏度向反应液滴加化合物5a(50g,299mmol)，反应液在氮气保护下在-78摄氏度搅拌1小时。反应完成后，向反应液中加入饱和氯化铵水溶液(2L)淬灭，反应液用乙酸乙酯(500mL×3)萃取。合并所得的有机相用饱和食盐水洗涤(1L×1)，无水硫酸钠干燥，过滤得到的滤液进行减压浓缩，粗产物经过硅胶柱层析法(石油醚/乙酸乙酯)分离纯化得到化合物5c。 1H NMR(400MHz,CDCl 3)δ＝5.83-5.70(m,1H),5.50(dd,J＝1.5,16.9Hz,1H),5.36-5.30(m,1H),4.22-4.17(m,2H),3.77-3.70(m,1H),2.81-2.71(m,1H),2.68-2.59(m,1H),1.29-1.26(m,3H)。
第二步
将化合物5c(60.7g,396mmol)溶于四氢呋喃(1.2L)中，在氮气保护下加入钛酸四异丙酯(113g,396mmol)，氮气保护下在20摄氏度向反应液滴加乙基溴化镁(89.8g,674mmol)，反应液在20摄氏度下搅拌3小时。反应完成后，向反应液中加入水(300mL)淬灭，过滤，滤液进行减压浓缩，粗产物经过硅胶柱层析法(石油醚/乙酸乙酯)分离纯化得到化合物5d。MS-ESI计算值[M+H] +138，实测138。
第三步
将化合物5d(81.0g,590.5mmol)溶于乙腈(500mL)中，依次加入4-二甲氨基吡啶(7.21g,59.1mmol)和二叔丁基二碳酸酯(155g，709mmol)，反应液在20摄氏度下搅拌3小时。反应完成后，向反应液中加入水(1L)淬灭，反应液用乙酸乙酯(500mL×3)萃取。合并所得的有机相用饱和食盐水洗涤(500mL×1)，无水硫酸钠干燥，过滤得到的滤液进行减压浓缩，粗产物经过硅胶柱层析法(石油醚/乙酸乙酯)分离纯化得到化合物5e。MS-ESI计算值[M+H] +238，实测238。
第四步
将化合物5e(10.8g,45.5mmol)溶于甲醇(48mL)和水(72mL)中，在20摄氏度下向反应中加入高碘酸钠(29.2g,136.4mmol)和四氧化锇(173mg,682μmol)，反应液在20摄氏度下搅拌2小时。反应完成后，向反应液中加入水(100mL)，反应液用乙酸乙酯(100mL×3)萃取。合并所得的有机相用饱和食盐水洗涤(100mL×1)，无水硫酸钠干燥，过滤得到的滤液进行减压浓缩，粗产物经过硅胶柱层析法(石油醚/乙酸乙酯)分离纯化得到化合物5f。
第五步
将化合物5f(4.00g,16.7mmol)溶于叔丁醇(50mL)和四氢呋喃(50mL)中，在0摄氏度下依次向反应中加入异戊烯(14.6g,208mmol)，次氯酸钠(1.66g,18.4mmol)，一水合磷酸二氢钠(4.61g,33.4mmol)和水(35mL)，反应液在20摄氏度下搅拌12小时。反应完成后，反应液用1N的盐酸水溶液将pH调节为4，并用乙酸乙酯萃取(50mL×3)。合并所得的有机相用饱和食盐水洗涤(100mL×1)，无水硫酸钠干燥，过滤得到的滤液进行减压浓缩得到残渣。残渣加入水(50mL)，用Na 2CO 3水溶液将pH调节为10，并用乙酸乙酯(50mL×1)萃取，收集水相。水相用1N的盐酸水溶液将pH调节为4，并用乙酸乙酯萃取(50mL×3)。合并有机相用饱和食盐水洗涤(100mL×1)，无水硫酸钠干燥，过滤，得到的滤液进行减压浓缩得到化合物5g。
第六步
将化合物5g(3.10g,12.1mmol)溶于甲苯(30mL)中，在0摄氏度下向反应液中加入N,N-二异丙基乙胺(2.04g,15.8mmol)，叠氮磷酸二苯酯(4.34g,15.8mmol,3.42mL)和4A分子筛(2.00g)，反应液在20摄氏度下搅拌0.5小时，90摄氏度下继续搅拌0.5小时后冷却至20摄氏度。在20摄氏度下向反应液中加入化合物5h(1.44g,13.4mmol)，反应液在20摄氏度下搅拌12小时。反应完成后，将反应液过滤，向滤液中加入水(30mL)并用乙酸乙酯(30mL×2)萃取。合并所得的有机相用饱和食盐水洗涤(50mL×1)，无水硫酸钠干燥，过滤得到的滤液进行减压浓缩，粗产物经过硅胶柱层析法(石油醚/乙酸乙酯)分离纯化得到化合物5i。
第七步
将化合物5i(500mg,1.39mmol)溶于四氢呋喃(5mL)中，在氮气保护下0摄氏度向反应液中加入硼烷四氢呋喃(1M,13.9mL)，反应液在25摄氏度下搅拌1小时。反应完成后，向反应液中加入饱和氯化铵水溶液(20mL)淬灭，反应液用乙酸乙酯(20mL×3)萃取。合并所得的有机相用饱和食盐水洗涤(20mL ×1)，无水硫酸钠干燥，过滤得到的滤液进行减压浓缩，粗产物经过制备薄层层析法(石油醚/乙酸乙酯)分离纯化得到化合物5j。
第八步
将化合物5j(295mg,852μmol)溶于乙酸乙酯(3mL)中，将盐酸乙酸乙酯(4M,5mL)加入其中，反应液于25摄氏度下搅拌0.5小时。反应完成后，反应液减压浓缩得到化合物5k。
第九步
将化合物5k(420mg,1.59mmol)溶于二氯甲烷(10mL)中，在0摄氏度氮气保护下向反应液中添加化合物1b(268mg,948μmol)和N,N-二异丙基乙胺(489.98mg,3.79mmol)，反应混合物在25摄氏度下搅拌12小时。反应完成后，向反应液中加入二氯甲烷(10mL)和水(15mL)，然后用二氯甲烷(10mL×2)萃取，合并所得的有机相用饱和食盐水洗涤(20mL×1)，无水硫酸钠干燥，过滤减压浓缩。粗产物经过硅胶板层析法(石油醚/乙酸乙酯)分离纯化得到化合物5l。MS-ESI计算值[M+H] +438，实测438。
第十步
参照中间体1第三步得到化合物5m。MS-ESI计算值[M+H] +454，实测值454。
第十一步
参照中间体1第四步得到中间体5。MS-ESI计算值[M+H] +454，实测值454。
中间体6
Figure PCTCN2020097503-appb-000065
第一步
参照中间体1第二步得到化合物6b。
第二步
参照中间体1第三步得到化合物6c。
第三步
参照中间体1第四步得到中间体6。MS-ESI计算值[M+H] +408，实测值408。
实施例1：化合物7
Figure PCTCN2020097503-appb-000066
合成路线：
Figure PCTCN2020097503-appb-000067
第一步
化合物7a(1g,4.99mmol)溶于二氯甲烷(30mL)和水(30mL)中，向其加入碳酸氢钠(1.68g,12.0mmol)和四丁基氟化铵(1M,499μL)，化合物7b(824mg,4.99mmol)溶于二氯甲烷(10mL)，并将该溶液在0摄氏度搅拌条件下加入至反应体系中，30摄氏度持续搅拌16小时。分离出有机相，有机相经无水硫酸镁干燥过滤后，减压浓缩得到化合物7c。
第二步
在0摄氏度下，中间体1(150mg,324μmol)溶于N,N-二甲基甲酰胺(6mL)中，在氮气条件下加入钠氢(15.6mg,389μmol,纯度：60％)，搅拌0.5小时后加入化合物7c(113mg,454μmol)，升温至25摄氏度搅拌2小时。反应液中缓慢加入冰水(30mL)，乙酸乙酯(20mL×3)萃取，有机相经无水硫酸钠干燥过滤后减压浓缩。残余物经制备硅胶板纯化得到化合物7d。MS-ESI计算值[M+Na] +628，实测值628。
第三步
化合物7d(96.0mg,154μmol)溶于二氯甲烷(20mL)中，向其加入三甲基硅三氟甲磺酸(68.6mg,309μmol)后于0-5摄氏度搅拌1小时。逐滴加入2,6二甲基吡啶(49.6mg,462μmol)，0-5摄氏度继续搅拌1小时。向反应液加入水(30mL)后，二氯甲烷(20mL×3)萃取，有机相经无水硫酸钠干燥过滤后减压浓缩。残余物经制备高效液相(甲酸条件)纯化得到化合物7的甲酸盐。 1H NMR(400MHz,CD 3OD)δ＝8.70(d,J＝7.8Hz,1H),8.52(s,1H),8.39(dd,J＝7.8,1.3Hz,1H),7.74(t,J＝7.8Hz,1H),7.67(d,J＝7.8Hz,1H),7.51(d,J＝7.8Hz,1H),6.00(s,2H),3.81-3.90(m,1H),3.57-3.66(m,1H),3.49-3.56(m,1H),3.42(dd,J＝10.8,4.1Hz,1H),3.30(d,J＝6.2Hz,1H),2.39(t,J＝7.4Hz,2H),2.26-2.36(m,1H),1.92-2.03(m,1H),1.55- 1.69(m,1H),1.55-1.69(m,2H),1.20-1.34(m,16H),0.91(t,J＝6.8Hz,3H)。MS-ESI计算值[M+H] +506，实测值506。
化合物7的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物7。
实施例2：化合物8
Figure PCTCN2020097503-appb-000068
合成路线：
Figure PCTCN2020097503-appb-000069
第一步
参照实施例1第一步得到化合物8b。 1H NMR(400MHz,CDCl 3)δ＝8.27(d,J＝1.6Hz,1H),7.94(dd,J＝8.8,1.7Hz,1H),7.60(d,J＝2.4Hz,1H),7.44(d,J＝8.8Hz,1H),6.74(dd,J＝2.2,0.7Hz,1H),5.89(s,2H)。
第二步
参照实施例1第二步得到化合物8c。MS-ESI计算值[M+Na] +590，实测值590。
第三步
参照实施例1第三步得到化合物8的甲酸盐。 1H NMR(400MHz,CD 3OD)δ＝8.72(d,J＝7.8Hz,1H),8.48(s,1H),8.37-8.42(m,2H),8.04(dd,J＝8.8,1.7Hz,1H),7.88(d,J＝2.2Hz,1H),7.82(d,J＝7.8Hz,1H),7.73(t,J＝7.8Hz,1H),7.58(dd,J＝19.8,8.4Hz,2H),6.97(dd,J＝2.2,0.7Hz,1H),6.27(s,2H),3.72-3.83(m,1H),3.49-3.63(m,2H),3.35(d,J＝1.4Hz,1H),2.20-2.33(m,1H),1.85-1.97(m,1H)。MS-ESI计算值[M+H] +468，实测值468。
化合物8的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯 萃取后浓缩干即可得到化合物8。
实施例3：化合物9
Figure PCTCN2020097503-appb-000070
合成路线：
Figure PCTCN2020097503-appb-000071
第一步
参照实施例1第一步得到化合物9b。 1H NMR(400MHz,CDCl 3)δ＝5.72(s,2H),4.63-4.77(m,1H),1.93(dd,J＝12.5,3.9Hz,2H),1.75(dd,J＝9.2,3.9Hz,2H),1.45-1.58(m,3H),1.23-1.42(m,3H)。
第二步
参照实施例1第二步得到化合物9c。MS-ESI计算值[M+Na] +572，实测值572。
第三步
参照实施例1第三步得到化合物9的甲酸盐。 1H NMR(400MHz,CD 3OD)δ＝8.68(d,J＝8.0Hz,1H),8.46(s,1H),8.39(dd,J＝7.8,1.2Hz,1H),7.73(t,J＝7.8Hz,1H),7.67(d,J＝7.8Hz,1H),7.51(d,J＝7.8Hz,1H),6.00(s,2H),4.62-4.71(m,1H),3.77-3.87(m,1H),3.50-3.64(m,2H),3.34-3.40(m,2H),2.24-2.36(m,1H),1.86-2.03(m,3H),1.75(dt,J＝6.4,3.1Hz,2H),1.24-1.61(m,6H)。MS-ESI计算值[M+H] +450，实测值450。
化合物9的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物9。
实施例4：化合物10
Figure PCTCN2020097503-appb-000072
合成路线：
Figure PCTCN2020097503-appb-000073
第一步
参照实施例1第一步得到化合物10b。 1H NMR(400MHz,CDCl 3)δ＝7.99(dd,J＝8.2,1.3Hz,1H),7.47(td,J＝7.4,1.4Hz,1H),7.25-7.32(m,2H),5.96(s,2H),2.65(s,3H)。
第二步
参照实施例1第二步得到化合物10c。MS-ESI计算值[M+Na] +564，实测值564。
第三步
参照实施例1第三步得到化合物10的甲酸盐。 1H NMR(400MHz,CD 3OD)δ＝8.69(d,J＝7.8Hz,1H),8.37(dd,J＝7.6,1.2Hz,1H),7.91(d,J＝7.8Hz,1H),7.79(d,J＝7.8Hz,1H),7.69-7.76(m,1H),7.53(d,J＝7.8Hz,1H),7.45(td,J＝7.4,1.2Hz,1H),7.22-7.33(m,2H),6.21(s,2H),3.81-3.92(m,1H),3.51-3.64(m,2H),3.41(dd,J＝10.8,4.2Hz,1H),3.32-3.33(m,1H),2.57(s,3H),2.24-2.40(m,1H),1.90-2.04(m,1H)。MS-ESI计算值[M+H] +442，实测值442。
化合物10的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物10。
实施例5：化合物11
Figure PCTCN2020097503-appb-000074
合成路线：
Figure PCTCN2020097503-appb-000075
第一步
参照实施例1第一步得到化合物11b。 1H NMR(400MHz,CDCl 3)δ＝7.94-7.98(m,2H),7.25(d,J＝8.4Hz,2H),5.93(s,2H),2.40(s,3H)。
第二步
参照实施例1第二步得到化合物11c。MS-ESI计算值[M+Na] +564，实测值564。
第三步
参照实施例1第三步得到化合物11的甲酸盐。 1H NMR(400MHz,CD 3OD)δ＝8.72(d,J＝8.6Hz,1H),8.39(d,J＝7.6Hz,1H),7.94(d,J＝8.0Hz,2H),7.68-7.84(m,2H),7.54(d,J＝7.8Hz,1H),7.31(d,J＝7.8Hz,2H),6.23(s,2H),3.84(s,1H),3.49-3.64(m,2H),3.39(d,J＝15.2Hz,2H),2.42(s,3H),2.30(s,1H),1.97(s,1H)。MS-ESI计算值[M+H] +442，实测值442。
化合物11的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物11。
实施例6：化合物12
Figure PCTCN2020097503-appb-000076
合成路线：
Figure PCTCN2020097503-appb-000077
第一步
参照实施例1第一步得到化合物12b。 1H NMR(400MHz,CDCl 3)δ＝7.92(d,J＝7.8Hz,1H),7.05-7.15(m,2H),5.95(s,2H),2.63(s,3H),2.39(s,3H)。
第二步
参照实施例1第二步得到化合物12c。MS-ESI计算值[M+Na] +578，实测值578。
第三步
参照实施例1第三步得到化合物12。 1H NMR(400MHz,CD 3OD)δ＝8.73(d,J＝7.8Hz,1H),8.40(dd,J＝7.8,1.3Hz,1H),7.83(dd,J＝18.2,8.0Hz,2H),7.74(t,J＝7.8Hz,1H),7.55(d,J＝7.8Hz,1H),7.14(s,1H),7.09(d,J＝8.4Hz,1H),6.20(s,2H),3.79-3.89(m,1H),3.50-3.65(m,2H),3.35-3.45(m,2H),2.56(s,3H),2.35(s,3H),2.24-2.34(m,1H),1.90-2.03(m,1H)。MS-ESI计算值[M+H] +456，实测值456。
实施例7：化合物13
Figure PCTCN2020097503-appb-000078
合成路线：
Figure PCTCN2020097503-appb-000079
第一步
参照实施例1第一步得到化合物13b。 1H NMR(400MHz,CDCl 3)δ＝7.79-7.85(m,1H),7.59(dd,J＝4.8,1.2Hz,1H),7.04-7.10(m,1H),5.79-5.90(m,2H)
第二步
参照实施例1第二步得到化合物13c。MS-ESI计算值[M+Na] +556，实测值556。
第三步
参照实施例1第三步得到化合物13的甲酸盐。 1H NMR(400MHz,CD 3OD)δ＝8.71(d,J＝7.8Hz,1H),8.40(s,1H),8.39(dd,J＝7.8,1.3Hz,1H),7.89(dd,J＝3.8,1.2Hz,1H),7.83(dd,J＝5.0,1.2Hz,1H),7.69-7.79(m,2H),7.54(d,J＝7.8Hz,1H),7.19(dd,J＝5.0,3.9Hz,1H),6.21(s,2H),3.70-3.83(m,1H),3.48-3.65(m,2H),3.33-3.35(m,2H),2.21-2.35(m,1H),1.84-1.99(m,1H)。MS-ESI计算值[M+H] +434，实测值434。
化合物13的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物13。
实施例8：化合物14
Figure PCTCN2020097503-appb-000080
合成路线：
Figure PCTCN2020097503-appb-000081
第一步
参照实施例1第一步得到化合物14b。 1H NMR(400MHz,CDCl 3)δ＝7.98-8.05(m,1H),7.37-7.42(m,1H),6.71(dd,J＝1.8,0.7Hz,1H),5.81(s,2H)。
第二步
参照实施例1第二步得到化合物14c。MS-ESI计算值[M+Na] +540，实测值540。
第三步
参照实施例1第三步得到化合物14的甲酸盐。 1H NMR(400MHz,CD 3OD)δ＝8.70(d,J＝7.8Hz,1H),8.49(s,1H),8.39(dd,J＝7.8,1.3Hz,1H),8.23-8.26(m,1H),7.69-7.78(m,2H),7.62(t,J＝1.8Hz,1H),7.53(d,J＝7.8Hz,1H),6.80(dd,J＝1.8,0.7Hz,1H),6.17(s,2H),3.74-3.83(m,1H),3.50-3.62(m,2H),3.34-3.38(m,1H),3.29-3.32(m,1H),2.20-2.34(m,1H),1.85-1.99(m,1H)。MS-ESI计算值[M+H] +418，实测值418。
化合物14的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物14。
实施例9：化合物15
Figure PCTCN2020097503-appb-000082
合成路线：
Figure PCTCN2020097503-appb-000083
第一步
参照实施例1第二步得到化合物15b。MS-ESI计算值[M+Na] +516，实测值516。
第二步
参照实施例1第三步得到化合物15的甲酸盐。 1H NMR(400MHz,CD 3OD)δ＝8.67(d,J＝7.8Hz,1H),8.39(s,1H),8.37(dd,J＝7.8,1.3Hz,1H),7.72(t,J＝7.8Hz,1H),7.66(d,J＝7.8Hz,1H),7.50(d,J＝7.8Hz,1H),5.99(s,2H),3.76-3.89(m,1H),3.50-3.65(m,2H),3.33(d,J＝1.6Hz,2H),2.62(spt,J＝7.0Hz,1H),2.22-2.37(m,1H),1.90-2.02(m,1H),1.17(d,J＝7.0Hz,6H),0.00-0.00(m,1H)。MS-ESI计算值[M+H] +394，实测值394。
化合物15的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物15。
实施例10：化合物16
Figure PCTCN2020097503-appb-000084
合成路线：
Figure PCTCN2020097503-appb-000085
第一步
参照实施例1第二步得到化合物16b。 1H NMR(400MHz,CDCl 3)δ＝8.72(dd,J＝8.0,1.2Hz,1H),8.32(dd,J＝7.8,1.2Hz,1H),7.59(t,J＝8.0Hz,1H),7.34-7.48(m,2H),5.95(s,2H),4.66(s,1H),4.18(s,1H),3.37-3.61(m,2H),3.27(s,2H),2.09-2.18(m,4H),1.84(d,J＝5.6Hz,1H),1.42(s,9H)。
第二步
参照实施例1第三步得到化合物16的甲酸盐。 1H NMR(400MHz,CD 3OD)δ＝8.68(d,J＝7.6Hz,1H),8.44(s,1H),8.37(dd,J＝7.6,1.3Hz,1H),7.72(t,J＝8.0Hz,1H),7.65(d,J＝8.0Hz,1H),7.50(d,J＝8.0Hz,1H),5.97(s,2H),3.75-3.88(m,1H),3.46-3.63(m,2H),3.32-3.43(m,2H),2.21-2.36(m,1H),2.09(s,3H),1.86-2.01(m,1H)。MS-ESI计算值[M+H] +366，实测值366。
化合物16的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物16。
实施例11：化合物17
Figure PCTCN2020097503-appb-000086
合成路线：
Figure PCTCN2020097503-appb-000087
第一步
参照实施例1第二步得到化合物17b。 1H NMR(400MHz,CDCl 3)δ＝8.66-8.78(m,1H),8.31(dd,J＝7.8,1.4Hz,1H),7.59(t,J＝7.8Hz,1H),7.36-7.48(m,2H),5.96(s,2H),4.68(s,1H),4.14-4.30(m,1H),3.36-3.64(m,2H),3.27(s,2H),2.36(t,J＝7.4Hz,2H),2.14(td,J＝13.8,6.8Hz,1H),1.78-1.88(m,1H),1.63-1.70(m,2H),1.42(s,9H),0.94(t,J＝7.4Hz,3H)。
第二步
参照实施例1第三步得到化合物17的甲酸盐。 1H NMR(400MHz,CD 3OD)δ＝8.67(d,J＝7.8Hz,1H),8.48(s,1H),8.37(dd,J＝7.8,1.2Hz,1H),7.71(t,J＝7.8Hz,1H),7.65(d,J＝7.8Hz,1H),7.49(d,J＝7.8Hz,1H),5.98(s,2H),3.73-3.89(m,1H),3.46-3.64(m,2H),3.32-3.41(m,2H),2.36(t,J＝7.3Hz,2H),2.18-2.30(m,1H),1.84-1.98(m,1H),1.64(sxt,J＝7.4Hz,2H),0.93(t,J＝7.4Hz,3H)。MS-ESI计算值[M+H] +394，实测值394。
化合物17的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物17。
实施例12：化合物18
Figure PCTCN2020097503-appb-000088
合成路线：
Figure PCTCN2020097503-appb-000089
第一步
参照实施例1第一步得到化合物18b。
第二步
参照实施例1第二步得到化合物18c。 1H NMR(400MHz,CDCl 3)δ＝8.72(d,J＝7.8Hz,1H),8.28-8.35(m,1H),7.59(t,J＝7.8Hz,1H),7.37-7.48(m,2H),5.90-6.03(m,1H),5.96(s,1H),4.64(s,1H),4.17(d,J＝9.4Hz,1H),3.38-3.60(m,2H),3.15-3.36(m,3H),2.13-2.37(m,5H),1.81-2.02(m,3H),1.43(s,9H)。
第三步
参照实施例1第三步得到化合物18的甲酸盐。 1H NMR(400MHz,CD 3OD)δ＝8.67(d,J＝7.8Hz,1H),8.38(s,1H),8.37(dd,J＝7.8,1.2Hz,1H),7.71(t,J＝7.8Hz,1H),7.65(d,J＝8.0Hz,1H),7.49(d,J＝8.0Hz,1H),5.98(s,2H),3.74-3.87(m,1H),3.45-3.64(m,2H),3.32-3.38(m,2H),3.14-3.27(m,1H),2.14-2.36(m,5H),1.83-2.07(m,3H)。MS-ESI计算值[M+H] +406，实测值406。
化合物18的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物18。
实施例13：化合物19
Figure PCTCN2020097503-appb-000090
合成路线：
Figure PCTCN2020097503-appb-000091
第一步
参照实施例1第一步得到化合物19b。
第二步
参照实施例1第二步得到化合物19c。MS-ESI计算值[M+Na] +542，实测值542。
第三步
参照实施例1第三步得到化合物19的甲酸盐。 1H NMR(400MHz,CD 3OD)δ＝8.68(d,J＝7.6Hz,1H),8.37(dd,J＝7.6,1.4Hz,2H),7.72(t,J＝8.0Hz,1H),7.65(d,J＝7.8Hz,1H),7.49(d,J＝8.4Hz,1H),5.97(s,2H),4.62(s,1H),3.78-3.87(m,1H),3.55-3.65(m,1H),3.51(dd,J＝10.8,6.4Hz,1H),3.38(dd,J＝10.8,4.0Hz,1H),2.76-2.86(m,1H),2.19-2.35(m,1H),1.84-2.01(m,3H),1.73-1.83(m,2H),1.53-1.72(m,4H)。MS-ESI计算值[M+H] +420，实测值420。
化合物19的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物19。
实施例14：化合物20
Figure PCTCN2020097503-appb-000092
合成路线：
Figure PCTCN2020097503-appb-000093
第一步
参照实施例1第一步得到化合物20b。
第二步
参照实施例1第二步得到化合物20c。
第三步
参照实施例1第三步得到化合物20的甲酸盐。 1H NMR(400MHz,CD 3OD)δ＝8.69(d,J＝7.8Hz,1H),8.40(s,1H),8.39(dd,J＝7.8,1.2Hz,1H),7.73(t,J＝7.8Hz,1H),7.66(d,J＝8.0Hz,1H),7.51(d,J＝8.0Hz,1H),5.99(s,2H),4.58(s,2H),3.71-3.83(m,1H),3.46-3.65(m,2H),2.40(tt,J＝11.0,3.6Hz,1H),2.21-2.33(m,1H),1.85-2.00(m,3H),1.71-1.82(m,2H),1.65(d,J＝8.8Hz,1H),1.22-1.50(m,5H)。MS-ESI计算值[M+H] +434，实测值434。
化合物20的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物20。
实施例15：化合物21
Figure PCTCN2020097503-appb-000094
合成路线：
Figure PCTCN2020097503-appb-000095
第一步
参照实施例1第一步得到化合物21b。
第二步
参照实施例1第二步得到化合物21c。 1H NMR(400MHz,CDCl 3)δ＝8.70(dd,J＝8.0,1.1Hz,1H),8.26-8.35(m,1H),7.59(t,J＝7.8Hz,1H),7.34-7.45(m,2H),5.97(s,2H),4.59-4.83(m,1H),4.06-4.29(m,1H),3.94(dt,J＝11.4,3.5Hz,2H),3.48-3.54(m,1H),3.34-3.42(m,2H),3.16-3.33(m,2H),2.56-2.69(m,1H),2.08-2.20(m,1H),1.74-1.84(m,6H),1.34-1.43(m,9H)。
第三步
参照实施例1第三步得到化合物21的甲酸盐。 1H NMR(400MHz,CD 3OD)δ＝8.67(d,J＝8.2Hz,1H),8.45(s,1H),8.37(d,J＝7.8Hz,1H),7.71(t,J＝8.0Hz,1H),7.65(d,J＝7.8Hz,1H),7.49(d,J＝8.0Hz,1H),7.45-7.53(m,1H),6.00(s,2H),3.89(dt,J＝11.7,3.5Hz,2H),3.72-3.82(m,1H),3.48-3.63(m,2H),3.43(td,J＝11.4,2.4Hz,2H),3.35(d,J＝3.6Hz,1H),2.59-2.73(m,1H),2.18-2.33(m,1H),1.92(td,J＝13.5,5.8Hz,1H),1.61-1.87(m,5H)。MS-ESI计算值[M+H] +436，实测值436。
化合物21的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物21。
实施例16：化合物22
Figure PCTCN2020097503-appb-000096
合成路线：
Figure PCTCN2020097503-appb-000097
第一步
参照实施例1第一步得到化合物22b。
第二步
参照实施例1第二步得到化合物22c。 1H NMR(400MHz,CDCl 3)δ＝8.72(dd,J＝8.0,0.8Hz,1H),8.32(dd,J＝7.8,1.4Hz,1H),7.59(t,J＝7.8Hz,1H),7.34-7.48(m,2H),5.96(s,2H),4.67(s,1H),4.18(s,1H),3.36-3.64(m,2H),3.27(s,2H),2.37(t,J＝7.6Hz,2H),2.14(dq,J＝14.4,6.6Hz,1H),1.75-1.91(m,1H),1.65-1.68(m,1H),1.59-1.62(m,1H),1.42(s,9H),1.27-1.33(m,4H),0.78-0.89(m,3H)。
第三步
参照实施例1第三步得到化合物22的甲酸盐。 1H NMR(400MHz,CD 3OD)δ＝8.67(d,J＝8.0Hz,1H),8.48(s,1H),8.37(d,J＝7.4Hz,1H),7.71(t,J＝7.8Hz,1H),7.64(d,J＝8.0Hz,1H),7.49(d,J＝7.8Hz,1H),5.98(s,2H),4.57(s,1H),3.71-3.74(m,1H),3.46-3.64(m,2H),2.37(t,J＝7.6Hz,2H),2.23-2.24(m,1H),1.88-1.89(m,1H),1.53-1.71(m,2H),1.27-1.30(m,5H),0.85(t,J＝6.8Hz,3H)。MS-ESI计算值[M+H] +422，实测值422。
化合物22的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物22。
实施例17：化合物23
Figure PCTCN2020097503-appb-000098
合成路线：
Figure PCTCN2020097503-appb-000099
第一步
将化合物23b(1.0g,7.76mmol)和吡啶(920mg,11.6mmol)溶于二氯甲烷(10mL)，0摄氏度下滴加入化合物23a(466mg,7.76mmol)，30摄氏度下搅拌16小时。反应液中加入盐酸(1M,10mL)，搅拌5分钟，有机相分离，用水(10mL)洗涤，无水硫酸镁干燥，过滤，浓缩得到化合物23c。 1H NMR(400MHz,CDCl 3)δ＝5.73(s,2H),4.19(t,J＝6.6Hz,2H),1.73(sxt,J＝7.2Hz,2H),0.97(t,J＝7.2Hz,3H)。
第二步
参照实施例1第二步得到化合物23d。MS-ESI计算值[M+Na] +532，实测值532。
第三步
参照实施例1第三步得到化合物23的甲酸盐。 1H NMR(400MHz,CD 3OD)δ＝8.67(d,J＝8.0Hz,1H),8.38(s,1H),8.37(d,J＝7.8Hz,1H),7.71(t,J＝7.8Hz,1H),7.65(d,J＝8.0Hz,1H),7.50(d,J＝8.0Hz,1H),5.99(s,2H),4.58(s,1H),4.13(t,J＝6.6Hz,2H),3.76-3.88(m,1H),3.46-3.64(m,2H),3.34-3.40(m,1H),2.20-2.34(m,1H),1.94(td,J＝13.6,5.8Hz,1H),1.68(sxt,J＝7.2Hz,2H),0.94(t,J＝7.6Hz,3H)。MS-ESI计算值[M+H] +410，实测值410。
化合物23的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物23。
实施例18：化合物24
Figure PCTCN2020097503-appb-000100
合成路线：
Figure PCTCN2020097503-appb-000101
第一步
参照实施例1第一步得到化合物24b。
第二步
参照实施例1第二步得到化合物24c。 1H NMR(400MHz,CDCl 3)δppm 8.72(d,J＝7.2Hz,1H),8.32(dd,J＝7.8,1.4Hz,1H),7.60(t,J＝7.8Hz,1H),7.33-7.43(m,3H),7.27-7.32(m,4H),5.97(s,2H),4.53-4.75(m,1H),4.18(s,1H),3.70(s,2H),3.37-3.60(m,2H),3.25(s,2H),2.08-2.24(m,1H),1.77-1.91(m,1H),1.43(s,9H)。
第三步
参照实施例1第三步得到化合物24的甲酸盐。 1H NMR(400MHz,CD 3OD)δ＝8.66(d,J＝7.8Hz,1H),8.45(s,1H),8.37(dd,J＝7.8,1.2Hz,1H),7.71(t,J＝8.0Hz,1H),7.60(d,J＝8.0Hz,1H),7.46(d,J＝7.8Hz,1H),7.16-7.32(m,4H),6.00(s,2H),3.74-3.85(m,1H),3.70(s,2H),3.46-3.61(m,2H),3.33-3.38(m,1H),3.25-3.30(m,1H),2.18-2.33(m,1H),1.83-2.02(m,1H)。MS-ESI计算值[M+Na] +464，实测值464。
化合物24的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物24。
实施例19：化合物25
Figure PCTCN2020097503-appb-000102
合成路线：
Figure PCTCN2020097503-appb-000103
第一步
参照实施例17第一步得到化合物25a。
第二步
参照实施例1第二步得到化合物25b。MS-ESI计算值[M+Na] +504，实测值504。
第三步
参照实施例1第三步得到化合物25的甲酸盐。 1H NMR(400MHz,CD 3OD)δ＝8.68(d,J＝7.8Hz,1H),8.38(dd,J＝7.8,1.2Hz,1H),7.72(t,J＝8.0Hz,1H),7.65(d,J＝7.8Hz,1H),7.50(d,J＝8.0Hz,1H),5.99(s,2H),3.83-3.90(m,1H),3.80(s,3H),3.59-3.68(m,1H),3.44-3.59(m,2H),3.37-3.42(m,1H),2.23-2.37(m,1H),1.97(td,J＝13.6,6.0Hz,1H)。MS-ESI计算值[M+H] +382，实测值382。
化合物25的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物25。
实施例20：化合物26
Figure PCTCN2020097503-appb-000104
合成路线：
Figure PCTCN2020097503-appb-000105
第一步
参照实施例17第一步得到化合物26b。
第二步
参照实施例1第二步得到化合物26c。 1H NMR(400MHz,CDCl 3)δ＝8.72(d,J＝8.0Hz,1H),8.32(d,J＝7.8Hz,1H),7.59(t,J＝8.0Hz,1H),7.43(s,2H),5.98(s,2H),4.65(s,1H),4.18(t,J＝6.8Hz,2H),3.46(d,J＝18.0Hz,2H),3.28(s,2H),2.14(dq,J＝13.6,7.2Hz,1H),1.84(s,1H),1.64-1.72(m,2H),1.43(s,9H),1.27-1.37(m,6H),0.88(t,J＝6.8Hz,3H)。
第三步
参照实施例1第三步得到化合物26的甲酸盐。 1H NMR(400MHz,CD 3OD)δ＝8.67(d,J＝8.0Hz,1H),8.45(s,1H),8.37(dd,J＝7.8,1.2Hz,1H),7.71(t,J＝8.0Hz,1H),7.65(d,J＝7.8Hz,1H),7.50(d,J＝8.0Hz,1H),5.99(s,2H),4.17(t,J＝6.6Hz,2H),3.76-3.85(m,1H),3.48-3.63(m,2H),3.32-3.40(m,2H),2.22-2.39(m,1H),1.89-1.99(m,1H),1.60-1.72(m,2H),1.30-1.40(m,6H),0.83-0.94(m,3H)。MS-ESI计算值[M+H] +452，实测值452。
化合物26的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物26。
实施例21：化合物27
Figure PCTCN2020097503-appb-000106
合成路线：
Figure PCTCN2020097503-appb-000107
第一步
参照实施例1第二步得到化合物27b。MS-ESI计算值[M+Na] +550，实测值550。
第二步
参照实施例1第三步得到化合物27的甲酸盐。 1H NMR(400MHz,CDCl 3)δ＝8.73(d,J＝8.0Hz,1H),8.35(d,J＝7.8Hz,1H),8.09(d,J＝7.4Hz,2H),7.54-7.64(m,3H),7.45(dt,J＝7.8,3.8Hz,3H),6.22(s,2H),3.62(s,1H),3.46-3.55(m,2H),3.31-3.42(m,1H),3.10(dd,J＝9.9,4.1Hz,1H),2.03-2.22(m,2H)。MS-ESI计算值[M+H] +428，实测值428。
化合物27的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物27。
实施例22：化合物28
Figure PCTCN2020097503-appb-000108
合成路线：
Figure PCTCN2020097503-appb-000109
第一步
参照实施例1第二步得到化合物28b。MS-ESI计算值[M+Na] +518，实测值518。
第二步
参照实施例1第三步得到化合物28的甲酸盐。 1H NMR(400MHz,氘代丙酮)δppm 8.63(d,J＝7.4Hz,1H),8.43(dd,J＝7.8,1.4Hz,1H),8.12(s,1H),7.64-7.74(m,2H),7.49(d,J＝8.0Hz,1H),6.03(d,J＝1.0Hz,2H),4.22(q,J＝7.0Hz,2H),4.16(t,J＝4.6Hz,1H),3.59(dd,J＝9.8,5.8Hz,1H),3.45-3.52(m,2H),3.22(dd,J＝9.8,3.9Hz,1H),2.11-2.16(m,1H),1.76(td,J＝12.4,5.2Hz,1H),1.27(t,J＝7.0Hz,3H)。MS-ESI计算值[M+H] +396，实测值396。
化合物28的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物28。
实施例23：化合物29
Figure PCTCN2020097503-appb-000110
合成路线：
Figure PCTCN2020097503-appb-000111
第一步
参照实施例1第二步得到化合物29b。MS-ESI计算值[M+Na] +532，实测值532。
第二步
参照实施例1第三步得到化合物29的甲酸盐。 1H NMR(400MHz,CD 3OD)δ＝8.69(d,J＝7.8Hz,1H),8.49(s,1H),8.39(dd,J＝7.8,1.3Hz,1H),7.73(t,J＝7.8Hz,1H),7.67(d,J＝7.8Hz,1H),7.51(d,J＝7.8Hz,1H),5.99(s,2H),3.76-3.88(m,1H),3.49-3.66(m,2H),3.28-3.40(m,3H),2.22-2.38(m,1H),1.87-2.01(m,1H),1.30(d,J＝6.4Hz,7H)。MS-ESI计算值[M+H] +410，实测值410。
化合物29的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯 萃取后浓缩干即可得到化合物29。
实施例24：化合物30
Figure PCTCN2020097503-appb-000112
合成路线：
Figure PCTCN2020097503-appb-000113
第一步
参照实施例1第二步得到化合物30b。MS-ESI计算值[M+Na] +530，实测值530。
第二步
参照实施例1第三步得到化合物30的甲酸盐。 1H NMR(400MHz,CDCl 3)δppm 8.63(d,J＝7.8Hz,1H),8.25(d,J＝7.6Hz,1H),8.21(s,1H),7.51(t,J＝7.8Hz,1H),7.34-7.40(m,1H),7.29-7.34(m,1H),5.87(s,2H),3.69(s,1H),3.50(s,1H),3.42(s,1H),3.26(s,2H),2.10(s,1H),1.85(s,1H),1.13(s,9H)。MS-ESI计算值[M+H] +408，实测值408。
化合物30的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物30。
实施例25：化合物31
Figure PCTCN2020097503-appb-000114
合成路线：
Figure PCTCN2020097503-appb-000115
第一步
参照实施例1第二步得到化合物31a。MS-ESI计算值[M+H] +554，实测值554。
第二步
向微波管中加入三氟乙酸(1.0mL)，将化合物31a(79mg,143μmol)加入到微波管中，在60摄氏度下微波1小时。减压浓缩除去溶剂，粗产物经过高效液相色谱法(酸性，甲酸体系)纯化得到化合物31的甲酸盐。 1H NMR(400MHz,CD 3OD)δ＝8.66(d,J＝8.1Hz,1H),8.50(s,1H),8.45-8.39(m,1H),7.73-7.63(m,2H),7.17(d,J＝7.9Hz,1H),5.97(s,2H),4.12-4.01(m,1H),3.66-3.55(m,1H),3.41(br d,J＝4.5Hz,1H),2.65-2.57(m,1H),2.56-2.46(m,1H),2.13-2.02(m,1H),1.23-1.17(m,1H),1.15(d,J＝7.0Hz,7H),0.80(t,J＝8.9Hz,2H)。MS-ESI计算值[M+H] +420，实测值420。
化合物31的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物31。
实施例26：化合物32
Figure PCTCN2020097503-appb-000116
合成路线：
Figure PCTCN2020097503-appb-000117
第一步
参照实施例1第二步得到化合物32a。MS-ESI计算值[M+Na] +590，实测值590。
第二步
参照实施例25第二步得到化合物32的甲酸盐。 1H NMR(400MHz,CD 3OD)δ＝8.67(d,J＝7.6Hz,1H),8.47(s,1H),8.45-8.41(m,1H),7.74-7.61(m,2H),7.19(d,J＝7.8Hz,1H),5.97(s,2H),4.12-3.99(m,1H),3.68-3.54(m,1H),3.36-3.33(m,1H),2.59-2.42(m,1H),2.08-1.94(m,1H),1.19(s,9H),1.18-1.06(m,2H),0.88-0.74(m,2H)。MS-ESI计算值[M+H]+434，实测值434。
化合物32的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物32。
实施例27：化合物33
Figure PCTCN2020097503-appb-000118
合成路线：
Figure PCTCN2020097503-appb-000119
第一步
参照实施例1第二步得到化合物33a。MS-ESI计算值[M+H] +588，实测值588。
第二步
参照实施例25第二步得到化合物33的甲酸盐。 1H NMR(400MHz,CD 3OD)δ＝8.66(d,J＝7.9Hz,1H),8.48(s,1H),8.43-8.37(m,1H),8.05-7.99(m,2H),7.78(d,J＝7.9Hz,1H),7.68(t,J＝7.9Hz,1H),7.64-7.57(m,1H),7.50-7.43(m,2H),7.19(d,J＝7.8Hz,1H),6.22(s,2H),4.12-4.00(m,1H),3.65-3.55(m,1H),3.47-3.39(m,1H),2.59-2.44(m,1H),2.15-2.03(m,1H),1.26-1.10(m,2H),0.83-0.74(m,2H)。MS-ESI计算值[M+H] +454，实测值454。
化合物33的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物33。
实施例28：化合物34
Figure PCTCN2020097503-appb-000120
合成路线：
Figure PCTCN2020097503-appb-000121
第一步
参照实施例1第二步得到化合物34a。MS-ESI计算值[M+Na] +592，实测值592。
第二步
参照实施例25第二步得到化合物34的甲酸盐。 1H NMR(400MHz,CD 3OD)δ＝8.66(d,J＝8.1Hz,1H),8.50(br s,1H),8.46-8.40(m,1H),7.72-7.63(m,2H),7.23(d,J＝7.8Hz,1H),5.97(s,2H),4.92-4.90(m,1H),4.02-3.92(m,1H),3.66-3.55(m,1H),3.29-3.20(m,1H),2.51-2.36(m,1H),2.00-1.88(m,1H),1.28(d,J＝6.4Hz,6H),1.18-1.02(m,2H),0.95-0.87(m,1H),0.79-0.72(m,1H)。MS-ESI计算值[M+H] +436，实测值436。
化合物34的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物34。
实施例29：化合物35
Figure PCTCN2020097503-appb-000122
合成路线：
Figure PCTCN2020097503-appb-000123
第一步
参照实施例1第二步得到化合物35a。MS-ESI计算值[M+Na] +600，实测值600。
第二步
参照实施例25第二步得到化合物35的甲酸盐。 1H NMR(400MHz,CD 3OD)δ＝8.68(d,J＝7.9Hz,1H),8.46(br s,1H),8.44-8.41(m,1H),8.23(s,1H),7.78-7.67(m,2H),7.60(t,J＝1.7Hz,1H),7.20(d,J＝7.8Hz,1H),6.79(d,J＝1.2Hz,1H),6.15(s,2H),4.12-4.02(m,1H),3.65-3.55(m,1H),3.43-3.35(m,1H),2.59-2.45(m,1H),2.11-2.00(m,1H),1.26-1.08(m,2H),0.87-0.74(m,2H)。MS-ESI计算值[M+H] +444，实测值444。
化合物35的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物35。
实施例30：化合物36
Figure PCTCN2020097503-appb-000124
合成路线：
Figure PCTCN2020097503-appb-000125
第一步
参照实施例1第二步得到化合物36a。MS-ESI计算值[M+H] +554，实测值554。
第二步
参照实施例25第二步得到化合物36的甲酸盐。 1H NMR(400MHz,CD 3OD)δ＝8.67(d,J＝7.8Hz,1H),8.53(br s,1H),8.49-8.43(m,1H),7.74-7.63(m,2H),7.25(d,J＝7.9Hz,1H),5.99(s,2H),4.02-3.89(m,1H),3.68-3.57(m,1H),3.27-3.19(m,1H),2.48-2.40(m,1H),2.38(t,J＝7.3Hz,2H),1.99-1.88(m,1H),1.72-1.60(m,2H),1.17-1.02(m,2H),0.99-0.91(m,4H),0.80-0.72(m,1H)。MS-ESI计算值[M+H] +420，实测值420。
化合物36的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物36。
实施例31：化合物37
Figure PCTCN2020097503-appb-000126
合成路线：
Figure PCTCN2020097503-appb-000127
第一步
参照实施例1第二步得到化合物37a。MS-ESI计算值[M+H] +580，实测值580。
第二步
参照实施例25第二步得到化合物37的甲酸盐。 1H NMR(400MHz,CD 3OD)δ＝8.66(d,J＝8.0Hz,1H),8.46(br s,1H),8.43-8.40(m,1H),7.74-7.62(m,2H),7.16(d,J＝7.8Hz,1H),5.97(s,2H),4.14-4.04(m,1H),3.64-3.55(m,1H),3.48-3.41(m,1H),2.86-2.76(m,1H),2.61-2.47(m,1H),2.16-2.05(m,1H),1.94-1.84(m,2H),1.83-1.73(m,2H),1.72-1.53(m,4H),1.25-1.11(m,2H),0.85-0.73(m,2H)。MS-ESI计算值[M+H] +446，实测值446。
化合物37的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物37。
实施例32：化合物38
Figure PCTCN2020097503-appb-000128
合成路线：
Figure PCTCN2020097503-appb-000129
第一步
参照实施例1第二步得到化合物38a。MS-ESI计算值[M+H] +594，实测值594。
第二步
参照实施例25第二步得到化合物38的甲酸盐。 1H NMR(400MHz,CD 3OD)δ＝8.64(d,J＝8.0Hz,1H),8.47-8.40(m,1H),7.74-7.59(m,2H),7.29(d,J＝7.9Hz,1H),5.97(s,2H),3.88-3.77(m,1H),3.67-3.56(m,1H),3.08-3.02(m,1H),2.44-2.26(m,2H),1.88(d,J＝13.4Hz,2H),1.82-1.68(m,3H),1.63(br d,J＝9.5Hz,1H),1.49-1.38(m,2H),1.34-1.27(m,3H),1.09-0.94(m,3H),0.75-0.67(m,1H)。MS-ESI计算值[M+H] +460，实测值460。
化合物38的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物38。
实施例33：化合物39
Figure PCTCN2020097503-appb-000130
合成路线：
Figure PCTCN2020097503-appb-000131
第一步
参照实施例1第二步得到化合物39a。MS-ESI计算值[M+H] +582，实测值582。
第二步
参照实施例25第二步得到化合物39。 1H NMR(400MHz,CD 3OD)δ＝8.66-8.59(m,1H),8.47-8.39(m,1H),7.72-7.60(m,2H),7.37-7.28(m,1H),5.97(s,2H),3.83-3.57(m,2H),3.01-2.93(m,1H),2.37(t,J＝7.4Hz,2H),2.32-2.21(m,1H),1.80-1.67(m,1H),1.65-1.56(m,2H),1.27(dd,J＝3.6,7.3Hz,4H),1.16-1.06(m,1H),1.03-0.95(m,1H),0.95-0.89(m,1H),0.84(t,J＝7.0Hz,3H),0.73-0.63(m,1H)。MS-ESI计算值[M+H] +448，实测值448。
化合物39的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物39。
实施例34：化合物40
Figure PCTCN2020097503-appb-000132
合成路线：
Figure PCTCN2020097503-appb-000133
第一步
参照实施例1第二步得到化合物40a。MS-ESI计算值[M+H] +602，实测值602。
第二步
参照实施例25第二步得到化合物40的甲酸盐。 1H NMR(400MHz,CD 3OD)δ＝8.64(d,J＝7.8Hz,1H),8.48(br s,1H),8.44-8.39(m,1H),7.69(t,J＝7.9Hz,1H),7.60(d,J＝7.9Hz,1H),7.29-7.17(m,4H),7.13(d,J＝7.9Hz,1H),5.99(s,2H),4.12-4.00(m,1H),3.70(s,2H),3.64-3.52(m,1H),3.44-3.36(m,1H),2.57-2.45(m,1H),2.16-1.99(m,1H),1.21-1.09(m,2H),0.83-0.73(m,2H)。MS-ESI计算值[M+H] +468，实测值468。
化合物40的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物40。
实施例35：化合物41
Figure PCTCN2020097503-appb-000134
合成路线：
Figure PCTCN2020097503-appb-000135
第一步
参照实施例1第二步得到化合物41a。MS-ESI计算值[M+H] +566，实测值566。
第二步
参照实施例25第二步得到化合物41的甲酸盐。 1H NMR(400MHz,CD 3OD)δ＝8.66(d,J＝7.9Hz,1H),8.50(br s,1H),8.45-8.39(m,1H),7.73-7.63(m,2H),7.18(d,J＝7.9Hz,1H),5.97(s,2H),4.10-3.99(m,1H),3.67-3.55(m,1H),3.39-3.33(m,1H),3.27-3.18(m,1H),2.57-2.44(m,1H),2.33-2.14(m,4H),2.09-1.95(m,2H),1.94-1.81(m,1H),1.24-1.07(m,2H),0.90-0.71(m,2H)。MS-ESI计算值[M+H] +432，实测值432。
化合物41的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物41。
实施例36：化合物42
Figure PCTCN2020097503-appb-000136
合成路线：
Figure PCTCN2020097503-appb-000137
第一步
参照实施例1第二步得到化合物42a。MS-ESI计算值[M+H] +594，实测值594。
第二步
参照实施例25第二步得到化合物42的甲酸盐。 1H NMR(400MHz,CD 3OD)δ＝8.68(d,J＝7.6Hz,1H),8.46(s,1H),8.44-8.41(m,1H),7.90-7.86(m,1H),7.83-7.79(m,1H),7.76(d,J＝8.1Hz,1H),7.70(t,J＝7.9Hz,1H),7.23-7.14(m,2H),6.18(s,2H),4.11-4.01(m,1H),3.65-3.56(m,1H),3.40-3.36(m,1H),2.59-2.45(m,1H),2.12-1.98(m,1H),1.27-1.06(m,2H),0.88-0.72(m,2H)。MS-ESI计算值[M+H] +460，实测值460。
化合物42的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物42。
实施例37：化合物43
Figure PCTCN2020097503-appb-000138
合成路线：
Figure PCTCN2020097503-appb-000139
第一步
参照实施例1第二步得到化合物43a。MS-ESI计算值[M+H] +628，实测值628。
第二步
参照实施例25第二步得到化合物43的甲酸盐。 1H NMR(400MHz,CD 3OD)δ＝8.69(d,J＝7.9Hz,1H),8.49(s,1H),8.45-8.41(m,1H),8.38(d,J＝1.6Hz,1H),8.05-8.00(m,1H),7.86(d,J＝2.3Hz,1H),7.81(d,J＝7.9Hz,1H),7.70(t,J＝7.9Hz,1H),7.58(d,J＝8.8Hz,1H),7.23(d,J＝7.9Hz,1H),6.95(d,J＝1.5Hz,1H),6.24(s,2H),4.10-3.96(m,1H),3.68-3.54(m,1H),3.36-3.32(m,1H),2.55-2.42(m,1H),2.08-1.94(m,1H),1.26-1.04(m,2H),0.89-0.72(m,2H)。MS-ESI计算值[M+H] +494，实测值494。
化合物43的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物43。
实施例38：化合物44
Figure PCTCN2020097503-appb-000140
合成路线：
Figure PCTCN2020097503-appb-000141
第一步
参照实施例1第二步得到化合物44a。MS-ESI计算值[M+H] +602，实测值602。
第二步
参照实施例25第二步得到化合物44的甲酸盐。 1H NMR(400MHz,CD 3OD)δ＝8.69(d,J＝8.0Hz,1H),8.50(s,1H),8.46-8.40(m,1H),7.91(d,J＝7.9Hz,1H),7.80(d,J＝7.9Hz,1H),7.74-7.67(m,1H),7.49-7.41(m,1H),7.32-7.19(m,3H),6.20(s,2H),4.15-4.05(m,1H),3.67-3.57(m,1H),3.49-3.43(m,1H),2.60-2.50(m,4H),2.17-2.05(m,1H),1.28-1.13(m,2H),0.86-0.75(m,2H)。MS-ESI计算值[M+H] +468，实测值468。
化合物44的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物44。
实施例39：化合物45
Figure PCTCN2020097503-appb-000142
合成路线：
Figure PCTCN2020097503-appb-000143
第一步
参照实施例1第二步得到化合物45a。MS-ESI计算值[M+H] +602，实测值602。
第二步
参照实施例25第二步得到化合物45的甲酸盐。 1H NMR(400MHz,CD 3OD)δ＝8.69(d,J＝8.0Hz,1H),8.46(s,1H),8.44-8.40(m,1H),7.92(d,J＝8.3Hz,2H),7.78(d,J＝8.0Hz,1H),7.70(t,J＝7.9Hz,1H),7.29(d,J＝8.2Hz,2H),7.20(d,J＝8.0Hz,1H),6.20(s,2H),4.12-4.01(m,1H),3.65-3.54(m,1H),3.43-3.36(m,1H),2.58-2.46(m,1H),2.39(s,3H),2.11-1.99(m,1H),1.26-1.08(m,2H),0.86-0.74(m,2H)。MS-ESI计算值[M+H] +468，实测值468。
化合物45的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物45。
实施例40：化合物46
Figure PCTCN2020097503-appb-000144
合成路线：
Figure PCTCN2020097503-appb-000145
第一步
参照实施例1第二步得到化合物46a。MS-ESI计算值[M+H] +556，实测值556。
第二步
参照实施例25第二步得到化合物46的甲酸盐。 1H NMR(400MHz,CD 3OD)δ＝8.66(d,J＝7.9Hz,1H),8.52(s,1H),8.46-8.40(m,1H),7.74-7.65(m,2H),7.18(d,J＝7.9Hz,1H),5.99(s,2H),4.27-4.19(m,2H),4.11-4.02(m,1H),3.67-3.56(m,1H),3.45-3.39(m,1H),2.59-2.47(m,1H),2.14-2.02(m,1H),1.29(t,J＝7.1Hz,3H),1.24-1.11(m,2H),0.88-0.76(m,2H)。MS-ESI计算值[M+H] +422，实测值422。
化合物46的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物46。
实施例41：化合物47
Figure PCTCN2020097503-appb-000146
合成路线：
Figure PCTCN2020097503-appb-000147
第一步
参照实施例1第二步得到化合物47a。MS-ESI计算值[M+H] +570，实测值570。
第二步
参照实施例25第二步得到化合物47的甲酸盐。 1H NMR(400MHz,CD 3OD)δ＝8.66(d,J＝7.9Hz,1H),8.49(s,1H),8.44-8.38(m,1H),7.74-7.63(m,2H),7.17(d,J＝7.8Hz,1H),6.01-5.94(m,2H),4.13(t,J＝6.6Hz,2H),4.10-4.02(m,1H),3.65-3.56(m,1H),3.45-3.39(m,1H),2.58-2.47(m,1H),2.13-2.03(m,1H),1.73-1.63(m,2H),1.24-1.10(m,2H),0.94(t,J＝7.5Hz,3H),0.80(t,J＝9.0Hz,2H)。计算值[M+H] +436，实测值436。
化合物47的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物47。
实施例42：化合物48
Figure PCTCN2020097503-appb-000148
合成路线：
Figure PCTCN2020097503-appb-000149
第一步
参照实施例1第二步得到化合物48a。MS-ESI计算值[M+H] +666，实测值666。
第二步
参照实施例25第二步得到化合物48的甲酸盐。 1H NMR(400MHz,CD 3OD)δ＝8.65(d,J＝7.6Hz,1H),8.48(s,1H),8.43-8.39(m,1H),7.74-7.60(m,2H),7.16(d,J＝7.9Hz,1H),5.97(s,2H),4.14-4.02(m,1H),3.65-3.54(m,1H),3.47-3.38(m,1H),2.61-2.47(m,1H),2.37(t,J＝7.3Hz,2H),2.14-2.03(m,1H),1.66-1.54(m,2H),1.30-1.15(m,18H),0.89(t,J＝7.0Hz,3H),0.83-0.73(m,2H)。MS-ESI计算值[M+H] +532，实测值532。
化合物48的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物48。
实施例43：化合物49
Figure PCTCN2020097503-appb-000150
合成路线：
Figure PCTCN2020097503-appb-000151
第一步
参照实施例1第二步得到化合物49a。MS-ESI计算值[M+H] +596，实测值596。
第二步
参照实施例25第二步得到化合物49的甲酸盐。 1H NMR(400MHz,CD 3OD)δ＝8.65(d,J＝7.6Hz,1H),8.49(s,1H),8.43-8.40(m,1H),7.75-7.61(m,2H),7.16(d,J＝7.8Hz,1H),5.99(s,2H),4.12-4.02(m,1H),3.92-3.83(m,2H),3.66-3.54(m,1H),3.47-3.37(m,3H),2.73-2.62(m,1H),2.59-2.45(m,1H),2.15-2.01(m,1H),1.88-1.78(m,2H),1.75-1.61(m,2H),1.24-1.10(m,2H),0.85-0.75(m,2H)。MS-ESI计算值[M+H] +462，实测值462。
化合物49的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物49。
实施例44：化合物50
Figure PCTCN2020097503-appb-000152
合成路线：
Figure PCTCN2020097503-appb-000153
第一步
参照实施例1第二步得到化合物50a。MS-ESI计算值[M+H] +542，实测值542。
第二步
参照实施例25第二步得到化合物50的甲酸盐。 1H NMR(400MHz,CD 3OD)δ＝8.64(d,J＝7.9Hz,1H),8.44(s,1H),8.42-8.38(m,1H),7.72-7.64(m,2H),7.14(d,J＝7.8Hz,1H),5.98(s,2H),4.14-4.05(m,1H),3.80(s,3H),3.64-3.56(m,1H),3.48(d,J＝5.1Hz,1H),2.61-2.50(m,1H),2.18-2.07(m,1H),1.26-1.14(m,2H),0.85-0.73(m,2H)。MS-ESI计算值[M+H] +408，实测值408。
化合物50的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物50。
实施例45：化合物51
Figure PCTCN2020097503-appb-000154
合成路线：
Figure PCTCN2020097503-appb-000155
第一步
参照实施例1第二步得到化合物51a。MS-ESI计算值[M+H] +616，实测值616。
第二步
参照实施例25第二步得到化合物51的甲酸盐。 1H NMR(400MHz,CD 3OD)δ＝8.64(d,J＝7.9Hz,1H),8.49(br s,1H),8.42-8.35(m,1H),7.77(t,J＝8.1Hz,2H),7.70-7.62(m,1H),7.18(d,J＝7.8Hz,1H),7.09-6.98(m,2H),6.15(s,2H),4.10-3.98(m,1H),3.63-3.53(m,1H),3.45-3.37(m,1H),2.57-2.44(m,4H),2.30(s,3H),2.14-2.01(m,1H),1.26-1.08(m,2H),0.79(t,J＝9.0Hz,2H)。MS-ESI计算值[M+H] +482，实测值482。
化合物51的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物51。
实施例46：化合物52
Figure PCTCN2020097503-appb-000156
合成路线：
Figure PCTCN2020097503-appb-000157
第一步
参照实施例1第二步得到化合物52a。MS-ESI计算值[M+Na] +634，实测值634。
第二步
参照实施例25第二步得到化合物52的甲酸盐。 1H NMR(400MHz,CD 3OD)δ＝8.66(d,J＝7.8Hz,1H),8.61(s,1H),8.42(d,J＝7.8Hz,1H),7.74-7.64(m,2H),7.14(d,J＝7.8Hz,1H),6.03-5.92(m,2H),4.22-4.05(m,3H),3.59-3.61(m,1H),3.50(d,J＝4.8Hz,1H),2.54-2.57(m,1H),2.20-2.08(m,1H),1.71-1.59(m,2H),1.41-1.12(m,8H),0.87(t,J＝6.8Hz,3H),0.84-0.67(m,2H)。MS-ESI计算值[M+H] +478，实测值478。
化合物52的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物52。
实施例47：化合物53
Figure PCTCN2020097503-appb-000158
合成路线：
Figure PCTCN2020097503-appb-000159
第一步
参照实施例17第一步得到化合物53b。
第二步
参照实施例1第二步得到化合物53c。MS-ESI计算值[M+Na] +606，实测值606。
第二步
参照实施例25第二步得到化合物53的甲酸盐。 1H NMR(400MHz,CD 3OD)δ＝8.66(d,J＝8.0Hz,1H),8.48(s,1H),8.42(dd,J＝1.1,7.8Hz,1H),7.75-7.62(m,2H),7.17(d,J＝7.8Hz,1H),6.04-5.91(m,2H),4.17(t,J＝6.6Hz,2H),4.05-4.07(m,1H),3.65-3.53(m,1H),3.41(dd,J＝3.2,7.6Hz,1H),2.51-2.53(m,1H),2.13-1.99(m,1H),1.69-1.56(m,2H),1.35-1.40(m,2H),1.25-1.08(m,2H),0.92(t,J＝7.4Hz,3H),0.85-0.75(m,2H)。MS-ESI计算值[M+H] +450，实测值450。
化合物53的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物53。
实施例48：化合物54
Figure PCTCN2020097503-appb-000160
合成路线：
Figure PCTCN2020097503-appb-000161
第一步
参照实施例1第二步得到化合物54a。MS-ESI计算值[M+Na] +610，实测值610。
第二步
参照实施例25第二步得到化合物54的甲酸盐。 1H NMR(400MHz,CD 3OD)δ＝8.66-8.64(d,J＝7.8Hz,1H),8.50(s,1H),8.43-8.41(d,J＝7.8Hz,1H),8.34(m,1H),7.76-7.63(m,2H),7.14(d,J＝7.8Hz,1H),5.96-5.93(m,2H),4.66-4.61(m,1H),3.94-3.59(m,J＝6.4,9.0,11.8Hz,1H),3.58-3.56(m,J＝4.8Hz,1H),3.56-3.24(m,J＝4.8Hz,1H),3.24-3.22(m,J＝4.8Hz,1H),2.41-1.89(dt,J＝8.4,14.0Hz,2H),1.87–1.72(m,2H),1.71-1.36(m,7H),1.36-1.39(m,2H),1.14-1.12(m,J＝6.8Hz,1H),0.90-0.75(m,1H)。MS-ESI计算值[M+H] +476，实测值476。
化合物54的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物54。
实施例49：化合物55
Figure PCTCN2020097503-appb-000162
合成路线：
Figure PCTCN2020097503-appb-000163
第一步
将化合物3(150mg,231μmol)，碳酸钾(63.8mg,462μmol)溶于无水四氢呋喃(5mL)中，在60摄氏度下搅拌1小时。然后在60摄氏度将化合物15b(70.4mg,462μmol)加入到反应体系中，控制温度60摄氏度搅拌12小时。减压浓缩除去溶剂，粗产物经硅胶板层析法(乙酸乙酯：乙醇)纯化，减压浓缩得到化合物55a。MS-ESI计算值[M+H] +538，实测值538。
第二步
参照实施例1第三步得到化合物55(中性制备高效液相色谱纯化)。 1H NMR(400MHz,CD 3OD)δ＝8.68(dd,J＝1.4,8.1Hz,1H),8.07(dd,J＝1.5,7.8Hz,1H),7.63(t,J＝7.9Hz,1H),7.42(d,J＝0.9Hz,1H),5.93(s,2H),4.93-4.89(m,1H),3.84(d,J＝12.9Hz,2H),3.18-3.09(m,2H),2.99-2.87(m,1H),2.68(d,J＝0.8Hz,3H),2.01-1.90(m,2H),1.55-1.42(m,2H),1.28(d,J＝6.3Hz,6H)。MS-ESI计算值[M+H] +438，实测值438。
实施例50：化合物56
Figure PCTCN2020097503-appb-000164
合成路线：
Figure PCTCN2020097503-appb-000165
第一步
将化合物2(435mg,1.07mmol)溶于N,N-二甲基甲酰胺(10mL)中，在0摄氏度下向反应液中加入叔丁醇钾(359mg,3.20mmol)，反应液在0摄氏度搅拌1小时。在0摄氏度下继续向反应液中加入化合物15a(226mg,1.17mmol)，反应液在25摄氏度搅拌13小时。向反应液中加入水(4mL)，用乙酸乙酯(3mL×3)萃取，合并有机相，用饱和食盐水(5mL×3)洗涤，无水硫酸钠干燥，过滤，减压浓缩，粗产物经过硅胶柱层析法(石油醚/乙酸乙酯)分离纯化得到化合物56a。
第二步
将化合物56a(150mg,0.266mmol)溶于无水乙酸乙酯(2mL)中，向反应液中加入盐酸乙酸乙酯(4M,16.0mmol)，反应液在20摄氏度搅拌反应3小时。减压浓缩除去溶剂，粗产物经过高效液相色谱法(盐酸体系)制备得到化合物56的盐酸盐。 1H NMR(400MHz,CD 3OD)δ8.68(d,J＝8.0Hz,1H),8.46(s,1H),8.39(dd,J＝7.8,1.2Hz,1H),7.73(t,J＝7.8Hz,1H),7.67(d,J＝7.8Hz,1H),7.51(d,J＝7.8Hz,1H),6.00(s,2H),4.62-4.71(m,1H),3.77-3.87(m,1H),3.50-3.64(m,2H),3.34-3.40(m,2H),2.24-2.36(m,1H),1.86-2.03(m,3H),1.75(dt,J＝6.4,3.1Hz,2H),1.24-1.61(m,6H)。MS-ESI计算值[M+H] +450，实测值450。
化合物56的盐酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物56。
实施例51：化合物57
Figure PCTCN2020097503-appb-000166
合成路线：
Figure PCTCN2020097503-appb-000167
第一步
参照实施例50第一步得到化合物57a。MS-ESI计算值[M+H] +510，实测值510。
第三步
参照实施例1第三步粗产物经过高效液相色谱法(甲酸体系)制备得到化合物57的甲酸盐。 1H NMR(400MHz,CDCl 3)δ8.69-8.63(m,1H),8.25-8.20(m,1H),7.64-7.61(m,1H),7.59-7.40(m,1H),5.96-5.74(m,2H),4.24-4.20(m,2H),3.70-3.66(m,3H),3.54(s,1H),3.20-3.18(m,1H),2.68-2.66(m,3H),2.28-2.27(m,1H),1.92-1.91(m,1H),1.31-1.26(m,3H)。MS-ESI计算值[M+H] +410，实测值410。
化合物57的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物57。
实施例52：化合物58
Figure PCTCN2020097503-appb-000168
合成路线：
Figure PCTCN2020097503-appb-000169
第一步
参照实施例1第二步得到化合物58a。MS-ESI计算值[M+H] +556，实测值556。
第二步
参照实施例1第三步粗产物经过高效液相色谱法(中性体系)制备得到化合物58。 1H NMR(400MHz,CD 3OD)δ＝8.72(d,J＝8.1Hz,1H),8.10(d,J＝7.7Hz,1H),8.04(d,J＝8.1Hz,2H),7.68-7.59(m,2H),7.56(s,1H),7.51-7.45(m,2H),6.20(s,2H),3.85(d,J＝13.0Hz,2H),3.14(t,J＝11.2Hz,2H),2.99-2.89(m,1H),2.72(s,3H),1.95(d,J＝10.9Hz,2H),1.55-1.42(m,2H)。MS-ESI计算值[M+H] +456，实测值456。
实施例53：化合物59
Figure PCTCN2020097503-appb-000170
合成路线：
Figure PCTCN2020097503-appb-000171
第一步
参照实施例49第一步得到化合物59a。MS-ESI计算值[M+H] +538，实测值538。
第二步
参照实施例1第三步得到化合物59的甲酸盐。 1H NMR(400MHz,CD 3OD)δ＝8.73(d,J＝7.7Hz,1H),8.55(s,1H),8.10(d,J＝7.6Hz,1H),7.66(t,J＝7.8Hz,1H),7.47(s,1H),5.96(s,2H),4.59(m,1H),3.99(d,J＝12.8Hz,2H),3.46-3.37(m,1H),3.23(t,J＝12.3Hz,2H),2.70(s,3H),2.14(d,J＝11.2Hz,2H),1.85-1.61(m,2H),1.30(d,J＝6.1Hz,6H)。MS-ESI计算值[M+H] +438，实测值438。
化合物59的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物59。
实施例54：化合物60
Figure PCTCN2020097503-appb-000172
合成路线：
Figure PCTCN2020097503-appb-000173
第一步
参照实施例49第一步得到化合物60a。MS-ESI计算值[M+H] +542，实测值542。
第二步
参照实施例1第三步粗产物经过高效液相色谱法(中性体系)制备得到化合物60。MS-ESI计算值[M+H] +442，实测值442。 1H NMR(400MHz,CD 3OD)δ＝8.72(dd,J＝1.41,8.01Hz,1H),8.25(dd,J＝1.47,7.70Hz,1H),7.98-8.11(m,2H),7.58-7.71(m,2H),7.56(d,J＝0.86Hz,1H),7.43-7.52(m,2H),6.21(s,2H),3.63-3.76(m,3H),3.51-3.60(m,1H),3.21(dd,J＝4.65,9.17Hz,1H),2.72(d,J＝0.86Hz,3H),2.24-2.35(m,1H),1.92(dd,J＝6.97,13.33Hz,1H)。
实施例55：化合物61
Figure PCTCN2020097503-appb-000174
合成路线：
Figure PCTCN2020097503-appb-000175
第一步
参照实施例49第一步得到化合物61a。MS-ESI计算值[M+Na] +502，实测值502。
第二步
参照实施例1第三步得到化合物61的甲酸盐。MS-ESI计算值[M+Na] +402，实测值402。 1H NMR(400MHz,CDCl 3)δ＝8.84-8.56(m,1H),8.30(d,J＝6.5Hz,1H),8.13(s,1H),7.56(s,1H),7.45(d,J＝7.5Hz,1H),7.28-7.23(m,1H),5.94(s,2H),4.10-3.96(m,2H),3.85(s,2H),3.79(s,2H),3.72-3.37(m,1H),2.74-2.46(m,1H),1.25-1.04(m,6H)。
化合物61的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物61。
实施例56：化合物62
Figure PCTCN2020097503-appb-000176
合成路线：
Figure PCTCN2020097503-appb-000177
第一步
将二甲胺盐酸盐(332mg,4.07mmol)和碳酸钾(1.23g,8.92mmol)溶于无水二氯甲烷(5mL)中，在-78摄氏度下向反应液中滴加氯甲酸氯甲酯23b(500mg,3.88mmol)，反应液在-78摄氏度搅拌3小时。趁冷将反应液过滤，浓缩得粗产物化合物62a，未经纯化直接用于下一步反应。 1H NMR(400MHz,CDCl 3)δ＝5.71(s,2H),2.89(d,J＝8.8Hz,6H)。
第二步
参照实施例49第一步得到化合物62b。MS-ESI计算值[M+H] +481，实测值481。
第三步
参照实施例1第三步得到化合物62的甲酸盐。MS-ESI计算值[M+H] +381，实测值381。 1H NMR(400MHz,CD 3OD)δ＝8.66(d,J＝7.6Hz,1H),8.37(s,1H),8.36(dd,J＝1.3,7.7Hz,1H),7.74-7.61(m,2H),7.32(d,J＝7.9Hz,1H),5.96(s,2H),4.13-4.06(m,2H),3.99-3.87(m,1H),3.87-3.77(m,2H),2.91(d,J＝2.7Hz,6H)。
化合物62的甲酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到化合物62。
实施例57：化合物63
Figure PCTCN2020097503-appb-000178
合成路线：
Figure PCTCN2020097503-appb-000179
第一步
参照实施例49第一步得到化合物63a。MS-ESI计算值[M+H] +570，实测值570。
第二步
参照实施例50第三步粗产物经过高效液相色谱法(中性体系)制备得到化合物63。MS-ESI计算值[M+H] +470，实测值470。 1H NMR(400MHz,CD 3OD)δ＝8.71(dd,J＝1.4,8.0Hz,1H),8.24(dd,J＝1.5,7.8 Hz,1H),7.81(d,J＝7.9Hz,1H),7.64(t,J＝7.9Hz,1H),7.54(d,J＝0.9Hz,1H),7.09(s,1H),7.05(d,J＝7.9Hz,1H),6.14(s,2H),3.77-3.62(m,3H),3.59-3.50(m,1H),3.20(dd,J＝4.9,9.5Hz,1H),2.70(d,J＝0.9Hz,3H),2.53(s,3H),2.32(s,3H),2.30-2.23(m,1H),1.96-1.86(m,1H)。
实施例58：化合物64
Figure PCTCN2020097503-appb-000180
合成路线：
Figure PCTCN2020097503-appb-000181
第一步
参照实施例49第一步得到化合物64a。MS-ESI计算值[M+H] +542，实测值542。
第二步
参照实施例1第三步粗产物经过高效液相色谱法(中性体系)制备得到化合物64。MS-ESI计算值[M+H] +442，实测值442。 1H NMR(400MHz,CD 3OD)δ＝8.69-8.63(m,1H),8.23-8.16(m,1H),8.04-7.96(m,2H),7.64-7.54(m,2H),7.51(s,1H),7.46-7.39(m,2H),6.17(s,2H),3.75-3.59(m,3H),3.57-3.48(m,1H),3.23-3.13(m,1H),2.67(s,3H),2.33-2.20(m,1H),1.96-1.81(m,1H)。
实施例59：对照化合物1
Figure PCTCN2020097503-appb-000182
第一步
将中间体2(360mg,0.82mmol)溶于乙酸乙酯(5mL)中，向体系中滴加盐酸乙酸乙酯溶液(1.86mL, 4M)。待反应完全后，将析出的固体过滤后用乙酸乙酯(5mL×3)洗涤、干燥后得到对照化合物1的盐酸盐。MS-ESI计算值[M+H] +308，实测值308。
对照化合物1的盐酸盐可以通过向体系中加饱和碳酸钠水溶液将反应液pH调节至8-9，然后用乙酸乙酯萃取后浓缩干即可得到对照化合物1。
实施例60：对照化合物2
Figure PCTCN2020097503-appb-000183
第一步
将中间体6(4g,9.57mmol)溶于四氢呋喃(40mL)中，控制反应液内温为0℃，向体系中滴加浓硫酸(1.88g,19.15mmol)。待反应完全后，将析出的固体过滤后经高效液相色谱法(中性体系)制备得到对照化合物2。MS-ESI计算值[M+H] +308，实测值308。 1H NMR(400MHz,CD 3OD)δ8.68(d,1H),8.24-8.26(m,1H),7.61-7.65(m,1H),7.13(s,1H),3.67-3.73(m,3H),3.57-3.66(m,1H),3.19-3.22(m,1H),2.69(s,3H),2.27-2.30(m,1H),1.91-1.95(m,1H)。
生物测试实验
实验例1.房水中药代动力学测试
实验目的：
化合物为含有酯基官能团的前药分子，滴眼给药时经眼组织中丰富的酯水解酶作用可水解为活性药物分子(母药)。本实验检测化合物在体内产生活性药物成分的速度和活性药物成分暴露量。
实验材料：
雄性新西兰大白兔，月龄3-6月，体重2.0-5.0kg，购自邳州东方养殖有限公司。
滴眼样品配置：
使用溶媒为1.2％羟丙基甲基纤维素E5/20.5％泊洛沙姆P407/1.6％泊洛沙姆P188。
实验操作：
滴眼给药剂量为0.5mg/眼，双眼滴眼给药。给药后0.25h，0.5h，2h，4h，8h，24h采集房水，制备房水样品。所有样品运用液相色谱偶联质谱质谱联用技术对给药化合物在实验动物房水中含量进行定量检测，所测浓度值运用WinNonlin非房室模型，根据房水浓度-时间数据，计算半衰期，房水药峰值浓度，房水药峰值时间，单位暴露量等参数。
表1 新西兰兔房水中药代动力学测试结果
Figure PCTCN2020097503-appb-000184
“--”：未检测。
结论：实验结果显示，房水中未检测到供试品化合物(前药分子)，而主要检测到其酯水解后的活性代谢产物(母药分子)，本发明化合物相比对照化合物1和对照化合物2，显著提高了活性药物的暴露量，同时，血药峰值浓度和作用时间均显著提高。
实验例2.正常眼压新西兰兔的降眼压试验
实验目的：
采用正常眼压的兔子，通过滴眼给药筛选潜在化合物的降眼压作用。
实验材料：
雄性新西兰大白兔，日龄97-127天，体重2.65-3.5kg，购自邳州东方养殖有限公司。
实验操作：
雄性新西兰大白兔，采用计算机生成的随机方法进行随机分组，8只/组。每组动物右眼滴眼给予不同的供试品，左眼滴眼给予生理盐水或溶媒，给药体积均为50μL/眼。给药前，给药后1，2，4，6，8和10小时分别测定动物眼压。实验结果见表2：
表2 不同供试品给药前后新西兰兔双眼眼压(Mean±SEM)的变化结果
Figure PCTCN2020097503-appb-000185
Figure PCTCN2020097503-appb-000186
结论:与K-115相比，本发明化合物展现了更大的降眼压幅度和更加持久的降眼压作用时间。且化合物60在2.5，5和10mg/mL浓度下，动物的眼压均存在极显著地下降。
实施例3.急性高眼压新西兰兔的降眼压试验
实验目的：
采用前房注射粘弹剂诱导兔子急性高眼压，通过滴眼给药来探究化合物60和化合物63在不同浓度下的降眼压作用。
实验材料：
雄性新西兰大白兔，日龄97-127天，体重2.5-3.4kg，购自邳州东方养殖有限公司。
实验操作一：
雄性新西兰大白兔，采用计算机生成的随机方法，根据体重进行随机分组，8只/组。各组动物右眼前房一 次性注射医用透明质酸钠凝胶，100μL/眼，诱导动物产生高眼压。右眼造模后5～15分钟，3和6小时，双眼滴眼给予溶媒、K-115或者供试品(不同浓度的化合物60)，给药体积均为50μL/眼，给药前，给药后1，2，4，6，8和10小时分别测定动物眼压。实验结果见表3：
表3 各组动物造模及给药前后双眼眼压(Mean±SEM)的变化结果
Figure PCTCN2020097503-appb-000187
实验操作二：
50只雄性新西兰大白兔，根据体重进行随机分组，共5组，10只/组。1-5组动物右眼前房一次性注射医用透明质酸钠凝胶，100μL/眼，诱导动物产生高眼压。造模后5～15分钟，右眼分别滴眼给予溶媒、K-115和供试品(不同浓度的化合物63)，左眼滴眼给予溶媒，给药体积均为50μL/眼，给药前，给药后2，4，6，8和10小时分别测定动物双眼眼压。实验结果见表4：
表4 各组动物造模及给药前后双眼眼压(Mean±SEM)的变化结果
Figure PCTCN2020097503-appb-000188
Figure PCTCN2020097503-appb-000189
结论:在急性高眼压模型中，本发明化合物在不同的测试剂量下都展示了良好的降压效果，同时具有一定的剂量相关性，降压幅度和持续作用时间均优于K-115。
实验例4. 14天重复滴眼给药在正常眼压新西兰兔的降眼压和眼部毒性试验
实验目的：
采用正常眼压的兔子，通过14天重复滴眼给药探索化合物63的降眼压作用和潜在的眼部毒性。
实验材料：
雄性新西兰大白兔，日龄97-127天，体重2.63.5kg，购自邳州东方养殖有限公司。
实验操作一：
雄性新西兰大白兔，随机分成7组，每组6只。将依据动物体重进行随机分组。1-7组动物双眼滴眼给予溶媒/对照品/供试品，给药体积均为50μL/眼，每天1次，连续14天，给药当天记为第1天。第1天给药前，给药后1，2，4，6，8和10小时分别测定动物眼压，第2-14天，K-115给药组在每天给药后1小时测定眼压，其余各组在每天给药后4小时测定动物眼压。实验结果见表5、6和7：
表5 各组动物第一天给药前后双眼眼压(Mean±SEM)的变化
Figure PCTCN2020097503-appb-000190
Figure PCTCN2020097503-appb-000191
表6 各组动物第2-7天重复给药前后双眼眼压(Mean±SEM)的变化
Figure PCTCN2020097503-appb-000192
Figure PCTCN2020097503-appb-000193
表7 各组动物第8-14天重复给药前后双眼眼压(Mean±SEM)的变化
Figure PCTCN2020097503-appb-000194
结论：化合物63单次给药在所有的测试剂量(0.5-8.0mg/mL)下都展示了更加优异的药效(最高降压效果和作用时间)，显著优于K-115。在14天连续给药的情况下，化合物63在0.5mg/mL剂量下可以持续的维持显著的降压效果，在峰值(Cmax)降压效果的评价中依然显著优于K-115。
实验操作二：
42只雄性新西兰大白兔，随机分成7组，每组6只。依据动物体重进行随机分组。1-7组动物左眼滴眼给生理盐水，右眼分别滴眼给予溶媒/对照品/供试品，给药体积均为50μL/眼，每天1次，连续14天，给药 当天记为第1天。第1天给药前，第1天给药后1，2，4，6，8和10小时分别测定动物眼压(表8)。试验开始前(第2天/第1天)、给药期间每天给药前(第1-14天)、末次(第14天)给药后1、2、4、24、48和72小时，用手持裂隙灯对动物双眼进行眼刺激反应检查和荧光素钠检查(参考评分标准进行评分)。
表8 各组动物第一天给药前后双眼眼压(Mean±SEM)的变化
Figure PCTCN2020097503-appb-000195
结论：化合物63单次给药在所有的测试剂量(0.25-4.0mg/mL)下都展示了更加优异的药效(最高降压效果和作用时间)，显著优于K-115。
试验开始前(第2天/第1天)、给药期间每天第一次给药前(第1-14天)以及末次药后1、2、4、24、48和72小时，用手持裂隙灯对动物双眼进行眼刺激反应检查，评分分值标准如下：
眼刺激反应 分值
角膜  
眼刺激反应 分值
无混浊 0
散在或弥漫性混浊，虹膜清晰可见 1
半透明区易分辨，虹膜模糊不清 2
出现灰白色半透明区，虹膜细节不清，瞳孔大小勉强可见 3
角膜不透明，虹膜无法辨认 4
虹膜  
正常 0
皱褶明显加深、充血、肿胀，角膜周围轻度充血，瞳孔对光仍有反应 1
出血/肉眼可见坏死/对光无反应(或其中一种) 2
结膜  
充血(指睑结膜和球结膜)  
血管正常 0
血管充血呈鲜红色 1
血管充血呈深红色，血管不易分辨 2
弥漫性充血呈紫红色 3
水肿  
无水肿 0
轻微水肿(含眼睑) 1
明显水肿伴部分眼睑外翻 2
水肿至眼睑近半闭合 3
水肿至眼睑超过半闭合 4
分泌物  
无分泌物 0
少量分泌物 1
分泌物使眼睑和睫毛潮湿或粘着 2
分泌物使整个眼区潮湿或粘着 3
最大总积分 16
眼刺激反应评价：将角膜、虹膜、结膜、水肿和分泌物的最大积分相加，得到每只动物眼每个时间点眼刺激症状的总积分。对于眼刺激症状评分分值，计算每个观察时间点、每组动物的积分均值，按下表判定每 个时间点、每组动物眼刺激程度。
眼刺激性评价标准
分值 评价
0-3 无刺激性
4-8 轻度刺激性
9-12 中度刺激性
13-16 重度刺激性
荧光素钠检查：每次眼刺激反应检查结束后，用手持裂隙灯进行荧光素钠检查，评分分值标准如下：
Figure PCTCN2020097503-appb-000196
实验结果如下：
根据眼刺激性评价标准进行评价，各组各时间点眼刺激反应总评分小于3，按标准分类均为无刺激性。
试验期间，各组动物生理盐水处理眼别、溶媒、K-115和化合物63处理眼的荧光素钠检查评分均低于1。每组动物在各个处理和个体时间点，均出现有角膜荧光染色评分为1的染色，考虑为生理性染色。各组各时间点均未出现角膜上皮损伤。
结论：在本试验条件下，K-115在4mg/mL浓度下，连续14天滴眼，50微升/眼/天，无刺激性。化合物63在0.25～4mg/mL浓度范围内，连续14天滴眼，50微升/眼/天，无刺激性。
实验例5.毒代动力学实验
实验目的：
检测连续14天给药后化合物在血浆中产生活性药物成分的速度和活性药物成分暴露量。
实验材料：
雄性新西兰大白兔，月龄3-6月，体重2.0-5.0kg，购自邳州东方养殖有限公司。
实验操作：
连续给药14天后，在第14-15天，选择化合物63(8.0mg/mL)给药组按采集0小时(给药前)和给药后0.5，1，2，4，8，和24小时血样。从毒代实验动物耳中动脉，或后肢隐静脉(或其它合适位点)采集大约0.8mL全血，置于以乙二胺四乙酸二钾(K 2EDTA)作为抗凝剂的贴有标签的采血管中。采血后60分钟内在3000转/分和2℃至8℃条件下离心10分钟获得血浆。所有样品运用液相色谱偶联质谱质谱联用技术对给药化合物在实验动物血浆中含量进行定量检测。
表9 连续给药14天后新西兰兔血浆中活性化合物的测试结果
Figure PCTCN2020097503-appb-000197
注：BQL表示低于检测限。
结论：化合物63在8mg/mL的高剂量下，给药4小时后，其代谢产物浓度为0.934ng/mL；给药8小时后，其代谢产物浓度低于检测限，系统安全性高。

Claims (25)

  1. 式(I)所示化合物、其异构体或其药学上可接受的盐，
    Figure PCTCN2020097503-appb-100001
    其中，
    T 1选自-(CH 2) n-；
    T 2选自-(CH 2) m-和-C(R 7)(R 8)-；
    R 1选自C 1-16烷基、苯基、C 3-7环烷基、3-8元杂环烷基和5-10元杂芳基，所述C 1-16烷基、苯基、C 3-7环烷基、3-8元杂环烷基和5-10元杂芳基分别独立地任选被1、2或3个R a取代；
    R 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和C 1-3烷基；
    R 4选自H、F、Cl、Br、I、OH、NH 2、CN和任选被1、2或3个R b取代C 1-3烷基；
    R 5选自NR 9R 10；
    R 6选自H、F、Cl、Br、I、OH、NH 2、CN和C 1-3烷基；
    R 7和R 8分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和任选被1、2或3个R c取代的C 1-3烷基；
    或者，R 7、R 8和与它们相连的原子共同构成任选被1、2或3个R d取代的C 3-5环烷基；
    R 9和R 10分别独立地选自H和任选被1、2或3个R e取代C 1-3烷基；
    L选自单键、-O-和-NR 11-；
    R 11自H和C 1-3烷基；
    n选自0、1和2；
    m选自0、1、2和3；
    R a选自F、Cl、Br、I、OH、NH 2、CN、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个R取代；
    R b、R c、R d和R e分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和C 1-3烷基；
    R选自F、Cl、Br、I、OH、NH 2、CN和CH 3；
    所述3-8元杂环烷基和5-10元杂芳基分别独立地包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。
  2. 根据权利要求1所述化合物、其异构体或其药学上可接受的盐，其中，R a选自F、Cl、Br、I、OH、NH 2、CN、CH 3、CF 3、CH 2F、CHF 2、CH 2CH 3和OCH 3。
  3. 根据权利要求1所述化合物、其异构体或其药学上可接受的盐，其中，R 1选自C 1-12烷基、苯基、环丁烷基、环戊烷基、环己烷基、四氢呋喃基、四氢吡喃基、哌啶基、噻吩基、呋喃基、吡咯基和苯并呋喃基，所述C 1-12烷基、苯基、环丁烷基、环戊烷基、环己烷基、四氢呋喃基、四氢吡喃基、哌啶基、噻吩基、呋喃基、吡咯基和苯并呋喃基分别独立地任选被1、2或3个R a取代。
  4. 根据权利要求3所述化合物、其异构体或其药学上可接受的盐，其中，R 1选自CH 3、CH 2CH 3、(CH 2) 2CH 3、(CH 2) 3CH 3、(CH 2) 4CH 3、(CH 2) 5CH 3、(CH 2) 6CH 3、(CH 2) 10CH 3、CH(CH 3) 2、C(CH 3) 3、
    Figure PCTCN2020097503-appb-100002
    Figure PCTCN2020097503-appb-100003
  5. 根据权利要求2或4所述化合物、其异构体或其药学上可接受的盐，其中，R 1选自CH 3、CH 2CH 3、(CH 2) 2CH 3、(CH 2) 3CH 3、(CH 2) 4CH 3、(CH 2) 5CH 3、(CH 2) 6CH 3、(CH 2) 10CH 3、CH(CH 3) 2、C(CH 3) 3、
    Figure PCTCN2020097503-appb-100004
    Figure PCTCN2020097503-appb-100005
  6. 根据权利要求1所述化合物、其异构体或其药学上可接受的盐，其中，R 2和R 3分别独立地选自H、F、Cl、Br、I、OH和NH 2。
  7. 根据权利要求1所述化合物、其异构体或其药学上可接受的盐，其中，R 4选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3和CH 2CH 3。
  8. 根据权利要求1所述化合物、其异构体或其药学上可接受的盐，其中，R 9和R 10分别独立地选自H、CH 3和CH 2CH 3。
  9. 根据权利要求1或8所述化合物、其异构体或其药学上可接受的盐，其中，R 5选自NH 2、NH(CH 3)和N(CH 3) 2。
  10. 根据权利要求1所述化合物、其异构体或其药学上可接受的盐，其中，R 6选自H、F、Cl、Br、I、OH、NH 2、CN和CH 3。
  11. 根据权利要求1所述化合物、其异构体或其药学上可接受的盐，其中，R 7和R 8分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和CH 3。
  12. 根据权利要求1所述化合物、其异构体或其药学上可接受的盐，其中，R 7、R 8和与它们相连的原子共同构成任选被1、2或3个R d取代的环丙烷基。
  13. 根据权利要求12所述化合物、其异构体或其药学上可接受的盐，其中，R 7、R 8和与它们相连的原子共同构成环丙烷基。
  14. 根据权利要求1所述化合物、其异构体或其药学上可接受的盐，其中，L选自单键、-O-、-NH-和-N(CH 3)-。
  15. 根据权利要求1、12或13任意一项所述化合物、其异构体或其药学上可接受的盐，其中，T 2选自-CH 2-、-(CH 2) 2-和
    Figure PCTCN2020097503-appb-100006
  16. 根据权利要求1所述化合物、其异构体或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2020097503-appb-100007
    选自
    Figure PCTCN2020097503-appb-100008
  17. 根据权利要求1或16所述化合物、其异构体或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2020097503-appb-100009
    选自
    Figure PCTCN2020097503-appb-100010
  18. 根据权利要求1所述化合物、其异构体或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2020097503-appb-100011
    选自CH 3、CH 2CH 3、(CH 2) 2CH 3、(CH 2) 3CH 3、(CH 2) 4CH 3、(CH 2) 5CH 3、(CH 2) 6CH 3、(CH 2) 10CH 3、CH(CH 3) 2、C(CH 3) 3、OCH 3、OCH 2CH 3、O(CH 2) 2CH 3、O(CH 2) 3CH 3、O(CH 2) 4CH 3、O(CH 2) 5CH 3、O(CH 2) 6CH 3、OCH(CH 3) 2、OC(CH 3) 3、N(CH 3) 2、
    Figure PCTCN2020097503-appb-100012
    Figure PCTCN2020097503-appb-100013
  19. 根据权利要求1、3～5、7、9或14任意一项所述化合物、其异构体或其药学上可接受的盐，其选自
    Figure PCTCN2020097503-appb-100014
    其中，
    R 1如权利要求1、3、4或5所定义；
    R 4如权利要求1或7所定义；
    R 5如权利要求1或9所定义；
    L如权利要求1或14所定义。
  20. 根据权利要求19所述化合物、其异构体或其药学上可接受的盐，其选自
    Figure PCTCN2020097503-appb-100015
    其中，
    R 1、R 4和L如权利要求19所定义。
  21. 下式所示化合物、其异构体或其药学上可接受的盐，
    Figure PCTCN2020097503-appb-100016
    Figure PCTCN2020097503-appb-100017
    Figure PCTCN2020097503-appb-100018
  22. 根据权利要求21所述化合物、其异构体或其药学上可接受的盐，其选自
    Figure PCTCN2020097503-appb-100019
    Figure PCTCN2020097503-appb-100020
    Figure PCTCN2020097503-appb-100021
    Figure PCTCN2020097503-appb-100022
    Figure PCTCN2020097503-appb-100023
    Figure PCTCN2020097503-appb-100024
  23. 一种药物组合物，包括作为活性成分的治疗有效量的根据权利要求1～22任意一项所述的化合物、其异构体或其药学上可接受的盐以及药学上可接受的载体。
  24. 根据权利要求1～22任意一项所述的化合物、其异构体或其药学上可接受的盐或者权利要求23所述的组合物在制备ROCK蛋白激酶抑制剂相关药物上的应用。
  25. 根据权利要求24所述的应用，其特征在于，所述ROCK蛋白激酶抑制剂相关药物是用于治疗青光眼或高眼压症的药物。
PCT/CN2020/097503 2019-06-21 2020-06-22 作为rock蛋白激酶抑制剂的异喹啉酮的衍生物及其应用 WO2020253882A1 (zh)

Priority Applications (9)

Application Number Priority Date Filing Date Title
US17/621,502 US20230024516A1 (en) 2019-06-21 2020-06-22 Isoquinolinone derivatives serving as rock protein kinase inhibitors and use thereof
CN202080041488.6A CN113906017B (zh) 2019-06-21 2020-06-22 作为rock蛋白激酶抑制剂的异喹啉酮的衍生物及其应用
EP20827811.9A EP3988544A4 (en) 2019-06-21 2020-06-22 ISOQUINOLINONE DERIVATIVES AS ROCK PROTEIN KINASE INHIBITORS AND THEIR USE
JP2021576289A JP7398137B2 (ja) 2019-06-21 2020-06-22 Ｒｏｃｋプロテインキナーゼ阻害薬としてのイソキノリンの誘導体及びその使用
AU2020296050A AU2020296050B2 (en) 2019-06-21 2020-06-22 Isoquinolinone derivatives serving as ROCK protein kinase inhibitors and use thereof
MX2021016068A MX2021016068A (es) 2019-06-21 2020-06-22 Derivados de isoquinolinona como inhibidores de la proteina quinasa rock y usos del mismo.
KR1020227002287A KR20220024868A (ko) 2019-06-21 2020-06-22 Rock단백질 키나아제 억제제인 이소퀴놀리논의 유도체 및 그 응용
CA3144211A CA3144211A1 (en) 2019-06-21 2020-06-22 Isoquinolinone derivatives serving as rock protein kinase inhibitors and uses thereof
ZA2022/00834A ZA202200834B (en) 2019-06-21 2022-01-18 Isoquinolinone derivatives serving as rock protein kinase inhibitors and use thereof

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201910544202.5 2019-06-21
CN201910544202 2019-06-21
CN201911078066 2019-11-06
CN201911078066.1 2019-11-06

Publications (1)

Publication Number Publication Date
WO2020253882A1 true WO2020253882A1 (zh) 2020-12-24

Family

ID=74040659

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/097503 WO2020253882A1 (zh) 2019-06-21 2020-06-22 作为rock蛋白激酶抑制剂的异喹啉酮的衍生物及其应用

Country Status (10)

Country Link
US (1) US20230024516A1 (zh)
EP (1) EP3988544A4 (zh)
JP (1) JP7398137B2 (zh)
KR (1) KR20220024868A (zh)
CN (1) CN113906017B (zh)
AU (1) AU2020296050B2 (zh)
CA (1) CA3144211A1 (zh)
MX (1) MX2021016068A (zh)
WO (1) WO2020253882A1 (zh)
ZA (1) ZA202200834B (zh)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022135421A1 (zh) * 2020-12-21 2022-06-30 广州润尔眼科生物科技有限公司 一种作为rock蛋白激酶抑制剂的异喹啉酮型化合物的盐型及其制备方法
WO2023241652A1 (zh) * 2022-06-16 2023-12-21 广州润尔眼科生物科技有限公司 一种药物组合物及其制备方法和应用

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004106325A1 (en) * 2003-05-29 2004-12-09 Schering Aktiengesellschaft Prodrugs of 1-(1-hydroxy-5-isoquinolinesulfonyl)homopiperazine
WO2006057397A1 (ja) 2004-11-29 2006-06-01 Kowa Co., Ltd. （ｓ）－（－）－１－（４－フルオロイソキノリン－５－イル）スルホニル－２－メチル－１，４－ホモピペラジン塩酸塩・二水和物
WO2007026664A1 (ja) 2005-08-30 2007-03-08 Asahi Kasei Pharma Corporation スルホンアミド化合物
CN101622243A (zh) * 2007-02-28 2010-01-06 旭化成制药株式会社 磺酰胺衍生物
CN105085478A (zh) * 2014-04-28 2015-11-25 南京明德新药研发股份有限公司 异喹啉磺胺衍生物及其药物组合物和制药用途
CN105085525A (zh) * 2014-04-28 2015-11-25 南京明德新药研发股份有限公司 作为rho激酶抑制剂的异喹啉磺酰衍生物

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0667926B2 (ja) * 1985-11-12 1994-08-31 旭化成工業株式会社 環状のイソキノリンスルホンアミド誘導体
JP3906284B2 (ja) 1995-04-14 2007-04-18 株式会社東芝 光ディスクからビデオ及びオーディオを再生する再生システム、その再生方法及び光ディスクの記録方法
JP2006290827A (ja) * 2005-04-13 2006-10-26 Kowa Co 緑内障予防又は治療剤
JP4831826B2 (ja) 2006-10-23 2011-12-07 日本プラスト株式会社 ベンチレータ及びベンチレータ装置
GB201107223D0 (en) * 2011-04-29 2011-06-15 Amakem Nv Novel rock inhibitors
ES2774923T3 (es) * 2014-04-28 2020-07-23 China Resources Pharmaceutical Holdings Company Ltd Derivados de isoquinolinsulfonilo como inhibidores de RHO quinasa
CN114644618A (zh) * 2020-12-21 2022-06-21 广州润尔眼科生物科技有限公司 一种作为rock蛋白激酶抑制剂的异喹啉酮型化合物的盐型及其制备方法

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004106325A1 (en) * 2003-05-29 2004-12-09 Schering Aktiengesellschaft Prodrugs of 1-(1-hydroxy-5-isoquinolinesulfonyl)homopiperazine
WO2006057397A1 (ja) 2004-11-29 2006-06-01 Kowa Co., Ltd. （ｓ）－（－）－１－（４－フルオロイソキノリン－５－イル）スルホニル－２－メチル－１，４－ホモピペラジン塩酸塩・二水和物
WO2007026664A1 (ja) 2005-08-30 2007-03-08 Asahi Kasei Pharma Corporation スルホンアミド化合物
CN101253166A (zh) * 2005-08-30 2008-08-27 旭化成制药株式会社 磺酰胺化合物
CN101622243A (zh) * 2007-02-28 2010-01-06 旭化成制药株式会社 磺酰胺衍生物
CN105085478A (zh) * 2014-04-28 2015-11-25 南京明德新药研发股份有限公司 异喹啉磺胺衍生物及其药物组合物和制药用途
CN105085525A (zh) * 2014-04-28 2015-11-25 南京明德新药研发股份有限公司 作为rho激酶抑制剂的异喹啉磺酰衍生物

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022135421A1 (zh) * 2020-12-21 2022-06-30 广州润尔眼科生物科技有限公司 一种作为rock蛋白激酶抑制剂的异喹啉酮型化合物的盐型及其制备方法
AU2021408195B2 (en) * 2020-12-21 2024-05-02 Guangzhou Ocusun Ophthalmic Biotechnology Co., Ltd. Salt form of isoquinolinone type compound as rock protein kinase inhibitor and preparation method therefor
WO2023241652A1 (zh) * 2022-06-16 2023-12-21 广州润尔眼科生物科技有限公司 一种药物组合物及其制备方法和应用

Also Published As

Publication number Publication date
JP2022538086A (ja) 2022-08-31
CN113906017A (zh) 2022-01-07
AU2020296050A1 (en) 2022-02-03
JP7398137B2 (ja) 2023-12-14
EP3988544A1 (en) 2022-04-27
CN113906017B (zh) 2024-07-02
MX2021016068A (es) 2022-04-20
US20230024516A1 (en) 2023-01-26
EP3988544A4 (en) 2023-08-09
ZA202200834B (en) 2022-10-26
KR20220024868A (ko) 2022-03-03
CA3144211A1 (en) 2020-12-24
AU2020296050B2 (en) 2023-04-06

Similar Documents

Publication Publication Date Title
CN103562186B (zh) 作为toll样受体调节剂的取代的苯并氮杂卓
WO2018137683A1 (zh) 羊毛甾醇前药化合物及其制备方法和应用
CN103547577B (zh) 作为盐皮质激素受体拮抗剂的并环类化合物
CN109641836A (zh) 氟化的2-氨基-4-(取代的氨基)苯基氨基甲酸酯衍生物
TW200911839A (en) New cyclic peptide compounds
WO2020253882A1 (zh) 作为rock蛋白激酶抑制剂的异喹啉酮的衍生物及其应用
JP2022511999A (ja) Ｍｔｏｒｃモジュレーターおよびその使用
WO2021031999A1 (zh) 麦考酚酸的前体药物及其制备方法
EP2488032B1 (en) Prostaglandin transporter inhibitors and uses thereof
CN108289893A (zh) 人类血浆激肽释放酶抑制剂
WO2022135421A1 (zh) 一种作为rock蛋白激酶抑制剂的异喹啉酮型化合物的盐型及其制备方法
JP2020536922A (ja) 眼疾患を治療するためのアザビシクロ及びジアゼピン誘導体
JP7245397B2 (ja) 複素環化合物
TW202321192A (zh) 化合物、異構體或其藥學上可接受的鹽
JP2024523552A (ja) 疾患の処置のためのベータ－ラクタム誘導体
JP2024517496A (ja) Ｒｏｃｋ阻害剤の酸付加塩及び塩の結晶形、組成物並びに薬物用途
WO2020216240A1 (zh) 用作血浆激肽释放酶抑制剂的双环烷类化合物
JP2003146972A (ja) カルボスチリル誘導体
AU2021296681A1 (en) Novel compound, and pharmaceutical composition for preventing or treating resistant cancer, comprising same
WO2021233133A1 (zh) 用作ret激酶抑制剂的化合物及其应用
JP7495758B2 (ja) マクロライド化合物及びその慢性呼吸器疾患の治療用途
WO2023051753A1 (zh) 一种rock抑制剂的制备方法、其中间体及中间体的制备方法
WO2021098817A1 (zh) 二氧代哌嗪类衍生物、其制备方法及其在医药上的应用
CN115677830A (zh) 肽酰胺类化合物及其制备方法与应用
WO2024051795A1 (zh) 用作泛素-特异性蛋白酶抑制剂的取代嘌呤酮衍生物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20827811

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 3144211

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2021576289

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 20227002287

Country of ref document: KR

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2020296050

Country of ref document: AU

Date of ref document: 20200622

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2020827811

Country of ref document: EP

Effective date: 20220121