WO2023041071A1 - 一种egfr抑制剂及其制备方法和用途 - Google Patents

一种egfr抑制剂及其制备方法和用途 Download PDF

Info

Publication number
WO2023041071A1
WO2023041071A1 PCT/CN2022/119451 CN2022119451W WO2023041071A1 WO 2023041071 A1 WO2023041071 A1 WO 2023041071A1 CN 2022119451 W CN2022119451 W CN 2022119451W WO 2023041071 A1 WO2023041071 A1 WO 2023041071A1
Authority
WO
WIPO (PCT)
Prior art keywords
amino
phenyl
pyrrolo
pyrimidin
methanone
Prior art date
Application number
PCT/CN2022/119451
Other languages
English (en)
French (fr)
Inventor
张贵民
张�浩
姚景春
袁将
赵桂芳
李蕊
李光艳
赵云
梁红宝
张振军
朱祥霞
Original Assignee
山东新时代药业有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from CN202111117969.3A external-priority patent/CN115838370A/zh
Priority claimed from CN202210197277.2A external-priority patent/CN116731020A/zh
Priority claimed from CN202210197158.7A external-priority patent/CN116726022A/zh
Application filed by 山东新时代药业有限公司 filed Critical 山东新时代药业有限公司
Publication of WO2023041071A1 publication Critical patent/WO2023041071A1/zh

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention relates to the fields of medicinal chemistry and pharmacotherapeutics, and includes a class of EGFR inhibitors and a preparation method thereof; the invention also relates to the application of the compounds in the preparation of anticancer drugs.
  • EGFR mutations mainly occur in exons 18 to 21, and the deletion mutation (Del19) in exon 19 and the L858R point mutation in exon 21 are the most common EGFR mutation subtypes, accounting for 90% of all mutation types.
  • a sensitive mutation of the EGFR gene For the first-generation EGFR inhibitors (gefitinib, erlotinib, and icotinib) developed for the above-mentioned EGFR mutations, most NSCLC patients will develop acquired drug resistance within 6-12 months after treatment. The T790M mutation is the main cause of drug resistance.
  • second-generation EGFR inhibitors such as afatinib, dacomitinib, and neratinib.
  • EGFR-WT wild-type EGFR
  • EGFR-WT wild-type EGFR
  • the third-generation EGFR inhibitors represented by Osimertinib have been successfully developed.
  • acquired resistance to third-generation inhibitors is still inevitable, and EGFR-C797S mutation accounts for about 20% of many drug resistance mechanisms, and is one of the main drug resistance mechanisms.
  • C797S mutation is in cis, there is currently no drug available clinically. Therefore, overcoming C797S drug resistance and developing fourth-generation EGFR-TKIs with high efficiency and low toxicity have become the consensus of colleagues at home and abroad, and are also the focus and difficulty of new drug development for NSCLC.
  • the fourth-generation EGFR small molecules have been reported one after another, most of them are in the preclinical research stage, and few compounds have entered clinical trials, let alone marketed drugs.
  • the invention discloses a class of EGFR inhibitors, a preparation method and medical application thereof.
  • the preparation method of this type of inhibitor in the invention has mild and easy-to-control conditions, convenient and simple post-treatment, and also has practicability and universality.
  • the results of pharmacological experiments show that the compound of the present invention has significant inhibitory activity on EGFR D770-N771 ins NPG and EGFR D770-N771 ins NPG/T790M kinases, and the compound of the present invention has excellent EGFR-Del19/T790M/C797S kinase inhibitory activity and KC -0122:Ba/F3 EGFR-L858R/T790M/C797S triple mutation cell line, KC-0116:Ba/F3EGFR-Del19/T790M/C797S triple mutation cell line inhibitory activity, at the same time, it also has strong inhibitory activity on single mutation and double mutation cells inhibitory activity.
  • One of the objects of the present invention is to provide the compound shown in formula I or its pharmaceutically acceptable salt or its stereoisomer:
  • Rc is
  • Rc 1 is 0, 1, 2 or 3; each Rc 1 is independently selected from at least one of halogen and C 1-3 alkyl;
  • Ra is substituted or unsubstituted phenyl, or substituted or unsubstituted
  • the substituents are independently selected from halogen, C 1-3 alkyl, C 1-3 alkoxy; the phenyl or The number of substituents is 0 or 1 or 2; the halogen is F, Cl, Br, I;
  • R 1 a is selected from H, Or a C 1-3 alkyl group; said Y and Z are independently selected from N, O and C, wherein N and C are substituted by 0 or 1 C 1-3 alkyl group, and the missing valence bonds are made up by H; Ra 1 is H or C 1-3 alkyl;
  • A is O or N, wherein N is replaced by at least one of H, C 1-3 alkyl;
  • t is selected from 0, 1, 2 or 3;
  • Rb is selected from any one or more groups of the following 1)-5):
  • substituted or unsubstituted 5-8 membered spiroheterocycles are substituted or unsubstituted 5-8 membered spiroheterocycles; the heteroatoms in the spiroheterocycles are O or S or N; the substituents of the spiroheterocycles are one or more independently substituted or non-substituted Substituted amino, C 1-3 alkyl, C 1-3 alkoxy, OH; the amino substituent is H or one or two C 1-3 alkyl;
  • a substituted or unsubstituted amino group is H or one or two C 1-3 alkyl groups, or -(CH 2 ) a -E-(CH 2 ) b -, and in the amino group N and -(CH 2 ) a -E-(CH 2 ) b - are linked to form a ring;
  • the E is C or O, the a is 1 or 2 or 3 or 4; the b is 1 or 2 or 3 or 4;
  • the number of double bonds a is 0, 1, 2 or 3; the position of a is the reasonable position of any valence bond in the ring; the insufficient valence bonds are made up by H;
  • n 0, 1, 2 or 3;
  • n 0, 1, 2 or 3;
  • Q and T are independently N, O, S or C; insufficient valence bonds are made up by H;
  • Rb 1 is 0 or 1 or 2;
  • Rb 1 is amino, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkyl substituted by hydroxyl, SO 2 R2b ,
  • the R 2 b is a substituted or unsubstituted C 1-3 alkyl group, a substituted or unsubstituted phenyl group, a C 3-6 cycloalkyl group, a C 2-5 alkenyl group or
  • the C 1-3 alkyl or phenyl substituent is halogen or hydroxyl;
  • the D is selected from C, P or S;
  • the g is 1, 2 or 3;
  • the e, d are independently selected from 0 or 1 or 2 or 3;
  • Y is selected from C, O or N;
  • R 1 b is H, NH 2 , hydroxyl, C 1-3 alkoxy, C 1-3 alkyl substituted by hydroxyl, SO 2 R 2 b, C 1-3 alkyl,
  • the R 2 b is independently substituted or unsubstituted C 1-3 alkyl, substituted or unsubstituted phenyl, C 3-6 cycloalkyl, C 2-5 alkenyl,
  • the C 1-3 alkyl or phenyl substituent is halogen or hydroxyl; the g is 1, 2 or 3; the e, d are independently selected from 0 or 1 or 2 or 3; Y is selected from C, O or N; the C 1-3 alkyl is methyl, ethyl, propyl or isopropyl; the C 1-3 alkoxy is methoxy, ethoxy, propoxy or isopropoxy; said halogen is F, Cl, Br or I.
  • the compound represented by formula I, its stereoisomer or its pharmaceutically acceptable salt, its substituent Rc is selected from any one of the following groups:
  • Rc 1 is 0, 1, 2 or 3; each Rc 1 is independently selected from at least one of F, Cl, Br, I and C 1-3 alkyl.
  • Rc is The number of Rc 1 is 1, 2 or 3; each Rc 1 is independently selected from at least one of F, Cl, Br, methyl, ethyl, and propyl.
  • Rc is The number of Rc 1 is 0, 1, 2 or 3; each Rc 1 is independently selected from at least one of F, Cl, C 1-3 alkyl.
  • Rc is The number of Rc 1 is 0, 1, 2 or 3; each Rc 1 is independently selected from at least one of F, Cl and methyl.
  • Rc is The number of Rc 1 is 0, 1, 2 or 3; each Rc 1 is independently selected from at least one of F, C 1-3 alkyl; further, the C 1-3 alkyl is selected from from methyl or ethyl.
  • Rc is The number of Rc 1 is 0, 1, 2 or 3; each Rc 1 is independently selected from at least one of F, Cl and methyl.
  • Rc is The number of Rc 1 is 1, 2 or 3; each Rc 1 is independently selected from at least one of F, Cl and methyl.
  • Rc is The number of Rc 1 is 0, 1 or 3; each Rc 1 is independently selected from at least one of F and methyl.
  • Rc is The number of Rc 1 is 1 or 3; each Rc 1 is independently selected from at least one of F.
  • Rc is Rc 1 is a single F.
  • Rc is Rc 1 is F; the number of Rc 1 is 3, at least two of which are in the ortho-position and para-position of the benzene ring respectively.
  • Rc is Rc 1 is F; the number of Rc 1 is 0, 1 or 3.
  • Rc is The number of Rc 1 is 0 or Rc 1 is 1 F or 3 F or a methyl group.
  • Rc is The number of Rc 1 is 0 or Rc 1 is 1 F or 3 F or a methyl group, and the preferred position is at the para position on the benzene ring.
  • Rc is The number of Rc 1 is 1, 2 or 3; each Rc 1 is independently selected from at least one of F and Cl.
  • Rc is The number of Rc 1 is 1 or 2; each Rc 1 is independently selected from at least one of F and Cl.
  • Rc is The number of Rc 1 is 1 or 2; each Rc 1 is independently selected from F or a combination of F and Cl.
  • Rc is Rc 1 is 1 or 2 or 3 F.
  • Rc is Rc 1 is 3 F's.
  • Rc is Rc 1 for 2 F's.
  • Rc is Rc 1 is 1 F, in the para position of the benzene ring.
  • the compound represented by formula I, its stereoisomer or its pharmaceutically acceptable salt, its substituent Ra is selected from any one of the following groups:
  • Ra is substituted or unsubstituted phenyl, or substituted or unsubstituted
  • the substituents are independently selected from F, C 1-3 alkyl, C 1-3 alkoxy; the phenyl or The number of the respective substituents is independently 0 or 1 or 2; in the Ra, the phenyl group or The substituent is F, Cl, C 1-3 alkyl, C 1-3 alkoxy; the phenyl or The number of the respective substituents is 0 or 1 or 2.
  • Phenyl in the Ra or The substituents are each independently selected from F, Cl, methyl, ethyl, methoxy, ethoxy; the phenyl or The number of the respective substituents is 0 or 1.
  • Phenyl in the Ra or The substituent is F, methyl, methoxy; the phenyl or The number of the respective substituents is 0 or 1.
  • the Ra is phenyl.
  • Phenyl in the Ra or The substituent is F, methyl, methoxy; the phenyl or The number of the respective substituents is 1.
  • the Ra is substituted or unsubstituted phenyl, or substituted or unsubstituted Phenyl in Ra or
  • the substituent is methyl; the phenyl or The number of the respective substituents is 1.
  • the compound represented by formula I, its stereoisomer or its pharmaceutically acceptable salt, its substituent R 1 a is selected from any one of the following groups:
  • R 1 a is selected from H or Or a C 1-3 alkyl group; said Y and Z are independently selected from N, O and C, and the missing valence bonds are made up by H; Ra 1 is H or a C 1-3 alkyl group;
  • R 1 a is selected from H or or C 1-3 alkyl; said Y is C, O or N; said Z is N or O, wherein N is substituted by 0 or 1 C 1-3 alkyl, and the missing valence bonds are made up by H; Ra 1 is H or C1-3 alkyl.
  • R 1 a is selected from H or or C 1-3 alkyl; said Y is C, O or N; said Z is N or O; wherein N is substituted by 0 or 1 C 1-3 alkyl, and the valence bond is made up by H.
  • R 1 a is selected from H or or C 1-3 alkyl; the Y is C or N; the Z is N or O; wherein N is substituted by 0 or 1 methyl group, and the insufficient valence bond is made up by H; Ra 1 is H or CH 3 , CH 2 CH 3 .
  • R 1 a is H or The Y is N; the Z is N or O; the missing valence bond is made up by H; Ra 1 is H or CH 3 .
  • R 1 a is The Y is N; the Z is N or O; the missing valence bond is made up by H; Ra 1 is H or CH 3 .
  • R 1 a is selected from H or Or C 1-3 alkyl; said Y is C or N; said Z is N or O; Ra 1 is H, C 1-3 alkyl.
  • R 1 a is selected from H or or C 1-3 alkyl; the Y is N; the Z is N or O; the Ra 1 is H or methyl.
  • R 1 a is selected from H or or C 1-3 alkyl; said Y is C or N; said Z is N; said Ra 1 is H or methyl.
  • R 1 a is selected from
  • substituent R is selected from any one of the following groups:
  • Ra 1 is H or C 1-3 alkyl.
  • Ra 1 is H, CH 3 , CH 2 CH 3 .
  • Ra 1 is CH 3 , CH 2 CH 3 .
  • Ra 1 is methyl
  • Ra 1 is ethyl
  • substituent A is selected from any one of the following groups:
  • A is O or N, wherein N is replaced by at least one of H, C 1-3 alkyl;
  • A is O or N, wherein N is substituted by at least one of H or methyl.
  • A is O or N, wherein N is replaced by H.
  • A is N, wherein N is replaced by H.
  • t is selected from any one of the following groups:
  • t is selected from 0,1 or 2.
  • t is selected from 0 or 2.
  • t is selected from 0.
  • t is selected from 1.
  • t is selected from 2.
  • t is selected from 3.
  • Rb 1 is 0 or 1 or 2;
  • Rb 1 is amino, hydroxyl, C 1- 3 alkyl, C 1-3 alkoxy or C 1-3 alkyl substituted by hydroxyl, SO 2 R 2 b,
  • Each R 2 b is independently substituted or unsubstituted C 1-3 alkyl, substituted or unsubstituted phenyl, C 3-6 cycloalkyl, C 2-5 alkenyl or
  • the C 1-3 alkyl or phenyl substituent is halogen or hydroxyl;
  • the D is selected from C or P;
  • the k is 1 or 2;
  • the g is 1, 2 or 3;
  • the e , d are independently selected from 0 or 1 or 2 or 3;
  • Y is selected from C, O or N.
  • the number of Rb 1 is 0 or 1 or 2; Rb 1 is amino, hydroxyl, C 1- 3 alkyl, C 1-3 alkoxy or C 1-3 alkyl substituted by hydroxy.
  • Rb is selected from any one or more groups of the following 1)-5):
  • a substituted or unsubstituted amino group is one or two C 1-3 alkyl groups, or -(CH 2 ) a -E-(CH 2 ) b -, and the N in the amino group Linked with both ends of -(CH 2 ) a -E-(CH 2 ) b- to form a ring;
  • the E is C or O, the a is 1 or 2 or 3; the b is 1 or 2 or 3;
  • Rb 1 is 0 or 1 or 2;
  • Rb 1 is amino, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy or C 1-3 alkyl substituted by hydroxyl, SO 2 R2b ,
  • Each R 2 b is independently substituted or unsubstituted C 1-3 alkyl, substituted or unsubstituted phenyl, C 3-6 cycloalkyl, C 2-5 alkenyl or
  • the C 1-3 alkyl or phenyl substituent is halogen or hydroxyl;
  • the g is 1, 2 or 3;
  • the e, d are independently selected from 0 or 1 or 2 or 3;
  • Y is selected from C, O or N.
  • Rb is selected from The number of double bonds a is 0, 1, 2 or 3; a position is any reasonable position of any valence bond in the ring; insufficient valence bonds are made up by H; m is 0, 1, 2 or 3; n is 0, 1, 2 or 3; Q and T are independently N, O, S or C; insufficient valence bonds are made up by H.
  • Rb 1 is 0 or 1;
  • Rb 1 is amino, hydroxyl, hydroxymethyl, C 1-3 alkyl, C 1-3 alkoxy or C 1-3 alkyl substituted by hydroxyl, SO 2 R 2 b,
  • Each R 2 b is independently substituted or unsubstituted C 1-3 alkyl, cyclopropanyl or C 2-3 alkenyl; the substituent of the C 1-3 alkyl is halogen or hydroxyl;
  • Said e, d are independently selected from 0 or 1 or 2 or 3;
  • Y is selected from C, O or N.
  • Rb 1 is 0 or 1 or 2; Rb 1 is selected from any of the following groups:
  • Rb 1 is amino, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy or C 1-3 alkyl substituted by hydroxy.
  • Rb 1 is C 1-3 alkyl or C 1-3 alkoxy.
  • Rb 1 is amino, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy or C 1-3 alkyl substituted by hydroxy.
  • Rb 1 is amino, hydroxyl or C 1-3 alkyl substituted by hydroxyl.
  • Rb 1 is amino or hydroxymethyl.
  • Rb 1 is hydroxymethyl
  • Rb 1 is amino
  • Rb 1 is hydroxyl
  • Rb 1 is hydroxyethyl
  • Rb 1 is methyl, ethyl or propyl.
  • Rb is selected from any of the following groups:
  • Rb is Wherein both Q and T are C; a is 0, and the insufficient valence bond is made up by H; m is 2; n is 2.
  • Rb is Wherein Q is C; T is C, O; a is 0 or 1, and the valence bond is made up by H; m is 1 or 2 or 3; n is 0 or 1 or 2.
  • Rb is Wherein Q is C; T is O or N; a is 0, and the valence bond is made up by H; m is 2 or 3; n is 1 or 2.
  • Rb is Among them, Q is C; T is O; a is 0, and the insufficient valence bond is made up by H; m is 3; n is 1.
  • Rb is Wherein both Q and T are C; a is 0, and the insufficient valence bond is made up by H; m is 1; n is 1.
  • Rb is Wherein both Q and T are C; a is 1, and the insufficient valence bond is made up by H;
  • Rb is Among them, Q is C; T is C; a is 0, and the insufficient valence bond is made up by H; m is 1; n is 0.
  • Rb is Wherein Q is C or N; T is C or O or N; a is 0 or 1 or 3, and the insufficient valence bond is made up by H; m is 1 or 2 or 3; n is 1 or 2.
  • Rb is Among them, Q is C; T is N; a is 0, and the insufficient valence bond is made up by H; m is 2 or 3; n is 1.
  • Rb is Wherein Q is C; T is O or N;
  • Rb is Wherein Q is C; T is O or N; a is 0, and the insufficient valence bond is made up by H;
  • Rb is Wherein Q is C; T is C or O; a is 0, and the insufficient valence bond is made up by H; m is 2; n is 2.
  • Rb is Wherein Q is C; T is C or O or N; a is 0, and the insufficient valence bond is made up by H; m is 2 or 3; n is 1 or 2.
  • Rb is Wherein, Q is C; T is C or N; a is 0, and the insufficient valence bond is made up by H; m is 2 or 3; n is 1 or 2.
  • Rb is Wherein Q is C or N; T is C or O or N; a is 0 or 1 or 3, and the insufficient valence bond is made up by H; m is 1 or 2 or 3; n is 1 or 2.
  • R 1 b is selected from any of the following groups: R 1 b is H, NH 2 , hydroxyl, C 1-3 alkoxy, C 1-3 alkyl substituted by hydroxy, SO 2 R 2 b, C 1-3 alkyl, each R 2 b is independently substituted or unsubstituted C 1-3 alkyl, substituted or unsubstituted phenyl, C 3-6 cycloalkyl, C 2-5 alkenyl or The C 1-3 alkyl or phenyl substituent is halogen or hydroxyl; the D is selected from C or P; the k is 1 or 2; the g is 1, 2 or 3; the e , d are independently selected from 0 or 1 or 2 or 3; Y is selected from C, O or N.
  • R 1 b is H, NH 2 , hydroxymethyl, hydroxyethyl, hydroxypropyl, methyl, ethyl, propyl, isopropyl, OH, SO 2 R 2 b, (CH 3 ) 2 CH 2 ,
  • Each R 2 b is independently substituted or unsubstituted C 1-3 alkyl, substituted or unsubstituted phenyl, C 3-5 cycloalkyl, C 2-3 alkenyl,
  • the substituent of the phenyl group is halogen or hydroxyl;
  • the D is selected from C, P or S;
  • the k is 1 or 2;
  • the g is 1, 2 or 3;
  • the g is 1, 2 or 3 .
  • R 1 b is H, NH 2 , hydroxymethyl, hydroxyethyl, hydroxypropyl, methyl, ethyl, propyl, isopropyl, OH, SO 2 R 2 b, (CH 3 ) 2 CH 2 ,
  • Each R 2 b is independently substituted or unsubstituted C 1-3 alkyl, substituted or unsubstituted phenyl, C 3-5 cycloalkyl, C 2-3 alkenyl,
  • the substituent of the phenyl group is halogen or hydroxyl;
  • the D is selected from C or P;
  • the k is 1 or 2;
  • the g is 1, 2 or 3;
  • the g is 1, 2 or 3.
  • R 1 b is H, NH 2 , HOCH 2 , OH, SO 2 R 2 b , CH 3 , CH 3 CH 2 , (CH 3 ) 2 CH 2 ,
  • Each R 2 b is independently substituted or unsubstituted C 1-3 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, vinyl, propenyl, Said g is 1, 2 or 3.
  • R 1 b is H, NH 2 , HOCH 2 , OH, SO 2 R 2 b , CH 3 , CH 3 CH 2 , (CH 3 ) 2 CH 2 ,
  • Each R2b is independently methyl, ethyl, propyl, isopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, ethylene base, propenyl, Said g is 1, 2 or 3.
  • R 1 b is H, amino, hydroxy, C 1-3 alkyl substituted by hydroxy, C 1-3 alkoxy, Or SO 2 R 2 b, each R 2 b is independently selected from C 1-3 alkyl or C 3-6 cycloalkyl; said e, d are independently selected from 1 or 2 or 3, so Said Y is selected from C or N or O.
  • R 1 b is H, amino, hydroxyl, C 1-3 alkyl, C 1-3 alkyl substituted by hydroxyl, C 1-3 alkoxy or SO 2 R 2 b, each R 2 b is independently selected from C 1-3 alkyl groups.
  • R 1b is H, amino, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy or C 1-3 alkyl substituted by hydroxy.
  • R 1 b is H, amino, hydroxy, C 1-3 alkyl substituted by hydroxy.
  • R 1 b is H, amino, C 1-3 alkyl substituted by hydroxy.
  • the C 1-3 alkyl group is methyl, ethyl, propyl or isopropyl ;
  • the C 1-3 alkoxy group is methoxy, ethoxy, propoxy or isopropoxy;
  • the halogen is F, Cl, Br or I.
  • the C 1-3 alkyl group is methyl or ethyl.
  • the C 1-3 alkoxy group is methoxy, ethoxy, propoxy or isopropoxy.
  • the halogen is F, Cl, Br or I.
  • the halogen is F or/and Cl.
  • Rc 1 is at least one of H, F, Cl, CH 3 .
  • the number of Rc 1 is 1, 2 or 3.
  • the position of Rc 1 is one or two or three of the 2, 3, 4, 5, and 6 positions on the benzene ring.
  • the phenyl group of Ra or The substituents are F, CH 3 O-.
  • Rb is a substituted or unsubstituted 5-8 membered spiro heterocyclic ring, a substituted or unsubstituted C 8 -C 11 bridging ring, a substituted or unsubstituted amino group
  • the heteroatom in the spiroheterocycle is O or S or N;
  • the substituent of the spiroheterocycle or bridged ring is one or more independent NH 2 , C 1-3 alkyl, C 1-3 Alkoxy, OH;
  • the substituent of the amino group is one or two C 1-3 alkyl groups;
  • m is 0, 1, 2 or 3;
  • n is 0, 1, 2 or 3;
  • Q and T are independent Is N, O, S or C; Insufficient valence bonds are made up by H;
  • f is 1, 2 or 3;
  • h is 0 or 1 or 2.
  • f is 2 or 3.
  • Rb 1 is methyl
  • each R 2 b is independently methyl, cyclopropanyl, vinyl, 2,2,2 trimethyl-ethyl.
  • Rb is a substituted or unsubstituted 5-8 membered spiroheterocycle, a substituted or unsubstituted C 8 -C 11 bridging ring, a substituted or unsubstituted amino group
  • the heteroatom in the spiro heterocycle is O or S or N; the substituent of the spiro heterocycle or bridged ring is one or more NH 2 , HOCH 2 , OH, CH 3 ; the substituent of the amino group is one or two C 1-3 alkyl groups; Substituted or unsubstituted 7-membered spiroheterocycle or C 10 bridged ring.
  • the Rb is Substituted or unsubstituted 3-oxaspiro[3,3]heptanyl or adamantyl.
  • the Rb is f is 1, 2 or 3.
  • Rb is adamantyl
  • Rb is 3-oxaspiro[3,3]heptyl.
  • the Rc is Ra is substituted or unsubstituted phenyl, or substituted or unsubstituted
  • the substituents are independently selected from F, methyl, methoxy; the phenyl or The number of substituents is independently 0 or 1; R 1 a is selected from H or or methyl; said Y is selected from N and O; said Z is N or O;
  • Ra 1 is H, methyl or ethyl; A is N, wherein N is substituted by an H; t is 0; Rb is selected from any one or more groups of the following 1)-4):
  • Substituted or unsubstituted adamantyl is one or more OH;
  • Substituted or unsubstituted amino is one or two C 1-3 alkyl groups
  • the number of double bond a is 0 or 1; the position of a is the reasonable position of any valence bond in the ring; m is 0, 1, 2 or 3; n is 0, 1, 2; Q is C; T is N, O or C; insufficient valence bonds are made up by H;
  • Rb 1 is 0 or 1 or 2;
  • Rb 1 is amino, hydroxyl or hydroxymethyl;
  • the substituent of the C 1-3 alkyl is halogen or hydroxyl;
  • R 1 b is H, amino, hydroxy or hydroxymethyl.
  • Rc is Rc 1 is F, located in the para position on the benzene ring; Ra is substituted or unsubstituted phenyl, or substituted or unsubstituted
  • the substituents are independently C 1-3 alkyl; the phenyl or The number of substituents is 0 or 1; R 1 a is selected from H or or C 1-3 alkyl; the Y is C or N; the Z is N; the Ra 1 is H, CH 3 , CH 2 CH 3 ; A is N, and N is substituted by one H; t selected from 0; Rb is Among them, both Q and T are C; a is 0, and the insufficient valence bond is made up by H; m is 2; n is 2;
  • Rb 1 is 0 or 1 or 2;
  • Rb 1 is NH 2 , hydroxymethyl or hydroxyethyl;
  • R 1 b is H, NH 2 or HOCH 2 .
  • the Rb is selected from any one or more groups of the following 1)-4):
  • Substituted or unsubstituted adamantyl is one or more OH;
  • a substituted or unsubstituted amino group is one or two C1-3 alkyl groups;
  • the number of double bond a is 0 or 1; the position of a is the reasonable position of any valence bond in the ring; m is 0, 1, 2 or 3; n is 0, 1, 2; Q is C; T is N, O or C; insufficient valence bonds are made up by H.
  • Rc is a substituted or unsubstituted phenyl group, as shown in formula II, said R 1 and R 2 are independently selected from at least one of H, halogen, and C 1-3 alkyl kind,
  • the R 1 and R 2 are independently selected from at least one of H, F, Cl, Br, methyl, and ethyl.
  • R 1 and R 2 are independently selected from at least one of H, F, Cl, and methyl.
  • Rc is a substituted or unsubstituted phenyl ring
  • the R a is selected from a substituted or unsubstituted phenyl ring
  • Rb is selected from R 1 b is H, as shown in formula III, Wherein, m is selected from 0,1,2; n is selected from 0,1,2;
  • t is selected from 0,1,2; W is C, O or N;
  • R 1 is selected from H, F, Cl;
  • R 2 is selected from H, F, Cl;
  • R 3 is selected from H, C 1-3 alkoxy
  • R 4 is selected from H, F;
  • R 5 is selected from the range defined above for R 1 a.
  • R 6 is selected from H, NH 2 , hydroxyl, C 1-3 alkoxy, C 1-3 alkyl substituted by hydroxy, SO 2 R 2 b, C 1-3 alkyl, Each R 2 b is independently substituted or unsubstituted C 1-3 alkyl, substituted or unsubstituted phenyl, C 3-6 cycloalkyl, C 2-5 alkenyl,
  • the C 1-3 alkyl or phenyl substituent is halogen or hydroxyl; the g is 1, 2 or 3; the e, d are independently selected from 0 or 1 or 2 or 3; Y is selected from C, O or N.
  • R is selected from H, methoxy, ethoxy.
  • R 6 is H, NH 2 , HOCH 2 , OH, SO 2 R 2 b, CH 3 , CH 3 CH 2 , (CH 3 ) 2 CH 2 ,
  • Each R2b is independently methyl, ethyl, propyl, isopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, ethylene base, propenyl, Said g is 1, 2 or 3.
  • R is H, amino, hydroxy, C 1-3 alkyl substituted by hydroxy, C 1-3 alkoxy, Or SO 2 R 2 b, each R 2 b is independently selected from C 1-3 alkyl or C 3-6 cycloalkyl; said e, d are independently selected from 1 or 2 or 3, so Said Y is selected from C or N or O.
  • R 6 is H, amino, hydroxyl, C 1-3 alkyl, C 1-3 alkyl substituted by hydroxy, C 1-3 alkoxy or SO 2 R 2 b, so Each R 2 b mentioned above is independently selected from C 1-3 alkyl groups.
  • R 6 is H, amino, hydroxy, C 1-3 alkyl, C 1-3 alkoxy or C 1-3 alkyl substituted by hydroxy.
  • R 6 is H, amino, hydroxy, C 1-3 alkyl substituted by hydroxy.
  • R 6 is H, amino, C 1-3 alkyl substituted by hydroxy.
  • R 6 is selected from H, OH, CH 2 OH,
  • R6 is CH2OH .
  • R is substituted or unsubstituted
  • the substituent is at least one of H, C 1-3 alkoxy, and C 1-3 alkyl; further, the substituent is H, methoxy, ethoxy, propoxy , isopropoxy, methyl, ethyl, propyl in one, two or three.
  • Ra is Rb is selected from R 1 b is H
  • formula IV wherein, m is selected from 0,1,2; n is selected from 0,1,2; t is selected from 0,1,2; W is C, O or N;
  • R 1 is selected from H, F, Cl;
  • R 2 is selected from H, F, Cl;
  • R 7 is selected from H or C 1-3 alkoxy; R 6 is selected from H, OH, CH 2 OH,
  • R 8 is selected from C 1-3 alkyl or piperidinyl substituted by C 1-3 alkyl.
  • R 8 is methyl
  • R 8 is ethyl
  • R 8 is methylpiperidinyl. In some embodiments the Rb is for Each of said v is 1 or 2 or 3 independently.
  • the substituent of the adamantyl group is at the 2- or 3-position of the adamantyl group.
  • linkage position between each group is any reasonable position of valence bond.
  • the substituents of the bridging ring are one or more independent amino groups, C 1-3 alkyl groups, C 1-3 alkoxy groups, and the independent interpretation in OH is that when there are multiple substituent groups, each The substituents can be the same or different, such as multiple amino groups or multiple C 1-3 alkyl groups or multiple C 1-3 alkoxy groups or multiple OH groups, or one amino group or one methyl group.
  • a combination of an ethoxy group, an ethoxy group, a hydroxyl group and a propyl group is used as a substituent for the bridged ring.
  • Each R 2 b is independently selected, only means that if there are multiple R 2 b in the same structural formula, each R 2 b can be the same or different, and they are independent of each other.
  • R 1 b is selected from any of the following groups refers to any of the following groups of "R 1 b is”, and the options end before a new paragraph (space before the paragraph).
  • R 1 b is means that the two can be the same or different groups, and when they are the same group, the further substituents can be the same or different; as for R 2 b in Rb 1 and R 2 b in R 1 b may take the same group or different groups.
  • the aforementioned compounds are selected from the following specific compounds:
  • the aforementioned compounds are selected from the following specific compounds: (S)-1-(3-((5-(4-fluorobenzoyl)-2-((4-(4-methylpiperazine-1 -yl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)-2,2-dimethylpropan-1-one, ( 4-fluorophenyl)(4-(((1r,4r)-4-hydroxycyclohexyl)amino)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)- 7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone, (4-fluorophenyl)(4-((1-(hydroxymethyl)cyclopropyl)amino)-2-(( 4-(4-Methylpiperazin-1-yl)phenyl)amino)
  • the aforementioned compounds are selected from the following specific compounds: (4-fluorophenyl)(4-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)amino)-2-((4- (4-methylpiperazin-1-yl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone, (4-fluorophenyl)(2-(( 4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((tetrahydro-2H-pyran-4-yl)methyl)amino)-7H-pyrrolo[2,3 -d]pyrimidin-5-yl)methanone, (4-((2-(dimethylamino)ethyl)amino)-2-((4-(4-methylpiperazin-1-yl)phenyl )amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)me
  • the aforementioned compounds are selected from the following specific compounds: (4-(cyclohexylamino)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-7H-pyrrole And[2,3-d]pyrimidin-5-yl)(4-fluorophenyl)methanone, (4-fluorophenyl)(4-((2-hydroxycyclohexyl)amino)-2-((4 -(4-methylpiperazin-1-yl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone, (R)-(4-fluorophenyl) (2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-4-(1-(methylsulfonyl)pyrrolidin-3-yl)amino)-7H-pyrrolo[ 2,3-d]pyrimidin-5-yl)
  • the aforementioned compounds are selected from the following specific compounds:
  • the aforementioned compounds are selected from the following specific compounds: (4-(((1s,4s)-4-aminocyclohexyl)amino)-2-((4-(4-methylpiperazin-1-yl )phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4-fluorophenyl)methanone, (2-((4-(4-ethylpiperazine-1 -yl)phenyl)amino)-4-(((1s,4s)-4-(hydroxymethyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)( 4-fluorophenyl)methanone, (4-fluorophenyl)(4-(((1s,4s)-4-(hydroxymethyl)cyclohexyl)amino)-2-((1-methyl-1H -pyrazol-4-yl)amin
  • the aforementioned compounds are selected from the following specific compounds: (R)-(4-(1-(cyclopropylsulfonyl)pyrrolidin-3-yl)amino)-2-((4-(4-methyl (Piperazin-1-yl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4-fluorophenyl)methanone, (S)-(4-(1 -(cyclopropylsulfonyl)pyrrolidin-3-yl)amino)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-7H-pyrrolo[2,3 -d]pyrimidin-5-yl)(4-fluorophenyl)methanone, (R)-1-(3-((5-(4-fluorobenzoyl)-2-((4-(4- Methylpiperazin-1-y
  • the present invention provides a method for preparing a compound of formula I, including its isomers, hydrates, solvates, pharmaceutically acceptable salts and prodrugs thereof, comprising the following steps:
  • N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N,N-diisopropylethylamine ( At least one of DIPEA), N-methyl-2-pyrrolidone (NMP), ethylene glycol dimethyl ether, isopropanol, n-butanol, sec-butanol, tert-butanol;
  • DMF N,N-dimethylformamide
  • DMA N,N-dimethylacetamide
  • N,N-diisopropylethylamine At least one of DIPEA
  • NMP N-methyl-2-pyrrolidone
  • ethylene glycol dimethyl ether isopropanol, n-butanol, sec-butanol, tert-butanol;
  • the base is an inorganic base or an organic base, wherein the inorganic base is selected from ammonia, potassium carbonate, sodium carbonate, cesium carbonate, and the organic base is selected from sodium acetate, triethylamine, diisopropyl At least one of ethylamine, triethylenediamine, pyridine, 4-dimethylaminopyridine, 1,8-diazabicycloundec-7-ene, and N-methylmorpholine;
  • the reaction temperature is 80-100°C;
  • reaction is carried out under the conditions of an organic solvent and a base, and the base and the organic solvent are independently selected from the relevant limitations in step 2);
  • reaction temperature is 100-130° C.
  • reaction is carried out under the conditions of an organic solvent and a base, and the base and the organic solvent independently selected from the relevant definitions in step 2;
  • the reaction is a Buchwald-hartwig coupling reaction using a palladium catalyst and an organic phosphine ligand
  • the palladium catalyst used is selected from palladium acetate, palladium dichloride, [1,1'-bis(diphenylphosphine)ferrocene] Palladium dichloride, tris(dibenzylideneacetone) dipalladium, tetrakistriphenylphosphine palladium, bistriphenylphosphine palladium dichloride
  • the organophosphine ligands used include but not limited to 2-dicyclohexylphosphine- 2',4',6'-triisopropylbiphenyl, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine, 2-dicyclohexylphosphine-2',6'-diisopropyl Oxy-1,1'-biphenyl;
  • I-d compound removes trimethylsilylethoxymethyl group (SEM group) under acid conditions, wherein the acid is an inorganic acid or an organic acid, wherein the inorganic acid is selected from hydrochloric acid, hydrobromic acid , hydrofluoric acid, at least one of hydroiodic acid, nitric acid, nitrous acid, and metaphosphoric acid, wherein the organic acid is selected from acetic acid, trichloroacetic acid, trifluoroacetic acid, glycolic acid, sulfamic acid, p-toluenesulfonic acid, ethyl At least one of diaminetetraacetic acid (EDTA), oxalic acid, and citric acid;
  • EDTA diaminetetraacetic acid
  • step 5 The product obtained in step 5 is neutralized under alkaline conditions to obtain the compound of formula I;
  • the base is an inorganic base or an organic base, wherein the inorganic base is selected from ammonia, potassium carbonate, sodium carbonate, cesium carbonate, and the organic base is selected from sodium acetate, triethylamine, diisopropylethylamine, triethylenediamine, At least one of pyridine, 4-dimethylaminopyridine, 1,8-diazabicycloundec-7-ene, and N-methylmorpholine.
  • the inorganic base is selected from ammonia, potassium carbonate, sodium carbonate, cesium carbonate
  • the organic base is selected from sodium acetate, triethylamine, diisopropylethylamine, triethylenediamine, At least one of pyridine, 4-dimethylaminopyridine, 1,8-diazabicycloundec-7-ene, and N-methylmorpholine.
  • Rc, Ra, Rb, R 1 a, R 1 b are as defined above
  • E is a protecting group, selected from SEM group, benzyloxycarbonyl, p-toluenesulfonyl, benzenesulfonyl, acetyl, trifluoroacetyl , fluorenylmethoxycarbonyl, benzyl.
  • the present invention provides a method for preparing a compound of formula II, including its isomers, hydrates, solvates, pharmaceutically acceptable salts and prodrugs thereof, comprising the following steps:
  • the present invention provides a method for preparing the compound of formula III, including its isomers, hydrates, solvates, pharmaceutically acceptable salts and prodrugs thereof, comprising the following steps:
  • the reaction temperature is 100-130°C;
  • the reaction is carried out under the conditions of an organic solvent and a base, and the base and the organic solvent are independently selected from the relevant limitations in the compound synthesis step 2) of the formula I;
  • the reaction is a Buchwald-hartwig coupling reaction using a palladium catalyst and an organophosphine ligand, and the palladium catalyst and the organophosphine ligand are independently selected from the relevant limitations in the compound synthesis step 2) of formula I;
  • Steps 5) and 6) adopt the same preparation method as the corresponding steps of formula I to prepare formula III.
  • the present invention provides a method for preparing a compound of formula IV, including its isomers, hydrates, solvates, pharmaceutically acceptable salts and prodrugs thereof, comprising the following steps:
  • the reaction temperature is 100-130°C;
  • the reaction is carried out under the conditions of an organic solvent and a base, and the base and the organic solvent are independently selected from the relevant restrictions in the synthesis step 2) of the compound of formula I;
  • the reaction is a Buchwald-hartwig coupling reaction using a palladium catalyst and an organophosphine ligand, and the palladium catalyst and the organophosphine ligand are independently selected from the relevant limitations in the compound synthesis step 2) of formula I;
  • Steps 5) and 6) adopt the same preparation method as the corresponding steps of formula I to prepare formula IV.
  • a further object of the present invention is to provide a pharmaceutical combination containing an effective dose of the compound of the present invention, its stereoisomer or its pharmaceutically acceptable salt, and one or more pharmaceutically acceptable pharmaceutical excipients thing.
  • the compound of the present invention can be made into different dosage forms alone or with one or more than one pharmaceutical carriers, such as tablets, pills, powders, capsules, granules, syrups, emulsions, microemulsions or injections, etc., specifically as intravenous Infusion, subcutaneous infusion, intramuscular infusion, intraperitoneal infusion, transdermal infusion and direct infusion into tissues for clinical oral, parenteral or topical administration.
  • ingredients known in the art can be used as pharmaceutically acceptable carriers without limitation as long as they do not interfere with the active expression of the active ingredients.
  • Carriers may include, for example, excipients, diluents, disintegrants, binders, glidants, surfactants, emulsifiers, suspending agents, diluents, etc., but are not limited thereto.
  • the carrier may include, for example, water, saline, aqueous dextrose, aqueous pseudosugar, alcohol, glycol, ether (for example, polyethylene glycol 400), oil, fatty acid, fatty acid ester, glyceride, surfactant, co- Suspending agents, emulsifying agents, etc., but not limited thereto.
  • the content of the compound of the present invention can be 0.1%-99.9%.
  • the dosage of the compound of the present invention can be 0.001-10000 mg/kg/0.3 day, which can be appropriately adjusted according to clinical needs.
  • the "pharmaceutically acceptable salt” in the present invention refers to a pharmaceutically acceptable acid or base addition salt, or a solvate or hydrate thereof.
  • Another object of the present invention is to provide such compounds, their stereoisomers or their pharmaceutically acceptable salts and their pharmaceutical compositions in the preparation of antitumor drugs.
  • the tumor is selected from lung cancer, liver cancer, colon cancer, pancreatic cancer, breast cancer, prostate cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, kidney cancer, head and neck cancer, lymphoma, melanoma or leukemia. Further, the tumor is selected from lung cancer, liver cancer or breast cancer. Lung cancer is preferred.
  • a series of tumor cell test results show that the compound of the present invention has broad-spectrum anti-tumor activity, and its IC50 value is in nanomolar to micromolar level, which is equivalent to the activity of positive control drugs Brigatinib, Avitinib, Osimertinib, and some compounds are better than positive drugs. .
  • the tumor is selected from lung cancer, liver cancer, ascites tumor, brain metastases, colon cancer, pancreatic cancer, breast cancer, prostate cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, kidney cancer, head and neck cancer, lymphoma, melanoma tumor or leukemia; preferably selected from lung cancer, liver cancer, breast cancer, ascites tumor, pancreatic cancer, brain metastases; wherein the lung cancer is selected from non-small cell lung cancer or small cell lung cancer; more preferably selected from non-small cell lung cancer, liver cancer, Breast cancer, ascites tumor; wherein said non-small cell lung cancer is lung adenocarcinoma.
  • the lung cancer is selected from EGFR mutation lung cancer, KRAS mutation lung cancer, HER2 mutation lung cancer, PIK3CA mutation lung cancer, BRAF mutation lung cancer, MET gene mutation lung cancer or ALK gene rearrangement lung cancer, ROS1 gene rearrangement lung cancer, Row of lung cancer, RET gene rearrangement of lung cancer.
  • the EGFR mutant lung cancer is selected from EGFR-Del19 mutant lung cancer, EGFR-L858R mutant lung cancer, EGFR-C797S mutant lung cancer, EGFR-C797S/T790M mutant lung cancer, EGFR-L858R /T790M mutant lung cancer, EGFR-Del19/T790M mutant lung cancer, EGFR-L858R/T790M/C797S mutant lung cancer, EGFR-Del19/T790M/C797S mutant lung cancer, EGFR-Del19/T790M/C797S mutant lung cancer, EGFR D770-N771 ins NPG mutant lung cancer or EGFR D770-N771 ins NPG/T790M Mutant lung cancer.
  • the EGFR mutation lung cancer is EGFR Del19/T790M/C797S mutation lung cancer.
  • the EGFR mutation lung cancer is EGFR D770-N771 ins NPG mutation lung cancer or EGFR D770-N771 ins NPG/T790M mutation lung cancer.
  • Yet another object of the present invention is to provide a method for treating tumors, comprising administering a therapeutically effective amount of the above-mentioned compounds, their stereoisomers or their pharmaceutically acceptable salts and their pharmaceutical compositions to the subject patients or patients.
  • the tumor is selected from lung cancer, liver cancer, ascites tumor, brain metastases, colon cancer, pancreatic cancer, breast cancer, prostate cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, kidney cancer, head and neck cancer, lymphoma , melanoma or leukemia; preferably selected from lung cancer, liver cancer, breast cancer, ascites tumor, pancreatic cancer, brain metastases; more preferably selected from non-small cell lung cancer, liver cancer, breast cancer, ascites tumor.
  • the results of a series of tumor cell tests show that the present invention provides a class of EGFR inhibitory active compounds with novel structures. Compared with existing similar compounds, the compounds of the present invention have lower tumor cell inhibitory concentration.
  • the compound of the present invention has significant inhibitory activity on EGFR D770-N771 ins NPG and EGFR D770-N771 ins NPG/T790M kinases, has a good inhibitory effect on EGFR-Del19/T790M/C797S kinases, and has a good inhibitory effect on KC-0122:Ba/F3EGFR -L858R/T790M/C797S triple mutant cell line and KC-0116:Ba/F3EGFR-Del19/T790M/C797S triple mutant cell line have a good inhibitory effect on cell proliferation, and the inhibitory effect on EGFR wild-type cell line A549 is weak , good selectivity.
  • the compound provided by the invention has excellent inhibitory activity on mutant EGFR or EGFR mutant cancer cells.
  • the compound provided by the invention has great industrialization and commercialization prospects and market value, and has remarkable economic benefits.
  • the compound provided by the invention has great industrialization and commercialization prospect and market value, and remarkable economic benefit.
  • Compound as used herein is meant to include all stereoisomers, geometric isomers, tautomers and isotopes.
  • Compounds of the present application may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers are included, such as enantiomers and diastereomers.
  • Compounds of the present application containing asymmetrically substituted carbon atoms can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or reagents.
  • Compounds of the present application also include tautomeric forms. Tautomeric forms result from the exchange of one single bond with an adjacent double bond accompanied by the migration of a proton.
  • the compounds of the present application also include all isotopic atoms, whether in intermediate or final compounds.
  • Isotopes include atoms that have the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium. That is to say, the compounds of the present application include compounds in which part or all of hydrogen (H) is replaced by tritium (T) and/or deuterium (D); also include part or all of 12 C replaced by 13 C and/or 14 C and other isotope (such as N, O, P, S) substitution compounds, such as 14 N and 15 N; 18 O and 17 O; 31 P and 32 P; 35 S and 36 S, etc.
  • the compounds described herein may possess one or more stereogenic centers, and each stereogenic center may exist in the R or S configuration or a combination thereof. Similarly, the compounds described herein may have one or more double bonds, and each double bond may exist in the E (trans) or Z (cis) configuration or combinations thereof.
  • a specific stereoisomer, structural isomer, diastereomer, enantiomer or epimer shall be understood to include all possible isomers, such as stereoisomers, structural Isomers, diastereomers, enantiomers or epimers and mixtures thereof. Accordingly, the compounds described herein include all configurationally different stereoisomers, structural isomers, diastereoisomers, enantiomers or epimeric forms and corresponding mixtures thereof. Techniques for converting or preserving a particular stereoisomer, and techniques for resolving mixtures of stereoisomers are well known in the art, and those skilled in the art can select an appropriate method for a particular situation.
  • C1-3 or C1-3 means that there are 1-3 carbon atoms in the moiety, that is, the group contains 1 carbon atom, 2 carbon atoms, or 3 carbon atoms. Therefore, for example, "C1-3 alkyl” refers to an alkyl group having 1-3 carbon atoms, that is, said alkyl group is selected from methyl, ethyl, propyl, isopropyl.
  • alkyl refers to optionally substituted straight chain or optionally substituted branched chain aliphatic hydrocarbons.
  • Alkyl herein may preferably have from 1 to about 20 carbon atoms, such as from 1 to about 10 carbon atoms, from 1 to about 8 carbon atoms, or from 1 to about 6 carbon atoms, or from 1 to about 4 carbon atoms or 1 to about 3 carbon atoms. Examples of alkyl herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, and the like.
  • Alkyl used in combination herein includes alkyl combined with other groups, such as alkyl in alkoxy.
  • halogen used herein alone or in combination is selected from F, Cl, Br, I.
  • the term "treat” and other similar synonyms include alleviating, alleviating or ameliorating the symptoms of a disease or disorder, inhibiting the disease or disorder, e. or a symptom resulting from a disease or disorder, or to abort a symptom of a disease or disorder, to prevent other symptoms, to ameliorate or prevent the underlying metabolic cause of the symptom, furthermore, the term encompasses the purpose of prophylaxis.
  • the term also includes obtaining a therapeutic and/or prophylactic effect.
  • the therapeutic effect refers to curing or improving the underlying disease being treated.
  • a cure or amelioration of one or more physical symptoms associated with the underlying disease is a therapeutic effect, eg, an improvement in a patient's condition is observed although the patient may still be affected by the underlying disease.
  • the composition may be administered to a patient at risk for a particular disease, or to a patient presenting with one or more physiological symptoms of the disease even if the disease has not yet been diagnosed.
  • a therapeutically effective amount refers to at least one active substance which, when administered, is sufficient to alleviate to some extent one or more symptoms of the disease or condition being treated (such as the amount of the compound of the present application). The result may be a reduction and/or alleviation of a sign, symptom or cause, or any other desired change in a biological system.
  • a therapeutically “effective amount” is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant disease-modifying effect. Effective amounts suitable for any individual case can be determined using techniques such as dose escalation assays.
  • pharmaceutically acceptable refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present application, and is relatively non-toxic, that is, the substance can be administered to an individual without causing adverse biological reactions or interact in an undesirable manner with any component contained in the composition.
  • composition refers to a mixture of a compound of the present application in admixture with at least one pharmaceutically acceptable substance.
  • pharmaceutically acceptable substances include, but are not limited to, carriers, stabilizers, diluents, dispersants, suspending agents, thickeners and/or excipients.
  • carrier refers to a relatively nontoxic substance that facilitates the introduction of the compounds of the present application into cells or tissues.
  • the term "pharmaceutically acceptable salt” refers to a salt that retains the biological effectiveness of the free acid and free base of the specified compound, and has no adverse effects, biological or otherwise.
  • the compounds of the present application also include pharmaceutically acceptable salts.
  • a pharmaceutically acceptable salt refers to the form in which the base group in the parent compound is converted into a salt.
  • Pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic groups such as amine (amino) groups.
  • the pharmaceutically acceptable salts of this application can be synthesized from the parent compound, that is, the basic group in the parent compound reacts with 1-4 equivalents of acid in a solvent system. Suitable salts are listed in Remingtong's Pharmaceutical Scicences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977).
  • the salts in this application refer to acid salts formed with organic acids/inorganic acids, and basic salts formed with organic bases/inorganic bases.
  • EGFR Epidermal Growth Factor Receptor
  • EGFR mutation negative usually means that no EGFR gene mutation is detected according to the commonly used gene detection methods for clinical diagnosis.
  • EGFR mutation status can be detected by a variety of methods.
  • DNA mutation detection is the preferred method to detect EGFR status.
  • a variety of DNA mutation detection analysis can be used to detect the EGFR mutation status of tumor cells. The most common EGFR mutation for non-small cell lung cancer patients is For exon 19 deletions and exon 21 mutations, direct DNA sequencing of exons 18–21 (or exons 19 and 21 only) is a reasonable option.
  • Advanced stage refers to the staging of non-small cell lung cancer according to the degree of lesions and concurrent diseases. For example, it can be stage III-IV non-small cell lung cancer according to the TNM classification in the AJCC cancer staging manual lung cancer staging system. In some implementations In the protocol, advanced non-small cell lung cancer is stage IIIB-IV non-small cell lung cancer.
  • the dosages and ranges provided herein are calculated based on the molecular weight of the free base form of the compounds of the invention.
  • the present invention provides a method for preparing the corresponding compound, and various synthetic methods can be used to prepare the compound described herein, including the methods involved in the following examples, the compound of the present invention or its pharmaceutically acceptable salt, isomer Or hydrates can be synthesized using the following methods and synthetic methods known in the field of organic chemical synthesis, or through variations of these methods understood by those skilled in the art. Preferred methods include but are not limited to the following methods.
  • Example 2 adopts the same preparation method as that of Example 1.
  • Example 3 adopts the same preparation method as that of Example 1.
  • Example 4 adopts the same preparation method as that of Example 1.
  • the compound of the present invention has good inhibitory activity on EGFR kinase, and the IC 50 values are all less than 10 ⁇ M.
  • the specific experiment is as follows:
  • the assay plate was centrifuged at 1000 g for 30 seconds and incubated at room temperature for 10 minutes.
  • test plate is centrifuged at 1000g for 30 seconds. Seal the assay plate and incubate at room temperature for 40 minutes.
  • the assay plate was centrifuged at 1000 g for 30 seconds and incubated at room temperature for 1 hour.
  • Inhibition rate 100-(Signalcmpd-SignalAve_PC)/(SignalAve_VC-SignalAve_PC) ⁇ 100.
  • IC50 values were calculated by using GraphPad 6.0 to make a nonlinear regression curve (dose-effect relationship - variable slope) of the logarithm of the compound concentration versus the inhibition rate.
  • X logarithm of inhibitor concentration
  • Y inhibition rate
  • Table 1 Some compounds of the present invention are to D770-N771 ins NPG/T790M kinase and to the active research of D770-N771 ins NPG kinase and BaF3-EGFR D770-N771 ins NPG cell
  • ND means not determined
  • the compound of the present invention has significant inhibitory activity and antiproliferative activity to EGFR D770-N771 ins NPG, EGFR D770-N771 ins NPG/T790M kinase and cells carrying insertion mutation BaF3-EGFR D770-N771 ins NPG, suggesting that the compound of the present invention can Inhibit EGFR D770-N771 ins NPG mutation, EGFR D770-N771 ins NPG/T790M mutation.
  • the compound activity test method and the data analysis please refer to the relevant limitations in Example 117, wherein the step c) of the compound activity test method is replaced by: prepare 2X EGFR Del19 T790M C797S in 1x kinase buffer.
  • the compound of the present invention has good inhibitory effect on EGFR-Del19/T790M/C797S kinase.
  • KC-0122 BaF3 EGFR-L858R/T790M/C797S ;
  • KC-0116 BaF3 EGFR-Del19/T790M/C797S ;
  • KC-1474 PC-9 EGFR-Del19/T790M/C797S ;
  • KC-0178 NCI-1975 EGFR-L858R/T790M/C797S .
  • the compound of the present invention has good inhibitory effect on cell proliferation of HCC827 EGFR-Del19 , PC-9 EGFR-Del19 mutant cell lines, H1975 EGFR-L858R/T790M double mutant cell lines.
  • the compound of the present invention has a good inhibitory effect on the cell proliferation of KC-1474: PC-9 EGFR-Del19/T790M/C797S triple mutation cell line and KC-0178: NCI-1975 EGFR-L858R/T790M/C797S triple mutation cell line .
  • the compound of the present invention has a good inhibitory effect on the cell proliferation of KC-0122: Ba/F3 EGFR-L858R/T790M/C797S triple mutant cell line and KC-0116: Ba/F3 EGFR-Del19/T790M/C797S triple mutant cell line .
  • the compound of the present invention has a good inhibitory effect on the cell proliferation of KC-0122: Ba/F3 EGFR-L858R/T790M/C797S triple mutant cell line and KC-0116: Ba/F3 EGFR-Del19/T790M/C797S triple mutant cell line , the inhibitory effect on the EGFR wild-type cell line A549 is weak and the selectivity is good.
  • Embodiment 120 In vivo drug effect research experiment
  • mice Female NPG mice, SPF grade, weighing 19-22 g, experimental animals provided by Beijing Weitongda Biotechnology Co., Ltd., experimental animal production license number SCXK (Beijing) 2019-0002, experimental animal quality certificate number: No. 110341211100087928.
  • Carbon dioxide incubator instrument manufacturer: Thermo, model: BB15;
  • Vernier caliper instrument manufacturer: SATA, model: SATA 91512.
  • the KC-1474 cells used in this experiment were cultured in RPMI1640 medium supplemented with 10% FBS and 0.5 ⁇ g/mL puromycin in a 37°C incubator containing 5% CO 2 .
  • concentration of KC-1474 cells was adjusted to 1 ⁇ 108 /mL, mixed with Matrigel at a volume ratio of 1:1, and 0.1 mL/only was inoculated subcutaneously on the right flank of NPG mice. The amount of cells inoculated in each mouse was 5 ⁇ 10 6 .
  • mice When the average tumor volume of mice reaches about 100-130mm , according to tumor volume and body weight, all mice are divided into six groups at random, are respectively model group (V), embodiment 60 compound oral group (po), implement Example 60 compound intravenously injected low dose group (L), Example 60 compound intravenously injected middle dose group (M). All groups were administered once a day, starting on the day of grouping, and administered continuously for 39 days.
  • the model group was intravenously given the same volume of vehicle, which was prepared by adding 2g of polyethylene glycol-15 hydroxystearate (HS15) to 4mL of dimethyl sulfoxide (DMSO), and then adding 40mL of purified water. Prepared by filtering with a ⁇ m sterile filter. At the end of the experiment or when the humane endpoint was implemented, the animals were anesthetized with pentobarbital sodium, and the animals were euthanized.
  • HS15 polyethylene glycol-15 hydroxystearate
  • DMSO dimethyl sulfoxide
  • TGI TV Tumor volume and tumor volume inhibition rate
  • the tumor volume was measured once when grouping, and once a week after grouping, the tumor volume was measured with a vernier caliper, and the tumor volume was measured before euthanasia. The tumor volume was measured by using a vernier caliper to measure the long diameter and short diameter of the tumor.
  • tumor volume 0.5 ⁇ long diameter ⁇ short diameter 2 .
  • TGI TV (%) [1-(Ti-T0)/(Vi-V0)] ⁇ 100%
  • Ti the average tumor volume of the treatment group on day i of administration
  • T0 the average tumor volume of the treatment group on day 0 of administration
  • Vi the average tumor volume of the model group on day i of administration
  • V0 the model group Mean tumor volume on day 0 of dosing
  • TGI TW Tumor weight and tumor weight inhibition rate
  • the animals were euthanized and the tumor tissue was stripped, the tumor weight was weighed, and the tumor weight inhibition rate was calculated.
  • the calculation formula is as follows:
  • TGI TW (%) (W model group -W treatment group )/W model group ⁇ 100%, W refers to tumor weight.
  • the po group L and M groups had inhibitory effects on tumor growth, and the difference between the M group and the model group was extremely significant (P ⁇ 0.001), and po group L and M group had the effect of shrinking the tumor volume, showing good antitumor efficacy.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

一种式I化合物或其可药用盐及其在制备调控EGFR酪氨酸激酶活性或防治EGFR相关疾病中的用途。式I的EGFR抑制剂对EGFR D770-N771 ins NPG和NPG/T790M激酶具有抑制活性，对EGFR-Del19/T790M/C797S激酶和KC-0122:Ba/F3EGFR-L858R/T790M/C797S三突变细胞系和KC-0116:Ba/F3EGFR-Del19/T790M/C797S三突变细胞系的细胞增殖有抑制作用。

Description

一种EGFR抑制剂及其制备方法和用途 技术领域
本发明涉及药物化学领域和药物治疗学领域，内容包括一类EGFR抑制剂及其制备方法；本发明还涉及该类化合物在制备抗癌药物中的应用。
技术背景
EGFR突变主要发生在18～21号外显子，其中19号外显子的缺失突变(Del19)和21号外显子的L858R点突变是最常见的EGFR突变亚型，占所有突变类型的90％，称为EGFR基因的敏感突变。针对于上述EGFR突变研发的第一代EGFR抑制剂(吉非替尼、厄洛替尼和埃克替尼)，大部分NSCLC患者用药后，会在6-12月内出现获得性耐药，T790M突变是耐药的主要原因。
为了克服T790M耐药，研究人员开发了第二代EGFR抑制剂，如阿法替尼(Afatinib)、达克替尼(Dacomitinib)和来那替尼(Neratinib)等。但是，第二代抑制剂选择性较差，对野生型的EGFR(EGFR-WT)也表现出较强的抑制活性，最大耐受剂量较低，治疗窗口窄，因此临床使用受限。
为了克服第二代EGFR-TKIs选择性差的问题，以奥希替尼(Osimertinib)为代表的第三代EGFR抑制剂被成功开发。但是，第三代抑制剂的获得性耐药仍不可避免，EGFR-C797S突变在众多耐药机制中占比约20％，是主要的耐药机制之一。当C797S突变为顺式时，目前临床无药可用。因此，克服C797S耐药、开发高效低毒的第四代EGFR-TKIs已经成为国内外同行的共识，也是NSCLC新药研发的重点和难点。目前，虽有第四代EGFR小分子陆续被报道，但是多处于临床前研究阶段，鲜有化合物进入临床试验，更没有上市药物。
研究开发选择性抑制C797S突变，开发一种抗耐药性的新型第四代EGFR抑制剂具有重大的临床意义和应用前景。
发明内容
本发明公开一类EGFR抑制剂及其制备方法和医药用途。发明中该类抑制剂的制备方法具有条件温和易控，后处理方便简单，同时还具有实用性和普适性。药理实验结果表明，本发明化合物对EGFR D770-N771 ins NPG、EGFR D770-N771 ins NPG/T790M激酶均具有显著的抑制活性，本发明化合物具有优良的EGFR-Del19/T790M/C797S激酶抑制活性和KC-0122:Ba/F3 EGFR-L858R/T790M/C797S三突变细系、KC-0116:Ba/F3EGFR-Del19/T790M/C797S三突变细胞系抑制活性，同时，对单突变、双突变细胞也有较强的抑制活性。
本发明的目的之一在于提供式Ⅰ所示的化合物或其药学上可接受的盐或其立体异构体：
Figure PCTCN2022119451-appb-000001
其中，Rc为
Figure PCTCN2022119451-appb-000002
Rc 1的个数为0，1，2或3；每个Rc 1独立选自卤素和C 1-3的烷基中的至少一种；
Ra为取代或未取代的苯基，或取代或未取代的
Figure PCTCN2022119451-appb-000003
所述取代基分别独立地选自卤素，C 1-3的烷基，C 1-3的烷氧基；所述苯基或
Figure PCTCN2022119451-appb-000004
各自的取代基个数为0或1或2；所述卤素为F，Cl，Br，I；
R 1a选自H，
Figure PCTCN2022119451-appb-000005
或C 1-3的烷基；所述的Y和Z分别独立地选自N,O和C，其中N、C被0或1个C 1-3烷基取代，不足价键由H补足；Ra 1为H或C 1-3的烷基；
A为O或N，其中N被H，C 1-3的烷基的中至少一个取代；
t选自0,1,2或3；
Rb选自以下1)-5)任一一组或多组中的基团：
1)取代或非取代的5-8元的螺杂环；所述螺杂环中的杂原子为O或S或N；所述螺杂环的取代基为一个或多个独立的取代或非取代的氨基，C 1-3的烷基，C 1-3的烷氧基，OH；所述氨基的取代基为H或一个或两个C 1-3的烷基；
2)取代或非取代的C 8-C 11的桥环；所述桥环的取代基为一个或多个独立的的取代或非取代氨基，C 1-3的烷基，C 1-3的烷氧基，OH；所述氨基的取代基为H或一个或两个C 1-3的烷基；
3)取代或非取代的氨基；所述氨基的取代基为H或一个或两个C 1-3的烷基，或-(CH 2) a-E-(CH 2) b-，且氨基中的N与-(CH 2) a-E-(CH 2) b-两端链接成环；所述E为C或O，所述a为1或2或3或4；所述b为1或2或3或4；
4)
Figure PCTCN2022119451-appb-000006
双键a的个数为0，1，2或3；a的位置为环内任何价键合理的位置；不足价键由H补足；
m为0，1，2或3；
n为0，1，2或3；
Q和T分别独立为N，O，S或C；不足价键由H补足；
5)
Figure PCTCN2022119451-appb-000007
f为1，2或3；h为0,1或2；
Rb 1的个数为0或1或2；Rb 1为氨基，羟基，C 1-3的烷基，C 1-3的烷氧基，被羟基取代的C 1-3的烷基，SO 2R 2b，
Figure PCTCN2022119451-appb-000008
所述R 2b为取代或非取代的C 1-3的烷基，取代或非取代的苯基，C 3-6的环烷基，C 2-5的烯基或
Figure PCTCN2022119451-appb-000009
所述C 1-3的烷基或苯基的取代基为卤素或羟基；所述D选自C，P或S；所述g为1，2或3；所述e，d分别独立选自0或1或2或3；Y选自C，O或N；
R 1b为H，NH 2，羟基，C 1-3的烷氧基，被羟基取代的C 1-3的烷基，SO 2R 2b，C 1-3的烷基，
Figure PCTCN2022119451-appb-000010
Figure PCTCN2022119451-appb-000011
所述的R 2b独立为取代或非取代的C 1-3的烷基，取代或非取代的苯基，C 3-6的环烷基，C 2-5的烯基，
Figure PCTCN2022119451-appb-000012
所述C 1-3的烷基或苯基的取代基为卤素或羟基；所述g为1，2或3；所述e，d分别独立选自0或1或2或3；Y选自C，O或N；所述C 1-3的烷基为甲基、乙基、丙基或异丙基；所述C 1-3的烷氧基为甲氧基、乙氧基、丙氧基或异丙氧基；所述卤素为F，Cl，Br或I。
在一些实施例中，如式Ⅰ所示的化合物，其立体异构体或其药学上可接受的盐，其取代基Rc选自如下任一一组：
Rc 1的个数为0，1，2或3；每个Rc 1独立选自F，Cl，Br，I和C 1-3的烷基中的至少一种。
Rc为
Figure PCTCN2022119451-appb-000013
Rc 1的个数为1,2或3；每个Rc 1独立选自F，Cl，Br，甲基，乙基，丙基中的至少一种。
Rc为
Figure PCTCN2022119451-appb-000014
Rc 1的个数为0，1，2或3；每个Rc 1独立选自F，Cl，C 1-3的烷基中的至少一种。
Rc为
Figure PCTCN2022119451-appb-000015
Rc 1的个数为0，1，2或3；每个Rc 1独立选自F，Cl，甲基中的至少一种。
Rc为
Figure PCTCN2022119451-appb-000016
Rc 1的个数为0，1，2或3；每个Rc 1独立选自F，C 1-3的烷基中的至少一种；进一步地，所述的C 1-3的烷基选自甲基或乙基。
Rc为
Figure PCTCN2022119451-appb-000017
Rc 1的个数为0，1，2或3；每个Rc 1独立选自F，Cl，甲基中的至少一种。
Rc为
Figure PCTCN2022119451-appb-000018
Rc 1的个数为1,2或3；每个Rc 1独立选自F，Cl，甲基中的至少一种。
Rc为
Figure PCTCN2022119451-appb-000019
Rc 1的个数为0，1或3；每个Rc 1独立选自F，甲基中的至少一种。
Rc为
Figure PCTCN2022119451-appb-000020
Rc 1的个数为1或3；每个Rc 1独立选自F中的至少一种。
Rc为
Figure PCTCN2022119451-appb-000021
Rc 1为单个F。
Rc为
Figure PCTCN2022119451-appb-000022
Rc 1为F；Rc 1的个数为3个，其中至少有两位分别在苯环的邻位和对位。
Rc为
Figure PCTCN2022119451-appb-000023
Rc 1为F；Rc 1的个数为0，1或3。
Rc为
Figure PCTCN2022119451-appb-000024
Rc 1的个数为0或Rc 1为1个F或3个F或一个甲基。
Rc为
Figure PCTCN2022119451-appb-000025
Rc 1的个数为0或Rc 1为1个F或3个F或一个甲基，优选位置在苯环上的对位。
Rc为
Figure PCTCN2022119451-appb-000026
Rc 1的个数为1,2或3；每个Rc 1独立选自F，Cl中的至少一种。
Rc为
Figure PCTCN2022119451-appb-000027
Rc 1的个数为1或2；每个Rc 1独立选自F，Cl中的至少一种。
Rc为
Figure PCTCN2022119451-appb-000028
Rc 1的个数为1或2；每个Rc 1独立选自F或F与Cl的组合。
Rc为
Figure PCTCN2022119451-appb-000029
Rc 1为1个或2个或3个F。
Rc为
Figure PCTCN2022119451-appb-000030
Rc 1为3个F。
Rc为
Figure PCTCN2022119451-appb-000031
Rc 1为2个F。
Rc为
Figure PCTCN2022119451-appb-000032
Rc 1为1个F，在苯环的对位。
在一些实施例中，如式Ⅰ所示的化合物，其立体异构体或其药学上可接受的盐，其取代基Ra选自如下任一一组：
Ra为取代或未取代的苯基，或取代或未取代的
Figure PCTCN2022119451-appb-000033
所述取代基分别独立地选自F，C 1-3的烷基，C 1-3的烷氧基；所述苯基或
Figure PCTCN2022119451-appb-000034
各自的取代基个数独立为0或1或2；所述Ra中苯基或
Figure PCTCN2022119451-appb-000035
的取代基为F，Cl，C 1-3的烷基，C 1-3的烷氧基；所述苯基或
Figure PCTCN2022119451-appb-000036
的各自取代基的个数为0或1或2。
所述Ra中苯基或
Figure PCTCN2022119451-appb-000037
的取代基各自独立选自F，Cl，甲基，乙基，甲氧基，乙氧基；所述苯 基或
Figure PCTCN2022119451-appb-000038
的各自取代基的个数为0或1。
所述Ra中苯基或
Figure PCTCN2022119451-appb-000039
的取代基为F，甲基，甲氧基；所述苯基或
Figure PCTCN2022119451-appb-000040
的各自取代基的个数为0或1。
所述Ra为苯基。
所述Ra中苯基或
Figure PCTCN2022119451-appb-000041
的取代基为F，甲基，甲氧基；所述苯基或
Figure PCTCN2022119451-appb-000042
的各自取代基的个数为1。
所述Ra为取代或未取代的苯基，或取代或未取代的
Figure PCTCN2022119451-appb-000043
Ra中苯基或
Figure PCTCN2022119451-appb-000044
的取代基为甲基；所述苯基或
Figure PCTCN2022119451-appb-000045
的各自取代基的个数为1。
在一些实施例中，如式Ⅰ所示的化合物，其立体异构体或其药学上可接受的盐，其取代基R 1a选自如下任一一组：
R 1a选自H或
Figure PCTCN2022119451-appb-000046
或C 1-3的烷基；所述的Y和Z分别独立地选自N,O和C，不足价键由H补足；Ra 1为H或C 1-3的烷基；
R 1a选自H或
Figure PCTCN2022119451-appb-000047
或C 1-3的烷基；所述Y为C，O或N；所述Z为N或O，其中N被0或1个C 1-3的烷基取代，不足价键由H补足；Ra 1为H或C1-3的烷基。
R 1a选自H或
Figure PCTCN2022119451-appb-000048
或C 1-3的烷基；所述Y为C，O或N；所述Z为N或O；其中N被0或1个C 1-3的烷基取代，不足价键由H补足。
R 1a选自H或
Figure PCTCN2022119451-appb-000049
或C 1-3的烷基；所述Y为C或N；所述Z为N或O；其中N被0 或1个甲基取代，不足价键由H补足；Ra 1为H或CH 3,CH 2CH 3。
R 1a为H或
Figure PCTCN2022119451-appb-000050
所述Y为N；所述Z为N或O；不足价键由H补足；Ra 1为H或CH 3。
R 1a为
Figure PCTCN2022119451-appb-000051
所述Y为N；所述Z为N或O；不足价键由H补足；Ra 1为H或CH 3。
R 1a选自H或
Figure PCTCN2022119451-appb-000052
或C 1-3的烷基；所述Y为C或N；所述Z为N或O；Ra 1为H，C 1-3的烷基。
R 1a选自H或
Figure PCTCN2022119451-appb-000053
或C 1-3的烷基；所述Y为N；所述Z为N或O；所述Ra 1为H或甲基。
R 1a选自H或
Figure PCTCN2022119451-appb-000054
或C 1-3的烷基；所述Y为C或N；所述Z为N；所述Ra 1为H或甲基。
R 1a选自
Figure PCTCN2022119451-appb-000055
在一些实施例中，如式Ⅰ所示的化合物，其立体异构体或其药学上可接受的盐，其取代基Ra 1选自如下任一一组：
Ra 1为H或C 1-3的烷基。
Ra 1为H，CH 3，CH 2CH 3。
Ra 1为CH 3，CH 2CH 3。
Ra 1为甲基。
Ra 1为乙基。
在一些实施例中，如式Ⅰ所示的化合物，其立体异构体或其药学上可接受的盐，其取代基A选自如下任一一组：
A为O或N，其中N被H，C 1-3的烷基中的至少一个取代；
A为O或N，其中N被H或甲基中的至少一个取代。
A为O或N，其中N被H取代。
A为N，其中N被H取代。
在一些实施例中，如式Ⅰ所示的化合物，其立体异构体或其药学上可接受的盐，t选自如下任一一组：
t选自0,1或2。
t选自0或2。
t选自0。
t选自1。
t选自2。
t选自3。
在一些实施例中，如式Ⅰ所示的化合物，其立体异构体或其药学上可接受的盐，Rb 1的个数为0或1或2；Rb 1为氨基，羟基，C 1-3的烷基，C 1-3的烷氧基或被羟基取代的C 1-3的烷基，SO 2R 2b，
Figure PCTCN2022119451-appb-000056
所述各R 2b独立为取代或非取代的C 1-3的烷基，取代或非取代的苯基，C 3-6的环烷基，C 2-5的烯基或
Figure PCTCN2022119451-appb-000057
所述C 1-3的烷基或苯基的取代基为卤素或羟基；所述D选自C或P；所述k为1或2；所述g为1，2或3；所述e，d分别独立选自0或1或2或3；Y选自C，O或N。
在一些实施例中，如式Ⅰ所示的化合物，其立体异构体或其药学上可接受的盐，Rb 1的个数为0或1或2；Rb 1为氨基，羟基，C 1-3的烷基，C 1-3的烷氧基或被羟基取代的C 1-3的烷基。
在一些实施例中，如式Ⅰ所示的化合物，其立体异构体或其药学上可接受的盐，Rb选自以下1)-5)任一一组或多组中的基团：
1)取代或非取代的5-8元的螺杂环；所述螺杂环中的杂原子为O；
2)取代或非取代的C 10的桥环；所述桥环的取代基为一个或多个独立的氨基，C 1-3的烷基，C 1-3的烷氧基，OH；
3)取代或非取代的氨基；所述氨基的取代基为一个或两个C 1-3的烷基，或-(CH 2) a-E-(CH 2) b-，且氨基中的N与-(CH 2) a-E-(CH 2) b-两端链接成环；所述E为C或O，所述a为1或2或3；所述b为1或2或3；
4)
Figure PCTCN2022119451-appb-000058
双键a的个数为0，1，2或3；a位置为环内任何价键合理的位置；不足价键由H补足；m为0，1，2或3；n为0，1，2或3；Q和T分别独立为N，O，S或C；不足价键由H补足；
5)
Figure PCTCN2022119451-appb-000059
f为1，2或3；h为0或1；
Rb 1的个数为0或1或2；Rb 1为氨基，羟基，C 1-3的烷基，C 1-3的烷氧基或被羟基取代的C 1-3的烷基，SO 2R 2b，
Figure PCTCN2022119451-appb-000060
所述各R 2b独立为取代或非取代的C 1-3的烷基，取代或非取代的苯基，C 3-6的环烷基，C 2-5的烯基或
Figure PCTCN2022119451-appb-000061
所述C 1-3的烷基或苯基的取代基为卤素或羟基；所述g为1，2或3；所述e，d分别独立选自0或1或2或3；Y选自C，O或N。
在一些实施例中，如式Ⅰ所示的化合物，其立体异构体或其药学上可接受的盐，Rb选自
Figure PCTCN2022119451-appb-000062
双键a的个数为0，1，2或3；a位置为环内任何价键合理的位置；不足价键由H补足；m为0，1，2或3；n为0，1，2或3；Q和T分别独立为N，O，S或C；不足价键由H补足。
在一些实施例中，如式Ⅰ所示的化合物，其立体异构体或其药学上可接受的盐，Rb 1的个数为0或1；Rb 1为氨基，羟基，羟甲基，C 1-3的烷基，C 1-3的烷氧基或被羟基取代的C 1-3的烷基，SO 2R 2b，
Figure PCTCN2022119451-appb-000063
所述各R 2b独立为取代或非取代的C 1-3的烷基，环丙烷基或C 2-3的烯基；所述C 1-3的烷基的取代基为卤素或羟基；所述e，d分别独立选自0或1或2或3；Y 选自C，O或N。
在一些实施例中，如式Ⅰ所示的化合物，其立体异构体或其药学上可接受的盐，Rb 1的个数为0或1或2；Rb 1选自如下任一组：
Rb 1为氨基，羟基，C 1-3的烷基，C 1-3的烷氧基或被羟基取代的C 1-3的烷基。
Rb 1为C 1-3的烷基或C 1-3的烷氧基。
Rb 1为氨基，羟基，C 1-3的烷基，C 1-3的烷氧基或被羟基取代的C 1-3的烷基。
Rb 1为氨基，羟基或被羟基取代的C 1-3的烷基。
Rb 1为氨基或羟甲基。
Rb 1为羟甲基。
Rb 1为氨基。
Rb 1为羟基。
Rb 1为羟乙基。
Rb 1为甲基，乙基或丙基。
在一些实施例中，如式Ⅰ所示的化合物，其立体异构体或其药学上可接受的盐，Rb选自如下任一组：
Rb为
Figure PCTCN2022119451-appb-000064
其中Q和T均为C；a为0，不足价键由H补足；m为2；n为2。
Rb为
Figure PCTCN2022119451-appb-000065
其中Q为C；T为C、O；a为0或1，不足价键由H补足；m为1或2或3；n为0或1或2。
Rb为
Figure PCTCN2022119451-appb-000066
其中Q为C；T为O或N；a为0，不足价键由H补足；m为2或3；n为1或2。
Rb为
Figure PCTCN2022119451-appb-000067
其中Q为C；T为O；a为0，不足价键由H补足；m为3；n为1。
Rb为
Figure PCTCN2022119451-appb-000068
其中Q和T均为C；a为0，不足价键由H补足；m为1；n为1。
Rb为
Figure PCTCN2022119451-appb-000069
其中Q和T均为C；a为1，不足价键由H补足；m为2；n为1。
Rb为
Figure PCTCN2022119451-appb-000070
其中Q为C；T为C；a为0，不足价键由H补足；m为1；n为0。
Rb为
Figure PCTCN2022119451-appb-000071
其中Q为C或N；T为C或O或N；a为0或1或3，不足价键由H补足；m为1或2或3；n为1或2。
Rb为
Figure PCTCN2022119451-appb-000072
其中Q为C；T为N；a为0，不足价键由H补足；m为2或3；n为1。
Rb为
Figure PCTCN2022119451-appb-000073
其中Q为C；T为O或N；a为0，不足价键由H补足；m为3；n为1。
Rb为
Figure PCTCN2022119451-appb-000074
其中Q为C；T为O或N；a为0，不足价键由H补足；m为2；n为2。
Rb为
Figure PCTCN2022119451-appb-000075
其中Q为C；T为C或O；a为0，不足价键由H补足；m为2；n为2。
Rb为
Figure PCTCN2022119451-appb-000076
其中Q为C；T为C或O或N；a为0，不足价键由H补足；m为2或3；n为1或2。
Rb为
Figure PCTCN2022119451-appb-000077
其中Q为C；T为C或N；a为0，不足价键由H补足；m为2或3；n为1或2。
Rb为
Figure PCTCN2022119451-appb-000078
其中Q为C或N；T为C或O或N；a为0或1或3，不足价键由H补足；m为1或2或3；n为1或2。
在一些实施例中，如式Ⅰ所示的化合物，其立体异构体或其药学上可接受的盐，R 1b选自如下任一组：R 1b为H，NH 2，羟基，C 1-3的烷氧基，羟基取代的C 1-3的烷基，SO 2R 2b，C 1-3的烷基，，
Figure PCTCN2022119451-appb-000079
所述各R 2b独立为取代或非取代的C 1-3的烷基，取代或非取代的苯基，C 3-6的环烷基，C 2-5的烯基或
Figure PCTCN2022119451-appb-000080
所述C 1-3的烷基或苯基的取代基为卤素或羟基；所述D选自C或P；所述k为1或2；所述g为1，2或3；所述e，d分别独立选自0或1或2或3；Y选自C，O或N。
R 1b为H，NH 2，羟甲基，羟乙基，羟丙基，甲基，乙基，丙基，异丙基，OH，SO 2R 2b，(CH 3) 2CH 2，
Figure PCTCN2022119451-appb-000081
所述各R 2b独立为取代或非取代的C 1-3的烷基，取代或非取代的苯基，C 3-5的环烷基，C 2-3的烯基，
Figure PCTCN2022119451-appb-000082
所述苯基的取代基为卤素或羟基；所述D选自 C，P或S；所述k为1或2；所述g为1，2或3；所述g为1，2或3。
R 1b为H，NH 2，羟甲基，羟乙基，羟丙基，甲基，乙基，丙基，异丙基，OH，SO 2R 2b，(CH 3) 2CH 2，
Figure PCTCN2022119451-appb-000083
所述各R 2b独立为取代或非取代的C 1-3的烷基，取代或非取代的苯基，C 3-5的环烷基，C 2-3的烯基，
Figure PCTCN2022119451-appb-000084
所述苯基的取代基为卤素或羟基；所述D选自C或P；所述k为1或2；所述g为1，2或3；所述g为1，2或3。
R 1b为H，NH 2，HOCH 2，OH，SO 2R 2b，CH 3，CH 3CH 2，(CH 3) 2CH 2，
Figure PCTCN2022119451-appb-000085
所述各R 2b独立为取代或非取代的C 1-3的烷基，环丙基，环丁基，环戊基，环辛基，乙烯基，丙烯基，
Figure PCTCN2022119451-appb-000086
所述g为1，2或3。
R 1b为H，NH 2，HOCH 2，OH，SO 2R 2b，CH 3，CH 3CH 2，(CH 3) 2CH 2，
Figure PCTCN2022119451-appb-000087
所述各R 2b独立为甲基，乙基，丙基，异丙基，羟甲基，羟乙基，羟丙基，环丙基，环丁基，环戊基，环辛基，乙烯基，丙烯基，
Figure PCTCN2022119451-appb-000088
所述g为1，2或3。
R 1b为H，氨基，羟基，被羟基取代的C 1-3的烷基，C 1-3的烷氧基，
Figure PCTCN2022119451-appb-000089
或SO 2R 2b，所述各R 2b独立选自C 1-3的烷基或C 3-6的环烷基；所述e、d分别独立地选自1或2或3，所述Y选自C或N或O。
R 1b为H，氨基，羟基，C 1-3的烷基，被羟基取代的C 1-3的烷基，C 1-3的烷氧基或SO 2R 2b，所述各R 2b独立选自C 1-3的烷基。
R 1b为H，氨基，羟基，C 1-3的烷基，C 1-3的烷氧基或被羟基取代的C 1-3的烷基。
R 1b为H，氨基，羟基，被羟基取代的C 1-3的烷基。
R 1b为H，氨基，被羟基取代的C 1-3的烷基。
在一些实施例中，如式Ⅰ所示的化合物，其立体异构体或其药学上可接受的盐，所述C 1-3的烷基为甲基、乙基、丙基或异丙基；所述C 1-3的烷氧基为甲氧基、乙氧基、丙氧基或异丙氧基；所述卤素为F，Cl，Br或I。
在一些实施例中，如式Ⅰ所示的化合物，其立体异构体或其药学上可接受的盐，所述C 1-3的烷基为甲基、乙基。
在一些实施例中，如式Ⅰ所示的化合物，其立体异构体或其药学上可接受的盐，所述C 1-3的烷氧基为甲氧基、乙氧基、丙氧基或异丙氧基。
在一些实施例中，如式Ⅰ所示的化合物，其立体异构体或其药学上可接受的盐，所述卤素为F，Cl，Br或I。
在一些实施例中，如式Ⅰ所示的化合物，其立体异构体或其药学上可接受的盐，所述卤素为F或/和Cl。
在有些实施例中Rc 1为H，F，Cl，CH 3中的至少一种。
在有些实施例中Rc 1的个数为1,2或3。
在有些实施例中Rc 1的位置为苯环上的2,3,4,5,6位中的一个或两个或三个。
在有些实施例中所述Ra的苯基或
Figure PCTCN2022119451-appb-000090
的取代基为F，CH 3O-。
在有些实施例中所述Rb为取代或非取代的5-8元的螺杂环，取代或非取代的C 8-C 11的桥环， 取代或非取代的氨基，
Figure PCTCN2022119451-appb-000091
所述螺杂环中的杂原子为O或S或N；所述螺杂环或桥环的取代基为一个或多个独立的NH 2，C 1-3的烷基，C 1-3的烷氧基，OH；所述氨基的取代基为一个或两个C 1-3的烷基；m为0，1，2或3；n为0，1，2或3；Q和T分别独立为N，O，S或C；不足价键由H补足；f为1，2或3；h为0或1或2。
在有些实施例中所述f为2或3。
在有些实施例中所述Rb 1为甲基。
在有些实施例中所述各R 2b独立为甲基，环丙烷基，乙烯基，2,2,2三甲基-乙基。
在有些实施例中所述Rb为取代或非取代的5-8元的螺杂环，取代或非取代的C 8-C 11的桥环，取代或非取代的氨基，
Figure PCTCN2022119451-appb-000092
所述螺杂环中的杂原子为O或S或N；所述螺杂环或桥环的取代基为一个或多个的NH 2，HOCH 2，OH，CH 3；所述氨基的取代基为一个或两个C 1-3的烷基；
Figure PCTCN2022119451-appb-000093
取代或非取代的7元的螺杂环或C 10的桥环。
在有些实施例中所述Rb为
Figure PCTCN2022119451-appb-000094
取代或非取代的3-氧杂螺[3,3]庚烷基或金刚烷基。
在有些实施例中所述Rb为
Figure PCTCN2022119451-appb-000095
在有些实施例中所述Rb为
Figure PCTCN2022119451-appb-000096
f为1，2或3。
在有些实施例中所述Rb为
Figure PCTCN2022119451-appb-000097
在有些实施例中所述Rb为金刚烷基。
在有些实施例中所述Rb为3-氧杂螺[3,3]庚烷基。
在有些实施例中所述Rc为
Figure PCTCN2022119451-appb-000098
Ra为取代或未取代的苯基，或取代或未取代的
Figure PCTCN2022119451-appb-000099
所述取代基分别独立地选自F，甲基，甲氧基；所述苯基或
Figure PCTCN2022119451-appb-000100
各自的取代基个数独立为0或 1；R 1a选自H或
Figure PCTCN2022119451-appb-000101
或甲基；所述Y选自N和O；所述Z为N或O；
Ra 1为H，甲基或乙基；A为N，其中N被一个H取代；t为0；Rb选自以下1)-4)任一一组或多组中的基团：
1)取代或非取代的7元的螺杂环；所述螺杂环中的杂原子为O；
2)取代或非取代的金刚烷基；所述金刚烷基的取代基为一个或多个OH；
3)取代或非取代的氨基；所述氨基的取代基为一个或两个C 1-3的烷基；
4)
Figure PCTCN2022119451-appb-000102
双键a的个数为0或1；a的位置为环内任何价键合理的位置；m为0，1，2或3；n为0，1，2；Q为C；T为N，O或C；不足价键由H补足；
Rb 1的个数为0或1或2；Rb 1为氨基，羟基或羟甲基；所述C 1-3的烷基的取代基为卤素或羟基；
R 1b为H，氨基，羟基或羟甲基。
在有些实施例中所述Rc为
Figure PCTCN2022119451-appb-000103
Rc 1为F，位于苯环上的对位；Ra为取代或未取代的苯基，或取代或未取代的
Figure PCTCN2022119451-appb-000104
所述取代基分别独立地C 1-3的烷基；所述苯基或
Figure PCTCN2022119451-appb-000105
各自的取代基个数为0或1；R 1a选自H或
Figure PCTCN2022119451-appb-000106
或C 1-3的烷基；所述Y为C或N；所述Z为N；所述Ra 1为H，CH 3，CH 2CH 3；A为N，且N被一个H取代；t选自0；Rb为
Figure PCTCN2022119451-appb-000107
其中Q和T均为C；a为0，不足价键由H补足；m为2；n为2；
Rb 1的个数为0或1或2；Rb 1为NH 2，羟甲基或羟乙基；R 1b为H，NH 2或HOCH 2。
在有些实施例中所述Rb选自以下1)-4)任一一组或多组中的基团：
1)取代或非取代的7元的螺杂环；所述螺杂环中的杂原子为O；
2)取代或非取代的金刚烷基；所述金刚烷基的取代基为一个或多个OH；
3)取代或非取代的氨基；所述氨基的取代基为一个或两个C1-3的烷基；
4)
Figure PCTCN2022119451-appb-000108
双键a的个数为0或1；a的位置为环内任何价键合理的位置；m为0，1，2或3；n为0，1，2；Q为C；T为N，O或C；不足价键由H补足。
如式I所述，其中Rc取取代或非取代的苯基，如式II所示，所述R 1、R 2分别独立地选自 H，卤素，C 1-3的烷基中的至少一种，
Figure PCTCN2022119451-appb-000109
在有些实施例中所述R 1、R 2分别独立地选自H，F，Cl，Br，甲基，乙基中的至少一种。
在有些实施例中所述R 1、R 2分别独立地选自H，F，Cl，甲基中的至少一种。
如式I所述，其中Rc取取代或非取代的苯基，所述R a选自取代或非取代的苯环，Rb选自
Figure PCTCN2022119451-appb-000110
R 1b为H，如式III所示，
Figure PCTCN2022119451-appb-000111
其中，m选自0,1,2；n选自0,1,2；
t选自0,1,2；W为C，O或N；
R 1选自H,F,Cl；
R 2选自H,F,Cl；
R 3选自H,C 1-3的烷氧基；
R 4选自H,F；
R 5选自上文对R 1a的限定范围。
在一些实施例中R 5选自
Figure PCTCN2022119451-appb-000112
在一些实施例中R 5为
Figure PCTCN2022119451-appb-000113
在一些实施例中R 6选自H，NH 2，羟基，C 1-3的烷氧基，羟基取代的C 1-3的烷基，SO 2R 2b，C 1-3的烷基，
Figure PCTCN2022119451-appb-000114
所述各R 2b独立为取代或非取代的C 1-3的烷基，取代或非取代的苯基，C 3-6的环烷基，C 2-5的烯基，
Figure PCTCN2022119451-appb-000115
所述C 1-3的烷基或苯基的取代基为卤素或羟基；所述g为1，2或3；所述e，d分别独立选自0或1或2或3；Y选自C，O或N。
在一些实施例中R 3选自H,甲氧基，乙氧基。
在一些实施例中R 6为H，NH 2，HOCH 2，OH，SO 2R 2b，CH 3，CH 3CH 2，(CH 3) 2CH 2，
Figure PCTCN2022119451-appb-000116
Figure PCTCN2022119451-appb-000117
所述各R 2b独立为甲基，乙基，丙基，异丙基，羟甲基，羟乙基，羟丙基，环丙 基，环丁基，环戊基，环辛基，乙烯基，丙烯基，
Figure PCTCN2022119451-appb-000118
所述g为1，2或3。
在一些实施例中R 6为H，氨基，羟基，被羟基取代的C 1-3的烷基，C 1-3的烷氧基，
Figure PCTCN2022119451-appb-000119
或SO 2R 2b，所述各R 2b独立选自C 1-3的烷基或C 3-6的环烷基；所述e、d分别独立地选自1或2或3，所述Y选自C或N或O。
在一些实施例中R 6为H，氨基，羟基，C 1-3的烷基，被羟基取代的C 1-3的烷基，C 1-3的烷氧基或SO 2R 2b，所述各R 2b独立选自C 1-3的烷基。
在一些实施例中R 6为H，氨基，羟基，C 1-3的烷基，C 1-3的烷氧基或被羟基取代的C 1-3的烷基。
在一些实施例中R 6为H，氨基，羟基，被羟基取代的C 1-3的烷基。
在一些实施例中R 6为H，氨基，被羟基取代的C 1-3的烷基。
在一些实施例中R 6选自H,OH,CH 2OH，
Figure PCTCN2022119451-appb-000120
Figure PCTCN2022119451-appb-000121
在一些实施例中R 6为CH 2OH。
在一些实施例中如式I所述，其中Ra取取代或非取代的
Figure PCTCN2022119451-appb-000122
所述取代基为H，C 1-3的烷氧基，C 1-3的烷基中的至少一种；进一步的，所述取代基为H，甲氧基、乙氧基、丙氧基、异丙氧基、甲基、乙基、丙基中的一个、两个或三个。
在一些实施例中如式I所述，其中Ra取
Figure PCTCN2022119451-appb-000123
Rb选自
Figure PCTCN2022119451-appb-000124
R 1b为H，如式IV所示，
Figure PCTCN2022119451-appb-000125
其中，m选自0,1,2；n选自0,1,2；t选自0,1,2；W为C，O或N；
R 1选自H,F,Cl；
R 2选自H,F,Cl；
R 7选自H或C 1-3的烷氧基；R 6选自H,OH,CH 2OH，
Figure PCTCN2022119451-appb-000126
Figure PCTCN2022119451-appb-000127
R 8选自C 1-3的烷基或被C 1-3的烷基取代的哌啶基。
在有些实施例中所述R 8为甲基。
在有些实施例中所述R 8为乙基。
在有些实施例中所述R 8为甲基哌啶基。在有些实施例中所述Rb为
Figure PCTCN2022119451-appb-000128
为
Figure PCTCN2022119451-appb-000129
Figure PCTCN2022119451-appb-000130
所述各v独立为1或2或3。
在有些实施例中所述金刚烷基的取代基在金刚烷基的2位或3位。
部分说明
本发明申请中所述通式描述中重点陈述了官能团或取代基或价键，如有不足价键，未经特别说明，均默认由H补足。
未特别说明的，各基团之间的链接位置为任一价键合理的位置。
所述桥环的取代基为一个或多个独立的氨基，C 1-3的烷基，C 1-3的烷氧基，OH中的独立的解释为当有多个取代基时，每个取代基时可以相同，也可以不同，如可以是多个氨基或多个C 1-3的烷基或多个C 1-3的烷氧基或多个OH，也可以是一个氨基、一个甲基、一个乙氧基、一个羟基和一个丙基的组合作为桥环的取代基。
各R 2b独立选自，只指在同一结构式若存在多个R 2b，则每个R 2b可以相同，也可以不同，彼此间是独立的。
“R 1b选自如下任一组”是指以下几组“R 1b为”中的任一一组，选项至新的段落(段前空格)前结束。
本文中有些新起行顶头撰写的格式，属于段内内容，分行是为了形式清晰，方便阅读，不应该作为如同新段落类似的隔离内容的依据。
“R 1b为”是指两者可以为相同或者不同的基团，为相同集团时，进一步的取代基可以相同也可以不同；如同为
Figure PCTCN2022119451-appb-000131
在Rb 1中的R 2b与在R 1b中的R 2b可以取相同基团，也可以取不同基团。
在有些实例中，上述化合物选自如下具体化合物：
(R)-(4-((1-(环丙基磺酰基)哌啶-3-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(4-氟苯基)甲酮，(R)-(4-(1-(环丙基磺酰基)哌啶-3-基)氨基)-2-((1-甲基-1H-吡唑-4-基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(4-氟苯基)甲酮，(R)-1-(4-((1-(环丙基磺酰基)哌啶-3-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)-2-甲基丙-1-酮，(S)-(4-(1-(环丙基磺酰基)哌啶-3-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(4-氟苯基)甲酮，(R)-1-(3-((5-(4-氟苯甲酰基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-4-基)氨基)哌啶-1-基)丙-2-烯-1-酮，(4-氟苯基)(2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-4-((四氢-2H-吡喃-4-基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-4-(1-(四氢-2H-吡喃-4-基)哌啶-4-基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(4-(((1r，4r)-4-(羟甲基)环己基)氨基)-2-((2-甲氧基-4-吗啉代苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(3，4-二氟苯基)(4-((1r，4r)-4-(羟甲基)环己基)氨基)-2-((4-吗啉代苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(3-氟苯基)(4-(((1r，4r)-4-(羟甲基)环己基)氨基)-2-((4-吗啉代苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(4-((1-异丙基哌啶-4-基)氨基)-2-((4-吗啉代苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(3，5-二氟苯基)(4-(((1r，4r)-4-(羟甲基)环己基)氨基)-2-((4-吗啉代苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(2-氯-4-氟苯基)(4-(((1r，4r)-4-(羟甲基)环己基)氨基)-2-((4-吗啉代苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮。
在有些实例中，上述化合物选自如下具体化合物：(S)-1-(3-((5-(4-氟苯甲酰基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-4-基)氨基)吡咯烷-1-基)-2，2-二甲基丙-1-酮，(4-氟苯基)(4-(((1r，4r)-4-羟基环己基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(4-((1-(羟甲基)环丙基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮， (2-((3-氟-4-(4-甲基哌嗪-1-基)苯基)氨基)-4-(((1r，4r)-4-(羟甲基)环己基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(4-氟苯基)甲酮，(4-氟苯基)(4-((3R，6S)-6-(羟甲基)四氢-2H-吡喃-3-基)氨基)-2-((4-吗啉代苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(4-((3R，6S)-6-(羟甲基)四氢-2H-吡喃-3-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(2，4-二氟苯基)(4-(((1r，4r)-4-(羟甲基)环己基)氨基)-2-((4-吗啉代苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-((2-氧杂螺[3.3]庚-6-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(4-氟苯基)甲酮，(4-氟苯基)(4-(((1s，4s)-4-(羟甲基)环己基)氨基)-2-((4-吗啉代苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(2-((3-氟-4-(4-甲基哌嗪-1-基)苯基)氨基)-4-(((1s，4s)-4-(羟甲基)环己基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(4-氟苯基)甲酮，(4-氟苯基)(4-(((1s，4s)-4-(羟甲基)环己基)氨基)-2-((2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(2-((4-(2-(二甲氨基)乙氧基)苯基)氨基)-4-(((1s，4s)-4-(羟甲基)环己基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(4-氟苯基)甲酮，(4-氟苯基)(4-(((1s，4s)-4-(羟甲基)环己基)氨基)-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(4-((1S，4R)-4-(羟甲基)环戊-2-烯-1-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(4-((1R，4S)-4-(羟甲基)环戊-2-烯-1-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(4-(((1r，3s，5R，7S)-3-羟基金刚烷-1-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(4-(((1s，3R，4s，5S，7s)-4-羟基金刚烷-1-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(4-(((1r，4r)-4-(羟甲基)环己基)氨基)-2-((1-甲基-1H-吡唑-4-基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮。
在有些实例中，上述化合物选自如下具体化合物：(4-氟苯基)(4-(((1r，4r)-4-(羟甲基)环己基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-4-((四氢-2H-吡喃-4-基)甲基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-((2-(二甲氨基)乙基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(4-氟苯基)甲酮，(4-氟苯基)(4-(((1r，4r)-4-(羟甲基)环己基)氨基)-2-((4-吗啉代苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-(((1r，4r)-4-(羟甲基)环己基)氨基)-2-((4-吗啉代苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(对甲苯基)甲酮。
在有些实例中，上述化合物选自如下具体化合物：(4-(环己胺基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(4-氟苯基)甲酮，(4-氟苯基)(4-((2-羟基环己基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(R)-(4-氟苯基)(2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-4-(1-(甲磺酰基)吡咯烷-3-基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(R)-(4-氟苯基)(2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-4-(1-(甲磺酰基)哌啶-3-基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(S)-(4-氟苯基)(2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-4-(四氢-2H-吡喃-3-基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(R)-(4-氟苯基)(2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-4-(四氢-2H-吡喃-3-基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-4-((四氢-2H-吡喃-4-基)甲基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-((1-(环丙基磺酰基)哌啶-4-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(4-氟苯基)甲酮，(4-氟苯基)(2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-4-((1-(甲磺酰基)哌啶-4-基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(S)-(4-氟苯基)(2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-4-(四氢呋喃-3-基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(R)-(4-氟苯基)(2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-4-(四氢呋喃-3-基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(4-((1-(羟甲基)环戊基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(4-((1r，4r)-4-甲氧基环己基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(4-(((1r，4r)-4-(羟甲基)环己基)氨基)-2-((2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(2-((3-氟-4-吗啉代苯基)氨基)-4-(((1r，4r)-4-(羟甲基)环己基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(4-氟苯基)甲酮，(4-氟苯基)(2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-4-((四氢-2H-吡喃-4-基)氧)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-4-((1-甲基哌啶-4-基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(4-(((1r，4r)-4-(羟甲基)环己基)氨基)-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，((1r，4r)-4-((2-((1-甲基-1H-吡唑-4-基)氨基)-7H-吡咯并[2，3-d]嘧啶-4-基)氨基)环己基)甲醇，(4-(((1r，4r)-4-(羟甲基)环己基)氨基)-2-((4-吗啉代苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(苯基)甲酮，(4-(((1r，4r)-4-(羟甲基)环己基)氨基)-2-((4-吗啉代苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(2，3，4-三氟苯基)甲酮。
在有些实例中，上述化合物选自如下具体化合物：
(S)-(4-(1-(环丙基磺酰基)哌啶-3-基)氨基)-2-((4-吗啉代苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(4-氟苯基)甲酮，((1r，4r)-4-((2-((4-吗啉苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-4-基)氨基)环己基)甲醇，(4-氟苯基)(4-((1-异丙基哌啶-4-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(4-((1-甲基哌啶-4-基)氨基)-2-((4-吗啉代苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮。
在有些实例中，上述化合物选自如下具体化合物：(4-(((1s，4s)-4-氨基环己基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(4-氟苯基)甲酮，(2-((4-(4-乙基哌嗪-1-基)苯基)氨基)-4-(((1s，4s)-4-(羟甲基)环己基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(4-氟苯基)甲酮，(4-氟苯基)(4-(((1s，4s)-4-(羟甲基)环己基)氨基)-2-((1-甲基-1H-吡唑-4-基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯 基)(4-(((1s，4s)-4-(羟甲基)环己基)氨基)-2-((1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(4-(((1s，4s)-4-(羟甲基)环己基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮。
在有些实例中，上述化合物选自如下具体化合物：(R)-(4-(1-(环丙基磺酰基)吡咯烷-3-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(4-氟苯基)甲酮，(S)-(4-(1-(环丙基磺酰基)吡咯烷-3-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(4-氟苯基)甲酮，(R)-1-(3-((5-(4-氟苯甲酰基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-4-基)氨基)哌啶-1-基)丙-2-烯-1-酮，(S)-1-(3-((5-(4-氟苯甲酰基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-4-基)氨基)哌啶-1-基)丙-2-烯-1-酮，(S)-1-(3-((5-(4-氟苯甲酰基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-4-基)氨基)吡咯烷-1-基)丙-2-烯-1-酮，(S)-(4-(1-(环丙基磺酰基)哌啶-3-基)氨基)-2-((3-氟-4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(4-氟苯基)甲酮，(S)-(4-(1-(环丙基磺酰基)哌啶-3-基)氨基)-2-((4-(4-乙基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(4-氟苯基)甲酮，(S)-(4-(1-(环丙基磺酰基)吡咯烷-3-基)氨基)-2-((4-吗啉代苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(4-氟苯基)甲酮，(S)-(4-(1-(环丙基磺酰基)吡咯烷-3-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(苯基)甲酮，(S)-1-(3-((5-苯甲酰基-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-4-基)氨基)吡咯烷-1-基)丙-2-烯-1-酮，(S)-(4-(1-(环丙基磺酰基)吡咯烷-3-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(3-氟苯基)甲酮，(S)-1-(3-((5-(3-氟苯甲酰基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-4-基)氨基)吡咯烷-1-基)丙-2-烯-1-酮，(S)-(4-(1-(环丙基磺酰基)吡咯烷-3-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(3，4-二氟苯基)甲酮，(S)-1-(3-((5-(3，4-二氟苯甲酰基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-4-基)氨基)吡咯烷-1-基)丙-2-烯-1-酮，(4-氟苯基)(2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-4-(吗啉代氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-4-(哌啶-1-基氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(S)-1-(3-((5-(2，4-二氟苯甲酰基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-4-基)氨基)吡咯烷-1-基)丙-2-烯-1-酮，(S)-(4-((1-(环丙基磺酰基)吡咯烷-3-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(2-氟苯基)甲酮，(S)-1-(3-((5-(2-氟苯甲酰基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-4-基)氨基)吡咯烷-1-基)丙-2-烯-1-酮，(R)-1-(3-((5-(4-氟苯甲酰基)-2-((1-甲基-1H-吡唑-4-基)氨基)-7H-吡咯并[2，3-d]嘧啶-4-基)氨基)吡咯烷-1-基)丙-2-烯-1-酮，(4-((2-(二甲基磷酰基)苯基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(4-氟苯基)甲酮，(S)-(4-((1-(环丙基磺酰基)吡咯烷-3-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(2，4-二氟苯基)甲酮，(S)-1-(3-((5-(4-氟苯甲酰基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-4-基)氨基)吡咯烷-1-基)-3，3-二甲基丁-1-酮，(S)-(3-((5-(4-氟苯甲酰基)-2-(4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-4-基)氨基)吡咯烷-1-基)(4-氟苯基)甲酮，(S)-1-(3-((5-(4-氟苯甲酰基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-4-基)氨基)吡咯烷-1-基)-2，2-二甲基丙-1-酮，(S)-1-(3-((5-(4-氟苯甲酰基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-4-基)氨基)吡咯烷-1-基)乙基-1-酮，(4-氟苯基)(4-(甲基(四氢-2H-吡喃-4-基)氨基)-2-(4-((4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，1-(4-((5-(4-氟苯甲酰基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-4-基)氨基)哌啶-1-基)丙-2-烯-1-酮，1-(4-((5-(4-氟苯甲酰基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-4-基)氨基)哌啶-1-基)-2，2-二甲基丙-1-酮，1-(4-((5-(4-氟苯甲酰基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-4-基)氨基)哌啶-1-基)-3，3-二甲基丁-1-酮，(4-氟苯基)(2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-4-(氧杂环丁烷-3-基氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(4-((3-甲基氧杂环丁烷-3-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(S)-(4-氟苯基)(4-((1-羟基-4-甲基戊烷-2-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(R)-(4-氟苯基)(4-((1-羟基-4-甲基戊烷-2-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(R)-(4-氟苯基)(4-(1-羟基-3，3-二甲基丁-2-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(S)-(4-氟苯基)(4-((1-羟基-3，3-二甲基丁-2-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-4-((2-(四氢-2H-吡喃-4-基)乙基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-4-((四氢-2H-吡喃-3-基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-4-((2-吗啉乙基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-((2-(二乙基氨基)乙基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(4-氟苯基)甲酮，(4-氟苯基)(2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-4-((2-(吡咯烷-1-基)乙基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-4-((2-(哌啶-1-基)乙基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(4-((4-羟基四氢-2H-吡喃-4-基)甲基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(4-((3-(羟甲基)苯基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(4-((6-(羟甲基)吡啶-3-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-(((1r，4r)-4-氨基环己基)氨基)-2-(4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(4-氟苯基)甲酮，(4-氟苯基)(4-(((1r，4r)-4-(羟甲基)环己基) 氨基)-2-((1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-((2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-4-基)氨基)哌啶-1-基)甲醇，(4-氟苯基)(4-(((1r，4r)-4-(羟甲基)环己基)氨基)-2-((3-甲氧基-1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，((1r，4r)-4-((2-((4-吗啉苯基)氨基)噻吩并[2，3-d]嘧啶-4-基)氨基)环己基)甲醇。
本发明提供一种制备式I化合物的方法，包含其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药的方法，包括如下步骤：
Figure PCTCN2022119451-appb-000132
1)2,4-二氯-7H-吡咯并[2,3-d]嘧啶与
Figure PCTCN2022119451-appb-000133
反应得到式Ⅰ-a化合物；优选该反应在有机溶剂中进行，所述有机溶剂为极性溶剂；优选所述的有机溶剂为二氯甲烷、丙酮。
2)化合物Ⅰ-a与2-(三甲基硅烷基)乙氧甲基氯(SEM-Cl)在加热条件下反应得到Ⅰ-b化合物；优选地，该反应温度为30～60℃；
该反应在有机溶剂中进行，所述有机溶剂：N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)、N,N-二异丙基乙胺(DIPEA)、N-甲基-2-吡咯烷酮(NMP)、乙二醇二甲醚、异丙醇、正丁醇、仲丁醇、叔丁醇中的至少的一种；
该反应在碱性条件下进行，所述碱为无机碱或有机碱，其中无机碱选自氨、碳酸钾、碳酸钠、碳酸铯，有机碱选自乙酸钠、三乙胺、二异丙基乙基胺、三乙烯二胺、吡啶、4-二甲氨基吡啶、1，8-二氮杂二环十一碳-7-稀、N-甲基吗啉中至少一种；
3)Ⅰ-b化合物与胺Pg或醇Pf在加热条件下反应得到Ⅰ-c化合物；
优选地，该反应温度为80～100℃；
该反应是在有机溶剂和碱条件下进行，所述碱和有机溶剂独立选自步骤2)中的相关限定；
4)Ⅰ-c化合物与胺L在加热条件下反应得到Ⅰ-d化合物，优选地，该反应温度为100～130℃；该反应是在有机溶剂和碱条件下进行，所述碱和有机溶剂独立选自步骤2中的相关限定；
该反应为应用钯催化剂和有机膦配体的Buchwald-hartwig偶联反应，所用的钯催化剂选自醋酸钯、二氯化钯、[1,1'-双(二苯基膦)二茂铁]二氯化钯、三(二亚苄基丙酮)二钯、四三苯基膦钯、双三苯基膦二氯化钯，所用的有机膦配体包含但不限于2-二环己基膦-2',4',6'-三异丙基联苯、1,1'-联萘-2,2'-双二苯膦、2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯；
5)Ⅰ-d化合物在酸条件下脱三甲基硅基乙氧基甲基(SEM基团)，其中所述酸为无机酸或有机酸，其中无机酸选自氢氯酸、氢溴酸、氢氟酸，氢碘酸、硝酸、亚硝酸、偏磷酸中至少一种，其中有机酸选自乙酸、三氯乙酸、三氟乙酸、羟基乙酸、氨基磺酸、对甲苯磺酰酸、乙二胺四乙酸(EDTA)、乙二酸、柠檬酸中至少一种；
6)步骤5所得产品在碱的条件下中和得到式Ⅰ化合物；
所述碱为无机碱或有机碱，其中无机碱选自氨、碳酸钾、碳酸钠、碳酸铯，有机碱选自乙酸钠、三乙胺、二异丙基乙基胺、三乙烯二胺、吡啶、4-二甲氨基吡啶、1，8-二氮杂二环十一碳-7-稀、N-甲基吗啉中至少一种。
其中，Rc、Ra、Rb、R 1a、R 1b如前文所定义，E为保护基，选自SEM基、苄氧羰基、对甲苯磺酰基、苯磺酰基、乙酰基、三氟乙酰基、芴甲氧羰基、苄基。
本发明提供一种制备式Ⅱ化合物的方法，包含其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药的方法，包括如下步骤：
Figure PCTCN2022119451-appb-000134
起始原料2,4-二氯-7H-吡咯并[2,3-d]嘧啶与
Figure PCTCN2022119451-appb-000135
反应得到化合物Ⅱ-a；接下来的各步骤采用上述反应式中的物质，反应条件同式I相应步骤中的反应条件，制备而得式Ⅱ；其中，反应式中各取代基的限定同通式I中合成路线中的相应各取代基的限定或同式Ⅱ中的相应限定。
本发明提供一种制备式Ⅲ化合物的方法，包含其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药的方法，包括如下步骤：
Figure PCTCN2022119451-appb-000136
1)起始原料2,4-二氯-7H-吡咯并[2,3-d]嘧啶与
Figure PCTCN2022119451-appb-000137
反应得到化合物Ⅲ-a；
接下来的步骤2)和3)采用上述反应式中的物质，反应条件同式I相应步骤中的反应条件，制备而得式Ⅲ-c；其中，反应式中各取代基的限定同通式I中合成路线中的相应各取代基的限定或同式Ⅱ中的相应限定；
4)化合物Ⅲ-c与
Figure PCTCN2022119451-appb-000138
在加热条件下反应得到化合物Ⅲ-d，
优选地，该反应温度为100～130℃；
该反应是在有机溶剂和碱条件下进行，所述碱和有机溶剂独立选自式Ⅰ化合物合成步骤2)中的相关限 定；
该反应为应用钯催化剂和有机膦配体的Buchwald-hartwig偶联反应，所述的钯催化剂和有机膦配体独立选自式Ⅰ化合物合成步骤2)中的相关限定；
步骤5)和6)采用与式Ⅰ相应步骤相同的制备方法，制备得式Ⅲ。
本发明提供一种制备式Ⅳ化合物的方法，包含其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药的方法，包括如下步骤：
Figure PCTCN2022119451-appb-000139
1)2,4-二氯-7H-吡咯并[2,3-d]嘧啶与
Figure PCTCN2022119451-appb-000140
反应得到Ⅳ-a化合物；
接下来的步骤2)和3)采用上述反应式中的物质，反应条件同式I相应步骤中的反应条件，制备而得式Ⅳ-c；其中，反应式中各取代基的限定同通式I中合成路线中的相应各取代基的限定或同式Ⅱ中的相应限定；
4)化合物Ⅳ-c与
Figure PCTCN2022119451-appb-000141
在加热条件下反应得到化合物Ⅳ-d，
优选地，该反应温度为100～130℃；
该反应是在有机溶剂和碱条件下进行，所述碱和有机溶剂独立选自式Ⅰ化合物合成步骤2)中的相关限定；
该反应为应用钯催化剂和有机膦配体的Buchwald-hartwig偶联反应，所述的钯催化剂和有机膦配体独立选自式Ⅰ化合物合成步骤2)中的相关限定；
步骤5)和6)采用与式Ⅰ相应步骤相同的制备方法，制备得式Ⅳ。
本发明的进一步目的在于提供一种含有有效剂量的本发明化合物，其立体异构体或其药学上可接受的盐，和一种或多种药学上可接受的药用辅料制成的药物组合物。本发明化合物可单独或者与一种或一种以上药用载体制成不同剂型，例如片剂、丸剂、散剂、胶囊剂、颗粒剂、糖浆剂、乳剂、微乳剂或注射剂等，具体为如静脉输注、皮下输注、肌肉输注、腹腔内输注、透皮输注和直接输注到组织中，以供临床口服、注射或局部用药。
当本发明的药物组合物以口服制剂的形式制备时，本领域已知的成分可以不受限制地用作药学上可接受的载体，只要它们不干扰活性成分的活性表达即可。载体可以包括，例如赋形剂、稀释剂、崩解剂、粘合剂、助流剂、表面活性剂、乳化剂、助悬剂、稀释剂等，但不限于此。
当本发明的药物组合物以注射剂形式制备时，本领域已知的成分可以不受限制地用作药学上可接受的载体，只要它们不干扰活性成分的活性表达即可。具体地，载体可以包括例如水、盐水、葡萄糖水溶液、伪糖水溶液、醇、二醇、醚(例如，聚乙二醇400)、油、脂肪酸、脂肪酸酯、甘油酯、表面活性剂、助悬剂、乳化剂等，但不限于此。
在这些不同制剂中，本发明化合物的含量可以是0.1％-99.9％。本发明化合物的给药量可以是0.001-10000mg/kg/0.3天，根据临床需要可以适度调整。
本发明所述的“药学上可接受的盐”是指药学上可接受的酸或碱加成盐，或其溶剂化物、水合物。
本发明的另一目的在于提供该类化合物，其立体异构体或其药学上可接受的盐及其药物组合物在制备抗肿瘤药物中的应用。所述肿瘤选自肺癌、肝癌、结肠癌、胰腺癌、乳腺癌、前列腺癌、脑癌、卵巢癌、宫颈癌、睾丸癌、肾癌、头颈癌、淋巴癌、黑色素瘤或白血病。进一步的，所述肿瘤选自肺癌、肝癌或乳腺癌。优选肺癌。一系列肿瘤细胞测试结果表明，本发明的化合物具有广谱抗肿瘤活性，其IC 50值均处于纳摩尔至微摩尔级，与阳性对照药Brigatinib、Avitinib、Osimertinib活性相当，部分化合物优于阳性药。
本发明的另一目的在于提供该类化合物，其立体异构体，其前药，其代谢产物或其药学上可接受的盐及其药物组合物在制备抗肿瘤药物中的应用。所述肿瘤选自肺癌、肝癌、腹水瘤、脑转移瘤、结肠癌、胰腺癌、乳腺癌、前列腺癌、脑癌、卵巢癌、宫颈癌、睾丸癌、肾癌、头颈癌、淋巴癌、黑色素瘤或白血病；优选选自肺癌、肝癌、乳腺癌、腹水瘤、胰腺癌、脑转移瘤；其中所述肺癌选自非小细胞肺癌或小细胞肺癌；更优选选自非小细胞肺癌、肝癌、乳腺癌、腹水瘤；其中所述的非小细胞肺癌为肺腺癌。在本发明的一个具体实施方案中，所述的肺癌选自EGFR突变肺癌、KRAS突变肺癌、HER2突变肺癌、PIK3CA突变肺癌、BRAF突变肺癌、MET基因突变肺癌或ALK基因重排肺癌、ROS1基因重排肺癌、RET基因重排肺癌。进一步地，在本发明的一个具体实施方案中，所述的EGFR突变肺癌选自EGFR-Del19突变肺癌、EGFR-L858R突变肺癌、EGFR-C797S突变肺癌、EGFR-C797S/T790M突变肺癌、EGFR-L858R/T790M突变肺癌、EGFR-Del19/T790M突变肺癌、EGFR-L858R/T790M/C797S突变肺癌、EGFR-Del19/T790M/C797S突变肺癌、EGFR D770-N771 ins NPG突变肺癌或EGFR D770-N771 ins NPG/T790M突变肺癌。在本发明的一个具体实施方案中，所述的EGFR突变肺癌为EGFR Del19/T790M/C797S突变肺癌。在本发明的另一个具体实施方案中，所述EGFR突变肺癌为EGFR D770-N771 ins NPG突变肺癌或EGFR D770-N771 insNPG/T790M突变肺癌。
本发明的再另外的目的在于提供一种治疗肿瘤的方法，包括将治疗有效量的上述的该类化合物，其立体异构体或其药学上可接受的盐及其药物组合物施用于受试者或患者。所述肿瘤选自选自肺癌、肝癌、腹水瘤、脑转移瘤、结肠癌、胰腺癌、乳腺癌、前列腺癌、脑癌、卵巢癌、宫颈癌、睾丸癌、肾癌、头颈癌、淋巴癌、黑色素瘤或白血病；优选选自肺癌、肝癌、乳腺癌、腹水瘤、胰腺癌、脑转移瘤；更优选选自非小细胞肺癌、肝癌、乳腺癌、腹水瘤。一系列肿瘤细胞测试结果表明：本发明提供了一类结构新颖的EGFR抑制活性化合物，与现有的近似化合物相比，本发明的化合物具有更低的肿瘤细胞抑制浓度。本发明化合物对EGFR D770-N771 ins NPG和EGFR D770-N771 ins NPG/T790M激酶具有显著的抑制活性，对EGFR-Del19/T790M/C797S激酶有着很好的抑制作用，对KC-0122:Ba/F3EGFR-L858R/T790M/C797S三突变细胞系和KC-0116:Ba/F3EGFR-Del19/T790M/C797S三突变细胞系的细胞增殖有很好的抑制作用，对EGFR野生型细胞系A549的抑制作用较弱，选择性好。本发明提供的化合物对突变型EGFR或EGFR突变的癌细胞具有优异的抑制活性。本发明提供的化合物具备极大的产业化和商品化前景以及市场价值，经济效益显著。本发明提供的化合物具有极大的产业化和商品化前景以及市场价值，经济效益显著。
虽然本文已经显示和描述了本发明的优选实施方案，但对本领域技术人员显而易见的是，此类实施方案仅通过举例的方式提供。现在，本领域技术人员会想到不背离本发明的许多改变、变化和替代。应理解的是，对本发明所述的本发明实施方案的各种替代可用于实施本发明。所附权利要求旨在限定本发明范围，并且由此覆盖了在这些权利要求范围内的方法和结构及其等同形式。
某些化学术语
除非另有定义，否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。除非另有说明，本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。
应理解，上述简述和下文的详述为示例性且仅用于解释，而不对本申请主题作任何限制。在本申请中，除非另有具体说明，否则使用单数时也包括复数。还应注意，除非另有说明，否则所用“或”、“或者”表示“和/或”。此外，所用术语“包括”以及其它形式，例如“包含”、“含”和“含有”都属非限制性描述。
可在参考文献(包括Carey and Sundberg"ADVANCED ORGANIC CHEMISTRY 4TH ED."Vols.A(2000)and B(2001),Plenum Press,NewYork)中找到对标准化学术语的定义。除非另有说明，否则采用本领域技术范围内的常规方法，如质谱、NMR和药理学方法。除非提出具体定义，否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送，以及对患者的治疗中使用标准技术。例如，可利用厂商对试剂盒的使用说明，或者按照本领域公知的方式或本申请的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述，按照本领域熟知的常规方法实施上述技术和方法。在本说明书 中，可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。
当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结
构式时所得到的在化学上等同的取代基。举例而言，CH2O等同于OCH2。
本申请所述的“化合物”是指包括所有立体异构体、几何异构体、互变异构体和同位素。本申请化合物可以是不对称的，例如，具有一个或多个立体异构体。除非另有说明，所有立体异构体都包括，如对映异构体和非对映异构体。本申请的含有不对称取代碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。本申请化合物还包括互变异构体形式。互变异构体形式来源于一个单键与相邻的双键交换并一起伴随一个质子的迁移。本申请的化合物还包括所有同位素的原子，无论是在中间体或最后的化合物。同位素的原子包括具有相同的原子数，但不同质量数。例如，氢的同位素包括氚和氘。也就是说，本申请的化合物包括部分氢或全部氢(H)被氚(T)和/或氘(D)所替代的化合物；还包括部分或全部 12C被 13C和/或 14C替代的化合物；以及其他同位素(如N,O,P,S)之间替代的化合物,如 14N与 15N； 18O与 17O； 31P与 32P； 35S与 36S等。本文所述化合物可具有一个或多个立体异构中心，且各个异构中心可以以R或S构型或其组合的形式存在。类似地，本文所述化合物可具有一个或多个双键，且各双键可以以E(反式)或Z(顺式)构型或其组合的形式存在。一个特定的立体异构体、结构异构体、非对映异构体、对映异构体或差向异构体应被理解为包括所有可能的异构体，如立体异构体、结构异构体、非对映异构体、对映异构体或差向异构体及其混合物。因此，本文所述化合物包括所有构型上不同的立体异构体、结构异构体、非对映异构体、对映异构体或差向异构体形式以及其相应的混合物。用于转化特定立体异构体或使特定立体异构体保持原状的技术，以及拆分立体异构体混合物的技术是本领域熟知的，本领域技术人员能够就具体情况选择适合的方法。
术语“任选/任意”或“任选地/任意地”是指随后描述的事件或情况可能发生或可能不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。
本文所用C 1-3或C1-3是指该部分中具有1-3个碳原子，即基团包含1个碳原子，2个碳原子、3个碳原子。因此，举例而言“C1-3烷基”是指在有1-3个碳原子的烷基，即所述烷基选自甲基、乙基、丙基、异丙基。
本文单独或组合使用的术语“烷基”是指任选取代的直链或任选取代的支链的脂肪族烃类。本文的“烷基”优选可具有1-约20个碳原子，例如具有1-约10个碳原子，具有1-约8个碳原子，或1-约6个碳原子，或1-约4个碳原子或1-约3个碳原子。本文的烷基实施例包括但不限于甲基、乙基、正丙基、异丙基等。
本文组合使用的“烷基”包括与其他基团结合的烷基，例如烷氧基中的烷基。
本文单独或组合使用的术语“卤素”选自F,Cl,Br,I。
本文所用的术语“治疗”和其它类似的同义词包括缓解、减轻或改善疾病或病症症状，抑制疾病或病症，例如阻止疾病或病症的发展，缓解疾病或病症，使疾病或病症好转，缓解由疾病或病症导致的症状，或者中止疾病或病症的症状，预防其它症状，改善或预防导致症状的潜在代谢原因，此外，该术语包含预防的目的。该术语还包括获得治疗效果和/或预防效果。所述治疗效果是指治愈或改善所治疗的潜在疾病。此外，对与潜在疾病相关的一种或多种生理症状的治愈或改善也是治疗效果，例如尽管患者可能仍然受到潜在疾病的影响，但观察到患者情况改善。就预防效果而言，可向具有患特定疾病风险的患者施用所述组合物，或者即便尚未做出疾病诊断，但向出现该疾病的一个或多个生理症状的患者施用所述组合物。
本文所使用术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种活性物质(如本申请的化合物)的量。其结果可以为迹象、症状或病因的消减和/或缓解，或生物系统的任何其它所需变化。例如，用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。
本文针对制剂、组合物或成分所用术语“可接受的”是指对接受治疗的受试者的一般健康情况没有长期的有害影响。
本文所用术语“药学可接受的”是指不影响本申请化合物的生物活性或性质的物质(如载体或稀释剂)，并且相对无毒，即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
本文所用术语“药物组合物”是指本申请的化合物与至少一种药学可接受的物质相混的混合物。所述药学可接受的物质包括但不限于载体、稳定剂、稀释剂、分散剂、悬浮剂、增稠剂和/或赋形剂。
本文所用术语“载体”是指相对无毒的物质，其有助于将本申请的化合物引入到细胞或组织中。
本文所用术语“药学可接受的盐”是指保留了指定化合物的游离酸和游离碱的生物效力，并且在生物学或其它方面上没有不良作用的盐。本申请化合物还包括药学可以接受的盐。药学可接受的盐是指把母体化合物中的碱基基团转换成盐的形式。药学可接受的盐包括，但不仅限于，碱基基团例如胺(氨)基 的无机或有机酸盐类。本申请药学可接受的盐可以由母体化合物合成，即母体化合物中的碱性基团与1-4当量的酸在一个溶剂系统中反应。合适的盐列举在Remingtong’s Pharmaceutical Scicences,17th ed.,Mack Publishing Company,Easton,Pa.,1985,p.1418和Journal of Pharmaceutical Science,66,2(1977)中。
除特别指示外，本申请中的盐指用有机酸/无机酸形成的酸式盐，以及用有机碱/无机碱形成的碱式盐。
“EGFR”是指表皮生长因子受体。
对本领域技术人员而言，“EGFR突变阴性”通常是指按照临床诊断常用的基因检测方法未检测到EGFR基因突变。EGFR突变状态可用多种方法进行检测，DNA突变检测是检测EGFR状态的首选方法，多种DNA突变检测分析可以用于检测肿瘤细胞的EGFR突变状态，对于非小细胞肺癌患者最常见的EGFR突变为外显子19缺失和外显子21突变，外显子18-21(或仅外显子19和21)的直接DNA测序是一种合理的选择。
“晚期”，是指根据病变的程度和并发疾病对非小细胞肺癌进行分期，例如可以是按照AJCC cancer staging manual肺癌分期系统中TNM分类法的Ⅲ-Ⅳ期的非小细胞肺癌，在一些实施方案中，晚期非小细胞肺癌为ⅢB-Ⅳ期的非小细胞肺癌。
本文中，除非另有说明，这里提供的剂量和范围都是基于本发明化合物游离碱形式的分子量计算得到。
附图说明
图1各组小鼠肿瘤体积曲线图
图2各组小鼠肿瘤重量曲线图
具体实施方式
为了更清晰阐述本发明，在此列举一系列的实施例。这些实施例是例证性的，不应当理解为对本发明的限制。
本发明提供了制备相应化合物的方法，可以使用多种合成方法制备本文所述的化合物，包括下述实施例中所涉及的方法，本发明的化合物或者其药学上可接受的盐、异构体或水合物可以使用下述方法与有机化学合成领域已知的合成方法，或通过本领域技术人员理解对这些方法的变化方法合成，优选方法包括但不限于下述方法。
实施例1
Figure PCTCN2022119451-appb-000142
向250mL圆底烧瓶中加入2,4-二氯-7H-吡咯并[2,3-d]嘧啶5.0g，二氯甲烷100mL，冰水浴搅拌下加入三氯化铝14.15g，搅拌0.5h，逐滴加入用50mL二氯甲烷稀释的异丁酰氯(化合物1)3.5mL。加毕，升温至回流反应12h。体系倒入冰水中，搅拌1h。水相用二氯甲烷萃取，合并有机相。有机相经饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩至干，残余物经硅胶柱色谱分离(石油醚：乙酸乙酯10:1)得2,4-二氯-5-(2-甲基丙酮基)-7H-吡咯并[2,3-d]嘧啶(中间体2)。
向100mL圆底烧瓶中加入2g中间体2、N,N-二甲基甲酰胺30mL、碳酸钾2.65g，油浴控温40℃下逐滴加入用20mLN,N-二甲基甲酰胺稀释的2-(三甲基硅烷基)乙氧甲基氯1.7mL，加毕，维持40℃搅拌4h。将体系倒入水中，水相用乙酸乙酯萃取，合并有机相，有机相经饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩至干，残余物经硅胶柱色谱分离(石油醚：乙酸乙酯15:1)得2,4-二氯-5-(2-甲基丙酮基)-7-(三甲基硅基乙氧基甲基)-7H-吡咯并[2,3-d]嘧啶(中间体3)。
向50mL茄形烧瓶中加入200mg中间体3、N,N-二甲基甲酰胺10mL、碳酸钾186mg和(R)-1- 环丙基磺酰基-3-氨基哌啶(化合物4)，油浴90℃搅拌3h。减压蒸除N,N-二甲基甲酰胺，残余物加水20mL，超声搅拌10min后抽滤，滤饼烘干得(R)-2-氯-4-(1-环丙基磺酰基-3-哌啶氨基)-5-(2-甲基丙酰基)-7-(三甲基硅基乙氧基甲基)-7H-吡咯并[2,3-d]嘧啶(中间体5)。
向100mL茄形烧瓶中加入中间体5(150mg)、4-(4-甲基-1-哌嗪基)-1-苯胺(化合物6)(45mg)、Pd 2(dba) 3(27mg)、X-Phos(43mg)、碳酸钾124mg和1,4-二氧六环10mL，氮气氛围保护下油浴110℃搅拌4h。减压浓缩至干，残余物经硅胶柱色谱分离(二氯甲烷：甲醇20:1)得2-(4-(4-甲基-1-哌嗪基)-1-苯氨基)-4-(四氢吡喃-4-氨基)-5-(2-甲基丙酰基)-7-(三甲基硅基乙氧基甲基)-7H-吡咯并[2,3-d]嘧啶(中间体7)。
向100mL茄形烧瓶中加110mg中间体5、二氯甲烷5mL、三氟乙酸2mL，室温搅拌2h。减压蒸除二氯甲烷和三氟乙酸，加入甲醇10mL、氨水4mL，室温搅拌4h。减压蒸除甲醇和氨水，残余物经硅胶柱色谱分离(二氯甲烷：甲醇20:1)得(R)-2-(4-(4-甲基-1-哌嗪基)-1-苯氨基)-4-(1-环丙基磺酰基-3-哌啶氨基)-5-(2-甲基丙酰基)-7H-吡咯并[2,3-d]嘧啶。 1H NMR(600MHz,DMSO-d 6)δ12.01(s,1H),9.09(d,J＝7.8Hz,1H),8.64(s,1H),8.08(s,1H),7.61(d,J＝9.0Hz,2H),6.84(d,J＝9.1Hz,2H),4.37–4.24(m,1H),3.70–3.61(m,1H),3.55–3.47(m,1H),3.41–3.37(m,1H),3.33–3.31(m,1H),3.11–2.98(m,6H),2.63–2.59(m,1H),2.53–2.52(m,2H),2.48–2.47(m,1H),2.24(s,3H),2.03–1.87(m,2H),1.70–1.54(m,2H),1.11(d,J＝6.8Hz,6H),0.97–0.89(m,4H).MS/[M+H]+:581.36
实施例2
Figure PCTCN2022119451-appb-000143
实施例2的制备采用与实施例1相同的制备方法。 1H NMR(600MHz,DMSO-d 6)δ11.88(s,1H),8.69(s,1H),7.96(dd,J＝8.5,5.7Hz,2H),7.62(d,J＝8.9Hz,2H),7.37(t,J＝8.7Hz,2H),7.32(d,J＝2.5Hz,1H),6.86(d,J＝9.0Hz,2H),4.41–4.27(m,1H),3.93–3.78(m,2H),3.21–3.11(m,2H),3.10–3.00(m,4H),2.79(s,3H),2.49–2.45(m,4H),2.23(s,3H),1.76–1.63(m,2H),1.56–1.43(m,2H).MS/[M+H] +:544.27
实施例3
Figure PCTCN2022119451-appb-000144
实施例3的制备采用与实施例1相同的制备方法。 1H NMR(600MHz,DMSO-d 6)δ12.21(s,1H),8.85(d,J＝7.8Hz,1H),8.74(s,1H),7.84(dd,J＝8.5,5.6Hz,2H),7.63(d,J＝8.9Hz,2H),7.48(s,1H),7.36(t,J＝8.8Hz,2H),6.86(d,J＝9.0Hz,2H),4.47–4.27(m,1H),3.70–3.56(m,1H),3.33–3.31(m,1H),3.17–3.07(m,2H),3.07–3.00(m,4H),2.62–2.58(m,1H),2.55–2.52(m,4H),2.26(s,3H),2.04–1.88(m,2H),1.73–1.58(m,2H),0.99–0.88(m,4H).MS/[M+H] +:633.31
实施例4
Figure PCTCN2022119451-appb-000145
实施例4的制备采用与实施例1相同的制备方法。 1H NMR(600MHz,DMSO-d 6)δ12.15(s,1H),9.04–8.71(m,2H),7.87(s,1H),7.84(dd,J＝8.1,5.7Hz,2H),7.54–7.39(m,J＝2.3Hz,2H),7.36(t,J＝8.7Hz,2H),4.42–4.20(m,1H),3.78(s,3H),3.47–3.38(m,1H),3.34–3.29(m,1H),3.13–3.04(m,1H),3.03–2.94(m,1H),2.63–2.59(m,1H),2.09–1.88(m,2H),1.74–1.58(m,2H),0.99–0.87(m,4H).MS/[M+H] +:539.24
在通式I的合成路线的指引下，参考实施例1的具体合成步骤，合成出如下实施例8-116的化合物。
Figure PCTCN2022119451-appb-000146
Figure PCTCN2022119451-appb-000147
Figure PCTCN2022119451-appb-000148
Figure PCTCN2022119451-appb-000149
Figure PCTCN2022119451-appb-000150
Figure PCTCN2022119451-appb-000151
Figure PCTCN2022119451-appb-000152
Figure PCTCN2022119451-appb-000153
Figure PCTCN2022119451-appb-000154
Figure PCTCN2022119451-appb-000155
Figure PCTCN2022119451-appb-000156
Figure PCTCN2022119451-appb-000157
Figure PCTCN2022119451-appb-000158
Figure PCTCN2022119451-appb-000159
Figure PCTCN2022119451-appb-000160
Figure PCTCN2022119451-appb-000161
Figure PCTCN2022119451-appb-000162
Figure PCTCN2022119451-appb-000163
实施例117体外酶学实验1
本发明化合物对EGFR激酶具有良好的抑制活性，IC 50值均小于10μM。具体实验如下：
1 1x倍浓度激酶缓冲液的制备：
1体积的5倍浓度的酶缓冲液用4体积的蒸馏水稀释；5mM氯化镁；1mM DTT；1mM MnCl 2。
2.化合物活性测试方法：
a)使用Echo 550将化合物稀释液转移到检测板(784075，Greiner)的每个孔中；
b)密封测定板，将检测板以1000g离心1分钟。
c)在1x激酶缓冲液中制备2X EGFR(D770-N771 ins NPG T790M)。
d)将5μl的2X EGFR(D770-N771 ins NPG T790M)加入384孔检测板(784075，Greiner)中。
e)检测板在1000g离心30秒，室温孵育10分钟。
f)在1X激酶缓冲液中加入2x TK-底物-生物素(2uM)和ATP混合。
g)加入5μl的TK-底物-生物素(2uM)和ATP混合物开始反应。
h)检测板在1000g离心30秒。密封检测板，室温孵育40分钟。
i)在HTRF检测缓冲液中制备4X Sa-XL 665。
j)在检测板的每个孔中加入5μl Sa-XL 665和5μl TK-antibody-Cryptate(TK-抗体穴合物)。
k)检测板在1000g离心30秒，室温孵育1小时。
l)在Envision 2104读板器上读取615nm(Cryptate)和665nm(XL665)的荧光信号。
3.数据分析
3.1计算每个孔的比值(665/615nm)。
3.2抑制率计算如下：
抑制率＝100-(Signalcmpd-SignalAve_PC)/(SignalAve_VC-SignalAve_PC)×100。
3.3计算化合物的IC 50值并绘制化合物的量效曲线：
使用GraphPad 6.0把化合物浓度的对数对抑制率作非线性回归曲线(量效关系-可变斜率)来计算IC 50值。
Y＝最低值+(最高值-最低值)/(1+10^((LogIC 50-X)*斜率))
X：抑制剂浓度的对数；Y：抑制率。
3.4报告双重检验：
3.4.1一名检测人员完成报告后，另一名检测人员再次检查报告以确保数据分析正确。
3.4.2数据从软件中导出并手动分析。
3.4.2.1将比率转换为抑制率。所有的IC 50值首次使用Prism GraphPad 6.0利用抑制率计算。
3.4.2.2然后利用比值再次计算IC 50值以检查分析结果的准确性。
3.4.3确保所有化合物的编号均正确。
用上述方法，测定本发明化合物对D770-N771 ins NPG激酶的活性。
部分化合物的活性结果见表1。
表1本发明部分化合物对D770-N771 ins NPG/T790M激酶和对D770-N771 ins NPG激酶和BaF3-EGFR D770-N771 ins NPG细胞的活性研究
Figure PCTCN2022119451-appb-000164
ND表示未测定
本发明化合物对EGFR D770-N771 ins NPG、EGFR D770-N771 ins NPG/T790M激酶和携带插入突变的细胞BaF3-EGFR D770-N771 ins NPG均具有显著的抑制活性和抗增殖活性，提示本发明化合物能够抑制EGFR D770-N771 ins NPG突变、EGFR D770-N771 ins NPG/T790M突变。
实施例118体外酶学实验2
激酶缓冲液的制备、化合物活性测试方法以及数据分析参见实施例117中的相关限定，其中化合物活性测试方法c)步骤替换为：在1x激酶缓冲液中制备2X EGFR Del19 T790M C797S。
部分化合物的活性结果见表2。
表2酶学抑制结果IC 50(nM)
Figure PCTCN2022119451-appb-000165
Figure PCTCN2022119451-appb-000166
A<10nM；B 10-100nM；C 100-600nM。
本发明化合物对EGFR-Del19/T790M/C797S激酶有着很好的抑制作用。
实施例119细胞增殖抑制实验
1、实验分组
实验组(As)：细胞+培养基+药物+cck-8；对照组(A 0)：细胞+培养基+cck-8，无药物；空白组(Ac)：培养基+cck-8，无细胞、药物。
2、实验细胞株
人肺癌细胞：
HCC827 EGFR-Del19；
PC-9 EGFR-Del19；
H1975 EGFR-L858R/T790M；
A549 EGFR-WT；
KC-0122：BaF3 EGFR-L858R/T790M/C797S；
KC-0116：BaF3 EGFR-Del19/T790M/C797S；
KC-1474：PC-9 EGFR-Del19/T790M/C797S；
KC-0178：NCI-1975 EGFR-L858R/T790M/C797S。
3、细胞培养
3.1细胞复苏
从液氮中取出上述细胞的冻存管，立即放入37℃温水中并快速晃动，直至冻存液完全溶解；将细胞冻存液转移到离心管中，加入约3ml培养液，轻轻吹打混匀并在1000r/min条件下离心5分钟；弃去上清液，加入适量培养液转移至培养瓶内进行培养。
3.2细胞传代
待培养瓶中的细胞覆盖率达到80％-90％时，将原有培养液吸掉并加入适量的胰酶；待细胞变圆后，将胰酶弃掉，加入适量的培养液并用移液枪吹打混匀；弃去适量的细胞悬液并加入等量的培养液，放到培养箱中继续培养。
4.药物对细胞株的影响
取上述对数生长期细胞，用培养液调整密度为2～3×104个/ml，每孔100μl，接种于96孔板，最外周每孔加入200μl生理盐水。在培养箱中培养24h后加入不同浓度的化合物，每个药物浓度6个复孔，给药100μl每孔。培养72h，然后加入CCK-8溶液，15μl/孔。继续培养2h后在450nm波长处用酶标仪检测吸光度值。抑制率％＝[(A0-AS)/(A0-AC)]×100％。用SPSS软件计算化合物对细胞的IC 50值。
5.测试结果
表3细胞增殖抑制实验结果IC 50(μM)
Figure PCTCN2022119451-appb-000167
*<0.1μM；**0.1-1.0μM；***1.0-2.0μM；ND代表未测定。
本发明化合物对HCC827 EGFR-Del19、PC-9 EGFR-Del19突变细胞系、H1975 EGFR-L858R/T790M双突变细胞系的细胞增殖有很好的抑制作用。
本发明化合物对KC-1474：PC-9 EGFR-Del19/T790M/C797S三突变细胞系和KC-0178：NCI-1975 EGFR-L858R/T790M/C797S三突变细胞系的细胞增殖有很好的抑制作用。
表4细胞增殖抑制实验结果IC 50(μM)
Figure PCTCN2022119451-appb-000168
Figure PCTCN2022119451-appb-000169
*<0.1μM；**0.1-1.0μM；***1.0-2.0μM；ND代表未测定。
本发明化合物对KC-0122:Ba/F3 EGFR-L858R/T790M/C797S三突变细胞系和KC-0116:Ba/F3 EGFR-Del19/T790M/C797S三突变细胞系的细胞增殖有很好的抑制作用。
表5细胞增殖抑制实验结果IC 50(μM)
Figure PCTCN2022119451-appb-000170
Figure PCTCN2022119451-appb-000171
本发明化合物对KC-0122:Ba/F3 EGFR-L858R/T790M/C797S三突变细胞系和KC-0116:Ba/F3 EGFR-Del19/T790M/C797S三突变细胞系的细胞增殖有很好的抑制作用，对EGFR野生型细胞系A549的抑制作用较弱，选择性好。
实施例120体内药效研究实验
1材料
1.1动物：
雌性NPG小鼠，SPF级，体重19～22g，实验动物由北京维通达生物技术有限公司提供，实验动物生产许可证号SCXK(京)2019-0002，实验动物质量合格证号：No.110341211100087928。
1.2主要试剂及仪器设备
试剂名称：
RPMI1640，生产厂家：gibco，批号：2120614；
FBS，生产厂家：gibco，批号：2094468CP；
仪器名称：
二氧化碳培养箱，仪器厂家：Thermo，型号：BB15；
超净工作台，仪器厂家：苏州安泰空气技术有限公司，型号：SW-CJ-2FD；
离心机，仪器厂家：上海安亭科学仪器厂，型号：TDL-5A；
倒置显微镜，仪器厂家：OLYMPUS，型号：CKX31；
天平，仪器厂家：梅特勒，型号：PL2002；
游标卡尺，仪器厂家：SATA，型号：世达91512。
2实验过程
2.1细胞培养与接种
用于本实验的KC-1474细胞，以RPMI1640培养基添加10％FBS、0.5μg/mLpuromycin培养于含5％CO 2的37℃培养箱中。细胞连续培养十代之前，将KC-1474细胞调整浓度为1×10 8个/mL，与Matrigel以体积比1:1混合，0.1mL/只接种于NPG小鼠右侧胁肋部皮下，每只小鼠接种的细胞量为5×10 6个。
2.2分组及给药
当小鼠的平均肿瘤体积达到100-130mm 3左右时，根据肿瘤体积和体重，将所有小鼠随机分为六组，分别为模型组(V)、实施例60化合物口服组(po)、实施例60化合物静脉注射低剂量组(L)、实施例60化合物静脉注射中剂量组(M)。所有组每天给药一次，分组当天开始给药，连续给药39天。模型组静脉注射给予同体积溶媒，溶媒通过将2g聚乙二醇-15羟基硬脂酸酯(HS15)加入4mL二甲基亚砜(DMSO)中，再加入40mL纯化水配制而成后用0.22μm的除菌过滤器过滤制备而成。实验结束或实施人道终点时，使用戊巴比妥钠麻醉，将动物执行安乐死。
具体分组、给药方案见下表：
Figure PCTCN2022119451-appb-000172
Figure PCTCN2022119451-appb-000173
2.3检测指标
2.3.1肿瘤体积与肿瘤体积抑制率(TGI TV)
分组时测量一次肿瘤体积、分组后每周使用游标卡尺对肿瘤体积进行1次测量，安乐死前测量肿瘤体积。肿瘤体积的测量方法为：使用游标卡尺测量肿瘤的长径和短径。
肿瘤体积的计算公式为：肿瘤体积＝0.5×长径×短径 2。
肿瘤体积抑制率的计算公式为：TGI TV(％)＝[1-(Ti-T0)/(Vi-V0)]×100％
(Ti：治疗组在给药第i天的肿瘤体积均值，T0：治疗组在给药第0天的肿瘤体积均值；Vi：模型组在给药第i天的肿瘤体积均值，V0：模型组在给药第0天的肿瘤体积均值)。
2.3.2肿瘤重量与瘤重抑制率(TGI TW)
实验结束，对动物实施安乐死后剥离肿瘤组织，称量肿瘤重量，计算瘤重抑制率，计算公式如下：
TGI TW(％)＝(W 模型组-W 治疗组)/W 模型组×100％，W指肿瘤重量。
3.结果及结论
基于原始数据进行分析处理，结果分析用平均数和标准差表示(Mean±SD)。同时对肿瘤体积和肿瘤重量进行统计学分析，P<0.05认为有显著性差异。
所有动物在给药和观察期间活动和进食状态良好，无腹泻和呕吐发生，无皮疹发生。如图1所示，实验结束时，模型组小鼠平均肿瘤体积为1082±225mm 3，po组L、M组的肿瘤体积抑制率分别为28％、31％、57％；如图2所示，模型组小鼠的平均肿瘤重量为1.1792±0.0989g，po组L、M组的瘤重抑制率分别为21％、22％、61％。
综上，在小鼠KC-1474细胞皮下移植瘤模型中，与模型组相比，po组L、M组对肿瘤生长具有抑制作用，其中M组与模型组相比差异具有极显著性(P<0.001)，并且po组L、M组具有缩小肿瘤体积的效果，显示了良好的抗肿瘤药效。

Claims (29)

  1. 一种如式I所示的化合物，其立体异构体或其可药用的盐：
    Figure PCTCN2022119451-appb-100001
    其中，Rc为
    Figure PCTCN2022119451-appb-100002
    Rc 1的个数为0，1，2或3；每个Rc 1独立选自卤素和C 1-3的烷基中的至少一种；
    Ra为取代或未取代的苯基，或取代或未取代的
    Figure PCTCN2022119451-appb-100003
    所述取代基分别独立地选自卤素，C 1-3的烷基，C 1-3的烷氧基；所述苯基或
    Figure PCTCN2022119451-appb-100004
    各自的取代基个数为0或1或2；所述卤素为F，Cl，Br，I；
    R 1a选自H，
    Figure PCTCN2022119451-appb-100005
    或C 1-3的烷基；所述的Y和Z分别独立地选自N，O和C，其中N、C被0或1个C 1-3的烷基取代，不足价键由H补足；Ra 1为H或C 1-3的烷基；
    A为O或N，其中N被H，C 1-3的烷基中的至少一个取代；
    t选自0，1，2或3；
    Rb选自以下1)-5)任一一组或多组中的基团：
    1)取代或非取代的5-8元的螺杂环；所述螺杂环中的杂原子为O或S或N；所述螺杂环的取代基为一个或多个独立的取代或非取代的氨基，C 1-3的烷基，C 1-3的烷氧基，OH；所述氨基的取代基为H或一个或两个C 1-3的烷基；
    2)取代或非取代的C 8-C 11的桥环；所述桥环的取代基为一个或多个独立的取代或非取代氨基，C 1-3的烷基，C 1-3的烷氧基，OH；所述氨基的取代基为H或一个或两个C 1-3的烷基；
    3)取代或非取代的氨基；所述氨基的取代基为H或一个或两个C 1-3的烷基，或-(CH 2) a-E-(CH 2) b-，且氨基中的N与-(CH 2) a-E-(CH 2) b-两端链接成环；所述E为C或O，所述a为1或2或3或4；所述b为1或2或3或4；
    4)
    Figure PCTCN2022119451-appb-100006
    双键a的个数为0，1，2或3；a的位置为环内任何价键合理的位置；不足价键由H补足；m为0，1，2或3；n为0，1，2或3；Q和T分别独立为N，O，S或C；不足价键由H补足；
    5)
    Figure PCTCN2022119451-appb-100007
    f为1，2或3；h为0，1或2；
    Rb 1的个数为0或1或2；Rb 1为氨基，羟基，C 1-3的烷基，C 1-3的烷氧基，被羟基取代的C 1-3的烷基，SO 2R 2b，
    Figure PCTCN2022119451-appb-100008
    所述R 2b为取代或非取代的C 1-3的烷基，取代或非取代的苯基，C 3-6的环烷基，C 2-5的烯基或
    Figure PCTCN2022119451-appb-100009
    所述C 1-3的烷基或苯基的取代基为卤素或羟基；所述D选自C，P或S；所述g为1，2或3；所述e，d分别独立选自0或1或2或3；Y选自C，O或N；
    R 1b为H，NH 2，羟基，C 1-3的烷氧基，被羟基取代的C 1-3的烷基，SO 2R 2b，C 1-3的烷基，
    Figure PCTCN2022119451-appb-100010
    所述的R 2b独立为取代或非取代的C 1-3的烷基，取代或非取代的苯基，C 3-6的环烷基，C 2-5的烯基，
    Figure PCTCN2022119451-appb-100011
    所述C 1-3的烷基或苯基的取代基为卤素或羟基；所述g为1，2或3；所述e，d分别独立选自0或1或2或3；Y选自C，O或N；
    所述C 1-3的烷基为甲基、乙基、丙基或异丙基；所述C 1-3的烷氧基为甲氧基、乙氧基、丙氧基或异丙氧基；所述卤素为F，Cl，Br或I。
  2. 如权利要求1所述的化合物，其立体异构体或其可药用的盐，其特征在于，如权利要求1所述的化合物及其可药用的盐，其特征在于，Rc为
    Figure PCTCN2022119451-appb-100012
    Rc 1的个数为0，1，2或3；每个Rc 1独立选自F，Cl，Br，I和C1-3的烷基中的至少一种；
    Ra为取代或未取代的苯基，或取代或未取代的
    Figure PCTCN2022119451-appb-100013
    所述取代基分别独立地选自F，C1-3的烷基，C1-3的烷氧基；所述苯基或
    Figure PCTCN2022119451-appb-100014
    各自的取代基个数独立为0或1或2；R 1a选自H或
    Figure PCTCN2022119451-appb-100015
    或C 1-3的烷基的烷基；所述Y为C或N；所述Z为N或O，其中N、C被0或1个C1-3的烷基取代；Ra 1为H或C1-3的烷基；
    Rb选自以下1)-5)任一一组或多组中的基团：
    1)取代或非取代的5-8元的螺杂环；所述螺杂环中的杂原子为O；
    2)取代或非取代的C10的桥环；所述桥环的取代基为一个或多个独立的氨基，C1-3的烷基，C1-3的烷氧基，OH；
    3)取代或非取代的氨基；所述氨基的取代基为一个或两个C1-3的烷基，或-(CH2)a-E-(CH2)b-，且氨基中的N与-(CH2)a-E-(CH2)b-两端链接成环；所述E为C或O，所述a为1或2或3；所述b为1或2或3；
    4)
    Figure PCTCN2022119451-appb-100016
    双键a的个数为0，1，2或3；a的位置为环内任何价键合理的位置；
    m为0，1，2或3；n为0，1，2或3；Q和T分别独立为N，O，S或C；不足价键由H补足；
    5)
    Figure PCTCN2022119451-appb-100017
    f为1，2或3；h为0或1；
    Rb 1的个数为0或1或2；Rb 1为氨基，羟基，C 1-3的烷基，C 1-3的烷氧基或被羟基取代的C 1-3的烷基，SO 2R 2b，
    Figure PCTCN2022119451-appb-100018
    所述各R 2b独立为取代或非取代的C 1-3的烷基，取代或非取代的苯基，C 3-6的环烷基，C 2-5的烯基或
    Figure PCTCN2022119451-appb-100019
    所述C 1-3的烷基或苯基的取代基为卤素或羟基；所述D选自C，P或S；所述k为1或2；所述g为1，2或3；所述e，d分别独立选自0或1或2或3；Y选自C，O或N；
    R 1b为H，NH 2，羟基，C 1-3的烷氧基，被羟基取代的C 1-3的烷基，SO 2R 2b，C 1-3的烷基，
    Figure PCTCN2022119451-appb-100020
    所述的各R 2b独立为取代或非取代的C 1-3的烷基，取代或非取代的苯基，C 3-6的环烷基，C 2-5的烯基，
    Figure PCTCN2022119451-appb-100021
    所述C 1-3的烷基或苯基的取代基为卤素或羟基；所述g为1，2或3；所述e，d分别独立选自0或1或2或3；Y选自C，O或N。
  3. 如权利要求1所述的化合物，其立体异构体或其可药用的盐，其特征在于，Rc为
    Figure PCTCN2022119451-appb-100022
    Rc 1的个数为0，1，2或3；每个Rc 1独立选自F，Cl，Br，I和C 1-3的烷基中的至少一种；
    Ra为取代或未取代的苯基，或取代或未取代的
    Figure PCTCN2022119451-appb-100023
    所述取代基分别独立地选自F，C1-3的烷基，C1-3的烷氧基；所述苯基或
    Figure PCTCN2022119451-appb-100024
    各自的取代基个数独立为0或1或2；
    R 1a选自H，
    Figure PCTCN2022119451-appb-100025
    或C 1-3的烷基；所述Y为C或N；所述Z为N或O，Ra 1为H或C 1-3的烷基；
    Rb选自以下1)-5)任一一组或多组中的基团：
    1)取代或非取代的5-8元的螺杂环；所述螺杂环中的杂原子为O；
    2)取代或非取代的C10的桥环；所述桥环的取代基为一个或多个独立的氨基，C 1-3的烷基，C 1-3的烷氧基，OH；
    3)取代或非取代的氨基；所述氨基的取代基为一个或两个C 1-3的烷基，或-(CH2)a-E-(CH2)b-，且氨基中的N与-(CH2)a-E-(CH2)b-两端链接成环；所述E为C或O，所述a为1或2或3；所述b为1或2或3；
    4)
    Figure PCTCN2022119451-appb-100026
    双键a的个数为0，1，2或3；a的位置为环内任何价键合理的位置；不足价键由H补足；m为0，1，2或3；n为0，1，2或3；Q和T分别独立为N，O，S或C；不足价键由H补足；
    5)
    Figure PCTCN2022119451-appb-100027
    f为1，2或3；h为0或1；
    Rb 1的个数为0或1或2；Rb 1为氨基，羟基，C 1-3的烷基，C 1-3的烷氧基或被羟基取代的C 1-3的烷基，SO 2R 2b，
    Figure PCTCN2022119451-appb-100028
    所述各R 2b独立为取代或非取代的C 1-3的烷基，取代或非取代的苯基，C 3-6的环烷基，C 2-5的烯基或
    Figure PCTCN2022119451-appb-100029
    所述C 1-3的烷基或苯基的取代基为卤素或羟基；所述D选自C，P或S；所述k为1或2；所述g为1，2或3；所述e，d分别独立选自0或1或2或3；Y选自C，O或N；
    R 1b为H，NH 2，羟基，C 1-3的烷氧基，被羟基取代的C 1-3的烷基，SO 2R 2b，C 1-3的烷基，
    Figure PCTCN2022119451-appb-100030
    所述的各R 2b独立为取代或非取代的C 1-3的烷基，取代或非取代的苯基，C 3-6的环烷基，C 2-5的烯基，
    Figure PCTCN2022119451-appb-100031
    所述C 1-3的烷基或苯基的取代基为卤素或羟基；所述g为1，2或3；所述e，d分别独立选自0或1或2或3；Y选自C，O或N。
  4. 如权利要求1所述的化合物，其立体异构体或其可药用的盐，其特征在于，Rc为
    Figure PCTCN2022119451-appb-100032
    Rc 1的个数为0，1，2或3；每个Rc1独立选自F，Cl，C 1-3的烷基中的至少一种；
    所述Ra为取代或未取代的苯基，或取代或未取代的
    Figure PCTCN2022119451-appb-100033
    所述Ra中的苯基或
    Figure PCTCN2022119451-appb-100034
    的取代基为F，甲基，甲氧基；所述苯基或
    Figure PCTCN2022119451-appb-100035
    的各自取代基的个数为1；
    R 1a选自H，
    Figure PCTCN2022119451-appb-100036
    或C 1-3的烷基；所述Y为C或N；所述Z为N或O，Ra 1为H，CH 3或CH 2CH 3；t选自0,1或2；
    Rb选自以下1)-5)任一一组或多组中的基团：
    1)取代或非取代的5-8元的螺杂环；所述螺杂环中的杂原子为O；
    2)取代或非取代的C10的桥环；所述桥环的取代基为一个或多个独立的氨基，C 1-3的烷基，C 1-3的烷氧基，OH；
    3)取代或非取代的氨基；所述氨基的取代基为一个或两个C1-3的烷基，或 -(CH2)a-E-(CH2)b-，且氨基中的N与-(CH2)a-E-(CH2)b-两端链接成环；所述E为C或O，所述a为1或2或3；所述b为1或2或3；
    4)
    Figure PCTCN2022119451-appb-100037
    双键a的个数为0，1，2或3；a的位置为环内任何价键合理的位置；不足价键由H补足；m为0，1，2或3；n为0，1，2或3；Q和T分别独立为N，O，S或C；不足价键由H补足；
    5)
    Figure PCTCN2022119451-appb-100038
    f为1，2或3；h为0或1；
    Rb 1的个数为0或1；Rb 1为氨基，羟基，C 1-3的烷基，C 1-3的烷氧基或被羟基取代的C 1-3的烷基，SO 2R 2b，
    Figure PCTCN2022119451-appb-100039
    所述各R 2b独立为取代或非取代的C 1-3的烷基，取代或非取代的苯基，C 3-6的环烷基，C 2-5的烯基或
    Figure PCTCN2022119451-appb-100040
    所述C 1-3的烷基或苯基的取代基为卤素或羟基；所述g为1，2或3；所述e，d分别独立选自0或1或2或3；Y选自C，O或N；
    R 1b为H，NH 2，羟甲基，羟乙基，羟丙基，甲基，乙基，丙基，异丙基，OH，SO 2R 2b，(CH 3) 2CH 2，
    Figure PCTCN2022119451-appb-100041
    所述的各R 2b独立为取代或非取代的C 1-3的烷基，取代或非取代的苯基，C 3-5的环烷基，C 2-3的烯基，
    Figure PCTCN2022119451-appb-100042
    所述苯基的取代基为卤素或羟基；所述g为1，2或3；所述e，d分别独立选自0或1或2或3；Y选自C，O或N；所述卤素为F，Cl，Br或I。
  5. 如权利要求1所述的化合物，其立体异构体或其可药用的盐，其特征在于，Rc为
    Figure PCTCN2022119451-appb-100043
    Rc 1的个数为0，1，2或3；每个Rc 1独立选自F，Cl，C 1-3的烷基中的至少一种；
    Ra为取代或未取代的苯基，或取代或未取代的
    Figure PCTCN2022119451-appb-100044
    所述Ra中的苯基或
    Figure PCTCN2022119451-appb-100045
    的取代基分别独立选自F，甲基，甲氧基；所述苯基或
    Figure PCTCN2022119451-appb-100046
    的各自取代基的个数独立为0或1或2；
    R 1a选自H，
    Figure PCTCN2022119451-appb-100047
    或C 1-3的烷基；所述Y选自N，O和C；所述Z为N或O；
    Ra 1为H，CH 3或CH 2CH 3；A为O或N，其中N被一个H取代；t选自0,1或2；
    Rb选自以下1)-4)任一一组或多组中的基团：
    1)取代或非取代的7元的螺杂环；所述螺杂环中的杂原子为O；
    2)取代或非取代的金刚烷基；所述金刚烷基的取代基为一个或多个OH；
    3)取代或非取代的氨基；所述氨基的取代基为一个或两个C 1-3的烷基；
    4)
    Figure PCTCN2022119451-appb-100048
    双键a的个数为0或1；a的位置为环内任何价键合理的位置；不足价键由H补足；m为0，1，2或3；n为0，1，2；Q为C；T为N，O或C；不足价键由H补足；
    Rb 1的个数为0或1；Rb 1为氨基，羟基，C 1-3的烷基，C 1-3的烷氧基或被羟基取代的C 1-3的烷基，SO 2R 2b，
    Figure PCTCN2022119451-appb-100049
    所述各R 2b独立为取代或非取代的C 1-3的烷基，环丙烷基或C 2-3的烯基；所述C 1-3的烷基的取代基为卤素或羟基；所述e，d分别独立选自0或1或2或3；Y选自C，O或N；
    R 1b为NH 2，羟基，被羟基取代的C 1-3的烷基，C 1-3的烷氧基，SO 2R 2b或
    Figure PCTCN2022119451-appb-100050
    所述的R 2b选自C 1-3的烷基或C 3-6的环烷基；所述e，d分别独立选自1或2或3；Y选自C，O或N。
  6. 如权利要求1所述的化合物，其立体异构体或其可药用的盐，其特征在于，Rc为
    Figure PCTCN2022119451-appb-100051
    Rc 1的个数为0，1，2或3；每个Rc 1独立选自F，Cl，C 1-3的烷基中的至少一种；
    Ra为取代或未取代的苯基，或取代或未取代的
    Figure PCTCN2022119451-appb-100052
    所述取代基分别独立选自F，甲基，甲氧基；所述苯基或
    Figure PCTCN2022119451-appb-100053
    的各自取代基的个数独立为0或1或2；
    R 1a选自H，
    Figure PCTCN2022119451-appb-100054
    或C 1-3的烷基；所述Y选自N，O和C；所述Z为N或O；
    Ra 1为H，CH 3或CH 2CH 3；A为O或N，其中N被一个H取代；t选自0,1或2；
    Rb选自以下1)-4)任一一组或多组中的基团：
    1)取代或非取代的7元的螺杂环；所述螺杂环中的杂原子为O；
    2)取代或非取代的金刚烷基；所述金刚烷基的取代基为一个或多个OH；
    3)取代或非取代的氨基；所述氨基的取代基为一个或两个C 1-3的烷基；
    4)
    Figure PCTCN2022119451-appb-100055
    双键a的个数为0或1；a的位置为环内任何价键合理的位置；不足价键由H补足；m为0，1，2或3；n为0，1，2；Q为C；T为N，O或C；不足价键由H补足；
    Rb 1的个数为0或1或2；Rb 1为氨基，羟基，C 1-3的烷基，C 1-3的烷氧基或被羟基取代的C 1-3的烷基，SO 2R 2b，
    Figure PCTCN2022119451-appb-100056
    所述各R 2b独立为取代或非取代的C 1-3的烷基，环丙烷基或C 2-3的烯基；所述C 1-3的烷基的取代基为卤素或羟基；所述e，d分别独立选自0或1或2或3；Y选自C，O或N；
    R 1b为H，氨基，羟基，被羟基取代的C 1-3的烷基，C 1-3的烷氧基，SO 2R 2b或
    Figure PCTCN2022119451-appb-100057
    所述的R 2b选自C 1-3的烷基或C 3-6的环烷基；所述e，d分别独立选自1或2或3；Y选自C，O或N。
  7. 如权利要求1所述的化合物，其立体异构体或其可药用的盐，其特征在于，式I中的Rc取取代或非取代的苯基，如式II所示，所述R 1、R 2分别独立地选自H，卤素，C1-3的烷基中的至少一种，
    Figure PCTCN2022119451-appb-100058
  8. 如权利要求1所述的化合物，其立体异构体或其可药用的盐，其特征在于，式I中Rc取取代或非取代的苯基，所述Ra为取代或非取代的苯环，
    Rb为
    Figure PCTCN2022119451-appb-100059
    R 1b为H，如式III所示，
    Figure PCTCN2022119451-appb-100060
    其中，m选自0,1,2；n选自0,1,2；t选自0,1,2；W为C，O或N；R1选自H,F,Cl；R 2选自H,F,Cl；R 3选自H,MeO；R 4选自H,F；R 5选自H或
    Figure PCTCN2022119451-appb-100061
    或C 1-3的烷基；所述的Y和Z分别独立地选自N，O和C，不足价键由H补足；Ra 1为H，C 1-3的烷基；Ra 1为H或C 1-3的烷基；R 6选自H，NH 2，羟基，C 1-3的烷氧基，羟基取代的C 1-3的烷基，SO 2R 2b，C 1-3的烷基，
    Figure PCTCN2022119451-appb-100062
    所述各R 2b独立为取代或非取代的C 1-3的烷基，取代或非取代 的苯基，C 3-6的环烷基，C 2-5的烯基，
    Figure PCTCN2022119451-appb-100063
    所述D选自C，P或S；所述k为1或2；所述C 1-3的烷基或苯基的取代基为卤素或羟基；所述g为1，2或3；所述e，d分别独立选自0或1或2或3；Y选自C，O或N。
  9. 如权利要求1所述的化合物，其立体异构体或其可药用的盐，其特征在于，式I中Ra为取代或非取代的
    Figure PCTCN2022119451-appb-100064
    所述取代基为C 1-3的烷氧基，C 1-3的烷基中的至少一种；进一步的，所述取代基为H，甲氧基、乙氧基、丙氧基、异丙氧基、甲基、乙基、丙基中的一个、两个或三个。
  10. 如权利要求1所述的化合物，其立体异构体或其可药用的盐，其特征在于，式I中Ra取
    Figure PCTCN2022119451-appb-100065
    Rb选自
    Figure PCTCN2022119451-appb-100066
    R 1b为H，如式IV所示，
    Figure PCTCN2022119451-appb-100067
    其中，m选自0,1,2；n选自0,1,2；t选自0,1,2；W为C，O或N；R 1选自H,F,Cl；R 2选自H,F,Cl；R 6选自H,OH,CH 2OH，
    Figure PCTCN2022119451-appb-100068
    Figure PCTCN2022119451-appb-100069
    R 7选自H或C 1-3的烷氧基；R 8选自C 1-3的烷基或被C 1-3的烷基取代的哌啶基。
  11. 如权利要求1所述的化合物，其立体异构体或其可药用的盐，其特征在于，所述化合物选自：
    (S)-N-(1-(5-(4-氟苯甲酰基)-2-((5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)-7H-吡咯并[2，3-d]嘧啶-4-基)哌啶-3-基)环丙烷磺酰胺，(S)-N-(1-(5-(4-氟苯甲酰基)-2-((5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)-7H-吡咯并[2，3-d]嘧啶-4-基)吡咯烷-3-基)环丙烷磺酰胺，(S)-N-(1-(5-(4-氟苯甲酰基)-2-((6-(4-甲基哌嗪-1-基)吡啶-3-基)氨基)-7H-吡咯并[2，3-d]嘧啶-4-基)吡咯烷-3-基)环丙烷磺酰胺，(S)-N-(1-(5-(4-氟苯甲酰基)-2-((1-甲基-1H-吡唑-4-基)氨基)-7H-吡咯并[2，3-d]嘧啶-4-基)吡咯烷-3-基)环丙烷磺酰胺，(S)-N-(1-(5-(4-氟苯甲酰基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-4-基)哌啶-3-基)环丙烷磺酰胺，(R)-(4-((1-(环丙基磺酰基)哌啶-3-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(4-氟苯基)甲酮，(R)-(4-(1-(环丙基磺酰基)哌啶-3-基)氨基)-2-((1-甲基-1H-吡唑-4-基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(4-氟苯基)甲酮，(R)-1-(4-((1-(环丙 基磺酰基)哌啶-3-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)-2-甲基丙-1-酮，(S)-(4-(1-(环丙基磺酰基)哌啶-3-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(4-氟苯基)甲酮，(R)-(4-(1-(环丙基磺酰基)吡咯烷-3-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(4-氟苯基)甲酮，(S)-(4-(1-(环丙基磺酰基)吡咯烷-3-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(4-氟苯基)甲酮，(S)-1-(3-((5-(4-氟苯甲酰基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-4-基)氨基)哌啶-1-基)丙-2-烯-1-酮，(S)-1-(3-((5-(4-氟苯甲酰基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-4-基)氨基)吡咯烷-1-基)丙-2-烯-1-酮，(S)-(4-(1-(环丙基磺酰基)哌啶-3-基)氨基)-2-((4-(4-乙基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(4-氟苯基)甲酮，(S)-(4-(1-(环丙基磺酰基)吡咯烷-3-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(苯基)甲酮，(S)-(4-(1-(环丙基磺酰基)吡咯烷-3-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(3-氟苯基)甲酮，(S)-(4-(1-(环丙基磺酰基)吡咯烷-3-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(3，4-二氟苯基)甲酮，(4-氟苯基)(2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-4-(吗啉代氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-4-((四氢-2H-吡喃-4-基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(4-(((1r，4r)-4-(羟甲基)环己基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(S)-1-(3-((5-(2，4-二氟苯甲酰基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-4-基)氨基)吡咯烷-1-基)丙-2-烯-1-酮，(S)-1-(3-((5-(2-氟苯甲酰基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-4-基)氨基)吡咯烷-1-基)丙-2-烯-1-酮，(R)-1-(3-((5-(4-氟苯甲酰基)-2-((1-甲基-1H-吡唑-4-基)氨基)-7H-吡咯并[2，3-d]嘧啶-4-基)氨基)吡咯烷-1-基)丙-2-烯-1-酮，(S)-(4-((1-(环丙基磺酰基)吡咯烷-3-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(2，4-二氟苯基)甲酮，(R)-(4-氟苯基)(2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-4-(1-(甲磺酰基)吡咯烷-3-基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(S)-1-(3-((5-(4-氟苯甲酰基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-4-基)氨基)吡咯烷-1-基)-3，3-二甲基丁-1-酮，(S)-1-(3-((5-(4-氟苯甲酰基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-4-基)氨基)吡咯烷-1-基)-2，2-二甲基丙-1-酮，(4-氟苯基)(4-(((1s，4s)-4-羟基环己基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(S)-(4-氟苯基)(2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-4-(四氢-2H-吡喃-3-基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-4-((四氢-2H-吡喃-4-基)甲基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(4-(甲基(四氢-2H-吡喃-4-基)氨基)-2-(4-((4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，1-(4-((5-(4-氟苯甲酰基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-4-基)氨基)哌啶-1-基)丙-2-烯-1-酮，(4-氟苯基)(2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-4-((1-(甲磺酰基)哌啶-4-基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，1-(4-((5-(4-氟苯甲酰基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-4-基)氨基)哌啶-1-基)-3，3-二甲基丁-1-酮，(R)-(4-氟苯基)(2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-4-(四氢呋喃-3-基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(4-((3-甲基氧杂环丁烷-3-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(4-(((1s，3R，4s，5S，7s)-4-羟基金刚烷-1-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(R)-(4-氟苯基)(4-((1-羟基-4-甲基戊烷-2-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(S)-(4-氟苯基)(4-((1-羟基-3，3-二甲基丁-2-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-4-((2-(四氢-2H-吡喃-4-基)乙基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(4-((1-(羟甲基) 环戊基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-4-((四氢-2H-吡喃-3-基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-((2-(二乙基氨基)乙基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(4-氟苯基)甲酮，(4-氟苯基)(2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-4-((2-(吡咯烷-1-基)乙基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(4-((4-羟基四氢-2H-吡喃-4-基)甲基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(4-(((1r，4r)-4-(羟甲基)环己基)氨基)-2-((4-吗啉代苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(4-(((1r，4r)-4-(羟甲基)环己基)氨基)-2-((2-甲氧基-4-吗啉代苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(4-(((1r，4r)-4-(羟甲基)环己基)氨基)-2-((1-甲基-1H-吡唑-4-基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-4-((四氢-2H-吡喃-4-基)氧)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-(((1s，4s)-4-氨基环己基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(4-氟苯基)甲酮，(4-氟苯基)(4-((6-(羟甲基)吡啶-3-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，((1r，4r)-4-((2-((4-吗啉苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-4-基)氨基)环己基)甲醇，(4-氟苯基)(4-((1-异丙基哌啶-4-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-((3，5-双(羟甲基)苯基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(4-氟苯基)甲酮，(4-((2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-4-基)氨基)哌啶-1-基)甲醇，(3-氟苯基)(4-(((1r，4r)-4-(羟甲基)环己基)氨基)-2-((4-吗啉代苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(4-((3R，6S)-6-(羟甲基)四氢-2H-吡喃-3-基)氨基)-2-((4-吗啉代苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(2，4-二氟苯基)(4-(((1r，4r)-4-(羟甲基)环己基)氨基)-2-((4-吗啉代苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(4-(((1r，4r)-4-(羟甲基)环己基)氨基)-2-((3-甲氧基-1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-((2-氧杂螺[3.3]庚-6-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(4-氟苯基)甲酮，((1r，4r)-4-((2-((1-甲基-1H-吡唑-4-基)氨基)-7H-吡咯并[2，3-d]嘧啶-4-基)氨基)环己基)甲醇，(4-氟苯基)(4-((1-异丙基哌啶-4-基)氨基)-2-((4-吗啉代苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(3，5-二氟苯基)(4-(((1r，4r)-4-(羟甲基)环己基)氨基)-2-((4-吗啉代苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(2-((3-氟-4-(4-甲基哌嗪-1-基)苯基)氨基)-4-(((1s，4s)-4-(羟甲基)环己基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(4-氟苯基)甲酮，(4-氟苯基)(4-(((1s，4s)-4-(羟甲基)环己基)氨基)-2-((1-甲基-1H-吡唑-4-基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(4-(((1s，4s)-4-(羟甲基)环己基)氨基)-2-((2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(2-((4-(2-(二甲氨基)乙氧基)苯基)氨基)-4-(((1s，4s)-4-(羟甲基)环己基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(4-氟苯基)甲酮，(4-氟苯基)(4-((1S，4R)-4-(羟甲基)环戊-2-烯-1-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-(((1r，4r)-4-(羟甲基)环己基)氨基)-2-((4-吗啉代苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(2，3，4-三氟苯基)甲酮，(R)-1-(3-((5-(4-氟苯甲酰基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-4-基)氨基)哌啶-1-基)丙-2-烯-1-酮，(R)-1-(3-((5-(4-氟苯甲酰基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-4-基)氨基)哌啶-1-基)丙-2-烯-1-酮，(S)-(4-(1-(环丙基磺酰基)哌啶-3-基)氨基)-2-((3-氟-4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(4-氟苯基)甲酮，(S)-(4-(1-(环丙基磺酰基)哌啶-3-基)氨基)-2-((4-吗啉代苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(4-氟苯基)甲酮，(S)-(4-(1-(环丙基磺酰基)吡咯烷-3-基)氨基)-2-((4-吗啉代苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(4-氟苯基)甲酮，(S)-1-(3-((5-苯甲酰基-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-4-基)氨基)吡咯烷-1-基)丙-2-烯-1-酮，(S)-1-(3-((5-(3-氟苯甲酰基)-2-((4-(4-甲基哌嗪 -1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-4-基)氨基)吡咯烷-1-基)丙-2-烯-1-酮，(S)-1-(3-((5-(3，4-二氟苯甲酰基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-4-基)氨基)吡咯烷-1-基)丙-2-烯-1-酮，(4-氟苯基)(2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-4-(哌啶-1-基氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-(环己胺基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(4-氟苯基)甲酮，(4-氟苯基)(4-((2-羟基环己基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(S)-(4-((1-(环丙基磺酰基)吡咯烷-3-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(2-氟苯基)甲酮，(4-((2-(二甲基磷酰基)苯基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(4-氟苯基)甲酮，(R)-(4-氟苯基)(2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-4-(1-(甲磺酰基)哌啶-3-基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(S)-(3-((5-(4-氟苯甲酰基)-2-(4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-4-基)氨基)吡咯烷-1-基)(4-氟苯基)甲酮，(S)-1-(3-((5-(4-氟苯甲酰基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-4-基)氨基)吡咯烷-1-基)乙基-1-酮，(4-氟苯基)(4-(((1r，4r)-4-羟基环己基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(R)-(4-氟苯基)(2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-4-(四氢-2H-吡喃-3-基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(4-(((1s，4s)-4-(羟甲基)环己基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-4-(1-(四氢-2H-吡喃-4-基)哌啶-4-基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-((1-(环丙基磺酰基)哌啶-4-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(4-氟苯基)甲酮，1-(4-((5-(4-氟苯甲酰基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-4-基)氨基)哌啶-1-基)-2，2-二甲基丙-1-酮，(S)-(4-氟苯基)(2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-4-(四氢呋喃-3-基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-4-(氧杂环丁烷-3-基氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(4-(((1r，3s，5R，7S)-3-羟基金刚烷-1-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(S)-(4-氟苯基)(4-((1-羟基-4-甲基戊烷-2-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(R)-(4-氟苯基)(4-(1-羟基-3，3-二甲基丁-2-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-4-((四氢-2H-吡喃-4-基)甲基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(4-((1-(羟甲基)环丙基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(4-((1r，4r)-4-甲氧基环己基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-4-((2-吗啉乙基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-((2-(二甲氨基)乙基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(4-氟苯基)甲酮，(4-氟苯基)(2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-4-((2-(哌啶-1-基)乙基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(2-((3-氟-4-(4-甲基哌嗪-1-基)苯基)氨基)-4-(((1r，4r)-4-(羟甲基)环己基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(4-氟苯基)甲酮，(4-氟苯基)(4-(((1r，4r)-4-(羟甲基)环己基)氨基)-2-((2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(2-((3-氟-4-吗啉代苯基)氨基)-4-(((1r，4r)-4-(羟甲基)环己基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(4-氟苯基)甲酮，(4-氟苯基)(4-((1-异丙基哌啶-4-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-4-((1-甲基哌啶-4-基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(4-((3-(羟甲基)苯基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(2-((4-((2-(二甲氨基)乙基)(甲基)氨基)-2-甲氧基苯基)氨基)-4-((1r，4r)-4-(羟甲基)环己基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(4-氟苯基)甲酮，(2-((4-(2-(二甲氨基)乙氧基)-2-甲氧基苯基)氨基)-4-((1r，4r)-4-(羟甲基)环己基)氨 基)-7H-吡咯并[2，3-d]嘧啶-5-基)(4-氟苯基)甲酮，(4-(((1r，4r)-4-氨基环己基)氨基)-2-(4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(4-氟苯基)甲酮，(4-氟苯基)(4-(((1r，4r)-4-(羟甲基)环己基)氨基)-2-((1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(3，4-二氟苯基)(4-((1r，4r)-4-(羟甲基)环己基)氨基)-2-((4-吗啉代苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(2-((4-(2-(二甲氨基)乙氧基)-2-甲氧基苯基)氨基)-4-(((1r，4r)-4-(羟甲基)环己基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(4-氟苯基)甲酮，(4-氟苯基)(4-((3R，6S)-6-(羟甲基)四氢-2H-吡喃-3-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(4-(((1r，4r)-4-(羟甲基)环己基)氨基)-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，((1r，4r)-4-((2-((4-吗啉苯基)氨基)噻吩并[2，3-d]嘧啶-4-基)氨基)环己基)甲醇，(4-(((1r，4r)-4-(羟甲基)环己基)氨基)-2-((4-吗啉代苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(对甲苯基)甲酮，(4-(((1r，4r)-4-(羟甲基)环己基)氨基)-2-((4-吗啉代苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(苯基)甲酮，(4-氟苯基)(4-((1-甲基哌啶-4-基)氨基)-2-((4-吗啉代苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(4-(((1s，4s)-4-(羟甲基)环己基)氨基)-2-((4-吗啉代苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(2-((4-(4-乙基哌嗪-1-基)苯基)氨基)-4-(((1s，4s)-4-(羟甲基)环己基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)(4-氟苯基)甲酮，(2-氯-4-氟苯基)(4-(((1r，4r)-4-(羟甲基)环己基)氨基)-2-((4-吗啉代苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(4-(((1s，4s)-4-(羟甲基)环己基)氨基)-2-((1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(4-(((1s，4s)-4-(羟甲基)环己基)氨基)-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮，(4-氟苯基)(4-((1R，4S)-4-(羟甲基)环戊-2-烯-1-基)氨基)-2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-7H-吡咯并[2，3-d]嘧啶-5-基)甲酮。
  12. 一种如权利要求1所述式I化合物的合成方法，其特征在于，合成方法如下：
    Figure PCTCN2022119451-appb-100070
    1)化合物Ⅰ-d在酸条件下脱E基团；所述E选自三甲基硅乙氧基甲基、苄氧羰基、对甲苯磺酰基、苯磺酰基、乙酰基、三氟乙酰基、芴甲氧羰基、苄基其中一种；
    2)步骤1)所得产品在碱条件下中和得到式Ⅰ化合物。
  13. 如权利要求12所述式Ⅰ化合物的制备方法，其特征在于，其中所述I-d的制备方法如下：
    Figure PCTCN2022119451-appb-100071
    Ⅰ-c化合物与胺L在加热条件下反应生成Ⅰ-d化合物。
  14. 如权利要求13所述式Ⅰ化合物的制备方法，其特征在于，其中所述I-c的制备方法如下：
    Figure PCTCN2022119451-appb-100072
    化合物Ⅰ-b与胺Pg或醇Pf在加热条件下反应生成化合物Ⅰ-c；优选所述加热温度为80～100℃。
  15. 如权利要求14所述式Ⅰ化合物的制备方法，其特征在于，其中所述I-b的制备方法如下：
    Figure PCTCN2022119451-appb-100073
    化合物Ⅰ-a与E-Cl在加热条件下反应生成化合物Ⅰ-b；优选所述加热温度为30～60℃。
  16. 如权利要求15所述式Ⅰ化合物的制备方法，其特征在于，其中所述I-a的制备方法如下：
    Figure PCTCN2022119451-appb-100074
    2,4-二氯-7H-吡咯并[2,3-d]嘧啶与
    Figure PCTCN2022119451-appb-100075
    在冰浴条件下反应得到化合物Ⅰ-a。
  17. 一种药物组合物，包含权利要求1-11中任一项所述化合物或其药学上可接受的盐，和一种或多种药学上可接受的药用辅料。
  18. 如权利要求1-11中任一项所述化合物或其药学上可接受的盐或权利要求18所述的药物组合物，在制备成口服剂型或肠胃外剂型中的用途，所述口服剂型为片剂、丸剂、颗粒剂、散剂、胶囊剂、糖浆剂、乳剂、微乳剂；所述肠胃外剂型为注射剂。
  19. 如权利要求1-11中任一项所述化合物或其药学上可接受的盐或权利要求18所述的药物组合物，在制备调控EGFR酪氨酸激酶活性或防治EGFR相关疾病中的用途。
  20. 如权利要求19所述的用途，其特征在于，所述调控EGFR酪氨酸激酶活性或防治EGFR相关疾病包括肿瘤、糖尿病、动脉粥样硬化、免疫系统疾病、神经退行性疾病或心血管疾病。
  21. 如权利要求20所述的用途，其特征在于，所述肿瘤选自肺癌、肝癌、腹水瘤、脑转移瘤、结肠癌、胰腺癌、乳腺癌、前列腺癌、脑癌、卵巢癌、宫颈癌、睾丸癌、肾癌、 头颈癌、淋巴癌、黑色素瘤、白血病、食道癌、胃癌、皮肤癌、直肠癌、肾上腺癌、甲状腺肿瘤及其并发症。
  22. 如权利要求21所述的用途，其特征在于，所述肿瘤选自肺癌、肝癌、乳腺癌、腹水瘤、胰腺癌、脑转移瘤。
  23. 如权利要求22所述的用途，其特征在于，所述肺癌选自非小细胞肺癌或小细胞肺癌。
  24. 如权利要求23所述的用途，其特征在于，所述非小细胞肺癌选自肺腺癌、肺鳞状细胞癌或肺大细胞癌。
  25. 如权利要求24所述的用途，其特征在于，所述非小细胞肺癌为肺腺癌。
  26. 如权利要求21所述的用途，其特征在于，所述的肺癌选自EGFR突变肺癌、KRAS突变肺癌、HER2突变肺癌、PIK3CA突变肺癌、BRAF突变肺癌、MET基因突变肺癌或ALK基因重排肺癌、ROS1基因重排肺癌、RET基因重排肺癌。
  27. 如权利要求27所述的用途，其特征在于，所述的EGFR突变肺癌选自EGFR-Del19突变肺癌、EGFR-L858R突变肺癌、EGFR-C797S突变肺癌、EGFR-C797S/T790M突变肺癌、EGFR-L858R/T790M突变肺癌、EGFR-Del19/T790M突变肺癌、EGFR-L858R/T790M/C797S突变肺癌、EGFR-Del19/T790M/C797S突变肺癌、EGFR D770-N771 ins NPG突变肺癌或EGFR D770-N771 ins NPG/T790M突变肺癌。
  28. 如权利要求27所述的用途，其特征在于，所述的EGFR突变肺癌非小细胞肺癌为EGFR Del19/T790M/C797S突变的肺腺癌。
  29. 如权利要求27所述的用途，其中所述EGFR突变肺癌非小细胞肺癌选自EGFR D770-N771 ins NPG突变或EGFR D770-N771 ins NPG/T790M突变。
PCT/CN2022/119451 2021-09-18 2022-09-16 一种egfr抑制剂及其制备方法和用途 WO2023041071A1 (zh)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
CN202111117969.3 2021-09-18
CN202111117969.3A CN115838370A (zh) 2021-09-18 2021-09-18 一种egfr抑制剂及其制备方法和用途
CN202210197277.2 2022-03-02
CN202210197277.2A CN116731020A (zh) 2022-03-02 2022-03-02 一种egfr抑制剂及其制备方法和用途
CN202210197158.7A CN116726022A (zh) 2022-03-02 2022-03-02 一种egfr抑制剂在制备治疗癌症药物中的用途
CN202210197158.7 2022-03-02

Publications (1)

Publication Number Publication Date
WO2023041071A1 true WO2023041071A1 (zh) 2023-03-23

Family

ID=85602112

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/119451 WO2023041071A1 (zh) 2021-09-18 2022-09-16 一种egfr抑制剂及其制备方法和用途

Country Status (1)

Country Link
WO (1) WO2023041071A1 (zh)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103814030A (zh) * 2011-09-22 2014-05-21 辉瑞大药厂 吡咯并嘧啶及嘌呤衍生物
WO2019223777A1 (zh) * 2018-05-24 2019-11-28 北京赛特明强医药科技有限公司 一种含有芳胺基取代的吡咯并嘧啶类化合物、制备方法及其应用
CN110526941A (zh) * 2018-05-24 2019-12-03 北京赛特明强医药科技有限公司 一种含有间氯苯胺类取代基的吡咯并嘧啶类化合物、制备方法及其应用
WO2020149723A1 (ko) * 2019-01-18 2020-07-23 주식회사 보로노이 피롤로피리미딘 유도체 및 이를 유효성분으로 함유하는 단백질 키나아제 관련 질환의 예방 또는 치료용 약학적 조성물
CN111825719A (zh) * 2019-04-15 2020-10-27 北京赛特明强医药科技有限公司 一种含有芳胺基取代的吡咯并嘧啶类化合物、制备方法及其应用

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103814030A (zh) * 2011-09-22 2014-05-21 辉瑞大药厂 吡咯并嘧啶及嘌呤衍生物
WO2019223777A1 (zh) * 2018-05-24 2019-11-28 北京赛特明强医药科技有限公司 一种含有芳胺基取代的吡咯并嘧啶类化合物、制备方法及其应用
CN110526941A (zh) * 2018-05-24 2019-12-03 北京赛特明强医药科技有限公司 一种含有间氯苯胺类取代基的吡咯并嘧啶类化合物、制备方法及其应用
WO2020149723A1 (ko) * 2019-01-18 2020-07-23 주식회사 보로노이 피롤로피리미딘 유도체 및 이를 유효성분으로 함유하는 단백질 키나아제 관련 질환의 예방 또는 치료용 약학적 조성물
CN111825719A (zh) * 2019-04-15 2020-10-27 北京赛特明强医药科技有限公司 一种含有芳胺基取代的吡咯并嘧啶类化合物、制备方法及其应用

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
"Journal of Pharmaceutical Science", vol. 66, 1977, pages: 2
"Remingtong's Pharmaceutical Scicences", 1985, MACK PUBLISHING COMPANY, pages: 1418
CAREYSUNDBERG: "ADVANCED ORGANIC CHEMISTRY", 2000, PLENUM PRESS

Similar Documents

Publication Publication Date Title
CN110382499B (zh) Fgfr抑制剂及其应用
CN107759587B (zh) [1,2,4]三唑并[1,5-a]吡啶类化合物及其制备方法和医药用途
AU2013300106B2 (en) Novel pyrrolopyrimidine compounds as inhibitors of protein kinases
TWI772291B (zh) 取代的吡咯並嘧啶類ｃｄｋ抑制劑、包含其藥物組合物及其用途
CN107286077B (zh) 一种选择性的c-kit激酶抑制剂
CN113677346A (zh) 周期蛋白依赖性激酶7(cdk7)的抑制剂
JP5592890B2 (ja) ピロロトリアジンキナーゼ阻害剤
KR20160145803A (ko) Irak 억제제 및 이의 용도
TWI753918B (zh) 作為ｊａｋ抑制劑的吡咯並嘧啶化合物的結晶
JP7446287B2 (ja) Ｆｇｆｒ４阻害剤及びその使用
WO2022135432A1 (zh) 作为egfr抑制剂的大环杂环类化合物及其应用
JP7164203B2 (ja) ピロロ芳香族複素環化合物及びその製造方法並びに医薬用途
TW201718583A (zh) 新的表皮生長因子受體抑制劑及其應用
JP2021501215A (ja) アミノ置換窒素含有縮合環化合物、その調製方法及び使用
TW201516048A (zh) Ｂｃｒ－ａｂｌ激酶抑制劑及其應用
CN105732615A (zh) Cdk激酶抑制剂
JP6785876B2 (ja) ピリド［３，４−ｄ］ピリミジン誘導体及びその薬学的に許容される塩
WO2023041071A1 (zh) 一种egfr抑制剂及其制备方法和用途
WO2023006088A1 (zh) 一种用于egfr激酶抑制剂的化合物、组合物及其应用
WO2022271630A1 (en) Egfr inhibitors
CN118103371A (zh) 一种egfr抑制剂及其制备方法和用途
WO2020207419A1 (zh) 哌嗪酰胺衍生物，其制备方法及其在医药上的用途
CN115838370A (zh) 一种egfr抑制剂及其制备方法和用途
CN116731020A (zh) 一种egfr抑制剂及其制备方法和用途
CN116444488A (zh) 一种嘧啶-2,4-二胺衍生物及其制备方法和用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22869437

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2022869437

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2022869437

Country of ref document: EP

Effective date: 20240418