WO2017005137A1 - Composé de quinazoline, intermédiaire associé, son procédé de préparation, composition pharmaceutique et utilisations associées - Google Patents

Composé de quinazoline, intermédiaire associé, son procédé de préparation, composition pharmaceutique et utilisations associées Download PDF

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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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substituted
group
phenyl
unsubstituted
quinazolin
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PCT/CN2016/088089
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English (en)
Chinese (zh)
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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
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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/fr

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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.

Abstract

La présente invention concerne un composé de quinazoline, un intermédiaire associé, son procédé de préparation, une composition pharmaceutique et une utilisation associées. Le composé de quinazoline de la présente invention présente un bon effet inhibiteur sur la protéine kinase JAK, et peut être utilisé pour la préparation d'un médicament pour la prévention, le traitement ou le traitement adjuvant de diverses maladies associées à l'expression ou à l'activité de JAK, en particulier de maladies tumorales et de maladies immunitaires.
PCT/CN2016/088089 2015-07-03 2016-07-01 Composé de quinazoline, intermédiaire associé, son procédé de préparation, composition pharmaceutique et utilisations associées WO2017005137A1 (fr)

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US10703748B2 (en) 2017-10-31 2020-07-07 Samumed, Llc Diazanaphthalen-3-yl carboxamides and preparation and use thereof
WO2022271630A1 (fr) * 2021-06-22 2022-12-29 Blueprint Medicines Corporation Inhibiteurs de l'egfr
WO2022271612A1 (fr) * 2021-06-22 2022-12-29 Blueprint Medicines Corporation Inhibiteurs hétérocycliques d'egfr destinés à être utilisés dans le traitement du cancer
WO2022271749A1 (fr) * 2021-06-22 2022-12-29 Blueprint Medicines Corporation Inhibiteurs hétérocycliques d'egfr destinés à être utilisés dans le traitement du cancer
WO2022271613A1 (fr) * 2021-06-22 2022-12-29 Blueprint Medicines Corporation Inhibiteurs hétérocycliques d'egfr destinés à être utilisés dans le traitement du cancer

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