WO2019201296A1 - Pyrazole compound used as rho kinase inhibitor - Google Patents

Pyrazole compound used as rho kinase inhibitor Download PDF

Info

Publication number
WO2019201296A1
WO2019201296A1 PCT/CN2019/083208 CN2019083208W WO2019201296A1 WO 2019201296 A1 WO2019201296 A1 WO 2019201296A1 CN 2019083208 W CN2019083208 W CN 2019083208W WO 2019201296 A1 WO2019201296 A1 WO 2019201296A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
compound
och
isomer
pharmaceutically acceptable
Prior art date
Application number
PCT/CN2019/083208
Other languages
French (fr)
Chinese (zh)
Inventor
吴凌云
尹军
王才林
肖哲明
黎健
陈曙辉
Original Assignee
南京明德新药研发有限公司
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 南京明德新药研发有限公司 filed Critical 南京明德新药研发有限公司
Publication of WO2019201296A1 publication Critical patent/WO2019201296A1/en

Links

Images

Classifications

    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to the field of medicine, and in particular to a class of pyrazole compounds as RHO kinase inhibitors, pharmaceutically acceptable salts thereof or isomers thereof, pharmaceutical compositions thereof and their use in the preparation of RHO inhibitor drugs.
  • Rho associated kinase a serine/threonine protein kinase
  • RHO-associated protein kinase is involved in the regulation of myosin light chain (MLC) and is suitable for the treatment of vasodilation.
  • MLC myosin light chain
  • New research supports the regulation of ROCK kinase involved in the immune response of TH17 cells and the activation of fibroblasts, which can be expanded and adapted.
  • the disease is used for lung fibrosis, asthma and other lung diseases, and further indications include autoimmune diseases.
  • the ROCK kinase family includes two subtypes, ROCK1 and ROCK2.
  • ROCK2 kinase is involved in inflammation and fibrosis. Selective ROCK2 inhibitors do not cause vasodilation at high concentrations in ex vivo vasodilation and reduce cardiovascular side effects. Although the embryonic mortality rate of ROCK1 knockout mice is not high, most of them die after cytoskeletal variation caused by decreased MLC phosphorylation, while 90% of ROCK2 knockout mice die during embryonic stage, but surviving mice and wild type Without distinction, selective inhibition of ROCK2 activity may be more secure. Therefore, selective ROCK2 protein kinase inhibitors can avoid the cardiovascular side effects of drugs.
  • KD025 (WO2006105081; WO2008054599; WO2010104851; WO2014055996) is an oral ROCK2 kinase selective inhibitor developed by Kadmon Corporation. Studies have shown that KD025 is a new mechanism for the treatment of idiopathic pulmonary fibrosis (IPF) by inhibiting proteins such as RHO kinase that regulate fibrosis. The cause of idiopathic pulmonary fibrosis (IPF) may be body damage.
  • IPF idiopathic pulmonary fibrosis
  • the body's response to injury involves the reorganization of the actin cytoskeleton of a variety of cells (such as epithelial cells, fibroblasts, endothelial cells, and macrophages, etc.), and the assembly of actin filaments and myospheres.
  • the contraction of the protein (actomyosin) is regulated by RHO kinase family proteins, including ROCK1 and ROCK2.
  • RHO kinase family proteins include ROCK1 and ROCK2.
  • Previous studies have shown that RHO kinase family proteins are activated in the lungs of IPF patients and animal models of the disease, while RHO kinase inhibitors can prevent tissue fibrosis in these models and induce regression of established fibrosis. .
  • Phase II clinical trials for the treatment of moderate to severe psoriasis have been completed and are in Phase II clinical studies at the stage of idiopathic pulmonary fibrosis (IPF).
  • IPPF idiopathic pulmonary
  • WO2014134388 and WO2016028971 also disclose a class of compounds having the general formula shown in formula (a) and formula (b). Such compounds are also useful in cardiovascular diseases, neuropathological diseases, tumors, autoimmune diseases, pulmonary fibrosis. , treatment of inflammatory diseases, etc.
  • the compound of the present invention is a ROCK2 inhibitor with a certain selectivity for ROCK2, which has remarkable kinase inhibitory activity, membrane permeability and solubility, and has excellent pharmacokinetic and pharmacodynamic properties.
  • the present invention provides a compound of the formula (I-1), a pharmaceutically acceptable salt thereof or an isomer thereof,
  • said C 1-6 alkyl group and C 3-6 cycloalkyl group are optionally 1, 2 or 3 independently selected from the group consisting of F, Cl, Br, I, -OH, -OCH 3 , -CN, -NH 2, -NO 2 or C 1-4 alkyl substituents;
  • T 1 and T 2 are each independently N or CH;
  • R 6 and R 7 are each independently H, F, Cl or C 1-6 alkyl, wherein said C 1-6 alkyl group is optionally 1, 2 or 3 independently selected from the group consisting of F, Cl, Br, CN Substituted by a substituent of -OR a or -NR d R e ;
  • Each R 8 is independently F, Cl, Br, CN, -OR a , C 1-6 alkyl or C 3-6 cycloalkyl, wherein said C 1-6 alkyl and C 3-6 cycloalkyl Optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of F, Cl, Br, I, -OH, -OCH 3 , -CN, -NH 2 , -NO 2 or C 1-4 alkyl;
  • R a , R b and R c are each independently H or C 1-6 alkyl, wherein the C 1-6 alkyl group is optionally 1, 2 or 3 independently selected from the group consisting of F, Cl, Br, -OH Substituted with a substituent of -OCH 3 , -CN, -NH 2 , C 1-6 alkylamino or -NO 2 ;
  • R d and R e are each independently H, C 1-6 alkyl, or R d and R e together with the N atom to which they are attached form a 4-8 membered heterocycloalkyl group, wherein said C 1-6 alkyl group And a 4-8 membered heterocycloalkyl group is optionally 1, 2 or 3 independently selected from the group consisting of F, Cl, Br, -OH, -OCH 3 , -CN, -NH 2 , C 1-6 alkylamino or -NO 2 substituents;
  • n 0, 1, 2, 3 or 4;
  • the 4-8 membered heterocycloalkyl contains 1, 2, 3 or 4 heteroatoms or heteroatoms independently selected from -O-, -S-, N or -NH-.
  • R a , R b and R c are each independently H, methyl, ethyl, n-propyl or isopropyl, wherein the methyl, ethyl, n-propyl and The isopropyl group is optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of F, Cl, Br, I, -OH, -OCH 3 , CN, -NH 2 , C 1-3 alkylamino or -NO 2
  • substituents independently selected from the group consisting of F, Cl, Br, I, -OH, -OCH 3 , CN, -NH 2 , C 1-3 alkylamino or -NO 2
  • other variables are as defined by the present invention.
  • R a , R b and R c are each independently H, methyl, ethyl, n-propyl, isopropyl, Other variables are as defined by the present invention.
  • the cyclohexyl group is optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of F, Cl, Br, I, -OH, -OCH 3 , CN, -NH 2 , -NO 2 , methyl, ethyl or propyl.
  • other variables are as defined by the present invention.
  • R 3 , R 4 and R 5 and other variables are as defined by the present invention.
  • R d and R e are each independently H, methyl, ethyl, n-propyl, isopropyl, or R d and R e are taken together with the N atom to which they are attached 5- a 6-membered heterocycloalkyl group, wherein the methyl, ethyl, n-propyl, isopropyl and 5-6 membered heterocycloalkyl are optionally 1, 2 or 3 independently selected from the group consisting of F, Cl, Br, I, -OH, -OCH 3, CN , -NH 2, C 1-3 alkylamino or a -NO 2 substituents other variables are as defined in the present invention.
  • R d and R e are each independently H, methyl, ethyl, n-propyl, isopropyl, Or R d and R e together with the N atom to which they are attached form a pyrrolidinyl or piperidinyl group, wherein the pyrrolidinyl and piperidinyl are optionally 1, 2 or 3 independently selected from the group consisting of F, Cl, Br, I, -OH, -OCH 3, CN , -NH 2, C 1-3 alkylamino or a -NO 2 substituents other variables are as defined in the present invention.
  • R 6 and R 7 are each independently H, F, Cl, -OH, -OCH 3 , -NH 2 , Methyl, ethyl, n-propyl, isopropyl, Other variables are as defined by the present invention.
  • R 6 and R 7 are each independently H, F, Cl, methyl, ethyl, n-propyl, isopropyl, Other variables are as defined by the present invention.
  • each of R 8 above is independently F, Cl, Br, CN, -OH, -OCH 3 , -OCH 2 F, -OCHF 2 , -OCF 3 , methyl, ethyl, ortho a propyl group, an isopropyl group, a cyclopropyl group, a cyclopentyl group or a cyclohexyl group, wherein the methyl group, ethyl group, n-propyl group, isopropyl group, cyclopropyl group, cyclopentyl group and cyclohexyl group are optionally 1, 2 or 3 substituents independently selected from the group consisting of F, Cl, Br, I, -OH, -OCH 3 , CN, -NH 2 , -NO 2 , methyl, ethyl or propyl, other variables such as The invention is defined.
  • each of R 8 above is independently F, Cl, Br, CN, -OH, -OCH 3 , -OCH 2 CH 3 , methyl, ethyl, n-propyl, isopropyl, Cyclopropyl, cyclopentyl, cyclohexyl, Other variables are as defined by the present invention.
  • the above compound, a pharmaceutically acceptable salt thereof or an isomer thereof has a structure represented by the formula (I-2) to (I-4),
  • R 1 , R 2 , R 3 , R 6 , R 7 , R 8 and n are as defined in the present invention.
  • the above compound, a pharmaceutically acceptable salt thereof or an isomer thereof has a structure represented by formula (I-5) to (I-7),
  • R 3 , R 6 , R 7 , R 8 and n are as defined in the present invention.
  • the above compound, a pharmaceutically acceptable salt thereof or an isomer thereof has a structure represented by the formula (I-8) to (I-10),
  • carbon atom bearing "*" is a chiral carbon atom, which is in the form of a single enantiomer of (R) or (S) or is enriched in one enantiomer form;
  • R 7 is F, Cl, -OH, -OCH 3 , -NH 2 , Methyl, ethyl, n-propyl, isopropyl, R 3 , R 8 and n are as defined in the present invention.
  • the above compound, a pharmaceutically acceptable salt thereof or an isomer thereof has a structure represented by the formula (I-8) to (I-10),
  • carbon atom bearing "*" is a chiral carbon atom, which is in the form of a single enantiomer of (R) or (S) or is enriched in one enantiomer form;
  • R 7 is F, Cl, methyl, ethyl, n-propyl, isopropyl, R 3 , R 8 and n are as defined in the present invention.
  • the above compound is selected from the group consisting of a compound of the formula: a pharmaceutically acceptable salt thereof or an isomer thereof:
  • the pharmaceutically acceptable salt of the above compound is a formate or hydrochloride salt.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of the above compound, a pharmaceutically acceptable salt thereof or an isomer thereof, and a pharmaceutically acceptable carrier.
  • the present invention provides the use of the above compound, a pharmaceutically acceptable salt thereof or an isomer thereof, and the above pharmaceutical composition for the preparation of a medicament for RHO inhibitor.
  • the present invention also provides the above compound, a pharmaceutically acceptable salt thereof or an isomer thereof, and the use of the above pharmaceutical composition for the preparation of a medicament for treating an autoimmune disease; in some embodiments, the autoimmune disease is I Type 2 diabetes, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, glaucoma, pulmonary fibrosis, psoriasis or multiple sclerosis.
  • the autoimmune disease is I Type 2 diabetes, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, glaucoma, pulmonary fibrosis, psoriasis or multiple sclerosis.
  • the compound of the present invention has remarkable kinase inhibitory activity against ROCK2, and has certain selectivity to ROCK2, and has certain membrane permeability and solubility, and has excellent pharmacokinetic and pharmacodynamic properties.
  • pharmaceutically acceptable as used herein is intended to mean that those compounds, materials, compositions and/or dosage forms are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues. Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, 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 me
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
  • the compounds of the invention may exist in specific geometric or stereoisomeric forms. All such compounds are contemplated by the present invention, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers , (D)-isomer, (L)-isomer, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to the present Within the scope of the invention. Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.
  • enantiomer or “optical isomer” refer to stereoisomers that are mirror images of one another.
  • cis-trans isomer or “geometric isomer” is caused by the inability to freely rotate a single bond due to a double bond or a ring-forming carbon atom.
  • diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirrored relationship.
  • wedge-shaped dashed keys Represents the absolute configuration of a solid center with straight solid keys
  • straight dashed keys Indicates the relative configuration of the stereocenter, using wavy lines Indicates a wedge solid key Or wedge-shaped dotted key Or with wavy lines Represents a straight solid key And straight dashed keys
  • a double bond structure exists in a compound, such as a carbon-carbon double bond, a carbon-nitrogen double bond, and a nitrogen-nitrogen double bond, and each atom on the double bond is bonded to two different substituents (including a nitrogen atom) Of the double bonds, a pair of lone pairs of electrons on the nitrogen atom are considered as a substituent to which they are attached), if a wavy line is used between the atom on the double bond and the substituent in the compound
  • the linkage means the (Z) isomer, the (E) isomer or a mixture of the two isomers of the compound.
  • the following formula (A) indicates that the compound exists as a single isomer of the formula (A-1) or the formula (A-2) or two isomers of the formula (A-1) and the formula (A-2) The mixture is present;
  • the following formula (B) indicates that the compound exists as a single isomer of formula (B-1) or formula (B-2) or two of formula (B-1) and formula (B-2) A mixture of isomers is present.
  • the following formula (C) indicates that the compound exists as a single isomer of the formula (C-1) or the formula (C-2) or two isomers of the formula (C-1) and the formula (C-2) The mixture is present.
  • tautomer or “tautomeric form” mean that the different functional isomers are in dynamic equilibrium at room temperature and can be rapidly converted into each other. If tautomers are possible (as in solution), the chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also known as prototropic tautomers
  • prototropic tautomers include interconversions by proton transfer, such as keto-enol isomerization and imine-enes. Amine isomerization.
  • the valence tautomer includes the mutual transformation of some of the bonding electrons.
  • keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms "enriched in one isomer”, “isomer enriched”, “enriched in one enantiomer” or “enantiomeric enriched” refer to one of the isomers or pairs
  • the content of the oligo is less than 100%, and the content of the isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, 98% or more, 99% or more, 99.5% or more, 99.6% or more, 99.7% or more, 99.8% or more, or greater than or equal to 99.9%.
  • the term “isomer excess” or “enantiomeric excess” refers to the difference between the two isomers or the relative percentages of the two enantiomers. For example, if one of the isomers or enantiomers is present in an amount of 90% and the other isomer or enantiomer is present in an amount of 10%, the isomer or enantiomeric excess (ee value) is 80%. .
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer.
  • a diastereomeric salt is formed with a suitable optically active acid or base, followed by conventional methods well known in the art.
  • the diastereomers are resolved and the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
  • the compounds of the invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C).
  • hydrogen can be replaced by heavy hydrogen to form a deuterated drug.
  • the bond composed of barium and carbon is stronger than the bond composed of common hydrogen and carbon.
  • deuterated drugs have reduced side effects and increased drug stability. Enhance the efficacy and prolong the biological half-life of the drug. Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, and may include variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable. of.
  • Oxygen substitution does not occur on the aromatic group.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with at most two R, and each case has an independent option.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of one linking group is 0, such as -(CRR) 0 -, it indicates that the linking group is a single bond.
  • one of the variables When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly linked. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.
  • substituent When a substituent is vacant, it means that the substituent is absent.
  • X when X is vacant in A-X, the structure is actually A.
  • substituents are not indicated by which atom is attached to the substituted group, such a substituent may be bonded through any atom thereof, for example, a pyridyl group as a substituent may be passed through any one of the pyridine rings. A carbon atom is attached to the substituted group.
  • the medium linking group L is -MW-, and at this time, -MW- can be connected in the same direction as the reading order from left to right to form ring A and ring B. It is also possible to connect the ring A and the ring B in a direction opposite to the reading order from left to right. Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • any one or more of the sites may be attached to the other group via a chemical bond.
  • the chemical bond connecting the site to other groups can be a straight solid bond Straight dotted key Or wavy line Said.
  • a straight solid bond in -OCH 3 indicates attachment to other groups through an oxygen atom in the group;
  • a straight dashed bond in the middle indicates that both ends of the nitrogen atom in the group are attached to other groups;
  • the wavy line in the middle indicates that it is attached to other groups through the carbon atoms at the 1 and 2 positions in the phenyl group.
  • hetero denotes a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), including atoms other than carbon (C) and hydrogen (H), and radicals containing such heteroatoms, including, for example, oxygen (O). ), nitrogen (N), sulfur (S) or -N (H)-.
  • the number of atoms on the ring is generally defined as the number of elements of the ring.
  • “5-7 membered ring” refers to a “ring” that is arranged around 5-7 atoms.
  • ring denotes cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl.
  • the ring includes a single ring, and also includes a bicyclic or polycyclic ring system such as a spiro ring, a ring and a bridge ring. Unless otherwise specified, the ring optionally contains from 1 to 3 heteroatoms.
  • a "5-7 membered ring” includes, for example, phenyl, pyridyl and piperidinyl; on the other hand, the term “5-7 membered heterocycloalkyl” includes piperidinyl, but does not include phenyl.
  • the term “ring” also includes ring systems containing at least one ring, each of which "ring” independently conforms to the above definition.
  • C1-6 alkyl is used to indicate a straight or branched saturated hydrocarbon group containing from 1 to 6 carbon atoms.
  • the C 1-6 alkyl group includes C 1-5 , C 1-4 , C 1-3 and C 1-2 alkyl groups and the like. It may be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine).
  • C 1-6 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 and the like.
  • heteroalkyl denotes a stable straight or branched alkyl radical or a combination thereof consisting of a number of carbon atoms and at least one heteroatom or heteroatom. Things.
  • the heteroatoms are selected from the group consisting of O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • the heteroalkyl group is a C1-6 heteroalkyl group; in other embodiments, the heteroalkyl group is a C1-3 heteroalkyl group.
  • the heteroatom or heteroatom group may be located at any internal position of the heteroalkyl group, including the position at which the alkyl group is attached to the rest of the molecule, but the term " C1-6 alkylamino" refers to those in which the amino group is attached to the remainder of the molecule.
  • the C 1-6 alkylamino group includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkylamino groups and the like.
  • Examples of the C 1-6 alkylamino group include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )(CH 2 CH 3 ), and the like.
  • Up to two heteroatoms
  • C 1-3 alkylamino refers to those alkyl groups containing from 1 to 3 carbon atoms which are attached to the remainder of the molecule.
  • the C 1-3 alkylamino group includes C 1-2 , C 1 , C 2 , C 3 alkylamino group and the like.
  • Examples of the C 1-3 alkylamino group include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )(CH 2 CH 3 ), and the like.
  • C 3-6 cycloalkyl is used to mean any stable cyclic alkyl group containing 3 to 6 carbon atoms, the C 3-6 cycloalkyl is a monocyclic ring system.
  • the C 3-6 cycloalkyl group includes C 3-5 , C 3-4 , C 4-6 , C 5-6 , C 3 and C 6 cycloalkyl groups and the like, and it may be monovalent, divalent or Multi-price.
  • Examples of C 3-6 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • the 4-8 membered heterocycloalkyl group includes 4-5 members, 4-6 members, 5-6 members, 5-membered and 6-membered heterocycloalkyl groups, and the like.
  • Examples of 4-8 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thioheterobutyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl ( 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
  • a hetero atom may occupy a position where a heterocycloalkyl group is bonded to the rest of the molecule.
  • the 5-6 membered heterocycloalkyl group includes 5-membered and 6-membered heterocycloalkyl groups.
  • 5-6 membered heterocycloalkyl examples include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (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.), dioxoalkyl, dithiaalkyl, isoxazolidinyl, isothiazole Alkyl, 1,2-oxazinyl, 1,2-thiaziny
  • C n-n+m or C n -C n+m includes any one 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 range of n to n+m, for example, C 1-12 includes C 1 - 3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 , etc.; similarly, n to n
  • the +m element indicates that the number of atoms on the ring is n to n+m, for example, the 3-12 element ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-
  • a 10-membered ring, a 11-membered ring, and a 12-membered ring and includes any one of n to n+m, for example, a 3-12-membered ring including a 3-6-membered ring, a 3-9-membered ring, and a 5-6-membered ring. Ring, 5-7 membered ring, 6-7 membered ring, 6-8 membered ring, and 6-10 membered ring.
  • leaving group refers to a functional group or atom which may be substituted by another functional group or atom by a substitution reaction (for example, an affinity substitution reaction).
  • substituent groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters and the like; 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 (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, e.g., tert-butoxycarbonyl (Boc) Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1, 1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-
  • hydroxy protecting group refers to a protecting group suitable for use in preventing hydroxy side reactions.
  • Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and t-butyl groups; acyl groups such as alkanoyl groups (e.g., acetyl); arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
  • alkyl groups such as methyl, ethyl and t-butyl groups
  • acyl groups such as alkanoyl groups (e.g., acetyl)
  • arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluoreny
  • 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 set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
  • the solvent used in the present invention is commercially available.
  • the present invention employs the following abbreviations: MeOH for methanol; DMSO for dimethyl sulfoxide; and CDCl 3 for deuterated chloroform.
  • the compounds of the invention are based on conventional nomenclature or use in the art Software naming, commercially available compounds using the supplier catalog name.
  • Figure 1 shows the inhibition of ⁇ -SMA gene expression by compounds 11, 12 (hydrochloride) and 13 (hydrochloride) of the present invention
  • Figure 2 is a pulmonary fibrosis score of compounds 11 and 12 (hydrochloride) of the present invention
  • Figure 3 shows the damage of bronchial and arterioles in the lesions of compounds 11 and 12 (hydrochloride) of the present invention
  • Figure 4 shows the damage of bronchial and arterioles at the margin of the lesion by compounds 11 and 12 (hydrochloride) of the present invention.
  • hydrochloride or formate salt of the compound of the present invention is adjusted to pH neutrality by adding a saturated sodium hydrogencarbonate solution, and is separated by high performance liquid chromatography (neutral, ammonium hydrogencarbonate system) to obtain a free base of the compound.
  • Trifluoroacetic acid (193 mg, 0.13 mL) was added to a solution of compound 5a (50.0 mg, 0.170 mmol) in dichloromethane (2 mL). After the addition was completed, the reaction solution was heated to 25 ° C and stirred for 12 hours. After completion of the reaction, a saturated aqueous solution of sodium hydrogen carbonate (20 mL) was evaporated and evaporated. The combined organic phases were washed with brine (20 mL EtOAc) After the desiccant was filtered off, the solvent was removed under reduced pressure and the residue was purified by preparative chromatography chromatography to afford compound 5b.
  • the compound 21b was obtained in the first step of Example 6.
  • the compound 21d was obtained by referring to the third step of Example 6.
  • the compound 21e was obtained by referring to the fourth step of Example 6.
  • buffer solution 20 mM 4-hydroxyethylpiperazine ethanesulfuric acid (pH 7.5), 10 mM magnesium chloride, 1 mM ethylene glycol diethyl ether diamine tetraacetic acid, 0.02% polyoxyethylene lauryl ether, 0.02 mg / mL bovine serum albumin , 0.1 mM sodium vanadate, 2 mM dithiothreitol, 1% DMSO.
  • the freshly prepared buffer solution was added to a ROCK protein kinase substrate Long S6 Kinase substrate, at a concentration of 20 ⁇ M, and then 1 nM ROCK protein kinase was added thereto, and uniformly stirred.
  • a series of DMSO dilutions containing the test compound (starting at 10 ⁇ M, serially diluted 3 times) were added using Echo 550, pre-incubated for 20 minutes at room temperature, and 33 P-ATP (radiation intensity 10 ⁇ Ci/ ⁇ L) was added to initiate the reaction. hour. It was then filtered using P81 ion exchange paper (Whatman #3698-915) and washed with 0.75% phosphoric acid. The intensity of the radiation was measured using the Filter-Binding method.
  • the protein kinase inhibitory activity of the compound is expressed as protein kinase activity remaining relative to the blank substrate (DMSO alone). And the values of IC 50 was calculated using the Prism software package curve (GraphPad Software, San Diego California, USA).
  • the compound of the present invention has high inhibitory activity against ROCK2 and has certain selective ROCK2 inhibitory activity.
  • NIH-3T3 cells were purchased from the Shanghai Cell Bank of the Chinese Academy of Sciences.
  • the TRIzol reagent was purchased from Infineon, and the genomic DNA reverse transcription kit was purchased from Tiangen Biochemical.
  • the real-time fluorescent quantitative PCR premix was purchased from Nanjing Nuoweizan, isopropanol and chloroform from the Chinese medicine.
  • NIH-3T3 cells with a growth confluence of 80% were digested with a 0.25% trypsin into a single cell suspension and plated in 6-well plates.
  • the cell plates were placed at 37 °, overnight culture incubator in 5% CO 2.
  • the compound was prepared the next day, and 10 mM of the compound (11, 12, 13) to be tested was diluted to 200 ⁇ M, and added to a 6-well plate at 10 ⁇ L per well, and cultured overnight.
  • the final concentration of the compound was 1 ⁇ M and the final concentration of DMSO was 1%.
  • the reaction conditions were 50 ° C for 2 minutes, 95 ° C for 10 minutes, 95 ° C for 30 seconds, 60 ° C for 30 seconds, 95 ° C for 30 seconds, and 60 ° C for 30 seconds for 40 cycles.
  • the CT value of the reaction was derivatized at the end of the reaction to calculate the relative expression amount of the sample. data analysis:
  • the relative gene expression amount was calculated by the 2 - ⁇ CT calculation method, and a significant analysis was performed using a two-tailed T test (the compound test concentration was 1 ⁇ M).
  • the compounds of the present invention have a good inhibitory activity on the expression of ⁇ -SMA gene.
  • Plasma samples were administered orally by two other rats at a dose of 2 mg/kg, and plasma samples of 0.25, 0.5, 1, 2, 3, 4, 6, 8, 24 hours after administration were collected. Collect whole blood samples within 24 hours, centrifuge at 3000g for 15 minutes, separate the supernatant to obtain plasma samples, add the internal standard acetonitrile solution to precipitate the protein, mix thoroughly and centrifuge to take the supernatant, and quantify by LC-MS/MS analysis. Analyze blood drug concentration and calculate pharmacokinetic parameters such as peak concentration (C max ), clearance rate (CL), half-life (T 1/2 ), tissue distribution (Vdss), area under the drug-time curve (AUC 0-last) ), bioavailability (F), etc.
  • C max peak concentration
  • CL clearance rate
  • T 1/2 half-life
  • Vdss tissue distribution
  • AUC 0-last area under the drug-time curve
  • bioavailability F
  • the compounds of the invention have good pharmacokinetic properties, including good oral bioavailability, oral exposure, half-life and clearance.
  • Model Left unilateral pulmonary pulmonary fibrosis model in SD rats: Rats were injected with bleomycin (3 mg/kg in 1.5 mL/kg) to induce pulmonary fibrosis.
  • bleomycin bleomycin
  • modeling was started 4 days after adaptive feeding. Animals were weighed and inhaled with isoflurane. After confirming the anesthesia of the animals, the neck was disinfected, the skin of the neck was cut, the main air tube was exposed to the muscles, and a small opening was made between the tracheal rings. The left main bronchus was directly injected into bleomycin, and the trachea and skin were sutured. After the operation, the animals were placed in a 37 ° C electric blanket to keep the animals fully awake, and it was confirmed that the animals were able to return to the cages for normal feeding after free feeding and drinking. Oral administration of the compound was started on the 8th day of modeling and continued for 14 days. 24 hours after the end of the last dose, all animals were euthanized; the lungs were collected by systemic perfusion with low temperature PBS, and replenished with formalin, and the tissue was fixed in 10% formalin solution for subsequent histopathology. analysis.
  • Pathological examination of the left lung H&E staining pathological evaluation: 1) pathological changes of the left lung terminal bronchioles and arterioles, 2) left lung pulmonary fibrosis area, 3) left lung pulmonary fibrosis Ashcroft score.
  • the compounds of the present invention have a significant improvement in bronchial and arteriolar lesions on the inside of the lesion or on the edge of the lesion ( Figures 3 and 4), and also reduce the pulmonary fibrosis score (Figure 2), at a lower level. At doses (10mpk), it is comparable to nidanib (100mpk).

Abstract

The invention relates to a pyrazole compound used as RHO kinase inhibitor, a pharmaceutical composition and uses thereof for preparing an RHO kinase inhibiting drug, and specifically to said compound of formula (I-1), a pharmaceutically acceptable salt and isomer thereof.

Description

作为RHO激酶抑制剂的吡唑类化合物Pyrazoles as RHO kinase inhibitors
相关申请的交叉引用Cross-reference to related applications
本申请主张如下优先权：CN201810349378.0，申请日2018年04月18日。This application claims the following priority: CN201810349378.0, application date April 18, 2018.
技术领域Technical field
本发明涉及药物领域，具体涉及一类作为RHO激酶抑制剂的吡唑类化合物，其药学上可接受的盐或其异构体，其药物组合物以及它们在制备RHO抑制剂药物中的应用。The present invention relates to the field of medicine, and in particular to a class of pyrazole compounds as RHO kinase inhibitors, pharmaceutically acceptable salts thereof or isomers thereof, pharmaceutical compositions thereof and their use in the preparation of RHO inhibitor drugs.
背景技术Background technique
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，新的研究支持ROCK激酶参与TH17细胞的免疫反应的调控和纤维母细胞的活化，可以扩展适应症用于肺纤维化，哮喘等肺部疾病，进一步的适应症拓展包括自身免疫疾病。ROCK激酶家族包括ROCK1和ROCK2两个亚型，ROCK2激酶和炎症作用和纤维化作用相关，选择性ROCK2抑制剂在离体血管舒张实验中在高浓度也没有引起血管舒张，可以减少心血管副作用。ROCK1敲除小鼠虽然胚胎死亡率不高，但是出生后大部分死于MLC磷酸化降低造成的细胞骨架变异，而ROCK2敲除小鼠90％在胚胎期死亡，但是存活的小鼠和野生型没有区别，选择性抑制ROCK2的活性可能具有更高的安全性。因此，选择性ROCK2蛋白激酶抑制剂可以避免药物的心血管副作用。Rho associated kinase (ROCK), a serine/threonine protein kinase, is a downstream target effector molecule of RHO and is widely expressed in humans. RHO-associated protein kinase (ROCK) is involved in the regulation of myosin light chain (MLC) and is suitable for the treatment of vasodilation. New research supports the regulation of ROCK kinase involved in the immune response of TH17 cells and the activation of fibroblasts, which can be expanded and adapted. The disease is used for lung fibrosis, asthma and other lung diseases, and further indications include autoimmune diseases. The ROCK kinase family includes two subtypes, ROCK1 and ROCK2. ROCK2 kinase is involved in inflammation and fibrosis. Selective ROCK2 inhibitors do not cause vasodilation at high concentrations in ex vivo vasodilation and reduce cardiovascular side effects. Although the embryonic mortality rate of ROCK1 knockout mice is not high, most of them die after cytoskeletal variation caused by decreased MLC phosphorylation, while 90% of ROCK2 knockout mice die during embryonic stage, but surviving mice and wild type Without distinction, selective inhibition of ROCK2 activity may be more secure. Therefore, selective ROCK2 protein kinase inhibitors can avoid the cardiovascular side effects of drugs.
KD025(WO2006105081；WO2008054599；WO2010104851；WO2014055996)是Kadmon公司开发的口服ROCK2激酶选择性的抑制剂。研究表明，KD025是通过抑制RHO激酶这类调节纤维化的蛋白来治疗特发性肺纤维化(IPF)这种新机制的代表。特发性肺纤维化(IPF)的诱因可能是肌体损伤。肌体对损伤的应答涉及多种细胞(比如上皮细胞、成纤维细胞、内皮细胞和巨噬细胞等)的肌动蛋白细胞骨架的重组，而肌动蛋白丝(actin filament)的组装和肌动球蛋白(actomyosin)的收缩则由RHO激酶家族蛋白质(包括ROCK1和ROCK2)指导调控。之前的研究显示，RHO激酶家族蛋白会在IPF患者以及这种疾病的动物模型肺部激活，而RHO激酶抑制剂可以预防这些模型中的组织纤维化过程，并且能诱导已经建立的纤维化出现消退。目前已完成中度至重度银屑病治疗的II期临床试验，并处于特发性肺纤维化(IPF)治疗的II期临床研究阶段。KD025 (WO2006105081; WO2008054599; WO2010104851; WO2014055996) is an oral ROCK2 kinase selective inhibitor developed by Kadmon Corporation. Studies have shown that KD025 is a new mechanism for the treatment of idiopathic pulmonary fibrosis (IPF) by inhibiting proteins such as RHO kinase that regulate fibrosis. The cause of idiopathic pulmonary fibrosis (IPF) may be body damage. The body's response to injury involves the reorganization of the actin cytoskeleton of a variety of cells (such as epithelial cells, fibroblasts, endothelial cells, and macrophages, etc.), and the assembly of actin filaments and myospheres. The contraction of the protein (actomyosin) is regulated by RHO kinase family proteins, including ROCK1 and ROCK2. Previous studies have shown that RHO kinase family proteins are activated in the lungs of IPF patients and animal models of the disease, while RHO kinase inhibitors can prevent tissue fibrosis in these models and induce regression of established fibrosis. . Phase II clinical trials for the treatment of moderate to severe psoriasis have been completed and are in Phase II clinical studies at the stage of idiopathic pulmonary fibrosis (IPF).
Figure PCTCN2019083208-appb-000001
Figure PCTCN2019083208-appb-000001
WO2014134388和WO2016028971也公开了一类化合物，其结构通式如式(a)和式(b)所示，这类化合物也可用于心血管疾病、神经病理学疾病、肿瘤、自免疫疾病、肺纤维化、炎症疾病等的治疗。WO2014134388 and WO2016028971 also disclose a class of compounds having the general formula shown in formula (a) and formula (b). Such compounds are also useful in cardiovascular diseases, neuropathological diseases, tumors, autoimmune diseases, pulmonary fibrosis. , treatment of inflammatory diseases, etc.
Figure PCTCN2019083208-appb-000002
Figure PCTCN2019083208-appb-000002
本发明化合物为ROCK2抑制剂，同时对ROCK2具有一定的选择性，其具有显著的激酶抑制活性、 透膜性和溶解性，同时具有优良的药代动力学和药效动力学性质。The compound of the present invention is a ROCK2 inhibitor with a certain selectivity for ROCK2, which has remarkable kinase inhibitory activity, membrane permeability and solubility, and has excellent pharmacokinetic and pharmacodynamic properties.
发明内容Summary of the invention
一方面，本发明提供了式(I-1)所示化合物、其药学上可接受的盐或其异构体，In one aspect, the present invention provides a compound of the formula (I-1), a pharmaceutically acceptable salt thereof or an isomer thereof,
Figure PCTCN2019083208-appb-000003
Figure PCTCN2019083208-appb-000003
其中，R 1和R 2各自独立地为H、F、Cl、Br、CN、-OR a、-C(＝O)NR bR c、C 1-6烷基或C 3-6环烷基，其中所述C 1-6烷基和C 3-6环烷基任选被1、2或3个独立选自F、Cl、Br、I、-OH、-OCH 3、-CN、-NH 2、-NO 2或C 1-4烷基的取代基所取代； Wherein R 1 and R 2 are each independently H, F, Cl, Br, CN, -OR a , -C(=O)NR b R c , C 1-6 alkyl or C 3-6 cycloalkyl Wherein said C 1-6 alkyl group and C 3-6 cycloalkyl group are optionally 1, 2 or 3 independently selected from the group consisting of F, Cl, Br, I, -OH, -OCH 3 , -CN, -NH 2, -NO 2 or C 1-4 alkyl substituents;
R 3、R 4和R 5各自独立地为H、F、Cl、Br、CN、-OR a、-C(＝O)NR bR c、C 1-6烷基或C 3-6环烷基，其中所述C 1-6烷基和C 3-6环烷基任选被1、2或3个独立选自F、Cl、Br、I、-OH、-OCH 3、-CN、-NH 2、-NO 2或C 1- 4烷基的取代基所取代； R 3 , R 4 and R 5 are each independently H, F, Cl, Br, CN, -OR a , -C(=O)NR b R c , C 1-6 alkyl or C 3-6 naphthenic a group wherein the C 1-6 alkyl group and the C 3-6 cycloalkyl group are optionally 1, 2 or 3 independently selected from the group consisting of F, Cl, Br, I, -OH, -OCH 3 , -CN, - Substituted by a substituent of NH 2 , -NO 2 or C 1 -4 alkyl;
T 1和T 2各自独立地为N或CH； T 1 and T 2 are each independently N or CH;
R 6和R 7各自独立地为H、F、Cl或C 1-6烷基，其中所述C 1-6烷基任选被1、2或3个独立选自F、Cl、Br、CN、-OR a或-NR dR e的取代基所取代； R 6 and R 7 are each independently H, F, Cl or C 1-6 alkyl, wherein said C 1-6 alkyl group is optionally 1, 2 or 3 independently selected from the group consisting of F, Cl, Br, CN Substituted by a substituent of -OR a or -NR d R e ;
各R 8独立地为F、Cl、Br、CN、-OR a、C 1-6烷基或C 3-6环烷基，其中所述C 1-6烷基和C 3-6环烷基任选被1、2或3个独立选自F、Cl、Br、I、-OH、-OCH 3、-CN、-NH 2、-NO 2或C 1-4烷基的取代基所取代； Each R 8 is independently F, Cl, Br, CN, -OR a , C 1-6 alkyl or C 3-6 cycloalkyl, wherein said C 1-6 alkyl and C 3-6 cycloalkyl Optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of F, Cl, Br, I, -OH, -OCH 3 , -CN, -NH 2 , -NO 2 or C 1-4 alkyl;
R a、R b和R c各自独立地为H或C 1-6烷基，其中所述C 1-6烷基任选被1、2或3个独立选自F、Cl、Br、-OH、-OCH 3、-CN、-NH 2、C 1-6烷氨基或-NO 2的取代基所取代； R a , R b and R c are each independently H or C 1-6 alkyl, wherein the C 1-6 alkyl group is optionally 1, 2 or 3 independently selected from the group consisting of F, Cl, Br, -OH Substituted with a substituent of -OCH 3 , -CN, -NH 2 , C 1-6 alkylamino or -NO 2 ;
R d和R e各自独立地为H、C 1-6烷基，或R d和R e与它们连接的N原子一起形成4-8元杂环烷基，其中所述C 1-6烷基和4-8元杂环烷基任选被1、2或3个独立选自F、Cl、Br、-OH、-OCH 3、-CN、-NH 2、C 1-6烷氨基或-NO 2的取代基所取代； R d and R e are each independently H, C 1-6 alkyl, or R d and R e together with the N atom to which they are attached form a 4-8 membered heterocycloalkyl group, wherein said C 1-6 alkyl group And a 4-8 membered heterocycloalkyl group is optionally 1, 2 or 3 independently selected from the group consisting of F, Cl, Br, -OH, -OCH 3 , -CN, -NH 2 , C 1-6 alkylamino or -NO 2 substituents;
n为0、1、2、3或4；n is 0, 1, 2, 3 or 4;
所述4-8元杂环烷基包含1、2、3或4个独立选自-O-、-S-、N或-NH-的杂原子或杂原子团。The 4-8 membered heterocycloalkyl contains 1, 2, 3 or 4 heteroatoms or heteroatoms independently selected from -O-, -S-, N or -NH-.
在本发明的一些方案中，上述R a、R b和R c各自独立地为H、甲基、乙基、正丙基或异丙基，其中所述甲基、乙基、正丙基和异丙基任选被1、2或3个独立选自F、Cl、Br、I、-OH、-OCH 3、CN、-NH 2、C 1-3烷氨基或-NO 2的取代基所取代，其他变量如本发明所定义。 In some embodiments of the invention, the above R a , R b and R c are each independently H, methyl, ethyl, n-propyl or isopropyl, wherein the methyl, ethyl, n-propyl and The isopropyl group is optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of F, Cl, Br, I, -OH, -OCH 3 , CN, -NH 2 , C 1-3 alkylamino or -NO 2 Instead, other variables are as defined by the present invention.
在本发明的一些方案中，上述R a、R b和R c各自独立地为H、甲基、乙基、正丙基、异丙基、
Figure PCTCN2019083208-appb-000004
Figure PCTCN2019083208-appb-000005
Figure PCTCN2019083208-appb-000006
其他变量如本发明所定义。 In some embodiments of the invention, the above R a , R b and R c are each independently H, methyl, ethyl, n-propyl, isopropyl,
Figure PCTCN2019083208-appb-000004
Figure PCTCN2019083208-appb-000005
Figure PCTCN2019083208-appb-000006
Other variables are as defined by the present invention.
在本发明的一些方案中，上述R 1和R 2各自独立地为H、F、Cl、Br、CN、-OH、-OCH 3、-OCH 2CH 3、-C(＝O)NH 2、甲基、乙基、正丙基、异丙基、环丙基、环戊基或环己基，其中所述甲基、乙基、正丙基、异 丙基、环丙基、环戊基和环己基任选被1、2或3个独立选自F、Cl、Br、I、-OH、-OCH 3、CN、-NH 2、-NO 2、甲基、乙基或丙基的取代基所取代，其他变量如本发明所定义。 In some aspects of the invention, each of R 1 and R 2 is independently H, F, Cl, Br, CN, -OH, -OCH 3 , -OCH 2 CH 3 , -C(=O)NH 2 , Methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopentyl or cyclohexyl, wherein the methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopentyl and The cyclohexyl group is optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of F, Cl, Br, I, -OH, -OCH 3 , CN, -NH 2 , -NO 2 , methyl, ethyl or propyl. Instead, other variables are as defined by the present invention.
在本发明的一些方案中，上述R 1和R 2各自独立地为H、F、Cl、Br、CN、-OH、-OCH 3、-OCH 2CH 3、-C(＝O)NH 2、甲基、乙基、正丙基、异丙基、
Figure PCTCN2019083208-appb-000007
Figure PCTCN2019083208-appb-000008
环丙基、环戊基、环己基、
Figure PCTCN2019083208-appb-000009
Figure PCTCN2019083208-appb-000010
其他变量如本发明所定义。 In some aspects of the invention, each of R 1 and R 2 is independently H, F, Cl, Br, CN, -OH, -OCH 3 , -OCH 2 CH 3 , -C(=O)NH 2 , Methyl, ethyl, n-propyl, isopropyl,
Figure PCTCN2019083208-appb-000007
Figure PCTCN2019083208-appb-000008
Cyclopropyl, cyclopentyl, cyclohexyl,
Figure PCTCN2019083208-appb-000009
Figure PCTCN2019083208-appb-000010
Other variables are as defined by the present invention.
在本发明的一些方案中，上述R 3、R 4和R 5各自独立地为H、F、Cl、Br、CN、-OH、-OCH 3、-OCH 2CH 3、-OCH 2CH 2NHCH 3、-OCH 2CH 2N(CH 3) 2、-C(＝O)NH 2、甲基、乙基、正丙基、异丙基、环丙基、环戊基或环己基，其中所述甲基、乙基、正丙基、异丙基、环丙基、环戊基和环己基任选被1、2或3个独立选自F、Cl、Br、I、-OH、-OCH 3、CN、-NH 2、-NO 2、甲基、乙基或丙基的取代基所取代，其他变量如本发明所定义。 In some embodiments of the invention, the above R 3 , R 4 and R 5 are each independently H, F, Cl, Br, CN, -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 NHCH 3 , -OCH 2 CH 2 N(CH 3 ) 2 , -C(=O)NH 2 , methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopentyl or cyclohexyl, wherein The methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopentyl and cyclohexyl groups are optionally 1, 2 or 3 independently selected from the group consisting of F, Cl, Br, I, -OH, -OCH 3, CN, -NH 2, -NO 2, methyl, ethyl or propyl substituents other variables are as defined in the present invention.
在本发明的一些方案中，上述R 3、R 4和R 5各自独立地为H、F、Cl、Br、CN、-OH、-OCH 3、-OCH 2CH 3、
Figure PCTCN2019083208-appb-000011
-C(＝O)NH 2、甲基、乙基、正丙基、异丙基、
Figure PCTCN2019083208-appb-000012
Figure PCTCN2019083208-appb-000013
环丙基、环戊基、环己基、
Figure PCTCN2019083208-appb-000014
Figure PCTCN2019083208-appb-000015
其他变量如本发明所定义。 In some aspects of the invention, the above R 3 , R 4 and R 5 are each independently H, F, Cl, Br, CN, -OH, -OCH 3 , -OCH 2 CH 3 ,
Figure PCTCN2019083208-appb-000011
-C(=O)NH 2 , methyl, ethyl, n-propyl, isopropyl,
Figure PCTCN2019083208-appb-000012
Figure PCTCN2019083208-appb-000013
Cyclopropyl, cyclopentyl, cyclohexyl,
Figure PCTCN2019083208-appb-000014
Figure PCTCN2019083208-appb-000015
Other variables are as defined by the present invention.
在本发明的一些方案中，上述结构单元
Figure PCTCN2019083208-appb-000016
为
Figure PCTCN2019083208-appb-000017
Figure PCTCN2019083208-appb-000018
R 3、R 4和R 5及其他变量如本发明所定义。 In some aspects of the invention, the structural unit
Figure PCTCN2019083208-appb-000016
for
Figure PCTCN2019083208-appb-000017
Figure PCTCN2019083208-appb-000018
R 3 , R 4 and R 5 and other variables are as defined by the present invention.
在本发明的一些方案中，上述结构单元
Figure PCTCN2019083208-appb-000019
为
Figure PCTCN2019083208-appb-000020
Figure PCTCN2019083208-appb-000021
Figure PCTCN2019083208-appb-000022
其他变量如本发明所定义。 In some aspects of the invention, the structural unit
Figure PCTCN2019083208-appb-000019
for
Figure PCTCN2019083208-appb-000020
Figure PCTCN2019083208-appb-000021
Figure PCTCN2019083208-appb-000022
Other variables are as defined by the present invention.
在本发明的一些方案中，上述R d和R e各自独立地为H、甲基、乙基、正丙基、异丙基，或R d和R e与它们连接的N原子一起形成5-6元杂环烷基，其中所述甲基、乙基、正丙基、异丙基和5-6元杂环烷基任选被1、2或3个独立选自F、Cl、Br、I、-OH、-OCH 3、CN、-NH 2、C 1-3烷氨基或-NO 2的取代基所取代，其他变量如本发明所定义。 In some embodiments of the invention, R d and R e are each independently H, methyl, ethyl, n-propyl, isopropyl, or R d and R e are taken together with the N atom to which they are attached 5- a 6-membered heterocycloalkyl group, wherein the methyl, ethyl, n-propyl, isopropyl and 5-6 membered heterocycloalkyl are optionally 1, 2 or 3 independently selected from the group consisting of F, Cl, Br, I, -OH, -OCH 3, CN , -NH 2, C 1-3 alkylamino or a -NO 2 substituents other variables are as defined in the present invention.
在本发明的一些方案中，上述R d和R e各自独立地为H、甲基、乙基、正丙基、异丙基、
Figure PCTCN2019083208-appb-000023
Figure PCTCN2019083208-appb-000024
Figure PCTCN2019083208-appb-000025
或R d和R e与它们连接的N原子一起形成吡咯烷基或哌啶基，其中所述吡咯烷基和哌啶基任选被1、2或3个独立选自F、Cl、Br、I、-OH、-OCH 3、CN、-NH 2、C 1-3烷氨基或-NO 2的取代基所取代，其他变量如本发明所定义。 In some embodiments of the invention, the above R d and R e are each independently H, methyl, ethyl, n-propyl, isopropyl,
Figure PCTCN2019083208-appb-000023
Figure PCTCN2019083208-appb-000024
Figure PCTCN2019083208-appb-000025
Or R d and R e together with the N atom to which they are attached form a pyrrolidinyl or piperidinyl group, wherein the pyrrolidinyl and piperidinyl are optionally 1, 2 or 3 independently selected from the group consisting of F, Cl, Br, I, -OH, -OCH 3, CN , -NH 2, C 1-3 alkylamino or a -NO 2 substituents other variables are as defined in the present invention.
在本发明的一些方案中，上述R 6和R 7各自独立地为H、F、Cl、-OH、-OCH 3、-NH 2、
Figure PCTCN2019083208-appb-000026
Figure PCTCN2019083208-appb-000027
甲基、乙基、正丙基、异丙基、
Figure PCTCN2019083208-appb-000028
Figure PCTCN2019083208-appb-000029
Figure PCTCN2019083208-appb-000030
其他 变量如本发明所定义。 In some aspects of the invention, R 6 and R 7 are each independently H, F, Cl, -OH, -OCH 3 , -NH 2 ,
Figure PCTCN2019083208-appb-000026
Figure PCTCN2019083208-appb-000027
Methyl, ethyl, n-propyl, isopropyl,
Figure PCTCN2019083208-appb-000028
Figure PCTCN2019083208-appb-000029
Figure PCTCN2019083208-appb-000030
Other variables are as defined by the present invention.
在本发明的一些方案中，上述R 6和R 7各自独立地为H、F、Cl、甲基、乙基、正丙基、异丙基、
Figure PCTCN2019083208-appb-000031
Figure PCTCN2019083208-appb-000032
Figure PCTCN2019083208-appb-000033
其他变量如本发明所定义。 In some embodiments of the invention, the above R 6 and R 7 are each independently H, F, Cl, methyl, ethyl, n-propyl, isopropyl,
Figure PCTCN2019083208-appb-000031
Figure PCTCN2019083208-appb-000032
Figure PCTCN2019083208-appb-000033
Other variables are as defined by the present invention.
在本发明的一些方案中，上述各R 8独立地为F、Cl、Br、CN、-OH、-OCH 3、-OCH 2F、-OCHF 2、-OCF 3、甲基、乙基、正丙基、异丙基、环丙基、环戊基或环己基，其中所述甲基、乙基、正丙基、异丙基、环丙基、环戊基和环己基任选被1、2或3个独立选自F、Cl、Br、I、-OH、-OCH 3、CN、-NH 2、-NO 2、甲基、乙基或丙基的取代基所取代，其他变量如本发明所定义。 In some embodiments of the invention, each of R 8 above is independently F, Cl, Br, CN, -OH, -OCH 3 , -OCH 2 F, -OCHF 2 , -OCF 3 , methyl, ethyl, ortho a propyl group, an isopropyl group, a cyclopropyl group, a cyclopentyl group or a cyclohexyl group, wherein the methyl group, ethyl group, n-propyl group, isopropyl group, cyclopropyl group, cyclopentyl group and cyclohexyl group are optionally 1, 2 or 3 substituents independently selected from the group consisting of F, Cl, Br, I, -OH, -OCH 3 , CN, -NH 2 , -NO 2 , methyl, ethyl or propyl, other variables such as The invention is defined.
在本发明的一些方案中，上述各R 8独立地为F、Cl、Br、CN、-OH、-OCH 3、-OCH 2CH 3、甲基、乙基、正丙基、异丙基、
Figure PCTCN2019083208-appb-000034
Figure PCTCN2019083208-appb-000035
环丙基、环戊基、环己基、
Figure PCTCN2019083208-appb-000036
Figure PCTCN2019083208-appb-000037
其他变量如本发明所定义。 In some embodiments of the invention, each of R 8 above is independently F, Cl, Br, CN, -OH, -OCH 3 , -OCH 2 CH 3 , methyl, ethyl, n-propyl, isopropyl,
Figure PCTCN2019083208-appb-000034
Figure PCTCN2019083208-appb-000035
Cyclopropyl, cyclopentyl, cyclohexyl,
Figure PCTCN2019083208-appb-000036
Figure PCTCN2019083208-appb-000037
Other variables are as defined by the present invention.
在本发明的一些方案中，上述结构单元
Figure PCTCN2019083208-appb-000038
为
Figure PCTCN2019083208-appb-000039
Figure PCTCN2019083208-appb-000040
Figure PCTCN2019083208-appb-000041
R 8及其他变量如本发明所定义。 In some aspects of the invention, the structural unit
Figure PCTCN2019083208-appb-000038
for
Figure PCTCN2019083208-appb-000039
Figure PCTCN2019083208-appb-000040
Figure PCTCN2019083208-appb-000041
R 8 and other variables are as defined by the present invention.
在本发明的一些方案中，上述结构单元
Figure PCTCN2019083208-appb-000042
为
Figure PCTCN2019083208-appb-000043
Figure PCTCN2019083208-appb-000044
Figure PCTCN2019083208-appb-000045
其他变量如本发明所定义。 In some aspects of the invention, the structural unit
Figure PCTCN2019083208-appb-000042
for
Figure PCTCN2019083208-appb-000043
Figure PCTCN2019083208-appb-000044
Figure PCTCN2019083208-appb-000045
Other variables are as defined by the present invention.
在本发明的一些方案中，上述化合物、其药学上可接受的盐或其异构体，其具有式(I-2)～(I-4)所示结构，In some embodiments of the invention, the above compound, a pharmaceutically acceptable salt thereof or an isomer thereof, has a structure represented by the formula (I-2) to (I-4),
Figure PCTCN2019083208-appb-000046
Figure PCTCN2019083208-appb-000046
其中，R 1、R 2、R 3、R 6、R 7、R 8和n如本发明所定义。 Wherein R 1 , R 2 , R 3 , R 6 , R 7 , R 8 and n are as defined in the present invention.
在本发明的一些方案中，上述化合物、其药学上可接受的盐或其异构体，其具有式(I-5)～(I-7)所示结构，In some embodiments of the invention, the above compound, a pharmaceutically acceptable salt thereof or an isomer thereof, has a structure represented by formula (I-5) to (I-7),
Figure PCTCN2019083208-appb-000047
Figure PCTCN2019083208-appb-000048
Figure PCTCN2019083208-appb-000047
Figure PCTCN2019083208-appb-000048
其中，R 3、R 6、R 7、R 8和n如本发明所定义。 Wherein R 3 , R 6 , R 7 , R 8 and n are as defined in the present invention.
在本发明的一些方案中，上述化合物、其药学上可接受的盐或其异构体，其具有式(I-8)～(I-10)所示结构，In some embodiments of the invention, the above compound, a pharmaceutically acceptable salt thereof or an isomer thereof, has a structure represented by the formula (I-8) to (I-10),
Figure PCTCN2019083208-appb-000049
Figure PCTCN2019083208-appb-000049
其中，带“*”的碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在；Wherein the carbon atom bearing "*" is a chiral carbon atom, which is in the form of a single enantiomer of (R) or (S) or is enriched in one enantiomer form;
R 7为F、Cl、-OH、-OCH 3、-NH 2、
Figure PCTCN2019083208-appb-000050
甲基、乙基、正丙基、异丙基、
Figure PCTCN2019083208-appb-000051
Figure PCTCN2019083208-appb-000052
R 3、R 8和n如本发明所定义。 R 7 is F, Cl, -OH, -OCH 3 , -NH 2 ,
Figure PCTCN2019083208-appb-000050
Methyl, ethyl, n-propyl, isopropyl,
Figure PCTCN2019083208-appb-000051
Figure PCTCN2019083208-appb-000052
R 3 , R 8 and n are as defined in the present invention.
在本发明的一些方案中，上述化合物、其药学上可接受的盐或其异构体，其具有式(I-8)～(I-10)所示结构，In some embodiments of the invention, the above compound, a pharmaceutically acceptable salt thereof or an isomer thereof, has a structure represented by the formula (I-8) to (I-10),
Figure PCTCN2019083208-appb-000053
Figure PCTCN2019083208-appb-000053
其中，带“*”的碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在；Wherein the carbon atom bearing "*" is a chiral carbon atom, which is in the form of a single enantiomer of (R) or (S) or is enriched in one enantiomer form;
R 7为F、Cl、甲基、乙基、正丙基、异丙基、
Figure PCTCN2019083208-appb-000054
Figure PCTCN2019083208-appb-000055
Figure PCTCN2019083208-appb-000056
R 3、R 8和n如本发明所定义。 R 7 is F, Cl, methyl, ethyl, n-propyl, isopropyl,
Figure PCTCN2019083208-appb-000054
Figure PCTCN2019083208-appb-000055
Figure PCTCN2019083208-appb-000056
R 3 , R 8 and n are as defined in the present invention.
本发明还有一些方案是由上述变量任意组合而来。Still other aspects of the invention are arbitrarily combined by the above variables.
在本发明的一些方案中，上述化合物选自下式化合物，其药学上可接受的盐或其异构体：In some embodiments of the invention, the above compound is selected from the group consisting of a compound of the formula: a pharmaceutically acceptable salt thereof or an isomer thereof:
Figure PCTCN2019083208-appb-000057
Figure PCTCN2019083208-appb-000057
Figure PCTCN2019083208-appb-000058
Figure PCTCN2019083208-appb-000058
在本发明的一些方案中，上述化合物的药学上可接受的盐为甲酸盐或盐酸盐。In some embodiments of the invention, the pharmaceutically acceptable salt of the above compound is a formate or hydrochloride salt.
另一方面，本发明提供了一种药物组合物，包括作为活性成分的治疗有效量的上述化合物、其药学上可接受的盐或其异构体以及药学上可接受的载体。In another aspect, the present invention provides a pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of the above compound, a pharmaceutically acceptable salt thereof or an isomer thereof, and a pharmaceutically acceptable carrier.
同时，本发明提供了上述化合物、其药学上可接受的盐或其异构体以及上述药物组合物在制备RHO抑制剂药物中的应用。Meanwhile, the present invention provides the use of the above compound, a pharmaceutically acceptable salt thereof or an isomer thereof, and the above pharmaceutical composition for the preparation of a medicament for RHO inhibitor.
本发明还提供了上述化合物、其药学上可接受的盐或其异构体以及上述药物组合物在制备治疗自身免疫疾病的药物中的应用；在一些实施方案中，所述自身免疫疾病为I型糖尿病、类风湿性关节炎、炎性肠病、***性红斑狼疮、青光眼、肺纤维化、银屑病或多发性硬化症。The present invention also provides the above compound, a pharmaceutically acceptable salt thereof or an isomer thereof, and the use of the above pharmaceutical composition for the preparation of a medicament for treating an autoimmune disease; in some embodiments, the autoimmune disease is I Type 2 diabetes, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, glaucoma, pulmonary fibrosis, psoriasis or multiple sclerosis.
技术效果Technical effect
本发明化合物对ROCK2具有显著的激酶抑制活性，同时对ROCK2具有一定的选择性，且具有一定的透膜性和溶解性，同时具有优良的药代动力学和药效动力学性质。The compound of the present invention has remarkable kinase inhibitory activity against ROCK2, and has certain selectivity to ROCK2, and has certain membrane permeability and solubility, and has excellent pharmacokinetic and pharmacodynamic properties.
定义和说明Definition and description
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。Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered undefined or unclear without a particular definition, but should be understood in the ordinary sense. When a trade name appears in this document, it is intended to refer to its corresponding commodity or its active ingredient.
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。The term "pharmaceutically acceptable" as used herein is intended to mean that those compounds, materials, compositions and/or dosage forms are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues. Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
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、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在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。The term "pharmaceutically acceptable salt" refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base. When a relatively acidic functional group is contained in the compound of the present invention, a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When a relatively basic functional group is contained in the compound of the present invention, an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat 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, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, 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; and salts of amino acids (such as arginine, etc.) And salts of organic acids such as glucuronic acid. Certain specific compounds of the invention contain both basic and acidic functional groups which can be converted to any base or acid addition salt.
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。The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods. In general, such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。The compounds of the invention may exist in specific geometric or stereoisomeric forms. All such compounds are contemplated by the present invention, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers , (D)-isomer, (L)-isomer, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to the present Within the scope of the invention. Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.
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。Unless otherwise indicated, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of one another.
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。Unless otherwise indicated, the term "cis-trans isomer" or "geometric isomer" is caused by the inability to freely rotate a single bond due to a double bond or a ring-forming carbon atom.
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。Unless otherwise indicated, the term "diastereomer" refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirrored relationship.
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。Unless otherwise indicated, "(D)" or "(+)" means dextrorotatory, "(L)" or "(-)" means left-handed, "(DL)" or "(±)" means racemic.
除非另有说明，用楔形实线键
Figure PCTCN2019083208-appb-000059
和楔形虚线键
Figure PCTCN2019083208-appb-000060
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2019083208-appb-000061
和直形虚线键
Figure PCTCN2019083208-appb-000062
表示立体中心的相对构型，用波浪线
Figure PCTCN2019083208-appb-000063
表示楔形实线键
Figure PCTCN2019083208-appb-000064
或楔形虚线键
Figure PCTCN2019083208-appb-000065
或用波浪线
Figure PCTCN2019083208-appb-000066
表示直形实线键
Figure PCTCN2019083208-appb-000067
和直形虚线键
Figure PCTCN2019083208-appb-000068
Wedge solid key unless otherwise stated
Figure PCTCN2019083208-appb-000059
And wedge-shaped dashed keys
Figure PCTCN2019083208-appb-000060
Represents the absolute configuration of a solid center with straight solid keys
Figure PCTCN2019083208-appb-000061
And straight dashed keys
Figure PCTCN2019083208-appb-000062
Indicates the relative configuration of the stereocenter, using wavy lines
Figure PCTCN2019083208-appb-000063
Indicates a wedge solid key
Figure PCTCN2019083208-appb-000064
Or wedge-shaped dotted key
Figure PCTCN2019083208-appb-000065
Or with wavy lines
Figure PCTCN2019083208-appb-000066
Represents a straight solid key
Figure PCTCN2019083208-appb-000067
And straight dashed keys
Figure PCTCN2019083208-appb-000068
除非另有说明，当化合物中存在双键结构，如碳碳双键、碳氮双键和氮氮双键，且双键上的各个原子均连接有两个不同的取代基时(包含氮原子的双键中，氮原子上的一对孤对电子视为其连接的一个取代基)，如果该化合物中双键上的原子与其取代基之间用波浪线
Figure PCTCN2019083208-appb-000069
连接，则表示该化合物的(Z)型异构体、(E)型异构体或两种异构体的混合物。例如下式(A)表示该化合物以式(A-1)或式(A-2)的单一异构体形式存在或以式(A-1)和式(A-2)两种异构体的混合物形式存在；下式(B)表示该化合物以式(B-1)或式(B-2)的单一异构体形式存在或以式(B-1)和式(B-2)两种异构体的混合物形式存在。下式(C)表示该化合物以式(C-1)或式(C-2)的单一异构体形式存在或以式(C-1)和式(C-2)两种异构体的混合物形式存在。 Unless otherwise stated, when a double bond structure exists in a compound, such as a carbon-carbon double bond, a carbon-nitrogen double bond, and a nitrogen-nitrogen double bond, and each atom on the double bond is bonded to two different substituents (including a nitrogen atom) Of the double bonds, a pair of lone pairs of electrons on the nitrogen atom are considered as a substituent to which they are attached), if a wavy line is used between the atom on the double bond and the substituent in the compound
Figure PCTCN2019083208-appb-000069
The linkage means the (Z) isomer, the (E) isomer or a mixture of the two isomers of the compound. For example, the following formula (A) indicates that the compound exists as a single isomer of the formula (A-1) or the formula (A-2) or two isomers of the formula (A-1) and the formula (A-2) The mixture is present; the following formula (B) indicates that the compound exists as a single isomer of formula (B-1) or formula (B-2) or two of formula (B-1) and formula (B-2) A mixture of isomers is present. The following formula (C) indicates that the compound exists as a single isomer of the formula (C-1) or the formula (C-2) or two isomers of the formula (C-1) and the formula (C-2) The mixture is present.
Figure PCTCN2019083208-appb-000070
Figure PCTCN2019083208-appb-000070
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。The compounds of the invention may be present in particular. Unless otherwise indicated, the terms "tautomer" or "tautomeric form" mean that the different functional isomers are in dynamic equilibrium at room temperature and can be rapidly converted into each other. If tautomers are possible (as in solution), the chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions by proton transfer, such as keto-enol isomerization and imine-enes. Amine isomerization. The valence tautomer includes the mutual transformation of some of the bonding electrons. A specific example of keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
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％。Unless otherwise indicated, the terms "enriched in one isomer", "isomer enriched", "enriched in one enantiomer" or "enantiomeric enriched" refer to one of the isomers or pairs The content of the oligo is less than 100%, and the content of the isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, 98% or more, 99% or more, 99.5% or more, 99.6% or more, 99.7% or more, 99.8% or more, or greater than or equal to 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％。Unless otherwise indicated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the two isomers or the relative percentages of the two enantiomers. For example, if one of the isomers or enantiomers is present in an amount of 90% and the other isomer or enantiomer is present in an amount of 10%, the isomer or enantiomeric excess (ee value) is 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)。The optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer. Alternatively, when a molecule contains a basic functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxyl group), a diastereomeric salt is formed with a suitable optically active acid or base, followed by conventional methods well known in the art. The diastereomers are resolved and the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
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。 The compounds of the invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C). For another example, hydrogen can be replaced by heavy hydrogen to form a deuterated drug. The bond composed of barium and carbon is stronger than the bond composed of common hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have reduced side effects and increased drug stability. Enhance the efficacy and prolong the biological half-life of the drug. Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
“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。"Optional" or "optionally" means that the subsequently described event or condition may, but is not necessarily, to occur, and that the description includes instances in which the event or condition occurs and instances in which the event or condition does not occur.
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。The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, and may include variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable. of. When the substituent is oxygen (ie, =0), it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on the aromatic group. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
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。When any variable (eg, R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 R, the group may optionally be substituted with at most two R, and each case has an independent option. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
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。 When the number of one linking group is 0, such as -(CRR) 0 -, it indicates that the linking group is a single bond.
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。When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly linked. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.
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。When a substituent is vacant, it means that the substituent is absent. For example, when X is vacant in A-X, the structure is actually A. When the listed substituents are not indicated by which atom is attached to the substituted group, such a substituent may be bonded through any atom thereof, for example, a pyridyl group as a substituent may be passed through any one of the pyridine rings. A carbon atom is attached to the substituted group.
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 PCTCN2019083208-appb-000071
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 PCTCN2019083208-appb-000072
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 PCTCN2019083208-appb-000073
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。 When the listed linking group does not indicate its direction of attachment, its connection direction is arbitrary, for example,
Figure PCTCN2019083208-appb-000071
The medium linking group L is -MW-, and at this time, -MW- can be connected in the same direction as the reading order from left to right to form ring A and ring B.
Figure PCTCN2019083208-appb-000072
It is also possible to connect the ring A and the ring B in a direction opposite to the reading order from left to right.
Figure PCTCN2019083208-appb-000073
Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
除非另有规定，当某一基团具有一个或多个可连接位点时，该基团的任意一个或多个位点可以通过化学键与其他基团相连。所述位点与其他基团连接的化学键可以用直形实线键
Figure PCTCN2019083208-appb-000074
直形虚线键
Figure PCTCN2019083208-appb-000075
或波浪线
Figure PCTCN2019083208-appb-000076
表示。例如-OCH 3中的直形实线键表示通过该基团中的氧原子与其他基团相连；
Figure PCTCN2019083208-appb-000077
中的直形虚线键表示通过该基团中的氮原子的两端与其他基团相连；
Figure PCTCN2019083208-appb-000078
中的波浪线表示通过该苯基基团中的1和2位碳原子与其他基团相连。 Unless otherwise specified, when a group has one or more attachable sites, any one or more of the sites may be attached to the other group via a chemical bond. The chemical bond connecting the site to other groups can be a straight solid bond
Figure PCTCN2019083208-appb-000074
Straight dotted key
Figure PCTCN2019083208-appb-000075
Or wavy line
Figure PCTCN2019083208-appb-000076
Said. For example, a straight solid bond in -OCH 3 indicates attachment to other groups through an oxygen atom in the group;
Figure PCTCN2019083208-appb-000077
a straight dashed bond in the middle indicates that both ends of the nitrogen atom in the group are attached to other groups;
Figure PCTCN2019083208-appb-000078
The wavy line in the middle indicates that it is attached to other groups through the carbon atoms at the 1 and 2 positions in the phenyl group.
除非另有规定，术语“杂”表示杂原子或杂原子团(即含有杂原子的原子团)，包括碳(C)和氢(H)以外的原子以及含有这些杂原子的原子团，例如包括氧(O)、氮(N)、硫(S)或-N(H)-。Unless otherwise specified, the term "hetero" denotes a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), including atoms other than carbon (C) and hydrogen (H), and radicals containing such heteroatoms, including, for example, oxygen (O). ), nitrogen (N), sulfur (S) or -N (H)-.
除非另有规定，环上原子的数目通常被定义为环的元数，例如，“5-7元环”是指环绕排列5-7个原子的“环”。Unless otherwise specified, the number of atoms on the ring is generally defined as the number of elements of the ring. For example, "5-7 membered ring" refers to a "ring" that is arranged around 5-7 atoms.
除非另有规定，术语“环”表示环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基、芳基或杂芳基。所述的环包括单环，也包括螺环、并环和桥环等双环或多环体系。除非另有规定，该环任选地包含1～3个杂原子。因此，“5～7元环”包括例如苯基、吡啶基和哌啶基；另一方面，术语“5～7元杂环烷基”包括哌啶基，但不包括苯基。术语“环”还包括含有至少一个环的环系，其中的每一个“环”均独立地符合上述定义。Unless otherwise specified, the term "ring" denotes cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. The ring includes a single ring, and also includes a bicyclic or polycyclic ring system such as a spiro ring, a ring and a bridge ring. Unless otherwise specified, the ring optionally contains from 1 to 3 heteroatoms. Thus, a "5-7 membered ring" includes, for example, phenyl, pyridyl and piperidinyl; on the other hand, the term "5-7 membered heterocycloalkyl" includes piperidinyl, but does not include phenyl. The term "ring" also includes ring systems containing at least one ring, each of which "ring" independently conforms to the above definition.
除非另有规定，术语“C 1-6烷基”用于表示包含1至6个碳原子的直链或支链的饱和的碳氢基团。所述C 1-6烷基包括C 1-5、C 1-4、C 1-3和C 1-2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 1-6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)、己基等。 Unless otherwise specified, the term " C1-6 alkyl" is used to indicate a straight or branched saturated hydrocarbon group containing from 1 to 6 carbon atoms. The C 1-6 alkyl group includes C 1-5 , C 1-4 , C 1-3 and C 1-2 alkyl groups and the like. It may be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine). Examples of C 1-6 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 and the like.
除非另有规定，术语“杂烷基”本身或者与另一术语联合，表示由一定数目碳原子和至少一个杂原子或杂原子团组成的，稳定的直链或支链的烷基原子团或其组合物。在一些实施方案中，杂原子选自O、N和S，其中氮和硫原子任选地被氧化，氮杂原子任选地被季铵化。在一些实施方案中，所述杂烷基为C 1-6杂烷 基；在另一些实施方案中，所述杂烷基为C 1-3杂烷基。杂原子或杂原子团可以位于杂烷基的任何内部位置，包括该烷基与分子其余部分的连接位置，但术语“C 1-6烷氨基”是指氨基连接到分子的其余部分的那些包含1至6个碳原子的烷基基团。所述C 1-6烷氨基包括C 1-5、C 1-4、C 1-3、C 1-2、C 1、C 2、C 3、C 4、C 5、C 6烷氨基等。C 1-6烷氨基的实例包括但不限于-NHCH 3、-N(CH 3) 2、-NHCH 2CH 3、-N(CH 3)(CH 2CH 3)等。杂烷基的实例包括但不限于-OCH 3、-OCH 2CH 3、-OCH 2CH 2CH 3、-OCH 2(CH 3) 2、-CH 2-CH 2-O-CH 3、-NHCH 3、-N(CH 3) 2、-NHCH 2CH 3、-N(CH 3)(CH 2CH 3)、-CH 2-CH 2-NH-CH 3、-CH 2-CH 2-N(CH 3)-CH 3、-SCH 3、-SCH 2CH 3、-SCH 2CH 2CH 3、-SCH 2(CH 3) 2、-CH 2-S-CH 2-CH 3、-CH 2-CH 2、-S(＝O)-CH 3、-CH 2-CH 2-S(＝O) 2-CH 3等。至多两个杂原子可以是连续的，例如-CH 2-NH-OCH 3。 Unless otherwise specified, the term "heteroalkyl", by itself or in conjunction with another term, denotes a stable straight or branched alkyl radical or a combination thereof consisting of a number of carbon atoms and at least one heteroatom or heteroatom. Things. In some embodiments, the heteroatoms are selected from the group consisting of O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized. In some embodiments, the heteroalkyl group is a C1-6 heteroalkyl group; in other embodiments, the heteroalkyl group is a C1-3 heteroalkyl group. The heteroatom or heteroatom group may be located at any internal position of the heteroalkyl group, including the position at which the alkyl group is attached to the rest of the molecule, but the term " C1-6 alkylamino" refers to those in which the amino group is attached to the remainder of the molecule. An alkyl group of up to 6 carbon atoms. The C 1-6 alkylamino group includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkylamino groups and the like. Examples of the C 1-6 alkylamino group include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )(CH 2 CH 3 ), and the like. Examples of heteroalkyl groups include, but are not limited to, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH 2 (CH 3 ) 2 , -CH 2 -CH 2 -O-CH 3 , -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )(CH 2 CH 3 ), -CH 2 -CH 2 -NH-CH 3 , -CH 2 -CH 2 -N ( CH 3 )-CH 3 , -SCH 3 , -SCH 2 CH 3 , -SCH 2 CH 2 CH 3 , -SCH 2 (CH 3 ) 2 , -CH 2 -S-CH 2 -CH 3 , -CH 2 - CH 2 , -S(=O)-CH 3 , -CH 2 -CH 2 -S(=O) 2 -CH 3 and the like. Up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3.
术语“C 1-3烷氨基”是指氨基连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C 1-3烷氨基包括C 1-2、C 1、C 2、C 3烷氨基等。C 1-3烷氨基的实例包括但不限于-NHCH 3、-N(CH 3) 2、-NHCH 2CH 3、-N(CH 3)(CH 2CH 3)等。 The term "C 1-3 alkylamino" refers to those alkyl groups containing from 1 to 3 carbon atoms which are attached to the remainder of the molecule. The C 1-3 alkylamino group includes C 1-2 , C 1 , C 2 , C 3 alkylamino group and the like. Examples of the C 1-3 alkylamino group include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )(CH 2 CH 3 ), and the like.
除非另有规定，术语“C 3-6环烷基”用于表示任何稳定的包含3至6个碳原子的环状烷基，所述C 3-6环烷基为单环体系。所述C 3-6环烷基包括C 3-5、C 3-4、C 4-6、C 5-6、C 3和C 6环烷基等，且其可以是一价、二价或者多价。C 3-6环烷基的实例包括但不限于，环丙基、环丁基、环戊基、环己基等。 Unless otherwise specified, the term "C 3-6 cycloalkyl" is used to mean any stable cyclic alkyl group containing 3 to 6 carbon atoms, the C 3-6 cycloalkyl is a monocyclic ring system. The C 3-6 cycloalkyl group includes C 3-5 , C 3-4 , C 4-6 , C 5-6 , C 3 and C 6 cycloalkyl groups and the like, and it may be monovalent, divalent or Multi-price. Examples of C 3-6 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
除非另有规定，术语“4-8元杂环烷基”本身或者与其他术语联合分别表示环化的“杂烷基”，所述“4-8元杂环烷基”包含4至8个环原子，且其包括单环和双环体系，其中双环包括螺环、并环和桥环。此外，就该“4-8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4-8元杂环烷基包括4-5元、4-6元、5-6元、5元和6元杂环烷基等。4-8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、高哌啶基或氧杂环庚烷基。Unless otherwise specified, the term "4-8 membered heterocycloalkyl", by itself or in combination with other terms, denotes a cyclized "heteroalkyl", respectively, and said "4-8 membered heterocycloalkyl" contains 4 to 8 A ring atom, and which includes both monocyclic and bicyclic systems, wherein the bicyclic ring includes a spiro ring, a hydrazine ring, and a bridge ring. Further, in the case of the "4-8 membered heterocycloalkyl group", a hetero atom may occupy a position at which a heterocycloalkyl group is bonded to the rest of the molecule. The 4-8 membered heterocycloalkyl group includes 4-5 members, 4-6 members, 5-6 members, 5-membered and 6-membered heterocycloalkyl groups, and the like. Examples of 4-8 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thioheterobutyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl ( 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.), Dioxoalkyl, dithiaalkyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, high piperazine Pyridyl or oxetanyl.
除非另有规定，术语“5-6元杂环烷基”本身或者与其他术语联合分别表示由5至6个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“5-6元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述5-6元杂环烷基包括5元和6元杂环烷基。5-6元杂环烷基的实例包括但不限于吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基或高哌啶基等。 Unless otherwise specified, the term "5-6 membered heterocycloalkyl", by itself or in combination with other terms, denotes a saturated cyclic group consisting of 5 to 6 ring atoms, respectively, having 1, 2, 3 or 4 ring atoms. Is a heteroatom independently selected from O, S and N, the remainder being a carbon atom, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (ie NO and S(O) p ,p Is 1 or 2). It includes both monocyclic and bicyclic systems, wherein the bicyclic system includes a spiro ring, a concentric ring, and a bridge ring. Further, in the case of the "5-6 membered heterocycloalkyl group", a hetero atom may occupy a position where a heterocycloalkyl group is bonded to the rest of the molecule. The 5-6 membered heterocycloalkyl group includes 5-membered and 6-membered heterocycloalkyl groups. Examples of 5-6 membered heterocycloalkyl include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (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.), dioxoalkyl, dithiaalkyl, isoxazolidinyl, isothiazole Alkyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl or homopiperidinyl, and the like.
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。 Unless otherwise specified, C n-n+m or C n -C n+m includes any one 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 range of n to n+m, for example, C 1-12 includes C 1 - 3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 , etc.; similarly, n to n The +m element indicates that the number of atoms on the ring is n to n+m, for example, the 3-12 element ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, and a 9-membered ring. a 10-membered ring, a 11-membered ring, and a 12-membered ring, and includes any one of n to n+m, for example, a 3-12-membered ring including a 3-6-membered ring, a 3-9-membered ring, and a 5-6-membered ring. Ring, 5-7 membered ring, 6-7 membered ring, 6-8 membered ring, and 6-10 membered ring.
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。The term "leaving group" refers to a functional group or atom which may be substituted by another functional group or atom by a substitution reaction (for example, an affinity substitution reaction). For example, representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters and the like; acyloxy groups such as acetoxy, trifluoroacetoxy and the like.
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。The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxy protecting group" or "thiol protecting group". The term "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 (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, e.g., tert-butoxycarbonyl (Boc) Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1, 1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS) and the like. The term "hydroxy protecting group" refers to a protecting group suitable for use in preventing hydroxy side reactions. Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and t-butyl groups; acyl groups such as alkanoyl groups (e.g., acetyl); arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
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。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 set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
本发明所使用的溶剂可经市售获得。The solvent used in the present invention is commercially available.
本发明采用下述缩略词：MeOH代表甲醇；DMSO代表二甲基亚砜；CDCl 3代表氘代氯仿。 The present invention employs the following abbreviations: MeOH for methanol; DMSO for dimethyl sulfoxide; and CDCl 3 for deuterated chloroform.
本发明化合物依据本领域常规命名原则或者使用
Figure PCTCN2019083208-appb-000079
软件命名，市售化合物采用供应商目录名称。 The compounds of the invention are based on conventional nomenclature or use in the art
Figure PCTCN2019083208-appb-000079
Software naming, commercially available compounds using the supplier catalog name.
附图说明DRAWINGS
图1为本发明化合物11、12(盐酸盐)和13(盐酸盐)对α-SMA基因表达的抑制作用Figure 1 shows the inhibition of α-SMA gene expression by compounds 11, 12 (hydrochloride) and 13 (hydrochloride) of the present invention
图2为本发明化合物11和12(盐酸盐)的肺纤维化评分Figure 2 is a pulmonary fibrosis score of compounds 11 and 12 (hydrochloride) of the present invention
图3为本发明化合物11和12(盐酸盐)对病灶内细支气管和小动脉损伤Figure 3 shows the damage of bronchial and arterioles in the lesions of compounds 11 and 12 (hydrochloride) of the present invention
图4为本发明化合物11和12(盐酸盐)对病灶边缘细支气管和小动脉损伤Figure 4 shows the damage of bronchial and arterioles at the margin of the lesion by compounds 11 and 12 (hydrochloride) of the present invention.
具体实施方式detailed description
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。本发明化合物的盐酸盐或甲酸盐，加入饱和碳酸氢钠溶液调节pH到中性，经过高效液相色谱法分离(中性,碳酸氢铵体系)得到化合物的游离碱。The invention is described in detail below by the examples, but is not intended to limit the invention. The present invention has been described in detail herein, the embodiments of the present invention are disclosed herein, and various modifications and changes may be made to the embodiments of the present invention without departing from the spirit and scope of the invention. It will be obvious. The hydrochloride or formate salt of the compound of the present invention is adjusted to pH neutrality by adding a saturated sodium hydrogencarbonate solution, and is separated by high performance liquid chromatography (neutral, ammonium hydrogencarbonate system) to obtain a free base of the compound.
实施例1Example 1
Figure PCTCN2019083208-appb-000080
Figure PCTCN2019083208-appb-000080
合成路线：synthetic route:
Figure PCTCN2019083208-appb-000081
Figure PCTCN2019083208-appb-000081
第一步first step
将化合物1a(120mg,0.780mmol)，化合物1b(86.0mg,0.480mmol)和四甲基脲六氟磷酸酯(362mg,0.950mmol)溶于二氯甲烷(4mL)中，三乙胺(193mg,1.90mmol)在氮气保护下加入反应液中，混合物在25摄氏度下搅拌2小时。液相色谱检测反应完成。反应液用水(10mL)淬灭，二氯甲烷(30mL x 2)萃取，合并有机相后用饱和食盐水洗(10mL x 2)，无水硫酸钠干燥，过滤，滤液减压浓缩得到化合物1c。Compound 1a (120 mg, 0.780 mmol), compound 1b (86.0 mg, 0.480 mmol) and tetramethylurea hexafluorophosphate (362 mg, 0.950 mmol) were dissolved in dichloromethane (4 mL), triethylamine (193 mg, 1.90 mmol) was added to the reaction solution under a nitrogen atmosphere, and the mixture was stirred at 25 ° C for 2 hours. The reaction was completed by liquid chromatography. The reaction mixture was quenched with EtOAc (EtOAc)EtOAc.
MS-ESI计算值[M+H] +417,实测值417。 MS-ESI calcd for [M+H] + 417.
第二步Second step
将化合物1c(200mg,0.480mmol)，化合物1d(112mg,0.580mmol)和磷酸钾(307mg,1.44mmol)溶于四氢呋喃(4mL)和水(1mL)的混合溶剂中，在氮气保护下加入1,1'-双(二叔丁基膦)二茂铁二氯化钯(35.0mg,0.0480mmol)，所得反应混合物在80摄氏度下搅拌5小时。液相色谱检测反应完成。反应液用水(10mL)淬灭，乙酸乙酯(30mL x 2)萃取，合并有机相后用饱和食盐水洗(10mL x 2)，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用高效液相色谱法(中性条件)纯化，得到目标化合物1。MS-ESI计算值[M+H] +403,实测值403。 Compound 1c (200 mg, 0.480 mmol), Compound 1d (112 mg, 0.580 mmol) and potassium phosphate (307 mg, 1.44 mmol) were dissolved in a mixture of tetrahydrofuran (4 mL) and water (1 mL) 1'-bis(di-tert-butylphosphine)ferrocene palladium dichloride (35.0 mg, 0.0480 mmol), and the resulting reaction mixture was stirred at 80 ° C for 5 hours. The reaction was completed by liquid chromatography. The reaction mixture was diluted with EtOAc EtOAc EtOAc. The residue was purified by high performance liquid chromatography (neutral conditions) to give the title compound 1. MS-ESI calcd for [M+H] + 403.
1H NMR(400MHz,MeOH-d 4)δ9.16(d,J＝2.0Hz,1H),8.77(s,1H),8.23-8.15(m,4H),8.09-8.07(m,1H),7.30(t,J＝8.0Hz,1H),7.07-7.05(m,2H),6.87-6.84(m,1H),5.37-5.33(m,1H),3.82(s,3H),3.75-3.65(m,2H),2.24-2.12(m,2H)。 1 H NMR (400 MHz, MeOH-d 4 ) δ 9.16 (d, J = 2.0 Hz, 1H), 8.77 (s, 1H), 8.23-8.15 (m, 4H), 8.09-8.07 (m, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.07-7.05 (m, 2H), 6.87-6.84 (m, 1H), 5.37-5.33 (m, 1H), 3.82 (s, 3H), 3.75-3.65 ( m, 2H), 2.24 - 2.12 (m, 2H).
实施例2Example 2
Figure PCTCN2019083208-appb-000082
Figure PCTCN2019083208-appb-000082
合成路线：synthetic route:
Figure PCTCN2019083208-appb-000083
Figure PCTCN2019083208-appb-000083
第一步first step
将化合物2a(138mg,0.550mmol)，化合物1b(100mg,0.550mmol)和四甲基脲六氟磷酸酯(419mg,1.10mmol)溶于二氯甲烷(10mL)中，三乙胺(167mg,1.66mmol)在氮气保护下加入反应液中，混合物在25摄氏度下搅拌2小时。液相色谱检测反应完成。反应液用水(20mL)淬灭，二氯甲烷(20mL x 2)萃取，合并有机相后用饱和食盐水洗(10mL x 2)，无水硫酸钠干燥，过滤，滤液减压除去溶剂后用制备薄层色谱板纯化得到化合物2b。MS-ESI计算值[M+H] +415,实测值415。 Compound 2a (138 mg, 0.550 mmol), compound 1b (100 mg, 0.550 mmol) and tetramethylurea hexafluorophosphate (419 mg, 1.10 mmol) in dichloromethane (10 mL), triethylamine (167 mg, 1.66) Methyl) was added to the reaction solution under a nitrogen atmosphere, and the mixture was stirred at 25 ° C for 2 hours. The reaction was completed by liquid chromatography. The reaction mixture was quenched with EtOAc (EtOAc) (EtOAc (EtOAc) The layer chromatography plate was purified to give the compound 2b. MS-ESI calcd for [M+H] + 415.
第二步Second step
将化合物2b(150mg,0.360mmol)，化合物1d(84.0mg,0.430mmol)和磷酸钾(230mg,1.09mmol)溶于四氢呋喃(4mL)和水(1mL)的混合溶剂中，在氮气保护下加入1,1'-双(二叔丁基膦)二茂铁二氯化钯(24.0mg,0.0360mmol)，所得反应混合物在80摄氏度下搅拌5小时。液相色谱检测反应完成。反应液用水(10mL)淬灭后用乙酸乙酯(15mL x 2)萃取，合并有机相后用饱和食盐水洗(10mL x 2)，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用高效液相色谱法(盐酸条件)纯化，得到目标化合物2的盐酸盐。Compound 2b (150 mg, 0.360 mmol), Compound 1d (84.0 mg, 0.430 mmol) and potassium phosphate (230 mg, 1.09 mmol) were dissolved in tetrahydrofuran (4 mL) and water (1 mL). 1'-bis(di-tert-butylphosphine)ferrocene palladium dichloride (24.0 mg, 0.0360 mmol), and the resulting reaction mixture was stirred at 80 ° C for 5 hours. The reaction was completed by liquid chromatography. The reaction mixture was quenched with EtOAc EtOAc (EtOAc)EtOAc. The residue was purified by high performance liquid chromatography (hydrochloric acid) to give the hydrochloride salt of title compound 2.
MS-ESI计算值[M+H] +402,实测值402。 MS-ESI calc. [M+H] + 402.
1H NMR(400MHz,MeOH-d 4)δ8.40(s,1H),8.33(s,2H),8.23(s,1H),7.98-7.93(m,2H),7.89-7.87(m,2H),7.31-7.27(m,1H),7.07-7.04(m,2H),6.86-6.83(m,1H),5.36-5.32(m,1H),3.82(s,3H),3.72-3.66(m,2H),2.24-2.12(m,2H)。 1 H NMR (400MHz, MeOH- d 4) δ8.40 (s, 1H), 8.33 (s, 2H), 8.23 (s, 1H), 7.98-7.93 (m, 2H), 7.89-7.87 (m, 2H ), 7.31-7.27 (m, 1H), 7.07-7.04 (m, 2H), 6.86-6.83 (m, 1H), 5.36-5.32 (m, 1H), 3.82 (s, 3H), 3.72-3.66 (m) , 2H), 2.24 - 2.12 (m, 2H).
实施例3Example 3
Figure PCTCN2019083208-appb-000084
Figure PCTCN2019083208-appb-000084
合成路线：synthetic route:
Figure PCTCN2019083208-appb-000085
Figure PCTCN2019083208-appb-000085
第一步first step
将化合物3a(139mg,0.550mmol)，化合物1b(100mg,0.550mmol)和四甲基脲六氟磷酸酯(419mg,1.10mmol)溶于二氯甲烷(10mL)中,三乙胺(167mg,1.66mmol)在氮气保护下加入反应液中，混合物在25摄氏度下搅拌2小时。液相色谱检测反应完成。反应液用水(20mL)淬灭后用二氯甲烷(20mL x 2)萃取，合并有机相后用饱和食盐水洗(10mL x 2)，无水硫酸钠干燥，过滤，滤液减压除去溶剂后用制备薄层色谱板纯化得到化合物3b。MS-ESI计算值[M+H] +416,实测值416。 Compound 3a (139 mg, 0.550 mmol), compound 1b (100 mg, 0.550 mmol) and tetramethylurea hexafluorophosphate (419 mg, 1.10 mmol) in dichloromethane (10 mL), triethylamine (167 mg, 1.66) Methyl) was added to the reaction solution under a nitrogen atmosphere, and the mixture was stirred at 25 ° C for 2 hours. The reaction was completed by liquid chromatography. The reaction mixture was quenched with water (20 mL), EtOAc (EtOAc) The thin layer chromatography plate was purified to give the compound 3b. MS-ESI calcd for [M+H] + 416.
第二步Second step
将化合物3b(110mg,0.260mmol),化合物1d(62.0mg,0.320mmol)和磷酸钾(168mg,0.790mmol)溶于四氢呋喃(4mL)和水(1mL)的混合溶剂中，在氮气保护下加入1,1'-双(二叔丁基膦)二茂铁二氯化钯(17.0mg,0.0260mmol)，所得反应混合物在80摄氏度下搅拌5小时。液相色谱检测反应完成。反应液用水(10mL)淬灭，乙酸乙酯(15mL x 2)萃取，合并有机相后用饱和食盐水洗(10mL x 2),无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用高效液相色谱法(盐酸条件)纯化，得到目标化合物3的盐酸盐。Compound 3b (110 mg, 0.260 mmol), compound 1d (62.0 mg, 0.320 mmol) and potassium phosphate (168 mg, 0.790 mmol) were dissolved in tetrahydrofuran (4 mL) and water (1 mL). 1'-bis(di-tert-butylphosphine)ferrocene palladium dichloride (17.0 mg, 0.0260 mmol), and the resulting reaction mixture was stirred at 80 ° C for 5 hours. The reaction was completed by liquid chromatography. The reaction mixture was diluted with EtOAc EtOAc EtOAc. The residue was purified by high performance liquid chromatography (hydrochloric acid) to give the hydrochloride salt of title compound 3.
MS-ESI计算值[M+H] +403,实测值403。 MS-ESI calcd for [M+H] + 403.
1H NMR(400MHz,MeOH-d 4)δ9.49(s,1H),8.82(s,1H),8.45-8.39(m,4H),8.32-8.29(m,1H),7.32-7.27(m,1H),7.07-7.06(m,2H),6.87-6.84(m,1H),5.41-5.36(m,1H),3.82(s,3H),3.74-3.64(m,2H),2.29-2.17(m,2H)。 1 H NMR (400MHz, MeOH- d 4) δ9.49 (s, 1H), 8.82 (s, 1H), 8.45-8.39 (m, 4H), 8.32-8.29 (m, 1H), 7.32-7.27 (m , 1H), 7.07-7.06 (m, 2H), 6.87-6.84 (m, 1H), 5.41-5.36 (m, 1H), 3.82 (s, 3H), 3.74-3.64 (m, 2H), 2.29-2. (m, 2H).
实施例4Example 4
Figure PCTCN2019083208-appb-000086
Figure PCTCN2019083208-appb-000086
合成路线：synthetic route:
Figure PCTCN2019083208-appb-000087
Figure PCTCN2019083208-appb-000087
第一步first step
将化合物4a(200mg,0.710mmol)溶于二氯甲烷(1mL)中，在0摄氏度和氮气保护下分批加入戴斯-马丁试剂(305mg,0.720mmol)，然后将反应液升温至25摄氏度继续搅拌2小时。反应液依次用饱和碳酸氢钠溶液(10mL)和饱和硫代硫酸钠溶液(10mL)淬灭，用乙酸乙酯(50mL x 3)萃取，有机相用饱和食盐水(20mL x 3)洗涤，无水硫酸钠干燥。滤去干燥剂后，减压除去溶剂后用制备薄层色谱板纯化得到化合物4b。MS-ESI计算值[M+H] +280,实测值280。 Compound 4a (200 mg, 0.710 mmol) was dissolved in dichloromethane <RTI ID=0.0>(1 </RTI><RTIID=0.0></RTI></RTI><RTIgt;</RTI><RTIgt; Stir for 2 hours. The reaction mixture was quenched with EtOAc EtOAc EtOAc (EtOAc (EtOAc) Dry with sodium sulfate. After filtering off the desiccant, the solvent was removed under reduced pressure and then purified by preparative thin layer chromatography to afford compound 4b. MS-ESI calcd [M+H] + 280.
1H NMR(400MHz,CDCl 3)δ9.77-9.73(brs,1H),7.29-7.25(m,1H),6.91-6.78(m,3H),5.18-5.09(m,1H),3.81(s,3H),3.11-2.78(m,2H),1.43(s,9H)。 1 H NMR (400MHz, CDCl 3 ) δ9.77-9.73 (brs, 1H), 7.29-7.25 (m, 1H), 6.91-6.78 (m, 3H), 5.18-5.09 (m, 1H), 3.81 (s , 3H), 3.11-2.78 (m, 2H), 1.43 (s, 9H).
第二步Second step
在25摄氏度和氮气保护下，将二甲胺盐酸盐(79.0mg,0.970mmol)，三乙胺(98.0mg,0.970mmol)和乙酸(3.00mg,0.0480mmol)依次加入到化合物4b(135mg,0.480mmol)的1,2-二氯乙烷(4mL)溶液中，加入完毕后搅拌0.5小时，然后向反应液中加入醋酸硼氢化钠(154mg,0.730mmol)，继续搅拌反应11.5小时。反应液用饱和碳酸氢钠溶液(10mL)淬灭，用乙酸乙酯(50mL x 3)萃取，然后有机相用饱和食盐水(20mL x3)洗涤，然后用无水硫酸钠干燥。过滤除去干燥剂，滤液减压除去溶剂得到粗品。粗品经制备薄层色谱板纯化得到化合物4c。Dimethylamine hydrochloride (79.0 mg, 0.970 mmol), triethylamine (98.0 mg, 0.970 mmol) and acetic acid (3.00 mg, 0.0480 mmol) were sequentially added to compound 4b (135 mg, A solution of 0.480 mmol) in 1,2-dichloroethane (4 mL) was added and the mixture was stirred for 0.5 hour, then sodium borohydride (154 mg, 0.730 mmol) was added to the reaction mixture, and the reaction was further stirred for 11.5 hours. The reaction mixture was quenched with EtOAc EtOAc (EtOAc)EtOAc. The desiccant was removed by filtration, and the filtrate was evaporated under reduced pressure to give a crude material. The crude product was purified by preparative thin layer chromatography to give compound 4c.
MS-ESI计算值[M+H] +309,实测值309。 MS-ESI calcd [M+H] + 303.
1H NMR(400MHz,CDCl 3)δ7.26-7.21(m,1H),6.90-6.76(m,3H),6.01(brs,0.5H),4.73(brs,0.5H),3.81(s,3H),2.36-2.25(m,2H),2.24(brs,6H),2.08-1.76(m,2H),1.43(brs,9H)。 1 H NMR (400MHz, CDCl 3 ) δ7.26-7.21 (m, 1H), 6.90-6.76 (m, 3H), 6.01 (brs, 0.5H), 4.73 (brs, 0.5H), 3.81 (s, 3H ), 2.36-2.25 (m, 2H), 2.24 (brs, 6H), 2.08-1.76 (m, 2H), 1.43 (brs, 9H).
第三步third step
在0摄氏度和氮气保护下，将三氟乙酸(422mg,3.70mmol)滴加到化合物4c(57.0mg,0.160mmol)的二 氯甲烷(2mL)溶液中，滴加完毕后在25摄氏度搅拌反应12小时。反应液用饱和碳酸氢钠溶液(20mL)淬灭，用乙酸乙酯(50mL x 3)萃取，然后有机相用饱和食盐水(20mL x 3)洗涤，然后用无水硫酸钠干燥。过滤除去干燥剂，滤液减压除去溶剂得到化合物4d。MS-ESI计算值[M+H] +209,实测值209。 Trifluoroacetic acid (422 mg, 3.70 mmol) was added dropwise to a solution of compound 4c (57.0 mg, 0.160 mmol) in dichloromethane (2 mL), and the mixture was stirred at 25 ° C. hour. The reaction mixture was diluted with EtOAc EtOAc (EtOAc)EtOAc. The desiccant was removed by filtration, and the filtrate was evaporated under reduced pressure to give Compound 4d. MS-ESI calcd for [M + H] + 209, found 209.
1H NMR(400MHz,MeOH-d 4)δ7.25(t,J＝7.6Hz,1H),6.95-6.88(m,2H),6.82(dd,J＝7.6,2.0Hz,1H),3.86(t,J＝7.2Hz,1H),3.80(s,3H),2.32-2.41(m,1H),2.22(brs,6H),2.21-2.15(m,1H),2.01-1.81(m,2H)。 1 H NMR (400 MHz, MeOH-d 4 ) δ 7.25 (t,J = 7.6 Hz, 1H), 6.95-6.88 (m, 2H), 6.82 (dd, J = 7.6, 2.0 Hz, 1H), 3.86 ( t, J=7.2 Hz, 1H), 3.80 (s, 3H), 2.32-2.41 (m, 1H), 2.22 (brs, 6H), 2.21-2.15 (m, 1H), 2.01-1.81 (m, 2H) .
第四步the fourth step
在25摄氏度和氮气保护下，将化合物3a(47.0mg,0.190mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(105mg,0.280mmol)和N,N-二异丙基乙胺(49.0mg,0.370mmol)依次加入到化合物4d(38.0mg,0.190mmol)的N,N-二甲基甲酰胺(1mL)溶液中。所得反应液在25摄氏度搅拌反应12小时。反应液用饱和食盐水(5mL)淬灭，用乙酸乙酯(50mL x 3)萃取，然后有机相用饱和食盐水(20mL×3)洗涤，然后用无水硫酸钠干燥。过滤除去干燥剂，滤液减压除去溶剂得到粗品。粗品经制备薄层色谱板纯化得到化合物4e。MS-ESI计算值[M+H] +442,444；实测值442,444。 Compound 3a (47.0 mg, 0.190 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate at 25 ° C under nitrogen protection The ester (105 mg, 0.280 mmol) and N,N-diisopropylethylamine (49.0 mg, 0.370 mmol) were added sequentially to compound 4d (38.0 mg, 0.190 mmol) of N,N-dimethylformamide (1 mL) In solution. The resulting reaction solution was stirred at 25 ° C for 12 hours. The reaction mixture was diluted with EtOAc EtOAc (EtOAc) The desiccant was removed by filtration, and the filtrate was evaporated under reduced pressure to give a crude material. The crude product was purified by preparative thin layer chromatography to give compound 4e. MS-ESI calcd for [M + H] + 442,444; 442,444 found.
1H NMR(400MHz,CDCl 3)δ9.19-9.14(m,2H),8.49(s,1H),8.15(s,1H),7.91(d,J＝8.8Hz,1H),7.79(d,J＝8.8Hz,1H),7.33-7.28(m,1H),7.02(brs,1H),6.97(d,J＝2.4Hz,1H),6.84(d,J＝2.4Hz,1H),5.31-5.22(m,1H),3.82(s,3H),2.64(t,J＝6.8Hz,2H),2.50(s,6H),2.29-2.17(m,2H)。 1 H NMR (400MHz, CDCl 3 ) δ9.19-9.14 (m, 2H), 8.49 (s, 1H), 8.15 (s, 1H), 7.91 (d, J = 8.8Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.33 - 7.28 (m, 1H), 7.02 (brs, 1H), 6.97 (d, J = 2.4 Hz, 1H), 6.84 (d, J = 2.4 Hz, 1H), 5.31 5.22 (m, 1H), 3.82 (s, 3H), 2.64 (t, J = 6.8 Hz, 2H), 2.50 (s, 6H), 2.29-2.17 (m, 2H).
第五步the fifth step
在25摄氏度和氮气保护下，将化合物1d(43.0mg,0.220mmol)，1,1'-双(二叔丁基膦)二茂铁二氯化钯(12.0mg,0.0190mmol)和磷酸钾(118mg,0.550mmol)依次加入到化合物4e(82.0mg,0.190mmol)的四氢呋喃(1.6mL)和水(0.4mL)溶液中。所得反应液在80摄氏度和氮气保护下搅拌4小时。反应液用饱和食盐水(5mL)淬灭，用乙酸乙酯(20mL x 3)萃取、然后有机相用饱和食盐水(10mL x 3)洗涤，然后用无水硫酸钠干燥。过滤除去干燥剂，滤液减压除去溶剂得到粗品。粗品经制备高效液相色谱法(中性条件)纯化得到化合物4。Compound 1d (43.0 mg, 0.220 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (12.0 mg, 0.0190 mmol) and potassium phosphate (under 25 ° C and nitrogen) 118 mg, 0.550 mmol) was added to a solution of compound 4e (82.0 mg, 0.190 mmol) in tetrahydrofuran (1.6 mL) and water (0.4 mL). The resulting reaction solution was stirred at 80 ° C for 4 hours under a nitrogen atmosphere. The reaction mixture was diluted with EtOAc EtOAc (EtOAc)EtOAc. The desiccant was removed by filtration, and the filtrate was evaporated under reduced pressure to give a crude material. The crude product was purified by preparative high performance liquid chromatography (neutral conditions) to give compound 4.
MS-ESI计算值[M+H] +430,实测值430。 MS-ESI calcd [M+H] + 430. Found 430.
1H NMR(400MHz,MeOH-d 4)δ9.22(s,1H),8.51(s,1H),8.24-8.23(m,3H),8.16-8.04(m,2H),7.35-7.31(m,1H),7.10-7.09(m,2H),6.91-6.89(m,1H),5.27-5.24(m,1H),3.81(s,3H),3.27-3.19(m,2H),2.90(s,6H),2.49-2.38(m,2H)。 1 H NMR (400 MHz, MeOH-d 4 ) δ 9.22 (s, 1H), 8.51 (s, 1H), 8.24 - 8.23 (m, 3H), 8.16-8.04 (m, 2H), 7.35-7.31 (m) , 1H), 7.10-7.09 (m, 2H), 6.91-6.89 (m, 1H), 5.27-5.24 (m, 1H), 3.81 (s, 3H), 3.27-3.19 (m, 2H), 2.90 (s , 6H), 2.49-2.38 (m, 2H).
实施例5Example 5
Figure PCTCN2019083208-appb-000088
Figure PCTCN2019083208-appb-000088
合成路线：synthetic route:
Figure PCTCN2019083208-appb-000089
Figure PCTCN2019083208-appb-000089
第一步first step
0摄氏度和氮气保护下，向化合物4a(200mg,0.710mmol)的N,N-二甲基甲酰胺(2mL)溶液中加入氢化钠(36.0mg,0.890mmol,含量60％)。所得反应液搅拌0.5小时后再加入碘甲烷(101mg,0.710mmol)。反应液升至25摄氏度并搅拌12小时。反应完毕后，冷却至0摄氏度，加入饱和碳酸氢钠溶液(5mL)，并用乙酸乙酯(50mL x 3)萃取。合并有机相，用饱和食盐水(20mL x 3)洗涤，无水硫酸钠干燥。滤去干燥剂后，减压除去溶剂，残余物经过制备薄层色谱板纯化得到化合物5a。Sodium hydride (36.0 mg, 0.890 mmol, content 60%) was added to a solution of compound 4a (200 mg, 0.710 mmol) in N, N-dimethylformamide (2 mL). The resulting reaction solution was stirred for 0.5 hr and then EtOAc (EtOAc, &lt The reaction solution was raised to 25 ° C and stirred for 12 hours. After the reaction was completed, it was cooled to 0.degree. C., and saturated sodium hydrogen carbonate solution (5 mL) was added and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (20 mL EtOAc) After filtering off the desiccant, the solvent was removed under reduced pressure, and the residue was purified by preparative chromatography chromatography to afford compound 5a.
MS-ESI计算值[M+H] +296,实测值296。 MS-ESI calcd for [M+H] + 296.
1H NMR(400MHz,CDCl 3)δ7.25-7.23(m,1H),6.87-6.78(m,3H),5.44(brs,0.5H),4.81(brs,0.5H),3.81(s,3H),3.36-3.33(m,5H),2.04-1.96(m,2H),1.43(brs,9H)。 1 H NMR (400MHz, CDCl 3 ) δ7.25-7.23 (m, 1H), 6.87-6.78 (m, 3H), 5.44 (brs, 0.5H), 4.81 (brs, 0.5H), 3.81 (s, 3H ), 3.36-3.33 (m, 5H), 2.04-1.96 (m, 2H), 1.43 (brs, 9H).
第二步Second step
0摄氏度和氮气保护下，向化合物5a(50.0mg,0.170mmol)的二氯甲烷(2mL)溶液中加入三氟乙酸(193mg,0.13mL)。加完后，反应溶液升温至25摄氏度并搅拌12小时。反应完毕后，加入饱和碳酸氢钠溶液(20mL)，并用乙酸乙酯(50mL x 3)萃取。合并的有机相用饱和食盐水(20mL x 3)洗涤，无水硫酸钠干燥。滤去干燥剂后，减压除去溶剂，残余物经过制备薄层色谱板纯化得到化合物5b。Trifluoroacetic acid (193 mg, 0.13 mL) was added to a solution of compound 5a (50.0 mg, 0.170 mmol) in dichloromethane (2 mL). After the addition was completed, the reaction solution was heated to 25 ° C and stirred for 12 hours. After completion of the reaction, a saturated aqueous solution of sodium hydrogen carbonate (20 mL) was evaporated and evaporated. The combined organic phases were washed with brine (20 mL EtOAc) After the desiccant was filtered off, the solvent was removed under reduced pressure and the residue was purified by preparative chromatography chromatography to afford compound 5b.
MS-ESI计算值[M+H] +196,实测值196。 MS-ESI calcd for [M+H] + 196.
1H NMR(400MHz,DMSO-d 6)δ7.21(t,J＝8.0Hz,1H),6.92-6.87(m,2H),6.87-6.78(m,1H),3.87-3.84(m,1H),3.73(s,3H),3.36-3.31(m,2H),3.19(s,3H),1.87-1.69(m,2H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.21 (t, J = 8.0 Hz, 1H), 6.92-6.87 (m, 2H), 6.87-6.78 (m, 1H), 3.87-3.84 (m, 1H) ), 3.73 (s, 3H), 3.36-3.31 (m, 2H), 3.19 (s, 3H), 1.87-1.69 (m, 2H).
第三步third step
25摄氏度和氮气保护下，向化合物5b(70.0mg,0.360mmol)的N,N-二甲基甲酰胺(1mL)溶液中加入化合物3a(90mg,0.360mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(204mg,0.540mmol)和N,N-二异丙基乙胺(48.0mg,0.370mmol)。加完后，反应溶液在25摄氏度下搅拌12小时。反应完毕后，加入饱和食盐水(5mL)，并用乙酸乙酯(50mL x 3)萃取。合并的有机相用饱和食盐水(20mL x 3)洗涤，无水硫酸钠干燥。滤去干燥剂后，减压除去溶剂，残余物经过制备薄层色谱板纯化得到化合物5c。Add compound 3a (90 mg, 0.360 mmol), 2-(7-azobenzene) to a solution of compound 5b (70.0 mg, 0.360 mmol) in N,N-dimethylformamide (1 mL). And triazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (204 mg, 0.540 mmol) and N,N-diisopropylethylamine (48.0 mg, 0.370 mmol). After the addition was completed, the reaction solution was stirred at 25 ° C for 12 hours. After completion of the reaction, saturated brine (5 mL) was added and evaporated. The combined organic phases were washed with brine (20 mL EtOAc) After filtering off the desiccant, the solvent was removed under reduced pressure and the residue was purified by preparative chromatography chromatography to afford compound 5c.
MS-ESI计算值[M+H] +429,431；实测值429,431。 MS-ESI calcd for [M + H] + 429,431; 429,431 found.
1H NMR(400MHz,CDCl 3)δ9.17(s,1H),8.99(brs,1H),8.51(s,1H),8.15(s,1H),7.92(d,J＝8.8Hz,1H),7.78(d,J＝8.8Hz,1H),7.30-7.28(m,1H),7.01(d,J＝7.6Hz,1H),6.96(s,1H),6.81(d,J＝7.6Hz,1H),5.41-5.36 (m,1H),3.81(s,3H),3.51-3.44(m,2H),3.36(s,3H),2.29-2.18(m,2H)。 1 H NMR (400MHz, CDCl 3 ) δ9.17 (s, 1H), 8.99 (brs, 1H), 8.51 (s, 1H), 8.15 (s, 1H), 7.92 (d, J = 8.8Hz, 1H) , 7.78 (d, J = 8.8 Hz, 1H), 7.30-7.28 (m, 1H), 7.01 (d, J = 7.6 Hz, 1H), 6.96 (s, 1H), 6.81 (d, J = 7.6 Hz, 1H), 5.41-5.36 (m, 1H), 3.81 (s, 3H), 3.51-3.44 (m, 2H), 3.36 (s, 3H), 2.29-2.18 (m, 2H).
第四步the fourth step
在25摄氏度和氮气保护下，将化合物1d(67.0mg,0.350mmol)，1,1'-双(二叔丁基膦)二茂铁二氯化钯(19.0mg,0.0290mmol)和磷酸钾(183mg,0.860mmol)依次加入到化合物5c(123mg,0.290mmol)的四氢呋喃(1.6mL)和水(0.4mL)溶液中。所得反应液在85摄氏度和氮气保护下搅拌4小时。反应液用饱和食盐水(10mL)淬灭，用乙酸乙酯(20mL x 3)萃取，然后有机相用饱和食盐水(10mL x 3)洗涤，然后用无水硫酸钠干燥。过滤除去干燥剂，滤液减压除去溶剂得到粗品。粗品经制备高效液相色谱法(中性条件)纯化得到化合物5。Compound 1d (67.0 mg, 0.350 mmol), 1,1'-bis(di-tert-butylphosphine)ferrocene palladium dichloride (19.0 mg, 0.0290 mmol) and potassium phosphate (25 ° C and nitrogen) 183 mg, 0.860 mmol) were added sequentially to a solution of compound 5c (123 mg, 0.290 mmol) in tetrahydrofuran (1.6 mL) and water (0.4 mL). The resulting reaction solution was stirred at 85 ° C for 4 hours under a nitrogen atmosphere. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc) The desiccant was removed by filtration, and the filtrate was evaporated under reduced pressure to give a crude material. The crude product was purified by preparative high performance liquid chromatography (neutral conditions) to give compound 5.
MS-ESI计算值[M+H] +417,实测值417。 MS-ESI calcd for [M+H] + 417.
1H NMR(400MHz,CDCl 3)δ9.13(s,1H),9.01(d,J＝8.4Hz,1H),8.57(s,1H),8.05-8.03(m,4H),7.87-7.85(m,1H),7.30-7.28(m,1H),7.03-7.01(m,1H),6.98-6.97(s,1H),6.82-6.81(m,1H),5.43-5.37(m,1H),3.81(s,3H),3.50-3.47(m,2H),3.38(s,3H),2.31-2.20(m,2H)。 1 H NMR (400 MHz, CDCl 3 ) δ 9.13 (s, 1H), 9.1 (d, J = 8.4 Hz, 1H), 8.57 (s, 1H), 8.05-8.03 (m, 4H), 7.87-7.85 ( m, 1H), 7.30-7.28 (m, 1H), 7.03-7.01 (m, 1H), 6.98-6.97 (s, 1H), 6.82-6.81 (m, 1H), 5.43-5.37 (m, 1H), 3.81 (s, 3H), 3.50-3.47 (m, 2H), 3.38 (s, 3H), 2.31-2.20 (m, 2H).
实施例6Example 6
Figure PCTCN2019083208-appb-000090
Figure PCTCN2019083208-appb-000090
合成路线：synthetic route:
Figure PCTCN2019083208-appb-000091
Figure PCTCN2019083208-appb-000091
第一步first step
将化合物6a(1.50g,12.1mmol,1.27mL)溶于二氯甲烷(20mL)中，向反应液中添加叔丁基亚磺酰胺(1.90g,15.7mmol)和碳酸铯(9.57g,29.4mmol)。反应混合物在20摄氏度下搅拌16小时，反应完成后，将 反应液减压浓缩，得粗品化合物6b。Compound 6a (1.50 g, 12.1 mmol, 1.27 mL) was dissolved in dichloromethane (20 mL). To the reaction mixture was added t-butylsulfenamide (1.90 g, 15.7 mmol) and cesium carbonate (9.57 g, 29.4 mmol). ). The reaction mixture was stirred at 20 ° C for 16 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give crude compound 6b.
MS-ESI计算值[M+H] +228,实测值228。 MS-ESI calcd for [M+H] + 228.
1H NMR(400MHz,CDCl 3)δ8.58(d,J＝1.2Hz,1H),7.61-7.58(m,2H),7.51-7.44(m,1H),7.22-7.23(m,1H),1.28(s,9H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.58 (d, J = 1.2 Hz, 1H), 7.61 - 7.58 (m, 2H), 7.51 - 7.44 (m, 1H), 7.22 - 7.23 (m, 1H), 1.28 (s, 9H).
第二步Second step
将化合物6b(1.00g,4.40mmol)溶于四氢呋喃(10mL)中，将温度降至零下78摄氏度，缓慢滴加烯丙基溴化镁(1M,8.80mL)，并在零下78摄氏度下搅拌1小时。反应完成后，反应液在0摄氏度下用饱和氯化铵(20mL)淬灭，并加水(20mL)稀释后用乙酸乙酯(20mL x 3)萃取，合并的有机相用饱和食盐水(30mL x 1)洗，无水硫酸钠干燥，过滤减压浓缩。剩余物经柱层析分离得到化合物6c。Compound 6b (1.00 g, 4.40 mmol) was dissolved in tetrahydrofuran (10 mL), the temperature was reduced to minus 78 ° C, and allyl magnesium bromide (1 M, 8.80 mL) was slowly added dropwise and stirred at minus 78 ° C. hour. After completion of the reaction, the reaction mixture was quenched with EtOAc EtOAc (EtOAc) (EtOAc) 1) Washed, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was subjected to column chromatography to give Compound 6c.
MS-ESI计算值[M+H] +270,实测值270。 MS-ESI calcd for [M+H] + 270.
第三步third step
将化合物6c(500mg,1.86mmol)溶于二氯甲烷(25mL)和甲醇(5mL)中，零下78摄氏度下通入臭氧(15Psi)至反应液变为蓝色，然后0摄氏度下加入硼氢化钠(140mg,3.71mmol)，并于25摄氏度下反应12小时。反应完成后，加入水(40mL)淬灭反应，并加入水(20mL)稀释后用二氯甲烷(30mLx 3)萃取，合并的有机相用饱和食盐水(50mL x 1)洗，无水硫酸钠干燥，过滤减压浓缩。经柱层析分离得到粗品化合物6d。MS-ESI计算值[M+H] +274,实测值274。 Compound 6c (500 mg, 1.86 mmol) was dissolved in dichloromethane (25 mL) and methanol (5 mL). Ozone (15 Psi) was passed at minus 78 ° C until the reaction mixture turned blue, then sodium borohydride was added at 0 ° C. (140 mg, 3.71 mmol) and reacted at 25 ° C for 12 hours. After completion of the reaction, the reaction was quenched with water (40 mL), EtOAc (EtOAc) (EtOAc (EtOAc) Dry, filter and concentrate under reduced pressure. The crude compound 6d was obtained by column chromatography. MS-ESI calcd [M+H] + 274.
1H NMR(400MHz,CDCl 3)δ7.35-7.33(m,1H),7.12-6.98(m,3H),5.04-4.78(m,1H),4.66(br dd,J＝5.0,8.1Hz,1H),3.90-3.63(m,2H),2.15-2.01(m,2H),1.32-1.21(m,9H)。 1 H NMR (400MHz, CDCl 3 ) δ7.35-7.33 (m, 1H), 7.12-6.98 (m, 3H), 5.04-4.78 (m, 1H), 4.66 (br dd, J = 5.0,8.1Hz, 1H), 3.90-3.63 (m, 2H), 2.15-2.01 (m, 2H), 1.32-1.21 (m, 9H).
第四步the fourth step
将化合物6d(430mg,1.57mmol)溶于二氧六环(5mL)中，加入氯化氢的二氧六环溶液(4M,5mL)，25摄氏度下搅拌4小时。反应完成后，将反应液浓缩，得粗品化合物6e的盐酸盐。Compound 6d (430 mg, 1.57 mmol) was dissolved in dioxane (5 mL), and hydrogen chloride in dioxane (4M, 5 mL) was added and stirred at 25 ° C for 4 hours. After completion of the reaction, the reaction mixture was concentrated to give the crude compound 6e.
第五步the fifth step
将化合物3a(612mg,2.43mmol)溶于N,N-二甲基甲酰胺(8mL)中，向反应液中添加2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(943mg,2.48mmol)和N,N-二异丙基乙胺(1.26g,9.72mmol,1.69mL)，并于20摄氏度下搅拌0.5小时。然后加入化合物6e(500mg,2.43mmol)，并继续搅拌11.5小时。反应完成后，加入水(40mL)稀释后用乙酸乙酯(40ml x 3)萃取，合并的有机相用饱和食盐水(40mL x 1)洗，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物经柱层析分离纯化得化合物6f。Compound 3a (612 mg, 2.43 mmol) was dissolved in N,N-dimethylformamide (8 mL), and 2-(7-benzotriazole)-N,N,N' was added to the reaction mixture. N'-Tetramethylurea hexafluorophosphate (943 mg, 2.48 mmol) and N,N-diisopropylethylamine (1.26 g, 9.72 mmol, 1.69 mL) were stirred at 20 ° C for 0.5 h. Compound 6e (500 mg, 2.43 mmol) was then added and stirring was continued for 11.5 hours. After completion of the reaction, the mixture was diluted with water (40 mL), and then evaporated. The residue was purified by column chromatography to give compound 6f.
MS-ESI计算值[M+H] +403,405实测值403,405。 MS-ESI calcd for [M+H] + 403, 405.
1H NMR(400MHz,CDCl 3)δ9.13(s,1H),8.69(br 1H),8.54(s,1H),8.17(br s,1H),7.93-7.82(m,1H),7.81(dd,J＝1.5,8.7Hz,1H),7.17-7.09(m,2H),7.03-6.99(m,2H),5.53-5.47(m,1H),3.76-3.72(m,2H),3.29(br s,1H),1.27-1.25(m,2H)。 1 H NMR (400 MHz, CDCl 3 ) δ 9.13 (s, 1H), 8.69 (br 1H), 8.54 (s, 1H), 8.17 (br s, 1H), 7.93-7.82 (m, 1H), 7.81 ( Dd, J=1.5, 8.7 Hz, 1H), 7.17-7.09 (m, 2H), 7.03-6.99 (m, 2H), 5.53-5.47 (m, 1H), 3.76-3.72 (m, 2H), 3.29 ( Br s, 1H), 1.27-1.25 (m, 2H).
第六步 Step 6
将化合物6f(70.0mg,174μmol)，化合物1d(67.4mg,347μmol)，三(二亚苄基丙酮)二钯(15.9mg,17.4μmol)，2-二环己基膦-2’,4’,6’-三异丙基联苯(8.28mg,17.4μmol)和碳酸铯(170mg,521μmol)溶于二氧六环(5mL)和水(1mL)中，反应液于95摄氏度下搅拌16小时。反应完成后，加入水(20mL)稀释后用乙酸乙酯(30mLx 3)萃取，合并的有机相用饱和食盐水(30mL x 1)洗，无.水硫酸钠干燥，过滤，滤液减压浓缩。剩余 物经高效液相色谱法分离得到化合物6。Compound 6f (70.0 mg, 174 μmol), Compound 1d (67.4 mg, 347 μmol), tris(dibenzylideneacetone)dipalladium (15.9 mg, 17.4 μmol), 2-dicyclohexylphosphine-2', 4', 6'-Triisopropylbiphenyl (8.28 mg, 17.4 μmol) and cesium carbonate (170 mg, 521 μmol) were dissolved in dioxane (5 mL) and water (1 mL), and the mixture was stirred at 95 ° C for 16 hours. After completion of the reaction, the mixture was diluted with water (20 mL), EtOAc (EtOAc) The residue was subjected to high performance liquid chromatography to give Compound 6.
MS-ESI计算值[M+H] +391,实测值391。 MS-ESI calcd for [M+H] + 391.
1H NMR(400MHz,DMSO-d 6)δ13.16(br s,1H),9.41(d,J＝8.8Hz,1H),9.32(s,1H),8.44-8.38(m,3H),8.24-8.09(m,3H),7.39-7.29(m,3H),7.07-7.24(m,1H),5.30-5.26(m,1H),4.68(br s,1H),3.44(br s,2H),2.19-2.03(m,2H)。 1 H NMR (400MHz, DMSO- d 6) δ13.16 (br s, 1H), 9.41 (d, J = 8.8Hz, 1H), 9.32 (s, 1H), 8.44-8.38 (m, 3H), 8.24 -8.09(m,3H),7.39-7.29(m,3H),7.07-7.24(m,1H),5.30-5.26(m,1H),4.68(br s,1H),3.44(br s,2H) , 2.19-2.03 (m, 2H).
实施例7Example 7
Figure PCTCN2019083208-appb-000092
Figure PCTCN2019083208-appb-000092
合成路线：synthetic route:
Figure PCTCN2019083208-appb-000093
Figure PCTCN2019083208-appb-000093
第一步first step
将化合物7a(2.00g,14.2mmol,1.61mL)溶于二氯甲烷(30mL)中，向反应液中添加叔丁基亚磺酰胺(2.24g,18.5mmol)和碳酸铯(9.27g,28.5mmol)。反应混合物在25摄氏度下搅拌7小时，反应完成后，将反应液减压浓缩得粗品化合物7b。Compound 7a (2.00 g, 14.2 mmol, 1.61 mL) was dissolved in dichloromethane (30 mL). To the reaction mixture was added t-butylsulfinamide (2.24 g, 18.5 mmol) and cesium carbonate (9.27 g, 28.5 mmol). ). The reaction mixture was stirred at 25 ° C for 7 hours. After completion of the reaction, the reaction mixture was evaporated.
1H NMR(400MHz,CDCl 3)δ8.47(s,1H),7.80(t,J＝1.8Hz,1H),7.62(td,J＝1.2,7.5Hz,1H),7.41-7.35(m,2H),1.20(s,9H)。 1 H NMR (400MHz, CDCl 3 ) δ8.47 (s, 1H), 7.80 (t, J = 1.8Hz, 1H), 7.62 (td, J = 1.2,7.5Hz, 1H), 7.41-7.35 (m, 2H), 1.20 (s, 9H).
第二步Second step
将化合物7b(1.50g,6.15mmol)溶于四氢呋喃(15mL)中，将温度降至零下78摄氏度，缓慢滴加烯丙基溴化镁(1M,12.3mL)，并在零下78摄氏度下搅拌1小时。反应完成后，反应液在0摄氏度下用饱和氯化铵(50mL)淬灭，并加水(20mL)稀释后用乙酸乙酯(60mL x 2)萃取，合并的有机相用饱和食盐水(60mL x 1) 洗，无水硫酸钠干燥，过滤减压浓缩。剩余物经柱层析分离得到化合物7c。Compound 7b (1.50 g, 6.15 mmol) was dissolved in tetrahydrofuran (15 mL), the temperature was reduced to minus 78 ° C, and allyl magnesium bromide (1 M, 12.3 mL) was slowly added dropwise and stirred at minus 78 ° C. hour. After completion of the reaction, the reaction mixture was quenched with EtOAc EtOAc (EtOAc) (EtOAc) 1) Washed, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was subjected to column chromatography to give Compound 7c.
MS-ESI计算值[M+H] +286,实测值286。 MS-ESI calcd for [M + H] + 286, found 286.
1H NMR(400MHz,CDCl 3)δ7.24-7.13(m,4H),5.66-5.49(m,1H),5.14-4.96(m,2H),4.38-4.33(m,1H),3.60-3.43(m,1H),2.66-2.44(m,2H),1.22-1.13(m,9H)。 1 H NMR (400MHz, CDCl 3 ) δ7.24-7.13 (m, 4H), 5.66-5.49 (m, 1H), 5.14-4.96 (m, 2H), 4.38-4.33 (m, 1H), 3.60-3.43 (m, 1H), 2.66-2.44 (m, 2H), 1.22-1.13 (m, 9H).
第三步third step
将化合物7c(700mg,2.34mmol)溶于二氯甲烷(25mL)和甲醇(5mL)中，零下78摄氏度下通入臭氧(15Psi)15分钟至反应液变为蓝色，然后0摄氏度下加入硼氢化钠(177mg,4.68mmol)，并于25摄氏度下反应12小时。反应完成后，加入水(10mL)淬灭反应，并加入水(20mL)稀释后用二氯甲烷(40mL x 2)萃取，合并的有机相用饱和食盐水(40mL x 1)洗，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物经柱层析分离得到化合物7d。Compound 7c (700 mg, 2.34 mmol) was dissolved in dichloromethane (25 mL) and methanol (5 mL). Ozone (15 Psi) was passed at minus 78 ° C for 15 minutes until the reaction mixture turned blue, then boron was added at 0 ° C. Sodium hydride (177 mg, 4.68 mmol) was reacted at 25 ° C for 12 hours. After completion of the reaction, the reaction was quenched with water (10 mL), diluted with water (20 mL), and then extracted with methylene chloride (40 mL x 2). The combined organic phase was washed with saturated brine (40 mL x 1) The sodium was dried, filtered, and the filtrate was concentrated under reduced pressure.
1H NMR(400MHz,CDCl 3)δ7.24-7.18(m,4H),4.67-4.56(m,1H),4.56-4.54(m,1H),3.80-3.42(m,1H),1.97-1.93(m,2H),1.20-1.19(m,9H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.24-7.18 (m, 4H), 4.67-4.56 (m, 1H), 4.56-4.54 (m, 1H), 3.80-3.42 (m, 1H), 1.97-1.93 (m, 2H), 1.20-1.19 (m, 9H).
第四步the fourth step
将化合物7d(240mg,828μmol)溶于二氧六环(2mL)中，加入氯化氢的二氧六环溶液(4M,4mL)，25摄氏度下搅拌1小时。反应完成后，将反应液浓缩得粗品化合物7e的盐酸盐。Compound 7d (240 mg, 828 μmol) was dissolved in dioxane (2 mL), and hydrogen chloride in dioxane (4M, 4 mL) was added and stirred at 25 ° C for one hour. After completion of the reaction, the reaction mixture was concentrated to give the crystals of crude compound 7e.
MS-ESI计算值[M+H] +186,实测值186。 MS-ESI calcd for [M+H] + 186.
第五步the fifth step
将化合物3a(295mg,1.17mmol)溶于N,N-二甲基甲酰胺(8mL)中，向反应液中添加2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(668mg,1.76mmol)和N,N-二异丙基乙胺(605mg,4.68mmol,816μL)，并于25摄氏度下搅拌0.5小时。然后加入化合物7e(260mg,1.17mmol)，并继续搅拌11.5小时。反应完成后,加入水(40mL)稀释后用乙酸乙酯(40mL x 2)萃取,合并的有机相用饱和食盐水(40mL x 1)洗,无水硫酸钠干燥,过滤减压浓缩。经柱层析分离纯化得化合物7f。Compound 3a (295 mg, 1.17 mmol) was dissolved in N,N-dimethylformamide (8 mL), and 2-(7-benzotriazole)-N,N,N' was added to the reaction mixture. N'-Tetramethylurea hexafluorophosphate (668 mg, 1.76 mmol) and N,N-diisopropylethylamine (605 mg, 4.68 mmol, 816 μL) were stirred at 25 ° C for 0.5 h. Compound 7e (260 mg, 1.17 mmol) was then added and stirring was continued for 11.5 hours. After completion of the reaction, the mixture was diluted with EtOAc EtOAc EtOAc. The compound 7f was obtained by column chromatography.
MS-ESI计算值[M+H] +419,421,实测值419,421。 MS-ESI calcd for [M + H] + 419,421, 419, 421 found.
1H NMR(400MHz,CDCl 3)δ9.06(s,1H),8.59(br d,J＝8.7Hz,1H),8.46(s,1H),8.09(s,1H),7.85(d,J＝8.6Hz,1H),7.73(dd,J＝1.6,8.7Hz,1H),7.37(s,1H),7.25-7.22(m,3H),5.40(dt,J＝4.1,9.6Hz,1H),3.70-3.66(m,2H),3.15(br s,1H),2.19(td,J＝4.5,9.4Hz,1H),1.97-1.91(m,1H)。 1 H NMR (400MHz, CDCl 3 ) δ9.06 (s, 1H), 8.59 (br d, J = 8.7Hz, 1H), 8.46 (s, 1H), 8.09 (s, 1H), 7.85 (d, J = 8.6 Hz, 1H), 7.73 (dd, J = 1.6, 8.7 Hz, 1H), 7.37 (s, 1H), 7.25 - 7.22 (m, 3H), 5.40 (dt, J = 4.1, 9.6 Hz, 1H) , 3.70-3.66 (m, 2H), 3.15 (br s, 1H), 2.19 (td, J = 4.5, 9.4 Hz, 1H), 1.97-1.91 (m, 1H).
第六步 Step 6
将化合物7f(70.0mg,167μmol)，化合物1d(64.7mg,334μmol)，三(二亚苄基丙酮)二钯(15.3mg,16.7μmol)，2-二环己基膦-2’,4’,6’-三异丙基联苯(7.95mg,16.7μmol)和碳酸铯(163mg,500μmol)溶于二氧六环(8mL)和水(2mL)中，反应液于100摄氏度下搅拌12小时。反应完成后，加入水(20mL)稀释后用乙酸乙酯(30mLx 2)萃取，合并的有机相用饱和食盐水(30mL x 1)洗，无水硫酸钠干燥，过滤，滤液减压浓缩。剩余物经高效液相色谱法分离得到化合物7。Compound 7f (70.0 mg, 167 μmol), compound 1d (64.7 mg, 334 μmol), tris(dibenzylideneacetone)dipalladium (15.3 mg, 16.7 μmol), 2-dicyclohexylphosphine-2', 4', 6'-Triisopropylbiphenyl (7.95 mg, 16.7 μmol) and cesium carbonate (163 mg, 500 μmol) were dissolved in dioxane (8 mL) and water (2 mL), and the mixture was stirred at 100 ° C for 12 hours. After completion of the reaction, the mixture was diluted with water (20 mL), and then evaporated. The residue was subjected to high performance liquid chromatography to give Compound 7.
MS-ESI计算值[M+H] +407，实测值407。 MS-ESI calcd [M+H] + 407.
1H NMR(400MHz,DMSO-d 6)δ13.18(br d,J＝1.7Hz,1H),9.47(d,J＝8.2Hz,1H),9.32(s,1H),8.47-8.39(m,3H),8.24-8.10(m,3H),7.54(s,1H),7.41-7.31(m,3H),5.27(br d,J＝5.9Hz,1H),4.71(br t,J＝4.5Hz,1H),3.44-3.34(m,2H),2.34-2.03(m,2H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.18 (brd, J = 1.7 Hz, 1H), 9.47 (d, J = 8.2 Hz, 1H), 9.32 (s, 1H), 8.47-8.39 (m) , 3H), 8.24-8.10 (m, 3H), 7.54 (s, 1H), 7.41-7.31 (m, 3H), 5.27 (br d, J = 5.9 Hz, 1H), 4.71 (br t, J = 4.5) Hz, 1H), 3.44 - 3.34 (m, 2H), 2.34 - 2.03 (m, 2H).
实施例8Example 8
Figure PCTCN2019083208-appb-000094
Figure PCTCN2019083208-appb-000094
合成路线：synthetic route:
Figure PCTCN2019083208-appb-000095
Figure PCTCN2019083208-appb-000095
第一步first step
将化合物8a(1.00g,5.81mmol)溶于二氯甲烷(10mL)中，向反应液中添加叔丁基亚磺酰胺(775mg,6.39mmol)和碳酸铯(3.79g,11.6mmol)。反应混合物在25摄氏度下搅拌12小时，反应完成后过滤，将滤液减压浓缩，残留物经柱层析纯化得化合物8b。MS-ESI计算值[M+H] +276,实测值276。 Compound 8a (1.00 g, 5.81 mmol) was dissolved in dichloromethane (10 mL), and then, to the reaction mixture, t-butylsulfinamide (775 mg, 6.39 mmol) and cesium carbonate (3.79 g, 11.6 mmol) were added. The reaction mixture was stirred at 25 ° C for 12 hours. After the reaction was completed, filtered, and the filtrate was concentrated under reduced pressure. MS-ESI calcd for [M+H] + 276.
1H NMR(400MHz,CDCl 3)δ8.58(s,1H),7.69-7.68(m,2H),7.50(t,J＝7.9Hz,1H),7.31-7.29(m,1H),6.77-6.41(m,1H),1.29(s,9H)。 1 H NMR (400MHz, CDCl 3 ) δ8.58 (s, 1H), 7.69-7.68 (m, 2H), 7.50 (t, J = 7.9Hz, 1H), 7.31-7.29 (m, 1H), 6.77- 6.41 (m, 1H), 1.29 (s, 9H).
第二步Second step
将化合物8b(1.00g,3.58mmol)溶于四氢呋喃(15mL)中，将温度降至零下78摄氏度，缓慢滴加乙烯基溴化镁(1M,7.17mL)，所得混合物在零下78摄氏度下搅拌0.5小时，并升温至25摄氏度再反应0.5小时。反应完成后，反应液在0摄氏度下用饱和氯化铵(30mL)淬灭，并加水(20mL)稀释后用乙酸乙酯(40mLx 2)萃取，合并的有机相用饱和食盐水(40mL x 1)洗，无水硫酸钠干燥，过滤减压浓缩。剩余物经柱层析分离得到化合物8c。Compound 8b (1.00 g, 3.58 mmol) was dissolved in tetrahydrofuran (15 mL), the temperature was reduced to <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> <RTIgt; </RTI> <RTIgt; Hours, and warmed to 25 degrees Celsius for another 0.5 hours. After completion of the reaction, the reaction mixture was quenched with EtOAc EtOAc (EtOAc) (EtOAc) The mixture was washed with anhydrous sodium sulfate and filtered and evaporated. The residue was subjected to column chromatography to give Compound 8c.
MS-ESI计算值[M+H] +304,实测值304。 MS-ESI calcd for [M+H] + 303.
1H NMR(400MHz,CDCl 3)δ7.29-7.28(m,1H),7.19-7.04(m,3H),6.62-6.25(m,1H),6.01-5.77(m,1H),5.33-5.14(m,2H),4.91(dt,J＝3.3,6.6Hz,1H),3.41(br dd,J＝2.9,6.4Hz,1H),1.17(d,J＝12.1Hz,9H)。 1 H NMR (400MHz, CDCl 3 ) δ7.29-7.28 (m, 1H), 7.19-7.04 (m, 3H), 6.62-6.25 (m, 1H), 6.01-5.77 (m, 1H), 5.33-5.14 (m, 2H), 4.91 (dt, J = 3.3, 6.6 Hz, 1H), 3.41 (br dd, J = 2.9, 6.4 Hz, 1H), 1.17 (d, J = 12.1 Hz, 9H).
第三步third step
将化合物8c(650mg,2.12mmol)溶于四氢呋喃(10mL)中，零度下缓慢滴加硼烷四氢呋喃溶液(1M,6.36mL)，然后25摄氏度下反应一小时，原料消失。将反应液降温至0摄氏度，缓慢加入氢氧化钠水溶液(3M,7.06mL)，然后加入过氧化氢(4.81g,42.4mmol,4.07mL,纯度30％)，并于25摄氏度下反应1小时。反应完成后，加入水(30mL)稀释后用乙酸乙酯(60mL x 2)萃取，合并的有机相依次用饱和亚硫酸钠水溶液(60mL x 2)和饱和食盐水(60mL x 1)洗，无水硫酸钠干燥，过滤减压浓缩。经高效液相色谱法分离得到化合物8d。MS-ESI计算值[M+H] +322,实测值322。 Compound 8c (650 mg, 2.12 mmol) was dissolved in tetrahydrofuran (10 mL), borane tetrahydrofuran solution (1M, 6.36 mL) was slowly added dropwise at zero temperature, and then reacted at 25 ° C for one hour, and the starting material disappeared. The reaction solution was cooled to 0 ° C, and aqueous sodium hydroxide solution (3M, 7.06 mL) was slowly added, then hydrogen peroxide (4.81 g, 42.4 mmol, 4.07 mL, purity 30%) was added, and the reaction was carried out at 25 ° C for 1 hour. After completion of the reaction, it was diluted with water (30 mL) and extracted with ethyl acetate (60 mL×2). The combined organic phases were washed successively with saturated aqueous sodium sulfite (60 mL x 2) and saturated brine (60 mL x 1). The sodium was dried, filtered and concentrated under reduced pressure. Compound 8d was isolated by high performance liquid chromatography. MS-ESI calcd for [M+H] + 422.
第四步the fourth step
将化合物8d(300mg,930μmol)溶于二氧六环(2mL)中，加入氯化氢的二氧六环溶液(4M,4mL)，25摄氏度下搅拌2小时。反应完成后，将反应液浓缩，得粗品化合物8e的盐酸盐。Compound 8d (300 mg, 930 μmol) was dissolved in dioxane (2 mL), and hydrogen chloride in dioxane (4M, 4 mL) was added and stirred at 25 ° C for 2 hours. After completion of the reaction, the reaction mixture was concentrated to give the crystals of crude compound 8e.
MS-ESI计算值[M+H] +218,实测值218。 MS-ESI calcd for [M + H] + 218, found 218.
第五步the fifth step
将化合物3a(378mg,1.50mmol)溶于N,N-二甲基甲酰胺(15mL)中，向反应液中添加2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(854mg,2.25mmol)和N,N-二异丙基乙胺(774mg,5.99mmol,1.04mL)，并于25摄氏度下搅拌0.5小时。然后加入化合物8e(380mg,1.50mmol)，并继续搅拌11.5小时。反应完成后，加入水(60mL)稀释后用乙酸乙酯(50mL x 2)萃取，合并的有机相用饱和食盐水(50mL x 1)洗，无水硫酸钠干燥，过滤，滤液减压浓缩。残留物经柱层析分离纯化得化合物8f。Compound 3a (378 mg, 1.50 mmol) was dissolved in N,N-dimethylformamide (15 mL), and 2-(7-benzotriazole)-N,N,N' was added to the reaction mixture. N'-Tetramethylurea hexafluorophosphate (854 mg, 2.25 mmol) and N,N-diisopropylethylamine (774 mg, 5.99 mmol, 1.04 mL) were stirred at 25 ° C for 0.5 h. Compound 8e (380 mg, 1.50 mmol) was then added and stirring was continued for 11.5 hours. After completion of the reaction, the mixture was diluted with EtOAc EtOAc EtOAc. The residue was purified by column chromatography to give Compound 8f.
MS-ESI计算值[M+H] +451,453,实测值451,453。 MS-ESI calcd for [M+H] + 451, 453.
1H NMR(400MHz,CDCl 3)δ9.06(s,1H),8.61(br d,J＝8.9Hz,1H),8.46(s,1H),8.09(s,1H),7.85(d,J＝8.8Hz,1H),7.73(dd,J＝1.8,8.8Hz,1H),7.33-7.25(m,2H),7.14(s,1H),7.06-6.95(m,1H),6.69-6.23(m,1H),5.45-5.40(m,1H),3.72-3.67(m,2H),3.26(br s,1H),2.21(br dd,J＝4.4,9.8Hz,1H),1.94-1.94(m,1H)。 1 H NMR (400MHz, CDCl 3 ) δ9.06 (s, 1H), 8.61 (br d, J = 8.9Hz, 1H), 8.46 (s, 1H), 8.09 (s, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.73 (dd, J = 1.8, 8.8 Hz, 1H), 7.33 - 7.25 (m, 2H), 7.14 (s, 1H), 7.06-6.95 (m, 1H), 6.69-6.23 ( m, 1H), 5.45-5.40 (m, 1H), 3.72-3.67 (m, 2H), 3.26 (br s, 1H), 2.21 (br dd, J = 4.4, 9.8 Hz, 1H), 1.94-1.94 ( m, 1H).
第六步 Step 6
将化合物8f(150mg,276μmol)，化合物1d(107mg,553μmol)，三(二亚苄基丙酮)二钯(25.3mg,27.6μmol)，2-二环己基膦-2’,4’,6’-三异丙基联苯(13.2mg,27.6μmol)和碳酸铯(270mg,829μmol)溶于二氧六环(8mL)和水(2mL)中，反应液于95摄氏度下搅拌12小时。反应完成后，加入水(20mL)稀释后用乙酸乙酯(30mL x 2)萃取，合并的有机相用饱和食盐水(30mL x 1)洗，无水硫酸钠干燥，过滤，滤液减压浓缩。剩余物经高效液相色谱法分离得到化合物8。Compound 8f (150 mg, 276 μmol), compound 1d (107 mg, 553 μmol), tris(dibenzylideneacetone)dipalladium (25.3 mg, 27.6 μmol), 2-dicyclohexylphosphine-2', 4', 6' Triisopropylbiphenyl (13.2 mg, 27.6 μmol) and cesium carbonate (270 mg, 829 μmol) were dissolved in dioxane (8 mL) and water (2 mL), and the mixture was stirred at 95 ° C for 12 hours. After the reaction was completed, water (20 mL) was evaporated, evaporated, evaporated, evaporated. The residue was subjected to high performance liquid chromatography to give Compound 8.
MS-ESI计算值[M+H] +439,实测值439。 MS-ESI calcd for [M + H] + 439, found 439.
1H NMR(400MHz,DMSO-d 6)δ13.19(br s,1H),9.43(d,J＝8.6Hz,1H),9.32(s,1H),8.47-8.42(m,3H),8.39-8.22(m,3H),7.41-7.04(m,5H),5.32-5.26(m,1H),4.71(br s,1H),3.45(br s,2H),2.51-2.01(m,2H)。 1 H NMR (400MHz, DMSO- d 6) δ13.19 (br s, 1H), 9.43 (d, J = 8.6Hz, 1H), 9.32 (s, 1H), 8.47-8.42 (m, 3H), 8.39 -8.22 (m, 3H), 7.41 - 7.04 (m, 5H), 5.32 - 5.26 (m, 1H), 4.71 (br s, 1H), 3.45 (br s, 2H), 2.51-2.01 (m, 2H) .
实施例9Example 9
Figure PCTCN2019083208-appb-000096
Figure PCTCN2019083208-appb-000096
合成路线：synthetic route:
Figure PCTCN2019083208-appb-000097
Figure PCTCN2019083208-appb-000097
第一步first step
将化合物9a(2.00g,14.7mmol)溶于二氯甲烷(30mL)中，向反应液中添加叔丁基亚磺酰胺(2.31g,19.1mmol)和碳酸铯(9.57g,29.4mmol)。反应混合物在25摄氏度下搅拌12小时，反应完成后，得粗品化合物9b。Compound 9a (2.00 g, 14.7 mmol) was dissolved in dichloromethane (30 mL), and t-butylsulfinamide (2.31 g, 19.1 mmol) and cesium carbonate (9.57 g, 29.4 mmol) were added to the reaction mixture. The reaction mixture was stirred at 25 ° C for 12 hours. After completion of the reaction, crude compound 9b was obtained.
1H NMR(400MHz,CDCl 3)δ9.08(s,1H),8.00(dd,J＝1.7,7.7Hz,1H),7.51-7.47(m,1H),7.05-6.97(m,2H),3.91(s,3H),1.28(s,9H)。 1 H NMR (400MHz, CDCl 3 ) δ9.08 (s, 1H), 8.00 (dd, J = 1.7,7.7Hz, 1H), 7.51-7.47 (m, 1H), 7.05-6.97 (m, 2H), 3.91 (s, 3H), 1.28 (s, 9H).
第二步Second step
将化合物9b(2.00g,8.36mmol)溶于四氢呋喃(30mL)中，将温度降至零下78摄氏度，缓慢滴加烯丙基溴化镁(1M,12.5mL)，并在零下78摄氏度下搅拌1小时。反应完成后，反应液在0摄氏度下用饱和氯化铵(40mL)淬灭，并加水(20mL)稀释后用乙酸乙酯(60mL x 2)萃取，合并的有机相用饱和食盐水(50mL x 1)洗，无水硫酸钠干燥，过滤减压浓缩。剩余物经柱层析分离得到化合物9c。Compound 9b (2.00 g, 8.36 mmol) was dissolved in tetrahydrofuran (30 mL), the temperature was reduced to minus 78 ° C, and allyl magnesium bromide (1 M, 12.5 mL) was slowly added dropwise and stirred at minus 78 ° C. hour. After completion of the reaction, the reaction mixture was quenched with EtOAc EtOAc (EtOAc) (EtOAc) 1) Washed, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was subjected to column chromatography to give Compound 9c.
MS-ESI计算值[M+H] +282,实测值282。 MS-ESI calcd for [M+H] + 282.
1H NMR(400MHz,CDCl 3)δ7.19-7.17(m,2H),6.89-6.80(m,2H),5.67-5.61(m,1H),5.09-5.03(m,2H),4.79-4.56(m,1H),3.82-3.73(m,3H),2.62-2.44(m,2H),1.13-1.09(m,9H)。 1 H NMR (400MHz, CDCl 3 ) δ7.19-7.17 (m, 2H), 6.89-6.80 (m, 2H), 5.67-5.61 (m, 1H), 5.09-5.03 (m, 2H), 4.79-4.56 (m, 1H), 3.82-3.73 (m, 3H), 2.62-2.44 (m, 2H), 1.13-1.09 (m, 9H).
第三步third step
将化合物9c(1.00g,3.55mmol)溶于二氯甲烷(25mL)和甲醇(5mL)中，零下78摄氏度下，通入臭氧(15Psi)至反应液变为蓝色，然后0摄氏度下加入硼氢化钠(269mg,7.11mmol)，并于25摄氏度下反应12小时。反应完成后，加入水(20mL)淬灭反应，并加入水(20mL)稀释后用乙酸乙酯(50ml x 3)萃取，合并的有机相用饱和食盐水(50mL x 1)洗，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物经柱层析分离得到化合物9d。Compound 9c (1.00 g, 3.55 mmol) was dissolved in dichloromethane (25 mL) and methanol (5 mL). At below 78 ° C, ozone (15 Psi) was passed until the reaction mixture turned blue, then boron was added at 0 ° C. Sodium hydride (269 mg, 7.11 mmol) was reacted at 25 ° C for 12 hours. After completion of the reaction, the reaction was quenched with water (20 mL), diluted with water (20 mL), and ethyl acetate (50 ml x 3), and the combined organic phase was washed with saturated brine (50 mL x 1) The sodium was dried, filtered, and the filtrate was concentrated under reduced pressure.
1H NMR(400MHz,CDCl 3)δ7.22-7.15(m,2H),6.89-6.70(m,2H),4.87-4.82(m,1H),4.44-4.04(m,1H),3.79-3.76(m,3H),3.66-3.54(m,2H),1.98-1.90(m,2H),1.19-1.11(m,9H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.22-7.15 (m, 2H), 6.89-6.70 (m, 2H), 4.87-4.82 (m, 1H), 4.44-4.04 (m, 1H), 3.79-3.76 (m, 3H), 3.66-3.54 (m, 2H), 1.98-1.90 (m, 2H), 1.19-1.11 (m, 9H).
第四步the fourth step
将化合物9d(300mg,1.05mmol)溶于二氧六环(3mL)中，加入氯化氢的二氧六环溶液(4M,5mL)，25摄氏度下搅拌2小时。反应完成后，将反应液浓缩，得粗品化合物9e的盐酸盐。Compound 9d (300 mg, 1.05 mmol) was dissolved in dioxane (3 mL), EtOAc (EtOAc) After completion of the reaction, the reaction mixture was concentrated to give the crude compound 9e.
第五步the fifth step
将化合物3a(417mg,1.65mmol)溶于N,N-二甲基甲酰胺(10mL)中，向反应液中添加2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(943mg,2.48mmol)和N,N-二异丙基乙胺(855mg,6.61mmol,1.15mL)，并于20摄氏度下搅拌0.5小时。然后加入化合物9e(360mg,1.65mmol)，并继续搅拌11.5小时。反应完成后，加入水(40mL)稀释后用乙酸乙酯(40mL x 2)萃取，合并的有机相用饱和食盐水(40mL x 1)洗，无水硫酸钠干燥，过滤，滤液减压浓缩。残留物经柱层析分离纯化得化合物9f。Compound 3a (417 mg, 1.65 mmol) was dissolved in N,N-dimethylformamide (10 mL), and 2-(7-benzotriazole)-N,N,N' was added to the reaction mixture. N'-Tetramethylurea hexafluorophosphate (943 mg, 2.48 mmol) and N,N-diisopropylethylamine (855 mg, 6.61 mmol, 1.15 mL) were stirred at 20 ° C for 0.5 h. Compound 9e (360 mg, 1.65 mmol) was then added and stirring was continued for 11.5 hours. After completion of the reaction, the mixture was diluted with water (40 mL) and evaporated. The residue was purified by column chromatography to give compound 9f.
MS-ESI计算值[M+H] +415,417,实测值415,417。 MS-ESI calcd for [M + H] + 415,417, 415, 417 found.
1H NMR(400MHz,CDCl 3)δ9.32(br d,J＝9.2Hz,1H),9.16(s,1H),8.56(s,1H),8.17(s,1H),7.92(d,J＝8.7Hz,1H),7.80(dd,J＝1.8,8.7Hz,1H),7.38-7.32(m,2H),7.01-6.99(m,2H),5.61(dt,J＝4.7,9.9Hz,1H),4.01(s,3H),3.72(br d,J＝5.1Hz,3H),2.18-2.07(m,2H),1.62(br d,J＝4.2Hz,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ 9.32 (brd, J = 9.2 Hz, 1H), 9.16 (s, 1H), 8.56 (s, 1H), 8.17 (s, 1H), 7.92 (d, J) = 8.7 Hz, 1H), 7.80 (dd, J = 1.8, 8.7 Hz, 1H), 7.38-7.32 (m, 2H), 7.01-6.99 (m, 2H), 5.61 (dt, J = 4.7, 9.9 Hz, 1H), 4.01 (s, 3H), 3.72 (br d, J = 5.1 Hz, 3H), 2.18-2.07 (m, 2H), 1.62 (br d, J = 4.2 Hz, 1H).
第六步 Step 6
将化合物9f(100mg,201μmol)，化合物1d(77.8mg,401μmol)，三(二亚苄基丙酮)二钯(18.4mg,20.0μmol)，2-二环己基膦-2’,4’,6’-三异丙基联苯(9.55mg,20.0μmol)和碳酸铯(195.9mg,601μmol)溶于二氧六环(8mL)和水(2mL)中，反应液于100摄氏度下搅拌12小时。反应完成后，加入水(20mL)稀释后用乙酸乙酯(30mLx 3)萃取，合并的有机相用饱和食盐水(30mL x 1)洗，无水硫酸钠干燥，过滤，滤液减压浓缩。剩余物经高效液相色谱法分离得到化合物9。Compound 9f (100 mg, 201 μmol), Compound 1d (77.8 mg, 401 μmol), tris(dibenzylideneacetone)dipalladium (18.4 mg, 20.0 μmol), 2-dicyclohexylphosphine-2', 4',6 '-Triisopropylbiphenyl (9.55 mg, 20.0 μmol) and cesium carbonate (195.9 mg, 601 μmol) were dissolved in dioxane (8 mL) and water (2 mL), and the mixture was stirred at 100 ° C for 12 hours. After the reaction was completed, water (20 mL) was evaporated, evaporated, evaporated, evaporated. The residue was subjected to high performance liquid chromatography to give Compound 9.
MS-ESI计算值[M+H] +403,实测值403。 MS-ESI calcd for [M+H] + 403.
1H NMR(400MHz,DMSO-d 6)δ13.18(br s,1H),9.41(br d,J＝8.9Hz,1H),9.31(s,1H),8.45-8.10(m,6H),7.33-7.24(m,2H),7.04-6.92(m,2H),5.53-5.47(m,1H),4.69(br d,J＝4.4Hz,1H),3.89(s,3H),3.42(br dd,J＝6.5,7.5Hz,2H),2.03-1.99(m,2H)。 1 H NMR (400MHz, DMSO- d 6) δ13.18 (br s, 1H), 9.41 (br d, J = 8.9Hz, 1H), 9.31 (s, 1H), 8.45-8.10 (m, 6H), 7.33-7.24 (m, 2H), 7.04-6.92 (m, 2H), 5.53-5.47 (m, 1H), 4.69 (br d, J = 4.4 Hz, 1H), 3.89 (s, 3H), 3.42 (br Dd, J = 6.5, 7.5 Hz, 2H), 2.03-1.99 (m, 2H).
实施例10Example 10
Figure PCTCN2019083208-appb-000098
Figure PCTCN2019083208-appb-000098
合成路线：synthetic route:
Figure PCTCN2019083208-appb-000099
Figure PCTCN2019083208-appb-000099
第一步first step
将化合物10a(2.00g,15.3mmol)溶于二氯甲烷(30mL)中，向反应液中添加叔丁基亚磺酰胺(2.40g,19.8mmol)和碳酸铯(9.94g,30.5mmol)。反应混合物在25摄氏度下搅拌12小时，反应完成后，将反应液减压浓缩得粗品化合物10b。Compound 10a (2.00 g, 15.3 mmol) was dissolved in dichloromethane (30 mL). EtOAc (t. The reaction mixture was stirred at 25 ° C for 12 hours. After completion of the reaction, the reaction mixture was evaporated.
1H NMR(400MHz,CDCl 3)δ8.61(s,1H),8.19(s,1H),8.06(td,J＝1.3,7.8Hz,1H),7.81(td,J＝1.3,7.8Hz,1H),7.67-7.62(m,1H),1.30(s,9H)。 1 H NMR (400MHz, CDCl 3 ) δ8.61 (s, 1H), 8.19 (s, 1H), 8.06 (td, J = 1.3,7.8Hz, 1H), 7.81 (td, J = 1.3,7.8Hz, 1H), 7.67-7.62 (m, 1H), 1.30 (s, 9H).
第二步Second step
将化合物10b(1.50g,6.40mmol)溶于四氢呋喃(20mL)中，将温度降至零下78摄氏度，缓慢滴加烯丙基溴化镁(1M,12.8mL)，并在零下78摄氏度下搅拌1小时。反应完成后，反应液在0摄氏度下用饱和氯化铵(50mL)淬灭，并加水(20mL)稀释后用乙酸乙酯(60mL x 2)萃取，合并的有机相用饱和食盐水(60mL x 1)洗，无水硫酸钠干燥，过滤，滤液减压浓缩。剩余物经柱层析分离得到化合物10c。Compound 10b (1.50 g, 6.40 mmol) was dissolved in tetrahydrofuran (20 mL), the temperature was reduced to minus 78 ° C, and allyl magnesium bromide (1 M, 12.8 mL) was slowly added dropwise and stirred at minus 78 ° C. hour. After completion of the reaction, the reaction mixture was quenched with EtOAc EtOAc (EtOAc) (EtOAc) 1) Washed, dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was subjected to column chromatography to give Compound 10c.
1H NMR(400MHz,CDCl 3)δ7.56-7.51(m,3H),7.42-7.39(m,1H),5.52-5.48(m,1H),5.15-4.95(m,1H),4.44-4.41(m,1H),3.65(s,1H),3.48(br d,J＝4.6Hz,1H),2.66-2.41(m,2H),1.19-1.14(m,9H)。 1 H NMR (400MHz, CDCl 3 ) δ7.56-7.51 (m, 3H), 7.42-7.39 (m, 1H), 5.52-5.48 (m, 1H), 5.15-4.95 (m, 1H), 4.44-4.41 (m, 1H), 3.65 (s, 1H), 3.48 (br d, J = 4.6 Hz, 1H), 2.66-2.41 (m, 2H), 1.19-1.14 (m, 9H).
第三步third step
将化合物10c(500mg,1.81mmol)溶于二氯甲烷(25mL)和甲醇(5mL)中，零下78摄氏度下通入臭氧(15Psi)至反应液变为蓝色，然后0摄氏度下加入硼氢化钠(137mg,3.62mmol)，并于25摄氏度下反应12小时。反应完成后，加入水(10mL)淬灭反应，并加入水(20mL)稀释后用二氯甲烷(40mL x 2)萃取，合并的有机相用饱和食盐水(40mL x 1)洗，无水硫酸钠干燥，过滤，滤液减压浓缩。残留物经柱层析分离得到化合物10d。Compound 10c (500 mg, 1.81 mmol) was dissolved in dichloromethane (25 mL) and methanol (5 mL). Ozone (15 Psi) was passed at minus 78 ° C until the reaction mixture turned blue, then sodium borohydride was added at 0 ° C. (137 mg, 3.62 mmol) and reacted at 25 ° C for 12 hours. After completion of the reaction, the reaction was quenched with water (10 mL), diluted with water (20 mL), and then extracted with methylene chloride (40 mL x 2). The combined organic phase was washed with saturated brine (40 mL x 1) The sodium was dried, filtered, and the filtrate was concentrated. The residue was subjected to column chromatography to give Compound 10d.
MS-ESI计算值[M+H] +281,实测值281。 MS-ESI calcd for [M + H] + 281, found 281.
1H NMR(400MHz,CDCl 3)δ7.58(s,1H),7.51-7.49(m,1H),7.43-7.41(m,1H),7.39-7.37(m,1H),4.80(t,J＝3.3Hz,1H),4.63-4.60(m,1H),3.81-3.78(m,2H),3.30-3.29(m,1H),1.98-1.89(m,2H),1.79(br d,J＝13.7 Hz,1H),1.17(s,9H)。 1 H NMR (400MHz, CDCl 3 ) δ7.58 (s, 1H), 7.51-7.49 (m, 1H), 7.43-7.41 (m, 1H), 7.39-7.37 (m, 1H), 4.80 (t, J =3.3 Hz, 1H), 4.63-4.60 (m, 1H), 3.81-3.78 (m, 2H), 3.30-3.29 (m, 1H), 1.98-1.89 (m, 2H), 1.79 (br d, J = 13.7 Hz, 1H), 1.17 (s, 9H).
第四步the fourth step
将化合物10d(120mg,428μmol)溶于二氧六环(2mL)中，加入氯化氢的二氧六环溶液(4M,5mL)，25摄氏度下搅拌2小时。反应完成后，将反应液浓缩得粗品化合物10e的盐酸盐。MS-ESI计算值[M+H] +177,实测值177。 Compound 10d (120 mg, 428 μmol) was dissolved in dioxane (2 mL), and hydrogen chloride in dioxane (4M, 5 mL) was added and stirred at 25 ° C for 2 hours. After completion of the reaction, the reaction mixture was concentrated to give the title compound of the crude compound 10e. MS-ESI calcd for [M+H] + 177.
第五步the fifth step
将化合物3a(190mg,752μmol)溶于N,N-二甲基甲酰胺(8mL)中，向反应液中添加2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(429mg,1.13mmol)和N,N-二异丙基乙胺(389mg,3.01mmol,524μL)，并于25摄氏度下搅拌0.5小时。然后加入化合物10e(160mg,752μmol)，并继续搅拌11.5小时。反应完成后，加入水(60mL)稀释后用乙酸乙酯(50mL x 2)萃取，合并的有机相用饱和食盐水(50mL x 1)洗，无水硫酸钠干燥，过滤，滤液减压浓缩。残留物经柱层析分离纯化得化合物10f。Compound 3a (190 mg, 752 μmol) was dissolved in N,N-dimethylformamide (8 mL), and 2-(7-benzotriazole)-N,N,N',N was added to the reaction mixture. '-Tetramethylurea hexafluorophosphate (429 mg, 1.13 mmol) and N,N-diisopropylethylamine (389 mg, 3.01 mmol, 524 μL) were stirred at 25 ° C for 0.5 h. Compound 10e (160 mg, 752 μmol) was then added and stirring was continued for 11.5 hours. After completion of the reaction, the mixture was diluted with EtOAc EtOAc EtOAc. The residue was purified by column chromatography to give compound 10f.
MS-ESI计算值[M+H] +410,412,实测值410,412。 MS-ESI calcd for [M+H] + 410, 412.
1H NMR(400MHz,CDCl 3)δ9.09-9.08(m,1H),8.72(br d,J＝8.6Hz,1H),8.45(s,1H),8.09(s,1H),7.86(d,J＝8.6Hz,1H),7.75-7.73(m,1H),7.72-7.68(m,2H),7.53(td,J＝1.3,7.8Hz,1H),7.45-7.43(m,1H),5.46(dt,J＝4.2,9.4Hz,1H),3.72-3.42(m,2H),2.82(br d,J＝4.6Hz,1H),2.20(tt,J＝4.2,9.4Hz,1H),2.10-2.00(m,1H),1.98-1.97(m,1H)。 1 H NMR (400MHz, CDCl 3 ) δ9.09-9.08 (m, 1H), 8.72 (br d, J = 8.6Hz, 1H), 8.45 (s, 1H), 8.09 (s, 1H), 7.86 (d , J=8.6 Hz, 1H), 7.75-7.73 (m, 1H), 7.72-7.68 (m, 2H), 7.53 (td, J=1.3, 7.8 Hz, 1H), 7.45-7.43 (m, 1H), 5.46 (dt, J = 4.2, 9.4 Hz, 1H), 3.72-3.42 (m, 2H), 2.82 (br d, J = 4.6 Hz, 1H), 2.20 (tt, J = 4.2, 9.4 Hz, 1H), 2.10-2.00 (m, 1H), 1.98-1.97 (m, 1H).
第六步 Step 6
将化合物10f(100mg,219μmol)，化合物1d(85.0mg,438μmol)，三(二亚苄基丙酮)二钯(20.1mg,21.9μmol)，2-二环己基膦-2’,4’,6’-三异丙基联苯(10.4mg,21.9μmol)和碳酸铯(214mg,657μmol)溶于二氧六环(8mL)和水(2mL)中，反应液于95摄氏度下搅拌12小时。反应完成后，加入水(20mL)稀释后用乙酸乙酯(30mLx 2)萃取，合并的有机相用饱和食盐水(30mL x 1)洗，无水硫酸钠干燥，过滤，滤液减压浓缩。剩余物经高效液相色谱法分离得到化合物10。Compound 10f (100 mg, 219 μmol), compound 1d (85.0 mg, 438 μmol), tris(dibenzylideneacetone)dipalladium (20.1 mg, 21.9 μmol), 2-dicyclohexylphosphine-2', 4',6 '-Triisopropylbiphenyl (10.4 mg, 21.9 μmol) and cesium carbonate (214 mg, 657 μmol) were dissolved in dioxane (8 mL) and water (2 mL), and the reaction mixture was stirred at 95 ° C for 12 hours. After completion of the reaction, the mixture was diluted with water (20 mL), and then evaporated. The residue was subjected to high performance liquid chromatography to give Compound 10.
MS-ESI计算值[M+H] +398,实测值398。 MS-ESI calcd [M+H] + 398.
1H NMR(400MHz,DMSO-d 6)δ13.21-13.18(m,1H),9.51(d,J＝8.3Hz,1H),9.33(s,1H),8.49-8.38(m,3H),8.23(d,J＝8.6Hz,2H),8.11(dd,J＝1.6,8.6Hz,1H),7.93(s,1H),7.79-7.73(m,2H),7.71-7.56(m,1H),5.35-5.29(m,1H),4.73(br s,1H),3.43(br d,J＝4.6Hz,2H),2.18-2.03(m,2H)。 1 H NMR (400MHz, DMSO- d 6) δ13.21-13.18 (m, 1H), 9.51 (d, J = 8.3Hz, 1H), 9.33 (s, 1H), 8.49-8.38 (m, 3H), 8.23 (d, J = 8.6 Hz, 2H), 8.11 (dd, J = 1.6, 8.6 Hz, 1H), 7.93 (s, 1H), 7.79-7.73 (m, 2H), 7.71-7.56 (m, 1H) , 5.35-5.29 (m, 1H), 4.73 (br s, 1H), 3.43 (br d, J = 4.6 Hz, 2H), 2.18-2.03 (m, 2H).
实施例11Example 11
Figure PCTCN2019083208-appb-000100
Figure PCTCN2019083208-appb-000100
合成路线：synthetic route:
Figure PCTCN2019083208-appb-000101
Figure PCTCN2019083208-appb-000101
第一步first step
将化合物11a(10.0g,66.6mmol)溶于乙腈(300mL)和水(60mL)中，在室温下加入三氟乙酸(9.86ml,0.133mol)和二(三氟乙酰氧基)碘苯(57.3g,0.133mol)，将所得溶液加热至100摄氏度并搅拌20小时。反应液冷却至室温，减压除去有机溶剂，水相用二氯甲烷萃取(100mL x 3)。有机相用无水硫酸钠干燥，过滤，滤液减压浓缩。剩余物经柱层析纯化得化合物11b。Compound 11a (10.0 g, 66.6 mmol) was dissolved in acetonitrile (300 mL) and water (60 mL) and trifluoroacetic acid (9.86 ml, 0.133 mol) and bis(trifluoroacetoxy)iodobenzene (57.3) g, 0.133 mol), the resulting solution was heated to 100 ° C and stirred for 20 hours. The reaction solution was cooled to room temperature, the organic solvent was evaporated under reduced pressure, and the aqueous phase was extracted with methylene chloride (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered and evaporated. The residue was purified by column chromatography to give compound 11b.
MS-ESI计算值[M+H] +167,实测值167。 MS-ESI calcd [M+H] + 167.
1H NMR(400MHz,CDCl 3)δ7.50-7.48(m,2H),7.45-7.40(m,1H),7.18-7.20(m,1H),4.89(s,2H),3.89(s,3H)。 1 H NMR (400MHz, CDCl 3 ) δ7.50-7.48 (m, 2H), 7.45-7.40 (m, 1H), 7.18-7.20 (m, 1H), 4.89 (s, 2H), 3.89 (s, 3H ).
第二步Second step
将化合物11b(3.50g,21.1mmol)溶于乙醇(80mL)中，在室温下加入盐酸羟胺(1.76g,25.3mol)和碳酸钠(3.35g,31.6mmol)，所得溶液加热至50摄氏度并搅拌15小时。反应液冷却至室温，过滤，滤液减压浓缩。剩余物水洗(20mL)，水相用二氯甲烷萃取(20mL x 3)。有机相用无水硫酸钠干燥，过滤，滤液减压浓缩。剩余物经柱层析纯化得化合物11c。Compound 11b (3.50 g, 21.1 mmol) was dissolved in ethanol (80 mL), and hydroxylamine hydrochloride (1.76 g, 25.3 mol) and sodium carbonate (3.35 g, 31.6 mmol) were added at room temperature, and the resulting solution was heated to 50 ° C and stirred. 15 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was evaporated. The residue was washed with water (20 mL). The organic phase was dried over anhydrous sodium sulfate and filtered and evaporated. The residue was purified by column chromatography to give compound 11c.
MS-ESI计算值[M+H] +182,实测值182。 MS-ESI calcd for [M+H] + 182.
1H NMR(400MHz,CDCl 3)δ7.32(d,J＝8.0Hz,1H),7.21-7.18(m,2H),6.98(dd,J＝2.4,8.0Hz,1H),4.75(s,2H),3.84(m,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.32 (d, J = 8.0 Hz, 1H), 7.21-7.18 (m, 2H), 6.98 (dd, J = 2.4, 8.0 Hz, 1H), 4.75 (s, 2H), 3.84 (m, 3H).
第三步third step
将化合物11c(230mg,1.27mmol)溶于甲醇(5mL)中，在室温下加入雷尼镍(40.0mg)。混合液用氮气置换三次，在氢气气压下(45psi)加热至30摄氏度并搅拌15小时。反应液冷却至室温，过滤，滤液减压浓缩得化合物11d。粗品无需纯化直接进行下一步反应。Compound 11c (230 mg, 1.27 mmol) was dissolved in MeOH (5 mL) and EtOAc (40.0 mg). The mixture was replaced three times with nitrogen, heated to 30 ° C under hydrogen pressure (45 psi) and stirred for 15 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was evaporated. The crude product was directly subjected to the next reaction without purification.
MS-ESI计算值[M–NH 2] +151,实测值151。 MS-ESI calcd for [M-NH 2] + 151 , found 151.
第四步the fourth step
将化合物11d(140mg,0.502mmol)，化合物3a(152mg,0.603mmol)，2-(7-氧化苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯(287mg,0.754mmol)和二异丙基乙胺(97.4mg,0.754mmol)溶于无水N,N-二甲基甲酰 胺(3mL)。反应液用氮气置换三次，在12摄氏度下搅拌15小时。反应液减压浓缩，剩余物溶于二氯甲烷(20mL)，并用水(20mL)洗涤，水相用二氯甲烷萃取(30mL x 3)。有机相用无水硫酸钠干燥，过滤，浓缩。剩余物经制备薄层色谱板纯化得化合物11e。Compound 11d (140 mg, 0.502 mmol), compound 3a (152 mg, 0.603 mmol), 2-(7-benzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (287 mg, 0.754 mmol) and diisopropylethylamine (97.4 mg, 0.754 mmol) were dissolved in anhydrous N,N-dimethylformamide (3 mL). The reaction solution was replaced with nitrogen three times and stirred at 12 ° C for 15 hours. The reaction mixture was concentrated with EtOAc EtOAc m. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by preparative thin layer chromatography to give compound 11e.
MS-ESI计算值[M+H] +401,403,实测值401,403。 MS-ESI calcd for [M+H] + 401, 403.
1H NMR(400MHz,CDCl 3)δ9.14(s,1H),8.86(br d,J＝7.2Hz,1H),8.53(s,1H),8.16(d,J＝1.2Hz,1H),7.92(d,J＝8.4Hz,1H),7.80(dd,J＝1.2,8.8Hz,1H),7.32(t,J＝8.0Hz,1H),7.03(d,J＝7.2Hz,1H),6.98(t,J＝2.0Hz,1H),6.87(dd,J＝2.0,8.0Hz,1H),5.33-5.31(m,1H),4.07-4.05(m,1H),3.83(s,3H),2.84-2.81(m,2H)。 1 H NMR (400MHz, CDCl 3 ) δ9.14 (s, 1H), 8.86 (br d, J = 7.2Hz, 1H), 8.53 (s, 1H), 8.16 (d, J = 1.2Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.80 (dd, J = 1.2, 8.8 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.03 (d, J = 7.2 Hz, 1H), 6.98 (t, J = 2.0 Hz, 1H), 6.87 (dd, J = 2.0, 8.0 Hz, 1H), 5.33-5.31 (m, 1H), 4.07-4.05 (m, 1H), 3.83 (s, 3H) , 2.84 - 2.81 (m, 2H).
第五步the fifth step
将化合物11e(100mg,0.249mmol)，化合物1d(72.5mg,0.374mmol)，三(二亚苄基丙酮)二钯(22.8mg,24.9mmol)，2-二环己基膦-2’,4’,6’-三异丙基联苯(21.1mg,49.8μmol)和碳酸铯(162mg,0.498mmol)溶于1,4-二氧六环(5mL)和水(1mL)。反应液用氮气置换三次，在90摄氏度下搅拌15小时。反应液减压浓缩，剩余物溶于二氯甲烷(10mL)，并用水(10mL)洗涤，水相用二氯甲烷萃取(20mL x 3)。有机相用无水硫酸钠干燥，过滤，浓缩。剩余物用高效液相色谱法纯化得化合物11。Compound 11e (100 mg, 0.249 mmol), compound 1d (72.5 mg, 0.374 mmol), tris(dibenzylideneacetone) dipalladium (22.8 mg, 24.9 mmol), 2-dicyclohexylphosphine-2', 4' 6'-Triisopropylbiphenyl (21.1 mg, 49.8 μmol) and cesium carbonate (162 mg, 0.498 mmol) were dissolved in 1,4-dioxane (5 mL) and water (1 mL). The reaction solution was replaced with nitrogen three times and stirred at 90 ° C for 15 hours. The reaction mixture was concentrated with EtOAc EtOAc m. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by high performance liquid chromatography to give Compound 11.
MS-ESI计算值[M+H] +389,实测值389。 MS-ESI calcd for [M + H] + 389, found 389.
1H NMR(400MHz,CDCl 3)δ9.26(s,1H),8.51(s,1H),8.27(s,3H),8.17(d,J＝8.4Hz,1H),8.06(dd,J＝1.2,8.4Hz,1H),7.29(t,J＝8.0Hz,1H),7.05-7.03(m,2H),6.86(dd,J＝1.2,8.0Hz,1H),5.23(t,J＝6.0Hz,1H),3.96(d,J＝6.0Hz,2H),3.81(s,3H)。 1 H NMR (400MHz, CDCl 3 ) δ9.26 (s, 1H), 8.51 (s, 1H), 8.27 (s, 3H), 8.17 (d, J = 8.4Hz, 1H), 8.06 (dd, J = 1.2, 8.4 Hz, 1H), 7.29 (t, J = 8.0 Hz, 1H), 7.05-7.03 (m, 2H), 6.86 (dd, J = 1.2, 8.0 Hz, 1H), 5.23 (t, J = 6.0) Hz, 1H), 3.96 (d, J = 6.0 Hz, 2H), 3.81 (s, 3H).
实施例12Example 12
Figure PCTCN2019083208-appb-000102
Figure PCTCN2019083208-appb-000102
合成路线：synthetic route:
Figure PCTCN2019083208-appb-000103
Figure PCTCN2019083208-appb-000103
第一步first step
将化合物11e(1.20g,2.99mmol)，化合物12a(440mg,2.99mmol)和三苯基膦(1.18g,4.49mmol)溶于无水四氢呋喃(25mL)，在0摄氏度下，向溶液中滴加偶氮二甲酸二异丙酯(907mg,4.49mmol)。反应液在 0摄氏度下搅拌2小时后，升温至15摄氏度继续搅拌13小时。反应液用饱和碳酸氢钠溶液(10mL)淬灭，混合液用乙酸乙酯萃取(20mL x 3)。有机相用无水硫酸钠干燥，过滤，浓缩。剩余物经柱层析纯化得化合物12b。Compound 11e (1.20 g, 2.99 mmol), compound 12a (440 mg, 2.99 mmol) and triphenylphosphine (1.18 g, 4.49 mmol) were dissolved in anhydrous tetrahydrofuran (25 mL) and added dropwise to the solution at 0 ° C. Diisopropyl azodicarboxylate (907 mg, 4.49 mmol). After the reaction solution was stirred at 0 ° C for 2 hours, the temperature was raised to 15 ° C and stirring was continued for 13 hours. The reaction mixture was quenched with EtOAc EtOAc (EtOAc) The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by column chromatography to give compound 12b.
MS-ESI计算值[M+H] +530,532,实测值530,532。 MS-ESI calcd for [M+H] + 530, 532.
1H NMR(400MHz,CDCl 3)δ9.14(s,1H),8.92(d,J＝8.8Hz,1H),8.28(s,1H),7.99(d,J＝1.6Hz,1H),7.83(d,J＝8.4Hz,1H),7.73(dd,J＝2.8,5.6Hz,2H),7.69(dd,J＝2.0,8.4Hz,1H),7.60(dd,J＝2.8,5.6Hz,2H),7.22(t,J＝8.0Hz,1H),7.04(d,J＝7.2Hz,1H),6.98(t,J＝2.0Hz,1H),6.76(dd,J＝2.0,8.0Hz,1H),5.59-5.53(m,1H),4.17(dd,J＝10.0,14.0Hz,1H),4.06-4.00(m,1H),3.70(s,3H)。 1 H NMR (400MHz, CDCl 3 ) δ9.14 (s, 1H), 8.92 (d, J = 8.8Hz, 1H), 8.28 (s, 1H), 7.99 (d, J = 1.6Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.73 (dd, J = 2.8, 5.6 Hz, 2H), 7.69 (dd, J = 2.0, 8.4 Hz, 1H), 7.60 (dd, J = 2.8, 5.6 Hz, 2H), 7.22 (t, J = 8.0 Hz, 1H), 7.04 (d, J = 7.2 Hz, 1H), 6.98 (t, J = 2.0 Hz, 1H), 6.76 (dd, J = 2.0, 8.0 Hz, 1H), 5.59-5.53 (m, 1H), 4.17 (dd, J = 10.0, 14.0 Hz, 1H), 4.06-4.00 (m, 1H), 3.70 (s, 3H).
第二步Second step
将化合物12b(690mg,1.30mmol)溶于乙醇(20mL)，在20摄氏度下，向溶液中滴加水合肼(0.60ml,10.4mmol,含量85％)。反应液升温至55摄氏度搅拌15小时。反应液降至室温，过滤，滤液减压浓缩。剩余物经柱层析纯化得化合物12c。Compound 12b (690 mg, 1.30 mmol) was dissolved in ethanol (20 mL), and hydrazine hydrate (0.60 ml, 10.4 mmol, content 85%) was added dropwise to the solution at 20 °C. The reaction solution was warmed to 55 ° C and stirred for 15 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was evaporated. The residue was purified by column chromatography to give compound 12c.
MS-ESI计算值[M+H] +400,402,实测值400,402； MS-ESI calculated [M+H] + 400, 402, found 400, 402;
1H NMR(400MHz,CDCl 3)δ9.17(s,1H),8.90(br d,J＝8.0Hz,1H),8.53(s,1H),8.16(s,1H),7.93(d,J＝8.4Hz,1H),7.80(dd,J＝1.6,8.8Hz,1H),7.32(t,J＝8.0Hz,1H),7.03(d,J＝7.6Hz,1H),6.98(s,1H),6.85(dd,J＝2.0,8.0Hz,1H),5.28-5.23(m,1H),3.83(s,3H),3.51(s,2H),3.29-3.18(m,2H)。 1 H NMR (400 MHz, CDCl 3 ) δ 9.17 (s, 1H), 8.90 (brd, J = 8.0 Hz, 1H), 8.53 (s, 1H), 8.16 (s, 1H), 7.93 (d, J) = 8.4 Hz, 1H), 7.80 (dd, J = 1.6, 8.8 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.98 (s, 1H) ), 6.85 (dd, J = 2.0, 8.0 Hz, 1H), 5.28-5.23 (m, 1H), 3.83 (s, 3H), 3.51 (s, 2H), 3.29-3.18 (m, 2H).
第三步third step
将化合物12c(250mg,0.624mmol)，化合物1d(182mg,0.937mmol)，三(二亚苄基丙酮)二钯(114mg,0.125mmol)，2-二环己基膦-2’,4’,6’-三异丙基联苯(101mg,0.250mol)和碳酸铯(407mg,0.498mmol)溶于1,4-二氧六环(8mL)和水(1mL)。反应液用氮气置换三次，在100摄氏度下搅拌15小时。反应液减压浓缩，剩余物溶于二氯甲烷(10mL)，并用水(10mL)洗涤，水相用二氯甲烷萃取(20mL x 3)。有机相用无水硫酸钠干燥，过滤，浓缩。剩余物用高效液相色谱法(盐酸条件)纯化得化合物12的盐酸盐。Compound 12c (250 mg, 0.624 mmol), compound 1d (182 mg, 0.937 mmol), tris(dibenzylideneacetone) dipalladium (114 mg, 0.125 mmol), 2-dicyclohexylphosphine-2',4',6 '-Triisopropylbiphenyl (101 mg, 0.250 mol) and cesium carbonate (407 mg, 0.498 mmol) were dissolved in 1,4-dioxane (8 mL) and water (1 mL). The reaction solution was replaced with nitrogen three times and stirred at 100 ° C for 15 hours. The reaction mixture was concentrated with EtOAc EtOAc m. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by high performance liquid chromatography (hydrochloric acid) to give the hydrochloride salt of Compound 12.
MS-ESI计算值[M+H] +388,实测值388。 MS-ESI calcd [M+H] + 388.
1H NMR(400MHz,CDCl 3)δ9.59(s,1H),9.24(s,1H),8.62(s,1H),8.52-8.51(m,3H),8.39(br d,J＝8.8Hz,1H),7.36(t,J＝8.0Hz,1H),7.20-7.15(m,2H),6.95(dd,J＝2.0,8.0Hz,1H),5.58-5.54(m,1H),3.83(s,3H),3.75-3.69(m,1H),3.51-3.46(m,1H)。 1 H NMR (400MHz, CDCl 3 ) δ9.59 (s, 1H), 9.24 (s, 1H), 8.62 (s, 1H), 8.52-8.51 (m, 3H), 8.39 (br d, J = 8.8Hz , 1H), 7.36 (t, J = 8.0 Hz, 1H), 7.20-7.15 (m, 2H), 6.95 (dd, J = 2.0, 8.0 Hz, 1H), 5.58-5.54 (m, 1H), 3.83 ( s, 3H), 3.75-3.69 (m, 1H), 3.51-3.46 (m, 1H).
实施例13Example 13
Figure PCTCN2019083208-appb-000104
Figure PCTCN2019083208-appb-000104
合成路线：synthetic route:
Figure PCTCN2019083208-appb-000105
Figure PCTCN2019083208-appb-000105
第一步first step
将化合物12c(150mg,0.375mmol)溶于无水甲醇(5mL)，在15摄氏度下，向溶液中滴加甲醛水溶液(0.42mL,5.62mmol,含量37％)。反应液在15摄氏度下搅拌半小时后，加入三乙酰氧基硼氢化钠(1.19g,5.62mmol)和醋酸(21.0μl,0.375mmol)。反应液继续搅拌3.5小时。反应液减压浓缩，剩余物用饱和碳酸氢钠溶液洗涤(5mL)，用二氯甲烷萃取(10mL x 3)。有机相用无水硫酸钠干燥，过滤，浓缩。剩余物经柱层析纯化得化合物13a。Compound 12c (150 mg, 0.375 mmol) was dissolved in anhydrous methanol (5 mL), and aqueous solution (0.42 mL, 5.62 mmol, content 37%) was added dropwise to the solution at 15 °C. After the reaction mixture was stirred at 15 ° C for half an hour, sodium triacetoxyborohydride (1.19 g, 5.62 mmol) and acetic acid (21.0 μl, 0.375 mmol) were added. The reaction solution was further stirred for 3.5 hours. The reaction mixture was concentrated with EtOAc EtOAc m. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by column chromatography to give Compound 13a.
MS-ESI计算值[M+H] +428,430,实测值428,430。 MS-ESI calcd for [M + H] + 428,430, 428, 430 found.
1H NMR(400MHz,CDCl 3)δ9.18(s,1H),8.94(br d,J＝7.6Hz,1H),8.49(s,1H),8.14(s,1H),7.91(d,J＝8.4Hz,1H),7.78(dd,J＝2.0,8.8Hz,1H),7.30-7.28(m,1H),7.03(d,J＝7.6Hz,1H),6.98(s,1H),6.81(dd,J＝2.0,8.0Hz,1H),5.35-5.30(m,1H),3.80(s,3H),3.50(s,2H),2.40(s,6H)。 1 H NMR (400MHz, CDCl 3 ) δ9.18 (s, 1H), 8.94 (br d, J = 7.6Hz, 1H), 8.49 (s, 1H), 8.14 (s, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.78 (dd, J = 2.0, 8.8 Hz, 1H), 7.30-7.28 (m, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.98 (s, 1H), 6.81 (dd, J = 2.0, 8.0 Hz, 1H), 5.35-5.30 (m, 1H), 3.80 (s, 3H), 3.50 (s, 2H), 2.40 (s, 6H).
第二步Second step
将化合物13a(110mg,0.257mmol)，化合物1d(74.8mg,0.358mmol)，三(二亚苄基丙酮)二钯(47.0mg,51.4μmol)，2-二环己基膦-2’,4’,6’-三异丙基联苯(41.4mg,0.103mmol)和碳酸铯(167mg,0.514mmol)溶于1,4-二氧六环(4mL)和水(0.8mL)。反应液用氮气置换三次，在100摄氏度下搅拌15小时。反应液减压浓缩，剩余物溶于二氯甲烷(10mL)，并用水(10mL)洗涤，水相用二氯甲烷萃取(20mL x 3)。有机相用无水硫酸钠干燥，过滤，浓缩。剩余物用高效液相色谱法(盐酸条件)纯化得化合物13的盐酸盐。Compound 13a (110 mg, 0.257 mmol), compound 1d (74.8 mg, 0.358 mmol), tris(dibenzylideneacetone) dipalladium (47.0 mg, 51.4 μmol), 2-dicyclohexylphosphine-2', 4' 6'-Triisopropylbiphenyl (41.4 mg, 0.103 mmol) and cesium carbonate (167 mg, 0.514 mmol) were dissolved in 1,4-dioxane (4 mL) and water (0.8 mL). The reaction solution was replaced with nitrogen three times and stirred at 100 ° C for 15 hours. The reaction mixture was concentrated with EtOAc EtOAc m. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by high performance liquid chromatography (hydrochloric acid) to give the hydrochloride salt of Compound 13.
MS-ESI计算值[M+H] +416,实测值416。 MS-ESI calcd for [M+H] + 416.
1H NMR(400MHz,CDCl 3)δ9.64(s,1H),9.42(s,1H),8.68(s,1H),8.61-8.56(m,3H),8.43(br d,J＝8.8Hz,1H),7.40-7.36(m,1H),7.28(br s,1H),7.23(br d,J＝7.6Hz,1H),6.96(br d,J＝8.4Hz,1H),5.82(br d,J＝9.2Hz,1H),4.13(t,J＝12.4Hz,1H),3.86(s,3H),3.65(br d,J＝12.8Hz,1H),3.12(s,3H),3.09(s,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 9.64 (s, 1H), 9.42 (s, 1H), 8.68 (s, 1H), 8.61 - 8.56 (m, 3H), 8.43 (brd, J = 8.8 Hz) , 1H), 7.40-7.36 (m, 1H), 7.28 (br s, 1H), 7.23 (br d, J = 7.6 Hz, 1H), 6.96 (br d, J = 8.4 Hz, 1H), 5.82 (br d, J = 9.2 Hz, 1H), 4.13 (t, J = 12.4 Hz, 1H), 3.86 (s, 3H), 3.65 (br d, J = 12.8 Hz, 1H), 3.12 (s, 3H), 3.09 (s, 3H).
实施例14Example 14
Figure PCTCN2019083208-appb-000106
Figure PCTCN2019083208-appb-000106
合成路线：synthetic route:
Figure PCTCN2019083208-appb-000107
Figure PCTCN2019083208-appb-000107
第一步first step
室温下，将化合物14a(2.00g,10.7mmol)溶于甲醇(20mL)中，向反应液中加入氯化氢的甲醇溶液(4M,10mL)。反应混合物在60摄氏度下搅拌1.5小时。反应完成后，反应液减压浓缩得到化合物14b的盐酸盐。MS-ESI计算值[M+H]+202,实测值202。Compound 14a (2.00 g, 10.7 mmol) was dissolved in methanol (20 mL), and a solution of hydrogen chloride in methanol (4M, 10 mL) was added to the mixture. The reaction mixture was stirred at 60 ° C for 1.5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give the hydrochloride salt of Compound 14b. MS-ESI calc. [M+H]
第二步Second step
室温下，将化合物14b(盐酸盐,5.40g,22.7mmol)溶于乙酸(200mL)中，向反应液中滴加液溴(10.7g,67.0mmol,3.46mL)。反应混合物在50摄氏度下搅拌加入乙酸钠(4.40g,53.7mmol)，并且在50摄氏度搅拌2.5小时。冷却至室温，继续向反应液中加入液溴(4.36g,27.3mmol,1.41mL)和乙酸钠(1.68g,20.5mmol)，在50摄氏度搅拌1.5小时。最后，向反应液中加入乙酸(160mL)，48％的氢溴酸水溶液(241g,1.43mol,162.00mL)和亚硫酸钠(34.4g,273mmol)，并且升温至120摄氏度搅拌16小时。反应完成后，反应液减压浓缩，剩余物加水(50mL)后用10％的氢氧化钠水溶液调节pH＝4-5，然后用乙酸乙酯/2-甲基四氢呋喃(1/1,150mL x 3)萃取，合并的有机相经无水硫酸钠干燥，过滤，滤液减压浓缩。剩余物经柱层析分离得到化合物14c。MS-ESI计算值[M+H] +266和268,实测值266和268。 Compound 14b (hydrochloride, 5.40 g, 22.7 mmol) was dissolved in acetic acid (200 mL), and liquid bromine (10.7 g, 67.0 mmol, 3.46 mL) was added dropwise to the reaction mixture. The reaction mixture was stirred at 50 ° C with sodium acetate (4.40 g, 53.7 mmol) and stirred at 50 ° C for 2.5 hours. After cooling to room temperature, liquid bromine (4.36 g, 27.3 mmol, 1.41 mL) and sodium acetate (1.68 g, 20.5 mmol) were added and the mixture was stirred at 50 ° C for 1.5 hours. Finally, acetic acid (160 mL), a 48% aqueous solution of hydrobromic acid (241 g, 1.43 mol, 162.00 mL) and sodium sulfite (34.4 g, 273 mmol) were added to the reaction mixture, and the mixture was heated to 120 ° C and stirred for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc) The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated. The residue was subjected to column chromatography to give Compound 14c. MS-ESI calculated [M+H] + 266 and 268, found 266 and 268.
第三步third step
室温下，将化合物14c(5.00g,18.8mmol)溶于甲醇(40mL)中，向反应液中加入氯化氢的甲醇溶液(4M,4.70mL)。将反应混合物在60摄氏度下搅拌3小时。反应完成后，反应液减压浓缩。剩余物经三乙胺中和后，通过柱层析分离得到化合物14d。Compound 14c (5.00 g, 18.8 mmol) was dissolved in methanol (40 mL), and a solution of hydrogen chloride in methanol (4M, 4. The reaction mixture was stirred at 60 ° C for 3 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. After the residue was neutralized with triethylamine, the compound 14d was obtained by column chromatography.
MS-ESI计算值[M+H]+280和282,实测值280和282。MS-ESI calculated [M+H]+ 280 and 282, found 280 and 282.
1H NMR(400MHz,CDCl 3)δ8.31(s,1H),8.00(s,1H),7.88(dd,J＝1.6,8.4Hz,1H),7.50(d,J＝8.4Hz,1H),7.01(s,1H),4.39(s,2H),3.93-3.89(s,3H)。 1 H NMR (400MHz, CDCl 3 ) δ8.31 (s, 1H), 8.00 (s, 1H), 7.88 (dd, J = 1.6,8.4Hz, 1H), 7.50 (d, J = 8.4Hz, 1H) , 7.01 (s, 1H), 4.39 (s, 2H), 3.93 - 3.89 (s, 3H).
第四步the fourth step
室温下，将氯化铜(255mg,1.90mmol)和亚硝酸叔丁酯(147mg,1.42mmol)加入乙腈(6mL)中，继续向溶液中加入化合物14d(300mg,1.07mmol)。将反应混合物在80摄氏度下搅拌1小时。反应完成后，向反 应液加入稀盐酸(1M,10mL)，然后用乙酸乙酯(50mL x 2)萃取，合并的有机相经食盐水(30mL)洗后，用无水硫酸钠干燥，过滤，滤液减压浓缩。剩余物经柱层析分离得到化合物14e。Copper chloride (255 mg, 1.90 mmol) and tert-butyl nitrite (147 mg, 1.42 mmol) were added to acetonitrile (6 mL) at room temperature and compound 14d (300 mg, 1.07 mmol) was then added to the solution. The reaction mixture was stirred at 80 ° C for 1 hour. After the reaction was completed, dilute hydrochloric acid (1M, 10 mL) was added to the reaction mixture, and then ethyl acetate (50 mL x 2), and the combined organic phase was washed with brine (30 mL) The filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography to give Compound 14e.
1H NMR(400MHz,CDCl 3)δ8.43(s,1H),8.20-8.19(m,1H),8.03(dd,J＝1.2,8.4Hz,1H),7.93(s,1H),7.72(d,J＝8.4Hz,1H),3.93-3.89(s,3H)。 1 H NMR (400MHz, CDCl 3 ) δ8.43 (s, 1H), 8.20-8.19 (m, 1H), 8.03 (dd, J = 1.2,8.4Hz, 1H), 7.93 (s, 1H), 7.72 ( d, J = 8.4 Hz, 1H), 3.93 - 3.89 (s, 3H).
第五步the fifth step
室温下，将化合物4e(80.0mg,267μmol)溶于四氢呋喃(4mL)和水(2mL)中，继续向溶液中加入一水合氢氧化锂(22.4mg,534μmol)。将反应混合物在20摄氏度下搅拌1小时。反应完成后，向反应液滴加稀盐酸(1M)至溶液pH为2～3，然后用乙酸乙酯和2-甲基四氢呋喃混合溶剂(1/1,30mL)萃取，有机相直接减压浓缩得到化合物14f。Compound 4e (80.0 mg, 267 μmol) was dissolved in tetrahydrofuran (4 mL) and water (2 mL) at room temperature, and then lithium hydroxide monohydrate (22.4 mg, 534 μmol) was added to the solution. The reaction mixture was stirred at 20 ° C for 1 hour. After the reaction was completed, dilute hydrochloric acid (1 M) was added to the reaction solution until the pH of the solution was 2 to 3, and then extracted with a mixed solvent of ethyl acetate and 2-methyltetrahydrofuran (1/1, 30 mL), and the organic phase was concentrated under reduced pressure. Compound 14f was obtained.
第六步 Step 6
室温下，将化合物14f(90.0mg,315μmol)和化合物1b(57.1mg,315μmol)溶于N,N-二甲基甲酰胺(5mL)中，继续分别向溶液中加入N,N-二异丙基乙胺(81.5mg,630μmol)和2-(7-氧化苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯(180mg,473μmol)。将反应混合物在20摄氏度下搅拌16小时。反应完成后，将反应液减压浓缩。剩余物经制备薄层色谱板分离得到化合物14g。Compound 14f (90.0 mg, 315 μmol) and Compound 1b (57.1 mg, 315 μmol) were dissolved in N,N-dimethylformamide (5 mL) at room temperature, and N,N-diisopropyl was added to the solution, respectively. Ethylethylamine (81.5 mg, 630 μmol) and 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (180 mg, 473 μmol). The reaction mixture was stirred at 20 ° C for 16 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was separated into a preparative thin layer chromatography plate to give compound 14 g.
MS-ESI计算值[M+H] +448和450,实测值448和450。 MS-ESI calculated [M+H] + 448 and 450, found 448 and 450.
第七步Seventh step
室温下，将化合物14g(20.0mg,44.6μmol)和化合物1d(17.3mg,89.1μmol)溶于二氧六环(2.5mL)，乙醇(1mL)和水(0.5mL)的混合溶剂，继续分别向溶液中加入碳酸钠(9.45mg,89.14μmol)和四(三苯基膦)钯(5.15mg,4.46μmol)。在氮气保护下，将反应混合物在90摄氏度下搅拌16小时。反应完成后，将反应液减压浓缩。剩余物经制备薄层色谱板分离得到粗品。粗品进一步经高效液相色谱法分离得到化合物14。Compound 14g (20.0mg, 44.6μmol) and compound 1d (17.3mg, 89.1μmol) were dissolved in a mixed solvent of dioxane (2.5mL), ethanol (1mL) and water (0.5mL) at room temperature, continue to separate Sodium carbonate (9.45 mg, 89.14 μmol) and tetrakis(triphenylphosphine)palladium (5.15 mg, 4.46 μmol) were added to the solution. The reaction mixture was stirred at 90 ° C for 16 hours under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was separated by preparative thin layer chromatography to give a crude material. The crude product was further separated by high performance liquid chromatography to give the compound 14.
MS-ESI计算值[M+H] +436,实测值436。 MS-ESI calcd [M+H] + 436.
1H NMR(400MHz,DMSO-d 6)δ8.95(d,J＝8.4Hz,1H),8.47(s,1H),8.28(s,1H),8.22(s,1H),8.13(s,2H),7.99-7.92(m,2H),7.26(t,J＝8.0Hz,1H),7.00(s,2H),6.81(d,J＝8.0Hz,1H),5.21-5.16(m,1H),3.75(s,3H),3.52-3.51(m,2H),2.07(d,J＝6.4Hz,1H),1.92(dd,J＝6.8,13.6Hz,1H)。 1 H NMR (400MHz, DMSO- d 6) δ8.95 (d, J = 8.4Hz, 1H), 8.47 (s, 1H), 8.28 (s, 1H), 8.22 (s, 1H), 8.13 (s, 2H), 7.99-7.92 (m, 2H), 7.26 (t, J = 8.0 Hz, 1H), 7.00 (s, 2H), 6.81 (d, J = 8.0 Hz, 1H), 5.21-5.16 (m, 1H) ), 3.75 (s, 3H), 3.52-3.51 (m, 2H), 2.07 (d, J = 6.4 Hz, 1H), 1.92 (dd, J = 6.8, 13.6 Hz, 1H).
实施例15Example 15
Figure PCTCN2019083208-appb-000108
Figure PCTCN2019083208-appb-000108
合成路线：synthetic route:
Figure PCTCN2019083208-appb-000109
Figure PCTCN2019083208-appb-000109
第一步first step
零度下，将四氟硼酸亚硝鎓盐(150mg,1.29mmol)加入二氯甲烷(9mL)中，向溶液中加入化合物14e(300mg,1.07mmol)。将反应混合物在0摄氏度下搅拌1小时。用氮气吹干反应液中的二氯甲烷，再加入邻二甲苯(9mL)，继续将反应混合物在150摄氏度下搅拌1小时。反应完成后，将反应液减压浓缩。剩余物经柱层析分离得到化合物15a。Nitrosium tetrafluoroborate (150 mg, 1.29 mmol) was added to dichloromethane (9 mL), and compound 14e (300 mg, 1.07 mmol) was added to the solution. The reaction mixture was stirred at 0 ° C for 1 hour. The dichloromethane in the reaction mixture was dried with nitrogen, then o-xylene (9 mL) was added and the mixture was stirred at 150 ° C for one hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was subjected to column chromatography to give Compound 15a.
第二步Second step
室温下，将化合物15a(140mg,495μmol)和化合物1d(115mg,593μmol)溶于二氧六环(4mL)和水(1mL)的混合溶剂中，继续分别向溶液中加入碳酸铯(322mg,989μmol)，2-二环己基膦-2’,4’,6’-三异丙基联苯(23.6mg,49.5μmol)，三(二亚苄基丙酮)二钯(45.3mg,49.5μmol)。在氮气保护下，将反应混合物在100摄氏度下搅拌16小时。反应完成后，反应液用乙酸乙酯和2-甲基四氢呋喃混合溶剂(1/1,20mL)萃取，有机相用无水硫酸钠干燥，过滤减压浓缩。剩余物经制备薄层色谱板分离得到化合物15b。Compound 15a (140 mg, 495 μmol) and Compound 1d (115 mg, 593 μmol) were dissolved in a mixed solvent of dioxane (4 mL) and water (1 mL) at room temperature, and then cesium carbonate (322 mg, 989 μmol) was added to the solution, respectively. 2,2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (23.6 mg, 49.5 μmol), tris(dibenzylideneacetone)dipalladium (45.3 mg, 49.5 μmol). The reaction mixture was stirred at 100 ° C for 16 hours under a nitrogen atmosphere. After the reaction was completed, the mixture was evaporated. The residue was isolated by preparative thin layer chromatography to give compound 15b.
MS-ESI计算值[M+H] +271,实测值271。 MS-ESI calcd [M+H] + 271.
第三步third step
室温下，将化合物15b(53.0mg,196μmol)溶于四氢呋喃(4mL)和水(2mL)中，向反应液中加入一水合氢氧化锂(41.1mg,981μmol)。将反应混合物在20摄氏度下搅拌1小时。反应完成后，向反应液中加入稀盐酸(1M,3mL)，然后用乙酸乙酯和2-甲基四氢呋喃混合溶剂(1/1,20mL)萃取，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到化合物15c。Compound 15b (53.0 mg, 196 μmol) was dissolved in tetrahydrofuran (4 mL) and water (2 mL), and lithium hydroxide monohydrate (41.1 mg, 981 μmol) was added to the reaction mixture. The reaction mixture was stirred at 20 ° C for 1 hour. After the reaction was completed, dilute hydrochloric acid (1M, 3 mL) was added to the mixture, and then ethyl acetate and 2-methyltetrahydrofuran mixed solvent (1/1, 20 mL), and the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give Compound 15c.
MS-ESI计算值[M+H]+257,实测值257。MS-ESI calc. [M+H]
第四步the fourth step
室温下，将化合物15c(50.0mg,195μmol)和化合物1b(35.4mg,195μmol)溶于N,N-二甲基甲酰胺(2mL)中，向反应液中加入N,N-二异丙基乙胺(75.7mg,585μmol,102μL)和2-(7-氧化苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯(111mg,293μmol)。将反应混合物在20摄氏度下搅拌16小时。反应完成后，向反应液中加入乙酸乙酯和2-甲基四氢呋喃混合溶剂(1/1,30mL)萃取，然后依次用稀盐酸(1M,15mL x 2)和饱和食盐水(15mL)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩。剩余物经高效液相色谱法(甲酸条 件)分离得到产物15的甲酸盐。Compound 15c (50.0 mg, 195 μmol) and Compound 1b (35.4 mg, 195 μmol) were dissolved in N,N-dimethylformamide (2 mL) at room temperature, and N,N-diisopropyl was added to the reaction mixture. Ethylamine (75.7 mg, 585 μmol, 102 μL) and 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (111 mg, 293 μmol). The reaction mixture was stirred at 20 ° C for 16 hours. After the completion of the reaction, ethyl acetate and 2-methyltetrahydrofuran mixed solvent (1/1, 30 mL) were added to the mixture, and then washed successively with dilute hydrochloric acid (1M, 15 mL x 2) and saturated brine (15 mL). The organic phase was dried over anhydrous sodium sulfate and filtered and evaporated. The residue was separated by high performance liquid chromatography (formic acid) to give the title compound of product 15.
MS-ESI计算值[M+H] +420,实测值420。 MS-ESI calcd for [M+H] + 420.
1H NMR(400MHz,DMSO-d 6)δ13.23(s,1H),8.94(d,J＝8.4Hz,1H),8.47-8.46(m,2H),8.44(s,1H),7.96-7.92(m,4H),7.85(d,J＝12.4Hz,1H),7.28-7.24(m,1H),7.01-7.01(m,2H),6.81(dd,J＝1.6,8.1Hz,1H),5.22-5.17(m,1H),4.60(s,1H),3.75(s,3H),3.45(dd,J＝5.2,10.8Hz,2H),2.12-2.05(m,1H),1.95-1.90(m,1H)。 1 H NMR (400MHz, DMSO- d 6) δ13.23 (s, 1H), 8.94 (d, J = 8.4Hz, 1H), 8.47-8.46 (m, 2H), 8.44 (s, 1H), 7.96- 7.92 (m, 4H), 7.85 (d, J = 12.4 Hz, 1H), 7.28-7.24 (m, 1H), 7.01-7.01 (m, 2H), 6.81 (dd, J = 1.6, 8.1 Hz, 1H) , 5.22-5.17 (m, 1H), 4.60 (s, 1H), 3.75 (s, 3H), 3.45 (dd, J = 5.2, 10.8 Hz, 2H), 2.12-2.05 (m, 1H), 1.95-1.90 (m, 1H).
实施例16Example 16
Figure PCTCN2019083208-appb-000110
Figure PCTCN2019083208-appb-000110
合成路线：synthetic route:
Figure PCTCN2019083208-appb-000111
Figure PCTCN2019083208-appb-000111
第一步first step
室温下，将化合物16a(1.00g,4.61mmol)和丙烯酸甲酯(2.43g,28.2mmol,2.54mL)溶于二甲亚砜(12mL)和水(1.5mL)中，向反应液中加入1,4-二氮杂二环[2.2.2]辛烷(517mg,4.61mmol)。反应混合物在20摄氏度下搅拌16小时。反应完成后，反应液用乙酸乙酯(80mL)萃取，有机相依次用稀盐酸(1M,60mL)和饱和食盐水(60mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到化合物16b。Compound 16a (1.00 g, 4.61 mmol) and methyl acrylate (2.43 g, 28.2 mmol, 2.54 mL) were dissolved in dimethyl sulfoxide (12 mL) and water (1.5 mL) at room temperature. 4-Diazabicyclo[2.2.2]octane (517 mg, 4.61 mmol). The reaction mixture was stirred at 20 ° C for 16 hours. After the completion of the reaction, the reaction mixture was evaporated. EtOAcjjjjjjjjjjjjjjjj .
第二步Second step
零度下，将化合物16b(1.41g,4.65mmol)和吡啶(736mg,9.30mmol,751μL)溶于甲苯(30mL)中，向反应液中滴加乙酸酐(1.90g,18.6mmol)。反应混合物在20摄氏度下搅拌16小时。反应完成后，反应液用乙酸乙酯(80mL)萃取，有机相依次用稀盐酸(1M,60mL)和饱和食盐水(60mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。剩余物经柱层析分离得到化合物16c。Compound 16b (1.41 g, 4.65 mmol) and pyridine (736 mg, 9.30 mmol, 751 μL) were dissolved in toluene (30 mL), and acetic anhydride (1.90 g, 18.6 mmol) was added dropwise to the reaction mixture. The reaction mixture was stirred at 20 ° C for 16 hours. After the reaction was completed, the mixture was evaporated, evaporated, evaporated, evaporated The residue was subjected to column chromatography to give Compound 16c.
第三步third step
氮气保护下，将硝基甲烷(1.95g,32.0mmol,1.73mL)加入混有碳酸铯(1.89g,5.79mmol)的二甲亚砜(15mL)中，升温至50摄氏度并搅拌20分钟。向反应液中缓慢滴加化合物16c(500mg,1.45mmol)的二甲亚砜(30mL)溶液。反应混合物在50摄氏度下搅拌3小时。反应完成后，向反应液加入水(50mL)，用乙酸乙酯(100mL x 2)萃取，合并的有机相用饱和食盐水(80mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。剩余物经柱层析分离得到化合物16d。Nitromethane (1.95 g, 32.0 mmol, 1.73 mL) was added to dimethyl sulfoxide (15 mL) mixed with cesium carbonate (1.89 g, 5.79 mmol), and the mixture was warmed to 50 ° C and stirred for 20 minutes. A solution of Compound 16c (500 mg, 1.45 mmol) in dimethylsulfoxide (30 mL) was slowly added dropwise to the mixture. The reaction mixture was stirred at 50 ° C for 3 hours. After the reaction was completed, water (50 mL) was evaporated, evaporated, evaporated. The residue was subjected to column chromatography to give Compound 16d.
1H NMR(400MHz,CDCl 3)δ8.41(s,1H),8.10(s,1H),7.97(d,J＝8.4Hz,1H),7.70(d,J＝8.4Hz,1H),7.66(s,1H),3.91(s,3H),2.52(s,3H)。 1 H NMR (400MHz, CDCl 3 ) δ8.41 (s, 1H), 8.10 (s, 1H), 7.97 (d, J = 8.4Hz, 1H), 7.70 (d, J = 8.4Hz, 1H), 7.66 (s, 1H), 3.91 (s, 3H), 2.52 (s, 3H).
第四步the fourth step
室温下，将化合物16d(20.0mg,71.7μmol)和化合物1b(27.8mg,143μmol)溶于二氧六环(2mL)和水(0.5mL)中，向反应液中加入碳酸铯(46.7mg,143μmol)，2-二环己基膦-2’,4’,6’-三异丙基联苯(3.42mg,7.17μmol)，三(二亚苄基丙酮)二钯(6.56mg,7.17μmol)。在氮气保护下，将反应混合物在90摄氏度下搅拌16小时。反应完成后，反应液用乙酸乙酯和2-甲基四氢呋喃混合溶剂(1/1,20mL)萃取，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩。剩余物经制备薄层色谱板分离得到化合物16e。Compound 16d (20.0 mg, 71.7 μmol) and Compound 1b (27.8 mg, 143 μmol) were dissolved in dioxane (2 mL) and water (0.5 mL) at room temperature, and cesium carbonate (46.7 mg, 143 μmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (3.42 mg, 7.17 μmol), tris(dibenzylideneacetone)dipalladium (6.56 mg, 7.17 μmol) . The reaction mixture was stirred at 90 ° C for 16 hours under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was evaporated, mjjjjjjjjj The residue was isolated by preparative thin layer chromatography to give compound 16e.
MS-ESI计算值[M+H] +267,实测值267。 MS-ESI calcd [M+H] + 266.
第五步the fifth step
室温下，将化合物16e(40.0mg,150μmol)溶于四氢呋喃(4mL)和水(1mL)中，向反应液中加入一水合氢氧化锂(31.5mg,751μmol)。将反应混合物在20摄氏度下搅拌1小时。反应完成后，向反应液中加入稀盐酸(1M,3mL)，然后用乙酸乙酯和2-甲基四氢呋喃混合溶剂(1/1,20mL)萃取，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到化合物16g。MS-ESI计算值[M+H] +253,实测值253。 Compound 16e (40.0 mg, 150 μmol) was dissolved in tetrahydrofuran (4 mL) and water (1 mL) at room temperature, and lithium hydroxide monohydrate (31.5 mg, 751 μmol) was added to the reaction mixture. The reaction mixture was stirred at 20 ° C for 1 hour. After the reaction was completed, dilute hydrochloric acid (1M, 3 mL) was added to the mixture, and then ethyl acetate and 2-methyltetrahydrofuran mixed solvent (1/1, 20 mL), and the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound 16 g. MS-ESI calcd for [M+H] + 253.
第六步 Step 6
室温下，将化合物16g(40.0mg,159μmol)和化合物1b(28.7mg,159μmol)溶于N,N-二甲基甲酰胺(2mL)中，向反应液中加入N,N-二异丙基乙胺(61.5mg,476μmol,82.9μL)和2-(7-氧化苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯(90.4mg,238μmol)。将反应混合物在20摄氏度下搅拌16小时。反应完成后，向反应液中加入乙酸乙酯和2-甲基四氢呋喃混合溶剂(1/1,30mL)萃取，然后分别用稀盐酸(1M,15mL x 2)和饱和食盐水(15mL)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩。剩余物经高效液相色谱法(甲酸条件)分离得到产物16的甲酸盐。The compound 16 g (40.0 mg, 159 μmol) and the compound 1b (28.7 mg, 159 μmol) were dissolved in N,N-dimethylformamide (2 mL) at room temperature, and N,N-diisopropyl was added to the reaction mixture. Ethylamine (61.5 mg, 476 μmol, 82.9 μL) and 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (90.4 mg, 238 μmol). The reaction mixture was stirred at 20 ° C for 16 hours. After the reaction was completed, ethyl acetate and 2-methyltetrahydrofuran mixed solvent (1/1, 30 mL) were added to the mixture, and then washed with dilute hydrochloric acid (1M, 15 mL x 2) and saturated brine (15 mL). The organic phase was dried over anhydrous sodium sulfate and filtered and evaporated. The residue was separated by high performance liquid chromatography (formic acid) to give the title compound of product 16.
MS-ESI计算值[M+H] +416,实测值416。 MS-ESI calcd for [M+H] + 416.
1H NMR(400MHz,DMSO-d 6)δ13.07(s,1H),8.88(d,J＝8.4Hz,1H),8.41(s,1H),8.03(s,1H),7.89(s,1H),7.87-7.84(m,3H),7.27-7.23(m,1H),7.01-6.99(m,2H),6.81(dd,J＝1.7,8.2Hz,1H),5.22-5.16(m,1H),4.59(s,1H),3.75(s,3H),3.46(dd,J＝5.6,10.8Hz,2H),2.56(s,3H),2.11-2.04(m,1H),1.95-1.90(m,1H)。 1 H NMR (400MHz, DMSO- d 6) δ13.07 (s, 1H), 8.88 (d, J = 8.4Hz, 1H), 8.41 (s, 1H), 8.03 (s, 1H), 7.89 (s, 1H), 7.87-7.84 (m, 3H), 7.27-7.23 (m, 1H), 7.01-6.99 (m, 2H), 6.81 (dd, J = 1.7, 8.2 Hz, 1H), 5.22-5.16 (m, 1H), 4.59 (s, 1H), 3.75 (s, 3H), 3.46 (dd, J = 5.6, 10.8 Hz, 2H), 2.56 (s, 3H), 2.11-2.04 (m, 1H), 1.95-1.90 (m, 1H).
实施例17Example 17
Figure PCTCN2019083208-appb-000112
Figure PCTCN2019083208-appb-000112
合成路线：synthetic route:
Figure PCTCN2019083208-appb-000113
Figure PCTCN2019083208-appb-000113
第一步first step
将化合物3(190mg,472μmol)溶于四氢呋喃(10mL)中，加入2a(104mg,708μmol)和三苯基膦(248mg,944μmol)，然后在零摄氏度下缓慢滴加偶氮二甲酸二异丙酯(191mg,944μmol,184μL)，滴加完后于20摄氏度下反应2小时。反应完成后，加入水(15mL×1)淬灭反应，然后用乙酸乙酯(15mL×3)萃取，合并的有机相用无水硫酸钠干燥，过滤，滤液减压浓缩。剩余物经柱层析分离得到化合物17a。Compound 3 (190 mg, 472 μmol) was dissolved in tetrahydrofuran (10 mL), 2a (104 mg, 708 μmol) and triphenylphosphine (248 mg, 944 μmol) were added, and then diisopropyl azodicarboxylate was slowly added dropwise at zero degrees Celsius. (191 mg, 944 μmol, 184 μL), and reacted at 20 ° C for 2 hours after the dropwise addition. After the reaction was completed, the mixture was evaporated. The residue was subjected to column chromatography to give Compound 17a.
MS-ESI计算值[M+H] +532，实测值532。 MS-ESI calcd for [M+H] + 532.
第二步Second step
将化合物17a(86.0mg,162μmol)溶于乙醇(3mL)中，加入水合肼(143mg,2.43mmol,139μL,85％purity)，反应在55摄氏度下搅拌16小时。反应完成后，将反应液浓缩，剩余物经高效液相色谱(盐酸条件)分离得到化合物17的盐酸盐。Compound 17a (86.0 mg, 162 μmol) was dissolved in ethanol (3 mL), hydrazine hydrate (143 mg, 2.43 mmol, 139 μL, 85% purity) was added, and the reaction was stirred at 55 ° C for 16 hours. After completion of the reaction, the reaction solution was concentrated, and the residue was subjected to high-purity liquid chromatography (hydrochloric acid) to give the hydrochloride salt of Compound 17.
MS-ESI计算值[M+H] +402，实测值402。 MS-ESI calc. [M+H] + 402.
1H NMR(400MHz,DMSO-d 6)δ9.40(d,J＝8.8Hz,1H),9.35(s,1H),8.50(s,1H),8.41(s,1H),8.34(s,2H),8.27(d,J＝8.8Hz,1H),8.19-8.10(m,1H),7.98-7.85(m,3H),7.29(t,J＝8.0Hz,1H),7.16-7.03(m,2H),6.86(dd,J＝2.4,8.0Hz,1H),5.27-5.17(m,1H),3.76(s,3H),2.95-2.81(m,1H),2.80-2.72(m,1H),2.34-2.26(m,1H),2.25-2.13(m,1H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.40 (d, J = 8.8 Hz, 1H), 9.35 (s, 1H), 8.50 (s, 1H), 8.41 (s, 1H), 8.34 (s, 2H), 8.27 (d, J = 8.8 Hz, 1H), 8.19-8.10 (m, 1H), 7.98-7.85 (m, 3H), 7.29 (t, J = 8.0 Hz, 1H), 7.16-7.03 (m , 2H), 6.86 (dd, J = 2.4, 8.0 Hz, 1H), 5.27-5.17 (m, 1H), 3.76 (s, 3H), 2.95-2.81 (m, 1H), 2.80-2.72 (m, 1H) ), 2.34 - 2.26 (m, 1H), 2.25 - 2.13 (m, 1H).
实施例18Example 18
Figure PCTCN2019083208-appb-000114
Figure PCTCN2019083208-appb-000114
合成路线：synthetic route:
Figure PCTCN2019083208-appb-000115
Figure PCTCN2019083208-appb-000115
第一步first step
参考实施例11第一步得到化合物18b。Reference Example 11 The first step gave Compound 18b.
第二步Second step
参考实施例11第二步得到化合物18c。The second step of Reference Example 11 gave compound 18c.
第三步third step
参考实施例11第三步得到化合物18d。The third step of Reference Example 11 gave Compound 18d.
第四步the fourth step
将化合物18d(827mg,3.28mmol)溶于N,N-二甲基甲酰胺(25mL)中，向反应液中添加2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(1.78g,4.69mmol)，N,N-二异丙基乙胺(606mg,4.69mmol,817μL)，反应混合物在20摄氏度下搅拌0.5小时，然后向反应液中添加化合物3a(512mg,2.34mmol)。反应完成后，反应液减压浓缩，剩余物加水(30mL)后用乙酸乙酯(30mL x 3)萃取，合并的有机相用饱和食盐水(50mL x 1)洗，无水硫酸钠干燥，过滤，滤液减压浓缩。剩余物经柱色谱法纯化得到化合物18e。Compound 18d (827 mg, 3.28 mmol) was dissolved in N,N-dimethylformamide (25 mL), and 2-(7-benzobenzotriazole)-N,N,N' was added to the reaction mixture. N'-tetramethylurea hexafluorophosphate (1.78 g, 4.69 mmol), N,N-diisopropylethylamine (606 mg, 4.69 mmol, 817 μL), the reaction mixture was stirred at 20 ° C for 0.5 h, then Compound 3a (512 mg, 2.34 mmol) was added to the reaction mixture. After the completion of the reaction, the reaction mixture was evaporated. EtOAcjjjjjjjjjjj The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give compound 18e.
MS-ESI计算值[M+H] +389和391，实测值389和391。 MS-ESI calculated [M+H] + </RTI> 389 and 391.
第五步the fifth step
将化合物18e(200mg,483μmol)，化合物1d(141mg,725μmol)，三(二亚苄基丙酮)二钯(44.3mg,48.3μmol)，2-二环己基膦-2’,4’,6’-三异丙基联苯(23.0mg,48.3μmol)，碳酸铯(472mg,1.45mmol)溶于二氧六环(5mL)和水(1mL)中，反应瓶用氮气置换三次，然后反应液在氮气保护下90摄氏度下搅拌12小时。薄层层析板检测原料未完全消耗，向反应液中补加化合物1d(88.0mg,453μmol)，三(二亚苄基丙酮)二钯(45.0mg,49.1μmol)和2-二环己基膦-2’,4’,6’-三异丙基联苯(24mg,50.3μmol)，反应瓶用氮气置换三次，然后反应液在氮气保护下90摄氏度下继续搅拌12小时。反应完成后，反应液减压浓缩，剩余物加水(20mL)后用乙酸乙酯(20mL x 3)萃取，合并的有机相用饱和食盐水(30mL x 1)洗，无水硫酸钠干燥，过滤，滤液减压浓缩。剩余物经高效液相色谱(盐酸条件)分离得到化合物18的盐酸盐。Compound 18e (200 mg, 483 μmol), compound 1d (141 mg, 725 μmol), tris(dibenzylideneacetone)dipalladium (44.3 mg, 48.3 μmol), 2-dicyclohexylphosphine-2', 4', 6' - Triisopropylbiphenyl (23.0 mg, 48.3 μmol), cesium carbonate (472 mg, 1.45 mmol) dissolved in dioxane (5 mL) and water (1 mL), the reaction flask was replaced with nitrogen three times, then the reaction mixture was Stir under 90 °C for 12 hours under nitrogen. The raw material was not completely consumed by the thin layer chromatography, and the compound 1d (88.0 mg, 453 μmol), tris(dibenzylideneacetone)dipalladium (45.0 mg, 49.1 μmol) and 2-dicyclohexylphosphine were added to the reaction solution. -2',4',6'-triisopropylbiphenyl (24 mg, 50.3 μmol), the reaction flask was replaced with nitrogen three times, and the reaction solution was further stirred at 90 ° C for 12 hours under nitrogen atmosphere. After the completion of the reaction, the reaction mixture was evaporated. EtOAcjjjjjjjjjjjjjj The filtrate was concentrated under reduced pressure. The residue was subjected to high performance liquid chromatography (hydrochloric acid) to give the hydrochloride salt of Compound 18.
MS-ESI计算值[M+H] +377,实测值377。 MS-ESI calcd for [M+H] + 377.
1H NMR(400MHz,MeOH-d 4)δ9.44(s,1H),8.83(s,1H),8.44-8.37(m,2H),8.35(s,2H),8.24(d,J＝8.8Hz,1H),7.45-7.36(m,1H),7.30(d,J＝8.0Hz,1H),7.23(d,J＝9.6Hz,1H),7.07-6.99(m,1H),5.29(t,J＝6.4Hz,1H),4.03-3.92(m,2H)。 1 H NMR (400MHz, MeOH- d 4) δ9.44 (s, 1H), 8.83 (s, 1H), 8.44-8.37 (m, 2H), 8.35 (s, 2H), 8.24 (d, J = 8.8 Hz, 1H), 7.45-7.36 (m, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 9.6 Hz, 1H), 7.07-6.99 (m, 1H), 5.29 (t , J = 6.4 Hz, 1H), 4.03-3.92 (m, 2H).
实施例19Example 19
Figure PCTCN2019083208-appb-000116
Figure PCTCN2019083208-appb-000116
合成路线：synthetic route:
Figure PCTCN2019083208-appb-000117
Figure PCTCN2019083208-appb-000117
第一步first step
将化合物11d(500mg,2.99mmol)溶于二氯甲烷(15mL)中，加入三乙胺(757mg,7.48mmol,1.04mL)和二碳酸二叔丁酯(848mg,3.89mmol,893μL)，20摄氏度下反应6个小时。反应完成后，将反应液减压浓缩，剩余物经柱层析分离纯化得化合物19a。Compound 11d (500 mg, 2.99 mmol) was dissolved in dichloromethane (15 mL), triethylamine (757 mg, 7.48 mmol, 1.04 mL) and di-tert-butyl dicarbonate (848 mg, 3.89 mmol, 893 μL), 20 ° C The reaction was carried out for 6 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure and the residue was purified by column chromatography.
1H NMR(400MHz,CDCl 3)δ7.23-7.18(m,1H),6.85-6.72(m,3H),5.20-5.10(m,1H),4.72-4.62(m,1H),3.80-3.75(m,2H),3.74(s,3H),2.22(br,1H),1.37(s,9H)ppm。 1 H NMR (400MHz, CDCl 3 ) δ7.23-7.18 (m, 1H), 6.85-6.72 (m, 3H), 5.20-5.10 (m, 1H), 4.72-4.62 (m, 1H), 3.80-3.75 (m, 2H), 3.74 (s, 3H), 2.22 (br, 1H), 1.37 (s, 9H) ppm.
第二步Second step
将化合物19a(200mg,748μmol)溶于二氯甲烷(8mL)中，加入三乙胺(151mg,1.50mmol,208μL)，0摄氏度下加入甲烷磺酰氯(103mg,898μmol,69.5μL)，并于20摄氏度下搅拌0.5个小时。TLC监测反应完成后，向反应液中加入水(15mL)稀释，用二氯甲烷(20mL×2)萃取，合并的有机相用饱和食盐水(20mL×1)洗涤，并用无水硫酸钠干燥，过滤，滤液减压浓缩得粗品化合物19b。Compound 19a (200 mg, 748 μmol) was dissolved in dichloromethane (8 mL), triethylamine (151 mg, 1.50 mmol, 208 μL) was added, methanesulfonyl chloride (103 mg, 898 μmol, 69.5 μL) was added at 0 ° C, and at 20 Stir for 0.5 hours at Celsius. After the reaction was completed by TLC, water (15 mL) was added to the mixture and the mixture was evaporated. Filtration and concentration of the filtrate under reduced pressure afforded crude compound 19b.
1H NMR(400MHz,CDCl 3)δ7.26-7.18(m,1H),6.93-6.66(m,3H),5.21-5.00(m,1H),4.96-4.80(m,1H),4.45-4.26(m,2H),3.74(s,3H),2.83(s,3H),1.45-1.30(m,9H)ppm。 1 H NMR (400 MHz, CDCl 3 ) δ 7.26-7.18 (m, 1H), 6.93-6.66 (m, 3H), 5.21 - 5.00 (m, 1H), 4.96 - 4.80 (m, 1H), 4.45 - 4.26 (m, 2H), 3.74 (s, 3H), 2.83 (s, 3H), 1.45-1.30 (m, 9H) ppm.
第三步third step
将化合物19b(280mg,811μmol)溶于四氢吡咯(4mL)中，氮气置换3次，并于50摄氏度下搅拌10个小时。反应完成后，将反应液减压浓缩，加入水(30mL)稀释，用乙酸乙酯(30mL×2)萃取，合并的有机相用饱和食盐水(30mL×1)洗涤，并用无水硫酸钠干燥，过滤，滤液减压浓缩的粗品。粗品经薄层色谱板分离得到化合物19c。Compound 19b (280 mg, 811 μmol) was dissolved in tetrahydropyrrole (4 mL), replaced with nitrogen three times, and stirred at 50 ° C for 10 hours. After the completion of the reaction, the reaction mixture was evaporated.jjjjjjjjjjjjjjjj The filtrate was filtered and the filtrate was concentrated under reduced pressure. The crude product was isolated on a thin layer chromatography plate to afford compound 19c.
MS-ESI计算值[M+H] +321,实测值321。 MS-ESI calculated [M+H] + 353.
第四步the fourth step
将化合物19c(120mg,375μmol)溶于1,4-二氧六环(2mL)中，加入氯化氢的1,4-二氧六环溶液(4M,4mL)，并于20摄氏度下反应0.5小时。反应完成后，将反应液减压浓缩得粗品化合物19d。Compound 19c (120 mg, 375 μmol) was dissolved in 1,4-dioxane (2 mL), and a solution of hydrogen chloride in 1,4-dioxane (4M, 4 mL) was obtained and reacted at 20 ° C for 0.5 hour. After completion of the reaction, the reaction mixture was concentrated under reduced vacuo toield Compound 19d.
MS-ESI计算值[M+H] +221,实测值221。 MS-ESI calcd for [M + H] + 221, found 221.
第五步the fifth step
将化合物3a(226mg,896μmol)溶于N,N-二甲基甲酰胺(8mL)中,向反应液中添加2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(409mg,1.07mmol)和N,N-二异丙基乙胺(463mg,3.58mmol,624μL)，并搅拌0.5小时。然后加入化合物19d(230mg,896μmol)，并于20摄氏度下搅拌3.5小时。反应完成后，加入水(80mL)稀释后用乙酸乙酯(50ml x 2)萃取，合并的有机相用饱和食盐水(60mL x 1)洗，无水硫酸钠干燥，过滤，滤液减压浓缩。剩余物经柱层析色谱法分离得到化合物19e。Compound 3a (226 mg, 896 μmol) was dissolved in N,N-dimethylformamide (8 mL), and 2-(7-benzotriazole)-N,N,N',N was added to the reaction mixture. '-Tetramethylurea hexafluorophosphate (409 mg, 1.07 mmol) and N,N-diisopropylethylamine (463 mg, 3.58 mmol, 624 μL), and stirred for 0.5 hour. Compound 19d (230 mg, 896 μmol) was then added and stirred at 20 ° C for 3.5 hours. After completion of the reaction, the mixture was diluted with EtOAc EtOAc EtOAc. The residue was subjected to column chromatography to give Compound 19e.
MS-ESI计算值[M+H] +454,456,实测值454,456。 MS-ESI calcd for [M+H] + 454, 456.
第六步 Step 6
将化合物19e(430mg,946μmol)，1d(367mg,1.89mmol)，三(二亚苄基丙酮)二钯(86.7mg,94.6μmol)，2-二环己基膦-2’,4’,6’-三异丙基联苯(45.1mg,94.6μmol)，碳酸钾(392mg,2.84mmol)溶于二氧六环(12mL)和水(3mL)中，反应液于95摄氏度下搅拌5小时。反应完成后，加入水(30mL)稀释后用乙酸乙酯(30mL x 2)萃取，合并的有机相用饱和食盐水(30mL x 1)洗，无水硫酸钠干燥，过滤，滤液减压浓缩。剩余物经高效液相色谱(盐酸条件)分离得到化合物19的盐酸盐。Compound 19e (430 mg, 946 μmol), 1 d (367 mg, 1.89 mmol), tris(dibenzylideneacetone)dipalladium (86.7 mg, 94.6 μmol), 2-dicyclohexylphosphine-2', 4', 6' Triisopropylbiphenyl (45.1 mg, 94.6 μmol), potassium carbonate (392 mg, 2.84 mmol) was dissolved in dioxane (12 mL) and water (3 mL), and the mixture was stirred at 95 ° C for 5 hours. After completion of the reaction, the mixture was diluted with water (30 mL) and evaporated. The residue was subjected to high performance liquid chromatography (hydrochloric acid) to give the hydrochloride salt of Compound 19.
MS-ESI计算值[M+H] +442,实测值442。 MS-ESI calcd for [M + H] + 442, found 442.
1H NMR(400MHz,MeOH-d 4)δ9.64(s,1H),9.39(s,1H),8.66(s,1H),8.61(s,2H),8.59-8.55(m,1H),8.42(dd,J＝1.2,8.8Hz,1H),7.43-7.32(m,1H),7.30-7.15(m,2H),6.96(dd,J＝2.0,8.0Hz,1H),5.82-5.72(m,1H),4.22-4.12(m,1H),3.94-3.81(m,5H),3.72-3.63(m,1H),3.48-3.38(m,1H),3.34-3.22(m,1H),2.32-2.06(m,4H)。 1 H NMR (400MHz, MeOH- d 4) δ9.64 (s, 1H), 9.39 (s, 1H), 8.66 (s, 1H), 8.61 (s, 2H), 8.59-8.55 (m, 1H), 8.42 (dd, J=1.2, 8.8 Hz, 1H), 7.43-7.32 (m, 1H), 7.30-7.15 (m, 2H), 6.96 (dd, J=2.0, 8.0 Hz, 1H), 5.82-5.72 ( m,1H),4.22-4.12 (m,1H),3.94-3.81 (m,5H),3.72-3.63 (m,1H), 3.48-3.38 (m,1H),3.34-3.22 (m,1H), 2.32-2.06 (m, 4H).
实施例20Example 20
Figure PCTCN2019083208-appb-000118
Figure PCTCN2019083208-appb-000118
合成路线：synthetic route:
Figure PCTCN2019083208-appb-000119
Figure PCTCN2019083208-appb-000119
第一步first step
将化合物4(100mg,241μmol)，5-甲基-4-吡唑硼酸频哪醇酯(75.2mg,361μmol)，三(二亚苄基丙酮)二钯(44.1mg,48.2μmol)，2-二环己基膦-2’,4’,6’-三异丙基联苯(23.0mg,48.2μmol)，碳酸钾(99.8mg,722μmol)溶于二氧六环(8mL)和水(2mL)中，反应液于95摄氏度下搅拌2小时。反应完成后，将反应液过滤，滤液减压浓缩。剩余物经高效液相色谱(盐酸条件)分离得到化合物20的盐酸盐。Compound 4 (100 mg, 241 μmol), 5-methyl-4-pyrazoleboronic acid pinacol ester (75.2 mg, 361 μmol), tris(dibenzylideneacetone)dipalladium (44.1 mg, 48.2 μmol), 2- Dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (23.0 mg, 48.2 μmol), potassium carbonate (99.8 mg, 722 μmol) dissolved in dioxane (8 mL) and water (2 mL) The reaction solution was stirred at 95 ° C for 2 hours. After completion of the reaction, the reaction solution was filtered, and the filtrate was evaporated. The residue was subjected to high performance liquid chromatography (hydrochloric acid) to give the hydrochloride salt of Compound 20.
MS-ESI计算值[M+H] +417,实测值417。 MS-ESI calcd for [M+H] + 417.
1H NMR(400MHz,DMSO-d 6)δ9.45-9.23(m,2H),8.54(s,1H),8.26(d,J＝8.8Hz,1H),8.22(s,1H),8.06(s,1H),7.99(d,J＝8.8Hz,1H),7.27-7.23(m,1H),7.04-6.99(m,2H),6.83-6.79(m,1H),5.26-5.24(m,1H),3.74(s,3H),2.52-2.52(m,3H),2.22-2.07(m,2H),2.07-1.94(m,2H)。 1 H NMR (400MHz, DMSO- d 6) δ9.45-9.23 (m, 2H), 8.54 (s, 1H), 8.26 (d, J = 8.8Hz, 1H), 8.22 (s, 1H), 8.06 ( s, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.27-7.23 (m, 1H), 7.04-6.99 (m, 2H), 6.83-6.79 (m, 1H), 5.26-5.24 (m, 1H), 3.74 (s, 3H), 2.52-2.52 (m, 3H), 2.22-2.07 (m, 2H), 2.07-1.94 (m, 2H).
实施例21Example 21
Figure PCTCN2019083208-appb-000120
Figure PCTCN2019083208-appb-000120
合成路线：synthetic route:
Figure PCTCN2019083208-appb-000121
Figure PCTCN2019083208-appb-000121
第一步first step
参照实施例6第一步得到化合物21b。The compound 21b was obtained in the first step of Example 6.
第二步Second step
参照实施例6第二步得到化合物21c。Compound 21c was obtained by referring to the second step of Example 6.
MS-ESI计算值[M+H] +270,实测值270。 MS-ESI calcd for [M+H] + 270.
第三步third step
参照实施例6第三步得到化合物21d。The compound 21d was obtained by referring to the third step of Example 6.
第四步the fourth step
参照实施例6第四步得到化合物21e。The compound 21e was obtained by referring to the fourth step of Example 6.
MS-ESI计算值[M+Na] +192,实测值192。 MS-ESI calcd for [M+Na] + 192.
第五步the fifth step
将化合物21e(100mg,486μmol)和化合物3a(123mg,486μmol)溶于N,N-二甲基甲酰胺(8mL)中，向反应液中添加1-乙基-3(3-二甲基丙胺)碳二亚胺(121mg,632μmol)，N,N-二异丙基乙胺(251mg,1.94mmol,339μL)和1-羟基苯并三氮唑(85.4mg,632μmol)，并于25摄氏度下搅拌12小时。反应完成后，加入水(120mL)稀释，用乙酸乙酯(100mL x 2)萃取，合并的有机相用饱和食盐水(100mL x 1)洗，无水硫酸钠干燥，过滤，滤液减压浓缩。剩余物经薄层层析色谱法分离得到化合物21f。Compound 21e (100 mg, 486 μmol) and compound 3a (123 mg, 486 μmol) were dissolved in N,N-dimethylformamide (8 mL), and 1-ethyl-3(3-dimethylpropylamine was added to the reaction mixture. Carbodiimide (121 mg, 632 μmol), N,N-diisopropylethylamine (251 mg, 1.94 mmol, 339 μL) and 1-hydroxybenzotriazole (85.4 mg, 632 μmol) at 25 ° C Stir for 12 hours. After completion of the reaction, the mixture was diluted with EtOAc EtOAc EtOAc. The residue was isolated by thin layer chromatography to give Compound 21f.
MS-ESI计算值[M+H] +403和405,实测值403和405。 MS-ESI calculated [M+H] + 403 and 405, found 403 and 405.
第六步 Step 6
将化合物21f(80mg,186μmol)，4-吡唑硼酸频哪醇酯(54.2mg,280μmol)，三(二亚苄基丙酮)二钯(34.1mg,37.3μmol)，2-二环己基膦-2’,4’,6’-三异丙基联苯(17.8mg,37.3μmol)，碳酸钾(77.3mg,559μmol)溶于二氧六环(4mL)和水(1mL)中，反应液于95摄氏度下搅拌6小时。反应完成后，加入水(50mL)稀释后用乙酸乙酯(50mL x 3)萃取，合并的有机相用饱和食盐水(50mL x 1)洗，无水硫酸钠干燥，过滤，滤液减压浓缩。剩余物经高效液相色谱分离得到化合物21。Compound 21f (80 mg, 186 μmol), 4-pyrazolboronic acid pinacol ester (54.2 mg, 280 μmol), tris(dibenzylideneacetone)dipalladium (34.1 mg, 37.3 μmol), 2-dicyclohexylphosphine- 2',4',6'-triisopropylbiphenyl (17.8mg, 37.3μmol), potassium carbonate (77.3mg, 559μmol) dissolved in dioxane (4mL) and water (1mL), the reaction solution Stir at 95 ° C for 6 hours. After completion of the reaction, the mixture was diluted with water (50 mL), EtOAc (EtOAc) The residue was subjected to high performance liquid chromatography to give Compound 21.
MS-ESI计算值[M+H] +391,实测值391。 MS-ESI calcd for [M+H] + 391.
1H NMR(400MHz,MeOH-d 4)δ9.25(s,1H),8.51(s,1H),8.29-8.12(m,4H),8.09-8.06(m,1H),7.54-7.50(m,1H),7.38-7.28(m,1H),7.22-7.10(m,2H),5.65(t,J＝6.8Hz,1H),3.70-3.67(t,J＝6.4Hz,2H),2.29-2.15(m,2H)。 1 H NMR (400MHz, MeOH- d 4) δ9.25 (s, 1H), 8.51 (s, 1H), 8.29-8.12 (m, 4H), 8.09-8.06 (m, 1H), 7.54-7.50 (m , 1H), 7.38-7.28 (m, 1H), 7.22-7.10 (m, 2H), 5.65 (t, J = 6.8 Hz, 1H), 3.70-3.67 (t, J = 6.4 Hz, 2H), 2.29- 2.15 (m, 2H).
活性测试Activity test
1.体外评价本发明化合物对ROCK蛋白激酶的抑制活性1. In vitro evaluation of the inhibitory activity of the compounds of the invention against ROCK protein kinase
实验目的：检测化合物的ROCK蛋白激酶抑制IC 50值。 Purpose: ROCK kinase inhibition 50 values of test compound IC.
实验材料:Experimental Materials:
测定緩沖溶液:20mM 4-羟乙基哌嗪乙硫磺酸(pH 7.5)，10mM氯化镁，1mM乙二醇二***二胺四乙酸，0.02％聚氧乙烯月桂醚，0.02mg/mL牛血清白蛋白，0.1mM钒酸钠，2mM二硫苏糖醇，1％DMSO。Determination of buffer solution: 20 mM 4-hydroxyethylpiperazine ethanesulfuric acid (pH 7.5), 10 mM magnesium chloride, 1 mM ethylene glycol diethyl ether diamine tetraacetic acid, 0.02% polyoxyethylene lauryl ether, 0.02 mg / mL bovine serum albumin , 0.1 mM sodium vanadate, 2 mM dithiothreitol, 1% DMSO.
实验操作:Experimental operation:
将新鲜制备的缓冲溶液中加入ROCK蛋白激酶底物Long S6 Kinase substrate peptide，浓度20μM，然后加入1nM ROCK蛋白激酶，均匀搅拌。使用Echo550加入含有待测化合物的系列DMSO稀释液(始于10μM， 按3倍系列稀释)，室温下预温育20分钟，加入 33P-ATP(放射强度10μCi/μL)引发反应，室温反应两小时。然后使用P81离子交换纸(Whatman#3698-915)过滤，用0.75％磷酸洗涤。使用Filter-Binding方法检测放射强度。 The freshly prepared buffer solution was added to a ROCK protein kinase substrate Long S6 Kinase substrate, at a concentration of 20 μM, and then 1 nM ROCK protein kinase was added thereto, and uniformly stirred. A series of DMSO dilutions containing the test compound (starting at 10 μM, serially diluted 3 times) were added using Echo 550, pre-incubated for 20 minutes at room temperature, and 33 P-ATP (radiation intensity 10 μCi/μL) was added to initiate the reaction. hour. It was then filtered using P81 ion exchange paper (Whatman #3698-915) and washed with 0.75% phosphoric acid. The intensity of the radiation was measured using the Filter-Binding method.
化合物的蛋白激酶抑制活性表达为相对空白底物(单纯DMSO)残存的蛋白激酶活性。利用Prism软件包(GraphPad Software,San Diego California,USA)计算IC 50值和曲线。 The protein kinase inhibitory activity of the compound is expressed as protein kinase activity remaining relative to the blank substrate (DMSO alone). And the values of IC 50 was calculated using the Prism software package curve (GraphPad Software, San Diego California, USA).
实验结果：Experimental results:
表1 ROCK抑制活性测试结果Table 1 ROCK inhibition activity test results
化合物Compound 对ROCK1的IC 50(nM) IC 50 (nM) for ROCK1 对ROCK2的IC 50(nM) IC 50 (nM) for ROCK2
11 15201520 110110
2(盐酸盐)2 (hydrochloride) 27852785 4141
3(盐酸盐)3 (hydrochloride) 15861586 2020
44 56315631 3535
55 58425842 7474
66 17921792 1212
77 ---- 2929
88 ---- 5757
99 ---- 7777
1111 445445 1010
12(盐酸盐)12 (hydrochloride) 15081508 2929
13(盐酸盐)13 (hydrochloride) 113113 33
15(甲酸盐)15 (formate) ---- 187187
17(盐酸盐)17 (hydrochloride) 426426 66
18(盐酸盐)18 (hydrochloride) 759759 3232
19(盐酸盐)19 (hydrochloride) 18241824 3636
20(盐酸盐)20 (hydrochloride) 15191519 3636
21twenty one 32733273 5656
--表示未测试-- indicates that it has not been tested
结论：本发明化合物对ROCK2有较高的抑制活性，同时具有一定的选择性ROCK2抑制活性。Conclusion: The compound of the present invention has high inhibitory activity against ROCK2 and has certain selective ROCK2 inhibitory activity.
2.体外评价本发明化合物对α-SMA表达的抑制作用2. In vitro evaluation of the inhibitory effect of the compounds of the invention on the expression of α-SMA
实验目的：检测化合物对α-SMA表达的抑制效果。Experimental purposes: To test the inhibitory effect of compounds on the expression of α-SMA.
实验材料：Experimental Materials:
NIH-3T3细胞购自中科院上海细胞库。TRIzol试剂购自英潍捷基，去除基因组DNA反转录试剂盒购自天根生化，实时荧光定量PCR预混液购自南京诺唯赞，异丙醇，氯仿购自国药。NIH-3T3 cells were purchased from the Shanghai Cell Bank of the Chinese Academy of Sciences. The TRIzol reagent was purchased from Infineon, and the genomic DNA reverse transcription kit was purchased from Tiangen Biochemical. The real-time fluorescent quantitative PCR premix was purchased from Nanjing Nuoweizan, isopropanol and chloroform from the Chinese medicine.
实验操作：Experimental operation:
将生长汇合度达到80％的NIH-3T3细胞使用0.25％胰酶进行消化成单细胞悬液，铺于6孔板中。将细胞板置于37度，5％CO 2的培养箱中进行过夜培养。第二天准备化合物，将待测10mM化合物(11,12,13)稀释到200μM，按照每孔10μL加入到6孔板中，过夜培养。化合物终浓度为1μM，DMSO终浓度为1％。 NIH-3T3 cells with a growth confluence of 80% were digested with a 0.25% trypsin into a single cell suspension and plated in 6-well plates. The cell plates were placed at 37 °, overnight culture incubator in 5% CO 2. The compound was prepared the next day, and 10 mM of the compound (11, 12, 13) to be tested was diluted to 200 μM, and added to a 6-well plate at 10 μL per well, and cultured overnight. The final concentration of the compound was 1 μM and the final concentration of DMSO was 1%.
药物处理达到孵育时间后，去掉培养基，6孔板每孔加入1ml Trizol试剂，按照说明书操作抽取RNA。总RNA提取后进行定量并使用1μg RNA按照反转录试剂盒操作方法进行cDNA合成。完成cDNA合成后使用cDNA模板，正反向引物和荧光定量PCR预混液配制qPCR体系上机反应。反应条件为50℃反应2分钟，95℃反应10分钟；95℃反应30秒，60℃反应30秒，重复95℃反应30秒，60℃反应30秒，共40个循环。反应结束导出反应的CT值进行样品相对表达量的计算。数据分析：After the drug treatment reached the incubation time, the medium was removed, and 1 ml of Trizol reagent was added to each well of a 6-well plate, and RNA was extracted according to the instructions. Total RNA was extracted and quantified and cDNA synthesis was performed according to the reverse transcription kit method using 1 μg of RNA. After the cDNA synthesis was completed, the cDNA template was used, and the positive and negative primers and the fluorescent quantitative PCR premix were used to prepare the qPCR system. The reaction conditions were 50 ° C for 2 minutes, 95 ° C for 10 minutes, 95 ° C for 30 seconds, 60 ° C for 30 seconds, 95 ° C for 30 seconds, and 60 ° C for 30 seconds for 40 cycles. The CT value of the reaction was derivatized at the end of the reaction to calculate the relative expression amount of the sample. data analysis:
相对基因表达量2 -△△CT计算方法得出，并使用双尾T检验进行显著性分析(化合物测试浓度为1μM)。 The relative gene expression amount was calculated by the 2 -ΔΔCT calculation method, and a significant analysis was performed using a two-tailed T test (the compound test concentration was 1 μM).
实验结果见图1(图中*表示P值小于0.05，差异显著；**表示P值小于0.01，差异非常显著；***表示P值小于0.001，差异极显著)。The experimental results are shown in Fig. 1 (in the figure, * indicates that the P value is less than 0.05, the difference is significant; ** indicates that the P value is less than 0.01, the difference is very significant; *** indicates that the P value is less than 0.001, and the difference is extremely significant).
结论：本发明化合物对α-SMA基因表达有很好的抑制活性。Conclusion: The compounds of the present invention have a good inhibitory activity on the expression of α-SMA gene.
3.本发明化合物药代动力学评价3. Pharmacokinetic evaluation of the compounds of the invention
实验目的：研究化合物在SD大鼠体内药代动力学Objective: To study the pharmacokinetics of compounds in SD rats
实验材料：SD大鼠(雄性，7-10周龄，WTLH/SLAC)Experimental material: SD rats (male, 7-10 weeks old, WTLH/SLAC)
实验操作：以标准方案测试化合物静脉注射及口服给药后的啮齿类动物药代特征，实验中候选化合物配成0.2mg/mL澄清溶液，给予大鼠单次静脉注射及口服给药。静注及口服溶媒均为5％DMSO/95％(10％羟丙基β环糊精)水溶液。该项目使用四只雄性SD大鼠，两只大鼠进行静脉注射给药，给药剂量为1mg/kg，收集给药后0.0833，0.25，0.5，1，2，4，6，8，24h的血浆样品，另外两只大鼠口服灌胃给药，给药剂量为2mg/kg，收集给药后0.25，0.5，1，2，3，4，6，8，24h的血浆样品。收集24小时内的全血样品，3000g离心15分钟，分离上清得血浆样品，加入含内标的乙腈溶液沉淀蛋白，充分混匀离心取上清液进样，以LC-MS/MS分析方法定量分析血药浓度，并计算药代参数，如达峰浓度(C max)，清除率(CL)，半衰期(T 1/2)，组织分布(Vdss)，药时曲线下面积(AUC 0-last)，生物利用度(F)等。 Experimental procedure: The rodent drug characteristics of the compound after intravenous injection and oral administration were tested by a standard protocol. In the experiment, the candidate compound was formulated into a 0.2 mg/mL clear solution, and the rats were administered a single intravenous injection and oral administration. Both the intravenous and oral vehicles were 5% DMSO/95% (10% hydroxypropyl beta cyclodextrin) aqueous solution. Four male Sprague-Dawley rats were used in this project. Two rats were administered intravenously at a dose of 1 mg/kg, and 0.0833, 0.25, 0.5, 1, 2, 4, 6, 8, 24 h after administration were collected. Plasma samples were administered orally by two other rats at a dose of 2 mg/kg, and plasma samples of 0.25, 0.5, 1, 2, 3, 4, 6, 8, 24 hours after administration were collected. Collect whole blood samples within 24 hours, centrifuge at 3000g for 15 minutes, separate the supernatant to obtain plasma samples, add the internal standard acetonitrile solution to precipitate the protein, mix thoroughly and centrifuge to take the supernatant, and quantify by LC-MS/MS analysis. Analyze blood drug concentration and calculate pharmacokinetic parameters such as peak concentration (C max ), clearance rate (CL), half-life (T 1/2 ), tissue distribution (Vdss), area under the drug-time curve (AUC 0-last) ), bioavailability (F), etc.
本发明实施例在大鼠体内的药代动力学相关参数如下表2所示。The pharmacokinetic related parameters of the examples of the present invention in rats are shown in Table 2 below.
表2 药代动力学测试结果Table 2 Pharmacokinetic test results
Figure PCTCN2019083208-appb-000122
Figure PCTCN2019083208-appb-000122
结论：本发明化合物具有良好的药代动力学性质，包括良好的口服生物利用度，口服暴露量，半衰期和清除率等。Conclusion: The compounds of the invention have good pharmacokinetic properties, including good oral bioavailability, oral exposure, half-life and clearance.
4.体内药效实验4. In vivo pharmacodynamic experiment
实验目的：测试化合物对博来霉素诱导SD大鼠肺纤维化的治疗作用。Experimental purposes: To test the therapeutic effect of compounds on bleomycin-induced pulmonary fibrosis in SD rats.
实验材料：Experimental Materials:
动物：雄性SD大鼠。Animal: Male SD rat.
模型：SD大鼠左侧单侧肺肺纤维化模型：大鼠气管注射博来霉素(3mg/kg in 1.5mL/kg)诱导肺纤维化模型。Model: Left unilateral pulmonary pulmonary fibrosis model in SD rats: Rats were injected with bleomycin (3 mg/kg in 1.5 mL/kg) to induce pulmonary fibrosis.
造模剂：博来霉素(BLM)。Molding agent: bleomycin (BLM).
实验过程：experiment procedure:
1.实验分组：实验分组如下表3所示，共四组，即模型组(Model)(第一组，n＝8，溶媒)，阳性对照药物(第二组，n＝8，尼达尼布(BIBF))，受试化合物11(第三组，n＝8，化合物11)，受试化合物12(盐酸盐)(第四组，n＝8，化合物12(盐酸盐))。1. Experimental grouping: The experimental grouping is shown in Table 3 below, a total of four groups, namely the model group (the first group, n=8, vehicle), the positive control drug (the second group, n=8, Nidani) Cloth (BIBF)), Test Compound 11 (Group 3, n=8, Compound 11), Test Compound 12 (hydrochloride) (Group 4, n=8, Compound 12 (hydrochloride)).
表3 博来霉素诱导的肺纤维化模型实验分组Table 3 Grouping of bleomycin-induced pulmonary fibrosis models
分组Grouping 动物数Number of animals 博来霉素(3.0mg/kg)Bleomycin (3.0mg/kg) 给药化合物Drug administration 剂量及频率Dose and frequency
第一组First group 88 注射injection N/AN/A N/AN/A
第二组Second Group 88 注射injection 尼达尼布Nidanib 100mpk,每天一次100mpk, once a day
第三组The third group 88 注射injection 1111 10mpk,每天一次10mpk, once a day
第四组 Fourth group 88 注射injection 12(盐酸盐)12 (hydrochloride) 10mpk,每天一次10mpk, once a day
2.实验操作：2. Experimental operation:
动物购入后，适应性饲养4天后开始建模。动物称重后采用异氟烷吸入麻醉，确认动物麻醉之后，消毒颈部，剪开颈部皮肤，顿性分离肌肉暴露主气管，沿气管环之间切开一小口，***PE-20管至左侧主支气管，直接注入博莱霉素，缝合气管以及皮肤。手术完毕后，将动物置于37℃电热毯保温至动物完全苏醒，确认能够自由采食和饮水后将动物返回饲养笼正常饲养。造模第8天开始口服给予化合物治疗，持续治疗14天。末次给药结束24小时后，将所有动物安乐死；以低温PBS经心脏全身灌流后收集肺脏，并以***再灌注饱满，组织固定于10％***溶液中用于后续组织病理分析。After the animals were purchased, modeling was started 4 days after adaptive feeding. Animals were weighed and inhaled with isoflurane. After confirming the anesthesia of the animals, the neck was disinfected, the skin of the neck was cut, the main air tube was exposed to the muscles, and a small opening was made between the tracheal rings. The left main bronchus was directly injected into bleomycin, and the trachea and skin were sutured. After the operation, the animals were placed in a 37 ° C electric blanket to keep the animals fully awake, and it was confirmed that the animals were able to return to the cages for normal feeding after free feeding and drinking. Oral administration of the compound was started on the 8th day of modeling and continued for 14 days. 24 hours after the end of the last dose, all animals were euthanized; the lungs were collected by systemic perfusion with low temperature PBS, and replenished with formalin, and the tissue was fixed in 10% formalin solution for subsequent histopathology. analysis.
3.实验动物生理观察：3. Physiological observation of experimental animals:
自造模当日开始，每2天记录动物体重变化；密切观察实验期间动物精神状况，如发现动物死亡，需做详细死亡记录并完成死亡报告。Animal weight changes were recorded every 2 days from the day of modeling; the animal's mental condition during the experiment was closely observed. If the animal was found dead, a detailed death record was required and a death report was completed.
实验结果测定：The experimental results were determined:
左肺组织病理学检测：H&E染色病理评价：1)左肺终末细支气管和小动脉病理变化，2)左肺肺纤维化面积，3)左肺肺纤维化Ashcroft评分。Pathological examination of the left lung: H&E staining pathological evaluation: 1) pathological changes of the left lung terminal bronchioles and arterioles, 2) left lung pulmonary fibrosis area, 3) left lung pulmonary fibrosis Ashcroft score.
实验结果见图2、图3和图4(实验数据采用双尾T检验进行显著性分析，三个图中的*表示P值小于0.05，差异显著；**表示P值小于0.01，差异非常显著；***表示P值小于0.001，差异极显著)；The experimental results are shown in Fig. 2, Fig. 3 and Fig. 4 (experimental data using a two-tailed T test for significant analysis, * in the three figures indicates that the P value is less than 0.05, the difference is significant; ** indicates that the P value is less than 0.01, the difference is very significant ; *** indicates that the P value is less than 0.001, the difference is extremely significant);
结论：本发明化合物无论是对病灶内部还是病灶边缘的细支气管和小动脉损伤都有明显的改善作用(图3和图4)，也能降低肺纤维化评分(图2)，在更低的剂量下(10mpk)就能达到和尼达尼布(100mpk)相当的药效。Conclusion: The compounds of the present invention have a significant improvement in bronchial and arteriolar lesions on the inside of the lesion or on the edge of the lesion (Figures 3 and 4), and also reduce the pulmonary fibrosis score (Figure 2), at a lower level. At doses (10mpk), it is comparable to nidanib (100mpk).

Claims (24)

  1. 式(I-1)所示化合物、其药学上可接受的盐或其异构体，a compound of the formula (I-1), a pharmaceutically acceptable salt thereof or an isomer thereof,
    Figure PCTCN2019083208-appb-100001
    Figure PCTCN2019083208-appb-100001
    其中，among them,
    R 1和R 2各自独立地为H、F、Cl、Br、CN、-OR a、-C(＝O)NR bR c、C 1-6烷基或C 3-6环烷基，其中所述C 1-6烷基和C 3-6环烷基任选被1、2或3个独立选自F、Cl、Br、I、-OH、-OCH 3、-CN、-NH 2、-NO 2或C 1-4烷基的取代基所取代； R 1 and R 2 are each independently H, F, Cl, Br, CN, -OR a , -C(=O)NR b R c , C 1-6 alkyl or C 3-6 cycloalkyl, wherein The C 1-6 alkyl group and the C 3-6 cycloalkyl group are optionally 1, 2 or 3 independently selected from the group consisting of F, Cl, Br, I, -OH, -OCH 3 , -CN, -NH 2 , Substituted with a substituent of -NO 2 or C 1-4 alkyl;
    R 3、R 4和R 5各自独立地为H、F、Cl、Br、CN、-OR a、-C(＝O)NR bR c、C 1-6烷基或C 3-6环烷基，其中所述C 1-6烷基和C 3-6环烷基任选被1、2或3个独立选自F、Cl、Br、I、-OH、-OCH 3、-CN、-NH 2、-NO 2或C 1- 4烷基的取代基所取代； R 3 , R 4 and R 5 are each independently H, F, Cl, Br, CN, -OR a , -C(=O)NR b R c , C 1-6 alkyl or C 3-6 naphthenic a group wherein the C 1-6 alkyl group and the C 3-6 cycloalkyl group are optionally 1, 2 or 3 independently selected from the group consisting of F, Cl, Br, I, -OH, -OCH 3 , -CN, - Substituted by a substituent of NH 2 , -NO 2 or C 1 -4 alkyl;
    T 1和T 2各自独立地为N或CH； T 1 and T 2 are each independently N or CH;
    R 6和R 7各自独立地为H、F、Cl或C 1-6烷基，其中所述C 1-6烷基任选被1、2或3个独立选自F、Cl、Br、CN、-OR a或-NR dR e的取代基所取代； R 6 and R 7 are each independently H, F, Cl or C 1-6 alkyl, wherein said C 1-6 alkyl group is optionally 1, 2 or 3 independently selected from the group consisting of F, Cl, Br, CN Substituted by a substituent of -OR a or -NR d R e ;
    各R 8独立地为F、Cl、Br、CN、-OR a、C 1-6烷基或C 3-6环烷基，其中所述C 1-6烷基和C 3-6环烷基任选被1、2或3个独立选自F、Cl、Br、I、-OH、-OCH 3、-CN、-NH 2、-NO 2或C 1-4烷基的取代基所取代； Each R 8 is independently F, Cl, Br, CN, -OR a , C 1-6 alkyl or C 3-6 cycloalkyl, wherein said C 1-6 alkyl and C 3-6 cycloalkyl Optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of F, Cl, Br, I, -OH, -OCH 3 , -CN, -NH 2 , -NO 2 or C 1-4 alkyl;
    R a、R b和R c各自独立地为H或C 1-6烷基，其中所述C 1-6烷基任选被1、2或3个独立选自F、Cl、Br、-OH、-OCH 3、-CN、-NH 2、C 1-6烷氨基或-NO 2的取代基所取代； R a , R b and R c are each independently H or C 1-6 alkyl, wherein the C 1-6 alkyl group is optionally 1, 2 or 3 independently selected from the group consisting of F, Cl, Br, -OH Substituted with a substituent of -OCH 3 , -CN, -NH 2 , C 1-6 alkylamino or -NO 2 ;
    R d和R e各自独立地为H、C 1-6烷基，或R d和R e与它们连接的N原子一起形成4-8元杂环烷基，其中所述C 1-6烷基和4-8元杂环烷基任选被1、2或3个独立选自F、Cl、Br、-OH、-OCH 3、-CN、-NH 2、C 1-6烷氨基或-NO 2的取代基所取代； R d and R e are each independently H, C 1-6 alkyl, or R d and R e together with the N atom to which they are attached form a 4-8 membered heterocycloalkyl group, wherein said C 1-6 alkyl group And a 4-8 membered heterocycloalkyl group is optionally 1, 2 or 3 independently selected from the group consisting of F, Cl, Br, -OH, -OCH 3 , -CN, -NH 2 , C 1-6 alkylamino or -NO 2 substituents;
    n为0、1、2、3或4；n is 0, 1, 2, 3 or 4;
    所述4-8元杂环烷基包含1、2、3或4个独立选自-O-、-S-、N或-NH-的杂原子或杂原子团。The 4-8 membered heterocycloalkyl contains 1, 2, 3 or 4 heteroatoms or heteroatoms independently selected from -O-, -S-, N or -NH-.
  2. 根据权利要求1所述的化合物、其药学上可接受的盐或其异构体，其中所述R a、R b和R c各自独立地为H、甲基、乙基、正丙基或异丙基，其中所述甲基、乙基、正丙基和异丙基任选被1、2或3个独立选自F、Cl、Br、I、-OH、-OCH 3、CN、-NH 2、C 1-3烷氨基或-NO 2的取代基所取代。 The compound according to claim 1, a pharmaceutically acceptable salt thereof or an isomer thereof, wherein said R a , R b and R c are each independently H, methyl, ethyl, n-propyl or iso a propyl group, wherein the methyl, ethyl, n-propyl and isopropyl groups are optionally 1, 2 or 3 independently selected from the group consisting of F, Cl, Br, I, -OH, -OCH 3 , CN, -NH 2. Substitution of a C 1-3 alkylamino group or a substituent of -NO 2 .
  3. 根据权利要求2所述的化合物、其药学上可接受的盐或其异构体，其中所述R a、R b和R c各自独立地为H、甲基、乙基、正丙基、异丙基、
    Figure PCTCN2019083208-appb-100002
    Figure PCTCN2019083208-appb-100003
    The compound according to claim 2, a pharmaceutically acceptable salt thereof or an isomer thereof, wherein said R a , R b and R c are each independently H, methyl, ethyl, n-propyl or iso Propyl,
    Figure PCTCN2019083208-appb-100002
    Figure PCTCN2019083208-appb-100003
  4. 根据权利要求1-3任一项所述的化合物、其药学上可接受的盐或其异构体，其中所述R 1和R 2各自独立地为H、F、Cl、Br、CN、-OH、-OCH 3、-OCH 2CH 3、-C(＝O)NH 2、甲基、乙基、正丙基、异丙基、环丙基、 环戊基或环己基，其中所述甲基、乙基、正丙基、异丙基、环丙基、环戊基和环己基任选被1、2或3个独立选自F、Cl、Br、I、-OH、-OCH 3、CN、-NH 2、-NO 2、甲基、乙基或丙基的取代基所取代。 The compound according to any one of claims 1 to 3, a pharmaceutically acceptable salt thereof or an isomer thereof, wherein each of R 1 and R 2 is independently H, F, Cl, Br, CN, - OH, -OCH 3 , -OCH 2 CH 3 , -C(=O)NH 2 , methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopentyl or cyclohexyl, wherein the The group, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopentyl and cyclohexyl are optionally 1, 2 or 3 independently selected from the group consisting of F, Cl, Br, I, -OH, -OCH 3 , Substituents of CN, -NH 2 , -NO 2 , methyl, ethyl or propyl are substituted.
  5. 根据权利要求4所述的化合物、其药学上可接受的盐或其异构体，其中所述R 1和R 2各自独立地为H、F、Cl、Br、CN、-OH、-OCH 3、-OCH 2CH 3、-C(＝O)NH 2、甲基、乙基、正丙基、异丙基、
    Figure PCTCN2019083208-appb-100004
    Figure PCTCN2019083208-appb-100005
    环丙基、环戊基、环己基、
    Figure PCTCN2019083208-appb-100006
    Figure PCTCN2019083208-appb-100007
    The compound according to claim 4, a pharmaceutically acceptable salt thereof or an isomer thereof, wherein each of R 1 and R 2 is independently H, F, Cl, Br, CN, -OH, -OCH 3 , -OCH 2 CH 3 , -C(=O)NH 2 , methyl, ethyl, n-propyl, isopropyl,
    Figure PCTCN2019083208-appb-100004
    Figure PCTCN2019083208-appb-100005
    Cyclopropyl, cyclopentyl, cyclohexyl,
    Figure PCTCN2019083208-appb-100006
    Figure PCTCN2019083208-appb-100007
  6. 根据权利要求1-3任一项所述的化合物、其药学上可接受的盐或其异构体，其中所述R 3、R 4和R 5各自独立地为H、F、Cl、Br、CN、-OH、-OCH 3、-OCH 2CH 3、-OCH 2CH 2NHCH 3、-OCH 2CH 2N(CH 3) 2、-C(＝O)NH 2、甲基、乙基、正丙基、异丙基、环丙基、环戊基或环己基，其中所述甲基、乙基、正丙基、异丙基、环丙基、环戊基和环己基任选被1、2或3个独立选自F、Cl、Br、I、-OH、-OCH 3、CN、-NH 2、-NO 2、甲基、乙基或丙基的取代基所取代。 The compound according to any one of claims 1 to 3, a pharmaceutically acceptable salt thereof or an isomer thereof, wherein each of R 3 , R 4 and R 5 is independently H, F, Cl, Br, CN, -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 NHCH 3 , -OCH 2 CH 2 N(CH 3 ) 2 , -C(=O)NH 2 , methyl, ethyl, N-propyl, isopropyl, cyclopropyl, cyclopentyl or cyclohexyl, wherein the methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopentyl and cyclohexyl are optionally 1 Substituting 2 or 3 substituents independently selected from F, Cl, Br, I, -OH, -OCH 3 , CN, -NH 2 , -NO 2 , methyl, ethyl or propyl.
  7. 根据权利要求6所述的化合物、其药学上可接受的盐或其异构体，其中所述R 3、R 4和R 5各自独立地为H、F、Cl、Br、CN、-OH、-OCH 3、-OCH 2CH 3、
    Figure PCTCN2019083208-appb-100008
    -C(＝O)NH 2、甲基、乙基、正丙基、异丙基、
    Figure PCTCN2019083208-appb-100009
    Figure PCTCN2019083208-appb-100010
    环丙基、环戊基、环己基、
    Figure PCTCN2019083208-appb-100011
    Figure PCTCN2019083208-appb-100012
    The compound according to claim 6, a pharmaceutically acceptable salt thereof or an isomer thereof, wherein each of R 3 , R 4 and R 5 is independently H, F, Cl, Br, CN, -OH, -OCH 3 , -OCH 2 CH 3 ,
    Figure PCTCN2019083208-appb-100008
    -C(=O)NH 2 , methyl, ethyl, n-propyl, isopropyl,
    Figure PCTCN2019083208-appb-100009
    Figure PCTCN2019083208-appb-100010
    Cyclopropyl, cyclopentyl, cyclohexyl,
    Figure PCTCN2019083208-appb-100011
    Figure PCTCN2019083208-appb-100012
  8. 根据权利要求1或7所述的化合物、其药学上可接受的盐或其异构体，其中结构单元
    Figure PCTCN2019083208-appb-100013
    为
    Figure PCTCN2019083208-appb-100014
    The compound according to claim 1 or 7, a pharmaceutically acceptable salt thereof or an isomer thereof, wherein the structural unit
    Figure PCTCN2019083208-appb-100013
    for
    Figure PCTCN2019083208-appb-100014
  9. 根据权利要求8所述的化合物、其药学上可接受的盐或其异构体，其中结构单元
    Figure PCTCN2019083208-appb-100015
    为
    Figure PCTCN2019083208-appb-100016
    The compound according to claim 8, a pharmaceutically acceptable salt thereof or an isomer thereof, wherein the structural unit
    Figure PCTCN2019083208-appb-100015
    for
    Figure PCTCN2019083208-appb-100016
  10. 根据权利要求1所述的化合物、其药学上可接受的盐或其异构体，其中所述R d和R e各自独立地为H、甲基、乙基、正丙基、异丙基，或R d和R e与它们连接的N原子一起形成5-6元杂环烷基，其中所述甲基、乙基、正丙基、异丙基和5-6元杂环烷基任选被1、2或3个独立选自F、Cl、Br、I、-OH、-OCH 3、CN、-NH 2、C 1-3烷氨基或-NO 2的取代基所取代。 The compound according to claim 1, a pharmaceutically acceptable salt thereof or an isomer thereof, wherein said R d and R e are each independently H, methyl, ethyl, n-propyl, isopropyl, Or R d and R e together with the N atom to which they are attached form a 5-6 membered heterocycloalkyl group, wherein said methyl, ethyl, n-propyl, isopropyl and 5-6 membered heterocycloalkyl are optional Substituted by 1, 2 or 3 substituents independently selected from F, Cl, Br, I, -OH, -OCH 3 , CN, -NH 2 , C 1-3 alkylamino or -NO 2 .
  11. 根据权利要求10所述的化合物、其药学上可接受的盐或其异构体，其中所述R d和R e各自独立地为H、甲基、乙基、正丙基、异丙基、
    Figure PCTCN2019083208-appb-100017
    Figure PCTCN2019083208-appb-100018
    或R d和R e与它们连接的N原子一起形成吡咯烷基或哌啶基，其中所述吡咯烷基和哌啶基任选被1、2或3个独立选自F、Cl、Br、I、-OH、-OCH 3、CN、-NH 2、C 1-3烷氨基或-NO 2的取代基所取代。     The compound according to claim 10, a pharmaceutically acceptable salt thereof or an isomer thereof, wherein said R d and R e are each independently H, methyl, ethyl, n-propyl, isopropyl,
    Figure PCTCN2019083208-appb-100017
    Figure PCTCN2019083208-appb-100018
    Or R d and R e together with the N atom to which they are attached form a pyrrolidinyl or piperidinyl group, wherein the pyrrolidinyl and piperidinyl are optionally 1, 2 or 3 independently selected from the group consisting of F, Cl, Br, Substituents of I, -OH, -OCH 3 , CN, -NH 2 , C 1-3 alkylamino or -NO 2 are substituted.
  12. 根据权利要求1、10或11任一项所述的化合物、其药学上可接受的盐或其异构体，其中所述R 6和R 7各自独立地为H、F、Cl、甲基、乙基、正丙基、异丙基、
    Figure PCTCN2019083208-appb-100019
    Figure PCTCN2019083208-appb-100020
    The compound according to any one of claims 1, 10 or 11, or a pharmaceutically acceptable salt thereof, or an isomer thereof, wherein each of R 6 and R 7 is independently H, F, Cl, methyl, Ethyl, n-propyl, isopropyl,
    Figure PCTCN2019083208-appb-100019
    Figure PCTCN2019083208-appb-100020
  13. 根据权利要求1所述的化合物、其药学上可接受的盐或其异构体，其中所述各R 8独立地为F、Cl、Br、 CN、-OH、-OCH 3、-OCH 2F、-OCHF 2、-OCF 3、甲基、乙基、正丙基、异丙基、环丙基、环戊基或环己基，其中所述甲基、乙基、正丙基、异丙基、环丙基、环戊基和环己基任选被1、2或3个独立选自F、Cl、Br、I、-OH、-OCH 3、CN、-NH 2、-NO 2、甲基、乙基或丙基的取代基所取代。 The compound according to claim 1, a pharmaceutically acceptable salt thereof or an isomer thereof, wherein each R 8 is independently F, Cl, Br, CN, -OH, -OCH 3 , -OCH 2 F , -OCHF 2 , -OCF 3 , methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopentyl or cyclohexyl, wherein the methyl, ethyl, n-propyl, isopropyl , cyclopropyl, cyclopentyl and cyclohexyl are optionally 1, 2 or 3 independently selected from the group consisting of F, Cl, Br, I, -OH, -OCH 3 , CN, -NH 2 , -NO 2 , methyl Substituted by a substituent of an ethyl or propyl group.
  14. 根据权利要求13所述的化合物、其药学上可接受的盐或其异构体，其中所述各R 8独立地为F、Cl、Br、CN、-OH、-OCH 3、-OCH 2CH 3、甲基、乙基、正丙基、异丙基、
    Figure PCTCN2019083208-appb-100021
    Figure PCTCN2019083208-appb-100022
    环丙基、环戊基、环己基、
    Figure PCTCN2019083208-appb-100023
    Figure PCTCN2019083208-appb-100024
    The compound according to claim 13, a pharmaceutically acceptable salt thereof or an isomer thereof, wherein each R 8 is independently F, Cl, Br, CN, -OH, -OCH 3 , -OCH 2 CH 3 , methyl, ethyl, n-propyl, isopropyl,
    Figure PCTCN2019083208-appb-100021
    Figure PCTCN2019083208-appb-100022
    Cyclopropyl, cyclopentyl, cyclohexyl,
    Figure PCTCN2019083208-appb-100023
    Figure PCTCN2019083208-appb-100024
  15. 根据权利要求1、13或14任一项所述的化合物、其药学上可接受的盐或其异构体，其中结构单元
    Figure PCTCN2019083208-appb-100025
    为
    Figure PCTCN2019083208-appb-100026
    Figure PCTCN2019083208-appb-100027
    The compound, a pharmaceutically acceptable salt thereof or an isomer thereof according to any one of claims 1, 13 or 14, wherein the structural unit
    Figure PCTCN2019083208-appb-100025
    for
    Figure PCTCN2019083208-appb-100026
    Figure PCTCN2019083208-appb-100027
  16. 根据权利要求15所述的化合物、其药学上可接受的盐或其异构体，其中结构单元
    Figure PCTCN2019083208-appb-100028
    为
    Figure PCTCN2019083208-appb-100029
    The compound according to claim 15, a pharmaceutically acceptable salt thereof or an isomer thereof, wherein the structural unit
    Figure PCTCN2019083208-appb-100028
    for
    Figure PCTCN2019083208-appb-100029
    Figure PCTCN2019083208-appb-100030
    Figure PCTCN2019083208-appb-100030
  17. 根据权利要求1～16任一项所述的化合物、其药学上可接受的盐或其异构体，其具有式(I-2)～(I-4)所示结构，The compound according to any one of claims 1 to 16, a pharmaceutically acceptable salt thereof or an isomer thereof, which has a structure represented by the formula (I-2) to (I-4),
    Figure PCTCN2019083208-appb-100031
    Figure PCTCN2019083208-appb-100031
    其中，R 1和R 2如权利要求1、4或5所定义； Wherein R 1 and R 2 are as defined in claim 1, 4 or 5;
    R 3如权利要求1、6或7所定义； R 3 is as defined in claim 1, 6 or 7;
    R 6和R 7如权利要求1或12所定义； R 6 and R 7 are as defined in claim 1 or 12;
    R 8如权利要求1、13或14所定义； R 8 is as defined in claim 1, 13 or 14;
    n如权利要求1所定义。n as defined in claim 1.
  18. 根据权利要求17所述的化合物、其药学上可接受的盐或其异构体，其具有式(I-5)～(I-7)所示结构，The compound according to claim 17, a pharmaceutically acceptable salt thereof or an isomer thereof having the structure represented by the formula (I-5) to (I-7),
    Figure PCTCN2019083208-appb-100032
    Figure PCTCN2019083208-appb-100032
    其中，R 3、R 6、R 7、R 8和n如权利要求17所定义。 Wherein R 3 , R 6 , R 7 , R 8 and n are as defined in claim 17.
  19. 根据权利要求18所述的化合物、其药学上可接受的盐或其异构体，其具有式(I-8)～(I-10)所示结构，The compound according to claim 18, a pharmaceutically acceptable salt thereof or an isomer thereof, which has a structure represented by the formula (I-8) to (I-10),
    Figure PCTCN2019083208-appb-100033
    Figure PCTCN2019083208-appb-100033
    其中，带“*”的碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在；Wherein the carbon atom bearing "*" is a chiral carbon atom, which is in the form of a single enantiomer of (R) or (S) or is enriched in one enantiomer form;
    R 7为F、Cl、甲基、乙基、正丙基、异丙基、
    Figure PCTCN2019083208-appb-100034
    Figure PCTCN2019083208-appb-100035
    Figure PCTCN2019083208-appb-100036
    R 3、R 8和n如权利要求18所定义。     R 7 is F, Cl, methyl, ethyl, n-propyl, isopropyl,
    Figure PCTCN2019083208-appb-100034
    Figure PCTCN2019083208-appb-100035
    Figure PCTCN2019083208-appb-100036
    R 3 , R 8 and n are as defined in claim 18.
  20. 下式化合物，其药学上可接受的盐或其异构体：a compound of the formula: a pharmaceutically acceptable salt thereof or an isomer thereof:
    Figure PCTCN2019083208-appb-100037
    Figure PCTCN2019083208-appb-100037
    Figure PCTCN2019083208-appb-100038
    Figure PCTCN2019083208-appb-100038
  21. 根据权利要求1～20任一项所述的化合物、其药学上可接受的盐或其异构体，其中所述药学上可接受的盐为甲酸盐或盐酸盐。The compound according to any one of claims 1 to 20, a pharmaceutically acceptable salt thereof or an isomer thereof, wherein the pharmaceutically acceptable salt is a formate or a hydrochloride.
  22. 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1～20任一项所述的化合物、其药学上可接受的盐或其异构体以及药学上可接受的载体。A pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of a compound according to any one of claims 1 to 20, a pharmaceutically acceptable salt thereof or an isomer thereof, and a pharmaceutically acceptable carrier.
  23. 根据权利要求1～20任一项所述的化合物、其药学上可接受的盐或其异构体或权利要求21所述的药物组合物在制备RHO抑制剂药物中的应用。Use of a compound according to any one of claims 1 to 20, a pharmaceutically acceptable salt thereof or an isomer thereof, or a pharmaceutical composition according to claim 21 for the preparation of a medicament for RHO inhibitor.
  24. 根据权利要求1～20任一项所述的化合物、其药学上可接受的盐或其异构体或权利要求21所述的药物组合物在制备治疗肺纤维化和放射性肺纤维化的药物中的应用。The compound according to any one of claims 1 to 20, a pharmaceutically acceptable salt thereof or an isomer thereof, or the pharmaceutical composition according to claim 21, in the preparation of a medicament for treating pulmonary fibrosis and radiation pulmonary fibrosis Applications.
PCT/CN2019/083208 2018-04-18 2019-04-18 Pyrazole compound used as rho kinase inhibitor WO2019201296A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201810349378 2018-04-18
CN201810349378.0 2018-04-18

Publications (1)

Publication Number Publication Date
WO2019201296A1 true WO2019201296A1 (en) 2019-10-24

Family

ID=68239916

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/083208 WO2019201296A1 (en) 2018-04-18 2019-04-18 Pyrazole compound used as rho kinase inhibitor

Country Status (1)

Country Link
WO (1) WO2019201296A1 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021093795A1 (en) * 2019-11-15 2021-05-20 武汉朗来科技发展有限公司 Rock inhibitor, preparation method therefor and use thereof
US11078161B2 (en) * 2017-06-16 2021-08-03 Hitgen Inc. Rock-inhibiting compound and uses thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105085525A (en) * 2014-04-28 2015-11-25 南京明德新药研发股份有限公司 Isoquinoline sulfonyl derivatives as RHO kinases inhibitor
WO2017091661A1 (en) * 2015-11-25 2017-06-01 Strovel Jeffrey William Bicyclic bet bromodomain inhibitors and uses thereof
WO2018081108A1 (en) * 2016-10-24 2018-05-03 Translational Drug Development, Llc Amide compounds as kinase inhibitors

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105085525A (en) * 2014-04-28 2015-11-25 南京明德新药研发股份有限公司 Isoquinoline sulfonyl derivatives as RHO kinases inhibitor
WO2017091661A1 (en) * 2015-11-25 2017-06-01 Strovel Jeffrey William Bicyclic bet bromodomain inhibitors and uses thereof
WO2018081108A1 (en) * 2016-10-24 2018-05-03 Translational Drug Development, Llc Amide compounds as kinase inhibitors

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11078161B2 (en) * 2017-06-16 2021-08-03 Hitgen Inc. Rock-inhibiting compound and uses thereof
WO2021093795A1 (en) * 2019-11-15 2021-05-20 武汉朗来科技发展有限公司 Rock inhibitor, preparation method therefor and use thereof

Similar Documents

Publication Publication Date Title
ES2426482T3 (en) IGF-1R inhibitor
CN110300589B (en) Bicyclic heteroaryl derivatives as CFTR potentiators
ES2626793T3 (en) Bipirazole derivatives as JAK inhibitors
JP2022071072A (en) Crystalline form of (s)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide, preparation thereof, and uses thereof
CN109970745B (en) Substituted pyrrolotriazine compound, pharmaceutical composition and application thereof
TW201625626A (en) Aminopyridazinone compounds as protein kinase inhibitors
CN106232599A (en) 4 aminooimidazoles quinoline compound
BR112018001469B1 (en) COMPOUND, PHARMACEUTICAL COMPOSITION AND USE OF A COMPOUND
JP6948659B1 (en) Pyridadinyl thiaazole carboxamide compound
WO2019201297A1 (en) Benzopyrazole compound used as rho kinase inhibitor
TW201315727A (en) Uracil derivatives and their medical use
WO2017092413A1 (en) Diaminopyrimidine compounds and composition comprising same
JP7409719B2 (en) Thiazololactam compounds and their use as ERK inhibitors
EA025840B1 (en) Pyrazine derivatives as cannabinoid receptor 2 agonists
WO2019201296A1 (en) Pyrazole compound used as rho kinase inhibitor
CN115413279A (en) P2X3 modulators
JP7201800B2 (en) 3,9-diazaspiro[5,5]undecane-based compounds as inhibitors of FLT3 and AXL
JP7397452B2 (en) Heteroarylcarboxamide compounds
WO2000043385A1 (en) Heterocyclic compounds and antitumor agents containing the same as the active ingredient
WO2021129841A1 (en) Compound used as ret kinase inhibitor and application thereof
WO2019091492A1 (en) Smac mimetics used as iap inhibitors and use thereof
WO2023041055A1 (en) Kif18a inhibitor
JP3588363B2 (en) Quinoxaline diones
WO2020177762A1 (en) Compounds having both effects of bet bromodomain protein inhibition and pd-l1 gene regulation
WO2019174576A1 (en) Imidaxopyrolone compound and application thereof

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: 19788523

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19788523

Country of ref document: EP

Kind code of ref document: A1

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 21/04/2021)

122 Ep: pct application non-entry in european phase

Ref document number: 19788523

Country of ref document: EP

Kind code of ref document: A1