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WO2017005137A1 - Quinazoline compound, intermediate, preparation method, pharmaceutical composition and uses thereof - Google Patents

Quinazoline compound, intermediate, preparation method, pharmaceutical composition and uses thereof Download PDF

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Publication number
WO2017005137A1
WO2017005137A1 PCT/CN2016/088089 CN2016088089W WO2017005137A1 WO 2017005137 A1 WO2017005137 A1 WO 2017005137A1 CN 2016088089 W CN2016088089 W CN 2016088089W WO 2017005137 A1 WO2017005137 A1 WO 2017005137A1
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Prior art keywords
substituted
group
phenyl
unsubstituted
quinazolin
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PCT/CN2016/088089
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French (fr)
Chinese (zh)
Inventor
柏旭
余建鑫
王万河
张永
郑连友
夏广新
张春玲
王余吉
周倩
张大鹏
Original Assignee
吉林大学
上海医药集团股份有限公司
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Publication of WO2017005137A1 publication Critical patent/WO2017005137A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
    • C07D239/84—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—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
    • 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

Definitions

  • the present invention relates to a quinazoline compound, an intermediate thereof, a preparation method, a pharmaceutical composition and use.
  • JAK inhibitors The development of small-molecule JAK inhibitors is currently concentrated in the two major diseases of autoimmune diseases and hematopoietic malignancies: autoimmune diseases including rheumatoid arthritis (RA), systemic lupus Erythematosus, With a variety of diseases such as Psoriatic/Psoriasis, sales of adalimumab in 2013 was $10,659 million, indicating a huge market prospect in this disease area.
  • the main therapeutic drugs for such diseases are traditional DMARD drugs, therapeutic antibodies, and small molecule targeted drugs, among which small molecule targeting drugs are mainly JAK inhibitors.
  • JAK inhibitors will become the main driving force for the growth of the RA drug market by 2022. Therefore, the development of a compound which has a good inhibitory effect on protein kinase JAK has become a hot spot in the field of medicinal chemistry.
  • the technical problem to be solved by the present invention is to provide a quinazoline compound, an intermediate thereof, a preparation method, a pharmaceutical composition and an application which are completely different from the prior art.
  • the quinazoline compound of the present invention has a good inhibitory effect on protein kinase JAK, and can be used for the preparation of a medicament for preventing, treating or adjuvant treatment of various diseases related to the expression or activity of JAK, particularly tumor diseases and immune diseases.
  • the present invention provides a quinazoline compound of the formula I, a pharmaceutically acceptable salt, solvate, metabolite, metabolic precursor or prodrug thereof;
  • R 1 , R 2 and R 3 are independently hydrogen, substituted C 5 -C 10 aryl, substituted or unsubstituted C 2 -C 6 heteroaryl or C 2 -C 6 heterocycloalkyl; Wherein R 1 , R 2 and R 3 are not hydrogen at the same time;
  • R 4 and R 5 are independently hydrogen, a substituted or unsubstituted C 1 -C 4 alkyl group, a substituted or unsubstituted C 5 -C 10 aryl group, a substituted C 2 -C 6 heteroaryl group or R 0 is a substituted C 1 -C 4 alkyl group or a C 3 -C 6 cycloalkyl group; when R 0 is a substituted C 1 -C 4 alkyl group, the substituted C 1 -C 4
  • the substitution in the alkyl group means that it is substituted by one or more (for example, 1-6, preferably 1-2) substituted or unsubstituted C 2 -C 6 heterocycloalkyl groups;
  • the substitution in the C 2 -C 6 heterocycloalkyl group means one or more (for example, 1-6, preferably 1-2) C 1 -C 4 alkyl groups (described C 1 -C 4 alkyl is preferably substituted with methyl,
  • R 1 , R 2 or R 3 the substitution described in the substituted C 5 -C 10 aryl group means one or more of the following substituents (R m ) (for example, 1-6 , preferably 1-3) substituted: hydroxy, halogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 alkoxy, substituted or unsubstituted C 2 -C 6 heterocycloalkyl, nitro,
  • R 6 is a C 1 -C 4 alkyl group, a C 3 -C 6 cycloalkyl group or R a1 and R a2 are independently hydrogen, substituted or unsubstituted C 1 -C 4 alkyl or C 5 -C 10 aryl;
  • R 7 and R 8 are independently hydrogen, C 1 -C 4 alkane base
  • R a3 is a C 1 -C 4 alkyl group or a C 3 -C 6
  • R 1 , R 2 or R 3 when the substituted C 5 -C 10 aryl group is a substituted phenyl group
  • the substitution is monosubstituted, the substituent is located at the meta or para position of the benzene ring, wherein when the substituent is located at the meta position of the benzene ring, the substituent is substituted or unsubstituted.
  • R 1 , R 2 or R 3 when the substituted C 5 -C 10 aryl group is a substituted phenyl group
  • the substituent is located at the meta and para positions of the phenyl ring, or the ortho and para positions; the substituent is preferably a halogen and a substituted or unsubstituted C 1 - An alkyl group of C 4 , a halogen and a substituted or unsubstituted C 1 -C 4 alkoxy group, or a substituted or unsubstituted C 1 -C 4 alkyl group and an unsubstituted C 1 -C 4 alkoxy group ;
  • the substitution in the substituted C 2 -C 6 heteroaryl group means one or more of the following substituents (R n ) (for example, 1-6 Substituted, preferably 1-2) substituted: C 1 -C 4 alkoxy, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 2 -C 6 heterocycloalkyl , R 10 is a C 1 -C 4 alkyl group; R 11 is R a5 and R a6 are independently C 1 -C 4 alkyl;
  • substitution in the substituted C 5 -C 10 aryl group when the substitution in the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group,
  • the substitution in the substituted C 1 -C 4 alkyl group means a C 2 -C 6 heterocycloalkane substituted or unsubstituted by one or more (for example, 1-6, preferably 1-2).
  • substitution in said substituted C 2 -C 6 heterocycloalkyl means one or more (for example 1-6, preferably 1-2) C 1 -C 4 Substituted by an alkyl group;
  • substitution described in the substituted C 1 -C 4 alkoxy group means that it is substituted by one or more of the following substituents (for example, 1-6, preferably 1-2): halogen (for example, fluorine) , chlorine, bromine or iodine, preferably fluorine), cyano, substituted or unsubstituted C 2 -C 6 heteroaryl, substituted or unsubstituted C 5 -C 10 aryl or C 2 -C 6 hetero a cycloalkyl group; said substitution in said substituted C 2 -C 6 heteroaryl group means substituted by one or more (for example, 1-6, preferably 1-2) cyano groups; Substituted in the substituted C 5 -C 10 aryl group means substituted by one
  • R 1 , R 2 or R 3 when the substitution described in the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group,
  • the substitution in the substituted C 2 -C 6 heterocycloalkyl group means that it is substituted by one or more (for example, 1-6, preferably 1-2) C 1 -C 4 alkyl groups. ;
  • R 6 when the substituted C 5 -C 10 aryl group is substituted as described Substituted, R 6 is When R a1 and R a2 are independently a substituted or unsubstituted C 1 -C 4 alkyl group, the substitution in the substituted C 1 -C 4 alkyl group means one or more (for example) 1-6, preferably 1-2) substituted by a cyano group;
  • R 7 and R 8 are independently When R a4 is a substituted or unsubstituted C 1 -C 4 alkyl group, the substitution described in the substituted C 1 -C 4 alkyl group means one or more of the following substituents (for example) 1-6, preferably 1-2) substituted: cyano or C 2 -C 6 heterocycloalkyl;
  • R 1 , R 2 or R 3 when the substituted C 5 -C 10 aryl group is substituted as described Substituted, when R 9 is a substituted or unsubstituted C 1 -C 4 alkyl group; the substitution described in the substituted C 1 -C 4 alkyl group means one or more (for example, 1- 6 (preferably 1-2) substituted with a cyano group;
  • substitution described in the substituted C 1 -C 4 alkyl group means that it is substituted by one or more of the following substituents (for example, 1-6, preferably 1-2): cyano, C 3 a C 6 cycloalkyl group, a substituted or unsubstituted C 2 -C 6 heteroaryl group or a substituted or unsubstituted C 5 -C 10 aryl group; said substituted C 2 -C 6 heteroaryl group
  • the substituent referred to in the substituted C 5 -C 10 aryl group means one or more (for example, 1-6, preferably 1-2) halogens (for example, fluorine, chlorine, bromine or iodine). Substituted by bromine or chlorine);
  • substitution in the substituted C 2 -C 6 heterocycloalkyl group means that it is substituted by one or more of the following substituents (for example, 1-6, preferably 1-2): C 1 -C 4 alkyl group, or R 12 is a C 1 -C 4 alkyl group or a C 3 -C 6 cycloalkyl group; R 13 is a C 1 -C 4 alkyl group; said substituted C 1 -C 4 alkyl group Substituted refers to being substituted by one or more of the following substituents (eg, 1-6, preferably 1-2): cyano or
  • the substitution described in the substituted C 1 -C 4 alkyl group means substituted or unsubstituted by one or more (for example, 1-6, preferably 1-2).
  • heteroaryl C 2 -C 6 aryl group being unsubstituted, a substituted aryl substituted heteroaryl C 2 -C 6 group of said means with one or more (e.g., 1-6, preferably 1-2 Substituted by a cyano group;
  • the substitution (R p ) described in the substituted C 5 -C 10 aryl group means one or more of the following substituents (for example, 1-6, preferably 1) -2) substituted: halogen (for example fluorine, chlorine, bromine or iodine, preferably chlorine), nitro, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 Alkoxy, substituted or unsubstituted C 2 -C 6 heterocycloalkyl, substituted or unsubstituted C 5 -C 10 aryl, or R 14 is a C 1 -C 4 alkoxy group or R a7 and R a8 are independently hydrogen or a substituted or unsubstituted C 1 -C 4 alkyl group; when R a7 and R a8 are independently a substituted C 1 -C 4 alkyl group, the substituted
  • R 4 or R 5 when the substitution described in the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group, the substituted
  • the substitution in the alkyl group of C 1 -C 4 means that it is substituted by one or more of the following substituents (for example, 1-6, preferably 1-2): halogen, substituted or unsubstituted C 2 -C 6 heterocycloalkyl or R 16 and R 17 are independently a C 1 -C 4 alkyl group;
  • the substitution described in the substituted C 2 -C 6 heterocycloalkyl group means one or more of the following substituents ( For example, 1-6, preferably 1-2) are substituted: C 1 -C 4 alkyl or R a11 is a C 1 -C 4 alkyl group;
  • R 4 or R 5 when the substitution described in the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkoxy group, the substituted
  • the substitution in the alkoxy group of C 1 -C 4 means that it is substituted by one or more of the following substituents (for example, 1-6, preferably 1-2): a heterocyclic ring of C 2 -C 6 Alkyl, C 1 -C 4 alkoxy, or R 18 is C 1 -C 4 alkyl or C 2 -C 6 heterocycloalkyl; R 19 and R 20 are independently C 1 -C 4 alkyl;
  • R 4 or R 5 when the substitution described in the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, the The substitution in the substituted C 2 -C 6 heterocycloalkyl group means that it is substituted by one or more of the following substituents (R t ) (for example, 1-6, preferably 1-2): hydroxy a substituted or unsubstituted C 1 -C 4 alkyl group, a C 2 -C 6 heterocycloalkyl group, or R 21 is a substituted or unsubstituted C 1 -C 4 alkyl group or R a11 and R a12 are independently a C 1 -C 4 alkyl group; when R 21 is a substituted C 1 -C 4 alkyl group, the substituted C 1 -C 4 alkyl group is as described Substituted means substituted by one or more (for example 1-6, preferably
  • R 4 or R 5 when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, the substitution is When the substitution in the C 2 -C 6 heterocycloalkyl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group, the substituted C 1 -C 4 alkyl group is said substitution means one or more (e.g., 1-6, preferably 1-2) is the following substituted with substituents: hydroxy, cyano, halogen, C 3 -C 6 cycloalkyl or substituted or An unsubstituted C 1 -C 4 alkoxy group; the substitution described in the substituted C 1 -C 4 alkoxy group means one or more (for example, 1-6, preferably 1-2) Substituted by a C 5 -C 10 aryl group;
  • substitution described in the substituted C 5 -C 10 aryl group when the substitution described in the substituted C 5 -C 10 aryl group is substituted with a substituted or unsubstituted C 5 -C 10 aryl group, the substitution or The substitution described in the substituted C 5 -C 10 aryl group described in the unsubstituted C 5 -C 10 aryl group means one or more (for example, 1-6, preferably 1-2) Substituted by a C 1 -C 4 alkoxy group;
  • substitution in the substituted C 2 -C 6 heteroaryl group means one or more of the following substituents (for example, 1-6, preferably 1-2)
  • substituents for example, 1-6, preferably 1-2
  • R 1 , R 2 or R 3 when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group, the The substitution described in the substituted C 1 -C 4 alkyl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, said substituted or unsubstituted C 2 -C 6 hetero.
  • the C 1 -C 4 alkyl group is preferably a methyl group, an ethyl group, a n-propyl group or an isopropyl group. , n-butyl, isobutyl or tert-butyl.
  • R 1 , R 2 or R 3 when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group, the substituted or unsubstituted C 2 -C 6 Heterocycloalkyl preferably refers to a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group wherein the hetero atom is selected from O, N and S and the number of heteroatoms is 1 to 4 (preferably 1 to 2). .
  • the substituted or unsubstituted C 2 -C 6 heterocycloalkyl group is preferably a substituted or unsubstituted morpholinyl group.
  • substituted or unsubstituted piperazinyl The substituted piperazinyl group is preferably
  • R 1 , R 2 or R 3 when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkoxy group, When the substitution described in the substituted C 1 -C 4 alkoxy group is substituted by a substituted or unsubstituted C 2 -C 6 heteroaryl group, the substituted or unsubstituted C 2 -C 6
  • the heteroaryl group preferably means a hetero atom selected from O, N and S, and a substituted or unsubstituted C 2 -C 6 heteroaryl group having 1 to 4 (preferably 1 to 2) hetero atoms.
  • the substituted or unsubstituted C 2 -C 6 heteroaryl group is preferably a substituted or unsubstituted pyridyl group.
  • the substituted pyridyl group is preferably a substituted or unsubstituted pyridyl group.
  • R 1 , R 2 or R 3 when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkoxy group, The substitution in the substituted C 1 -C 4 alkoxy group is substituted by a substituted or unsubstituted C 5 -C 10 aryl group, wherein the substituted C 5 -C 10 aryl group is
  • the C 2 -C 6 heteroaryl group preferably means that the hetero atom is selected from O, N and S, and the number of heteroatoms is 1. ⁇ 4 (preferably 1 to 2) C 2 -C 6 heteroaryl groups.
  • the C 2 -C 6 heteroaryl group is preferably pyrazolyl
  • R 1 , R 2 or R 3 when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkoxy group, When the substitution described in the substituted C 1 -C 4 alkoxy group is substituted by a substituted or unsubstituted C 5 -C 10 aryl group, the substituted or unsubstituted C 5 -C 10
  • the aryl group is preferably a substituted or unsubstituted phenyl group.
  • the substituted phenyl group is preferably
  • R 1 , R 2 or R 3 when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkoxy group,
  • the C 2 -C 6 heterocycloalkyl group is preferably The hetero atom is selected from the group consisting of O, N and S, and a C 2 -C 6 heterocycloalkyl group having 1 to 4 (preferably 1 to 2) hetero atoms.
  • the C 2 -C 6 heterocycloalkyl group is preferably a tetrahydropyrrolyl group.
  • R 1 , R 2 or R 3 when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, When the substitution described in the substituted C 2 -C 6 heterocycloalkyl group is substituted by one or more (for example, 1-6, preferably 1-2) C 1 -C 4 alkyl groups,
  • the C 1 -C 4 alkyl group is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
  • the halogen is preferably fluorine, chlorine, bromine or Iodine, preferably fluorine.
  • R 1 , R 2 or R 3 when the substitution in the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group,
  • the substituted or unsubstituted C 1 -C 4 alkyl group is preferably a substituted or unsubstituted methyl group, a substituted or unsubstituted ethyl group, a substituted or unsubstituted n-propyl group, a substituted or unsubstituted isopropyl group.
  • the substituted C 1 -C 4 alkyl group is preferably
  • R 1 , R 2 or R 3 when the substitution described in the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkoxy group,
  • the substituted or unsubstituted C 1 -C 4 alkoxy group is preferably a substituted or unsubstituted methoxy group, a substituted or unsubstituted ethoxy group, a substituted or unsubstituted n-propoxy group, a substituted or Unsubstituted isopropoxy group, substituted or unsubstituted n-butoxy group, substituted or unsubstituted isobutoxy group or substituted or unsubstituted tert-butoxy group.
  • the substituted C 1 -C 4 alkoxy group is preferably or
  • R 1 , R 2 or R 3 when the substitution described in the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group,
  • the substituted or unsubstituted C 2 -C 6 heterocycloalkyl group preferably means a substituent in which the hetero atom is selected from O, N and S, and the number of hetero atoms is from 1 to 4 (preferably from 1 to 2).
  • unsubstituted C 2 -C 6 heterocycloalkyl is preferably a substituted or unsubstituted morpholinyl group.
  • substituted or unsubstituted piperazinyl The substituted piperazinyl group is preferably
  • R 1 , R 2 or R 3 when the substituted C 5 -C 10 aryl group is substituted as described
  • the C 1 -C 4 alkyl group is preferably a methyl group, an ethyl group, a n-propyl group, an isopropyl group or a n-butyl group.
  • Base isobutyl or tert-butyl.
  • R 1 , R 2 or R 3 when the substituted C 5 -C 10 aryl group is substituted as described
  • the C 3 -C 6 cycloalkyl group is preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.
  • R 6 when the substituted C 5 -C 10 aryl group is substituted as described Substituted, the R 6 is When R a1 and R a2 are independently a substituted or unsubstituted C 1 -C 4 alkyl group, the substituted or unsubstituted C 1 -C 4 alkyl group is preferably a substituted or unsubstituted methyl group.
  • substituted or unsubstituted ethyl substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl or substituted or unsubstituted Tert-butyl.
  • R 6 when the substituted C 5 -C 10 aryl group is substituted as described Substituted, the R 6 is When R a1 and R a2 are independently a C 5 -C 10 aryl group, the C 5 -C 10 aryl group is preferably a phenyl group or a naphthyl group.
  • R 1 , R 2 or R 3 when the substituted C 5 -C 10 aryl group is substituted as described
  • the C 1 -C 4 alkyl group is preferably a methyl group, an ethyl group, a n-propyl group or a different group.
  • R 7 and R 8 are independently When R a3 is a C 1 -C 4 alkyl group, the C 1 -C 4 alkyl group is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or Tert-butyl.
  • R 7 and R 8 are independently When R a3 is a C 3 -C 6 cycloalkyl group, the C 3 -C 6 cycloalkyl group is preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.
  • R 7 and R 8 are independently R a4 is a substituted or unsubstituted C 1 -C 4 alkyl group, and the substituent described in the substituted C 1 -C 4 alkyl group is substituted by a C 2 -C 6 heterocycloalkyl group.
  • said C 2 -C 6 heterocycloalkyl means is preferably a heteroatom selected from O, N and S, the number of hetero atoms of 1 to 4 (preferably 1 to 2) a C 2 -C 6 Heteroaryl.
  • the C 2 -C 6 heteroaryl group is preferably morpholinyl (for example ).
  • R 7 and R 8 are independently When R a4 is a substituted or unsubstituted C 1 -C 4 alkyl group, the substituted or unsubstituted C 1 -C 4 alkyl group is preferably a substituted or unsubstituted methyl group, substituted or unsubstituted.
  • R 7 and R 8 are independently When R a4 is a C 3 -C 6 cycloalkyl group, the C 3 -C 6 cycloalkyl group is preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.
  • R 7 and R 8 are independently
  • R a4 is a C 2 -C 6 heteroaryl group
  • the C 2 -C 6 heteroaryl group means that the hetero atom is selected from O, N and S, and the number of hetero atoms is from 1 to 4 (preferably 1 to).
  • the C 2 -C 6 heteroaryl group is preferably a thienyl group (for example ).
  • R 1 , R 2 or R 3 when the substituted C 5 -C 10 aryl group is substituted as described
  • the substituted or unsubstituted C 1 -C 4 alkyl group is preferably a substituted or unsubstituted A group.
  • R 1 , R 2 or R 3 when the substitution described in the substituted C 2 -C 6 heteroaryl group is substituted by a C 1 -C 4 alkoxy group, the C 1 The alkoxy group of -C 4 is preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy.
  • R 1 , R 2 or R 3 when the substituted C 2 -C 6 heteroaryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group, when the substitution in the substituted C 1 -C 4 alkyl group is substituted by a C 3 -C 6 cycloalkyl group, the C 3 -C 6 cycloalkyl group is preferably a cyclopropyl group. , cyclobutyl, cyclopentyl or cyclohexyl.
  • R 1 , R 2 or R 3 when the substituted C 2 -C 6 heteroaryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group, When the substitution described in the substituted C 1 -C 4 alkyl group is substituted by a substituted or unsubstituted C 2 -C 6 heteroaryl group, the substituted or unsubstituted C 2 -C 6 hetero
  • the aryl group preferably means a substituted or unsubstituted C 2 -C 6 heteroaryl group in which the hetero atom is selected from O, N and S, and the number of hetero atoms is 1 to 4 (preferably 1 to 2).
  • the substituted or unsubstituted C 2 -C 6 heteroaryl group is preferably a substituted or unsubstituted pyridyl group.
  • the substituted pyridyl group is preferably
  • R 1 , R 2 or R 3 when the substituted C 2 -C 6 heteroaryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group, when the substitution described in the substituted C 1 -C 4 alkyl group is substituted with a substituted or unsubstituted C 5 -C 10 aryl group, the substituted or unsubstituted C 5 -C 10 aryl group
  • the group is preferably a substituted or unsubstituted phenyl group.
  • the substituted phenyl group is preferably
  • R 1 , R 2 or R 3 when the substituent described in the substituted C 2 -C 6 heteroaryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group,
  • the substituted or unsubstituted C 1 -C 4 alkyl group is preferably a substituted or unsubstituted methyl group, a substituted or unsubstituted ethyl group, a substituted or unsubstituted n-propyl group, a substituted or unsubstituted iso A propyl group, a substituted or unsubstituted n-butyl group, a substituted or unsubstituted isobutyl group or a substituted or unsubstituted tert-butyl group.
  • the substituted C 1 -C 4 alkyl group is preferably
  • R 1 , R 2 or R 3 when the substituted C 2 -C 6 heteroaryl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, when the substitution described in the substituted C 2 -C 6 heterocycloalkyl group is substituted by a substituted C 1 -C 4 alkyl group, the substituted C 1 -C 4 alkyl group is more Preferably, it is a substituted methyl group, a substituted ethyl group, a substituted n-propyl group, a substituted isopropyl group, a substituted n-butyl group, a substituted isobutyl group or a substituted t-butyl group.
  • the substituted C 1 -C 4 alkyl group is preferably
  • R 1 , R 2 or R 3 when the substituted C 2 -C 6 heteroaryl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group,
  • the substitution described in the substituted C 2 -C 6 heterocycloalkyl group is
  • the R 12 is a C 1 -C 4 alkyl group
  • the C 1 -C 4 alkyl group is preferably a methyl group, an ethyl group, a n-propyl group, an isopropyl group or a n-butyl group.
  • Base isobutyl or tert-butyl.
  • R 1 , R 2 or R 3 when the substituted C 2 -C 6 heteroaryl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group,
  • the substitution described in the substituted C 2 -C 6 heterocycloalkyl group is
  • the R 12 is a C 3 -C 6 cycloalkyl group
  • the C 3 -C 6 cycloalkyl group is preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.
  • R 1 , R 2 or R 3 when the substituted C 2 -C 6 heteroaryl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, The substitution described in the substituted C 2 -C 6 heterocycloalkyl group is When replaced, the stated Preferably or
  • R 1 , R 2 or R 3 when the substituted C 2 -C 6 heteroaryl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group,
  • the substitution described in the substituted C 2 -C 6 heterocycloalkyl group is
  • the R 13 is a C 1 -C 4 alkyl group
  • the C 1 -C 4 alkyl group is preferably a methyl group, an ethyl group, a n-propyl group, an isopropyl group or a n-butyl group.
  • Base isobutyl or tert-butyl. Said Preferably
  • R 1 , R 2 or R 3 when the substitution described in the substituted C 2 -C 6 heteroaryl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group the substituted or unsubstituted C 2 -C 6 heterocycloalkyl is preferably a heteroatom selected from O, N or S, the number of from 1 to 4 hetero atoms substituted or unsubstituted C 2 - Heterocycloalkyl of C 6 .
  • the substituted or unsubstituted C 2 -C 6 heterocycloalkyl group is preferably a substituted or unsubstituted morpholinyl group (for example) , substituted or unsubstituted piperidinyl Or substituted or unsubstituted azetidinyl
  • the substituted C 2 -C 6 heterocycloalkyl group is preferably
  • R 1 , R 2 or R 3 when the substituted C 2 -C 6 heteroaryl group is substituted as described
  • R 10 is a C 1 -C 4 alkyl group
  • the C 1 -C 4 alkyl group is preferably a methyl group, an ethyl group, a n-propyl group, an isopropyl group, an n-butyl group or a different group. Butyl or tert-butyl. Said Preferably
  • R 11 is When R a5 or R a6 is independently a C 1 -C 4 alkyl group, the C 1 -C 4 alkyl group is preferably methyl, ethyl, n-propyl, isopropyl or n-butyl. , isobutyl or tert-butyl. Said Preferably
  • R 4 or R 5 when the substituent described in the substituted C 1 -C 4 alkyl group is substituted with a substituted or unsubstituted C 2 -C 6 heteroaryl group, the substitution Or an unsubstituted C 2 -C 6 heteroaryl group preferably means a hetero atom selected from O, N and S, and a substituted or unsubstituted C having 1 to 4 (preferably 1 to 2) hetero atoms. 2- C6 heteroaryl.
  • the substituted or unsubstituted C 2 -C 6 heteroaryl group is preferably a substituted or unsubstituted pyridyl group.
  • the substituted pyridyl group is preferably
  • the substituted C 1 -C 4 alkyl group is preferably
  • R 4 or R 5 when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group, the substitution or not When the substitution described in the substituted C 1 -C 4 alkyl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, the substituted C 2 -C 6 heterocycloalkane
  • the C 1 -C 4 alkyl group is preferably a methyl group, an ethyl group, a n-propyl group, an isopropyl group, an n-butyl group or a different group. Butyl or tert-butyl.
  • R 4 or R 5 when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group, the substitution or not The substitution described in the substituted C 1 -C 4 alkyl group is
  • R a11 is a C 1 -C 4 alkyl group
  • the C 1 -C 4 alkyl group is preferably a methyl group, an ethyl group, a n-propyl group, an isopropyl group or a positive group. Butyl, isobutyl or tert-butyl.
  • R 4 or R 5 when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group, the substitution or not When the substitution described in the substituted C 1 -C 4 alkyl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, the substituted or unsubstituted C 2 -C 6 Heterocycloalkyl preferably refers to a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group wherein the hetero atom is selected from O, N and S and the number of heteroatoms is 1 to 4 (preferably 1 to 2). .
  • the substituted or unsubstituted C 2 -C 6 heterocycloalkyl group is preferably a substituted or unsubstituted morpholinyl group. Or substituted or unsubstituted piperazinyl
  • R 4 or R 5 when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group, the substitution or not The substitution described in the substituted C 1 -C 4 alkyl group is
  • R 16 and R 17 are independently a C 1 -C 4 alkyl group, in the case of R 16 or R 17 , the C 1 -C 4 alkyl group is preferably a methyl group, an ethyl group or a positive group.
  • R 4 or R 5 when the substitution described in the substituted C 5 -C 10 aryl group is substituted with a substituted or unsubstituted C 1 -C 4 alkyl group, the substitution or The unsubstituted C 1 -C 4 alkyl group is preferably a substituted or unsubstituted methyl group, a substituted or unsubstituted ethyl group, a substituted or unsubstituted n-propyl group, a substituted or unsubstituted isopropyl group, a substitution group. Or unsubstituted n-butyl, substituted or unsubstituted isobutyl or substituted or unsubstituted t-butyl.
  • R 4 or R 5 when the substitution described in the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group, the substituted The C 1 -C 4 alkyl group is preferably or
  • R 4 or R 5 when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkoxy group, the substituted C is substituted
  • the C 2 -C 6 heterocycloalkyl group preferably means a hetero atom From O, N and S, a C 2 -C 6 heterocycloalkyl group having 1 to 4 (preferably 1 to 2) hetero atoms.
  • the C 2 -C 6 heterocycloalkyl group is preferably a tetrahydropyrrolyl group. Morpholinyl
  • R 4 or R 5 when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkoxy group, the substituted C is substituted
  • the C 1 -C 4 alkoxy group is preferably a methoxy group or an ethoxy group.
  • Base n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy.
  • R 4 or R 5 when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkoxy group, the substituted C is substituted
  • the substitution described in the alkoxy group of 1 -C 4 is When substituted, the R 18 is a C 1 -C 4 alkyl group, the R 18, C 1 -C 4 alkyl group is preferably a methyl, ethyl, n-propyl, isopropyl, Base, n-butyl, isobutyl or tert-butyl.
  • R 4 or R 5 when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkoxy group, the substituted C is substituted
  • the substitution described in the alkoxy group of 1 -C 4 is When substituted, the R 18 is C 2 -C 6 heterocycloalkyl is, R 18, said C 2 -C 6 heterocycloalkyl means is preferably a heteroatom selected from O, N And S, a C 2 -C 6 heterocycloalkyl group having 1 to 4 (preferably 1 to 2) hetero atoms.
  • the C 2 -C 6 heterocycloalkyl group is preferably a tetrahydropyrrolyl group.
  • R 4 or R 5 when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkoxy group, the substituted C is substituted
  • the substitution described in the alkoxy group of 1 -C 4 is In the case where R 19 and R 20 are independently a C 1 -C 4 alkyl group, in the case of R 19 and R 20 , the C 1 -C 4 alkyl group is preferably a methyl group or a B group.
  • Base n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
  • R 4 or R 5 when the substitution described in the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkoxy group, the substitution or The unsubstituted C 1 -C 4 alkoxy group is preferably a substituted or unsubstituted methoxy group, a substituted or unsubstituted ethoxy group, a substituted or unsubstituted n-propoxy group, a substituted or unsubstituted iso Propyloxy, substituted or unsubstituted n-butoxy, substituted or unsubstituted isobutoxy or substituted or unsubstituted tert-butoxy.
  • R 4 or R 5 when the substitution described in the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkoxy group, the substituted The C 1 -C 4 alkoxy group is preferably
  • R 4 or R 5 when the substituted C 5 -C 10 aryl group is substituted with a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, the substitution or The substituent described in the unsubstituted C 2 -C 6 heterocycloalkyl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group, wherein the substituted C 1 -C 4 alkyl group is When the substitution is substituted by a C 3 -C 6 cycloalkyl group, the C 3 -C 6 cycloalkyl group is preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.
  • R 4 or R 5 when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, the substituted The substitution in the C 2 -C 6 heterocycloalkyl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group as described in the substituted C 1 -C 4 alkyl group.
  • substitution is a substituted or unsubstituted C 1 -C 4 alkoxy group
  • substitution described in the substituted C 1 -C 4 alkoxy group is a C 5 -C 10 aryl group
  • the C 5 -C 10 aryl group is preferably a phenyl group.
  • the substituted or unsubstituted C 1 -C 4 alkoxy group is preferably a substituted or unsubstituted methoxy group, a substituted or unsubstituted ethoxy group, a substituted or unsubstituted n-propoxy group, or a substituted group.
  • an unsubstituted isopropoxy group a substituted or unsubstituted n-butoxy group, a substituted or unsubstituted isobutoxy group or a substituted or unsubstituted tert-butoxy group.
  • R 4 or R 5 when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, the substituted The substituted or unsubstituted C 1 -C 4 alkyl group when the substituent described in the C 2 -C 6 heterocycloalkyl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group Preferred are substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted Substituted isobutyl or substituted or unsubstituted t-butyl.
  • R 4 or R 5 when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, the substituted The substitution described in the C 2 -C 6 heterocycloalkyl group is When R 21 is a substituted or unsubstituted C 1 -C 4 alkyl group, the substituted or unsubstituted C 1 -C 4 alkyl group is preferably a substituted or unsubstituted methyl group, substituted Or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl or substituted or unsubstituted tert-butyl base.
  • R 4 or R 5 when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, the substituted The substitution described in the C 2 -C 6 heterocycloalkyl group is Substituted, R 21 is When R a11 or R a12 is independently a C 1 -C 4 alkyl group, the C 1 -C 4 alkyl group is preferably methyl, ethyl, n-propyl, isopropyl or n-butyl. , isobutyl or tert-butyl.
  • R 4 or R 5 when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, the substituted The substitution described in the C 2 -C 6 heterocycloalkyl group is
  • R 22 is a C 1 -C 4 alkyl group
  • the C 1 -C 4 alkyl group is preferably a methyl group, an ethyl group, a n-propyl group, an isopropyl group, an n-butyl group or a different group. Butyl or tert-butyl.
  • R 4 or R 5 when the substitution described in the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, the substitution Or an unsubstituted C 2 -C 6 heterocycloalkyl group preferably means a hetero atom selected from O, N and S, and a heteroatom number of 1 to 4 (preferably 1 to 2) substituted or unsubstituted C 2 -C 6 heterocycloalkyl.
  • the substituted or unsubstituted C 2 -C 6 heterocycloalkyl group is preferably a substituted or unsubstituted tetrahydropyrrolyl group.
  • substituted piperazinyl substituted or unsubstituted piperidinyl
  • morpholinyl substituted or unsubstituted piperazinyl
  • the substituent is preferably located on the N atom of the piperazinyl group, for example Wherein R t represents a substituent, and R t is preferably from 1 to 2, and when two, a quaternary ammonium salt is formed.
  • the substituted C 2 -C 6 heterocycloalkyl group is preferably or
  • R 4 or R 5 when the substituted C 5 -C 10 aryl group is substituted with a substituted or unsubstituted C 5 -C 10 aryl group, the substituted or unsubstituted the C 5 -C 10 substituted in the aryl group in the C 5 -C 10 substituent is substituted by C 1 -C 4 alkoxy, said C 1 -C 4 alkyl is The oxy group is preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy.
  • R 4 or R 5 when the substitution described in the substituted C 5 -C 10 aryl group is substituted with a substituted or unsubstituted C 5 -C 10 aryl group, the substitution or The unsubstituted C 5 -C 10 aryl group is preferably a substituted or unsubstituted phenyl group.
  • R 4 or R 5 when the substituted C 5 -C 10 aryl group is substituted as described
  • the R 14 is a C 1 -C 4 alkoxy group
  • the C 1 -C 4 alkoxy group is preferably a methoxy group, an ethoxy group, a n-propoxy group or a different group.
  • R 4 or R 5 when the substituted C 5 -C 10 aryl group is substituted as described Substituted, the R 14 is R a7 or R a8 is independently a substituted or unsubstituted C 1 -C 4 alkyl group, and the substituted C 1 -C 4 alkyl group is substituted by a C 2 -C 6 heterocycloalkyl group.
  • said C 2 -C 6 heterocycloalkyl means is preferably a heteroatom selected from O, N and S, the number of hetero atoms of 1 to 4 (preferably 1 to 2) a C 2 -C 6 Heterocycloalkyl.
  • the C 2 -C 6 heterocycloalkyl group is preferably a tetrahydropyrrolyl group.
  • the substituted or unsubstituted C 1 -C 4 alkyl group is preferably a substituted or unsubstituted methyl group, a substituted or unsubstituted ethyl group, a substituted or unsubstituted n-propyl group.
  • R 4 or R 5 when the substituted C 5 -C 10 aryl group is substituted as described
  • R 15 is a C 1 -C 4 alkyl group
  • the C 1 -C 4 alkyl group is preferably a methyl group, an ethyl group, a n-propyl group, an isopropyl group, an n-butyl group or a different group. Butyl or tert-butyl.
  • R 15 is R a9 or R a10 is independently a substituted or unsubstituted C 1 -C 4 alkyl group, and the substituent described in the substituted C 1 -C 4 alkyl group is a C 2 -C 6 heterocyclic ring
  • the C 2 -C 6 heterocycloalkyl group preferably means that the hetero atom is selected from O, N and S, and the number of hetero atoms is from 1 to 4 (preferably from 1 to 2).
  • C 2 -C 6 heterocycloalkyl when the substituted C 5 -C 10 aryl group is substituted as described Substituted, R 15 is R a9 or R a10 is independently a substituted or unsubstituted C 1 -C 4 alkyl group, and the substituent described in the substituted C 1 -C 4 alkyl group is a C 2 -C 6 heterocyclic ring
  • the C 2 -C 6 heterocycloalkyl group preferably means that the hetero atom
  • the C 2 -C 6 heterocycloalkyl group is preferably a tetrahydropyrrolyl group.
  • Morpholinyl The substituted or unsubstituted C 1 -C 4 alkyl group is preferably a substituted or unsubstituted methyl group, a substituted or unsubstituted ethyl group, a substituted or unsubstituted n-propyl group, a substituted or unsubstituted one. Isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl or substituted or unsubstituted t-butyl.
  • R 15 is a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, and the substituted C 2 -C 6 heterocycloalkyl group is substituted by a C 1 -C 4 alkyl group.
  • the C 1 -C 4 alkyl group is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
  • the substituted or unsubstituted C 2 -C 6 heterocycloalkyl group preferably means a C atom having a hetero atom selected from O, N and S and having 1 to 4 (preferably 1 to 2) hetero atoms.
  • 2- C 6 heterocycloalkyl preferably piperazinyl
  • the substituted C 5 -C 10 aryl group is preferably a substituted phenyl group.
  • the substituted phenyl group is preferably or
  • the substituted or unsubstituted C 2 -C 6 heteroaryl group preferably means that the hetero atom is selected from O, N and S, and the number of hetero atoms is 1 to 4 (preferably 1 to 2) substituted or unsubstituted C 2 -C 6 heteroaryl groups.
  • the substituted or unsubstituted C 2 -C 6 heteroaryl group is preferably a substituted or unsubstituted pyridyl group (for example Or a substituted or unsubstituted pyrazolyl group (eg ).
  • the substituted pyridyl group is R n represents a substituent; when the substituted C 2 -C 6 heteroaryl group is a substituted pyridyl group, the pyridyl group is R n represents a substituent.
  • the substituted pyridyl group is preferably or The substituted pyrazolyl group is preferably or
  • the C 2 -C 6 heterocycloalkyl group preferably means that the hetero atom is selected from O, N and S, and the number of hetero atoms is from 1 to 4 (preferably 1 to). 2) C 2 -C 6 heterocycloalkyl.
  • the C 2 -C 6 heterocycloalkyl group is preferably morpholinyl
  • the substituted or unsubstituted C 1 -C 4 alkyl group is preferably a substituted or unsubstituted methyl group, a substituted or unsubstituted ethyl group, a substituted or unsubstituted n-propyl group.
  • the substituted C 1 -C 4 alkyl group is preferably a substituted or unsubstituted methyl group, a substituted or unsubstituted ethyl group, a substituted or unsubstituted n-propyl group.
  • the substituted or unsubstituted C 5 -C 10 aryl group is preferably a substituted or unsubstituted phenyl group.
  • the substituted phenyl group is preferably
  • the substituted C 2 -C 6 heteroaryl group preferably means that the hetero atom is selected from O, N and S, and the number of hetero atoms is from 1 to 4 (preferably from 1 to 2).
  • Substituted C 2 -C 6 heteroaryl is preferably a substituted pyridyl group ( R m represents a substituent) or a substituted pyrimidinyl group ( R m represents a substituent).
  • the substituted pyridyl group is preferably The substituted pyrimidinyl group is preferably
  • R 4 or R 5 is When R 0 is a substituted C 1 -C 4 alkyl group, the substituted C 1 -C 4 alkyl group is preferably a substituted methyl group, a substituted ethyl group, a substituted n-propyl group, Substituted isopropyl, substituted n-butyl, substituted isobutyl or substituted t-butyl.
  • the substituted C 1 -C 4 alkyl group is preferably
  • R 4 or R 5 is When R 0 is a C 3 -C 6 cycloalkyl group, the C 3 -C 6 cycloalkyl group is preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.
  • R 1 and R 2 are hydrogen; R 3 is a substituted C 5 -C 10 aryl group or a substituted or unsubstituted a C 2 -C 6 heteroaryl group.
  • the quinazoline compound of formula I is preferably of formula I-a, formula I- b, a compound of the formula I-c, formula I-d, formula I-e, formula I-f, formula I-g, formula I-h, formula I-i, formula I-k;
  • R p1 , R p2 and R p3 are independently hydrogen, substituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 alkoxy or R 15 is a C 1 -C 4 alkyl group or R a9 and R a10 are independently hydrogen or a C 1 -C 4 alkyl group; R p1 , R p2 and R p3 are not simultaneously hydrogen;
  • R m1 is a C 1 -C 4 alkoxy group, a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, or Wherein R 6 is a C 1 -C 4 alkyl group or R a1 and R a2 are independently hydrogen, a substituted or unsubstituted C 1 -C 4 alkyl group or a C 5 -C 10 aryl group; R 9 is a substituted or unsubstituted C 1 -C 4 alkyl group;
  • R m2 , R m3 and R m4 are independently hydrogen, hydroxy, substituted or unsubstituted C 1 -C 4 alkoxy, C 2 -C 6 heterocycloalkyl, nitro, Wherein R 6 is a C 1 -C 4 alkyl group, a C 3 -C 6 cycloalkyl group or R a1 and R a2 are independently hydrogen or a substituted or unsubstituted C 1 -C 4 alkyl group; R 7 and R 8 are independently hydrogen, C 1 -C 4 alkyl, R a3 is a C 1 -C 4 alkyl group or a C 3 -C 6 cycloalkyl group; R a4 is a substituted or unsubstituted C 1 -C 4 alkyl group or a C 3 -C 6 cycloalkyl group; 9 is a substituted or unsubstituted C 1 -C 4 alkyl group;
  • R 5 is hydrogen or a substituted C 1 -C 4 alkyl group; in R 5 , the substitution described in the substituted C 1 -C 4 alkyl group means one or more (for example, 1-6 Substituted, preferably 1-2, substituted or unsubstituted C 2 -C 6 heteroaryl groups, said substituted C 2 -C 6 heteroaryl group referred to as one or more Substituted (for example, 1-6, preferably 1-2) cyano groups;
  • R p4 is hydrogen or halogen
  • R t1 is a substituted or unsubstituted C 1 -C 4 alkyl group or R 21 is a substituted or unsubstituted C 1 -C 4 alkyl group or R a11 and R a12 are independently a C 1 -C 4 alkyl group; when R 21 is a substituted C 1 -C 4 alkyl group, the substitution means one or more (for example, 1-6 , preferably 1-2) substituted by a cyano group; R m2 , R m3 and R m4 are not simultaneously hydrogen;
  • R t3 is a C 1 -C 4 alkyl group
  • R t2 is a substituted C 1 -C 4 alkyl group or O, and in R t2 , the substitution in the substituted C 1 -C 4 alkyl group is one or more (for example, 1-6 , preferably 1-2) substituted by halogen;
  • R m5 is a C 1 -C 4 alkyl group
  • R m6 is a substituted C 1 -C 4 alkyl group, a substituted or unsubstituted C 1 -C 4 alkoxy group, a C 2 -C 6 heterocycloalkyl group, a nitro group, Wherein R 6 is a C 1 -C 4 alkyl group, a C 3 -C 6 cycloalkyl group or R a1 and R a2 are independently hydrogen or a substituted or unsubstituted C 1 -C 4 alkyl group; R 7 and R 8 are independently hydrogen or R a4 is a substituted or unsubstituted C 1 -C 4 alkyl group; R 9 is a substituted or unsubstituted C 1 -C 4 alkyl group;
  • R p5 is hydrogen, nitro or substituted C 1 -C 4 alkyl
  • R t4 is a substituted or unsubstituted C 1 -C 4 alkyl group or R 21 is a substituted or unsubstituted C 1 -C 4 alkyl group; when R 21 is a substituted C 1 -C 4 alkyl group, the substitution means one or more (for example, 1-6 , preferably 1-2) substituted by a cyano group;
  • R m7 is Where R 6 is R 9 is a substituted C 1 -C 4 alkyl group.
  • R m8 is a C 1 -C 4 alkoxy group
  • R n1 and R n2 are independently hydrogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 2 -C 6 heterocycloalkyl or R 10 is a C 1 -C 4 alkyl group;
  • R t5 and R t6 are independently a substituted or unsubstituted C 1 -C 4 alkyl group or R 21 is a C 1 -C 4 alkyl group;
  • R t7 is C 1 -C 4 alkyl
  • R n3 is C 1 -C 4 alkoxy
  • R m9 is a C 1 -C 4 alkoxy group
  • R t8 and R t9 are independently hydrogen, hydroxy or C 2 -C 6 heterocycloalkyl; R m10 is C 1 -C 4 alkoxy;
  • the substitution in the substituted C 1 -C 4 alkyl group means one or more of the following substituents (for example, 1-6, Preferably 1-2) substituted: substituted or unsubstituted C 2 -C 6 heterocycloalkyl or R 16 and R 17 are independently a C 1 -C 4 alkyl group; the substitution described in the substituted C 2 -C 6 heterocycloalkyl group means one or more of the following substituents ( For example, 1-6, preferably 1-2) are substituted: C 1 -C 4 alkyl or R a11 is a C 1 -C 4 alkyl group;
  • the substitution described in the substituted C 1 -C 4 alkoxy group means one or more of the following substituents (for example, 1-6, preferably 1) -2) substituted: C 2 -C 6 heterocycloalkyl, C 1 -C 4 alkoxy, or R 18 is C 2 -C 6 heterocycloalkyl; R 19 and R 20 are independently C 1 -C 4 alkyl;
  • the substitution in the substituted C 1 -C 4 alkoxy group means one or more of the following substituents (for example, 1-6 , preferably 1-2) substituted: halogen (eg fluorine, chlorine, bromine or iodine, preferably fluorine), cyano, substituted or unsubstituted C 2 -C 6 heteroaryl, substituted or unsubstituted C 5 -C 10 aryl or C 2 -C 6 heterocycloalkyl; said substituted in the substituted C 2 -C 6 heteroaryl refers to one or more (eg 1-6 , preferably 1-2) substituted by a cyano group; said substitution in said substituted C 5 -C 10 aryl group means one or more (for example, 1-6, preferably 1-2) Substituted by a C 2 -C 6 heteroaryl group;
  • substituents for example, 1-6 , preferably 1-2
  • halogen eg fluorine, chlorine, bromine or i
  • the substitution in the substituted C 2 -C 6 heterocycloalkyl group means one or more (for example, 1-6, Preferably 1-2) C 1 -C 4 alkyl groups are substituted;
  • substitution in the substituted C 1 -C 4 alkyl group means substitution by one or more (for example, 1-6, preferably 1-2) cyano groups;
  • the substitution in the substituted C 1 -C 4 alkyl group means that it is substituted by one or more of the following substituents (for example, 1-6, preferably 1-2): a cyano group or a C 2 -C 6 heterocycloalkyl group;
  • R 9 in the substituted C 1 -C 4 alkyl group means substituted by one or more (for example, 1-6, preferably 1-2) cyano groups;
  • the substitution in the substituted C 1 -C 4 alkyl group means one or more of the following substituents (for example, 1-6, Preferably 1-2) are substituted: hydroxy, cyano, halogen, C 3 -C 6 cycloalkyl or substituted or unsubstituted C 1 -C 4 alkoxy; substituted C 1 -C
  • the substitution in the alkoxy group of 4 means that it is substituted by one or more (for example, 1-6, preferably 1-2) C 5 -C 10 aryl groups;
  • the substitution in the substituted C 1 -C 4 alkyl group means one or more of the following substituents (for example, 1-6, preferably 1-2). Substituted: cyano, C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 6 heteroaryl or substituted or unsubstituted C 5 -C 10 aryl; substituted
  • the substitution in the C 2 -C 6 heteroaryl group or the substituted C 5 -C 10 aryl group means one or more (for example, 1-6, preferably 1-2) halogens ( For example, fluorine, chlorine, bromine or iodine, preferably bromine or chlorine;
  • the substitution in the substituted C 2 -C 6 heterocycloalkyl group means one or more of the following substituents (for example, 1-6, preferably 1-2) Substituted: substituted C 1 -C 4 alkyl, or R 12 is a C 1 -C 4 alkyl group or a C 3 -C 6 cycloalkyl group; R 13 is a C 1 -C 4 alkyl group; said substituted C 1 -C 4 alkyl group Substituted refers to being substituted by one or more of the following substituents (eg, 1-6, preferably 1-2): cyano or
  • each group in R m1 to R m10 is substituted with the substituted C 5 -C 10 aryl group described in R 1 , R 2 or R 3 .
  • Definition of a group; each group of R n1 to R n3 is as defined for a substituent in a substituted C 2 -C 6 aryl group as described in R 1 , R 2 or R 3 ;
  • R p1 to R p5 The definition of each group is the same as the definition of the substituent in the substituted C 5 -C 10 aryl group described in R 4 or R 5 ;
  • the definition of each group in R t1 to R t9 is the same as R 4 or R a substituted or unsubstituted C 5 heterocycloalkyl claim 2 -C 6 substituted C 5 -C 10 aryl group substituted in the heterocyclyl a C 2 -C 6 alkyl group in the definition of substituent group.
  • R p1 , R p2 and R p3 are C 1 -C 4 alkoxy groups
  • R m1 is a C 1 -C 4 alkoxy group or R 6 is a C 1 -C 4 alkyl group
  • R p1 is When R 15 is a C 1 -C 4 alkyl group; R m1 is a C 1 -C 4 alkyl group;
  • R p1 and R p3 are hydrogen, R p2 is R 15 is Time;
  • R m1 is a substituted C 1 -C 4 alkoxy group or a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group; wherein R 6 is a C 1 -C 4 alkyl group;
  • R p1 is a substituted C 1 -C 4 alkyl group, and the substitution in the substituted C 1 -C 4 alkyl group is a substituted C 2 -C 6 Substituted by a heterocycloalkyl group, wherein the substitution in the substituted C 2 -C 6 heterocycloalkyl group is substituted by a C 1 -C 4 alkyl group; R m1 is R 6 is
  • R p1 and R p3 are hydrogen
  • R p2 is a substituted C 1 -C 4 alkyl group
  • the substituent in the substituted C 1 -C 4 alkyl group is a substituted C 2 -C 6 hetero a cycloalkyl group, wherein the substitution in the substituted C 2 -C 6 heterocycloalkyl group is substituted by a C 1 -C 4 alkyl group
  • R m1 is a C 1 -C 4 alkoxy group
  • R p1 is a substituted C 1 -C 4 alkyl group
  • the substituent in the substituted C 1 -C 4 alkyl group is a substituted C 2 -C 6 hetero a cycloalkyl group, the substitution described in the substituted C 2 -C 6 heterocycloalkyl group
  • R m1 is or Where R 6 is
  • R p1 is a substituted C 1 -C 4 alkyl group, and the substitution in the substituted C 1 -C 4 alkyl group is a C 2 -C 6 impurity When a cycloalkyl group is substituted; R m1 is or Where R 6 is R 9 is a substituted C 1 -C 4 alkyl group;
  • R p1 and R p3 are hydrogen and R p2 is a substituted C 1 -C 4 alkoxy group
  • R m1 is a C 1 -C 4 alkoxy group, Or a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, wherein R 6 is a C 1 -C 4 alkyl group
  • R p2 and R p3 are hydrogen and R p1 is a substituted C 1 -C 4 alkoxy group
  • R m1 is a C 1 -C 4 alkoxy group.
  • R 5 is hydrogen
  • R p4 is hydrogen
  • R t1 is a substituted or unsubstituted C 1 -C 4 alkyl group
  • R m3 and R m4 are hydrogen
  • R m2 is a substituted or unsubstituted C 1 -C 4 Alkoxy group
  • Nitro or Wherein R 6 is a C 1 -C 4 alkyl group or R 7 and R 8 are independently hydrogen, C 1 -C 4 alkyl
  • R a3 is a C 1 -C 4 alkyl group or a C 3 -C 6 cycloalkyl group
  • R a4 is a substituted or unsubstituted C 1 -C 4 alkyl group or a C 3 -C 6 cycloalkyl group
  • 9 is a substituted or unsubstituted C 1 -C 4 alkyl group
  • R p4 is hydrogen
  • R t1 is a substituted or unsubstituted C 1
  • R 5 is hydrogen
  • R p4 is hydrogen
  • R t1 is a substituted or unsubstituted C 1 -C 4 alkyl group
  • R m3 and R m4 are one hydrogen and the other C 1 -C 4 alkyl or In the case of halogen, the halogen is fluorine
  • R m2 is a C 1 -C 4 alkoxy group or a substituted C 1 -C 4 alkyl group
  • R 5 is hydrogen
  • R p4 is halogen
  • R t1 is a substituted or unsubstituted C 1 -C 4 alkyl group
  • R m3 and R m4 are hydrogen
  • R m2 is a C 1 -C 4 alkoxy group
  • R 5 is a substituted C 1 -C 4 alkyl group
  • R p4 is hydrogen
  • R t1 is a C 1 -C 4 alkyl group
  • R m3 and R m4 are hydrogen
  • R m2 is a hydroxyl group
  • R 5 is hydrogen
  • R p4 is hydrogen
  • R t1 is a substituted or unsubstituted C 1 -C 4 alkyl group
  • R m2 and R m4 are hydrogen
  • R m3 is a C 1 -C 4 alkoxy group or a heterocycloalkyl group of C 2 -C 6 ;
  • R 5 is hydrogen
  • R p4 is hydrogen and R t1 is R 21 is a C 1 -C 4 alkyl group
  • R m3 and R m4 are hydrogen
  • R m2 is
  • R 6 is a C 1 -C 4 alkyl group or R a1 and R a2 are independently hydrogen or a substituted or unsubstituted C 1 -C 4 alkyl group
  • R 7 and R 8 are independently hydrogen, C 1 -C 4 alkyl
  • R a3 is a C 1 -C 4 alkyl group
  • R a4 is a substituted or unsubstituted C 1 -C 4 alkyl group
  • R a4 is as defined in the substituted C 1 -C 4 alkyl group
  • Substituted means substituted by one or more (for example 1-6, preferably 1-2) cyano groups
  • R 9 is a substituted C 1 -C 4 alkyl group
  • R 9 is a substituted C 1
  • R 5 is hydrogen
  • R p4 is hydrogen and R t1 is R 21 is a substituted C 1 -C 4 alkyl group or
  • R m3 and R m4 are hydrogen, R m2 is a C 1 -C 4 alkoxy group.
  • R t4 is a substituted or unsubstituted C 1 -C 4 alkyl group
  • R m6 is a substituted or unsubstituted C 1 -C 4 alkoxy group, Wherein R 6 is a C 1 -C 4 alkyl group
  • R 7 and R 8 are independently hydrogen or R a4 is a substituted or unsubstituted C 1 -C 4 alkyl group
  • R 9 is a substituted or unsubstituted C 1 -C 4 alkyl group
  • R p5 is a nitro group or a substituted C 1 -C 4 alkyl group
  • R t4 is a substituted or unsubstituted C 1 -C 4 alkyl group
  • R m6 is a C 1 -C 4 alkoxy group
  • R t4 is When R 21 is a substituted or unsubstituted C 1 -C 4 alkyl group, R m6 is a C 1 -C 4 -substituted alkyl group, a C 1 -C 4 alkoxy group or a C 2 -C 6 heterocycloalkane.
  • base, R 7 and R 8 are independently hydrogen or R a4 is a substituted or unsubstituted C 1 -C 4 alkyl group; R 9 is a substituted C 1 -C 4 alkyl group.
  • the compound of formula I is any of the following compounds:
  • the present invention also provides the quinazoline compound of the above formula I, a pharmaceutically acceptable salt, solvate, metabolite, metabolic precursor or prodrug thereof, which can be commercially used
  • the available starting materials are synthesized by known methods, preferably including the following methods:
  • Method 1 under the protection of a gas, in a solvent, in the presence of a base, catalyzed by a palladium catalyst, a compound of the formula II and a compound of the formula III are subjected to a Suzuki coupling reaction as shown below.
  • a quinazoline compound of the formula I the solvent is an organic solvent or a mixed solvent of an organic solvent and water;
  • X 1 , X 2 and X 3 are independently halogen (for example, chlorine, bromine or iodine, preferably chlorine), and R 4 or R 5 are as defined above;
  • R S1 is R 1 , R 2 or R 3 , wherein R 1 , R 2 and R 3 are as defined above;
  • R sa1 is In the compounds of formula I, R 1 , R 2 , R 3 , R 4 and R 5 are as defined above;
  • R 1 , R 2 and R 3 are as defined above; in the compound III-a, X 4 is a halogen (for example, chlorine, bromine or iodine), and R s2 is R 4 .
  • halogen for example, chlorine, bromine or iodine
  • R 5 wherein R 4 and R 5 are a substituted or unsubstituted C 1 -C 4 alkyl group, a substituted or unsubstituted C 5 -C 10 aryl group or a substituted C 2 -C 6 heteroaryl group;
  • R 1 , R 2 , R 3 are as defined above, and R 4 and R 5 are independently hydrogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or Unsubstituted C 5 -C 10 aryl or substituted C 2 -C 6 heteroaryl;
  • Method 3 In an organic solvent, a compound represented by the formula II-a and a compound represented by the formula III-b are subjected to an acid halide reaction as shown below to obtain a quinazoline compound represented by the formula I;
  • R 1 , R 2 and R 3 are as defined above; in the compound III-b, X 5 is a halogen (e.g., fluorine, chlorine, bromine or iodine), R 0 Definitions as defined above; in the compounds of formula I, R 1 , R 2 and R 3 are as defined above, and R 4 and R 5 are independently hydrogen or Wherein, the definition of R 0 is as described above.
  • halogen e.g., fluorine, chlorine, bromine or iodine
  • the gas in the gas protection is preferably a gas which does not react with the compound as shown in the formula I, II or III, generally nitrogen and helium. And one or more of argon.
  • the organic solvent may be a conventional solvent for such a reaction in the art, as long as it is not reacted with a compound as shown in Formula I, II or III; preferably an amide solvent.
  • the ratio of the organic solvent to water may not be specifically limited, as long as the reaction does not affect the progress; the volume of the organic solvent and water is preferably 20 : 1-1:1, more preferably 19:1-9:1.
  • the amide solvent is preferably N,N-dimethylformamide and/or N-methylpyrrolidone.
  • the palladium catalyst can be a conventional palladium catalyst of this type in the art, preferably Pd(PPh 3 ) 4 and/or Pd(Pcy 3 ) 2 Cl 2 .
  • the base may be a conventional base for such reaction in the art, preferably one or more of potassium carbonate, cesium carbonate and cesium fluoride.
  • the base may be used in the form of an aqueous alkali solution when used.
  • the molar concentration of the aqueous alkali solution may not be specifically limited, and the purpose thereof is to facilitate the operation and has no substantial influence on the reaction.
  • the molar concentration of the aqueous alkali solution is preferably 1 M.
  • the amount of the compound of the formula II and the compound of the formula III may be a conventional amount for such a reaction in the art, preferably the compound of the formula II and the formula
  • the molar ratio of the compound is 1:1 to 1:1.5.
  • the amount of the base used may be a conventional amount for such a reaction in the art, and preferably the molar ratio of the compound of the formula II to the base is from 1:2 to 1:8.
  • the amount of the palladium catalyst used may be a conventional amount for such a reaction in the art, and preferably the molar ratio of the compound represented by the formula II to the palladium catalyst is preferably 1:0.01-1:0.1.
  • the amount of the solvent used may be a conventional amount for such a reaction in the art, and the volume of the solvent and the compound of the formula II is preferably 10 mg/L as long as the reaction is not affected. 50 mL / g.
  • the reaction temperature of the Suzuki coupling reaction may be a conventional temperature for such a reaction in the art, preferably from 90 to 150 ° C, more preferably from 100 to 110 ° C.
  • the progress of the Suzuki coupling reaction can be monitored according to conventional test methods in the art (such as TLC, GC, HPLC or NMR), generally as the end point of the reaction when the compound as shown in Formula II disappears, the reaction
  • the time is preferably from 6 to 50 hours.
  • the gas in the gas protection is preferably a gas which does not react with the compound represented by the formula I, II or III, generally nitrogen, helium or argon. gas.
  • the organic solvent may be a conventional solvent for such a reaction in the art, as long as it is not reacted with a compound as shown in Formula I, II-a or III-a; preferably an ether solvent.
  • the ether solvent is preferably dioxane.
  • the palladium catalyst may be a conventional palladium catalyst of this type in the art, preferably Pd(dba) 2 (tris(dibenzylideneacetone)dipalladium).
  • the ligand may be a conventional ligand for such reactions in the art, preferably 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (Xantphos).
  • the base may be a conventional base for such reactions in the art, preferably potassium carbonate and/or cesium carbonate.
  • the amount of the compound of the formula II-a and the compound of the formula III-a may be a conventional amount for such a reaction in the art, preferably the compound of the formula II-a.
  • the molar ratio to the compound as shown in formula III-a is from 1:1 to 1:0.5.
  • the amount of the base used may be a conventional amount for such a reaction in the art, and preferably the molar ratio of the compound of the formula II to the base is from 1:1 to 1:2.
  • the amount of the palladium catalyst used may be a conventional amount for such a reaction in the art.
  • the molar ratio of the compound represented by the formula II-a to the palladium catalyst is preferably 1:0.01-1. :0.5.
  • the amount of the organic solvent used may be a conventional amount for such a reaction in the art, and the volume of the organic solvent and the compound of the formula II is preferably 10 mg/m. as long as the reaction is not affected. L ⁇ 50mL / g.
  • the reaction temperature of the substitution reaction may be a conventional temperature for such a reaction in the art, preferably from 80 to 120 °C.
  • the progress of the substitution reaction can be monitored according to conventional test methods in the art (such as TLC, GC, HPLC or NMR), generally as the end point of the reaction when the compound as shown in formula II-a disappears, the reaction
  • the time is preferably from 6 to 20 hours.
  • the method and conditions of the acid halide reaction may be conventional methods and conditions for such reactions in the art, and preferably include the following steps: after mixing the compound of the formula II-a with an organic solvent, The acid halide reaction is carried out by adding a compound represented by the formula III-b at -5 to 0 °C.
  • the organic solvent may be a conventional solvent for such a reaction in the art, preferably a nitrogen-containing aromatic hydrocarbon solvent.
  • the nitrogen-containing aromatic hydrocarbon solvent is preferably pyridine.
  • the amount of the compound of the formula II-a and the compound of the formula III-b may be a conventional amount for such a reaction in the art, preferably the compound of the formula II-a.
  • the molar ratio to the compound as shown in formula III-b is from 1:1 to 1:1.2.
  • the amount of the organic solvent used may be a conventional amount for such a reaction in the art, and the volume of the organic solvent and the compound of the formula II is preferably 1 mg/m. as long as the reaction is not affected. L ⁇ 10mL / g.
  • the reaction temperature of the acid halide reaction may be a conventional temperature for such a reaction in the art, preferably 10 to 30 °C.
  • the progress of the acid halide reaction can be monitored according to conventional test methods in the art (e.g., TLC, GC, HPLC or NMR), generally as the end of the reaction when the compound as shown in formula II-a disappears, the reaction
  • the time is preferably from 1 to 2.5 hours.
  • the present invention also provides an intermediate compound of the quinazoline compound represented by Formula I as shown in Formula II or II-a:
  • X 1 , X 2 and X 3 are independently halogen (for example chlorine, bromine or iodine, preferably chlorine); R 4 and R 5 are as defined above; in compound II-a, R 1 , The definitions of R 2 and R 3 are as described above.
  • the present invention also provides a quinazoline compound of the formula I, one or more of which are pharmaceutically acceptable salts, solvates, metabolites, metabolic precursors and prodrugs, which are prepared for use in the preparation.
  • a medicament for the prevention and/or treatment (adjuvant therapy) of a disease associated with the expression or activity of JAK generally include autoimmune diseases and/or hematopoietic malignancies.
  • the autoimmune diseases include rheumatoid arthritis (RA), systemic Lupus Erythematosus, and Psoriatic/Psoriasis.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a quinazoline compound of the formula I, a pharmaceutically acceptable salt, solvate, metabolite, metabolic precursor and prodrug thereof One or more of them, and one or more pharmaceutically acceptable carriers and/or diluents thereof.
  • the carrier and the diluent may be conventional carriers and diluents in the pharmaceutical compositions of the art.
  • the pharmaceutical composition of the present invention may be in a form suitable for oral administration or in the form of a sterile injectable aqueous solution, and the oral or injectable composition may be prepared according to any method known in the art for preparing a pharmaceutical composition.
  • terapéuticaally effective amount refers to an amount of a compound that is sufficient to effectively treat a disease or condition described herein when administered to a subject. While the amount of the compound that constitutes a “therapeutically effective amount” will vary depending on the compound, the condition and its severity, and the age of the subject to be treated, it can be determined in a conventional manner by those skilled in the art.
  • salt pharmaceutical composition, composition, adjuvant, etc.
  • pharmaceutically acceptable it is meant that the salt, pharmaceutical composition, composition, excipient, etc. are generally non-toxic, safe, and Suitable for use by a subject, preferably a mammalian subject, more preferably a human subject.
  • salts refers to a pharmaceutically acceptable organic or inorganic salt of a compound of the invention.
  • exemplary salts include, but are not limited to, sulfates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, hydrogen sulfates, phosphates, acid phosphates, isonicotinic acid Salt, lactate, salicylate, acid citrate, tartrate, oleate, tannic acid, pantothenate, hydrogen tartrate, ascorbate, succinate, maleate, dragon Gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methane sulfonate, ethane sulfonic acid Salt, besylate, p-toluenesulfonate and pamoate (i.e., 1-1-methylene-bis(
  • solvate refers to a crystalline form of a compound of the invention which further comprises one or more solvent molecules incorporated into the crystal structure.
  • Solvates may include stoichiometric or non-stoichiometric solvents, and Solvent molecules in the solvent may exist in an ordered or non-ordered arrangement.
  • Solvates containing non-stoichiometric solvent molecules may be obtained by solvating at least one, but not all, solvent molecules.
  • a solvate is a hydrate, meaning that the crystalline form of the compound further comprises water molecules with water molecules as a solvent.
  • prodrug refers to a compound obtained by chemically modifying a compound of the present invention which is inactive or less active in vitro and which exhibits pharmacological effects by enzymatic or non-enzymatic conversion of the active compound in vivo. .
  • the term "subject” refers to any animal that is or has been administered a compound or pharmaceutical composition according to an embodiment of the invention, which is superior to mammals and optimal for humans.
  • the term "mammal” as used herein includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., which are optimal for humans.
  • treating refers to the improvement, prevention, or reversal of a disease or condition, or at least one discernible symptom thereof.
  • “treating” or “treating” refers to an improvement, prevention or reversal of at least one measurable physical parameter of a disease or condition being treated, which may not be recognized in a mammal.
  • “treating” or “treating” refers to slowing the progression of a disease or condition, or physical, such as the identification of stable symptoms, or physiological, for example, stabilization of body parameters. , or both.
  • “treating” or “treating” refers to delaying the onset of a disease or condition.
  • the compounds of the invention are administered as a prophylactic measure.
  • preventing or “preventing” refers to reducing the risk of obtaining a given disease or condition.
  • the indicated compound is administered to the subject as a preventive measure, such as a subject having a family history or predisposition to cancer or an autoimmune disease.
  • the reagents and starting materials used in the present invention are commercially available.
  • the present invention provides a quinazoline compound which is completely different from the prior art, a process for the preparation thereof, a pharmaceutical composition and an application.
  • the quinazoline compound of the present invention has a good inhibitory effect on protein kinase JAK, and can be used for the preparation of a medicament for preventing, treating or adjuvant treatment of various diseases related to the expression or activity of JAK, particularly tumor diseases and immune diseases.
  • the raw material 2-chloro-6-fluorobenzaldehyde (3.02 g, 19.1 mmol) was dissolved in 10 mL of DMAC, and cesium carbonate (4 eq) was added thereto, and the mixture was heated to 140 ° C and stirred for 3 hours.
  • the TLC was monitored for no material remaining, heating was stopped, cooled to room temperature, 100 mL of water was added and the mixture was cooled overnight at 0 °C. After suction filtration, the crude product was crystallised from methylene chloride.
  • Example 2 and Example 3 were prepared by reacting the intermediates (1-3) with different boronic acids or boronic esters in the same manner as in Example 1.
  • the specific experimental data are shown in Table 1.
  • Example 5 The compounds of Example 5 and Example 6 were prepared in the same manner as in Example 4, using the intermediate (4-1) with a different boronic acid or boronic acid ester.
  • the specific experimental data are shown in Table 2.
  • the TLC monitored no material remaining, the heating was stopped, the temperature was cooled to room temperature, 100 mL of water was added, and the mixture was cooled at 0 ° C overnight and then suction filtered.
  • the solid was recrystallized from methylene chloride to afford product (9-2). Melting point: 202-204 ° C.
  • Example 10 and Example 11 were prepared in the same manner as in Example 9 except that the intermediate (9-3) was combined with a different boronic acid or boronic acid ester.
  • Example 14 In the same manner as in Example 12, the intermediate (9-2) was first subjected to a substitution reaction with a different halogenated product, and then with different boronic acids or boric acid esters, the compounds of Examples 14 to 18 were prepared. Table 4.
  • Example 19 In the same manner as in Example 19, the intermediate (19-2) was subjected to a substitution reaction with a different halogenated substance, and then reacted with a different boronic acid or a boronic acid ester to prepare the compounds of Examples 20 to 180, and the specific experiment was carried out.
  • the data is shown in Table 5.
  • Example 181 8-(4-(Methoxy)phenyl)-N-(3-(4-ethylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 181)
  • Example 182 In the same manner as in Example 181, starting material 19-2 was first subjected to a Suzuki coupling reaction with a different boronic acid or boronic ester to give 181-2 analog, and then substituted with a different substituent for the amino hydrogen on the quinazoline.
  • the compounds of Examples 182 to 215 were prepared, and the specific experimental data are shown in Table 6.
  • Example 216 8-(1H-pyrazol-4-yl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 216)
  • Example 217 3-Cyclopentyl-3-(4-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-1H- Pyrazole -1-yl)propionitrile (compound 217)
  • Example 216 Following the similar synthetic procedure of Example 216 and Example 217, the aminohydrogen on the intermediate 19-2 quinazoline was replaced with various bromobenzenes, followed by the 1-tert-butoxycarbonyl-4-boronic acid pinacol ester-
  • the compound 216 analog was prepared by Suzuki coupling reaction of 1H-pyrazole, and finally the pyrazole cyclic amino hydrogen was substituted, and the compounds of Examples 218 to 232 were prepared.
  • the specific experimental data are shown in Table 7.
  • Example 235 1-Methyl-4-(3-((8-(4-methoxyphenyl)quinazolin-2-yl)amino)phenyl)-1-ethylpiperazine ammonium bromide (Compound 235)
  • Example 236 8-(4-(Methoxy)phenyl)-N-(3-(4-methyl-4-oxypiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 236)
  • Example 237 8-(4-(Methoxy)phenyl)-N-((2-(4-methylpiperazin-1-yl)acetamide))quinazolin-2-amine (Compound 237 )
  • Step 1 Preparation of 8-(4-methoxyphenyl)-N-(3-bromophenyl)quinazolin-2-amine (239-1)
  • Step 2 Preparation of 8-(4-methoxyphenyl)-Nmethyl-(3-bromophenyl)quinazolin-2-amine. (239-2)
  • Step 3 Preparation of 8-(4-methoxyphenyl)-N-methyl-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine (239)
  • Example 240 8-(4-Hydroxyphenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-N-(6-cyanomethylpyridin-3-yl) Quinazoline-2-amine (compound 240)
  • N-ethyl-4-bromobenzenesulfonamide (5b): Take a 25 mL round bottom flask and add 12 ml of LDCM, 4-bromobenzenesulfonyl chloride (1.5 g, 5.9 mmol), ethylamine hydrochloride, with stirring in an ice water bath. (2.5g, 29mmol), DIPEA 6.6mL; remove the ice water bath, and warm to room temperature for 2.5h; TLC monitoring the reaction is complete, stop the reaction. The mixture was extracted with DCM (60 mL, 40 mL). : 1-4:1 v/v) The title compound was obtained as a white solid (yield: 1.47 g, 95%).
  • N-ethyl-4-boronic acid pinacol ester benzenesulfonamide (6b): To a round bottom flask was added DMSO 40 mL, N-ethyl-4-bromobenzenesulfonamide (2.62 g, 10 mmol). Bornyl borate (3.04g, 12mmol), KOAc (2.94g, 30mmol), Pd(dppf)Cl 2 (234mg, 0.032mmol), heated at 100 ° C for 12 h under nitrogen, the reaction was completely monitored by TLC.
  • reaction was incomplete by TLC, and then added 6b (105 mg, 0.34 mmol), CsF (68 mg, 0.45 mmol), Pd(PCy 2 ) 2 Cl 2 (16 mg, 0.045 mmol), continue After 12 h of reaction, there was still a small amount of raw material remaining in the TLC monitoring reaction, but the product was obviously stopped. The reaction was terminated, and the temperature was lowered to room temperature. The mixture was filtered, and the filtrate was added with water (30 mL), DCM (30 mL, 20 mL), and the organic phase was washed with water (20 mL ⁇ 3). Washed with brine (10 mL), EtOAc (EtOAc m.
  • N-phenyl-4-(2-((3-methylsulfonyl)phenyl)amino)quinazolin-8-yl)benzenesulfonamide (7f): NMP:H was added sequentially to a round bottom flask 2 O 9:1 (2 mL), 6f (162 mg, 0.45 mmol H 2 O), 3 (100 mg, 0.3 mmol), CsF (91 mg, 0.6 mmol), Pd(PCy 2 ) 2 Cl 2 (22 mg, 0.03 mmol) The reaction was heated at 140 ° C for 45 h under nitrogen atmosphere. The reaction was incomplete by TLC, but the product was spotted, and the reaction was terminated.
  • NMP N-tert-butyl-4-(2-((3-methylsulfonyl)phenyl)amino)quinazolin-8-yl)benzenesulfonamide
  • IC 50 values expressed kinase inhibitory activity.
  • the inhibitory effect of the compound on JAK1 kinase was determined by Homogeneous Time-Resolved Fluorescence (HTRF) technique. JAK1 was purchased from Invitrogen (Cat. No. PV4774), ATP was purchased from Sigma-Aldrich (Cat. No. A7699), HTRF kinEASE-TK kit (Cat. No. 62TK0PEC) and related components, purchased from Cisbio Bioassays; other conventional chemicals were purchased from Sinopharm Group Chemical Reagent Co., Ltd.
  • HTRF Homogeneous Time-Resolved Fluorescence
  • the test method was carried out according to the product specification.
  • the general procedure was as follows: The compound was formulated into a 10 mM solution using DMSO, and then the sample was formulated into a 5 ⁇ compound using 1 ⁇ reaction buffer and DMSO. In this experiment, the compound was diluted into 10 concentrations by a 3-fold gradient dilution method. Then transfer 2 ul of 5 ⁇ compound to a 384-well plate, and mix the kinase, substrate (TK Substrate-biotin) and ATP into a 2.5 ⁇ enzyme/substrate mixture and a 2.5 ⁇ ATP solution, respectively, using 1 ⁇ reaction buffer.

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Abstract

Disclosed are a quinazoline compound, intermediate, preparation method, pharmaceutical composition and use thereof. The quinazoline compound of the present invention has a good inhibitory effect on the protein kinase JAK, and can be used for the preparation of a medicine for the prevention, treatment or adjuvant treatment of a variety of diseases associated with the expression or activity of JAK, in particular tumour diseases and immune diseases.

Description

喹唑啉类化合物、其中间体、制备方法、药物组合物和应用Quinazoline compound, intermediate thereof, preparation method, pharmaceutical composition and application
本申请要求申请日为2015年7月3日的中国专利申请CN201510390298.6的优先权。本申请引用上述中国专利申请的全文。The present application claims priority from Chinese Patent Application No. CN201510390298.6, filed on July 3, 2015. This application cites the entire text of the above-mentioned Chinese patent application.
技术领域Technical field
本发明涉及一种喹唑啉类化合物、其中间体、制备方法、药物组合物和应用。The present invention relates to a quinazoline compound, an intermediate thereof, a preparation method, a pharmaceutical composition and use.
背景技术Background technique
小分子JAK抑制剂的开发，目前主要集中在自身免疫系统疾病与造血系统恶性肿瘤两大疾病领域：自身免疫性疾病包括类风湿性关节炎(RA)、系统性红斑狼疮(Systemic Lupus Erythematosus)、银屑病(Psoriatic/Psoriasis)等多种疾病，阿达木单抗2013一年的销售额为106.59亿美元显示着这一疾病领域的巨大市场前景。当前此类疾病的主要治疗药物是传统的DMARD药物、治疗性抗体，以及小分子靶向药物，这其中的小分子靶向性药物主要是JAK抑制剂。曾有分析人士指出，JAK抑制剂将成为2022年前RA药物市场增长的主要驱动力。因此，开发出对蛋白激酶JAK有良好地抑制效果的化合物成为药物化学领域研究的热点。The development of small-molecule JAK inhibitors is currently concentrated in the two major diseases of autoimmune diseases and hematopoietic malignancies: autoimmune diseases including rheumatoid arthritis (RA), systemic lupus Erythematosus, With a variety of diseases such as Psoriatic/Psoriasis, sales of adalimumab in 2013 was $10,659 million, indicating a huge market prospect in this disease area. The main therapeutic drugs for such diseases are traditional DMARD drugs, therapeutic antibodies, and small molecule targeted drugs, among which small molecule targeting drugs are mainly JAK inhibitors. Some analysts have pointed out that JAK inhibitors will become the main driving force for the growth of the RA drug market by 2022. Therefore, the development of a compound which has a good inhibitory effect on protein kinase JAK has become a hot spot in the field of medicinal chemistry.
发明内容Summary of the invention
本发明所要解决的技术问题是提供了一种与现有技术完全不同的喹唑啉类化合物、其中间体、制备方法、药物组合物和应用。本发明的喹唑啉类化合物对蛋白激酶JAK有良好地抑制效果，可以用于制备预防、治疗或辅助治疗与JAK的表达或活性有关的多种疾病，尤其是肿瘤疾病和免疫疾病的药物。The technical problem to be solved by the present invention is to provide a quinazoline compound, an intermediate thereof, a preparation method, a pharmaceutical composition and an application which are completely different from the prior art. The quinazoline compound of the present invention has a good inhibitory effect on protein kinase JAK, and can be used for the preparation of a medicament for preventing, treating or adjuvant treatment of various diseases related to the expression or activity of JAK, particularly tumor diseases and immune diseases.
本发明提供了一种通式I所示的喹唑啉类化合物，其药学上可接受的盐、溶剂化物、代谢产物、代谢前体或药物前体；The present invention provides a quinazoline compound of the formula I, a pharmaceutically acceptable salt, solvate, metabolite, metabolic precursor or prodrug thereof;
Figure PCTCN2016088089-appb-000001
Figure PCTCN2016088089-appb-000001
R1、R2和R3独立地为氢、取代的C5-C10的芳基、取代或未取代的C2-C6的杂芳基或者C2-C6的杂环烷基；其中，R1、R2和R3不同时为氢；R 1 , R 2 and R 3 are independently hydrogen, substituted C 5 -C 10 aryl, substituted or unsubstituted C 2 -C 6 heteroaryl or C 2 -C 6 heterocycloalkyl; Wherein R 1 , R 2 and R 3 are not hydrogen at the same time;
R4和R5独立地为氢、取代或未取代的C1-C4的烷基、取代或未取代的C5-C10的芳基、 取代的C2-C6的杂芳基或者
Figure PCTCN2016088089-appb-000002
R0为取代的C1-C4的烷基或者C3-C6的环烷基；当R0为取代的C1-C4的烷基时，所述的取代的C1-C4的烷基中所述的取代是指被一个或多个(例如1-6个，优选1-2个)取代或未取代的C2-C6的杂环烷基所取代；所述的取代的C2-C6的杂环烷基中所述的取代是指被一个或多个(例如1-6个，优选1-2个)C1-C4的烷基(所述的C1-C4的烷基较佳地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基)所取代；当R4和R5同时为氢时，R1不为氢；R 4 and R 5 are independently hydrogen, a substituted or unsubstituted C 1 -C 4 alkyl group, a substituted or unsubstituted C 5 -C 10 aryl group, a substituted C 2 -C 6 heteroaryl group or
Figure PCTCN2016088089-appb-000002
R 0 is a substituted C 1 -C 4 alkyl group or a C 3 -C 6 cycloalkyl group; when R 0 is a substituted C 1 -C 4 alkyl group, the substituted C 1 -C 4 The substitution in the alkyl group means that it is substituted by one or more (for example, 1-6, preferably 1-2) substituted or unsubstituted C 2 -C 6 heterocycloalkyl groups; The substitution in the C 2 -C 6 heterocycloalkyl group means one or more (for example, 1-6, preferably 1-2) C 1 -C 4 alkyl groups (described C 1 -C 4 alkyl is preferably substituted with methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or t-butyl; when R 4 and R 5 are simultaneously hydrogen, R 1 is not hydrogen;
R1、R2或R3中，所述的取代的C5-C10的芳基中所述的取代是指被下列取代基(Rm)中的一个或多个(例如1-6个，优选1-3个)所取代：羟基、卤素、取代或未取代的C1-C4的烷基、取代或未取代的C1-C4的烷氧基、取代或未取代的C2-C6的杂环烷基、硝基、
Figure PCTCN2016088089-appb-000003
Figure PCTCN2016088089-appb-000004
其中R6为C1-C4的烷基、C3-C6的环烷基或者
Figure PCTCN2016088089-appb-000005
Ra1和Ra2独立地为氢、取代或未取代的C1-C4的烷基或C5-C10的芳基；R7和R8独立地为氢、C1-C4的烷基、
Figure PCTCN2016088089-appb-000006
Ra3为C1-C4的烷基或者C3-C6的环烷基；Ra4为取代或未取代的C1-C4的烷基、C3-C6的环烷基或者C2-C6的杂芳基；R9为取代或未取代的C1-C4的烷基；In R 1 , R 2 or R 3 , the substitution described in the substituted C 5 -C 10 aryl group means one or more of the following substituents (R m ) (for example, 1-6 , preferably 1-3) substituted: hydroxy, halogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 alkoxy, substituted or unsubstituted C 2 -C 6 heterocycloalkyl, nitro,
Figure PCTCN2016088089-appb-000003
Figure PCTCN2016088089-appb-000004
Wherein R 6 is a C 1 -C 4 alkyl group, a C 3 -C 6 cycloalkyl group or
Figure PCTCN2016088089-appb-000005
R a1 and R a2 are independently hydrogen, substituted or unsubstituted C 1 -C 4 alkyl or C 5 -C 10 aryl; R 7 and R 8 are independently hydrogen, C 1 -C 4 alkane base,
Figure PCTCN2016088089-appb-000006
R a3 is a C 1 -C 4 alkyl group or a C 3 -C 6 cycloalkyl group; R a4 is a substituted or unsubstituted C 1 -C 4 alkyl group, a C 3 -C 6 cycloalkyl group or C a heteroaryl group of 2 -C 6 ; R 9 is a substituted or unsubstituted C 1 -C 4 alkyl group;
R1、R2或R3中，当所述的取代的C5-C10的芳基为取代的苯基
Figure PCTCN2016088089-appb-000007
所述的取代为单取代时，所述的取代基位于苯环的间位或对位，其中，当所述的取代基位于苯环的间位时，所述的取代基为取代或未取代的C1-C4的烷氧基、取代或未取代的C2-C6的杂环烷基、
Figure PCTCN2016088089-appb-000008
In R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is a substituted phenyl group
Figure PCTCN2016088089-appb-000007
When the substitution is monosubstituted, the substituent is located at the meta or para position of the benzene ring, wherein when the substituent is located at the meta position of the benzene ring, the substituent is substituted or unsubstituted. a C 1 -C 4 alkoxy group, a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group,
Figure PCTCN2016088089-appb-000008
R1、R2或R3中，当所述的取代的C5-C10的芳基为取代的苯基
Figure PCTCN2016088089-appb-000009
所述的取代为双取代或三取代时，所述的取代基位于苯环的间位和对位，或者邻位和对位；所述的取代基优选卤素和取代或未取代的C1-C4的烷基、卤素和取代或未取代的C1-C4的烷氧基，或者取代或未取代的C1-C4的烷基和未取代的C1-C4的烷氧基； In R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is a substituted phenyl group
Figure PCTCN2016088089-appb-000009
When the substitution is a di- or tri-substitution, the substituent is located at the meta and para positions of the phenyl ring, or the ortho and para positions; the substituent is preferably a halogen and a substituted or unsubstituted C 1 - An alkyl group of C 4 , a halogen and a substituted or unsubstituted C 1 -C 4 alkoxy group, or a substituted or unsubstituted C 1 -C 4 alkyl group and an unsubstituted C 1 -C 4 alkoxy group ;
R1、R2或R3中，所述的取代的C2-C6的杂芳基中所述的取代是指被下列取代基(Rn)中的一个或多个(例如1-6个，优选1-2个)所取代：C1-C4的烷氧基、取代或未取代的C1-C4的烷基、取代或未取代的C2-C6的杂环烷基、
Figure PCTCN2016088089-appb-000010
R10为C1-C4的烷基；R11为
Figure PCTCN2016088089-appb-000011
Ra5和Ra6独立地为C1-C4的烷基；In R 1 , R 2 or R 3 , the substitution in the substituted C 2 -C 6 heteroaryl group means one or more of the following substituents (R n ) (for example, 1-6 Substituted, preferably 1-2) substituted: C 1 -C 4 alkoxy, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 2 -C 6 heterocycloalkyl ,
Figure PCTCN2016088089-appb-000010
R 10 is a C 1 -C 4 alkyl group; R 11 is
Figure PCTCN2016088089-appb-000011
R a5 and R a6 are independently C 1 -C 4 alkyl;
R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷基所取代时，所述的取代的C1-C4的烷基中所述的取代是指被一个或多个(例如1-6个，优选1-2个)取代或未取代的C2-C6的杂环烷基所取代；所述的取代的C2-C6的杂环烷基中所述的取代是指被一个或多个(例如1-6个，优选1-2个)C1-C4的烷基所取代；In R 1 , R 2 or R 3 , when the substitution in the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group, The substitution in the substituted C 1 -C 4 alkyl group means a C 2 -C 6 heterocycloalkane substituted or unsubstituted by one or more (for example, 1-6, preferably 1-2). Substituted; said substitution in said substituted C 2 -C 6 heterocycloalkyl means one or more (for example 1-6, preferably 1-2) C 1 -C 4 Substituted by an alkyl group;
R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷氧基所取代时，所述的取代的C1-C4的烷氧基中所述的取代是指被下列取代基中的一个或多个(例如1-6个，优选1-2个)所取代：卤素(例如氟、氯、溴或碘，优选氟)、氰基、取代或未取代的C2-C6的杂芳基、取代或未取代的C5-C10的芳基或者C2-C6的杂环烷基；所述的取代的C2-C6的杂芳基中所述的取代是指被一个或多个(例如1-6个，优选1-2个)氰基所取代；所述的取代的C5-C10的芳基中所述的取代是指被一个或多个(例如1-6个，优选1-2个)C2-C6的杂芳基所取代；In R 1 , R 2 or R 3 , when the substitution described in the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkoxy group, The substitution described in the substituted C 1 -C 4 alkoxy group means that it is substituted by one or more of the following substituents (for example, 1-6, preferably 1-2): halogen (for example, fluorine) , chlorine, bromine or iodine, preferably fluorine), cyano, substituted or unsubstituted C 2 -C 6 heteroaryl, substituted or unsubstituted C 5 -C 10 aryl or C 2 -C 6 hetero a cycloalkyl group; said substitution in said substituted C 2 -C 6 heteroaryl group means substituted by one or more (for example, 1-6, preferably 1-2) cyano groups; Substituted in the substituted C 5 -C 10 aryl group means substituted by one or more (for example 1-6, preferably 1-2) C 2 -C 6 heteroaryl groups;
R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代时，所述的取代的C2-C6的杂环烷基中所述的取代是指被一个或多个(例如1-6个，优选1-2个)C1-C4的烷基所取代；In R 1 , R 2 or R 3 , when the substitution described in the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, The substitution in the substituted C 2 -C 6 heterocycloalkyl group means that it is substituted by one or more (for example, 1-6, preferably 1-2) C 1 -C 4 alkyl groups. ;
R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被
Figure PCTCN2016088089-appb-000012
所取代，R6为
Figure PCTCN2016088089-appb-000013
Ra1和Ra2独立地为取代或未取代的C1-C4的烷基时，所述的取代的C1-C4的烷基中所述的取代是指被一个或多个(例如1-6个，优选1-2个)氰基所取代；In R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is substituted as described
Figure PCTCN2016088089-appb-000012
Substituted, R 6 is
Figure PCTCN2016088089-appb-000013
When R a1 and R a2 are independently a substituted or unsubstituted C 1 -C 4 alkyl group, the substitution in the substituted C 1 -C 4 alkyl group means one or more (for example) 1-6, preferably 1-2) substituted by a cyano group;
R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被
Figure PCTCN2016088089-appb-000014
所取代，R7和R8独立地为
Figure PCTCN2016088089-appb-000015
Ra4为取代或未取代的C1-C4的烷基时，所述的取代的C1-C4的烷基中所述的取代是指被下列取代基中的一个或多个(例如1-6个，优选1-2个)所取代： 氰基或者C2-C6的杂环烷基；In R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is substituted as described
Figure PCTCN2016088089-appb-000014
Substituted, R 7 and R 8 are independently
Figure PCTCN2016088089-appb-000015
When R a4 is a substituted or unsubstituted C 1 -C 4 alkyl group, the substitution described in the substituted C 1 -C 4 alkyl group means one or more of the following substituents (for example) 1-6, preferably 1-2) substituted: cyano or C 2 -C 6 heterocycloalkyl;
R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被
Figure PCTCN2016088089-appb-000016
所取代，R9为取代或未取代的C1-C4的烷基时；所述的取代的C1-C4的烷基中所述的取代是指被一个或多个(例如1-6个，优选1-2个)氰基所取代；In R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is substituted as described
Figure PCTCN2016088089-appb-000016
Substituted, when R 9 is a substituted or unsubstituted C 1 -C 4 alkyl group; the substitution described in the substituted C 1 -C 4 alkyl group means one or more (for example, 1- 6 (preferably 1-2) substituted with a cyano group;
R1、R2或R3中，当所述的取代的C2-C6的杂芳基中所述的取代为被取代或未取代的C1-C4的烷基所取代时，所述的取代的C1-C4的烷基中所述的取代是指被下列取代基中的一个或多个(例如1-6个，优选1-2个)所取代：氰基、C3-C6的环烷基、取代或未取代的C2-C6的杂芳基或者取代或未取代的C5-C10的芳基；所述的取代的C2-C6的杂芳基或所述的取代的C5-C10的芳基中所述的取代是指被一个或多个(例如1-6个，优选1-2个)卤素(例如氟、氯、溴或碘，优选溴或氯)所取代；In R 1 , R 2 or R 3 , when the substitution described in the substituted C 2 -C 6 heteroaryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group, The substitution described in the substituted C 1 -C 4 alkyl group means that it is substituted by one or more of the following substituents (for example, 1-6, preferably 1-2): cyano, C 3 a C 6 cycloalkyl group, a substituted or unsubstituted C 2 -C 6 heteroaryl group or a substituted or unsubstituted C 5 -C 10 aryl group; said substituted C 2 -C 6 heteroaryl group The substituent referred to in the substituted C 5 -C 10 aryl group means one or more (for example, 1-6, preferably 1-2) halogens (for example, fluorine, chlorine, bromine or iodine). Substituted by bromine or chlorine);
R1、R2或R3中，当所述的取代的C2-C6的杂芳基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代时，所述的取代的C2-C6的杂环烷基中所述的取代是指被下列取代基中的一个或多个(例如1-6个，优选1-2个)所取代：取代的C1-C4的烷基、
Figure PCTCN2016088089-appb-000017
或者
Figure PCTCN2016088089-appb-000018
R12为C1-C4的烷基或C3-C6的环烷基；R13为C1-C4的烷基；所述的取代的C1-C4的烷基中所述的取代是指被下列取代基中的一个或多个(例如1-6个，优选1-2个)所取代：氰基或
Figure PCTCN2016088089-appb-000019
In R 1 , R 2 or R 3 , when the substitution described in the substituted C 2 -C 6 heteroaryl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group The substitution in the substituted C 2 -C 6 heterocycloalkyl group means that it is substituted by one or more of the following substituents (for example, 1-6, preferably 1-2): C 1 -C 4 alkyl group,
Figure PCTCN2016088089-appb-000017
or
Figure PCTCN2016088089-appb-000018
R 12 is a C 1 -C 4 alkyl group or a C 3 -C 6 cycloalkyl group; R 13 is a C 1 -C 4 alkyl group; said substituted C 1 -C 4 alkyl group Substituted refers to being substituted by one or more of the following substituents (eg, 1-6, preferably 1-2): cyano or
Figure PCTCN2016088089-appb-000019
R4或R5中，所述的取代的C1-C4的烷基中所述的取代是指被一个或多个(例如1-6个，优选1-2个)取代或未取代的C2-C6的杂芳基所取代，所述的取代的C2-C6的杂芳基中所述的取代是指被一个或多个(例如1-6个，优选1-2个)氰基所取代；In R 4 or R 5 , the substitution described in the substituted C 1 -C 4 alkyl group means substituted or unsubstituted by one or more (for example, 1-6, preferably 1-2). heteroaryl C 2 -C 6 aryl group being unsubstituted, a substituted aryl substituted heteroaryl C 2 -C 6 group of said means with one or more (e.g., 1-6, preferably 1-2 Substituted by a cyano group;
R4或R5中，所述的取代的C5-C10的芳基中所述的取代(Rp)是指被下列取代基中的一个或多个(例如1-6个，优选1-2个)所取代：卤素(例如氟、氯、溴或碘，优选氯)、硝基、取代或未取代的C1-C4的烷基、取代或未取代的C1-C4的烷氧基、取代或未取代的C2-C6的杂环烷基、取代或未取代的C5-C10的芳基、
Figure PCTCN2016088089-appb-000020
或者
Figure PCTCN2016088089-appb-000021
R14为C1-C4的烷氧基或者
Figure PCTCN2016088089-appb-000022
Ra7和Ra8独立地为氢或者取代或未取代的C1-C4的烷基；当Ra7和Ra8 独立地为取代的C1-C4的烷基时，所述的取代的C1-C4的烷基中所述的取代是指被一个或多个C2-C6的杂环烷基所取代；R15为C1-C4的烷基、
Figure PCTCN2016088089-appb-000023
或者取代或未取代的C2-C6的杂环烷基；Ra9和Ra10独立地为氢或者取代或未取代的C1-C4的烷基；当Ra9和Ra10独立地为取代的C1-C4的烷基时，所述的取代的C1-C4的烷基中的所述的取代是指被一个或多个(例如1-6个，优选1-2个)C2-C6的杂环烷基所取代；当R15为取代的C2-C6的杂环烷基时，所述的取代是指被一个或多个(例如1-6个，优选1-2个)C1-C4的烷基所取代；In R 4 or R 5 , the substitution (R p ) described in the substituted C 5 -C 10 aryl group means one or more of the following substituents (for example, 1-6, preferably 1) -2) substituted: halogen (for example fluorine, chlorine, bromine or iodine, preferably chlorine), nitro, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 Alkoxy, substituted or unsubstituted C 2 -C 6 heterocycloalkyl, substituted or unsubstituted C 5 -C 10 aryl,
Figure PCTCN2016088089-appb-000020
or
Figure PCTCN2016088089-appb-000021
R 14 is a C 1 -C 4 alkoxy group or
Figure PCTCN2016088089-appb-000022
R a7 and R a8 are independently hydrogen or a substituted or unsubstituted C 1 -C 4 alkyl group; when R a7 and R a8 are independently a substituted C 1 -C 4 alkyl group, the substituted The substitution in the alkyl group of C 1 -C 4 means that it is substituted by one or more C 2 -C 6 heterocycloalkyl groups; R 15 is a C 1 -C 4 alkyl group,
Figure PCTCN2016088089-appb-000023
Or a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group; R a9 and R a10 are independently hydrogen or a substituted or unsubstituted C 1 -C 4 alkyl group; when R a9 and R a10 are independently In the case of a substituted C 1 -C 4 alkyl group, the substitution in the substituted C 1 -C 4 alkyl group means one or more (for example, 1-6, preferably 1-2) a C 2 -C 6 heterocycloalkyl group; when R 15 is a substituted C 2 -C 6 heterocycloalkyl group, the substitution means one or more (for example, 1-6, Preferably 1-2) C 1 -C 4 alkyl groups are substituted;
R4或R5中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷基所取代时，所述的取代的C1-C4的烷基中所述的取代是指被下列取代基中的一个或多个(例如1-6个，优选1-2个)所取代：卤素、取代或未取代的C2-C6的杂环烷基或者
Figure PCTCN2016088089-appb-000024
R16和R17独立地为C1-C4的烷基；所述的取代的C2-C6的杂环烷基中所述的取代是指被下列取代基中的一个或多个(例如1-6个，优选1-2个)所取代：C1-C4的烷基或者
Figure PCTCN2016088089-appb-000025
Ra11为C1-C4的烷基；In R 4 or R 5 , when the substitution described in the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group, the substituted The substitution in the alkyl group of C 1 -C 4 means that it is substituted by one or more of the following substituents (for example, 1-6, preferably 1-2): halogen, substituted or unsubstituted C 2 -C 6 heterocycloalkyl or
Figure PCTCN2016088089-appb-000024
R 16 and R 17 are independently a C 1 -C 4 alkyl group; the substitution described in the substituted C 2 -C 6 heterocycloalkyl group means one or more of the following substituents ( For example, 1-6, preferably 1-2) are substituted: C 1 -C 4 alkyl or
Figure PCTCN2016088089-appb-000025
R a11 is a C 1 -C 4 alkyl group;
R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷氧基所取代时，所述的取代的C1-C4的烷氧基中所述的取代是指被下列取代基中的一个或多个(例如1-6个，优选1-2个)所取代：C2-C6的杂环烷基、C1-C4的烷氧基、
Figure PCTCN2016088089-appb-000026
或者
Figure PCTCN2016088089-appb-000027
R18为C1-C4的烷基或者C2-C6的杂环烷基；R19和R20独立地为C1-C4的烷基；In R 4 or R 5 , when the substitution described in the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkoxy group, the substituted The substitution in the alkoxy group of C 1 -C 4 means that it is substituted by one or more of the following substituents (for example, 1-6, preferably 1-2): a heterocyclic ring of C 2 -C 6 Alkyl, C 1 -C 4 alkoxy,
Figure PCTCN2016088089-appb-000026
or
Figure PCTCN2016088089-appb-000027
R 18 is C 1 -C 4 alkyl or C 2 -C 6 heterocycloalkyl; R 19 and R 20 are independently C 1 -C 4 alkyl;
R4或R5中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代时，所述的取代的C2-C6的杂环烷基中所述的取代是指被下列取代基(Rt)中的一个或多个(例如1-6个，优选1-2个)所取代：羟基、取代或未取代的C1-C4的烷基、C2-C6的杂环烷基、
Figure PCTCN2016088089-appb-000028
或者
Figure PCTCN2016088089-appb-000029
R21为取代或未取代的C1-C4的烷基或者
Figure PCTCN2016088089-appb-000030
Ra11和Ra12独立地为C1-C4的烷基；当R21为取代的C1-C4的烷基时，所述的取 代的C1-C4的烷基中所述的取代是指被一个或多个(例如1-6个，优选1-2个)氰基所取代；R22为C1-C4的烷基；In R 4 or R 5 , when the substitution described in the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, the The substitution in the substituted C 2 -C 6 heterocycloalkyl group means that it is substituted by one or more of the following substituents (R t ) (for example, 1-6, preferably 1-2): hydroxy a substituted or unsubstituted C 1 -C 4 alkyl group, a C 2 -C 6 heterocycloalkyl group,
Figure PCTCN2016088089-appb-000028
or
Figure PCTCN2016088089-appb-000029
R 21 is a substituted or unsubstituted C 1 -C 4 alkyl group or
Figure PCTCN2016088089-appb-000030
R a11 and R a12 are independently a C 1 -C 4 alkyl group; when R 21 is a substituted C 1 -C 4 alkyl group, the substituted C 1 -C 4 alkyl group is as described Substituted means substituted by one or more (for example 1-6, preferably 1-2) cyano groups; R 22 is C 1 -C 4 alkyl;
R4或R5中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代，所述的取代的C2-C6的杂环烷基中所述的取代为被取代或未取代的C1-C4的烷基所取代时，所述的取代的C1-C4的烷基中所述的取代是指被下列取代基中的一个或多个(例如1-6个，优选1-2个)所取代：羟基、氰基、卤素、C3-C6的环烷基或者取代或未取代的C1-C4的烷氧基；所述的取代的C1-C4的烷氧基中所述的取代是指被一个或多个(例如1-6个，优选1-2个)C5-C10的芳基所取代；In R 4 or R 5 , when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, the substitution is When the substitution in the C 2 -C 6 heterocycloalkyl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group, the substituted C 1 -C 4 alkyl group is said substitution means one or more (e.g., 1-6, preferably 1-2) is the following substituted with substituents: hydroxy, cyano, halogen, C 3 -C 6 cycloalkyl or substituted or An unsubstituted C 1 -C 4 alkoxy group; the substitution described in the substituted C 1 -C 4 alkoxy group means one or more (for example, 1-6, preferably 1-2) Substituted by a C 5 -C 10 aryl group;
R4或R5中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C5-C10的芳基所取代时，所述的取代或未取代的C5-C10的芳基中所述的取代的C5-C10的芳基中所述的取代是指被一个或多个(例如1-6个，优选1-2个)C1-C4的烷氧基所取代；In R 4 or R 5 , when the substitution described in the substituted C 5 -C 10 aryl group is substituted with a substituted or unsubstituted C 5 -C 10 aryl group, the substitution or The substitution described in the substituted C 5 -C 10 aryl group described in the unsubstituted C 5 -C 10 aryl group means one or more (for example, 1-6, preferably 1-2) Substituted by a C 1 -C 4 alkoxy group;
R4或R5中，所述的取代的C2-C6的杂芳基中所述的取代是指被下列取代基中的一个或多个(例如1-6个，优选1-2个)所取代：取代或为未取代的C2-C6的杂环烷基；所述的取代的C2-C6的杂环烷基中所述的取代是指被一个或多个(例如1-6个，优选1-2个)C1-C4的烷基所取代；In R 4 or R 5 , the substitution in the substituted C 2 -C 6 heteroaryl group means one or more of the following substituents (for example, 1-6, preferably 1-2) Substituted: substituted or unsubstituted C 2 -C 6 heterocycloalkyl; substituted as described in the substituted C 2 -C 6 heterocycloalkyl refers to one or more (eg, 1-6, preferably 1-2) C 1 -C 4 alkyl groups;
上述各取代中，当取代基为多个时，所述的取代基相同或不同。In each of the above substitutions, when there are a plurality of substituents, the substituents are the same or different.
R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷基所取代，所述的取代的C1-C4的烷基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代，所述的取代或未取代的C2-C6的杂环烷基中所述的取代为被C1-C4的烷基所取代时，所述的C1-C4的烷基较佳地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基。In R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group, the The substitution described in the substituted C 1 -C 4 alkyl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, said substituted or unsubstituted C 2 -C 6 hetero When the substitution in the cycloalkyl group is substituted by a C 1 -C 4 alkyl group, the C 1 -C 4 alkyl group is preferably a methyl group, an ethyl group, a n-propyl group or an isopropyl group. , n-butyl, isobutyl or tert-butyl.
R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷基所取代，所述的取代的C1-C4的烷基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代时，所述的取代或未取代的C2-C6的杂环烷基较佳地是指杂原子选自O、N和S，杂原子数为1～4个(优选1～2个)的取代或未取代的C2-C6的杂环烷基。所述的取代或未取代的C2-C6的杂环烷基较佳地为取代或未取代的吗啉基
Figure PCTCN2016088089-appb-000031
或者取代或未取代的哌嗪基
Figure PCTCN2016088089-appb-000032
所述的取代的哌嗪基较佳地为
Figure PCTCN2016088089-appb-000033
In R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group, the When the substitution described in the substituted C 1 -C 4 alkyl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, the substituted or unsubstituted C 2 -C 6 Heterocycloalkyl preferably refers to a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group wherein the hetero atom is selected from O, N and S and the number of heteroatoms is 1 to 4 (preferably 1 to 2). . The substituted or unsubstituted C 2 -C 6 heterocycloalkyl group is preferably a substituted or unsubstituted morpholinyl group.
Figure PCTCN2016088089-appb-000031
Or substituted or unsubstituted piperazinyl
Figure PCTCN2016088089-appb-000032
The substituted piperazinyl group is preferably
Figure PCTCN2016088089-appb-000033
R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷氧基所取代，所述的取代的C1-C4的烷氧基中所述的取代为被取代或未取代的C2-C6的杂芳基所取代时，所述的取代或未取代的C2-C6的杂芳基较佳地是指杂原子选自O、N和S，杂原子数为1～4个(优选1～2个)的取代或未取代的C2-C6的杂芳基。所述的 取代或未取代的C2-C6的杂芳基较佳地为取代或未取代的吡啶基
Figure PCTCN2016088089-appb-000034
所述的取代的吡啶基较佳地为
Figure PCTCN2016088089-appb-000035
In R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkoxy group, When the substitution described in the substituted C 1 -C 4 alkoxy group is substituted by a substituted or unsubstituted C 2 -C 6 heteroaryl group, the substituted or unsubstituted C 2 -C 6 The heteroaryl group preferably means a hetero atom selected from O, N and S, and a substituted or unsubstituted C 2 -C 6 heteroaryl group having 1 to 4 (preferably 1 to 2) hetero atoms. The substituted or unsubstituted C 2 -C 6 heteroaryl group is preferably a substituted or unsubstituted pyridyl group.
Figure PCTCN2016088089-appb-000034
The substituted pyridyl group is preferably
Figure PCTCN2016088089-appb-000035
R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷氧基所取代，所述的取代的C1-C4的烷氧基中所述的取代为被取代或未取代的C5-C10的芳基所取代，所述的取代的C5-C10的芳基中所述的取代为被C2-C6的杂芳基所取代时，所述的C2-C6的杂芳基较佳地是指杂原子选自O、N和S，杂原子数为1～4个(优选1～2个)的C2-C6的杂芳基。所述的C2-C6的杂芳基较佳地为吡唑基
Figure PCTCN2016088089-appb-000036
In R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkoxy group, The substitution in the substituted C 1 -C 4 alkoxy group is substituted by a substituted or unsubstituted C 5 -C 10 aryl group, wherein the substituted C 5 -C 10 aryl group is When the substitution is substituted by a C 2 -C 6 heteroaryl group, the C 2 -C 6 heteroaryl group preferably means that the hetero atom is selected from O, N and S, and the number of heteroatoms is 1. ～4 (preferably 1 to 2) C 2 -C 6 heteroaryl groups. The C 2 -C 6 heteroaryl group is preferably pyrazolyl
Figure PCTCN2016088089-appb-000036
R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷氧基所取代，所述的取代的C1-C4的烷氧基中所述的取代为被取代或未取代的C5-C10的芳基所取代时，所述的取代或未取代的C5-C10的芳基较佳地为取代或未取代的苯基。所述的取代的苯基较佳地为
Figure PCTCN2016088089-appb-000037
In R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkoxy group, When the substitution described in the substituted C 1 -C 4 alkoxy group is substituted by a substituted or unsubstituted C 5 -C 10 aryl group, the substituted or unsubstituted C 5 -C 10 The aryl group is preferably a substituted or unsubstituted phenyl group. The substituted phenyl group is preferably
Figure PCTCN2016088089-appb-000037
R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷氧基所取代，所述的取代的C1-C4的烷氧基中所述的取代为被C2-C6的杂环烷基所取代时，所述的C2-C6的杂环烷基较佳地是指杂原子选自O、N和S，杂原子数为1～4个(优选1～2个)的C2-C6的杂环烷基。所述的C2-C6的杂环烷基较佳地为四氢吡咯基
Figure PCTCN2016088089-appb-000038
In R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkoxy group, When the substitution described in the substituted C 1 -C 4 alkoxy group is substituted by a C 2 -C 6 heterocycloalkyl group, the C 2 -C 6 heterocycloalkyl group is preferably The hetero atom is selected from the group consisting of O, N and S, and a C 2 -C 6 heterocycloalkyl group having 1 to 4 (preferably 1 to 2) hetero atoms. The C 2 -C 6 heterocycloalkyl group is preferably a tetrahydropyrrolyl group.
Figure PCTCN2016088089-appb-000038
R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代，所述的取代的C2-C6的杂环烷基中所述的取代为被一个或多个(例如1-6个，优选1-2个)C1-C4的烷基所取代时，所述的C1-C4的烷基较佳地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基。In R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, When the substitution described in the substituted C 2 -C 6 heterocycloalkyl group is substituted by one or more (for example, 1-6, preferably 1-2) C 1 -C 4 alkyl groups, The C 1 -C 4 alkyl group is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被卤素所取代时，所述的卤素较佳地为氟、氯、溴或碘，优选氟。In R 1 , R 2 or R 3 , when the substitution in the substituted C 5 -C 10 aryl group is substituted by a halogen, the halogen is preferably fluorine, chlorine, bromine or Iodine, preferably fluorine.
R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷基所取代时，所述的取代或未取代的C1-C4的烷基较佳地为取代或未取代的甲基、取代或未取代的乙基、取代或未取代的正丙基、取代或未取代的异丙基、取代或未取代的正丁基、取代或未取代的异丁基或者取代或未取代的叔丁基。所述的取代的C1-C4的 烷基较佳地为
Figure PCTCN2016088089-appb-000039
In R 1 , R 2 or R 3 , when the substitution in the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group, The substituted or unsubstituted C 1 -C 4 alkyl group is preferably a substituted or unsubstituted methyl group, a substituted or unsubstituted ethyl group, a substituted or unsubstituted n-propyl group, a substituted or unsubstituted isopropyl group. A substituted, unsubstituted or n-butyl, substituted or unsubstituted isobutyl or substituted or unsubstituted t-butyl. The substituted C 1 -C 4 alkyl group is preferably
Figure PCTCN2016088089-appb-000039
R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷氧基所取代时，所述的取代或未取代的C1-C4的烷氧基较佳地为取代或未取代的甲氧基、取代或未取代的乙氧基、取代或未取代的正丙氧基、取代或未取代的异丙氧基、取代或未取代的正丁氧基、取代或未取代的异丁氧基或者取代或未取代的叔丁氧基。所述的取代的C1-C4的烷氧基较佳地为
Figure PCTCN2016088089-appb-000040
Figure PCTCN2016088089-appb-000041
或者
Figure PCTCN2016088089-appb-000042
In R 1 , R 2 or R 3 , when the substitution described in the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkoxy group, The substituted or unsubstituted C 1 -C 4 alkoxy group is preferably a substituted or unsubstituted methoxy group, a substituted or unsubstituted ethoxy group, a substituted or unsubstituted n-propoxy group, a substituted or Unsubstituted isopropoxy group, substituted or unsubstituted n-butoxy group, substituted or unsubstituted isobutoxy group or substituted or unsubstituted tert-butoxy group. The substituted C 1 -C 4 alkoxy group is preferably
Figure PCTCN2016088089-appb-000040
Figure PCTCN2016088089-appb-000041
or
Figure PCTCN2016088089-appb-000042
R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代时，所述的取代或未取代的C2-C6的杂环烷基较佳地是指杂原子选自O、N和S，杂原子数为1～4个(优选1～2个)的取代或未取代的C2-C6的杂环烷基。所述的取代或未取代的C2-C6的杂环烷基较佳地为取代或未取代的吗啉基
Figure PCTCN2016088089-appb-000043
或取代或未取代的哌嗪基
Figure PCTCN2016088089-appb-000044
所述的取代的哌嗪基较佳地
Figure PCTCN2016088089-appb-000045
In R 1 , R 2 or R 3 , when the substitution described in the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, The substituted or unsubstituted C 2 -C 6 heterocycloalkyl group preferably means a substituent in which the hetero atom is selected from O, N and S, and the number of hetero atoms is from 1 to 4 (preferably from 1 to 2). Or unsubstituted C 2 -C 6 heterocycloalkyl. The substituted or unsubstituted C 2 -C 6 heterocycloalkyl group is preferably a substituted or unsubstituted morpholinyl group.
Figure PCTCN2016088089-appb-000043
Or substituted or unsubstituted piperazinyl
Figure PCTCN2016088089-appb-000044
The substituted piperazinyl group is preferably
Figure PCTCN2016088089-appb-000045
R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被
Figure PCTCN2016088089-appb-000046
所取代，所述的R6为C1-C4的烷基时，所述的C1-C4的烷基较佳地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或者叔丁基。In R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is substituted as described
Figure PCTCN2016088089-appb-000046
When the R 6 is a C 1 -C 4 alkyl group, the C 1 -C 4 alkyl group is preferably a methyl group, an ethyl group, a n-propyl group, an isopropyl group or a n-butyl group. Base, isobutyl or tert-butyl.
R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被
Figure PCTCN2016088089-appb-000047
所取代，所述的R6为C3-C6的环烷基时，所述的C3-C6的环烷基较佳地为环丙基、环丁基、环戊基或环己基。In R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is substituted as described
Figure PCTCN2016088089-appb-000047
When the R 6 is a C 3 -C 6 cycloalkyl group, the C 3 -C 6 cycloalkyl group is preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group. .
R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被
Figure PCTCN2016088089-appb-000048
所取代，所述的R6为
Figure PCTCN2016088089-appb-000049
Ra1和Ra2独立地为取代或未取代的C1-C4的烷基时，所述的取代或未取代的C1-C4的烷基较佳地为取代或未取代的甲基、取代或未取代的乙基、取代或未 取代的正丙基、取代或未取代的异丙基、取代或未取代的正丁基、取代或未取代的异丁基或者取代或未取代的叔丁基。In R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is substituted as described
Figure PCTCN2016088089-appb-000048
Substituted, the R 6 is
Figure PCTCN2016088089-appb-000049
When R a1 and R a2 are independently a substituted or unsubstituted C 1 -C 4 alkyl group, the substituted or unsubstituted C 1 -C 4 alkyl group is preferably a substituted or unsubstituted methyl group. , substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl or substituted or unsubstituted Tert-butyl.
R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被
Figure PCTCN2016088089-appb-000050
所取代，所述的R6为
Figure PCTCN2016088089-appb-000051
Ra1和Ra2独立地为C5-C10的芳基时，所述的C5-C10的芳基较佳地为苯基或萘基。In R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is substituted as described
Figure PCTCN2016088089-appb-000050
Substituted, the R 6 is
Figure PCTCN2016088089-appb-000051
When R a1 and R a2 are independently a C 5 -C 10 aryl group, the C 5 -C 10 aryl group is preferably a phenyl group or a naphthyl group.
R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被
Figure PCTCN2016088089-appb-000052
所取代时，所述的
Figure PCTCN2016088089-appb-000053
较佳地为
Figure PCTCN2016088089-appb-000054
Figure PCTCN2016088089-appb-000055
In R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is substituted as described
Figure PCTCN2016088089-appb-000052
When replaced, the stated
Figure PCTCN2016088089-appb-000053
Preferably
Figure PCTCN2016088089-appb-000054
Figure PCTCN2016088089-appb-000055
R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被
Figure PCTCN2016088089-appb-000056
所取代，所述的R7和R8独立地为C1-C4的烷基时，所述的C1-C4的烷基较佳地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或者叔丁基。In R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is substituted as described
Figure PCTCN2016088089-appb-000056
When the R 7 and R 8 are independently a C 1 -C 4 alkyl group, the C 1 -C 4 alkyl group is preferably a methyl group, an ethyl group, a n-propyl group or a different group. Propyl, n-butyl, isobutyl or tert-butyl.
R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被
Figure PCTCN2016088089-appb-000057
所取代，所述的R7和R8独立地为
Figure PCTCN2016088089-appb-000058
Ra3为C1-C4的烷基时，所述的C1-C4的烷基较佳地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或者叔丁基。In R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is substituted as described
Figure PCTCN2016088089-appb-000057
Substituted, R 7 and R 8 are independently
Figure PCTCN2016088089-appb-000058
When R a3 is a C 1 -C 4 alkyl group, the C 1 -C 4 alkyl group is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or Tert-butyl.
R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被
Figure PCTCN2016088089-appb-000059
所取代，所述的R7和R8独立地为
Figure PCTCN2016088089-appb-000060
Ra3为C3-C6的环烷基时，所述的C3-C6的环烷基较佳地为环丙基、环丁基、环戊基或环己基。In R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is substituted as described
Figure PCTCN2016088089-appb-000059
Substituted, R 7 and R 8 are independently
Figure PCTCN2016088089-appb-000060
When R a3 is a C 3 -C 6 cycloalkyl group, the C 3 -C 6 cycloalkyl group is preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.
R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被
Figure PCTCN2016088089-appb-000061
所取代，所 述的R7和R8独立地为
Figure PCTCN2016088089-appb-000062
Ra4为取代或未取代的C1-C4的烷基，所述的取代的C1-C4的烷基中所述的取代为被C2-C6的杂环烷基所取代时，所述的C2-C6的杂环烷基较佳地是指杂原子选自O、N和S，杂原子数为1～4个(优选1～2个)的C2-C6的杂芳基。所述的C2-C6的杂芳基较佳地吗啉基(例如
Figure PCTCN2016088089-appb-000063
)。In R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is substituted as described
Figure PCTCN2016088089-appb-000061
Substituted, R 7 and R 8 are independently
Figure PCTCN2016088089-appb-000062
R a4 is a substituted or unsubstituted C 1 -C 4 alkyl group, and the substituent described in the substituted C 1 -C 4 alkyl group is substituted by a C 2 -C 6 heterocycloalkyl group. said C 2 -C 6 heterocycloalkyl means is preferably a heteroatom selected from O, N and S, the number of hetero atoms of 1 to 4 (preferably 1 to 2) a C 2 -C 6 Heteroaryl. The C 2 -C 6 heteroaryl group is preferably morpholinyl (for example
Figure PCTCN2016088089-appb-000063
).
R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被
Figure PCTCN2016088089-appb-000064
所取代，所述的R7和R8独立地为
Figure PCTCN2016088089-appb-000065
Ra4为取代或未取代的C1-C4的烷基时，所述的取代或未取代的C1-C4的烷基较佳地为取代或未取代的甲基、取代或未取代的乙基、取代或未取代的正丙基、取代或未取代的异丙基、取代或未取代的正丁基、取代或未取代的异丁基或者取代或未取代的叔丁基。In R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is substituted as described
Figure PCTCN2016088089-appb-000064
Substituted, R 7 and R 8 are independently
Figure PCTCN2016088089-appb-000065
When R a4 is a substituted or unsubstituted C 1 -C 4 alkyl group, the substituted or unsubstituted C 1 -C 4 alkyl group is preferably a substituted or unsubstituted methyl group, substituted or unsubstituted. Ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl or substituted or unsubstituted t-butyl.
R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被
Figure PCTCN2016088089-appb-000066
所取代，所述的R7和R8独立地为
Figure PCTCN2016088089-appb-000067
Ra4为C3-C6的环烷基时，所述的C3-C6的环烷基较佳地为环丙基、环丁基、环戊基或环己基。In R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is substituted as described
Figure PCTCN2016088089-appb-000066
Substituted, R 7 and R 8 are independently
Figure PCTCN2016088089-appb-000067
When R a4 is a C 3 -C 6 cycloalkyl group, the C 3 -C 6 cycloalkyl group is preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.
R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被
Figure PCTCN2016088089-appb-000068
所取代，所述的R7和R8独立地为
Figure PCTCN2016088089-appb-000069
Ra4为C2-C6的杂芳基时，所述的C2-C6的杂芳基是指杂原子选自O、N和S，杂原子数为1～4个(优选1～2个)的C2-C6的杂芳基。所述的C2-C6的杂芳基较佳地为噻吩基(例如
Figure PCTCN2016088089-appb-000070
)。In R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is substituted as described
Figure PCTCN2016088089-appb-000068
Substituted, R 7 and R 8 are independently
Figure PCTCN2016088089-appb-000069
When R a4 is a C 2 -C 6 heteroaryl group, the C 2 -C 6 heteroaryl group means that the hetero atom is selected from O, N and S, and the number of hetero atoms is from 1 to 4 (preferably 1 to). 2) C 2 -C 6 heteroaryl groups. The C 2 -C 6 heteroaryl group is preferably a thienyl group (for example
Figure PCTCN2016088089-appb-000070
).
R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被
Figure PCTCN2016088089-appb-000071
所取代时， 所述的
Figure PCTCN2016088089-appb-000072
较佳地为
Figure PCTCN2016088089-appb-000073
Figure PCTCN2016088089-appb-000074
In R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is substituted as described
Figure PCTCN2016088089-appb-000071
When replaced, the
Figure PCTCN2016088089-appb-000072
Preferably
Figure PCTCN2016088089-appb-000073
Figure PCTCN2016088089-appb-000074
R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被
Figure PCTCN2016088089-appb-000075
所取代，所述的R9为取代或未取代的C1-C4的烷基时，所述的取代或未取代的C1-C4的烷基较佳地为取代或未取代的甲基、取代或未取代的乙基、取代或未取代的正丙基、取代或未取代的异丙基、取代或未取代的正丁基、取代或未取代的异丁基或者取代或未取代的叔丁基。所述的
Figure PCTCN2016088089-appb-000076
较佳地为
Figure PCTCN2016088089-appb-000077
In R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is substituted as described
Figure PCTCN2016088089-appb-000075
When the R 9 is a substituted or unsubstituted C 1 -C 4 alkyl group, the substituted or unsubstituted C 1 -C 4 alkyl group is preferably a substituted or unsubstituted A group. Equivalent, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl or substituted or unsubstituted Tert-butyl. Said
Figure PCTCN2016088089-appb-000076
Preferably
Figure PCTCN2016088089-appb-000077
R1、R2或R3中，当所述的取代的C2-C6的杂芳基中所述的取代为被C1-C4的烷氧基所取代时，所述的C1-C4的烷氧基优选甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基或叔丁氧基。In R 1 , R 2 or R 3 , when the substitution described in the substituted C 2 -C 6 heteroaryl group is substituted by a C 1 -C 4 alkoxy group, the C 1 The alkoxy group of -C 4 is preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy.
R1、R2或R3中，当所述的取代的C2-C6的杂芳基中所述的取代为被取代或未取代的C1-C4的烷基所取代，所述的取代的C1-C4的烷基中所述的取代为被C3-C6的环烷基所取代时，所述的C3-C6的环烷基较佳地为环丙基、环丁基、环戊基或环己基。In R 1 , R 2 or R 3 , when the substituted C 2 -C 6 heteroaryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group, When the substitution in the substituted C 1 -C 4 alkyl group is substituted by a C 3 -C 6 cycloalkyl group, the C 3 -C 6 cycloalkyl group is preferably a cyclopropyl group. , cyclobutyl, cyclopentyl or cyclohexyl.
R1、R2或R3中，当所述的取代的C2-C6的杂芳基中所述的取代为被取代或未取代的C1-C4的烷基所取代，所述的取代的C1-C4的烷基中所述的取代为被取代或未取代的C2-C6的杂芳基所取代时，所述的取代或未取代C2-C6的杂芳基较佳地是指杂原子选自O、N和S，杂原子数为1～4个(优选1～2个)的取代或未取代C2-C6的杂芳基。所述的取代或未取代的C2-C6的杂芳基较佳地为取代或未取代的吡啶基。所述的取代的吡啶基较佳地为
Figure PCTCN2016088089-appb-000078
In R 1 , R 2 or R 3 , when the substituted C 2 -C 6 heteroaryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group, When the substitution described in the substituted C 1 -C 4 alkyl group is substituted by a substituted or unsubstituted C 2 -C 6 heteroaryl group, the substituted or unsubstituted C 2 -C 6 hetero The aryl group preferably means a substituted or unsubstituted C 2 -C 6 heteroaryl group in which the hetero atom is selected from O, N and S, and the number of hetero atoms is 1 to 4 (preferably 1 to 2). The substituted or unsubstituted C 2 -C 6 heteroaryl group is preferably a substituted or unsubstituted pyridyl group. The substituted pyridyl group is preferably
Figure PCTCN2016088089-appb-000078
R1、R2或R3中，当所述的取代的C2-C6的杂芳基中所述的取代为被取代或未取代的C1-C4的烷基所取代，所述的取代的C1-C4的烷基中所述的取代为被取代或未取代的C5-C10的芳基所取代时，所述的取代或未取代的C5-C10的芳基较佳地为取代或未取代的苯基。所述的取代的苯基较佳地为
Figure PCTCN2016088089-appb-000079
In R 1 , R 2 or R 3 , when the substituted C 2 -C 6 heteroaryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group, When the substitution described in the substituted C 1 -C 4 alkyl group is substituted with a substituted or unsubstituted C 5 -C 10 aryl group, the substituted or unsubstituted C 5 -C 10 aryl group The group is preferably a substituted or unsubstituted phenyl group. The substituted phenyl group is preferably
Figure PCTCN2016088089-appb-000079
R1、R2或R3中，当所述的取代的C2-C6的杂芳基中所述的取代为被取代或未取代的 C1-C4的烷基所取代时，所述的取代或未取代的C1-C4的烷基较佳地为取代或未取代的甲基、取代或未取代的乙基、取代或未取代的正丙基、取代或未取代的异丙基、取代或未取代的正丁基、取代或未取代的异丁基或者取代或未取代的叔丁基。所述的取代的C1-C4的烷基较佳地为
Figure PCTCN2016088089-appb-000080
Figure PCTCN2016088089-appb-000081
In R 1 , R 2 or R 3 , when the substituent described in the substituted C 2 -C 6 heteroaryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group, The substituted or unsubstituted C 1 -C 4 alkyl group is preferably a substituted or unsubstituted methyl group, a substituted or unsubstituted ethyl group, a substituted or unsubstituted n-propyl group, a substituted or unsubstituted iso A propyl group, a substituted or unsubstituted n-butyl group, a substituted or unsubstituted isobutyl group or a substituted or unsubstituted tert-butyl group. The substituted C 1 -C 4 alkyl group is preferably
Figure PCTCN2016088089-appb-000080
Figure PCTCN2016088089-appb-000081
R1、R2或R3中，当所述的取代的C2-C6的杂芳基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代，所述的取代的C2-C6的杂环烷基中所述的取代为被取代的C1-C4的烷基所取代时，所述的取代的C1-C4的烷基较佳地为取代的甲基、取代的乙基、取代的正丙基、取代的异丙基、取代的正丁基、取代的异丁基或者取代的叔丁基。所述的取代的C1-C4的烷基较佳地为
Figure PCTCN2016088089-appb-000082
In R 1 , R 2 or R 3 , when the substituted C 2 -C 6 heteroaryl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, When the substitution described in the substituted C 2 -C 6 heterocycloalkyl group is substituted by a substituted C 1 -C 4 alkyl group, the substituted C 1 -C 4 alkyl group is more Preferably, it is a substituted methyl group, a substituted ethyl group, a substituted n-propyl group, a substituted isopropyl group, a substituted n-butyl group, a substituted isobutyl group or a substituted t-butyl group. The substituted C 1 -C 4 alkyl group is preferably
Figure PCTCN2016088089-appb-000082
R1、R2或R3中，当所述的取代的C2-C6的杂芳基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代，所述的取代的C2-C6的杂环烷基中所述的取代为被
Figure PCTCN2016088089-appb-000083
所取代，所述的R12为C1-C4的烷基时，所述的C1-C4的烷基较佳地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或者叔丁基。In R 1 , R 2 or R 3 , when the substituted C 2 -C 6 heteroaryl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, The substitution described in the substituted C 2 -C 6 heterocycloalkyl group is
Figure PCTCN2016088089-appb-000083
When the R 12 is a C 1 -C 4 alkyl group, the C 1 -C 4 alkyl group is preferably a methyl group, an ethyl group, a n-propyl group, an isopropyl group or a n-butyl group. Base, isobutyl or tert-butyl.
R1、R2或R3中，当所述的取代的C2-C6的杂芳基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代，所述的取代的C2-C6的杂环烷基中所述的取代为被
Figure PCTCN2016088089-appb-000084
所取代，所述的R12为C3-C6的环烷基时，所述的C3-C6的环烷基较佳地为环丙基、环丁基、环戊基或环己基。In R 1 , R 2 or R 3 , when the substituted C 2 -C 6 heteroaryl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, The substitution described in the substituted C 2 -C 6 heterocycloalkyl group is
Figure PCTCN2016088089-appb-000084
When the R 12 is a C 3 -C 6 cycloalkyl group, the C 3 -C 6 cycloalkyl group is preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group. .
R1、R2或R3中，当所述的取代的C2-C6的杂芳基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代，所述的取代的C2-C6的杂环烷基中所述的取代为被
Figure PCTCN2016088089-appb-000085
所取代时，所述的
Figure PCTCN2016088089-appb-000086
较佳地为
Figure PCTCN2016088089-appb-000087
或者
Figure PCTCN2016088089-appb-000088
In R 1 , R 2 or R 3 , when the substituted C 2 -C 6 heteroaryl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, The substitution described in the substituted C 2 -C 6 heterocycloalkyl group is
Figure PCTCN2016088089-appb-000085
When replaced, the stated
Figure PCTCN2016088089-appb-000086
Preferably
Figure PCTCN2016088089-appb-000087
or
Figure PCTCN2016088089-appb-000088
R1、R2或R3中，当所述的取代的C2-C6的杂芳基中所述的取代为被取代或未取代的 C2-C6的杂环烷基所取代，所述的取代的C2-C6的杂环烷基中所述的取代为被
Figure PCTCN2016088089-appb-000089
所取代，所述的R13为C1-C4的烷基时，所述的C1-C4的烷基较佳地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或者叔丁基。所述的
Figure PCTCN2016088089-appb-000090
较佳地为
Figure PCTCN2016088089-appb-000091
In R 1 , R 2 or R 3 , when the substituted C 2 -C 6 heteroaryl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, The substitution described in the substituted C 2 -C 6 heterocycloalkyl group is
Figure PCTCN2016088089-appb-000089
When the R 13 is a C 1 -C 4 alkyl group, the C 1 -C 4 alkyl group is preferably a methyl group, an ethyl group, a n-propyl group, an isopropyl group or a n-butyl group. Base, isobutyl or tert-butyl. Said
Figure PCTCN2016088089-appb-000090
Preferably
Figure PCTCN2016088089-appb-000091
R1、R2或R3中，当所述的取代的C2-C6的杂芳基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代时，所述的取代或未取代的C2-C6的杂环烷基较佳地为杂原子选自O、N或S，杂原子数为1-4个的取代或未取代的C2-C6的杂环烷基。所述的取代或未取代的C2-C6的杂环烷基较佳地为取代或未取代的吗啉基(例如
Figure PCTCN2016088089-appb-000092
)、取代或未取代的哌啶基
Figure PCTCN2016088089-appb-000093
或取代或未取代的氮杂环丁基
Figure PCTCN2016088089-appb-000094
所述的取代的C2-C6的杂环烷基较佳地为
Figure PCTCN2016088089-appb-000095
In R 1 , R 2 or R 3 , when the substitution described in the substituted C 2 -C 6 heteroaryl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group the substituted or unsubstituted C 2 -C 6 heterocycloalkyl is preferably a heteroatom selected from O, N or S, the number of from 1 to 4 hetero atoms substituted or unsubstituted C 2 - Heterocycloalkyl of C 6 . The substituted or unsubstituted C 2 -C 6 heterocycloalkyl group is preferably a substituted or unsubstituted morpholinyl group (for example)
Figure PCTCN2016088089-appb-000092
, substituted or unsubstituted piperidinyl
Figure PCTCN2016088089-appb-000093
Or substituted or unsubstituted azetidinyl
Figure PCTCN2016088089-appb-000094
The substituted C 2 -C 6 heterocycloalkyl group is preferably
Figure PCTCN2016088089-appb-000095
R1、R2或R3中，当所述的取代的C2-C6的杂芳基中所述的取代为被
Figure PCTCN2016088089-appb-000096
所取代，R10为C1-C4的烷基时，所述的C1-C4的烷基较佳地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或者叔丁基。所述的
Figure PCTCN2016088089-appb-000097
较佳地为
Figure PCTCN2016088089-appb-000098
In R 1 , R 2 or R 3 , when the substituted C 2 -C 6 heteroaryl group is substituted as described
Figure PCTCN2016088089-appb-000096
When R 10 is a C 1 -C 4 alkyl group, the C 1 -C 4 alkyl group is preferably a methyl group, an ethyl group, a n-propyl group, an isopropyl group, an n-butyl group or a different group. Butyl or tert-butyl. Said
Figure PCTCN2016088089-appb-000097
Preferably
Figure PCTCN2016088089-appb-000098
R1、R2或R3中，当所述的取代的C2-C6的杂芳基中所述的取代为被
Figure PCTCN2016088089-appb-000099
所取代，R11为
Figure PCTCN2016088089-appb-000100
Ra5或Ra6独立地为C1-C4的烷基时，所述的C1-C4的烷基较佳地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或者叔丁基。所述的
Figure PCTCN2016088089-appb-000101
较佳地为
Figure PCTCN2016088089-appb-000102
In R 1 , R 2 or R 3 , when the substituted C 2 -C 6 heteroaryl group is substituted as described
Figure PCTCN2016088089-appb-000099
Substituted, R 11 is
Figure PCTCN2016088089-appb-000100
When R a5 or R a6 is independently a C 1 -C 4 alkyl group, the C 1 -C 4 alkyl group is preferably methyl, ethyl, n-propyl, isopropyl or n-butyl. , isobutyl or tert-butyl. Said
Figure PCTCN2016088089-appb-000101
Preferably
Figure PCTCN2016088089-appb-000102
R4或R5中，当所述的取代的C1-C4的烷基中所述的取代为被取代或未取代的C2-C6的杂芳基所取代时，所述的取代或未取代的C2-C6的杂芳基较佳地是指杂原子选自O、N和S，杂原子数为1～4个(优选1～2个)的取代或未取代的C2-C6的杂芳基。所述的取代或 未取代的C2-C6的杂芳基较佳地为取代或未取代的吡啶基
Figure PCTCN2016088089-appb-000103
所述的取代的吡啶基较佳地为
Figure PCTCN2016088089-appb-000104
所述的取代的C1-C4的烷基较佳地为
Figure PCTCN2016088089-appb-000105
In R 4 or R 5 , when the substituent described in the substituted C 1 -C 4 alkyl group is substituted with a substituted or unsubstituted C 2 -C 6 heteroaryl group, the substitution Or an unsubstituted C 2 -C 6 heteroaryl group preferably means a hetero atom selected from O, N and S, and a substituted or unsubstituted C having 1 to 4 (preferably 1 to 2) hetero atoms. 2- C6 heteroaryl. The substituted or unsubstituted C 2 -C 6 heteroaryl group is preferably a substituted or unsubstituted pyridyl group.
Figure PCTCN2016088089-appb-000103
The substituted pyridyl group is preferably
Figure PCTCN2016088089-appb-000104
The substituted C 1 -C 4 alkyl group is preferably
Figure PCTCN2016088089-appb-000105
R4或R5中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷基所取代，所述的取代或未取代的C1-C4的烷基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代时，所述的取代的C2-C6的杂环烷基为被C1-C4的烷基所述取代时，所述的C1-C4的烷基较佳地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或者叔丁基。In R 4 or R 5 , when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group, the substitution or not When the substitution described in the substituted C 1 -C 4 alkyl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, the substituted C 2 -C 6 heterocycloalkane When the group is substituted by a C 1 -C 4 alkyl group, the C 1 -C 4 alkyl group is preferably a methyl group, an ethyl group, a n-propyl group, an isopropyl group, an n-butyl group or a different group. Butyl or tert-butyl.
R4或R5中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷基所取代，所述的取代或未取代的C1-C4的烷基中所述的取代为被
Figure PCTCN2016088089-appb-000106
所取代；Ra11为C1-C4的烷基时，Ra11中，所述的C1-C4的烷基较佳地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或者叔丁基。In R 4 or R 5 , when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group, the substitution or not The substitution described in the substituted C 1 -C 4 alkyl group is
Figure PCTCN2016088089-appb-000106
When R a11 is a C 1 -C 4 alkyl group, in the R a11 , the C 1 -C 4 alkyl group is preferably a methyl group, an ethyl group, a n-propyl group, an isopropyl group or a positive group. Butyl, isobutyl or tert-butyl.
R4或R5中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷基所取代，所述的取代或未取代的C1-C4的烷基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代时，所述的取代或未取代的C2-C6的杂环烷基较佳地是指杂原子选自O、N和S，杂原子数为1～4个(优选1～2个)的取代或未取代的C2-C6的杂环烷基。所述的取代或未取代的C2-C6的杂环烷基较佳地为取代或未取代的吗啉基
Figure PCTCN2016088089-appb-000107
或者取代或未取代的哌嗪基
Figure PCTCN2016088089-appb-000108
In R 4 or R 5 , when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group, the substitution or not When the substitution described in the substituted C 1 -C 4 alkyl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, the substituted or unsubstituted C 2 -C 6 Heterocycloalkyl preferably refers to a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group wherein the hetero atom is selected from O, N and S and the number of heteroatoms is 1 to 4 (preferably 1 to 2). . The substituted or unsubstituted C 2 -C 6 heterocycloalkyl group is preferably a substituted or unsubstituted morpholinyl group.
Figure PCTCN2016088089-appb-000107
Or substituted or unsubstituted piperazinyl
Figure PCTCN2016088089-appb-000108
R4或R5中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷基所取代，所述的取代或未取代的C1-C4的烷基中所述的取代为被
Figure PCTCN2016088089-appb-000109
所取代，R16和R17独立地为C1-C4的烷基时，R16或R17中，所述的C1-C4的烷基较佳地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或者叔丁基。In R 4 or R 5 , when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group, the substitution or not The substitution described in the substituted C 1 -C 4 alkyl group is
Figure PCTCN2016088089-appb-000109
When R 16 and R 17 are independently a C 1 -C 4 alkyl group, in the case of R 16 or R 17 , the C 1 -C 4 alkyl group is preferably a methyl group, an ethyl group or a positive group. Propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
R4或R5中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷基所取代时，所述的取代或未取代的C1-C4的烷基较佳地为取代或未取代的甲基、取代或未取代的乙基、取代或未取代的正丙基、取代或未取代的异丙基、取代或未取代的正丁基、取代或未取代的异丁基或者取代或未取代的叔丁基。 In R 4 or R 5 , when the substitution described in the substituted C 5 -C 10 aryl group is substituted with a substituted or unsubstituted C 1 -C 4 alkyl group, the substitution or The unsubstituted C 1 -C 4 alkyl group is preferably a substituted or unsubstituted methyl group, a substituted or unsubstituted ethyl group, a substituted or unsubstituted n-propyl group, a substituted or unsubstituted isopropyl group, a substitution group. Or unsubstituted n-butyl, substituted or unsubstituted isobutyl or substituted or unsubstituted t-butyl.
R4或R5中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷基所取代时，所述的取代的C1-C4的烷基较佳地为
Figure PCTCN2016088089-appb-000110
Figure PCTCN2016088089-appb-000111
或者
Figure PCTCN2016088089-appb-000112
In R 4 or R 5 , when the substitution described in the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group, the substituted The C 1 -C 4 alkyl group is preferably
Figure PCTCN2016088089-appb-000110
Figure PCTCN2016088089-appb-000111
or
Figure PCTCN2016088089-appb-000112
R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷氧基所取代，所述的取代的C1-C4的烷氧基中所述的取代为被C2-C6的杂环烷基所取代时，所述的C2-C6的杂环烷基较佳地是指杂原子选自O、N和S，杂原子数为1～4个(优选1～2个)的C2-C6的杂环烷基。所述的C2-C6的杂环烷基较佳地为四氢吡咯基
Figure PCTCN2016088089-appb-000113
或吗啉基
Figure PCTCN2016088089-appb-000114
In R 4 or R 5 , when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkoxy group, the substituted C is substituted When the substitution in the alkoxy group of 1 -C 4 is substituted by a C 2 -C 6 heterocycloalkyl group, the C 2 -C 6 heterocycloalkyl group preferably means a hetero atom From O, N and S, a C 2 -C 6 heterocycloalkyl group having 1 to 4 (preferably 1 to 2) hetero atoms. The C 2 -C 6 heterocycloalkyl group is preferably a tetrahydropyrrolyl group.
Figure PCTCN2016088089-appb-000113
Morpholinyl
Figure PCTCN2016088089-appb-000114
R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷氧基所取代，所述的取代的C1-C4的烷氧基中所述的取代为被C1-C4的烷氧基所取代时，所述的C1-C4的烷氧基较佳地为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基或者叔丁氧基。In R 4 or R 5 , when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkoxy group, the substituted C is substituted When the substitution in the alkoxy group of 1 -C 4 is substituted by a C 1 -C 4 alkoxy group, the C 1 -C 4 alkoxy group is preferably a methoxy group or an ethoxy group. Base, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy.
R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷氧基所取代，所述的取代的C1-C4的烷氧基中所述的取代为被
Figure PCTCN2016088089-appb-000115
所取代，所述的R18为C1-C4的烷基时，R18中，所述的C1-C4的烷基较佳地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或者叔丁基。In R 4 or R 5 , when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkoxy group, the substituted C is substituted The substitution described in the alkoxy group of 1 -C 4 is
Figure PCTCN2016088089-appb-000115
When substituted, the R 18 is a C 1 -C 4 alkyl group, the R 18, C 1 -C 4 alkyl group is preferably a methyl, ethyl, n-propyl, isopropyl, Base, n-butyl, isobutyl or tert-butyl.
R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷氧基所取代，所述的取代的C1-C4的烷氧基中所述的取代为被
Figure PCTCN2016088089-appb-000116
所取代，所述的R18为C2-C6的杂环烷基时，R18中，所述的C2-C6的杂环烷基较佳地是指杂原子选自O、N和S，杂原子数为1～4个(优选1～2个)的C2-C6的杂环烷基。所述的C2-C6的杂环烷基较佳地为四氢吡咯基
Figure PCTCN2016088089-appb-000117
In R 4 or R 5 , when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkoxy group, the substituted C is substituted The substitution described in the alkoxy group of 1 -C 4 is
Figure PCTCN2016088089-appb-000116
When substituted, the R 18 is C 2 -C 6 heterocycloalkyl is, R 18, said C 2 -C 6 heterocycloalkyl means is preferably a heteroatom selected from O, N And S, a C 2 -C 6 heterocycloalkyl group having 1 to 4 (preferably 1 to 2) hetero atoms. The C 2 -C 6 heterocycloalkyl group is preferably a tetrahydropyrrolyl group.
Figure PCTCN2016088089-appb-000117
R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷氧基所取代，所述的取代的C1-C4的烷氧基中所述的取代为被
Figure PCTCN2016088089-appb-000118
所取代，所述的R19和R20独立地为C1-C4的烷基时，R19和R20中，所述的C1-C4的烷基较佳地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或者叔丁基。In R 4 or R 5 , when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkoxy group, the substituted C is substituted The substitution described in the alkoxy group of 1 -C 4 is
Figure PCTCN2016088089-appb-000118
In the case where R 19 and R 20 are independently a C 1 -C 4 alkyl group, in the case of R 19 and R 20 , the C 1 -C 4 alkyl group is preferably a methyl group or a B group. Base, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷氧基所取代时，所述的取代或未取代的C1-C4的烷氧基较佳地为取代或未取代的甲氧基、取代或未取代的乙氧基、取代或未取代的正丙氧基、取代或未取代的异丙氧基、取代或未取代的正丁氧基、取代或未取代的异丁氧基或者取代或未取代的叔丁氧基。In R 4 or R 5 , when the substitution described in the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkoxy group, the substitution or The unsubstituted C 1 -C 4 alkoxy group is preferably a substituted or unsubstituted methoxy group, a substituted or unsubstituted ethoxy group, a substituted or unsubstituted n-propoxy group, a substituted or unsubstituted iso Propyloxy, substituted or unsubstituted n-butoxy, substituted or unsubstituted isobutoxy or substituted or unsubstituted tert-butoxy.
R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷氧基所取代时，所述的取代的C1-C4的烷氧基较佳地为
Figure PCTCN2016088089-appb-000119
Figure PCTCN2016088089-appb-000120
In R 4 or R 5 , when the substitution described in the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkoxy group, the substituted The C 1 -C 4 alkoxy group is preferably
Figure PCTCN2016088089-appb-000119
Figure PCTCN2016088089-appb-000120
R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代，所述的取代或未取代的C2-C6的杂环烷基中所述的取代为被取代或未取代的C1-C4的烷基所取代，所述的取代的C1-C4的烷基中所述的取代为被C3-C6的环烷基所取代时，所述的C3-C6的环烷基较佳地为环丙基、环丁基、环戊基或环己基。In R 4 or R 5 , when the substituted C 5 -C 10 aryl group is substituted with a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, the substitution or The substituent described in the unsubstituted C 2 -C 6 heterocycloalkyl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group, wherein the substituted C 1 -C 4 alkyl group is When the substitution is substituted by a C 3 -C 6 cycloalkyl group, the C 3 -C 6 cycloalkyl group is preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.
R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代，所述的取代的C2-C6的杂环烷基中所述的取代为被取代或未取代的C1-C4的烷基所取代，所述的取代的C1-C4的烷基中所述的取代为被取代或未取代的C1-C4的烷氧基所取代，所述的取代的C1-C4的烷氧基中所述的取代为C5-C10的芳基时，所述的C5-C10的芳基较佳地为苯基。所述的取代或未取代的C1-C4的烷氧基较佳地为取代或未取代的甲氧基、取代或未取代的乙氧基、取代或未取代的正丙氧基、取代或未取代的异丙氧基、取代或未取代的正丁氧基、取代或未取代的异丁氧基或者取代或未取代的叔丁氧基。In R 4 or R 5 , when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, the substituted The substitution in the C 2 -C 6 heterocycloalkyl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group as described in the substituted C 1 -C 4 alkyl group. When the substitution is a substituted or unsubstituted C 1 -C 4 alkoxy group, when the substitution described in the substituted C 1 -C 4 alkoxy group is a C 5 -C 10 aryl group, The C 5 -C 10 aryl group is preferably a phenyl group. The substituted or unsubstituted C 1 -C 4 alkoxy group is preferably a substituted or unsubstituted methoxy group, a substituted or unsubstituted ethoxy group, a substituted or unsubstituted n-propoxy group, or a substituted group. Or an unsubstituted isopropoxy group, a substituted or unsubstituted n-butoxy group, a substituted or unsubstituted isobutoxy group or a substituted or unsubstituted tert-butoxy group.
R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代，所述的取代的C2-C6的杂环烷基中所述的取代为被取代或未取代的C1-C4的烷基所取代时，所述的取代或未取代的C1-C4的烷基较佳地为取代或未取代的甲基、取代或未取代的乙基、取代或未取代的正丙基、取代或未取代的异丙基、取代或未取代的正丁基、取代或未取代的异丁基或者取代或未取代的叔丁基。In R 4 or R 5 , when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, the substituted The substituted or unsubstituted C 1 -C 4 alkyl group when the substituent described in the C 2 -C 6 heterocycloalkyl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group Preferred are substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted Substituted isobutyl or substituted or unsubstituted t-butyl.
R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被取代或未取代的C2-C6的 杂环烷基所取代，所述的取代的C2-C6的杂环烷基中所述的取代为被
Figure PCTCN2016088089-appb-000121
所取代，R21为取代或未取代的C1-C4的烷基时，所述的取代或未取代的C1-C4的烷基较佳地为取代或未取代的甲基、取代或未取代的乙基、取代或未取代的正丙基、取代或未取代的异丙基、取代或未取代的正丁基、取代或未取代的异丁基或者取代或未取代的叔丁基。In R 4 or R 5 , when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, the substituted The substitution described in the C 2 -C 6 heterocycloalkyl group is
Figure PCTCN2016088089-appb-000121
When R 21 is a substituted or unsubstituted C 1 -C 4 alkyl group, the substituted or unsubstituted C 1 -C 4 alkyl group is preferably a substituted or unsubstituted methyl group, substituted Or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl or substituted or unsubstituted tert-butyl base.
R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代，所述的取代的C2-C6的杂环烷基中所述的取代为被
Figure PCTCN2016088089-appb-000122
所取代，R21为
Figure PCTCN2016088089-appb-000123
Ra11或Ra12独立地为C1-C4的烷基时，所述的C1-C4的烷基较佳地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基。In R 4 or R 5 , when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, the substituted The substitution described in the C 2 -C 6 heterocycloalkyl group is
Figure PCTCN2016088089-appb-000122
Substituted, R 21 is
Figure PCTCN2016088089-appb-000123
When R a11 or R a12 is independently a C 1 -C 4 alkyl group, the C 1 -C 4 alkyl group is preferably methyl, ethyl, n-propyl, isopropyl or n-butyl. , isobutyl or tert-butyl.
R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代，所述的取代的C2-C6的杂环烷基中所述的取代为被
Figure PCTCN2016088089-appb-000124
所取代，R22为C1-C4的烷基时，所述的C1-C4的烷基较佳地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基。In R 4 or R 5 , when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, the substituted The substitution described in the C 2 -C 6 heterocycloalkyl group is
Figure PCTCN2016088089-appb-000124
When R 22 is a C 1 -C 4 alkyl group, the C 1 -C 4 alkyl group is preferably a methyl group, an ethyl group, a n-propyl group, an isopropyl group, an n-butyl group or a different group. Butyl or tert-butyl.
R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代时，所述的取代或未取代的C2-C6的杂环烷基较佳地是指杂原子选自O、N和S，杂原子数为1～4个(优选1～2个)的取代或未取代的C2-C6的杂环烷基。所述的取代或未取代的C2-C6的杂环烷基较佳地为取代或未取代的四氢吡咯基
Figure PCTCN2016088089-appb-000125
取代或未取代的哌啶基
Figure PCTCN2016088089-appb-000126
取代或未取代的吗啉基
Figure PCTCN2016088089-appb-000127
或者取代或未取代的哌嗪基
Figure PCTCN2016088089-appb-000128
所述的取代的哌嗪基中，取代基较佳地位于哌嗪基的N原子上，例如
Figure PCTCN2016088089-appb-000129
其中，Rt表示取代基，Rt较佳地为1-2个，当为两个时，形成季铵盐。所述的取代的C2-C6的杂环烷基较佳地为
Figure PCTCN2016088089-appb-000130
Figure PCTCN2016088089-appb-000131
Figure PCTCN2016088089-appb-000132
或者
Figure PCTCN2016088089-appb-000133
In R 4 or R 5 , when the substitution described in the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, the substitution Or an unsubstituted C 2 -C 6 heterocycloalkyl group preferably means a hetero atom selected from O, N and S, and a heteroatom number of 1 to 4 (preferably 1 to 2) substituted or unsubstituted C 2 -C 6 heterocycloalkyl. The substituted or unsubstituted C 2 -C 6 heterocycloalkyl group is preferably a substituted or unsubstituted tetrahydropyrrolyl group.
Figure PCTCN2016088089-appb-000125
Substituted or unsubstituted piperidinyl
Figure PCTCN2016088089-appb-000126
Substituted or unsubstituted morpholinyl
Figure PCTCN2016088089-appb-000127
Or substituted or unsubstituted piperazinyl
Figure PCTCN2016088089-appb-000128
In the substituted piperazinyl group, the substituent is preferably located on the N atom of the piperazinyl group, for example
Figure PCTCN2016088089-appb-000129
Wherein R t represents a substituent, and R t is preferably from 1 to 2, and when two, a quaternary ammonium salt is formed. The substituted C 2 -C 6 heterocycloalkyl group is preferably
Figure PCTCN2016088089-appb-000130
Figure PCTCN2016088089-appb-000131
Figure PCTCN2016088089-appb-000132
or
Figure PCTCN2016088089-appb-000133
R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被取代或未取代的C5-C10的芳基所取代，所述的取代或未取代的C5-C10中所述的取代的C5-C10的芳基中所述的取代为被C1-C4的烷氧基所取代时，所述的C1-C4的烷氧基较佳地为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基或者叔丁氧基。In R 4 or R 5 , when the substituted C 5 -C 10 aryl group is substituted with a substituted or unsubstituted C 5 -C 10 aryl group, the substituted or unsubstituted the C 5 -C 10 substituted in the aryl group in the C 5 -C 10 substituent is substituted by C 1 -C 4 alkoxy, said C 1 -C 4 alkyl is The oxy group is preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy.
R4或R5中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C5-C10的芳基所取代时，所述的取代或未取代的C5-C10的芳基较佳地为取代或未取代的苯基。In R 4 or R 5 , when the substitution described in the substituted C 5 -C 10 aryl group is substituted with a substituted or unsubstituted C 5 -C 10 aryl group, the substitution or The unsubstituted C 5 -C 10 aryl group is preferably a substituted or unsubstituted phenyl group.
R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被
Figure PCTCN2016088089-appb-000134
所取代，所述的R14为C1-C4的烷氧基时，所述的C1-C4的烷氧基较佳地为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基或者叔丁氧基。In R 4 or R 5 , when the substituted C 5 -C 10 aryl group is substituted as described
Figure PCTCN2016088089-appb-000134
When the R 14 is a C 1 -C 4 alkoxy group, the C 1 -C 4 alkoxy group is preferably a methoxy group, an ethoxy group, a n-propoxy group or a different group. Propyloxy, n-butoxy, isobutoxy or tert-butoxy.
R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被
Figure PCTCN2016088089-appb-000135
所取代，所述的R14为
Figure PCTCN2016088089-appb-000136
Ra7或Ra8独立地为取代或未取代的C1-C4的烷基，所述的取代的C1-C4的烷基为被C2-C6的杂环烷基所取代时，所述的C2-C6的杂环烷基较佳地是指杂原子选自O、N和S，杂原子数为1～4个(优选1～2个)的C2-C6的杂环烷基。所述的C2-C6的杂环烷基较佳地为四氢吡咯基
Figure PCTCN2016088089-appb-000137
Ra7或Ra8中，所述的取代或未取代的C1-C4的烷基较佳地为取代或未取代的甲基、取代或未取代的乙基、取代或未取代的正丙基、取代或未取代 的异丙基、取代或未取代的正丁基、取代或未取代的异丁基或者取代或未取代的叔丁基。In R 4 or R 5 , when the substituted C 5 -C 10 aryl group is substituted as described
Figure PCTCN2016088089-appb-000135
Substituted, the R 14 is
Figure PCTCN2016088089-appb-000136
R a7 or R a8 is independently a substituted or unsubstituted C 1 -C 4 alkyl group, and the substituted C 1 -C 4 alkyl group is substituted by a C 2 -C 6 heterocycloalkyl group. said C 2 -C 6 heterocycloalkyl means is preferably a heteroatom selected from O, N and S, the number of hetero atoms of 1 to 4 (preferably 1 to 2) a C 2 -C 6 Heterocycloalkyl. The C 2 -C 6 heterocycloalkyl group is preferably a tetrahydropyrrolyl group.
Figure PCTCN2016088089-appb-000137
In R a7 or R a8 , the substituted or unsubstituted C 1 -C 4 alkyl group is preferably a substituted or unsubstituted methyl group, a substituted or unsubstituted ethyl group, a substituted or unsubstituted n-propyl group. A benzyl, substituted or unsubstituted isopropyl group, a substituted or unsubstituted n-butyl group, a substituted or unsubstituted isobutyl group or a substituted or unsubstituted tert-butyl group.
R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被
Figure PCTCN2016088089-appb-000138
所取代时，所述的
Figure PCTCN2016088089-appb-000139
较佳地为
Figure PCTCN2016088089-appb-000140
或者
Figure PCTCN2016088089-appb-000141
In R 4 or R 5 , when the substituted C 5 -C 10 aryl group is substituted as described
Figure PCTCN2016088089-appb-000138
When replaced, the stated
Figure PCTCN2016088089-appb-000139
Preferably
Figure PCTCN2016088089-appb-000140
or
Figure PCTCN2016088089-appb-000141
R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被
Figure PCTCN2016088089-appb-000142
所取代，R15为C1-C4的烷基时，所述的C1-C4的烷基较佳地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或者叔丁基。In R 4 or R 5 , when the substituted C 5 -C 10 aryl group is substituted as described
Figure PCTCN2016088089-appb-000142
When R 15 is a C 1 -C 4 alkyl group, the C 1 -C 4 alkyl group is preferably a methyl group, an ethyl group, a n-propyl group, an isopropyl group, an n-butyl group or a different group. Butyl or tert-butyl.
R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被
Figure PCTCN2016088089-appb-000143
所取代，R15为
Figure PCTCN2016088089-appb-000144
Ra9或Ra10独立地为取代或未取代的C1-C4的烷基，所述的取代的C1-C4的烷基中所述的取代为被C2-C6的杂环烷基所取代时，所述的C2-C6的杂环烷基较佳地是指杂原子选自O、N和S，杂原子数为1～4个(优选1～2个)的C2-C6的杂环烷基。所述的C2-C6的杂环烷基较佳地为四氢吡咯基
Figure PCTCN2016088089-appb-000145
或者吗啉基
Figure PCTCN2016088089-appb-000146
所述的取代或未取代的C1-C4的烷基较佳地为取代或未取代的甲基、取代或未取代的乙基、取代或未取代的正丙基、取代或未取代的异丙基、取代或未取代的正丁基、取代或未取代的异丁基或者取代或未取代的叔丁基。In R 4 or R 5 , when the substituted C 5 -C 10 aryl group is substituted as described
Figure PCTCN2016088089-appb-000143
Substituted, R 15 is
Figure PCTCN2016088089-appb-000144
R a9 or R a10 is independently a substituted or unsubstituted C 1 -C 4 alkyl group, and the substituent described in the substituted C 1 -C 4 alkyl group is a C 2 -C 6 heterocyclic ring When the alkyl group is substituted, the C 2 -C 6 heterocycloalkyl group preferably means that the hetero atom is selected from O, N and S, and the number of hetero atoms is from 1 to 4 (preferably from 1 to 2). C 2 -C 6 heterocycloalkyl. The C 2 -C 6 heterocycloalkyl group is preferably a tetrahydropyrrolyl group.
Figure PCTCN2016088089-appb-000145
Morpholinyl
Figure PCTCN2016088089-appb-000146
The substituted or unsubstituted C 1 -C 4 alkyl group is preferably a substituted or unsubstituted methyl group, a substituted or unsubstituted ethyl group, a substituted or unsubstituted n-propyl group, a substituted or unsubstituted one. Isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl or substituted or unsubstituted t-butyl.
R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被
Figure PCTCN2016088089-appb-000147
所取代，R15为取代或未取代的C2-C6的杂环烷基，所述的取代的C2-C6的杂环烷基为被C1-C4的烷基所取代时，所述的C1-C4的烷基较佳地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基。所述的取代或未取代的C2-C6的杂环烷基较佳地是指杂原子选自O、N和S，杂原子数为1～4个(优选1～2个)的C2-C6的杂环烷基。所述的C2-C6的杂环烷基较佳地为哌嗪基
Figure PCTCN2016088089-appb-000148
In R 4 or R 5 , when the substituted C 5 -C 10 aryl group is substituted as described
Figure PCTCN2016088089-appb-000147
Substituted, R 15 is a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, and the substituted C 2 -C 6 heterocycloalkyl group is substituted by a C 1 -C 4 alkyl group. The C 1 -C 4 alkyl group is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. The substituted or unsubstituted C 2 -C 6 heterocycloalkyl group preferably means a C atom having a hetero atom selected from O, N and S and having 1 to 4 (preferably 1 to 2) hetero atoms. 2- C 6 heterocycloalkyl. The C 2 -C 6 heterocycloalkyl group is preferably piperazinyl
Figure PCTCN2016088089-appb-000148
R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被
Figure PCTCN2016088089-appb-000149
所取代时，所述 的
Figure PCTCN2016088089-appb-000150
较佳地为
Figure PCTCN2016088089-appb-000151
Figure PCTCN2016088089-appb-000152
In R 4 or R 5 , when the substituted C 5 -C 10 aryl group is substituted as described
Figure PCTCN2016088089-appb-000149
When replaced, the
Figure PCTCN2016088089-appb-000150
Preferably
Figure PCTCN2016088089-appb-000151
Figure PCTCN2016088089-appb-000152
R1、R2或R3中，所述的取代的C5-C10的芳基较佳地为取代的苯基。所述的取代的苯基较佳地为
Figure PCTCN2016088089-appb-000153
Figure PCTCN2016088089-appb-000154
Figure PCTCN2016088089-appb-000155
Figure PCTCN2016088089-appb-000156
或者
Figure PCTCN2016088089-appb-000157
In R 1 , R 2 or R 3 , the substituted C 5 -C 10 aryl group is preferably a substituted phenyl group. The substituted phenyl group is preferably
Figure PCTCN2016088089-appb-000153
Figure PCTCN2016088089-appb-000154
Figure PCTCN2016088089-appb-000155
Figure PCTCN2016088089-appb-000156
or
Figure PCTCN2016088089-appb-000157
R1、R2或R3中，所述的取代或未取代的C2-C6的杂芳基较佳地是指杂原子选自O、N和S，杂原子数为1～4个(优选1～2个)的取代或未取代的C2-C6的杂芳基。所述的取代或未取代的C2-C6的杂芳基较佳地为取代或未取代的吡啶基(例如
Figure PCTCN2016088089-appb-000158
)或者取代或未取代的吡唑基(例如
Figure PCTCN2016088089-appb-000159
)。当所述的取代的C2-C6的杂芳基为取代的吡唑基时，所述的取代的吡啶基为
Figure PCTCN2016088089-appb-000160
Rn表示取代基；当所述的取代的C2-C6的杂芳基为取代的吡啶基时，所述的吡啶基为
Figure PCTCN2016088089-appb-000161
Rn表示取代基。所述的取代的吡啶基较佳地为
Figure PCTCN2016088089-appb-000162
或者
Figure PCTCN2016088089-appb-000163
所述的取代的吡唑基较佳地为
Figure PCTCN2016088089-appb-000164
Figure PCTCN2016088089-appb-000165
Figure PCTCN2016088089-appb-000166
或者
Figure PCTCN2016088089-appb-000167
In R 1 , R 2 or R 3 , the substituted or unsubstituted C 2 -C 6 heteroaryl group preferably means that the hetero atom is selected from O, N and S, and the number of hetero atoms is 1 to 4 (preferably 1 to 2) substituted or unsubstituted C 2 -C 6 heteroaryl groups. The substituted or unsubstituted C 2 -C 6 heteroaryl group is preferably a substituted or unsubstituted pyridyl group (for example
Figure PCTCN2016088089-appb-000158
Or a substituted or unsubstituted pyrazolyl group (eg
Figure PCTCN2016088089-appb-000159
). When the substituted C 2 -C 6 heteroaryl group is a substituted pyrazolyl group, the substituted pyridyl group is
Figure PCTCN2016088089-appb-000160
R n represents a substituent; when the substituted C 2 -C 6 heteroaryl group is a substituted pyridyl group, the pyridyl group is
Figure PCTCN2016088089-appb-000161
R n represents a substituent. The substituted pyridyl group is preferably
Figure PCTCN2016088089-appb-000162
or
Figure PCTCN2016088089-appb-000163
The substituted pyrazolyl group is preferably
Figure PCTCN2016088089-appb-000164
Figure PCTCN2016088089-appb-000165
Figure PCTCN2016088089-appb-000166
or
Figure PCTCN2016088089-appb-000167
R1、R2或R3中，所述的C2-C6的杂环烷基较佳地是指杂原子选自O、N和S，杂原子数为1～4个(优选1～2个)的C2-C6的杂环烷基。所述的C2-C6的杂环烷基较佳地为吗啉基
Figure PCTCN2016088089-appb-000168
In R 1 , R 2 or R 3 , the C 2 -C 6 heterocycloalkyl group preferably means that the hetero atom is selected from O, N and S, and the number of hetero atoms is from 1 to 4 (preferably 1 to). 2) C 2 -C 6 heterocycloalkyl. The C 2 -C 6 heterocycloalkyl group is preferably morpholinyl
Figure PCTCN2016088089-appb-000168
R4或R5中，所述的取代或未取代的C1-C4的烷基较佳地为取代或未取代的甲基、取代或未取代的乙基、取代或未取代的正丙基、取代或未取代的异丙基、取代或未取代的正丁基、取代或未取代的异丁基或者取代或未取代的叔丁基。所述的取代的C1-C4的烷基较佳地为
Figure PCTCN2016088089-appb-000169
In R 4 or R 5 , the substituted or unsubstituted C 1 -C 4 alkyl group is preferably a substituted or unsubstituted methyl group, a substituted or unsubstituted ethyl group, a substituted or unsubstituted n-propyl group. A benzyl, substituted or unsubstituted isopropyl group, a substituted or unsubstituted n-butyl group, a substituted or unsubstituted isobutyl group or a substituted or unsubstituted tert-butyl group. The substituted C 1 -C 4 alkyl group is preferably
Figure PCTCN2016088089-appb-000169
R4或R5中，所述的取代或未取代的C5-C10的芳基较佳地为取代或未取代的苯基。所述的取代的苯基较佳地为
Figure PCTCN2016088089-appb-000170
Figure PCTCN2016088089-appb-000171
In R 4 or R 5 , the substituted or unsubstituted C 5 -C 10 aryl group is preferably a substituted or unsubstituted phenyl group. The substituted phenyl group is preferably
Figure PCTCN2016088089-appb-000170
Figure PCTCN2016088089-appb-000171
Figure PCTCN2016088089-appb-000172
Figure PCTCN2016088089-appb-000172
Figure PCTCN2016088089-appb-000173
或者
Figure PCTCN2016088089-appb-000174
Figure PCTCN2016088089-appb-000173
or
Figure PCTCN2016088089-appb-000174
R4或R5中，所述的取代的C2-C6的杂芳基较佳地是指杂原子选自O、N和S，杂原子数为1～4个(优选1～2个)的取代的C2-C6的杂芳基。所述的取代的C2-C6的杂芳基较佳地为取代的吡啶基(
Figure PCTCN2016088089-appb-000175
Rm表示取代基)或取代的嘧啶基(
Figure PCTCN2016088089-appb-000176
Rm表示取代基)。所述的取代的吡啶基较佳地为
Figure PCTCN2016088089-appb-000177
所述的取代的嘧啶基较佳地为
Figure PCTCN2016088089-appb-000178
In R 4 or R 5 , the substituted C 2 -C 6 heteroaryl group preferably means that the hetero atom is selected from O, N and S, and the number of hetero atoms is from 1 to 4 (preferably from 1 to 2). Substituted C 2 -C 6 heteroaryl. The substituted C 2 -C 6 heteroaryl group is preferably a substituted pyridyl group (
Figure PCTCN2016088089-appb-000175
R m represents a substituent) or a substituted pyrimidinyl group (
Figure PCTCN2016088089-appb-000176
R m represents a substituent). The substituted pyridyl group is preferably
Figure PCTCN2016088089-appb-000177
The substituted pyrimidinyl group is preferably
Figure PCTCN2016088089-appb-000178
当R4或R5为
Figure PCTCN2016088089-appb-000179
时，R0为取代的C1-C4的烷基时，所述的取代的C1-C4的烷基较佳地为取代的甲基、取代的乙基、取代的正丙基、取代的异丙基、取代的正丁基、取代的异丁基或者取代的叔丁基。所述的取代的C1-C4的烷基较佳地为
Figure PCTCN2016088089-appb-000180
Figure PCTCN2016088089-appb-000181
When R 4 or R 5 is
Figure PCTCN2016088089-appb-000179
When R 0 is a substituted C 1 -C 4 alkyl group, the substituted C 1 -C 4 alkyl group is preferably a substituted methyl group, a substituted ethyl group, a substituted n-propyl group, Substituted isopropyl, substituted n-butyl, substituted isobutyl or substituted t-butyl. The substituted C 1 -C 4 alkyl group is preferably
Figure PCTCN2016088089-appb-000180
Figure PCTCN2016088089-appb-000181
当R4或R5为
Figure PCTCN2016088089-appb-000182
时，R0为C3-C6的环烷基时，所述的C3-C6的环烷基较佳地为环丙基、环丁基、环戊基或环己基。When R 4 or R 5 is
Figure PCTCN2016088089-appb-000182
When R 0 is a C 3 -C 6 cycloalkyl group, the C 3 -C 6 cycloalkyl group is preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.
所述的
Figure PCTCN2016088089-appb-000183
较佳地为
Figure PCTCN2016088089-appb-000184
或者
Figure PCTCN2016088089-appb-000185
Said
Figure PCTCN2016088089-appb-000183
Preferably
Figure PCTCN2016088089-appb-000184
or
Figure PCTCN2016088089-appb-000185
在本发明一较佳实施例中，通式I所示的喹唑啉类化合物中，R1和R2为氢；R3为取代的C5-C10的芳基或者取代或未取代的C2-C6的杂芳基。In a preferred embodiment of the invention, in the quinazoline compound of the formula I, R 1 and R 2 are hydrogen; R 3 is a substituted C 5 -C 10 aryl group or a substituted or unsubstituted a C 2 -C 6 heteroaryl group.
在本发明一较佳实施例中，通式I所示的喹唑啉类化合物较佳地为通式I-a、通式I- b、通式I-c、通式I-d、通式I-e、通式I-f、通式I-g、通式I-h、通式I-i、通式I-k所示的化合物；In a preferred embodiment of the invention, the quinazoline compound of formula I is preferably of formula I-a, formula I- b, a compound of the formula I-c, formula I-d, formula I-e, formula I-f, formula I-g, formula I-h, formula I-i, formula I-k;
Figure PCTCN2016088089-appb-000186
Figure PCTCN2016088089-appb-000186
Figure PCTCN2016088089-appb-000187
Figure PCTCN2016088089-appb-000187
通式I-a化合物中，In the compound of formula I-a,
Rp1、Rp2和Rp3独立地为氢、取代的C1-C4的烷基、取代或未取代的C1-C4的烷氧基或者
Figure PCTCN2016088089-appb-000188
R15为C1-C4的烷基或者
Figure PCTCN2016088089-appb-000189
Ra9和Ra10独立地为氢或者C1-C4的烷基；Rp1、Rp2和Rp3不同时为氢；R p1 , R p2 and R p3 are independently hydrogen, substituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 alkoxy or
Figure PCTCN2016088089-appb-000188
R 15 is a C 1 -C 4 alkyl group or
Figure PCTCN2016088089-appb-000189
R a9 and R a10 are independently hydrogen or a C 1 -C 4 alkyl group; R p1 , R p2 and R p3 are not simultaneously hydrogen;
Rm1为C1-C4的烷氧基、取代或未取代的C2-C6的杂环烷基、
Figure PCTCN2016088089-appb-000190
或者
Figure PCTCN2016088089-appb-000191
其中R6为C1-C4的烷基或者
Figure PCTCN2016088089-appb-000192
Ra1和Ra2独立地为氢、取代或未取代的C1-C4的烷基或C5-C10的芳基；R9为取代或未取代的C1-C4的烷基；R m1 is a C 1 -C 4 alkoxy group, a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group,
Figure PCTCN2016088089-appb-000190
or
Figure PCTCN2016088089-appb-000191
Wherein R 6 is a C 1 -C 4 alkyl group or
Figure PCTCN2016088089-appb-000192
R a1 and R a2 are independently hydrogen, a substituted or unsubstituted C 1 -C 4 alkyl group or a C 5 -C 10 aryl group; R 9 is a substituted or unsubstituted C 1 -C 4 alkyl group;
通式I-b化合物中，In the compound of formula I-b,
Rm2、Rm3和Rm4独立地为氢、羟基、取代或未取代的C1-C4的烷氧基、C2-C6的杂环烷基、硝基、
Figure PCTCN2016088089-appb-000193
其中R6为C1-C4的烷基、C3-C6的环烷基或者
Figure PCTCN2016088089-appb-000194
Ra1和Ra2独立地为氢或者取代或未取代的C1-C4的烷基；R7和R8独立地为 氢、C1-C4的烷基、
Figure PCTCN2016088089-appb-000195
Ra3为C1-C4的烷基或者C3-C6的环烷基；Ra4为取代或未取代的C1-C4的烷基或者C3-C6的环烷基；R9为取代或未取代的C1-C4的烷基；R m2 , R m3 and R m4 are independently hydrogen, hydroxy, substituted or unsubstituted C 1 -C 4 alkoxy, C 2 -C 6 heterocycloalkyl, nitro,
Figure PCTCN2016088089-appb-000193
Wherein R 6 is a C 1 -C 4 alkyl group, a C 3 -C 6 cycloalkyl group or
Figure PCTCN2016088089-appb-000194
R a1 and R a2 are independently hydrogen or a substituted or unsubstituted C 1 -C 4 alkyl group; R 7 and R 8 are independently hydrogen, C 1 -C 4 alkyl,
Figure PCTCN2016088089-appb-000195
R a3 is a C 1 -C 4 alkyl group or a C 3 -C 6 cycloalkyl group; R a4 is a substituted or unsubstituted C 1 -C 4 alkyl group or a C 3 -C 6 cycloalkyl group; 9 is a substituted or unsubstituted C 1 -C 4 alkyl group;
R5为氢或取代的C1-C4的烷基；R5中，所述的取代的C1-C4的烷基中所述的取代是指被一个或多个(例如1-6个，优选1-2个)取代或未取代的C2-C6的杂芳基所取代，所述的取代的C2-C6的杂芳基中所述的取代是指被一个或多个(例如1-6个，优选1-2个)氰基所取代；R 5 is hydrogen or a substituted C 1 -C 4 alkyl group; in R 5 , the substitution described in the substituted C 1 -C 4 alkyl group means one or more (for example, 1-6 Substituted, preferably 1-2, substituted or unsubstituted C 2 -C 6 heteroaryl groups, said substituted C 2 -C 6 heteroaryl group referred to as one or more Substituted (for example, 1-6, preferably 1-2) cyano groups;
Rp4为氢或卤素；R p4 is hydrogen or halogen;
Rt1为取代或未取代的C1-C4的烷基或者
Figure PCTCN2016088089-appb-000196
R21为取代或未取代的C1-C4的烷基或者
Figure PCTCN2016088089-appb-000197
Ra11和Ra12独立地为C1-C4的烷基；当R21为取代的C1-C4的烷基时，所述的取代是指被一个或多个(例如1-6个，优选1-2个)氰基所取代；Rm2、Rm3和Rm4不同时为氢；R t1 is a substituted or unsubstituted C 1 -C 4 alkyl group or
Figure PCTCN2016088089-appb-000196
R 21 is a substituted or unsubstituted C 1 -C 4 alkyl group or
Figure PCTCN2016088089-appb-000197
R a11 and R a12 are independently a C 1 -C 4 alkyl group; when R 21 is a substituted C 1 -C 4 alkyl group, the substitution means one or more (for example, 1-6 , preferably 1-2) substituted by a cyano group; R m2 , R m3 and R m4 are not simultaneously hydrogen;
通式I-c化合物中，In the compound of formula I-c,
Rt3为C1-C4的烷基；R t3 is a C 1 -C 4 alkyl group;
Rt2为取代的C1-C4的烷基或O，Rt2中，所述的取代的C1-C4的烷基中所述的取代为被一个或多个(例如1-6个，优选1-2个)卤素所取代；R t2 is a substituted C 1 -C 4 alkyl group or O, and in R t2 , the substitution in the substituted C 1 -C 4 alkyl group is one or more (for example, 1-6 , preferably 1-2) substituted by halogen;
Rm5为C1-C4的烷基；R m5 is a C 1 -C 4 alkyl group;
通式I-d化合物中，In the compound of formula I-d,
Rm6为取代的C1-C4的烷基、取代或未取代的C1-C4的烷氧基、C2-C6的杂环烷基、硝基、
Figure PCTCN2016088089-appb-000198
其中R6为C1-C4的烷基、C3-C6的环烷基或者
Figure PCTCN2016088089-appb-000199
Ra1和Ra2独立地为氢或者取代或未取代的C1-C4的烷基；R7和R8独立地为氢或
Figure PCTCN2016088089-appb-000200
Ra4为取代或未取代的C1-C4的烷基；R9为取代或未取代的C1-C4的烷基；R m6 is a substituted C 1 -C 4 alkyl group, a substituted or unsubstituted C 1 -C 4 alkoxy group, a C 2 -C 6 heterocycloalkyl group, a nitro group,
Figure PCTCN2016088089-appb-000198
Wherein R 6 is a C 1 -C 4 alkyl group, a C 3 -C 6 cycloalkyl group or
Figure PCTCN2016088089-appb-000199
R a1 and R a2 are independently hydrogen or a substituted or unsubstituted C 1 -C 4 alkyl group; R 7 and R 8 are independently hydrogen or
Figure PCTCN2016088089-appb-000200
R a4 is a substituted or unsubstituted C 1 -C 4 alkyl group; R 9 is a substituted or unsubstituted C 1 -C 4 alkyl group;
Rp5为氢、硝基或者取代的C1-C4的烷基；R p5 is hydrogen, nitro or substituted C 1 -C 4 alkyl;
Rt4为取代或未取代的C1-C4的烷基或者
Figure PCTCN2016088089-appb-000201
R21为取代或未取代的C1-C4的烷 基；当R21为取代的C1-C4的烷基时，所述的取代是指被一个或多个(例如1-6个，优选1-2个)氰基所取代；R t4 is a substituted or unsubstituted C 1 -C 4 alkyl group or
Figure PCTCN2016088089-appb-000201
R 21 is a substituted or unsubstituted C 1 -C 4 alkyl group; when R 21 is a substituted C 1 -C 4 alkyl group, the substitution means one or more (for example, 1-6 , preferably 1-2) substituted by a cyano group;
通式化合物I-e中，Rm7为
Figure PCTCN2016088089-appb-000202
其中，R6为
Figure PCTCN2016088089-appb-000203
R9为取代的C1-C4的烷基。In the general formula Ie, R m7 is
Figure PCTCN2016088089-appb-000202
Where R 6 is
Figure PCTCN2016088089-appb-000203
R 9 is a substituted C 1 -C 4 alkyl group.
通式化合物I-f中，Rm8为C1-C4的烷氧基；In the compound of the formula If, R m8 is a C 1 -C 4 alkoxy group;
通式化合物I-g或I-h化合物中，In the compound of the formula I-g or I-h,
Rn1和Rn2独立地为氢、取代或未取代的C1-C4的烷基、取代或未取代的C2-C6的杂环烷基或者
Figure PCTCN2016088089-appb-000204
R10为C1-C4的烷基；R n1 and R n2 are independently hydrogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 2 -C 6 heterocycloalkyl or
Figure PCTCN2016088089-appb-000204
R 10 is a C 1 -C 4 alkyl group;
Rt5和Rt6独立地为取代或未取代的C1-C4的烷基或者
Figure PCTCN2016088089-appb-000205
R21为C1-C4的烷基；R t5 and R t6 are independently a substituted or unsubstituted C 1 -C 4 alkyl group or
Figure PCTCN2016088089-appb-000205
R 21 is a C 1 -C 4 alkyl group;
化合物I-i中，Rt7为C1-C4的烷基；Rn3为C1-C4的烷氧基；In compound Ii, R t7 is C 1 -C 4 alkyl; R n3 is C 1 -C 4 alkoxy;
化合物I-j中，Rm9为C1-C4的烷氧基；In compound Ij, R m9 is a C 1 -C 4 alkoxy group;
化合物I-k中，Rt8和Rt9独立地为氢、羟基或者C2-C6的杂环烷基；Rm10为C1-C4的烷氧基；In compound Ik, R t8 and R t9 are independently hydrogen, hydroxy or C 2 -C 6 heterocycloalkyl; R m10 is C 1 -C 4 alkoxy;
上述各通式化合物中，Among the above compounds of the general formula,
Rp1、Rp2、Rp3或Rp5中，所述的取代的C1-C4的烷基中所述的取代是指被下列取代基中的一个或多个(例如1-6个，优选1-2个)所取代：取代或未取代的C2-C6的杂环烷基或者
Figure PCTCN2016088089-appb-000206
R16和R17独立地为C1-C4的烷基；所述的取代的C2-C6的杂环烷基中所述的取代是指被下列取代基中的一个或多个(例如1-6个，优选1-2个)所取代：C1-C4的烷基或者
Figure PCTCN2016088089-appb-000207
Ra11为C1-C4的烷基；In R p1 , R p2 , R p3 or R p5 , the substitution in the substituted C 1 -C 4 alkyl group means one or more of the following substituents (for example, 1-6, Preferably 1-2) substituted: substituted or unsubstituted C 2 -C 6 heterocycloalkyl or
Figure PCTCN2016088089-appb-000206
R 16 and R 17 are independently a C 1 -C 4 alkyl group; the substitution described in the substituted C 2 -C 6 heterocycloalkyl group means one or more of the following substituents ( For example, 1-6, preferably 1-2) are substituted: C 1 -C 4 alkyl or
Figure PCTCN2016088089-appb-000207
R a11 is a C 1 -C 4 alkyl group;
Rp1、Rp2和Rp3中，所述的取代的C1-C4的烷氧基中所述的取代是指被下列取代基中的一个或多个(例如1-6个，优选1-2个)所取代：C2-C6的杂环烷基、C1-C4的烷氧基、
Figure PCTCN2016088089-appb-000208
或者
Figure PCTCN2016088089-appb-000209
R18为C2-C6的杂环烷基；R19和R20独立地为C1-C4的烷基；In R p1 , R p2 and R p3 , the substitution described in the substituted C 1 -C 4 alkoxy group means one or more of the following substituents (for example, 1-6, preferably 1) -2) substituted: C 2 -C 6 heterocycloalkyl, C 1 -C 4 alkoxy,
Figure PCTCN2016088089-appb-000208
or
Figure PCTCN2016088089-appb-000209
R 18 is C 2 -C 6 heterocycloalkyl; R 19 and R 20 are independently C 1 -C 4 alkyl;
Rm1、Rm2、Rm3或Rm4中，所述的取代的C1-C4的烷氧基中所述的取代是指被下列取代基中的一个或多个(例如1-6个，优选1-2个)所取代：卤素(例如氟、氯、溴或碘，优选 氟)、氰基、取代或未取代的C2-C6的杂芳基、取代或未取代的C5-C10的芳基或者C2-C6的杂环烷基；所述的取代的C2-C6的杂芳基中所述的取代是指被一个或多个(例如1-6个，优选1-2个)氰基所取代；所述的取代的C5-C10的芳基中所述的取代是指被一个或多个(例如1-6个，优选1-2个)C2-C6的杂芳基所取代；In R m1 , R m2 , R m3 or R m4 , the substitution in the substituted C 1 -C 4 alkoxy group means one or more of the following substituents (for example, 1-6 , preferably 1-2) substituted: halogen (eg fluorine, chlorine, bromine or iodine, preferably fluorine), cyano, substituted or unsubstituted C 2 -C 6 heteroaryl, substituted or unsubstituted C 5 -C 10 aryl or C 2 -C 6 heterocycloalkyl; said substituted in the substituted C 2 -C 6 heteroaryl refers to one or more (eg 1-6 , preferably 1-2) substituted by a cyano group; said substitution in said substituted C 5 -C 10 aryl group means one or more (for example, 1-6, preferably 1-2) Substituted by a C 2 -C 6 heteroaryl group;
Rm1、Rm2、Rm3、Rm4或Rm6中，所述的取代的C2-C6的杂环烷基中所述的取代是指被一个或多个(例如1-6个，优选1-2个)C1-C4的烷基所取代；In R m1 , R m2 , R m3 , R m4 or R m6 , the substitution in the substituted C 2 -C 6 heterocycloalkyl group means one or more (for example, 1-6, Preferably 1-2) C 1 -C 4 alkyl groups are substituted;
Ra1或Ra2中，所述的取代的C1-C4的烷基中所述的取代是指被一个或多个(例如1-6个，优选1-2个)氰基所取代；In R a1 or R a2 , the substitution in the substituted C 1 -C 4 alkyl group means substitution by one or more (for example, 1-6, preferably 1-2) cyano groups;
Ra4中，所述的取代的C1-C4的烷基中所述的取代是指被下列取代基中的一个或多个(例如1-6个，优选1-2个)所取代：氰基或者C2-C6的杂环烷基；In R a4 , the substitution in the substituted C 1 -C 4 alkyl group means that it is substituted by one or more of the following substituents (for example, 1-6, preferably 1-2): a cyano group or a C 2 -C 6 heterocycloalkyl group;
R9中；所述的取代的C1-C4的烷基中所述的取代是指被一个或多个(例如1-6个，优选1-2个)氰基所取代；R 9 in the substituted C 1 -C 4 alkyl group means substituted by one or more (for example, 1-6, preferably 1-2) cyano groups;
Rt1、Rt4、Rt5或Rt6中，所述的取代的C1-C4的烷基中所述的取代是指被下列取代基中的一个或多个(例如1-6个，优选1-2个)所取代：羟基、氰基、卤素、C3-C6的环烷基或者取代或未取代的C1-C4的烷氧基；所述的取代的C1-C4的烷氧基中所述的取代是指被一个或多个(例如1-6个，优选1-2个)C5-C10的芳基所取代；In R t1 , R t4 , R t5 or R t6 , the substitution in the substituted C 1 -C 4 alkyl group means one or more of the following substituents (for example, 1-6, Preferably 1-2) are substituted: hydroxy, cyano, halogen, C 3 -C 6 cycloalkyl or substituted or unsubstituted C 1 -C 4 alkoxy; substituted C 1 -C The substitution in the alkoxy group of 4 means that it is substituted by one or more (for example, 1-6, preferably 1-2) C 5 -C 10 aryl groups;
Rn1或Rn2中，所述的取代的C1-C4的烷基中所述的取代是指被下列取代基中的一个或多个(例如1-6个，优选1-2个)所取代：氰基、C3-C6的环烷基、取代或未取代的C2-C6的杂芳基或者取代或未取代的C5-C10的芳基；所述的取代的C2-C6的杂芳基或所述的取代的C5-C10的芳基中所述的取代是指被一个或多个(例如1-6个，优选1-2个)卤素(例如氟、氯、溴或碘，优选溴或氯)所取代；In R n1 or R n2 , the substitution in the substituted C 1 -C 4 alkyl group means one or more of the following substituents (for example, 1-6, preferably 1-2). Substituted: cyano, C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 6 heteroaryl or substituted or unsubstituted C 5 -C 10 aryl; substituted The substitution in the C 2 -C 6 heteroaryl group or the substituted C 5 -C 10 aryl group means one or more (for example, 1-6, preferably 1-2) halogens ( For example, fluorine, chlorine, bromine or iodine, preferably bromine or chlorine;
Rn1或Rn2中，所述的取代的C2-C6的杂环烷基中所述的取代是指被下列取代基中的一个或多个(例如1-6个，优选1-2个)所取代：取代的C1-C4的烷基、
Figure PCTCN2016088089-appb-000210
或者
Figure PCTCN2016088089-appb-000211
R12为C1-C4的烷基或C3-C6的环烷基；R13为C1-C4的烷基；所述的取代的C1-C4的烷基中所述的取代是指被下列取代基中的一个或多个(例如1-6个，优选1-2个)所取代：氰基或
Figure PCTCN2016088089-appb-000212
In R n1 or R n2 , the substitution in the substituted C 2 -C 6 heterocycloalkyl group means one or more of the following substituents (for example, 1-6, preferably 1-2) Substituted: substituted C 1 -C 4 alkyl,
Figure PCTCN2016088089-appb-000210
or
Figure PCTCN2016088089-appb-000211
R 12 is a C 1 -C 4 alkyl group or a C 3 -C 6 cycloalkyl group; R 13 is a C 1 -C 4 alkyl group; said substituted C 1 -C 4 alkyl group Substituted refers to being substituted by one or more of the following substituents (eg, 1-6, preferably 1-2): cyano or
Figure PCTCN2016088089-appb-000212
上述各通式化合物中，如未作特别说明，Rm1～Rm10中各基团的定义均同R1、R2或R3中所述的取代的C5-C10的芳基中取代基的定义；Rn1～Rn3中各基团的定义均同R1、R2或R3中所述的取代的C2-C6的芳基中取代基的定义；Rp1～Rp5中各基团的定义均同R4或R5中所述的取代的C5-C10的芳基中取代基的定义；Rt1～Rt9中各基团的定义均同R4或R5中所述的取代或未取代的C2-C6的杂环烷基取代的C5-C10的芳基中取代的C2-C6的杂环烷 基中取代基的定义。In the above compounds of the general formula, unless otherwise specified, the definition of each group in R m1 to R m10 is substituted with the substituted C 5 -C 10 aryl group described in R 1 , R 2 or R 3 . Definition of a group; each group of R n1 to R n3 is as defined for a substituent in a substituted C 2 -C 6 aryl group as described in R 1 , R 2 or R 3 ; R p1 to R p5 The definition of each group is the same as the definition of the substituent in the substituted C 5 -C 10 aryl group described in R 4 or R 5 ; the definition of each group in R t1 to R t9 is the same as R 4 or R a substituted or unsubstituted C 5 heterocycloalkyl claim 2 -C 6 substituted C 5 -C 10 aryl group substituted in the heterocyclyl a C 2 -C 6 alkyl group in the definition of substituent group.
较佳地，通式I-a化合物中，Preferably, in the compound of formula I-a,
当Rp1、Rp2和Rp3为C1-C4的烷氧基时，Rm1为C1-C4的烷氧基或
Figure PCTCN2016088089-appb-000213
R6为C1-C4的烷基；When R p1 , R p2 and R p3 are C 1 -C 4 alkoxy groups, R m1 is a C 1 -C 4 alkoxy group or
Figure PCTCN2016088089-appb-000213
R 6 is a C 1 -C 4 alkyl group;
当Rp2和Rp3为氢，Rp1为
Figure PCTCN2016088089-appb-000214
R15为C1-C4的烷基时；Rm1为C1-C4的烷基；When R p2 and R p3 are hydrogen, R p1 is
Figure PCTCN2016088089-appb-000214
When R 15 is a C 1 -C 4 alkyl group; R m1 is a C 1 -C 4 alkyl group;
当Rp1和Rp3为氢，Rp2为
Figure PCTCN2016088089-appb-000215
R15为
Figure PCTCN2016088089-appb-000216
时；Rm1为
Figure PCTCN2016088089-appb-000217
取代的C1-C4的烷氧基或者取代或未取代的C2-C6的杂环烷基；其中，R6为C1-C4的烷基；When R p1 and R p3 are hydrogen, R p2 is
Figure PCTCN2016088089-appb-000215
R 15 is
Figure PCTCN2016088089-appb-000216
Time; R m1 is
Figure PCTCN2016088089-appb-000217
a substituted C 1 -C 4 alkoxy group or a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group; wherein R 6 is a C 1 -C 4 alkyl group;
当Rp2和Rp3为氢，Rp1为取代的C1-C4的烷基，所述的取代的C1-C4的烷基中所述的取代为被取代的C2-C6的杂环烷基所取代，所述的取代的C2-C6的杂环烷基中所述的取代被C1-C4的烷基所取代时；Rm1为
Figure PCTCN2016088089-appb-000218
R6为
Figure PCTCN2016088089-appb-000219
When R p2 and R p3 are hydrogen, R p1 is a substituted C 1 -C 4 alkyl group, and the substitution in the substituted C 1 -C 4 alkyl group is a substituted C 2 -C 6 Substituted by a heterocycloalkyl group, wherein the substitution in the substituted C 2 -C 6 heterocycloalkyl group is substituted by a C 1 -C 4 alkyl group; R m1 is
Figure PCTCN2016088089-appb-000218
R 6 is
Figure PCTCN2016088089-appb-000219
当Rp1和Rp3为氢，Rp2为取代的C1-C4的烷基，所述的取代的C1-C4的烷基中的取代基为取代的C2-C6的杂环烷基，所述的取代的C2-C6的杂环烷基中所述的取代被C1-C4的烷基所取代时；Rm1为C1-C4的烷氧基；When R p1 and R p3 are hydrogen, R p2 is a substituted C 1 -C 4 alkyl group, and the substituent in the substituted C 1 -C 4 alkyl group is a substituted C 2 -C 6 hetero a cycloalkyl group, wherein the substitution in the substituted C 2 -C 6 heterocycloalkyl group is substituted by a C 1 -C 4 alkyl group; R m1 is a C 1 -C 4 alkoxy group;
当Rp2和Rp3为氢，Rp1为取代的C1-C4的烷基，所述的取代的C1-C4的烷基中的取代基为取代的C2-C6的杂环烷基，所述的取代的C2-C6的杂环烷基中所述的取代被
Figure PCTCN2016088089-appb-000220
所取代时，Rm1为
Figure PCTCN2016088089-appb-000221
或者
Figure PCTCN2016088089-appb-000222
其中R6为
Figure PCTCN2016088089-appb-000223
When R p2 and R p3 are hydrogen, R p1 is a substituted C 1 -C 4 alkyl group, and the substituent in the substituted C 1 -C 4 alkyl group is a substituted C 2 -C 6 hetero a cycloalkyl group, the substitution described in the substituted C 2 -C 6 heterocycloalkyl group
Figure PCTCN2016088089-appb-000220
When substituted, R m1 is
Figure PCTCN2016088089-appb-000221
or
Figure PCTCN2016088089-appb-000222
Where R 6 is
Figure PCTCN2016088089-appb-000223
当Rp2和Rp3为氢，Rp1为取代的C1-C4的烷基，所述的取代的C1-C4的烷基中所述的取代为被C2-C6的杂环烷基所取代时；Rm1为
Figure PCTCN2016088089-appb-000224
或者
Figure PCTCN2016088089-appb-000225
其中R6为
Figure PCTCN2016088089-appb-000226
R9为取代的C1-C4的烷基；When R p2 and R p3 are hydrogen, R p1 is a substituted C 1 -C 4 alkyl group, and the substitution in the substituted C 1 -C 4 alkyl group is a C 2 -C 6 impurity When a cycloalkyl group is substituted; R m1 is
Figure PCTCN2016088089-appb-000224
or
Figure PCTCN2016088089-appb-000225
Where R 6 is
Figure PCTCN2016088089-appb-000226
R 9 is a substituted C 1 -C 4 alkyl group;
当Rp1和Rp3为氢，Rp2为取代的C1-C4的烷氧基时，Rm1为C1-C4的烷氧基、
Figure PCTCN2016088089-appb-000227
或者取代或未取代的C2-C6的杂环烷基，其中R6为C1-C4的烷基； When R p1 and R p3 are hydrogen and R p2 is a substituted C 1 -C 4 alkoxy group, R m1 is a C 1 -C 4 alkoxy group,
Figure PCTCN2016088089-appb-000227
Or a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, wherein R 6 is a C 1 -C 4 alkyl group;
当Rp2和Rp3为氢，Rp1为取代的C1-C4的烷氧基时，Rm1为C1-C4的烷氧基。When R p2 and R p3 are hydrogen and R p1 is a substituted C 1 -C 4 alkoxy group, R m1 is a C 1 -C 4 alkoxy group.
较佳地，通式I-b化合物中，Preferably, in the compound of formula I-b,
当R5为氢，Rp4为氢，Rt1为取代或未取代的C1-C4的烷基；Rm3和Rm4为氢时，Rm2为取代或未取代的C1-C4的烷氧基、
Figure PCTCN2016088089-appb-000228
硝基、
Figure PCTCN2016088089-appb-000229
或者
Figure PCTCN2016088089-appb-000230
其中R6为C1-C4的烷基或者
Figure PCTCN2016088089-appb-000231
R7和R8独立地为氢、C1-C4的烷基、
Figure PCTCN2016088089-appb-000232
Ra3为C1-C4的烷基或者C3-C6的环烷基；Ra4为取代或未取代的C1-C4的烷基或者C3-C6的环烷基；R9为取代或未取代的C1-C4的烷基；When R 5 is hydrogen, R p4 is hydrogen, R t1 is a substituted or unsubstituted C 1 -C 4 alkyl group; when R m3 and R m4 are hydrogen, R m2 is a substituted or unsubstituted C 1 -C 4 Alkoxy group,
Figure PCTCN2016088089-appb-000228
Nitro,
Figure PCTCN2016088089-appb-000229
or
Figure PCTCN2016088089-appb-000230
Wherein R 6 is a C 1 -C 4 alkyl group or
Figure PCTCN2016088089-appb-000231
R 7 and R 8 are independently hydrogen, C 1 -C 4 alkyl,
Figure PCTCN2016088089-appb-000232
R a3 is a C 1 -C 4 alkyl group or a C 3 -C 6 cycloalkyl group; R a4 is a substituted or unsubstituted C 1 -C 4 alkyl group or a C 3 -C 6 cycloalkyl group; 9 is a substituted or unsubstituted C 1 -C 4 alkyl group;
当R5为氢，Rp4为氢，Rt1为取代或未取代的C1-C4的烷基；Rm3和Rm4为一个为氢，另一个为C1-C4的烷基或者卤素时，所述的卤素为氟；Rm2为C1-C4的烷氧基或者取代的C1-C4的烷基；When R 5 is hydrogen, R p4 is hydrogen, R t1 is a substituted or unsubstituted C 1 -C 4 alkyl group; R m3 and R m4 are one hydrogen and the other C 1 -C 4 alkyl or In the case of halogen, the halogen is fluorine; R m2 is a C 1 -C 4 alkoxy group or a substituted C 1 -C 4 alkyl group;
当R5为氢，Rp4为卤素，Rt1为取代或未取代的C1-C4的烷基；Rm3和Rm4为氢时，Rm2为C1-C4的烷氧基；When R 5 is hydrogen, R p4 is halogen, R t1 is a substituted or unsubstituted C 1 -C 4 alkyl group; when R m3 and R m4 are hydrogen, R m2 is a C 1 -C 4 alkoxy group;
当R5为取代的C1-C4的烷基，Rp4为氢，Rt1为C1-C4的烷基；Rm3和Rm4为氢时，Rm2为羟基；When R 5 is a substituted C 1 -C 4 alkyl group, R p4 is hydrogen, R t1 is a C 1 -C 4 alkyl group; when R m3 and R m4 are hydrogen, R m2 is a hydroxyl group;
当R5为氢，Rp4为氢，Rt1为取代或未取代的C1-C4的烷基；Rm2和Rm4为氢时，Rm3为C1-C4的烷氧基或者C2-C6的杂环烷基；When R 5 is hydrogen, R p4 is hydrogen, R t1 is a substituted or unsubstituted C 1 -C 4 alkyl group; when R m2 and R m4 are hydrogen, R m3 is a C 1 -C 4 alkoxy group or a heterocycloalkyl group of C 2 -C 6 ;
当R5为氢，Rp4为氢，Rt1为
Figure PCTCN2016088089-appb-000233
R21为C1-C4的烷基，Rm3和Rm4为氢时，Rm2为
Figure PCTCN2016088089-appb-000234
其中R6为C1-C4的烷基或者
Figure PCTCN2016088089-appb-000235
Ra1和Ra2独立地为氢或者取代或未取代的C1-C4的烷基；R7和R8独立地为氢、C1-C4的烷基、
Figure PCTCN2016088089-appb-000236
Figure PCTCN2016088089-appb-000237
Ra3为C1-C4的烷基；Ra4为取代或未取代的C1-C4的烷基，Ra4中，所述的取代的C1-C4的烷基中所述的取代是指被一个或多个(例如1-6个，优选1-2个)氰基所取代；R9为取代的C1-C4的烷基；When R 5 is hydrogen, R p4 is hydrogen and R t1 is
Figure PCTCN2016088089-appb-000233
R 21 is a C 1 -C 4 alkyl group, and when R m3 and R m4 are hydrogen, R m2 is
Figure PCTCN2016088089-appb-000234
Wherein R 6 is a C 1 -C 4 alkyl group or
Figure PCTCN2016088089-appb-000235
R a1 and R a2 are independently hydrogen or a substituted or unsubstituted C 1 -C 4 alkyl group; R 7 and R 8 are independently hydrogen, C 1 -C 4 alkyl,
Figure PCTCN2016088089-appb-000236
Figure PCTCN2016088089-appb-000237
R a3 is a C 1 -C 4 alkyl group; R a4 is a substituted or unsubstituted C 1 -C 4 alkyl group, and R a4 is as defined in the substituted C 1 -C 4 alkyl group; Substituted means substituted by one or more (for example 1-6, preferably 1-2) cyano groups; R 9 is a substituted C 1 -C 4 alkyl group;
当R5为氢，Rp4为氢，Rt1为
Figure PCTCN2016088089-appb-000238
R21为取代的C1-C4的烷基或者
Figure PCTCN2016088089-appb-000239
Rm3 和Rm4为氢时，Rm2为C1-C4的烷氧基。When R 5 is hydrogen, R p4 is hydrogen and R t1 is
Figure PCTCN2016088089-appb-000238
R 21 is a substituted C 1 -C 4 alkyl group or
Figure PCTCN2016088089-appb-000239
When R m3 and R m4 are hydrogen, R m2 is a C 1 -C 4 alkoxy group.
较佳地，通式I-d化合物中，Preferably, in the compound of formula I-d,
当Rp5为氢，Rt4为取代或未取代的C1-C4的烷基；Rm6为取代或未取代的C1-C4的烷氧基、
Figure PCTCN2016088089-appb-000240
其中R6为C1-C4的烷基；R7和R8独立地为氢或
Figure PCTCN2016088089-appb-000241
Ra4为取代或未取代的C1-C4的烷基；R9为取代或未取代的C1-C4的烷基；When R p5 is hydrogen, R t4 is a substituted or unsubstituted C 1 -C 4 alkyl group; R m6 is a substituted or unsubstituted C 1 -C 4 alkoxy group,
Figure PCTCN2016088089-appb-000240
Wherein R 6 is a C 1 -C 4 alkyl group; R 7 and R 8 are independently hydrogen or
Figure PCTCN2016088089-appb-000241
R a4 is a substituted or unsubstituted C 1 -C 4 alkyl group; R 9 is a substituted or unsubstituted C 1 -C 4 alkyl group;
当Rp5为硝基或者取代的C1-C4的烷基，Rt4为取代或未取代的C1-C4的烷基；Rm6为C1-C4的烷氧基；When R p5 is a nitro group or a substituted C 1 -C 4 alkyl group, R t4 is a substituted or unsubstituted C 1 -C 4 alkyl group; R m6 is a C 1 -C 4 alkoxy group;
当Rp5为氢，Rt4为
Figure PCTCN2016088089-appb-000242
R21为取代或未取代的C1-C4的烷基时，Rm6为取代C1-C4的烷基、C1-C4的烷氧基、C2-C6的杂环烷基、
Figure PCTCN2016088089-appb-000243
R7和R8独立地为氢或
Figure PCTCN2016088089-appb-000244
Ra4为取代或未取代的C1-C4的烷基；R9为取代的C1-C4的烷基。When R p5 is hydrogen, R t4 is
Figure PCTCN2016088089-appb-000242
When R 21 is a substituted or unsubstituted C 1 -C 4 alkyl group, R m6 is a C 1 -C 4 -substituted alkyl group, a C 1 -C 4 alkoxy group or a C 2 -C 6 heterocycloalkane. base,
Figure PCTCN2016088089-appb-000243
R 7 and R 8 are independently hydrogen or
Figure PCTCN2016088089-appb-000244
R a4 is a substituted or unsubstituted C 1 -C 4 alkyl group; R 9 is a substituted C 1 -C 4 alkyl group.
较佳地，所述的通式I所示的化合物为如下任一化合物：Preferably, the compound of formula I is any of the following compounds:
5-(4-甲氧基苯基)-N-(环丙甲酰胺)喹唑啉-2-胺(化合物1)；5-(4-methoxyphenyl)-N-(cyclopropanecarboxamide) quinazolin-2-amine (Compound 1);
5-(4-甲磺酰基苯基)-N-(环丙甲酰胺)喹唑啉-2-胺(化合物2)；5-(4-methanesulfonylphenyl)-N-(cyclopropanecarboxamide) quinazolin-2-amine (Compound 2);
5-(4-吗啡啉基苯基)-N-(环丙甲酰胺)喹唑啉-2-胺(化合物3)；5-(4-morpholinephenyl)-N-(cyclopropanecarboxamide) quinazolin-2-amine (compound 3);
5-(4-(甲氧基)苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物4)；5-(4-(methoxy)phenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 4);
5-(4-(甲磺酰基)苯基)-N-(3-(4-甲基哌嗪)苯基)喹唑啉-2-胺(化合物5)；5-(4-(methylsulfonyl)phenyl)-N-(3-(4-methylpiperazine)phenyl)quinazolin-2-amine (Compound 5);
5-(4-吗啡啉基苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物6)；5-(4-morpholinephenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 6);
5-(4-甲磺酰基苯基)-喹唑啉-2-胺(化合物7)；5-(4-methanesulfonylphenyl)-quinazolin-2-amine (compound 7);
5-(4-甲氧基苯基)-喹唑啉-2-胺(化合物8)；5-(4-methoxyphenyl)-quinazolin-2-amine (compound 8);
7-(4-(甲氧基)苯基)-N-(环丙甲酰基)喹唑啉-2-胺(化合物9)；7-(4-(Methoxy)phenyl)-N-(cyclopropanoyl)quinazolin-2-amine (Compound 9);
7-(4-吗啡啉基苯基)-N-(环丙甲酰胺)喹唑啉-2-胺(化合物10)；7-(4-morphinolinylphenyl)-N-(cyclopropanecarboxamide)quinazolin-2-amine (Compound 10);
7-(4-甲磺酰基苯基)-N-(环丙甲酰胺)喹唑啉-2-胺(化合物11)；7-(4-Methanesulfonylphenyl)-N-(cyclopropanecarboxamide) quinazolin-2-amine (Compound 11);
7-(4-甲氧基苯基)-N-(3,4,5-三甲氧基苯基)喹唑啉-2-胺(化合物12)；7-(4-Methoxyphenyl)-N-(3,4,5-trimethoxyphenyl)quinazolin-2-amine (Compound 12);
7-(4-甲磺酰基苯基)-N-(3,4,5-三甲氧基苯基)喹唑啉-2-胺(化合物14)；7-(4-Methanesulfonylphenyl)-N-(3,4,5-trimethoxyphenyl)quinazolin-2-amine (Compound 14);
7-(4-甲氧基苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物15)； 7-(4-Methoxyphenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 15);
7-(4-吗啡啉基苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物16)；7-(4-morphinolinylphenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 16);
7-(4-(甲磺酰基)苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物17)；7-(4-(Methanesulfonyl)phenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 17);
7-吗啡啉-N-(3-(4-甲基哌嗪)苯基)喹唑啉-2-胺(化合物18)；7-morpholine-N-(3-(4-methylpiperazine)phenyl)quinazolin-2-amine (Compound 18);
8-(4-(甲氧基)苯基)-N-(3,4,5-三甲氧基苯基)喹唑啉-2-胺(化合物19)；8-(4-(Methoxy)phenyl)-N-(3,4,5-trimethoxyphenyl)quinazolin-2-amine (Compound 19);
8-(4-(甲磺酰基)苯基)-N-(3,4,5,-三甲氧基苯基)喹唑啉-2-胺(化合物20)；8-(4-(Methanesulfonyl)phenyl)-N-(3,4,5,-trimethoxyphenyl)quinazolin-2-amine (Compound 20);
8-(4-(苄氧基)苯基)-N-(3,4,5-三甲氧基苯基)喹唑啉-2-胺(化合物21)；8-(4-(Benzyloxy)phenyl)-N-(3,4,5-trimethoxyphenyl)quinazolin-2-amine (Compound 21);
8-(4-吗啡啉苯基)-N-(3,4,5-三甲氧基苯基)喹唑啉-2-胺(化合物22)；8-(4-morpholinephenyl)-N-(3,4,5-trimethoxyphenyl)quinazolin-2-amine (Compound 22);
8-(4-三氟甲基苯氧基)-N-(3,4,5-三甲氧基苯基)喹唑啉-2-胺(化合物23)；8-(4-Trifluoromethylphenoxy)-N-(3,4,5-trimethoxyphenyl)quinazolin-2-amine (Compound 23);
8-(4-(甲氧基)苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物24)；8-(4-(Methoxy)phenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 24);
N-(3-(4-甲基哌嗪-1-基)苯基)-8-(4-(甲磺酰基)苯基)喹唑啉-2-胺(化合物25)；N-(3-(4-Methylpiperazin-1-yl)phenyl)-8-(4-(methylsulfonyl)phenyl)quinazolin-2-amine (Compound 25);
8-(3-氟-4-(吗啉甲基)苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物27)；8-(3-Fluoro-4-(morpholinyl)phenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 27) ;
N-(3-(4-甲基哌嗪-1-基)苯基)-8-(6-吗啉吡啶-3-基)-喹唑啉-2-胺(化合物28)；N-(3-(4-Methylpiperazin-1-yl)phenyl)-8-(6-morpholinpyridin-3-yl)-quinazolin-2-amine (Compound 28);
N-甲基-4-(2-((3-(4-甲基哌嗪-1-基)苯基)氨基)喹唑啉-8-基)苯磺酰胺(化合物29)；N-methyl-4-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)benzenesulfonamide (Compound 29);
N-(3-(4-甲基哌嗪-1-基)苯基)-8-(4-(三氟甲氧基)苯基)喹唑啉-2-胺(化合物30)；N-(3-(4-Methylpiperazin-1-yl)phenyl)-8-(4-(trifluoromethoxy)phenyl)quinazolin-2-amine (Compound 30);
8-(4-(苄氧基)苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物31)；8-(4-(Benzyloxy)phenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 31);
8-(3-吗啡啉苯基)-N-(3-(4-甲基哌嗪))喹唑啉-2-胺(化合物32)；8-(3-morpholinephenyl)-N-(3-(4-methylpiperazine))quinazolin-2-amine (Compound 32);
8-(6-甲氧基吡啶-3-基)苯基)-N-(3-(甲基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物33)；8-(6-Methoxypyridin-3-yl)phenyl)-N-(3-(methylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 33);
8-(3-氟-4-甲氧苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物34)；8-(3-Fluoro-4-methoxyphenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 34);
8-(2-氟-4-甲氧苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物35)；8-(2-Fluoro-4-methoxyphenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 35);
8-(4-甲氧基-3,5-二甲基苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物36)；8-(4-Methoxy-3,5-dimethylphenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 36 );
8-(3-氯-4-甲氧苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物37)；8-(3-Chloro-4-methoxyphenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 37);
8-(4-甲氧基-3-甲基苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物38)；8-(4-Methoxy-3-methylphenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 38);
8-(4-(二乙基氨基)苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物39)；8-(4-(Diethylamino)phenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 39);
8-(3-甲氧基苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物40)；8-(3-Methoxyphenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 40);
N-(3-(4-甲基哌嗪-1-基)苯基)-8-(3-(甲磺酰基)苯基)喹唑啉-2-胺(化合物41)；N-(3-(4-methylpiperazin-1-yl)phenyl)-8-(3-(methylsulfonyl)phenyl)quinazolin-2-amine (Compound 41);
N-(3-(4-甲基哌嗪-1-基)苯基)-8-(4-硝基苯基)喹唑啉-2-胺(化合物42)；N-(3-(4-Methylpiperazin-1-yl)phenyl)-8-(4-nitrophenyl)quinazolin-2-amine (Compound 42);
8-(4-氨基苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物43)；8-(4-Aminophenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 43);
8-(4-(甲氨基)苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物44)；8-(4-(Methylamino)phenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 44);
8-(4-正丙基苯胺基)-N-(3-(1-甲基哌嗪-4-基)苯基)喹唑啉-2-胺(化合物45)；8-(4-n-propylanilino)-N-(3-(1-methylpiperazin-4-yl)phenyl)quinazolin-2-amine (Compound 45);
8-(4-戊酰基苯胺基)-N-(3-(1-甲基哌嗪-4-基)苯基)喹唑啉-2-胺(化合物46)；8-(4-pentanoylanilino)-N-(3-(1-methylpiperazin-4-yl)phenyl)quinazolin-2-amine (Compound 46);
8-(4-N-(乙酰基吗啡啉)苯胺基)-N-(3-(1-甲基哌嗪-4-基)苯基)喹唑啉-2-胺(化合物47)；8-(4-N-(acetylmorpholine)anilino)-N-(3-(1-methylpiperazin-4-yl)phenyl)quinazolin-2-amine (Compound 47);
8-(4-吗啡啉苯基)-N-(3-(1-甲基哌嗪-4-基)苯基)喹唑啉-2-胺(化合物48)；8-(4-morpholinephenyl)-N-(3-(1-methylpiperazin-4-yl)phenyl)quinazolin-2-amine (Compound 48);
8-(4-(二甲基氨基)苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物49)；8-(4-(Dimethylamino)phenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 49);
N-(叔丁基)-4-(2-((3-(4-甲基哌嗪-1-基)苯基)氨基)喹唑啉-8-基)苯磺酰胺(化合物50)； N-(tert-butyl)-4-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)benzenesulfonamide (Compound 50);
N-(4-(2-((3-(4-甲基哌嗪-1-基)苯基)氨基)喹唑啉-8-基)苯基)环丙基甲酰胺(化合物51)；N-(4-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)cyclopropylcarboxamide (Compound 51);
N-(2-氰乙基)-4-(2-((3-(4-甲基哌嗪-1-基)苯基)氨基)喹唑啉-8-基)苯磺酰胺(化合物52)；N-(2-cyanoethyl)-4-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)benzenesulfonamide (Compound 52 );
8-(4-乙氧苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物53)；8-(4-Ethoxyphenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 53);
8-(4-(2-氰基乙酰胺基)苯基)-N-(3-(4-甲基哌嗪)苯基)喹唑啉-2-胺(化合物54)；8-(4-(2-Cyanoacetamido)phenyl)-N-(3-(4-methylpiperazine)phenyl)quinazolin-2-amine (Compound 54);
8-(4-异丙氧基苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物55)；8-(4-Isopropoxyphenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 55);
N-异丁基-4-(2-((3-(4-甲基哌嗪-1-基)苯基)氨基)喹唑啉-8-基)苯磺酰胺(化合物56)；N-isobutyl-4-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)benzenesulfonamide (Compound 56);
N-(4-(2-((3-(4-甲基哌嗪-1-基)苯基)氨基)喹唑啉-8-基)苯基)甲基磺酰胺(化合物57)；N-(4-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)methylsulfonamide (Compound 57);
N,N-二甲基-4-(2-((3-(4-甲基哌嗪-1-基)苯基)氨基)喹唑啉-8-基)苯磺酰胺(化合物58)；N,N-Dimethyl-4-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)benzenesulfonamide (Compound 58);
8-(4-N-(乙酰基)苯胺基)-N-(3-(1-甲基哌嗪-4-基)苯基)喹唑啉-2-胺(化合物59)；8-(4-N-(Acetyl)anilino)-N-(3-(1-methylpiperazin-4-yl)phenyl)quinazolin-2-amine (Compound 59);
8-(4-(环丙基磺酰胺基)苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物60)；8-(4-(Cyclopropylsulfonamido)phenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 60);
8-(4-N-(氰基甲基)苯甲酰胺基)-N-(3-(1-甲基哌嗪-4-基)苯基)喹唑啉-2-胺(化合物61)；8-(4-N-(Cyanomethyl)benzamide)-N-(3-(1-methylpiperazin-4-yl)phenyl)quinazolin-2-amine (Compound 61) ;
8-(4-异丁氧基苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物62)；8-(4-Isobutoxyphenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 62);
N-甲基-3-(2-((3-(4-甲基哌嗪-1-基)苯基)氨基)喹唑啉-8-基)苯甲酰胺(化合物63)；N-methyl-3-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)benzamide (Compound 63);
8-(4-(6-氰基甲基吡啶-3-基)苯氧基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物64)；8-(4-(6-Cyanomethylpyridin-3-yl)phenoxy)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 64);
8-(4-((4-(1H-吡唑-1-基)苄基)氧代)苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物65)；8-(4-((4-H-pyrazol-1-yl)benzyl)oxy)phenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quine Oxazolin-2-amine (compound 65);
2-(4-(2-((3-(4-甲基哌嗪-1-甲基)苯基)胺基)喹唑啉-8-基)苯氧基)乙腈(化合物66)；2-(4-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino) quinazolin-8-yl)phenoxy)acetonitrile (Compound 66);
8-(4-(甲氧基)苯基)-N-(4-三氟甲基苯基)喹唑啉-2-胺(化合物67)；8-(4-(Methoxy)phenyl)-N-(4-trifluoromethylphenyl)quinazolin-2-amine (Compound 67);
8-(4-(甲氧基)苯基)-N-苯基喹唑啉-2-胺(化合物68)；8-(4-(Methoxy)phenyl)-N-phenylquinazolin-2-amine (Compound 68);
8-(4-(甲氧基)苯基)-N-(3-(甲氧基)苯基)喹唑啉-2-胺(化合物69)；8-(4-(Methoxy)phenyl)-N-(3-(methoxy)phenyl)quinazolin-2-amine (Compound 69);
8-(4-(甲氧基)苯基)-N-(4-(N,N-二乙基甲酰胺)苯基)喹唑啉-2-胺(化合物70)；8-(4-(Methoxy)phenyl)-N-(4-(N,N-diethylformamide)phenyl)quinazolin-2-amine (Compound 70);
8-(4-(甲氧基)苯基)-N-(3-甲磺酰基苯基)喹唑啉-2-胺(化合物71)；8-(4-(Methoxy)phenyl)-N-(3-methanesulfonylphenyl)quinazolin-2-amine (Compound 71);
8-(4-(甲氧基)苯基)-N-(4-氯苯基)喹唑啉-2-胺(化合物72)；8-(4-(Methoxy)phenyl)-N-(4-chlorophenyl)quinazolin-2-amine (Compound 72);
8-(4-(甲氧基)苯基)-N-(4-(N-甲基磺酰胺)苯基)喹唑啉-2-胺(化合物73)；8-(4-(Methoxy)phenyl)-N-(4-(N-methylsulfonamide)phenyl)quinazolin-2-amine (Compound 73);
8-(4-(甲氧基)苯基)-N-(3-(4-吗啡啉基)苯基)喹唑啉-2-胺(化合物74)；8-(4-(Methoxy)phenyl)-N-(3-(4-morphinolinyl)phenyl)quinazolin-2-amine (Compound 74);
8-(4-(甲氧基)苯基)-N-(3-((4-甲基哌嗪-1-基)磺酰基)苯基)喹唑啉-2-胺(化合物75)；8-(4-(Methoxy)phenyl)-N-(3-((4-methylpiperazin-1-yl)sulfonyl)phenyl)quinazolin-2-amine (Compound 75);
8-(4-(甲氧基)苯基)-N-(4-(甲基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物76)；8-(4-(Methoxy)phenyl)-N-(4-(methylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 76);
8-(4-(甲氧基)苯基)-N-(4-(甲氧羰基)苯基)喹唑啉-2-胺(化合物77)；8-(4-(Methoxy)phenyl)-N-(4-(methoxycarbonyl)phenyl)quinazolin-2-amine (Compound 77);
8-(4-(甲氧基)苯基)-N-(3-((4-甲基哌嗪-1-基)甲基)苯基)喹唑啉-2-胺(化合物78)；8-(4-(Methoxy)phenyl)-N-(3-((4-methylpiperazin-1-yl)methyl)phenyl)quinazolin-2-amine (Compound 78);
8-(4-(甲氧基)苯基)-N-(4-(2-(吡咯烷基)乙氧基)苯基)喹唑啉-2-胺(化合物79)；8-(4-(Methoxy)phenyl)-N-(4-(2-(pyrrolidinyl)ethoxy)phenyl)quinazolin-2-amine (Compound 79);
8-(4-(甲氧基)苯基)-N-(4-甲氧基苯基)喹唑啉-2-胺(化合物80)；8-(4-(Methoxy)phenyl)-N-(4-methoxyphenyl)quinazolin-2-amine (Compound 80);
8-(4-(甲氧基)苯基)-N-(4-(吗啡啉-1-基)苯基)喹唑啉-2-胺(化合物81)；8-(4-(Methoxy)phenyl)-N-(4-(morphinolin-1-yl)phenyl)quinazolin-2-amine (Compound 81);
8-(4-(甲氧基)苯基)-N-(4-(6-吗啡啉基吡啶-3-基)苯基)喹唑啉-2-胺(化合物82)； 8-(4-(Methoxy)phenyl)-N-(4-(6-morphinolinylpyridin-3-yl)phenyl)quinazolin-2-amine (Compound 82);
8-(4-(甲氧基)苯基)-N-(3-((吡咯烷-1-基)乙基)苯甲酰胺)喹唑啉-2-胺(化合物83)；8-(4-(Methoxy)phenyl)-N-(3-((pyrrolidin-1-yl)ethyl)benzamide)quinazolin-2-amine (Compound 83);
8-(4-(甲氧基)苯基)-N-(4-吡咯烷基苯基)喹唑啉-2-胺(化合物84)；8-(4-(Methoxy)phenyl)-N-(4-pyrrolidinylphenyl)quinazolin-2-amine (Compound 84);
8-(4-(甲氧基)苯基)-N-(4-(甲氧基甲氧基)苯基)喹唑啉-2-胺(化合物85)；8-(4-(Methoxy)phenyl)-N-(4-(methoxymethoxy)phenyl)quinazolin-2-amine (Compound 85);
8-(4-(甲氧基)苯基)-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)喹唑啉-2-胺(化合物86)；8-(4-(Methoxy)phenyl)-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)quinazolin-2-amine (Compound 86);
8-(4-(甲氧基)苯基)-N-(4-((吡咯烷-1-基)乙酰基)苯氧基)喹唑啉-2-胺(化合物87)；8-(4-(Methoxy)phenyl)-N-(4-((pyrrolidin-1-yl)acetyl)phenoxy)quinazolin-2-amine (Compound 87);
8-(4-(甲氧基)苯基)-N-(4-(2-(二甲氨基)乙氧基)苯基)喹唑啉-2-胺(化合物88)；8-(4-(Methoxy)phenyl)-N-(4-(2-(dimethylamino)ethoxy)phenyl)quinazolin-2-amine (Compound 88);
8-(4-(甲氧基)苯基)-N-(3-((吡咯烷-1-基)乙基)苯磺酰胺)喹唑啉-2-胺(化合物89)；8-(4-(Methoxy)phenyl)-N-(3-((pyrrolidin-1-yl)ethyl)benzenesulfonamide) quinazolin-2-amine (Compound 89);
8-(4-(甲氧基)苯基)-N-(4-(4-(吡咯烷-1-基)哌啶-1-基)苯基)喹唑啉-2-胺(化合物90)；8-(4-(Methoxy)phenyl)-N-(4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)quinazolin-2-amine (Compound 90 );
8-(4-(甲氧基)苯基)-N-(3-((吡咯烷基)乙氧基)苯基)喹唑啉-2-胺(化合物91)；8-(4-(Methoxy)phenyl)-N-(3-((pyrrolidinyl)ethoxy)phenyl)quinazolin-2-amine (Compound 91);
8-(4-(甲氧基)苯基)-N-(4-((吗啡啉-1-基)乙氧基)苯基)喹唑啉-2-胺(化合物92)；8-(4-(Methoxy)phenyl)-N-(4-((morphinolin-1-yl)ethoxy)phenyl)quinazolin-2-amine (Compound 92);
8-(4-(甲氧基)苯基)-N-(4-((吡咯烷-1-基)丙氧基)苯基)喹唑啉-2-胺(化合物93)；8-(4-(Methoxy)phenyl)-N-(4-((pyrrolidin-1-yl)propoxy)phenyl)quinazolin-2-amine (Compound 93);
8-(4-(甲氧基)苯基)-N-(3-((吗啡啉-1-基)乙基)苯磺酰胺基)喹唑啉-2-胺(化合物94)；8-(4-(Methoxy)phenyl)-N-(3-((morphinolin-1-yl)ethyl)benzenesulfonamido)quinazoline-2-amine (Compound 94);
8-(4-(甲氧基)苯基)-N-(3-(N-甲基磺酰胺)苯基)喹唑啉-2-胺(化合物95)；8-(4-(Methoxy)phenyl)-N-(3-(N-methylsulfonamide)phenyl)quinazolin-2-amine (Compound 95);
8-(4-(甲氧基)苯基)-N-(3-(2-((苄氧基)甲基)吡咯烷-1-基)苯基)喹唑啉-2-胺(化合物96)；8-(4-(Methoxy)phenyl)-N-(3-(2-((benzyloxy)methyl)pyrrolidin-1-yl)phenyl)quinazolin-2-amine (compound) 96);
8-(4-(甲氧基)苯基)-N-(3-(2-((甲氧基)甲基)吡咯烷基-1-基)苯基)喹唑啉-2-胺(化合物97)；8-(4-(Methoxy)phenyl)-N-(3-(2-((methoxy)methyl)pyrrolidin-1-yl)phenyl)quinazolin-2-amine ( Compound 97);
8-(4-(甲氧基)苯基)-N-(3-((3-羟基吡咯烷)-1-基)苯基)喹唑啉-2-胺(化合物98)；8-(4-(Methoxy)phenyl)-N-(3-((3-hydroxypyrrolidin)-1-yl)phenyl)quinazolin-2-amine (Compound 98);
8-(4-(甲氧基)苯基)-N-(3-((3-羟基哌啶)-1-基)苯基)喹唑啉-2-胺(化合物99)；8-(4-(Methoxy)phenyl)-N-(3-((3-hydroxypiperidin)-1-yl)phenyl)quinazolin-2-amine (Compound 99);
8-(4-(甲氧基)苯基)-N-(2-(4-甲基哌嗪-1-基)嘧啶-5-基)喹唑啉-2-胺(化合物100)；8-(4-(Methoxy)phenyl)-N-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)quinazolin-2-amine (Compound 100);
8-(4-甲磺酰基)-N-(4-(N-甲基磺酰胺)苯基)喹唑啉-2-胺(化合物101)；8-(4-Methanesulfonyl)-N-(4-(N-methylsulfonamide)phenyl)quinazolin-2-amine (Compound 101);
8-(4-甲磺酰基)-N-(4-((2-吡咯烷-1-基)乙氧基)苯基)喹唑啉-2-胺(化合物102)；8-(4-Methanesulfonyl)-N-(4-((2-pyrrolidin-1-yl)ethoxy)phenyl)quinazolin-2-amine (Compound 102);
8-(4-甲磺酰基苯基)-N-(4-(4-乙酰基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物103)；8-(4-Methanesulfonylphenyl)-N-(4-(4-acetylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 103);
8-(4-(N-甲基磺酰胺基)苯基)-N-(3-(4-乙酰基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物104)；8-(4-(N-methylsulfonamido)phenyl)-N-(3-(4-acetylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 104);
8-(4-(N-叔丁胺基磺酰胺)苯基)-N-(3-(4-乙酰基哌嗪)苯基)喹唑啉-2-胺(化合物105)；8-(4-(N-tert-butylaminosulfonamide)phenyl)-N-(3-(4-acetylpiperazine)phenyl)quinazolin-2-amine (Compound 105);
8-(4-(N-乙基磺酰胺)苯基)-N-(3-(4-乙酰基哌嗪)苯基)喹唑啉-2-胺(化合物106)；8-(4-(N-Ethylsulfonamide)phenyl)-N-(3-(4-acetylpiperazine)phenyl)quinazolin-2-amine (Compound 106);
8-(4-(N-氰甲基磺酰胺)苯基)-N-(3-(4-乙酰基哌嗪)苯基)喹唑啉-2-胺(化合物107)；8-(4-(N-Cyanomethylsulfonamide)phenyl)-N-(3-(4-acetylpiperazine)phenyl)quinazolin-2-amine (Compound 107);
8-(4-N-(氰基乙基)苯甲磺酰基)-N-(3-(1-乙酰基哌嗪-4-基)苯基)喹唑啉-2-胺(化合物108)；8-(4-N-(Cyanoethyl)benzenesulfonyl)-N-(3-(1-acetylpiperazin-4-yl)phenyl)quinazolin-2-amine (Compound 108) ;
2-氰基-N-(4-(2-((3-(4-甲基哌嗪-1-基)苯基)氨基)喹唑啉-8-基)苯基)乙酰胺(化合物109)；2-cyano-N-(4-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acetamide (Compound 109 );
8-(4-N-(叔丁基)苯甲酰胺基)-N-(3-(1-乙酰基哌嗪-4-基)苯基)喹唑啉-2-胺(化合物110)；8-(4-N-(tert-butyl)benzamide)-N-(3-(1-acetylpiperazin-4-yl)phenyl)quinazolin-2-amine (Compound 110);
8-(4-(N-(2-吗啡啉基乙酰胺))苯基)-N-(3-(4-乙酰氨基)苯基)喹唑啉-2-胺(化合物111)；8-(4-(N-(2-morphinolinylacetamide))phenyl)-N-(3-(4-acetylamino)phenyl)quinazolin-2-amine (Compound 111);
8-(4-N-(氰基乙基)苯甲酰胺基)-N-(3-(1-乙酰基哌嗪-4-基)苯基)喹唑啉-2-胺(化合物112)； 8-(4-N-(Cyanoethyl)benzamide)-N-(3-(1-acetylpiperazin-4-yl)phenyl)quinazolin-2-amine (Compound 112) ;
8-(4-氨基苯)-N-(3-(1-乙酰基哌嗪-4-基)苯基)喹唑啉-2-胺(化合物113)；8-(4-Aminophenyl)-N-(3-(1-acetylpiperazin-4-yl)phenyl)quinazolin-2-amine (Compound 113);
8-(4-N-乙酰胺基苯)-N-(3-(1-乙酰基哌嗪-4-基)苯基)喹唑啉-2-胺(化合物114)；8-(4-N-acetamidophenyl)-N-(3-(1-acetylpiperazin-4-yl)phenyl)quinazolin-2-amine (Compound 114);
8-(4-正丙基苯胺基)-N-(3-(1-乙酰基哌嗪-4-基)苯基)喹唑啉-2-胺(化合物115)；8-(4-n-propylanilino)-N-(3-(1-acetylpiperazin-4-yl)phenyl)quinazolin-2-amine (Compound 115);
8-(4-戊酰基苯胺基)-N-(3-(1-乙酰基哌嗪-4-基)苯基)喹唑啉-2-胺(化合物116)；8-(4-pentanoylanilino)-N-(3-(1-acetylpiperazin-4-yl)phenyl)quinazolin-2-amine (Compound 116);
8-(4-N-环丙基甲酰基苯胺基)-N-(3-(1-乙酰基哌嗪-4-基)苯基)喹唑啉-2-胺(化合物117)；8-(4-N-cyclopropylformylanilino)-N-(3-(1-acetylpiperazin-4-yl)phenyl)quinazolin-2-amine (Compound 117);
8-(4-N-甲基苯胺磺酰基)-N-(3-(1-乙酰基哌嗪-4-基)苯基)喹唑啉-2-胺(化合物118)；8-(4-N-Methylanilinesulfonyl)-N-(3-(1-acetylpiperazin-4-yl)phenyl)quinazolin-2-amine (Compound 118);
8-(1-甲基-1H-吡唑-4-基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物119)；8-(1-Methyl-1H-pyrazol-4-yl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 119);
2-(4-(2-((3-(4-甲基哌嗪-1-基)苯基)氨基)喹唑啉-8-基)-1H-吡唑-1-基)乙腈(化合物120)；2-(4-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-1H-pyrazol-1-yl)acetonitrile (compound) 120);
4-(4-(2-((3-(4-甲基哌嗪-1-基)苯基)氨基)喹唑啉-8-基)-1H-吡唑-1-基)丁腈(化合物121)；4-(4-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-1H-pyrazol-1-yl)butyronitrile Compound 121);
8-(1-(3-N环丁基磺酰胺基环丙基氰丙基)吡唑基)-N-(3-(1-甲基哌嗪-4-基)苯基)喹唑啉-2-胺(化合物122)；8-(1-(3-N-Cyclobutylsulfonamidocyclopropylcyanopropyl)pyrazolyl)-N-(3-(1-methylpiperazin-4-yl)phenyl)quinazoline -2-amine (compound 122);
3-(4-(2-((3-(4-甲基哌嗪-1-基)苯基)氨基)喹唑啉-8-基)-1H-吡唑-1-基)丙腈(化合物123)；3-(4-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-1H-pyrazol-1-yl)propanenitrile ( Compound 123);
N-(3-(4-甲基哌嗪-1-基)苯基)-8-(1-(吡啶-3-甲基)-1H-吡唑-4-基)喹唑啉-2-胺(化合物124)；N-(3-(4-Methylpiperazin-1-yl)phenyl)-8-(1-(pyridine-3-methyl)-1H-pyrazol-4-yl)quinazolin-2- Amine (compound 124);
N-(3-(4-甲基哌嗪-1-基)苯基)-8-(1-丙基-1H-吡唑-4-基)喹唑啉-2-胺(化合物125)；N-(3-(4-Methylpiperazin-1-yl)phenyl)-8-(1-propyl-1H-pyrazol-4-yl)quinazolin-2-amine (Compound 125);
-(1-(环丙基甲基)-1H-吡唑-4-基)-N-(3-(4-甲基哌嗪-1-甲基)苯基)喹唑啉-2-胺(化合物126)；-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-N-(3-(4-methylpiperazin-1-methyl)phenyl)quinazolin-2-amine (Compound 126);
N,N-二甲基-4-(2-((3-(4-甲基哌嗪-1-基)苯基)氨基)喹唑啉-8-基)-1H-吡唑-1-甲酰胺(化合物127)；N,N-Dimethyl-4-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-1H-pyrazole-1- Formamide (compound 127);
2-(1-(环丙基磺酰胺)-3-(4-(2-((3-(4-甲基哌嗪-1-基)苯基)氨基)喹唑啉-8-基)-1H-吡唑-1-基)氮杂环丁烷-3-基)乙酰胺(化合物128)；2-(1-(cyclopropylsulfonamide)-3-(4-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)) -1H-pyrazol-1-yl)azetidin-3-yl)acetamide (Compound 128);
2-(1-(乙基磺酰基)-3-(4-(2-((3-(4-甲基哌嗪-1-基)苯基)氨基)喹唑啉-8-基)-1H-吡唑-1-基)氮杂环丁烷-3-基)乙酰胺(化合物129)；2-(1-(ethylsulfonyl)-3-(4-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-) 1H-pyrazol-1-yl)azetidin-3-yl)acetamide (compound 129);
3-(4-(2-((3-(4-甲基哌嗪-1-基)苯基)氨基)喹唑啉-8-基)-1H-吡唑-1-基)异戊腈(化合物130)；3-(4-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-1H-pyrazol-1-yl)isovaleronitrile (Compound 130);
8-(4-(N-叔丁胺基磺酰胺)苯基)-N-(3-(4-乙基哌嗪)苯基)喹唑啉-2-胺(化合物131)；8-(4-(N-tert-butylaminosulfonamide)phenyl)-N-(3-(4-ethylpiperazine)phenyl)quinazolin-2-amine (Compound 131);
8-(4-(N-甲基磺酰胺)苯基)-N-(3-(4-乙基哌嗪)苯基)喹唑啉-2-胺(化合物132)；8-(4-(N-Methylsulfonamide)phenyl)-N-(3-(4-ethylpiperazine)phenyl)quinazolin-2-amine (Compound 132);
8-(4-N-(氰基乙基)苯甲酰胺基)-N-(3-(1-乙基哌嗪-4-基)苯基)喹唑啉-2-胺(化合物133)；8-(4-N-(Cyanoethyl)benzamide)-N-(3-(1-ethylpiperazin-4-yl)phenyl)quinazolin-2-amine (Compound 133) ;
8-(4-N-(乙基)苯甲磺酰基)-N-(3-(1-乙基哌嗪-4-基)苯基)喹唑啉-2-胺(化合物134)；8-(4-N-(ethyl)benzenesulfonyl)-N-(3-(1-ethylpiperazin-4-yl)phenyl)quinazolin-2-amine (Compound 134);
8-(4-N，N-二甲基苯磺酰基)-N-(3-(1-乙基哌嗪-4-基)苯基)喹唑啉-2-胺(化合物135)；8-(4-N,N-Dimethylbenzenesulfonyl)-N-(3-(1-ethylpiperazin-4-yl)phenyl)quinazolin-2-amine (Compound 135);
8-(4-N-(叔丁基)苯甲酰胺基)-N-(3-(1-乙基哌嗪-4-基)苯基)喹唑啉-2-胺(化合物136)；8-(4-N-(tert-butyl)benzamide)-N-(3-(1-ethylpiperazin-4-yl)phenyl)quinazolin-2-amine (Compound 136);
8-(4-N-(氰基甲基)苯甲酰胺基)-N-(3-(1-乙基哌嗪-4-基)苯基)喹唑啉-2-胺(化合物137)；8-(4-N-(Cyanomethyl)benzamide)-N-(3-(1-ethylpiperazin-4-yl)phenyl)quinazolin-2-amine (Compound 137) ;
8-(2-氟-4-甲氧基苯基)-N-(3-(4-乙基哌嗪)苯基)喹唑啉-2-胺(化合物138)； 8-(2-Fluoro-4-methoxyphenyl)-N-(3-(4-ethylpiperazine)phenyl)quinazolin-2-amine (Compound 138);
8-(4-(N-甲基磺酰胺)苯基)-N-(3-吗啡啉苯基)喹唑啉-2-胺(化合物139)；8-(4-(N-methylsulfonamide)phenyl)-N-(3-morphinphyrinphenyl)quinazolin-2-amine (compound 139);
8-(4-(N-叔丁基磺酰胺)苯基)-N-(3-吗啡啉苯基)喹唑啉-2-胺(化合物140)；8-(4-(N-tert-butylsulfonamide)phenyl)-N-(3-morphinphyrinphenyl)quinazolin-2-amine (Compound 140);
8-(4-(N-氰乙基磺酰胺)苯基)-N-(3-吗啡啉苯基)喹唑啉-2-胺(化合物141)；8-(4-(N-Cyanoethylsulfonamide)phenyl)-N-(3-morpholinephenyl)quinazolin-2-amine (Compound 141);
8-(4-N-(氰基甲基)苯甲酰胺基)-N-(3-(吗啡啉-4-基)苯基)喹唑啉-2-胺(化合物142)；8-(4-N-(Cyanomethyl)benzamide)-N-(3-(morphinolin-4-yl)phenyl)quinazolin-2-amine (Compound 142);
8-(4-N-(乙基)苯磺酰基)-N-(3-(吗啡啉-4-基)苯基)喹唑啉-2-胺(化合物143)；8-(4-N-(ethyl)benzenesulfonyl)-N-(3-(morphinolin-4-yl)phenyl)quinazolin-2-amine (Compound 143);
8-(4-(N-甲基磺酰胺)苯基)-N-(3-(吗啡啉甲基)苯基)喹唑啉-2-胺(化合物144)；8-(4-(N-Methylsulfonamide)phenyl)-N-(3-(morpholinemethyl)phenyl)quinazolin-2-amine (Compound 144);
8-(4-(N-乙基磺酰胺)苯基)-N-(3-(吗啡啉甲基)苯基)喹唑啉-2-胺(化合物145)；8-(4-(N-Ethylsulfonamide)phenyl)-N-(3-(morpholinemethyl)phenyl)quinazolin-2-amine (Compound 145);
8-(4-(N-氰甲基磺酰胺)苯基)-N-(3-(吗啡啉甲基)苯基)喹唑啉-2-胺(化合物146)；8-(4-(N-Cyanomethylsulfonamide)phenyl)-N-(3-(morpholinemethyl)phenyl)quinazolin-2-amine (Compound 146);
8-(4-(N-氰乙基磺酰胺)苯基)-N-(3-(吗啡啉甲基)苯基)喹唑啉-2-胺(化合物147)；8-(4-(N-Cyanoethylsulfonamide)phenyl)-N-(3-(morpholinemethyl)phenyl)quinazolin-2-amine (Compound 147);
8-(4-N-(氰基乙基)苯磺酰基)-N-(3-(1-吗啡啉甲基)苯基)喹唑啉-2-胺(化合物148)；8-(4-N-(Cyanoethyl)benzenesulfonyl)-N-(3-(1-morpholinemethyl)phenyl)quinazolin-2-amine (Compound 148);
8-(4-(N-叔丁基酰胺)苯基)-N-(3-(吗啡啉甲基)苯基)喹唑啉-2-胺(化合物149)；8-(4-(N-tert-butylamide)phenyl)-N-(3-(morpholinemethyl)phenyl)quinazolin-2-amine (compound 149);
8-(4-(N-叔丁基磺酰胺)苯基)-N-(3-(吗啡啉甲基)苯基)喹唑啉-2-胺(化合物150)；8-(4-(N-tert-butylsulfonamide)phenyl)-N-(3-(morpholinemethyl)phenyl)quinazolin-2-amine (Compound 150);
8-(4-(N-(2-吗啡啉基乙酰胺))苯基)-N-(4-(乙基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物151)；8-(4-(N-(2-morphinolinylacetamide))phenyl)-N-(4-(ethylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 151 );
8-(4-(N-氰乙基酰胺)苯基)-N-(4-(4-乙基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物153)；8-(4-(N-Cyanoethylamide)phenyl)-N-(4-(4-ethylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 153);
8-(4-(N-氰乙基酰胺)苯基)-N-(4-(4-乙酰基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物154)；8-(4-(N-Cyanoethylamide)phenyl)-N-(4-(4-acetylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 154);
8-(4-(N-氰乙基酰胺)苯基)-N-(4-(4-乙酰基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物155)；8-(4-(N-Cyanoethylamide)phenyl)-N-(4-(4-acetylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 155);
8-(4-N-(乙酰基)苯胺基)-N-(4-(1-乙酰基哌嗪-4-基)苯基)喹唑啉-2-胺(化合物156)；8-(4-N-(Acetyl)anilino)-N-(4-(1-acetylpiperazin-4-yl)phenyl)quinazolin-2-amine (Compound 156);
8-(4-N-(2-甲酰基噻吩)苯胺基)-N-(4-(1-氰乙酰基哌嗪-4-基)苯基)喹唑啉-2-胺(化合物157)；8-(4-N-(2-Formylthiophene)anilino)-N-(4-(1-cyanoacetylpiperazin-4-yl)phenyl)quinazolin-2-amine (Compound 157) ;
8-(4-吗啡啉苯基)-N-(4-(1-乙酰基哌嗪-4-基)苯基)喹唑啉-2-胺(化合物158)；8-(4-morpholinephenyl)-N-(4-(1-acetylpiperazin-4-yl)phenyl)quinazolin-2-amine (compound 158);
8-(4-((N-甲基哌嗪-1-基)甲基)苯基)-N-(4-(4-乙酰基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物159)；8-(4-((N-Methylpiperazin-1-yl)methyl)phenyl)-N-(4-(4-acetylpiperazin-1-yl)phenyl)quinazoline-2 - amine (compound 159);
8-(4-(2-吗啡啉乙酰基)苯胺基)-N-(4-(4-乙酰基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物160)；8-(4-(2-morpholineacetyl)anilino)-N-(4-(4-acetylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 160);
8-(4-(2-氰基乙酰基)苯胺基)-N-(4-(4-(2-氰基乙酰基)哌嗪-1-基)苯基)喹唑啉-2-胺(化合物161)；8-(4-(2-Cyanoacetyl)anilino)-N-(4-(4-(2-cyanoacetyl)piperazin-1-yl)phenyl)quinazolin-2-amine (Compound 161);
8-(4-(N-(2-吗啡啉基乙酰胺))苯基)-N-(4-(4-(2-氰基乙酰基)哌嗪-1-基)苯基)喹唑啉-2-胺(化合物162)；8-(4-(N-(2-morphinolinylacetamide))phenyl)-N-(4-(4-(2-cyanoacetyl)piperazin-1-yl)phenyl)quinazole Oxa-2-amine (compound 162);
8-(4-吗啡啉苯基)-N-(4-(1-氰乙酰基哌嗪-4-基)苯基)喹唑啉-2-胺(化合物163)；8-(4-morpholinephenyl)-N-(4-(1-cyanoacetylpiperazin-4-yl)phenyl)quinazolin-2-amine (compound 163);
8-(4-N-(乙酰基)苯胺基)-N-(4-(1-氰乙酰基哌嗪-4-基)苯基)喹唑啉-2-胺(化合物164)；8-(4-N-(Acetyl)anilino)-N-(4-(1-cyanoacetylpiperazin-4-yl)phenyl)quinazolin-2-amine (Compound 164);
8-(4-(吗啡啉甲基)苯基)-N-(4-(1-氰基乙酰基哌嗪-4-基)苯基)喹唑啉-2-胺(化合物165)；8-(4-(morpholinemethyl)phenyl)-N-(4-(1-cyanoacetylpiperazin-4-yl)phenyl)quinazolin-2-amine (Compound 165);
8-(4-(N-乙基磺酰胺)苯基)-N-(3-((4-乙酰基哌嗪-1-基)甲基)苯基)喹唑啉-2-胺(化合物166)； 8-(4-(N-Ethylsulfonamide)phenyl)-N-(3-((4-acetylpiperazin-1-yl)methyl)phenyl)quinazolin-2-amine (compound) 166);
8-(4-N-(氰基甲基)苯甲酰胺基)-N-(4-(1-乙基哌嗪-4-基)苯基)喹唑啉-2-胺(化合物167)；8-(4-N-(Cyanomethyl)benzamide)-N-(4-(1-ethylpiperazin-4-yl)phenyl)quinazolin-2-amine (Compound 167) ;
8-(4-N-(叔丁基)苯磺酰基)-N-(3-(1-乙酰基哌嗪-4-甲基)苯基)喹唑啉-2-胺(化合物168)；8-(4-N-(tert-butyl)benzenesulfonyl)-N-(3-(1-acetylpiperazine-4-methyl)phenyl)quinazolin-2-amine (Compound 168);
8-(4-N-(氰基乙基)苯磺酰基)-N-(3-(1-乙酰基哌嗪-4-甲基)苯基)喹唑啉-2-胺(化合物169)；8-(4-N-(Cyanoethyl)benzenesulfonyl)-N-(3-(1-acetylpiperazine-4-methyl)phenyl)quinazolin-2-amine (Compound 169) ;
8-(4-N-(氰基甲基)苯甲酰胺基)-N-(3-(1-乙酰基哌嗪-4-甲基)苯基)喹唑啉-2-胺(化合物170)；8-(4-N-(Cyanomethyl)benzamide)-N-(3-(1-acetylpiperazine-4-methyl)phenyl)quinazolin-2-amine (Compound 170 );
8-(4-N-(氰基乙基)苯甲酰胺基)-N-(3-(1-乙酰基哌嗪-4-甲基)苯基)喹唑啉-2-胺(化合物171)；8-(4-N-(Cyanoethyl)benzamide)-N-(3-(1-acetylpiperazine-4-methyl)phenyl)quinazolin-2-amine (Compound 171 );
8-(4-N-(叔丁基)苯甲酰胺基)-N-(3-(1-乙酰基哌嗪-4-甲基)苯基)喹唑啉-2-胺(化合物172)；8-(4-N-(tert-Butyl)benzamide)-N-(3-(1-acetylpiperazine-4-methyl)phenyl)quinazolin-2-amine (Compound 172) ;
8-(4-N-(乙基)苯磺酰基)-N-(3-(1-乙基哌嗪-4-甲基)苯基)喹唑啉-2-胺(化合物173)；8-(4-N-(ethyl)benzenesulfonyl)-N-(3-(1-ethylpiperazine-4-methyl)phenyl)quinazolin-2-amine (Compound 173);
8-(4-N-(氰基甲基)苯甲酰胺基)-N-(3-(1-乙基哌嗪-4-甲基)苯基)喹唑啉-2-胺(化合物174)；8-(4-N-(Cyanomethyl)benzamide)-N-(3-(1-ethylpiperazine-4-methyl)phenyl)quinazolin-2-amine (Compound 174 );
8-(4-N-(甲基)苯磺酰基)-N-(3-(1-乙基哌嗪-4-甲基)苯基)喹唑啉-2-胺(化合物175)；8-(4-N-(methyl)benzenesulfonyl)-N-(3-(1-ethylpiperazine-4-methyl)phenyl)quinazolin-2-amine (compound 175);
8-(4-N-(氰基乙基)苯甲酰胺基)-N-(3-(1-乙基哌嗪-4-甲基)苯基)喹唑啉-2-胺(化合物176)；8-(4-N-(Cyanoethyl)benzamide)-N-(3-(1-ethylpiperazine-4-methyl)phenyl)quinazolin-2-amine (Compound 176 );
8-(4-N-(叔丁基)苯甲酰胺基)-N-(3-(1-乙基哌嗪-4-甲基)苯基)喹唑啉-2-胺(化合物177)；8-(4-N-(tert-Butyl)benzamide)-N-(3-(1-ethylpiperazine-4-methyl)phenyl)quinazolin-2-amine (Compound 177) ;
8-(4-N-(乙酰基吗啡啉基)苯胺基)-N-(4-(1-甲基哌嗪-4-基)苯基)喹唑啉-2-胺(化合物178)；8-(4-N-(Acetylmorphinyl)anilino)-N-(4-(1-methylpiperazin-4-yl)phenyl)quinazolin-2-amine (Compound 178);
8-(4-(氰甲基)苯氧基)-N-(4-(甲基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物179)；8-(4-(Cyanomethyl)phenoxy)-N-(4-(methylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 179);
8-(4-N-(2-甲酰基噻吩)苯胺基)-N-(3-(1-乙酰基哌嗪-4-基)苯基)喹唑啉-2-胺(化合物180)；8-(4-N-(2-Formylthiophene)anilino)-N-(3-(1-acetylpiperazin-4-yl)phenyl)quinazolin-2-amine (Compound 180);
8-(4-(甲氧基)苯基)-N-(3-(4-乙基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物181)；8-(4-(Methoxy)phenyl)-N-(3-(4-ethylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 181);
8-(4-(甲氧基)苯基)-N-(3-(4-甲磺酰基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物182)；8-(4-(Methoxy)phenyl)-N-(3-(4-methanesulfonylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 182);
8-(4-(甲氧基)苯基)-N-(3-(4-乙酰基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物183)；8-(4-(Methoxy)phenyl)-N-(3-(4-acetylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 183);
8-(4-(甲氧基)苯基)-N-(3-(4-异丁酰胺基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物184)；8-(4-(Methoxy)phenyl)-N-(3-(4-isobutyrylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 184);
8-(4-(甲氧基)苯基)-N-(3-(4-氰丙酰基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物185)；8-(4-(Methoxy)phenyl)-N-(3-(4-cyanopropionylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 185);
8-(4-(甲氧基)苯基)-N-(3-(4-(N,N-二甲基甲酰胺基)哌嗪-1-基)苯基)喹唑啉-2-胺(化合物186)；8-(4-(Methoxy)phenyl)-N-(3-(4-(N,N-dimethylformamido)piperazin-1-yl)phenyl)quinazoline-2- Amine (compound 186);
8-(4-(甲氧基)苯基)-N-(3-(4-异丙基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物187)；8-(4-(Methoxy)phenyl)-N-(3-(4-isopropylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 187);
8-(4-(甲氧基)苯基)-N-(3-(4-氰甲基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物188)；8-(4-(Methoxy)phenyl)-N-(3-(4-cyanomethylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 188);
8-(4-(甲氧基)苯基)-N-(3-(4-哌嗪-1-乙醇基)苯基)喹唑啉-2-胺(化合物189)；8-(4-(Methoxy)phenyl)-N-(3-(4-piperazin-1-ethanol)phenyl)quinazolin-2-amine (Compound 189);
8-(4-(甲氧基)苯基)-N-(3-(4-异丁基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物190)；8-(4-(Methoxy)phenyl)-N-(3-(4-isobutylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 190);
8-(4-(甲氧基)苯基)-N-(3-(4-(环丙甲基)哌嗪-1-基)苯基)喹唑啉-2-胺(化合物191)； 8-(4-(Methoxy)phenyl)-N-(3-(4-(cyclopropylmethyl)piperazin-1-yl)phenyl)quinazolin-2-amine (Compound 191);
8-(4-(甲氧基)苯基)-N-(3-(4-丙基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物192)；8-(4-(Methoxy)phenyl)-N-(3-(4-propylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 192);
8-(4-(甲氧基)苯基)-N-(3-(4-氰乙基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物193)；8-(4-(Methoxy)phenyl)-N-(3-(4-cyanoethylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 193);
8-(4-(甲氧基)苯基)-N-(4-(4-乙酰基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物194)；8-(4-(Methoxy)phenyl)-N-(4-(4-acetylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 194);
8-(4-(甲氧基)苯基)-N-(4-(氰乙酰基哌嗪)苯基)喹唑啉-2-胺(化合物195)；8-(4-(Methoxy)phenyl)-N-(4-(cyanoacetylpiperazine)phenyl)quinazolin-2-amine (Compound 195);
8-(4-(甲氧基)苯基)-N-(4-(乙基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物196)；8-(4-(Methoxy)phenyl)-N-(4-(ethylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 196);
8-(4-(甲氧基)苯基)-N-(4-(4-(环丙基甲基)哌嗪)苯基)喹唑啉-2-胺(化合物197)；8-(4-(Methoxy)phenyl)-N-(4-(4-(cyclopropylmethyl)piperazine)phenyl)quinazolin-2-amine (compound 197);
8-(4-(甲氧基)苯基)-N-(4-(异丁基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物198)；8-(4-(Methoxy)phenyl)-N-(4-(isobutylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 198);
8-(4-(甲氧基)苯基)-N-(4-(4-丙基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物199)；8-(4-(Methoxy)phenyl)-N-(4-(4-propylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 199);
8-(4-甲磺酰基苯基)-N-(4-(4-甲基哌嗪)苯基)喹唑啉-2-胺(化合物200)；8-(4-Methanesulfonylphenyl)-N-(4-(4-methylpiperazine)phenyl)quinazolin-2-amine (Compound 200);
8-(4-(N-甲基磺酰胺基)苯基)-N-(4-((2-吡咯烷基)乙氧基)苯基)喹唑啉-2-胺(化合物201)；8-(4-(N-methylsulfonamido)phenyl)-N-(4-((2-pyrrolidinyl)ethoxy)phenyl)quinazolin-2-amine (Compound 201);
8-(4-(N-甲基磺酰胺基)苯基)-N-(4-(N-甲基磺酰胺基)苯基)喹唑啉-2-胺(化合物202)；8-(4-(N-Methylsulfonamido)phenyl)-N-(4-(N-methylsulfonamido)phenyl)quinazolin-2-amine (Compound 202);
N-甲基-4-(2-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氨基)喹唑啉-8-基)苯磺酰胺(化合物203)；N-methyl-4-(2-((2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)amino)quinazolin-8-yl)benzenesulfonamide (Compound 203);
8-(4-((2-吡咯烷-1-基)乙氧基)苯基)-N-(4-(N-甲基磺酰胺)苯基)喹唑啉-2-胺(化合物204)；8-(4-((2-Pyrrolidin-1-yl)ethoxy)phenyl)-N-(4-(N-methylsulfonamide)phenyl)quinazolin-2-amine (Compound 204 );
8-(4-((2-吡咯烷-1-基)乙氧基)苯基)-N-(4-((2-吡咯烷-1-基)乙氧基)苯基)喹唑啉-2-胺(化合物205)；8-(4-((2-Pyrrolidin-1-yl)ethoxy)phenyl)-N-(4-((2-pyrrolidin-1-yl)ethoxy)phenyl)quinazoline 2-amine (compound 205);
8-(4-((2-吡咯烷-1-基)乙氧基)苯基)-N-(4-(4-甲基哌嗪)苯基)喹唑啉-2-胺(化合物206)；8-(4-((2-Pyrrolidin-1-yl)ethoxy)phenyl)-N-(4-(4-methylpiperazine)phenyl)quinazolin-2-amine (Compound 206 );
8-(4-(甲氧基)苯基)-N-(3-(N-甲基哌嗪-1-基)-4-甲磺酰基苯基)喹唑啉-2-胺(化合物207)；8-(4-(Methoxy)phenyl)-N-(3-(N-methylpiperazin-1-yl)-4-methanesulfonylphenyl)quinazolin-2-amine (Compound 207 );
8-(4-(甲氧基)苯基)-N-(3-(N-甲基哌嗪-1-基)-4-(N-甲基磺酰胺基)苯基)喹唑啉-2-胺(化合物208)；8-(4-(Methoxy)phenyl)-N-(3-(N-methylpiperazin-1-yl)-4-(N-methylsulfonamido)phenyl)quinazoline- 2-amine (compound 208);
8-(4-(甲氧基)苯基)-N-(3-((N.N-二甲氨基)甲基)-4-(N-甲基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物209)；8-(4-(Methoxy)phenyl)-N-(3-((NN-dimethylamino)methyl)-4-(N-methylpiperazin-1-yl)phenyl)quinazole Benzin-2-amine (compound 209);
8-(4-(甲氧基)苯基)-N-(3-(甲基哌嗪-1-基)-4-氟苯基)喹唑啉-2-胺(化合物210)；8-(4-(Methoxy)phenyl)-N-(3-(methylpiperazin-1-yl)-4-fluorophenyl)quinazolin-2-amine (Compound 210);
8-(4-(甲氧基)苯基)-N-(3-硝基-4-(甲基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物211)；8-(4-(Methoxy)phenyl)-N-(3-nitro-4-(methylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 211);
8-(4-((4-甲基哌嗪-1-基)甲基)苯基)-N-(4-(N-甲基磺酰胺)苯基)喹唑啉-2-胺(化合物212)；8-(4-((4-Methylpiperazin-1-yl)methyl)phenyl)-N-(4-(N-methylsulfonamide)phenyl)quinazolin-2-amine (compound) 212);
8-(4-((4-甲基哌嗪-1-基)甲基)苯基)-N-(4-(2-吡咯烷-1-基)乙氧基)苯基)喹唑啉-2-胺(化合物213)；8-(4-((4-Methylpiperazin-1-yl)methyl)phenyl)-N-(4-(2-pyrrolidin-1-yl)ethoxy)phenyl)quinazoline 2-amine (compound 213);
8-(4-(4-甲基哌嗪)苯基)-N-(4-((2-吡咯烷-1-基)乙氧基)苯基)喹唑啉-2-胺(化合物214)；8-(4-(4-Methylpiperazine)phenyl)-N-(4-((2-pyrrolidin-1-yl)ethoxy)phenyl)quinazolin-2-amine (Compound 214 );
8-(4-(4-甲基哌嗪)苯基)-N-(4-(N-甲基磺酰胺)苯基)喹唑啉-2-胺(化合物215)；8-(4-(4-Methylpiperazine)phenyl)-N-(4-(N-methylsulfonamide)phenyl)quinazolin-2-amine (Compound 215);
8-(1H-吡唑-4-基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物216)； 8-(1H-pyrazol-4-yl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 216);
3-环戊基-3-(4-(2-((3-(4-甲基哌嗪-1-基)苯基)氨基)喹唑啉-8-基)-1H-吡唑-1-基)丙腈(化合物217)；3-cyclopentyl-3-(4-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-1H-pyrazole-1 -yl)propionitrile (compound 217);
三丁基4-(氰基甲基)-4-(4-(2-((3-(4-甲基哌嗪-1-基)苯基)氨基)喹唑啉-8-基)-1H-吡唑-1-基)哌啶-1-叔丁氧羰基(化合物218)；Tributyl 4-(cyanomethyl)-4-(4-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)- 1H-pyrazol-1-yl)piperidine-1-tert-butoxycarbonyl (compound 218);
3-环丙基-3-(4-(2-((3-(4-甲基哌嗪-1-基)苯基)氨基)喹唑啉-8-基)-1H-吡唑-1-基)丙腈(化合物219)；3-cyclopropyl-3-(4-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-1H-pyrazole-1 -yl)propionitrile (compound 219);
N-(3-(4-甲基哌嗪-1-基)苯基)-8-(1-(甲磺酸)-1H-吡唑-4-基)喹唑啉-2-胺(化合物220)；N-(3-(4-Methylpiperazin-1-yl)phenyl)-8-(1-(methanesulfonic acid)-1H-pyrazol-4-yl)quinazolin-2-amine (compound) 220);
3-(5-溴吡啶-3-基)-3-(4-(2-((3-(4-甲基哌嗪-1-基)苯基)氨基)喹唑啉-8-基)-1H-吡唑-1-基)丙腈(化合物221)；3-(5-bromopyridin-3-yl)-3-(4-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)quinazoline-8-yl)) -1H-pyrazol-1-yl)propanenitrile (compound 221);
3-(3-氯苯基)-3-(4-(2-((3-(4-甲基哌嗪-1-基)苯基)氨基)喹唑啉-8-基)-1H-吡唑-1-基)丙腈(化合物222)；3-(3-Chlorophenyl)-3-(4-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-1H- Pyrazol-1-yl)propionitrile (compound 222);
8-(1-(1-环丙基氰乙基)吡唑基)-N-(3-(1-乙基哌嗪-4-基)苯基)喹唑啉-2-胺(化合物223)；8-(1-(1-Cyclopropylcyanoethyl)pyrazolyl)-N-(3-(1-ethylpiperazin-4-yl)phenyl)quinazolin-2-amine (Compound 223 );
8-(1-(1-环戊基氰乙基)吡唑基)-N-(3-(1-乙基哌嗪-4-基)苯基)喹唑啉-2-胺(化合物224)；8-(1-(1-Cyclopentylcyanoethyl)pyrazolyl)-N-(3-(1-ethylpiperazin-4-yl)phenyl)quinazolin-2-amine (Compound 224 );
8-(1-(1-甲基氰乙基)吡唑基)-N-(3-(1-乙基哌嗪-4-基)苯基)喹唑啉-2-胺(化合物225)；8-(1-(1-Methylcyanoethyl)pyrazolyl)-N-(3-(1-ethylpiperazin-4-yl)phenyl)quinazolin-2-amine (Compound 225) ;
8-(1-(1-环戊基氰乙基)吡唑基)-N-(4-(1-甲基哌嗪-4-基)苯基)喹唑啉-2-胺(化合物226)；8-(1-(1-Cyclopentylcyanoethyl)pyrazolyl)-N-(4-(1-methylpiperazin-4-yl)phenyl)quinazolin-2-amine (Compound 226 );
8-(1-(1-甲基氰丙基)吡唑基)-N-(4-(1-甲基哌嗪-4-基)苯基)喹唑啉-2-胺(化合物227)；8-(1-(1-Methylcyanopropyl)pyrazolyl)-N-(4-(1-methylpiperazin-4-yl)phenyl)quinazolin-2-amine (Compound 227) ;
8-(1-(3-氯苯基氰丙基)吡唑基)-N-(3-(1-乙酰基哌嗪-4-基)苯基)喹唑啉-2-胺(化合物228)；8-(1-(3-Chlorophenylcyanopropyl)pyrazolyl)-N-(3-(1-acetylpiperazin-4-yl)phenyl)quinazolin-2-amine (Compound 228 );
8-(1-(1-环丙基氰丙基)吡唑基)-N-(3-(1-乙酰基哌嗪-4-基)苯基)喹唑啉-2-胺(化合物229)；8-(1-(1-Cyclopropylcyanopropyl)pyrazolyl)-N-(3-(1-acetylpiperazin-4-yl)phenyl)quinazolin-2-amine (Compound 229 );
8-(1-(1-环戊基氰丙基)吡唑基)-N-(3-(1-乙酰基哌嗪-4-基)苯基)喹唑啉-2-胺(化合物230)；8-(1-(1-Cyclopentylcyanopropyl)pyrazolyl)-N-(3-(1-acetylpiperazin-4-yl)phenyl)quinazolin-2-amine (Compound 230 );
8-(1-(1-甲基氰丙基)吡唑基)-N-(3-(1-乙酰基哌嗪-4-基)苯基)喹唑啉-2-胺(化合物231)；8-(1-(1-Methylcyanopropyl)pyrazolyl)-N-(3-(1-acetylpiperazin-4-yl)phenyl)quinazolin-2-amine (Compound 231) ;
8-(1-(3-N环丁基磺酰胺基环丙基氰丙基)吡唑基)-N-(3-(1-乙酰基哌嗪-4-基)苯基)喹唑啉-2-胺(化合物232)；8-(1-(3-N-Cyclobutylsulfonamidocyclopropylcyanopropyl)pyrazolyl)-N-(3-(1-acetylpiperazin-4-yl)phenyl)quinazoline -2-amine (compound 232);
8-(4-(甲氧基)苯基)-N-(环丙甲酰胺基)喹唑啉-2-胺(化合物233)；8-(4-(Methoxy)phenyl)-N-(cyclopropylamido)quinazolin-2-amine (Compound 233);
8-(4-(苄氧基)苯基)-N-(环丙甲酰胺)喹唑啉-2-胺(化合物234)；8-(4-(Benzyloxy)phenyl)-N-(cyclopropanecarboxamide) quinazolin-2-amine (Compound 234);
8-(4-(甲氧基)苯基)-N-(3-(4-甲基-4-乙基-哌嗪-1-基)苯基)喹唑啉-2-胺(化合物235)；8-(4-(Methoxy)phenyl)-N-(3-(4-methyl-4-ethyl-piperazin-1-yl)phenyl)quinazolin-2-amine (Compound 235 );
8-(4-(甲氧基)苯基)-N-(3-(4-甲基-4-氧基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物236)；8-(4-(Methoxy)phenyl)-N-(3-(4-methyl-4-oxypiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 236) ;
8-(4-(甲氧基)苯基)-N-((2-(4-甲基哌嗪-1-基)乙酰胺))喹唑啉-2-胺(化合物237)；8-(4-(Methoxy)phenyl)-N-((2-(4-methylpiperazin-1-yl)acetamide))quinazolin-2-amine (Compound 237);
8-(4-N-(甲基)苯磺酰基)-N-(1-乙酰基吗啡啉)喹唑啉-2-胺(化合物238)；8-(4-N-(Methyl)benzenesulfonyl)-N-(1-acetylmorpholine)quinazolin-2-amine (Compound 238);
8-(4-甲氧基苯基)-N-甲基-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物239)；8-(4-Methoxyphenyl)-N-methyl-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 239);
8-(4-羟基苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)-N-(6-氰基甲基吡啶-3-基)喹唑啉-2-胺(化合物240)； 8-(4-Hydroxyphenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-N-(6-cyanomethylpyridin-3-yl)quinazoline- 2-amine (compound 240);
N-甲基-4-(2-((3-甲磺酰基)苯基)氰基)喹唑啉-8-基)苯磺酰胺(化合物7a)；N-methyl-4-(2-((3-methylsulfonyl)phenyl)cyano)quinazolin-8-yl)benzenesulfonamide (compound 7a);
N-乙基-4-(2-((3-甲磺酰基)苯基)氰基)喹唑啉-8-基)苯磺酰胺(化合物7b)；N-ethyl-4-(2-((3-methylsulfonyl)phenyl)cyano)quinazolin-8-yl)benzenesulfonamide (compound 7b);
N-异丙基-4-(2-((3-甲磺酰基)苯基)氰基)喹唑啉-8-基)苯磺酰胺(化合物7c)；N-isopropyl-4-(2-((3-methylsulfonyl)phenyl)cyano)quinazolin-8-yl)benzenesulfonamide (compound 7c);
N-叔丁基-4-(2-((3-甲磺酰基)苯基)氰基)喹唑啉-8-基)苯磺酰胺(化合物7d)；N-tert-butyl-4-(2-((3-methylsulfonyl)phenyl)cyano)quinazolin-8-yl)benzenesulfonamide (compound 7d);
N-异丁基-4-(2-((3-甲磺酰基)苯基)氰基)喹唑啉-8-基)苯磺酰胺(化合物7e)；N-isobutyl-4-(2-((3-methylsulfonyl)phenyl)cyano)quinazolin-8-yl)benzenesulfonamide (compound 7e);
N-苯基-4-(2-((3-甲磺酰基)苯基)氰基)喹唑啉-8-基)苯磺酰胺(化合物7f)。N-Phenyl-4-(2-((3-methylsulfonyl)phenyl)cyano)quinazolin-8-yl)benzenesulfonamide (Compound 7f).
本发明还提供了所述的通式I所示的喹唑啉类化合物，其药学上可接受的盐、溶剂化物、代谢产物、代谢前体或药物前体的制备方法，其可以用商业上可获得的原料，通过已知的方法合成得到，较佳地包括下列方法：The present invention also provides the quinazoline compound of the above formula I, a pharmaceutically acceptable salt, solvate, metabolite, metabolic precursor or prodrug thereof, which can be commercially used The available starting materials are synthesized by known methods, preferably including the following methods:
方法一：气体保护下，溶剂中，碱的存在下，在钯催化剂的催化下，将如式II所示的化合物与如式III所示的化合物进行如下所示的Suzuki偶联反应，制得通式I所示的喹唑啉类化合物；所述的溶剂为有机溶剂或者有机溶剂与水的混合溶剂；Method 1: under the protection of a gas, in a solvent, in the presence of a base, catalyzed by a palladium catalyst, a compound of the formula II and a compound of the formula III are subjected to a Suzuki coupling reaction as shown below. a quinazoline compound of the formula I; the solvent is an organic solvent or a mixed solvent of an organic solvent and water;
Figure PCTCN2016088089-appb-000245
Figure PCTCN2016088089-appb-000245
方法一中，化合物II中，X1、X2和X3独立地为卤素(例如氯、溴或碘，优选氯)，R4或R5的定义均同前所述；化合物III中，Rs1为R1、R2或R3，其中，R1、R2和R3的定义均同前所述；Rsa1为
Figure PCTCN2016088089-appb-000246
通式I化合物中，R1、R2、R3、R4和R5的定义均同前所述；In the first method, in the compound II, X 1 , X 2 and X 3 are independently halogen (for example, chlorine, bromine or iodine, preferably chlorine), and R 4 or R 5 are as defined above; in compound III, R S1 is R 1 , R 2 or R 3 , wherein R 1 , R 2 and R 3 are as defined above; R sa1 is
Figure PCTCN2016088089-appb-000246
In the compounds of formula I, R 1 , R 2 , R 3 , R 4 and R 5 are as defined above;
方法二：气体保护下，有机溶剂中，碱和配体的存在下，在钯催化剂的催化下，将如式II-a所示的化合物与如式III-a所示的化合物进行如下所示的取代反应，制得通式I所示的喹唑啉类化合物；Method 2: Under the protection of gas, in the presence of a base and a ligand in an organic solvent, the compound represented by the formula II-a and the compound represented by the formula III-a are subjected to the catalysis of a palladium catalyst as shown below. a substitution reaction to obtain a quinazoline compound of the formula I;
Figure PCTCN2016088089-appb-000247
Figure PCTCN2016088089-appb-000247
方法二中，化合物II-a中，R1、R2和R3的定义均同前所述；化合物III-a中，X4为卤素(例如氯、溴或碘)，Rs2为R4或R5，其中，R4和R5为取代或未取代的C1-C4的烷基、取代或未取代的C5-C10的芳基或者取代的C2-C6的杂芳基；通式I化合物中，R1、R2、R3的定义均同前所述，R4和R5独立地为氢、取代或未取代的C1-C4的烷基、取代或未取代 的C5-C10的芳基或者取代的C2-C6的杂芳基；In the second method, in the compound II-a, R 1 , R 2 and R 3 are as defined above; in the compound III-a, X 4 is a halogen (for example, chlorine, bromine or iodine), and R s2 is R 4 . Or R 5 , wherein R 4 and R 5 are a substituted or unsubstituted C 1 -C 4 alkyl group, a substituted or unsubstituted C 5 -C 10 aryl group or a substituted C 2 -C 6 heteroaryl group; In the compound of formula I, R 1 , R 2 , R 3 are as defined above, and R 4 and R 5 are independently hydrogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or Unsubstituted C 5 -C 10 aryl or substituted C 2 -C 6 heteroaryl;
方法三：有机溶剂中，将如式II-a所示的化合物与如式III-b所示的化合物进行如下所示的酰卤化反应，制得通式I所示的喹唑啉类化合物；Method 3: In an organic solvent, a compound represented by the formula II-a and a compound represented by the formula III-b are subjected to an acid halide reaction as shown below to obtain a quinazoline compound represented by the formula I;
Figure PCTCN2016088089-appb-000248
Figure PCTCN2016088089-appb-000248
方法三中，化合物II-a中，R1、R2和R3的定义均同前所述；化合物III-b中，X5为卤素(例如氟、氯、溴或碘)，R0的定义如前所述；通式I化合物中，R1、R2和R3的定义均同前所述，R4和R5独立地为氢或者
Figure PCTCN2016088089-appb-000249
其中，R0的定义如前所述。In the third method, in the compound II-a, R 1 , R 2 and R 3 are as defined above; in the compound III-b, X 5 is a halogen (e.g., fluorine, chlorine, bromine or iodine), R 0 Definitions as defined above; in the compounds of formula I, R 1 , R 2 and R 3 are as defined above, and R 4 and R 5 are independently hydrogen or
Figure PCTCN2016088089-appb-000249
Wherein, the definition of R 0 is as described above.
上述三种方法中涉及的化学反应所采用的条件和步骤均可参照本领域常规的此类反应的条件和步骤进行，并且上述方法所得的通式I所示的喹唑啉类化合物还可以进一步通过对外周位置进行修饰而获得本发明的其它目标化合物。The conditions and procedures employed in the chemical reactions involved in the above three methods can be carried out with reference to the conditions and procedures of such reactions conventional in the art, and the quinazoline compounds of the formula I obtained by the above methods can be further Other target compounds of the present invention are obtained by modifying the peripheral position.
方法一中，所述的Suzuki偶联反应中，所述的气体保护中所述的气体较佳地为不与如式I、II或III所示的化合物反应的气体，一般为氮气、氦气和氩气中的一种或多种。所述的有机溶剂可为本领域此类反应常规的溶剂，只要不与如式I、II或III所示的化合物进行反应，即可；较佳地为酰胺类溶剂。所述的有机溶剂与水的混合溶剂中，所述的有机溶剂与水的比例可不作具体限定，只要不影响反应的进行，即可；所述的有机溶剂与水的体积比较佳地为20:1-1:1，更佳地为19:1-9:1。所述的酰胺类溶剂较佳地为N,N-二甲基甲酰胺和/或N-甲基吡咯烷酮。所述的钯催化剂可为本领域此类反应常规的钯催化剂，较佳地为Pd(PPh3)4和/或Pd(Pcy3)2Cl2。所述的碱可为本领域此类反应常规的碱，较佳地为碳酸钾、碳酸铯和氟化铯中的一种或多种。所述的碱在使用时，还可配置成碱水溶液的形式使用，所述的碱水溶液的摩尔浓度可不作具体限定，其目的是为了方便操作，对反应没有实质性影响。所述的碱水溶液的摩尔浓度较佳地为1M。所述的如式II所示的化合物与如式III所示的化合物的用量可为本领域此类反应常规的用量，较佳地所述的如式II所示的化合物与如式III所示的化合物的摩尔比为1:1～1:1.5。所述的碱的用量可为本领域此类反应常规的用量，较佳地所述的如式II所示的化合物与所述的碱的摩尔比为1:2～1:8。所述的钯催化剂的用量可为本领域此类反应常规的用量，较佳地所述的如式II所示的化合物与所述的钯催化剂的摩尔比较佳地为1:0.01-1:0.1，更佳地为1:0.05～1:0.1。所述的溶剂的用量可为本领域此类反应常规的用量，只要不影响反应的进行，即可，所述的溶剂与如式II所示的化合物的体积质量比较佳地为10mg/L～50mL/g。所述的Suzuki 偶联反应的反应温度可为本领域此类反应常规的温度，较佳地为90-150℃，更佳地为100-110℃。所述的Suzuki偶联反应的进程可按照本领域常规测试方法(如TLC、GC、HPLC或NMR)进行监控，一般以如式II所示的化合物消失时作为反应的终点，所述的反应的时间较佳地为6～50小时。In the first method, in the Suzuki coupling reaction, the gas in the gas protection is preferably a gas which does not react with the compound as shown in the formula I, II or III, generally nitrogen and helium. And one or more of argon. The organic solvent may be a conventional solvent for such a reaction in the art, as long as it is not reacted with a compound as shown in Formula I, II or III; preferably an amide solvent. In the mixed solvent of the organic solvent and water, the ratio of the organic solvent to water may not be specifically limited, as long as the reaction does not affect the progress; the volume of the organic solvent and water is preferably 20 : 1-1:1, more preferably 19:1-9:1. The amide solvent is preferably N,N-dimethylformamide and/or N-methylpyrrolidone. The palladium catalyst can be a conventional palladium catalyst of this type in the art, preferably Pd(PPh 3 ) 4 and/or Pd(Pcy 3 ) 2 Cl 2 . The base may be a conventional base for such reaction in the art, preferably one or more of potassium carbonate, cesium carbonate and cesium fluoride. The base may be used in the form of an aqueous alkali solution when used. The molar concentration of the aqueous alkali solution may not be specifically limited, and the purpose thereof is to facilitate the operation and has no substantial influence on the reaction. The molar concentration of the aqueous alkali solution is preferably 1 M. The amount of the compound of the formula II and the compound of the formula III may be a conventional amount for such a reaction in the art, preferably the compound of the formula II and the formula The molar ratio of the compound is 1:1 to 1:1.5. The amount of the base used may be a conventional amount for such a reaction in the art, and preferably the molar ratio of the compound of the formula II to the base is from 1:2 to 1:8. The amount of the palladium catalyst used may be a conventional amount for such a reaction in the art, and preferably the molar ratio of the compound represented by the formula II to the palladium catalyst is preferably 1:0.01-1:0.1. More preferably, it is 1:0.05 to 1:0.1. The amount of the solvent used may be a conventional amount for such a reaction in the art, and the volume of the solvent and the compound of the formula II is preferably 10 mg/L as long as the reaction is not affected. 50 mL / g. The reaction temperature of the Suzuki coupling reaction may be a conventional temperature for such a reaction in the art, preferably from 90 to 150 ° C, more preferably from 100 to 110 ° C. The progress of the Suzuki coupling reaction can be monitored according to conventional test methods in the art (such as TLC, GC, HPLC or NMR), generally as the end point of the reaction when the compound as shown in Formula II disappears, the reaction The time is preferably from 6 to 50 hours.
方法二中，所述的取代反应中，所述的气体保护中所述的气体较佳地为不与如式I、II或III所示的化合物反应的气体，一般为氮气、氦气或氩气。所述的有机溶剂可为本领域此类反应常规的溶剂，只要不与如式I、II-a或III-a所示的化合物进行反应，即可；较佳地为醚类溶剂。所述的醚类溶剂较佳地为二氧六环。所述的钯催化剂可为本领域此类反应常规的钯催化剂，较佳地为Pd(dba)2(三(二亚苄基丙酮)二钯)。所述的配体可为本领域此类反应常规的配体，较佳地为4,5-双二苯基膦-9,9-二甲基氧杂蒽(Xantphos)。所述的碱可为本领域此类反应常规的碱，较佳地为碳酸钾和/或碳酸铯。所述的如式II-a所示的化合物与如式III-a所示的化合物的用量可为本领域此类反应常规的用量，较佳地所述的如式II-a所示的化合物与如式III-a所示的化合物的摩尔比为1:1～1:0.5。所述的碱的用量可为本领域此类反应常规的用量，较佳地所述的如式II所示的化合物与所述的碱的摩尔比为1:1～1:2。所述的钯催化剂的用量可为本领域此类反应常规的用量，较佳地所述的如式II-a所示的化合物与所述的钯催化剂的摩尔比较佳地为1:0.01～1:0.5。所述的有机溶剂的用量可为本领域此类反应常规的用量，只要不影响反应的进行，即可，所述的有机溶剂与如式II所示的化合物的体积质量比较佳地为10mg/L～50mL/g。所述的取代反应的反应温度可为本领域此类反应常规的温度，较佳地为80-120℃。所述的取代反应的进程可按照本领域常规测试方法(如TLC、GC、HPLC或NMR)进行监控，一般以如式II-a所示的化合物消失时作为反应的终点，所述的反应的时间较佳地为6～20小时。In the second substitution method, in the substitution reaction, the gas in the gas protection is preferably a gas which does not react with the compound represented by the formula I, II or III, generally nitrogen, helium or argon. gas. The organic solvent may be a conventional solvent for such a reaction in the art, as long as it is not reacted with a compound as shown in Formula I, II-a or III-a; preferably an ether solvent. The ether solvent is preferably dioxane. The palladium catalyst may be a conventional palladium catalyst of this type in the art, preferably Pd(dba) 2 (tris(dibenzylideneacetone)dipalladium). The ligand may be a conventional ligand for such reactions in the art, preferably 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (Xantphos). The base may be a conventional base for such reactions in the art, preferably potassium carbonate and/or cesium carbonate. The amount of the compound of the formula II-a and the compound of the formula III-a may be a conventional amount for such a reaction in the art, preferably the compound of the formula II-a. The molar ratio to the compound as shown in formula III-a is from 1:1 to 1:0.5. The amount of the base used may be a conventional amount for such a reaction in the art, and preferably the molar ratio of the compound of the formula II to the base is from 1:1 to 1:2. The amount of the palladium catalyst used may be a conventional amount for such a reaction in the art. Preferably, the molar ratio of the compound represented by the formula II-a to the palladium catalyst is preferably 1:0.01-1. :0.5. The amount of the organic solvent used may be a conventional amount for such a reaction in the art, and the volume of the organic solvent and the compound of the formula II is preferably 10 mg/m. as long as the reaction is not affected. L ~ 50mL / g. The reaction temperature of the substitution reaction may be a conventional temperature for such a reaction in the art, preferably from 80 to 120 °C. The progress of the substitution reaction can be monitored according to conventional test methods in the art (such as TLC, GC, HPLC or NMR), generally as the end point of the reaction when the compound as shown in formula II-a disappears, the reaction The time is preferably from 6 to 20 hours.
方法三中，所述的酰卤化反应的方法和条件可为本领域此类反应常规的方法和条件，较佳地包括下列步骤：将如式II-a所示的化合物与有机溶剂混合后，在-5-0℃下加入如式III-b所示的化合物，进行所述的酰卤化反应。所述的有机溶剂可为本领域此类反应常规的溶剂，较佳地为含氮芳烃类溶剂。所述的含氮芳烃类溶剂较佳地为吡啶。所述的如式II-a所示的化合物与如式III-b所示的化合物的用量可为本领域此类反应常规的用量，较佳地所述的如式II-a所示的化合物与如式III-b所示的化合物的摩尔比为1:1～1:1.2。所述的有机溶剂的用量可为本领域此类反应常规的用量，只要不影响反应的进行，即可，所述的有机溶剂与如式II所示的化合物的体积质量比较佳地为1mg/L～10mL/g。所述的酰卤化反应的反应温度可为本领域此类反应常规的温度，较佳地为10-30℃。所述的酰卤化反应的进程可按照本领域常规测试方法(如TLC、GC、HPLC或NMR)进行监控，一般以如式II-a所示的化合物消失时作为反应的终点，所述的反应的时间较佳地为1～2.5小时。In the third method, the method and conditions of the acid halide reaction may be conventional methods and conditions for such reactions in the art, and preferably include the following steps: after mixing the compound of the formula II-a with an organic solvent, The acid halide reaction is carried out by adding a compound represented by the formula III-b at -5 to 0 °C. The organic solvent may be a conventional solvent for such a reaction in the art, preferably a nitrogen-containing aromatic hydrocarbon solvent. The nitrogen-containing aromatic hydrocarbon solvent is preferably pyridine. The amount of the compound of the formula II-a and the compound of the formula III-b may be a conventional amount for such a reaction in the art, preferably the compound of the formula II-a. The molar ratio to the compound as shown in formula III-b is from 1:1 to 1:1.2. The amount of the organic solvent used may be a conventional amount for such a reaction in the art, and the volume of the organic solvent and the compound of the formula II is preferably 1 mg/m. as long as the reaction is not affected. L ~ 10mL / g. The reaction temperature of the acid halide reaction may be a conventional temperature for such a reaction in the art, preferably 10 to 30 °C. The progress of the acid halide reaction can be monitored according to conventional test methods in the art (e.g., TLC, GC, HPLC or NMR), generally as the end of the reaction when the compound as shown in formula II-a disappears, the reaction The time is preferably from 1 to 2.5 hours.
本发明还提供了一种如式II或者II-a所示的通式I所示的喹唑啉类化合物的中间体化合物： The present invention also provides an intermediate compound of the quinazoline compound represented by Formula I as shown in Formula II or II-a:
Figure PCTCN2016088089-appb-000250
Figure PCTCN2016088089-appb-000250
化合物II中，X1、X2和X3独立地为卤素(例如氯、溴或碘，优选氯)；R4和R5的定义均同前所述；化合物II-a中，R1、R2和R3的定义均同前所述。In compound II, X 1 , X 2 and X 3 are independently halogen (for example chlorine, bromine or iodine, preferably chlorine); R 4 and R 5 are as defined above; in compound II-a, R 1 , The definitions of R 2 and R 3 are as described above.
本发明还提供了通式I所示的喹唑啉类化合物，其药学上可接受的盐、溶剂化物、代谢产物、代谢前体和药物前体中的一种或多种，在制备用于预防和/或治疗(辅助治疗)与JAK的表达或活性有关的疾病的药物中的应用。所述的与JAK的表达或活性有关的疾病一般包括自身免疫系统疾病和/或造血系统恶性肿瘤疾病。其中，所述的自身免疫系统疾病包括类风湿性关节炎(RA)、系统性红斑狼疮(Systemic Lupus Erythematosus)、银屑病(Psoriatic/Psoriasis)等多种疾病。The present invention also provides a quinazoline compound of the formula I, one or more of which are pharmaceutically acceptable salts, solvates, metabolites, metabolic precursors and prodrugs, which are prepared for use in the preparation. The use of a medicament for the prevention and/or treatment (adjuvant therapy) of a disease associated with the expression or activity of JAK. The diseases associated with the expression or activity of JAK generally include autoimmune diseases and/or hematopoietic malignancies. Among them, the autoimmune diseases include rheumatoid arthritis (RA), systemic Lupus Erythematosus, and Psoriatic/Psoriasis.
本发明还提供了一种药物组合物，其含有治疗有效量的通式I所示的喹唑啉类化合物，其药学上可接受的盐、溶剂化物、代谢产物、代谢前体和药物前体中的一种或多种，及其药学上可接受的一种或多种载体和/或稀释剂。所述药物组合物中，所述载体和所述的稀释剂可为本领域药物组合物中常规的载体和稀释剂。The invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a quinazoline compound of the formula I, a pharmaceutically acceptable salt, solvate, metabolite, metabolic precursor and prodrug thereof One or more of them, and one or more pharmaceutically acceptable carriers and/or diluents thereof. In the pharmaceutical composition, the carrier and the diluent may be conventional carriers and diluents in the pharmaceutical compositions of the art.
本发明中所述药物组合物可以是适用于口服的形式，也可以是无菌注射水溶液形式，可按照本领域任何已知制备药用组合物的方法制备口服或注射组合物。The pharmaceutical composition of the present invention may be in a form suitable for oral administration or in the form of a sterile injectable aqueous solution, and the oral or injectable composition may be prepared according to any method known in the art for preparing a pharmaceutical composition.
在此使用的术语“治疗有效量”是指在给予受试者时足以有效治疗本文所述的疾病或病症的化合物的量。虽然构成“治疗有效量”的化合物的量将根据化合物、病症及其严重度、以及欲治疗受试者的年龄而变化，但可由本领域技术人员以常规方式确定。The term "therapeutically effective amount" as used herein, refers to an amount of a compound that is sufficient to effectively treat a disease or condition described herein when administered to a subject. While the amount of the compound that constitutes a "therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the subject to be treated, it can be determined in a conventional manner by those skilled in the art.
如本文中所用，当提到具体盐、药物组合物、组合物、辅料等“药学上可接受的”时，是指该盐、药物组合物、组合物、辅料等一般无毒、安全，并且适合于受试者使用，优选哺乳动物受试者，更优选为人受试者。As used herein, when reference is made to a particular salt, pharmaceutical composition, composition, adjuvant, etc. "pharmaceutically acceptable", it is meant that the salt, pharmaceutical composition, composition, excipient, etc. are generally non-toxic, safe, and Suitable for use by a subject, preferably a mammalian subject, more preferably a human subject.
在此使用的术语“药学上可接受的盐”指本发明化合物的药学上可接受的有机或无机盐。示例性盐包括但不限于：硫酸盐、柠檬酸盐、乙酸盐、草酸盐、氯化物、溴化物、碘化物、硝酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、异烟酸盐、乳酸盐、水杨酸盐、酸式柠檬酸盐、酒石酸盐、油酸盐、单宁酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、龙胆酸盐(gentisinate)、富马酸盐、葡糖酸盐、葡糖醛酸盐、糖酸盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲烷磺酸盐、乙烷磺酸盐、苯磺酸盐、对甲苯磺酸盐和双羟萘酸盐(即1-1-亚甲基-双(2-羟基-3-萘甲酸盐))。The term "pharmaceutically acceptable salt" as used herein refers to a pharmaceutically acceptable organic or inorganic salt of a compound of the invention. Exemplary salts include, but are not limited to, sulfates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, hydrogen sulfates, phosphates, acid phosphates, isonicotinic acid Salt, lactate, salicylate, acid citrate, tartrate, oleate, tannic acid, pantothenate, hydrogen tartrate, ascorbate, succinate, maleate, dragon Gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methane sulfonate, ethane sulfonic acid Salt, besylate, p-toluenesulfonate and pamoate (i.e., 1-1-methylene-bis(2-hydroxy-3-naphthoate)).
如本文所用，术语“溶剂化物”是指本发明化合物的一种晶体形式，它还包含一种或多种融入晶体结构中的溶剂分子。溶剂化物可包括化学计量量或非化学计量的溶剂，并且 溶剂中的溶剂分子可能以有序或非有序排列的形式存在。含有非化学计量溶剂分子的溶剂化物可能是溶剂化物至少丢失一个(但并非全部)溶剂分子得到的。在一个特定实施例中，一种溶剂化物是一种水合物，意味着化合物的结晶形式进一步包括水分子，以水分子作为溶剂。As used herein, the term "solvate" refers to a crystalline form of a compound of the invention which further comprises one or more solvent molecules incorporated into the crystal structure. Solvates may include stoichiometric or non-stoichiometric solvents, and Solvent molecules in the solvent may exist in an ordered or non-ordered arrangement. Solvates containing non-stoichiometric solvent molecules may be obtained by solvating at least one, but not all, solvent molecules. In a particular embodiment, a solvate is a hydrate, meaning that the crystalline form of the compound further comprises water molecules with water molecules as a solvent.
如本文所用，术语“药物前体”是指本发明化合物经过化学结构修饰后得到的在体外无活性或活性较小，在体内经酶或非酶的转化释放出活性化合物而发挥药效的化合物。As used herein, the term "prodrug" refers to a compound obtained by chemically modifying a compound of the present invention which is inactive or less active in vitro and which exhibits pharmacological effects by enzymatic or non-enzymatic conversion of the active compound in vivo. .
如本文所用，术语“受试者”是指根据本发明的实施例，即将或已经接受了该化合物或药物组合物给药的任何动物，哺乳动物为优，人类最优。如本文所用术语“哺乳动物”包括任何哺乳动物。哺乳动物的实例包括但不限于牛、马、羊、猪、猫、狗、小鼠、大鼠、家兔、豚鼠、猴、人等，以人类为最优。As used herein, the term "subject" refers to any animal that is or has been administered a compound or pharmaceutical composition according to an embodiment of the invention, which is superior to mammals and optimal for humans. The term "mammal" as used herein includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., which are optimal for humans.
在一个实施例中，“治疗”或“正在治疗”是指疾病或病症或其至少一个可辨别症状的改善、预防或逆转。在另一个实施例中，“治疗”或“正在治疗”是指正在治疗的疾病或病症的至少一个可测量身体参数的改善、预防或逆转，可能并未在哺乳动物中识别所述疾病或病症。然而在另一个实施例中，“治疗”或“正在治疗”是指减慢疾病或病症的进展，或者是身体上的，例如可辨别症状的稳定，或生理学上的，例如，身体参数的稳定，或两者兼而有之。在另一个实施例中，“治疗”或“正在治疗”是指延迟疾病或病症的发作。In one embodiment, "treating" or "treating" refers to the improvement, prevention, or reversal of a disease or condition, or at least one discernible symptom thereof. In another embodiment, "treating" or "treating" refers to an improvement, prevention or reversal of at least one measurable physical parameter of a disease or condition being treated, which may not be recognized in a mammal. . In yet another embodiment, "treating" or "treating" refers to slowing the progression of a disease or condition, or physical, such as the identification of stable symptoms, or physiological, for example, stabilization of body parameters. , or both. In another embodiment, "treating" or "treating" refers to delaying the onset of a disease or condition.
在某些实施例中，本发明的化合物作为预防措施给药。如本文所用，“预防”或“正在预防”是指降低获得给定疾病或病症的风险。在实施例的优选模式中，将指定化合物作为预防措施给予受试者，例如有癌症或自身免疫性疾病家族病史或倾向的受试者。In certain embodiments, the compounds of the invention are administered as a prophylactic measure. As used herein, "preventing" or "preventing" refers to reducing the risk of obtaining a given disease or condition. In a preferred mode of embodiment, the indicated compound is administered to the subject as a preventive measure, such as a subject having a family history or predisposition to cancer or an autoimmune disease.
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。The above preferred conditions can be arbitrarily combined without departing from the ordinary knowledge in the art, that is, preferred embodiments of the present invention.
本发明所用试剂和原料均市售可得。The reagents and starting materials used in the present invention are commercially available.
本发明的积极进步效果在于：The positive effects of the present invention are:
本发明提供了一种与现有技术完全不同的喹唑啉类化合物、其制备方法、药物组合物和应用。本发明的喹唑啉类化合物对蛋白激酶JAK有良好地抑制效果，可以用于制备预防、治疗或辅助治疗与JAK的表达或活性有关的多种疾病，尤其是肿瘤疾病和免疫疾病的药物。The present invention provides a quinazoline compound which is completely different from the prior art, a process for the preparation thereof, a pharmaceutical composition and an application. The quinazoline compound of the present invention has a good inhibitory effect on protein kinase JAK, and can be used for the preparation of a medicament for preventing, treating or adjuvant treatment of various diseases related to the expression or activity of JAK, particularly tumor diseases and immune diseases.
具体实施方式Detailed ways
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。The invention is further illustrated by the following examples, which are not intended to limit the invention. The experimental methods in the following examples which do not specify the specific conditions are selected according to conventional methods and conditions, or according to the product specifications.
实施例1：5-(4-甲氧基苯基)-N-(环丙甲酰胺)喹唑啉-2-胺(化合物1) Example 1: 5-(4-Methoxyphenyl)-N-(cyclopropanecarboxamide)quinazolin-2-amine (Compound 1)
Figure PCTCN2016088089-appb-000251
Figure PCTCN2016088089-appb-000251
步骤1制备5-氯喹唑啉-2-胺(化合物1-2)Step 1 Preparation of 5-chloroquinazolin-2-amine (Compound 1-2)
将原料2-氯-6-氟苯甲醛(3.02g,19.1mmol)溶于10mL DMAC中，加入碳酸胍(4eq)，升温至140℃搅拌反应3小时。TLC监测无原料剩余，停止加热，冷却至室温，加入100mL水，于0℃下冷却过夜。抽滤后，粗品用二氯甲烷重结晶，得目标产物，黄色固体，熔点:202-204℃。The raw material 2-chloro-6-fluorobenzaldehyde (3.02 g, 19.1 mmol) was dissolved in 10 mL of DMAC, and cesium carbonate (4 eq) was added thereto, and the mixture was heated to 140 ° C and stirred for 3 hours. The TLC was monitored for no material remaining, heating was stopped, cooled to room temperature, 100 mL of water was added and the mixture was cooled overnight at 0 °C. After suction filtration, the crude product was crystallised from methylene chloride.
步骤2制备5-氯-N-(环丙甲酰基)喹唑啉-2-胺(化合物1-3)Step 2 Preparation of 5-chloro-N-(cyclopropanoyl)quinazolin-2-amine (Compound 1-3)
取圆底烧瓶，依次加入5-氯喹唑啉-2-胺(5.388g,30mmol)和30mL吡啶，冰浴冷却至0℃，在磁力搅拌下缓慢滴加环丙甲酰氯(1.2eq)。滴毕，撤去冰浴，升至室温反应2.5小时。TLC监测无原料剩余，减压浓缩。残余物加水50mL，用二氯甲烷萃取3次(50mLx3)。合并有机相，再用饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析，得目标产物，棕色固体，熔点209-211℃。1H NMR(300MHz,DMSO-d6)δ11.23(s,1H),9.64(d,J＝0.9Hz,1H),7.91(m,1H),7.76(m,1H),7.71(dd,J＝7.5,0.9Hz,1H),2.23(m,1H),0.89–0.83(m,4H).ESI-MS:m/z 248[M+H]+。A round bottom flask was taken, and 5-chloroquinazolin-2-amine (5.388 g, 30 mmol) and 30 mL of pyridine were sequentially added, and the mixture was cooled to 0 ° C in an ice bath, and cyclopropanoyl chloride (1.2 eq) was slowly added dropwise under magnetic stirring. After the dropwise addition, the ice bath was removed and the reaction was allowed to rise to room temperature for 2.5 hours. TLC was monitored without any remaining material and concentrated under reduced pressure. The residue was added with 50 mL of water and extracted three times with dichloromethane (50 mL×3). The organic phase was combined, washed with EtOAc EtOAc. 1 H NMR (300MHz, DMSO- d 6) δ11.23 (s, 1H), 9.64 (d, J = 0.9Hz, 1H), 7.91 (m, 1H), 7.76 (m, 1H), 7.71 (dd, J = 7.5, 0.9 Hz, 1H), 2.23 (m, 1H), 0.89 - 0.83 (m, 4H). ESI-MS: m/z 248[M+H] + .
步骤3制备5-(4-甲氧基苯基)-N-(环丙甲酰基)喹唑啉-2-胺(化合物1)Step 3 Preparation of 5-(4-methoxyphenyl)-N-(cyclopropanoyl)quinazolin-2-amine (Compound 1)
向圆底烧瓶依次加入5-氯-N-(环丙甲酰基)喹唑啉-2-胺(124mg,0.5mmol)，DMF(5mL)，4-甲氧基苯基硼酸(115mg，0.75mmol)，Pd(PPh3)4(29mg,0.05mmol)，碳酸钾(277mg,2mmol)，在氮气保护下于100℃加热反应24小时。反应完毕，待反应液降至室温后，减压蒸除溶剂。向残余物中加水20mL，用乙酸乙酯(3×15mL)萃取，饱和食盐水洗，无水硫酸钠干燥后，浓缩得粗品。经硅胶柱层析得产物80mg，收率50％，白色固体，熔点198-200℃。1H NMR(300MHz,DMSO-d6)δ11.07(s,1H),9.24(d,J＝0.9Hz,1H),7.96(m,1H),7.80–7.73(m,1H),7.56–7.50(m,2H),7.49(dd,J＝7.2,1.2Hz,1H),7.20–7.08(m,2H),3.86(s,3H),2.23(m,1H),0.97–0.69(m,4H).ESI-MS:m/z 320[M+H]+。To the round bottom flask was added 5-chloro-N-(cyclopropanoyl)quinazolin-2-amine (124 mg, 0.5 mmol), DMF (5 mL), 4-methoxyphenylboronic acid (115 mg, 0.75 mmol) ), Pd(PPh 3 ) 4 (29 mg, 0.05 mmol), potassium carbonate (277 mg, 2 mmol), and the reaction was heated at 100 ° C for 24 hours under a nitrogen atmosphere. After completion of the reaction, after the reaction solution was cooled to room temperature, the solvent was evaporated under reduced pressure. Water (20 mL) was added to the residue, and the mixture was evaporated. The product was obtained by silica gel column chromatography (yield: ield: 50%) 1 H NMR (300MHz, DMSO- d 6) δ11.07 (s, 1H), 9.24 (d, J = 0.9Hz, 1H), 7.96 (m, 1H), 7.80-7.73 (m, 1H), 7.56- 7.50 (m, 2H), 7.49 (dd, J = 7.2, 1.2 Hz, 1H), 7.20 - 7.08 (m, 2H), 3.86 (s, 3H), 2.23 (m, 1H), 0.97 - 0.69 (m, 4H). ESI-MS: m/z 320 [M+H] + .
实施例2和实施例3Embodiment 2 and Embodiment 3
按照实施例1的相同方法，中间体(1-3)与不同的硼酸或硼酸酯进行反应，制备实施例2和实施例3的化合物，具体实验数据见表1。The compounds of Example 2 and Example 3 were prepared by reacting the intermediates (1-3) with different boronic acids or boronic esters in the same manner as in Example 1. The specific experimental data are shown in Table 1.
表1化合物2和化合物3的实验数据表Table 1 Experimental data sheets for Compound 2 and Compound 3
Figure PCTCN2016088089-appb-000252
Figure PCTCN2016088089-appb-000252
Figure PCTCN2016088089-appb-000253
Figure PCTCN2016088089-appb-000253
实施例4：5-(4-(甲氧基)苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物4)Example 4: 5-(4-(Methoxy)phenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 4)
Figure PCTCN2016088089-appb-000254
Figure PCTCN2016088089-appb-000254
步骤1制备5-氯-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺(4-1)Step 1 Preparation of 5-chloro-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine (4-1)
向圆底烧瓶依次加入5-氯喹唑啉-2-胺(90mg，0.5mmol)，二氧六环(2mL)，1-(3-溴苯基)-4-甲基哌嗪(128mg，0.5mmol)，Pd2(dba)3(5mg,0.0165mmol)，Xantphos(5mg，0.0165mmol)，碳酸铯(228mg,0.7mmol)，在氮气保护下115℃加热反应15小时。TLC检测反应完全，停止反应，降至室温，减压蒸除溶剂后，加水20mL，乙酸乙酯(3×15mL)萃取，饱和食盐水洗，无水硫酸钠干燥。浓缩，粗品经硅胶柱层析(DCM/EtOAc＝30:1至20:1,v/v)得产物，黄色固体，熔点133-135℃。1H NMR(300MHz,DMSO-d6)δ9.95(s,1H),9.44(d,J＝0.6Hz,1H),7.77(dd,J＝8.7,7.5Hz,1H),7.71(s,1H),7.60(dt,J＝8.4,0.9Hz,1H),7.47(dd,J＝7.8,1.2Hz,1H),7.42–7.36(m,1H),7.16(t,J＝8.1Hz,1H),6.62(dd,J＝8.1,1.8Hz,1H),3.23–3.07(m,4H),2.57–2.42(m,7H),2.24(s,3H).ESI-MS:m/z 354[M+H]+。To the round bottom flask was added 5-chloroquinazolin-2-amine (90 mg, 0.5 mmol), dioxane (2 mL), 1-(3-bromophenyl)-4-methylpiperazine (128 mg, 0.5). Methyl), Pd 2 (dba) 3 (5 mg, 0.0165 mmol), Xantphos (5 mg, 0.015 mmol), cesium carbonate (228 mg, 0.7 mmol), and the reaction was heated at 115 ° C for 15 hours under nitrogen atmosphere. The reaction was completed by TLC, the reaction was stopped, and the mixture was cooled to room temperature. The solvent was evaporated under reduced pressure. Water (20 mL), ethyl acetate (3×15 mL) was evaporated and evaporated. Concentration, EtOAc EtOAc EtOAc:EtOAc 1 H NMR (300MHz, DMSO- d 6) δ9.95 (s, 1H), 9.44 (d, J = 0.6Hz, 1H), 7.77 (dd, J = 8.7,7.5Hz, 1H), 7.71 (s, 1H), 7.60 (dt, J = 8.4, 0.9 Hz, 1H), 7.47 (dd, J = 7.8, 1.2 Hz, 1H), 7.42 - 7.36 (m, 1H), 7.16 (t, J = 8.1 Hz, 1H) ), 6.62 (dd, J = 8.1, 1.8 Hz, 1H), 3.23 - 3.07 (m, 4H), 2.57 - 2.42 (m, 7H), 2.24 (s, 3H). ESI-MS: m/z 354 [ M+H] + .
步骤2制备5-(4-(甲氧基)苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物4) Step 2 Preparation of 5-(4-(methoxy)phenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 4)
取10毫升圆底烧瓶，将5-氯-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺(106mg，0.3mmol)溶于干燥DMF(3mL)中，然后依次加入(4-甲氧基苯基)硼酸(56mg，0.36mmol)，Pd(PPh3)4(18mg,0.015mmol)，无水碳酸钾(168mg,1.2mmol)。在氮气保护下100℃加热反应36小时。TLC检测反应完全，停止加热。待反应液降至室温后，加水20mL，用乙酸乙酯(3×15mL)萃取。合并有机层，再用饱和食盐水洗，无水硫酸钠干燥。浓缩，粗品经硅胶柱层析(DCM:MeOH＝50:1至10:1,v/v)得产物，黄色固体，熔点112-114℃。1H NMR(300MHz,DMSO-d6)δ9.75(s,1H),9.07(s,1H),7.89–7.78(m,1H),7.75(s,1H),7.62(d,J＝8.4Hz,1H),7.50(d,J＝8.7Hz,2H),7.41(d,J＝7.8Hz,1H),7.26(d,J＝6.9Hz,1H),7.14(m,3H),6.59(d,J＝8.4Hz,1H),3.85(s,3H),3.16(s,4H),2.50–2.42(m,4H),2.24(s,3H).ESI-MS:m/z 411[M+H]+。A 10 mL round bottom flask was taken and 5-chloro-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine (106 mg, 0.3 mmol) was dissolved in dry DMF. (3 mL), then (4-methoxyphenyl)boronic acid (56 mg, 0.36 mmol), Pd(PPh 3 ) 4 (18 mg, 0.015 mmol), anhydrous potassium carbonate (168 mg, 1.2 mmol). The reaction was heated at 100 ° C for 36 hours under a nitrogen atmosphere. The reaction was completed by TLC and the heating was stopped. After the reaction solution was cooled to room temperature, water (20 mL) was added and ethyl acetate (3×15 mL) was evaporated. The organic layer was combined, washed with brine and dried over anhydrous sodium sulfate. Concentration, the crude product was obtainedjjjjjjjjjjjjjjjj 1 H NMR (300MHz, DMSO- d 6) δ9.75 (s, 1H), 9.07 (s, 1H), 7.89-7.78 (m, 1H), 7.75 (s, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 8.7 Hz, 2H), 7.41 (d, J = 7.8 Hz, 1H), 7.26 (d, J = 6.9 Hz, 1H), 7.14 (m, 3H), 6.59 ( d, J = 8.4 Hz, 1H), 3.85 (s, 3H), 3.16 (s, 4H), 2.50 - 2.42 (m, 4H), 2.24 (s, 3H). ESI-MS: m/z 411 [M +H] + .
实施例5和实施例6Example 5 and Example 6
按照实施例4的相同方法，中间体(4-1)与不同的硼酸或硼酸酯，制备实施例5和实施例6的化合物，具体实验数据见表2。The compounds of Example 5 and Example 6 were prepared in the same manner as in Example 4, using the intermediate (4-1) with a different boronic acid or boronic acid ester. The specific experimental data are shown in Table 2.
表2化合物5和化合物6的实验数据表Table 2 Experimental data sheets for Compound 5 and Compound 6
Figure PCTCN2016088089-appb-000255
Figure PCTCN2016088089-appb-000255
Figure PCTCN2016088089-appb-000256
Figure PCTCN2016088089-appb-000256
实施例75-(4-甲磺酰基苯基)-喹唑啉-2-胺(化合物7)Example 75-(4-Methanesulfonylphenyl)-quinazolin-2-amine (Compound 7)
Figure PCTCN2016088089-appb-000257
Figure PCTCN2016088089-appb-000257
向10毫升圆底烧瓶中依次加入5-氯喹唑啉-2-胺(90mg，0.5mmol)，DMF(2mL)，(4-甲磺酰基苯基)硼酸(120mg，0.5mmol)，Pd(PPh3)4(29mg,0.05mmol)和1M碳酸钾水溶液(1mL,1mmol)。然后在氮气保护下加热至100℃反应6小时。停止反应，降至室温，加水20mL，乙酸乙酯(3×15mL)萃取。合并有机相再用饱和食盐水洗，无水硫酸钠干燥。浓缩，粗品经硅胶柱层析(DCM/EtOAc＝3:1至1:1,v/v)得产物，黄色固体，熔点297-299℃。1H NMR(300MHz,DMSO-d6)δ8.88(s,1H),8.08(d,J＝8.4Hz,2H),7.81(d,J＝8.4Hz,2H),7.79–7.74(m,1H),7.51(d,J＝8.4Hz,1H),7.21(d,J＝7.2Hz,1H),6.99(s,2H),3.32(s,4H).ESI-MS:m/z 300[M+H]+。To a 10 ml round bottom flask was added 5-chloroquinazolin-2-amine (90 mg, 0.5 mmol), DMF (2 mL), (4-methanesulfonylphenyl)boronic acid (120 mg, 0.5 mmol), Pd (PPh) 3 ) 4 (29 mg, 0.05 mmol) and 1M aqueous potassium carbonate (1 mL, 1 mmol). It was then heated to 100 ° C under nitrogen for 6 hours. The reaction was quenched, cooled to room temperature, and water (20 mL) was evaporated. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. Concentration, the title compound wasjjjjjjjjjjjjjjjj 1 H NMR (300MHz, DMSO- d 6) δ8.88 (s, 1H), 8.08 (d, J = 8.4Hz, 2H), 7.81 (d, J = 8.4Hz, 2H), 7.79-7.74 (m, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.21 (d, J = 7.2 Hz, 1H), 6.99 (s, 2H), 3.32 (s, 4H). ESI-MS: m/z 300 [ M+H] + .
实施例8 5-(4-甲氧基苯基)-喹唑啉-2-胺(化合物8)Example 8 5-(4-Methoxyphenyl)-quinazolin-2-amine (Compound 8)
Figure PCTCN2016088089-appb-000258
Figure PCTCN2016088089-appb-000258
按照实施例7的相同方法，中间体(1-2)与对甲氧基苯硼酸反应制备化合物8。黄色固体，熔点271-273℃。1H NMR(300MHz,DMSO-d6)δ8.91(d,J＝0.6Hz,1H),7.71(dd,J＝8.4,7.2Hz,1H),7.48–7.43(m,2H),7.41(dd,J＝8.6,0.9Hz,1H),7.14–7.06(m,3H),6.89(s,2H),3.84(s,3H).ESI-MS:m/z 252[M+H]+。Compound 8 was prepared by reacting Intermediate (1-2) with p-methoxybenzeneboronic acid in the same manner as in Example 7. Yellow solid, mp 271-273 ° C. 1 H NMR (300MHz, DMSO- d 6) δ8.91 (d, J = 0.6Hz, 1H), 7.71 (dd, J = 8.4,7.2Hz, 1H), 7.48-7.43 (m, 2H), 7.41 ( Dd, J = 8.6, 0.9 Hz, 1H), 7.14 - 7.06 (m, 3H), 6.89 (s, 2H), 3.84 (s, 3H). ESI-MS: m/z 252 [M+H] + .
实施例9 7-(4-(甲氧基)苯基)-N-(环丙甲酰胺)喹唑啉-2-胺(化合物9)Example 9 7-(4-(Methoxy)phenyl)-N-(cyclopropanecarboxamide)quinazolin-2-amine (Compound 9)
Figure PCTCN2016088089-appb-000259
Figure PCTCN2016088089-appb-000259
步骤1制备7-氯喹唑啉-2-胺(9-2)Step 1 Preparation of 7-chloroquinazolin-2-amine (9-2)
将原料4-氯-6-氟苯甲醛(3.02g,19.1mmol)溶于10mL DMAC中，加入4倍量碳酸胍(4eq)，在140℃反应3小时。TLC监测无原料剩余，停止加热，冷却至室温，加入100mL水，0℃冷却过夜后抽滤。固体用二氯甲烷重结晶，得产物(9-2)，黄色固体。熔点:202-204℃。 The starting material 4-chloro-6-fluorobenzaldehyde (3.02 g, 19.1 mmol) was dissolved in 10 mL of DMAC, and 4 times the amount of cesium carbonate (4 eq) was added and reacted at 140 ° C for 3 hours. The TLC monitored no material remaining, the heating was stopped, the temperature was cooled to room temperature, 100 mL of water was added, and the mixture was cooled at 0 ° C overnight and then suction filtered. The solid was recrystallized from methylene chloride to afford product (9-2). Melting point: 202-204 ° C.
步骤2制备7-氯-N-(环丙甲酰胺)喹唑啉-2-胺(9-3)Step 2 Preparation of 7-chloro-N-(cyclopropanecarboxamide) quinazolin-2-amine (9-3)
取圆底烧瓶，依次加入7-氯喹唑啉-2-胺(1.796g,10mmol)和吡啶(10mL)，于0℃下滴加1.2倍当量环丙甲酰氯。滴毕，升至室温继续搅拌反应2.5小时。TLC监测无原料剩余。减压蒸除溶剂后，加水30mL，用二氯甲烷(3×10mL)萃取。合并有机相再经饱和食盐水洗，无水硫酸钠干燥后，浓缩。粗品经硅胶柱层析得产物(9-3)。黄色固体，熔点209-211℃；1H NMR(300MHz,CDCl3)δ9.29(s,1H),8.99(s,1H),7.91(d,J＝1.5Hz,1H),7.80(d,J＝8.7Hz,1H),7.46(dd,J＝8.7,2.1Hz,1H),2.70(s,1H),1.36–1.12(m,2H),1.12–0.87(m,2H).ESI-MS:m/z 248[M+H]+。A round bottom flask was taken, and 7-chloroquinazolin-2-amine (1.796 g, 10 mmol) and pyridine (10 mL) were sequentially added, and 1.2-fold equivalent of cyclopropionyl chloride was added dropwise at 0 °C. After the dropwise addition, the reaction was further stirred at room temperature for 2.5 hours. TLC monitored no raw material remaining. After evaporating the solvent under reduced pressure, water (30 mL) was evaporated and evaporated. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate The crude product was subjected to silica gel column chromatography to give the product (9-3). Yellow solid, mp 209-211 ° C; 1 H NMR (300 MHz, CDCl 3 ) δ 9.29 (s, 1H), 8.99 (s, 1H), 7.91 (d, J = 1.5 Hz, 1H), 7.80 (d, J=8.7 Hz, 1H), 7.46 (dd, J=8.7, 2.1 Hz, 1H), 2.70 (s, 1H), 1.36–1.12 (m, 2H), 1.12–0.87 (m, 2H). ESI-MS :m/z 248[M+H] + .
步骤3制备7-(4-(甲氧基)苯基)-N-(环丙甲酰基)喹唑啉-2-胺(化合物9)Step 3 Preparation of 7-(4-(methoxy)phenyl)-N-(cyclopropanoyl)quinazolin-2-amine (Compound 9)
向圆底烧瓶中依次加入7-氯-N-(环丙甲酰胺)喹唑啉-2-胺(124mg,0.5mmol)，DMF(5mL)，(4-甲氧基苯基)硼酸(115mg，0.75mmol)，Pd(PPh3)4(29mg,0.05mmol),无水碳酸钾(277mg,2mmol)，在氮气保护下100℃加热搅拌反应24小时。TLC监测原料无剩余，停止加热。待反应液降至室温后，加水20mL，用乙酸乙酯(3×15mL)萃取，合并有机相经饱和食盐水洗，无水硫酸钠干燥后，浓缩，粗品经硅胶柱层析(石油醚/乙酸乙酯＝5:1-2：1v/v)得目标产物，黄色固体，熔点227-228℃；1H NMR(300MHz,DMSO-d6)δ10.98(s,1H),9.46(s,1H),8.10(d,J＝8.4Hz,1H),7.96–7.88(m,2H),7.84(d,J＝9.0Hz,2H),7.10(d,J＝9.0Hz,2H),3.84(s,3H),2.39–2.20(m,1H),0.90–0.73(m,4H).ESI-MS:m/z 320[M+H]+。Add 7-chloro-N-(cyclopropanecarboxamide)quinazolin-2-amine (124 mg, 0.5 mmol), DMF (5 mL), (4-methoxyphenyl)boronic acid (115 mg) to a round bottom flask. , 0.75 mmol), Pd(PPh 3 ) 4 (29 mg, 0.05 mmol), anhydrous potassium carbonate (277 mg, 2 mmol), and the reaction was stirred under heating at 100 ° C for 24 hours under nitrogen atmosphere. The TLC monitored the raw material without remaining and stopped heating. After the reaction mixture was cooled to room temperature, water (20 mL) was added, and ethyl acetate (3×15 mL) was evaporated. ethyl ester = 5: 1-2: 1v / v ) to give the desired product as a yellow solid, m.p. 227-228 ℃; 1H NMR (300MHz, DMSO-d 6) δ10.98 (s, 1H), 9.46 (s, 1H ), 8.10 (d, J = 8.4 Hz, 1H), 7.96 - 7.88 (m, 2H), 7.84 (d, J = 9.0 Hz, 2H), 7.10 (d, J = 9.0 Hz, 2H), 3.84 (s) , 3H), 2.39 - 2.20 (m, 1H), 0.90 - 0.73 (m, 4H). ESI-MS: m/z 320[M+H]+.
实施例10和实施例11Example 10 and Example 11
按照实施例9的相同方法，中间体(9-3)与不同的硼酸或硼酸酯，制备实施例10和实施例11的化合物，具体实验数据见表3。The compounds of Example 10 and Example 11 were prepared in the same manner as in Example 9 except that the intermediate (9-3) was combined with a different boronic acid or boronic acid ester.
表3化合物10和化合物11的实验数据表Table 3 Experimental data sheets for Compound 10 and Compound 11
Figure PCTCN2016088089-appb-000260
Figure PCTCN2016088089-appb-000260
Figure PCTCN2016088089-appb-000261
Figure PCTCN2016088089-appb-000261
实施例12：7-(4-甲氧基苯基)-N-(3,4,5-三甲氧基苯基)喹唑啉-2-胺(化合物12)Example 12: 7-(4-Methoxyphenyl)-N-(3,4,5-trimethoxyphenyl)quinazolin-2-amine (Compound 12)
Figure PCTCN2016088089-appb-000262
Figure PCTCN2016088089-appb-000262
步骤1制备7-氯-N-(3,4,5-三甲氧基苯基)喹唑啉-2-胺(12-1)Step 1 Preparation of 7-chloro-N-(3,4,5-trimethoxyphenyl)quinazolin-2-amine (12-1)
向圆底烧瓶中依次加入7-氯喹唑啉-2-胺(1.2g,6.6mmol)，二氧六环(50mL)，5-溴-1,2,3-三甲氧基苯(1.45g，5.8mmol)，Pd2(dba)3(200mg,0.2mmol),碳酸铯(3.0g,9.2mmol)和Xantphos(120mg,0.2mmol)。在氮气保护下加热至80℃反应6小时。反应完毕，减压蒸除溶剂。向残余物中加水200mL，用二氯甲烷(3×60mL)萃取。合并有机相经饱和食盐水洗，无水硫酸钠干燥后浓缩得粗品，经硅胶柱层析(石油醚/乙酸乙酯＝3:1至2:1,v/v)得产物(12-1)，黄色固体，熔点203-204℃；1H NMR(300MHz,CDCl3)δ9.04(d,J＝0.7Hz,1H),7.75–7.59(m,2H),7.33(s,1H),7.30(d,J＝1.8Hz,1H),7.28(d,J＝1.8Hz,0H),7.15(s,2H),3.93(s,7H),3.85(s,3H).ESI-MS:m/z 346[M+H]+。To the round bottom flask was added 7-chloroquinazolin-2-amine (1.2 g, 6.6 mmol), dioxane (50 mL), 5-bromo-1,2,3-trimethoxybenzene (1.45 g, 5.8 mmol), Pd 2 (dba) 3 (200 mg, 0.2 mmol), cesium carbonate (3.0 g, 9.2 mmol) and Xantphos (120 mg, 0.2 mmol). The reaction was heated to 80 ° C for 6 hours under a nitrogen atmosphere. After completion of the reaction, the solvent was evaporated under reduced pressure. Water (200 mL) was added to the residue and extracted with dichloromethane (3×60 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. , yellow solid, melting point 203-204 ° C; 1 H NMR (300 MHz, CDCl 3 ) δ 9.04 (d, J = 0.7 Hz, 1H), 7.75 - 7.59 (m, 2H), 7.33 (s, 1H), 7.30 (d, J = 1.8 Hz, 1H), 7.28 (d, J = 1.8 Hz, 0H), 7.15 (s, 2H), 3.93 (s, 7H), 3.85 (s, 3H). ESI-MS: m/ z 346[M+H] + .
步骤2制备7-(4-甲氧基苯基)-N-(3,4,5-三甲氧基苯基)喹唑啉-2-胺(化合物12)Step 2 Preparation of 7-(4-methoxyphenyl)-N-(3,4,5-trimethoxyphenyl)quinazolin-2-amine (Compound 12)
向圆底烧瓶中依次加入7-氯-N-(3,4,5-三甲氧基苯基)喹唑啉-2-胺(173mg,0.5mmol)，DMF(5mL)，(4-甲氧基苯基)硼酸(115mg，0.75mmol)，Pd(PPh3)4(29mg,0.05mmol)，无水碳酸钾(277mg,2mmol)，在氮气保护下加热至100℃反应24小时。TLC监测原料无剩余，冷却至室温。加水20mL，用乙酸乙酯萃取三次(3×15mL)，合并有机相再经饱和食盐水洗，无水硫酸钠干燥后，浓缩。粗品经硅胶柱层析(石油醚/乙酸乙酯＝5:1-2：1v/v)得产物，黄色固体，熔点171-173℃；1H NMR(300MHz,DMSO-d6)δ9.73(s,1H),9.27(s,1H),7.95(d,J＝8.4Hz,1H),7.81(d,J＝8.7Hz,4H),7.68(dd,J＝8.4,1.8Hz,1H),7.49(s,2H),7.10(d,J＝9.0Hz,2H),3.83(d,J＝1.6Hz,9H),3.65(s,3H).ESI-MS:m/z 418[M+H]+。To the round bottom flask was added 7-chloro-N-(3,4,5-trimethoxyphenyl)quinazolin-2-amine (173 mg, 0.5 mmol), DMF (5 mL), 4-methoxy Phenyl) boric acid (115 mg, 0.75 mmol), Pd(PPh 3 ) 4 (29 mg, 0.05 mmol), anhydrous potassium carbonate (277 mg, 2 mmol), heated to 100 ° C under nitrogen atmosphere for 24 hours. The TLC monitored the starting material without remaining and was cooled to room temperature. After adding 20 mL of water and extracting three times with ethyl acetate (3×15 mL), the organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5: 1-2: 1v / v ) to give the product as a yellow solid, m.p. 171-173 ℃; 1 H NMR (300MHz , DMSO-d 6) δ9.73 (s, 1H), 9.27 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 8.7 Hz, 4H), 7.68 (dd, J = 8.4, 1.8 Hz, 1H) , 7.49 (s, 2H), 7.10 (d, J = 9.0 Hz, 2H), 3.83 (d, J = 1.6 Hz, 9H), 3.65 (s, 3H). ESI-MS: m/z 418 [M+ H] + .
实施例14～实施例18Example 14 to Example 18
按照实施例12的相同方法，中间体(9-2)先与不同的卤代物进行取代反应，然后与不同的硼酸或硼酸酯，制备实施例14～实施例18的化合物，具体实验数据见表4。In the same manner as in Example 12, the intermediate (9-2) was first subjected to a substitution reaction with a different halogenated product, and then with different boronic acids or boric acid esters, the compounds of Examples 14 to 18 were prepared. Table 4.
表4化合物14～18的实验数据表Table 4 Experimental data sheets for compounds 14-18
Figure PCTCN2016088089-appb-000263
Figure PCTCN2016088089-appb-000263
Figure PCTCN2016088089-appb-000264
Figure PCTCN2016088089-appb-000264
Figure PCTCN2016088089-appb-000265
Figure PCTCN2016088089-appb-000265
实施例19：8-(4-(甲氧基)苯基)-N-(3,4,5-三甲氧基苯基)喹唑啉-2-胺(化合物19)Example 19: 8-(4-(Methoxy)phenyl)-N-(3,4,5-trimethoxyphenyl)quinazolin-2-amine (Compound 19)
Figure PCTCN2016088089-appb-000266
Figure PCTCN2016088089-appb-000266
步骤1制备8-氯喹唑啉-2-胺(19-2)Step 1 Preparation of 8-chloroquinazolin-2-amine (19-2)
将原料3-氯-2-氟苯甲醛(3.02g,19.1mmol)溶于DMAC(10mL)中，加入4倍量碳酸胍(4eq)，在140℃反应3小时。TLC监测无原料剩余，停止加热，冷却至室温，加入100mL水，0℃冷却过夜。抽滤，所得固体用二氯甲烷重结晶，得产物(19-2)，黄色固体,熔点202-204℃。The raw material 3-chloro-2-fluorobenzaldehyde (3.02 g, 19.1 mmol) was dissolved in DMAC (10 mL), and a 4-fold amount of cesium carbonate (4 eq) was added thereto, and the mixture was reacted at 140 ° C for 3 hours. The TLC monitored no material remaining, the heating was stopped, cooled to room temperature, 100 mL of water was added and the mixture was cooled overnight at 0 °C. Filtration, the solid obtained was crystallised from methylene chloride (EtOAc)
步骤2制备8-氯-N-(3,4,5-三甲氧基)喹唑啉-2-胺(19-3)Step 2 Preparation of 8-chloro-N-(3,4,5-trimethoxy)quinazolin-2-amine (19-3)
向圆底烧瓶中依次加入8-氯喹唑啉-2-胺(1.8g，10.02mmol)，二氧六环(75mL)，5-溴-1,2,3-三甲氧基苯(2.175g，8.8mmol)，Pd2(dba)3(300mg,0.33mmol)，碳酸铯(4.5g,13.8mmol)和Xantphos(180mg,0.31mmol)。然后在氮气保护下加热至80℃反应6小时。停止反应，降至室温，减压蒸除溶剂。向残余物中加水20mL，用二氯甲烷萃取3次(3×60mL)，合并有机相，再经饱和食盐水洗，无水硫酸钠干燥后浓缩，粗品经硅胶柱层析(石油醚/乙酸乙酯＝4:1-2:1,v/v)，得产物，黄色固体，熔点182-183℃；1H NMR(300MHz,CDCl3)δ9.07(s,1H),7.87(dd,J＝7.6,1.3Hz,1H),7.67(dd,J＝7.5,1.2Hz,1H),7.45(s,1H),7.38(s,2H),7.27(m,2H),3.97(s,6H),3.85(s,3H).ESI-MS:m/z 346[M+H]+。To the round bottom flask was added 8-chloroquinazolin-2-amine (1.8 g, 10.02 mmol), dioxane (75 mL), 5-bromo-1,2,3-trimethoxybenzene (2.175 g, 8.8 mmol), Pd 2 (dba) 3 (300 mg, 0.33 mmol), cesium carbonate (4.5 g, 13.8 mmol) and Xantphos (180 mg, 0.31 mmol). It was then heated to 80 ° C under nitrogen for 6 hours. The reaction was stopped, the temperature was lowered to room temperature, and the solvent was evaporated under reduced pressure. 20 mL of water was added to the residue, and the mixture was extracted with dichloromethane (3×60 mL), and the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. acetate = 4: 1-2: 1, v / v), to give the product as a yellow solid, m.p. 182-183 ℃; 1 H NMR (300MHz , CDCl 3) δ9.07 (s, 1H), 7.87 (dd, J = 7.6, 1.3 Hz, 1H), 7.67 (dd, J = 7.5, 1.2 Hz, 1H), 7.45 (s, 1H), 7.38 (s, 2H), 7.27 (m, 2H), 3.97 (s, 6H) , 3.85 (s, 3H). ESI-MS: m/z 346 [M+H] + .
步骤3制备8-(4-(甲氧基)苯基)-N-(3,4,5-三甲氧基苯基)喹唑啉-2-胺(化合物19)Step 3 Preparation of 8-(4-(methoxy)phenyl)-N-(3,4,5-trimethoxyphenyl)quinazolin-2-amine (Compound 19)
向圆底烧瓶中依次加入8-氯-N-(3,4,5-三甲氧基)喹唑啉-2-胺(104mg,0.3mmol)，DMF(2mL)，(4-甲氧基苯基)硼酸(56mg，0.36mmol)，Pd(PPh3)4(18mg,0.015mmol),碳酸钾(332mg,2.4mmol)，在氮气保护下100℃加热反应15小时。TLC监测原料无剩余，停止反应，降至室温，加水20mL，乙酸乙酯萃取三次(3×5mL)，合并有机相，用饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(DCM/MeOH＝50:1-20:1,v/v)得得 产物，黄色固体，熔点190-192℃。1H NMR(300MHz,CDCl3)δ9.11(s,1H),7.71(ddd,J＝8.4,6.6,1.5Hz,2H),7.67–7.60(m,2H),7.39(dd,J＝8.1,7.2Hz,2H),7.03–6.95(m,4H),3.87(s,3H),3.80(s,3H),3.56(s,6H).ESI-MS:m/z 418[M+H]+。To the round bottom flask was added 8-chloro-N-(3,4,5-trimethoxy)quinazolin-2-amine (104 mg, 0.3 mmol), DMF (2 mL), (4-methoxybenzene) Boric acid (56 mg, 0.36 mmol), Pd(PPh 3 ) 4 (18 mg, 0.015 mmol), potassium carbonate (332 mg, 2.4 mmol), and the reaction was heated at 100 ° C for 15 hours under nitrogen atmosphere. TLC was used to monitor the reaction. The reaction mixture was cooled to room temperature. Water (20 mL) and ethyl acetate (3×5 mL) were evaporated. (DCM / MeOH = 50:1 - 20:1, v/v) 1 H NMR (300 MHz, CDCl 3 ) δ 9.11 (s, 1H), 7.71 (ddd, J = 8.4, 6.6, 1.5 Hz, 2H), 7.67 - 7.60 (m, 2H), 7.39 (dd, J = 8.1 , 7.2 Hz, 2H), 7.03 - 6.95 (m, 4H), 3.87 (s, 3H), 3.80 (s, 3H), 3.56 (s, 6H). ESI-MS: m/z 418 [M+H] + .
实施例20～实施例105Example 20 to Example 105
按照实施例19的相同方法，中间体(19-2)先与不同的卤代物进行取代反应，然后与不同的硼酸或硼酸酯进行反应，制备实施例20～实施例180的化合物，具体实验数据见表5。In the same manner as in Example 19, the intermediate (19-2) was subjected to a substitution reaction with a different halogenated substance, and then reacted with a different boronic acid or a boronic acid ester to prepare the compounds of Examples 20 to 180, and the specific experiment was carried out. The data is shown in Table 5.
表5化合物20～180的实验数据表Table 5 Experimental data sheets for compounds 20-180
Figure PCTCN2016088089-appb-000267
Figure PCTCN2016088089-appb-000267
Figure PCTCN2016088089-appb-000268
Figure PCTCN2016088089-appb-000268
Figure PCTCN2016088089-appb-000269
Figure PCTCN2016088089-appb-000269
Figure PCTCN2016088089-appb-000270
Figure PCTCN2016088089-appb-000270
Figure PCTCN2016088089-appb-000271
Figure PCTCN2016088089-appb-000271
Figure PCTCN2016088089-appb-000272
Figure PCTCN2016088089-appb-000272
Figure PCTCN2016088089-appb-000273
Figure PCTCN2016088089-appb-000273
Figure PCTCN2016088089-appb-000274
Figure PCTCN2016088089-appb-000274
Figure PCTCN2016088089-appb-000275
Figure PCTCN2016088089-appb-000275
Figure PCTCN2016088089-appb-000276
Figure PCTCN2016088089-appb-000276
Figure PCTCN2016088089-appb-000277
Figure PCTCN2016088089-appb-000277
Figure PCTCN2016088089-appb-000278
Figure PCTCN2016088089-appb-000278
Figure PCTCN2016088089-appb-000279
Figure PCTCN2016088089-appb-000279
Figure PCTCN2016088089-appb-000280
Figure PCTCN2016088089-appb-000280
Figure PCTCN2016088089-appb-000281
Figure PCTCN2016088089-appb-000281
Figure PCTCN2016088089-appb-000282
Figure PCTCN2016088089-appb-000282
Figure PCTCN2016088089-appb-000283
Figure PCTCN2016088089-appb-000283
Figure PCTCN2016088089-appb-000284
Figure PCTCN2016088089-appb-000284
Figure PCTCN2016088089-appb-000285
Figure PCTCN2016088089-appb-000285
Figure PCTCN2016088089-appb-000286
Figure PCTCN2016088089-appb-000286
Figure PCTCN2016088089-appb-000287
Figure PCTCN2016088089-appb-000287
Figure PCTCN2016088089-appb-000288
Figure PCTCN2016088089-appb-000288
Figure PCTCN2016088089-appb-000289
Figure PCTCN2016088089-appb-000289
Figure PCTCN2016088089-appb-000290
Figure PCTCN2016088089-appb-000290
Figure PCTCN2016088089-appb-000291
Figure PCTCN2016088089-appb-000291
Figure PCTCN2016088089-appb-000292
Figure PCTCN2016088089-appb-000292
Figure PCTCN2016088089-appb-000293
Figure PCTCN2016088089-appb-000293
Figure PCTCN2016088089-appb-000294
Figure PCTCN2016088089-appb-000294
Figure PCTCN2016088089-appb-000295
Figure PCTCN2016088089-appb-000295
Figure PCTCN2016088089-appb-000296
Figure PCTCN2016088089-appb-000296
Figure PCTCN2016088089-appb-000297
Figure PCTCN2016088089-appb-000297
Figure PCTCN2016088089-appb-000298
Figure PCTCN2016088089-appb-000298
Figure PCTCN2016088089-appb-000299
Figure PCTCN2016088089-appb-000299
Figure PCTCN2016088089-appb-000300
Figure PCTCN2016088089-appb-000300
Figure PCTCN2016088089-appb-000301
Figure PCTCN2016088089-appb-000301
Figure PCTCN2016088089-appb-000302
Figure PCTCN2016088089-appb-000302
Figure PCTCN2016088089-appb-000303
Figure PCTCN2016088089-appb-000303
Figure PCTCN2016088089-appb-000304
Figure PCTCN2016088089-appb-000304
Figure PCTCN2016088089-appb-000305
Figure PCTCN2016088089-appb-000305
Figure PCTCN2016088089-appb-000306
Figure PCTCN2016088089-appb-000306
Figure PCTCN2016088089-appb-000307
Figure PCTCN2016088089-appb-000307
Figure PCTCN2016088089-appb-000308
Figure PCTCN2016088089-appb-000308
Figure PCTCN2016088089-appb-000309
Figure PCTCN2016088089-appb-000309
Figure PCTCN2016088089-appb-000310
Figure PCTCN2016088089-appb-000310
Figure PCTCN2016088089-appb-000311
Figure PCTCN2016088089-appb-000311
Figure PCTCN2016088089-appb-000312
Figure PCTCN2016088089-appb-000312
Figure PCTCN2016088089-appb-000313
Figure PCTCN2016088089-appb-000313
Figure PCTCN2016088089-appb-000314
Figure PCTCN2016088089-appb-000314
实施例181：8-(4-(甲氧基)苯基)-N-(3-(4-乙基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物181)Example 181: 8-(4-(Methoxy)phenyl)-N-(3-(4-ethylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 181)
Figure PCTCN2016088089-appb-000315
Figure PCTCN2016088089-appb-000315
步骤1制备8-(4-(甲氧基)苯基)喹唑啉-2-胺(181-2)Step 1 Preparation of 8-(4-(methoxy)phenyl)quinazolin-2-amine (181-2)
向10毫升圆底烧瓶中依次加入8-氯喹唑啉-2-胺(108mg，0.6mmol)，DMF(3mL)，(4-甲氧基苯基)硼酸(112mg，0.72mmol)，Pd(PPh3)4(36mg,0.03mmol)，无水碳酸钾(336mg,2.4mmol)。然后在氮气保护下100℃加热反应36小时。TLC检测反应完全，停止反应，降至室温，加水20mL，用乙酸乙酯萃取三次(3×5mL)，合并有机相再经饱和食盐水洗，无水硫酸钠干燥后，浓缩，粗品经硅胶柱层析(DCM:MeOH＝50:1-10:1,v/v)得产物，黄色固体，熔点196-198℃；1H NMR(300MHz,CDCl3)δ9.06(s,1H),7.73(dd,J＝7.2,1.5Hz,1H),7.69–7.62(m,3H),7.41–7.29(m,1H),7.08–6.95(m,2H),5.24(s,2H),3.87(s,3H).ESI-MS:m/z 252[M+H]+。To a 10 ml round bottom flask was added 8-chloroquinazolin-2-amine (108 mg, 0.6 mmol), DMF (3 mL), (4-methoxyphenyl)boronic acid (112 mg, 0.72 mmol), Pd (PPh) 3 ) 4 (36 mg, 0.03 mmol), anhydrous potassium carbonate (336 mg, 2.4 mmol). The reaction was then heated at 100 ° C for 36 hours under a nitrogen atmosphere. TLC detected the reaction was complete, the reaction was stopped, the reaction was cooled to room temperature, 20 mL of water was added, and the mixture was extracted with ethyl acetate (3×5 mL). The organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate and evaporated. Analysis (DCM: MeOH = 50: 1-10 : 1, v / v) to give the product as a yellow solid, m.p. 196-198 ℃; 1 H NMR (300MHz , CDCl 3) δ9.06 (s, 1H), 7.73 ( Dd, J = 7.2, 1.5 Hz, 1H), 7.69 - 7.62 (m, 3H), 7.41 - 7.29 (m, 1H), 7.08 - 6.95 (m, 2H), 5.24 (s, 2H), 3.87 (s, 3H). ESI-MS: m/z 252 [M+H] + .
步骤2制备8-(4-(甲氧基)苯基)-N-(3-(4-叔丁氧羰基哌嗪-1-基)苯基)喹唑啉-2-胺(181-3)Step 2 Preparation of 8-(4-(methoxy)phenyl)-N-(3-(4-tert-butoxycarbonylpiperazin-1-yl)phenyl)quinazolin-2-amine (181-3 )
向圆底烧瓶中依次加入8-(4-(甲氧基)苯基)喹唑啉-2-胺(101mg，0.4mmol)，二氧六环(20mL)，1-溴-3-((叔丁氧羰基)哌嗪-1-基)苯基(74.4mg，0.4mmol)，Pd2(dba)3(16mg,0.0175mmol),碳酸铯(182mg,0.56mmol)和Xantphos(11mg,0.0175mmol)。然后在氮气保护下80℃加热反应16.5小时。停止反应，降至室温，减压蒸除溶剂，加水20mL，用二氯甲烷萃取三次(3×15mL)。合并有机相，再经饱和食盐水洗，无水硫酸钠干燥后，浓缩，粗品经硅胶柱层析(DCM/MeOH＝40:1-20:1,v/v)得产物，黄色固体，熔点145.7-147.2℃；1H NMR(300MHz,CDCl3)δ9.11(s,1H),7.77(dd,J＝7.2,1.5Hz,1H),7.73–7.68(m,3H),7.40(t,J＝7.5Hz,2H),7.21(s,1H),7.18(d,J＝8.1Hz,1H),7.08–6.98(m,2H),6.63(s,1H),3.89(d,J＝2.7Hz,3H),3.50(s,4H),2.94(s,4H),1.60–1.41(m,9H).ESI-MS:m/z512.1[M+H]+。To the round bottom flask was added 8-(4-(methoxy)phenyl)quinazolin-2-amine (101 mg, 0.4 mmol), dioxane (20 mL), 1-bromo-3-(( tert-Butoxycarbonyl)piperazin-1-yl)phenyl (74.4 mg, 0.4 mmol), Pd 2 (dba) 3 (16 mg, 0.0175 mmol), cesium carbonate (182 mg, 0.56 mmol) and Xantphos (11 mg, 0.0175 mmol) ). The reaction was then heated at 80 ° C for 16.5 hours under a nitrogen atmosphere. The reaction was quenched and the mixture was cooled to room temperature. The solvent was evaporated evaporated evaporated. The organic phase was combined, washed with EtOAc EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH -147.2 ° C; 1 H NMR (300 MHz, CDCl 3 ) δ 9.11 (s, 1H), 7.77 (dd, J = 7.2, 1.5 Hz, 1H), 7.73 - 7.68 (m, 3H), 7.40 (t, J = 7.5 Hz, 2H), 7.21 (s, 1H), 7.18 (d, J = 8.1 Hz, 1H), 7.08 - 6.98 (m, 2H), 6.63 (s, 1H), 3.89 (d, J = 2.7 Hz) , 3H), 3.50 (s, 4H), 2.94 (s, 4H), 1.60 - 1.41 (m, 9H). ESI-MS: m/z 512.1 [M+H] + .
步骤3制备8-(4-(甲氧基)苯基)-N-(3-(哌嗪-1-基)苯基)喹唑啉-2-胺(181-4)Step 3 Preparation of 8-(4-(methoxy)phenyl)-N-(3-(piperazin-1-yl)phenyl)quinazolin-2-amine (181-4)
将8-(4-(甲氧基)苯基)-N-(3-(4-叔丁氧羰基哌嗪-1-基)苯基)喹唑啉-2-胺(101mg,0.4mmol)加至50％三氟乙酸/二氯甲烷溶液(10mL)中，室温搅拌反应10小时。反 应完毕，减压蒸除溶剂。残余物溶于10mL水，用饱和碳酸钠溶液调pH＝8后，二氯甲烷萃取三次(3×15mL)。合并有机相再经饱和食盐水洗，无水硫酸钠干燥后，浓缩，得产物，黄色固体，熔点163.2-165.3℃；1H NMR(300MHz,CDCl3)δ9.10(s,1H),7.78–7.71(m,3H),7.69(dd,J＝7.8,1.5Hz,1H),7.40–7.32(m,1H),7.28(t,J＝2.1Hz,2H),7.23(s,1H),7.14(t,J＝8.1Hz,1H),7.02(d,J＝8.7Hz,2H),3.90(s,3H),2.94(s,8H).ESI-MS:m/z412.3.[M+H]+。8-(4-(Methoxy)phenyl)-N-(3-(4-tert-butoxycarbonylpiperazin-1-yl)phenyl)quinazolin-2-amine (101 mg, 0.4 mmol) It was added to a 50% trifluoroacetic acid/dichloromethane solution (10 mL), and the reaction was stirred at room temperature for 10 hours. After the reaction was completed, the solvent was evaporated under reduced pressure. The residue was dissolved in 10 mL of water. The combined organic phases were then by brine, dried over anhydrous sodium sulfate, and concentrated to give the product as a yellow solid, m.p. 163.2-165.3 ℃; 1 H NMR (300MHz , CDCl 3) δ9.10 (s, 1H), 7.78- 7.71 (m, 3H), 7.69 (dd, J = 7.8, 1.5 Hz, 1H), 7.40 - 7.32 (m, 1H), 7.28 (t, J = 2.1 Hz, 2H), 7.23 (s, 1H), 7.14 (t, J = 8.1 Hz, 1H), 7.02 (d, J = 8.7 Hz, 2H), 3.90 (s, 3H), 2.94 (s, 8H). ESI-MS: m/z 412.3. [M+ H] + .
步骤4制备8-(4-(甲氧基)苯基)-N-(3-(4-乙基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物181)Step 4 Preparation of 8-(4-(methoxy)phenyl)-N-(3-(4-ethylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 181)
将8-(4-(甲氧基)苯基)-N-(3-(哌嗪-1-基)苯基)喹唑啉-2-胺(50mg,0.12mmol)溶于干燥乙腈(5mL)中，然后依次加入溴乙烷(34uL，0.44mmol)和无水碳酸钾(67mg，0.486mmol)。在搅拌下加热至70℃反应24小时。冷却至室温，减压蒸除溶剂。残余物加水20mL，再用二氯甲烷萃取三次(3×15mL)，合并有机相后，用饱和食盐水洗，无水硫酸钠干燥。浓缩，粗品经硅胶柱层析纯化(DCM：MeOH＝80:1v/v)，得目标产物，黄色固体，熔点195-197℃；1H NMR(300MHz,CDCl3)δ9.09(s,1H),7.78–7.71(m,3H),7.68(dd,J＝8.1,1.5Hz,1H),7.43–7.33(m,1H),7.28(d,J＝5.7Hz,2H),7.24(t,J＝2.1Hz,1H),7.14(t,J＝8.1Hz,1H),7.07–6.97(m,2H),6.58(dd,J＝8.1,2.1Hz,1H),3.90(s,3H),3.14–2.99(m,4H),2.58-2.50(m,4H),2.46(t,J＝7.2Hz,2H),1.14(t,J＝7.2Hz,3H).ESI-MS:m/z 440.2[M+H]+。8-(4-(Methoxy)phenyl)-N-(3-(piperazin-1-yl)phenyl)quinazolin-2-amine (50 mg, 0.12 mmol) was dissolved in dry acetonitrile (5 mL) Then, bromoethane (34 uL, 0.44 mmol) and anhydrous potassium carbonate (67 mg, 0.486 mmol) were added in that order. The mixture was heated to 70 ° C with stirring for 24 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure. After the residue was added with water (20 mL), EtOAc (EtOAc) Concentrated and the crude product was purified by silica gel column chromatography (DCM: MeOH = 80: 1v / v), to give the desired product as a yellow solid, m.p. 195-197 ℃; 1 H NMR (300MHz , CDCl 3) δ9.09 (s, 1H ), 7.78–7.71 (m, 3H), 7.68 (dd, J=8.1, 1.5 Hz, 1H), 7.43–7.33 (m, 1H), 7.28 (d, J=5.7 Hz, 2H), 7.24 (t, J=2.1 Hz, 1H), 7.14 (t, J=8.1 Hz, 1H), 7.07–6.97 (m, 2H), 6.58 (dd, J=8.1, 2.1 Hz, 1H), 3.90 (s, 3H), 3.14–2.99 (m, 4H), 2.58-2.50 (m, 4H), 2.46 (t, J = 7.2 Hz, 2H), 1.14 (t, J = 7.2 Hz, 3H). ESI-MS: m/z 440.2 [M+H] + .
实施例182～实施例215Example 182 to Example 215
按照实施例181的相同方法，起始原料19-2先与不同的硼酸或硼酸酯进行Suzuki偶联反应，生成181-2类似物，然后用不同的取代基取代喹唑啉上的氨基氢，制备实施例182～实施例215的化合物，具体实验数据见表6。In the same manner as in Example 181, starting material 19-2 was first subjected to a Suzuki coupling reaction with a different boronic acid or boronic ester to give 181-2 analog, and then substituted with a different substituent for the amino hydrogen on the quinazoline. The compounds of Examples 182 to 215 were prepared, and the specific experimental data are shown in Table 6.
表6化合物111～147的实验数据表Table 6 Experimental data sheets for compounds 111-147
Figure PCTCN2016088089-appb-000316
Figure PCTCN2016088089-appb-000316
Figure PCTCN2016088089-appb-000317
Figure PCTCN2016088089-appb-000317
Figure PCTCN2016088089-appb-000318
Figure PCTCN2016088089-appb-000318
Figure PCTCN2016088089-appb-000319
Figure PCTCN2016088089-appb-000319
Figure PCTCN2016088089-appb-000320
Figure PCTCN2016088089-appb-000320
Figure PCTCN2016088089-appb-000321
Figure PCTCN2016088089-appb-000321
Figure PCTCN2016088089-appb-000322
Figure PCTCN2016088089-appb-000322
Figure PCTCN2016088089-appb-000323
Figure PCTCN2016088089-appb-000323
Figure PCTCN2016088089-appb-000324
Figure PCTCN2016088089-appb-000324
Figure PCTCN2016088089-appb-000325
Figure PCTCN2016088089-appb-000325
Figure PCTCN2016088089-appb-000326
Figure PCTCN2016088089-appb-000326
实施例216：8-(1H-吡唑-4-基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物216)Example 216: 8-(1H-pyrazol-4-yl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 216)
Figure PCTCN2016088089-appb-000327
Figure PCTCN2016088089-appb-000327
步骤1制备8-氯-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺(216-1)Step 1 Preparation of 8-chloro-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine (216-1)
向50毫升圆底烧瓶中依次加入8-氯喹唑啉-2-胺(580mg，3.23mmol)，二氧六环(20mL)，1-(3-溴苯基)-4-甲基哌嗪(824mg，3.23mmol)，Pd2(dba)3(89mg,0.097mmol),碳酸铯(1.473g,4.52mmol)和Xantphos(62mg,0.11mmol)。然后在氮气保护下加热至80℃反应16.5小时。停止反应，降至室温，减压蒸除溶剂。残余物加水20mL，用二氯甲烷萃取三次(3×60mL)，合并有机相再经饱和食盐水洗，无水硫酸钠干燥后，浓缩。粗品经硅胶柱层析纯化(DCM/MeOH＝50:1-30:1,v/v)，得产物。To a 50 ml round bottom flask was added 8-chloroquinazolin-2-amine (580 mg, 3.23 mmol), dioxane (20 mL), 1-(3-bromophenyl)-4-methylpiperazine ( 824 mg, 3.23 mmol), Pd 2 (dba) 3 (89 mg, 0.097 mmol), cesium carbonate (1.473 g, 4.52 mmol) and Xantphos (62 mg, 0.11 mmol). It was then heated to 80 ° C under nitrogen for 16.5 hours. The reaction was stopped, the temperature was lowered to room temperature, and the solvent was evaporated under reduced pressure. After the residue was added with water (20 mL), EtOAc (EtOAc) The crude product was purified by EtOAc EtOAcjjjjjj
步骤2制备8-(1H-吡唑-4-基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物216)Step 2 Preparation of 8-(1H-pyrazol-4-yl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 216)
向圆底烧瓶中充入氮气，依次添加8-氯-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺(106mg,0.3mmol)，DMF(2mL)，1-叔丁氧羰基-4-联硼酸频那醇酯-1H-吡唑(56mg，0.36mmol)，Pd(Pcy3)2Cl2(18mg,0.015mmol),碳酸钾(332mg,2.4mmol)，抽真空，充入氮气，反复三次排净空气，在氮气保护下100℃加热反应23小时。TLC监测原料无剩余，停止反应，降至室温，减压蒸除溶剂，残余物加水20ml，乙酸乙酯(3×15mL)萃取，合并有机相再经饱和食盐水洗，无水硫酸钠干燥后，浓缩。粗品经硅胶柱层析(DCM:MeOH＝40:1-20：1v/v)得产物。黄色固体(20％),mp:233-235℃；1H NMR(300MHz,DMSO-d6)δ12.98(s,1H),9.64(s,1H),9.29(s,1H),8.06(dd,J＝7.2,1.5Hz,1H),7.75(dd,J＝8.1,1.5Hz,1H),7.55–7.28(m,3H),7.15(t,J＝8.4Hz,1H),6.61(dd,J＝7.5,1.8Hz,1H),3.14–2.99(m,4H),2.45–2.35(m,4H),2.18(d,J＝16.5Hz,3H)。The round bottom flask was charged with nitrogen, and then 8-chloro-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine (106 mg, 0.3 mmol), DMF. (2 mL), 1-tert-Butoxycarbonyl-4-boronic acid pinacol ester-1H-pyrazole (56 mg, 0.36 mmol), Pd(Pcy 3 ) 2 Cl 2 (18 mg, 0.015 mmol), potassium carbonate (332 mg) , 2.4 mmol), vacuumed, filled with nitrogen, air was purged three times repeatedly, and the reaction was heated at 100 ° C for 23 hours under a nitrogen atmosphere. TLC was used to monitor the reaction, and the reaction was stopped. The mixture was cooled to room temperature. The solvent was evaporated to dryness. concentrate. The crude product was purified by EtOAc EtOAcjjjjjj Yellow solid (20%), mp: 233-235 ° C; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.98 (s, 1H), 9.64 (s, 1H), 9.29 (s, 1H), 8.06 ( Dd, J = 7.2, 1.5 Hz, 1H), 7.75 (dd, J = 8.1, 1.5 Hz, 1H), 7.55 - 7.28 (m, 3H), 7.15 (t, J = 8.4 Hz, 1H), 6.61 (dd , J = 7.5, 1.8 Hz, 1H), 3.14 - 2.99 (m, 4H), 2.45 - 2.35 (m, 4H), 2.18 (d, J = 16.5 Hz, 3H).
实施例217：3-环戊基-3-(4-(2-((3-(4-甲基哌嗪-1-基)苯基)氨基)喹唑啉-8-基)-1H-吡唑 -1-基)丙腈(化合物217)Example 217: 3-Cyclopentyl-3-(4-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-1H- Pyrazole -1-yl)propionitrile (compound 217)
Figure PCTCN2016088089-appb-000328
Figure PCTCN2016088089-appb-000328
向圆底烧瓶中加入8-(1H-吡唑-4-基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺(81mg，0.21mmol)，DMF(5mL)，3-环戊基丙烯腈(76mg，0.63mmol)，DBU(0.03ml,0.21mmol)加热至80℃反应48小时。停止反应，降至室温，减压蒸除溶剂。残余物加水20mL，用乙酸乙酯萃取三次(3×60mL)，合并有机相再经饱和食盐水洗，无水硫酸钠干燥后，浓缩，粗品经硅胶柱层析纯化(DCM/MeOH＝70:1-50:1,v/v)，得产物。黄色固体,mp:76-78℃；1H NMR(300MHz,CDCl3)δ9.09(s,1H),8.63(s,1H),8.09(s,1H),7.96(dd,J＝7.5,1.5Hz,1H),7.60(dd,J＝8.1,1.5Hz,1H),7.42–7.35(m,2H),7.34–7.28(m,2H),7.03(t,J＝2.1Hz,1H),6.77–6.71(m,1H),4.16(ddd,J＝10.2,7.8,4.8Hz,1H),3.30–3.23(m,4H),3.10(dd,J＝16.8,7.8Hz,1H),2.93(dd,J＝16.8,4.8Hz,1H),2.70–2.57(m,4H),2.50(dd,J＝17.1,7.5Hz,1H),2.39(s,3H),1.92(dt,J＝15.6,6.0Hz,1H),1.57(dddd,J＝27.0,19.5,10.2,4.8Hz,4H),1.35–1.05(m,4H)。Add 8-(1H-pyrazol-4-yl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine (81 mg, 0.21) to a round bottom flask Methyl), DMF (5 mL), 3-cyclopentylacrylonitrile (76 mg, 0.63 mmol), DBU (0.03 mL, 0.21 mmol). The reaction was stopped, the temperature was lowered to room temperature, and the solvent was evaporated under reduced pressure. The residue was added with water (20 mL), EtOAc (EtOAc)EtOAc. -50:1, v/v), the product. Yellow solid, mp: 76-78 ° C; 1 H NMR (300 MHz, CDCl 3 ) δ 9.09 (s, 1H), 8.63 (s, 1H), 8.09 (s, 1H), 7.96 (dd, J = 7.5, 1.5 Hz, 1H), 7.60 (dd, J = 8.1, 1.5 Hz, 1H), 7.42 - 7.35 (m, 2H), 7.34 - 7.28 (m, 2H), 7.03 (t, J = 2.1 Hz, 1H), 6.77–6.71 (m, 1H), 4.16 (ddd, J = 10.2, 7.8, 4.8 Hz, 1H), 3.30–3.23 (m, 4H), 3.10 (dd, J = 16.8, 7.8 Hz, 1H), 2.93 ( Dd, J = 16.8, 4.8 Hz, 1H), 2.70 - 2.57 (m, 4H), 2.50 (dd, J = 17.1, 7.5 Hz, 1H), 2.39 (s, 3H), 1.92 (dt, J = 15.6, 6.0 Hz, 1H), 1.57 (dddd, J = 27.0, 19.5, 10.2, 4.8 Hz, 4H), 1.35 - 1.05 (m, 4H).
实施例218～实施例232Example 218 to Example 232
按照实施例216及实施例217类似合成方法，中间体19-2喹唑啉上的氨基氢被各种溴代苯取代，然后与1-叔丁氧羰基-4-联硼酸频那醇酯-1H-吡唑发生Suzuki偶联反应制备出化合物216类似物，最后吡唑环氨基氢被取代，制备实施例218～实施例232的化合物，具体实验数据见表7。Following the similar synthetic procedure of Example 216 and Example 217, the aminohydrogen on the intermediate 19-2 quinazoline was replaced with various bromobenzenes, followed by the 1-tert-butoxycarbonyl-4-boronic acid pinacol ester- The compound 216 analog was prepared by Suzuki coupling reaction of 1H-pyrazole, and finally the pyrazole cyclic amino hydrogen was substituted, and the compounds of Examples 218 to 232 were prepared. The specific experimental data are shown in Table 7.
表7化合物218～232的实验数据表Table 7 Experimental data sheets for compounds 218-232
Figure PCTCN2016088089-appb-000329
Figure PCTCN2016088089-appb-000329
Figure PCTCN2016088089-appb-000330
Figure PCTCN2016088089-appb-000330
Figure PCTCN2016088089-appb-000331
Figure PCTCN2016088089-appb-000331
Figure PCTCN2016088089-appb-000332
Figure PCTCN2016088089-appb-000332
Figure PCTCN2016088089-appb-000333
Figure PCTCN2016088089-appb-000333
Figure PCTCN2016088089-appb-000334
Figure PCTCN2016088089-appb-000334
实施例233：8-(4-(甲氧基)苯基)-N-(环丙甲酰胺基)喹唑啉-2-胺(化合物233)Example 233: 8-(4-(Methoxy)phenyl)-N-(cyclopropylamido)quinazolin-2-amine (Compound 233)
Figure PCTCN2016088089-appb-000335
Figure PCTCN2016088089-appb-000335
步骤1制备8氯-N-(环丙甲酰胺)喹唑啉-2-胺(233-1) Step 1 Preparation of 8 chloro-N-(cyclopropanecarboxamide) quinazolin-2-amine (233-1)
取圆底烧瓶，依次加入8-氯喹唑啉-2-胺(1.796g,10mmol)和吡啶(10mL)，于0℃下滴加1.2倍当量环丙甲酰氯。滴毕，升至室温继续搅拌反应2.5小时。TLC监测无原料剩余。减压蒸除溶剂后，加水30mL，用二氯甲烷(3×10mL)萃取。合并有机相再经饱和食盐水洗，无水硫酸钠干燥后，浓缩。再经EtOAc重结晶，得黄色固体(熔点235-237℃)。1H NMR(300MHz,DMSO-d6)δ9.56(s,1H),8.11(dd,J＝7.5,1.2Hz,1H),8.07(dd,J＝8.1,1.2Hz,1H),7.58(t,J＝7.8Hz,1H),2.51–2.38(m,1H),0.89(dd,J＝7.2,3.6Hz,4H).ESI-MS:m/z 248[M+H]+.A round bottom flask was taken, and 8-chloroquinazolin-2-amine (1.796 g, 10 mmol) and pyridine (10 mL) were successively added, and 1.2-fold equivalent of cyclopropionyl chloride was added dropwise at 0 °C. After the dropwise addition, the reaction was further stirred at room temperature for 2.5 hours. TLC monitored no raw material remaining. After evaporating the solvent under reduced pressure, water (30 mL) was evaporated and evaporated. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate Recrystallization from EtOAc gave a yellow solid (m. 1 H NMR (300MHz, DMSO- d 6) δ9.56 (s, 1H), 8.11 (dd, J = 7.5,1.2Hz, 1H), 8.07 (dd, J = 8.1,1.2Hz, 1H), 7.58 ( t, J = 7.8 Hz, 1H), 2.51 - 2.38 (m, 1H), 0.89 (dd, J = 7.2, 3.6 Hz, 4H). ESI-MS: m/z 248 [M+H] + .
步骤2制备8-(4-(甲氧基)苯基)-N-(环丙甲酰胺)喹唑啉-2-胺(化合物233)Step 2 Preparation of 8-(4-(methoxy)phenyl)-N-(cyclopropanecarboxamide)quinazolin-2-amine (Compound 233)
向圆底烧瓶中依次加入8-氯-N-(环丙甲酰胺)喹唑啉-2-胺(124mg,0.5mmol)，DMF(5mL)，(4-甲氧基苯基)硼酸(115mg，0.75mmol)，Pd(PPh3)4(29mg,0.05mmol),无水碳酸钾(277mg,2mmol)，在氮气保护下100℃加热搅拌反应24小时。TLC监测原料无剩余，停止加热。待反应液降至室温后，加水20mL，用乙酸乙酯(3×15mL)萃取，合并有机相经饱和食盐水洗，无水硫酸钠干燥后，浓缩，粗品经硅胶柱层析(二氯甲烷/乙酸乙酯＝50:1-30:1,v/v)得目标产物，白色固体，(熔点221.6-224.3℃)。1H NMR(300MHz,CDCl3)δ9.36(s,1H),8.77(s,1H),7.86(dd,J＝10.5,7.8Hz,2H),7.63(d,J＝8.7Hz,2H),7.56(t,J＝7.5Hz,1H),6.99(d,J＝8.7Hz,2H),3.87(s,3H),3.05(s,1H),1.16(dt,J＝7.8,3.6Hz,2H),0.82(td,J＝6.9,3.6Hz,2H).ESI-MS:m/z 320[M+H]+.To the round bottom flask was added 8-chloro-N-(cyclopropanecarboxamide) quinazolin-2-amine (124 mg, 0.5 mmol), DMF (5 mL), (4-methoxyphenyl)boronic acid (115 mg). , 0.75 mmol), Pd(PPh 3 ) 4 (29 mg, 0.05 mmol), anhydrous potassium carbonate (277 mg, 2 mmol), and the reaction was stirred under heating at 100 ° C for 24 hours under nitrogen atmosphere. The TLC monitored the raw material without remaining and stopped heating. After the reaction mixture was cooled to room temperature, 20 mL of water was added, and the mixture was combined with ethyl acetate (3×15 mL). Ethyl acetate = 50:1 - 30:1, v/v) mp. 1 H NMR (300 MHz, CDCl 3 ) δ 9.36 (s, 1H), 8.77 (s, 1H), 7.86 (dd, J = 10.5, 7.8 Hz, 2H), 7.63 (d, J = 8.7 Hz, 2H) , 7.56 (t, J = 7.5 Hz, 1H), 6.99 (d, J = 8.7 Hz, 2H), 3.87 (s, 3H), 3.05 (s, 1H), 1.16 (dt, J = 7.8, 3.6 Hz, 2H), 0.82 (td, J = 6.9, 3.6 Hz, 2H). ESI-MS: m/z 320 [M+H] + .
实施例234：8-(4-(苄氧基)苯基)-N-(环丙甲酰胺)喹唑啉-2-胺(化合物234)Example 234: 8-(4-(Benzyloxy)phenyl)-N-(cyclopropanecarboxamide) quinazolin-2-amine (Compound 234)
Figure PCTCN2016088089-appb-000336
Figure PCTCN2016088089-appb-000336
按照实施例233的类似方法，中间体233-1与4-(苄氧基)苯硼酸反应制备化合物234。黄色固体(熔点174-176℃)；1H NMR(300MHz,CDCl3)δ9.34(s,1H),8.59(s,1H),7.93–7.77(m,2H),7.62(d,J＝8.7Hz,2H),7.56(t,J＝7.8Hz,1H),7.50–7.45(m,2H),7.45–7.38(m,2H),7.38–7.33(m,1H),7.06(d,J＝8.7Hz,2H),5.14(s,2H),2.99(d,J＝21.6Hz,1H),1.17–1.06(m,2H),0.83–0.71(m,2H).ESI-MS:m/z 396[M+H]+。Compound 234 was reacted with 4-(benzyloxy)benzeneboronic acid in a similar manner to Example 233 to afford compound 234. Yellow solid (melting point 174-176 ° C); 1 H NMR (300 MHz, CDCl 3 ) δ 9.34 (s, 1H), 8.59 (s, 1H), 7.93 - 7.77 (m, 2H), 7.62 (d, J = 8.7 Hz, 2H), 7.56 (t, J = 7.8 Hz, 1H), 7.50 - 7.45 (m, 2H), 7.45 - 7.38 (m, 2H), 7.38 - 7.33 (m, 1H), 7.06 (d, J) = 8.7 Hz, 2H), 5.14 (s, 2H), 2.99 (d, J = 21.6 Hz, 1H), 1.17 - 1.06 (m, 2H), 0.83 - 0.71 (m, 2H). ESI-MS: m/ z 396[M+H] + .
实施例235：1-甲基-4-(3-((8-(4-甲氧基苯基)喹唑啉-2-基)氨基)苯基)-1-乙基哌嗪溴化铵(化合物235)Example 235: 1-Methyl-4-(3-((8-(4-methoxyphenyl)quinazolin-2-yl)amino)phenyl)-1-ethylpiperazine ammonium bromide (Compound 235)
Figure PCTCN2016088089-appb-000337
Figure PCTCN2016088089-appb-000337
向圆底烧瓶中依次加入8-(4-甲氧基苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺(85mg,0.2mmol)，溴乙烷(17uL,0.22mmol)，乙腈(2mL)回流反应5.5h，然后补加溴乙烷(17uL,0.22mmol)，继续回流反应12.5h，反应完毕，减压蒸除溶剂，经硅胶柱层析(二氯甲烷/甲醇＝40:1至1:1v/v)得产物。黄色固体(熔点195-197℃)；1H NMR(300MHz,DMSO-d6)δ9.74(s,1H),9.34(s,1H),7.89(dd,J＝8.1,1.5Hz,1H),7.79(dd,J＝7.2,1.5Hz,1H),7.74–7.67(m,2H),7.56(d,J＝8.1Hz,1H),7.48–7.40(m,1H),7.37(s,1H),7.15–7.03(m,3H),6.63(dd,J＝8.1,2.1Hz,1H),3.86(s,3H),3.48(dd,J＝15.6,6.3Hz,6H),3.24(s,3H),3.06(s,3H),1.29(t,J＝7.2Hz,3H).ESI-MS:m/z 535[M+H]+。To the round bottom flask was added 8-(4-methoxyphenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine (85 mg, 0.2). Ethyl bromide (17 uL, 0.22 mmol), acetonitrile (2 mL) was refluxed for 5.5 h, then ethyl bromide (17 uL, 0.22 mmol) was added, and refluxing was continued for 12.5 h. After completion of the reaction, the solvent was evaporated under reduced pressure. The product was obtained by silica gel column chromatography (dichloromethane / methanol = 40:1 to 1:1 v/v). Yellow solid (melting point 195-197 ° C); 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.74 (s, 1H), 9.34 (s, 1H), 7.89 (dd, J = 8.1, 1.5 Hz, 1H) , 7.79 (dd, J = 7.2, 1.5 Hz, 1H), 7.74 - 7.67 (m, 2H), 7.56 (d, J = 8.1 Hz, 1H), 7.48 - 7.40 (m, 1H), 7.37 (s, 1H) ), 7.15 - 7.03 (m, 3H), 6.63 (dd, J = 8.1, 2.1 Hz, 1H), 3.86 (s, 3H), 3.48 (dd, J = 15.6, 6.3 Hz, 6H), 3.24 (s, 3H), 3.06 (s, 3H), 1.29 (t,J = 7.2 Hz, 3H). ESI-MS: m/z 535[M+H] + .
实施例236：8-(4-(甲氧基)苯基)-N-(3-(4-甲基-4-氧基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物236)Example 236: 8-(4-(Methoxy)phenyl)-N-(3-(4-methyl-4-oxypiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 236)
Figure PCTCN2016088089-appb-000338
Figure PCTCN2016088089-appb-000338
向圆底烧瓶中依次加入8-(4-甲氧基苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺(93mg,0.218mmol)，m-CPBA(56mg,0.321mmol×85％)，二氯乙烷(5mL)，室温下过夜反应，反应完毕，加入饱和硫代硫酸钠溶液和碳酸钠溶液洗涤，残余物加水20mL，用二氯甲烷萃取3次(20mLx3)。合并有机相，再用饱和食盐水洗，无水硫酸钠干燥，浓缩，粗品经硅胶柱层析(二氯甲烷/甲醇/氨水)＝100:10:5,v/v)得产物，黄色固体(熔点207-209℃)；1H NMR(300MHz,DMSO-d6)δ9.84(s,1H),9.32(s,1H),7.94–7.83(m,1H),7.83–7.74(m,1H),7.69(d,J＝8.7Hz,2H),7.53(d,J＝8.1Hz,1H),7.41(dd,J＝15.6,8.1Hz,2H),7.04(dd,J＝10.8,8.4Hz,3H),6.58(d,J＝9.9Hz,1H),3.86(s,3H),3.45–3.24(m,4H),3.17(d,J＝10.2Hz,2H),3.10(s,3H),2.92(d,J＝9.0Hz,2H).ESI-MS:m/z 442[M+H]+。To the round bottom flask was added 8-(4-methoxyphenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine (93 mg, 0.218). Methyl), m-CPBA (56 mg, 0.321 mmol × 85%), dichloroethane (5 mL), reacted at room temperature overnight, the reaction was completed, washed with saturated sodium thiosulfate solution and sodium carbonate solution, and the residue was added with water (20 mL). It was extracted 3 times with dichloromethane (20 mL x 3). The organic phase was combined, washed with brine, dried over anhydrous sodium sulfate and evaporated. Mp 207-209°C); 1 H NMR (300MHz, DMSO-d 6 ) δ 9.84 (s, 1H), 9.32 (s, 1H), 7.94–7.83 (m, 1H), 7.83–7.74 (m, 1H) ), 7.69 (d, J = 8.7 Hz, 2H), 7.53 (d, J = 8.1 Hz, 1H), 7.41 (dd, J = 15.6, 8.1 Hz, 2H), 7.04 (dd, J = 10.8, 8.4 Hz) , 3H), 6.58 (d, J = 9.9 Hz, 1H), 3.86 (s, 3H), 3.45 - 3.24 (m, 4H), 3.17 (d, J = 10.2 Hz, 2H), 3.10 (s, 3H) , 2.92 (d, J = 9.0 Hz, 2H). ESI-MS: m/z 442[M+H] + .
实施例237:8-(4-(甲氧基)苯基)-N-((2-(4-甲基哌嗪-1-基)乙酰胺))喹唑啉-2-胺(化合物237)Example 237: 8-(4-(Methoxy)phenyl)-N-((2-(4-methylpiperazin-1-yl)acetamide))quinazolin-2-amine (Compound 237 )
Figure PCTCN2016088089-appb-000339
Figure PCTCN2016088089-appb-000339
向10毫升圆底烧瓶中充入氮气，依次添加8-(4-(甲氧基)苯基)喹唑啉-2-胺(100mg,0.4mmol)，DCM(2mL)，2-氯乙酰氯(65mg,0.44mmol)，三乙胺(49mg，0.48mmol)室温反应3小时。加入氮甲基哌嗪(120mg，1.2mmol)，室温反应3小时，停止反应，减压蒸干，加水20ml，二氯甲烷(3×5mL)萃取，饱和食盐水洗，无水硫酸钠干燥，合并有机相，浓缩，粗品经硅胶柱层析(DCM/MeOH＝100:1-50:1,v/v)，得目标产物，黄色固体，熔点 190-192℃；1H NMR(300MHz,DMSO-d6)δ9.84(s,1H),9.32(s,1H),7.94–7.83(m,1H),7.83–7.74(m,1H),7.69(d,J＝8.7Hz,2H),7.53(d,J＝8.1Hz,1H),7.41(dd,J＝15.6,8.1Hz,2H),7.04(dd,J＝10.8,8.4Hz,3H),6.58(d,J＝9.9Hz,1H),3.86(s,3H),3.45–3.24(m,4H),3.17(d,J＝10.2Hz,2H),3.10(s,3H),2.92(d,J＝9.0Hz,2H).ESI-MS:m/z 442[M+H]+。A 10 ml round bottom flask was charged with nitrogen, and then 8-(4-(methoxy)phenyl)quinazolin-2-amine (100 mg, 0.4 mmol), DCM (2 mL), 2-chloroacetyl chloride (65 mg, 0.44 mmol), triethylamine (49 mg, 0.48 mmol). Nitromethylpiperazine (120 mg, 1.2 mmol) was added, and the reaction was stirred at room temperature for 3 hours. The reaction was quenched, evaporated, evaporated, evaporated, evaporated, evaporated. The organic phase was concentrated and the crude product was purified by silica gel column chromatography (DCM / MeOH = 100: 1-50 : 1, v / v), to give the desired product as a yellow solid, m.p. 190-192 ℃; 1 H NMR (300MHz , DMSO- d 6 ) δ 9.84 (s, 1H), 9.32 (s, 1H), 7.94 - 7.83 (m, 1H), 7.83 - 7.74 (m, 1H), 7.69 (d, J = 8.7 Hz, 2H), 7.53 (d, J = 8.1 Hz, 1H), 7.41 (dd, J = 15.6, 8.1 Hz, 2H), 7.04 (dd, J = 10.8, 8.4 Hz, 3H), 6.58 (d, J = 9.9 Hz, 1H) , 3.86 (s, 3H), 3.45 - 3.24 (m, 4H), 3.17 (d, J = 10.2 Hz, 2H), 3.10 (s, 3H), 2.92 (d, J = 9.0 Hz, 2H). ESI- MS: m/z 442 [M + H] + .
实施例238：8-(4-N-(甲基)苯磺酰基)-N-(1-乙酰基吗啡啉)喹唑啉-2-胺(化合物238)Example 238: 8-(4-N-(Methyl)benzenesulfonyl)-N-(1-acetylmorpholine)quinazolin-2-amine (Compound 238)
Figure PCTCN2016088089-appb-000340
Figure PCTCN2016088089-appb-000340
向10毫升圆底烧瓶中充入氩气，依次添加8-(4-N-(甲基)苯磺酰基)喹唑啉-2-胺(94mg,0.3mmol)，二氯甲烷(2mL)，三乙胺(36mg,0.36mmol)冰水浴下加入氯乙酰氯(38mg,0.33mmol)搅拌3小时，在室温下加入吗啡啉(78mg,0.9mmol),反应3小时。停止反应，降至室温，减压蒸干，加水10ml，二氯甲烷(3×5mL)萃取，饱和食盐水洗，无水硫酸镁干燥，合并有机相，浓缩，粗品经硅胶柱层析(DCM/MeOH＝100:1-30:1,V/V)得目标产物，黄色固体，熔点237-240℃；1H NMR(300MHz,cdcl3)δ9.84(s,1H),9.38(s,1H),8.13(d,J＝8.4Hz,2H),8.05–7.99(m,3H),7.95(dd,J＝8.1,1.5Hz,1H),7.70–7.61(m,1H),4.40(q,J＝5.4Hz,1H),3.85–3.76(m,4H),3.26(s,2H),2.76(d,J＝5.4Hz,3H),2.69–2.57(m,4H).ESI-MS:m/z 443[M+H]+.A 10 ml round bottom flask was charged with argon, and then 8-(4-N-(methyl)benzenesulfonyl)quinazolin-2-amine (94 mg, 0.3 mmol). Triethylamine (36 mg, 0.36 mmol) was added to a solution of chloroacetyl chloride (38 mg, 0.33 mmol), and the mixture was stirred for 3 hours, and morpholine (78 mg, 0.9 mmol) was added at room temperature for 3 hours. The reaction was quenched, the mixture was cooled to room temperature, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. MeOH = 100: 1-30: 1, V / V) to give the desired product as a yellow solid, m.p. 237-240 ℃; 1 H NMR (300MHz , cdcl 3) δ9.84 (s, 1H), 9.38 (s, 1H ), 8.13 (d, J = 8.4 Hz, 2H), 8.05 - 7.99 (m, 3H), 7.95 (dd, J = 8.1, 1.5 Hz, 1H), 7.70 - 7.61 (m, 1H), 4.40 (q, J = 5.4 Hz, 1H), 3.85 - 3.76 (m, 4H), 3.26 (s, 2H), 2.76 (d, J = 5.4 Hz, 3H), 2.69 - 2.57 (m, 4H). ESI-MS: m /z 443[M+H] + .
实施例239：8-(4-甲氧基苯基)-N-甲基-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺(化合物239)Example 239: 8-(4-Methoxyphenyl)-N-methyl-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine (Compound 239)
Figure PCTCN2016088089-appb-000341
Figure PCTCN2016088089-appb-000341
步骤1：制备8-(4-甲氧基苯基)-N-(3-溴苯基)喹唑啉-2-胺(239-1)Step 1: Preparation of 8-(4-methoxyphenyl)-N-(3-bromophenyl)quinazolin-2-amine (239-1)
向圆底烧瓶中依次加入8-(4-(甲氧基)苯基)喹唑啉-2-胺(126mg，0.5mmol)，二氧六环(2mL)，1-溴-3-碘苯(156mg，0.55mmol)，Pd2(dba)3(23mg,0.025mmol),叔丁醇钠(68mg,0.7mmol)和Xantphos(29mg,0.05mmol)。然后在氮气保护下90℃加热反应16小时。停止反应，降至室温，减压蒸除溶剂，加水20mL，用二氯甲烷萃取三次(3×15mL)。合并有机相，再经饱和食盐水洗，无水硫酸钠干燥后，浓缩，得粗品235mg，黄色固体，8-(4-甲氧基苯基)-N-(3-溴苯基)喹唑啉-2-胺。To the round bottom flask was added 8-(4-(methoxy)phenyl)quinazolin-2-amine (126 mg, 0.5 mmol), dioxane (2 mL), 1-bromo-3-iodobenzene. (156 mg, 0.55 mmol), Pd 2 (dba) 3 (23 mg, 0.025 mmol), sodium tert-butoxide (68 mg, 0.7 mmol) and Xantphos (29 mg, 0.05 mmol). The reaction was then heated at 90 ° C for 16 hours under nitrogen. The reaction was quenched and the mixture was cooled to room temperature. The solvent was evaporated evaporated evaporated. The organic phase was combined, washed with brine, dried over anhydrous sodium sulfate 2-amine.
步骤2：制备8-(4-甲氧基苯基)-N甲基-(3-溴苯基)喹唑啉-2-胺。(239-2) Step 2: Preparation of 8-(4-methoxyphenyl)-Nmethyl-(3-bromophenyl)quinazolin-2-amine. (239-2)
向圆底烧瓶中依次加入8-(4-甲氧基苯基)-N-(3-溴苯基)喹唑啉-2-胺(235mg，0.579mmol)，DMF(2ml)，氢化钠(25mg,1.05mmol)，零度下滴加碘甲烷(99mg,0.695mmol)然后室温反应5小时。停止反应，降至室温，减压蒸除溶剂，加水20mL，用乙酸乙酯萃取三次(3×15mL)。合并有机相，再经饱和食盐水洗，无水硫酸钠干燥后，浓缩，得粗品225mg，黄色固体，8-(4-甲氧基苯基)-N甲基-(3-溴苯基)喹唑啉-2-胺。To the round bottom flask was added 8-(4-methoxyphenyl)-N-(3-bromophenyl)quinazolin-2-amine (235 mg, 0.579 mmol), DMF (2 mL) 25 mg, 1.05 mmol), iodomethane (99 mg, 0.695 mmol) was added dropwise at zero temperature and then reacted at room temperature for 5 hours. The reaction was quenched and the mixture was evaporated to dryness. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate Oxazolin-2-amine.
步骤3：制备8-(4-甲氧基苯基)-N-甲基-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺(239)Step 3: Preparation of 8-(4-methoxyphenyl)-N-methyl-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine (239)
向圆底烧瓶中依次加入8-(4-甲氧基苯基)-N-甲基-(3-溴苯基)喹唑啉-2-胺(225mg，0.54mmol)，二氧六环(2mL)，N-甲基哌嗪(65mg，0.648mmol)，Pd2(dba)3(15mg,0.0162mmol),叔丁醇钠(78mg,0.81mmol)和BINAP(21mg,0.0324mmol)。然后在氮气保护下110℃加热反应16小时。停止反应，降至室温，减压蒸除溶剂，加水20mL，用二氯甲烷萃取三次(3×15mL)。合并有机相，再经饱和食盐水洗，无水硫酸钠干燥后，浓缩，粗品经硅胶柱层析(DCM/MeOH＝50:1-40:1,V/V)得目标产物，黄色固体，熔点142-146℃，黄色固体，8-(4-甲氧基苯基)-N-甲基-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺。1H NMR(300MHz,CDCl3)δ9.01(s,1H),7.84–7.72(m,3H),7.62(dd,J＝8.1,1.5Hz,1H),7.29(t,J＝7.8Hz,2H),7.02–6.93(m,2H),6.88(t,J＝2.1Hz,1H),6.82(dd,J＝8.1,2.2Hz,2H),3.88(s,3H),3.56(s,3H),3.28–3.17(m,4H),2.65–2.51(m,4H),2.36(s,3H).ESI-MS:m/z 440[M+H]+。To the round bottom flask was added 8-(4-methoxyphenyl)-N-methyl-(3-bromophenyl)quinazolin-2-amine (225 mg, 0.54 mmol), dioxane ( 2 mL), N-methylpiperazine (65 mg, 0.648 mmol), Pd 2 (dba) 3 (15 mg, 0.0162 mmol), sodium tert-butoxide (78 mg, 0.81 mmol) and BINAP (21 mg, 0.0324 mmol). The reaction was then heated at 110 ° C under nitrogen for 16 hours. The reaction was quenched and the mixture was cooled to room temperature. The solvent was evaporated evaporated evaporated. The organic phase was combined, washed with brine, dried over anhydrous sodium sulfate 142-146 ° C, yellow solid, 8-(4-methoxyphenyl)-N-methyl-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine . 1 H NMR (300MHz, CDCl 3 ) δ9.01 (s, 1H), 7.84-7.72 (m, 3H), 7.62 (dd, J = 8.1,1.5Hz, 1H), 7.29 (t, J = 7.8Hz, 2H), 7.02–6.93 (m, 2H), 6.88 (t, J=2.1 Hz, 1H), 6.82 (dd, J=8.1, 2.2 Hz, 2H), 3.88 (s, 3H), 3.56 (s, 3H) ), 3.28 - 3.17 (m, 4H), 2.65 - 2.51 (m, 4H), 2.36 (s, 3H). ESI-MS: m/z 440 [M+H] + .
实施例240：8-(4-羟基苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)-N-(6-氰基甲基吡啶-3-基)喹唑啉-2-胺(化合物240)Example 240: 8-(4-Hydroxyphenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-N-(6-cyanomethylpyridin-3-yl) Quinazoline-2-amine (compound 240)
Figure PCTCN2016088089-appb-000342
Figure PCTCN2016088089-appb-000342
向10毫升圆底烧瓶中充入氮气，依次加入化合物240-1(58mg,0.13mmol)，DMF:H2O混合溶剂(95：5，v/v，2mL)，4-硼酸频那醇酯基苯酚(22mg,0.156mmol),Pd(PCy3)4Cl2(5mg,0.0065mmol),CsF(40mg,0.26mmol)，抽真空，充入氮气，反复三次排净空气，在氮气保护下100度加热反应47小时。停止反应，降至室温，减压蒸干，加水20ml，二氯甲烷萃取(3×10mL)，饱和食盐水洗，无水硫酸钠干燥，合并有机相，浓缩，粗品经(DCM/MeOH＝50:1-30:1,v/v)，经PE/EtOAc重结晶,得到黄色固体(熔点110-112℃)1H NMR(300MHz,c6d6)δ9.04(s,1H),8.52(s,1H),7.70(dd,J＝7.2,1.5Hz,1H),7.65(dd,J＝8.1,1.5Hz,1H),7.59(dd,J＝8.1,2.1Hz,1H),7.47(d,J＝8.1Hz,1H),7.38–7.28(m,4H),6.82(t,J＝7.8Hz,4H),6.72(d,J＝8.4Hz,1H),5.23(s,2H),3.22–3.11(m,4H),2.72–2.59(m,4H),2.41(s,3H).ESI-MS:m/z 528[M+H]+.A 10 ml round bottom flask was charged with nitrogen, and compound 240-1 (58 mg, 0.13 mmol), DMF:H 2 O mixed solvent (95:5, v/v, 2 mL), 4-boronic acid pinacol ester were sequentially added. Phenol (22mg, 0.156mmol), Pd(PCy 3 ) 4 Cl 2 (5mg, 0.0065mmol), CsF (40mg, 0.26mmol), vacuumed, filled with nitrogen, three times to purge the air, under nitrogen protection 100 The reaction was heated for 47 hours. The reaction was quenched, and the mixture was evaporated to dryness. 1-30: 1, v / v) , via the PE / EtOAc and recrystallized to give a yellow solid (m.p. 110-112 ℃) 1 H NMR (300MHz , c 6 d 6) δ9.04 (s, 1H), 8.52 ( s, 1H), 7.70 (dd, J = 7.2, 1.5 Hz, 1H), 7.65 (dd, J = 8.1, 1.5 Hz, 1H), 7.59 (dd, J = 8.1, 2.1 Hz, 1H), 7.47 (d , J = 8.1 Hz, 1H), 7.38 - 7.28 (m, 4H), 6.82 (t, J = 7.8 Hz, 4H), 6.72 (d, J = 8.4 Hz, 1H), 5.23 (s, 2H), 3.22 -3.11 (m, 4H), 2.72 - 2.59 (m, 4H), 2.41 (s, 3H). ESI-MS: m/z 528 [M+H] + .
实施例241：化合物7a-7f的合成 Example 241: Synthesis of compound 7a-7f
Figure PCTCN2016088089-appb-000343
Figure PCTCN2016088089-appb-000343
一般反应条件：(a)碳酸胍(Guanidine carbonate),DMAC,140℃；(b)Pd2(dba)3,4,5-双二苯基膦-9,9-二甲基氧杂蒽(Xantphos),Cs2CO3,1,4-二氧六环(Dioxane),115℃；(c)DIPEA,RNH2,DCM,r.t；(d)Pd(dppf)Cl2,KOAc,DMSO,90℃；(e)Pd(PCy3)2Cl2,CsF,NMP(10％H2O),140℃.General reaction conditions: (a) Guanidine carbonate, DMAC, 140 ° C; (b) Pd 2 (dba) 3 , 4,5-bisdiphenylphosphino-9,9-dimethyloxaxime ( Xantphos), Cs 2 CO 3 , 1,4-dioxane (Dioxane), 115 ° C; (c) DIPEA, RNH 2 , DCM, rt; (d) Pd (dppf) Cl 2 , KOAc, DMSO, 90 °C; (e) Pd(PCy 3 ) 2 Cl 2 , CsF, NMP (10% H 2 O), 140 ° C.
实施例241-1：化合物7b的制备Example 241-1: Preparation of Compound 7b
N-乙基-4-溴苯磺酰胺(5b)的合成：取25mL圆底烧瓶，冰水浴搅拌下依次加入12mLDCM，4-溴苯磺酰氯(1.5g，5.9mmol)，乙胺盐酸盐(2.5g，29mmol)，DIPEA 6.6mL；撤去冰水浴，升至室温反应2.5h；TLC监测反应完全，停止反应。加水70mL，用DCM(60mL，40mL)萃取，用40mL水洗涤有机相两次，有机相用15mL饱和食盐水洗涤，无水硫酸镁干燥后浓缩，粗品经硅胶柱层析(PE:EA＝6:1-4:1v/v)分离得到目标产物，白色固体粗品(1.47g，95％)。Synthesis of N-ethyl-4-bromobenzenesulfonamide (5b): Take a 25 mL round bottom flask and add 12 ml of LDCM, 4-bromobenzenesulfonyl chloride (1.5 g, 5.9 mmol), ethylamine hydrochloride, with stirring in an ice water bath. (2.5g, 29mmol), DIPEA 6.6mL; remove the ice water bath, and warm to room temperature for 2.5h; TLC monitoring the reaction is complete, stop the reaction. The mixture was extracted with DCM (60 mL, 40 mL). : 1-4:1 v/v) The title compound was obtained as a white solid (yield: 1.47 g, 95%).
N-乙基-4-硼酸频哪醇酯基苯磺酰胺(6b)的合成：向圆底烧瓶中依次加入DMSO 40mL，N-乙基-4-溴苯磺酰胺(2.62g，10mmol)，联硼酸频那醇酯(3.04g，12mmol)，KOAc(2.94g，30mmol)，Pd(dppf)Cl2(234mg，0.032mmol)，在氮气保护下于100℃加热反应12h，TLC监测反应完全，终止反应，降至室温，加水300mL，乙酸乙酯(200mL，100mL，100mL)萃取，用水(70mL×3)洗涤有机相，饱和食盐水洗涤(70mL×2)两次，无水硫酸镁干燥浓缩，粗品经柱层析(PE:EA＝3:1v/v)得到产品，淡绿色固体(2.17g，70％)。Synthesis of N-ethyl-4-boronic acid pinacol ester benzenesulfonamide (6b): To a round bottom flask was added DMSO 40 mL, N-ethyl-4-bromobenzenesulfonamide (2.62 g, 10 mmol). Bornyl borate (3.04g, 12mmol), KOAc (2.94g, 30mmol), Pd(dppf)Cl 2 (234mg, 0.032mmol), heated at 100 ° C for 12 h under nitrogen, the reaction was completely monitored by TLC. The reaction was terminated, the mixture was cooled to room temperature, and water (300 mL), ethyl acetate (200 mL, 100 mL, 100 mL) was evaporated. The organic phase was washed with water (70 mL×3), washed with brine (70 mL×2) twice The crude product was obtained by column chromatography (PE: EA=3:1 v/v) to give the product as a pale green solid (2.17 g, 70%).
N-乙基-4-(2-((3-甲磺酰基)苯基)氨基)喹唑啉-8-基)苯磺酰胺(7b)的合成：向圆底烧瓶中依次加入NMP：H2O＝9：1(3mL)，6b(211mg，0.68mmol)，3(150mg，0.45mmol)，CsF(137mg，0.9mmol)，Pd(PCy2)2Cl2(33mg，0.045mmol)，在氮气保护下于140℃加热反应24h，TLC监测反应未完全，补加6b(105mg，0.34mmol)，CsF(68mg，0.45mmol)，Pd(PCy2)2Cl2(16mg，0.045mmol)，继续反应12h，TLC监测反应仍有少量原料剩余，但产物点明显，终止反应，降至室温，过滤，滤液加水30mL，DCM(30mL，20mL)萃取，用水(20mL×3)洗涤有机相，用饱和食盐水(10mL)洗涤，无水硫酸镁干燥浓缩，粗品经柱层析(PE:EA＝3：1-DCM：MeOH＝-190：1)，得到淡黄色油状物，用少量甲醇洗涤，抽滤得产物，白色粉末27mg，产率12.5％，熔点：241-242℃。1H NMR(300MHz,DMSO-d6)δ10.30(s,1H),9.46(s,1H), 8.50(d,J＝9.0Hz,1H),8.05(dd,J＝8.0,1.2Hz,1H),8.00(t,J＝1.8Hz,1H),7.98–7.89(m,5H),7.69(t,J＝5.7Hz,1H),7.55(t,J＝7.5Hz,1H),7.51–7.44(m,J＝8.1Hz,1H),7.38(t,J＝7.8Hz,1H),3.14(s,3H),2.97–2.80(m,2H),1.05(t,J＝7.2Hz,3H).MS(ESI):m/z 483.4[M+H]+.Synthesis of N-ethyl-4-(2-((3-methylsulfonyl)phenyl)amino)quinazolin-8-yl)benzenesulfonamide (7b): NMP:H was added sequentially to a round bottom flask 2 O=9:1 (3 mL), 6b (211 mg, 0.68 mmol), 3 (150 mg, 0.45 mmol), CsF (137 mg, 0.9 mmol), Pd(PCy 2 ) 2 Cl 2 (33 mg, 0.045 mmol) The reaction was heated at 140 ° C for 24 h under a nitrogen atmosphere. The reaction was incomplete by TLC, and then added 6b (105 mg, 0.34 mmol), CsF (68 mg, 0.45 mmol), Pd(PCy 2 ) 2 Cl 2 (16 mg, 0.045 mmol), continue After 12 h of reaction, there was still a small amount of raw material remaining in the TLC monitoring reaction, but the product was obviously stopped. The reaction was terminated, and the temperature was lowered to room temperature. The mixture was filtered, and the filtrate was added with water (30 mL), DCM (30 mL, 20 mL), and the organic phase was washed with water (20 mL×3). Washed with brine (10 mL), EtOAc (EtOAc m. The product was obtained by filtration,yield white powder (yield: </RTI><RTIgt; 1 H NMR (300MHz, DMSO- d 6) δ10.30 (s, 1H), 9.46 (s, 1H), 8.50 (d, J = 9.0Hz, 1H), 8.05 (dd, J = 8.0,1.2Hz, 1H), 8.00 (t, J = 1.8 Hz, 1H), 7.98 - 7.89 (m, 5H), 7.69 (t, J = 5.7 Hz, 1H), 7.55 (t, J = 7.5 Hz, 1H), 7.51 - 7.44 (m, J = 8.1 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 3.14 (s, 3H), 2.97 - 2.80 (m, 2H), 1.05 (t, J = 7.2 Hz, 3H) MS (ESI): m/z 483.4 [M+H] + .
实施例241-2：化合物7f的制备Example 241-2: Preparation of Compound 7f
N-苯基-4-溴苯磺酰胺(5f)的合成：取25mL圆底烧瓶，冰水浴冷却至0℃，在磁力搅拌下依次加入苯胺(0.6mL，7.6mmol)，DIPEA(2mL，11.7mmol)，并将4-溴苯磺酰氯(1.5g，5.9mmol)溶于15mL DCM中，缓慢滴入反应体系中，滴毕，撤去冰浴，升至室温反应2h，TLC监测反应完全，加50mL水，用DCM(50mL，30mL)萃取，用水(25mL×3)洗涤有机相，用饱和食盐水(20mL)洗涤有机相，无水硫酸镁干燥后浓缩，粗品经硅胶柱层析得到产品，淡黄色固体(678mg，37.6％)。Synthesis of N-phenyl-4-bromobenzenesulfonamide (5f): Take a 25 mL round bottom flask, cool to 0 ° C in an ice water bath, and then add aniline (0.6 mL, 7.6 mmol), DIPEA (2 mL, 11.7). Methyl), 4-bromobenzenesulfonyl chloride (1.5g, 5.9mmol) was dissolved in 15mL DCM, slowly dropped into the reaction system, dripped, removed the ice bath, raised to room temperature for 2h, TLC monitoring reaction complete, plus The organic phase was washed with water (25 mL×3), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate and evaporated. Light yellow solid (678 mg, 37.6%).
N-苯基-4-硼酸频哪醇酯基苯磺酰胺(6f)的合成：向圆底烧瓶中依次加入DMSO 10mL，N-苯基-4-溴苯磺酰胺(775mg，2.5mmol)，联硼酸频那醇酯(763mg，3mmol)，KOAc(0.735g，6mmol)，Pd(dppf)Cl2(59mg，0.0064mmol)，在氮气保护下于100℃加热反应12h，TLC监测反应完全，终止反应，降至室温，加水75mL，乙酸乙酯(50mL，25mL)萃取，有机相用水(25mL×3)洗涤，用饱和食盐水(20mL)洗涤有机相，无水硫酸镁干燥浓缩，粗品经柱层析(PE:EA＝3:1v/v)得到产品，淡绿色固体(826mg，92％)。Synthesis of N-phenyl-4-boronic acid pinacol ester benzenesulfonamide (6f): 10 mL of DMSO, N-phenyl-4-bromobenzenesulfonamide (775 mg, 2.5 mmol) was added sequentially to a round bottom flask. Bornyl borate (763mg, 3mmol), KOAc (0.735g, 6mmol), Pd(dppf)Cl 2 (59mg, 0.0064mmol), heated at 100 ° C for 12h under nitrogen protection, TLC monitoring reaction is complete, termination The reaction was cooled to room temperature, and water (75 mL), EtOAc (50 mL, EtOAc) Chromatography (PE: EA = 3:1 v/v) afforded product as pale green solid ( 826mg, 92%).
N-苯基-4-(2-((3-甲磺酰基)苯基)氨基)喹唑啉-8-基)苯磺酰胺(7f)的合成：向圆底烧瓶中依次加入NMP：H2O＝9：1(2mL)，6f(162mg，0.45mmolH2O)，3(100mg，0.3mmol)，CsF(91mg，0.6mmol)，Pd(PCy2)2Cl2(22mg，0.03mmol)，在氮气保护下于140℃加热反应45h，TLC监测反应未完全，但产物点明显，终止反应，降至室温，过滤，滤液加水20mL，DCM(20mL×2)萃取，用饱和食盐水(10mL)洗涤有机相，无水硫酸镁干燥浓缩，粗品经柱层析(PE:EA＝3：1-DCM：MeOH＝-190：1)，,得到黄色油状物，用少量甲醇洗涤，抽滤得到产物，淡黄色固体粉末18mg,产率11.3％，熔点：247-248℃。1H NMR(300MHz,DMSO-d6):δ10.52(s,1H),10.29(s,1H),9.43(s,1H),8.46(d,J＝8.4Hz,1H),8.03(d,J＝7.8Hz,1H),7.99–7.88(m,6H),7.53(t,J＝7.5Hz,1H),7.42(d,J＝8.1Hz,1H),7.32–7.19(m,4H),7.11–7.00(m,2H),3.15(s,3H).MS(ESI):m/z 531.3[M+H]+,m/z 553.2[M+Na]+.Synthesis of N-phenyl-4-(2-((3-methylsulfonyl)phenyl)amino)quinazolin-8-yl)benzenesulfonamide (7f): NMP:H was added sequentially to a round bottom flask 2 O=9:1 (2 mL), 6f (162 mg, 0.45 mmol H 2 O), 3 (100 mg, 0.3 mmol), CsF (91 mg, 0.6 mmol), Pd(PCy 2 ) 2 Cl 2 (22 mg, 0.03 mmol) The reaction was heated at 140 ° C for 45 h under nitrogen atmosphere. The reaction was incomplete by TLC, but the product was spotted, and the reaction was terminated. The reaction was cooled to room temperature, filtered, and the filtrate was added with water (20 mL), DCM (20 mL×2), and washed with saturated brine (10 mL) The organic phase was dried (MgSO4), EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Light yellow solid powder 18 mg, yield 11.3%, melting point: 247-248 °C. 1 H NMR (300MHz, DMSO- d 6): δ10.52 (s, 1H), 10.29 (s, 1H), 9.43 (s, 1H), 8.46 (d, J = 8.4Hz, 1H), 8.03 (d , J = 7.8 Hz, 1H), 7.99 - 7.88 (m, 6H), 7.53 (t, J = 7.5 Hz, 1H), 7.42 (d, J = 8.1 Hz, 1H), 7.32 - 7.19 (m, 4H) , 7.11 - 7.00 (m, 2H), 3.15 (s, 3H). MS (ESI): m/z 531.3 [M+H] + , m/z 553.2 [M+Na] + .
实施例241-3：化合物7d的制备Example 241-3: Preparation of Compound 7d
N-叔丁基-4-(2-((3-甲磺酰基)苯基)氨基)喹唑啉-8-基)苯磺酰胺(7d)的合成：向圆底烧瓶中依次加入NMP：H2O＝9：1(3mL)，6d(230mg，0.68mmol)，3(150mg，0.45mmol)，CsF(137mg，0.9mmol)，Pd(PCy2)2Cl2(33mg，0.045mmol)，在氮气保护下于140℃加热反应24h，TLC监测未反应完全，补加初始加料量一半的6d，CsF与Pd(PCy2)2Cl2，继续反应14h，TLC监测有微量原料剩余，终止反应降至室温，过滤，滤液加水30mL，DCM(20mL×2)萃取，用饱和食盐水(10mL)洗涤有机相，无水硫酸镁干燥浓缩，粗品经柱 层析(PE:EA＝3：1-DCM：MeOH＝-190：1),得到黄色油状物，用少量MeOH洗涤，抽滤得到产物，淡黄色固体粉末50mg,产率22％，熔点：265-266℃。1H NMR(300MHz,DMSO-d6)δ10.31(s,1H),9.45(s,1H),8.59(d,J＝8.1Hz,1H),8.08–8.01(m,1H),8.01–7.86(m,6H),7.67(s,1H),7.55(t,J＝7.5Hz,1H),7.50–7.44(m,1H),7.40(t,J＝7.8Hz,1H),3.15(s,3H),1.18(s,9H).MS(ESI)：m/z 533.2[M+H]+.Synthesis of N-tert-butyl-4-(2-((3-methylsulfonyl)phenyl)amino)quinazolin-8-yl)benzenesulfonamide (7d): NMP was added sequentially to a round bottom flask: H 2 O=9:1 (3 mL), 6d (230 mg, 0.68 mmol), 3 (150 mg, 0.45 mmol), CsF (137 mg, 0.9 mmol), Pd(PCy 2 ) 2 Cl 2 (33 mg, 0.045 mmol), The reaction was heated at 140 ° C for 24 h under nitrogen protection. The TLC monitoring was not completed completely. The initial feed amount was added for 6 d, CsF and Pd(PCy 2 ) 2 Cl 2 , and the reaction was continued for 14 h. TLC was monitored for trace amount of raw materials remaining, and the reaction was terminated. The mixture was cooled to room temperature, filtered, and the filtrate was added with water (30 mL), EtOAc (EtOAc, EtOAc (EtOAc) DCM: MeOH = - 190: 1) EtOAc (EtOAc: EtOAc) 1 H NMR (300MHz, DMSO- d 6) δ10.31 (s, 1H), 9.45 (s, 1H), 8.59 (d, J = 8.1Hz, 1H), 8.08-8.01 (m, 1H), 8.01- 7.86 (m, 6H), 7.67 (s, 1H), 7.55 (t, J = 7.5 Hz, 1H), 7.50 - 7.44 (m, 1H), 7.40 (t, J = 7.8 Hz, 1H), 3.15 (s) , 3H), 1.18 (s, 9H). MS (ESI): m/z 533.2 [M+H] + .
参照实施例241-1和实施例241-2相同的方法，中间体6b或6f替换为6a、6c或6e，制得化合物7a、7c和7e。Referring to the same procedure as in Example 241-1 and Example 241-2, the intermediate 6b or 6f was replaced with 6a, 6c or 6e to give the compounds 7a, 7c and 7e.
效果实施例1本发明化合物对JAK1激酶的抑制作用Effect Example 1 Inhibition of JAK1 kinase by the compound of the present invention
受试化合物对激酶的抑制活性用半抑制浓度IC50值来表示。采用均相时间分辨荧光HTRF(Homogeneous Time-Resolved Fluorescence)技术，测定化合物对JAK1激酶的抑制作用。JAK1购自Invitrogen(货号：PV4774)，ATP购自Sigma-Aldrich(货号：A7699)，HTRF kinEASE-TK kit(货号为：62TK0PEC)及相关组分，购自Cisbio Bioassays；其他常规化学药品购自国药集团化学试剂有限公司。% Inhibition test compound concentration IC 50 values expressed kinase inhibitory activity. The inhibitory effect of the compound on JAK1 kinase was determined by Homogeneous Time-Resolved Fluorescence (HTRF) technique. JAK1 was purchased from Invitrogen (Cat. No. PV4774), ATP was purchased from Sigma-Aldrich (Cat. No. A7699), HTRF kinEASE-TK kit (Cat. No. 62TK0PEC) and related components, purchased from Cisbio Bioassays; other conventional chemicals were purchased from Sinopharm Group Chemical Reagent Co., Ltd.
试验方法按照产品说明书进行，大致流程如下：化合物采用DMSO配制成10mM溶液后，之后采用1×反应缓冲液及DMSO将样品配成5×化合物。本实验中，采用3倍梯度稀释的方法，将化合物稀共释成10个浓度。之后转移2ul的5×化合物至384孔板中，用1×反应缓冲液将激酶、底物(TK Substrate-biotin)、ATP分别配制成2.5×的酶/底物混合液和2.5×ATP溶液，向384孔板中加入4ul的2.5×的酶/底物混合液，室温孵育5分钟；之后加入4ul的2.5×ATP溶液，室温反应30分钟。反应体系中JAK1激酶终浓度为：0.5ng/ul，ATP浓度为6uM。酶反应进行时，用HTRF Detection buffer配制2×的TK Antibody-Eu(K)与Sa-XL665的混合液，酶反应进行30分钟后，向微孔板中加入上述两种液体各5ul，室温反应1小时。于2000rpm条件下离心2分钟，之后于EnVisionTM上，选用337nM波长的激光作为激发光，测定RFU665nM以及RFU620nM，并以RFU665nM/RFU620nM×10000作为最终数据进行分析。采用Graphpad Prism 5.0对数据进行Log(inhibitor)vs.response-Variable slope(four parameters)曲线拟合，计算相应的IC50(half maximal inhibitory concentration)。The test method was carried out according to the product specification. The general procedure was as follows: The compound was formulated into a 10 mM solution using DMSO, and then the sample was formulated into a 5× compound using 1× reaction buffer and DMSO. In this experiment, the compound was diluted into 10 concentrations by a 3-fold gradient dilution method. Then transfer 2 ul of 5× compound to a 384-well plate, and mix the kinase, substrate (TK Substrate-biotin) and ATP into a 2.5× enzyme/substrate mixture and a 2.5×ATP solution, respectively, using 1× reaction buffer. 4 ul of a 2.5 x enzyme/substrate mixture was added to a 384-well plate and incubated for 5 minutes at room temperature; then 4 ul of 2.5 x ATP solution was added and allowed to react at room temperature for 30 minutes. The final concentration of JAK1 kinase in the reaction system was 0.5 ng/ul and the ATP concentration was 6 uM. When the enzyme reaction was carried out, a mixture of 2×TK Antibody-Eu(K) and Sa-XL665 was prepared with HTRF Detection buffer. After 30 minutes of enzymatic reaction, 5 ul of the above two liquids were added to the microplate, and the reaction was carried out at room temperature. 1 hour. Centrifuged for 2 minutes at 2000rpm conditions, then on the EnVision TM, 337nM selected laser as the excitation light wavelength, and measured RFU 665nM RFU 620nM, and in RFU 665nM / RFU 620nM × 10000 as the final data analysis. The data was subjected to Log (inhibitor) vs. response-Variable slope (four parameters) curve fitting using Graphpad Prism 5.0, and the corresponding IC 50 (half maximal inhibitory concentration) was calculated.
Figure PCTCN2016088089-appb-000344
Figure PCTCN2016088089-appb-000344
Figure PCTCN2016088089-appb-000345
Figure PCTCN2016088089-appb-000345
Figure PCTCN2016088089-appb-000346
Figure PCTCN2016088089-appb-000346
Figure PCTCN2016088089-appb-000347
Figure PCTCN2016088089-appb-000347
Figure PCTCN2016088089-appb-000348
Figure PCTCN2016088089-appb-000348
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。 While the invention has been described with respect to the preferred embodiments of the embodiments of the embodiments of the invention modify. Accordingly, the scope of the invention is defined by the appended claims.

Claims (15)

  1. 一种通式I所示的喹唑啉类化合物，其药学上可接受的盐、溶剂化物、代谢产物、代谢前体或药物前体，A quinazoline compound of the formula I, a pharmaceutically acceptable salt, solvate, metabolite, metabolic precursor or prodrug thereof,
    Figure PCTCN2016088089-appb-100001
    Figure PCTCN2016088089-appb-100001
    R1、R2和R3独立地为氢、取代的C5-C10的芳基、取代或未取代的C2-C6的杂芳基或者C2-C6的杂环烷基；其中，R1、R2和R3不同时为氢；R 1 , R 2 and R 3 are independently hydrogen, substituted C 5 -C 10 aryl, substituted or unsubstituted C 2 -C 6 heteroaryl or C 2 -C 6 heterocycloalkyl; Wherein R 1 , R 2 and R 3 are not hydrogen at the same time;
    R4和R5独立地为氢、取代或未取代的C1-C4的烷基、取代或未取代的C5-C10的芳基、取代的C2-C6的杂芳基或者
    Figure PCTCN2016088089-appb-100002
    R0为取代的C1-C4的烷基或者C3-C6的环烷基；当R0为取代的C1-C4的烷基时，所述的取代的C1-C4的烷基中所述的取代是指被一个或多个取代或未取代的C2-C6的杂环烷基所取代；所述的取代的C2-C6的杂环烷基中所述的取代是指被一个或多个C1-C4的烷基所取代；当R4和R5同时为氢时，R1不为氢；    R 4 and R 5 are independently hydrogen, a substituted or unsubstituted C 1 -C 4 alkyl group, a substituted or unsubstituted C 5 -C 10 aryl group, a substituted C 2 -C 6 heteroaryl group or
    Figure PCTCN2016088089-appb-100002
    R 0 is a substituted C 1 -C 4 alkyl group or a C 3 -C 6 cycloalkyl group; when R 0 is a substituted C 1 -C 4 alkyl group, the substituted C 1 -C 4 The substitution in the alkyl group means that it is substituted by one or more substituted or unsubstituted C 2 -C 6 heterocycloalkyl groups; the substituted C 2 -C 6 heterocycloalkyl group Said substitution means substitution by one or more C 1 -C 4 alkyl groups; when R 4 and R 5 are simultaneously hydrogen, R 1 is not hydrogen;
    R1、R2或R3中，所述的取代的C5-C10的芳基中所述的取代是指被下列取代基中的一个或多个所取代：羟基、卤素、取代或未取代的C1-C4的烷基、取代或未取代的C1-C4的烷氧基、取代或未取代的C2-C6的杂环烷基、硝基、
    Figure PCTCN2016088089-appb-100003
    其中R6为C1-C4的烷基、C3-C6的环烷基或者
    Figure PCTCN2016088089-appb-100004
    Ra1和Ra2独立地为氢、取代或未取代的C1-C4的烷基或C5-C10的芳基；R7和R8独立地为氢、C1-C4的烷基、
    Figure PCTCN2016088089-appb-100005
    Ra3为C1-C4的烷基或者C3-C6的环烷基；Ra4为取代或未取代的C1-C4的烷基、C3-C6的环烷基或者C2-C6的杂芳基；R9为取代或未取代的C1-C4的烷基；    In R 1 , R 2 or R 3 , the substitution in the substituted C 5 -C 10 aryl group means substitution by one or more of the following substituents: hydroxy, halogen, substituted or not Substituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 alkoxy, substituted or unsubstituted C 2 -C 6 heterocycloalkyl, nitro,
    Figure PCTCN2016088089-appb-100003
    Wherein R 6 is a C 1 -C 4 alkyl group, a C 3 -C 6 cycloalkyl group or
    Figure PCTCN2016088089-appb-100004
    R a1 and R a2 are independently hydrogen, substituted or unsubstituted C 1 -C 4 alkyl or C 5 -C 10 aryl; R 7 and R 8 are independently hydrogen, C 1 -C 4 alkane base,
    Figure PCTCN2016088089-appb-100005
    R a3 is a C 1 -C 4 alkyl group or a C 3 -C 6 cycloalkyl group; R a4 is a substituted or unsubstituted C 1 -C 4 alkyl group, a C 3 -C 6 cycloalkyl group or C a heteroaryl group of 2 -C 6 ; R 9 is a substituted or unsubstituted C 1 -C 4 alkyl group;
    R1、R2或R3中，当所述的取代的C5-C10的芳基为取代的苯基，所述的取代为单取代时，所述的取代基位于苯环的间位或对位，其中，当所述的取代基位于苯环的间位时，所述的取代基为取代或未取代的C1-C4的烷氧基、取代或未取代的C2-C6的杂环烷基、
    Figure PCTCN2016088089-appb-100006
    In R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is a substituted phenyl group, and the substitution is a mono-substitution, the substituent is located at the meta position of the benzene ring. Or para to wherein, when the substituent is at the meta position of the phenyl ring, the substituent is a substituted or unsubstituted C 1 -C 4 alkoxy group, a substituted or unsubstituted C 2 -C 6 heterocycloalkyl,
    Figure PCTCN2016088089-appb-100006
    R1、R2或R3中，当所述的取代的C5-C10的芳基为取代的苯基，所述的取代为双取代或三取代时，所述的取代基位于苯环的间位和对位，或者邻位和对位；In R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is a substituted phenyl group, and the substitution is a di- or tri-substitution, the substituent is located in the benzene ring. The position and alignment, or the ortho and alignment;
    R1、R2或R3中，所述的取代的C2-C6的杂芳基中所述的取代是指被下列取代基中的一个或多个所取代：C1-C4的烷氧基、取代或未取代的C1-C4的烷基、取代或未取代的C2-C6的杂环烷基、
    Figure PCTCN2016088089-appb-100007
    R10为C1-C4的烷基；R11为
    Figure PCTCN2016088089-appb-100008
    Ra5和Ra6独立地为C1-C4的烷基；    In R 1 , R 2 or R 3 , the substitution in the substituted C 2 -C 6 heteroaryl group means substitution by one or more of the following substituents: C 1 -C 4 Alkoxy, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 2 -C 6 heterocycloalkyl,
    Figure PCTCN2016088089-appb-100007
    R 10 is a C 1 -C 4 alkyl group; R 11 is
    Figure PCTCN2016088089-appb-100008
    R a5 and R a6 are independently C 1 -C 4 alkyl;
    R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷基所取代时，所述的取代的C1-C4的烷基中所述的取代是指被一个或多个取代或未取代的C2-C6的杂环烷基所取代；所述的取代的C2-C6的杂环烷基中所述的取代是指被一个或多个C1-C4的烷基所取代；In R 1 , R 2 or R 3 , when the substitution in the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group, The substitution in the substituted C 1 -C 4 alkyl group means substitution by one or more substituted or unsubstituted C 2 -C 6 heterocycloalkyl groups; said substituted C 2 -C The substitution in the heterocycloalkyl group of 6 means that it is substituted by one or more C 1 -C 4 alkyl groups;
    R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷氧基所取代时，所述的取代的C1-C4的烷氧基中所述的取代是指被下列取代基中的一个或多个所取代：卤素、氰基、取代或未取代的C2-C6的杂芳基、取代或未取代的C5-C10的芳基或者C2-C6的杂环烷基；所述的取代的C2-C6的杂芳基中所述的取代是指被一个或多个氰基所取代；所述的取代的C5-C10的芳基中所述的取代是指被一个或多个C2-C6的杂芳基所取代；In R 1 , R 2 or R 3 , when the substitution described in the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkoxy group, The substitution described in the substituted C 1 -C 4 alkoxy refers to being substituted by one or more of the following substituents: halogen, cyano, substituted or unsubstituted C 2 -C 6 An aryl group, a substituted or unsubstituted C 5 -C 10 aryl group or a C 2 -C 6 heterocycloalkyl group; the substituted group described in the substituted C 2 -C 6 heteroaryl group means Substituted by one or more cyano groups; said substitution in said substituted C 5 -C 10 aryl group means substituted by one or more C 2 -C 6 heteroaryl groups;
    R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代时，所述的取代的C2-C6的杂环烷基中所述的取代是指被一个或多个C1-C4的烷基所取代；In R 1 , R 2 or R 3 , when the substitution described in the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, The substitution in the substituted C 2 -C 6 heterocycloalkyl group means that it is substituted by one or more C 1 -C 4 alkyl groups;
    R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被
    Figure PCTCN2016088089-appb-100009
    所取代，R6为
    Figure PCTCN2016088089-appb-100010
    Ra1和Ra2独立地为取代或未取代的C1-C4的烷基时，所述的取代的C1-C4的烷基中所述的取代是指被一个或多个氰基所取代；    In R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is substituted as described
    Figure PCTCN2016088089-appb-100009
    Substituted, R 6 is
    Figure PCTCN2016088089-appb-100010
    When R a1 and R a2 are independently a substituted or unsubstituted C 1 -C 4 alkyl group, the substitution in the substituted C 1 -C 4 alkyl group means one or more cyano groups. Replaced
    R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被
    Figure PCTCN2016088089-appb-100011
    所取代，R7和R8独立地为
    Figure PCTCN2016088089-appb-100012
    Ra4为取代或未取代的C1-C4的烷基时，所述的取代的C1-C4的烷基中所述的取代是指被下列取代基中的一个或多个所取代：氰基或者C2-C6的杂环烷基；     In R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is substituted as described
    Figure PCTCN2016088089-appb-100011
    Substituted, R 7 and R 8 are independently
    Figure PCTCN2016088089-appb-100012
    When R a4 is a substituted or unsubstituted C 1 -C 4 alkyl group, the substituent described in the substituted C 1 -C 4 alkyl group means substituted by one or more of the following substituents. : cyano or C 2 -C 6 heterocycloalkyl;
    R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被
    Figure PCTCN2016088089-appb-100013
    所取代，R9为取代或未取代的C1-C4的烷基时；所述的取代的C1-C4的烷基中所述的取代是指被一个或多个氰基所取代；    In R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is substituted as described
    Figure PCTCN2016088089-appb-100013
    Substituted, when R 9 is a substituted or unsubstituted C 1 -C 4 alkyl group; the substituted group described in the substituted C 1 -C 4 alkyl group means substituted by one or more cyano groups ;
    R1、R2或R3中，当所述的取代的C2-C6的杂芳基中所述的取代为被取代或未取代的C1-C4的烷基所取代时，所述的取代的C1-C4的烷基中所述的取代是指被下列取代基中的一个或多个所取代：氰基、C3-C6的环烷基、取代或未取代的C2-C6的杂芳基或者取代或未取代的C5-C10的芳基；所述的取代的C2-C6的杂芳基或所述的取代的C5-C10的芳基中所述的取代是指被一个或多个卤素所取代；In R 1 , R 2 or R 3 , when the substitution described in the substituted C 2 -C 6 heteroaryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group, The substitution described in the substituted C 1 -C 4 alkyl group means substituted by one or more of the following substituents: cyano, C 3 -C 6 cycloalkyl, substituted or unsubstituted a C 2 -C 6 heteroaryl group or a substituted or unsubstituted C 5 -C 10 aryl group; said substituted C 2 -C 6 heteroaryl group or said substituted C 5 -C 10 The substitution described in the aryl group means that it is substituted by one or more halogens;
    R1、R2或R3中，当所述的取代的C2-C6的杂芳基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代时，所述的取代的C2-C6的杂环烷基中所述的取代是指被下列取代基中的一个或多个所取代：取代的C1-C4的烷基、
    Figure PCTCN2016088089-appb-100014
    R12为C1-C4的烷基或C3-C6的环烷基；R13为C1-C4的烷基；所述的取代的C1-C4的烷基中所述的取代是指被下列取代基中的一个或多个所取代：氰基或
    Figure PCTCN2016088089-appb-100015
    In R 1 , R 2 or R 3 , when the substitution described in the substituted C 2 -C 6 heteroaryl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group The substitution in the substituted C 2 -C 6 heterocycloalkyl group means that it is substituted by one or more of the following substituents: a substituted C 1 -C 4 alkyl group,
    Figure PCTCN2016088089-appb-100014
    R 12 is a C 1 -C 4 alkyl group or a C 3 -C 6 cycloalkyl group; R 13 is a C 1 -C 4 alkyl group; said substituted C 1 -C 4 alkyl group Substitution refers to being substituted by one or more of the following substituents: cyano or
    Figure PCTCN2016088089-appb-100015
    R4或R5中，所述的取代的C1-C4的烷基中所述的取代是指被一个或多个取代或未取代的C2-C6的杂芳基所取代，所述的取代的C2-C6的杂芳基中所述的取代是指被一个或多个氰基所取代；In R 4 or R 5 , the substitution in the substituted C 1 -C 4 alkyl group means that it is substituted by one or more substituted or unsubstituted C 2 -C 6 heteroaryl groups. Said substituted in the substituted C 2 -C 6 heteroaryl group means substituted by one or more cyano groups;
    R4或R5中，所述的取代的C5-C10的芳基中所述的取代是指被下列取代基中的一个或多个所取代：卤素、硝基、取代或未取代的C1-C4的烷基、取代或未取代的C1-C4的烷氧基、取代或未取代的C2-C6的杂环烷基、取代或未取代的C5-C10的芳基、
    Figure PCTCN2016088089-appb-100016
    或者
    Figure PCTCN2016088089-appb-100017
    R14为C1-C4的烷氧基或者
    Figure PCTCN2016088089-appb-100018
    Ra7和Ra8独立地为氢或者取代或未取代的C1-C4的烷基；当Ra7和Ra8独立地为取代的C1-C4的烷基时，所述的取代是指被C2-C6的杂环烷基所取代；R15为C1-C4的烷基、
    Figure PCTCN2016088089-appb-100019
    或者取代或未取代的C2-C6的杂环烷基；Ra9和Ra10独立地为氢或者取代或未取代的C1-C4的烷基；当Ra9和Ra10独立地为取代的 C1-C4的烷基时，所述的取代是指被一个或多个C2-C6的杂环烷基所取代；当R15为取代的C2-C6的杂环烷基时，所述的取代是指被一个或多个C1-C4的烷基所取代；    In R 4 or R 5 , the substitution in the substituted C 5 -C 10 aryl group means substitution by one or more of the following substituents: halogen, nitro, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 alkoxy, substituted or unsubstituted C 2 -C 6 heterocycloalkyl, substituted or unsubstituted C 5 -C 10 Aryl group,
    Figure PCTCN2016088089-appb-100016
    or
    Figure PCTCN2016088089-appb-100017
    R 14 is a C 1 -C 4 alkoxy group or
    Figure PCTCN2016088089-appb-100018
    R a7 and R a8 are independently hydrogen or a substituted or unsubstituted C 1 -C 4 alkyl group; when R a7 and R a8 are independently a substituted C 1 -C 4 alkyl group, the substitution is Means substituted by a C 2 -C 6 heterocycloalkyl group; R 15 is a C 1 -C 4 alkyl group,
    Figure PCTCN2016088089-appb-100019
    Or a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group; R a9 and R a10 are independently hydrogen or a substituted or unsubstituted C 1 -C 4 alkyl group; when R a9 and R a10 are independently When substituted C 1 -C 4 alkyl, the substitution is substituted by one or more C 2 -C 6 heterocycloalkyl; when R 15 is a substituted C 2 -C 6 heterocycle In the case of an alkyl group, the substitution means substitution by one or more C 1 -C 4 alkyl groups;
    R4或R5中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷基所取代时，所述的取代的C1-C4的烷基中所述的取代是指被下列取代基中的一个或多个所取代；卤素、取代或未取代的C2-C6的杂环烷基或者
    Figure PCTCN2016088089-appb-100020
    R16和R17独立地为C1-C4的烷基；所述的取代的C2-C6的杂环烷基中所述的取代是指被下列取代基中的一个或多个所取代：C1-C4的烷基或者
    Figure PCTCN2016088089-appb-100021
    Ra11为C1-C4的烷基；    In R 4 or R 5 , when the substitution described in the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group, the substituted The substitution in the alkyl group of C 1 -C 4 means that it is substituted by one or more of the following substituents; halogen, substituted or unsubstituted C 2 -C 6 heterocycloalkyl or
    Figure PCTCN2016088089-appb-100020
    R 16 and R 17 are independently C 1 -C 4 alkyl; the substitution as described in the substituted C 2 -C 6 heterocycloalkyl means one or more of the following substituents Substitution: C 1 -C 4 alkyl or
    Figure PCTCN2016088089-appb-100021
    R a11 is a C 1 -C 4 alkyl group;
    R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷氧基所取代时，所述的取代的C1-C4的烷氧基中所述的取代是指被下列取代基中的一个或多个所取代：C2-C6的杂环烷基、C1-C4的烷氧基、
    Figure PCTCN2016088089-appb-100022
    R18为C1-C4的烷基或者C2-C6的杂环烷基；R19和R20独立地为C1-C4的烷基；    In R 4 or R 5 , when the substitution described in the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkoxy group, the substituted The substitution in the alkoxy group of C 1 -C 4 means that it is substituted by one or more of the following substituents: a C 2 -C 6 heterocycloalkyl group, a C 1 -C 4 alkoxy group,
    Figure PCTCN2016088089-appb-100022
    R 18 is C 1 -C 4 alkyl or C 2 -C 6 heterocycloalkyl; R 19 and R 20 are independently C 1 -C 4 alkyl;
    R4或R5中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代时，所述的取代的C2-C6的杂环烷基中所述的取代是指被下列取代基中的一个或多个所取代：羟基、取代或未取代的C1-C4的烷基、C2-C6的杂环烷基、
    Figure PCTCN2016088089-appb-100023
    Figure PCTCN2016088089-appb-100024
    R21为取代或未取代的C1-C4的烷基或者
    Figure PCTCN2016088089-appb-100025
    Ra11和Ra12独立地为C1-C4的烷基；当R21为取代的C1-C4的烷基时，所述的取代是指被一个或多个氰基所取代；R22为C1-C4的烷基；    In R 4 or R 5 , when the substitution described in the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, the The substitution in the substituted C 2 -C 6 heterocycloalkyl group means that it is substituted by one or more of the following substituents: a hydroxy group, a substituted or unsubstituted C 1 -C 4 alkyl group, C 2 -C 6 heterocycloalkyl,
    Figure PCTCN2016088089-appb-100023
    Figure PCTCN2016088089-appb-100024
    R 21 is a substituted or unsubstituted C 1 -C 4 alkyl group or
    Figure PCTCN2016088089-appb-100025
    R a11 and R a12 are independently a C 1 -C 4 alkyl group; when R 21 is a substituted C 1 -C 4 alkyl group, the substitution means substitution by one or more cyano groups; 22 is a C 1 -C 4 alkyl group;
    R4或R5中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代，所述的取代的C2-C6的杂环烷基中所述的取代为被取代或未取代的C1-C4的烷基所取代时，所述的取代的C1-C4的烷基中所述的取代是指被下列取代基中的一个或多个所取代：羟基、氰基、卤素、C3-C6的环烷基或者取代或未取代的C1-C4的烷氧基；所述的取代的C1-C4的烷氧基中所述的取代是指被一个或多个C5-C10的芳基所取代；In R 4 or R 5 , when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, the substitution is When the substitution in the C 2 -C 6 heterocycloalkyl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group, the substituted C 1 -C 4 alkyl group is Substituted refers to being substituted by one or more of the following substituents: hydroxy, cyano, halogen, C 3 -C 6 cycloalkyl or substituted or unsubstituted C 1 -C 4 alkoxy; The substitution in the substituted C 1 -C 4 alkoxy group means that it is substituted by one or more C 5 -C 10 aryl groups;
    R4或R5中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C5-C10的芳基所取代时，所述的取代或未取代的C5-C10的芳基中所述的取代的C5-C10的芳基中 所述的取代是指被一个或多个C1-C4的烷氧基所取代；In R 4 or R 5 , when the substitution described in the substituted C 5 -C 10 aryl group is substituted with a substituted or unsubstituted C 5 -C 10 aryl group, the substitution or The substitution in the substituted C 5 -C 10 aryl group described in the unsubstituted C 5 -C 10 aryl group means that it is substituted by one or more C 1 -C 4 alkoxy groups;
    R4或R5中，所述的取代的C2-C6的杂芳基中所述的取代是指被下列取代基中的一个或多个所取代：取代或为未取代的C2-C6的杂环烷基；所述的取代的C2-C6的杂环烷基中所述的取代是指被一个或多个C1-C4的烷基所取代；In R 4 or R 5 , the substituent described in the substituted C 2 -C 6 heteroaryl group means substituted by one or more of the following substituents: substituted or unsubstituted C 2 - a heterocycloalkyl group of C 6 ; said substitution in said substituted C 2 -C 6 heterocycloalkyl group means substituted by one or more C 1 -C 4 alkyl groups;
    上述各基团或各取代基中，所述的取代或未取代的C2-C6的杂芳基、所述的C2-C6的杂芳基或者所述的取代的C2-C6的杂芳基中所述的C2-C6的杂芳基是指杂原子选自O、N和S，杂原子数为1～4个的C2-C6的杂芳基；所述的取代或未取代的C2-C6的杂环烷基、所述的C2-C6的杂环烷基或者所述的取代的C2-C6的杂环烷基中所述的C2-C6的杂环烷基是指杂原子选自O、N和S，杂原子数为1～4个的C2-C6的杂环烷基；In each of the above groups or substituents, the substituted or unsubstituted C 2 -C 6 heteroaryl group, the C 2 -C 6 heteroaryl group or the substituted C 2 -C heteroaryl claim 6 C 2 -C 6 heteroaryl refers to heteroatom selected from O, N and S, the number of hetero atoms, 1 to 4 of C 2 -C 6 heteroaryl; and the Said substituted or unsubstituted C 2 -C 6 heterocycloalkyl, said C 2 -C 6 heterocycloalkyl or said substituted C 2 -C 6 heterocycloalkyl a C 2 -C 6 heterocycloalkyl refers to a heteroatom selected from O, N and S, the number of hetero atoms, 1 to 4 of C 2 -C 6 heterocycloalkyl; and
    上述各取代中，当取代基为多个时，所述的取代基相同或不同。In each of the above substitutions, when there are a plurality of substituents, the substituents are the same or different.
  2. 如权利要求1所述的通式I所示的喹唑啉类化合物，其药学上可接受的盐、溶剂化物、代谢产物、代谢前体或药物前体，其特征在于，A quinazoline compound of the formula I according to claim 1, which is a pharmaceutically acceptable salt, solvate, metabolite, metabolic precursor or prodrug thereof, characterized in that
    R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷基所取代，所述的取代的C1-C4的烷基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代，所述的取代或未取代的C2-C6的杂环烷基中所述的取代为被C1-C4的烷基所取代时，所述的C1-C4的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基；In R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group, the The substitution described in the substituted C 1 -C 4 alkyl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, said substituted or unsubstituted C 2 -C 6 hetero When the substitution in the cycloalkyl group is substituted by a C 1 -C 4 alkyl group, the C 1 -C 4 alkyl group is a methyl group, an ethyl group, a n-propyl group, an isopropyl group or a n-butyl group. Base, isobutyl or tert-butyl;
    和/或，R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷基所取代，所述的取代的C1-C4的烷基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代时，所述的取代或未取代的C2-C6的杂环烷基为取代或未取代的吗啉基或者取代或未取代的哌嗪基；And/or, in R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group when the substituted C 1 -C 4 alkyl group substituted by the substituted or unsubstituted heterocycloalkyl substituted C 2 -C 6 according to, the substituted or unsubstituted C 2 a heterocyclic alkyl group of -C 6 is a substituted or unsubstituted morpholinyl group or a substituted or unsubstituted piperazinyl group;
    和/或，R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷氧基所取代，所述的取代的C1-C4的烷氧基中所述的取代为被取代或未取代的C2-C6的杂芳基所取代时，所述的取代或未取代的C2-C6的杂芳基为取代或未取代的吡啶基；And/or, in R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkoxy group Substituted, when the substituted C 1 -C 4 alkoxy group is substituted by a substituted or unsubstituted C 2 -C 6 heteroaryl group, the substituted or unsubstituted C a heteroaryl group of 2 -C 6 is a substituted or unsubstituted pyridyl group;
    和/或，R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷氧基所取代，所述的取代的C1-C4的烷氧基中所述的取代为被取代或未取代的C5-C10的芳基所取代，所述的取代的C5-C10的芳基中所述的取代为被C2-C6的杂芳基所取代时，所述的C2-C6的杂芳基为吡唑基；And/or, in R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkoxy group Substituting, the substitution described in the substituted C 1 -C 4 alkoxy group is substituted by a substituted or unsubstituted C 5 -C 10 aryl group, said substituted C 5 -C 10 When the substitution in the aryl group is substituted by a C 2 -C 6 heteroaryl group, the C 2 -C 6 heteroaryl group is pyrazolyl;
    和/或，R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷氧基所取代，所述的取代的C1-C4的烷氧基中所述的取代为被取代或未取代的C5-C10的芳基所取代时，所述的取代或未取代的C5-C10的芳基为取代或未取代的苯基；And/or, in R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkoxy group When the substitution described in the substituted C 1 -C 4 alkoxy group is substituted by a substituted or unsubstituted C 5 -C 10 aryl group, the substituted or unsubstituted C 5 The aryl group of -C 10 is a substituted or unsubstituted phenyl group;
    和/或，R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未 取代的C1-C4的烷氧基所取代，所述的取代的C1-C4的烷氧基中所述的取代为被C2-C6的杂环烷基所取代时，所述的C2-C6的杂环烷基为四氢吡咯基；And/or, in R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkoxy group When the substitution described in the substituted C 1 -C 4 alkoxy group is substituted by a C 2 -C 6 heterocycloalkyl group, the C 2 -C 6 heterocycloalkyl group Is tetrahydropyrrolyl;
    和/或，R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代，所述的取代的C2-C6的杂环烷基中所述的取代为被一个或多个C1-C4的烷基所取代时，所述的C1-C4的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基；And/or, in R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is substituted as a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group Substituted, wherein the substitution in the substituted C 2 -C 6 heterocycloalkyl group is substituted by one or more C 1 -C 4 alkyl groups, the C 1 -C 4 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl;
    和/或，R1、R2或R3中，所述的取代的C5-C10的芳基中所述的取代为被
    Figure PCTCN2016088089-appb-100026
    所取代，所述的R6为C1-C4的烷基时，所述的C1-C4的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基或者叔丁基；    And/or, in R 1 , R 2 or R 3 , the substitution described in the substituted C 5 -C 10 aryl group is
    Figure PCTCN2016088089-appb-100026
    When the R 6 is a C 1 -C 4 alkyl group, the C 1 -C 4 alkyl group is a methyl group, an ethyl group, a n-propyl group, an isopropyl group, an n-butyl group or a different group. Butyl or tert-butyl;
    和/或，R1、R2或R3中，所述的取代的C5-C10的芳基中所述的取代为被
    Figure PCTCN2016088089-appb-100027
    所取代，所述的R6为C3-C6的环烷基时，所述的C3-C6的环烷基为环丙基、环丁基、环戊基或环己基；    And/or, in R 1 , R 2 or R 3 , the substitution described in the substituted C 5 -C 10 aryl group is
    Figure PCTCN2016088089-appb-100027
    When the R 6 is a C 3 -C 6 cycloalkyl group, the C 3 -C 6 cycloalkyl group is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group;
    和/或，R1、R2或R3中，所述的取代的C5-C10的芳基中所述的取代为被
    Figure PCTCN2016088089-appb-100028
    所取代，所述的R6为
    Figure PCTCN2016088089-appb-100029
    Ra1和Ra2独立地为取代或未取代的C1-C4的烷基时，所述的取代或未取代的C1-C4的烷基为取代或未取代的甲基、取代或未取代的乙基、取代或未取代的正丙基、取代或未取代的异丙基、取代或未取代的正丁基、取代或未取代的异丁基或者取代或未取代的叔丁基；    And/or, in R 1 , R 2 or R 3 , the substitution described in the substituted C 5 -C 10 aryl group is
    Figure PCTCN2016088089-appb-100028
    Substituted, the R 6 is
    Figure PCTCN2016088089-appb-100029
    When R a1 and R a2 are independently a substituted or unsubstituted C 1 -C 4 alkyl group, the substituted or unsubstituted C 1 -C 4 alkyl group is a substituted or unsubstituted methyl group, a substituted or Unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl or substituted or unsubstituted t-butyl ;
    和/或，R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被
    Figure PCTCN2016088089-appb-100030
    所取代，所述的R6为
    Figure PCTCN2016088089-appb-100031
    Ra1和Ra2独立地为C5-C10的芳基时，所述的C5-C10的芳基为苯基或萘基；    And/or, in R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is substituted as described
    Figure PCTCN2016088089-appb-100030
    Substituted, the R 6 is
    Figure PCTCN2016088089-appb-100031
    When R a1 and R a2 are independently a C 5 -C 10 aryl group, the C 5 -C 10 aryl group is a phenyl group or a naphthyl group;
    和/或，R1、R2或R3中，所述的取代的C5-C10的芳基中所述的取代为被
    Figure PCTCN2016088089-appb-100032
    所取代，所述的R7和R8独立地为C1-C4的烷基时，所述的C1-C4的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基或者叔丁基；    And/or, in R 1 , R 2 or R 3 , the substitution described in the substituted C 5 -C 10 aryl group is
    Figure PCTCN2016088089-appb-100032
    When the R 7 and R 8 are independently a C 1 -C 4 alkyl group, the C 1 -C 4 alkyl group is a methyl group, an ethyl group, a n-propyl group, an isopropyl group, N-butyl, isobutyl or tert-butyl;
    和/或，R1、R2或R3中，所述的取代的C5-C10的芳基中所述的取代为被
    Figure PCTCN2016088089-appb-100033
    所取 代，所述的R7和R8独立地为
    Figure PCTCN2016088089-appb-100034
    Ra3为C1-C4的烷基时，所述的C1-C4的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基或者叔丁基；    And/or, in R 1 , R 2 or R 3 , the substitution described in the substituted C 5 -C 10 aryl group is
    Figure PCTCN2016088089-appb-100033
    Substituted, R 7 and R 8 are independently
    Figure PCTCN2016088089-appb-100034
    When R a3 is a C 1 -C 4 alkyl group, the C 1 -C 4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. ;
    和/或，R1、R2或R3中，所述的取代的C5-C10的芳基中所述的取代为被
    Figure PCTCN2016088089-appb-100035
    所取代，所述的R7和R8独立地为
    Figure PCTCN2016088089-appb-100036
    Ra3为C3-C6的环烷基时，所述的C3-C6的环烷基为环丙基、环丁基、环戊基或环己基；    And/or, in R 1 , R 2 or R 3 , the substitution described in the substituted C 5 -C 10 aryl group is
    Figure PCTCN2016088089-appb-100035
    Substituted, R 7 and R 8 are independently
    Figure PCTCN2016088089-appb-100036
    When R a3 is a C 3 -C 6 cycloalkyl group, the C 3 -C 6 cycloalkyl group is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group;
    和/或，R1、R2或R3中，所述的取代的C5-C10的芳基中所述的取代为被
    Figure PCTCN2016088089-appb-100037
    所取代，所述的R7和R8独立地为
    Figure PCTCN2016088089-appb-100038
    Ra4为取代或未取代的C1-C4的烷基，所述的取代的C1-C4的烷基中所述的取代为被C2-C6的杂环烷基所取代时，所述的C2-C6的杂芳基为吗啉基；    And/or, in R 1 , R 2 or R 3 , the substitution described in the substituted C 5 -C 10 aryl group is
    Figure PCTCN2016088089-appb-100037
    Substituted, R 7 and R 8 are independently
    Figure PCTCN2016088089-appb-100038
    R a4 is a substituted or unsubstituted C 1 -C 4 alkyl group, and the substituent described in the substituted C 1 -C 4 alkyl group is substituted by a C 2 -C 6 heterocycloalkyl group. The C 2 -C 6 heteroaryl group is a morpholinyl group;
    和/或，R1、R2或R3中，所述的取代的C5-C10的芳基中所述的取代为被
    Figure PCTCN2016088089-appb-100039
    所取代，所述的R7和R8独立地为
    Figure PCTCN2016088089-appb-100040
    Ra4为取代或未取代的C1-C4的烷基时，所述的取代或未取代的C1-C4的烷基为取代或未取代的甲基、取代或未取代的乙基、取代或未取代的正丙基、取代或未取代的异丙基、取代或未取代的正丁基、取代或未取代的异丁基或者取代或未取代的叔丁基；    And/or, in R 1 , R 2 or R 3 , the substitution described in the substituted C 5 -C 10 aryl group is
    Figure PCTCN2016088089-appb-100039
    Substituted, R 7 and R 8 are independently
    Figure PCTCN2016088089-appb-100040
    When R a4 is a substituted or unsubstituted C 1 -C 4 alkyl group, the substituted or unsubstituted C 1 -C 4 alkyl group is a substituted or unsubstituted methyl group, a substituted or unsubstituted ethyl group. , substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl or substituted or unsubstituted t-butyl;
    和/或，R1、R2或R3中，所述的取代的C5-C10的芳基中所述的取代为被
    Figure PCTCN2016088089-appb-100041
    所取代，所述的R7和R8独立地为
    Figure PCTCN2016088089-appb-100042
    Ra4为C3-C6的环烷基时，所述的C3-C6的环烷基为环丙基、环丁基、环戊基或环己基；    And/or, in R 1 , R 2 or R 3 , the substitution described in the substituted C 5 -C 10 aryl group is
    Figure PCTCN2016088089-appb-100041
    Substituted, R 7 and R 8 are independently
    Figure PCTCN2016088089-appb-100042
    When R a4 is a C 3 -C 6 cycloalkyl group, the C 3 -C 6 cycloalkyl group is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group;
    和/或，R1、R2或R3中，所述的取代的C5-C10的芳基中所述的取代为被
    Figure PCTCN2016088089-appb-100043
    所取 代，所述的R7和R8独立地为
    Figure PCTCN2016088089-appb-100044
    Ra4为C2-C6的杂芳基时，所述的C2-C6的杂芳基为噻吩基；    And/or, in R 1 , R 2 or R 3 , the substitution described in the substituted C 5 -C 10 aryl group is
    Figure PCTCN2016088089-appb-100043
    Substituted, R 7 and R 8 are independently
    Figure PCTCN2016088089-appb-100044
    When R a4 is a C 2 -C 6 heteroaryl group, the C 2 -C 6 heteroaryl group is a thienyl group;
    和/或，R1、R2或R3中，所述的取代的C5-C10的芳基中所述的取代为被
    Figure PCTCN2016088089-appb-100045
    所取代，所述的R9为取代或未取代的C1-C4的烷基时，所述的取代或未取代的C1-C4的烷基为取代或未取代的甲基、取代或未取代的乙基、取代或未取代的正丙基、取代或未取代的异丙基、取代或未取代的正丁基、取代或未取代的异丁基或者取代或未取代的叔丁基；    And/or, in R 1 , R 2 or R 3 , the substitution described in the substituted C 5 -C 10 aryl group is
    Figure PCTCN2016088089-appb-100045
    When R 9 is a substituted or unsubstituted C 1 -C 4 alkyl group, the substituted or unsubstituted C 1 -C 4 alkyl group is a substituted or unsubstituted methyl group, substituted Or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl or substituted or unsubstituted tert-butyl base;
    和/或，R1、R2或R3中，当所述的取代的C2-C6的杂芳基中所述的取代为被取代或未取代的C1-C4的烷基所取代，所述的取代的C1-C4的烷基中所述的取代为被C3-C6的环烷基所取代时，所述的C3-C6的环烷基为环丙基、环丁基、环戊基或环己基；And/or, in R 1 , R 2 or R 3 , when the substituted C 2 -C 6 heteroaryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group When the substitution in the substituted C 1 -C 4 alkyl group is substituted by a C 3 -C 6 cycloalkyl group, the C 3 -C 6 cycloalkyl group is a cyclopropyl group. Base, cyclobutyl, cyclopentyl or cyclohexyl;
    和/或，R1、R2或R3中，当所述的取代的C2-C6的杂芳基中所述的取代为被取代或未取代的C1-C4的烷基所取代，所述的取代的C1-C4的烷基中所述的取代为被取代或未取代的C2-C6的杂芳基所取代时，所述的取代或未取代的C2-C6的杂芳基为取代或未取代的吡啶基；And/or, in R 1 , R 2 or R 3 , when the substituted C 2 -C 6 heteroaryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group Substituted, when the substitution described in the substituted C 1 -C 4 alkyl group is substituted by a substituted or unsubstituted C 2 -C 6 heteroaryl group, the substituted or unsubstituted C 2 a heteroaryl group of -C 6 is a substituted or unsubstituted pyridyl group;
    和/或，R1、R2或R3中，当所述的取代的C2-C6的杂芳基中所述的取代为被取代或未取代的C1-C4的烷基所取代，所述的取代的C1-C4的烷基中所述的取代为被取代或未取代的C5-C10的芳基所取代时，所述的取代或未取代的C5-C10的芳基为取代或未取代的苯基；And/or, in R 1 , R 2 or R 3 , when the substituted C 2 -C 6 heteroaryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group Substituted, when the substituted C 1 -C 4 alkyl group is substituted by a substituted or unsubstituted C 5 -C 10 aryl group, the substituted or unsubstituted C 5 - The aryl group of C 10 is a substituted or unsubstituted phenyl group;
    和/或，R1、R2或R3中，当所述的取代的C2-C6的杂芳基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代，所述的取代的C2-C6的杂环烷基中所述的取代为被
    Figure PCTCN2016088089-appb-100046
    所取代，所述的R12为C1-C4的烷基时，所述的C1-C4的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基或者叔丁基；    And/or, in R 1 , R 2 or R 3 , when the substituted C 2 -C 6 heteroaryl group is substituted as a substituted or unsubstituted C 2 -C 6 heterocycloalkane Substituted, the substitution described in the substituted C 2 -C 6 heterocycloalkyl group is
    Figure PCTCN2016088089-appb-100046
    When the R 12 is a C 1 -C 4 alkyl group, the C 1 -C 4 alkyl group is a methyl group, an ethyl group, a n-propyl group, an isopropyl group, an n-butyl group or a different group. Butyl or tert-butyl;
    和/或，R1、R2或R3中，当所述的取代的C2-C6的杂芳基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代，所述的取代的C2-C6的杂环烷基中所述的取代为被
    Figure PCTCN2016088089-appb-100047
    所取代，所述的R12为C3-C6的环烷基时，所述的C3-C6的环烷基为环丙基、环丁基、环戊基或环己基；    And/or, in R 1 , R 2 or R 3 , when the substituted C 2 -C 6 heteroaryl group is substituted as a substituted or unsubstituted C 2 -C 6 heterocycloalkane Substituted, the substitution described in the substituted C 2 -C 6 heterocycloalkyl group is
    Figure PCTCN2016088089-appb-100047
    When the R 12 is a C 3 -C 6 cycloalkyl group, the C 3 -C 6 cycloalkyl group is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group;
    和/或，R1、R2或R3中，所述的取代的C2-C6的杂芳基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代，所述的取代的C2-C6的杂环烷基中所述的取代为被
    Figure PCTCN2016088089-appb-100048
    所取代，所述的R13为C1-C4的烷基时，所述的C1-C4的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基或者叔丁基；    And/or, in R 1 , R 2 or R 3 , the substituent described in the substituted C 2 -C 6 heteroaryl group is a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group. Substituted, the substitution described in the substituted C 2 -C 6 heterocycloalkyl group is
    Figure PCTCN2016088089-appb-100048
    When the R 13 is a C 1 -C 4 alkyl group, the C 1 -C 4 alkyl group is a methyl group, an ethyl group, a n-propyl group, an isopropyl group, an n-butyl group or a different group. Butyl or tert-butyl;
    和/或，R1、R2或R3中，所述的取代的C2-C6的杂芳基中所述的取代为被
    Figure PCTCN2016088089-appb-100049
    所取代，R10为C1-C4的烷基时，所述的C1-C4的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基或者叔丁基；    And/or, in R 1 , R 2 or R 3 , the substitution described in the substituted C 2 -C 6 heteroaryl group is
    Figure PCTCN2016088089-appb-100049
    When R 10 is a C 1 -C 4 alkyl group, the C 1 -C 4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or Tert-butyl;
    和/或，R1、R2或R3中，所述的取代的C2-C6的杂芳基中所述的取代为被
    Figure PCTCN2016088089-appb-100050
    所取代，R11为
    Figure PCTCN2016088089-appb-100051
    Ra5和Ra6独立地为C1-C4的烷基时，所述的C1-C4的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基或者叔丁基；    And/or, in R 1 , R 2 or R 3 , the substitution described in the substituted C 2 -C 6 heteroaryl group is
    Figure PCTCN2016088089-appb-100050
    Substituted, R 11 is
    Figure PCTCN2016088089-appb-100051
    When R a5 and R a6 are independently a C 1 -C 4 alkyl group, the C 1 -C 4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl Base or tert-butyl;
    和/或，R4或R5中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷基所取代，所述的取代或未取代的C1-C4的烷基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代时，所述的取代的C2-C6的杂环烷基为被C1-C4的烷基所述取代时，所述的C1-C4的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基或者叔丁基；And/or, in R 4 or R 5 , when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group, When the substitution described in the substituted or unsubstituted C 1 -C 4 alkyl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, the substituted C 2 -C 6 When the heterocycloalkyl group is substituted by a C 1 -C 4 alkyl group, the C 1 -C 4 alkyl group is a methyl group, an ethyl group, a n-propyl group, an isopropyl group, an n-butyl group, Isobutyl or tert-butyl;
    和/或，R4或R5中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷基所取代，所述的取代或未取代的C1-C4的烷基中所述的取代为被
    Figure PCTCN2016088089-appb-100052
    所取代；Ra11为C1-C4的烷基时，Ra11中，所述的C1-C4的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基或者叔丁基；    And/or, in R 4 or R 5 , when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group, The substitution in the substituted or unsubstituted C 1 -C 4 alkyl group is
    Figure PCTCN2016088089-appb-100052
    When R a11 is a C 1 -C 4 alkyl group, in the R a11 , the C 1 -C 4 alkyl group is a methyl group, an ethyl group, a n-propyl group, an isopropyl group or an n-butyl group. Isobutyl or tert-butyl;
    和/或，R4或R5中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷基所取代，所述的取代或未取代的C1-C4的烷基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代时，所述的取代或未取代的C2-C6的杂环烷基为取代或未取代的吗啉基或者取代或未取代的哌嗪基；And/or, in R 4 or R 5 , when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group, When the substitution described in the substituted or unsubstituted C 1 -C 4 alkyl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, the substituted or unsubstituted C 2 a heterocyclic alkyl group of -C 6 is a substituted or unsubstituted morpholinyl group or a substituted or unsubstituted piperazinyl group;
    和/或，R4或R5中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷基所取代，所述的取代或未取代的C1-C4的烷基中所述的取代为被
    Figure PCTCN2016088089-appb-100053
    所取代，R16和R17独立地为C1-C4的烷基时，R16或R17中，所述的C1-C4的烷基为甲基、 乙基、正丙基、异丙基、正丁基、异丁基或者叔丁基；    And/or, in R 4 or R 5 , when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group, The substitution in the substituted or unsubstituted C 1 -C 4 alkyl group is
    Figure PCTCN2016088089-appb-100053
    When R 16 and R 17 are independently a C 1 -C 4 alkyl group, in the case of R 16 or R 17 , the C 1 -C 4 alkyl group is a methyl group, an ethyl group, a n-propyl group, Isopropyl, n-butyl, isobutyl or tert-butyl;
    和/或，R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷氧基所取代，所述的取代的C1-C4的烷氧基中所述的取代为被C2-C6的杂环烷基所取代时，所述的C2-C6的杂环烷基为四氢吡咯基或吗啉基；And/or, in R 4 or R 5 , when the substitution described in the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkoxy group, When the substitution described in the substituted C 1 -C 4 alkoxy group is substituted by a C 2 -C 6 heterocycloalkyl group, the C 2 -C 6 heterocycloalkyl group is a tetrahydropyrrole Or morpholinyl;
    和/或，R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷氧基所取代，所述的取代的C1-C4的烷氧基中所述的取代为被C1-C4的烷氧基所取代时，所述的C1-C4的烷氧基为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基或者叔丁氧基；And/or, in R 4 or R 5 , when the substitution described in the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkoxy group, substituted C 1 -C 4 alkoxy substituents in the substituted as being when the C 1 -C 4 alkoxy, said C 1 -C 4 alkoxy are methoxy, ethoxy, Oxyl, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy;
    和/或，R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷氧基所取代，所述的取代的C1-C4的烷氧基中所述的取代为被
    Figure PCTCN2016088089-appb-100054
    所取代，所述的R18为C1-C4的烷基时，R18中，所述的C1-C4的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基或者叔丁基；    And/or, in R 4 or R 5 , when the substitution described in the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkoxy group, The substitution in the substituted C 1 -C 4 alkoxy group is
    Figure PCTCN2016088089-appb-100054
    When substituted, the R 18 is a C 1 -C 4 alkyl, R 18, said C 1 -C 4 alkyl groups are methyl, ethyl, n-propyl, isopropyl, n Butyl, isobutyl or tert-butyl;
    和/或，R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷氧基所取代，所述的取代的C1-C4的烷氧基中所述的取代为被
    Figure PCTCN2016088089-appb-100055
    所取代，所述的R18为C2-C6的杂环烷基时，R18中，所述的C2-C6的杂环烷基为四氢吡咯基；    And/or, in R 4 or R 5 , when the substitution described in the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkoxy group, The substitution in the substituted C 1 -C 4 alkoxy group is
    Figure PCTCN2016088089-appb-100055
    When R 18 is a C 2 -C 6 heterocycloalkyl group, in the R 18 , the C 2 -C 6 heterocycloalkyl group is a tetrahydropyrrolyl group;
    和/或，R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷氧基所取代，所述的取代的C1-C4的烷氧基中所述的取代为被
    Figure PCTCN2016088089-appb-100056
    所取代，所述的R19和R20独立地为C1-C4的烷基时，R19和R20中，所述的C1-C4的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基或者叔丁基；    And/or, in R 4 or R 5 , when the substitution described in the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkoxy group, The substitution in the substituted C 1 -C 4 alkoxy group is
    Figure PCTCN2016088089-appb-100056
    In the case where R 19 and R 20 are independently a C 1 -C 4 alkyl group, in the case of R 19 and R 20 , the C 1 -C 4 alkyl group is a methyl group, an ethyl group, a positive group. Propyl, isopropyl, n-butyl, isobutyl or tert-butyl;
    和/或，R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代，所述的取代或未取代的C2-C6的杂环烷基中所述的取代为被取代或未取代的C1-C4的烷基所取代，所述的取代的C1-C4的烷基中所述的取代为被C3-C6的环烷基所取代时，所述的C3-C6的环烷基为环丙基、环丁基、环戊基或环己基；And/or, in R 4 or R 5 , when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, The substitution described in the substituted or unsubstituted C 2 -C 6 heterocycloalkyl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group, said substituted C 1 -C 4 When the substitution in the alkyl group is substituted by a C 3 -C 6 cycloalkyl group, the C 3 -C 6 cycloalkyl group is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group. ;
    和/或，R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代，所述的取代的C2-C6的杂环烷基中所述的取代为被取代或未取代的C1-C4的烷基所取代，所述的取代的C1-C4的烷基中所述的取代为被取代或未取代的C1-C4的烷氧基所取代，所述的取代的C1-C4的烷氧基中所述的取代为C5-C10的芳基时，所述的C5-C10的芳基为苯基；和/或，R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代，所述的取代的C2-C6的杂环烷基中所 述的取代为被取代或未取代的C1-C4的烷基所取代时，所述的取代或未取代的C1-C4的烷基为取代或未取代的甲基、取代或未取代的乙基、取代或未取代的正丙基、取代或未取代的异丙基、取代或未取代的正丁基、取代或未取代的异丁基或者取代或未取代的叔丁基；And/or, in R 4 or R 5 , when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, The substitution described in the substituted C 2 -C 6 heterocycloalkyl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group, said substituted C 1 -C 4 alkyl group The substitution described in the above is substituted by a substituted or unsubstituted C 1 -C 4 alkoxy group, and the substitution described in the substituted C 1 -C 4 alkoxy group is C 5 -C 10 In the case of an aryl group, the C 5 -C 10 aryl group is a phenyl group; and/or, in R 4 or R 5 , when the substituted C 5 -C 10 aryl group is substituted as described Substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, the substituent described in the substituted C 2 -C 6 heterocycloalkyl group is a substituted or unsubstituted C 1 -C 4 When substituted with an alkyl group, the substituted or unsubstituted C 1 -C 4 alkyl group is a substituted or unsubstituted methyl group, a substituted or unsubstituted ethyl group, a substituted or unsubstituted n-propyl group, a substitution group. Or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl or taken Unsubstituted or tert-butyl;
    和/或，R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代，所述的取代的C2-C6的杂环烷基中所述的取代为被
    Figure PCTCN2016088089-appb-100057
    所取代，R21为取代或未取代的C1-C4的烷基时，所述的取代或未取代的C1-C4的烷基为取代或未取代的甲基、取代或未取代的乙基、取代或未取代的正丙基、取代或未取代的异丙基、取代或未取代的正丁基、取代或未取代的异丁基或者取代或未取代的叔丁基；    And/or, in R 4 or R 5 , when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, The substitution described in the substituted C 2 -C 6 heterocycloalkyl group is
    Figure PCTCN2016088089-appb-100057
    When R 21 is a substituted or unsubstituted C 1 -C 4 alkyl group, the substituted or unsubstituted C 1 -C 4 alkyl group is a substituted or unsubstituted methyl group, substituted or unsubstituted Ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl or substituted or unsubstituted t-butyl;
    和/或，R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代，所述的取代的C2-C6的杂环烷基中所述的取代为被
    Figure PCTCN2016088089-appb-100058
    所取代，R21为
    Figure PCTCN2016088089-appb-100059
    Ra11和Ra12独立地为C1-C4的烷基时，所述的C1-C4的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基；    And/or, in R 4 or R 5 , when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, The substitution described in the substituted C 2 -C 6 heterocycloalkyl group is
    Figure PCTCN2016088089-appb-100058
    Substituted, R 21 is
    Figure PCTCN2016088089-appb-100059
    When R a11 and R a12 are independently a C 1 -C 4 alkyl group, the C 1 -C 4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl Base or tert-butyl;
    和/或，R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代，所述的取代的C2-C6的杂环烷基中所述的取代为被
    Figure PCTCN2016088089-appb-100060
    所取代，R22为C1-C4的烷基时，所述的C1-C4的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基；    And/or, in R 4 or R 5 , when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, The substitution described in the substituted C 2 -C 6 heterocycloalkyl group is
    Figure PCTCN2016088089-appb-100060
    When R 22 is a C 1 -C 4 alkyl group, the C 1 -C 4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or Tert-butyl;
    和/或，R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被取代或未取代的C5-C10的芳基所取代，所述的取代的C5-C10的芳基中所述的取代为被C1-C4的烷氧基所取代时，所述的C1-C4的烷氧基为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基或者叔丁氧基；And/or, in R 4 or R 5 , when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 5 -C 10 aryl group, When the substitution in the substituted C 5 -C 10 aryl group is substituted by a C 1 -C 4 alkoxy group, the C 1 -C 4 alkoxy group is a methoxy group or an ethoxy group. , n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy;
    和/或，R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被
    Figure PCTCN2016088089-appb-100061
    所取代，所述的R14为C1-C4的烷氧基时，所述的C1-C4的烷氧基为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基或者叔丁氧基；    And/or, in R 4 or R 5 , when the substituted C 5 -C 10 aryl group is substituted as described
    Figure PCTCN2016088089-appb-100061
    When the R 14 is a C 1 -C 4 alkoxy group, the C 1 -C 4 alkoxy group is a methoxy group, an ethoxy group, a n-propoxy group or an isopropoxy group. , n-butoxy, isobutoxy or tert-butoxy;
    和/或，R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被
    Figure PCTCN2016088089-appb-100062
    所取代， 所述的R14为
    Figure PCTCN2016088089-appb-100063
    Ra7和Ra8独立地为取代或未取代的C1-C4的烷基，所述的取代的C1-C4的烷基为被C2-C6的杂环烷基所取代时，所述的C2-C6的杂环烷基为四氢吡咯基；    And/or, in R 4 or R 5 , when the substituted C 5 -C 10 aryl group is substituted as described
    Figure PCTCN2016088089-appb-100062
    Substituted, the R 14 is
    Figure PCTCN2016088089-appb-100063
    R a7 and R a8 are independently a substituted or unsubstituted C 1 -C 4 alkyl group, and the substituted C 1 -C 4 alkyl group is substituted by a C 2 -C 6 heterocycloalkyl group. The C 2 -C 6 heterocycloalkyl group is a tetrahydropyrrolyl group;
    和/或，R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被
    Figure PCTCN2016088089-appb-100064
    所取代，R15为C1-C4的烷基时，所述的C1-C4的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基或者叔丁基；    And/or, in R 4 or R 5 , when the substituted C 5 -C 10 aryl group is substituted as described
    Figure PCTCN2016088089-appb-100064
    When R 15 is a C 1 -C 4 alkyl group, the C 1 -C 4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or Tert-butyl;
    和/或，R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被
    Figure PCTCN2016088089-appb-100065
    所取代，R15为
    Figure PCTCN2016088089-appb-100066
    Ra9或Ra10独立地为取代或未取代的C1-C4的烷基，所述的取代的C1-C4的烷基中所述的取代为被C2-C6的杂环烷基所取代时，所述的C2-C6的杂环烷基为四氢吡咯基或者吗啉基；和/或，R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被
    Figure PCTCN2016088089-appb-100067
    所取代，R15为取代或未取代的C2-C6的杂环烷基，所述的取代的C2-C6的杂环烷基为被C1-C4的烷基所取代时，所述的C1-C4的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基；所述的C2-C6的杂环烷基为哌嗪基。    And/or, in R 4 or R 5 , when the substituted C 5 -C 10 aryl group is substituted as described
    Figure PCTCN2016088089-appb-100065
    Substituted, R 15 is
    Figure PCTCN2016088089-appb-100066
    R a9 or R a10 is independently a substituted or unsubstituted C 1 -C 4 alkyl group, and the substituent described in the substituted C 1 -C 4 alkyl group is a C 2 -C 6 heterocyclic ring When substituted with an alkyl group, the C 2 -C 6 heterocycloalkyl group is tetrahydropyrrolyl or morpholinyl; and/or, in R 4 or R 5 , when substituted C 5 -C 10 The substitution in the aryl group is
    Figure PCTCN2016088089-appb-100067
    Substituted, R 15 is a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, and the substituted C 2 -C 6 heterocycloalkyl group is substituted by a C 1 -C 4 alkyl group. The C 1 -C 4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or t-butyl; the C 2 -C 6 heterocyclic ring The alkyl group is piperazinyl.
  3. 如权利要求2所述的通式I所示的喹唑啉类化合物，其药学上可接受的盐、溶剂化物、代谢产物、代谢前体或药物前体；其特征在于，A quinazoline compound of the formula I, a pharmaceutically acceptable salt, solvate, metabolite, metabolic precursor or prodrug thereof, according to claim 2;
    R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷基所取代，所述的取代的C1-C4的烷基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代，所述的取代的C2-C6的杂环烷基为取代的哌嗪基时；所述的取代的哌嗪基为
    Figure PCTCN2016088089-appb-100068
    In R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group, the The substitution in the substituted C 1 -C 4 alkyl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, said substituted C 2 -C 6 heterocycloalkyl group When substituted with piperazinyl; the substituted piperazinyl group is
    Figure PCTCN2016088089-appb-100068
    和/或，R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷氧基所取代，所述的取代的C1-C4的烷氧基中所述的取代为被取代或未取代的C2-C6的杂芳基所取代，所述的取代的C2-C6的杂芳基为取代的吡啶基时；所述的取代的吡啶基为
    Figure PCTCN2016088089-appb-100069
    And/or, in R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkoxy group Substituting, the substitution described in the substituted C 1 -C 4 alkoxy group is substituted by a substituted or unsubstituted C 2 -C 6 heteroaryl group, said substituted C 2 -C 6 When the heteroaryl group is a substituted pyridyl group; the substituted pyridyl group is
    Figure PCTCN2016088089-appb-100069
    和/或，R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷氧基所取代，所述的取代的C1-C4的烷氧基中所述的取代为被取代或未 取代的C5-C10的芳基所取代，所述的取代的C5-C10的芳基为取代的苯基时；所述的取代的苯基为
    Figure PCTCN2016088089-appb-100070
    And/or, in R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkoxy group Substituting, the substitution described in the substituted C 1 -C 4 alkoxy group is substituted by a substituted or unsubstituted C 5 -C 10 aryl group, said substituted C 5 -C 10 When the aryl group is a substituted phenyl group; the substituted phenyl group is
    Figure PCTCN2016088089-appb-100070
    和/或，R1、R2或R3中，当所述的取代的C2-C6的杂芳基中所述的取代为被取代或未取代的C1-C4的烷基所取代，所述的取代的C1-C4的烷基中所述的取代为被取代或未取代的C2-C6的杂芳基所取代，所述的取代的C2-C6的杂芳基为取代的吡啶基时；所述的取代的吡啶基为
    Figure PCTCN2016088089-appb-100071
    And/or, in R 1 , R 2 or R 3 , when the substituted C 2 -C 6 heteroaryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group Substituting, the substitution described in the substituted C 1 -C 4 alkyl group is substituted by a substituted or unsubstituted C 2 -C 6 heteroaryl group, said substituted C 2 -C 6 When the heteroaryl group is a substituted pyridyl group; the substituted pyridyl group is
    Figure PCTCN2016088089-appb-100071
    和/或，R1、R2或R3中，当所述的取代的C2-C6的杂芳基中所述的取代为被取代或未取代的C1-C4的烷基所取代，所述的取代的C1-C4的烷基中所述的取代为被取代或未取代的C5-C10的芳基所取代，所述的取代的C5-C10的芳基为取代的苯基时；所述的取代的苯基为
    Figure PCTCN2016088089-appb-100072
    And/or, in R 1 , R 2 or R 3 , when the substituted C 2 -C 6 heteroaryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group Substituting, the substitution described in the substituted C 1 -C 4 alkyl group is substituted by a substituted or unsubstituted C 5 -C 10 aryl group, the substituted C 5 -C 10 aryl group When the group is a substituted phenyl group; the substituted phenyl group is
    Figure PCTCN2016088089-appb-100072
    和/或，R1、R2或R3中，当所述的取代的C2-C6的杂芳基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代，所述的取代的C2-C6的杂环烷基中所述的取代为被
    Figure PCTCN2016088089-appb-100073
    所取代，所述的R12为C1-C4的烷基时，所述的
    Figure PCTCN2016088089-appb-100074
    为
    Figure PCTCN2016088089-appb-100075
    And/or, in R 1 , R 2 or R 3 , when the substituted C 2 -C 6 heteroaryl group is substituted as a substituted or unsubstituted C 2 -C 6 heterocycloalkane Substituted, the substitution described in the substituted C 2 -C 6 heterocycloalkyl group is
    Figure PCTCN2016088089-appb-100073
    When the R 12 is a C 1 -C 4 alkyl group, the
    Figure PCTCN2016088089-appb-100074
    for
    Figure PCTCN2016088089-appb-100075
    和/或，R1、R2或R3中，当所述的取代的C2-C6的杂芳基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代，所述的取代的C2-C6的杂环烷基中所述的取代为被
    Figure PCTCN2016088089-appb-100076
    所取代，所述的R12为C3-C6的环烷基时，所述的
    Figure PCTCN2016088089-appb-100077
    为
    Figure PCTCN2016088089-appb-100078
    And/or, in R 1 , R 2 or R 3 , when the substituted C 2 -C 6 heteroaryl group is substituted as a substituted or unsubstituted C 2 -C 6 heterocycloalkane Substituted, the substitution described in the substituted C 2 -C 6 heterocycloalkyl group is
    Figure PCTCN2016088089-appb-100076
    When the R 12 is a C 3 -C 6 cycloalkyl group, the
    Figure PCTCN2016088089-appb-100077
    for
    Figure PCTCN2016088089-appb-100078
    和/或，R1、R2或R3中，所述的取代的C2-C6的杂芳基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代，所述的取代的C2-C6的杂环烷基中所述的取代为被
    Figure PCTCN2016088089-appb-100079
    所取代，所述的R13为C1-C4的烷基时，所述的
    Figure PCTCN2016088089-appb-100080
    为
    Figure PCTCN2016088089-appb-100081
    And/or, in R 1 , R 2 or R 3 , the substituent described in the substituted C 2 -C 6 heteroaryl group is a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group. Substituted, the substitution described in the substituted C 2 -C 6 heterocycloalkyl group is
    Figure PCTCN2016088089-appb-100079
    When the R 13 is a C 1 -C 4 alkyl group, the
    Figure PCTCN2016088089-appb-100080
    for
    Figure PCTCN2016088089-appb-100081
    和/或，R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代，所述的取代的C2-C6的杂环烷基中所述的取代为被取代或未取代的C1-C4的烷基所取代，所述的取代的C1-C4的烷基中所述的取代为被取代或未取代的C1-C4的烷氧基所取代时，所述的取代或未取代的C1-C4的烷氧基为取代或未取代的甲氧基、取代或未取代的乙氧基、取代或未取代的正丙氧基、取代或未取代的异丙氧基、取代或未取代的正丁氧基、取代或未取代的异丁氧基或者取代或未取代的叔丁氧基； And/or, in R 4 or R 5 , when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, The substitution described in the substituted C 2 -C 6 heterocycloalkyl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group, said substituted C 1 -C 4 alkyl group When the substitution described is substituted by a substituted or unsubstituted C 1 -C 4 alkoxy group, the substituted or unsubstituted C 1 -C 4 alkoxy group is a substituted or unsubstituted methoxy group. Alkyl, substituted or unsubstituted ethoxy, substituted or unsubstituted n-propoxy, substituted or unsubstituted isopropoxy, substituted or unsubstituted n-butoxy, substituted or unsubstituted isobutoxy Or a substituted or unsubstituted tert-butoxy group;
    和/或，R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被
    Figure PCTCN2016088089-appb-100082
    所取代，所述的R14为
    Figure PCTCN2016088089-appb-100083
    Ra7和Ra8独立地为取代或未取代的C1-C4的烷基时，Ra7或Ra8中，所述的取代或未取代的C1-C4的烷基为取代或未取代的甲基、取代或未取代的乙基、取代或未取代的正丙基、取代或未取代的异丙基、取代或未取代的正丁基、取代或未取代的异丁基或者取代或未取代的叔丁基；    And/or, in R 4 or R 5 , when the substituted C 5 -C 10 aryl group is substituted as described
    Figure PCTCN2016088089-appb-100082
    Substituted, the R 14 is
    Figure PCTCN2016088089-appb-100083
    When R a7 and R a8 are independently a substituted or unsubstituted C 1 -C 4 alkyl group, in the R a7 or R a8 , the substituted or unsubstituted C 1 -C 4 alkyl group is substituted or not. Substituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl or substituted Or unsubstituted tert-butyl;
    和/或，R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被
    Figure PCTCN2016088089-appb-100084
    所取代，R15为
    Figure PCTCN2016088089-appb-100085
    Ra9或Ra10独立地为取代或未取代的C1-C4的烷基时，所述的取代或未取代的C1-C4的烷基为取代或未取代的甲基、取代或未取代的乙基、取代或未取代的正丙基、取代或未取代的异丙基、取代或未取代的正丁基、取代或未取代的异丁基或者取代或未取代的叔丁基。    And/or, in R 4 or R 5 , when the substituted C 5 -C 10 aryl group is substituted as described
    Figure PCTCN2016088089-appb-100084
    Substituted, R 15 is
    Figure PCTCN2016088089-appb-100085
    When R a9 or R a10 is independently a substituted or unsubstituted C 1 -C 4 alkyl group, the substituted or unsubstituted C 1 -C 4 alkyl group is a substituted or unsubstituted methyl group, a substituted or Unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl or substituted or unsubstituted t-butyl .
  4. 如权利要求1-3中至少一项所述的通式I所示的喹唑啉类化合物，其药学上可接受的盐、溶剂化物、代谢产物、代谢前体或药物前体；其特征在于，A quinazoline compound of the formula I according to at least one of claims 1 to 3, which is a pharmaceutically acceptable salt, solvate, metabolite, metabolic precursor or prodrug thereof; ,
    R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被卤素所取代时，所述的卤素为氟、氯、溴或碘；In R 1 , R 2 or R 3 , when the substitution described in the substituted C 5 -C 10 aryl group is substituted by halogen, the halogen is fluorine, chlorine, bromine or iodine;
    和/或，R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷基所取代时，所述的取代或未取代的C1-C4的烷基为取代或未取代的甲基、取代或未取代的乙基、取代或未取代的正丙基、取代或未取代的异丙基、取代或未取代的正丁基、取代或未取代的异丁基或者取代或未取代的叔丁基；And/or, in R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group The substituted or unsubstituted C 1 -C 4 alkyl group is a substituted or unsubstituted methyl group, a substituted or unsubstituted ethyl group, a substituted or unsubstituted n-propyl group, a substituted or unsubstituted iso a propyl group, a substituted or unsubstituted n-butyl group, a substituted or unsubstituted isobutyl group or a substituted or unsubstituted tert-butyl group;
    和/或，R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷氧基所取代时，所述的取代或未取代的C1-C4的烷氧基为取代或未取代的甲氧基、取代或未取代的乙氧基、取代或未取代的正丙氧基、取代或未取代的异丙氧基、取代或未取代的正丁氧基、取代或未取代的异丁氧基或者取代或未取代的叔丁氧基；And/or, in R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkoxy group When substituted, the substituted or unsubstituted C 1 -C 4 alkoxy group is a substituted or unsubstituted methoxy group, a substituted or unsubstituted ethoxy group, a substituted or unsubstituted n-propoxy group, a substitution. Or an unsubstituted isopropoxy group, a substituted or unsubstituted n-butoxy group, a substituted or unsubstituted isobutoxy group or a substituted or unsubstituted tert-butoxy group;
    和/或，R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代时，所述的取代或未取代的C2-C6的杂环烷基为取代或未取代的吗啉基或取代或未取代的哌嗪基；And/or, in R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is substituted as a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group When substituted, the substituted or unsubstituted C 2 -C 6 heterocycloalkyl group is a substituted or unsubstituted morpholinyl group or a substituted or unsubstituted piperazinyl group;
    和/或，R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被
    Figure PCTCN2016088089-appb-100086
    所 取代时，所述的
    Figure PCTCN2016088089-appb-100087
    为
    Figure PCTCN2016088089-appb-100088
    Figure PCTCN2016088089-appb-100089
    And/or, in R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is substituted as described
    Figure PCTCN2016088089-appb-100086
    When replaced, the stated
    Figure PCTCN2016088089-appb-100087
    for
    Figure PCTCN2016088089-appb-100088
    Figure PCTCN2016088089-appb-100089
    和/或，R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被
    Figure PCTCN2016088089-appb-100090
    所取代时，所述的
    Figure PCTCN2016088089-appb-100091
    为
    Figure PCTCN2016088089-appb-100092
    Figure PCTCN2016088089-appb-100093
    And/or, in R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is substituted as described
    Figure PCTCN2016088089-appb-100090
    When replaced, the stated
    Figure PCTCN2016088089-appb-100091
    for
    Figure PCTCN2016088089-appb-100092
    Figure PCTCN2016088089-appb-100093
    和/或，R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被
    Figure PCTCN2016088089-appb-100094
    所取代时，所述的
    Figure PCTCN2016088089-appb-100095
    为
    Figure PCTCN2016088089-appb-100096
    和/或，R1、R2或R3中，当所述的取代的C2-C6的杂芳基中所述的取代为被C1-C4的烷氧基所取代时，所述的C1-C4的烷氧基为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基或叔丁氧基；    And/or, in R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is substituted as described
    Figure PCTCN2016088089-appb-100094
    When replaced, the stated
    Figure PCTCN2016088089-appb-100095
    for
    Figure PCTCN2016088089-appb-100096
    And/or, in R 1 , R 2 or R 3 , when the substitution described in the substituted C 2 -C 6 heteroaryl group is substituted by a C 1 -C 4 alkoxy group, The C 1 -C 4 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy;
    和/或，R1、R2或R3中，当所述的取代的C2-C6的杂芳基中所述的取代为被取代或未取代的C1-C4的烷基所取代时，所述的取代或未取代的C1-C4的烷基为取代或未取代的甲基、取代或未取代的乙基、取代或未取代的正丙基、取代或未取代的异丙基、取代或未取代的正丁基、取代或未取代的异丁基或者取代或未取代的叔丁基；和/或，R1、R2或R3中，当所述的取代的C2-C6的杂芳基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代，所述的取代的C2-C6的杂环烷基中所述的取代为被取代的C1-C4的烷基所取代时，所述的取代的C1-C4的烷基为取代的甲基、取代的乙基、取代的正丙基、取代的异丙基、取代的正丁基、取代的异丁基或者取代的叔丁基；And/or, in R 1 , R 2 or R 3 , when the substituted C 2 -C 6 heteroaryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group When substituted, the substituted or unsubstituted C 1 -C 4 alkyl group is a substituted or unsubstituted methyl group, a substituted or unsubstituted ethyl group, a substituted or unsubstituted n-propyl group, a substituted or unsubstituted group. Isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl or substituted or unsubstituted t-butyl; and/or, in R 1 , R 2 or R 3 , when said substitution the heteroaryl C 2 -C 6 aryl group in the substituent is substituted with a substituted or unsubstituted C 2 -C 6 heterocycloalkyl, and said substituted C 2 -C 6 heterocycloalkyl of When the substitution described is substituted with a substituted C 1 -C 4 alkyl group, the substituted C 1 -C 4 alkyl group is a substituted methyl group, a substituted ethyl group, a substituted n-propyl group. Substituted isopropyl, substituted n-butyl, substituted isobutyl or substituted t-butyl;
    和/或，R1、R2或R3中，当所述的取代的C2-C6的杂芳基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代，所述的取代或未取代的C2-C6的杂环烷基为杂原子选自O、N或S，杂原子数为1-4个的取代或未取代的C2-C6的杂环烷基；所述的取代或未取 代的C2-C6的杂环烷基较佳地为取代或未取代的吗啉基、取代或未取代的哌啶基或取代或未取代的氮杂环丁基；And/or, in R 1 , R 2 or R 3 , when the substituted C 2 -C 6 heteroaryl group is substituted as a substituted or unsubstituted C 2 -C 6 heterocycloalkane group substituted with a substituted or unsubstituted C 2 -C 6 heterocycloalkyl, a heteroatom selected from O, N or S, the number of from 1 to 4 hetero atoms substituted or unsubstituted C 2 - a heterocycloalkyl group of C 6 ; said substituted or unsubstituted C 2 -C 6 heterocycloalkyl group is preferably a substituted or unsubstituted morpholinyl group, a substituted or unsubstituted piperidinyl group or a substituted or Unsubstituted azetidinyl;
    和/或，R1、R2或R3中，当所述的取代的C2-C6的杂芳基中所述的取代为被
    Figure PCTCN2016088089-appb-100097
    所取代时，所述的
    Figure PCTCN2016088089-appb-100098
    为
    Figure PCTCN2016088089-appb-100099
    And/or, in R 1 , R 2 or R 3 , when the substituted C 2 -C 6 heteroaryl group is described as being substituted
    Figure PCTCN2016088089-appb-100097
    When replaced, the stated
    Figure PCTCN2016088089-appb-100098
    for
    Figure PCTCN2016088089-appb-100099
    和/或，R1、R2或R3中，当所述的取代的C2-C6的杂芳基中所述的取代为被
    Figure PCTCN2016088089-appb-100100
    所取代时，所述的
    Figure PCTCN2016088089-appb-100101
    为
    Figure PCTCN2016088089-appb-100102
    And/or, in R 1 , R 2 or R 3 , when the substituted C 2 -C 6 heteroaryl group is described as being substituted
    Figure PCTCN2016088089-appb-100100
    When replaced, the stated
    Figure PCTCN2016088089-appb-100101
    for
    Figure PCTCN2016088089-appb-100102
    和/或，R4或R5中，当所述的取代的C1-C4的烷基中所述的取代为被取代或未取代的C2-C6的杂芳基所取代时，所述的取代或未取代的C2-C6的杂芳基为取代或未取代的吡啶基；和/或，R4或R5中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷基所取代时，所述的取代或未取代的C1-C4的烷基为取代或未取代的甲基、取代或未取代的乙基、取代或未取代的正丙基、取代或未取代的异丙基、取代或未取代的正丁基、取代或未取代的异丁基或者取代或未取代的叔丁基；And/or, in R 4 or R 5 , when the substitution described in the substituted C 1 -C 4 alkyl group is substituted by a substituted or unsubstituted C 2 -C 6 heteroaryl group, The substituted or unsubstituted C 2 -C 6 heteroaryl group is a substituted or unsubstituted pyridyl group; and/or, in R 4 or R 5 , when substituted C 5 -C 10 aryl when the substituted group is substituted with a substituted or unsubstituted C 1 -C 4 alkyl group, said substituted or unsubstituted C 1 -C 4 alkyl substituted or unsubstituted methyl, Substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl or substituted or unsubstituted tau Butyl
    和/或，R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷氧基所取代时，所述的取代或未取代的C1-C4的烷氧基为取代或未取代的甲氧基、取代或未取代的乙氧基、取代或未取代的正丙氧基、取代或未取代的异丙氧基、取代或未取代的正丁氧基、取代或未取代的异丁氧基或者取代或未取代的叔丁氧基；And/or, in R 4 or R 5 , when the substitution described in the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkoxy group, The substituted or unsubstituted C 1 -C 4 alkoxy group is a substituted or unsubstituted methoxy group, a substituted or unsubstituted ethoxy group, a substituted or unsubstituted n-propoxy group, a substituted or unsubstituted one. Isopropoxy, substituted or unsubstituted n-butoxy, substituted or unsubstituted isobutoxy or substituted or unsubstituted tert-butoxy;
    和/或，R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代时，所述的取代或未取代的C2-C6的杂环烷基为取代或未取代的四氢吡咯基、取代或未取代的哌啶基、取代或未取代的吗啉基或者取代或未取代的哌嗪基；And/or, in R 4 or R 5 , when the substitution described in the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, The substituted or unsubstituted C 2 -C 6 heterocycloalkyl group is a substituted or unsubstituted tetrahydropyrrolyl group, a substituted or unsubstituted piperidinyl group, a substituted or unsubstituted morpholinyl group or a substituted or unsubstituted Substituted piperazinyl;
    和/或，R4或R5中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C5-C10的芳基所取代时，所述的取代或未取代的C5-C10的芳基为取代或未取代的苯基；And/or, in R 4 or R 5 , when the substitution described in the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 5 -C 10 aryl group, The substituted or unsubstituted C 5 -C 10 aryl group is a substituted or unsubstituted phenyl group;
    和/或，R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被
    Figure PCTCN2016088089-appb-100103
    所取代时，所述的
    Figure PCTCN2016088089-appb-100104
    为
    Figure PCTCN2016088089-appb-100105
    And/or, in R 4 or R 5 , when the substituted C 5 -C 10 aryl group is substituted as described
    Figure PCTCN2016088089-appb-100103
    When replaced, the stated
    Figure PCTCN2016088089-appb-100104
    for
    Figure PCTCN2016088089-appb-100105
    和/或，R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被
    Figure PCTCN2016088089-appb-100106
    所取代时，所述的
    Figure PCTCN2016088089-appb-100107
    为
    Figure PCTCN2016088089-appb-100108
    And/or, in R 4 or R 5 , when the substituted C 5 -C 10 aryl group is substituted as described
    Figure PCTCN2016088089-appb-100106
    When replaced, the stated
    Figure PCTCN2016088089-appb-100107
    for
    Figure PCTCN2016088089-appb-100108
  5. 如权利要求4所述的通式I所示的喹唑啉类化合物，其药学上可接受的盐、溶剂化物、代谢产物、代谢前体或药物前体；其特征在于，A quinazoline compound of the formula I, a pharmaceutically acceptable salt, solvate, metabolite, metabolic precursor or prodrug thereof, according to claim 4;
    R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷基所取代时，所述的取代的C1-C4的烷基为
    Figure PCTCN2016088089-appb-100109
    In R 1 , R 2 or R 3 , when the substitution in the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group, Substituted C 1 -C 4 alkyl group is
    Figure PCTCN2016088089-appb-100109
    和/或，R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷氧基所取代时，所述的取代的C1-C4的烷氧基为
    Figure PCTCN2016088089-appb-100110
    Figure PCTCN2016088089-appb-100111
    And/or, in R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkoxy group When substituted, the substituted C 1 -C 4 alkoxy group is
    Figure PCTCN2016088089-appb-100110
    Figure PCTCN2016088089-appb-100111
    和/或，R1、R2或R3中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代，所述的取代或未取代的C2-C6的杂环烷基为取代或未取代的哌嗪基时；所述的取代的哌嗪基为
    Figure PCTCN2016088089-appb-100112
    And/or, in R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is substituted as a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group When the substituted or unsubstituted C 2 -C 6 heterocycloalkyl group is a substituted or unsubstituted piperazinyl group; the substituted piperazinyl group is
    Figure PCTCN2016088089-appb-100112
    和/或，R1、R2或R3中，当所述的取代的C2-C6的杂芳基中所述的取代为被取代或未取代的C1-C4的烷基所取代时，所述的取代的C1-C4的烷基为
    Figure PCTCN2016088089-appb-100113
    Figure PCTCN2016088089-appb-100114
    And/or, in R 1 , R 2 or R 3 , when the substituted C 2 -C 6 heteroaryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group When substituted, the substituted C 1 -C 4 alkyl group is
    Figure PCTCN2016088089-appb-100113
    Figure PCTCN2016088089-appb-100114
    和/或，R1、R2或R3中，当所述的取代的C2-C6的杂芳基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代，所述的取代的C2-C6的杂环烷基中所述的取代为被取代 的C1-C4的烷基所取代时，所述的取代的C1-C4的烷基为
    Figure PCTCN2016088089-appb-100115
    And/or, in R 1 , R 2 or R 3 , when the substituted C 2 -C 6 heteroaryl group is substituted as a substituted or unsubstituted C 2 -C 6 heterocycloalkane Substituted, when the substituted C 2 -C 6 heterocycloalkyl group is substituted by a substituted C 1 -C 4 alkyl group, the substituted C 1 -C 4 Alkyl group
    Figure PCTCN2016088089-appb-100115
    和/或，R1、R2或R3中，当所述的取代的C2-C6的杂芳基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代时，所述的取代的C2-C6的杂环烷基为
    Figure PCTCN2016088089-appb-100116
    Figure PCTCN2016088089-appb-100117
    And/or, in R 1 , R 2 or R 3 , when the substituted C 2 -C 6 heteroaryl group is substituted as a substituted or unsubstituted C 2 -C 6 heterocycloalkane When substituted, the substituted C 2 -C 6 heterocycloalkyl group is
    Figure PCTCN2016088089-appb-100116
    Figure PCTCN2016088089-appb-100117
    和/或，R4或R5中，当所述的取代的C1-C4的烷基中所述的取代为被取代或未取代的C2-C6的杂芳基所取代，所述的取代或未取代的C2-C6的杂芳基为取代或未取代的吡啶基时；所述的取代的吡啶基为
    Figure PCTCN2016088089-appb-100118
    所述的取代的C1-C4的烷基为
    Figure PCTCN2016088089-appb-100119
    和/或，R4或R5中，当所述的取代的C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷基所取代时，所述的取代的C1-C4的烷基为
    Figure PCTCN2016088089-appb-100120
    Figure PCTCN2016088089-appb-100121
    And/or, in R 4 or R 5 , when the substituted C 1 -C 4 alkyl group is substituted by a substituted or unsubstituted C 2 -C 6 heteroaryl group, When the substituted or unsubstituted C 2 -C 6 heteroaryl group is a substituted or unsubstituted pyridyl group; the substituted pyridyl group is
    Figure PCTCN2016088089-appb-100118
    The substituted C 1 -C 4 alkyl group is
    Figure PCTCN2016088089-appb-100119
    And/or, in R 4 or R 5 , when the substitution described in the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkyl group, The substituted C 1 -C 4 alkyl group is
    Figure PCTCN2016088089-appb-100120
    Figure PCTCN2016088089-appb-100121
    和/或，R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被取代或未取代的C1-C4的烷氧基所取代时，所述的取代的C1-C4的烷氧基为
    Figure PCTCN2016088089-appb-100122
    Figure PCTCN2016088089-appb-100123
    And/or, in R 4 or R 5 , when the substitution described in the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 1 -C 4 alkoxy group, The substituted C 1 -C 4 alkoxy group is
    Figure PCTCN2016088089-appb-100122
    Figure PCTCN2016088089-appb-100123
    和/或，R4或R5中，当所述的取代C5-C10的芳基中所述的取代为被取代或未取代的C2-C6的杂环烷基所取代时，所述的取代的C2-C6的杂环烷基为
    Figure PCTCN2016088089-appb-100124
    And/or, in R 4 or R 5 , when the substitution described in the substituted C 5 -C 10 aryl group is substituted by a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, The substituted C 2 -C 6 heterocycloalkyl group is
    Figure PCTCN2016088089-appb-100124
    Figure PCTCN2016088089-appb-100125
    Figure PCTCN2016088089-appb-100125
  6. 如权利要求1-5中至少一项所述的通式I所示的喹唑啉类化合物，其药学上可接受的盐、溶剂化物、代谢产物、代谢前体或药物前体；其特征在于，A quinazoline compound of the formula I according to at least one of claims 1 to 5, which is a pharmaceutically acceptable salt, solvate, metabolite, metabolic precursor or prodrug thereof; ,
    R1、R2或R3中，所述的取代的C5-C10的芳基为取代的苯基；In R 1 , R 2 or R 3 , the substituted C 5 -C 10 aryl group is a substituted phenyl group;
    和/或，R1、R2或R3中，所述的取代或未取代的C2-C6的杂芳基为取代或未取代的吡啶基或者取代或未取代的吡唑基；And/or, in R 1 , R 2 or R 3 , the substituted or unsubstituted C 2 -C 6 heteroaryl group is a substituted or unsubstituted pyridyl group or a substituted or unsubstituted pyrazolyl group;
    和/或，R1、R2或R3中，所述的C2-C6的杂环烷基为吗啉基；And/or, in R 1 , R 2 or R 3 , the C 2 -C 6 heterocycloalkyl group is a morpholinyl group;
    和/或，R4或R5中，所述的取代或未取代的C1-C4的烷基为取代或未取代的甲基、取代或未取代的乙基、取代或未取代的正丙基、取代或未取代的异丙基、取代或未取代的正丁基、取代或未取代的异丁基或者取代或未取代的叔丁基；And/or, in R 4 or R 5 , the substituted or unsubstituted C 1 -C 4 alkyl group is a substituted or unsubstituted methyl group, a substituted or unsubstituted ethyl group, a substituted or unsubstituted positive group. a propyl group, a substituted or unsubstituted isopropyl group, a substituted or unsubstituted n-butyl group, a substituted or unsubstituted isobutyl group or a substituted or unsubstituted tert-butyl group;
    和/或，R4或R5中，所述的取代或未取代的C5-C10的芳基为取代或未取代的苯基；和/或，R4或R5中，所述的取代的C2-C6的杂芳基为取代的吡啶基或取代的嘧啶基；And/or, in R 4 or R 5 , the substituted or unsubstituted C 5 -C 10 aryl group is a substituted or unsubstituted phenyl group; and/or, in R 4 or R 5 , Substituted C 2 -C 6 heteroaryl is substituted pyridyl or substituted pyrimidinyl;
    和/或，当R4或R5为
    Figure PCTCN2016088089-appb-100126
    时，R0为取代的C1-C4的烷基时，所述的取代的C1-C4的烷基为取代的甲基、取代的乙基、取代的正丙基、取代的异丙基、取代的正丁基、取代的异丁基或者取代的叔丁基；当R4或R5为
    Figure PCTCN2016088089-appb-100127
    时，R0为C3-C6的环烷基时，所述的C3-C6的环烷基为环丙基、环丁基、环戊基或环己基。    And / or when R 4 or R 5 is
    Figure PCTCN2016088089-appb-100126
    When R 0 is a substituted C 1 -C 4 alkyl group, the substituted C 1 -C 4 alkyl group is a substituted methyl group, a substituted ethyl group, a substituted n-propyl group, a substituted iso group. a propyl group, a substituted n-butyl group, a substituted isobutyl group or a substituted tert-butyl group; when R 4 or R 5 is
    Figure PCTCN2016088089-appb-100127
    When R 0 is a C 3 -C 6 cycloalkyl group, the C 3 -C 6 cycloalkyl group is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.
  7. 如权利要求6所述的通式I所示的喹唑啉类化合物，其药学上可接受的盐、溶剂化物、代谢产物、代谢前体或药物前体；其特征在于，A quinazoline compound of the formula I, a pharmaceutically acceptable salt, solvate, metabolite, metabolic precursor or prodrug thereof, according to claim 6;
    R1、R2或R3中，当所述的取代的C5-C10的芳基为取代的苯基时；所述的取代的苯基 为
    Figure PCTCN2016088089-appb-100128
    Figure PCTCN2016088089-appb-100129
    In R 1 , R 2 or R 3 , when the substituted C 5 -C 10 aryl group is a substituted phenyl group; the substituted phenyl group is
    Figure PCTCN2016088089-appb-100128
    Figure PCTCN2016088089-appb-100129
    Figure PCTCN2016088089-appb-100130
    Figure PCTCN2016088089-appb-100130
    和/或，R1、R2或R3中，当所述的取代或未取代的C2-C6的杂芳基为取代或未取代的吡啶基或者取代或未取代的吡唑基时；所述的取代的吡啶基为
    Figure PCTCN2016088089-appb-100131
    或者
    Figure PCTCN2016088089-appb-100132
    所述的取代的吡唑基为
    Figure PCTCN2016088089-appb-100133
    Figure PCTCN2016088089-appb-100134
    And/or, in R 1 , R 2 or R 3 , when the substituted or unsubstituted C 2 -C 6 heteroaryl group is a substituted or unsubstituted pyridyl group or a substituted or unsubstituted pyrazolyl group The substituted pyridyl group is
    Figure PCTCN2016088089-appb-100131
    or
    Figure PCTCN2016088089-appb-100132
    The substituted pyrazolyl group is
    Figure PCTCN2016088089-appb-100133
    Figure PCTCN2016088089-appb-100134
    和/或，R4或R5中，所述的取代的C1-C4的烷基为
    Figure PCTCN2016088089-appb-100135
    And/or, in R 4 or R 5 , the substituted C 1 -C 4 alkyl group is
    Figure PCTCN2016088089-appb-100135
    和/或，R4或R5中，当所述的取代或未取代的C5-C10的芳基为取代或未取代的苯基时；所述的取代的苯基为
    Figure PCTCN2016088089-appb-100136
    And/or, in R 4 or R 5 , when the substituted or unsubstituted C 5 -C 10 aryl group is a substituted or unsubstituted phenyl group; the substituted phenyl group is
    Figure PCTCN2016088089-appb-100136
    Figure PCTCN2016088089-appb-100137
    Figure PCTCN2016088089-appb-100137
    Figure PCTCN2016088089-appb-100138
    Figure PCTCN2016088089-appb-100139
    Figure PCTCN2016088089-appb-100138
    Figure PCTCN2016088089-appb-100139
    和/或，R4或R5中，当所述的取代的C2-C6的杂芳基为取代的吡啶基或取代的嘧啶基时；所述的取代的吡啶基为
    Figure PCTCN2016088089-appb-100140
    所述的取代的嘧啶基为
    Figure PCTCN2016088089-appb-100141
    And/or, in R 4 or R 5 , when the substituted C 2 -C 6 heteroaryl group is a substituted pyridyl group or a substituted pyrimidinyl group; the substituted pyridyl group is
    Figure PCTCN2016088089-appb-100140
    The substituted pyrimidinyl group is
    Figure PCTCN2016088089-appb-100141
    和/或，当R4或R5为
    Figure PCTCN2016088089-appb-100142
    时，所述的
    Figure PCTCN2016088089-appb-100143
    为
    Figure PCTCN2016088089-appb-100144
    Figure PCTCN2016088089-appb-100145
    And / or when R 4 or R 5 is
    Figure PCTCN2016088089-appb-100142
    When said
    Figure PCTCN2016088089-appb-100143
    for
    Figure PCTCN2016088089-appb-100144
    Figure PCTCN2016088089-appb-100145
  8. 如权利要求1-7中至少一项所述的通式I所示的喹唑啉类化合物，其药学上可接受的盐、溶剂化物、代谢产物、代谢前体或药物前体，其特征在于，通式I所示的喹唑啉类化合物中，R1和R2为氢；R3为取代的C5-C10的芳基或者取代或未取代的C2-C6的杂芳基。A quinazoline compound of the formula I according to at least one of claims 1 to 7, which is a pharmaceutically acceptable salt, solvate, metabolite, metabolic precursor or prodrug thereof, characterized in that In the quinazoline compound of the formula I, R 1 and R 2 are hydrogen; R 3 is a substituted C 5 -C 10 aryl group or a substituted or unsubstituted C 2 -C 6 heteroaryl group; .
  9. 如权利要求1-8中至少一项所述的通式I所示的喹唑啉类化合物，其药学上可接受的盐、溶剂化物、代谢产物、代谢前体或药物前体，其特征在于，通式I所示的喹唑啉类化合物为通式I-a、通式I-b、通式I-c、通式I-d、通式I-e、通式I-f、通式I-g、通式I-h、通式I-i、通式I-j或通式I-k所示的化合物；A quinazoline compound of the formula I according to at least one of claims 1 to 8, which is a pharmaceutically acceptable salt, solvate, metabolite, metabolic precursor or prodrug thereof, characterized in that The quinazoline compound represented by the formula I is a formula Ia, a formula Ib, a formula Ic, a formula Id, a formula Ie, a formula If, a formula Ig, a formula Ih, a formula Ii, a pass a compound of formula Ij or formula Ik;
    Figure PCTCN2016088089-appb-100146
    Figure PCTCN2016088089-appb-100146
    Figure PCTCN2016088089-appb-100147
    Figure PCTCN2016088089-appb-100147
    通式I-a化合物中， In the compound of formula I-a,
    Rp1、Rp2和Rp3独立地为氢、取代的C1-C4的烷基、取代或未取代的C1-C4的烷氧基或者
    Figure PCTCN2016088089-appb-100148
    R15为C1-C4的烷基或者
    Figure PCTCN2016088089-appb-100149
    Ra9和Ra10独立地为氢或者C1-C4的烷基；Rp1、Rp2和Rp3不同时为氢；    R p1 , R p2 and R p3 are independently hydrogen, substituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 alkoxy or
    Figure PCTCN2016088089-appb-100148
    R 15 is a C 1 -C 4 alkyl group or
    Figure PCTCN2016088089-appb-100149
    R a9 and R a10 are independently hydrogen or a C 1 -C 4 alkyl group; R p1 , R p2 and R p3 are not simultaneously hydrogen;
    Rm1为C1-C4的烷氧基、取代或未取代的C2-C6的杂环烷基、
    Figure PCTCN2016088089-appb-100150
    其中R6为C1-C4的烷基或者
    Figure PCTCN2016088089-appb-100151
    Ra1和Ra2独立地为氢、取代或未取代的C1-C4的烷基或C5-C10的芳基；R9为取代或未取代的C1-C4的烷基；    R m1 is a C 1 -C 4 alkoxy group, a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group,
    Figure PCTCN2016088089-appb-100150
    Wherein R 6 is a C 1 -C 4 alkyl group or
    Figure PCTCN2016088089-appb-100151
    R a1 and R a2 are independently hydrogen, a substituted or unsubstituted C 1 -C 4 alkyl group or a C 5 -C 10 aryl group; R 9 is a substituted or unsubstituted C 1 -C 4 alkyl group;
    通式I-b化合物中，In the compound of formula I-b,
    Rm2、Rm3和Rm4独立地为氢、羟基、取代或未取代的C1-C4的烷氧基、C2-C6的杂环烷基、硝基、
    Figure PCTCN2016088089-appb-100152
    其中R6为C1-C4的烷基、C3-C6的环烷基或者
    Figure PCTCN2016088089-appb-100153
    Ra1和Ra2独立地为氢或者取代或未取代的C1-C4的烷基；R7和R8独立地为氢、C1-C4的烷基、
    Figure PCTCN2016088089-appb-100154
    Ra3为C1-C4的烷基或者C3-C6的环烷基；Ra4为取代或未取代的C1-C4的烷基或者C3-C6的环烷基；R9为取代或未取代的C1-C4的烷基；    R m2 , R m3 and R m4 are independently hydrogen, hydroxy, substituted or unsubstituted C 1 -C 4 alkoxy, C 2 -C 6 heterocycloalkyl, nitro,
    Figure PCTCN2016088089-appb-100152
    Wherein R 6 is a C 1 -C 4 alkyl group, a C 3 -C 6 cycloalkyl group or
    Figure PCTCN2016088089-appb-100153
    R a1 and R a2 are independently hydrogen or a substituted or unsubstituted C 1 -C 4 alkyl group; R 7 and R 8 are independently hydrogen, C 1 -C 4 alkyl,
    Figure PCTCN2016088089-appb-100154
    R a3 is a C 1 -C 4 alkyl group or a C 3 -C 6 cycloalkyl group; R a4 is a substituted or unsubstituted C 1 -C 4 alkyl group or a C 3 -C 6 cycloalkyl group; 9 is a substituted or unsubstituted C 1 -C 4 alkyl group;
    R5为氢或取代的C1-C4的烷基；R5中，所述的取代的C1-C4的烷基中所述的取代是指被一个或多个取代或未取代的C2-C6的杂芳基所取代，所述的取代的C2-C6的杂芳基中所述的取代是指被一个或多个氰基所取代；R 5 is hydrogen or a substituted C 1 -C 4 alkyl group; in R 5 , the substitution in the substituted C 1 -C 4 alkyl group means one or more substituted or unsubstituted heteroaryl C 2 -C 6 substituted aryl, the substituted heteroaryl C 2 -C 6 aryl group is meant that the substituent is substituted with one or more cyano;
    Rp4为氢或卤素；R p4 is hydrogen or halogen;
    Rt1为取代或未取代的C1-C4的烷基或者
    Figure PCTCN2016088089-appb-100155
    R21为取代或未取代的C1-C4的烷基或者
    Figure PCTCN2016088089-appb-100156
    Ra11和Ra12独立地为C1-C4的烷基；当R21为取代的C1-C4的烷基时，所述的取代是指被一个或多个氰基所取代；Rm2、Rm3和Rm4不同时为氢；     R t1 is a substituted or unsubstituted C 1 -C 4 alkyl group or
    Figure PCTCN2016088089-appb-100155
    R 21 is a substituted or unsubstituted C 1 -C 4 alkyl group or
    Figure PCTCN2016088089-appb-100156
    R a11 and R a12 are independently a C 1 -C 4 alkyl group; when R 21 is a substituted C 1 -C 4 alkyl group, the substitution means substitution by one or more cyano groups; M2 , R m3 and R m4 are not hydrogen at the same time;
    通式I-c化合物中，In the compound of formula I-c,
    Rt3为C1-C4的烷基；R t3 is a C 1 -C 4 alkyl group;
    Rt2为取代的C1-C4的烷基或O，Rt2中，所述的取代的C1-C4的烷基中所述的取代为被一个或多个卤素所取代；R t2 is a substituted C 1 -C 4 alkyl group or O, and in R t2 , the substitution described in the substituted C 1 -C 4 alkyl group is substituted by one or more halogens;
    Rm5为C1-C4的烷基；R m5 is a C 1 -C 4 alkyl group;
    通式I-d化合物中，In the compound of formula I-d,
    Rm6为取代的C1-C4的烷基、取代或未取代的C1-C4的烷氧基、C2-C6的杂环烷基、硝基、
    Figure PCTCN2016088089-appb-100157
    其中R6为C1-C4的烷基、C3-C6的环烷基或者
    Figure PCTCN2016088089-appb-100158
    Ra1和Ra2独立地为氢或者取代或未取代的C1-C4的烷基；R7和R8独立地为氢或
    Figure PCTCN2016088089-appb-100159
    Ra4为取代或未取代的C1-C4的烷基；R9为取代或未取代的C1-C4的烷基；    R m6 is a substituted C 1 -C 4 alkyl group, a substituted or unsubstituted C 1 -C 4 alkoxy group, a C 2 -C 6 heterocycloalkyl group, a nitro group,
    Figure PCTCN2016088089-appb-100157
    Wherein R 6 is a C 1 -C 4 alkyl group, a C 3 -C 6 cycloalkyl group or
    Figure PCTCN2016088089-appb-100158
    R a1 and R a2 are independently hydrogen or a substituted or unsubstituted C 1 -C 4 alkyl group; R 7 and R 8 are independently hydrogen or
    Figure PCTCN2016088089-appb-100159
    R a4 is a substituted or unsubstituted C 1 -C 4 alkyl group; R 9 is a substituted or unsubstituted C 1 -C 4 alkyl group;
    Rp5为氢、硝基或者取代的C1-C4的烷基；R p5 is hydrogen, nitro or substituted C 1 -C 4 alkyl;
    Rt4为取代或未取代的C1-C4的烷基或者
    Figure PCTCN2016088089-appb-100160
    R21为取代或未取代的C1-C4的烷基；当R21为取代的C1-C4的烷基时，所述的取代是指被一个或多个氰基所取代；    R t4 is a substituted or unsubstituted C 1 -C 4 alkyl group or
    Figure PCTCN2016088089-appb-100160
    R 21 is a substituted or unsubstituted C 1 -C 4 alkyl group; when R 21 is a substituted C 1 -C 4 alkyl group, the substitution means substitution by one or more cyano groups;
    通式化合物I-e中，Rm7为
    Figure PCTCN2016088089-appb-100161
    其中，R6为
    Figure PCTCN2016088089-appb-100162
    R9为取代的C1-C4的烷基；    In the general formula Ie, R m7 is
    Figure PCTCN2016088089-appb-100161
    Where R 6 is
    Figure PCTCN2016088089-appb-100162
    R 9 is a substituted C 1 -C 4 alkyl group;
    通式化合物I-f中，Rm8为C1-C4的烷氧基；In the compound of the formula If, R m8 is a C 1 -C 4 alkoxy group;
    通式化合物I-g或I-h化合物中，In the compound of the formula I-g or I-h,
    Rn1和Rn2独立地为氢、取代或未取代的C1-C4的烷基、取代或未取代的C2-C6的杂环烷基或者
    Figure PCTCN2016088089-appb-100163
    R10为C1-C4的烷基；    R n1 and R n2 are independently hydrogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 2 -C 6 heterocycloalkyl or
    Figure PCTCN2016088089-appb-100163
    R 10 is a C 1 -C 4 alkyl group;
    Rt5和Rt6独立地为取代或未取代的C1-C4的烷基或者
    Figure PCTCN2016088089-appb-100164
    R21为C1-C4的烷基；    R t5 and R t6 are independently a substituted or unsubstituted C 1 -C 4 alkyl group or
    Figure PCTCN2016088089-appb-100164
    R 21 is a C 1 -C 4 alkyl group;
    化合物I-i中，Rt7为C1-C4的烷基；Rn3为C1-C4的烷氧基；In compound Ii, R t7 is C 1 -C 4 alkyl; R n3 is C 1 -C 4 alkoxy;
    化合物I-j中，Rm9为C1-C4的烷氧基；In compound Ij, R m9 is a C 1 -C 4 alkoxy group;
    化合物I-k中，Rt8和Rt9独立地为氢、羟基或者C2-C6的杂环烷基；Rm10为C1-C4的烷氧基； In compound Ik, R t8 and R t9 are independently hydrogen, hydroxy or C 2 -C 6 heterocycloalkyl; R m10 is C 1 -C 4 alkoxy;
    上述各通式化合物中，Among the above compounds of the general formula,
    Rp1、Rp2、Rp3或Rp5中，所述的取代的C1-C4的烷基中所述的取代是指被下列取代基中的一个或多个所取代：取代或未取代的C2-C6的杂环烷基或者
    Figure PCTCN2016088089-appb-100165
    R16和R17独立地为C1-C4的烷基；所述的取代的C2-C6的杂环烷基中所述的取代是指被下列取代基中的一个或多个所取代：C1-C4的烷基或者
    Figure PCTCN2016088089-appb-100166
    Ra11为C1-C4的烷基；    In R p1 , R p2 , R p3 or R p5 , the substitution in the substituted C 1 -C 4 alkyl group means substitution by one or more of the following substituents: substituted or unsubstituted C 2 -C 6 heterocycloalkyl or
    Figure PCTCN2016088089-appb-100165
    R 16 and R 17 are independently C 1 -C 4 alkyl; the substitution as described in the substituted C 2 -C 6 heterocycloalkyl means one or more of the following substituents Substitution: C 1 -C 4 alkyl or
    Figure PCTCN2016088089-appb-100166
    R a11 is a C 1 -C 4 alkyl group;
    Rp1、Rp2和Rp3中，所述的取代的C1-C4的烷氧基中所述的取代是指被下列取代基中的一个或多个所取代：C2-C6的杂环烷基、C1-C4的烷氧基、
    Figure PCTCN2016088089-appb-100167
    R18为C2-C6的杂环烷基；R19和R20独立地为C1-C4的烷基；    In R p1 , R p2 and R p3 , the substitution in the substituted C 1 -C 4 alkoxy group means substitution by one or more of the following substituents: C 2 -C 6 Heterocycloalkyl, C 1 -C 4 alkoxy,
    Figure PCTCN2016088089-appb-100167
    R 18 is C 2 -C 6 heterocycloalkyl; R 19 and R 20 are independently C 1 -C 4 alkyl;
    Rm1、Rm2、Rm3或Rm4中，所述的取代的C1-C4的烷氧基中所述的取代是指被下列取代基中的一个或多个所取代：卤素、氰基、取代或未取代的C2-C6的杂芳基、取代或未取代的C5-C10的芳基或者C2-C6的杂环烷基；所述的取代的C2-C6的杂芳基中所述的取代是指被一个或多个氰基所取代；所述的取代的C5-C10的芳基中所述的取代是指被一个或多个C2-C6的杂芳基所取代；In R m1 , R m2 , R m3 or R m4 , the substitution in the substituted C 1 -C 4 alkoxy group means substitution by one or more of the following substituents: halogen, cyanide a substituted, unsubstituted C 2 -C 6 heteroaryl group, a substituted or unsubstituted C 5 -C 10 aryl group or a C 2 -C 6 heterocycloalkyl group; said substituted C 2 - The substitution in the heteroaryl group of C 6 means that it is substituted by one or more cyano groups; the substitution in the substituted C 5 -C 10 aryl group means one or more C 2 Substituted with a heteroaryl group of -C 6 ;
    Rm1、Rm2、Rm3、Rm4或Rm6中，所述的取代的C2-C6的杂环烷基中所述的取代是指被一个或多个C1-C4的烷基所取代；In R m1 , R m2 , R m3 , R m4 or R m6 , the substitution in the substituted C 2 -C 6 heterocycloalkyl group means one or more C 1 -C 4 alkane Substituted by
    Ra1或Ra2中，所述的取代的C1-C4的烷基中所述的取代是指被一个或多个氰基所取代；In R a1 or R a2 , the substitution in the substituted C 1 -C 4 alkyl group means substitution by one or more cyano groups;
    Ra4中，所述的取代的C1-C4的烷基中所述的取代是指被下列取代基中的一个或多个所取代：氰基或者C2-C6的杂环烷基；In R a4 , the substitution in the substituted C 1 -C 4 alkyl group means substitution by one or more of the following substituents: cyano or C 2 -C 6 heterocycloalkyl. ;
    R9中；所述的取代的C1-C4的烷基中所述的取代是指被一个或多个氰基所取代；R 9 in the substituted C 1 -C 4 alkyl group means substituted by one or more cyano groups;
    Rt1、Rt4、Rt5或Rt6中，所述的取代的C1-C4的烷基中所述的取代是指被下列取代基中的一个或多个所取代：羟基、氰基、卤素、C3-C6的环烷基或者取代或未取代的C1-C4的烷氧基；所述的取代的C1-C4的烷氧基中所述的取代是指被一个或多个C5-C10的芳基所取代；In R t1 , R t4 , R t5 or R t6 , the substitution in the substituted C 1 -C 4 alkyl group means substitution by one or more of the following substituents: hydroxyl group, cyano group a halogen, a C 3 -C 6 cycloalkyl group or a substituted or unsubstituted C 1 -C 4 alkoxy group; said substituted C 1 -C 4 alkoxy group as described above means Substituted by one or more C 5 -C 10 aryl groups;
    Rn1或Rn2中，所述的取代的C1-C4的烷基中所述的取代是指被下列取代基中的一个或多个所取代：氰基、C3-C6的环烷基、取代或未取代的C2-C6的杂芳基或者取代或未取代的C5-C10的芳基；所述的取代的C2-C6的杂芳基或所述的取代的C5-C10的芳基中所述的取代是指被一个或多个卤素所取代；In R n1 or R n2 , the substitution in the substituted C 1 -C 4 alkyl group means substitution by one or more of the following substituents: a cyano group, a C 3 -C 6 ring An alkyl group, a substituted or unsubstituted C 2 -C 6 heteroaryl group or a substituted or unsubstituted C 5 -C 10 aryl group; said substituted C 2 -C 6 heteroaryl group or said The substitution in the substituted C 5 -C 10 aryl group means that it is substituted by one or more halogens;
    Rn1或Rn2中，所述的取代的C2-C6的杂环烷基中所述的取代是指被下列取代基中的 一个或多个所取代：取代的C1-C4的烷基、
    Figure PCTCN2016088089-appb-100168
    R12为C1-C4的烷基或C3-C6的环烷基；R13为C1-C4的烷基；所述的取代的C1-C4的烷基中所述的取代是指被下列取代基中的一个或多个所取代：氰基或
    Figure PCTCN2016088089-appb-100169
    In R n1 or R n2 , the substitution in the substituted C 2 -C 6 heterocycloalkyl group means substitution by one or more of the following substituents: substituted C 1 -C 4 alkyl,
    Figure PCTCN2016088089-appb-100168
    R 12 is a C 1 -C 4 alkyl group or a C 3 -C 6 cycloalkyl group; R 13 is a C 1 -C 4 alkyl group; said substituted C 1 -C 4 alkyl group Substitution refers to being substituted by one or more of the following substituents: cyano or
    Figure PCTCN2016088089-appb-100169
  10. 如权利要求9所述的通式I所示的喹唑啉类化合物，其药学上可接受的盐、溶剂化物、代谢产物、代谢前体或药物前体，其特征在于，A quinazoline compound of the formula I according to claim 9, which is a pharmaceutically acceptable salt, solvate, metabolite, metabolic precursor or prodrug thereof, characterized in that
    通式I-a化合物中，当Rp1、Rp2和Rp3为C1-C4的烷氧基时，Rm1为C1-C4的烷氧基或
    Figure PCTCN2016088089-appb-100170
    R6为C1-C4的烷基；和/或，当Rp2和Rp3为氢，Rp1为
    Figure PCTCN2016088089-appb-100171
    R15为C1-C4的烷基时；Rm1为C1-C4的烷基；和/或，当Rp1和Rp3为氢，Rp2为
    Figure PCTCN2016088089-appb-100172
    R15为
    Figure PCTCN2016088089-appb-100173
    时；Rm1为
    Figure PCTCN2016088089-appb-100174
    取代的C1-C4的烷氧基或者取代或未取代的C2-C6的杂环烷基；其中，R6为C1-C4的烷基；和/或，当Rp2和Rp3为氢，Rp1为取代的C1-C4的烷基，所述的取代的C1-C4的烷基中所述的取代为被取代的C2-C6的杂环烷基所取代，所述的取代的C2-C6的杂环烷基中所述的取代被C1-C4的烷基所取代时；Rm1为
    Figure PCTCN2016088089-appb-100175
    R6为
    Figure PCTCN2016088089-appb-100176
    和/或，当Rp1和Rp3为氢，Rp2为取代的C1-C4的烷基，所述的取代的C1-C4的烷基中的取代基为取代的C2-C6的杂环烷基，所述的取代的C2-C6的杂环烷基中所述的取代被C1-C4的烷基所取代时；Rm1为C1-C4的烷氧基；和/或，当Rp2和Rp3为氢，Rp1为取代的C1-C4的烷基，所述的取代的C1-C4的烷基中的取代基为取代的C2-C6的杂环烷基，所述的取代的C2-C6的杂环烷基中所述的取代被
    Figure PCTCN2016088089-appb-100177
    所取代时，Rm1为
    Figure PCTCN2016088089-appb-100178
    其中R6为
    Figure PCTCN2016088089-appb-100179
    和/或，当Rp2和Rp3为氢，Rp1为取代的C1-C4的烷基，所述的取代的C1-C4的烷基中所述的取代为被C2-C6的杂环烷基所取代时；Rm1为
    Figure PCTCN2016088089-appb-100180
    其中R6为
    Figure PCTCN2016088089-appb-100181
    R9为取代的C1-C4的烷基；和/或，当Rp1和Rp3为氢，Rp2为取代的C1-C4的烷氧基时，Rm1为C1-C4的烷氧基、
    Figure PCTCN2016088089-appb-100182
    或者取代或未取代的C2-C6的杂环烷基，其中R6为C1-C4的烷基；和/或，当Rp2和Rp3为氢，Rp1为取代的C1-C4的烷氧基时，Rm1为C1-C4的烷氧基；    In the compound of the formula Ia, when R p1 , R p2 and R p3 are C 1 -C 4 alkoxy groups, R m1 is a C 1 -C 4 alkoxy group or
    Figure PCTCN2016088089-appb-100170
    R 6 is a C 1 -C 4 alkyl group; and/or, when R p2 and R p3 are hydrogen, R p1 is
    Figure PCTCN2016088089-appb-100171
    When R 15 is a C 1 -C 4 alkyl group; R m1 is a C 1 -C 4 alkyl group; and/or, when R p1 and R p3 are hydrogen, R p2 is
    Figure PCTCN2016088089-appb-100172
    R 15 is
    Figure PCTCN2016088089-appb-100173
    Time; R m1 is
    Figure PCTCN2016088089-appb-100174
    a substituted C 1 -C 4 alkoxy group or a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group; wherein R 6 is a C 1 -C 4 alkyl group; and/or, when R p2 and R p3 is hydrogen, R p1 is a substituted C 1 -C 4 alkyl group, and the substitution in the substituted C 1 -C 4 alkyl group is a substituted C 2 -C 6 heterocycloalkane Substituted, when the substitution in the substituted C 2 -C 6 heterocycloalkyl group is substituted by a C 1 -C 4 alkyl group; R m1 is
    Figure PCTCN2016088089-appb-100175
    R 6 is
    Figure PCTCN2016088089-appb-100176
    And/or, when R p1 and R p3 are hydrogen, R p2 is a substituted C 1 -C 4 alkyl group, and the substituent in the substituted C 1 -C 4 alkyl group is a substituted C 2 - a heterocycloalkyl group of C 6 wherein the substitution in the substituted C 2 -C 6 heterocycloalkyl group is substituted by a C 1 -C 4 alkyl group; R m1 is a C 1 -C 4 group Alkoxy; and/or, when R p2 and R p3 are hydrogen, R p1 is a substituted C 1 -C 4 alkyl group, and the substituent in the substituted C 1 -C 4 alkyl group is substituted a C 2 -C 6 heterocycloalkyl group, the substitution described in the substituted C 2 -C 6 heterocycloalkyl group
    Figure PCTCN2016088089-appb-100177
    When substituted, R m1 is
    Figure PCTCN2016088089-appb-100178
    Where R 6 is
    Figure PCTCN2016088089-appb-100179
    And/or, when R p2 and R p3 are hydrogen, R p1 is a substituted C 1 -C 4 alkyl group, and the substitution in the substituted C 1 -C 4 alkyl group is C 2 - When C 6 heterocycloalkyl is substituted; R m1 is
    Figure PCTCN2016088089-appb-100180
    Where R 6 is
    Figure PCTCN2016088089-appb-100181
    R 9 is a substituted C 1 -C 4 alkyl group; and/or, when R p1 and R p3 are hydrogen and R p2 is a substituted C 1 -C 4 alkoxy group, R m1 is C 1 -C 4 alkoxy groups,
    Figure PCTCN2016088089-appb-100182
    Or a substituted or unsubstituted C 2 -C 6 heterocycloalkyl group, wherein R 6 is a C 1 -C 4 alkyl group; and/or, when R p2 and R p3 are hydrogen, R p1 is a substituted C 1 When alkoxy is -C 4 , R m1 is a C 1 -C 4 alkoxy group;
    和/或，and / or,
    通式I-b化合物中，当R5为氢，Rp4为氢，Rt1为取代或未取代的C1-C4的烷基；Rm3和Rm4为氢时，Rm2为取代或未取代的C1-C4的烷氧基、
    Figure PCTCN2016088089-appb-100183
    硝基、
    Figure PCTCN2016088089-appb-100184
    或者
    Figure PCTCN2016088089-appb-100185
    其中R6为C1-C4的烷基或者
    Figure PCTCN2016088089-appb-100186
    R7和R8独立地为氢、C1-C4的烷基、
    Figure PCTCN2016088089-appb-100187
    Ra3为C1-C4的烷基或者C3-C6的环烷基；Ra4为取代或未取代的C1-C4的烷基或者C3-C6的环烷基；R9为取代或未取代的C1-C4的烷基；和/或，当R5为氢，Rp4为氢，Rt1为取代或未取代的C1-C4的烷基；Rm3和Rm4为一个为氢，另一个为C1-C4的烷基或者卤素时，所述的卤素为氟；Rm2为C1-C4的烷氧基或者取代的C1-C4的烷基；和/或，当R5为氢，Rp4为卤素，Rt1为取代或未取代的C1-C4的烷基；Rm3和Rm4为氢时，Rm2为C1-C4的烷氧基；和/或，当R5为取代的C1-C4的烷基，Rp4为氢，Rt1为C1-C4的烷基；Rm3和Rm4为氢时，Rm2为羟基；和/或，当R5为氢，Rp4为氢，Rt1为取代或未取代的C1-C4的烷基；Rm2和Rm4为氢时，Rm3为C1-C4的烷氧基或者C2-C6的杂环烷基；和/或，当R5为氢，Rp4为氢，Rt1为
    Figure PCTCN2016088089-appb-100188
    R21为C1-C4的烷基，Rm3和Rm4为氢时，Rm2为
    Figure PCTCN2016088089-appb-100189
    其中R6为C1-C4的烷基或者
    Figure PCTCN2016088089-appb-100190
    Ra1和Ra2独立地为氢或者取代或未取代的C1-C4的烷基；R7和R8独立地为氢、C1-C4的烷基、
    Figure PCTCN2016088089-appb-100191
    Figure PCTCN2016088089-appb-100192
    Ra3为C1-C4的烷基；Ra4为取代或未取代的C1-C4的烷基，Ra4中，所述的取代 的C1-C4的烷基中所述的取代是指被一个或多个氰基所取代；R9为取代的C1-C4的烷基；和/或，当R5为氢，Rp4为氢，Rt1为
    Figure PCTCN2016088089-appb-100193
    R21为取代的C1-C4的烷基或者
    Figure PCTCN2016088089-appb-100194
    Rm3和Rm4为氢时，Rm2为C1-C4的烷氧基；    In the compound of the formula Ib, when R 5 is hydrogen, R p4 is hydrogen, R t1 is a substituted or unsubstituted C 1 -C 4 alkyl group; when R m3 and R m4 are hydrogen, R m2 is substituted or unsubstituted C 1 -C 4 alkoxy group,
    Figure PCTCN2016088089-appb-100183
    Nitro,
    Figure PCTCN2016088089-appb-100184
    or
    Figure PCTCN2016088089-appb-100185
    Wherein R 6 is a C 1 -C 4 alkyl group or
    Figure PCTCN2016088089-appb-100186
    R 7 and R 8 are independently hydrogen, C 1 -C 4 alkyl,
    Figure PCTCN2016088089-appb-100187
    R a3 is a C 1 -C 4 alkyl group or a C 3 -C 6 cycloalkyl group; R a4 is a substituted or unsubstituted C 1 -C 4 alkyl group or a C 3 -C 6 cycloalkyl group; 9 is a substituted or unsubstituted C 1 -C 4 alkyl; and / or, when R 5 is hydrogen, R p4 is hydrogen, R t1 is a substituted or unsubstituted C 1 -C 4 alkyl group of; R m3 And when R m4 is one hydrogen and the other C 1 -C 4 alkyl or halogen, the halogen is fluorine; R m2 is a C 1 -C 4 alkoxy group or a substituted C 1 -C 4 And / or, when R 5 is hydrogen, R p4 is halogen, R t1 is a substituted or unsubstituted C 1 -C 4 alkyl group; when R m3 and R m4 are hydrogen, R m2 is C 1 a C 4 alkoxy group; and/or, when R 5 is a substituted C 1 -C 4 alkyl group, R p4 is hydrogen, R t1 is a C 1 -C 4 alkyl group; R m3 and R m4 are In the case of hydrogen, R m2 is a hydroxyl group; and/or, when R 5 is hydrogen, R p4 is hydrogen, R t1 is a substituted or unsubstituted C 1 -C 4 alkyl group; when R m2 and R m4 are hydrogen, R M3 is a C 1 -C 4 alkoxy group or a C 2 -C 6 heterocycloalkyl group; and/or, when R 5 is hydrogen, R p4 is hydrogen, and R t1 is
    Figure PCTCN2016088089-appb-100188
    R 21 is a C 1 -C 4 alkyl group, and when R m3 and R m4 are hydrogen, R m2 is
    Figure PCTCN2016088089-appb-100189
    Wherein R 6 is a C 1 -C 4 alkyl group or
    Figure PCTCN2016088089-appb-100190
    R a1 and R a2 are independently hydrogen or a substituted or unsubstituted C 1 -C 4 alkyl group; R 7 and R 8 are independently hydrogen, C 1 -C 4 alkyl,
    Figure PCTCN2016088089-appb-100191
    Figure PCTCN2016088089-appb-100192
    R a3 is a C 1 -C 4 alkyl group; R a4 is a substituted or unsubstituted C 1 -C 4 alkyl group, and R a4 is as defined in the substituted C 1 -C 4 alkyl group; Substituted refers to being substituted by one or more cyano groups; R 9 is a substituted C 1 -C 4 alkyl group; and/or, when R 5 is hydrogen, R p4 is hydrogen, and R t1 is
    Figure PCTCN2016088089-appb-100193
    R 21 is a substituted C 1 -C 4 alkyl group or
    Figure PCTCN2016088089-appb-100194
    When R m3 and R m4 are hydrogen, R m2 is a C 1 -C 4 alkoxy group;
    和/或，and / or,
    通式I-d化合物中，当Rp5为氢，Rt4为取代或未取代的C1-C4的烷基；Rm6为取代或未取代的C1-C4的烷氧基、
    Figure PCTCN2016088089-appb-100195
    其中R6为C1-C4的烷基；R7和R8独立地为氢或
    Figure PCTCN2016088089-appb-100196
    Ra4为取代或未取代的C1-C4的烷基；R9为取代或未取代的C1-C4的烷基；和/或，当Rp5为硝基或者取代的C1-C4的烷基，Rt4为取代或未取代的C1-C4的烷基；Rm6为C1-C4的烷氧基；和/或，当Rp5为氢，Rt4为
    Figure PCTCN2016088089-appb-100197
    R21为取代或未取代的C1-C4的烷基时，Rm6为取代C1-C4的烷基、C1-C4的烷氧基、C2-C6的杂环烷基、
    Figure PCTCN2016088089-appb-100198
    Figure PCTCN2016088089-appb-100199
    R7和R8独立地为氢或
    Figure PCTCN2016088089-appb-100200
    Ra4为取代或未取代的C1-C4的烷基；R9为取代的C1-C4的烷基。    In the compound of the formula Id, when R p5 is hydrogen, R t4 is a substituted or unsubstituted C 1 -C 4 alkyl group; R m6 is a substituted or unsubstituted C 1 -C 4 alkoxy group,
    Figure PCTCN2016088089-appb-100195
    Wherein R 6 is a C 1 -C 4 alkyl group; R 7 and R 8 are independently hydrogen or
    Figure PCTCN2016088089-appb-100196
    R a4 is a substituted or unsubstituted C 1 -C 4 alkyl group; R 9 is a substituted or unsubstituted C 1 -C 4 alkyl group; and/or, when R p5 is a nitro group or a substituted C 1 - An alkyl group of C 4 , R t4 is a substituted or unsubstituted C 1 -C 4 alkyl group; R m6 is a C 1 -C 4 alkoxy group; and/or, when R p5 is hydrogen, R t4 is
    Figure PCTCN2016088089-appb-100197
    When R 21 is a substituted or unsubstituted C 1 -C 4 alkyl group, R m6 is a C 1 -C 4 -substituted alkyl group, a C 1 -C 4 alkoxy group or a C 2 -C 6 heterocycloalkane. base,
    Figure PCTCN2016088089-appb-100198
    Figure PCTCN2016088089-appb-100199
    R 7 and R 8 are independently hydrogen or
    Figure PCTCN2016088089-appb-100200
    R a4 is a substituted or unsubstituted C 1 -C 4 alkyl group; R 9 is a substituted C 1 -C 4 alkyl group.
  11. 如权利要求1-10中至少一项所述的通式I所示的喹唑啉类化合物，其药学上可接受的盐、溶剂化物、代谢产物、代谢前体或药物前体，其特征在于，所述的通式I所示的喹唑啉类化合物为如下任一化合物：A quinazoline compound of the formula I according to at least one of claims 1 to 10, which is a pharmaceutically acceptable salt, solvate, metabolite, metabolic precursor or prodrug thereof, characterized in that The quinazoline compound represented by the above formula I is any one of the following compounds:
    5-(4-甲氧基苯基)-N-(环丙甲酰胺)喹唑啉-2-胺；5-(4-methoxyphenyl)-N-(cyclopropanecarboxamide) quinazolin-2-amine;
    5-(4-甲磺酰基苯基)-N-(环丙甲酰胺)喹唑啉-2-胺；5-(4-methanesulfonylphenyl)-N-(cyclopropanecarboxamide) quinazolin-2-amine;
    5-(4-吗啡啉基苯基)-N-(环丙甲酰胺)喹唑啉-2-胺；5-(4-morpholinephenyl)-N-(cyclopropanecarboxamide) quinazolin-2-amine;
    5-(4-(甲氧基)苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺；5-(4-(methoxy)phenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    5-(4-(甲磺酰基)苯基)-N-(3-(4-甲基哌嗪)苯基)喹唑啉-2-胺；5-(4-(methylsulfonyl)phenyl)-N-(3-(4-methylpiperazine)phenyl)quinazolin-2-amine;
    5-(4-吗啡啉基苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺；5-(4-morphinolinylphenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    5-(4-甲磺酰基苯基)-喹唑啉-2-胺；5-(4-methanesulfonylphenyl)-quinazolin-2-amine;
    5-(4-甲氧基苯基)-喹唑啉-2-胺； 5-(4-methoxyphenyl)-quinazolin-2-amine;
    7-(4-(甲氧基)苯基)-N-(环丙甲酰基)喹唑啉-2-胺；7-(4-(Methoxy)phenyl)-N-(cyclopropanoyl)quinazolin-2-amine;
    7-(4-吗啡啉基苯基)-N-(环丙甲酰胺)喹唑啉-2-胺；7-(4-morpholinephenyl)-N-(cyclopropanecarboxamide) quinazolin-2-amine;
    7-(4-甲磺酰基苯基)-N-(环丙甲酰胺)喹唑啉-2-胺；7-(4-Methanesulfonylphenyl)-N-(cyclopropanecarboxamide) quinazolin-2-amine;
    7-(4-甲氧基苯基)-N-(3,4,5-三甲氧基苯基)喹唑啉-2-胺；7-(4-Methoxyphenyl)-N-(3,4,5-trimethoxyphenyl)quinazolin-2-amine;
    7-(4-甲磺酰基苯基)-N-(3,4,5-三甲氧基苯基)喹唑啉-2-胺；7-(4-Methanesulfonylphenyl)-N-(3,4,5-trimethoxyphenyl)quinazolin-2-amine;
    7-(4-甲氧基苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺；7-(4-Methoxyphenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    7-(4-吗啡啉基苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺；7-(4-morphinolinylphenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    7-(4-(甲磺酰基)苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺；7-(4-(Methanesulfonyl)phenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    7-吗啡啉-N-(3-(4-甲基哌嗪)苯基)喹唑啉-2-胺；7-morpholine-N-(3-(4-methylpiperazine)phenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(3,4,5-三甲氧基苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(3,4,5-trimethoxyphenyl)quinazolin-2-amine;
    8-(4-(甲磺酰基)苯基)-N-(3,4,5,-三甲氧基苯基)喹唑啉-2-胺；8-(4-(Methanesulfonyl)phenyl)-N-(3,4,5,-trimethoxyphenyl)quinazolin-2-amine;
    8-(4-(苄氧基)苯基)-N-(3,4,5-三甲氧基苯基)喹唑啉-2-胺；8-(4-(Benzyloxy)phenyl)-N-(3,4,5-trimethoxyphenyl)quinazolin-2-amine;
    8-(4-吗啡啉苯基)-N-(3,4,5-三甲氧基苯基)喹唑啉-2-胺；8-(4-morpholinephenyl)-N-(3,4,5-trimethoxyphenyl)quinazolin-2-amine;
    8-(4-三氟甲基苯氧基)-N-(3,4,5-三甲氧基苯基)喹唑啉-2-胺；8-(4-Trifluoromethylphenoxy)-N-(3,4,5-trimethoxyphenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    N-(3-(4-甲基哌嗪-1-基)苯基)-8-(4-(甲磺酰基)苯基)喹唑啉-2-胺；N-(3-(4-Methylpiperazin-1-yl)phenyl)-8-(4-(methylsulfonyl)phenyl)quinazolin-2-amine;
    8-(3-氟-4-(吗啉甲基)苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(3-Fluoro-4-(morpholinyl)phenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    N-(3-(4-甲基哌嗪-1-基)苯基)-8-(6-吗啉吡啶-3-基)-喹唑啉-2-胺；N-(3-(4-methylpiperazin-1-yl)phenyl)-8-(6-morpholinpyridin-3-yl)-quinazolin-2-amine;
    N-甲基-4-(2-((3-(4-甲基哌嗪-1-基)苯基)氨基)喹唑啉-8-基)苯磺酰胺；N-methyl-4-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)benzenesulfonamide;
    N-(3-(4-甲基哌嗪-1-基)苯基)-8-(4-(三氟甲氧基)苯基)喹唑啉-2-胺；N-(3-(4-methylpiperazin-1-yl)phenyl)-8-(4-(trifluoromethoxy)phenyl)quinazolin-2-amine;
    8-(4-(苄氧基)苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(4-(Benzyloxy)phenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    8-(3-吗啡啉苯基)-N-(3-(4-甲基哌嗪))喹唑啉-2-胺；8-(3-morpholinephenyl)-N-(3-(4-methylpiperazine))quinazolin-2-amine;
    8-(6-甲氧基吡啶-3-基)苯基)-N-(3-(甲基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(6-Methoxypyridin-3-yl)phenyl)-N-(3-(methylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    8-(3-氟-4-甲氧苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(3-Fluoro-4-methoxyphenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    8-(2-氟-4-甲氧苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(2-Fluoro-4-methoxyphenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    8-(4-甲氧基-3,5-二甲基苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(4-methoxy-3,5-dimethylphenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    8-(3-氯-4-甲氧苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(3-Chloro-4-methoxyphenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    8-(4-甲氧基-3-甲基苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(4-methoxy-3-methylphenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    8-(4-(二乙基氨基)苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(4-(Diethylamino)phenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    8-(3-甲氧基苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(3-methoxyphenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    N-(3-(4-甲基哌嗪-1-基)苯基)-8-(3-(甲磺酰基)苯基)喹唑啉-2-胺；N-(3-(4-methylpiperazin-1-yl)phenyl)-8-(3-(methylsulfonyl)phenyl)quinazolin-2-amine;
    N-(3-(4-甲基哌嗪-1-基)苯基)-8-(4-硝基苯基)喹唑啉-2-胺；N-(3-(4-methylpiperazin-1-yl)phenyl)-8-(4-nitrophenyl)quinazolin-2-amine;
    8-(4-氨基苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(4-Aminophenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    8-(4-(甲氨基)苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺； 8-(4-(methylamino)phenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    8-(4-正丙基苯胺基)-N-(3-(1-甲基哌嗪-4-基)苯基)喹唑啉-2-胺；8-(4-n-propylanilino)-N-(3-(1-methylpiperazin-4-yl)phenyl)quinazolin-2-amine;
    8-(4-戊酰基苯胺基)-N-(3-(1-甲基哌嗪-4-基)苯基)喹唑啉-2-胺；8-(4-pentanoylanilino)-N-(3-(1-methylpiperazin-4-yl)phenyl)quinazolin-2-amine;
    8-(4-N-(乙酰基吗啡啉)苯胺基)-N-(3-(1-甲基哌嗪-4-基)苯基)喹唑啉-2-胺；8-(4-N-(acetylmorpholine)anilino)-N-(3-(1-methylpiperazin-4-yl)phenyl)quinazolin-2-amine;
    8-(4-吗啡啉苯基)-N-(3-(1-甲基哌嗪-4-基)苯基)喹唑啉-2-胺；8-(4-morpholinephenyl)-N-(3-(1-methylpiperazin-4-yl)phenyl)quinazolin-2-amine;
    8-(4-(二甲基氨基)苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(4-(Dimethylamino)phenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    N-(叔丁基)-4-(2-((3-(4-甲基哌嗪-1-基)苯基)氨基)喹唑啉-8-基)苯磺酰胺；N-(tert-butyl)-4-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)benzenesulfonamide;
    N-(4-(2-((3-(4-甲基哌嗪-1-基)苯基)氨基)喹唑啉-8-基)苯基)环丙基甲酰胺；N-(4-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)cyclopropylformamide;
    N-(2-氰乙基)-4-(2-((3-(4-甲基哌嗪-1-基)苯基)氨基)喹唑啉-8-基)苯磺酰胺；N-(2-cyanoethyl)-4-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)benzenesulfonamide;
    8-(4-乙氧苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(4-ethoxyphenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    8-(4-(2-氰基乙酰胺基)苯基)-N-(3-(4-甲基哌嗪)苯基)喹唑啉-2-胺；8-(4-(2-Cyanoacetamido)phenyl)-N-(3-(4-methylpiperazine)phenyl)quinazolin-2-amine;
    8-(4-异丙氧基苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(4-Isopropoxyphenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    N-异丁基-4-(2-((3-(4-甲基哌嗪-1-基)苯基)氨基)喹唑啉-8-基)苯磺酰胺N-isobutyl-4-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)benzenesulfonamide
    N-(4-(2-((3-(4-甲基哌嗪-1-基)苯基)氨基)喹唑啉-8-基)苯基)甲基磺酰胺；N-(4-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)methylsulfonamide;
    N,N-二甲基-4-(2-((3-(4-甲基哌嗪-1-基)苯基)氨基)喹唑啉-8-基)苯磺酰胺；N,N-Dimethyl-4-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)benzenesulfonamide;
    8-(4-N-(乙酰基)苯胺基)-N-(3-(1-甲基哌嗪-4-基)苯基)喹唑啉-2-胺；8-(4-N-(acetyl)anilino)-N-(3-(1-methylpiperazin-4-yl)phenyl)quinazolin-2-amine;
    8-(4-(环丙基磺酰胺基)苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(4-(Cyclopropylsulfonamido)phenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    8-(4-N-(氰基甲基)苯甲酰胺基)-N-(3-(1-甲基哌嗪-4-基)苯基)喹唑啉-2-胺；8-(4-N-(Cyanomethyl)benzamide)-N-(3-(1-methylpiperazin-4-yl)phenyl)quinazolin-2-amine;
    8-(4-异丁氧基苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(4-Isobutoxyphenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    N-甲基-3-(2-((3-(4-甲基哌嗪-1-基)苯基)氨基)喹唑啉-8-基)苯甲酰胺；N-methyl-3-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)benzamide;
    8-(4-(6-氰基甲基吡啶-3-基)苯氧基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(4-(6-Cyanomethylpyridin-3-yl)phenoxy)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine ;
    8-(4-((4-(1H-吡唑-1-基)苄基)氧代)苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(4-((4-H-pyrazol-1-yl)benzyl)oxy)phenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quine Oxazolin-2-amine;
    2-(4-(2-((3-(4-甲基哌嗪-1-甲基)苯基)胺基)喹唑啉-8-基)苯氧基)乙腈；2-(4-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino) quinazolin-8-yl)phenoxy)acetonitrile;
    8-(4-(甲氧基)苯基)-N-(4-三氟甲基苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(4-trifluoromethylphenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-苯基喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-phenylquinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(3-(甲氧基)苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(3-(methoxy)phenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(4-(N,N-二乙基甲酰胺)苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(4-(N,N-diethylformamide)phenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(3-甲磺酰基苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(3-methanesulfonylphenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(4-氯苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(4-chlorophenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(4-(N-甲基磺酰胺)苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(4-(N-methylsulfonamide)phenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(3-(4-吗啡啉基)苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(3-(4-morphinolinyl)phenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(3-((4-甲基哌嗪-1-基)磺酰基)苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(3-((4-methylpiperazin-1-yl)sulfonyl)phenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(4-(甲基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(4-(methylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(4-(甲氧羰基)苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(4-(methoxycarbonyl)phenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(3-((4-甲基哌嗪-1-基)甲基)苯基)喹唑啉-2-胺； 8-(4-(Methoxy)phenyl)-N-(3-((4-methylpiperazin-1-yl)methyl)phenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(4-(2-(吡咯烷基)乙氧基)苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(4-(2-(pyrrolidinyl)ethoxy)phenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(4-甲氧基苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(4-methoxyphenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(4-(吗啡啉-1-基)苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(4-(morphinolin-1-yl)phenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(4-(6-吗啡啉基吡啶-3-基)苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(4-(6-morphinolinylpyridin-3-yl)phenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(3-((吡咯烷-1-基)乙基)苯甲酰胺)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(3-((pyrrolidin-1-yl)ethyl)benzamide) quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(4-吡咯烷基苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(4-pyrrolidinylphenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(4-(甲氧基甲氧基)苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(4-(methoxymethoxy)phenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(4-((吡咯烷-1-基)乙酰基)苯氧基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(4-((pyrrolidin-1-yl)acetyl)phenoxy)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(4-(2-(二甲氨基)乙氧基)苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(4-(2-(dimethylamino)ethoxy)phenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(3-((吡咯烷-1-基)乙基)苯磺酰胺)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(3-((pyrrolidin-1-yl)ethyl)benzenesulfonamide) quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(4-(4-(吡咯烷-1-基)哌啶-1-基)苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(3-((吡咯烷基)乙氧基)苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(3-((pyrrolidinyl)ethoxy)phenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(4-((吗啡啉-1-基)乙氧基)苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(4-((morphinolin-1-yl)ethoxy)phenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(4-((吡咯烷-1-基)丙氧基)苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(4-((pyrrolidin-1-yl)propoxy)phenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(3-((吗啡啉-1-基)乙基)苯磺酰胺基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(3-((morphinolin-1-yl)ethyl)benzenesulfonamido)quinazoline-2-amine;
    8-(4-(甲氧基)苯基)-N-(3-(N-甲基磺酰胺)苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(3-(N-methylsulfonamide)phenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(3-(2-((苄氧基)甲基)吡咯烷-1-基)苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(3-(2-((benzyloxy)methyl)pyrrolidin-1-yl)phenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(3-(2-((甲氧基)甲基)吡咯烷基-1-基)苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(3-(2-((methoxy)methyl)pyrrolidin-1-yl)phenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(3-((3-羟基吡咯烷)-1-基)苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(3-((3-hydroxypyrrolidin)-1-yl)phenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(3-((3-羟基哌啶)-1-基)苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(3-((3-hydroxypiperidin)-1-yl)phenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(2-(4-甲基哌嗪-1-基)嘧啶-5-基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)quinazolin-2-amine;
    8-(4-甲磺酰基)-N-(4-(N-甲基磺酰胺)苯基)喹唑啉-2-胺；8-(4-Methanesulfonyl)-N-(4-(N-methylsulfonamide)phenyl)quinazolin-2-amine;
    8-(4-甲磺酰基)-N-(4-((2-吡咯烷-1-基)乙氧基)苯基)喹唑啉-2-胺；8-(4-Methanesulfonyl)-N-(4-((2-pyrrolidin-1-yl)ethoxy)phenyl)quinazolin-2-amine;
    8-(4-甲磺酰基苯基)-N-(4-(4-乙酰基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(4-Methanesulfonylphenyl)-N-(4-(4-acetylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    8-(4-(N-甲基磺酰胺基)苯基)-N-(3-(4-乙酰基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(4-(N-methylsulfonamido)phenyl)-N-(3-(4-acetylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    8-(4-(N-叔丁胺基磺酰胺)苯基)-N-(3-(4-乙酰基哌嗪)苯基)喹唑啉-2-胺；8-(4-(N-tert-butylaminosulfonamide)phenyl)-N-(3-(4-acetylpiperazine)phenyl)quinazolin-2-amine;
    8-(4-(N-乙基磺酰胺)苯基)-N-(3-(4-乙酰基哌嗪)苯基)喹唑啉-2-胺；8-(4-(N-ethylsulfonamide)phenyl)-N-(3-(4-acetylpiperazine)phenyl)quinazolin-2-amine;
    8-(4-(N-氰甲基磺酰胺)苯基)-N-(3-(4-乙酰基哌嗪)苯基)喹唑啉-2-胺；8-(4-(N-Cyanomethylsulfonamide)phenyl)-N-(3-(4-acetylpiperazine)phenyl)quinazolin-2-amine;
    8-(4-N-(氰基乙基)苯甲磺酰基)-N-(3-(1-乙酰基哌嗪-4-基)苯基)喹唑啉-2-胺；8-(4-N-(Cyanoethyl)benzenesulfonyl)-N-(3-(1-acetylpiperazin-4-yl)phenyl)quinazolin-2-amine;
    2-氰基-N-(4-(2-((3-(4-甲基哌嗪-1-基)苯基)氨基)喹唑啉-8-基)苯基)乙酰胺；2-cyano-N-(4-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acetamide;
    8-(4-N-(叔丁基)苯甲酰胺基)-N-(3-(1-乙酰基哌嗪-4-基)苯基)喹唑啉-2-胺；8-(4-N-(tert-butyl)benzamide)-N-(3-(1-acetylpiperazin-4-yl)phenyl)quinazolin-2-amine;
    8-(4-(N-(2-吗啡啉基乙酰胺))苯基)-N-(3-(4-乙酰氨基)苯基)喹唑啉-2-胺；8-(4-(N-(2-morphinolinylacetamide))phenyl)-N-(3-(4-acetamido)phenyl)quinazolin-2-amine;
    8-(4-N-(氰基乙基)苯甲酰胺基)-N-(3-(1-乙酰基哌嗪-4-基)苯基)喹唑啉-2-胺； 8-(4-N-(Cyanoethyl)benzamide)-N-(3-(1-acetylpiperazin-4-yl)phenyl)quinazolin-2-amine;
    8-(4-氨基苯)-N-(3-(1-乙酰基哌嗪-4-基)苯基)喹唑啉-2-胺；8-(4-Aminophenyl)-N-(3-(1-acetylpiperazin-4-yl)phenyl)quinazolin-2-amine;
    8-(4-N-乙酰胺基苯)-N-(3-(1-乙酰基哌嗪-4-基)苯基)喹唑啉-2-胺；8-(4-N-acetamidophenyl)-N-(3-(1-acetylpiperazin-4-yl)phenyl)quinazolin-2-amine;
    8-(4-正丙基苯胺基)-N-(3-(1-乙酰基哌嗪-4-基)苯基)喹唑啉-2-胺；8-(4-n-propylanilino)-N-(3-(1-acetylpiperazin-4-yl)phenyl)quinazolin-2-amine;
    8-(4-戊酰基苯胺基)-N-(3-(1-乙酰基哌嗪-4-基)苯基)喹唑啉-2-胺；8-(4-pentanoylanilino)-N-(3-(1-acetylpiperazin-4-yl)phenyl)quinazolin-2-amine;
    8-(4-N-环丙基甲酰基苯胺基)-N-(3-(1-乙酰基哌嗪-4-基)苯基)喹唑啉-2-胺；8-(4-N-cyclopropylformylanilino)-N-(3-(1-acetylpiperazin-4-yl)phenyl)quinazolin-2-amine;
    8-(4-N-甲基苯胺磺酰基)-N-(3-(1-乙酰基哌嗪-4-基)苯基)喹唑啉-2-胺；8-(4-N-methylanilinosulfonyl)-N-(3-(1-acetylpiperazin-4-yl)phenyl)quinazolin-2-amine;
    8-(1-甲基-1H-吡唑-4-基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(1-methyl-1H-pyrazol-4-yl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    2-(4-(2-((3-(4-甲基哌嗪-1-基)苯基)氨基)喹唑啉-8-基)-1H-吡唑-1-基)乙腈；2-(4-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-1H-pyrazol-1-yl)acetonitrile;
    4-(4-(2-((3-(4-甲基哌嗪-1-基)苯基)氨基)喹唑啉-8-基)-1H-吡唑-1-基)丁腈(化合物121)；4-(4-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-1H-pyrazol-1-yl)butyronitrile Compound 121);
    8-(1-(3-N环丁基磺酰胺基环丙基氰丙基)吡唑基)-N-(3-(1-甲基哌嗪-4-基)苯基)喹唑啉-2-胺；8-(1-(3-N-Cyclobutylsulfonamidocyclopropylcyanopropyl)pyrazolyl)-N-(3-(1-methylpiperazin-4-yl)phenyl)quinazoline -2-amine;
    3-(4-(2-((3-(4-甲基哌嗪-1-基)苯基)氨基)喹唑啉-8-基)-1H-吡唑-1-基)丙腈；3-(4-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-1H-pyrazol-1-yl)propanenitrile;
    N-(3-(4-甲基哌嗪-1-基)苯基)-8-(1-(吡啶-3-甲基)-1H-吡唑-4-基)喹唑啉-2-胺；N-(3-(4-Methylpiperazin-1-yl)phenyl)-8-(1-(pyridine-3-methyl)-1H-pyrazol-4-yl)quinazolin-2- amine;
    N-(3-(4-甲基哌嗪-1-基)苯基)-8-(1-丙基-1H-吡唑-4-基)喹唑啉-2-胺；N-(3-(4-methylpiperazin-1-yl)phenyl)-8-(1-propyl-1H-pyrazol-4-yl)quinazolin-2-amine;
    -(1-(环丙基甲基)-1H-吡唑-4-基)-N-(3-(4-甲基哌嗪-1-甲基)苯基)喹唑啉-2-胺；-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-N-(3-(4-methylpiperazin-1-methyl)phenyl)quinazolin-2-amine ;
    N,N-二甲基-4-(2-((3-(4-甲基哌嗪-1-基)苯基)氨基)喹唑啉-8-基)-1H-吡唑-1-甲酰胺；N,N-Dimethyl-4-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-1H-pyrazole-1- Formamide
    2-(1-(环丙基磺酰胺)-3-(4-(2-((3-(4-甲基哌嗪-1-基)苯基)氨基)喹唑啉-8-基)-1H-吡唑-1-基)氮杂环丁烷-3-基)乙酰胺；2-(1-(cyclopropylsulfonamide)-3-(4-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)) -1H-pyrazol-1-yl)azetidin-3-yl)acetamide;
    2-(1-(乙基磺酰基)-3-(4-(2-((3-(4-甲基哌嗪-1-基)苯基)氨基)喹唑啉-8-基)-1H-吡唑-1-基)氮杂环丁烷-3-基)乙酰胺；2-(1-(ethylsulfonyl)-3-(4-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-) 1H-pyrazol-1-yl)azetidin-3-yl)acetamide;
    3-(4-(2-((3-(4-甲基哌嗪-1-基)苯基)氨基)喹唑啉-8-基)-1H-吡唑-1-基)异戊腈；3-(4-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-1H-pyrazol-1-yl)isovaleronitrile ;
    8-(4-(N-叔丁胺基磺酰胺)苯基)-N-(3-(4-乙基哌嗪)苯基)喹唑啉-2-胺；8-(4-(N-tert-butylaminosulfonamide)phenyl)-N-(3-(4-ethylpiperazine)phenyl)quinazolin-2-amine;
    8-(4-(N-甲基磺酰胺)苯基)-N-(3-(4-乙基哌嗪)苯基)喹唑啉-2-胺；8-(4-(N-methylsulfonamide)phenyl)-N-(3-(4-ethylpiperazine)phenyl)quinazolin-2-amine;
    8-(4-N-(氰基乙基)苯甲酰胺基)-N-(3-(1-乙基哌嗪-4-基)苯基)喹唑啉-2-胺；8-(4-N-(Cyanoethyl)benzamide)-N-(3-(1-ethylpiperazin-4-yl)phenyl)quinazolin-2-amine;
    8-(4-N-(乙基)苯甲磺酰基)-N-(3-(1-乙基哌嗪-4-基)苯基)喹唑啉-2-胺；8-(4-N-(ethyl)phenylsulfonyl)-N-(3-(1-ethylpiperazin-4-yl)phenyl)quinazolin-2-amine;
    8-(4-N，N-二甲基苯磺酰基)-N-(3-(1-乙基哌嗪-4-基)苯基)喹唑啉-2-胺；8-(4-N,N-Dimethylbenzenesulfonyl)-N-(3-(1-ethylpiperazin-4-yl)phenyl)quinazolin-2-amine;
    8-(4-N-(叔丁基)苯甲酰胺基)-N-(3-(1-乙基哌嗪-4-基)苯基)喹唑啉-2-胺；8-(4-N-(tert-butyl)benzamide)-N-(3-(1-ethylpiperazin-4-yl)phenyl)quinazolin-2-amine;
    8-(4-N-(氰基甲基)苯甲酰胺基)-N-(3-(1-乙基哌嗪-4-基)苯基)喹唑啉-2-胺；8-(4-N-(Cyanomethyl)benzamide)-N-(3-(1-ethylpiperazin-4-yl)phenyl)quinazolin-2-amine;
    8-(2-氟-4-甲氧基苯基)-N-(3-(4-乙基哌嗪)苯基)喹唑啉-2-胺；8-(2-Fluoro-4-methoxyphenyl)-N-(3-(4-ethylpiperazine)phenyl)quinazolin-2-amine;
    8-(4-(N-甲基磺酰胺)苯基)-N-(3-吗啡啉苯基)喹唑啉-2-胺；8-(4-(N-methylsulfonamide)phenyl)-N-(3-morphinphyrinphenyl)quinazolin-2-amine;
    8-(4-(N-叔丁基磺酰胺)苯基)-N-(3-吗啡啉苯基)喹唑啉-2-胺；8-(4-(N-tert-butylsulfonamide)phenyl)-N-(3-morphinphyrinphenyl)quinazolin-2-amine;
    8-(4-(N-氰乙基磺酰胺)苯基)-N-(3-吗啡啉苯基)喹唑啉-2-胺；8-(4-(N-Cyanoethylsulfonamide)phenyl)-N-(3-morpholinephenyl)quinazolin-2-amine;
    8-(4-N-(氰基甲基)苯甲酰胺基)-N-(3-(吗啡啉-4-基)苯基)喹唑啉-2-胺；8-(4-N-(Cyanomethyl)benzamide)-N-(3-(morpholine-4-yl)phenyl)quinazolin-2-amine;
    8-(4-N-(乙基)苯磺酰基)-N-(3-(吗啡啉-4-基)苯基)喹唑啉-2-胺； 8-(4-N-(ethyl)benzenesulfonyl)-N-(3-(morphinolin-4-yl)phenyl)quinazolin-2-amine;
    8-(4-(N-甲基磺酰胺)苯基)-N-(3-(吗啡啉甲基)苯基)喹唑啉-2-胺；8-(4-(N-methylsulfonamide)phenyl)-N-(3-(morpholinemethyl)phenyl)quinazolin-2-amine;
    8-(4-(N-乙基磺酰胺)苯基)-N-(3-(吗啡啉甲基)苯基)喹唑啉-2-胺；8-(4-(N-ethylsulfonamide)phenyl)-N-(3-(morpholinemethyl)phenyl)quinazolin-2-amine;
    8-(4-(N-氰甲基磺酰胺)苯基)-N-(3-(吗啡啉甲基)苯基)喹唑啉-2-胺；8-(4-(N-Cyanomethylsulfonamide)phenyl)-N-(3-(morpholinemethyl)phenyl)quinazolin-2-amine;
    8-(4-(N-氰乙基磺酰胺)苯基)-N-(3-(吗啡啉甲基)苯基)喹唑啉-2-胺；8-(4-(N-Cyanoethylsulfonamide)phenyl)-N-(3-(morpholinemethyl)phenyl)quinazolin-2-amine;
    8-(4-N-(氰基乙基)苯磺酰基)-N-(3-(1-吗啡啉甲基)苯基)喹唑啉-2-胺；8-(4-N-(Cyanoethyl)benzenesulfonyl)-N-(3-(1-morpholinemethyl)phenyl)quinazolin-2-amine;
    8-(4-(N-叔丁基酰胺)苯基)-N-(3-(吗啡啉甲基)苯基)喹唑啉-2-胺；8-(4-(N-tert-butylamide)phenyl)-N-(3-(morpholinemethyl)phenyl)quinazolin-2-amine;
    8-(4-(N-叔丁基磺酰胺)苯基)-N-(3-(吗啡啉甲基)苯基)喹唑啉-2-胺；8-(4-(N-tert-butylsulfonamide)phenyl)-N-(3-(morpholinemethyl)phenyl)quinazolin-2-amine;
    8-(4-(N-(2-吗啡啉基乙酰胺))苯基)-N-(4-(乙基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(4-(N-(2-morphinolinylacetamide))phenyl)-N-(4-(ethylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    8-(4-(N-氰乙基酰胺)苯基)-N-(4-(4-乙基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(4-(N-Cyanoethylamide)phenyl)-N-(4-(4-ethylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    8-(4-(N-氰乙基酰胺)苯基)-N-(4-(4-乙酰基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(4-(N-Cyanoethylamide)phenyl)-N-(4-(4-acetylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    8-(4-(N-氰乙基酰胺)苯基)-N-(4-(4-乙酰基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(4-(N-Cyanoethylamide)phenyl)-N-(4-(4-acetylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    8-(4-N-(乙酰基)苯胺基)-N-(4-(1-乙酰基哌嗪-4-基)苯基)喹唑啉-2-胺；8-(4-N-(acetyl)anilino)-N-(4-(1-acetylpiperazin-4-yl)phenyl)quinazolin-2-amine;
    8-(4-N-(2-甲酰基噻吩)苯胺基)-N-(4-(1-氰乙酰基哌嗪-4-基)苯基)喹唑啉-2-胺；8-(4-N-(2-formylthiophene)anilino)-N-(4-(1-cyanoacetylpiperazin-4-yl)phenyl)quinazolin-2-amine;
    8-(4-吗啡啉苯基)-N-(4-(1-乙酰基哌嗪-4-基)苯基)喹唑啉-2-胺；8-(4-morpholinephenyl)-N-(4-(1-acetylpiperazin-4-yl)phenyl)quinazolin-2-amine;
    8-(4-((N-甲基哌嗪-1-基)甲基)苯基)-N-(4-(4-乙酰基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(4-((N-Methylpiperazin-1-yl)methyl)phenyl)-N-(4-(4-acetylpiperazin-1-yl)phenyl)quinazoline-2 -amine;
    8-(4-(2-吗啡啉乙酰基)苯胺基)-N-(4-(4-乙酰基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(4-(2-morpholine acetyl)anilino)-N-(4-(4-acetylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    8-(4-(2-氰基乙酰基)苯胺基)-N-(4-(4-(2-氰基乙酰基)哌嗪-1-基)苯基)喹唑啉-2-胺；8-(4-(2-Cyanoacetyl)anilino)-N-(4-(4-(2-cyanoacetyl)piperazin-1-yl)phenyl)quinazolin-2-amine ;
    8-(4-(N-(2-吗啡啉基乙酰胺))苯基)-N-(4-(4-(2-氰基乙酰基)哌嗪-1-基)苯基)喹唑啉-2-胺；8-(4-(N-(2-morphinolinylacetamide))phenyl)-N-(4-(4-(2-cyanoacetyl)piperazin-1-yl)phenyl)quinazole Benzin-2-amine;
    8-(4-吗啡啉苯基)-N-(4-(1-氰乙酰基哌嗪-4-基)苯基)喹唑啉-2-胺；8-(4-morpholinephenyl)-N-(4-(1-cyanoacetylpiperazin-4-yl)phenyl)quinazolin-2-amine;
    8-(4-N-(乙酰基)苯胺基)-N-(4-(1-氰乙酰基哌嗪-4-基)苯基)喹唑啉-2-胺；8-(4-N-(acetyl)anilino)-N-(4-(1-cyanoacetylpiperazin-4-yl)phenyl)quinazolin-2-amine;
    8-(4-(吗啡啉甲基)苯基)-N-(4-(1-氰基乙酰基哌嗪-4-基)苯基)喹唑啉-2-胺；8-(4-(morpholinemethyl)phenyl)-N-(4-(1-cyanoacetylpiperazin-4-yl)phenyl)quinazolin-2-amine;
    8-(4-(N-乙基磺酰胺)苯基)-N-(3-((4-乙酰基哌嗪-1-基)甲基)苯基)喹唑啉-2-胺；8-(4-(N-ethylsulfonamide)phenyl)-N-(3-((4-acetylpiperazin-1-yl)methyl)phenyl)quinazolin-2-amine;
    8-(4-N-(氰基甲基)苯甲酰胺基)-N-(4-(1-乙基哌嗪-4-基)苯基)喹唑啉-2-胺；8-(4-N-(Cyanomethyl)benzamide)-N-(4-(1-ethylpiperazin-4-yl)phenyl)quinazolin-2-amine;
    8-(4-N-(叔丁基)苯磺酰基)-N-(3-(1-乙酰基哌嗪-4-甲基)苯基)喹唑啉-2-胺；8-(4-N-(tert-butyl)benzenesulfonyl)-N-(3-(1-acetylpiperazine-4-methyl)phenyl)quinazolin-2-amine;
    8-(4-N-(氰基乙基)苯磺酰基)-N-(3-(1-乙酰基哌嗪-4-甲基)苯基)喹唑啉-2-胺；8-(4-N-(Cyanoethyl)benzenesulfonyl)-N-(3-(1-acetylpiperazine-4-methyl)phenyl)quinazolin-2-amine;
    8-(4-N-(氰基甲基)苯甲酰胺基)-N-(3-(1-乙酰基哌嗪-4-甲基)苯基)喹唑啉-2-胺；8-(4-N-(Cyanomethyl)benzamide)-N-(3-(1-acetylpiperazine-4-methyl)phenyl)quinazolin-2-amine;
    8-(4-N-(氰基乙基)苯甲酰胺基)-N-(3-(1-乙酰基哌嗪-4-甲基)苯基)喹唑啉-2-胺；8-(4-N-(Cyanoethyl)benzamide)-N-(3-(1-acetylpiperazine-4-methyl)phenyl)quinazolin-2-amine;
    8-(4-N-(叔丁基)苯甲酰胺基)-N-(3-(1-乙酰基哌嗪-4-甲基)苯基)喹唑啉-2-胺；8-(4-N-(tert-butyl)benzamide)-N-(3-(1-acetylpiperazine-4-methyl)phenyl)quinazolin-2-amine;
    8-(4-N-(乙基)苯磺酰基)-N-(3-(1-乙基哌嗪-4-甲基)苯基)喹唑啉-2-胺；8-(4-N-(ethyl)benzenesulfonyl)-N-(3-(1-ethylpiperazine-4-methyl)phenyl)quinazolin-2-amine;
    8-(4-N-(氰基甲基)苯甲酰胺基)-N-(3-(1-乙基哌嗪-4-甲基)苯基)喹唑啉-2-胺；8-(4-N-(Cyanomethyl)benzamide)-N-(3-(1-ethylpiperazine-4-methyl)phenyl)quinazolin-2-amine;
    8-(4-N-(甲基)苯磺酰基)-N-(3-(1-乙基哌嗪-4-甲基)苯基)喹唑啉-2-胺；8-(4-N-(methyl)benzenesulfonyl)-N-(3-(1-ethylpiperazine-4-methyl)phenyl)quinazolin-2-amine;
    8-(4-N-(氰基乙基)苯甲酰胺基)-N-(3-(1-乙基哌嗪-4-甲基)苯基)喹唑啉-2-胺；8-(4-N-(Cyanoethyl)benzamide)-N-(3-(1-ethylpiperazine-4-methyl)phenyl)quinazolin-2-amine;
    8-(4-N-(叔丁基)苯甲酰胺基)-N-(3-(1-乙基哌嗪-4-甲基)苯基)喹唑啉-2-胺； 8-(4-N-(tert-butyl)benzamide)-N-(3-(1-ethylpiperazine-4-methyl)phenyl)quinazolin-2-amine;
    8-(4-N-(乙酰基吗啡啉基)苯胺基)-N-(4-(1-甲基哌嗪-4-基)苯基)喹唑啉-2-胺；8-(4-N-(acetylmorpholino)anilino)-N-(4-(1-methylpiperazin-4-yl)phenyl)quinazolin-2-amine;
    8-(4-(氰甲基)苯氧基)-N-(4-(甲基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(4-(Cyanomethyl)phenoxy)-N-(4-(methylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    8-(4-N-(2-甲酰基噻吩)苯胺基)-N-(3-(1-乙酰基哌嗪-4-基)苯基)喹唑啉-2-胺；8-(4-N-(2-formylthiophene)anilino)-N-(3-(1-acetylpiperazin-4-yl)phenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(3-(4-乙基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(3-(4-ethylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(3-(4-甲磺酰基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(3-(4-methanesulfonylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(3-(4-乙酰基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(3-(4-acetylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(3-(4-异丁酰胺基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(3-(4-isobutyrylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(3-(4-氰丙酰基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(3-(4-cyanopropionylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(3-(4-(N,N-二甲基甲酰胺基)哌嗪-1-基)苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(3-(4-(N,N-dimethylformamido)piperazin-1-yl)phenyl)quinazoline-2- amine;
    8-(4-(甲氧基)苯基)-N-(3-(4-异丙基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(3-(4-isopropylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(3-(4-氰甲基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(3-(4-cyanomethylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(3-(4-哌嗪-1-乙醇基)苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(3-(4-piperazin-1-ethanolyl)phenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(3-(4-异丁基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(3-(4-isobutylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(3-(4-(环丙甲基)哌嗪-1-基)苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(3-(4-(cyclopropylmethyl)piperazin-1-yl)phenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(3-(4-丙基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(3-(4-propylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(3-(4-氰乙基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(3-(4-cyanoethylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(4-(4-乙酰基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(4-(4-acetylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(4-(氰乙酰基哌嗪)苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(4-(cyanoacetylpiperazine)phenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(4-(乙基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(4-(ethylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(4-(4-(环丙基甲基)哌嗪)苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(4-(4-(cyclopropylmethyl)piperazine)phenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(4-(异丁基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(4-(isobutylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(4-(4-丙基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(4-(4-propylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    8-(4-甲磺酰基苯基)-N-(4-(4-甲基哌嗪)苯基)喹唑啉-2-胺；8-(4-Methanesulfonylphenyl)-N-(4-(4-methylpiperazine)phenyl)quinazolin-2-amine;
    8-(4-(N-甲基磺酰胺基)苯基)-N-(4-((2-吡咯烷基)乙氧基)苯基)喹唑啉-2-胺；8-(4-(N-methylsulfonamido)phenyl)-N-(4-((2-pyrrolidinyl)ethoxy)phenyl)quinazolin-2-amine;
    8-(4-(N-甲基磺酰胺基)苯基)-N-(4-(N-甲基磺酰胺基)苯基)喹唑啉-2-胺；8-(4-(N-methylsulfonamido)phenyl)-N-(4-(N-methylsulfonamido)phenyl)quinazolin-2-amine;
    N-甲基-4-(2-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)氨基)喹唑啉-8-基)苯磺酰胺；N-methyl-4-(2-((2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)amino)quinazolin-8-yl)benzenesulfonamide;
    8-(4-((2-吡咯烷-1-基)乙氧基)苯基)-N-(4-(N-甲基磺酰胺)苯基)喹唑啉-2-胺；8-(4-((2-Pyrrolidin-1-yl)ethoxy)phenyl)-N-(4-(N-methylsulfonamide)phenyl)quinazolin-2-amine;
    8-(4-((2-吡咯烷-1-基)乙氧基)苯基)-N-(4-((2-吡咯烷-1-基)乙氧基)苯基)喹唑啉-2-胺；8-(4-((2-Pyrrolidin-1-yl)ethoxy)phenyl)-N-(4-((2-pyrrolidin-1-yl)ethoxy)phenyl)quinazoline -2-amine;
    8-(4-((2-吡咯烷-1-基)乙氧基)苯基)-N-(4-(4-甲基哌嗪)苯基)喹唑啉-2-胺)；8-(4-((2-Pyrrolidin-1-yl)ethoxy)phenyl)-N-(4-(4-methylpiperazine)phenyl)quinazolin-2-amine);
    8-(4-(甲氧基)苯基)-N-(3-(N-甲基哌嗪-1-基)-4-甲磺酰基苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(3-(N-methylpiperazin-1-yl)-4-methanesulfonylphenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(3-(N-甲基哌嗪-1-基)-4-(N-甲基磺酰胺基)苯基喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(3-(N-methylpiperazin-1-yl)-4-(N-methylsulfonamido)phenylquinazoline-2 -amine;
    8-(4-(甲氧基)苯基)-N-(3-((N.N-二甲氨基)甲基)-4-(N-甲基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(3-((NN-dimethylamino)methyl)-4-(N-methylpiperazin-1-yl)phenyl)quinazole Benzin-2-amine;
    8-(4-(甲氧基)苯基)-N-(3-(甲基哌嗪-1-基)-4-氟苯基)喹唑啉-2-胺； 8-(4-(Methoxy)phenyl)-N-(3-(methylpiperazin-1-yl)-4-fluorophenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(3-硝基-4-(甲基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(3-nitro-4-(methylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    8-(4-((4-甲基哌嗪-1-基)甲基)苯基)-N-(4-(N-甲基磺酰胺)苯基)喹唑啉-2-胺；8-(4-((4-Methylpiperazin-1-yl)methyl)phenyl)-N-(4-(N-methylsulfonamide)phenyl)quinazolin-2-amine;
    8-(4-((4-甲基哌嗪-1-基)甲基)苯基)-N-(4-(2-吡咯烷-1-基)乙氧基)苯基)喹唑啉-2-胺；8-(4-((4-Methylpiperazin-1-yl)methyl)phenyl)-N-(4-(2-pyrrolidin-1-yl)ethoxy)phenyl)quinazoline -2-amine;
    8-(4-(4-甲基哌嗪)苯基)-N-(4-((2-吡咯烷-1-基)乙氧基)苯基)喹唑啉-2-胺；8-(4-(4-Methylpiperazine)phenyl)-N-(4-((2-pyrrolidin-1-yl)ethoxy)phenyl)quinazolin-2-amine;
    8-(4-(4-甲基哌嗪)苯基)-N-(4-(N-甲基磺酰胺)苯基)喹唑啉-2-胺；8-(4-(4-Methylpiperazine)phenyl)-N-(4-(N-methylsulfonamide)phenyl)quinazolin-2-amine;
    8-(1H-吡唑-4-基)-N-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(1H-pyrazol-4-yl)-N-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    3-环戊基-3-(4-(2-((3-(4-甲基哌嗪-1-基)苯基)氨基)喹唑啉-8-基)-1H-吡唑-1-基)丙腈；3-cyclopentyl-3-(4-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-1H-pyrazole-1 -based) propionitrile;
    三丁基4-(氰基甲基)-4-(4-(2-((3-(4-甲基哌嗪-1-基)苯基)氨基)喹唑啉-8-基)-1H-吡唑-1-基)哌啶-1-叔丁氧羰基；Tributyl 4-(cyanomethyl)-4-(4-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)- 1H-pyrazol-1-yl)piperidine-1-tert-butoxycarbonyl;
    3-环丙基-3-(4-(2-((3-(4-甲基哌嗪-1-基)苯基)氨基)喹唑啉-8-基)-1H-吡唑-1-基)丙腈；3-cyclopropyl-3-(4-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-1H-pyrazole-1 -based) propionitrile;
    N-(3-(4-甲基哌嗪-1-基)苯基)-8-(1-(甲磺酸)-1H-吡唑-4-基)喹唑啉-2-胺；N-(3-(4-methylpiperazin-1-yl)phenyl)-8-(1-(methanesulfonic acid)-1H-pyrazol-4-yl)quinazolin-2-amine;
    3-(5-溴吡啶-3-基)-3-(4-(2-((3-(4-甲基哌嗪-1-基)苯基)氨基)喹唑啉-8-基)-1H-吡唑-1-基)丙腈；3-(5-bromopyridin-3-yl)-3-(4-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)quinazoline-8-yl)) -1H-pyrazol-1-yl)propionitrile;
    3-(3-氯苯基)-3-(4-(2-((3-(4-甲基哌嗪-1-基)苯基)氨基)喹唑啉-8-基)-1H-吡唑-1-基)丙腈；3-(3-Chlorophenyl)-3-(4-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-1H- Pyrazol-1-yl)propionitrile;
    8-(1-(1-环丙基氰乙基)吡唑基)-N-(3-(1-乙基哌嗪-4-基)苯基)喹唑啉-2-胺；8-(1-(1-cyclopropylcyanoethyl)pyrazolyl)-N-(3-(1-ethylpiperazin-4-yl)phenyl)quinazolin-2-amine;
    8-(1-(1-环戊基氰乙基)吡唑基)-N-(3-(1-乙基哌嗪-4-基)苯基)喹唑啉-2-胺；8-(1-(1-Cyclopentylcyanoethyl)pyrazolyl)-N-(3-(1-ethylpiperazin-4-yl)phenyl)quinazolin-2-amine;
    8-(1-(1-甲基氰乙基)吡唑基)-N-(3-(1-乙基哌嗪-4-基)苯基)喹唑啉-2-胺；8-(1-(1-methylcyanoethyl)pyrazolyl)-N-(3-(1-ethylpiperazin-4-yl)phenyl)quinazolin-2-amine;
    8-(1-(1-环戊基氰乙基)吡唑基)-N-(4-(1-甲基哌嗪-4-基)苯基)喹唑啉-2-胺；8-(1-(1-cyclopentylcyanoethyl)pyrazolyl)-N-(4-(1-methylpiperazin-4-yl)phenyl)quinazolin-2-amine;
    8-(1-(1-甲基氰丙基)吡唑基)-N-(4-(1-甲基哌嗪-4-基)苯基)喹唑啉-2-胺；8-(1-(1-methylcyanopropyl)pyrazolyl)-N-(4-(1-methylpiperazin-4-yl)phenyl)quinazolin-2-amine;
    8-(1-(3-氯苯基氰丙基)吡唑基)-N-(3-(1-乙酰基哌嗪-4-基)苯基)喹唑啉-2-胺；8-(1-(3-Chlorophenylcyanopropyl)pyrazolyl)-N-(3-(1-acetylpiperazin-4-yl)phenyl)quinazolin-2-amine;
    8-(1-(1-环丙基氰丙基)吡唑基)-N-(3-(1-乙酰基哌嗪-4-基)苯基)喹唑啉-2-胺；8-(1-(1-cyclopropylcyanopropyl)pyrazolyl)-N-(3-(1-acetylpiperazin-4-yl)phenyl)quinazolin-2-amine;
    8-(1-(1-环戊基氰丙基)吡唑基)-N-(3-(1-乙酰基哌嗪-4-基)苯基)喹唑啉-2-胺；8-(1-(1-Cyclopentylcyanopropyl)pyrazolyl)-N-(3-(1-acetylpiperazin-4-yl)phenyl)quinazolin-2-amine;
    8-(1-(1-甲基氰丙基)吡唑基)-N-(3-(1-乙酰基哌嗪-4-基)苯基)喹唑啉-2-胺；8-(1-(1-methylcyanopropyl)pyrazolyl)-N-(3-(1-acetylpiperazin-4-yl)phenyl)quinazolin-2-amine;
    8-(1-(3-N环丁基磺酰胺基环丙基氰丙基)吡唑基)-N-(3-(1-乙酰基哌嗪-4-基)苯基)喹唑啉-2-胺；8-(1-(3-N-Cyclobutylsulfonamidocyclopropylcyanopropyl)pyrazolyl)-N-(3-(1-acetylpiperazin-4-yl)phenyl)quinazoline -2-amine;
    8-(4-(甲氧基)苯基)-N-(环丙甲酰胺基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(cyclopropylamido)quinazolin-2-amine;
    8-(4-(苄氧基)苯基)-N-(环丙甲酰胺)喹唑啉-2-胺；8-(4-(Benzyloxy)phenyl)-N-(cyclopropanecarboxamide) quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(3-(4-甲基-4-乙基-哌嗪-1-基)苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(3-(4-methyl-4-ethyl-piperazin-1-yl)phenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-(3-(4-甲基-4-氧基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-(3-(4-methyl-4-oxypiperazin-1-yl)phenyl)quinazolin-2-amine;
    8-(4-(甲氧基)苯基)-N-((2-(4-甲基哌嗪-1-基)乙酰胺))喹唑啉-2-胺；8-(4-(Methoxy)phenyl)-N-((2-(4-methylpiperazin-1-yl)acetamide))quinazolin-2-amine;
    8-(4-N-(甲基)苯磺酰基)-N-(1-乙酰基吗啡啉)喹唑啉-2-胺；8-(4-N-(methyl)benzenesulfonyl)-N-(1-acetylmorpholine)quinazolin-2-amine;
    8-(4-甲氧基苯基)-N-甲基-(3-(4-甲基哌嗪-1-基)苯基)喹唑啉-2-胺；8-(4-methoxyphenyl)-N-methyl-(3-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine;
    8-(4-羟基苯基)-N-(3-(4-甲基哌嗪-1-基)苯基)-N-(6-氰基甲基吡啶-3-基)喹唑啉-2-胺； 8-(4-Hydroxyphenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-N-(6-cyanomethylpyridin-3-yl)quinazoline- 2-amine;
    N-甲基-4-(2-((3-甲磺酰基)苯基)氰基)喹唑啉-8-基)苯磺酰胺；N-methyl-4-(2-((3-methylsulfonyl)phenyl)cyano)quinazolin-8-yl)benzenesulfonamide;
    N-乙基-4-(2-((3-甲磺酰基)苯基)氰基)喹唑啉-8-基)苯磺酰胺；N-ethyl-4-(2-((3-methylsulfonyl)phenyl)cyano)quinazolin-8-yl)benzenesulfonamide;
    N-异丙基-4-(2-((3-甲磺酰基)苯基)氰基)喹唑啉-8-基)苯磺酰胺；N-isopropyl-4-(2-((3-methylsulfonyl)phenyl)cyano)quinazolin-8-yl)benzenesulfonamide;
    N-叔丁基-4-(2-((3-甲磺酰基)苯基)氰基)喹唑啉-8-基)苯磺酰胺；N-tert-butyl-4-(2-((3-methylsulfonyl)phenyl)cyano)quinazolin-8-yl)benzenesulfonamide;
    N-异丁基-4-(2-((3-甲磺酰基)苯基)氰基)喹唑啉-8-基)苯磺酰胺；N-isobutyl-4-(2-((3-methylsulfonyl)phenyl)cyano)quinazolin-8-yl)benzenesulfonamide;
    N-苯基-4-(2-((3-甲磺酰基)苯基)氰基)喹唑啉-8-基)苯磺酰胺。N-Phenyl-4-(2-((3-methylsulfonyl)phenyl)cyano)quinazolin-8-yl)benzenesulfonamide.
  12. 一种如权利要求1～11任一项中所述的通式I所示的喹唑啉类化合物的制备方法，其特征在于，其包括下列方法：A process for producing a quinazoline compound of the formula I according to any one of claims 1 to 11, which comprises the following method:
    方法一：气体保护下，溶剂中，碱的存在下，在钯催化剂的催化下，将如式II所示的化合物与如式III所示的化合物进行如下所示的Suzuki偶联反应，制得通式I所示的喹唑啉类化合物；所述的溶剂为有机溶剂或者有机溶剂与水的混合溶剂；Method 1: under the protection of a gas, in a solvent, in the presence of a base, catalyzed by a palladium catalyst, a compound of the formula II and a compound of the formula III are subjected to a Suzuki coupling reaction as shown below. a quinazoline compound of the formula I; the solvent is an organic solvent or a mixed solvent of an organic solvent and water;
    Figure PCTCN2016088089-appb-100201
    Figure PCTCN2016088089-appb-100201
    方法一中，化合物II中，X1、X2和X3独立地为卤素，R4或R5的定义均如权利要求1～11任一项所述；化合物III中，Rs1为R1、R2或R3，其中，R1、R2和R3的定义均如权利要求1～11任一项所述；Rsa1为
    Figure PCTCN2016088089-appb-100202
    通式I化合物中，R1、R2、R3、R4和R5的定义均如权利要求1～11任一项所述；    In the first method, in the compound II, X 1 , X 2 and X 3 are independently halogen, and R 4 or R 5 are as defined in any one of claims 1 to 11; in the compound III, R s1 is R 1 And R 2 or R 3 , wherein R 1 , R 2 and R 3 are as defined in any one of claims 1 to 11; R sa1 is
    Figure PCTCN2016088089-appb-100202
    In the compound of formula I, R 1 , R 2 , R 3 , R 4 and R 5 are as defined in any one of claims 1 to 11;
    方法二：气体保护下，有机溶剂中，碱和配体的存在下，在钯催化剂的催化下，将如式II-a所示的化合物与如式III-a所示的化合物进行如下所示的取代反应，制得通式I所示的喹唑啉类化合物；Method 2: Under the protection of gas, in the presence of a base and a ligand in an organic solvent, the compound represented by the formula II-a and the compound represented by the formula III-a are subjected to the catalysis of a palladium catalyst as shown below. a substitution reaction to obtain a quinazoline compound of the formula I;
    Figure PCTCN2016088089-appb-100203
    Figure PCTCN2016088089-appb-100203
    方法二中，化合物II-a中，R1、R2和R3的定义均如权利要求1～11任一项所述；化合物III-a中，X4为卤素，Rs2为R4或R5，其中，R4和R5为取代或未取代的C1-C4的烷基、取代或未取代的C5-C10的芳基或者取代的C2-C6的杂芳基；通式I化合物中，R1、R2、R3的定义均如权利要求1～11任一项所述，R4和R5的定义同权利要求1-11任一项所 述，但不为
    Figure PCTCN2016088089-appb-100204
    In the second method, in the compound II-a, R 1 , R 2 and R 3 are as defined in any one of claims 1 to 11; in the compound III-a, X 4 is a halogen, and R s2 is R 4 or R 5 , wherein R 4 and R 5 are a substituted or unsubstituted C 1 -C 4 alkyl group, a substituted or unsubstituted C 5 -C 10 aryl group or a substituted C 2 -C 6 heteroaryl group In the compound of the formula I, R 1 , R 2 and R 3 are as defined in any one of claims 1 to 11, and R 4 and R 5 are as defined in any one of claims 1 to 11, but Not for
    Figure PCTCN2016088089-appb-100204
    方法三：有机溶剂中，将如式II-a所示的化合物与如式III-b所示的化合物进行如下所示的酰卤化反应，制得通式I所示的喹唑啉类化合物；Method 3: In an organic solvent, a compound represented by the formula II-a and a compound represented by the formula III-b are subjected to an acid halide reaction as shown below to obtain a quinazoline compound represented by the formula I;
    Figure PCTCN2016088089-appb-100205
    Figure PCTCN2016088089-appb-100205
    方法三中，化合物II-a中，R1、R2和R3的定义均如权利要求1～11任一项所述；化合物III-b中，X5为卤素，R0的定义如权利要求1～11任一项所述；通式I化合物中，R1、R2和R3的定义均如权利要求1～11任一项所述，R4和R5独立地为氢或者
    Figure PCTCN2016088089-appb-100206
    其中，R0的定义如权利要求1～11任一项所述。    In the third method, in the compound II-a, R 1 , R 2 and R 3 are as defined in any one of claims 1 to 11; in the compound III-b, X 5 is a halogen, and R 0 is as defined in the right. Claims 1 to 11; wherein, in the compound of Formula I, R 1 , R 2 and R 3 are as defined in any one of claims 1 to 11, and R 4 and R 5 are independently hydrogen or
    Figure PCTCN2016088089-appb-100206
    Wherein R 0 is as defined in any one of claims 1 to 11.
  13. 一种如式II或者II-a所示的通式I所示的喹唑啉类化合物的中间体化合物：An intermediate compound of a quinazoline compound of the formula I as shown in formula II or II-a:
    Figure PCTCN2016088089-appb-100207
    Figure PCTCN2016088089-appb-100207
    化合物II中，X1、X2和X3独立地为卤素；R4和R5的定义均如权利要求1～11任一项所述；化合物II-a中，R1、R2和R3的定义均如权利要求1～11任一项所述。In the compound II, X 1 , X 2 and X 3 are independently halogen; R 4 and R 5 are as defined in any one of claims 1 to 11; in the compound II-a, R 1 , R 2 and R The definition of 3 is as described in any one of claims 1 to 11.
  14. 一种如权利要求1～11任一项所述的通式I所示的喹唑啉类化合物，其药学上可接受的盐、溶剂化物、代谢产物、代谢前体和药物前体中的一种或多种，在制备用于预防和/或治疗与JAK的表达或活性有关的疾病的药物中的应用。A quinazoline compound of the formula I according to any one of claims 1 to 11, wherein one of a pharmaceutically acceptable salt, a solvate, a metabolite, a metabolic precursor and a prodrug Use of one or more of the agents for the preparation of a medicament for the prevention and/or treatment of a disease associated with the expression or activity of JAK.
  15. 一种药物组合物，其含有治疗有效量的如权利要求1～11任一项所述的通式I所示的喹唑啉类化合物，其药学上可接受的盐、溶剂化物、代谢产物、代谢前体和药物前体中的一种或多种，及其药学上可接受的一种或多种载体和/或稀释剂。 A pharmaceutical composition comprising a quinazoline compound of the formula I according to any one of claims 1 to 11 in a pharmaceutically acceptable salt, solvate, metabolite, One or more of a metabolic precursor and a prodrug, and one or more pharmaceutically acceptable carriers and/or diluents thereof.
PCT/CN2016/088089 2015-07-03 2016-07-01 Quinazoline compound, intermediate, preparation method, pharmaceutical composition and uses thereof WO2017005137A1 (en)

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