CN104415028B - Application of benzopyrone compound in preparation of anti-tumor drugs - Google Patents

Application of benzopyrone compound in preparation of anti-tumor drugs Download PDF

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CN104415028B
CN104415028B CN201310377457.XA CN201310377457A CN104415028B CN 104415028 B CN104415028 B CN 104415028B CN 201310377457 A CN201310377457 A CN 201310377457A CN 104415028 B CN104415028 B CN 104415028B
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alkyl
halo
alkoxyl
carbonyl
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CN104415028A (en
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刘长令
关爱莹
杨小平
柴宝山
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Shenyang Research Institute of Chemical Industry Co Ltd
Sinochem Corp
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Shenyang Research Institute of Chemical Industry Co Ltd
Sinochem Corp
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Priority to JP2016537112A priority patent/JP6178010B2/en
Priority to PCT/CN2014/084990 priority patent/WO2015027863A1/en
Priority to KR1020167005378A priority patent/KR101885219B1/en
Priority to US14/909,124 priority patent/US9895346B2/en
Priority to AU2014314799A priority patent/AU2014314799B2/en
Priority to CN201480042638.XA priority patent/CN105431150B/en
Priority to EP14839919.9A priority patent/EP3040073B1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/453—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/539—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines having two or more oxygen atoms in the same ring, e.g. dioxazines

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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Abstract

The invention discloses an application of a benzopyrone compound represented by the general formula I in preparation of anti-tumor drugs, wherein in the formula, definitions of substituents are described the specification. The compound represented by the general formula I has a good anti-tumor activity, and especially has superior activity for resisting leukemia cell line HL-60, lung cancer A549, lung cancer H157, lung cancer H460, lung cancer H520, bladder cancer T24, bladder cancer J82, bladder cancer LNCap, prostate cancer PC-3 and the like.

Description

Benzofurantone compound is used as the application for preparing antitumor drug
Technical field
The invention belongs to field of medicaments, is related to a kind of field of antineoplastic medicaments.More particularly to a kind of Benzofurantone Application of the compound as antitumor drug.
Background technology
As the Benzofurantone compound of Periodical and patent report containing methoxy acrylate structure has agriculture Use bactericidal activity：Pest Management Science,Volume:67,Issue:6,Pages:647-655；Natural Product Communications,Volume:6,Issue:12,Pages:1917-1920；Nongyao,Volume:50, Issue:2,Pages:90-92；Nongyaoxue Xuebao,Volume:12,Issue:4,Pages:453-457；Natural Product Communications,Volume:2,Issue:8,Pages:845-848；Chinese Chemical Letters,Volume:22,Issue:6,Pages:663-666；WO2005044813.
Journal of Medicinal Chemistry,Volume:50,Issue:12,Pages:2886-2895 is reported Following general formula compound containing benzopyrone structure has anti-platelet activity.
In prior art, the compound simultaneously containing Structures of Natural Products fragment coumarin and methoxy acrylate is only made Use for disinfectant use in agriculture, compound of the structure as shown in formula I of the present invention has no the report as antitumor drug application.
The content of the invention
It is an object of the invention to provide Benzofurantone compound of the structure as shown in formula I is preparing antineoplastic agent Application in thing.
Technical scheme is as follows：
, used as the application for preparing antitumor drug, compound structure is as shown in formula I for Benzofurantone compound：
In formula：
Ar is selected from Ar1, Ar2, Ar3 or Ar4 as follows：
Q is selected from one of group shown in following Q1 to Q22：
R1、R2、R3、R4、R5、R6May be the same or different, be each independently selected from respectively hydrogen, halogen, cyano group, nitro, hydroxyl, Amino, CHO, CO2H、CO2Na、CO2NH4、C1-C12Alkyl, halo C1-C12Alkyl, C3-C8Cycloalkyl, C1-C12Alkoxyl, halo C1-C12Alkoxyl, C1-C12Alkylthio group, halo C1-C12Alkylthio group, C1-C12Alkoxy C1-C12Alkyl, halo C1-C12Alkoxyl C1-C12Alkyl, C1-C12Alkoxy C1-C12Alkoxyl, halo C1-C12Alkoxy C1-C12Alkoxyl, C1-C12Alkylthio group C1-C12 Alkyl, halo C1-C12Alkylthio group C1-C12Alkyl, C1-C12Alkyl amino, halo C1-C12Alkyl amino, C2-C12Dialkyl amino Base, halo C2-C12Dialkyl amido, piperidyl, nafoxidine base, N methyl piperazine base, morpholinyl, C2-C12Thiazolinyl, halo C2-C12Thiazolinyl, C2-C12Alkynyl, halo C2-C12Alkynyl, C2-C12Alkenyloxy group, halo C2-C12Alkenyloxy group, C2-C12Alkynyloxy group, halogen For C2-C12Alkynyloxy group, C1-C12Alkyl sulphonyl, halo C1-C12Alkyl sulphonyl, C1-C12Alkyl sulphinyl, halo C1-C12 Alkyl sulphinyl, C1-C12Alkyl-carbonyl, halo C1-C12Alkyl-carbonyl, C1-C12Alkyl carbonyl epoxide, C1-C12Alkyl-carbonyl Amino, C1-C12Alkyl sulphonyl epoxide, C1-C12Alkoxy carbonyl, halo C1-C12Alkoxy carbonyl, C1-C12Alkyl amino sulphur Acyl group, C1-C12Alkoxycarbonyl amino, C1-C12Alkoxy carbonyl C1-C12Alkyl, C1-C12Alkoxy carbonyl C1-C12Alkoxyl, Amino C1-C12Alkyl, C1-C12Alkyl amino C1-C12Alkyl, C2-C12Dialkyl amido C1-C12Alkyl, C (=O) NR10R11、OC (=O)NR10R11、C(=S)NR10R11、SO2NR10R11、C(=NOR9)R8Or R7；Or R1With R2Between formed five-membered ring, hexatomic ring Or heptatomic ring；
R7Selected from unsubstituted or be independently selected from the phenyl, phenoxy group, phenoxy group that following group is further substituted with by 1-5 C1-C12Alkyl, benzoyl, phenyloxycarbonyl, phenyl amino carbonyl, phenyl C1-C12Alkyl, phenyl C1-C12Alkoxyl, phenyl C1-C12Alkoxy C1-C12Alkyl, naphthyl, naphthoxy, naphthoxy C1-C12Alkyl, naphthyl carbonyl, naphthyl C1-C12Alkyl, naphthyl C1-C12Alkoxyl, naphthyl C1-C12Alkoxy C1-C12Alkyl, heteroaryl, heteroaryl epoxide, heteroaryl C1-C12Alkoxy C1-C12 Alkyl, heteroaryl epoxide C1-C12Alkyl, Heteroarylcarbonyl, heteroaryloxycarbonyl, heteroarylaminocarbonyl, heteroaryl C1-C12 Alkyl or heteroaryl C1-C12Alkoxyl：Halogen, nitro, cyano group, sulfydryl, C1-C6Alkyl, halo C1-C6Alkyl, C3-C8Cycloalkanes Base, C1-C6Alkoxyl, halo C1-C6Alkoxyl, C1-C6Alkylthio group, halo C1-C6Alkylthio group, C2-C6Thiazolinyl, halo C2-C6Alkene Base, C2-C6Alkynyl, halo C2-C6Alkynyl, C3-C6Alkenyloxy group, halo C3-C6Alkenyloxy group, C3-C6Alkynyloxy group, halo C3-C6Alkynes oxygen Base, C1-C6Alkyl sulphinyl, halo C1-C6Alkyl sulphinyl, C1-C6Alkyl sulphonyl, halo C1-C6Alkyl sulphonyl, C1-C6Alkoxy C1-C6Alkyl, C1-C6Alkyl-carbonyl, halo C1-C6Alkyl-carbonyl, C1-C6Alkyl carbonyl epoxide, C1-C6Alkyl Carbonylamino, C1-C6Alkyl sulphonyl epoxide, C1-C6Alkoxy carbonyl, C1-C6Alkoxy C1-C6Alkoxyl, C1-C6Alkoxyl Carbonyl C1-C6Alkyl, C1-C6Alkoxycarbonyl amino, C1-C6Alkoxy carbonyl C1-C6Alkoxyl, CHO, CO2H、CO2Na、 CO2NH4、NR10R11、C(=O)NR10R11、OC(=O)NR10R11、C(=S)NR10R11Or SO2NR10R11；
R8、R9It is respectively selected from hydrogen, C1-C6Alkyl, aryl or aryl C1-C6Alkyl；
R10、R11May be the same or different, be respectively selected from hydrogen, C1-C6Alkyl, halo C1-C6Alkyl, C1-C6Alkoxyl, halo C1-C6Alkoxyl, C1-C6Alkylthio group, halo C1-C6Alkylthio group or C3-C8Cycloalkyl；
And its stereoisomer.
In above-mentioned Benzofurantone compound, as during antitumor drug application, more preferably compound is：In formula I
Ar is selected from Ar1, Ar2, Ar3 or Ar4 as follows；
Q is selected from Q1、Q2、Q3、Q4、Q5、Q6、Q7、Q8、Q9、Q19、Q20、Q21Or Q22；
R1、R2、R3、R4、R5、R6May be the same or different, be each independently selected from respectively hydrogen, halogen, cyano group, nitro, hydroxyl, Amino, CHO, CO2H、CO2Na、CO2NH4、C1-C6Alkyl, halo C1-C6Alkyl, C3-C6Cycloalkyl, C1-C6Alkoxyl, halo C1-C6Alkoxyl, C1-C6Alkylthio group, halo C1-C6Alkylthio group, C1-C6Alkoxy C1-C6Alkyl, halo C1-C6Alkoxy C1-C6 Alkyl, C1-C6Alkoxy C1-C6Alkoxyl, halo C1-C6Alkoxy C1-C6Alkoxyl, C1-C6Alkylthio group C1-C6Alkyl, halo C1-C6Alkylthio group C1-C6Alkyl, C1-C6Alkyl amino, halo C1-C6Alkyl amino, C2-C8Dialkyl amido, halo C2-C8Two Alkyl amino, piperidyl, nafoxidine base, N methyl piperazine base, morpholinyl, C2-C6Thiazolinyl, halo C2-C6Thiazolinyl, C2-C6Alkynes Base, halo C2-C6Alkynyl, C2-C6Alkenyloxy group, halo C2-C6Alkenyloxy group, C2-C6Alkynyloxy group, halo C2-C6Alkynyloxy group, C1-C6Alkane Base sulfonyl, halo C1-C6Alkyl sulphonyl, C1-C6Alkyl sulphinyl, halo C1-C6Alkyl sulphinyl, C1-C6Alkyl oxycarbonyl Base, halo C1-C6Alkyl-carbonyl, C1-C6Alkyl carbonyl epoxide, C1-C6Alkyl-carbonyl-amino, C1-C6Alkyl sulphonyl epoxide, C1- C6Alkoxy carbonyl, halo C1-C6Alkoxy carbonyl, C1-C6Alkyl amino sulfonyl, C1-C6Alkoxycarbonyl amino, C1-C6Alkane Epoxide carbonyl C1-C6Alkyl, C1-C6Alkoxy carbonyl C1-C6Alkoxyl, amino C1-C6Alkyl, C1-C6Alkyl amino C1-C6Alkane Base, C2-C8Dialkyl amido C1-C6Alkyl, C (=O) NR10R11、OC(=O)NR10R11、C(=S)NR10R11、SO2NR10R11、C(= NOR9)R8Or R7；Or R1With R2Between form five-membered ring or hexatomic ring；
R7Selected from unsubstituted or be independently selected from the phenyl, phenoxy group, phenoxy group that following group is further substituted with by 1-5 C1-C6Alkyl, benzoyl, phenyloxycarbonyl, phenyl amino carbonyl, phenyl C1-C6Alkyl, phenyl C1-C6Alkoxyl, phenyl C1-C6Alkoxy C1-C6Alkyl, naphthyl, naphthoxy, naphthoxy C1-C6Alkyl, naphthyl carbonyl, naphthyl C1-C6Alkyl, naphthyl C1- C6Alkoxyl, naphthyl C1-C6Alkoxy C1-C6Alkyl, heteroaryl, heteroaryl epoxide, heteroaryl C1-C6Alkoxy C1-C6Alkyl, Heteroaryl epoxide C1-C6Alkyl, Heteroarylcarbonyl, heteroaryloxycarbonyl, heteroarylaminocarbonyl, heteroaryl C1-C6Alkyl or Heteroaryl C1-C6Alkoxyl：Halogen, nitro, cyano group, sulfydryl, C1-C4Alkyl, halo C1-C4Alkyl, C3-C6Cycloalkyl, C1-C4 Alkoxyl, halo C1-C4Alkoxyl, C1-C4Alkylthio group, halo C1-C4Alkylthio group, C2-C4Thiazolinyl, halo C2-C4Thiazolinyl, C2-C4 Alkynyl, halo C2-C4Alkynyl, C3-C4Alkenyloxy group, halo C3-C4Alkenyloxy group, C3-C4Alkynyloxy group, halo C3-C4Alkynyloxy group, C1-C4 Alkyl sulphinyl, halo C1-C4Alkyl sulphinyl, C1-C4Alkyl sulphonyl, halo C1-C4Alkyl sulphonyl, C1-C4Alcoxyl Base C1-C4Alkyl, C1-C4Alkyl-carbonyl, halo C1-C4Alkyl-carbonyl, C1-C4Alkyl carbonyl epoxide, C1-C4Alkyl-carbonyl-amino, C1-C4Alkyl sulphonyl epoxide, C1-C4Alkoxy carbonyl, C1-C4Alkoxy C1-C4Alkoxyl, C1-C4Alkoxy carbonyl C1-C4Alkane Base, C1-C4Alkoxycarbonyl amino, C1-C4Alkoxy carbonyl C1-C4Alkoxyl, CHO, CO2H、CO2Na、CO2NH4、NR10R11、C (=O)NR10R11、OC(=O)NR10R11、C(=S)NR10R11Or SO2NR10R11；
R8、R9It is respectively selected from hydrogen, C1-C4Alkyl, aryl or aryl C1-C4Alkyl；
R10、R11May be the same or different, be respectively selected from hydrogen, C1-C4Alkyl, halo C1-C4Alkyl, C1-C4Alkoxyl, halo C1-C4Alkoxyl, C1-C4Alkylthio group, halo C1-C4Alkylthio group or C3-C6Cycloalkyl.
In above-mentioned Benzofurantone compound as compound further preferred during antitumor drug application it is：Formula In I
Ar is selected from Ar1, Ar2, Ar3 or Ar4 as follows；
Q is selected from Q1、Q2、Q3、Q4、Q5、Q6、Q7、Q8、Q9、Q19、Q20、Q21Or Q22；
R1、R2、R3、R4、R5、R6May be the same or different, be each independently selected from respectively hydrogen, halogen, cyano group, nitro, hydroxyl, Amino, CHO, CO2H、CO2Na、CO2NH4、C1-C4Alkyl, halo C1-C4Alkyl, C3-C6Cycloalkyl, C1-C4Alkoxyl, halo C1-C4Alkoxyl, C1-C4Alkylthio group, halo C1-C4Alkylthio group, C1-C4Alkoxy C1-C4Alkyl, halo C1-C4Alkoxy C1-C4 Alkyl, C1-C4Alkoxy C1-C4Alkoxyl, halo C1-C4Alkoxy C1-C4Alkoxyl, C1-C4Alkylthio group C1-C4Alkyl, halo C1-C4Alkylthio group C1-C4Alkyl, C1-C4Alkyl amino, halo C1-C4Alkyl amino, C2-C6Dialkyl amido, halo C2-C6Two Alkyl amino, piperidyl, nafoxidine base, N methyl piperazine base, morpholinyl, C2-C4Thiazolinyl, halo C2-C4Thiazolinyl, C2-C4Alkynes Base, halo C2-C4Alkynyl, C2-C4Alkenyloxy group, halo C2-C4Alkenyloxy group, C2-C4Alkynyloxy group, halo C2-C4Alkynyloxy group, C1-C4Alkane Base sulfonyl, halo C1-C4Alkyl sulphonyl, C1-C4Alkyl sulphinyl, halo C1-C4Alkyl sulphinyl, C1-C4Alkyl oxycarbonyl Base, halo C1-C4Alkyl-carbonyl, C1-C4Alkyl carbonyl epoxide, C1-C4Alkyl-carbonyl-amino, C1-C4Alkyl sulphonyl epoxide, C1- C4Alkoxy carbonyl, halo C1-C4Alkoxy carbonyl, C1-C4Alkyl amino sulfonyl, C1-C4Alkoxycarbonyl amino, C1-C4Alkane Epoxide carbonyl C1-C4Alkyl, C1-C4Alkoxy carbonyl C1-C4Alkoxyl, amino C1-C4Alkyl, C1-C4Alkyl amino C1-C4Alkane Base, C2-C6Dialkyl amido C1-C4Alkyl, C (=O) NR10R11、OC(=O)NR10R11、C(=S)NR10R11、SO2NR10R11、C(= NOR9)R8Or R7；Or R1With R2Between form saturation five-membered ring or hexatomic ring；
R7Selected from unsubstituted or be independently selected from the phenyl, phenoxy group, phenoxy group that following group is further substituted with by 1-5 C1-C4Alkyl, benzoyl, phenyloxycarbonyl, phenyl amino carbonyl, phenyl C1-C4Alkyl, phenyl C1-C4Alkoxyl, phenyl C1-C4Alkoxy C1-C4Alkyl, naphthyl, naphthoxy, naphthoxy C1-C4Alkyl, naphthyl carbonyl, naphthyl C1-C4Alkyl, naphthyl C1- C4Alkoxyl, naphthyl C1-C4Alkoxy C1-C4Alkyl, heteroaryl, heteroaryl epoxide, heteroaryl C1-C4Alkoxy C1-C4Alkyl, Heteroaryl epoxide C1-C4Alkyl, Heteroarylcarbonyl, heteroaryloxycarbonyl, heteroarylaminocarbonyl, heteroaryl C1-C4Alkyl or Heteroaryl C1-C4Alkoxyl：Halogen, nitro, cyano group, sulfydryl, C1-C4Alkyl, halo C1-C4Alkyl, C3-C6Cycloalkyl, C1-C4 Alkoxyl, halo C1-C4Alkoxyl, C1-C4Alkylthio group, halo C1-C4Alkylthio group, C2-C4Thiazolinyl, halo C2-C4Thiazolinyl, C2-C4 Alkynyl, halo C2-C4Alkynyl, C3-C4Alkenyloxy group, halo C3-C4Alkenyloxy group, C3-C4Alkynyloxy group, halo C3-C4Alkynyloxy group, C1-C4 Alkyl sulphinyl, halo C1-C4Alkyl sulphinyl, C1-C4Alkyl sulphonyl, halo C1-C4Alkyl sulphonyl, C1-C4Alcoxyl Base C1-C4Alkyl, C1-C4Alkyl-carbonyl, halo C1-C4Alkyl-carbonyl, C1-C4Alkyl carbonyl epoxide, C1-C4Alkyl-carbonyl-amino, C1-C4Alkyl sulphonyl epoxide, C1-C4Alkoxy carbonyl, C1-C4Alkoxy C1-C4Alkoxyl, C1-C4Alkoxy carbonyl C1-C4Alkane Base, C1-C4Alkoxycarbonyl amino, C1-C4Alkoxy carbonyl C1-C4Alkoxyl, CHO, CO2H、CO2Na、CO2NH4、NR10R11、C (=O)NR10R11、OC(=O)NR10R11、C(=S)NR10R11Or SO2NR10R11；
R8、R9It is respectively selected from hydrogen, C1-C4Alkyl, aryl or aryl C1-C4Alkyl；
R10、R11May be the same or different, be respectively selected from hydrogen, C1-C4Alkyl, halo C1-C4Alkyl, C1-C4Alkoxyl, halo C1-C4Alkoxyl, C1-C4Alkylthio group, halo C1-C4Alkylthio group or C3-C6Cycloalkyl.
In above-mentioned Benzofurantone compound as compound during antitumor drug application still more preferably it is：It is logical In Formulas I
Ar is selected from Ar1, Ar2 or Ar3；
Q is selected from Q1、Q2、Q3、Q4、Q5、Q6、Q7Or Q8；
R1、R2、R3、R4、R5、R6May be the same or different, be each independently selected from hydrogen, halogen, cyano group, C respectively1-C4Alkyl, Halo C1-C4Alkyl, C3-C6Cycloalkyl, C1-C4Alkoxyl, halo C1-C4Alkoxyl, C1-C4Alkylthio group, C1-C4Alkoxy C1-C4 Alkyl, C1-C4Alkyl amino, C2-C6Dialkyl amido, C1-C4Alkyl sulphonyl, C1-C4Alkoxy carbonyl or R7；Or R1With R2 Between form saturation five-membered ring or hexatomic ring；
R7Selected from it is unsubstituted or by 1-5 be independently selected from phenyl, benzyl, phenethyl that following group is further substituted with, Heteroaryl：Halogen, nitro, C1-C4Alkyl, halo C1-C4Alkyl, C1-C4Alkoxyl or halo C1-C4Alkoxyl.
In above-mentioned Benzofurantone compound as compound during antitumor drug application still further preferably it is：It is logical In Formulas I
Ar is selected from Ar1, Ar2 or Ar3；
Q is selected from Q1；
R1、R2、R3、R4、R5、R6May be the same or different, be each independently selected from hydrogen, halogen, cyano group, C respectively1-C4Alkyl, Halo C1-C4Alkyl or R7；Or R1With R2Between form saturation five-membered ring or hexatomic ring；
R7Selected from unsubstituted or be independently selected from the phenyl, benzyl, heteroaryl that following group is further substituted with by 1-5： Halogen, nitro, C1-C4Alkyl, halo C1-C4Alkyl, C1-C4Alkoxyl or halo C1-C4Alkoxyl.
In above-mentioned Benzofurantone compound as most preferred compound during antitumor drug application it is：In formula I
Ar is selected from Ar3；
Q is selected from Q1；
R1、R2、R3、R4、R5、R6May be the same or different, be each independently selected from hydrogen, halogen, cyano group, C respectively1-C4Alkyl, Halo C1-C4Alkyl or R7；Or R1With R2Between form saturation five-membered ring or hexatomic ring；
R7Selected from unsubstituted or be independently selected from the phenyl, benzyl, heteroaryl that following group is further substituted with by 1-5： Halogen, nitro, C1-C4Alkyl, halo C1-C4Alkyl, C1-C4Alkoxyl or halo C1-C4Alkoxyl.
In the definition of compound of Formula I given above, collect the following substituent group of term general proxy used：
Halogen：Refer to fluorine, chlorine, bromine or iodine.Alkyl：Straight or branched alkyl, such as methyl, ethyl, propyl group, isopropyl, just Butyl or the tert-butyl group.Cycloalkyl：Substituted or unsubstituted cyclic alkyl, such as cyclopropyl, cyclopenta or cyclohexyl.Substituent group is such as Methyl, halogen etc..Haloalkyl：Straight or branched alkyl, the hydrogen atom on these alkyl can partly or entirely by halogen atom Replaced, for example, chloromethyl, dichloromethyl, trichloromethyl, methyl fluoride, difluoromethyl, trifluoromethyl etc..Alkoxyl：Straight chain or Branched alkyl, Jing oxygen atoms are bonded and are connected in structure.Halogenated alkoxy：Straight or branched alkoxyl, on these alkoxyls Hydrogen atom partly or entirely can be replaced by halogen atom.For example, chloromethane epoxide, dichloro methoxyl group, trichloromethoxy, fluorine methoxy Base, difluoro-methoxy, trifluoromethoxy, chlorine fluorine methoxyl group, trifluoro ethoxy etc..Alkylthio group：Straight or branched alkyl, Jing sulfur are former Sub-key is connected in structure.Halogenated alkylthio：Straight or branched alkylthio group, the hydrogen atom on these alkyl can be part or all of Replaced by halogen atom.For example, chloromethane sulfenyl, dichloro methyl mercapto, trichloro-methylthio, fluorine methyl mercapto, difluoro methyl mercapto, fluoroform Sulfenyl, chlorine fluorine methyl mercapto etc..Alkoxyalkyl：Alkoxyl Jing alkyl is connected in structure.Such as-CH2OCH2,-CH2OCH2CH3.Halogen For alkoxyalkyl：Hydrogen atom on the alkyl of alkoxyalkyl partly or entirely can be replaced by halogen atom.As- CH2OCH2CH2Cl.Alkyloxy-alkoxy：Such as-OCH2OCH2CH3Deng.Halogenated alkoxy alkoxyl：Such as-OCH2OCH2CH2Cl etc.. Alkylthio alkyl：Alkylthio group Jing alkyl is connected in structure.Such as-CH2SCH3.Haloalkylthioalkyl：Halogenated alkylthio Jing alkyl It is connected in structure.Alkyl amino：Straight or branched alkyl, Jing nitrogen-atoms are bonded and are connected in structure.Haloalkylamino：Straight chain Or branched alkyl amino, the hydrogen atom on these alkyl partly or entirely can replace by halogen atom.Dialkyl amido：Such as-N (CH3)2,-N (CH2CH3)2.Halo dialkyl amido：Dialkyl amido, the hydrogen atom on these alkyl can part or all of quilts Halogen atom is replaced.Thiazolinyl：Straight or branched alkenes, such as vinyl, 1- acrylic, 2- acrylic and different cyclobutenyls, Pentenyl and hexenyl isomers.Thiazolinyl also includes many alkenes, such as 1,2- allene base and 2,4- hexadienyl.Haloalkenyl group： Straight or branched alkenes, the hydrogen atom on these thiazolinyls partly or entirely can be replaced by halogen atom.Alkynyl：Straight or branched Acetylenic, such as acetenyl, 1- propinyls, 2-propynyl and different butynyls, pentynyl and hexynyl isomers.Alkynyl is also wrapped The group being made up of multiple three keys is included, such as 2,5- adipic alkynyls.Halo alkynyl：Straight or branched acetylenic, on these alkynyls Hydrogen atom partly or entirely can be replaced by halogen atom.Alkenyloxy group：Straight or branched alkenes, Jing oxygen atoms are bonded and are connected to structure On.Halo alkenyloxy group：Straight or branched alkenyloxy group, the hydrogen atom in these alkenyloxy groups partly or entirely can be taken by halogen atom Generation.Alkynyloxy group：Straight or branched acetylenic, Jing oxygen atoms are bonded and are connected in structure.Halo alkynyloxy group：Straight or branched alkynyloxy group, Hydrogen atom on these alkynyloxy groups partly or entirely can be replaced by halogen atom.Alkyl sulphonyl：Straight or branched alkyl Jing Sulfonyl（-SO2-）It is connected in structure, such as methyl sulphonyl.Halogenated alkyl sulfonyl：Straight or branched alkyl sulfonyl, its Hydrogen atom on alkyl partly or entirely can be replaced by halogen atom.Alkyl sulphinyl：Straight or branched alkyl Jing sulfenyl Base（-SO-）It is connected in structure, such as methylsulfinyl.Alkylsulfinyl：Straight or branched alkyl sulfinyl, Hydrogen atom on its alkyl partly or entirely can be replaced by halogen atom.Alkyl-carbonyl：Alkyl Jing carbonyls are connected in structure, Such as-COCH3,-COCH2CH3.Halogenated alkyl carbonyl：Hydrogen atom on the alkyl of alkyl-carbonyl can partly or entirely by halogen atom institute Replace, such as-COCF3.Alkyl carbonyl epoxide：Such as-OCOCH3,-OCOC (CH3)3.Alkyl-carbonyl-amino：Such as-NHCOCH3,-NHCOC (CH3)3.Alkyl sulphonyl epoxide：Alkyl-O-S (O)2.Alkoxy carbonyl：Alkoxyl Jing carbonyls are connected in structure.As- COOCH3,-COOCH2CH3.Halo alkoxy carbonyl：Hydrogen atom on the alkyl of alkoxy carbonyl can be partly or entirely former by halogen Son is replaced, such as-COOCH2CF3,-COOCH2CH2Cl etc..Alkyl amino sulfonyl：Such as-S (O)2NHCH3,-S (O)2NHCH2CH3.Alkoxycarbonyl amino：Such as-NHCOOCH3,-NHCOOCH2CH3.Alkoxy carbonyl alkyl：Such as-CH2COOCH3,- CH2COOCH2CH3.Alkoxycarbonylalkoxy：Such as-OCH2COOCH3,-OCH2COOCH2CH3.Aminoalkyl：Such as-CH2NH2,- CH2CH2NH2.Alkylaminoalkyl group：Such as-CH2NHCH3,-CH2NHCH2CH3.Dialkyl aminoalkyl：Such as-CH2NH(CH3)2。 （It is miscellaneous）Aryl,（It is miscellaneous）Aryloxy,（It is miscellaneous）Alkoxy aryl alkyl,（It is miscellaneous）Aromatic yloxy yl alkyl,（It is miscellaneous）Aryl carbonyl,（It is miscellaneous）Virtue Base Epoxide carbonyl,（It is miscellaneous）Aromatic yl aminocarbonyl,（It is miscellaneous）Aryl alkyl or（It is miscellaneous）Aryl moiety in alkoxy aryl includes phenyl Or naphthyl etc..Heteroaryl is containing the heteroatomic five-membered ring of one or more N, O, S or hexatomic ring.Such as pyridine radicals, pyrimidine radicals, pyrrole Piperazine base, pyridazinyl, triazine radical, furyl, thiazolyl, quinolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazoles base, thiophene Di azoly, pyrazolyl, pyranose, triazolyl, tetrazole radical, benzothiazolyl, benzofuranyl etc..（It is miscellaneous）Aryloxy：Such as benzene Epoxide, pyridyloxy, 2-pyrimidinyl oxy, quinoline oxy etc..（It is miscellaneous）Alkoxy aryl alkyl：Such as-CH2OCH2Ph, 6- chloropyridine -3- Ylmethoxy etc..（It is miscellaneous）Aromatic yloxy yl alkyl：Such as-CH2OPh, 4,6- dimethoxypyridin -2- base epoxide ethyls etc..（It is miscellaneous）Virtue Base carbonyl：Such as benzoyl, 4- chlorobenzene formacyls etc..（It is miscellaneous）Aryloxycarbonyl：Such as phenyloxycarbonyl, 4- chlorophenoxy carbonyls Base, 4-nitrophenoxy carbonyl, naphthoxycarbonyl etc..（It is miscellaneous）Aromatic yl aminocarbonyl：Such as-CONHPh, pyridine -2- base amino carbonyls Deng.（It is miscellaneous）Aryl alkyl：As benzyl, phenethyl, to chlorophenylmethyl, 6- chloropyridine 3- ylmethyls, 2- diuril azoles -5- ylmethyls Deng.（It is miscellaneous）Alkoxy aryl：Such as-OCH2Ph ,-OCH2Ph-Cl-4。
In the compound of the present invention, can be formed due to the carbon-to-carbon double bond substituent group different with the connection of carbon-to-nitrogen double bond Geometric isomer（Respectively with Z and E representing different configurations）.The present invention includes Z-type isomer and E-isomer and its any The mixture of ratio.
In the form of the Benzofurantone compound shown in formula I is prepared into oral or parenteral approach as active component The medicine being administered, or the medicine being administered by the form of internal transplant medicine pump.
Further, treatment, prevention or slow are prepared by active component of the Benzofurantone compound shown in formula I The medicine of solution tumor, pharmaceutical dosage form are tablet, pill, capsule, electuary, syrup, injection or freeze-dried powder dosage form.
Treatment, prevention or alleviation colon cancer, hepatocarcinoma, lymphoma, pulmonary carcinoma, food are prepared further, being applied to Pipe cancer, breast carcinoma, central nerve neuroma, melanoma, ovarian cancer, cervical cancer, renal carcinoma, leukemia, carcinoma of prostate, pancreas In cancer, bladder cancer, rectal cancer or gastric cancer medicament.
Table 1 lists in formula I R in Ar structures1、R2、R3、R4、R5And R6The concrete substituent group in part, but they are not only It is limited to these substituent groups.
Table 1R1(R2、R3、R4、R5、R6) substituent group
The compound that the present invention has anti-tumor activity illustrated by the particular compound listed in table 2- tables 53, but and The present invention is not limited.
When Ar is selected from Q selected from Ar1, Q1When, representation compound 2-1 to 2-112 is shown in Table 2.
The ring substituents as Ar=Ar1 of table 2
Numbering R1 R3 R4 R5 R6
2-1 H H H H H
2-2 CH3 H H H H
2-3 C2H5 H H H H
2-4 i-C3H7 H H H H
2-5 n-C3H7 H H H H
2-6 n-C4H9 H H H H
2-7 t-C4H9 H H H H
2-8 OCH3 H H H H
2-9 OC2H5 H H H H
2-10 CH2Cl H H H H
2-11 CH2NH2 H H H H
2-12 CH2CH2NH2 H H H H
2-13 CH2CH2CN H H H H
2-14 NH2 H H H H
2-15 NO2 H H H H
2-16 OH H H H H
2-17 CO2H H H H H
2-18 F H H H H
2-19 Cl H H H H
2-20 Br H H H H
2-21 I H H H H
2-22 CH2-CH=CH2 H H H H
2-38 CH2-C≡CH H H H H
2-39 H CH3 H H H
2-40 H C2H5 H H H
2-41 H i-C3H7 H H H
2-42 H n-C3H7 H H H
2-43 H n-C4H9 H H H
2-44 H t-C4H9 H H H
2-45 H OCH3 H H H
2-46 H OC2H5 H H H
2-47 H CH2Cl H H H
2-48 H CO2H H H H
2-49 H F H H H
2-50 H Cl H H H
2-51 H Br H H H
2-52 H I H H H
2-53 H Ph H H H
2-54 H H CH3 H H
2-55 H H C2H5 H H
2-56 H H i-C3H7 H H
2-57 H H n-C3H7 H H
2-58 H H n-C4H9 H H
2-59 H H t-C4H9 H H
2-60 H H OCH3 H H
2-61 H H OC2H5 H H
2-62 H H NH2 H H
2-63 H H OH H H
2-64 H H CO2H H H
2-65 H H F H H
2-66 H H Cl H H
2-67 H H Br H H
2-68 H H I H H
2-69 H H Ph H H
2-70 H H H CH3 H
2-71 H H H C2H5 H
2-72 H H H i-C3H7 H
2-73 H H H n-C3H7 H
2-74 H H H n-C4H9 H
2-75 H7 H H t-C4H9 H
2-76 H H H OCH3 H
2-77 H H H OC2H5 H
2-78 H H H CH2Cl H
2-79 H H H N(CH3)2 H
2-80 H H H OCOOCH3 H
2-81 H H H OCOCH3 H
2-82 H H H NH2 H
2-83 H H H CN H
2-84 H H H OH H
2-85 H H H CO2H H
2-86 H H H F H
2-87 H H H Cl H
2-88 H H H Br H
2-89 H H H I H
2-90 H H H CH2-CH=CH2 H
2-91 H H H CH2-C≡CH H
2-92 H H H H CH3
2-93 H H H H C2H5
2-94 H H H H OCH3
2-95 H H H H CHO
2-96 H H H H F
2-97 H H H H Cl
2-98 H H H H Br
2-99 H H H H I
2-100 H H H H Ph
2-101 H H H H CH2Ph
2-102 CH3 H H H CH3
2-103 H H CH3 CH3 H
2-104 H H CH3 H CH3
2-105 H H OCH3 H OCH3
2-106 H H Cl H Cl
2-107 H H H CH3 CH3
2-108 CH3 H H CH3 H
2-109 H H Cl CH3 H
2-110 H H C2H5 C2H5 H
2-111 CH3 H CH3 H H
2-112 H CH3 CH3 H CH3
Table 3：When Ar is selected from Q selected from Ar1, Q2When, representation compound 3-1 to 3-112 substituent groups are with 2 compound 2-1 of table extremely 2-112 is consistent；
Table 4：When Ar is selected from Q selected from Ar1, Q3When, representation compound 4-1 to 4-112 substituent groups are with 2 compound 2-1 of table extremely 2-112 is consistent；
Table 5：When Ar is selected from Q selected from Ar1, Q4When, representation compound 5-1 to 5-112 substituent groups are with 2 compound 2-1 of table extremely 2-112 is consistent；
Table 6：When Ar is selected from Q selected from Ar1, Q5When, representation compound 6-1 to 6-112 substituent groups are with 2 compound 2-1 of table extremely 2-112 is consistent；
Table 7：When Ar is selected from Q selected from Ar1, Q6When, representation compound 7-1 to 7-112 substituent groups are with 2 compound 2-1 of table extremely 2-112 is consistent；
Table 8：When Ar is selected from Q selected from Ar1, Q7When, representation compound 8-1 to 8-112 substituent groups are with 2 compound 2-1 of table extremely 2-112 is consistent；
Table 9：When Ar is selected from Q selected from Ar1, Q8When, representation compound 9-1 to 9-112 substituent groups are with 2 compound 2-1 of table extremely 2-112 is consistent；
Table 10：When Ar is selected from Q selected from Ar1, Q9When, representation compound 10-1 to 10-112 substituent groups and 2 compound 2-1 of table It is consistent to 2-112；
Table 11：When Ar is selected from Q selected from Ar1, Q19When, representation compound 11-1 to 11-112 substituent groups and 2 compound 2-1 of table It is consistent to 2-112；
Table 12：When Ar is selected from Q selected from Ar1, Q20When, representation compound 12-1 to 12-112 substituent groups and 2 compound 2-1 of table It is consistent to 2-112；
Table 13：When Ar is selected from Q selected from Ar1, Q21When, representation compound 13-1 to 13-112 substituent groups and 2 compound 2-1 of table It is consistent to 2-112；
Table 14：When Ar is selected from Q selected from Ar1, Q22When, representation compound 14-1 to 14-112 substituent groups and 2 compound 2-1 of table It is consistent to 2-112.
When Ar is selected from Q selected from Ar2, Q1When, representation compound 15-1 to 15-121 is shown in Table 15.
The ring substituents as Ar=Ar2 of table 15
Table 16：When Ar is selected from Q selected from Ar2, Q2When, representation compound 16-1 to 16-121 substituent groups and 15 compound of table 15-1 to 15-121 is consistent；
Table 17：When Ar is selected from Q selected from Ar2, Q3When, representation compound 17-1 to 17-121 substituent groups and 15 compound of table 15-1 to 15-121 is consistent；
Table 18：When Ar is selected from Q selected from Ar2, Q4When, representation compound 18-1 to 18-121 substituent groups and 15 compound of table 15-1 to 15-121 is consistent；
Table 19：When Ar is selected from Q selected from Ar2, Q5When, representation compound 19-1 to 19-121 substituent groups and 15 compound of table 15-1 to 15-121 is consistent；
Table 20：When Ar is selected from Q selected from Ar2, Q6When, representation compound 20-1 to 20-121 substituent groups and 15 compound of table 15-1 to 15-121 is consistent；
Table 21：When Ar is selected from Q selected from Ar2, Q7When, representation compound 21-1 to 21-121 substituent groups and 15 compound of table 15-1 to 15-121 is consistent；
Table 22：When Ar is selected from Q selected from Ar2, Q8When, representation compound 22-1 to 22-121 substituent groups and 15 compound of table 15-1 to 15-121 is consistent；
Table 23：When Ar is selected from Q selected from Ar2, Q9When, representation compound 23-1 to 23-121 substituent groups and 15 compound of table 15-1 to 15-121 is consistent；
Table 24：When Ar is selected from Q selected from Ar2, Q19When, representation compound 24-1 to 24-121 substituent groups and 15 compound of table 15-1 to 15-121 is consistent；
Table 25：When Ar is selected from Q selected from Ar2, Q20When, representation compound 25-1 to 25-121 substituent groups and 15 compound of table 15-1 to 15-121 is consistent；
Table 26：When Ar is selected from Q selected from Ar2, Q21When, representation compound 26-1 to 26-121 substituent groups and 15 compound of table 15-1 to 15-121 is consistent；
Table 27：When Ar is selected from Q selected from Ar2, Q22When, representation compound 27-1 to 27-121 substituent groups and 15 compound of table 15-1 to 15-121 is consistent.
When Ar is selected from Q selected from Ar3, Q1When, representation compound 28-1 to 28-131 is shown in Table 28.
The ring substituents as Ar=Ar3 of table 28
Note：E is C (CH3)=NOCH3；M is C6H3-3,4-(OCH3)2。
Table 29：When Ar is selected from Q selected from Ar3, Q2When, representation compound 29-1 to 29-131 substituent groups and 28 compound of table 28-1 to 28-131 is consistent；
Table 30：When Ar is selected from Q selected from Ar3, Q3When, representation compound 30-1 to 30-131 substituent groups and 28 compound of table 28-1 to 28-131 is consistent；
Table 31：When Ar is selected from Q selected from Ar3, Q4When, representation compound 31-1 to 31-131 substituent groups and 28 compound of table 28-1 to 28-131 is consistent；
Table 32：When Ar is selected from Q selected from Ar3, Q5When, representation compound 32-1 to 32-131 substituent groups and 2 compound 28- of table 1 to 28-131 is consistent；
Table 33：When Ar is selected from Q selected from Ar3, Q6When, representation compound 33-1 to 33-131 substituent groups and 28 compound of table 28-1 to 28-131 is consistent；
Table 34：When Ar is selected from Q selected from Ar3, Q7When, representation compound 34-1 to 34-131 substituent groups and 28 compound of table 28-1 to 28-131 is consistent；
Table 35：When Ar is selected from Q selected from Ar3, Q8When, representation compound 35-1 to 35-131 substituent groups and 28 compound of table 28-1 to 28-131 is consistent；
Table 36：When Ar is selected from Q selected from Ar3, Q9When, representation compound 36-1 to 36-131 substituent groups and 28 compound of table 28-1 to 28-131 is consistent；
Table 37：When Ar is selected from Q selected from Ar3, Q19When, representation compound 37-1 to 37-131 substituent groups and 28 compound of table 28-1 to 28-131 is consistent；
Table 38：When Ar is selected from Q selected from Ar3, Q20When, representation compound 38-1 to 38-131 substituent groups and 28 compound of table 28-1 to 28-131 is consistent；
Table 39：When Ar is selected from Q selected from Ar3, Q21When, representation compound 39-1 to 39-131 substituent groups and 28 compound of table 28-1 to 28-131 is consistent；
Table 40：When Ar is selected from Q selected from Ar3, Q22When, representation compound 40-1 to 40-131 substituent groups and 28 compound of table 28-1 to 28-131 is consistent.
When Ar is selected from Q selected from Ar4, Q1When, representation compound 41-1 to 41-116 is shown in Table 41.
The ring substituents as Ar=Ar4 of table 41
Table 42：When Ar is selected from Q selected from Ar4, Q2When, representation compound 42-1 to 42-116 substituent groups and 41 compound of table 41-1 to 41-116 is consistent；
Table 43：When Ar is selected from Q selected from Ar4, Q3When, representation compound 43-1 to 43-116 substituent groups and 41 compound of table 41-1 to 41-116 is consistent；
Table 44：When Ar is selected from Q selected from Ar4, Q4When, representation compound 44-1 to 44-116 substituent groups and 41 compound of table 41-1 to 41-116 is consistent；
Table 45：When Ar is selected from Q selected from Ar4, Q5When, representation compound 45-1 to 45-116 substituent groups and 41 compound of table 41-1 to 41-116 is consistent；
Table 46：When Ar is selected from Q selected from Ar4, Q6When, representation compound 46-1 to 46-116 substituent groups and 41 compound of table 41-1 to 41-116 is consistent；
Table 47：When Ar is selected from Q selected from Ar4, Q7When, representation compound 47-1 to 47-116 substituent groups and 41 compound of table 41-1 to 41-116 is consistent；
Table 48：When Ar is selected from Q selected from Ar4, Q8When, representation compound 48-1 to 48-116 substituent groups and 41 compound of table 41-1 to 41-116 is consistent；
Table 49：When Ar is selected from Q selected from Ar4, Q9When, representation compound 49-1 to 49-116 substituent groups and 41 compound of table 41-1 to 41-116 is consistent；
Table 50：When Ar is selected from Q selected from Ar4, Q19When, representation compound 50-1 to 50-116 substituent groups and 41 compound of table 41-1 to 41-116 is consistent；
Table 51：When Ar is selected from Q selected from Ar4, Q20When, representation compound 51-1 to 51-116 substituent groups and 41 compound of table 41-1 to 41-116 is consistent；
Table 52：When Ar is selected from Q selected from Ar4, Q21When, representation compound 52-1 to 52-116 substituent groups and 41 compound of table 41-1 to 41-116 is consistent；
Table 53：When Ar is selected from Q selected from Ar4, Q22When, representation compound 53-1 to 53-116 substituent groups and 41 compound of table 41-1 to 41-116 is consistent.
The highly preferred compound of the present invention is as follows：
Compound 28-5：Turbo cornutus Solander bacterium ester.
Compound 28-72：SYP-3375（coumoxystrobin）.
Compound of Formula I involved in the present invention is in the prior art it has been reported that easily can obtain.It is concrete to prepare Method refer to USP7642364, CNP1869032, Pest Manag.Sci.2011,67,647, Nat.Prod.Commun.2011,6,1917、Chin.Chem.Lett.2011,22,663、Chin.J.Pestic.2011,50, 90。
Formulation ingredients and its preparation that the present invention is configured to for active component including the compound included by above-mentioned formula I The preparation of composition.Formulation preparation method is：The compound dissolution covered by the present invention is to water miscible organic solvent, nonionic Make in the surfactant of property, water miscible lipoid, various cyclodextrin, fatty acid, fatty acid ester, phospholipid or its combination solvent Obtain formulation soln；Normal saline is added to obtain the carbohydrate of 1-20%.The organic solvent includes Polyethylene Glycol（PEG）, second The combination solvent of alcohol, Propylene Glycol or these solvents.
The compound covered in formula I of the present invention and stereoisomer and prodrug be used to preparing treatment, prevention or Alleviate antitumor drug or pharmaceutical preparation, active constituents of medicine is the Benzofurantone shown in one or more formulas I Compound.It is particularly suited for treating or alleviating the cancer that tissue or organ tumor cell cause.The preferred colon of indication cancer Cancer, hepatocarcinoma, lymphoma, pulmonary carcinoma, the esophageal carcinoma, breast carcinoma, central nerve neuroma, melanoma, ovarian cancer, cervical cancer, kidney Cancer, leukemia, carcinoma of prostate, cancer of pancreas, bladder cancer, rectal cancer or gastric cancer etc..
The compound of present invention synthesis can be used for the active component of antitumor drug, can be used alone, it is also possible to which Its antitumor, antiviral drugs drug combination.It is in the drug combination therapeutic process of indication of the present invention, at least one originally including utilization Invention compound and its reactive derivative are used together to increase totality with other one or more anti-tumor virus drugs Curative effect.Depending on dose and administration time during drug combination should be according to most rational therapy effect acquired in the case of difference.
The medicament compatibility covered includes the effective dose of the compound in formula I." effective dose " herein is referred to For institute's treatment target can produce the consumption of the compound required for therapeutic effect.The effective dose or dosage can be by there is experience Person is different according to the suggestion of different situations.Such as, the tumor class treated is different, and the usage of medicine is different；Whether with which Its Therapeutic Method such as other antitumor drug or antiviral drugs are shared etc., and dosage can change.Can make any The preparation formulation that can be used.If some have alkalescence or acid compound and can form avirulent acid or salt, it is possible to use The form of the salt of the compound.The acylate that can be used in pharmacy includes the anion salt that can physiologically use, such as to methyl Benzene sulfonate, metilsulfate, acetate, benzoate, citrate, malate, tartrate, maleate, succinum Hydrochlorate, Ascorbate or glycerophosphate etc.；The inorganic salt that can be used include chloride, bromide, fluoride, iodide, Sulfate, nitrate, bicarbonate, carbonate or phosphate etc.；If any the compound of alkalescence and suitable acid as amine The form of described salt can be made；The compound of carboxylic acidss can form the salt that can be used with alkali metal or alkaline-earth metal.
The compound covered in formula of I of the present invention is typically readily soluble organic solvent, water-soluble solvent and organic molten In the mixed solvent of agent and water-soluble solvent and water.Water-soluble solvent preferred alcohols, many Polyethylene Glycol, N- methyl -2- pyrrolinones, DMAC N,N' dimethyl acetamide, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile and its share.The preferred methanol of described alcohol, second Alcohol, isopropanol, glycerol or ethylene glycol.The compounds of this invention can be mixed with conventional preparations carrier and make preparation.Chemical combination During thing is dissolved into water miscible organic solvent, non-protonic solvent, water-soluble lipid, cyclodextrin, fatty acid, phospholipid or these are molten Drug solution is obtained in the mixed solvent of agent；The carbohydrate that normal saline obtains 1-20% is added, such as glucose is water-soluble Liquid.Obtained preparation stabilization it is used for animal and clinic therefrom.
The product medicine that compound is prepared into as active component with above-mentioned formula I, can pass through oral or parenteral way Footpath is administered, and also can pass through internal transplant medicine pump and additive method is administered, and the parenteral administration of indication refers to skin herein Lower Intradermal, intramuscular, intravenouss, intra-arterial, in atrium, in intrasynovial, breastbone, in intrathecal, wound site, intracranial injection or drop Note technology etc..By technical staff with conventional method proportioning, mixing eventually becomes required pharmaceutical dosage form.It can be piece Agent, pill, capsule, electuary, syrup, injection, freeze-dried powder dosage form, Emulsion, powder, lyophilized powder, drop pill, emulsion suspension liquid, water hang Solution, aqueous solution, colloid, colloid solution, slow releasing preparation, nanometer formulation or dosage form otherwise are used for animal or clinic.
Compound in formula I of the present invention is used for the preparation of the cancer drug for treating or alleviating a certain tissue or organ.Institute Refer to that cancer includes but be not limited solely to colon cancer, hepatocarcinoma, lymphoma, pulmonary carcinoma, the esophageal carcinoma, breast carcinoma, central nerve neuroma, black Melanoma, ovarian cancer, cervical cancer, renal carcinoma, leukemia, carcinoma of prostate, cancer of pancreas, bladder cancer, rectal cancer or gastric cancer etc..
Specific embodiment
Specific examples below is used for further illustrating the present invention, but the present invention is not limited to these examples.
Antitumor cytolytic activity
The external test experience to inhibiting tumour cells effect is as follows：
Institute's employment tumor cell strain：Bladder cancer J82, LNCap, T24, carcinoma of prostate PC-3, human lung cancer A549, H157, H460, H520, human leukemia HL-60 etc..
Embodiment 1：To human bladder cancer cell J82, LNCap, T24, prostate gland cancer cell PC-3, lung cell A549, About 1000 to 3000 cell kinds, using Cell culture invitro technology, are entered 24 holes by the growth inhibition ratio of H157, H460, H520 In plate, 1 milliliter of cell training for being capable of culture experiment tumor cell line well known to those skilled in the art is then added again per hole The nutrient solution, (CO in cell culture incubator25%, 370 DEG C) after culture 24 hours, then by the comparison medicine of debita spissitudo and above-mentioned preparation institute Obtain in material medicine addition hole to be measured, it is noted that add the volume of liquid less than the 0.5% of cumulative volume.Cell is allowed to continue in cell culture Grow in case, after a week, cell culture fluid is suctioned out, washed once with 1 milliliter of cold PBS.Then, with 1% formalin Room temperature fixes 10 minutes, then is washed once with 1 milliliter of cold PBS.Add 0.1% violet staining 30 minutes.Crystal violet is reclaimed again Utilize.The lustful cell deionized water of dye is slowly rinsed, and after room temperature is dried, is preserved.By the remaining cell that each concentration is processed Cell inhibitory rate is calculated with the remaining cell of the matched group processed without medicine.Comparison medicament AZD6244, adopted name Selumetinib。
Remaining cell × 100% of the remaining cell that suppression ratio=each concentration is processed/matched group without medicine process
Partial test the results are shown in Table 54：
The suppression ratio that table 54 is grown to human cancer cell
Note：1. "/" is represented and is not surveyed.
2. bladder cancer J82, LNCap, T24, carcinoma of prostate PC-3, human lung cancer A549, H157, all bacterial strains of H460, H520 Culture medium is RMPI-1640.
Embodiment 2：Growth inhibition ratio to human leukemia HL-60 cell, determines test sample to each one with conventional mtt assay The suppression ratio of growth of cancer cells.Cell is taken out from incubator, is cleaned with PBS liquid twice, is disappeared with 0.25% trypsin solution Change, add the culture medium for being capable of culture experiment tumor cell line well known to those skilled in the art, make each cell strain terminate disappearing Change, be allowed to form cell suspension with suction pipe piping and druming after centrifugation, and counted under inverted microscope.And with cultivating each tumor Cell is configured to concentration for 5x10 by the culture medium of cell strain4The cell suspension of/ml, adds 100 μ l of cell in 96 orifice plates per hole, 5% carbon dioxide is positioned over, overnight incubation in 37 DEG C of humidified airs adds the above-mentioned medicine to be measured for being diluted to variable concentrations gradient, After making its effect 48h, MTT is added, reacted 4 hours, the reduction of MTT tetrazolium compositions was produced by living cells Formazan, adds DMSO afterwards to dissolve formazan, finally the light absorption value to measure 570nm on 96 hole plate readout instruments.
Partial test the results are shown in Table 55：
The suppression ratio (%) that table 55 is grown to human leukemia cell HL60
Note：Human leukemia HL-60 culture medium is OPTI-MEM.

Claims (9)

1. Benzofurantone compound is used as the application for preparing antitumor drug, it is characterised in that compound structure such as formula I It is shown：
In formula：
Ar is selected from Ar1, Ar2, Ar3 or Ar4 as follows：
Q is selected from one of group shown in following Q1 to Q9：
R1、R2、R3、R4、R5、R6May be the same or different, be each independently selected from hydrogen, halogen, cyano group, nitro, hydroxyl, ammonia respectively Base, CHO, CO2H、CO2Na、CO2NH4、C1‐C12Alkyl, halo C1‐C12Alkyl, C3‐C8Cycloalkyl, C1‐C12Alkoxyl, halo C1‐C12Alkoxyl, C1‐C12Alkylthio group, halo C1‐C12Alkylthio group, C1‐C12Alkoxy C1‐C12Alkyl, halo C1‐C12Alkoxyl C1‐C12Alkyl, C1‐C12Alkoxy C1‐C12Alkoxyl, halo C1‐C12Alkoxy C1‐C12Alkoxyl, C1‐C12Alkylthio group C1‐C12 Alkyl, halo C1‐C12Alkylthio group C1‐C12Alkyl, C1‐C12Alkyl amino, halo C1‐C12Alkyl amino, C2‐C12Dialkyl amino Base, halo C2‐C12Dialkyl amido, piperidyl, nafoxidine base, N methyl piperazine base, morpholinyl, C2‐C12Thiazolinyl, halo C2‐C12Thiazolinyl, C2‐C12Alkynyl, halo C2‐C12Alkynyl, C2‐C12Alkenyloxy group, halo C2‐C12Alkenyloxy group, C2‐C12Alkynyloxy group, halogen For C2‐C12Alkynyloxy group, C1‐C12Alkyl sulphonyl, halo C1‐C12Alkyl sulphonyl, C1‐C12Alkyl sulphinyl, halo C1‐C12 Alkyl sulphinyl, C1‐C12Alkyl-carbonyl, halo C1‐C12Alkyl-carbonyl, C1‐C12Alkyl carbonyl epoxide, C1‐C12Alkyl-carbonyl Amino, C1‐C12Alkyl sulphonyl epoxide, C1‐C12Alkoxy carbonyl, halo C1‐C12Alkoxy carbonyl, C1‐C12Alkyl amino sulphur Acyl group, C1‐C12Alkoxycarbonyl amino, C1‐C12Alkoxy carbonyl C1‐C12Alkyl, C1‐C12Alkoxy carbonyl C1‐C12Alkoxyl, Amino C1‐C12Alkyl, C1‐C12Alkyl amino C1‐C12Alkyl, C2‐C12Dialkyl amido C1‐C12Alkyl, C (=O) NR10R11、OC (=O) NR10R11, C (=S) NR10R11、SO2NR10R11, C (=NOR9)R8Or R7；Or R1With R2Between form five-membered ring, hexa-atomic Ring or heptatomic ring；
R7Selected from unsubstituted or be independently selected from the phenyl, phenoxy group, phenoxy group C that following group is further substituted with by 1-51‐C12 Alkyl, benzoyl, phenyloxycarbonyl, phenyl amino carbonyl, phenyl C1‐C12Alkyl, phenyl C1‐C12Alkoxyl, phenyl C1‐C12 Alkoxy C1‐C12Alkyl, naphthyl, naphthoxy, naphthoxy C1‐C12Alkyl, naphthyl carbonyl, naphthyl C1‐C12Alkyl, naphthyl C1‐C12 Alkoxyl, naphthyl C1‐C12Alkoxy C1‐C12Alkyl, heteroaryl, heteroaryl epoxide, heteroaryl C1‐C12Alkoxy C1‐C12Alkyl, Heteroaryl epoxide C1‐C12Alkyl, Heteroarylcarbonyl, heteroaryloxycarbonyl, heteroarylaminocarbonyl, heteroaryl C1‐C12Alkyl Or heteroaryl C1‐C12Alkoxyl：Halogen, nitro, cyano group, sulfydryl, C1‐C6Alkyl, halo C1‐C6Alkyl, C3‐C8Cycloalkyl, C1‐ C6Alkoxyl, halo C1‐C6Alkoxyl, C1‐C6Alkylthio group, halo C1‐C6Alkylthio group, C2‐C6Thiazolinyl, halo C2‐C6Thiazolinyl, C2‐ C6Alkynyl, halo C2‐C6Alkynyl, C3‐C6Alkenyloxy group, halo C3‐C6Alkenyloxy group, C3‐C6Alkynyloxy group, halo C3‐C6Alkynyloxy group, C1‐ C6Alkyl sulphinyl, halo C1‐C6Alkyl sulphinyl, C1‐C6Alkyl sulphonyl, halo C1‐C6Alkyl sulphonyl, C1‐C6Alkane Epoxide C1‐C6Alkyl, C1‐C6Alkyl-carbonyl, halo C1‐C6Alkyl-carbonyl, C1‐C6Alkyl carbonyl epoxide, C1‐C6Alkyl-carbonyl ammonia Base, C1‐C6Alkyl sulphonyl epoxide, C1‐C6Alkoxy carbonyl, C1‐C6Alkoxy C1‐C6Alkoxyl, C1‐C6Alkoxy carbonyl C1‐ C6Alkyl, C1‐C6Alkoxycarbonyl amino, C1‐C6Alkoxy carbonyl C1‐C6Alkoxyl, CHO, CO2H、CO2Na、CO2NH4、 NR10R11, C (=O) NR10R11, OC (=O) NR10R11, C (=S) NR10R11Or SO2NR10R11；
R8、R9It is respectively selected from hydrogen, C1‐C6Alkyl, aryl or aryl C1‐C6Alkyl；
R10、R11May be the same or different, be respectively selected from hydrogen, C1‐C6Alkyl, halo C1‐C6Alkyl, C1‐C6Alkoxyl, halo C1‐C6 Alkoxyl, C1‐C6Alkylthio group, halo C1‐C6Alkylthio group or C3‐C8Cycloalkyl；
And its stereoisomer；
The tumor is bladder cancer, carcinoma of prostate, pulmonary carcinoma or leukemia.
2. application according to claim 1, it is characterised in that：In formula I
Ar is selected from Ar1, Ar2, Ar3 or Ar4 as follows；
Q is selected from Q1、Q2、Q3、Q4、Q5、Q6、Q7、Q8Or Q9；
R1、R2、R3、R4、R5、R6May be the same or different, be each independently selected from hydrogen, halogen, cyano group, nitro, hydroxyl, ammonia respectively Base, CHO, CO2H、CO2Na、CO2NH4、C1‐C6Alkyl, halo C1‐C6Alkyl, C3‐C6Cycloalkyl, C1‐C6Alkoxyl, halo C1‐C6 Alkoxyl, C1‐C6Alkylthio group, halo C1‐C6Alkylthio group, C1‐C6Alkoxy C1‐C6Alkyl, halo C1‐C6Alkoxy C1‐C6Alkyl, C1‐C6Alkoxy C1‐C6Alkoxyl, halo C1‐C6Alkoxy C1‐C6Alkoxyl, C1‐C6Alkylthio group C1‐C6Alkyl, halo C1‐C6Alkane Sulfenyl C1‐C6Alkyl, C1‐C6Alkyl amino, halo C1‐C6Alkyl amino, C2‐C8Dialkyl amido, halo C2‐C8Dialkyl amino Base, piperidyl, nafoxidine base, N methyl piperazine base, morpholinyl, C2‐C6Thiazolinyl, halo C2‐C6Thiazolinyl, C2‐C6Alkynyl, halo C2‐C6Alkynyl, C2‐C6Alkenyloxy group, halo C2‐C6Alkenyloxy group, C2‐C6Alkynyloxy group, halo C2‐C6Alkynyloxy group, C1‐C6Alkyl sulfonyl Base, halo C1‐C6Alkyl sulphonyl, C1‐C6Alkyl sulphinyl, halo C1‐C6Alkyl sulphinyl, C1‐C6Alkyl-carbonyl, halogen For C1‐C6Alkyl-carbonyl, C1‐C6Alkyl carbonyl epoxide, C1‐C6Alkyl-carbonyl-amino, C1‐C6Alkyl sulphonyl epoxide, C1‐C6Alkane Epoxide carbonyl, halo C1‐C6Alkoxy carbonyl, C1‐C6Alkyl amino sulfonyl, C1‐C6Alkoxycarbonyl amino, C1‐C6Alkoxyl Carbonyl C1‐C6Alkyl, C1‐C6Alkoxy carbonyl C1‐C6Alkoxyl, amino C1‐C6Alkyl, C1‐C6Alkyl amino C1‐C6Alkyl, C2‐ C8Dialkyl amido C1‐C6Alkyl, C (=O) NR10R11, OC (=O) NR10R11, C (=S) NR10R11、SO2NR10R11, C (= NOR9)R8Or R7；Or R1With R2Between form five-membered ring or hexatomic ring；
R7Selected from unsubstituted or be independently selected from the phenyl, phenoxy group, phenoxy group C that following group is further substituted with by 1-51‐C6 Alkyl, benzoyl, phenyloxycarbonyl, phenyl amino carbonyl, phenyl C1‐C6Alkyl, phenyl C1‐C6Alkoxyl, phenyl C1‐C6Alkane Epoxide C1‐C6Alkyl, naphthyl, naphthoxy, naphthoxy C1‐C6Alkyl, naphthyl carbonyl, naphthyl C1‐C6Alkyl, naphthyl C1‐C6Alcoxyl Base, naphthyl C1‐C6Alkoxy C1‐C6Alkyl, heteroaryl, heteroaryl epoxide, heteroaryl C1‐C6Alkoxy C1‐C6Alkyl, heteroaryl Epoxide C1‐C6Alkyl, Heteroarylcarbonyl, heteroaryloxycarbonyl, heteroarylaminocarbonyl, heteroaryl C1‐C6Alkyl or heteroaryl C1‐C6Alkoxyl：Halogen, nitro, cyano group, sulfydryl, C1‐C4Alkyl, halo C1‐C4Alkyl, C3‐C6Cycloalkyl, C1‐C4Alkoxyl, Halo C1‐C4Alkoxyl, C1‐C4Alkylthio group, halo C1‐C4Alkylthio group, C2‐C4Thiazolinyl, halo C2‐C4Thiazolinyl, C2‐C4Alkynyl, halogen For C2‐C4Alkynyl, C3‐C4Alkenyloxy group, halo C3‐C4Alkenyloxy group, C3‐C4Alkynyloxy group, halo C3‐C4Alkynyloxy group, C1‐C4Alkyl Asia sulphur Acyl group, halo C1‐C4Alkyl sulphinyl, C1‐C4Alkyl sulphonyl, halo C1‐C4Alkyl sulphonyl, C1‐C4Alkoxy C1‐C4 Alkyl, C1‐C4Alkyl-carbonyl, halo C1‐C4Alkyl-carbonyl, C1‐C4Alkyl carbonyl epoxide, C1‐C4Alkyl-carbonyl-amino, C1‐C4Alkane Base sulfonyl epoxide, C1‐C4Alkoxy carbonyl, C1‐C4Alkoxy C1‐C4Alkoxyl, C1‐C4Alkoxy carbonyl C1‐C4Alkyl, C1‐ C4Alkoxycarbonyl amino, C1‐C4Alkoxy carbonyl C1‐C4Alkoxyl, CHO, CO2H、CO2Na、CO2NH4、NR10R11, C (=O) NR10R11, OC (=O) NR10R11, C (=S) NR10R11Or SO2NR10R11；
R8、R9It is respectively selected from hydrogen, C1‐C4Alkyl, aryl or aryl C1‐C4Alkyl；
R10、R11May be the same or different, be respectively selected from hydrogen, C1‐C4Alkyl, halo C1‐C4Alkyl, C1‐C4Alkoxyl, halo C1‐C4 Alkoxyl, C1‐C4Alkylthio group, halo C1‐C4Alkylthio group or C3‐C6Cycloalkyl.
3. application according to claim 2, it is characterised in that：In formula I
Ar is selected from Ar1, Ar2, Ar3 or Ar4 as follows；
Q is selected from Q1、Q2、Q3、Q4、Q5、Q6、Q7、Q8Or Q9；
R1、R2、R3、R4、R5、R6May be the same or different, be each independently selected from hydrogen, halogen, cyano group, nitro, hydroxyl, ammonia respectively Base, CHO, CO2H、CO2Na、CO2NH4、C1‐C4Alkyl, halo C1‐C4Alkyl, C3‐C6Cycloalkyl, C1‐C4Alkoxyl, halo C1‐C4 Alkoxyl, C1‐C4Alkylthio group, halo C1‐C4Alkylthio group, C1‐C4Alkoxy C1‐C4Alkyl, halo C1‐C4Alkoxy C1‐C4Alkyl, C1‐C4Alkoxy C1‐C4Alkoxyl, halo C1‐C4Alkoxy C1‐C4Alkoxyl, C1‐C4Alkylthio group C1‐C4Alkyl, halo C1‐C4Alkane Sulfenyl C1‐C4Alkyl, C1‐C4Alkyl amino, halo C1‐C4Alkyl amino, C2‐C6Dialkyl amido, halo C2‐C6Dialkyl amino Base, piperidyl, nafoxidine base, N methyl piperazine base, morpholinyl, C2‐C4Thiazolinyl, halo C2‐C4Thiazolinyl, C2‐C4Alkynyl, halo C2‐C4Alkynyl, C2‐C4Alkenyloxy group, halo C2‐C4Alkenyloxy group, C2‐C4Alkynyloxy group, halo C2‐C4Alkynyloxy group, C1‐C4Alkyl sulfonyl Base, halo C1‐C4Alkyl sulphonyl, C1‐C4Alkyl sulphinyl, halo C1‐C4Alkyl sulphinyl, C1‐C4Alkyl-carbonyl, halogen For C1‐C4Alkyl-carbonyl, C1‐C4Alkyl carbonyl epoxide, C1‐C4Alkyl-carbonyl-amino, C1‐C4Alkyl sulphonyl epoxide, C1‐C4Alkane Epoxide carbonyl, halo C1‐C4Alkoxy carbonyl, C1‐C4Alkyl amino sulfonyl, C1‐C4Alkoxycarbonyl amino, C1‐C4Alkoxyl Carbonyl C1‐C4Alkyl, C1‐C4Alkoxy carbonyl C1‐C4Alkoxyl, amino C1‐C4Alkyl, C1‐C4Alkyl amino C1‐C4Alkyl, C2‐ C6Dialkyl amido C1‐C4Alkyl, C (=O) NR10R11, OC (=O) NR10R11, C (=S) NR10R11、SO2NR10R11, C (= NOR9)R8Or R7；Or R1With R2Between form saturation five-membered ring or hexatomic ring；
R7Selected from unsubstituted or be independently selected from the phenyl, phenoxy group, phenoxy group C that following group is further substituted with by 1-51‐C4 Alkyl, benzoyl, phenyloxycarbonyl, phenyl amino carbonyl, phenyl C1‐C4Alkyl, phenyl C1‐C4Alkoxyl, phenyl C1‐C4Alkane Epoxide C1‐C4Alkyl, naphthyl, naphthoxy, naphthoxy C1‐C4Alkyl, naphthyl carbonyl, naphthyl C1‐C4Alkyl, naphthyl C1‐C4Alcoxyl Base, naphthyl C1‐C4Alkoxy C1‐C4Alkyl, heteroaryl, heteroaryl epoxide, heteroaryl C1‐C4Alkoxy C1‐C4Alkyl, heteroaryl Epoxide C1‐C4Alkyl, Heteroarylcarbonyl, heteroaryloxycarbonyl, heteroarylaminocarbonyl, heteroaryl C1‐C4Alkyl or heteroaryl C1‐C4Alkoxyl：Halogen, nitro, cyano group, sulfydryl, C1‐C4Alkyl, halo C1‐C4Alkyl, C3‐C6Cycloalkyl, C1‐C4Alkoxyl, Halo C1‐C4Alkoxyl, C1‐C4Alkylthio group, halo C1‐C4Alkylthio group, C2‐C4Thiazolinyl, halo C2‐C4Thiazolinyl, C2‐C4Alkynyl, halogen For C2‐C4Alkynyl, C3‐C4Alkenyloxy group, halo C3‐C4Alkenyloxy group, C3‐C4Alkynyloxy group, halo C3‐C4Alkynyloxy group, C1‐C4Alkyl Asia sulphur Acyl group, halo C1‐C4Alkyl sulphinyl, C1‐C4Alkyl sulphonyl, halo C1‐C4Alkyl sulphonyl, C1‐C4Alkoxy C1‐C4 Alkyl, C1‐C4Alkyl-carbonyl, halo C1‐C4Alkyl-carbonyl, C1‐C4Alkyl carbonyl epoxide, C1‐C4Alkyl-carbonyl-amino, C1‐C4Alkane Base sulfonyl epoxide, C1‐C4Alkoxy carbonyl, C1‐C4Alkoxy C1‐C4Alkoxyl, C1‐C4Alkoxy carbonyl C1‐C4Alkyl, C1‐ C4Alkoxycarbonyl amino, C1‐C4Alkoxy carbonyl C1‐C4Alkoxyl, CHO, CO2H、CO2Na、CO2NH4、NR10R11, C (=O) NR10R11, OC (=O) NR10R11, C (=S) NR10R11Or SO2NR10R11；
R8、R9It is respectively selected from hydrogen, C1‐C4Alkyl, aryl or aryl C1‐C4Alkyl；
R10、R11May be the same or different, be respectively selected from hydrogen, C1‐C4Alkyl, halo C1‐C4Alkyl, C1‐C4Alkoxyl, halo C1‐C4 Alkoxyl, C1‐C4Alkylthio group, halo C1‐C4Alkylthio group or C3‐C6Cycloalkyl.
4. application according to claim 3, it is characterised in that：In formula I
Ar is selected from Ar1, Ar2 or Ar3；
Q is selected from Q1、Q2、Q3、Q4、Q5、Q6、Q7Or Q8；
R1、R2、R3、R4、R5、R6May be the same or different, be each independently selected from hydrogen, halogen, cyano group, C respectively1‐C4Alkyl, halo C1‐C4Alkyl, C3‐C6Cycloalkyl, C1‐C4Alkoxyl, halo C1‐C4Alkoxyl, C1‐C4Alkylthio group, C1‐C4Alkoxy C1‐C4Alkane Base, C1‐C4Alkyl amino, C2‐C6Dialkyl amido, C1‐C4Alkyl sulphonyl, C1‐C4Alkoxy carbonyl or R7；Or R1With R2It Between form saturation five-membered ring or hexatomic ring；
R7Selected from unsubstituted or be independently selected from the phenyl, benzyl, phenethyl, heteroaryl that following group is further substituted with by 1-5 Base：Halogen, nitro, C1‐C4Alkyl, halo C1‐C4Alkyl, C1‐C4Alkoxyl or halo C1‐C4Alkoxyl.
5. application according to claim 4, it is characterised in that：
Ar is selected from Ar1, Ar2 or Ar3；
Q is selected from Q1；
R1、R2、R3、R4、R5、R6May be the same or different, be each independently selected from hydrogen, halogen, cyano group, C respectively1‐C4Alkyl, halo C1‐C4Alkyl or R7；Or R1With R2Between form saturation five-membered ring or hexatomic ring；
R7Selected from unsubstituted or be independently selected from the phenyl, benzyl, heteroaryl that following group is further substituted with by 1-5：Halogen, Nitro, C1‐C4Alkyl, halo C1‐C4Alkyl, C1‐C4Alkoxyl or halo C1‐C4Alkoxyl.
6. application according to claim 5, it is characterised in that：
Ar is selected from Ar3；
Q is selected from Q1；
R1、R2、R3、R4、R5、R6May be the same or different, be each independently selected from hydrogen, halogen, cyano group, C respectively1‐C4Alkyl, halo C1‐C4Alkyl or R7；Or R1With R2Between form saturation five-membered ring or hexatomic ring；
R7Selected from unsubstituted or be independently selected from the phenyl, benzyl, heteroaryl that following group is further substituted with by 1-5：Halogen, Nitro, C1‐C4Alkyl, halo C1‐C4Alkyl, C1‐C4Alkoxyl or halo C1‐C4Alkoxyl.
7. the application according to claim 1-6 any one, it is characterised in that：With the Benzofurantone shown in formula I The medicine that compound is administered for the form that active component is prepared into oral or parenteral approach, or pass through internal transplant medicine The medicine that the form of pump is administered.
8. application according to claim 7, it is characterised in that：With the Benzofurantone compound shown in formula I as work Property composition prepare treatment, prevention or alleviate tumor medicine, pharmaceutical dosage form be tablet, pill, capsule, electuary, syrup, injection Or freeze-dried powder dosage form.
9. application according to claim 8, it is characterised in that：Active constituents of medicine is one or more formulas I institutes The Benzofurantone compound for showing.
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