WO2019120213A1 - 喹唑啉衍生物及其应用 - Google Patents

喹唑啉衍生物及其应用 Download PDF

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WO2019120213A1
WO2019120213A1 PCT/CN2018/122016 CN2018122016W WO2019120213A1 WO 2019120213 A1 WO2019120213 A1 WO 2019120213A1 CN 2018122016 W CN2018122016 W CN 2018122016W WO 2019120213 A1 WO2019120213 A1 WO 2019120213A1
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group
compound
alkyl
pharmaceutically acceptable
isomer
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PCT/CN2018/122016
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French (fr)
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陈新海
魏霞蔚
张丽
于衍新
周凯
胡伯羽
陈兆国
章晖宇
陈曙辉
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南京明德新药研发股份有限公司
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Priority to EP18890726.5A priority Critical patent/EP3733663B1/en
Priority to US16/955,510 priority patent/US20210078958A1/en
Priority to CN201880081130.9A priority patent/CN111630046B/zh
Priority to JP2020534454A priority patent/JP7296641B2/ja
Publication of WO2019120213A1 publication Critical patent/WO2019120213A1/zh

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    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
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    • C07D401/14—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 three or more hetero rings
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
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    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the present invention relates to a series of quinazoline compounds, in particular compounds of formula (I), isomers thereof or pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof and their use as Pan-HER tyrosine kinase inhibitors Applications.
  • HER Human epidermal growth factor receptor
  • EGFR Human epidermal growth factor receptor
  • HER has overexpression or abnormality in various tumor cells such as breast cancer, non-small cell lung cancer, gastric cancer, pancreatic cancer, ovarian cancer, colorectal cancer, head and neck squamous cell carcinoma, malignant glioma and prostate cancer.
  • tumor cells such as breast cancer, non-small cell lung cancer, gastric cancer, pancreatic cancer, ovarian cancer, colorectal cancer, head and neck squamous cell carcinoma, malignant glioma and prostate cancer.
  • overexpression or abnormal activation of HER is closely related to tumor differentiation, malignancy and prognosis (Baselga. J., Oncologist 2002, 7, 2-8). Therefore, inhibition of HER has become a hot spot in anti-tumor drug research.
  • the irreversible inhibitor of Pan-HER tyrosine kinase inhibits both HER1, HER2 and HER4. Studies have shown that this irreversible inhibition of the HER family receptor can not only increase the activity of the drug, but also reduce the emergence of drug resistance. Some drug-resistant tumor cell lines, such as the H1975 cell line resistant to erlotinib, have significant inhibitory effects. The only irreversible inhibitors of pan-HER tyrosine kinase that have been approved for marketing are Afatinib and Neratinib. Several inhibitors are in clinical research, such as Poziotinib, Dacomitinib, and Canertinib, and there are still unmet market demands.
  • Poziotinib (Comparative Compound 1) is a pan-HER inhibitor developed by WO2008150118, which has the following structure.
  • Patent WO2015043515 discloses Control Compound 2, which has EGFR and HER2 inhibition, and its structure is as follows.
  • the present invention provides a compound of the formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof,
  • T is selected from N and CR';
  • Each R 1 is independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl or C 1-3 alkoxy is optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of F, Cl, Br, I, OH, NH 2 and CN;
  • R 2 and R 3 are each independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 and C 1-3 alkyl, and the C 1-3 alkyl group is optionally 1, 2 or 3 independently Substituted by a substituent selected from the group consisting of F, Cl, Br, and I;
  • R 4 is selected from C 1-6 alkyl, C 1-6 alkoxy, 3-7 membered heterocycloalkyl-O-, 3-7 membered heterocycloalkyl-C 1-6 alkyl-O-, C 3-6 cycloalkyl-O- and C 3-6 cycloalkyl-C 1-6 alkyl-O-, said C 1-6 alkyl, C 1-6 alkoxy, 3-7 Heterocycloalkyl-O-, 3-7 membered heterocycloalkane-C 1-6 alkyl-O-, C 3-6 cycloalkyl-O- and C 3-6 cycloalkyl-C 1-6 alkane
  • the bases -O- are each independently optionally substituted by 1, 2 or 3 R;
  • R 5 and R 6 are each independently selected from the group consisting of H, C 1-3 alkyl and 3-7 membered heterocycloalkyl, and the C 1-3 alkyl and 3-7 membered heterocycloalkyl are optionally substituted. 2 or 3 R substitutions;
  • L is selected from -O -, - NR a -, - CR b1 R b2 -, - CR b1 R b2 -O- and -CR b1 R b2 -NH-;
  • R a is H; or R 4 is bonded to R a to form a 5-7 membered heterocycloalkyl optionally substituted by 1, 2, 3 or 4 R';
  • Ring A is selected from the group consisting of phenyl and 5-10 membered heteroaryl
  • Ring B is selected from n is selected from 1, 2, 3, 4, and 5;
  • R' is each independently selected from the group consisting of F, Cl, Br, I, OH, NH 2 , CN, and C 1-3 alkyl;
  • R b1 and R b2 are each independently selected from the group consisting of H, F, Cl, Br, I, and C 1-3 alkyl;
  • R c1 and R c2 are each independently selected from H and C 1-3 alkyl;
  • the 5-7 membered heterocycloalkyl group, the 5-10 membered heteroaryl group and the 3-7 membered heterocycloalkyl group respectively comprise 1, 2, 3 or 4 independently selected from the group consisting of N, -O-, -S-, a hetero atom or a hetero atom of -NH-.
  • each of the above R is independently selected from the group consisting of F, Cl, Br, I, OH, NH 2 , CN, Me, Et, Piperidinyl, pyrrolidinyl, azetidinyl, morpholinyl and oxabutyl, said Me, Et,
  • the piperidinyl, pyrrolidinyl, azetidinyl, morpholinyl and oxabutylcyclo groups are optionally 1, 2 or 3 independently selected from the group consisting of F, Cl, Br, I, OH, NH 2 and C 1-3 alkyl. Substituted by a substituent, other variables are as defined by the present invention.
  • each of the above R is independently selected from the group consisting of F, Cl, Br, I, OH, NH 2 , CN, Me, Et, Other variables are as defined by the present invention.
  • R 1 are independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, Me, and The Me and It is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of F, Cl, Br, I, OH, NH 2 and CN, and other variables are as defined in the present invention.
  • R 1 is independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, Me, CH 2 F, CHF 2 , CF 3 , Other variables are as defined by the present invention.
  • R 2 and R 3 are each independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , Me, and CF 3 , and other variables are as defined herein.
  • the above R 4 is selected from Rhenylcyclo-O-, piperidinyl-C 1-3 alkyl-O-, morpholinyl-C 1-3 alkyl-O-, azetidinyl-O-, tetrahydrofuranyl-O-, cyclopropane -O-, pyrrolidinyl-C 1-3 alkyl-O- and azetidinyl-C 1-3 alkyl-O-, said Rhenylcyclo-O-, piperidinyl-C 1-3 alkyl-O-, morpholinyl-C 1-3 alkyl-O-, azetidinyl-O-, tetrahydrofuranyl-O-, cyclopropane
  • the base-O-, pyrrolidinyl-C 1-3 alkyl-O- and azetidinyl-C 1-3 alkyl-O- are optionally substituted by 1, 2 or
  • R 4 is selected from Other variables are as defined by the present invention.
  • R 5 and R 6 are independently selected from the group consisting of H, Me, Et, and The Me, Et, and Optionally substituted by 1, 2 or 3 R, other variables are as defined by the present invention.
  • R 5 and R 6 are each independently selected from H, Other variables are as defined by the present invention.
  • T is selected from the group consisting of N and C (CN), and other variables are as defined herein.
  • the above-mentioned L is selected from -O -, - NH -, - CH 2 -, - CH 2 -O- and -CH 2 -NH-, other variables are as defined herein.
  • the structural unit Selected from Other variables are as defined by the present invention.
  • the above ring A is selected from the group consisting of phenyl, hydrazinyl, benzo[b]thienyl, imidazo[1,2-a]pyridyl and benzo[d]isoxazolyl, others Variables are as defined by the present invention.
  • the structural unit Selected from Other variables are as defined by the present invention.
  • the structural unit Selected from Other variables are as defined by the present invention.
  • the structural unit Selected from Other variables are as defined by the present invention.
  • the ring B is selected from the group consisting of Other variables are as defined by the present invention.
  • the structural unit Selected from Other variables are as defined by the present invention.
  • the present invention also provides a compound of the formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof,
  • T is selected from N and CR';
  • R 1 is independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl or C 1 -3 alkoxy is optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of F, Cl, Br, I, OH, NH 2 and CN;
  • R 2 and R 3 are each independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 and C 1-3 alkyl, and the C 1-3 alkyl group is optionally 1, 2 or 3 independently Substituted by a substituent selected from the group consisting of F, Cl, Br, and I;
  • R 4 is selected from C 1-6 alkyl, C 1-6 alkoxy, 3-7 membered heterocycloalkyl-O-, 3-7 membered heterocycloalkyl-C 1-6 alkyl-O-, C 3-6 cycloalkyl-O- and C 3-6 cycloalkyl-C 1-6 alkyl-O-, said C 1-6 alkyl, C 1-6 alkoxy, 3-7 Heterocycloalkyl-O-, 3-7 membered heterocycloalkane-C 1-6 alkyl-O-, C 3-6 cycloalkyl-O- and C 3-6 cycloalkyl-C 1-6 alkane
  • the bases -O- are each independently optionally substituted by 1, 2 or 3 R;
  • R 5 and R 6 are each independently selected from the group consisting of H, C 1-3 alkyl and 3-7 membered heterocycloalkyl, and the C 1-3 alkyl and 3-7 membered heterocycloalkyl are optionally substituted. 2 or 3 R substitutions;
  • L is selected from -O -, - NR a -, - CR b1 R b2 -, - CR b1 R b2 -O- and -CR b1 R b2 -NH-;
  • R a is H
  • R 4 is bonded to R a to form a 5-7 membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 R';
  • Ring A is selected from the group consisting of phenyl and 5-10 membered heteroaryl
  • Ring B is selected from n is selected from 1, 2, 3, 4, and 5;
  • Each R is independently selected from the group consisting of F, Cl, Br, I, OH, NH 2 , CN, NR c1 R c2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio and a 3-7 membered heterocycloalkyl group, said C 1-3 alkyl group, C 1-3 alkoxy group, C 1-3 alkylthio group and 3-7 membered heterocycloalkyl group optionally being 1, 2 or 3 Replaced by R';
  • R' is each independently selected from the group consisting of F, Cl, Br, I, OH, NH 2 , CN, and C 1-3 alkyl;
  • R b1 and R b2 are each independently selected from the group consisting of H, F, Cl, Br, I, and C 1-3 alkyl;
  • R c1 and R c2 are each independently selected from H and C 1-3 alkyl;
  • the 5-7 membered heterocycloalkyl group, the 5-10 membered heteroaryl group and the 3-7 membered heterocycloalkyl group respectively comprise 1, 2, 3 or 4 independently selected from N, -O-, -S-, a hetero atom or a hetero atom of -NH-.
  • each of the above R is independently selected from the group consisting of F, Cl, Br, I, OH, NH 2 , CN, Me, Et, Piperidinyl, pyrrolidinyl, azetidinyl, morpholinyl and oxabutyl, said Me, Et,
  • the piperidinyl, pyrrolidinyl, azetidinyl, morpholinyl and oxabutylcyclo groups are optionally 1, 2 or 3 independently selected from the group consisting of F, Cl, Br, I, OH, NH 2 and C 1-3 alkyl. Substituted by a substituent, other variables are as defined by the present invention.
  • each of the above R is independently selected from the group consisting of F, Cl, Br, I, OH, NH 2 , CN, Me, Other variables are as defined by the present invention.
  • R 1 are independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, Me, and The Me and It is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of F, Cl, Br, I, OH, NH 2 and CN, and other variables are as defined in the present invention.
  • R 1 are independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, Me, Other variables are as defined by the present invention.
  • R 2 and R 3 are each independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , Me, and CF 3 , and other variables are as defined herein.
  • the above R 4 is selected from Rhenylcyclo-O-, morpholinyl-C 1-3 alkyl-O-, azetidinyl-O-, tetrahydrofuranyl-O-, cyclopropane-O-, pyrrolidinyl-C 1-3 alkane Base-O- and azetidinyl-C 1-3 alkyl-O-, said Rhenylcyclo-O-, morpholinyl-C 1-3 alkyl-O-, azetidinyl-O-, tetrahydrofuranyl-O-, cyclopropane-O-, pyrrolidinyl-C 1-3 alkane
  • the base-O- and azetidinyl-C 1-3 alkyl-O- are optionally substituted by 1, 2 or 3 R, and other variables are as defined in the present invention.
  • R 4 is selected from Other variables are as defined by the present invention.
  • R 5 and R 6 are independently selected from the group consisting of H, Me, Et, and The Me, Et, and Optionally substituted by 1, 2 or 3 R, other variables are as defined by the present invention.
  • T is selected from the group consisting of N and C (CN), and other variables are as defined herein.
  • the above-mentioned L is selected from -O -, - NH -, - CH 2 -, - CH 2 -O- and -CH 2 -NH-, other variables are as defined herein.
  • the structural unit Selected from Other variables are as defined by the present invention.
  • Ring A is selected from the group consisting of phenyl, aziridine, benzo[b]thiophene, and benzo[d]isoxazole, and other variables are as defined herein.
  • the structural unit Selected from Other variables are as defined by the present invention.
  • the structural unit Selected from Other variables are as defined by the present invention.
  • the structural unit Selected from Other variables are as defined by the present invention.
  • the ring B is selected from the group consisting of Other variables are as defined by the present invention.
  • the structural unit Selected from Other variables are as defined by the present invention.
  • T, L, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined in the present invention.
  • T, L, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined in the present invention.
  • the present invention also provides the following compounds, isomers thereof or pharmaceutically acceptable salts thereof,
  • the above compound is selected from the group consisting of
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the above compound or a pharmaceutically acceptable salt thereof as an active ingredient together with a pharmaceutically acceptable carrier.
  • the present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof or the above composition for the preparation of a Pan-HER tyrosine kinase inhibitor-related drug.
  • 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 ammonia 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.
  • the present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is 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
  • 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 present 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.
  • pharmaceutically acceptable carrier refers to any formulation or carrier medium that is capable of delivering an effective amount of an active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or patient, including water, oil, Vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, tackifiers, transdermal enhancers and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts.
  • 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.
  • a substituent When a substituent is vacant, it means that the substituent is absent.
  • X when X is vacant in AX, 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 listed linking group does not indicate its direction of attachment, its connection direction is arbitrary, for example, 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.
  • 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).
  • ring means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. So-called rings include single rings, interlocking rings, spiral rings, parallel rings or bridge rings. The number of atoms on the ring is usually defined as the number of elements of the ring. For example, "5 to 7-membered ring” means 5 to 7 atoms arranged in a circle. Unless otherwise specified, the ring optionally contains from 1 to 3 heteroatoms.
  • 5- to 7-membered ring includes, for example, phenyl, pyridine, and piperidinyl; on the other hand, the term “5- to 7-membered heterocycloalkyl ring” includes pyridyl and piperidinyl, but does not include phenyl.
  • ring also includes ring systems containing at least one ring, each of which "ring” independently conforms to the above definition.
  • heterocycle or “heterocyclyl” means a stable monocyclic, bicyclic or tricyclic ring containing a hetero atom or a heteroatom group which may be saturated, partially unsaturated or unsaturated ( Aromatic) which comprise a carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles may be fused to a phenyl ring to form a bicyclic ring.
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the heterocyclic ring can be attached to the side groups of any hetero atom or carbon atom to form a stable structure. If the resulting compound is stable, the heterocycles described herein can undergo substitutions at the carbon or nitrogen sites.
  • the nitrogen atom in the heterocycle is optionally quaternized.
  • a preferred embodiment is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred embodiment is that the total number of S and O atoms in the heterocycle does not exceed one.
  • aromatic heterocyclic group or "heteroaryl” as used herein means a stable 5, 6, or 7 membered monocyclic or bicyclic or aromatic ring of a 7, 8, 9 or 10 membered bicyclic heterocyclic group, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S.
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
  • bridged rings are also included in the definition of heterocycles.
  • a bridged ring is formed when one or more atoms (ie, C, O, N, or S) join two non-adjacent carbon or nitrogen atoms.
  • Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitro group. It is worth noting that a bridge always converts a single ring into a three ring. In the bridged ring, a substituent on the ring can also be present on the bridge.
  • heterocyclic compounds include, but are not limited to, acridinyl, octanoyl, benzimidazolyl, benzofuranyl, benzofuranylfuranyl, benzindenylphenyl, benzoxazolyl, benzimidin Oxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, oxazolyl, 4aH-carbazolyl, Porphyrin, chroman, chromene, porphyrin-decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b] Tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-carbazolyl, nonenyl,
  • hydrocarbyl or its subordinate concept (such as alkyl, alkenyl, alkynyl, aryl, etc.), by itself or as part of another substituent, is meant to be straight-chain, branched or cyclic.
  • the hydrocarbon atom group or a combination thereof may be fully saturated (such as an alkyl group), a unit or a polyunsaturated (such as an alkenyl group, an alkynyl group, an aryl group), may be monosubstituted or polysubstituted, and may be monovalent (such as Methyl), divalent (such as methylene) or polyvalent (such as methine), may include divalent or polyvalent radicals with a specified number of carbon atoms (eg, C 1 -C 12 represents 1 to 12 carbons) , C 1-12 is selected from 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 ; C 3-12 is selected from C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 .).
  • C 1-12 is selected from C 1
  • Hydrocarbyl includes, but is not limited to, aliphatic hydrocarbyl groups including chain and cyclic, including but not limited to alkyl, alkenyl, alkynyl groups including, but not limited to, 6-12 members.
  • An aromatic hydrocarbon group such as benzene, naphthalene or the like.
  • hydrocarbyl means a straight or branched chain radical or a combination thereof, which may be fully saturated, unitary or polyunsaturated, and may include divalent and multivalent radicals.
  • saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl).
  • a homolog or isomer of a methyl group, a cyclopropylmethyl group, and an atomic group such as n-pentyl, n-hexyl, n-heptyl, n-octyl.
  • the unsaturated hydrocarbon group has one or more double or triple bonds, and examples thereof include, but are not limited to, a vinyl group, a 2-propenyl group, a butenyl group, a crotyl group, a 2-isopentenyl group, and a 2-(butadienyl group). , 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers body.
  • heterohydrocarbyl or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), by itself or in conjunction with another term, is represented by a number of carbon atoms and at least A stable, linear, branched or cyclic hydrocarbon radical consisting of a hetero atom or a combination thereof.
  • heteroalkyl by itself or in conjunction with another term, refers to a stable straight or branched alkyl radical or composition thereof consisting of a number of carbon atoms and at least one heteroatom.
  • the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • the hetero atom or heteroatom group may be located at any internal position of the heterohydrocarbyl group, including the position at which the hydrocarbyl group is attached to the rest of the molecule, but the terms "alkoxy”, “alkylamino” and “alkylthio” (or thioalkoxy).
  • alkyl groups which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
  • Up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3.
  • cycloalkyl refers to any heterocyclic alkynyl group, etc., by itself or in combination with other terms, denotes a cyclized “hydrocarbyl group” or “heterohydrocarbyl group”, respectively.
  • a hetero atom may occupy a position at which the hetero ring is attached to the rest of the molecule.
  • cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocyclic groups include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.
  • heterocycloalkyl by itself or in conjunction with other terms, denotes a cyclized “heteroalkyl”, respectively, and further, in the case of the "heterocycloalkyl", a heteroatom may occupy a heterocycloalkyl group.
  • the heterocycloalkyl group is a 4-6 membered heterocycloalkyl group; in other embodiments, the heterocycloalkyl group is a 5-6 membered heterocycloalkane.
  • heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thioheterobutyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetra Hydropyranyl, piperidinyl, piperazinyl, morpholinyl, dioxoalkyl, dithiaalkyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2- Thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl or oxetanyl.
  • alkyl is used to denote a straight or branched saturated hydrocarbon group, which may be monosubstituted (eg, -CH 2 F) or polysubstituted (eg, -CF 3 ), and may be monovalent (eg, Methyl), divalent (such as methylene) or polyvalent (such as methine).
  • alkyl group include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl). , t-butyl), pentyl (eg, n-pentyl, isopentyl, neopentyl) and the like.
  • a cycloalkyl group includes any stable cyclic or polycyclic hydrocarbon group, any carbon atom which is saturated, may be monosubstituted or polysubstituted, and may be monovalent, divalent or multivalent.
  • Examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclononane, and the like.
  • halo or “halogen”, by itself or as part of another substituent, denotes a fluorine, chlorine, bromine or iodine atom.
  • haloalkyl is intended to include both monohaloalkyl and polyhaloalkyl.
  • halo(C 1 -C 4 )alkyl is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Wait.
  • examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • alkoxy represents attached through an oxygen bridge
  • C 1-6 alkoxy groups include C 1, C 2, C 3 , C 4, C 5 , and C 6 alkoxy groups.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- Pentyloxy.
  • aryl denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted or polysubstituted, which may be monovalent, divalent or polyvalent, which may be monocyclic or polycyclic ( For example, 1 to 3 rings; at least one of which is aromatic), they are fused together or covalently linked.
  • heteroaryl refers to an aryl (or ring) containing one to four heteroatoms. In an illustrative example, the heteroatoms are selected from the group consisting of B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • aryl or heteroaryl groups include phenyl, naphthyl, biphenyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, phenyl-oxazolyl, isomerism Azyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidinyl, benzothiazolyl, indolyl, benzimidazolyl, indolyl, isoquinolyl, quinoxalinyl, quinolinyl, 1 -naphthyl, 2-naphthyl, 4-biphenylyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl
  • aryl groups when used in conjunction with other terms (e.g., aryloxy, arylthio, aralkyl), include aryl and heteroaryl rings as defined above.
  • aralkyl is intended to include those radicals to which an aryl group is attached to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl, and the like), including wherein the carbon atom (eg, methylene) has been, for example, oxygen.
  • alkyl groups substituted by an atom such as phenoxymethyl, 2-pyridyloxymethyl 3-(1-naphthyloxy)propyl and the like.
  • 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), para 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), para Oxybenzyl (PMB), 9-fluor
  • 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 compounds of the invention may be used in a variety of uses or indications, including but not limited to the specific uses or indications listed herein.
  • the solvent used in the present invention is commercially available.
  • the present invention employs the following abbreviations: aq for water; HATU for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent; CDI stands for Carbonyldiimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for acetic acid Esters; EtOH for ethanol; MeOH for methanol; CBz for benzyl
  • the compounds of the present invention have significant inhibitory activities against HER1, HER2 and HER4, and have markedly inhibited proliferation of BT-474 cells in NCI-N87 cells.
  • NCI-N87 cells subcutaneous xenograft tumor BALB/c nude mouse model showed that the compound of the present invention has a significant effect of inhibiting tumor growth and has no significant effect on the body weight of the mice at the effective dose, safety better.
  • Figure 1 Relative body weight change in human BALB/c nude mouse model of human esophageal cancer OE21 cells subcutaneous xenograft tumor (%)
  • Relative body weight changes were calculated based on animal body weight at the start of dosing. Data points represent the percentage change in average body weight within the group, and error bars represent standard errors (SEM).
  • PO Oral administration
  • QD once daily
  • D1-D7 Day 1 to Day 7
  • D8-D21 Day 8 to Day 21
  • D1-D2 Day 1 to Day 2
  • D3-D21 administration from 3 days to 21 days
  • n 6: 6 mice per group.
  • the compound 6-3 was obtained by the second step of Example 2.
  • 1 H NMR (400MHz, DMSO- d 6) ⁇ 10.01 (s, 1H), 8.57 (s, 1H), 8.33 (s, 1H), 8.00-8.10 (m, 2H), 7.55-7.70 (m, 1H ), 7.32 (s, 1H), 4.80-4.90 (m, 1H), 4.00 (s, 3H), 3.00-3.20 (m, 4H), 1.80-2.10 (m, 2H), 1.10 - 1.30 (m, 2H) ).
  • LC-MS: m/z 481.1 [M+H] + .
  • the monohydrogen on the piperidine ring and the aromatic ammonia-bonded carbon is strongly correlated with the methylene group on the amino group of the piperidine ring, but not related to the methylene hydrogen on the bridged ring.
  • Cis structure. LC-MS: m/z 444.2 [M+Na] + .
  • LC-MS: m/z 5021. [M+H] + .
  • Example 10-3 was obtained in the sixth step of Reference Example 9.
  • LC-MS: m/z 387.2 [M+Na] + .
  • Example 10-5 was obtained in the eighth step of Example 9.
  • LC-MS: m/z 383.1 [M+H] + .
  • Example 12 The compound of Example 12 was obtained in the third step of Reference Example 11.
  • the hydrochloride salt of compound 16-6 (50.0 mg, 92.10 ⁇ mol) was dissolved in tetrahydrofuran (0.5 mL) and water (0.5 mL), and sodium hydrogencarbonate (38.7 mg, 460.52 ⁇ mol) was added at 0 ° C, and the ally was slowly added dropwise.
  • the acid chloride (3.3 mg, 36.84 ⁇ mol) was stirred at 0 ° C for 0.5 hour and at 20-25 ° C for 18 hours. Additional allylic acid chloride (2.2 mg, 23.95 ⁇ mol) was added, and the reaction solution was further stirred at 20-25 ° C for 2 hours.
  • the hydrochloride salt of the compound 20-8 (30.0 mg, 52.84 ⁇ mol) was dissolved in a mixed solvent of tetrahydrofuran (3 mL) and water (3 mL), and sodium hydrogencarbonate (13.3 mg, 158.51 ⁇ mol) was slowly added dropwise at 0 °C.
  • Acryloyl chloride (3.8 mg, 42.27 ⁇ mol) was added, and the reaction solution was further stirred at 0 ° C for 0.5 hour. It was quenched by the addition of MeOH (1 mL), EtOAc evaporated.
  • Example 21 was obtained in the ninth step of Reference Example 20.
  • Example 22-2 The compound of Example 22-2 was obtained in the first step of Reference Example 21.
  • 1 H NMR 400MHz, DMSO- d 6) ⁇ 9.63 (s, 1H), 8.40 (s, 1H), 7.86 (s, 1H), 7.63-7.57 (m, 2H), 7.26 (s, 1H), 4.92-4.74(m,1H),4.34-4.26(m,2H), 4.19-4.14(m,2H), 3.79-3.72(m,2H), 3.36(s,3H),2.18(m,2H), 1.96-1.86 (m, 3H), 1.63 (m, 3H), 1.44 (s, 9H).
  • Example 24-2 The compound of Example 24-2 was obtained in the first step of Reference Example 23.
  • LC-MS: m/z 676.3 [M+H] + .
  • Example 25-3 The compound of Example 25-3 was obtained in the first step of Reference Example 21.
  • LC-MS: m / z 493.0 [M + H] +.
  • Example 27-2 The compound of Example 27-2 was obtained in the first step of Reference Example 26.
  • LC-MS: m/z 619.2 [M+H] + .
  • Example 27-3 The compound of Example 27-3 was obtained in the first step of Reference Example 21.
  • LC-MS: m/z 519.0 [M+H] + .
  • the compound 31-2 (400.0 mg, 1.14 mmol) was dissolved in ethanol (10 mL), and a solution of sodium hydroxide (228.4 mg, 5.71 mmol) in water (2 mL) was added, and the mixture was stirred at 10 ° C for 1 hour.
  • the reaction solution was added with acetic acid (0.5 mL) and water (10 mL).
  • Example 31-2 The compound of Example 31-2 was obtained in the first step of Reference Example 31.
  • LC-MS: m/z 378.0 [M+H] + .
  • Example 33-2 The compound of Example 33-2 was obtained in the first step of Reference Example 31.
  • LC-MS: m/z 362.0 [M+H] + . .
  • Example 34-2 The compound of Example 34-2 was obtained in the first step of Reference Example 31.
  • LC-MS: m/z 380.0 [M+H] + .
  • Example 35-2 The compound of Example 35-2 was obtained in the first step of Reference Example 31.
  • LC-MS: m/z 350.0 [M+H] + .
  • the hydrochloride of Compound 36-3 was obtained in the second step of Reference Example 21.
  • Example 41-2 was obtained in the first step of Reference Example 40.
  • 1 H NMR 400MHz, DMSO- d 6) ⁇ 8.95 (s, 1H), 8.29 (s, 1H), 8.07 (s, 1H), 7.93-8.02 (m, 2H), 7.40 (s, 1H), 4.05 (s, 3H).
  • LC-MS: m/z 370.0 [M+H] + .
  • Example 48 (160.0 mg) was obtained.
  • the purpose of this test was to examine the in vitro inhibitory activity of the compounds against HER1 (ErbB1), HER2 (ErbB2), and HER4 (ErbB4).
  • the enzymes used in this experiment were human ErbB1, ErbB2 and ErbB4, and the Eurofins Pharma Discovery Service provided an activity assay.
  • the results of the test compound against HER1, HER2, and HER4 were shown in Table 1.
  • test compound buffer 5 ⁇ L
  • peptide substrate poly(Glu, Tyr) 4:1) (2.5 ⁇ L)
  • ErbB 4-20 ng, 2.5 ⁇ L
  • MnCl 2 50 mM, 1.25 ⁇ L
  • dH 2 O 3.75 ⁇ L
  • [ ⁇ - 33 P]ATP 10 ⁇ L
  • the reaction was stopped by adding 3% phosphoric acid, 10 ⁇ L of the sample was transferred to Filtermate A, the filter was washed 3 times with 75 mM phosphoric acid, washed once with methanol, and the filter was transferred to a sealed plastic bag, and a scintillation liquid mixture (4 mL) was added thereto.
  • the intensity of the emitted photons is measured, and the cpm (number of times/minute) of the enzyme sample is compared with the cpm of the internal control sample.
  • the intensity of the photon reflects the activity of the tyrosine kinase.
  • Example 1 Compound HER1IC 50 (nM) HER2IC 50 (nM) HER4IC 50 (nM) Example 1 2 3 10 Example 3 2 5 17 Example 4 2 3 13 Example 5 9 twenty four 157 Example 6 2 4 17 Example 7 40 69 61 Example 8 6.0 b 5.5 b 3.5 b Example 9 9 13 8 Example 13 5 8 7 Example 18 9 12 5 Example 20 18 11 10 Example 21 12 5 3 Example 22 12 7 3 Example 23 8 4 2 Example 24 10 6 3 Example 25 6 3 6 Example 26 8 5 4 Example 27 16 5 3 Example 32 15 5 3 Example 33 7 6 3 Example 34 5 4 2 Example 38 8 5 3 Example 40 11 5 2 Example 44 5 4 3 Example 45 8 7 10 Example 48 9 11 4
  • the compounds of the present invention have significant inhibitory activities against HER1, HER2 and HER4.
  • Luciferase in the Cell-Titer-Glo reagent uses fluorescein, oxygen and ATP as reaction substrates to produce oxidized fluorescein and release energy in the form of light. Since ATP is required for the luciferase reaction, the total amount of light produced by the reaction is proportional to the total amount of ATP in the cell viability.
  • Cell line NCI-N87 cell line (ATCC-CRL-5822), BT-474 cell line (ATCC-HTB-20), OE21 (ECACC-96062201) cell culture medium: (RPMI 1640 medium (Invitrogen #22400-105) ; 10% serum Invitrogen #10090148; L-glutamine 1 ⁇ , Gibco #25030-081; double-resistant Hyclone #SV30010)
  • Multi-purpose microplate reader (Envision Reader)
  • the mother liquor of the compound was 10 mM, and the compound was diluted with DMSO to have an initial concentration of 4 mM. Compounds were added to the compound mother liquor plate at 9 ⁇ L per well.
  • the cells were centrifuged at 1000 rpm for 1 min, and the cell plates were placed in a 37 ° C, 5% CO 2 incubator for 3 days.
  • the cell plates were removed from the incubator and equilibrated for 30 minutes at room temperature. 25 ⁇ L of Cell-Titer-Glo reagent was added to each well, shaken for one minute to allow it to be thoroughly mixed, and centrifuged at 1000 rpm for 1 minute. After 10 minutes, the plate was read on a PerkinElmer Envision and the fluorescence reading time was set to 0.2 seconds. Test results: The test results are shown in Table 2.
  • OE19 cells with a saturation of 80%-90% were digested with trypsin, resuspended by centrifugation, adjusted to a cell concentration of 90 ml/well, and added to a 96-well cell culture plate to make OE19 cells have 8000 per well. Incubate overnight at 37 ° C in a cell incubator containing 5% CO 2 .
  • the mother liquor of the test compound was diluted 3-fold in DMSO with a total of 10 concentrations.
  • the gradient-diluted test compound was further diluted with a cell culture solution into a 10 ⁇ compound solution under sterile conditions (the highest concentration of 100 compound containing 1% DMSO).
  • the prepared 10 ⁇ compound solution was added to the cell culture plate, and 10 substances were added to each well.
  • the final concentration of the model standard control Staurosporine (staphylocin) and all test compounds was 10 ⁇ M, and the gradient was diluted 3 times for a total of 10 test concentration points.
  • the inhibition rate is calculated as:
  • % inhibition (ZPE - sample detection value) / (ZPE-HPE) ⁇ 100%
  • the well containing 10 mM staurosporine was used as the HPE (100% inhibition control) well on the DAY3 (the first day of the experiment, and the day of the reading on the DAY3), and the 0.1% DMSO well of the DAY3 was used as the ZPE (0% inhibition control). )hole. Two replicate wells were set at each concentration point of the test compound.
  • the processed data will be subjected to non-linear regression analysis using GraphPad Prism 6 analysis software to obtain a dose-response curve, and the half-inhibitory concentration (IC 50 ) of the test compound to OE19 cells was calculated.
  • IC 50 half-inhibitory concentration
  • Table 2 Screening test results of in vitro cell proliferation inhibitory activity of the compound of the present invention
  • the compounds of the present invention have significant inhibitory activities on proliferation of NCI-N87, BT-474, OE21 and OE19 cells.
  • OBJECTIVE To evaluate the efficacy of test compounds in human gastric cancer NCI-N87 cells subcutaneous xenografts in a BALB/c nude mouse model.
  • mice female BALB/c nude mice, 6-8 weeks old, weighing 18-22 g; supplier: Shanghai Xipuer-Beikai Experimental Animal Co., Ltd. Experimental methods and procedures:
  • Human gastric cancer NCI-N87 cells were cultured in vitro in a single layer, cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum, 100 U/mL penicillin, 100 ⁇ g/mL streptomycin and 2 mM glutamine, 37 ° C 5% CO 2 to cultivate. Passage was routinely digested with trypsin-EDTA twice a week. When the cell saturation is 80%-90%, the cells are collected, counted, and inoculated.
  • NCI-N87 cells were subcutaneously inoculated into the right back of each nude mouse (PBS + Matrigel, 1:1). Group administration was started when the average tumor volume reached 145 mm 3 .
  • test compound was formulated into a clear solution of 0.3 mg/mL, and the solvent was 10% NMP (N-methylpyrrolidone) + 10% ethylene glycol stearate + 80% water.
  • the experimental indicator is to investigate whether tumor growth is inhibited, delayed or cured.
  • Tumor diameters were measured twice a week using vernier calipers.
  • TGI (%) [1- (mean tumor volume at the end of administration of a treatment group - mean tumor volume at the start of administration of the treatment group) / (mean tumor volume at the end of treatment of the solvent control group - The mean tumor volume at the start of treatment in the solvent control group)] ⁇ control group.
  • T/C% TRTV/CRTV group started treatment (TRTV: treatment group RTV; CRTV: negative control group RTV).
  • T weight and C weight respectively indicate the tumor weight of the drug-administered group and the vehicle control group.
  • Statistical analysis included mean and standard error (SEM) of tumor volume at each time point for each group.
  • the treatment group showed the best therapeutic effect on the 21st day after the administration at the end of the trial, and therefore statistical analysis was performed based on this data to evaluate the difference between the groups.
  • T-test was used for comparison between the two groups, and one-way ANOVA was used for comparison between three groups or groups. If there was a significant difference in F values, the Games-Howell method was used for the test. If there is no significant difference in F values, the Dunnet (2-sided) method is used for analysis. All data analysis was performed with SPSS 17.0. A significant difference was considered at p ⁇ 0.05.
  • the weight of experimental animals was used as a reference indicator for indirect determination of drug toxicity.
  • all drug-administered groups (except Poziotinib group) showed no significant weight loss.
  • 2 mice lost more than 20% of their body weight, and 3 of them lost more than 15% of their body weight, 1
  • the weight loss was over 10%, and 2 mice were euthanized on the 8th day after the administration, and the remaining mice gradually recovered after the dose was lowered, and there was no morbidity or death.
  • the results of the drug efficacy are shown in Table 3.
  • Example 1 The control group Poziotinib and Inventive Example 1, Example 7 and Example 8 exhibited excellent tumor growth inhibition effects compared to the vehicle group, with TGI of 115.6%, 103.98%, 92.63% and 119.71%, respectively. Moreover, in the present invention, Example 1, Example 7 and Example 8 were significantly safer than the control compound Poziotinib for the model animal weight index.
  • the c.p value is based on the tumor volume.
  • OBJECTIVE To evaluate the efficacy of the test compounds in this patent on the human gastric cancer NCI-N87 cells subcutaneous xenografts in a BALB/c nude mouse model.
  • mice female BALB/c nude mice, 6-8 weeks old, weighing 18-22 g; supplier: Shanghai Lingchang Biotechnology Co., Ltd. provides experimental methods and steps:
  • Human gastric cancer NCI-N87 cells cultured in vitro, cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum, 100 U/mL penicillin, 100 U/mL 0 streptomycin and 2 mM glutamine, 37 ° C, 5% CO 2 culture. Passage was routinely digested with trypsin-EDTA twice a week. When the cell saturation is 80%-90%, the cells are collected, counted, and inoculated.
  • NCI-N87 cells (PBS + Matrigel, 1:1) were subcutaneously inoculated into the right back of each mouse, and the group was administered at an average tumor volume of 158 mm 3 .
  • test compound was formulated into a clear solution of 0.04 mg/mL and 0.08 mg/mL, and the solvent was 10% NMP (N-methylpyrrolidone) + 10% ethylene glycol stearate + 80% water.
  • the experimental indicator is to investigate whether tumor growth is inhibited, delayed or cured.
  • Tumor diameters were measured twice a week using vernier calipers.
  • TGI (%) [1 - (average tumor volume at the end of administration of a treatment group - mean tumor volume at the start of administration of the treatment group) / (mean tumor volume at the end of treatment of the solvent control group - The mean tumor volume at the start of treatment in the solvent control group)] ⁇ 100%.
  • T/C (%) mean tumor volume at the end of administration of a treatment group / mean tumor volume at the end of treatment of the solvent control group ⁇ 100%.
  • the weight of experimental animals was used as a reference indicator for indirect determination of drug toxicity.
  • the body weight of the mice decreased, and there was no other morbidity or death.
  • the c.p value is calculated from the tumor volume.
  • the in vivo efficacy of the compound of the present invention in a human gastric cancer NCI-N87 cell subcutaneous xenograft model was evaluated.
  • the treatment group Example 38@0.8 mg/kg was equivalent to the reference compound Poziotinib@0.8 mg/kg, and both exhibited significant antitumor effect; the low dose group Example 38 and the reference compound Poziotinib drug Equivalent or better.
  • OBJECTIVE To evaluate the efficacy of the test compounds in this patent on the human gastric cancer NCI-N87 cells subcutaneous xenografts in a BALB/c nude mouse model.
  • mice female BALB/c nude mice, 6-8 weeks old, weighing 18-22 g; supplier: Shanghai Xipuer-Beikai Experimental Animal Co., Ltd. Experimental methods and procedures:
  • Human gastric cancer NCI-N87 cells were cultured in vitro in a single layer, cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum, 100 U/mL penicillin, 100 ⁇ g/mL streptomycin, and cultured at 37 ° C, 5% CO 2 . Passage was routinely digested with trypsin-EDTA twice a week. When the cell saturation is 80%-90%, the cells are collected, counted, and inoculated.
  • NCI-N87 cells PBS + Matrigel, 1:1 were subcutaneously inoculated into the right back of each mouse, and the group administration was started when the average tumor volume reached 156 mm 3 .
  • test compound was formulated into a clear solution of 0.05 mg/mL, and the solvent was 10% NMP (N-methylpyrrolidone) + 10% ethylene glycol stearate + 80% water.
  • the experimental indicator is to investigate whether tumor growth is inhibited, delayed or cured.
  • Tumor diameters were measured twice a week using vernier calipers.
  • TGI (%) [1 - (average tumor volume at the end of administration of a treatment group - mean tumor volume at the start of administration of the treatment group) / (mean tumor volume at the end of treatment of the solvent control group - The mean tumor volume at the start of treatment in the solvent control group)] ⁇ 100%.
  • T/C (%) mean tumor volume at the end of administration of a treatment group / mean tumor volume at the end of treatment of the solvent control group ⁇ 100%.
  • the weight of experimental animals was used as a reference indicator for indirect determination of drug toxicity.
  • the body weight of the mice decreased, and there was no other morbidity or death.
  • the c.p value is calculated from the tumor volume.
  • OBJECTIVE To investigate the efficacy of the test compound in the in vivo model of human esophageal cancer OE21 cell subcutaneous xenograft tumor BALB/c nude mice.
  • mice female BALB/c nude mice, 6-8 weeks old, weighing 17-23 g; supplier: Shanghai Xipuer-Beikai Experimental Animal Co., Ltd. Experimental methods and procedures:
  • Human esophageal cancer OE21 cells were cultured in vitro in a single layer, cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum, 100 U/mL penicillin, 100 U/mL 0 streptomycin and 2 mM glutamine, cultured at 37 ° C 5% CO 2 . Passage was routinely digested with trypsin-EDTA twice a week. When the cell saturation is 80%-90%, the cells are collected, counted, and inoculated.
  • OE21 cells PBS
  • test compound is formulated into a clear or suspension solution of 0.15 mg/mL to 0.3 mg/mL, and the solvent is 10% NMP + 10% ethylene glycol stearate + 80% water.
  • the experimental indicator is to investigate whether tumor growth is inhibited, delayed or cured.
  • Tumor diameters were measured twice a week using vernier calipers.
  • TGI (%) [(1 - mean tumor volume at the end of administration of a treatment group - mean tumor volume at the start of administration of the treatment group)) / (mean tumor at the end of treatment at the solvent control group) Volume-solvent control group started treatment at the mean tumor volume)] ⁇ 100%.
  • T/C (%) mean tumor volume at the end of administration of a treatment group / mean tumor volume at the end of treatment of the solvent control group ⁇ 100.
  • Statistical analysis included mean and standard error (SEM) of tumor volume at each time point for each group. One-way ANOVA was used for comparison between three or more groups. If there is a significant difference in F values, multiple comparisons should be made after ANOVA analysis. All data analysis was performed with SPSS 17.0. A significant difference was considered at p ⁇ 0.05.
  • mice in the model group of Poziotinib@2/1.5 mg/kg, Example 8/Example 38@2/0.5 mg/kg and Example 38@2/1.5 mg/kg showed varying degrees of body weight in this model. Decreased and dandruff; Poziotinib@2/1.5mg/kg, on the 6th and 7th day after group administration, one and three mice lost more than 15% of their body weight, and they were discontinued. There is a deep yellow toxicity suggestion of the whole group of mice urine; the test group starting from the third day of the test group, the Example 8@2mg/kg group was replaced with the example 38@0.5mg/kg, and the Poziotinib@2mg/kg dose was reduced to 1.5mg. /kg, Example 38@2 mg/kg reduced dose to 1.5 mg/kg. After dose adjustment, body weight was significantly restored in each group ( Figure 1).
  • Tumor growth inhibition was calculated from T/C and TGI, refer to Experimental Example 4.
  • the c.p value was calculated from the tumor volume on the 21st day after administration, and was compared with the Vehicle group using the statistical method of One-Way ANOVA.
  • the in vivo efficacy of the compound of the invention and the reference compound Poziotinib in the OE21 xenograft model was evaluated in this experiment.
  • the tumor volume of the tumor-bearing mice in the solvent control group reached 948 mm 3
  • the test substance Poziotinib@2/1.5 mg/kg, Example 8/Example 38 @2/0.5 mg/kg, and Example 38@ The 2/1.5mg/kg group had significant antitumor effect compared with the solvent control group.
  • Example 38 The low dose 0.5 mpk efficacy was comparable to the reference compound Poziotnib and the Example 38 high dose 1.5 mpk.
  • Example 38 The anti-tumor effect of Example 38 was remarkable, and the pharmacodynamic effect was comparable to that of the reference compound Poziotinib, but the weight of the reference compound high-dose group was significantly decreased, the weight loss of the three mice was more than 15%, the drug was discontinued, and the whole group had mouse urine. Deep yellow toxicity tips.
  • Example 38 had little effect on the body weight of mice, no drug withdrawal, no urine dark yellow toxicity, and the tolerance was significantly better than the reference compound.
  • Example 38 had a lower onset dose, better tolerance, and a safer window than the reference compound Poziotinib.
  • EXPERIMENTAL OBJECTIVE This experiment was conducted to investigate the plasma pharmacokinetics of female BALB/c mice after single intravenous injection and intragastric administration of the reference examples of the present patent and the reference compound.
  • Experimental animals female BALB/c nude mice, 7-9 weeks old, weighing 17-23 g; supplier: Shanghai Xipuer-Beikai Experimental Animal Co., Ltd.
  • Sample collection experimental animals were collected from saphenous vein puncture at each time point A blood sample of 0.03 mL was recorded and the actual blood collection time was recorded. All blood samples were added to a commercialized EDTA-K2 anticoagulant tube with a specification of 1.5 mL (supplier is Jiangsu Kangjian Medical Products Co., Ltd.).
  • the supernatant plasma was aspirated at 4 ° C and 3000 g for 10 minutes in half an hour, quickly as it was in dry ice, and stored in a refrigerator at -80 ° C for LC-MS/MS analysis.
  • WinNonlin TM Version6.3 (Pharsight, MountainView, CA) noncompartmental pharmacokinetic software processing plasma concentration, calculated using linear pharmacokinetic parameters C max log trapezoidal method method, T max, T 1 / 2 , AUC 0-last
  • C max peak concentration
  • T max peak time
  • T 1/2 length of time required to clear half of the compound
  • AUC 0-last 0 - concentration integral area in the last sampling time.
  • mice show that the compound of the present invention has a longer half-life than the reference compound, and the oral plasma exposure is significantly superior to the reference compound Poziotinib and the control compound 2.
  • Example 38 The results of CYP inhibitory activity of the compounds of the present invention in human liver microsomes showed that Example 38 and Poziotinib had no inhibitory activity against CYP1A2 and CYP3A4.
  • the inhibitory activity of CYP2C19 in Example 38 was comparable to that of the reference compound Poziotinib, and the activities of CYP2C9 and CYP2D6 were improved, which were 2 and 6 times better than the reference compounds, respectively.
  • Example 38 improved CYP activity and was superior to the reference compound and therefore had a lower risk of drug-drug interaction.

Abstract

本发明涉及一系列喹唑啉类化合物，尤其是式(I)所示化合物、其异构体或其药学上可接受的盐，其药物组合物以及它们作为Pan-HER酪氨酸激酶抑制剂的应用。

Description

喹唑啉衍生物及其应用
相关申请的引用
本申请主张如下优先权：
CN201711376757.0，申请日2017-12-19；
CN201810225742.2，申请日2018-03-19；
CN201810576529.6，申请日2018-06-05。
技术领域
本发明涉及一系列喹唑啉类化合物，尤其是式(I)所示化合物、其异构体或其药学上可接受的盐，其药物组合物以及它们作为Pan-HER酪氨酸激酶抑制剂的应用。
技术背景
人类表皮生长因子受体(HER,EGFR)是蛋白酪氨酸激酶家族的一员，广泛分布于人体各组织细胞膜上，可以调节细胞的增殖，生长，转移和凋亡。其结构由三部分组成：胞外的配体结合区、跨膜区以及胞内的酪氨酸激酶区。根据受体的结构差异，可以将HER区分为四种亚型，分别为HER1(EGFR,ErbB-1)、HER2(ErbB-2)、HER3(ErbB-3)及HER4(ErbB-4)。研究发现，HER在乳腺癌、非小细胞肺癌、胃癌、胰腺癌、卵巢癌、结直肠癌、头颈部鳞癌、恶性胶质瘤以及前列腺癌等多种肿瘤细胞中均存在过表达或异常激活的现象。另外，研究表明，HER的过表达或异常激活与肿瘤的分化程度、恶性程度及预后等密切相关(Baselga.J.,Oncologist 2002,7,2-8)。因此，抑制HER成为了抗肿瘤药物研究的热点。
目前，已经上市的靶向性的HER抑制剂包括吉非替尼(Gefitinib)、埃罗替尼(Erlotinib)、拉帕替尼(Lapatinib)等。然而，由于这些上市药物有效应答率不高，容易产生耐药性以及存在一些毒副作用，因此迫切需要研发其他具有优良抗肿瘤效果，同时能够克服耐药性，并且耐受性良好的抗肿瘤药物。
Pan-HER酪氨酸激酶不可逆抑制剂同时抑制HER1、HER2以及HER4，研究表明，这种对HER家族受体的不可逆抑制除了能提高药物的活性外，还能减少耐药性的产生，同时对一些产生耐药的肿瘤细胞系，如对埃罗替尼耐药的H1975细胞系，具有显著的抑制效果。目前已经被批准上市的pan-HER酪氨酸激酶不可逆抑制剂只有Afatinib和Neratinib，多个抑制剂处于临床研究，如：Poziotinib,Dacomitinib,Canertinib，仍有未满足的市场需求。
因此，有必要进一步开发Pan-HER酪氨酸激酶不可逆抑制剂，用于癌症的治疗。
Poziotinib(对照化合物1)是WO2008150118开发的pan-HER抑制剂，其结构如下。
Figure PCTCN2018122016-appb-000001
专利WO2015043515公开了对照化合物2，具有EGFR和HER2抑制作用，其结构如下。
Figure PCTCN2018122016-appb-000002
发明内容
本发明提供了式(Ⅰ)所示化合物、其异构体或其药学上可接受的盐，
Figure PCTCN2018122016-appb-000003
其中，
T选自N和CR’；
各R 1分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基或C 1-3烷氧基任选被1、2或3个独立选自F、Cl、Br、I、OH、NH 2和CN的取代基所取代；
R 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2和C 1-3烷基，所述C 1-3烷基任选被1、2或3个独立选自F、Cl、Br和I的取代基所取代；
R 4选自C 1-6烷基、C 1-6烷氧基、3-7元杂环烷基-O-、3-7元杂环烷基-C 1-6烷基-O-、C 3-6环烷基-O-和C 3-6环烷基-C 1-6烷基-O-，所述C 1-6烷基、C 1-6烷氧基、3-7元杂环烷基-O-、3-7元杂环烷-C 1-6烷基-O-、C 3-6环烷基-O-和C 3-6环烷基-C 1-6烷基-O-分别独立地任选被1、2或3个R取代；
R 5和R 6分别独立地选自H、C 1-3烷基和3-7元杂环烷基，所述C 1-3烷基和3-7元杂环烷基任选被1、2或3个R取代；
L选自-O-、-NR a-、-CR b1R b2-、-CR b1R b2-O-和-CR b1R b2-NH-；
R a为H；或者R 4与R a连接形成一个任选被1、2、3或4个R’取代的5-7元杂环烷基；
环A选自苯基和5-10元杂芳基；
环B选自
Figure PCTCN2018122016-appb-000004
n选自1、2、3、4和5；
各R分别独立地选自F、Cl、Br、I、OH、NH 2、CN、NR c1R c2、C 1-3烷基、C 1-3烷氧基、C 1-3烷基-NH-C(＝O)-、C 1-3烷硫基和3-7元杂环烷基，所述C 1-3烷基、C 1-3烷氧基、C 1-3烷基-NH-C(＝O)-、C 1-3烷硫基和3-7元杂环烷基任选被1、2或3个R’所取代；
R’各自独立地选自F、Cl、Br、I、OH、NH 2、CN和C 1-3烷基；
R b1和R b2分别独立地选自H、F、Cl、Br、I和C 1-3烷基；
R c1和R c2分别独立地选自H和C 1-3烷基；
所述5-7元杂环烷基、5-10元杂芳基和3-7元杂环烷基分别包含1、2、3或4个独立选自N、-O-、-S-、-NH-的杂原子或杂原子团。
本发明的一些方案中，上述各R分别独立地选自F、Cl、Br、I、OH、NH 2、CN、
Figure PCTCN2018122016-appb-000005
Me、Et、
Figure PCTCN2018122016-appb-000006
哌啶基、吡咯烷基、吖丁啶基、吗啉基和噁丁环基，所述Me、Et、
Figure PCTCN2018122016-appb-000007
哌啶基、吡咯烷基、吖丁啶基、吗啉基和噁丁环基任选被1、2或3个独立选自F、Cl、Br、I、OH、NH 2和C 1-3烷基的取代基所取代，其他变量如本发明所定义。
本发明的一些方案中，上述各R分别独立地选自F、Cl、Br、I、OH、NH 2、CN、
Figure PCTCN2018122016-appb-000008
Me、Et、
Figure PCTCN2018122016-appb-000009
Figure PCTCN2018122016-appb-000010
其他变量如本发明所定义。
本发明的一些方案中，上述R 1分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、Me和
Figure PCTCN2018122016-appb-000011
所述Me和
Figure PCTCN2018122016-appb-000012
任选被1、2或3个独立选自F、Cl、Br、I、OH、NH 2和CN的取代基所取代，其他变量如本发明所定义。
本发明的一些方案中，上述R 1分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、Me、CH 2F、CHF 2、CF 3、
Figure PCTCN2018122016-appb-000013
其他变量如本发明所定义。
本发明的一些方案中，上述R 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、Me和CF 3，其他变量如本发明所定义。
本发明的一些方案中，上述R 4选自
Figure PCTCN2018122016-appb-000014
噁丁环基-O-、哌啶基-C 1-3烷基-O-、吗啉基-C 1-3烷基-O-、吖丁啶基-O-、四氢呋喃基-O-、环丙烷基-O-、吡咯烷基-C 1-3烷基-O-和吖丁啶基-C 1-3烷基-O-，所述
Figure PCTCN2018122016-appb-000015
噁丁环基-O-、哌啶基-C 1-3烷基-O-、吗啉基-C 1-3烷基-O-、吖丁啶基-O-、四氢呋喃基-O-、环丙烷基-O-、吡咯烷基-C 1-3烷基-O-和吖丁啶基-C 1-3烷基-O-任选被1、2或3个R取代，其他变量如本发明所定义。
本发明的一些方案中，上述R 4选自
Figure PCTCN2018122016-appb-000016
Figure PCTCN2018122016-appb-000017
Figure PCTCN2018122016-appb-000018
其他变量如本发明所定义。
本发明的一些方案中，上述R 5和R 6分别独立地选自H、Me、Et和
Figure PCTCN2018122016-appb-000019
所述Me、Et和
Figure PCTCN2018122016-appb-000020
任选被1、2或3个R取代，其他变量如本发明所定义。
本发明的一些方案中，上述R 5和R 6分别独立地选自H、
Figure PCTCN2018122016-appb-000021
其他变量如本发明所定义。
本发明的一些方案中，上述T选自N和C(CN)，其他变量如本发明所定义。
本发明的一些方案中，上述L选自-O-、-NH-、-CH 2-、-CH 2-O-和-CH 2-NH-，其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2018122016-appb-000022
选自
Figure PCTCN2018122016-appb-000023
Figure PCTCN2018122016-appb-000024
其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2018122016-appb-000025
为
Figure PCTCN2018122016-appb-000026
其他变量如本发明所定义。
本发明的一些方案中，上述环A选自苯基、氮茚基、苯并[b]噻吩基、咪唑并[1,2-a]吡啶基和苯并[d]异噁唑基，其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2018122016-appb-000027
选自
Figure PCTCN2018122016-appb-000028
Figure PCTCN2018122016-appb-000029
其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2018122016-appb-000030
选自
Figure PCTCN2018122016-appb-000031
Figure PCTCN2018122016-appb-000032
其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2018122016-appb-000033
选自
Figure PCTCN2018122016-appb-000034
Figure PCTCN2018122016-appb-000035
Figure PCTCN2018122016-appb-000036
其他变量如本发明所定义。
本发明的一些方案中，上述环B选自
Figure PCTCN2018122016-appb-000037
Figure PCTCN2018122016-appb-000038
Figure PCTCN2018122016-appb-000039
其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2018122016-appb-000040
选自
Figure PCTCN2018122016-appb-000041
Figure PCTCN2018122016-appb-000042
Figure PCTCN2018122016-appb-000043
其他变量如本发明所定义。
本发明还提供了式(Ⅰ)所示化合物、其异构体或其药学上可接受的盐，
Figure PCTCN2018122016-appb-000044
其中，
T选自N和CR’；
R 1分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基或C 1-3烷氧基任选被1、2或3个独立选自F、Cl、Br、I、OH、NH 2和CN的取代基所取代；
R 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2和C 1-3烷基，所述C 1-3烷基任选被1、2或3个独立选自F、Cl、Br和I的取代基所取代；
R 4选自C 1-6烷基、C 1-6烷氧基、3-7元杂环烷基-O-、3-7元杂环烷基-C 1-6烷基-O-、C 3-6环烷基-O-和C 3-6环烷基-C 1-6烷基-O-，所述C 1-6烷基、C 1-6烷氧基、3-7元杂环烷基-O-、3-7元杂环烷-C 1-6烷基-O-、C 3-6环烷基-O-和C 3-6环烷基-C 1-6烷基-O-分别独立地任选被1、2或3个R取代；
R 5和R 6分别独立地选自H、C 1-3烷基和3-7元杂环烷基，所述C 1-3烷基和3-7元杂环烷基任选被1、2或3个R取代；
L选自-O-、-NR a-、-CR b1R b2-、-CR b1R b2-O-和-CR b1R b2-NH-；
R a为H；
或者R 4与R a连接形成一个任选被1、2、3或4个R’取代的5-7元杂环烷基；
环A选自苯基和5-10元杂芳基；
环B选自
Figure PCTCN2018122016-appb-000045
n选自1、2、3、4和5；
各R分别独立地选自F、Cl、Br、I、OH、NH 2、CN、NR c1R c2、C 1-3烷基、C 1-3烷氧基、C 1-3烷硫基和3-7元杂环烷基，所述C 1-3烷基、C 1-3烷氧基、C 1-3烷硫基和3-7元杂环烷基任选被1、2或3个R’所取代；
R’各自独立地选自F、Cl、Br、I、OH、NH 2、CN和C 1-3烷基；
R b1和R b2分别独立地选自H、F、Cl、Br、I和C 1-3烷基；
R c1和R c2分别独立地选自H和C 1-3烷基；
所述5-7元杂环烷基、5-10元杂芳基和3～7元杂环烷基分别包含1、2、3或4个独立选自N、-O-、-S-、-NH-的杂原子或杂原子团。
本发明的一些方案中，上述各R分别独立地选自F、Cl、Br、I、OH、NH 2、CN、
Figure PCTCN2018122016-appb-000046
Me、Et、
Figure PCTCN2018122016-appb-000047
哌啶基、吡咯烷基、吖丁啶基、吗啉基和噁丁环基，所述Me、Et、
Figure PCTCN2018122016-appb-000048
哌啶基、吡咯烷基、吖 丁啶基、吗啉基和噁丁环基任选被1、2或3个独立选自F、Cl、Br、I、OH、NH 2和C 1-3烷基的取代基所取代，其他变量如本发明所定义。
本发明的一些方案中，上述各R分别独立地选自F、Cl、Br、I、OH、NH 2、CN、
Figure PCTCN2018122016-appb-000049
Me、
Figure PCTCN2018122016-appb-000050
Figure PCTCN2018122016-appb-000051
其他变量如本发明所定义。
本发明的一些方案中，上述R 1分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、Me和
Figure PCTCN2018122016-appb-000052
所述Me和
Figure PCTCN2018122016-appb-000053
任选被1、2或3个独立选自F、Cl、Br、I、OH、NH 2和CN的取代基所取代，其他变量如本发明所定义。
本发明的一些方案中，上述R 1分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、Me、
Figure PCTCN2018122016-appb-000054
其他变量如本发明所定义。
本发明的一些方案中，上述R 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、Me和CF 3，其他变量如本发明所定义。
本发明的一些方案中，上述R 4选自
Figure PCTCN2018122016-appb-000055
噁丁环基-O-、吗啉基-C 1-3烷基-O-、吖丁啶基-O-、四氢呋喃基-O-、环丙烷基-O-、吡咯烷基-C 1-3烷基-O-和吖丁啶基-C 1-3烷基-O-，所述
Figure PCTCN2018122016-appb-000056
Figure PCTCN2018122016-appb-000057
噁丁环基-O-、吗啉基-C 1-3烷基-O-、吖丁啶基-O-、四氢呋喃基-O-、环丙烷基-O-、吡咯烷基-C 1-3烷基-O-和吖丁啶基-C 1-3烷基-O-任选被1、2或3个R取代，其他变量如本发明所定义。
本发明的一些方案中，上述R 4选自
Figure PCTCN2018122016-appb-000058
Figure PCTCN2018122016-appb-000059
Figure PCTCN2018122016-appb-000060
其他变量如本发明所定义。
本发明的一些方案中，上述R 5和R 6分别独立地选自H、Me、Et和
Figure PCTCN2018122016-appb-000061
所述Me、Et和
Figure PCTCN2018122016-appb-000062
任选被1、2或3个R取代，其他变量如本发明所定义。
本发明的一些方案中，上述R 5和R 6分别独立地选自H、
Figure PCTCN2018122016-appb-000063
其他变量如本发明所定义。
本发明的一些方案中，上述T选自N和C(CN)，其他变量如本发明所定义。
本发明的一些方案中，上述L选自-O-、-NH-、-CH 2-、-CH 2-O-和-CH 2-NH-，其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2018122016-appb-000064
选自
Figure PCTCN2018122016-appb-000065
Figure PCTCN2018122016-appb-000066
其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2018122016-appb-000067
为
Figure PCTCN2018122016-appb-000068
其他变量如本发明所定义。
本发明的一些方案中，上述环A选自苯基、氮茚、苯并[b]噻吩和苯并[d]异噁唑，其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2018122016-appb-000069
选自
Figure PCTCN2018122016-appb-000070
Figure PCTCN2018122016-appb-000071
其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2018122016-appb-000072
选自
Figure PCTCN2018122016-appb-000073
Figure PCTCN2018122016-appb-000074
其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2018122016-appb-000075
选自
Figure PCTCN2018122016-appb-000076
Figure PCTCN2018122016-appb-000077
其他变量如本发明所定义。
本发明的一些方案中，上述环B选自
Figure PCTCN2018122016-appb-000078
Figure PCTCN2018122016-appb-000079
Figure PCTCN2018122016-appb-000080
其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2018122016-appb-000081
选自
Figure PCTCN2018122016-appb-000082
Figure PCTCN2018122016-appb-000083
其他变量如本发明所定义。
本发明还有一些方案由上述变量任意组合而来。
本发明的一些方案中，上述化合物、其异构体或其药学上可接受的盐，其选自
Figure PCTCN2018122016-appb-000084
Figure PCTCN2018122016-appb-000085
其中，T、L、R 1、R 2、R 3、R 4、R 5和R 6如本发明所定义。
本发明的一些方案中，上述化合物、其异构体或其药学上可接受的盐，其选自
Figure PCTCN2018122016-appb-000086
Figure PCTCN2018122016-appb-000087
Figure PCTCN2018122016-appb-000088
其中，T、L、R 1、R 2、R 3、R 4、R 5和R 6如本发明所定义。
本发明还提供了下列化合物、其异构体或其药学上可接受的盐，
Figure PCTCN2018122016-appb-000089
Figure PCTCN2018122016-appb-000090
Figure PCTCN2018122016-appb-000091
Figure PCTCN2018122016-appb-000092
Figure PCTCN2018122016-appb-000093
Figure PCTCN2018122016-appb-000094
本发明的一些方案中，上述化合物，其选自
Figure PCTCN2018122016-appb-000095
Figure PCTCN2018122016-appb-000096
Figure PCTCN2018122016-appb-000097
Figure PCTCN2018122016-appb-000098
Figure PCTCN2018122016-appb-000099
Figure PCTCN2018122016-appb-000100
本发明还提供了一种药物组合物，包括治疗有效量的上述的化合物或其药学上可接受的盐作为活性成分以及药学上可接受的载体。
本发明还提供了上述的化合物或其药学上可接受的盐或者上述组合物在制备Pan-HER酪氨酸激酶抑制剂相关药物上的应用。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。
除非另有说明，“(D)”或者“(+)”表示右旋，“(L)”或者“(-)”表示左旋，“(DL)”或者“(±)”表示外消旋。
除非另有说明，用楔形实线键
Figure PCTCN2018122016-appb-000101
和楔形虚线键
Figure PCTCN2018122016-appb-000102
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2018122016-appb-000103
和直形虚线键
Figure PCTCN2018122016-appb-000104
表示立体中心的相对构型，用波浪线
Figure PCTCN2018122016-appb-000105
表示楔形实线键
Figure PCTCN2018122016-appb-000106
或楔形虚线键
Figure PCTCN2018122016-appb-000107
或用波浪线
Figure PCTCN2018122016-appb-000108
表示直形实线键
Figure PCTCN2018122016-appb-000109
和直形虚线键
Figure PCTCN2018122016-appb-000110
本发明的化合物可以存在特定的。除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构 体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。术语“药学上可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂或载体介质代表性的载体包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。它们的制剂为化妆品领域或局部药物领域的技术人员所周知。
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。当所列举 的连接基团没有指明其连接方向，其连接方向是任意的，例如，
Figure PCTCN2018122016-appb-000111
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 PCTCN2018122016-appb-000112
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 PCTCN2018122016-appb-000113
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
除非另有规定，术语“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)、硅(Si)、锗(Ge)、铝(Al)、硼(B)、-O-、-S-、＝O、＝S、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O) 2-，以及任选被取代的-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O) 2N(H)-或-S(＝O)N(H)-。
除非另有规定，“环”表示被取代或未被取代的环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基、芳基或杂芳基。所谓的环包括单环、联环、螺环、并环或桥环。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。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、吡啶和哌啶基；另一方面，术语“5～7元杂环烷基环”包括吡啶基和哌啶基，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。
除非另有规定，术语“杂环”或“杂环基”意指稳定的含杂原子或杂原子团的单环、双环或三环，它们可以是饱和的、部分不饱和的或不饱和的(芳族的)，它们包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子，其中上述任意杂环可以稠合到一个苯环上形成双环。氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已经定义过的其他取代基)。该杂环可以附着到任何杂原子或碳原子的侧基上从而形成稳定的结构。如果产生的化合物是稳定的，本文所述的杂环可以发生碳位或氮位上的取代。杂环中的氮原子任选地被季铵化。一个优选方案是，当杂环中S及O原子的总数超过1时，这些杂原子彼此不相邻。另一个优选方案是，杂环中S及O原子的总数不超过1。如本文所用，术语“芳族杂环基团”或“杂芳基”意指稳定的5、6、7元单环或双环或7、8、9或10元双环杂环基的芳香环，它包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子。氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已经定义过的其他取代基)。氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。值得注意的是，芳香杂环上S和O原子的总数不超过1。桥环也包含在杂环的定义中。当一个或多个原子(即C、O、N或S)连接两个不相邻的碳原子或氮原子时形成桥环。优选的桥环包括但不限于：一个碳原子、两个碳原子、一个氮原子、两个氮原 子和一个碳-氮基。值得注意的是，一个桥总是将单环转换成三环。桥环中，环上的取代基也可以出现在桥上。
杂环化合物的实例包括但不限于：吖啶基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并巯基呋喃基、苯并巯基苯基、苯并噁唑基、苯并噁唑啉基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异噁唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、苯并二氢吡喃基、色烯、噌啉基十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、吲哚烯基、二氢吲哚基、中氮茚基、吲哚基、3H-吲哚基、异苯并呋喃基、异吲哚基、异二氢吲哚基、异喹啉基、异噻唑基、异噁唑基、亚甲二氧基苯基、吗啉基、萘啶基，八氢异喹啉基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、噁唑烷基、噁唑基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪、吩噻嗪、苯并黄嘌呤基、酚噁嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、哒嗪基、吡啶并噁唑、吡啶并咪唑、吡啶并噻唑、吡啶基、吡咯烷基、吡咯啉基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、四唑基，6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、异噻唑基噻吩基、噻吩并噁唑基、噻吩并噻唑基、噻吩并咪唑基、噻吩基、三嗪基、1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基、4H-1,2,4-三唑基和呫吨基。还包括稠环和螺环化合物。
除非另有规定，术语“烃基”或者其下位概念(比如烷基、烯基、炔基、芳基等等)本身或者作为另一取代基的一部分表示直链的、支链的或环状的烃原子团或其组合，可以是完全饱和的(如烷基)、单元或多元不饱和的(如烯基、炔基、芳基)，可以是单取代或多取代的，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)，可以包括二价或多价原子团，具有指定数量的碳原子(如C 1-C 12表示1至12个碳，C 1-12选自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；C 3-12选自C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11和C 12。)。“烃基”包括但不限于脂肪烃基和芳香烃基，所述脂肪烃基包括链状和环状，具体包括但不限于烷基、烯基、炔基，所述芳香烃基包括但不限于6-12元的芳香烃基，例如苯、萘等。在一些实施例中，术语“烃基”表示直链的或支链的原子团或它们的组合，可以是完全饱和的、单元或多元不饱和的，可以包括二价和多价原子团。饱和烃原子团的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、异丁基、环己基、(环己基)甲基、环丙基甲基，以及正戊基、正己基、正庚基、正辛基等原子团的同系物或异构体。不饱和烃基具有一个或多个双键或三键，其实例包括但不限于乙烯基、2-丙烯基、丁烯基、巴豆基、2-异戊烯基、2-(丁二烯基)、2，4-戊二烯基、3-(1，4-戊二烯基)、乙炔基、1-和3-丙炔基，3-丁炔基，以及更高级的同系物和异构体。
除非另有规定，术语“杂烃基”或者其下位概念(比如杂烷基、杂烯基、杂炔基、杂芳基等等)本身或 者与另一术语联合表示由一定数目的碳原子和至少一个杂原子组成的，稳定的直链、支链或环状的烃原子团或其组合。在一些实施例中，术语“杂烷基”本身或者与另一术语联合表示由一定数目的碳原子和至少一个杂原子组成的，稳定的直链或支链的烷基原子团或其组合物。在一个典型实施例中，杂原子选自B、O、N和S，其中氮和硫原子任选地被氧化，氮杂原子任选地被季铵化。杂原子或杂原子团可以位于杂烃基的任何内部位置，包括该烃基与分子其余部分的连接位置，但术语“烷氧基”、“烷氨基”和“烷硫基”(或硫代烷氧基)属于惯用表达，是指分别通过一个氧原子、氨基或硫原子连接到分子的其余部分的那些烷基基团。实例包括但不限于-CH 2-CH 2-O-CH 3、-CH 2-CH 2-NH-CH 3、-CH 2-CH 2-N(CH 3)-CH 3、-CH 2-S-CH 2-CH 3、-CH 2-CH 2、-S(O)-CH 3、-CH 2-CH 2-S(O) 2-CH 3、-CH＝CH-O-CH 3、-CH 2-CH＝N-OCH 3和–CH＝CH-N(CH 3)-CH 3。至多两个杂原子可以是连续的，例如-CH 2-NH-OCH 3。
除非另有规定，术语“环烃基”、“杂环烃基”或者其下位概念(比如芳基、杂芳基、环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基等等)本身或与其他术语联合分别表示环化的“烃基”、“杂烃基”。此外，就杂烃基或杂环烃基(比如杂烷基、杂环烷基)而言，杂原子可以占据该杂环附着于分子其余部分的位置。环烃基的实例包括但不限于环戊基、环己基、1-环己烯基、3-环己烯基、环庚基等。杂环基的非限制性实例包括1-(1,2,5,6-四氢吡啶基)、1-哌啶基、2-哌啶基，3-哌啶基、4-吗啉基、3-吗啉基、四氢呋喃-2-基、四氢呋喃吲哚-3-基、四氢噻吩-2-基、四氢噻吩-3-基，1-哌嗪基和2-哌嗪基。
除非另有规定，术语“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”，此外，就该“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。在一些实施方案中，所述杂环烷基为4～6元杂环烷基；在另一些实施方案中，所述杂环烷基为5～6元杂环烷。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、四氢呋喃基、四氢吡喃基、哌啶基、哌嗪基、吗啉基、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。
除非另有规定，术语“烷基”用于表示直链或支链的饱和烃基,可以是单取代(如-CH 2F)或多取代的(如-CF 3)，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。烷基的例子包括甲基(Me)，乙基(Et)，丙基(如，n-丙基和异丙基)，丁基(如，n-丁基，异丁基，s-丁基，t-丁基)，戊基(如，n-戊基，异戊基，新戊基)等。
除非另有规定，环烷基包括任何稳定的环状或多环烃基，任何碳原子都是饱和的，可以是单取代或多取代的，可以是一价、二价或者多价。这些环烷基的实例包括，但不限于，环丙基、降冰片烷基、[2.2.2]二环辛烷、[4.4.0]二环癸烷等。
除非另有规定，术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。此外，术语“卤代烷基”意在包括单卤代烷基和多卤代烷基。例如，术语“卤代(C 1-C 4)烷基”意在包括但不仅 限于三氟甲基、2，2，2-三氟乙基、4-氯丁基和3-溴丙基等等。除非另有规定，卤代烷基的实例包括但不仅限于：三氟甲基、三氯甲基、五氟乙基，和五氯乙基。
“烷氧基”代表通过氧桥连接的具有特定数目碳原子的上述烷基，除非另有规定，C 1-6烷氧基包括C 1、C 2、C 3、C 4、C 5和C 6的烷氧基。烷氧基的例子包括但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基和S-戊氧基。
除非另有规定，术语“芳基”表示多不饱和的芳族烃取代基，可以是单取代或多取代的，可以是一价、二价或者多价，它可以是单环或多环(比如1至3个环；其中至少一个环是芳族的)，它们稠合在一起或共价连接。术语“杂芳基”是指含有一至四个杂原子的芳基(或环)。在一个示范性实例中，杂原子选自B、N、O和S，其中氮和硫原子任选地被氧化，氮原子任选地被季铵化。杂芳基可通过杂原子连接到分子的其余部分。芳基或杂芳基的非限制性实施例包括苯基、萘基、联苯基、吡咯基、吡唑基、咪唑基、吡嗪基、噁唑基、苯基-噁唑基、异噁唑基、噻唑基、呋喃基、噻吩基、吡啶基、嘧啶基、苯并噻唑基、嘌呤基、苯并咪唑基、吲哚基、异喹啉基、喹喔啉基、喹啉基、1-萘基、2-萘基、4-联苯基、1-吡咯基、2-吡咯基、3-吡咯基、3-吡唑基、2-咪唑基、4-咪唑基、吡嗪基、2-噁唑基、4-噁唑基、2-苯基-4-噁唑基、5-噁唑基、3-异噁唑基、4-异噁唑基、5-异噁唑基、2-噻唑基、4-噻唑基、5-噻唑基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-苯并噻唑基、嘌呤基、2-苯并咪唑基、5-吲哚基、1-异喹啉基、5-异喹啉基、2-喹喔啉基、5-喹喔啉基、3-喹啉基和6-喹啉基。上述任意一个芳基和杂芳基环系的取代基选自下文所述的可接受的取代基。
除非另有规定，芳基在与其他术语联合使用时(例如芳氧基、芳硫基、芳烷基)包括如上定义的芳基和杂芳基环。因此，术语“芳烷基”意在包括芳基附着于烷基的那些原子团(例如苄基、苯乙基、吡啶基甲基等)，包括其中碳原子(如亚甲基)已经被例如氧原子代替的那些烷基，例如苯氧基甲基、2-吡啶氧甲基3-(1-萘氧基)丙基等。
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲和取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基； 酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明的化合物可以有多种用途或适应症，包括但不限于本申请所列举的具体用途或适应症。
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词：aq代表水；HATU代表O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐；EDC代表N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐；m-CPBA代表3-氯过氧苯甲酸；eq代表当量、等量；CDI代表羰基二咪唑；DCM代表二氯甲烷；PE代表石油醚；DIAD代表偶氮二羧酸二异丙酯；DMF代表N,N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；CBz代表苄氧羰基，是一种胺保护基团；BOC代表叔丁氧羰基是一种胺保护基团；HOAc代表乙酸；NaCNBH 3代表氰基硼氢化钠；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc 2O代表二-叔丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；SOCl 2代表氯化亚砜；CS 2代表二硫化碳；TsOH代表对甲苯磺酸；NFSI代表N-氟-N-(苯磺酰基)苯磺酰胺；NCS代表1-氯吡咯烷-2,5-二酮；n-Bu 4NF代表氟化四丁基铵；iPrOH代表2-丙醇；mp代表熔点；LDA代表二异丙基胺基锂；DEA代表二乙胺；ACN代表乙腈；HATU代表2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；DIEA代表N,N-二异丙基乙胺；PBS代表磷酸盐缓冲溶液；Matrigel代表基质胶。
化合物依据本领域常规命名原则或者使用
Figure PCTCN2018122016-appb-000114
软件命名，市售化合物采用供应商目录名称。
技术效果：本发明化合物对HER1、HER2和HER4抑制活性明显，并且对NCI-N87细胞BT-474细胞增殖抑制活性明显。人胃癌NCI-N87细胞皮下异种移植肿瘤BALB/c裸小鼠模型的体内药效学研究结果显示本发明化合物有显著抑制肿瘤生长的效果且起效剂量下对小鼠体重无显著影响，安全性更好。
附图说明
图1：人食管癌OE21细胞皮下异种移植肿瘤BALB/c裸小鼠模型的相对体重变化(％)
相对体重变化基于开始给药时动物体重计算得出。数据点代表组内平均体重变化百分比，误差线代表标准误(SEM)。
PO：口服给药；QD：每天一次；D1-D7：给药第1天到第7天；D8-D21：给药8天到第21天；D1-D2：给药1天到第2天；D3-D21：给药3天到第21天；n＝6：每组6只小鼠。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述 了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
参考例1
Figure PCTCN2018122016-appb-000115
合成路线：
Figure PCTCN2018122016-appb-000116
将化合物A-1(500.0mg,4.42mmol)和三乙胺(1.12g,11.05mmol)溶于二氯甲烷(20mL)中，加入二碳酸二叔丁酯(1.01g,4.64mmol)，反应液在10℃搅拌16小时。反应液用饱和氯化铵溶液(20mL)洗涤两次，无水硫酸钠干燥。过滤，滤液减压浓缩，剩余物用石油醚(3mL)打浆得化合物A-2。 1H NMR(400MHz,CDCl 3)δ4.05-4.15(m,1H),3.50-3.62(m,4H),2.40-2.60(m,2H),2.04(d,J＝7.2Hz,1H),1.52-1.60(m,1H),1.47(s,9H)1.30-1.40(m,1H)。
实施例1
Figure PCTCN2018122016-appb-000117
合成路线：
Figure PCTCN2018122016-appb-000118
第一步
将金属钠(1.84g,80.15mmol)加入到无水甲醇(100mL)，氮气保护下于30℃搅拌30分钟。反应液冷却到0℃，加入化合物1-1(10g,53.44mmol)，反应液在70℃搅拌16小时。反应液冷却到0℃，倒入1N稀盐酸(100mL)，加水(200mL)稀释，用二氯甲烷萃取(200mLx2)。合并有机相，用无水硫酸钠干燥。过滤，滤液减压浓缩，剩余物用硅胶柱层析法分离纯化(乙酸乙酯:石油醚＝1:8)，得到化合物1-2。 1H NMR(400MHz,CDCl 3)δ7.53(d,J＝12.4Hz,1H),6.15(d,J＝6.8Hz,1H),5.69(brs,2H),3.87(s,3H),3.84(s,3H)。LC-MS:m/z＝199.9[M+H] +。
第二步
在90℃，将化合物1-2(5.00g,25.10mmol)的二氯乙烷(100mL)溶液缓慢滴加到间氯过氧苯甲酸(85％,20.39g,100.41mmol)的二氯乙烷(200mL)溶液中。反应液在90℃搅拌2小时。反应液冷却到0℃，加饱和亚硫酸钠水溶液(300mL)淬灭，混合物用二氯甲烷萃取(300mLx2)。合并有机相，依次用饱和碳酸氢钠溶液(300mLx2)，水(300mLx2)，饱和食盐水(300mLx2)洗涤，用无水硫酸钠干燥。过滤，滤液减压浓缩，剩余物用硅胶柱层析法分离纯化(乙酸乙酯:石油醚＝1:8)，得到化合物1-3。 1H NMR(400MHz,CDCl 3)δ7.47(d,J＝10.4Hz,1H),7.43(d,J＝7.2Hz,1H),3.98(s,3H),3.89(s,3H)。
第三步
将化合物1-3(730.0mg,3.19mmol)溶于N,N-二甲基甲酰胺(10mL)，加入碳酸铯(2.08g,6.37mmol)和化合物A-2(679.0mg,3.19mmol)，反应液加热至65℃，搅拌3小时。反应液冷却到20℃，加入水(30.0mL)稀释，用乙酸乙酯(30mLx2)萃取。合并有机相，依次用水(40mLx2)，饱和食盐水(40mLx2)洗涤，用无水硫酸钠干燥。过滤，滤液减压浓缩，剩余物用硅胶柱层析法分离纯化(石油醚:乙酸乙酯＝8:1)，得到化合物1-4。 1H NMR(400MHz,CDCl 3)δ7.44(s,1H),7.03(s,1H),4.54(t,J＝5.6Hz,1H),3.92(s,3H),3.89(s,3H),3.89(td,J 1＝12.0Hz,J 2＝3.2Hz,2H),3.51(t,J＝11.2Hz,2H),2.80-2.95(m,2H),1.75-1.85(m,1H),1.55-1.65(m,1H),1.47(s,9H)。LC-MS:m/z＝445.2[M+Na] +。
第四步
将化合物1-4(740.0mg,1.75mmol)溶于甲醇(100mL)中，加入湿钯碳(10％,150mg)，反应液在20℃，氢气氛围下(氢气球)搅拌0.5小时。反应液经硅藻土过滤，滤液减压浓缩，得到化合物1-5。 1H NMR(400MHz,CDCl 3)δ7.29(s,1H),6.12(s,1H),4.30-4.40(m,1H),3.83(s,3H),3.81(s,3H),3.55-3.65(m,4H),2.70-2.85(m,2H),1.65-1.75(m,1H),1.50-1.55(m,1H),1.47(s,9H)。
第五步
将化合物1-5(687.0mg,1.75mmol)和醋酸氨(675.0mg,8.75mmol)加入原甲酸三甲酯(17.09g,161.02mmol)中，反应液加热至70℃，搅拌10小时。反应液冷却到30℃，减压浓缩。残余物加水(10mL)打浆，过滤，滤饼干燥得到化合物1-6。 1H NMR(400MHz,DMSO-d 6)δ12.08(brs,1H),7.99(s,1H),7.47(s,1H),7.15(s,1H),4.65(t,J＝5.6Hz,1H),3.89(s,3H),3.45-3.60(m,2H),3.10-3.20(m,2H),2.75-2.90(m,2H),1.75-1.85(m,1H),1.40-1.50(m,1H),1.40(s,9H)。LC-MS:m/z＝410.1[M+Na] +。
第六步
将化合物1-6(640.0mg,1.65mmol)加入氯化氢的二氧六环溶液(4N,10mL)，反应液在0℃下搅拌0.4小时。减压浓缩得到合物1-7的盐酸盐。 1H NMR(400MHz,DMSO-d 6)δ9.72(brs,1H),9.02(brs,1H),8.34(s,1H),7.56(s,1H),7.27(s,1H),4.76(t,J＝6.0Hz,1H),3.96(s,3H),3.35-3.45(m,2H),3.20-3.35(m,2H),2.89-2.95(m,2H),2.01-2.08(m,1H),1.90-2.00(m,1H)。
第七步
在0℃，将1-7的盐酸盐(640.0mg,1.98mmol)，三乙胺(2.00g,19.77mmol)溶入二氯甲烷(10mL)中，滴加三氟乙酸酐(830.0mg,3.95mmol)。反应液在20℃下搅拌2小时。向反应液中加入饱和碳酸氢钠水溶液(10mL)淬灭，用二氯甲烷(10mLx2)萃取。合并有机相，用无水硫酸钠干燥。过滤，滤液减压浓缩得到化合物1-8。 1H NMR(400MHz,DMSO-d 6)δ12.10(s,1H),8.00(s,1H),7.52(s,1H),7.15(s,1H),4.84(t,J＝5.6Hz,1H),3.90-4.00(m,1H),3.87(s,3H),3.65-3.85(m,2H),3.45-3.55(m,1H),2.90-3.00(m,2H),1.90-2.00(m,1H),1.50-1.60(m,1H)。
第八步
将化合物1-8(270.0mg,704.37μmol)溶于氯化亚砜(13.1mL,180.28mmol)，加入N,N-二甲基甲酰胺(26.0μL,338.10μmol)。反应液加热至80℃，搅拌1小时。反应液减压浓缩，剩余物室温下加入3,4-二氯-2-氟苯胺(392.0mg,2.18mmol)的异丙醇(10mL)溶液，加热至90℃，搅拌1小时。反应液冷却到20℃，加入饱和碳酸氢钠溶液(10mL)淬灭，用乙酸乙酯(10mLx2)萃取。合并有机相，用无水硫酸钠干燥。过滤，滤液减压浓缩，剩余物用硅胶柱层析法分离纯化(乙酸乙酯:石油醚＝2:1)，得到化合物1-9。 1H NMR(400MHz,DMSO-d 6)δ9.68(s,1H),8.41(s,1H),7.80(s,1H),7.60(s,2H),7.24(s,1H),4.82(t,J＝6.0Hz,1H),3.95-4.05(m,1H),3.91(s,3H),3.70-3.95(m,2H),3.50-3.60(m,1H),3.05-3.15(m,2H),1.85-1.95(m,1H),1.55-1.65(m,1H)。LC-MS:m/z＝545.0[M+H] +。
第九步
将化合物1-9(300.0mg,551.14umol)溶于甲醇(15mL)中，加入碳酸钾(380.9mg,2.76mmol)。反应液在40℃下搅拌14个小时。减压浓缩，加水(10mL)稀释，用乙酸乙酯(40mLx4)萃取。合并有机相，用无水硫酸钠干燥。过滤，滤液减压浓缩得到化合物1-10。 1H NMR(400MHz,DMSO-d 6)δ9.81(s,1H),8.41(s,2H),7.76(s,1H),7.59(s,2H),7.29(s,1H),4.73(t,J＝6.0Hz,1H),3.99(s,3H),3.20-3.30(m,4H),2.95-3.05(m,2H),1.95-2.05(m,1H),1.75-1.85(m,1H)。LC-MS:m/z＝449.1[M+H] +。
第十步
在0℃下，将化合物1-10(240.0mg,534.16μmol)溶于四氢呋喃(6mL)和水(6mL)的混合溶剂，加入碳酸氢钠(134.6mg,1.60mmol)后，缓慢滴加丙烯酰氯(48.4mg,534.16μmol)。反应液在0℃继续搅拌0.5小时。加入甲醇(1mL)淬灭，反应液减压浓缩，剩余物用制备薄层层析板分离纯化(二氯甲烷:甲醇＝10:1)，得到化合物实施例1。 1H NMR(400MHz,CDCl 3)δ8.68(s,1H),8.43(t,J＝8.8Hz,1H),7.34-7.45(m,2H),7.10(s,1H),6.60(dd,J 1＝16.8Hz,J 2＝9.6Hz,1H),5.71(dd,J 1＝16.8Hz,J 2＝2.0,Hz,1H),6.60(dd,J 1＝9.6Hz,J 2＝2.0Hz,1H),4.66(t,J＝5.6Hz,1H),3.96(s,3H),3.85-3.95(m,2H),3.65-3.75(m,2H),2.95-3.05(m,2H),1.85-1.95(m,1H),1.55-1.65(m,1H)。LC-MS:m/z＝503.1[M+H] +。
实施例2
Figure PCTCN2018122016-appb-000119
合成路线：
Figure PCTCN2018122016-appb-000120
第一步
参照实施例1第八步得到化合物2-2。 1H NMR(400MHz,DMSO-d 6)δ11.79(s,1H),8.44(s,1H),8.37(s,1H),7.60-7.70(m,1H),7.45-7.55(m,1H),7.35(s,1H),4.95(t,J＝5.6Hz,1H),4.00-4.05(m,1H),3.97(s,3H),3.70-3.90(m,3H),3.10-3.20(m,2H),1.80-1.90(m,1H),1.61(d,J＝10.4Hz,1H)。LC-MS:m/z＝529.1[M+H] +。
第二步
将化合物2-2(70.0mg,132.61μmol)溶于甲醇(2mL)中，加入碳酸钾(91.6mg,663.04μmol)。反应液在50℃搅拌14个小时。反应液减压浓缩，加水(10mL)稀释，用乙酸乙酯(20mLx4)萃取。合并有机相，用无水硫酸钠干燥。过滤，滤液减压浓缩得到化合物2-3。 1H NMR(400MHz,DMSO-d 6)δ9.78(s,1H),8.39(s,2H),7.79(s,1H),7.50-7.60(m,1H),7.38-7.48(m,1H),7.29(s,1H),4.74(t,J＝6.0Hz,1H),3.99(s,3H),3.40-3.50(m,4H),2.95-3.05(m,2H),1.98(d,J＝11.2Hz,1H),1.80-1.90(m,1H)。LC-MS:m/z＝433.1[M+H] +。
第三步
参照实施例1第十步得到化合物实施例2。 1H NMR(400MHz,DMSO-d 6)δ9.66(s,1H),8.37(s,1H),7.79(s,1H),7.55-7.65(m,1H),7.41(t,J＝8.4Hz,1H),7.22(s,1H),6.75(dd,J 1＝16.8Hz,J 2＝10.4Hz,1H),6.16(d,J＝16.8,Hz,1H),5.68(d,J＝9.6Hz,1H),4.65-4.75(m,1H),3.90-3.95(m,1H),3.90(s,3H),3.65-3.85(m,2H), 3.45-3.55(m,1H),3.02-3.12(m,2H),1.75-1.85(m,1H),1.51(d,J＝10.0Hz,1H)。LC-MS:m/z＝487.0[M+H] +.
实施例3
Figure PCTCN2018122016-appb-000121
合成路线：
Figure PCTCN2018122016-appb-000122
第一步
参照实施例1第八步得到化合物3-2。 1H NMR(400MHz,DMSO-d 6)δ11.45(s,1H),8.87(s,1H),8.35(s,1H),8.01-8.07(m,1H),7.70-7.80(m,1H),7.57(t,J＝8.8Hz,1H),7.31(s,1H),4.98(t,J＝5.6Hz,1H),3.96-4.44(m,1H),3.96(s,3H),3.70-3.85(m,2H),3.50-3.55(m,1H),1.80-1.90(m,1H),1.62(d,J＝10.4Hz,1H)。LC-MS:m/z＝511.1[M+H] +。
第二步
参照实施例2第二步得到化合物3-3。 1H NMR(400MHz,DMSO-d 6)δ9.60(s,1H),8.50(s,1H),8.05-8.12(m,1H),7.70-7.85(m,2H),7.46(t,J＝9.2Hz,1H),7.26(s,1H),4.75(t,J＝5.6Hz,1H),3.98(s,3H),3.15-3.30(m,2H),2.95-3.10(m,2H),2.88-2.95(m,2H),1.90-2.00(m,1H),1.70-1.80(m,1H)。LC-MS:m/z＝415.1[M+H] +。
第三步
在0℃下，将化合物3-3(40.0mg,96.42μmol)溶于四氢呋喃(4mL)和水(4mL)的混合溶剂，加入碳酸氢钠(24.3mg,289.25μmol)，缓慢滴加丙烯酰氯(10.57mg,115.70μmol)。反应液在0℃继续搅拌0.5小时。反应液加入甲醇(1mL)淬灭，反应液用乙酸乙酯(20mLx2)萃取，合并有机相，用无水硫酸钠干燥。过滤，滤液减压浓 缩，剩余物用制备薄层层析板分离纯化(二氯甲烷:甲醇＝10:1)得到化合物实施例3。 1H NMR(400MHz,DMSO-d 6)δ9.59(s,1H),8.49(s,1H),8.08-8.12(m,1H),7.75-7.85(m,2H),7.46(t,J＝9.2Hz,1H),7.22(s,1H),6.74(dd,J 1＝16.4Hz,J 2＝10.0Hz,1H),6.17(d,J＝12.0Hz,1H),5.69(d,J＝10.0Hz,1H),4.73(t,J＝5.6,Hz,1H),3.95-4.00(m,1H),3.89(s,3H),3.65-3.80(m,2H),3.40-3.50(m,1H),3.05-3.10(m,2H),1.75-1.90(m,1H),1.51(d,J＝10.0Hz,1H)。LC-MS:m/z＝469.1[M+H] +。
实施例4
Figure PCTCN2018122016-appb-000123
合成路线：
Figure PCTCN2018122016-appb-000124
第一步
参照实施例1第八步得到化合物4-2。 1H NMR(400MHz,DMSO-d 6)δ11.50(s,1H),8.94(s,1H),8.47(s,1H),8.39(d,J＝2.0Hz 1H),8.10-8.15(m,1H),8.05-8.10(m,1H),7.35(s,1H),5.06(t,J＝5.6Hz,1H),3.97(s,3H),3.70-3.90(m,4H),3.10-3.20(m,2H),1.80-1.90(m,1H),1.61(d,J＝10.4Hz,1H)。LC-MS:m/z＝518.1[M+H] +。
第二步
参照实施例1第九步得到化合物4-3。 1H NMR(400MHz,DMSO-d 6)δ9.90(s,1H),8.64(s,1H),8.37(s,1H),8.05-8.15(m,1H),7.90-8.00(m,1H),7.72(s,1H),7.30(s,1H),4.70-4.80(m,1H),3.99(s,3H),3.02-3.10(m,2H),2.75-2.85(m,4H),1.93(d,J＝9.6Hz,1H),1.60-1.70(m,1H)。LC-MS:m/z＝422.1[M+H] +。
第三步
参照实施例3第三步得到化合物实施例4。 1H NMR(400MHz,DMSO-d 6)δ9.91(s,1H),8.65(s,1H),8.39(s,1H),8.05-8.15(m,1H),7.92-8.00(m,1H),7.85(s,1H),7.28(s,1H),6.74(dd,J 1＝16.4Hz,J 2＝10.4Hz,1H),6.18(dd,J 1＝16.4Hz,J 2＝2.4Hz,1H),5.60(dd,J 1＝10.4Hz,J 2＝2.4Hz,1H),4.77(t,J＝5.6Hz,1H),3.92(s,3H),3.85-3.90(m,1H),3.65-3.80(m,2H),3.40-3.50(m,1H),3.00-3.10(m,2H),1.80-1.90(m,1H),1.52(d,J＝10.0Hz,1H)。LC-MS:m/z＝476.0[M+H] +。
实施例5
Figure PCTCN2018122016-appb-000125
合成路线：
Figure PCTCN2018122016-appb-000126
第一步
参照实施例1第八步得到化合物5-2。 1H NMR(400MHz,DMSO-d 6)δ11.92(s,1H),8.87(s,1H),8.41(s,1H),7.65-7.75(m,1H),7.50-7.65(m,1H),7.35-7.45(m,2H),4.97(t,J＝5.6Hz,1H),3.98-4.00(m,1H),3.98(s,3H),3.70-3.90(m,3H),3.10-3.20(m,2H),1.80-1.90(m,1H),1.62(d,J＝10.0Hz,1H)。LC-MS:m/z＝511.2[M+H] +。
第二步
参照实施例1第九步得到化合物5-3。 1H NMR(400MHz,DMSO-d 6)δ9.87(s,1H),8.40(s,1H),7.85(s,1H),7.45-7.60(m,1H),7.20-7.40(m,2H),4.60(t,J＝5.6Hz1H),3.99(s,3H),3.30-3.50(m,4H),3.00-3.15(m,2H),2.00-2.10(m,1H),1.80-1.90(m,1H)。LC-MS:m/z＝415.1[M+H] +。
第三步
参照实施例3第三步得到化合物实施例5。 1H NMR(400MHz,DMSO-d 6)δ9.67(s,1H),8.38(s,1H),7.76(s,1H),7.50-7.60(m,2H),7.25-7.35(m,1H),7.22(s,1H),6.75(dd,J 1＝16.4,J 2＝10.4Hz,1H),6.18(dd,J 1＝16.4Hz,J 2＝2.0Hz,1H),5.69(dd,J 1＝10.4Hz,J 2＝2.4Hz,1H),4.71(t,J＝5.6Hz,1H),3.95-4.00(m,1H),3.92(s,3H),3.65-3.80(m,2H),3.42-3.50(m,1H),3.00-3.10(m,2H),1.75-1.85(m,1H),1.52(d,J＝10.0Hz,1H)。LC-MS:m/z＝469.0[M+H] +。
实施例6
Figure PCTCN2018122016-appb-000127
合成路线：
Figure PCTCN2018122016-appb-000128
第一步
参照实施例1第八步得到化合物6-2。 1H NMR(400MHz,DMSO-d 6)δ9.77(s,1H),8.56(s,1H),8.27(s,1H),7.90-7.80(m,2H),7.55-7.65(m,1H),7.25(s,1H),4.90(t,J＝5.6Hz,1H),3.92-4.00(m,1H),3.95(s,3H),3.80-3.90(m,1H),3.70-3.80(m,1H),3.50-3.60(m,1H),3.00-3.10(m,2H),1.80-1.90(m,1H),1.60(d,J＝10.0Hz,1H)。LC-MS:m/z＝577.1[M+H] +。
第二步
参照实施例2第二步得到化合物6-3。 1H NMR(400MHz,DMSO-d 6)δ10.01(s,1H),8.57(s,1H),8.33(s,1H),8.00-8.10(m,2H),7.55-7.70(m,1H),7.32(s,1H),4.80-4.90(m,1H),4.00(s,3H),3.00-3.20(m,4H),1.80-2.10(m,2H),1.10-1.30(m,2H)。LC-MS:m/z＝481.1[M+H] +。
第三步
参照实施例1第十步得到化合物实施例6。 1H NMR(400MHz,DMSO-d 6)δ9.68(s,1H),8.54(s,1H),8.23(s,1H),7.90-8.00(m,1H),7.81(s,1H),7.55-7.65(m,1H),7.24(s,1H),6.65-6.80(m,1H),6.17(d,J＝15.2Hz,1H),5.68(d,J＝8.8Hz,1H),4.70-4.80(m,1H),3.90(s,3H),3.80-3.90(m,1H),3.50-3.80(m,3H),3.00-3.10(m,2H),1.80-1.90(m,1H),1.45-1.55(m,1H)。LC-MS:m/z＝535.1[M+H] +。
实施例7
Figure PCTCN2018122016-appb-000129
合成路线：
Figure PCTCN2018122016-appb-000130
第一步
将化合物B-1(2.60g,11.54mmol)溶于乙醇(30mL)，加入硼氢化钠(1.09g,28.85mmol)，反应液在30℃搅拌2小时。加入饱和氯化铵溶液(30mL)淬灭，用二氯甲烷(40mLx2)萃取。合并有机相，用饱和食盐水(40mLx2)洗涤，无水硫酸钠干燥。过滤，滤液并减压浓缩得到化合物B-2。 1H NMR(400MHz,CDCl 3)δ4.00-4.32 (m,3H),2.10-2.20(m,1H),1.90-2.00(m,3H),1.60-1.90(m,4H),1.40-1.50(m,9H)。
第二步
将化合物B-2(2.60g,11.44mmol)和三乙胺(3.2mL,22.88mmol)，4-二甲氨基吡啶(1.68g,13.73mmol)溶于二氯甲烷(60mL)中，加入对甲基苯磺酰氯(2.62g,13.73mmol)，反应液在25℃搅拌16小时。加入饱和氯化铵水溶液(60mLx3)淬灭，有机相用饱和食盐水(60mL)洗涤，无水硫酸钠干燥。过滤，滤液减压浓缩得到化合物B-3。 1H NMR(400MHz,CDCl 3)δ7.77(d,J＝8.0Hz,2H),7.33(d,J＝8.0Hz,2H),4.75-4.90(m,1H),4.05-4.25(m,2H),2.45(s,3H),1.50-1.90(m,4H),1.85-2.20(m,4H),1.30-1.45(s,9H)。LC-MS:m/z＝404.1[M+Na] +。
第三步
将化合物7-1(2.00g,5.65mmol)和碳酸钾(1.56g,11.29mmol)加入N,N-二甲基乙酰胺(20mL)中，再加入化合物B-3(4.20g,8.47mmol)。反应加热至70℃，搅拌16小时。反应液冷却到30℃，倒入水(30mL)中，用乙酸乙酯(20mLx3)萃取。合并有机相，依次用水(30mLx3)和饱和食盐水(30mLx3)洗涤，用无水硫酸钠干燥。过滤，滤液减压浓缩，剩余物用硅胶柱层析法分离纯化(石油醚:乙酸乙酯＝1:1)，得到化合物7-2和8-1。
化合物7-2: 1H NMR(400MHz,CDCl 3)δ8.67(s,1H),8.42(t,J＝8.4Hz,1H),7.26-7.40(m,3H),6.96(s,1H),4.80-4.90(m,1H),4.15-4.35(m,2H),4.00(s,3H),2.10-2.35(m,4H),1.90-2.10(m,4H),1.48(s,9H)。根据二维核磁NOE鉴定:哌啶环与氧原子相连碳上的单氢与桥环上的亚甲基氢未见相关，确定为顺式结构。LC-MS:m/z 563.2[M+H] +。
化合物8-1: 1H NMR(400MHz,CDCl 3)δ8.70(s,1H),8.53(t,J＝8.4Hz,1H),7.26-7.40(m,3H),7.21(s,1H),4.70-4.80(m,1H),4.20-4.40(m,2H),4.01(s,3H),2.10-2.20(m,4H),1.85-2.00(m,2H),1.65-1.80(m,2H),1.50(s,9H)。根据二维核磁NOE鉴定:哌啶环与氧原子相连碳上的单氢与桥环上的亚甲基氢哪个相关，确定为反式结构。LC-MS:m/z 563.2[M+H] +。
第四步
将化合物7-2(400.0mg,709.92μmol)溶于氯化氢的二氧六环溶液(4N,6mL)中，反应液在0℃反应0.3小时。反应液减压浓缩，加水(10mL)稀释，用乙酸乙酯(10mL)洗涤。水相用碳酸钾固体调整pH＝10，用乙酸乙酯(10mLx3)萃取。合并有机相，用无水硫酸钠干燥，滤液减压浓缩，剩余物用制备薄层层析板分离纯化(甲醇:二氯甲烷＝1:10)，得到化合物7-3。 1H NMR(400MHz,DMSO-d 6)δ9.96(s,1H),8.39(s,1H),7.96(s,1H),7.55-7.65(m,2H),7.26(s,1H),4.95-5.00(m,1H),3.90-4.05(m,5H),2.45-2.50(m,2H),2.25-2.35(m,2H),2.10-2.20(m,2H),1.90-2.05(m,2H)。
第五步
在0℃下将化合物7-3(230.0mg,496.41μmol)溶于四氢呋喃(6mL)和水(6mL)的混合溶剂，加入碳酸氢钠(125.1mg,1.49mmol)后，缓慢滴入丙烯酰氯(35.9mg,397.12μmol)。反应液在0℃下，继续搅拌0.5小时。加入甲醇(1mL)淬灭，减压浓缩，剩余物用制备薄层层析板分离纯化(二氯甲烷:甲醇＝10:1)，得到化合物实施例7。 1H NMR(400MHz,DMSO-d 6)δ9.63(s,1H),8.39(s,1H),7.74(s,1H),7.50-7.60(m,2H),7.26(s,1H),6.75(dd,J 1＝16.4Hz,J 2＝10.0Hz,1H),6.19(dd,J 1＝16.4Hz,J 2＝2.4Hz,1H),5.70(dd,J 1＝10.0Hz,J 2＝2.4Hz,1H),4.88-4.90(m,1H),4.50-4.61(m,2H),3.97(s,3H),2.20-2.30(m,2H),1.95-2.15(m,5H),1.80-1.95(m,1H)。LC-MS:m/z＝517.1[M+H] +。
实施例8
Figure PCTCN2018122016-appb-000131
合成路线：
Figure PCTCN2018122016-appb-000132
第一步
参考实施例7第四步得到化合物8-2。 1H NMR(400MHz,DMSO-d 6)δ10.13(s,1H),8.39(s,1H),8.10(s,1H),7.55-7.70(m,2H),7.23(s,1H),4.90-5.00(m,1H),3.90-4.05(m,2H),3.94(s,3H),2.30-2.40(m,2H),2.10-2.20(m,2H),1.80-2.00(m,4H)。
第二步
参考实施例7第五步得到化合物实施例8。 1H NMR(400MHz,DMSO-d 6)δ9.67(s,1H),8.39(s,1H),7.80(s,1H),7.55-7.70(m,2H),7.26(s,1H),6.77(dd,J 1＝16.4Hz,J 2＝10.4Hz,1H),6.23(dd,J 1＝16.4Hz,J 2＝2.4Hz,1H),5.72(dd,J 1＝10.4Hz,J 2＝2.4Hz,1H),4.90-5.10(m,1H),4.55-4.60(m,2H),3.92(s,3H),2.20-2.40(m,2H),1.80-2.10(m,4H),1.66(t,J＝10.4Hz,1H),1.50(t,J＝10.4Hz,1H)。LC-MS:m/z＝517.1[M+H] +。
实施例9
Figure PCTCN2018122016-appb-000133
合成路线：
Figure PCTCN2018122016-appb-000134
第一步
将化合物A-2(2.00g,9.38mmol)溶于二氯甲烷(50mL)，加入戴斯-马丁氧化剂(4.77g,11.25mmol)，反应液在25℃搅拌2小时。加入饱和碳酸氢钠水溶液(30mL)淬灭，用二氯甲烷萃取(30mLx2)。合并有机相，用无水硫酸钠干燥。过滤，滤液减压浓缩。剩余物用硅胶柱层析法分离纯化(乙酸乙酯:石油醚＝1:4)，得到化合物C-2。 1H NMR(400MHz,CDCl 3)δ3.95-4.10(m,2H),3.85-3.95(m,2H),3.10-3.20(m,2H),2.10-2.20 (m,1H),1.75-1.80(m,1H),1.45(s,9H)。
第二步
将化合物C-2(1.70g,8.05mmol)溶于甲醇(20mL)中，加入盐酸羟胺(671.0mg,9.66mmol)和碳酸钠(511.7mg,4.83mmol)，反应液在25℃搅拌16小时。反应液减压浓缩，加入二氯甲烷(30mL)稀释，用饱和碳酸氢钠水溶液(20mL)洗涤，无水硫酸钠干燥。过滤，滤液减压浓缩得到化合物C-3。 1H NMR(400MHz,CDCl 3)δ7.40-7.50(m,1H),3.70-3.90(m,4H),3.45-3.60(m,1H),3.05-3.20(m,1H),2.10-2.20(m,1H),1.60-1.65(m,1H),1.46(s,9H)。
第三步
将化合物C-3(2.00g,8.84mmol)溶于甲醇(20mL)，加入雷尼镍(0.50g)，反应液在20℃，氢气氛围下(氢气球)搅拌16小时。反应液经过硅藻土过滤，滤液减压浓缩，干燥得到化合物C-4。 1H NMR(400MHz,CDCl 3)δ3.85-4.10(m,1H),3.45-3.75(m,4H),2.60-2.80(m,2H),1.85-1.95(m,1H),1.50-1.60(m,1H),1.47(s,9H)。
第四步
将化合物9-1(900.0mg,3.93mmol)溶于N,N-二甲基甲酰胺(20mL)，加入碳酸钾(1.09g,7.85mmol)和化合物C-4(1.50g,7.07mmol)。反应液在90℃搅拌16小时。反应液冷却到20℃，加水(30mL)稀释，用乙酸乙酯(30mLx2)萃取。合并有机相，依次用水(40mLx2)，饱和食盐水(40mLx2)洗涤，用无水硫酸钠干燥。过滤，滤液减压浓缩。剩余物经制备薄层层析板分离纯化(石油醚:乙酸乙酯＝3:1)，得到化合物9-2和10-1。
化合物10-1: 1H NMR(400MHz,CDCl 3)δ7.51(s,1H),6.27(s,1H),5.36(d,J＝4Hz,1H),3.97(s,3H),3.93(s,3H),3.80-3.90(m,1H),3.55-3.70(m,2H),3.45-3.53(m,1H),3.35-3.45(m,1H),2.65-2.85(m,2H),1.90-2.00(m,1H),1.45-1.55(m,1H),1.51(s,9H)。根据二维核磁NOE鉴定:哌啶环与芳氨相连碳上的单氢与哌啶环氨基边上亚甲基强相关，而与桥环上的亚甲基氢未见相关异面，确定为顺式结构。LC-MS:m/z＝444.2[M+Na] +。化合物9-2: 1H NMR(400MHz,CDCl 3)δ7.47(s,1H),6.56(s,1H),5.15-5.25(m,1H),3.97(s,3H),3.91(s,3H),3.65-3.80(m,4H),3.40-3.50(m,1H),2.45-2.60(m,2H),2.40-2.45(m,1H),1.50-1.55(m,1H),1.51(s,9H)。LC-MS:m/z＝444.2[M+Na] +。根据化合物10-2结构鉴定结果推断化合物9-2结构。
第五步
将化合物9-2(580.0mg,1.38mmol)溶于甲醇(100mL)中，加入湿钯碳(10％,150.0mg)，反应液在20℃，氢气的氛围下(氢气球)搅拌0.5小时。反应液经硅藻土过滤，滤液减压浓缩，干燥得到化合物9-3。 1H NMR(400MHz,CDCl 3)δ7.04(s,1H),6.10(s,1H),3.83(s,3H),3.82(s,3H),3.70-3.80(m,1H),3.40-3.60(m,4H),2.60-2.70(m,2H),1.85-1.95(m,1H),1.45(s,9H),1.40-1.45(m,1H)。
第六步
将化合物9-3(500.0mg,1.28mmol)和醋酸铵(984.6mg,12.77mmol)加入原甲酸三甲酯(12.47g,117.48mmol)，反应液在70℃搅拌10小时。反应液冷却到20℃，减压浓缩，剩余物加入水(10mL)打浆，过滤，干燥得到化合物9-4。 1H NMR(400MHz,DMSO-d 6)δ7.87(s,1H),7.06(s,1H),7.04(s,1H),5.18(d,J＝5.2Hz,1H),3.94(s,3H),3.75-3.80(m,1H),3.35-3.55(m,4H),2.65-2.75(m,2H),1.92-2.00(m,1H),1.40(s,9H),1.30-1.40(m,1H)。LC-MS:m/z＝387.2[M+Na] +。
第七步
将化合物9-4(400.0mg,1.04mmol)加入氯化氢的二氧六环溶液(4N,10mL)，反应液在0℃搅拌0.4小时。反应液减压浓缩，得到化合物9-5的盐酸盐。LC-MS:m/z＝287.0[M+H] +。
第八步
在0℃，将9-5的盐酸盐(340.0mg,1.19mmol)，三乙胺(1.7mL,11.87mmol)溶入二氯甲烷(10mL)，滴加三氟乙酸酐(498.8mg,2.37mmol)，反应液在20℃搅拌1小时。减压浓缩，剩余物加水(40mL)打浆，过滤，干燥得到化合物9-6。 1H NMR(400MHz,DMSO-d 6)δ11.93(s,1H),7.87(s,1H),7.02-7.88(m,2H),4.95-5.05(m,1H),3.98(s,3H),3.80-3.95(m,3H),3.60-3.70(m,1H),3.51-3.60(m,1H),2.80-2.90(m,2H),2.00-2.10(m,1H),1.52(d,J＝10.0Hz,1H)。LC-MS:m/z＝383.1[M+H] +。
第九步
将化合物9-6(280.0mg,732.34μmol)溶于三氯氧磷(20mL,215.22mmol)中，加入N,N二甲基甲酰胺(53.5mg,732.34μmol)，反应液在100℃搅拌5小时。减压浓缩，剩余物加入3,4-二氯-2-氟苯胺(263.65mg,1.46mmol)的异丙醇(10mL)溶液。反应液在90℃搅拌1小时。反应液冷却到20℃，加入饱和碳酸氢钠水溶液(10mL)淬灭，用乙酸乙酯(10mLx2)萃取。合并有机相，用无水硫酸钠干燥。过滤，滤液减压浓缩，剩余物用硅胶柱层析法分离纯化(乙酸乙酯:石油醚＝2:1)，得到化合物9-7。 1H NMR(400MHz,DMSO-d 6)δ9.46(s,1H),8.29(s,1H),7.52-7.65(m,2H),7.12-7.20(m,2H),5.64(d,J＝3.6Hz,1H),3.98(s,3H),3.82-3.98(m,3H),3.65-3.75(m,1H),3.55-3.60(m,1H),2.95-3.05(m,2H),2.00-2.10(m,1H),1.56(d,J＝10.0Hz,1H)。LC-MS:m/z＝544.2[M+H] +。
第十步
将化合物9-7(290.0mg,533.74μmol)溶于甲醇(15mL)中，加入碳酸钾(369.0mg,2.67mmol)。反应液在55℃搅拌14个小时。反应液减压浓缩，加入水(10mL)淬灭，用乙酸乙酯(20mLx4)萃取。合并有机相，用无水硫酸钠干燥。过滤，滤液减压浓缩，得到化合物9-8。 1H NMR(400MHz,DMSO-d 6)δ9.50(s,1H),8.28(s,1H),7.50-7.65(m,2H),7.16(s,1H),7.14(s,1H),5.91(d,J＝4.8Hz,1H),4.01(s,3H),3.85-3.95(m,1H),3.15-3.20(m,2H),2.80-2.90(m,2H),1.90-2.00(m,2H),1.70-1.80(m,1H),1.10(d,J＝6.4Hz,1H)。LC-MS:m/z＝ 448.2[M+H] +。
第十一步
在0℃下，将化合物9-8(200.0mg,446.11μmol)溶于四氢呋喃(6mL)和水(6mL)的混合溶剂，加入碳酸氢钠(112.4mg,1.34mmol)，缓慢滴入丙烯酰氯(36.3mg,401.50μmol)。反应液在0℃继续搅拌0.5小时。加入MeOH(1mL)淬灭，减压浓缩，剩余物用制备薄层层析板分离纯化(二氯甲烷:甲醇＝10:1)，得到化合物
实施例9。 1H NMR(400MHz,DMSO-d 6)δ9.45(s,1H),8.28(s,1H),7.55-7.65(m,2H),7.17(s,1H),7.12(s,1H),6.75(dd,J 1＝16.4Hz,J 2＝10.4Hz,1H),6.18(dd,J 1＝16.4Hz,J 2＝2.4Hz,1H),5.68(dd,J 1＝10.4Hz,J 2＝2.4Hz,1H),5.40(d,J＝4.8Hz,1H),3.96(s,3H),3.80-3.90(m,2H),3.65-3.75(m,2H),3.45-3.52(m,1H),2.90-3.05(m,2H),1.90-2.00(m,1H),1.47(d,J＝9.6Hz,1H)。LC-MS:m/z＝502.1[M+H] +。
实施例10
Figure PCTCN2018122016-appb-000135
合成路线：
Figure PCTCN2018122016-appb-000136
第一步
参考实施例9第五步得到化合物10-2。 1H NMR(400MHz,CDCl 3)δ6.78(s,1H),6.13(s,1H),3.86(s,3H),3.84(s,3H),3.60-3.80(m,4H),3.32-3.36(m,1H),2.50-2.60(m,1H),2.40-2.48(m,1H),2.30-2.40(m,1H),1.51(s,9H),1.40-1.45(m,1H)。
第二步
参考实施例9第六步得到化合物10-3。 1H NMR(400MHz,DMSO-d 6)δ7.85(s,1H),7.05(s,1H),6.72(s,1H),5.95(d,J＝3.2Hz,1H),3.97(s,3H),3.55-3.80(m,4H),3.25-3.30(m,1H),2.51-2.60(m,2H),1.75-1.80(m,1H),1.46(s,9H)，1.35-1.40(m,1H)。LC-MS:m/z＝387.2[M+Na] +。
第三步
参考实施例9第七步得到化合物10-4的盐酸盐。LC-MS:m/z＝287.0[M+H] +。
第四步
参考实施例9第八步得到化合物10-5。 1H NMR(400MHz,DMSO-d 6)δ11.92(s,1H),7.85(d,J＝3.2Hz,1H),7.06(s,1H),6.76(s,1H),6.02(d,J＝3.2Hz,1H),4.05-4.15(m,2H),3.98(s,3H),3.85-3.95(m,1H),3.75-3.80(m,1H),3.45-3.50(m,1H),2.55-2.70(m,3H),1.50-1.60(m,1H)。LC-MS:m/z＝383.1[M+H] +。
第五步
参考实施例9第九步得到化合物10-6。 1H NMR(400MHz,DMSO-d 6)δ9.35(s,1H),8.29(s,1H),7.60-7.70(m,1H),7.55-7.60(m,1H),7.15(s,1H),6.81(s,1H),6.18(d,J＝3.6Hz,1H),4.10-4.25(m,2H),4.03(s,3H),3.80-4.00(m,2H),3.50-3.63(m,1H),2.65-2.75(m,2H),2.55-2.60(m,1H),1.50-1.56(m,1H)。LC-MS:m/z＝544.2[M+H] +。
第六步
参考实施例9第十步得到化合物10-7。 1H NMR(400MHz,DMSO-d 6)δ9.69(s,1H),8.26(s,1H),7.50-7.65(m,2H),7.12(s,1H),6.95(d,J＝8.0Hz,1H),4.10-4.20(m,1H),4.01(s,3H),3.60-3.70(m,2H),3.20-3.30(m,2H),2.40-2.50(m,3H),1.60-1.70(m,1H)。LC-MS:m/z＝448.2[M+H] +。
第七步
参考实施例9第十一步得到化合物实施例10。 1H NMR(400MHz,DMSO-d 6)δ9.38(s,1H),8.27(s,1H),7.55-7.65(m,2H),7.14(s,1H),6.75-6.85(m,2H),6.18(dd,J 1＝16.8Hz,J 2＝2.4Hz,1H),6.14(d,J 1＝4.0Hz,1H),5.73(dd,J 1＝10.4Hz,J 2＝2.4Hz,1H),4.10-4.20(m,1H),4.02(s,3H),3.85-3.95(m,2H),3.75-3.80(m,1H),3.50-3.55(m,1H),2.50-2.65(m,3H),1.40-1.50(m,1H)。LC-MS:m/z＝502.1[M+H] +。
实施例11
Figure PCTCN2018122016-appb-000137
合成路线：
Figure PCTCN2018122016-appb-000138
第一步
将化合物E-1(500.0mg,2.79mmol)加入到二氯甲烷(6mL)中，在氮气保护下加入化合物E-2(475.7mg,5.59mmol)，反应液在25℃搅拌2小时。反应液减压浓缩，剩余物用硅胶柱层析法分离纯化(石油醚:乙酸乙酯＝3:1)，得到化合物E-3。 1H NMR(400MHz,CDCl 3)δ7.03-6.95(m,1H),5.89-6.03(m,1H),3.72(s,3H),3.09(dd,J 1＝6.4Hz,J 2＝1.6Hz,2H),2.20-2.50(m,4H),1.63-1.56(m,4H),1.38-1.46(m,2H)。LC-MS:m/z＝184.0[M+H] +。
第二步
向化合物E-3(367.0mg,2.00mmol)溶于四氢呋喃(10mL)和水(10mL)得到的混合溶液中，加入氢氧化锂一水合物(168.1mg,4.01mmol)，反应液在25℃搅拌1小时。加入乙酸乙酯(10mL)萃取，水相加稀盐酸调节pH＝3，冻干得到化合物E-4。 1H NMR(400MHz,DMSO-d 6)δ11.28(brs,1H),7.10-6.86(m,1H),6.17(d,J＝15.6Hz,1H),3.85(d,J＝6.8Hz,2H),3.31-3.20(m,4H)1.61-1.89(m,6H)。LC-MS:m/z＝170.2[M+H] +。
第三步
将化合物1-10(50.0mg,111.28μmol)，HATU(63.5mg,166.92μmol)和DIEA(36.0mg,278.21μmol)溶于N,N-二甲基甲酰胺(8mL)中，加入化合物E-4(56.5mg,333.85μmol)，反应液在25℃搅拌16小时。反应液减压浓缩，剩余物用制备高效液相色谱法(碱性)分离纯化，得到化合物实施例11。 1H NMR(400MHz,DMSO-d 6)δ9.69(brs,1H),8.39(s,1H),7.74(s,1H),7.60(s,1H),7.23(s,1H),6.45-6.71(m,2H),4.69(s,1H),3.80-4.00(m,4H),3.62-3.80(m,3H),2.90-3.10(m,4H),2.25-2.35(m,3H),1.78-1.85(m,1H),1.33-1.52(m,7H)。LC-MS:m/z＝600.2[M+H] +。
实施例12
Figure PCTCN2018122016-appb-000139
合成路线：
Figure PCTCN2018122016-appb-000140
第一步
将化合物F-1(1.00g,5.59mmol)和DIEA(1.44g,11.17mmol)溶于四氢呋喃(10mL)中，滴加二甲胺水溶液(33％,1.53g,11.17mmol)，反应液在70℃搅拌1小时。反应液降至室温，加水(10mL)淬灭，用乙酸乙酯(15mLx2)萃取。合并有机相，减压浓缩，剩余物用制备薄层层析板分离纯化(石油醚:乙酸乙酯＝0:1)，得到化合物F-2。 1H NMR(400MHz,CDCl 3)δ7.00-6.80(m,1H),6.00-5.85(m,1H),3.67(s,3H),3.07-2.93(m,2H),2.18(s,6H)。
第二步
参考实施例11第二步得到化合物F-3。 1H NMR(400MHz,DMSO-d 6)δ11.42(brs,1H),6.78-6.94(m,1H),6.19(d,J＝15.6Hz,1H),3.87-3.91(m,2H),2.73-2.60(m,6H)。
第三步
参考实施例11第三步得到化合物实施例12。 1H NMR(400MHz,DMSO-d 6)δ8.35(s,1H),7.73(s,1H),7.51-7.63(m,2H),7.20(s,1H),6.59-6.69(m,1H),6.47-6.56(m,1H),4.68(t,J＝5.6Hz,1H),3.84-3.94(m,4H),3.64-3.78(m,2H),3.50-3.45(m,1H),2.98-3.10(m,4H),2.14(s,6H),1.74-1.91(m,1H),1.50(d,J＝10.0Hz,1H)。
实施例13
Figure PCTCN2018122016-appb-000141
合成路线：
Figure PCTCN2018122016-appb-000142
第一步
将化合物1-9(6.80g,10.62mmol)加入到吡啶盐酸盐(57.94g,501.35mmol)中，反应液在180-185℃搅拌1小时。反应液降至室温，加水(30mL)和乙酸乙酯(30mL)在20-25℃打浆1小时，过滤，干燥得到化合物13-2。LC-MS:m/z530.9[M+H] +。
第二步
将化合物13-2(500.0mg,941.11μmol)溶于N,N-二甲基甲酰胺(5mL)中，加入1,3-二氧戊环-2-酮(165.8mg,1.88mmol)和氟化钾(54.7mg,941.11μmol)。反应液在110℃搅拌18小时，补加氟化钾(164.0mg,2.82mmol)和1,3-二氧戊环-2-酮(414.4mg,4.71mmol)，反应液在110℃下搅拌3小时。减压浓缩，剩余物用制备薄层层析板分离纯化(二氯甲烷:甲醇＝15:1)，得到化合物13-3。LC-MS:m/z＝575.2[M+H] +。
第三步
将化合物13-3(170.0mg,295.48μmol)溶到甲醇(10mL)中，加入碳酸钾(163.4mg,1.18mmol)，反应液在80℃搅拌3小时。减压浓缩，剩余物用制备薄层层析板分离纯化(二氯甲烷:甲醇＝15:1)，得到化合物13-4。LC-MS:m/z＝479.2[M+H] +。
第四步
参考实施例1第十步得到化合物实施例13。 1H NMR(400MHz,DMSO-d 6)δ9.69(s,1H),8.39(s,1H),7.78(s,1H),7.64-7.57(m,2H),7.24(s,1H),6.74(dd,J 1＝16.8Hz,J 2＝10.4Hz,1H),6.16(dd,J 1＝16.8Hz,J 2＝2.4Hz,1H),5.68(dd,J 1＝10.4Hz,J 2＝2.4Hz,1H),4.84(t,J＝5.2Hz,1H),4.73-4.71(m,1H),4.11(t,J＝5.2Hz,2H),4.00-3.90(m,1H),3.76-3.70(m,4H),3.49(d,J＝13.2Hz,1H),3.05(brs,2H),1.86-1.77(m,1H),1.51(d,J＝10.0Hz,1H)。LC-MS:m/z＝533.3[M+H] +。
实施例14
Figure PCTCN2018122016-appb-000143
合成路线：
Figure PCTCN2018122016-appb-000144
第一步
将化合物G-1(3.00g,40.50mmol)溶于二氯甲烷(30mL)，加入4-甲基苯磺酰氯(7.72g,40.50mmol)，三乙胺(10.24g,101.24mmol)和4-二甲氨基吡啶(247.4mg,2.02mmol)，反应液在室温下搅拌8小时。减压浓缩，加入水(150mL)打浆，过滤，滤饼用水洗涤，干燥得到化合物G-2。 1H NMR(400MHz,CDCl 3)δ7.79(d,J＝8.0Hz,2H),7.37(d,J＝8.4Hz,2H),5.38-5.23(m,1H),4.80-4.60(m,4H),2.47(s,3H)。
第二步
将化合物13-2(200.0mg,376.44μmol)溶于N,N-二甲基甲酰胺(5mL)中，加入氟化钾(65.6mg,1.13mmol)，和化合物G-2(257.8mg,1.13mmol)，反应液在110℃搅拌18小时。加氟化钾(65.6mg,1.13mmol)，碳酸钾(52.0mg,376.44μmol)和化合物G-2(257.8mg,1.13mmol)，反应液在110℃搅拌5小时。加化合物G-2(100.0mg,438.09μmol)和碳酸钾(30.0mg,217.07μmol)。反应液减压浓缩，剩余物用制备薄层层析板分离纯化(二氯甲烷:甲醇＝15:1)，得到化合物14-2。LC-MS:m/z＝587.2[M+H] +。
第三步
参考实施例13第三步得到化合物14-3。LCMS:m/z＝587.2[M+H] +。
第四步
参考实施例1第十步得到化合物将化合物实施例14。 1H NMR(400MHz,DMSO-d 6)δ9.74(s,1H),8.39(s,1H),7.86(s,1H),7.60(s,2H),6.88(s,1H),6.75(dd,J 1＝16.8Hz,J 2＝10.4Hz,1H),6.18(dd,J 1＝16.8Hz,J 2＝2.4Hz,1H),5.68(dd,J 1＝10.4Hz,J 2＝2.4Hz,1H),5.51-5.40(m,1H),5.02-4.90(m,2H),4.85-4.75(m,1H),4.57-4.47(m,2H),3.96-3.85(m,1H),3.77-3.66(m,2H),3.56-3.46(m,1H),3.06(m,2H),1.89-1.78(m,1H),1.53(d,J＝10.4Hz,1H)。LC＝MS:m/z＝545.3[M+H] +。
实施例15
Figure PCTCN2018122016-appb-000145
合成路线：
Figure PCTCN2018122016-appb-000146
第一步
将化合物13-2(200.0mg,376.44μmol)溶于N,N-二甲基甲酰胺(2mL)中，再在室温下加入碘化钠(112.9mg,752.89μmol)，氟化钾(87.5mg,1.51mmol)和1-溴-2甲氧基乙烷(130.8mg,941.11μmol)。反应液在110℃搅拌5小时。补加氟化钾(87.5mg,1.51mmol)和1-溴-2甲氧基乙烷(157.0mg,1.13mmol)，反应液在110℃继续搅拌18小时。反应液减压浓缩，用制备薄层层析板分离纯化(二氯甲烷:甲醇＝7:1)，得到化合物15-2。LC-MS:m/z＝589.3[M+H] +。
第二步
参考实施例13第三步得到化合物15-3。
第三步
Figure PCTCN2018122016-appb-000147
参考实施例1第十步得到化合物实施例15。 1H NMR(400MHz,DMSO-d 6)δ7.89(s,1H),7.64(s,1H),7.33(d,J＝8.4Hz,1H),7.03(s,1H),6.91(s,1H),6.74(dd,J 1＝16.8Hz,J 2＝10.4Hz,1H),6.16(dd,J 1＝16.8Hz,J 2＝2.4Hz,1H),5.71-5.65(m,1H),4.70-4.63(m,1H),4.15-4.25(m,2H),3.80-3.90(m,2H),3.65-3.75(m,1H),3.59(t,J＝4.8Hz,2H),3.51-3.46(m,1H),3.23(s,3H),2.84-2.90(m,2H),1.80-1.85(m,1H),1.47-1.40(m,1H)；LC-MS:m/z＝547.2[M+H] +。
实施例16
Figure PCTCN2018122016-appb-000148
合成路线：
Figure PCTCN2018122016-appb-000149
第一步
将化合物13-2(1.00g,1.88mmol)溶于甲醇(20mL)，在20-25℃下一次性加入碳酸钾(1.30g,9.41mmol)。反应液在20-25℃搅拌反应18小时。升温至50℃反应5小时。过滤反应液，滤液减压浓缩，剩余物用饱和柠檬酸水溶液(50mL)稀释，用乙酸乙酯萃取(50mLx3)。合并有机相，用饱和食盐水(50mL)洗涤，用无水硫酸钠干燥。过滤，滤液减压浓缩得到化合物16-2。
第二步
将化合物16-2(850.0mg,1.95mmol)溶于甲醇(10mL)，在20℃加入三乙胺(988.0mg,9.76mmol)和二碳酸二叔丁酯(1.28g,5.86mmol)，反应液在20-25℃搅拌2小时。减压浓缩反应液，加水(20mL)打浆0.5小时，过滤，干燥滤饼得到化合物16-3。LC-MS:m/z＝635.3[M+H] +。
第三步
将化合物16-3(1.00g,1.57mmol)溶于甲醇(15mL)，在20-25℃下一次性加入碳酸钾(1.09g,7.87mmol)，反应液在20-25℃搅拌反应18小时。减压浓缩，剩余物用饱和柠檬酸水溶液调节至pH＝5，在20-25℃下搅拌0.5小时。过滤，干燥滤饼得到化合物16-4。LC-MS:m/z＝535.3[M+H] +。
第四步
将化合物16-4(150.0mg,280.17μmol)溶于N,N-二甲基甲酰胺(3mL)，再在0℃下一次性加入钠氢(60％,28.0mg,700.42μmol)，反应液在0℃下搅拌0.5小时，加入2-溴-N,N-二甲基乙胺(55.4mg,364.22μmol)。反应液在20℃下搅拌2小时。加入水(2mL)淬灭，用乙酸乙酯萃取(3mLx3)。合并有机相，用无水硫酸钠干燥。过滤，滤液减压浓缩，剩余物用制备薄层层析板分离纯化(二氯甲烷:甲醇＝5:1)，得到化合物16-5。LC-MS:m/z＝606.4[M+H] +。
第五步
将化合物16-5(60.0mg,98.93μmol)溶于氯化氢的二氧六环溶液(4N,4mL)中，在20-25℃下搅拌0.5小时。减压浓缩反应液得到化合物16-6的盐酸盐。LC-MS:m/z＝506.3[M+H] +。
第六步
将化合物16-6的盐酸盐(50.0mg,92.10μmol)溶于四氢呋喃(0.5mL)和水(0.5mL)，0℃下加入碳酸氢钠(38.7mg,460.52μmol)，缓慢滴加烯丙基酰氯(3.3mg,36.84μmol)，反应液在0℃下搅拌0.5小时，在20-25℃下搅拌18小时。补加烯丙基酰氯(2.2mg,23.95μmol)，反应液在20-25℃下继续搅拌反应2小时。减压浓缩反应液，剩余物用制备薄层层析板分离纯化(二氯甲烷:甲醇＝3:1)，得到化合物实施例16。 1H NMR(400MHz,CD 3OD)δ8.34(s,1H),7.58(s,1H),7.50-7.47(m,2H),6.69(s,1H),6.21-6.12(m,1H),6.11-6.04(m,1H),5.75(dd,J 1＝16.8Hz,J 2＝2.4Hz,1H),5.58-5.51(m,1H),4.73-4.65(m,1H),4.39(t,J＝6.2Hz,2H),4.19(d,J＝10.8Hz,1H),3.96-3.83(m,2H),3.66-3.58(m,1H),3.22-3.13(m,1H),3.05-3.10(m,1H),2.79(t,J＝6.2Hz,2H),2.32(s,6H),2.00-1.91(m,1H),1.59(d,J＝10.0Hz,1H)。LC-MS:m/z＝560.4[M+H] +。
实施例17
Figure PCTCN2018122016-appb-000150
合成路线：
Figure PCTCN2018122016-appb-000151
第一步
将化合物16-4(150.0mg,280.17μmol)溶于N,N-二甲基甲酰胺(3mL)，在0℃下一次性加入钠氢(60％,44.82mg,1.12mmol)，反应液在0℃下搅拌0.5小时，加入4-(2-溴乙基)吗啡啉(163.1mg,840.50μmol)，反应液在0℃下继续搅拌2小时，加水(20mL)淬灭反应，用乙酸乙酯(20mLx3)萃取，合并有机相，用饱和食盐水(30mL)洗涤，用无水硫酸钠干燥。过滤，滤液减压浓缩，剩余物用制备薄层层析板板分离纯化(二氯甲烷:甲醇＝10:1)，得到化合物17-2。LC-MS:m/z＝648.4[M+H] +。
第二步
参考实施例16第五步得到化合物17-3。LC-MS:m/z＝548.3[M+H] +。
第三步
参考实施例1第十步得到化合物实施例17。 1H NMR(400MHz,CD 3OD)δ8.39(s,1H),7.77(s,1H),7.67-7.55(m,1H),7.49-7.45(m,1H),7.22(s,1H),6.79(dd,J 1＝16.8Hz,J 2＝10.4Hz,1H),6.34(dd,J 1＝16.8Hz,J 2＝2.4Hz,1H),5.80(dd,J 1＝10.4Hz,J 2＝2.4Hz,1H),4.40-4.25(m,2H),3.92-3.81(m,2H),3.75-3.68(m,6H),3.60-3.56(m,2H),3.17-3.05(m,2H),2.89(t,J＝5.2Hz,2H),2.69-2.62(m,3H),2.07-1.90(m,1H),1.62(d,J＝10.4Hz,1H)。LC-MS:m/z＝602.4[M+H] +。
实施例18
Figure PCTCN2018122016-appb-000152
合成路线：
Figure PCTCN2018122016-appb-000153
第一步
将H-1(2.00g,13.77mmol)溶于四氢呋喃(20mL)中，加入三苯基膦(3.97g,15.15mmol)，冷却至0℃，氮气保护下，向反应液中分批次加入四溴化碳(5.02g,15.15mmol)，反应液升至室温，搅拌10小时。减压浓缩反应液，加水(50mL)稀释，用乙酸乙酯(30mLx3)萃取，水相用4N的氢氧化钠溶液调节至pH＝11，浓缩除去水，固体加入甲醇(100mL)，在室温下搅拌15分钟，过滤。滤液减压浓缩，加入二氯甲烷(50mL)，继续搅拌15分钟，过滤，滤液减压浓缩得到化合物H-2。 1H NMR(400MHz,CDCl 3)δ3.76-3.66(m,4H),3.48(t,J＝6.4Hz,2H),2.51-2.46(m,2H),2.46-2.41(m,4H),2.11-1.97(m,2H)。
第二步
将化合物16-4(200.0mg,373.56μmol)溶于N,N-二甲基甲酰胺(3mL)中，在0℃下一次性加入钠氢(60％,44.8mg,1.12mmol)，搅拌0.5小时，再加入化合物H-2(155.5mg,747.11μmol)，反应液在0℃搅拌1.5小时。加水(5mL)稀释，用乙酸乙酯(15mLx3)萃取，合并有机相，用饱和食盐水(20mL)洗涤，用无水硫酸钠干燥。过滤，滤液减压浓缩，剩余物用制备薄层层析板分离纯化(二氯甲烷:甲醇＝10:1)，得到化合物18-2。LC-MS:m/z＝662.5[M+H]
第三步
参考实施例16第五步得到化合物18-3的盐酸盐。LC-MS:m/z＝562.3[M+H]
第四步
Figure PCTCN2018122016-appb-000154
参考实施例1第十步得到化合物实施例18。 1H NMR(400MHz,CD 3OD)δ8.39(s,1H),7.75(s,1H),7.61-7.59(m,1H),7.49-7.46(m,1H),7.21(s,1H),6.79(dd,J 1＝16.8Hz,J 2＝10.4Hz,1H),6.32(dd,J 1＝16.8Hz,J 2＝2.0Hz,1H),5.78(dd,J 1＝10.4Hz,J 2＝2.0Hz,1H),4.27-4.17(m,2H),4.03-3.94(m,1H),3.92-3.83(m,2H),3.77-3.60(m,5H),3.37-3.35(m,1H),3.10(t,J＝5.4Hz,2H),2.65-2.44(m,6H),2.12-1.94(m,3H),1.63(d,J＝10.0Hz,1H)。LC-MS:m/z＝616.4[M+H] +。
实施例19
Figure PCTCN2018122016-appb-000155
合成路线：
Figure PCTCN2018122016-appb-000156
第一步
将化合物I-1(300.0mg,2.60mmol)加入到甲苯(5.0mL)中，加入氯化亚砜(309.8mg,2.60mmol)，混合物在70℃搅拌3小时。反应液减压浓缩得到化合物I-2。 1H NMR(400MHz,DMSO-d 6)δ4.16(dd,J 1＝12.0Hz,J 2＝6.0Hz,1H),4.00(dd,J 1＝12.0Hz,J 2＝6.0Hz,1H),3.70(m,1H),3.56(m,1H),3.09(m,1H),2.87(s,3H),2.36-2.21(m,1H),2.07-1.72(m,4H)。
第二步
将化合物16-4(100.0mg,186.78μmol)加入到N,N-二甲基甲酰胺(1.0mL)，在0℃下加入氢化钠(60％,29.8mg,747.12μmol,)，搅拌0.2小时，反应液升到16℃，加入化合物I-2(49.9mg,373.56μmol)，40℃下搅拌0.5小时。加水(10mL)淬灭，用乙酸乙酯(10mLx3)萃取，合并有机相，依次用水(10mL)，饱和食盐水(10mL)洗涤，用无水硫酸钠干燥。过滤，滤液减压浓缩，剩余物用制备高效液相色谱法(碱性)分离纯化，得到化合物19-2。LC-MS:m/z＝632.5[M+H] +。
第三步
将化合物19-2(33.0mg,52.17μmol)加入到氯化氢的乙酸乙酯溶液(2.0mL)，反应液在16℃搅拌0.5小时。
反应液减压浓缩得到化合物19-3的盐酸盐。LC-MS:m/z＝532.4[M+H] +。
第四步
将化合物19-3的盐酸盐(30.0mg,56.34μmol)加入到无水四氢呋喃(0.5mL)和水(0.5mL)的混合溶剂中，加入碳酸氢钠(14.2mg,169.03μmol)，0℃下搅拌0.05小时，缓慢加入丙烯酰氯(3.8mg,42.26μmol)，0℃下搅拌0.2小时。反应液减压浓缩，加水(5mL)稀释，用乙酸乙酯(10mLx3)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，剩余物用制备高效液相色谱法(碱性)分离纯化，得到实施例19。 1H NMR(400MHz,CDCl 3)δ8.71-8.68(m,1H),8.54-8.45(m,1H),7.35(m,1H),7.08-7.00(m,1H),6.66-6.53(m,1H),6.47-6.36(m,1H),5.71(m,1H),4.77-4.68(m,1H),4.13(m,3H),4.02-3.85(m,3H),3.76-3.66(m,1H),3.50(s,1H),3.00(m,2H),2.97(s,1H),2.89(s,1H),2.55(m,1H),2.31(s,2H),2.05(s,3H),1.93(m,2H),1.86(m,2H)；LC-MS:m/z＝586.4[M+H] +。
实施例20
Figure PCTCN2018122016-appb-000157
合成路线：
Figure PCTCN2018122016-appb-000158
第一步
将化合物J-1(6.40g,28.16mmol)溶于吡啶(20mL)，加入对甲苯磺酰氯(8.05g,42.24mmol)，混合物在10℃下搅拌16小时。反应液减压浓缩，加入乙酸乙酯(300mL)稀释，依次用1N稀盐酸(100mLx2)，饱和食盐水(100mL)洗涤，用无水硫酸钠干燥。过滤，滤液减压浓缩，剩余物用硅胶柱层析法分离纯化(乙酸乙酯:石油醚＝1:8)得到化合物J-2。 1H NMR(400MHz,CDCl 3)δ7.77(d,J＝8.4Hz,2H),7.34(d,J＝8.4Hz,2H),5.69(t,J＝4.8Hz,1H),4.05-4.30(m,2H),2.45(s,3H),1.90-2.15(m,6H),1.70-1.90(m,2H),1.43(s,9H)。LC-MS:m/z＝282.0[M+H-100] +。
第二步
将化合物K-1(1.00g,10.00mmol)溶于吡啶(5mL)，加入对甲苯磺酰氯(2.86g,14.99mmol)，反应液在10℃下搅拌16小时。反应液减压浓缩，剩余物溶于乙酸乙酯(40mL)，依次用饱和氯化铵溶液(60mLx3)，饱和食盐水(60mL)洗涤，用无水硫酸钠干燥。过滤，滤液减压浓缩。剩余物用硅胶柱层析法分离纯化(乙酸乙酯:石油醚＝1:8)得到化合物K-2。 1H NMR(400MHz,CDCl 3)δ7.82(d,J＝8.4Hz,2H),7.38(d,J＝8.0 Hz,2H),4.34(q,J＝8.8Hz,2H),2.47(s,3H)。
第三步
将化合物7-1(4.00g,11.29mmol)溶于N,N-二甲基乙酰胺(20mL)，加入碳酸钾(2.34g,16.94mmol)和化合物J-2(5.60g,14.68mmol)，反应液在75℃下搅拌16小时。反应液冷却到30℃，加入水(60mL)稀释，用乙酸乙酯(60mLx3)萃取。合并有机相，依次用水溶液(100mLx3)，饱和食盐水(60mLx2)洗涤，用无水硫酸钠干燥。过滤，滤液减压浓缩，剩余物用硅胶柱层析法分离纯化(乙酸乙酯:石油醚＝1:1)，得到化合物20-2。 1H NMR(400MHz,CDCl 3)δ8.64(s,1H),8.49(t,J＝8.4Hz,1H),7.26-7.40(m,3H),7.13(s,1H),4.60-4.75(m,1H),4.15-4.40(m,2H),3.94(s,3H),1.75-2.20(m,6H),1.55-1.70(m,2H),1.43(s,9H)。LC-MS:m/z＝563.1[M+H] +。
第四步
将化合物20-2(2.70g,4.80mmol)和吡啶盐酸盐(10.80g,93.46mmol)的混合物，在氮气保护下加热到170℃，搅拌3小时，得到化合物20-3。LC-MS:m/z＝449.0[M+H] +。
第五步
将化合物20-3(13.00g,4.63mmol)和三乙胺(7.00g,69.18mmol)溶于甲醇(20mL)中，加入二碳酸二叔丁酯(9.63g,44.12mmol)，反应液在10℃下搅拌1小时。反应液减压浓缩，剩余物用水(20mL)打浆，过滤得到的固体依次用饱和氯化铵溶液(10mLx3)，石油醚(10mL)洗涤，干燥后得到化合物20-4。LC-MS:m/z＝649.1[M+H] +。
第六步
将化合物20-4(3.00g,4.62mmol)溶于甲醇(50mL)中，加入碳酸钾(3.19g,23.09mmol)，在40℃搅拌14小时。向反应液中加水(30mL)，用醋酸调至pH＝6。过滤，固体用水(30mL)洗涤，在空气下干燥得到化合物20-5。 1H NMR(400MHz,DMSO-d 6)δ9.54(brs,1H),8.22(s,1H),7.68(s,1H),7.61(t,J＝8.4Hz,1H),7.50-7.60(m,1H),6.94(s,1H),4.90-5.00(m,1H),4.10-4.20(m,2H),2.10-2.20(m,2H),1.70-2.00(m,4H),1.60-1.70(m,2H),1.44(s,9H)。LC-MS:m/z＝549.1[M+H] +。
第七步
将化合物20-5(70.0mg,127.41μmol)溶于N,N-二甲基甲酰胺(3mL)，加入碳酸钾(35.2mg,254.81μmol)和化合物K-2(64.78mg,254.81μmol)，混合物在70℃下搅拌16小时。反应液冷却到30℃，加水(10mL)，用乙酸乙酯(10mLx3)萃取。合并的有机相，依次用水(30mLx2)和饱和食盐水(30mL)洗涤，无水硫酸钠干燥。过滤，滤液减压浓缩，剩余物用硅胶柱层析法(乙酸乙酯:石油醚＝1:1)分离纯化，得到化合物20-6。 1H NMR(400MHz,CDCl 3)δ9.77(s,1H),8.43(s,1H),7.97(s,1H),7.55-7.65(m,2H),7.43(s,1H),4.95-5.05(m,2H),4.75-4.90(m,1H),4.10-4.20(m,2H),2.10-2.20(m,2H),1.90-2.20(m,2H),1.70-1.80(m,2H),1.55- 1.70(m,2H),1.44(s,9H)。LC-MS:m/z＝631.1[M+H] +。
第八步
将化合物20-7(35.0mg,55.43μmol)溶于氯化氢的二氧六环溶液(4N,5mL)中，反应液在10℃搅拌0.3小时。反应液减压浓缩，得到化合物20-8的盐酸盐。LC-MS:m/z＝531.0[M+H] +。
第九步
在0℃下，将化合物20-8的盐酸盐(30.0mg,52.84μmol)溶于四氢呋喃(3mL)和水(3mL)的混合溶剂，加入碳酸氢钠(13.3mg,158.51μmol)，缓慢滴入丙烯酰氯(3.8mg,42.27μmol)，反应液在0℃继续搅拌0.5小时。加入甲醇(1mL)淬灭，减压浓缩，剩余物用制备薄层层析板分离纯化(二氯甲烷:甲醇＝10:1)，得到实施例20。 1H NMR(400MHz,DMSO-d 6)δ9.78(s,1H),8.42(s,1H),7.93(s,1H),7.60-7.70(m,2H),7.43(s,1H),6.77(dd,J 1＝16.8Hz,J 2＝10.4Hz,1H),6.19(dd,J 1＝16.8Hz,J 2＝2.0Hz,1H),5.70(dd,J 1＝10.4Hz,J 2＝2.0Hz,1H),4.95-5.05(m,2H),4.85-4.95(m,1H),4.55-4.65(m,2H),2.20-2.35(m,2H),1.80-2.10(m,4H),1.60-1.75(m,1H),1.50-1.60(m,1H)。LC-MS:m/z＝585.1[M+H] +。
实施例21
Figure PCTCN2018122016-appb-000159
合成路线：
Figure PCTCN2018122016-appb-000160
第一步
将化合物20-5(150.0mg,273.0μmol)加入到N,N-二甲基甲酰胺(3mL)中，氮气保护下加入钠氢(60％,32.8mg, 819.1μmol)，0℃下搅拌30分钟，加入溴乙烷(74.4mg,682.54μmol)，升至15℃继续搅拌30分钟。向反应液中加入水(5mL)淬灭，用乙酸乙酯(10mLx3)萃取，合并的有机相，依次用水(10mLx3)，饱和食盐水(10mLx1)洗涤，用硫酸钠干燥，过滤，滤液减压浓缩，剩余物用硅胶柱层析法分离纯化(乙酸乙酯:石油醚＝1:0)，得到化合物21-2。 1H NMR(400MHz,DMSO-d 6)δ9.62(br s,1H),8.39(s,1H),7.82(s,1H),7.68-7.55(m,1H),7.21(s,1H),4.82(m,1H),4.25-4.19(m,2H),4.18-4.13(m,2H),2.19(m,2H),1.92(m,2H),1.79(m,2H),1.65(m,2H),1.45(s,9H),1.43-1.41(m,3H)。LC-MS:m/z＝577.3[M+H] +。
第二步
将化合物21-2(50.0mg,86.6μmol)加入到乙酸乙酯(0.5mL)中，室温下加入氯化氢的乙酸乙酯溶液(4N,1.7mL)，15℃下搅拌10分钟。反应液减压浓缩得到化合物21-3的盐酸盐。LC-MS:m/z＝477.1[M+H] +.
第三步
参考实施例20第九步得到化合物实施例21。 1H NMR(400MHz,DMSO-d 6)δ9.65(s,1H),8.39(s,1H),7.80(s,1H),7.67-7.55(m,2H),7.21(s,1H),6.78(dd,J 1＝16.8Hz,J 2＝10.4Hz,1H),6.22(dd,J 1＝16.8Hz,J 2＝2.4Hz,1H),5.73(dd,J 1＝10.4Hz,J 2＝2.4Hz,1H),5.00-4.85(m,1H),4.62(m,2H),4.20(q,J＝6.8Hz,2H),3.17(d,J＝5.2Hz,3H),2.39-2.30(m,1H),2.25(m,1H),2.06-1.93(m,2H),1.89(m,2H),1.67(m,1H),1.52(m,1H)。LC-MS:m/z＝531.2[M+H] +。
实施例22
Figure PCTCN2018122016-appb-000161
合成路线：
Figure PCTCN2018122016-appb-000162
第一步
参考实施例21第一步得到化合物22-2。 1H NMR(400MHz,DMSO-d 6)δ9.63(s,1H),8.40(s,1H),7.86(s,1H),7.63-7.57(m,2H),7.26(s,1H),4.92-4.74(m,1H),4.34-4.26(m,2H),4.19-4.14(m,2H),3.79-3.72(m,2H),3.36(s,3H),2.18(m,2H),1.96-1.86(m,3H),1.63(m,3H),1.44(s,9H)。LC-MS:m/z＝607.3[M+H] +。
第二步
参考实施例21第一步得到化合物22-3的盐酸盐。LC-MS:m/z＝507.1[M+H] +。
第三步
参考实施例20第九步得到化合物实施例22。 1H NMR(400MHz,DMSO-d 6)δ9.68(s,1H),8.40(s,1H),7.85(s,1H),7.69-7.55(m,2H),7.26(s,1H),6.77(dd,J 1＝16.8Hz,J 2＝10.4Hz,1H),6.22(dd,J 1＝16.8Hz,J 2＝2.4Hz,1H),5.80-5.68(m,1H),5.00-4.84(m,1H),4.61(m,2H),4.34-4.23(m,2H),3.79-3.70(m,2H),3.35(s,3H),2.36-2.15(m,2H),2.04-1.82(m,4H),1.68(m,1H),1.52(m,1H)。LC-MS:m/z＝561.3[M+H] +。
实施例23
Figure PCTCN2018122016-appb-000163
合成路线：
Figure PCTCN2018122016-appb-000164
第一步
在室温下，将化合物20-5(200.0mg,364.02μmol)加入到N,N-二甲基甲酰胺(5mL)中，然后加入碳酸铯(474.4mg,1.46mmol)，2-氯-N-甲基乙酰胺(47.0mg,436.82μmol)和碘化钾(60.4mg,364.02μmol)。混合物加热至50℃，搅拌3小时。反应液降至室温，加水(10mL)淬灭，用乙酸乙酯(10mLx3)萃取，合并的有机相，依次用水(5mLx3)，饱和食盐水(5mL)洗涤，用无水硫酸钠干燥，过滤，滤液减压浓缩，剩余物用制备薄层层析板分离纯化(二氯甲烷:甲醇＝20:1)，得到化合物23-2。LC-MS:m/z＝620.3[M+H] +。
第二步
参考实施例21第一步得到化合物23-3的盐酸盐。LC-MS:m/z＝520.2[M+H] +.
第三步
参考实施例20第九步得到化合物实施例22。 1H NMR(400MHz,MeOD-d 4)δ8.38(s,1H),7.82(s,1H),7.61(t,J＝8.4Hz,1H),7.47(dd,J 1＝8.8Hz,J 2＝1.6Hz,1H),7.19(s,1H),6.77(dd,J 1＝16.8Hz,J 2＝10.4Hz,1H),6.36(dd,J 1＝16.8Hz,J 2＝2.0Hz,1H),5.82(dd,J 1＝10.8Hz,J 2＝1.6Hz,1H),5.22-5.09(m,1H),4.79(m,1H),4.73(s,2H),4.69-4.64(m,1H),2.85(s,3H),2.53-2.31(m,2H),2.20-2.08(m,2H),2.07-2.01(m,2H),1.96-1.86(m,1H),1.80(m,1H).LC-MS:m/z＝574.1[M+H] +。
实施例24
Figure PCTCN2018122016-appb-000165
合成路线：
Figure PCTCN2018122016-appb-000166
第一步
参考实施例23第一步得到化合物24-2。LC-MS:m/z＝676.3[M+H] +。
第二步
参考实施例21第一步得到化合物24-3盐酸盐。LC-MS:m/z＝576.1[M+H] +。
第三步
参考实施例20第九步得到化合物实施例24。 1H NMR(400MHz,MeOD-d 4)δ8.38(s,1H),7.79(s,1H),7.62(t,J＝8.4Hz,1H),7.46(dd,J 1＝8.8Hz,J 2＝1.6Hz,1H),7.22(s,1H),6.77(dd,J 1＝16.8Hz,J 2＝10.4Hz,1H),6.36(dd,J 1＝16.4Hz,1.6Hz,1H),5.82(dd,J 1＝10.4Hz,J 2＝1.6Hz,1H),5.13-4.98(m,1H),4.80-4.78(m,1H),4.68-4.61(m,1H),4.24(t,J＝6.0Hz,2H),3.77-3.67(m,4H),2.68-2.58(m,2H),2.53(m,4H),2.42(m,1H),2.37-2.30(m,1H),2.20-1.99(m,6H),1.91-1.82(m,1H),1.74(m,1H)。LC-MS:m/z＝630.2[M+H] +。
实施例25
Figure PCTCN2018122016-appb-000167
合成路线：
Figure PCTCN2018122016-appb-000168
第一步
将化合物20-5(150.0mg,273.02μmol)加入到N,N-二甲基甲酰胺(5mL)中，然后加入氟化钾(47.6mg,819.05μmol)，碳酸亚乙酯(72.1mg,819.05μmol)。反应液加热至110℃，搅拌3小时。反应液降至室温，加水(20mL)淬灭，用乙酸乙酯(10mLx3)萃取，合并的有机相，依次用水(5mLx3)，饱和食盐水(5mL)洗涤，用硫酸钠干燥，过滤，滤液减压浓缩，剩余物经制备薄层层析板分离纯化(二氯甲烷:甲醇＝20:1)，得到化合物25-2。LC-MS:m/z＝593.2[M+H] +。
第二步
参考实施例21第一步得到化合物25-3盐酸盐。LC-MS:m/z＝493.0[M+H] +。
第三步
参考实施例20第九步得到化合物实施例25。 1H NMR(400MHz,MeOD-d 4)δ8.27(s,1H),7.69(s,1H),7.50(t,J＝8.0Hz,1H),7.35(br d,J＝8.8Hz,1H),7.12(s,1H),6.65(dd,J 1＝16.8Hz,J 2＝10.8Hz,1H),6.24(dd,J 1＝16.8Hz,J 2＝1.6Hz,1H),5.70(dd,J 1＝10.4Hz,J 2＝1.6Hz,1H),5.03-4.90(m,1H),4.66(m,1H),4.52(m,1H),4.14(m,2H),3.94-3.83(m,2H),2.38-2.27(m,1H),2.23(m,1H),2.07-1.93(m,2H),1.89(m,2H),1.77(m,1H),1.66(m,1H).LC-MS:m/z＝547.1[M+H] +。
实施例26
Figure PCTCN2018122016-appb-000169
合成路线：
Figure PCTCN2018122016-appb-000170
第一步
室温下，将化合物20-5(200.0mg,364.02umol)加入到N,N-二甲基甲酰胺(5mL)中，然后加入碳酸铯(55.8mg,1.09mmol)，化合物L-1(97.0mg,400.42μmol)。反应液加热至100℃，搅拌3小时。反应液降至室温，加水(10mL)淬灭，用乙酸乙酯(10mLx3)萃取，合并有机相，依次用水(5mLx3)，饱和食盐水(5mL)洗涤，用硫酸钠干燥，过滤，滤液减压浓缩，剩余物用制备薄层层析板分离纯化(二氯甲烷:甲醇＝20:1)，得到化合物26-2。LC-MS:m/z＝619.2[M+H] +。
第二步
参考实施例21第一步得到化合物26-3的盐酸盐。LC-MS:m/z＝519.0[M+H] +。
第三步
参考实施例20第九步得到化合物实施例26。 1H NMR(400MHz,MeOD-d 4)δ8.39(s,1H),7.81(s,1H),7.62(t,J＝8.4Hz,1H),7.45(dd,J 1＝9.2Hz,J 2＝2.0Hz,1H),7.17(s,1H),6.76(dd,J 1＝16.8Hz,J 2＝10.4Hz,1H),6.36(dd,J 1＝16.8Hz,J 2＝2.0Hz,1H),5.81(dd,J 1＝10.4Hz,J 2＝1.6Hz,1H),5.22(m,1H),5.07-4.94(m,1H),4.80-4.73(m,1H),4.67-4.60(m,1H),4.05(s,2H),4.04-3.98(m,1H),3.93(m,1H),2.46-2.35(m,2H),2.32(m,1H),2.26-2.18(m,1H),2.17-2.09(m,1H),2.06-1.93(m,3H),1.92-1.82(m,1H),1.75(m,1H)；LC-MS:m/z＝573.3[M+H] +。
实施例27
Figure PCTCN2018122016-appb-000171
合成路线：
Figure PCTCN2018122016-appb-000172
第一步
参考实施例26第一步得到化合物27-2。LC-MS:m/z＝619.2[M+H] +。
第二步
参考实施例21第一步得到化合物27-3盐酸盐。LC-MS:m/z＝519.0[M+H] +。
第三步
参考实施例20第九步得到化合物实施例27。 1H NMR(400MHz,MeOD-d 4)δ8.39(s,1H),7.82(s,1H),7.62(t,J＝8.4Hz,1H),7.46(dd,J 1＝8.8Hz,J 2＝1.6Hz,1H),7.19(s,1H),6.76(dd,J 1＝16.4Hz,J 2＝10.4Hz,1H),6.36(dd,J 1＝16.8Hz,J 2＝1.6Hz,1H),5.81(dd,J 1＝10.4Hz,J 2＝1.6Hz,1H),5.23(m,1H),5.08-4.94(m,1H),4.78(m,1H),4.68-4.61(m,1H),4.06(s,2H),4.04-3.99(m,1H),3.93(m,1H),2.46-2.36(m,2H),2.32(m,1H),2.26-2.19(m,1H),2.18-2.10(m,1H),2.06-1.94(m,3H),1.87(m,1H),1.76(m,1H).LC-MS:m/z＝573.3[M+H] +。
实施例28
Figure PCTCN2018122016-appb-000173
合成路线：
Figure PCTCN2018122016-appb-000174
第一步
将化合物8-2(83.6mg,647.49μmol)溶于N,N-二甲基甲酰胺(1.0mL)，加入HATU(123.1mg,323.74μmol)，反应液在16℃搅拌0.5小时，加入DIEA(69.7mg,539.57μmol)和化合物N-1(100.0mg,215.83μmol)，继续搅拌16小时。过滤反应液，滤液减压浓缩，剩余物用制备高效液相色谱法(中性)分离纯化得到化合物实施例28。 1H NMR(400MHz,MeOD-d 4)δ8.37(s,1H),7.76(s,1H),7.60(t,J＝8.3Hz,1H),7.45(dd,J 1＝8.8Hz,J 2＝1.6Hz,1H),7.20(s,1H),6.90(m,1H),6.60(d,J＝15.2Hz,1H),5.11-5.01(m,1H),4.75(m,1H),4.63(m,1H),3.99(s,3H),3.19(d,J＝6.0Hz,2H),2.44-2.37(m,1H),2.33(m,1H),2.30(s,6H),2.19-2.10(m,1H),2.09-1.96(m,3H),1.85(m,1H),1.75(m,1H)。LC-MS:m/z＝574.4[M+H] +。
实施例29
Figure PCTCN2018122016-appb-000175
合成路线：
Figure PCTCN2018122016-appb-000176
第一步
将化合物7-1(250.0mg,470.56μmol)溶于N,N-二甲基甲酰胺(4mL)，加入氟化钾(65.6mg,1.13mmol)、碳酸钾(130.07mg,941.11μmol)和化合物L-1(171.0mg,705.83μmol)到反应液中，反应液在118℃搅拌18小时。减压浓缩除去溶剂，剩余物经制备薄层层析板(乙酸乙酯)分离纯化，得到化合物29-2。LC-MS:m/z＝601.3[M+H] +。
第二步
将化合物29-2(147.0mg,244.44μmol)溶于甲醇(10mL)中，加入碳酸钾(168.9mg,1.22mmol)，反应液在50℃搅拌5小时。减压浓缩反应液，剩余物溶于甲醇(5mL)，加入碳酸钾(33.8mg,244.44μmol)，反应液在50℃搅拌反应5小时。减压浓缩反应液，剩余物经制备薄层层析板(二氯甲烷:甲醇＝10:1)分离纯化得到化合物29-3。LC-MS:m/z＝505.3[M+H] +。
第三步
参考实施例20第九步得到化合物实施例29。
1H NMR(400MHz,CDCl 3)δ8.68(s,1H),8.39(t,J＝8.4Hz,1H),7.33(dd,J＝8.8,1.6Hz,1H),7.19(d,J＝5.2Hz,1H),7.16(s,1H),6.61(dd,J＝16.8,10.4Hz,1H),6.42(dt,J＝16.4,2.4Hz,1H),5.72(dd,J＝10.4,2.0Hz,1H),5.07-5.02(m,1H),4.70-4.65(m,1H),4.09-4.03(m,1H),4.02-3.95(m,3H),3.94-3.83(m,3H),3.70-3.65(m,1H),3.00-2.97(m,2H),2.36-2.23(m,1H),2.18-2.15(m,1H),1.92-1.87(m,2H)；LC-MS:m/z＝559.3[M+H] +。
实施例30
Figure PCTCN2018122016-appb-000177
合成路线：
Figure PCTCN2018122016-appb-000178
第一步
将化合物O-1(2.00g,22.44mmol)溶于吡啶(5mL)，加入对甲苯磺酰氯(4.28g,22.44mmol)，反应液在10℃下搅拌16小时。反应液加入乙酸乙酯(50mL)，过滤，滤液浓缩得到化合物O-2。 1H NMR(400MHz,CDCl 3)δ7.49(d,J＝7.6Hz,2H),7.12(d,J＝7.6Hz,2H),3.98(t,J＝6.4Hz,2H),3.49(t,J＝6.4Hz,2H),2.76(s,3H),2.30(s,6H)。LC-MS:m/z＝244.0[M+H] +。
第二步
将化合物20-5(200.0mg,364.02μmol)溶于N,N-二甲基甲酰胺(3mL)，加入碳酸钾(100.6mg,728.04μmol)和化合物O-2(177.2mg,728.04μmol)，混合物在70℃搅拌16小时。反应液冷却到30℃，加水(10mL)稀释，用乙酸乙酯(10mLx3)萃取。合并的有机相，依次用水(30mLx2)，饱和食盐水(30mL)洗涤，用无水硫酸钠干燥。过滤，滤液减压浓缩，剩余物经制备薄层层析板分离纯化(二氯甲烷:甲醇＝10:1)，得到化合物30-2。 1H NMR(400MHz,CDCl 3)δ8.70(s,1H),8.53(t,J＝8.4Hz,1H),7.20-7.40(m,4H),4.65-4.85(m,1H),4.20-4.45(m,4H),2.90-3.00(m,2H),2.44(s,6H),2.10-2.20(m,2H),1.95-2.10(m,2H),1.75-1.95(m,2H),1.60-1.75(m,2H),1.50(s,9H)。LC-MS:m/z＝620.1[M+H] +。
第三步
参考实施例20第八步得到化合物30-3盐酸盐。LC-MS:m/z＝520.1[M+H] +。
第四步
参考实施例20第九步得到化合物实施例30。 1H NMR(400MHz,DMSO-d 6)δ9.68(s,1H),8.40(s,1H),7.86(s,1H),7.55-7.70(m,2H),7.26(s,1H),6.77(dd,J 1＝16.8Hz,J 2＝10.4Hz,1H),6.22(d,J＝16.8Hz 1H),5.72(d,J ＝10.4Hz 1H),4.90-5.00(m,1H),4.55-4.60(m,2H),4.20-4.30(m,2H),2.70-2.80(m,2H),2.31(s,6H),1.80-2.10(m,6H),1.60-1.70(m,1H),1.45-1.60(m,1H)。LC-MS:m/z＝574.1[M+H] +。
实施例31
Figure PCTCN2018122016-appb-000179
合成路线：
Figure PCTCN2018122016-appb-000180
第一步
将化合物31-1(300.0mg,1.28mmol)溶于氯化亚砜(3.0mL,41.45mmol)，加入N,N-二甲基甲酰胺(47.30μL,614.84μmol)，反应液加热至80℃，搅拌1小时。反应液减压浓缩，剩余物室温下加入化合物P-1(171.8mg,1.28mmol)的异丙醇(10mL)溶液，混合物加热至90℃，搅拌1小时。反应液冷却到20℃，过滤，固体用异丙醇(10mL)洗涤，在空气中干燥得化合物31-2。 1H NMR(400MHz,DMSO-d 6)δ11.51(s,1H),9.35(s,1H),8.90(s,1H),8.72(s,1H),8.23(s,1H),7.85-8.00(m,2H),7.50(s,1H),4.03(s,3H),2.41(s,3H)。LC-MS:m/z＝351.0[M+H] +。
第二步
将化合物31-2(400.0mg,1.14mmol)溶于乙醇(10mL)，加入氢氧化钠(228.4mg,5.71mmol)的水(2mL)溶液，反应液在10℃下搅拌1小时。反应液加入醋酸(0.5mL)和水(10mL)，继续搅拌0.5小时。过滤反应液，固体用水(10mL)洗涤，减压干燥，得到化合物31-3。 1H NMR(400MHz,DMSO-d 6)δ10.89(s,1H),9.67(s,1H),9.38(s,1H),8.42(s,1H),8.08(d,J＝2.8Hz,1H),7.80-7.90(m,1H),7.74(s,1H),7.19(s,1H),7.03(d,J＝8.8Hz, 1H),3.97(s,3H)。LC-MS:m/z＝309.0[M+H] +。
第三步
将化合物31-3(100.0mg,324.37μmol)溶于N,N-二甲基乙酰胺(5mL)，加入碳酸钾(89.,7mg,648.74μmol)和化合物P-2(1034mg,308.15μmol)，反应液在70℃下搅拌16小时。反应液冷却到20℃，加水(30mL)稀释，用乙酸乙酯(20mLx3)萃取。合并的有机相，依次用水(30mLx3)，饱和食盐水(30mLx2)洗涤，用无水硫酸钠干燥。过滤，滤液减压浓缩，剩余物用制备薄层层析板分离纯化(二氯甲烷:甲醇＝15:1)，得到实施例31。 1H NMR(400MHz,DMSO-d 6)δ9.68(s,1H),9.46(s,1H),8.44(s,1H),8.23(d,J＝2.4Hz 1H),8.00-8.10(m,1H),7.76(s,1H),7.50(d,J＝9.6Hz 1H),6.77(dd,J 1＝16.8Hz,J 2＝10.4Hz,1H),6.22(dd,J 1＝16.8Hz,J 2＝2.4Hz,1H),5.73(dd,J 1＝10.4Hz,J 2＝2.4Hz,1H),4.90-5.10(m,1H),4.55-4.65(m,2H),3.98(s,3H),2.15-2.35(m,2H),1.80-2.00(m,4H),1.60-1.70(m,1H),1.45-1.55(m,1H)。LC-MS:m/z＝472.1[M+H] +。
实施例32
Figure PCTCN2018122016-appb-000181
合成路线：
Figure PCTCN2018122016-appb-000182
第一步
参考实施例31第一步得到化合物31-2。 1H NMR(400MHz,DMSO-d 6)δ11.21(s,1H),8.97(s,1H),8.71(s,1H),8.18(d,J＝2.0Hz,1H),7.71-7.81(m,2H),7.49(s,1H),4.02(s,3H),2.40(s,3H)。LC-MS:m/z＝378.0[M+H] +。
第二步
参考实施例31第二步得到化合物31-3。 1H NMR(400MHz,DMSO-d 6)δ9.77(s,1H),9.61(s,1H),8.54(s,1H),8.34(d,J＝2.4Hz,1H),7.80-7.90(m,1H),7.81(s,1H),7.61(d,J＝8.8Hz,1H),7.24(s,1H),3.99(s,3H)。LC-MS:m/z＝335.9[M+H] +。
第三步
参考实施例31第三步得到化合物实施例32。 1H NMR(400MHz,DMSO-d 6)δ9.62(s,1H),8.58(s,1H),8.32(d,J＝2.8Hz 1H),7.85-7.95(m,2H),7.68(d,J＝8.8Hz 1H),7.24(s,1H),6.77(dd,J 1＝16.8Hz,J 2＝10.4Hz,1H),6.22(dd,J 1＝16.8Hz,J 2＝2.4Hz,1H),5.72(dd,J 1＝10.4Hz,J 2＝2.4Hz,1H),4.90-5.10(m,1H),4.60-4.65(m,2H),3.92(s,3H),2.20-2.40(m,2H),1.80-2.10(m,4H),1.60-1.70(m,1H),1.40-1.50(m,1H)。LC-MS:m/z＝499.1[M+H] +。
实施例33
Figure PCTCN2018122016-appb-000183
合成路线：
Figure PCTCN2018122016-appb-000184
第一步
参考实施例31第一步得到化合物33-2。LC-MS:m/z＝362.0[M+H] +。。
第二步
参考实施例31第二步得到化合物33-3。 1H NMR(400MHz,DMSO-d 6)δ9.76(s,1H),9.50(s,1H),8.35(s,1H),7.66(s,1H),7.42-7.60(m,2H),7.20-7.30(m,1H),7.21(s,1H),3.98(s,3H)。LC-MS:m/z＝319.9[M+H] +。
第三步
参考实施例31第三步得到化合物实施例33。 1H NMR(400MHz,DMSO-d 6)δ9.57(s,1H),8.38(s,1H),7.78(s,1H),7.50-7.65(m,2H),7.25-7.35(m,1H),7.21(s,1H),6.77(dd,J 1＝16.8Hz,J 2＝10.4Hz,1H),6.22(dd,J 1＝16.8Hz,J 2＝2.0Hz,1H),5.77(dd,J 1＝10.4Hz,J 2＝2.0Hz,1H),4.90-5.10(m,1H),4.55-4.65(m,2H),3.98(s,3H),2.20-2.40(m,2H),1.85-2.10(m,4H),1.60-1.70(m,1H),1.45-1.55(m,1H)。LC-MS:m/z＝483.0[M+H] +。
实施例34
Figure PCTCN2018122016-appb-000185
合成路线：
Figure PCTCN2018122016-appb-000186
第一步
参考实施例31第一步得到化合物34-2。LC-MS:m/z＝380.0[M+H] +。
第二步
参考实施例31第二步得到化合物34-3。 1H NMR(400MHz,DMSO-d 6)δ9.76(s,1H),9.49(s,1H),8.33(s,1H),7.65(s,1H),7.50-7.60(m,1H),7.32-7.40(m,1H),7.21(s,1H),3.98(s,3H)。LC-MS:m/z＝337.9[M+H] +。
第三步
参考实施例31第三步得到化合物实施例34。 1H NMR(400MHz,DMSO-d 6)δ9.60(s,1H),8.37(s,1H),7.78(s,1H),7.56-7.65(m,1H),7.38-7.50(m,1H),7.21(s,1H),6.77(dd,J 1＝16.8Hz,J 2＝10.4Hz,1H),6.22(dd,J 1＝16.8Hz,J 2＝2.0Hz,1H),5.72(dd,J 1＝10.4Hz,J 2＝2.0Hz,1H),4.90-5.05(m,1H),4.55-4.65(m,2H),3.98(s, 3H),2.20-2.40(m,2H),1.85-2.10(m,4H),1.60-1.70(m,1H),1.45-1.55(m,1H)。LC-MS:m/z＝501.1[M+H] +。
实施例35
Figure PCTCN2018122016-appb-000187
合成路线：
Figure PCTCN2018122016-appb-000188
第一步
参考实施例31第一步得到化合物35-2。LC-MS:m/z＝350.0[M+H] +。
第二步
参考实施例31第二步得到化合物35-3。 1H NMR(400MHz,DMSO-d 6)δ9.74(s,1H),9.51(s,1H),9.37(s,1H),8.49(s,1H),8.07(s,1H),7.91(s,1H),7.60-7.70(m,3H),7.22(s,1H),3.98(s,3H)。LC-MS:m/z＝307.9[M+H] +。
第三步
参考实施例31第三步得到化合物实施例35。 1H NMR(400MHz,DMSO-d 6)δ9.68(s,1H),9.27(s,1H),8.49(s,1H),8.00-8.10(m,2H),7.55-7.70(m,3H),7.21(s,1H),6.77(dd,J 1＝16.8Hz,J 2＝10.4Hz,1H),6.22(dd,J 1＝16.8Hz,J 2＝2.0Hz,1H),5.72(dd,J 1＝10.4Hz,J 2＝2.0Hz,1H),5.10-5.15(m,1H),4.55-4.65(m,2H),3.98(s,3H),2.20-2.40(m,2H),1.80-2.10(m,4H),1.60-1.70(m,1H),1.40-1.50(m,1H)。LC-MS:m/z＝471.2[M+H] +。
实施例36
Figure PCTCN2018122016-appb-000189
合成路线：
Figure PCTCN2018122016-appb-000190
第一步
将化合物16-4(100.0mg,470.56μmol)溶于N,N-二甲基甲酰胺(2mL)中，向反应液中加入NaH(60％。22.4mg,560.34μmol)，反应液在0℃搅拌0.5小时，加入化合物1-(2-溴乙基)哌啶(55.1mg,373.56μmol)的N,N-二甲基甲酰胺(0.5mL)溶液，反应液在15℃搅拌5小时。加水(10mL)稀释，用乙酸乙酯(5mLx3)萃取，合并的有机相用无水硫酸钠干燥。过滤，滤液减压浓缩，剩余物用制备薄层层析板分离纯化(二氯甲烷:甲醇＝7:1)，得到化合物36-2。
第二步
参考实施例21第二步得到化合物36-3的盐酸盐。
第三步
参考实施例20第九步得到化合物实施例36。 1H NMR(400MHz,CDCl 3)δ8.70(s,1H),8.49(t,J＝8.4Hz,1H),7.34(d,J＝8.8Hz,1H),7.27-7.25(m,1H),7.07(s,1H),6.66-6.57(m,1H),6.43(d,J＝16.8Hz,1H),5.73(d,J＝10.0Hz,1H),4.69-4.67(m,1H),4.28-4.28(m,2H),3.99-3.94(m,2H),3.90-3.87(m,1H),3.74-3.71(m,1H),3.01-3.00(m,2H),2.89(m,2H),2.59(m,4H),2.05-2.01(m,2H),1.65-1.61(m,4H),1.48-1.46(m,2H)；LC-MS:m/z＝600.3[M+H] +。
实施例37
Figure PCTCN2018122016-appb-000191
合成路线：
Figure PCTCN2018122016-appb-000192
第一步
将化合物13-2(250.0mg,470.56μmol)溶于N,N-二甲基甲酰胺(4mL)中，加入碳酸钾(130.0mg,941.11μmol)，和化合物M-1(171.0mg,705.83μmol)到反应液中，反应液在110℃搅拌18小时。减压浓缩除去溶剂，剩余物经制备薄层层析板(二氯甲烷:甲醇＝15:1)分离纯化，得到化合物37-2。LC-MS:m/z＝601.3[M+H] +。
第二步
将化合物37-2(100.0mg,166.29μmol)溶于甲醇(5mL)中，加入碳酸钾(68.9mg,498.86μmol)，反应液在40-50℃搅拌3小时。然后在60℃再搅拌12小时。减压浓缩反应液，剩余物经制备薄层层析板(二氯甲烷:甲醇＝10:1)分离纯化得到化合物37-3。LC-MS:m/z＝505.2[M+H] +。
第三步
参考实施例20第九步得到化合物实施例37。 1H NMR(400MHz,CDCl 3)δ8.40(s,1H),7.79(s,1H),7.65-7.58(m,1H),7.47(d,J＝10.8Hz,1H),7.18(s,1H),6.84-6.73(m,1H),6.36-6.29(m,1H),5.82-5.75(m,1H),5.19(s,1H),4.09-4.03(m,1H),3.99-3.87(m,5H),3.84-3.78(m,1H),3.60-3.75(m,1H),3.37(s,1H),3.17-3.03(m,2H),2.39-2.26(m,1H),2.16(s,1H),2.04-1.93(s,1H),1.61(d,J＝10.4Hz,1H)。LC-MS:m/z＝559.3[M+H] +。
实施例38
Figure PCTCN2018122016-appb-000193
合成路线：
Figure PCTCN2018122016-appb-000194
第一步
将化合物38-1(900.0mg,3.93mmol)溶于N,N-二甲基甲酰胺(20mL)，加入碳酸钾(1.09g,7.85mmol)和化合物Q-1(1.60g,7.07mmol)。反应液在75℃搅拌16小时。反应液冷却到20℃，加水(30mL)稀释，用乙酸乙酯(30mLx2)萃取。合并的有机相，依次用水(40mLx2)，饱和食盐水(40mLx2)洗涤，用无水硫酸钠干燥。过滤，滤液减压浓缩。剩余物经硅胶柱层析法分离纯化(乙酸乙酯:石油醚＝1:3)，得到化合物38-2。 1H NMR(400MHz,CDCl 3)δ7.42(s,1H),6.45(s,1H),4.75(d,J＝8.4Hz,1H),4.10-4.40(m,2H),3.87(s,3H),3.86(s,3H),3.75-3.80(m,1H),1.90-2.10(m,4H),1.50-1.70(m,4H),1.41(s,9H)。LC-MS:m/z＝458.1 [M+Na] +。
第二步
将化合物38-2(1.50g,3.44mmol)溶于甲醇(30mL)中，加入湿钯碳(10％,50.0mg)，反应液在20℃，氢气氛围下搅拌0.5小时。过滤反应液，滤液减压浓缩，干燥得到化合物38-3。 1H NMR(400MHz,CDCl 3)δ7.09(s,1H),6.10(s,1H),5.36(brs,2H),4.15-4.40(m,2H),3.85(s,3H),3.82(s,3H),3.65-3.80(m,1H),1.95-2.15(m,4H),1.90-1.85(m,2H),1.47(s,9H),1.30-1.45(m,2H)。LC-MS:m/z＝406.2[M+H] +。
第三步
将化合物38-3(1.30g,3.21mmol)和醋酸铵(2.47g,32.06mmol)加入原甲酸三甲酯(31.29g,294.89mmol)中，反应液在70℃搅拌10小时。降温至20℃，反应液减压浓缩，剩余物加入水(10mL)打浆，过滤，固体干燥后得到化合物38-4。 1H NMR(400MHz,DMSO-d 6)δ7.83(s,1H),7.08(s,1H),7.00(s,1H),5.17(d,J＝8.4Hz,1H),4.10-4.20(m,2H),3.95-4.00(m,1H),3.92(s,3H),1.90-2.00(m,4H),1.75-1.90(m,2H),1.50-1.60(m,2H),1.43(s,9H)。LC-MS:m/z＝401.1[M+H] +。
第四步
将化合物38-4(1.20g,3.00mmol)加入氯化氢的二氧六环溶液(4N,10mL)，反应液在0℃搅拌0.4小时。反应液减压浓缩，得到化合物38-5的盐酸盐。LC-MS:m/z＝301.0[M+H] +。
第五步
在0℃，将38-5的盐酸盐(1.10g,3.27mmol)，三乙胺(4.6mL,32.66mmol)溶入二氯甲烷(30mL)中，滴加三氟乙酸酐(1.37g,6.53mmol)，反应液在20℃搅拌1小时。减压浓缩，剩余物加水(40mL)打浆，过滤，固体干燥得到化合物38-6。 1H NMR(400MHz,DMSO-d 6)δ11.90(s,1H),7.80-7.90(m,1H),7.13(m,1H),7.00(m,1H),5.28(d,J＝9.2Hz,1H),4.60-4.70(m,1H),4.40-4.50(m,1H),4.00-4.10(m,1H),3.91(s,3H),1.90-2.20(m,6H),1.55-1.75(m,2H)。LC-MS:m/z＝397.0[M+H] +。
第六步
将化合物38-6(500.0mg,1.26mmol)溶于三氯氧磷(24.1mL,260.22mmol)中，加入N,N二甲基甲酰胺(92.2mg,1.26mmol)，反应液在100℃搅拌5小时。减压浓缩，剩余物加入3,4-二氯-2-氟苯胺(340.6mg,1.89mmol)的异丙醇(5mL)溶液。反应液在90℃搅拌1小时。反应液冷却到20℃，加入饱和碳酸氢钠水溶液(10mL)淬灭，用乙酸乙酯(10mLx2)萃取。合并有机相，用无水硫酸钠干燥。过滤，滤液减压浓缩，剩余物用硅胶柱层析法分离纯化(乙酸乙酯:石油醚＝2:1)，得到化合物38-7。 1H NMR(400MHz,CDCl 3)δ8.50-8.65(m,2H),7.40-7.50(m,1H),7.15-7.25(m,2H),6.59(s,1H),4.75-4.85(m,1H),4.55-4.65(m,2H),4.05-4.10(m,1H),3.98(s,3H),2.10-2.40(m,4H),1.90-2.00(m,2H),1.60-1.75(m,2H)。LC-MS:m/z＝557.9[M+H] +。
第七步
将化合物38-7(305.0mg,547.2μmol)溶于甲醇(15mL)中，加入碳酸钾(378.2mg,2.74mmol)。反应液在50℃搅拌14个小时。反应液减压浓缩，剩余物用硅胶制备板分离纯化(二氯甲烷:甲醇＝10:1)，得到化合物38-8。 1H NMR(400MHz,DMSO-d 6)δ9.45(s,1H),8.28(s,1H),7.67(t,J＝8.0Hz,1H),7.58(d,J＝10.0Hz,1H),7.20(s,1H),7.14(s,1H),5.17(d,J＝8.4Hz,1H),4.05-4.10(m,2H),3.98-4.05(m,1H),3.93(s,3H),2.15-2.30(m,4H),1.95-2.10(m,2H),1.70-1.80(m,2H)。LC-MS:m/z＝462.0[M+H] +。
第八步
在0℃下，将化合物38-8(220.0mg,475.8μmol)溶于四氢呋喃(6mL)和水(6mL)的混合溶剂，加入碳酸氢钠(119.9mg,1.43mmol)，缓慢滴入丙烯酰氯(38.8mg,428.3μmol)。反应液在0℃继续搅拌0.5小时。加入MeOH(1mL)淬灭，减压浓缩，剩余物用制备薄层层析板分离纯化(二氯甲烷:甲醇＝10:1)，得到化合物
实施例38(R f＝0.3)。 1H NMR(400MHz,DMSO-d 6)δ9.35(s,1H),8.24(s,1H),7.66(t,J＝8.0Hz,1H),7.57(d,J＝8.8Hz,1H),7.14(s,1H),7.06(s,1H),6.72(dd,J 1＝16.8Hz,J 2＝10.4Hz,1H),6.18(dd,J 1＝16.8Hz,J 2＝1.6Hz,1H),5.68(dd,J 1＝10.4Hz,J 2＝1.6Hz,1H),5.35(d,J＝9.2Hz,1H),4.50-4.60(m,2H),4.05-4.15(m,1H),3.92(s,3H),1.85-2.20(m,6H),1.60-1.70(m,1H),1.50-1.60(m,1H)。LC-MS:m/z＝538.0[M+Na] +。
实施例39
Figure PCTCN2018122016-appb-000195
合成路线：
Figure PCTCN2018122016-appb-000196
第一步
参考实施例38第八步得到化合物实施例39(R f＝0.4)。 1H NMR(400MHz,DMSO-d 6)δ9.38(s,1H),8.27(s,1H),7.50-7.60(m,2H),7.14(s,1H),7.05(s,1H),6.74(dd,J 1＝16.8Hz,J 2＝10.4Hz,1H),6.18(dd,J 1＝16.8Hz,J 2＝2.0Hz,1H),5.69(dd,J 1＝10.4Hz,J 2＝2.0Hz,1H),5.47(d,J＝4.8Hz,1H),4.50-4.60(m,2H),4.01(s,3H),3.80-3.90(m,1H),2.20-2.30(m,1H),1.85-2.15(m,7H)。LC-MS:m/z＝538.0[M+Na] +。
实施例40
Figure PCTCN2018122016-appb-000197
合成路线：
Figure PCTCN2018122016-appb-000198
第一步
将化合物40-1(200.0mg,853.94μmol)溶于氯化亚砜(3mL)，加入N,N-二甲基甲酰胺(6μL 85.39μmol)。反应液加热至80℃，搅拌1小时。反应液减压浓缩，剩余物室温下加入3-氯-4-氟苯胺(130.0mg,893.09μmol)的异丙醇(5mL)溶液，混合物加热至90℃并搅拌3小时。反应液减压浓缩，剩余物室温下加入乙酸乙酯(15mL)，悬浊液室温下搅拌1小时，悬浊液过滤后滤饼真空干燥，得到化合物40-2。LC-MS:m/z＝320.1[M+H] +。
第二步
将化合物40-2(50.0mg,156.39μmol)溶于N,N-二甲基甲酰胺(1mL)中，加入碳酸铯(100.0mg,306.92μmol)和化合物P-2(50.0mg,149.07μmol)，反应液在90℃搅拌45分钟。反应液冷却到15℃，倒入水(30mL)中，用乙酸乙酯(20mLx3)萃取。合并的有机相，依次用水(30mL)和饱和食盐水(30mL)洗涤，用无水硫酸钠干燥。过滤，滤液减压浓缩，剩余物用制备薄层层析板分离纯化(乙酸乙酯:四氢呋喃＝4:1)，得到化合物实施例40。 1H NMR(400MHz,DMSO-d 6)δ9.68(s,1H),8.51(s,1H),8.19(dd,J 1＝6.8Hz,J 2＝2.8Hz,,1H),7.95(s,1H),7.78-7.84(m,1H),7.46(t,J＝9.2Hz,1H),7.21(s,1H),6.77(dd,J 1＝16.4Hz,J 2＝10.4Hz,1H),6.22(dd,J 1＝16.4Hz,J 2＝2.4Hz,1H),5.73(dd,J 1＝10.4Hz,J 2＝2.4Hz,1H),4.97-5.11(m,1H),4.58-4.63(m,2H),3.92(s,3H),2.30-2.38(m,1H),2.20-2.27(m,1H),2.00-2.09(m,2H),1.84-1.97(m,2H),1.65(t,J＝10.4Hz,1H),1.49(t,J＝10.4Hz,1H)。LC-MS:m/z＝483.1[M+H] +。
实施例41
Figure PCTCN2018122016-appb-000199
合成路线：
Figure PCTCN2018122016-appb-000200
第一步
参考实施例40第一步得到化合物41-2。 1H NMR(400MHz,DMSO-d 6)δ8.95(s,1H),8.29(s,1H),8.07(s,1H),7.93-8.02(m,2H),7.40(s,1H),4.05(s,3H)。LC-MS:m/z＝370.0[M+H] +。
第二步
参考实施例40第二步得到化合物实施例41。 1H NMR(400MHz,DMSO-d 6)δ9.82(s,1H),8.65(s,1H),8.44(s,1H),8.04-8.09(m,1H),7.87-7.94(m,2H),7.28(s,1H),6.77(dd,J 1＝16.4Hz,J 2＝10.4Hz,1H),6.22(dd,J 1＝16.4Hz,J 2＝2.4Hz,1H),5.73(dd,J 1＝10.4Hz,J 2＝2.4Hz,1H),4.96-5.08(m,1H),4.58-4.63(m,2H),3.94(s,3H),2.23-2.37(m,2H),1.80-2.12(m,4H),1.65(t,J＝10.4Hz,1H),1.49(t,J＝10.4Hz,1H)。LC-MS:m/z＝532.9[M+H] +。
实施例42
Figure PCTCN2018122016-appb-000201
合成路线：
Figure PCTCN2018122016-appb-000202
第一步
将化合物20-5(200.0mg,364.02μmol)溶于N,N-二甲基甲酰胺(2mL)中，加入碳酸铯(240.0mg,736.60μmol)，碘化钠(4.0mg,26.69μmol)和3-碘氧杂环丁烷(80.0mg,434.84μmol)，反应液在90℃搅拌1小时。反应液冷却到15℃，倒入水(30mL)中，用乙酸乙酯(20mLx3)萃取。合并的有机相，依次用水(30mL)和饱和食盐水(30mL)洗涤，用无水硫酸钠干燥。过滤，滤液减压浓缩，剩余物用制备薄层层析板分离纯化(乙酸乙酯)，得到化合物42-2。 1H NMR(400MHz,CDCl 3)δ8.63(s,1H),8.48(t,J＝8.8Hz,1H),7.27(dd,J 1＝9.2Hz,J 2＝2.0Hz,1H),7.18(s,1H),6.76(s,1H),5.28-5.32(m,1H),4.99-5.05(m,2H),4.68-4.80(m,3H),4.21-4.40(m,2H),2.10-2.15(m,2H),2.00-2.06(m,2H),1.82-1.96(m,2H),1.58-1.64(m,2H),1.45(s,9H)。LC-MS:m/z＝605.3[M+H] +。
第二步
将化合物42-2(400.0mg,709.92μmol)溶于二氯甲烷(2mL)中，加入三氟乙酸(1mL)，反应液在15℃反应0.5小时。反应液直接减压浓缩，得到化合物42-3的三氟乙酸盐。LC-MS:m/z＝505.2[M+H] +。
第三步
在0℃下将化合物42-3的三氟乙酸盐(50.0mg,98.94μmol)溶于四氢呋喃(2mL)和水(2mL)的混合溶剂，加入碳酸氢钠(26.0mg,309.50μmol)后，缓慢滴入丙烯酰氯(10.0mg,110.49μmol)。反应液在0℃下，继续搅拌1小时。加入甲醇(10mL)淬灭，减压浓缩，剩余物用制备薄层层析板分离纯化(乙酸乙酯:四氢呋喃＝4:1)，得到化合物实施例42。 1H NMR(400MHz,DMSO-d 6)δ9.72(br s,1H),8.38(s,1H),7.84(s,1H),7.61(s,2H),6.84-6.89(m,1H),6.77(dd,J 1＝16.4Hz,J 2＝10.4Hz,1H),6.22(dd,J 1＝16.4Hz,J 2＝2.4Hz,1H),5.73(dd,J 1＝10.4Hz,J 2＝2.4Hz,1H),5.40-5.52(m,1H),4.95-5.08(m,3H),4.55-4.69(m,4H),2.25-2.43(m,2H),1.86-2.05 (m,4H),1.65(t,J＝10.4Hz,1H),1.49(t,J＝10.4Hz,1H)。LC-MS:m/z＝559.0[M+H] +。
实施例43
Figure PCTCN2018122016-appb-000203
合成路线：
Figure PCTCN2018122016-appb-000204
第一步
将化合物20-5(300.0mg,546.03μmol)溶于N,N-二甲基甲酰胺(3mL)，再在0℃下一次性加入钠氢(60％,45.0mg,1.12mmol)，反应液在0℃下搅拌0.5小时，加入1,2-二溴乙烷(149.4mg,795.27μmol)。反应液在15℃下搅拌11.5小时。加入水(50mL)淬灭，用乙酸乙酯萃取(50mLx3)。合并有机相，用无水硫酸钠干燥。过滤，滤液减压浓缩，剩余物用制备薄层层析板分离纯化(乙酸乙酯)，得到化合物43-2。 1H NMR(400MHz,CDCl 3)δ8.64(s,1H),8.46(t,J＝8.53Hz,1H),7.20-7.29(m,4H),4.66-4.77(m,1H),4.40-4.45(m,2H),4.18-4.32(m,2H),3.70-3.75(m,2H),2.03-2.15(m,2H),1.90-1.95(m,2H),1.72-1.82(m,2H),1.58-1.65(m,2H),1.45(s,9H)。LC-MS:m/z＝657.2[M+H] +。
第二步
将化合物43-2(170.0mg,259.00μmol)溶于四氢呋喃(3mL)中，加入氮杂环丁烷(42.3mg,740.88μmol)，反应液在50℃搅拌1.5小时。反应液减压浓缩，得到化合物43-3。LC-MS:m/z＝632.2[M+H] +。
第三步
参考实施例42第二步，得到化合物43-4的三氟乙酸盐。LC-MS:m/z＝532.3[M+H] +。
第四步
参考实施例42第三步，得到化合物实施例43。 1H NMR(400MHz,DMSO-d 6)δ9.63(s,1H),8.39(s,1H),7.80(s,1H),7.56-7.67(m,2H),7.19(s,1H),6.77(dd,J 1＝16.4Hz,J 2＝10.4Hz,1H),6.22(dd,J 1＝16.4Hz,J 2＝2.4Hz,1H),5.73(dd,J 1＝10.4Hz,J 2＝2.4Hz,1H),4.88-5.06(m,1H),4.54-4.66(m,2H),4.04-4.14(m,2H),3.22-3.26(m,4H),2.76-2.84(m,2H),2.16-2.32(m,2H),1.85-2.07(m,6H),1.65(t,J＝10.4Hz,1H),1.49(t,J＝10.4Hz,1H)。LC-MS:m/z＝586.1[M+H] +。
实施例44
Figure PCTCN2018122016-appb-000205
合成路线：
Figure PCTCN2018122016-appb-000206
第一步
参考实施例43第一步，得到化合物44-2。LC-MS:m/z＝607.3[M+H] +。
第二步
将化合物44-2(170.0mg,279.84μmol)溶于氯化氢的乙酸乙酯溶液(4N,10mL)中，在20-25℃下搅拌15分钟。减压浓缩反应液得到化合物44-3的盐酸盐。LC-MS:m/z＝507.2[M+H] +。
第三步
参考实施例42第三步，得到化合物实施例44。 1H NMR(400MHz,DMSO-d 6)δ9.63(s,1H),8.37(s,1H),7.80(s,1H),7.46-7.68(m,2H),7.21(s,1H),6.77(dd,J 1＝16.4Hz,J 2＝10.4Hz,1H),6.22(dd,J 1＝16.4Hz,J 2＝2.4Hz,1H),5.73(dd,J 1＝10.4Hz,J 2＝2.4Hz,1H),4.82-4.94(m,1H),4.57-4.62(m,2H),4.16-4.24(m,2H),3.53-3.64(m,2H),2.16-2.32(m,2H),1.75-2.10(m,6H),1.65(t,J＝10.4Hz,1H),1.49(t,J＝10.4Hz,1H)。LC-MS:m/z＝560.9[M+H] +。
实施例45
Figure PCTCN2018122016-appb-000207
合成路线：
Figure PCTCN2018122016-appb-000208
第一步
参考实施例42第一步，得到化合物45-2。 1H NMR(400MHz,CDCl 3)δ8.71(s,1H),8.53(t,J＝8.4Hz,1H),7.27-7.37(m,3H),7.17(s,1H),4.71-4.84(m,1H),4.28-4.44(m,3H),2.14-2.22(m,J＝7.8Hz,2H),1.54-2.01(m,10H),1.51(s,9H),1.33(s,6H)。LC-MS:m/z＝635.3[M+H] +。
第三步
参考实施例44第二步，得到化合物45-3的盐酸盐。LC-MS:m/z＝535.3[M+H] +。
第四步
参考实施例42第三步，得到化合物实施例45。 1H NMR(400MHz,DMSO-d 6)δ9.75(s,1H),8.37(s,1H),7.84(s,1H),7.49-7.66(m,2H),7.22(s,1H),6.77(dd,J 1＝16.4Hz,J 2＝10.4Hz,1H),6.22(dd,J 1＝16.4Hz,J 2＝2.4Hz,1H),5.73(dd,J 1＝10.4Hz,J 2＝2.4Hz,1H),4.88-5.03(m,1H),4.55-4.64(m,2H),4.18-4.27(m,2H),2.17-2.39(m,2H),1.82-2.07(m,6H),1.65(t,J＝10.4Hz,1H),1.49(t,J＝10.4Hz,1H),1.17(s,6H)。LC-MS:m/z＝589.3[M+H] +。
实施例46
Figure PCTCN2018122016-appb-000209
合成路线：
Figure PCTCN2018122016-appb-000210
第一步
参考实施例40第一步，得到化合物46-2。 1H NMR(400MHz,DMSO-d 6)δ11.43(s,1H),8.90(s,2H),8.34(d,J＝2.4Hz,1H),8.19(s,1H),8.15(dd,J 1＝8.4Hz,J 2＝2.4Hz,1H),7.83(d,J＝8.4Hz,1H),7.51(s,1H),4.03(s,3H)。LC-MS:m/z＝370.1[M+H] +。
第二步
参考实施例40第二步，得到化合物实施例46。 1H NMR(400MHz,DMSO-d 6)δ10.16(s,1H),8.50-8.62(m,2H),8.30-8.38(m,1H),8.17(s,1H),7.73(d,J＝8.8Hz,1H),7.23(s,1H),6.77(dd,J 1＝16.4Hz,J 2＝10.4Hz,1H),6.22(dd,J 1＝16.4Hz,J 2＝2.4Hz,1H),5.73(dd,J 1＝10.4Hz,J 2＝2.4Hz,1H),5.09-5.21(m,1H),4.54-4.65(m,2H),3.93(s,3H),2.20-2.34(m,2H),1.87-2.10(m,4H),1.65(t,J＝10.4Hz,1H),1.49(t,J＝10.4Hz,1H)。LC-MS:m/z＝533.1[M+H] +。
实施例47
Figure PCTCN2018122016-appb-000211
合成路线：
Figure PCTCN2018122016-appb-000212
第一步
参考实施例40第一步，得到化合物47-2。LC-MS:m/z＝354.1[M+H] +。
第二步
参考实施例40第二步，得到化合物实施例47。 1H NMR(400MHz,DMSO-d 6)δ9.81(s,1H),8.52(s,1H),8.29-8.38(m,1H),8.17-8.25(m,1H),7.95(s,1H),7.56(t,J＝9.54Hz,1H),7.23(s,1H),6.77(dd,J 1＝16.4Hz,J 2＝10.4Hz,1H),6.22(dd,J 1＝16.4Hz,J 2＝2.4Hz,1H),5.73(dd,J 1＝10.4Hz,J 2＝2.4Hz,1H),4.97-5.12(m,1H),4.57-4.69(m,2H),3.93(s,3H),2.19-2.31(m,2H),1.88-2.03(m,4H),1.65(t,J＝10.4Hz,1H),1.49(t,J＝10.4Hz,1H)。LC-MS:m/z＝517.1[M+H] +。
实施例48
Figure PCTCN2018122016-appb-000213
合成路线：
Figure PCTCN2018122016-appb-000214
第一步
参考实施例38第六步，得到化合物48-2(2.7g)。LC-MS:m/z＝542.2[M+H]+。
第二步
参考实施例38第七步，得到化合物48-3(0.9g)。LC-MS:m/z＝446.1[M+H]+。
第三步
参考实施例38第八步，得到实施例48(160.0mg)。 1H NMR(400MHz,CD 3OD)D 8.23(s,1H),7.61-7.52(m,1H),7.27-7.17(m,2H),7.09(s,1H),6.75(dd,J 1＝12.8Hz,J 2＝10.4Hz,1H),6.33(dd,J 1＝16.8Hz,J 2＝2.0Hz,1H),5.79(dd,J 1＝6.4Hz,J 2＝2.0Hz,1H),4.79-4.75(m,1H),4.63-4.61(m,1H),4.29-4.23(m,1H),4.03(s,3H),2.34-2.31(m,1H),2.27-2.21(m,1H),2.19-2.14(m,2H),2.13-2.03(m,2H),1.76-1.66(m,1H),1.64-1.53(m,1H)。LC-MS:m/z＝500.2[M+H]+。
生物化学检测：体外评价
实验例1 酶活性评价
本试验目的是检测化合物对HER1(ErbB1)，HER2(ErbB2)，HER4(ErbB4)的体外抑制活性。本试验采用的酶为人源ErbB1，ErbB2和ErbB4，Eurofins Pharma Discovery Service提供活性检测方法，测试化合物对HER1，HER2，HER4抑制活性结果如表1所示。
实验步骤和方法(96孔板)：
加入5倍稀释的测试化合物缓冲液(5μL)，多肽底物poly(Glu,Tyr)(4:1)(2.5μL)，ErbB(4-20ng,2.5μL)，MnCl 2(50mM,1.25μL)，dH 2O(3.75μL)，[γ- 33P]ATP(10μL)，在30℃孵化10分钟。加入3％磷酸终止反应，取10μL标本转移至Filtermate A，用75mM磷酸清洗滤片3次，用甲醇清洗1次，滤片转移到密封塑料口袋， 加入闪烁液混合物(4mL)，在闪烁发光计数仪检测发出的光子强度，将酶样本的cpm(次数/分钟)与内控样品的cpm进行比较，光子强度的高低反映了酪氨酸激酶活性的强弱。
表1：本发明化合物体外酶活性筛选试验结果
化合物 HER1IC 50(nM) HER2IC 50(nM) HER4IC 50(nM)
实施例1 2 3 10
实施例3 2 5 17
实施例4 2 3 13
实施例5 9 24 157
实施例6 2 4 17
实施例7 40 69 61
实施例8 6.0 b 5.5 b 3.5 b
实施例9 9 13 8
实施例13 5 8 7
实施例18 9 12 5
实施例20 18 11 10
实施例21 12 5 3
实施例22 12 7 3
实施例23 8 4 2
实施例24 10 6 3
实施例25 6 3 6
实施例26 8 5 4
实施例27 16 5 3
实施例32 15 5 3
实施例33 7 6 3
实施例34 5 4 2
实施例38 8 5 3
实施例40 11 5 2
实施例44 5 4 3
实施例45 8 7 10
实施例48 9 11 4
b:测试2次的平均值。
结论：本发明化合物对HER1,HER2和HER4抑制活性明显。
实验例2 细胞增殖抑制活性评价：
实验目的：检测待测化合物对细胞增殖抑制活性。
实验原理：Cell-Titer-Glo试剂中的荧光素酶利用荧光素、氧和ATP作为反应底物，产生氧化荧光素，并以光的形式释放能量。由于荧光素酶反应需要ATP，因而反应产生的光的总量和反应细胞活力的ATP数总量成正比。
实验材料:
细胞系：NCI-N87细胞系(ATCC-CRL-5822)，BT-474细胞系(ATCC-HTB-20)，OE21(ECACC-96062201)细胞培养基：(RPMI 1640培养基(Invitrogen#22400-105；10％血清Invitrogen#10090148；左旋谷酰胺1×，Gibco#25030-081；双抗Hyclone#SV30010)
Cell
Figure PCTCN2018122016-appb-000215
发光法细胞活力检测试剂盒(Promega#G7573)
384孔细胞培养板(Greiner#781090)
化合物板(LABCYTE#LP-0200)
CO 2培养箱(Thermo#371)
Vi-cell细胞计数仪(Beckman Coulter)
移液器(Eppendorf)
移液管(Greiner)
移液枪(Eppendorf)
多功能酶标仪(Envision Reader)
ECHO Liquid-handling workstation(Labcyte-ECHO555)
实验步骤和方法：
2.1第1天：
按照细胞种板示意图在384或96孔板中分别按每孔1000个细胞，25μL每孔的密度种板，边缘孔不种细胞补25μL PBS。
2.2第0天:
(1)化合物母液为10mM，用DMSO稀释化合物使其初始浓度为4mM。在化合物母液板上加入化合物，每孔9μL。
(2)用ECHO液体工作站做化合物稀释并向细胞板每孔加入125nL化合物，第2列和23列细胞孔每孔加125nL DMSO，第1列和24列PBS孔每孔加125nL DMSO。
(3)细胞板每孔补加25μL培养基，最终细胞板每孔为50μL，化合物浓度为1μM，3倍稀释，10个浓度，左右复孔，DMSO终浓度为0.25％。
2.3加好化合物后，1000rpm离心1min，将细胞板放置于37℃、5％CO 2培养箱中培养3天。
2.4第3天:
从培养箱中取出细胞板，在室温下平衡30分钟。向每孔加入25μL Cell-Titer-Glo试剂，振摇一分钟使它被充分混匀，1000rpm离心1分钟。10分钟后，在PerkinElmer Envision上读板，设置荧光读取时间0.2秒。试验结果：试验结果如表2。
OE19细胞CTG实验
用胰酶消化饱和度已达到80％-90％的OE19细胞，离心重悬计数，调整细胞浓度，90ml/孔，加入96孔细胞培养板，使OE19细胞每孔个数为8000个。在含5％CO 2的细胞培养箱中37℃培养过夜。
用DMSO将待测化合物母液3倍梯度稀释，共10个浓度。在实验开始前，在无菌条件下将梯度稀释好的待测化合物用细胞培养液进一步稀释为10×化合物溶液(最高浓度100合物含1％DMSO)。将配制好的10×化合物溶液加入到细胞培养板中，每孔加入10物溶。这样，模型标准对照Staurosporine(星形孢菌素)及所有受试化合物的终浓度均以10μM为起始浓度，梯度3倍稀释，共10个测试浓度点。
细胞培养72小时后，取出96孔细胞培养板，加入Cell Titer Glo试剂，50ml/孔，混匀离心，室温避光孵育10分钟。将细胞板放入Envision进行读数。
根据原始数据计算抑制率，抑制率计算公式为：
抑制百分比％＝(ZPE-样本检测值)/(ZPE-HPE)×100％
以DAY3(以加化合物记为实验第一天，DAY3为读数当天)的含10mM staurosporine的孔作为HPE(100％抑制对照)孔，以DAY3的含0.1％的DMSO孔为ZPE(0％抑制对照)孔。受试化合物每个浓度点设两个复孔。
处理后的数据将用GraphPad Prism 6分析软件来做非线性回归分析，得到剂量效应曲线，并计算出待测化合物对OE19细胞的半抑制浓度(IC 50)。试验结果如表2
表2：本发明化合物体外细胞增殖抑制活性筛选试验结果
Figure PCTCN2018122016-appb-000216
Figure PCTCN2018122016-appb-000217
ND:未测试；b:测试2次的平均值；d:化合物起始稀释浓度为10μM
结论：本发明化合物对NCI-N87，BT-474，OE21和OE19细胞增殖抑制活性明显。
实验例3 人胃癌NCI-N87细胞皮下异种移植肿瘤BALB/c裸小鼠模型的体内药效学研究:
实验目的：研究待测化合物对人胃癌NCI-N87细胞皮下异种移植瘤在BALB/c裸小鼠模型体内药效进行评估
实验动物：雌性BALB/c裸小鼠,6－8周龄，体重18-22克；供应商：上海西普尔-必凯实验动物有限公司实验方法与步骤：
3.1细胞培养
人胃癌NCI-N87细胞体外单层培养，培养条件为RPMI-1640培养基中加10％胎牛血清，100U/mL青霉素，100μg/mL链霉素和2mM谷氨酰胺，37℃5％CO 2培养。一周两次用胰酶-EDTA进行常规消化处理传代。当细胞饱和度为80％-90％时，收取细胞，计数，接种。
3.2肿瘤细胞接种(肿瘤接种)
将0.2mL(10×106个)NCI-N87细胞皮下接种于每只裸小鼠的右后背(PBS+Matrigel，1:1)。肿瘤平均体 积达到145mm 3时开始分组给药。
3.3受试物的配制:
受试化合物配制成0.3mg/mL的澄清溶液，溶媒为10％NMP(N-甲基吡咯烷酮)+10％乙二醇硬脂酸酯+80％水
3.4肿瘤测量和实验指标
实验指标是考察肿瘤生长是否被抑制、延缓或治愈。每周两次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为：V＝0.5a×b 2，a和b分别表示肿瘤的长径和短径。
化合物的抑瘤疗效用TGI(％)或相对肿瘤增殖率T/C(％)评价。TGI(％)，反映肿瘤生长抑制率。TGI(％)的计算：TGI(％)＝【1-(某处理组给药结束时平均瘤体积－该处理组开始给药时平均瘤体积)/(溶剂对照组治疗结束时平均瘤体积－溶剂对照组开始治疗时平均瘤体积)】×对照组。
相对肿瘤增殖率T/C(％)：计算公式如下：T/C％＝TRTV/CRTV组开始治疗时平(TRTV：治疗组RTV；CRTV：阴性对照组RTV)。根据肿瘤测量的结果计算出相对肿瘤体积(relative tumor volume，RTV)，计算公式为RTV＝V t/V 0，其中V 0是分组给药时(即d 0)测量所得平均肿瘤体积，V t为某一次测量时的平均肿瘤体积，TRTV与CRTV取同一天数据。
在实验结束后将检测肿瘤重量，并计算T/重量百分比，T重量和C重量分别表示给药组和溶媒对照组的瘤重。
3.5统计分析
统计分析，包括每个组的每个时间点的肿瘤体积的平均值和标准误(SEM)。治疗组在试验结束时给药后第21天表现出最好的治疗效果，因此基于此数据进行统计学分析评估组间差异。两组间比较用T-test进行分析，三组或多组间比较用one-way ANOVA进行分析，如果F值有显著性差异，应用Games-Howell法进行检验。如果F值无显著性差异，应用Dunnet(2-sided)法进行分析。用SPSS 17.0进行所有数据分析。p<0.05认为有显著性差异。
3.6试验结果
实验动物的体重作为间接测定药物毒性的参考指标。在此模型中所有给药组(除Poziotinib组)均未显示有显著性体重下降，Poziotinib组给药后第7天2只小鼠体重下降超过20％，3只体重下降超过15％，1只体重下降超过10％，给药后第8天2只小鼠安乐死，剩余小鼠降低给药剂量后逐渐恢复，无发病或死亡现象。药效结果如表3所示。
3.7试验结论和讨论
与溶媒组相比，对照组Poziotinib和本发明实施例1，实施例7和实施例8都展现了优异的抑制肿瘤生长的效 果，TGI分别为115.6％，103.98％，92.63％和119.71％。且本本发明中实施例1，实施例7和实施例8对模型动物体重指标的安全性显著优于对照化合物Poziotinib。
表3.本发明化合物对人胃癌NCI-N87异种移植瘤模型的抑瘤药效评价(基于给药后第21天肿瘤体积计算得出)
Figure PCTCN2018122016-appb-000218
注：
“--”不需计算
a.平均值±SEM。
b.肿瘤生长抑制由T/C和TGI(TGI(％)＝[1-(T 21-T 0)/(V 21-V 0)]×100)计算。
c.p值根据肿瘤体积。
实验例4 人胃癌NCI-N87细胞皮下异种移植肿瘤BALB/c裸小鼠模型的体内药效学研究:
实验目的：研究本专利待测化合物对人胃癌NCI-N87细胞皮下异种移植瘤在BALB/c裸小鼠模型体内药效进行评估
实验动物：雌性BALB/c裸小鼠,6－8周龄，体重18-22克；供应商：上海灵畅生物科技有限公司提供实验方法与步骤:
4.1细胞培养
人胃癌NCI-N87细胞，体外单层培养，培养条件为RPMI-1640培养基中加10％胎牛血清，100U/mL青霉素，100U/mL0链霉素和2mM谷氨酰胺，37℃，5％CO 2培养。一周两次用胰酶-EDTA进行常规消化处理传代。当细胞饱和度为80％-90％时，收取细胞，计数，接种。
4.2肿瘤细胞接种(肿瘤接种)
将0.2ml(10×106)NCI-N87细胞(PBS+Matrigel，1:1)皮下接种于每只小鼠的右后背，肿瘤平均体积达到158mm 3时开始分组给药
4.3受试物的配制:
受试化合物配制成0.04mg/mL和0.08mg/mL的澄清溶液，溶媒为10％NMP(N-甲基吡咯烷酮)+10％乙二醇硬脂酸酯+80％水
4.4肿瘤测量和实验指标
实验指标是考察肿瘤生长是否被抑制、延缓或治愈。每周两次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为：V＝0.5a×b 2，a和b分别表示肿瘤的长径和短径。
化合物的抑瘤疗效用TGI(％)或肿瘤增殖率T/C(％)评价。TGI(％)，反映肿瘤生长抑制率。TGI(％)的计算：TGI(％)＝[1-(某处理组给药结束时平均瘤体积－该处理组开始给药时平均瘤体积)/(溶剂对照组治疗结束时平均瘤体积－溶剂对照组开始治疗时平均瘤体积)]×100％。
肿瘤增殖率T/C(％)：计算公式如下：T/C(％)＝某处理组给药结束时平均瘤体积/溶剂对照组治疗结束时平均瘤体积×100％。
4.5统计分析
统计分析，包括每个组的每个时间点的肿瘤体积的平均值和标准误(SEM)(具体数据见表5-1)。治疗组在试验结束时给药后第28天表现出最好的治疗效果，因此基于此数据进行统计学分析评估组间差异。两组间比较用T-test进行分析，三组或多组间比较用one-way ANOVA进行分析，经检验，F值有显著性差异，应用Games-Howell法进行检验。用SPSS 17.0进行所有数据分析。p<0.05认为有显著性差异。
4.6试验结果
4.6.1死亡率、发病率及体重变化情况
实验动物的体重作为间接测定药物毒性的参考指标。在此模型治疗组小鼠体重有下降趋势，无其他发病或死亡现象。
4.6.2抗肿瘤药效评价指标
表4本发明化合物对人胃癌NCI-N87细胞皮下异种移植瘤模型的抑瘤药效评价(基于给药后第28天肿瘤体积计算得出)
Figure PCTCN2018122016-appb-000219
Figure PCTCN2018122016-appb-000220
注：
a.平均值±SEM。
b.肿瘤生长抑制由T/C和TGI(TGI(％)＝[1-(T28-T0)/(V28-V0)]×100)计算。
c.p值根据肿瘤体积计算。
4.7试验结论和讨论
在本实验评价了本专利化合物在人胃癌NCI-N87细胞皮下异种移植瘤模型中的体内药效。与溶剂对照组相比，治疗组实施例38@0.8mg/kg与参照化合物Poziotinib@0.8mg/kg药效相当，都展现了显著的抑瘤作用；低剂量组实施例38与参照化合物Poziotinib药效相当或者更优。
实验例5 人胃癌NCI-N87细胞皮下异种移植肿瘤BALB/c裸小鼠模型的体内药效学研究:
实验目的：研究本专利待测化合物对人胃癌NCI-N87细胞皮下异种移植瘤在BALB/c裸小鼠模型体内药效进行评估
实验动物:雌性BALB/c裸小鼠，6－8周龄，体重18-22克；供应商：上海西普尔-必凯实验动物有限公司实验方法与步骤:
5.1细胞培养
人胃癌NCI-N87细胞，体外单层培养，培养条件为RPMI-1640培养基中加10％胎牛血清，100U/mL青霉素，100μg/mL链霉素，37℃，5％CO 2培养。一周两次用胰酶-EDTA进行常规消化处理传代。当细胞饱和度为80％-90％时，收取细胞，计数，接种。
5.2肿瘤细胞接种(肿瘤接种)
将0.2ml(10×10 6)NCI-N87细胞(PBS+Matrigel，1:1)皮下接种于每只小鼠的右后背，肿瘤平均体积达到156mm 3时开始分组给药
5.3受试物的配制:
受试化合物配制成0.05mg/mL的澄清溶液，溶媒为10％NMP(N-甲基吡咯烷酮)+10％乙二醇硬脂酸酯+80％ 水
5.4肿瘤测量和实验指标
实验指标是考察肿瘤生长是否被抑制、延缓或治愈。每周两次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为：V＝0.5a×b 2，a和b分别表示肿瘤的长径和短径。
化合物的抑瘤疗效用TGI(％)或肿瘤增殖率T/C(％)评价。TGI(％)，反映肿瘤生长抑制率。TGI(％)的计算：TGI(％)＝[1-(某处理组给药结束时平均瘤体积－该处理组开始给药时平均瘤体积)/(溶剂对照组治疗结束时平均瘤体积－溶剂对照组开始治疗时平均瘤体积)]×100％。
肿瘤增殖率T/C(％)：计算公式如下：T/C(％)＝某处理组给药结束时平均瘤体积/溶剂对照组治疗结束时平均瘤体积×100％。
5.5统计分析
统计分析，包括每个组的每个时间点的肿瘤体积的平均值和标准误(SEM)(具体数据见表5-1)。治疗组在试验结束时给药后第28天表现出最好的治疗效果，因此基于此数据进行统计学分析评估组间差异。两组间比较用T-test进行分析，三组或多组间比较用one-way ANOVA进行分析，经检验，F值有显著性差异，应用Games-Howell法进行检验。用SPSS 17.0进行所有数据分析。p<0.05认为有显著性差异。
5.6试验结果
5.6.1死亡率、发病率及体重变化情况
实验动物的体重作为间接测定药物毒性的参考指标。在此模型治疗组小鼠体重有下降趋势，无其他发病或死亡现象。
5.6.2抗肿瘤药效评价指标
表5本专利化合物对人胃癌NCI-N87细胞皮下异种移植瘤模型的抑瘤药效评价(基于给药后第21天肿瘤体积计算得出)
Figure PCTCN2018122016-appb-000221
注：
a.平均值±SEM。
b.肿瘤生长抑制由T/C和TGI(TGI(％)＝[1-(T21-T0)/(V21-V0)]×100)计算。
c.p值根据肿瘤体积计算。
4.7试验结论和讨论
在本实验评价了本发明化合物和对照化合物2在人胃癌NCI-N87细胞皮下异种移植瘤模型中的体内药效。与溶剂对照组相比，治疗组实施例38@0.5mg/kg展现了显著的抑瘤作用，抑瘤率为T/C＝10.69％，
TGI＝119.41％,p＝0.007；同剂量下对照化合物2药效不明显T/C＝89.35％，TGI＝18.83％；本发明化合物药效显著优于对照化合物2。
实验例6 人食管癌OE21细胞皮下异种移植肿瘤BALB/c裸小鼠模型的体内药效学研究:
实验目的：研究待测化合物对人食管癌OE21细胞皮下异种移植肿瘤BALB/c裸小鼠模型体内药效进行评估。
实验动物：雌性BALB/c裸小鼠,6－8周龄，体重17-23克；供应商：上海西普尔-必凯实验动物有限公司实验方法与步骤:
6.1细胞培养
人食管癌OE21细胞体外单层培养，培养条件为RPMI-1640培养基中加10％胎牛血清，100U/mL青霉素，100U/mL0链霉素和2mM谷氨酰胺，37℃5％CO 2培养。一周两次用胰酶-EDTA进行常规消化处理传代。当细胞饱和度为80％-90％时，收取细胞，计数，接种。
6.2肿瘤细胞接种(肿瘤接种)
将0.1ml(20.1)OE21细胞(PBS)皮下接种于每只小鼠的右后背，肿瘤平均体积达到112mm 3时开始分组给药。
6.3受试物的配制:
受试化合物配制成0.15mg/mL～0.3mg/mL的澄清或混悬液溶液，溶媒为10％NMP+10％乙二醇硬脂酸酯+80％水
6.4肿瘤测量和实验指标
实验指标是考察肿瘤生长是否被抑制、延缓或治愈。每周两次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为：V＝0.5a生长 2，a和b分别表示肿瘤的长径和短径。
化合物的抑瘤疗效用TGI(％)或相对肿瘤增殖率T/C(％)评价。TGI(％)，反映肿瘤生长抑制率。TGI(％)的计算：TGI(％)＝[(1-(某处理组给药结束时平均瘤体积－该处理组开始给药时平均瘤体积))/(溶剂对照组治疗结束时平均瘤体积－溶剂对照组开始治疗时平均瘤体积)]×100％。
相对肿瘤增殖率T/C(％)：计算公式如下：T/C(％)＝某处理组给药结束时平均瘤体积/溶剂对照组治疗结束时平均瘤体积×100。
6.5统计分析
统计分析，包括每个组的每个时间点的肿瘤体积的平均值和标准误(SEM)。三组或多组间比较用one-wayANOVA。如果F值有显著性差异，应在ANOVA分析之后再进行多重比较。用SPSS 17.0进行所有数据分析。p<0.05认为有显著性差异。
6.6试验结果
6.6.1死亡率、发病率及体重变化情况
在此模型中Poziotinib@2/1.5mg/kg、实施例8/实施例38@2/0.5mg/kg和实施例38@2/1.5mg/kg给药组的动物均显示有不同程度的体重下降和出现皮屑的现象；Poziotinib@2/1.5mg/kg在分组给药后第6天和第7天开始依次有1只和3只小鼠体重下降超过15％，作停药处理，且有整组小鼠尿液深黄色的毒性提示；给药第3天开始测试组实施例8@2mg/kg组替换成实施例38@0.5mg/kg，Poziotinib@2mg/kg降低剂量到1.5mg/kg，实施例38@2mg/kg降低剂量到1.5mg/kg。剂量调整后，各组体重明显恢复(图1)。
6.6.2抗肿瘤药效评价指标
表6本发明化合物对OE21异种移植瘤模型的抑瘤药效评价(基于给药后第21天肿瘤体积计算得出)
Figure PCTCN2018122016-appb-000222
注：
a.平均值±SEM。
b.肿瘤生长抑制由T/C和TGI,计算，参考实验例4。
c.p值根据给药后第21天的肿瘤体积计算，采用One-Way ANOVA的统计方法，分别和Vehicle组比较得出。
6.7试验结论和讨论
在本实验评价了本发明化合物和参照化合物Poziotinib对OE21异种移植瘤模型中的体内药效。开始给药21天后，溶剂对照组荷瘤鼠的瘤体积达到948mm 3，受试物Poziotinib@2/1.5mg/kg、实施例8/实施例38 @2/0.5mg/kg和实施例38@2/1.5mg/kg组与溶剂对照组比较有显著的抑瘤作用，抑瘤率分别为Poziotinib@2/1.5mg/kg组：T/C＝6.05％,TGI＝106.65％,p＝0.008；实施例8/实施例38@2/0.5mg/kg组：T/C＝5.89％,TGI＝106.87％,p＝0.008；实施例38@2/1.5mg/kg组：T/C＝5.82％,TGI＝106.65％,p＝0.008。实施例38低剂量0.5mpk药效与参照化合物Poziotnib和实施例38高剂量1.5mpk药效相当。
实施例38抑瘤效果显著，药效与参考化合物Poziotinib相当，但是参考化合物高剂量组小鼠体重下降显著，3只小鼠体重下降超过15％，予以停药，并且全组有小鼠尿液深黄色毒性提示。实施例38对小鼠体重影响小，无停药，无尿液深黄色毒性提示，耐受性显著优于参考化合物。实施例38起效剂量更低，耐受性更好，安全窗口更优于参考化合物Poziotinib。
实验例7 小鼠药代动力学研究试验
实验目的：本实验旨在考察本专利实施例与参照化合物单次静脉注射和灌胃给药后雌性BALB/c小鼠体内血浆药代动力学。
实验动物：雌性BALB/c裸小鼠,7－9周龄，体重17-23克；供应商：上海西普尔-必凯实验动物有限公司样品采集：实验动物每个时间点从隐静脉穿刺采集血液样本0.03mL，记录实际采血时间。所有血样均加入规格为1.5mL的商品化EDTA-K2抗凝管中(供应商为江苏康健医疗用品有限公司)。血样采集后，在半小时内，于4℃、3000g离心10分钟吸取上清血浆，迅速至于干冰中，于-80℃冰箱保存，用于LC-MS/MS分析。
数据分析：采用WinNonlin TMVersion6.3(Pharsight,MountainView,CA)药动学软件的非房室模型处理血浆浓度，使用线性对数梯形法方法计算药动学参数C max,T max,T 1/2,AUC 0-last
表7本发明化合物与参考化合物PK结果对比
Figure PCTCN2018122016-appb-000223
C max：达峰浓度；T max：达峰时间；T 1/2：清除一半化合物所需时长；AUC 0-last：0-末次取样时间内的浓度积分面积。
在小鼠药代动力学研究结果显示，本发明化合物半衰期比参考化合物更长，口服血浆暴露量显著优于参照化合物Poziotinib和对照化合物2。
实验例8 CYP酶抑制活性评价
本发明化合物和参考化合物Poziotinib在人肝微粒体中CYP酶活性测试结果如下表所示(表8)
表8本发明化合物与参考化合物CYP酶抑制结果对比
Figure PCTCN2018122016-appb-000224
本发明化合物在人肝微粒体CYP抑制活性结果显示，实施例38和Poziotinib对CYP1A2和CYP3A4无抑制活性。实施例38对CYP2C19抑制活性与参考化合物Poziotinib相当，对CYP2C9和CYP2D6的活性有改善，分别优于参考化合物2倍和6倍。综合比较，实施例38对CYP活性有改善并优于参考化合物，因此药物-药物相互作用风险更低。

Claims (26)

  1. 式(Ⅰ)所示化合物、其异构体或其药学上可接受的盐，
    Figure PCTCN2018122016-appb-100001
    其中，
    T选自N和CR’；
    各R 1分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基或C 1-3烷氧基任选被1、2或3个独立选自F、Cl、Br、I、OH、NH 2和CN的取代基所取代；
    R 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2和C 1-3烷基，所述C 1-3烷基任选被1、2或3个独立选自F、Cl、Br和I的取代基所取代；
    R 4选自C 1-6烷基、C 1-6烷氧基、3-7元杂环烷基-O-、3-7元杂环烷基-C 1-6烷基-O-、C 3-6环烷基-O-和C 3-6环烷基-C 1-6烷基-O-，所述C 1-6烷基、C 1-6烷氧基、3-7元杂环烷基-O-、3-7元杂环烷-C 1-6烷基-O-、C 3-6环烷基-O-和C 3-6环烷基-C 1-6烷基-O-分别独立地任选被1、2或3个R取代；
    R 5和R 6分别独立地选自H、C 1-3烷基和3-7元杂环烷基，所述C 1-3烷基和3-7元杂环烷基任选被1、2或3个R取代；
    L选自-O-、-NR a-、-CR b1R b2-、-CR b1R b2-O-和-CR b1R b2-NH-；
    R a为H；
    或者R 4与R a连接形成一个任选被1、2、3或4个R’取代的5-7元杂环烷基；
    环A选自苯基和5-10元杂芳基；
    环B选自
    Figure PCTCN2018122016-appb-100002
    n选自1、2、3、4和5；
    各R分别独立地选自F、Cl、Br、I、OH、NH 2、CN、NR c1R c2、C 1-3烷基、C 1-3烷氧基、C 1-3烷基-NH-C(＝O)-、C 1-3烷硫基和3-7元杂环烷基，所述C 1-3烷基、C 1-3烷氧基、C 1-3烷基-NH-C(＝O)-、C 1-3烷硫基和3-7元杂环烷基任选被1、2或3个R’所取代；
    R’各自独立地选自F、Cl、Br、I、OH、NH 2、CN和C 1-3烷基；
    R b1和R b2分别独立地选自H、F、Cl、Br、I和C 1-3烷基；
    R c1和R c2分别独立地选自H和C 1-3烷基；
    所述5-7元杂环烷基、5-10元杂芳基和3-7元杂环烷基分别包含1、2、3或4个独立选自N、-O-、-S-、-NH-的杂原子或杂原子团。
  2. 根据权利要求1所述化合物、其异构体或其药学上可接受的盐，其中，各R分别独立地选自F、Cl、Br、I、OH、NH 2、CN、
    Figure PCTCN2018122016-appb-100003
    Me、Et、
    Figure PCTCN2018122016-appb-100004
    哌啶基、吡咯烷基、吖丁啶基、吗啉基和噁丁环基，所述Me、Et、
    Figure PCTCN2018122016-appb-100005
    哌啶基、吡咯烷基、吖丁啶基、吗啉基和噁丁环基任选被1、2或3个独立选自F、Cl、Br、I、OH、NH 2和C 1-3烷基的取代基所取代。
  3. 根据权利要求2所述化合物、其异构体或其药学上可接受的盐，其中，各R分别独立地选自F、Cl、Br、I、OH、NH 2、CN、
    Figure PCTCN2018122016-appb-100006
    Me、Et、
    Figure PCTCN2018122016-appb-100007
    Figure PCTCN2018122016-appb-100008
  4. 根据权利要求1～3任一项所述化合物、其异构体或其药学上可接受的盐，其中，各R 1分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、Me和
    Figure PCTCN2018122016-appb-100009
    所述Me和
    Figure PCTCN2018122016-appb-100010
    任选被1、2或3个独立选自F、Cl、Br、I、OH、NH 2和CN的取代基所取代。
  5. 根据权利要求4所述化合物、其异构体或其药学上可接受的盐，其中，各R 1分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、Me、CH 2F、CHF 2、CF 3、
    Figure PCTCN2018122016-appb-100011
  6. 根据权利要求1～3任一项所述化合物、其异构体或其药学上可接受的盐，其中，R 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、Me和CF 3。
  7. 根据权利要求1～3任一项所述化合物、其异构体或其药学上可接受的盐，其中，R 4选自
    Figure PCTCN2018122016-appb-100012
    Figure PCTCN2018122016-appb-100013
    哌啶基-C 1-3烷基-O-、噁丁环基-O-、吗啉基-C 1-3烷基-O-、吖丁啶基-O-、四氢呋喃基-O-、环丙烷基-O-、吡咯烷基-C 1-3烷基-O-和吖丁啶基-C 1-3烷基-O-，所述
    Figure PCTCN2018122016-appb-100014
    哌啶基-C 1-3烷基 -O-、噁丁环基-O-、吗啉基-C 1-3烷基-O-、吖丁啶基-O-、四氢呋喃基-O-、环丙烷基-O-、吡咯烷基-C 1-3烷基-O-和吖丁啶基-C 1-3烷基-O-任选被1、2或3个R取代。
  8. 根据权利要求7所述化合物、其异构体或其药学上可接受的盐，其中，R 4选自
    Figure PCTCN2018122016-appb-100015
    Figure PCTCN2018122016-appb-100016
  9. 根据权利要求1～3任一项所述化合物、其异构体或其药学上可接受的盐，其中，R 5和R 6分别独立地选自H、Me、Et和
    Figure PCTCN2018122016-appb-100017
    所述Me、Et和
    Figure PCTCN2018122016-appb-100018
    任选被1、2或3个R取代。
  10. 根据权利要求9所述化合物、其异构体或其药学上可接受的盐，其中，R 5和R 6分别独立地选自H、
    Figure PCTCN2018122016-appb-100019
  11. 根据权利要求1～3任一项所述化合物、其异构体或其药学上可接受的盐，其中，T选自N和C(CN)。
  12. 根据权利要求1～3任一项所述化合物、其异构体或其药学上可接受的盐，其中，L选自-O-、-NH-、-CH 2-、-CH 2-O-和-CH 2-NH-。
  13. 根据权利要求1～3任一项所述化合物、其异构体或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2018122016-appb-100020
    选自
    Figure PCTCN2018122016-appb-100021
    Figure PCTCN2018122016-appb-100022
  14. 根据权利要求1或11所述化合物、其异构体或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2018122016-appb-100023
    为
    Figure PCTCN2018122016-appb-100024
  15. 根据权利要求1～3任一项所述化合物、其异构体或其药学上可接受的盐，其中，环A选自苯基、氮茚基、苯并[b]噻吩基、咪唑并[1,2-a]吡啶基和苯并[d]异噁唑基。
  16. 根据权利要求15所述化合物、其异构体或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2018122016-appb-100025
    选自
    Figure PCTCN2018122016-appb-100026
  17. 根据权利要16所述化合物、其异构体或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2018122016-appb-100027
    选自
    Figure PCTCN2018122016-appb-100028
  18. 根据权利要求1或17所述化合物、其异构体或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2018122016-appb-100029
    选自
    Figure PCTCN2018122016-appb-100030
    Figure PCTCN2018122016-appb-100031
  19. 根据权利要求1～3任一项所述化合物、其异构体或其药学上可接受的盐，其中，环B选自
    Figure PCTCN2018122016-appb-100032
    Figure PCTCN2018122016-appb-100033
  20. 根据权利要求12或19所述化合物、其异构体或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2018122016-appb-100034
    选自
    Figure PCTCN2018122016-appb-100035
    Figure PCTCN2018122016-appb-100036
  21. 根据权利要求1～12任一项所述化合物、其异构体或其药学上可接受的盐，其选自
    Figure PCTCN2018122016-appb-100037
    Figure PCTCN2018122016-appb-100038
    其中，T、L、R 1、R 2、R 3、R 4、R 5和R 6如权利要求1～12所定义。
  22. 根据权利要求21所述化合物、其异构体或其药学上可接受的盐，其选自
    Figure PCTCN2018122016-appb-100039
    Figure PCTCN2018122016-appb-100040
    其中，T、L、R 1、R 2、R 3、R 4、R 5和R 6如权利要求1～12所定义。
  23. 下列化合物、其异构体或其药学上可接受的盐，
    Figure PCTCN2018122016-appb-100041
    Figure PCTCN2018122016-appb-100042
    Figure PCTCN2018122016-appb-100043
    Figure PCTCN2018122016-appb-100044
    Figure PCTCN2018122016-appb-100045
    Figure PCTCN2018122016-appb-100046
  24. 根据权利要求23所述的化合物，其选自
    Figure PCTCN2018122016-appb-100047
    Figure PCTCN2018122016-appb-100048
    Figure PCTCN2018122016-appb-100049
    Figure PCTCN2018122016-appb-100050
    Figure PCTCN2018122016-appb-100051
    Figure PCTCN2018122016-appb-100052
  25. 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1～24任一项所述的化合物、其异构体或其药学上可接受的盐以及药学上可接受的载体。
  26. 根据权利要求1～24任一项所述的化合物、其异构体或其药学上可接受的盐或者权利要求25所述的药物组合物在制备Pan-HER酪氨酸激酶抑制剂相关药物上的应用。
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CN111763215B (zh) * 2020-07-21 2021-05-18 成都海博为药业有限公司 一种具有含氮杂环结构的化合物及其制备方法和用途
CN111763215A (zh) * 2020-07-21 2020-10-13 成都海博为药业有限公司 一种具有含氮杂环结构的化合物及其制备方法和用途
CN112125890B (zh) * 2020-09-25 2022-12-06 华东理工大学 一种含异吲哚酮基喹唑啉基羧酸酯类衍生物及其应用
CN112125890A (zh) * 2020-09-25 2020-12-25 华东理工大学 一种含异吲哚酮基喹唑啉基羧酸酯类衍生物及其应用

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