WO2021164697A1 - Dérivé d'amide substitué et composition de celui-ci et son utilisation - Google Patents

Dérivé d'amide substitué et composition de celui-ci et son utilisation Download PDF

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WO2021164697A1
WO2021164697A1 PCT/CN2021/076684 CN2021076684W WO2021164697A1 WO 2021164697 A1 WO2021164697 A1 WO 2021164697A1 CN 2021076684 W CN2021076684 W CN 2021076684W WO 2021164697 A1 WO2021164697 A1 WO 2021164697A1
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group
alkyl
membered heterocyclic
optionally substituted
haloalkyl
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Chinese (zh)
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王义汉
邢青峰
赵九洋
李焕银
艾义新
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深圳市塔吉瑞生物医药有限公司
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    • 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
    • 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
    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention belongs to the field of medical technology, and particularly relates to substituted amide derivatives that have inhibitory effects on wild and/or mutant EGFR and/or HER2, pharmaceutical compositions containing them, and their preparation methods and uses.
  • EGFR is a receptor tyrosine kinase that binds to epidermal growth factor (hereinafter also referred to as EGF) as a ligand to exert its physiological functions in normal tissues, and contributes to the inhibition of epithelial tissue growth and apoptosis .
  • EGF epidermal growth factor
  • Somatic mutations of the EGFR gene are known to be carcinogenic: for example, the EGFR and exon 21 regions where amino acids 746 to 750 in the exon 19 region are deleted (hereinafter also referred to as "exon 19 deletion mutations”) EGFR whose amino acid at position 858 is mutated from leucine to arginine (hereinafter also referred to as "L858R mutation”) continuously induces EGF-independent kinase activity and leads to the growth and survival of cancer cells. For example, these mutations are observed in about 30%-50% of non-small cell lung cancers in East Asia, and these mutations are also observed in about 10% of non-small cell lung cancers in Europe and the United States, so they are considered to be one of the causes of cancer. .
  • gefitinib, erlotinib, and afatinib have high anti-tumor effects in EGFR-positive lung cancers with exon 19 deletion mutations and L858R mutations, but they can cause digestive tract diseases when used in their therapeutic doses. And skin diseases and other side effects.
  • point mutations or deletion mutations in exon 18 and point mutations in exon 21 are several rarer EGFR mutations.
  • a new EGFR point mutation of lung cancer has been discovered, in which the 719th glycine in the exon 18 region is replaced by any amino acid (hereinafter referred to as the G719X mutation), and the 861th leucine in the exon 21 region is replaced by glutathione.
  • Aminoamide substitution hereinafter referred to as L861Q mutation).
  • HER2 (also known as ErbB2) is a receptor tyrosine kinase belonging to the ErbB2 family. HER2 is considered to be a proto-oncogene, and gene amplification, mutation, and overexpression of HER2 have been reported in various cancers. In these cancer cells with abnormal and overexpression of HER2 gene, the signal activation of HER2 and downstream pathways enhances the survival and proliferation signals of cancer cells.
  • HER2 mutation is one of the common driver mutation genes in lung cancer, mainly manifested as gene amplification, point mutation, exon 20 insertion mutation and other mutation types (such as deletion insertion mutation, frameshift mutation, etc.), of which exon 20 Insertion mutations are the most common.
  • the HER2 mutant contains a YVMA inserted into exon 20 (hereinafter referred to as ex20insYVMA). Mutant HER2 activates signal transduction, phosphorylates EGFR, and induces tumor formation and spread more effectively than wild-type HER2.
  • an inhibitor capable of controlling the kinase activity of HER2 exerts an antitumor effect by inhibiting the signal transduction of HER2 and downstream pathways in cancer cells, and therefore, it can be considered that it can be effectively used as a cancer therapeutic agent.
  • the present invention provides a new amide derivative and a composition containing the compound and uses thereof, which include exon 20 insertion (exon 20ins) mutant EGFR, exon 18 point mutant EGFR, and exon 21 point mutation Type EGFR, exon19del mutant EGFR, L858R mutant EGFR, exon 19 deletion/T790M mutant EGFR, L858R/T790M mutant EGFR, etc. have better inhibitory activity and high selectivity, and It has inhibitory activity on wild HER2 and/or mutant HER2, thus providing an antitumor drug with low toxicity and side effects.
  • the present invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof:
  • Ring A is an aromatic ring
  • a 1 is CR A1 or N atom
  • a 2 , A 3 and A 5 are each independently a C or N atom;
  • a 4 is CR A4 , N atom or NR A4 ;
  • R A1 and R A4 are each independently H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C (O )R a , -C(O)OR a , -C(O)NR b R c , -NR b R c , -NR a C(O)R b , -NR a C(O)OR b , -NR a C(O)NR b R c , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c , C 3-7 cycloalkyl, 3 to 7-membered heterocyclic group, C 6-10 aryl group or 5 to 10-membered heteroaryl group; and the above-mentioned groups are optionally substituted by one or more R′′;
  • B 1 is CR B1 or N
  • B 2 is CR B2 or N
  • B 3 is CR B3 or N
  • B 4 is CR B4 or N
  • R B1 , R B2 , R B3 and R B4 are each independently selected from H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 Alkynyl, -C(O)R a , -C(O)OR a , -C(O)NR b R c , -NR b R c , -NR a C(O)R b , -NR a C( O)OR b , -NR a C(O)NR b R c , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c , C 3- 7 cycloalkyl, 3 to 7 membered heterocyclyl, C 6-10 aryl or 5 to 10 membered heteroaryl; or, R B1 and R B2 , R B3
  • W is selected from bond, O, S, NR N or CR C1 R C2 ;
  • R N is selected from H, C 1-6 alkyl or C 1-6 haloalkyl, and the above groups are optionally substituted by one or more R*;
  • R C1 and R C2 are each independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl, and the above groups are optionally substituted by one or more R*;
  • L is selected from bond, O, S, NR N or (CR C1 R C2 ) p ;
  • Y is selected from C 1-6 alkyl, C 3-7 cycloalkyl or 3- to 7-membered heterocyclic group, and the above group is optionally substituted with m R;
  • Z is selected from -C(O)-, -C(O)NR N -*, -S(O) 2 -or -S(O) 2 NR N -*, where * means connected to Y;
  • R 3 is selected from H, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3 to 7 membered heterocyclic group, C 6-10 aryl or 5 to 10-membered heteroaryl group, and the above-mentioned groups are optionally substituted by one or more R*;
  • R 4 and R 5 are each independently selected from H, halogen, -CN, C 1-6 alkyl or C 1-6 haloalkyl, and the above groups are optionally substituted by one or more R*; or, R 4 and R 5 together with the double bond they are connected to form a triple bond;
  • R 1 and R 2 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 3 to A 7-membered heterocyclic group, a C 6-10 aryl group, or a 5- to 10-membered heteroaryl group; alternatively, R 1 and R 2 together with the N atom to which they are attached form a 3- to 7-membered heterocyclic group or a 5- to 10-membered heterocyclic group Aryl; and the above-mentioned groups are optionally substituted by one or more R';
  • n 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9;
  • Each R a , R b and R c is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 ring Alkyl, 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group, or R b and R c together with the N atom to which they are attached form a 3 to 7 membered heterocyclic group or 5 to 10 membered heteroaryl; wherein R a, R b and R c are defined in each group is optionally substituted by one or more D, until completely deuterated.
  • the present invention provides a pharmaceutical composition containing the compound of the present invention or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvent Compound, and pharmaceutically acceptable excipients.
  • the compound of the invention is provided in a therapeutically effective amount.
  • the compound of the invention is provided in a prophylactically effective amount.
  • the present invention provides a compound of the present invention or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or the present invention
  • the present invention provides a method of treating and/or preventing a disease in a subject, such as a wild and/or mutant EGFR kinase-mediated tumor, comprising administering to the subject
  • a disease in a subject such as a wild and/or mutant EGFR kinase-mediated tumor
  • administering comprising administering to the subject
  • the mutant EGFR is selected from exon 20 insertion mutant EGFR, exon 18 point mutant EGFR, exon 21 point mutant EGFR, exon 19 deletion mutant EGFR, or L858R mutant EGFR.
  • the exon 20 insertion mutation is a mutation in which one or more amino acids are inserted into the exon 20 region. In a specific embodiment, the exon 20 insertion mutation is a mutation in which 1 to 7 amino acids are inserted into the exon 20 region. In a specific embodiment, the exon 20 insertion mutation is a mutation in which 1 to 4 amino acids are inserted into the exon 20 region.
  • the exon 20 insertion mutation is A763_Y764insFQEA, V769_D770insASV, D770_N771insSVD, D770_N771insNPG, D770_N771insG, D770>GY, N771_P772insN, P772_R773insPR, H773_V774ins_V774ins, H773insPR, H773_V774ins_V774ins, H773_H773_H773HinsPR, H773_V774ins_V774ins, H773_VH774ins, H773_VH774ins, H773_H773_H774ins, H773_H773_H774ins_V774ins, H773_H774ins, H773_H774ins, H773_H774ins, H773_
  • the exon 18 point mutation is selected from the G719X mutation of exon 18 or the E709X mutation of exon 18.
  • the G719X mutation is selected from at least one mutation of G719A, G719S and G719C.
  • the E709X mutation is selected from at least one mutation of E709K and E709A.
  • the exon 21 point mutation is selected from the L861X mutation of exon 21.
  • the L861X mutation is a L861Q mutation.
  • the mutated EGFR has a T790M mutation and is selected from the group consisting of exon 20 insertion mutation, exon 18 point mutation, exon 21 point mutation, exon 19 deletion mutation, or L858R mutation. At least one mutation.
  • the compound of the present invention or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates are used for the treatment of expression with exon 20 Tumor patients with inserted mutated EGFR.
  • the compound of the present invention or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates are used for the treatment of expression with T790M mutation and with Tumor patients with exon 20 insertion mutation of EGFR.
  • the compound of the present invention or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates are used for the treatment of expression with exon 18 Tumor patients with point mutant EGFR.
  • the compound of the present invention or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates are used for the treatment of expression with T790M mutation and with Tumor patients with exon 18 point mutation EGFR.
  • the compound of the present invention or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates are used for the treatment of expression with exon 21 Tumor patients with point mutant EGFR.
  • the compound of the present invention or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates are used for the treatment of expression with T790M mutation and with Cancer patients with exon 21 point mutant EGFR.
  • the compound of the present invention or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates are used for the treatment of expression with exon 19 Tumor patients with deletion of mutant EGFR.
  • the compound of the present invention or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates are used for the treatment of expression with T790M mutation and with Cancer patients with exon 19 deletion mutant EGFR.
  • the compound of the present invention or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates are used for the treatment of expressing the L858R mutant EGFR Of cancer patients.
  • the compound of the present invention or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates are used for the treatment of expression with T790M mutation and with Tumor patients with L858R mutant EGFR.
  • the present invention provides a compound of the present invention or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or the present invention
  • the use of the pharmaceutical composition of the invention in the preparation of a medicament for the treatment and/or prevention of the following tumors, or the invention provides a method for the treatment and/or prevention of the following tumors in a subject, comprising:
  • the present invention provides a compound of the present invention or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or the present invention
  • the pharmaceutical composition is used in the preparation of a medicament for the treatment and/or prevention of wild and/or mutant HER2 kinase-mediated tumors.
  • the present invention provides a method of treating and/or preventing a disease in a subject, such as a wild and/or mutant HER2 kinase-mediated tumor, comprising administering to the subject
  • a disease in a subject such as a wild and/or mutant HER2 kinase-mediated tumor
  • administering comprising administering to the subject
  • the mutant HER2 is selected from G309A mutant HER2, S310F mutant HER2, R678Q mutant HER2, L775_T759 deletion mutant HER2, D769H mutant HER2, V777L mutant HER2, V842I mutant HER2, R869C Mutant HER2, L755S mutant HER2 or ex20insYVMA mutant HER2.
  • the ex20insYVMA mutant HER2 is selected from the group consisting of A775_G776insYVMA mutant HER2 mutations.
  • the present invention provides a compound of the present invention or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or the present invention
  • Figure 1 shows the growth curve of the tumor volume of each group of mice in the NCI-N87 cell in vivo model.
  • Figure 2 Curves of relative tumor volume percentage changes in each group with treatment time in the NCI-N87 cell in vivo model.
  • Figure 3 The growth curve of the tumor volume of each group of mice in the BT-474 cell in vivo model.
  • Figure 4 Curves of relative tumor volume percentage changes in each group with treatment time in the BT-474 cell in vivo model.
  • Figure 5 The body weight change curve of each group with treatment time in the NCI-N87 cell in vivo model.
  • Fig. 6 The change curve of body weight percentage of each group with treatment time in the NCI-N87 cell in vivo model.
  • Fig. 7 The change curve of body weight of each group with treatment time in the BT-474 cell in vivo model.
  • Fig. 8 The change curve of body weight percentage of each group with treatment time in the BT-474 cell in vivo model.
  • C 1-6 alkyl includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1 -2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 and C 5 -6 alkyl.
  • C 1-6 alkyl group refers to a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms, and is also referred to herein as a "lower alkyl group”. In some embodiments, C 1-4 alkyl is particularly preferred.
  • alkyl group examples include but are not limited to: methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), tert Butyl (C 4 ), sec-butyl (C 4 ), isobutyl (C 4 ), n-pentyl (C 5 ), 3-pentyl (C 5 ), pentyl (C 5 ), neopentyl (C 5 ), 3-methyl-2-butyl (C 5 ), tert-amyl (C 5 ) and n-hexyl (C 6 ).
  • each of the alkyl groups is independently optionally substituted, for example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent.
  • the appropriate substituents are as follows definition.
  • C 2-6 alkenyl group refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2-4 alkenyl is preferred. Examples of C 2-6 alkenyl groups include: vinyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), and so on.
  • C 2-6 alkenyl also includes heteroalkenyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, Phosphorus) substitution. Regardless of whether the alkenyl group is modified with “substituted", each of the alkenyl groups is independently optionally substituted, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Suitable substituents are as follows definition.
  • C 2-6 alkynyl refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 2-4 alkynyl is preferred. Examples of C 2-6 alkynyl groups include but are not limited to: ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ), pentynyl (C 5 ), hexynyl (C 6 ), and so on.
  • C 2-6 alkynyl also includes heteroalkynyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, Phosphorus) substitution. Regardless of whether the alkynyl group is modified with “substituted” in front of it, each of the alkynyl groups is independently optionally substituted, for example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent. Suitable substituents are as follows definition.
  • C 1-6 alkoxy refers to the group -OR, where R is a substituted or unsubstituted C 1-6 alkyl group. In some embodiments, C 1-4 alkoxy is particularly preferred. Specific alkoxy groups include but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, N-hexyloxy and 1,2-dimethylbutoxy. Regardless of whether the alkoxy group is modified with "substituted", each of the alkoxy groups is independently optionally substituted, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, as appropriate. The basis is defined as follows.
  • C 1-6 alkylamino refers to the group -NHR or -NR 2 , where R is a substituted or unsubstituted C 1-6 alkyl group. In some embodiments, C 1-4 alkylamino is particularly preferred.
  • the specific alkylamino group includes but is not limited to: methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, dimethylamino, methylethylamino and diethylamino.
  • each of the alkylamino groups is independently optionally substituted, for example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent.
  • the appropriate substituents are as follows definition.
  • Halo or halogen refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).
  • the halogen group is F, Cl, or Br.
  • the halogen group is F or Cl.
  • the halogen group is F.
  • C 1-6 haloalkyl and “C 1-6 haloalkoxy” refer to the above-mentioned “C 1-6 alkyl” and “C 1-6 alkoxy", which are substituted by one or more halogen groups. The group replaces.
  • C 1-4 haloalkyl is particularly preferred, and C 1-2 haloalkyl is more preferred.
  • C 1-4 haloalkoxy is particularly preferred, and C 1-2 haloalkoxy is more preferred.
  • haloalkyl groups include, but the are not limited to: -CF 3, -CH 2 F, -CHF 2, -CHFCH 2 F, -CH 2 CHF 2, -CF 2 CF 3, -CCl 3, -CH 2 Cl , -CHCl 2 , 2,2,2-trifluoro-1,1-dimethyl-ethyl, etc.
  • exemplary halogenated alkoxy groups include, but are not limited to: -OCH 2 F, -OCHF 2 , -OCF 3 , and the like.
  • C 3-10 cycloalkyl refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, C 3-7 cycloalkyl is preferred, C 3-6 cycloalkyl is particularly preferred, and C 5-6 cycloalkyl is more preferred. Cycloalkyl also includes ring systems in which the above-mentioned cycloalkyl ring is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring, and in such cases, the number of carbons continues to indicate The number of carbons in the cycloalkyl system.
  • Exemplary cycloalkyl groups include but are not limited to: cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl ( C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), cycloheptyl (C 7 ), cycloheptene Group (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1] Heptyl (C 7 ), bicyclo[2.2.2]octyl (C 8 ), cyclononyl (C 9 ), cyclononeny
  • each of the cycloalkyl groups is independently optionally substituted, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, as appropriate.
  • the basis is defined as follows.
  • heterocyclic group or a group of 3 to 10 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen and oxygen , Sulfur, boron, phosphorus and silicon.
  • the point of attachment may be a carbon or nitrogen atom.
  • a 3 to 7 membered heterocyclic group is preferred, which is a 3 to 7 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; in some embodiments, 3 to 6
  • the membered heterocyclic group is particularly preferred, which is a 3 to 6 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; more preferably a 5 to 6 membered heterocyclic group, which is a ring system having ring carbon atoms and A 5- to 6-membered non-aromatic ring system with 1 to 3 ring heteroatoms.
  • Heterocyclyl also includes ring systems in which the aforementioned heterocyclyl ring is fused with one or more cycloalkyl, aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring; and in this case, the ring The number of members continues to indicate the number of ring members in the heterocyclyl ring system.
  • each of the heterocyclic groups is independently optionally substituted, for example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent, suitably substituted
  • the basis is defined as follows.
  • Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to: aziridinyl, oxiranyl, and thiorenyl.
  • Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to: azetidinyl, oxetanyl, and thietane.
  • Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2, 5-dione.
  • Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to: dioxolane, oxasulfuranyl, disulfuranyl, and oxasulfuranyl. Oxazolidin-2-one.
  • Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridyl, and thianyl.
  • Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, dithiacyclohexyl, dioxanyl.
  • Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazinanyl.
  • Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to: azepanyl, oxepanyl, and thieppanyl.
  • Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to: azacyclooctyl, oxetanyl, and thietanyl.
  • Exemplary 5-membered heterocyclic groups fused to a C 6 aryl ring include, but are not limited to: indolinyl, isoindolinyl , Dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, etc.
  • Exemplary 6-membered heterocyclic groups fused to a C 6 aryl ring include, but are not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, and many more.
  • C 6-14 aryl refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6-14 ring carbon atoms and zero heteroatoms)
  • the shared 6, 10, or 14 ⁇ electrons) groups are arranged in a ring.
  • an aryl group having six ring carbon atoms ( “C 6 aryl”; e.g., phenyl).
  • an aryl group has ten ring carbon atoms ("C 10 aryl”; for example, naphthyl, for example, 1-naphthyl and 2-naphthyl).
  • an aryl group has fourteen ring carbon atoms ("C 14 aryl"; for example, anthryl). In some embodiments, C 6-10 aryl groups are particularly preferred, and C 6 aryl groups are more preferred.
  • the aryl group also includes a ring system in which the above-mentioned aryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the point of attachment is on the aryl ring. In this case, the number of carbon atoms continues to indicate The number of carbon atoms in the aryl ring system.
  • each of the aryl groups is independently optionally substituted, for example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent.
  • the appropriate substituents are as follows definition.
  • 5 to 10 membered heteroaryl refers to a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms (for example, having a shared ring arrangement 6 or 10 ⁇ electrons), where each heteroatom is independently selected from nitrogen, oxygen and sulfur.
  • the point of attachment may be a carbon or nitrogen atom.
  • Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heteroaryl also includes a ring system in which the above-mentioned heteroaryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the point of attachment is on the heteroaryl ring, in this case, the carbon atom The number continues to indicate the number of carbon atoms in the heteroaryl ring system.
  • a 5- to 6-membered heteroaryl group is particularly preferred, which is a 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms.
  • each of the heteroaryl groups is independently optionally substituted, for example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent, suitably substituted
  • the basis is defined as follows.
  • Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyrrolyl, furyl, and thienyl.
  • Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to: imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to: triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to: tetrazolyl.
  • Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyridyl.
  • Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to: pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively.
  • Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to: azepinyl, oxepinyl, and thiepinyl.
  • Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to: indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl , Benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, Indenazinyl and purinyl.
  • Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to: naphthyridinyl, pterridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl .
  • Carbonyl refers to the -C(O)- group.
  • Each of Raa is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclyl, aryl, and heteroaryl, or two Raa groups are combined to form a heterocyclic group or Heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently covered by 0, 1, 2, 3, 4 or 5 R dd groups Group replacement
  • Each of R cc is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R cc groups are combined to form a heterocyclic ring Group or heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently covered by 0, 1, 2, 3, 4 or 5 R dd group substitution;
  • R ee is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbon Cyclic, heterocyclic, aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5 R gg groups;
  • Each of R ff is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl, or two R ff groups are combined to form a heterocyclic group Or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently covered by 0, 1, 2, 3, 4 or 5 R gg Group substitution
  • Deuteration or “D” means that one or more hydrogens in a compound or group are replaced by deuterium; deuteration can be mono-, di-, multi-, or full-substitution.
  • deuteration can be mono-, di-, multi-, or full-substitution.
  • deuteration can be mono-, di-, multi-, or full-substitution.
  • deuterated and “one or more deuterated” are used interchangeably.
  • Non-deuterated compound refers to a compound that contains a proportion of deuterium atoms not higher than the natural deuterium isotope content (0.015%).
  • the deuterium isotope content of deuterium at the deuterated position is at least 0.015% greater than the natural deuterium isotope content, preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, more preferably greater than 95%, more preferably Greater than 99%.
  • pharmaceutically acceptable salt means that within the scope of reliable medical judgment, it is suitable for contact with human and lower animal tissues without excessive toxicity, irritation, allergic reactions, etc., and is compatible with reasonable benefits/risks. The salt in proportion.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe the pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19.
  • Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and inorganic and organic bases.
  • non-toxic acid addition salts examples include salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or salts formed with organic acids, such as acetic acid, oxalic acid, Maleic acid, tartaric acid, citric acid, succinic acid or malonic acid. It also includes salts formed using conventional methods in the art, for example, ion exchange methods.
  • salts include: adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphor Acid salt, camphor sulfonate, citrate, cypionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, gluconate, glycerin Phosphate, gluconate, hemisulfate, heptanoate, caproate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate , Malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoic acid Salt, pectinate, pers
  • Pharmaceutically acceptable salts derived from suitable bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • other pharmaceutically acceptable salts include non-toxic ammonium salts, quaternary ammonium salts and amine cations formed with counter ions such as halide, hydroxide, formate, sulfate, phosphate, Nitrate, lower alkyl sulfonate and aryl sulfonate.
  • the "subject" to be administered includes, but is not limited to: humans (ie, men or women of any age group, for example, pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young Adults, middle-aged adults or older adults)) and/or non-human animals, for example, mammals, for example, primates (for example, cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep , Goats, rodents, cats and/or dogs.
  • the subject is a human.
  • the subject is a non-human animal.
  • the terms "human", “patient” and “subject” are used interchangeably herein.
  • treatment includes the effect that occurs when a subject suffers from a specific disease, disorder, or condition, which reduces the severity of the disease, disorder, or condition, or delays or slows the disease, disorder Or the development of a condition ("therapeutic treatment"), and also includes effects that occur before the subject begins to suffer from a specific disease, disorder, or condition ("prophylactic treatment").
  • Combination and related terms refer to the simultaneous or sequential administration of the therapeutic agents of the present invention.
  • the compound of the present invention can be administered simultaneously or sequentially in separate unit dosage forms with another therapeutic agent, or simultaneously administered in a single unit dosage form with another therapeutic agent.
  • the compound of the present invention refers to the following compound of formula (I) (including a subset of each formula), or a pharmaceutically acceptable salt, hydrate or solvate thereof.
  • the present invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof:
  • Ring A is an aromatic ring
  • a 1 is CR A1 or N atom
  • a 2 , A 3 and A 5 are each independently a C or N atom;
  • a 4 is CR A4 , N atom or NR A4 ;
  • R A1 and R A4 are each independently H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C (O )R a , -C(O)OR a , -C(O)NR b R c , -NR b R c , -NR a C(O)R b , -NR a C(O)OR b , -NR a C(O)NR b R c , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c , C 3-7 cycloalkyl, 3 to 7-membered heterocyclic group, C 6-10 aryl group or 5 to 10-membered heteroaryl group; and the above-mentioned groups are optionally substituted by one or more R′′;
  • B 1 is CR B1 or N
  • B 2 is CR B2 or N
  • B 3 is CR B3 or N
  • B 4 is CR B4 or N
  • R B1 , R B2 , R B3 and R B4 are each independently selected from H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 Alkynyl, -C(O)R a , -C(O)OR a , -C(O)NR b R c , -NR b R c , -NR a C(O)R b , -NR a C( O)OR b , -NR a C(O)NR b R c , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c , C 3- 7 cycloalkyl, 3 to 7 membered heterocyclyl, C 6-10 aryl or 5 to 10 membered heteroaryl; or, R B1 and R B2 , R B3
  • W is selected from bond, O, S, NR N or CR C1 R C2 ;
  • R N is selected from H, C 1-6 alkyl or C 1-6 haloalkyl, and the above groups are optionally substituted by one or more R*;
  • R C1 and R C2 are each independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl, and the above groups are optionally substituted by one or more R*;
  • L is selected from bond, O, S, NR N or (CR C1 R C2 ) p ;
  • Y is selected from C 1-6 alkyl, C 3-7 cycloalkyl or 3- to 7-membered heterocyclic group, and the above group is optionally substituted with m R;
  • Z is selected from -C(O)-, -C(O)NR N -*, -S(O) 2 -or -S(O) 2 NR N -*, where * means connected to Y;
  • R 3 is selected from H, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3 to 7 membered heterocyclic group, C 6-10 aryl or 5 to 10-membered heteroaryl group, and the above-mentioned groups are optionally substituted by one or more R*;
  • R 4 and R 5 are each independently selected from H, halogen, -CN, C 1-6 alkyl or C 1-6 haloalkyl, and the above groups are optionally substituted by one or more R*; or, R 4 and R 5 together with the double bond they are connected to form a triple bond;
  • R 1 and R 2 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 3 to A 7-membered heterocyclic group, a C 6-10 aryl group, or a 5- to 10-membered heteroaryl group; alternatively, R 1 and R 2 together with the N atom to which they are attached form a 3- to 7-membered heterocyclic group or a 5- to 10-membered heterocyclic group Aryl; and the above-mentioned groups are optionally substituted by one or more R';
  • n 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9;
  • Each R a , R b and R c is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 ring Alkyl, 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group, or R b and R c together with the N atom to which they are attached form a 3 to 7 membered heterocyclic group or 5 to 10 membered heteroaryl; wherein R a, R b and R c are defined in each group is optionally substituted by one or more D, until completely deuterated.
  • a 1 is selected from CR A1 or N; in another embodiment, A 1 is CR A1 ; in another embodiment, A 1 is N.
  • R A1 is selected from H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C(O)R a , -C(O)OR a , -C(O)NR b R c , -NR b R c , -NR a C(O)R b , -NR a C(O)OR b , -NR a C(O)NR b R c , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c , C 3-7 cycloalkane Group, 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group, and the above groups are optionally substituted by one or more R′′.
  • R A1 is H; in another embodiment, R A1 is D; in another embodiment, R A1 is halogen; in another embodiment, R A1 is -CN; In one embodiment, R A1 is C 1-6 alkyl; in another embodiment, R A1 is C 1-6 haloalkyl; in another embodiment, R A1 is C 2-6 alkenyl; In another embodiment, R A1 is C 2-6 alkynyl; in another embodiment, R A1 is -C(O)R a ; In another embodiment, R A1 is -C(O)OR a ; In another embodiment, R A1 is -C(O)NR b R c ; In another embodiment, R A1 is -NR b R c ; In another embodiment, R A1 is -NR a C(O)R b ; in another embodiment, R A1 is -NR a C(O)OR b ; in another embodiment, R A1 is -NR a C(O)NR b R c ; In
  • R A1 is selected from H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 alkylamino, wherein The group is optionally substituted with one or more R"; in another embodiment, R A1 is selected from H, D, halogen, -CN, C 1-6 alkyl or C 1-6 haloalkyl, Wherein the group is optionally substituted with one or more R"; in another embodiment, R A1 is selected from H, D, F, Cl, Br, -CN, -Me, -CD 3 , -CHF 2 , -CH 2 F or CF 3 ; in another embodiment, R A1 is selected from H, D, F, -Me or -CD 3 ; in another embodiment, R A1 is selected from H or D; in In another embodiment, R A1 is selected from H.
  • a 2 is selected from C or N atoms; in another embodiment, A 2 is a C atom; in another embodiment, A 2 is a N atom.
  • a 3 is selected from C or N atoms; in another embodiment, A 3 is a C atom; in another embodiment, A 3 is a N atom.
  • a 4 is selected from CR A4 , N atom or NR A4 ; in another embodiment, A 2 is CR A4 ; in another embodiment, A 2 is a N atom; in another embodiment Among them, A 2 is NR A4 .
  • R A4 is selected from H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C(O)R a , -C(O)OR a , -C(O)NR b R c , -NR b R c , -NR a C(O)R b , -NR a C(O)OR b , -NR a C(O)NR b R c , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c , C 3-7 cycloalkane Group, 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group, and the above groups are optionally substituted by one or more R′′.
  • R A4 is H; in another embodiment, R A4 is D; in another embodiment, R A4 is halogen; in another embodiment, R A4 is -CN; In one embodiment, R A4 is C 1-6 alkyl; in another embodiment, R A4 is C 1-6 haloalkyl; in another embodiment, R A4 is C 2-6 alkenyl; In another embodiment, R A4 is C 2-6 alkynyl; in another embodiment, R A4 is -C(O)R a ; in another embodiment, R A4 is -C(O)OR a ; In another embodiment, R A4 is -C(O)NR b R c ; In another embodiment, R A4 is -NR b R c ; In another embodiment, R A4 is -NR a C(O)R b ; in another embodiment, R A4 is -NR a C(O)OR b ; in another embodiment, R A4 is -NR a C(O)NR b R c ; In
  • R A4 is selected from H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 alkylamino, wherein The groups are optionally substituted with one or more R"; in another embodiment, R A4 is selected from H, D, halogen, -CN, C 1-6 alkyl or C 1-6 haloalkyl, wherein The group is optionally substituted with one or more R"; in another embodiment, R A4 is selected from H, D, F, Cl, Br, -CN, -Me, -CD 3 , -CHF 2 , -CH 2 F or CF 3 ; in another embodiment, R A4 is selected from H, D, F, -Me or -CD 3 ; in another embodiment, R A4 is selected from H or D; in another In one embodiment, R A4 is selected from H.
  • a 5 is selected from C or N atoms; in another embodiment, A 5 is a C atoms; in another embodiment, A 5 is N atom.
  • B 1 is selected from CR B1 or N; in another embodiment, B 1 is selected from CR B1 ; in another embodiment, B 1 is selected from N.
  • B 2 is selected from CR B2 or N; in another embodiment, B 2 is selected from CR B2 ; in another embodiment, B 2 is selected from N.
  • B 3 is selected from CR B1 or N; In another embodiment, B 3 is selected from CR B3; In another embodiment, B 3 is selected from N.
  • B 4 is selected from CR B4 or N; In another embodiment, B 4 is selected from CR B4; In another embodiment, B 4 is selected from N.
  • R B1 , R B2 , R B3 and R B4 are each independently selected from H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkene Group, C 2-6 alkynyl, -C(O)R a , -C(O)OR a , -C(O)NR b R c , -NR b R c , -NR a C(O)R b , -NR a C(O)OR b , -NR a C(O)NR b R c , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c , C 3-7 cycloalkyl, 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group; alternatively, R B1 and R B
  • R B1 , R B2 , R B3 and R B4 are each independently H; in another embodiment, R B1 , R B2 , R B3 and R B4 are each independently D; in another In one embodiment, R B1 , R B2 , R B3 and R B4 are each independently halogen; in another embodiment, R B1 , R B2 , R B3 and R B4 are each independently -CN; in another embodiment In the scheme, R B1 , R B2 , R B3 and R B4 are each independently C 1-6 alkyl; in another embodiment, R B1 , R B2 , R B3 and R B4 are each independently C 1- 6 haloalkyl; in another embodiment, R B1 , R B2 , R B3 and R B4 are each independently C 2-6 alkenyl; in another embodiment, R B1 , R B2 , R B3 and R B4 are each independently a C 2-6 alkynyl group; in another embodiment, R B1, R B
  • R B1 and R B2 together with the C atom to which they are attached form a C 3-7 cycloalkyl group; in another embodiment, R B1 and R B2 together with the C atom to which they are attached form A 3- to 7-membered heterocyclic group; in another embodiment, R B1 and R B2 together with the C atom to which they are attached form a C 6-10 aryl group; in another embodiment, R B1 and R B2 and their The attached C atoms together form a 5- to 10-membered heteroaryl group; in another embodiment, RB3 and RB4 together with the C atom to which they are attached form a C 3-7 cycloalkyl group; in another embodiment , R B3 and R B4 together with the C atom to which they are attached form a 3- to 7-membered heterocyclic group; in another embodiment, R B3 and R B4 together with the C atom to which they are attached form a C 6-10 aryl group In another embodiment, R B3 and R B2 together with
  • R B1 , R B2 , R B3 and R B4 are each independently selected from H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 Alkoxy, C 1-6 alkylamino, C 3-7 cycloalkyl, 3 to 7 membered heterocyclic group, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl or 5 to A 10-membered heteroaryl group, or R B1 and R B2 , or R B3 and R B4 can form a C 3-7 cycloalkyl group, a 3 to 7-membered heterocyclic group, a C 6- 10- aryl or 5- to 10-membered heteroaryl; wherein the group is optionally substituted with one or more R′′; In another embodiment, R B1 , R B2 , R B3 and R B4 are each independently Selected from H, D, halogen, -CN, C 1-6 alkyl
  • W is selected from bond, O, S, NR N or CR C1 R C2 ; in another embodiment, W is selected from bond; in another embodiment, W is selected from O; in another In an embodiment, W is selected from S; in another embodiment, W is selected from NR N ; in another embodiment, W is selected from CR C1 R C2 .
  • W is selected from O or CR C1 R C2 .
  • R N is selected from H, C 1-6 alkyl or C 1-6 haloalkyl, wherein the group is optionally substituted with one or more R*; in another embodiment, RN is selected from H or methyl.
  • R C1 and R C2 are each independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl, wherein the group is optionally substituted by one or more R *Substitution; in another embodiment, R C1 and R C2 are each independently selected from H, D, or methyl; in another embodiment, R C1 and R C2 are each independently H.
  • R 1 and R 2 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 Cycloalkyl, 3 to 7 membered heterocyclyl, C 6-10 aryl or 5 to 10 membered heteroaryl; alternatively, R 1 and R 2 together with the N atom to which they are attached form a 3 to 7 membered heterocyclic group Or a 5- to 10-membered heteroaryl group; and the above-mentioned groups are optionally substituted with one or more R′.
  • R 1 and R 2 are each independently H; in another embodiment, R 1 and R 2 are each independently C 1-6 alkyl; in another embodiment, R 1 and R 2 is each independently C 1-6 haloalkyl; in another embodiment, R 1 and R 2 are each independently C 2-6 alkenyl; in another embodiment, R 1 and R 2 are each independently for C 2-6 alkynyl; in another embodiment, R 1 and R 2 are each independently a C 3-7 cycloalkyl group; in another embodiment, R 1 and R 2 are each independently 3 To 7 membered heterocyclyl; in another embodiment, R 1 and R 2 are each independently a C 6-10 aryl group; in another embodiment, R 1 and R 2 are each independently 5 to 10 membered Heteroaryl; In another embodiment, R 1 and R 2 together with the N atom to which they are attached form a 3- to 7-membered heterocyclic group; in another embodiment, R 1 and R 2 together with the N atom to which they are attached Together, the N atoms form a 3- to
  • R 1 and R 2 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, 3 To 7-membered heterocyclic group, C 6-10 aryl group or 5 to 10-membered heteroaryl group, or R 1 and R 2 together with the N atom to which they are attached form a 3- to 7-membered heterocyclic group; wherein the group The group is optionally substituted with one or more R'; in another embodiment, R 1 and R 2 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 Alkoxy or C 6-10 aryl, or, R 1 and R 2 together with the N atom to which they are attached form a 3- to 7-membered heterocyclic group; wherein the group is optionally substituted by one or more R′ Substituted; In another embodiment, R 1 and R 2 are each independently selected from H, -OMe, -
  • L is selected from bond, O, S, NR N or (CR C1 R C2 ) p ; in another embodiment, L is a bond; in another embodiment, L is O; in another In one embodiment, L is S; in another embodiment, L is NR N ; in another embodiment, L is (CR C1 R C2 ) p .
  • L is selected from bond, O, NR N or (CR C1 R C2 ) p ; in another embodiment, L is selected from bond or (CR C1 R C2 ) p ; in another embodiment, L is (CR C1 R C2 ) p .
  • p is selected from 1 or 2; in another embodiment, p is 1.
  • R N is selected from H, C 1-6 alkyl or C 1-6 haloalkyl, wherein the group is optionally substituted with one or more R*; in another embodiment, R N is selected from H or methyl; in another embodiment, R N is H; in another embodiment, R N is C 1-6 alkyl; in another embodiment, R N is described in The C 1-6 alkyl group of is optionally substituted with one or more R*.
  • R C1 and R C2 are each independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl, wherein the group is optionally substituted by one or more R* substitution; in another embodiment, R C1 and R C2 are each independently selected from H, D, or methyl; in another embodiment, R C1 and R C2 are each independently H; in another embodiment In another embodiment, R C1 and R C2 are each independently D; in another embodiment, R C1 and R C2 are each independently halogen; in another embodiment, R C1 and R C2 are each independently C 1 -6 alkyl; in another embodiment, the C 1-6 alkyl group described in R L1 and R L2 is optionally substituted with one or more R; in another embodiment, R C1 and R C2 Each is independently C 1-6 haloalkyl.
  • R C1 and R C2 are each independently selected from H, D, halogen, C 1-6 alkyl, or C 1-6 haloalkyl, wherein the group is substituted with one or more R*
  • R C1 and R C2 are each independently selected from H, D or methyl;
  • R C1 and R C2 are each independently H.;
  • Y is selected from C 1-6 alkyl, C 3-7 cycloalkyl or 3 to 7 membered heterocyclyl, wherein said group is optionally substituted with m R; in another embodiment, Y is C 1-6 alkyl; in another embodiment, Y is C 3-7 cycloalkyl; in another embodiment, Y is 3 to 7 membered heterocyclyl; in another embodiment In the scheme, the C 1-6 alkyl, C 3-7 cycloalkyl or 3- to 7-membered heterocyclic group described in Y is optionally substituted with m Rs.
  • Y is selected from 3 to 7 membered heterocyclic groups containing at least one N atom, and the N atom is connected to Z, wherein the 3 to 7 membered heterocyclic groups are optionally substituted with m R
  • Y is selected from a 3- to 7-membered heterocyclic group containing at least one N atom, and the N atom is connected to Z, wherein the 3- to 7-membered heterocyclic group is optionally selected by m Substitution from D, halogen, C 1-6 alkyl or C 1-6 haloalkyl substituents; in another embodiment, Y is selected from pyrrolidinyl or piperidinyl, and the N atom is connected to Z, wherein The pyrrolidinyl or piperidinyl group is optionally substituted with m substituents selected from D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; in another embodiment, Y is selected from pyrrole Alkyl,
  • Z is selected from -C(O)-, -C(O)NR N -*, -S(O) 2 -or -S(O) 2 NR N -*, where * represents the same as Y
  • Z is -C(O)-
  • Z is -C(O)NR N -*, where * means that it is connected to Y
  • Z is -S(O) 2 -
  • Z is -S(O) 2 NR N -*, where * means that it is connected to Y.
  • Z is selected from -C(O)- or -C(O)NR N -*, where * means that it is connected to Y.
  • R N is selected from H, C 1-6 alkyl or C 1-6 haloalkyl, and the aforementioned groups are optionally substituted with one or more R*; in another embodiment, RN is H; in another embodiment, RN is C 1-6 alkyl; in another embodiment, RN is C 1-6 haloalkyl.
  • R N is selected from H or C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with one or more R*; in another embodiment, R Z is selected from H or methyl.
  • R 3 is selected from H, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3 to 7 membered heterocyclyl, C 6 -10 aryl or 5- to 10-membered heteroaryl, wherein the group is optionally substituted with one or more R*; in another embodiment, R 3 is H; in another embodiment, R 3 is halogen; in another embodiment, R 3 is CN; in another embodiment, R 3 is C 1-6 alkyl; in another embodiment, R 3 is C 1-6 haloalkyl; In another embodiment, R 3 is C 3-7 cycloalkyl; in another embodiment, R 3 is 3 to 7 membered heterocyclyl; in another embodiment, R 3 is C 6-10 an aryl group; in another embodiment, R 3 is 5 to 10 membered heteroaryl; in another embodiment, R 3 in said C 1-6 alkyl, C 3-7 cycloalkyl, 3 The to 7-membered
  • R 3 is selected from H, halogen, -CN, C 1-6 alkyl, or C 1-6 haloalkyl, wherein the group is optionally substituted with one or more R*; In another embodiment, R 3 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl, wherein said group is optionally substituted with one or more R*; in another embodiment, R 3 is selected from H or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more dialkylamino groups.
  • R 4 and R 5 are each independently selected from H, halogen, -CN, C 1-6 alkyl, or C 1-6 haloalkyl, wherein the group is optionally substituted by one or more R* substitution; or, R 4 and R 5 together with the double bond to which they are attached form a triple bond; in another embodiment, R 4 and R 5 are each independently H; in another embodiment, R 4 and R 5 are each independently halogen; in another embodiment, R 4 and R 5 are each independently CN; in another embodiment, R 4 and R 5 are each independently C 1-6 alkyl In another embodiment, R 4 and R 5 are each independently C 1-6 haloalkyl; in another embodiment, R 4 and R 5 together with the double bond to which they are attached form a triple bond.
  • R 4 and R 5 are each independently selected from H, halogen, or CN; in another embodiment, R 4 and R 5 are each independently H.
  • Y-Z-V is selected from the following structures:
  • Y-Z-V is selected from the following structures:
  • any technical solution or any combination of any of the above specific embodiments can be combined with any technical solution or any combination of other specific embodiments.
  • the present invention is intended to include all the combinations of these technical solutions, limited to space, and will not be listed one by one.
  • the present invention relates to the compound of formula (I) described above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or Solvates, in which,
  • the present invention relates to the compound of formula (I) described above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or Solvates, in which,
  • Y is selected from a 3- to 7-membered heterocyclic group containing at least one N atom, and the N atom is connected to Z, wherein the 3- to 7-membered heterocyclic group is optionally substituted with m Rs;
  • Z is selected from -C(O)-;
  • Y is selected from 3 to 7 membered heterocyclic groups containing at least one N atom, and the N atom is connected to Z, wherein the 3 to 7 membered heterocyclic groups are optionally selected from D, halogen, C 1-6 Substituent substitution of alkyl or C 1-6 haloalkyl;
  • Z is selected from -C(O)-;
  • Y is selected from pyrrolidinyl or piperidinyl, and the N atom is connected to Z, wherein said pyrrolidinyl and piperidinyl are optionally substituted by one or more selected from D, halogen, C 1-6 alkyl or C Substituent substitution of 1-6 haloalkyl;
  • Z is selected from -C(O)-;
  • Y is selected from pyrrolidinyl, methylpyrrolidinyl, piperidinyl or fluoropiperidinyl, and the N atom is connected to Z;
  • Z is selected from -C(O)-;
  • -Y-Z-V is selected from the following structures:
  • n 0, 1 or 2, and other groups are as described above;
  • -Y-Z-V is selected from the following structures:
  • -Y-Z-V is selected from the following structures:
  • the present invention relates to the compound of formula (I) described above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or Solvates, where W is CH 2 , CHD or CD 2 .
  • the present invention relates to the compound of formula (I) described above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or Solvates, wherein R 1 and R 2 are each independently selected from H, -OMe, -Me or phenyl, or R 1 and R 2 together with the N atom to which they are attached form a nitrogen optionally substituted by a hydroxyl group Etanyl, pyrrolidinyl or piperidinyl.
  • the present invention relates to the compound described above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, It is a compound of formula (II), formula (III) or formula (IV):
  • each group is as defined above.
  • the present invention relates to the compound described above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, It is the formula (III-1):
  • each group is as defined above;
  • a 2 and A 3 are each independently a C or N atom
  • R B1 , R B2 , R B3 and R B4 are each independently selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl,- C(O)R a , -C(O)OR a , -C(O)NR b R c , -NR b R c , -NR a C(O)R b , -NR a C(O)OR b , -NR a C(O)NR b R c , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c , C 3-7 cycloalkyl , 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group; or, R B1 and R B2 can form a C 3-7
  • R 3 is selected from H, halogen, -CN, C 1-6 alkyl or C 1-6 haloalkyl, and the above groups are optionally substituted by one or more R*;
  • R 4 and R 5 are each independently selected from H, halogen, -CN, C 1-6 alkyl or C 1-6 haloalkyl, and the above groups are optionally substituted by one or more R*; or, R 4 and R 5 together with the double bond they are connected to form a triple bond;
  • R 1 and R 2 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 3 to A 7-membered heterocyclic group, a C 6-10 aryl group, or a 5- to 10-membered heteroaryl group; alternatively, R 1 and R 2 together with the N atom to which they are attached form a 3- to 7-membered heterocyclic group or a 5- to 10-membered heterocyclic group Aryl; and the above-mentioned groups are optionally substituted by one or more R';
  • n 0, 1, 2, 3, 4 or 5;
  • n 0, 1 or 2;
  • Each R a , R b and R c is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 ring Alkyl, 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group, or R b and R c together with the N atom to which they are attached form a 3 to 7 membered heterocyclic group or 5 to 10 membered heteroaryl; wherein R a, R b and R c are defined in each group is optionally substituted by one or more D, until completely deuterated.
  • the present invention relates to the compound described above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, It is the formula (III-2):
  • a 2 and A 3 are each independently a C or N atom
  • R B1 and R B2 are each independently selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C (O) R a , -C(O)OR a , -C(O)NR b R c , -NR b R c , -NR a C(O)R b , -NR a C(O)OR b , -NR a C( O)NR b R c , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c , C 3-7 cycloalkyl, 3 to 7 membered hetero Cyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group; or, R B1 and R B2 can form a C 3-7 cycloalkyl group, 3
  • R 1 and R 2 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 3 to A 7-membered heterocyclic group, a C 6-10 aryl group, or a 5- to 10-membered heteroaryl group; alternatively, R 1 and R 2 together with the N atom to which they are attached form a 3- to 7-membered heterocyclic group or a 5- to 10-membered heterocyclic group Aryl; and the above-mentioned groups are optionally substituted by one or more R';
  • Each R a , R b and R c is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 ring Alkyl, 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group, or R b and R c together with the N atom to which they are attached form a 3 to 7 membered heterocyclic group or 5 to 10 membered heteroaryl; wherein R a, R b and R c are defined in each group is optionally substituted by one or more D, until completely deuterated.
  • the present invention relates to the compound (III-2) described above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate thereof Or solvates, in which,
  • a 2 and A 3 are each independently a C or N atom
  • R B1 and R B2 are each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl; alternatively, R B1 and R B2 may be connected to them
  • the C atoms of together form a C 3-7 cycloalkyl group, a 3 to 7 membered heterocyclic group, a C 6-10 aryl group or a 5 to 10 membered heteroaryl group; and the above groups are optionally substituted by one or more R"replace;
  • R 1 and R 2 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl; alternatively, R 1 and R 2 together with them
  • Each R a , R b and R c is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 ring Alkyl, 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group, or R b and R c together with the N atom to which they are attached form a 3 to 7 membered heterocyclic group or 5 to 10 membered heteroaryl; wherein R a, R b and R c are defined in each group is optionally substituted by one or more D, until completely deuterated.
  • the present invention relates to the compound (III-2) described above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate thereof Or solvates, in which,
  • a 2 and A 3 are each independently a C or N atom
  • R B1 and R B2 are each independently selected from C 1-6 alkyl or C 1-6 haloalkyl; alternatively, R B1 and R B2 may form a C 3-7 cycloalkyl group together with the C atom to which they are attached, 3 To 7-membered heterocyclic group, C 6-10 aryl group or 5 to 10-membered heteroaryl group; and the above-mentioned groups are optionally substituted by one or more R′′;
  • R 1 and R 2 are each independently selected from C 1-6 alkyl or C 1-6 haloalkyl; alternatively, R 1 and R 2 together with the N atom to which they are attached form a 3- to 7-membered heterocyclic group or 5-to- 10-membered heteroaryl; and the above-mentioned groups are optionally substituted by one or more R';
  • Each R a , R b and R c is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl, or R b and R c together with the N atom to which they are attached form a 3 to 7 membered heterocyclic group or a 5 to 10 membered heteroaryl group; wherein each group in the definition of R a , R b and R c is optionally substituted by one or more D substitution, until fully deuterated.
  • the present invention relates to the compound (III-2) described above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate thereof Or solvates, in which,
  • a 2 and A 3 are each independently a C or N atom
  • R B1 and R B2 are both methyl, and they are optionally substituted with one or more R′′;
  • R 1 and R 2 are both methyl, and they are optionally substituted with one or more R′;
  • the present invention relates to the compound described above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, It is the formula (IV-1):
  • each group is as defined above;
  • a 1 is CR A1 or N atom
  • a 4 is CR A4 or N atom
  • a 1 and A 4 are not N atoms at the same time;
  • R A1 and R A4 are each independently H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C (O )R a , -C(O)OR a , -C(O)NR b R c , -NR b R c , -NR a C(O)R b , -NR a C(O)OR b , -NR a C(O)NR b R c , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c , C 3-7 cycloalkyl, 3 to 7-membered heterocyclic group, C 6-10 aryl group or 5 to 10-membered heteroaryl group; and the above-mentioned groups are optionally substituted by one or more R′′;
  • R B1 , R B2 , R B3 and R B4 are each independently selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl,- C(O)R a , -C(O)OR a , -C(O)NR b R c , -NR b R c , -NR a C(O)R b , -NR a C(O)OR b , -NR a C(O)NR b R c , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c , C 3-7 cycloalkyl , 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group; or, R B1 and R B2 , R B3 and R
  • R 3 is selected from H, halogen, -CN, C 1-6 alkyl or C 1-6 haloalkyl, and the above groups are optionally substituted by one or more R*;
  • R 4 and R 5 are each independently selected from H, halogen, -CN, C 1-6 alkyl or C 1-6 haloalkyl, and the above groups are optionally substituted by one or more R*; or, R 4 and R 5 together with the double bond they are connected to form a triple bond;
  • R 1 and R 2 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 3 to A 7-membered heterocyclic group, a C 6-10 aryl group, or a 5- to 10-membered heteroaryl group; alternatively, R 1 and R 2 together with the N atom to which they are attached form a 3- to 7-membered heterocyclic group or a 5- to 10-membered heterocyclic group Aryl; and the above-mentioned groups are optionally substituted by one or more R';
  • n 0, 1, 2, 3, 4 or 5;
  • n 0, 1 or 2;
  • Each R a , R b and R c is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 ring Alkyl, 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group, or R b and R c together with the N atom to which they are attached form a 3 to 7 membered heterocyclic group or 5 to 10 membered heteroaryl; wherein R a, R b and R c are defined in each group is optionally substituted by one or more D, until completely deuterated.
  • the present invention relates to the compound described above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, It is the formula (IV-2):
  • a 1 is CR A1 or N atom
  • a 4 is CR A4 or N atom
  • a 1 and A 4 are not N atoms at the same time;
  • R A1 and R A4 are each independently H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C (O )R a , -C(O)OR a , -C(O)NR b R c , -NR b R c , -NR a C(O)R b , -NR a C(O)OR b , -NR a C(O)NR b R c , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c , C 3-7 cycloalkyl, 3 to 7-membered heterocyclic group, C 6-10 aryl group or 5 to 10-membered heteroaryl group; and the above-mentioned groups are optionally substituted by one or more R′′;
  • R B1 and R B2 are each independently selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C (O) R a , -C(O)OR a , -C(O)NR b R c , -NR b R c , -NR a C(O)R b , -NR a C(O)OR b , -NR a C( O)NR b R c , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c , C 3-7 cycloalkyl, 3 to 7 membered hetero Cyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group; or, R B1 and R B2 can form a C 3-7 cycloalkyl group, 3
  • R 1 and R 2 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 3 to A 7-membered heterocyclic group, a C 6-10 aryl group, or a 5- to 10-membered heteroaryl group; alternatively, R 1 and R 2 together with the N atom to which they are attached form a 3- to 7-membered heterocyclic group or a 5- to 10-membered heterocyclic group Aryl; and the above-mentioned groups are optionally substituted by one or more R';
  • Each R a , R b and R c is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 ring Alkyl, 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group, or R b and R c together with the N atom to which they are attached form a 3 to 7 membered heterocyclic group or 5 to 10 membered heteroaryl; wherein R a, R b and R c are defined in each group is optionally substituted by one or more D, until completely deuterated.
  • the present invention relates to the compound of formula (IV-2) described above, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrated ⁇ or solvate, in which,
  • a 1 is CR A1 or N atom
  • a 4 is CR A4 or N atom
  • R A1 and R A4 are each independently H or D;
  • R B1 and R B2 are each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl; alternatively, R B1 and R B2 may be connected to them
  • the C atoms of together form a C 3-7 cycloalkyl group, a 3 to 7 membered heterocyclic group, a C 6-10 aryl group or a 5 to 10 membered heteroaryl group; and the above groups are optionally substituted by one or more R"replace;
  • R 1 and R 2 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl; alternatively, R 1 and R 2 together with them
  • Each R a , R b and R c is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 ring Alkyl, 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group, or R b and R c together with the N atom to which they are attached form a 3 to 7 membered heterocyclic group or 5 to 10 membered heteroaryl; wherein R a, R b and R c are defined in each group is optionally substituted by one or more D, until completely deuterated.
  • the present invention relates to the compound of formula (IV-2) described above, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrated ⁇ or solvate, in which,
  • a 1 is CR A1 or N atom
  • a 4 is CR A4 or N atom
  • R A1 and R A4 are each independently H or D;
  • a 1 and A 4 are not N atoms at the same time;
  • R B1 and R B2 are each independently selected from C 1-6 alkyl or C 1-6 haloalkyl; alternatively, R B1 and R B2 may form a C 3-7 cycloalkyl group together with the C atom to which they are attached, 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group; and the above groups are optionally substituted by one or more R′′;
  • R 1 and R 2 are each independently selected from C 1-6 alkyl or C 1-6 haloalkyl; alternatively, R 1 and R 2 together with the N atom to which they are attached form a 3- to 7-membered heterocyclic group or 5-to- 10-membered heteroaryl; and the above-mentioned groups are optionally substituted by one or more R';
  • Each R a , R b and R c is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl, or R b and R c together with the N atom to which they are attached form a 3 to 7 membered heterocyclic group or a 5 to 10 membered heteroaryl group; wherein each group in the definition of R a , R b and R c is optionally substituted by one or more D substitution, until fully deuterated.
  • the present invention relates to the compound of formula (IV-2) described above, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrated ⁇ or solvate, in which,
  • a 1 is CR A1 or N atom
  • a 4 is CR A4 or N atom
  • a 1 and A 4 are not N atoms at the same time;
  • R A1 and R A4 are both H;
  • R B1 and R B2 are both methyl, and they are optionally substituted with one or more R′′;
  • R 1 and R 2 are both methyl, and they are optionally substituted with one or more R′;
  • the present invention relates to the following compounds or tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, the compounds selected from :
  • the compounds of the present invention may include one or more asymmetric centers, and thus may exist in various stereoisomeric forms, for example, enantiomeric and/or diastereomeric forms.
  • the compounds of the present invention may be individual enantiomers, diastereomers, or geometric isomers (such as cis and trans isomers), or may be in the form of a mixture of stereoisomers, Including racemate mixtures and mixtures rich in one or more stereoisomers.
  • the isomers can be separated from the mixture by methods known to those skilled in the art, including: chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or the preferred isomers can be separated by Prepared by asymmetric synthesis.
  • HPLC high pressure liquid chromatography
  • Tautomers means that a functional group in some compounds changes its structure into another functional group isomer, and can quickly convert between each other, and the two isomers are in dynamic equilibrium. This kind of isomer is called tautomer.
  • an organic compound can form a complex with a solvent, which reacts in the solvent or precipitates or crystallizes out of the solvent. These complexes are called “solvates”. When the solvent is water, the complex is called “hydrate”. The present invention covers all solvates of the compounds of the present invention.
  • solvate refers to a compound or a salt form thereof combined with a solvent, usually formed by a solvolysis reaction. This physical association may include hydrogen bonding.
  • solvents include water, methanol, ethanol, acetic acid, DMSO, THF, ether and the like.
  • Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate will be able to separate, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid.
  • “Solvate” includes a solvate in a solution state and an isolable solvate. Representative solvates include hydrates, ethanolates and methanolates.
  • hydrate refers to a compound that binds to water. Generally, the ratio of the number of water molecules contained in the hydrate of a compound to the number of molecules of the compound in the hydrate is determined. Therefore, a hydrate of a compound can be represented by, for example, the general formula R ⁇ x H 2 O, where R is the compound, and x is a number greater than zero.
  • a given compound can form more than one type of hydrate, including, for example, monohydrate (x is 1), lower hydrate (x is a number greater than 0 and less than 1, for example, hemihydrate (R ⁇ 0.5H 2 O)) and polyhydrates (x is a number greater than 1, for example, dihydrate (R ⁇ 2H 2 O) and hexahydrate (R ⁇ 6H 2 O)).
  • monohydrate x is 1
  • lower hydrate x is a number greater than 0 and less than 1, for example, hemihydrate (R ⁇ 0.5H 2 O)
  • polyhydrates x is a number greater than 1, for example, dihydrate (R ⁇ 2H 2 O) and hexahydrate (R ⁇ 6H 2 O)).
  • the compounds of the present invention may be in amorphous or crystalline form (crystalline or polymorphic).
  • the compounds of the present invention may exist in one or more crystalline forms. Therefore, the present invention includes all amorphous or crystalline forms of the compounds of the present invention within its scope.
  • the term "polymorph” refers to a crystalline form (or a salt, hydrate or solvate thereof) of a compound in a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, photoelectric properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors can cause one crystalline form to dominate.
  • Various polymorphs of the compound can be prepared by crystallization under different conditions.
  • the present invention also includes isotopically-labeled compounds, which are equivalent to those described in formula (I), but one or more atoms are replaced by atoms having an atomic mass or mass number different from those commonly found in nature.
  • isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, and 18 respectively. O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • isotopically-labeled compounds of formula (I) of the present invention and their prodrugs can generally be prepared in this way.
  • the non-isotope-labeled reagents are replaced with readily available isotope-labeled reagents. Labeled reagents.
  • prodrugs are also included in the context of the present invention.
  • the term "prodrug” as used herein refers to a compound that is converted into its active form with a medical effect by, for example, hydrolysis in the blood in the body.
  • Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, ASSymposium Series Vol. 14, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon, and H. Barbra "Improved oral drug delivery: solubility limits overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19(2) 115-130, each introduced This article serves as a reference.
  • a prodrug is any covalently bonded compound of the invention, and when such a prodrug is administered to a patient, it releases the parent compound in the body.
  • Prodrugs are usually prepared by modifying functional groups, and the modification is performed in such a way that the modification can be performed by conventional operations or cleavage in vivo to produce the parent compound.
  • Prodrugs include, for example, the compounds of the present invention in which a hydroxyl, amino, or sulfhydryl group is bonded to any group, which can be cleaved to form a hydroxyl, amino, or sulfhydryl group when administered to a patient.
  • prodrugs include, but are not limited to, acetate/amide, formate/amide, and benzoate/amide derivatives of the hydroxyl, sulfhydryl, and amino functional groups of the compound of formula (I).
  • esters such as methyl esters, ethyl esters, and the like can be used.
  • the ester itself can be active and/or can be hydrolyzed under conditions in the human body.
  • Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include those groups that are easily decomposed in the human body to release the parent acid or salt thereof.
  • the present invention provides a method for treating and/or preventing diseases in a subject, such as wild and/or mutant EGFR kinase-mediated cancer, comprising administering to the subject a compound of the present invention or its interaction Tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the pharmaceutical composition of the present invention.
  • the mutant EGFR is selected from exon 20 insertion mutant EGFR, exon 18 point mutant EGFR, exon 21 point mutant EGFR, exon 19 deletion mutant EGFR, or L858R mutant EGFR.
  • the mutated EGFR has a T790M mutation and is selected from the group consisting of exon 20 insertion mutation, exon 18 point mutation, exon 21 point mutation, exon 19 deletion mutation, or L858R mutation. At least one mutation.
  • EGFR refers to human epidermal growth factor receptor protein, also known as ErbB-1 or HER1.
  • wild-type EGFR refers to EGFR without somatic cell mutation.
  • exon 20 insertion mutation means that one or more amino acids (preferably 1 to 7, more preferably 1 to 4) are inserted into the exon 20 region of EGFR (such as the 761st to the 823th position).
  • Amino acid sequence preferably, the mutation is in which the amino acid sequence FQEA (in the order of phenylalanine, glutamine, glutamic acid and alanine from the N-terminus) is inserted into the exon 20 region
  • the mutation between alanine 763 and tyrosine 764 (A763_Y764insFQEA); preferably, the mutation is in which the amino acid sequence ASV (in the order of alanine, serine and valine from the N-terminus) is inserted outside
  • the mutation between the 769th valine and the 770th aspartic acid in the region of exon 20 V769_D770insASV); preferably, the mutation is wherein the amino acid sequence SVD (from the N-terminus with se
  • the mutation is in which the amino acid sequence ASV (in the order of alanine, serine and valine from the N-terminus) is inserted into the 769th valine and the 770th aspartic acid in the exon 20 region (V769_D770insASV); More preferably, the mutation is in which the amino acid sequence SVD (in the order of serine, valine and aspartic acid from the N-terminus) is inserted into the aspartic acid at position 770 in the exon 20 region Mutation between amino acid and asparagine at position 771 (D770_N771insSVD); more preferably, the mutation is in which the amino acid sequence NPG (from the N-terminus in the order of asparagine, proline and glycine) is inserted into the exon The mutation between aspartic acid at position 770 and asparagine at position 771 in region 20 (D770_N771insNPG); more preferably, the mutation is in which amino acid G (glycine)
  • cancer patients expressing EGFR with exon 20 insertion mutations refer to cancer patients expressing EGFR with exon 20 insertion mutations in at least a part of the exon 20 region of EGFR.
  • EGFR may have exon 20 insertion mutations in two or more different parts, but one part is preferred.
  • EGFR may also have mutations other than the insertion mutation in exon 20 (such as exon 19 deletion mutation, L858R mutation, or T790M mutation).
  • the method for detecting insertion mutations in exon 20 expressing EGFR in cancer patients is not particularly limited, as long as the method can detect mutations, and any known detection method can be used.
  • the detection target for detecting the insertion mutation of exon 20 can be any one of the gene sequence of the EGFR gene, the transcription product of the EGFR gene, and the EGFR protein.
  • the sample used to detect the insertion mutation of exon 20 is not particularly limited, as long as the sample is a biological sample isolated from a cancer patient, especially a sample obtained from a cancer patient and containing malignant tumor cells.
  • biological samples include body fluids (for example, blood, urine, etc.), tissues, extracts thereof, and cultures obtained from tissues.
  • the method of separating the biological sample can be appropriately selected according to the type of the biological sample.
  • reagents used for detection for example, reagents containing primers or probes
  • the step of detecting the presence of insertion mutations in exon 20 of EGFR expressed in patients with malignant tumors may be performed before administering anti-tumor agents to patients with cancer.
  • exon 18 point mutation means a point mutation in an amino acid in the exon 18 region of wild-type EGFR.
  • the mutation is a point mutation or deletion mutation in which one amino acid in the exon 18 region is replaced; more preferably, the mutation is a point mutation in which the glutamic acid encoded by codon 709 in exon 18 is replaced by any amino acid (Ie E790X), and a point mutation in which the glycine encoded by codon 719 in exon 18 is replaced by any amino acid (ie G719X).
  • E790X can be, for example, a point mutation in which the glutamic acid coded by codon 709 in the exon 18 region is replaced by lysine (ie E709K), and the valley coded by codon 709 in the exon 18 region A point mutation in which the amino acid is replaced by alanine (ie E709A).
  • G719X can be, for example, a point mutation in which the glycine encoded by codon 719 in the exon 18 region is replaced by alanine (ie G719A), and a point mutation in which the glycine encoded by codon 719 in the exon 18 region is replaced by serine ( That is G719S), and the point mutation in which the glycine encoded by codon 719 in the exon 18 region is replaced by cysteine (namely G719C), of which G719A is the most common.
  • G719A a point mutation in which the glycine encoded by codon 719 in the exon 18 region is replaced by alanine
  • G719S a point mutation in which the glycine encoded by codon 719 in the exon 18 region is replaced by serine
  • cysteine namely G719C
  • exon 18 point mutant EGFR means EGFR with at least one exon 18 point mutation; preferably, the EGFR has more than two related exon 18 point mutations; more preferably, the EGFR It has an 18-point mutation in one exon.
  • the EGFR may also have mutations other than exon 18 point mutations (for example, exon 19 deletion mutation, L858R mutation, T790M mutation, etc.).
  • exon 21 represents the region 824-875 in the amino acid sequence of wild-type EGFR.
  • exon 21 point mutation means a point mutation in an amino acid in the exon 21 region of wild-type EGFR.
  • the 21 point mutation of exon is a point mutation in which one amino acid in the region of exon 21 is replaced; more preferably, the 21 point mutation of exon is a leucine encoded by codon 861 in the region of exon 21.
  • a point mutation in which an acid is replaced by any amino acid ie L861X
  • a point mutation in which the leucine encoded by codon 861 in the exon 21 region is replaced by glutamine ie, L861Q).
  • exon 21 point mutant EGFR means EGFR with at least one exon 21 point mutation; preferably, the EGFR has more than two related exon 21 point mutations; more preferably, the EGFR There is a 21-point mutation in one exon.
  • the EGFR may also have mutations other than exon 21 point mutations (for example, exon 19 deletion mutation, L858R mutation, T790M mutation, etc.).
  • the mutant EGFR has a T790M mutation and is selected from the group consisting of exon 20 insertion mutation, exon 18 point mutation, exon 21 point mutation, exon 19 deletion mutation, or L858R mutation. At least one mutation in.
  • the present invention has a T790M mutation and is selected from exon 18 point mutant EGFR, exon 21 point mutant EGFR is any one of the following: has T790M mutation and has exon 18 region E709X and / Or G719X mutant EGFR; L861X mutant EGFR with T790M mutation and exon 21 region.
  • T790M mutation and E709K or E709A mutant EGFR is any one of the following: T790M mutation and E709K or E709A mutant EGFR; T790M mutation and G719A, G719S, or G719C mutant EGFR; T790M mutation and L861Q mutant EGFR; among them, T790M Mutations with G719A and T790M mutations with L861Q mutant EGFR are more common.
  • the detection method for EGFR expressed by cancer patients with exon 18 and/or exon 21 point mutations should only be able to detect the above-mentioned mutations, and known detection methods can be used.
  • the sample used for detecting exon 18 and/or exon 21 point mutations is not particularly limited, as long as the sample is a biological sample isolated from a cancer patient, especially a sample obtained from a cancer patient and containing malignant tumor cells.
  • biological samples include body fluids (e.g., blood, urine, etc.), tissues, extracts thereof, and cultures obtained from tissues.
  • the method of separating the biological sample can be appropriately selected according to the type of the biological sample.
  • reagents used for detection for example, reagents containing primers or probes
  • the step of detecting the presence of exon 18 and/or exon 21 point mutations expressed in patients with malignant tumors may be performed before administering the anti-tumor agent to the cancer patients.
  • tumors mediated by mutant EGFR kinase in the present invention include, but are not limited to: head and neck cancer, gastrointestinal cancer (esophageal cancer, gastric cancer, duodenal cancer, liver cancer, cholangiocarcinoma (eg, gallbladder and bile duct cancer), pancreas Cancer, colorectal cancer (for example, colon cancer and rectal cancer), lung cancer (for example, non-small cell lung cancer, small cell lung cancer, and mesothelioma), breast cancer, genital cancer (ovarian cancer, uterine cancer (for example, child Cervical cancer and endometrial cancer), urinary tract cancer (for example, kidney cancer, bladder cancer, prostate cancer, and testicular cancer), hematopoietic tumors (for example, leukemia, malignant lymphoma and multiple myeloma), osteosarcoma , Soft tissue sarcoma, skin cancer, brain tumor, etc.
  • Preferred examples include lung cancer, breast cancer, head and neck
  • the mutant EGFR is selected from exon 20 insertion mutant EGFR, exon 18 point mutant EGFR, exon 21 point mutant EGFR, exon 19 deletion mutant EGFR, or L858R mutant EGFR.
  • the mutant EGFR has a T790M mutation and is selected from the group consisting of exon 18 point mutant EGFR, exon 21 point mutant EGFR, exon 19 deletion mutant EGFR, or L858R mutant EGFR .
  • the present invention also provides a method for treating tumor patients, including expressing a mutant EGFR selected from the group consisting of exon 20 insertion mutant EGFR, exon 18 point mutant EGFR, exon 21 point mutant EGFR, and exon 19 deletion mutant type.
  • the present invention also provides the compound of the present invention or a pharmaceutically acceptable salt thereof, which is used for therapeutic expression of a compound selected from the group consisting of exon 20 insertion mutant EGFR, exon 18 point mutant EGFR, and exon 21 point mutant EGFR. , Tumor patients with exon 19 deletion mutant EGFR or L858R mutant EGFR.
  • the present invention also provides that the compound of the present invention or a pharmaceutically acceptable salt thereof is selected from the group consisting of exon 20 insertion mutant EGFR, exon 18 point mutant EGFR, exon 21 point mutant EGFR, exon 19 Use in tumor patients with deletion of mutant EGFR or L858R mutant EGFR.
  • the present invention also provides a method for predicting the therapeutic effect of using an anti-tumor agent in tumor patients, the anti-tumor agent is the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient, and the method includes the following steps (1) and ( 2):
  • step (1) finds that the EGFR gene has a mutation selected from exon 20 insertion mutation, exon 18 point mutation, exon 21 point mutation, exon 19 deletion mutation or L858R mutation, A step that predicts that chemotherapy is highly likely to show a sufficient therapeutic effect on the patient.
  • the present invention also provides a method for treating tumor patients, the method comprising the following steps (1) to (2):
  • step (1) finds that the EGFR gene has a mutation selected from exon 20 insertion mutation, exon 18 point mutation, exon 21 point mutation, exon 19 deletion mutation or L858R mutation, Steps of using the compound of the present invention or a pharmaceutically acceptable salt thereof to treat the patient.
  • the present invention provides a method of treating and/or preventing a disease in a subject, such as a wild and/or mutant HER2 kinase-mediated tumor, comprising administering to the subject
  • a disease in a subject such as a wild and/or mutant HER2 kinase-mediated tumor
  • administering comprising administering to the subject
  • the mutant HER2 is selected from G309A mutant HER2, S310F mutant HER2, R678Q mutant HER2, L775_T759 deletion mutant HER2, D769H mutant HER2, V777L mutant HER2, V842I mutant HER2, R869C Mutant HER2, L755S mutant HER2 or ex20insYVMA mutant HER2.
  • the ex20insYVMA mutant HER2 is selected from the group consisting of A775_G776insYVMA mutant HER2 mutations.
  • HER2 includes HER2 of human or non-human mammals. Also, the term “HER2” includes subtypes.
  • HER2 kinase-mediated tumors are preferably tumors with HER2 overexpression, HER2 gene amplification or HER2 mutation.
  • the above-mentioned “tumor” is not particularly limited, and may be, for example, head and neck cancer, esophageal cancer, gastric cancer, colon cancer, rectal cancer, liver cancer, gallbladder-biliary duct cancer, biliary tract cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer , Uterine cancer, kidney cancer, bladder cancer, prostate cancer, testicular tumor, bone-soft tissue sarcoma, blood cancer, multiple myeloma, skin cancer, brain tumor, mesothelial cancer, etc.
  • breast cancer gastric cancer, esophageal cancer, ovarian cancer, lung cancer, esophageal cancer, gallbladder-cholangiocarcinoma, biliary tract cancer, bladder cancer, colon cancer, more preferably breast cancer, stomach cancer, esophageal cancer, biliary cancer, ovarian cancer, lung cancer, esophagus Cancer, breast cancer, stomach cancer, and lung cancer are more preferable.
  • effective amount refers to an amount or dose sufficient to produce the desired therapeutic benefit in the individual in need of the treatment.
  • the effective amount or dosage of the compound of the present invention can be determined by conventional methods (e.g., modeling, dose escalation, or clinical trials) and conventional factors (e.g., the mode or route of drug delivery, the pharmacokinetics of the agent, the severity and course of the infection, and the individual Health status and weight, and the judgment of the treating physician) to determine.
  • Exemplary dosages are in the range of about 0.1 mg to 1 g per day, or about 1 mg to 50 mg per day, or about 50 mg to 250 mg per day, or about 250 mg to 1 g per day.
  • the total dose can be administered in a single dose or in divided dose units (e.g., BID, TID, QID).
  • the dosage can be adjusted for preventive or maintenance treatment.
  • the dosage or frequency of administration or both can be reduced to an amount that maintains the desired therapeutic or preventive effect based on symptoms.
  • treatment can be stopped.
  • the patient may require long-term intermittent treatment. Patients may also require long-term slow treatment.
  • compositions preparations and kits
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition contains an effective amount of active ingredient.
  • the pharmaceutical composition includes a therapeutically effective amount of the active ingredient.
  • the pharmaceutical composition includes a prophylactically effective amount of the active ingredient.
  • the pharmaceutically acceptable excipient used in the present invention refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound formulated together.
  • Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the composition of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin) ), buffer substances (such as phosphate), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated plant fatty acids, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, Sodium chloride, zinc salt, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax, polyethylene-polyoxypropylene-inlay Segment polymers, poly
  • kits e.g., pharmaceutical packaging.
  • the kit provided may include the compound of the present invention, other therapeutic agents, and first and second containers (for example, vials, ampoules, bottles, syringes, and/or dispersible packages or other Suitable container).
  • the provided kit may also optionally include a third container, which contains pharmaceutical excipients for diluting or suspending the compound of the present invention and/or other therapeutic agents.
  • the compound of the present invention and the other therapeutic agent provided in the first container and the second container are combined to form a unit dosage form.
  • parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intraarticular administration, intraarterial administration, intrasynovial administration, intrasternal administration , Intracerebrospinal membrane administration, intralesional administration, and intracranial injection or infusion technology.
  • an effective amount of the compound provided herein is administered.
  • the doctor can determine the amount of the compound actually administered .
  • the compound provided herein is administered to a subject at risk of developing the condition, typically based on the doctor's recommendation and under the supervision of the doctor, and the dosage level is as described above.
  • Subjects at risk of developing a particular disorder generally include subjects with a family history of the disorder, or those subjects who are particularly sensitive to the development of the disorder as determined by genetic testing or screening.
  • long-term administration refers to the administration of the compound or its pharmaceutical composition over a long period of time, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or the administration can be continued indefinitely, For example, the rest of the subject's life.
  • long-term administration is intended to provide a constant level of the compound in the blood over a long period of time, for example, within a therapeutic window.
  • the pharmaceutical composition may be administered as a bolus, for example, in order to rapidly increase the concentration of the compound in the blood to an effective level.
  • the bolus dose depends on the target systemic level of the active ingredient.
  • an intramuscular or subcutaneous bolus dose releases the active ingredient slowly, while a bolus injection delivered directly to a vein (for example, via IV infusion) can be more effective.
  • the rapid delivery allows the concentration of the active ingredient in the blood to rise rapidly to an effective level.
  • the pharmaceutical composition may be administered as a continuous infusion, for example, by IV infusion, to provide a steady-state concentration of the active ingredient in the subject's body.
  • a bolus dose of the pharmaceutical composition may be administered first, followed by continuous infusion.
  • Oral compositions can take the form of bulk liquid solutions or suspensions or bulk powders. However, more generally, in order to facilitate precise dosing, the composition is provided in unit dosage form.
  • unit dosage form refers to physically discrete units suitable as unit dosages for human patients and other mammals, each unit containing a predetermined number of active substances suitable for producing the desired therapeutic effect and suitable pharmaceutical excipients.
  • Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions, or pills, tablets, capsules, etc. in the case of solid compositions.
  • the compound is usually a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), and the remaining part is useful for forming the desired administration form.
  • Kinds of carriers or excipients and processing aids are used for forming the desired administration form.
  • the representative regimen is one to five oral doses per day, especially two to four oral doses, typically three oral doses.
  • each dose provides about 0.01 to about 20 mg/kg of the compound of the present invention, with preferred doses each providing about 0.1 to about 10 mg/kg, especially about 1 to about 5 mg/kg.
  • the transdermal dose is usually selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, and preferably about 0.1 To about 10% by weight, and more preferably about 0.5 to about 15% by weight.
  • the injection dose level is in the range of about 0.1 mg/kg/hour to at least 10 mg/kg/hour.
  • a preload bolus of about 0.1 mg/kg to about 10 mg/kg or more can also be given.
  • the maximum total dose cannot exceed approximately 2 g/day.
  • Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous carriers as well as buffers, suspending and dispersing agents, coloring agents, flavoring agents, and the like.
  • the solid form may include, for example, any of the following components, or compounds with similar properties: binders, for example, microcrystalline cellulose, tragacanth, or gelatin; excipients, for example, starch or lactose, disintegrants, For example, alginic acid, Primogel or corn starch; lubricants, for example, magnesium stearate; glidants, for example, colloidal silicon dioxide; sweeteners, for example, sucrose or saccharin; or flavoring agents, for example, mint, water Methyl salicylate or orange flavoring agent.
  • binders for example, microcrystalline cellulose, tragacanth, or gelatin
  • excipients for example, starch or lactose, disintegrants, For example, alginic acid, Primogel or corn starch
  • Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art.
  • the active compound is typically a minor component, often about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.
  • the transdermal composition is typically formulated as a topical ointment or cream containing the active ingredients.
  • the active ingredient When formulated as an ointment, the active ingredient is typically combined with paraffin or a water-miscible ointment base.
  • the active ingredient can be formulated as a cream with, for example, an oil-in-water cream base.
  • Such transdermal formulations are well known in the art, and generally include other components for enhancing the active ingredient or stable skin penetration of the formulation. All such known transdermal preparations and components are included within the scope provided by the present invention.
  • transdermal administration can be achieved using a reservoir or porous membrane type, or a variety of solid matrix patches.
  • compositions for oral administration, injection or topical administration are only representative.
  • Other materials and processing techniques are described in Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania in Part 8, which is incorporated herein by reference.
  • the compounds of the present invention can also be administered in a sustained release form or from a sustained release drug delivery system.
  • sustained-release materials can be found in Remington's Pharmaceutical Sciences.
  • the invention also relates to pharmaceutically acceptable formulations of the compounds of the invention.
  • the formulation contains water.
  • the formulation comprises a cyclodextrin derivative.
  • the most common cyclodextrins are ⁇ -, ⁇ - and ⁇ -cyclodextrins composed of 6, 7 and 8 ⁇ -1,4-linked glucose units, respectively, which optionally include one on the linked sugar moiety Or multiple substituents, including but not limited to: methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substitution.
  • the cyclodextrin is a sulfoalkyl ether ⁇ -cyclodextrin, for example, sulfobutyl ether ⁇ -cyclodextrin, also known as Captisol. See, for example, U.S. 5,376,645.
  • the formulation includes hexapropyl- ⁇ -cyclodextrin (e.g., 10-50% in water).
  • the compounds of the invention described herein can be used in pharmaceutical compositions or methods in combination with one or more other active ingredients to treat the diseases and conditions described herein.
  • additional active ingredients include other therapeutic agents or agents that mitigate the adverse effects of the treatment on the intended disease target.
  • the combination can be used to increase efficacy, improve symptoms of other diseases, reduce one or more side effects, or reduce the required dosage of the compound of the present invention.
  • the additional active ingredient may be formulated into a pharmaceutical composition separate from the compound of the present invention or may be included in a single pharmaceutical composition with the compound of the present invention.
  • the additional active ingredient may be administered at the same time, before or after the administration of the compound of the invention.
  • Combination agents include those active ingredients that are known or observed to be effective in the treatment of the diseases and conditions described herein, including those that are effective against another target associated with the disease.
  • the compositions and preparations and treatment methods of the present invention may further include other drugs, such as other drugs that can be used to treat or alleviate the target disease or related symptoms or conditions.
  • the other agents include (but are not limited to) kinase inhibitors, such as EGFR inhibitors (e.g., erlotinib, gefitinib); Raf inhibitors (e.g., Vero Vemurafenib), VEGFR inhibitors (for example, sunitinib); standard chemotherapeutic agents, such as alkylating agents, antimetabolites, antitumor antibiotics, topoisomerase inhibitors, platinum drugs , Mitosis inhibitors, antibodies, hormone therapy or corticosteroids.
  • suitable combination agents include anti-inflammatory agents, such as NSAIDs.
  • the pharmaceutical composition of the present invention may additionally include one or more of the active agents, and the treatment method may additionally include administering an effective amount of one or more of the active agents.
  • each reaction is carried out in an inert solvent at room temperature to reflux temperature (such as 0°C to 100°C, preferably 0°C to 80°C).
  • the reaction time is usually 0.1-60 hours, preferably 0.5-24 hours.
  • Pd(PPh 3 ) 4 Tetra(triphenylphosphine) palladium
  • tert-Butyl nitrite tert-butyl nitrite
  • DIAD Diisopropyl azodicarboxylate
  • DIPEA N,N-Diisopropylethylamine
  • Step 6 Synthesis of (R)-3-(4-amino-5-bromoimidazo[5,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylic acid benzyl ester
  • Step 8 (R)-4-amino-7-(1-((benzyloxy)carbonyl)piperidin-3-yl)imidazo[5,1-f][1,2,4]triazine-5 -Synthesis of formic acid (intermediate A4)
  • Step 1 (R)-3-(4-amino-5-((4-(2-(dimethylamino)-2-oxoethyl)-2,3-dimethylphenyl)carbamoyl )-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylic acid tert-butyl ester
  • Step 1 3-(4-Amino-5-((4-(2-(dimethylamino)-2-oxoethyl)phenyl)carbamoyl)pyrrolo[2,1-f][1 ,2,4]Triazine-7-yl)piperidine-1-carboxylic acid tert-butyl ester
  • Step 3 7-(1-acryloylpiperidin-3-yl)-4-amino-N-(4-(2-(dimethylamino)-2-oxoethyl)phenyl)pyrrolo[2 Synthesis of ,1-f][1,2,4]triazine-5-carboxamide
  • Chiral preparative chromatography column CHIRALPAK IC (trade name), 10mm ⁇ 250mm (inner diameter ⁇ length), 5 ⁇ m (filler particle size)
  • UV detection wavelength 254nm
  • Chiral preparative chromatography column CHIRALPAK IC (trade name), 10mm ⁇ 250mm (inner diameter ⁇ length), 5 ⁇ m (filler particle size)
  • UV detection wavelength 254nm
  • Step 1 3-(4-Amino-5-((4-(2-(dimethylamino)-2-oxoethyl)-2,3-dimethylphenyl)carbamoyl)pyrrolo[ Synthesis of 2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylic acid tert-butyl ester
  • Step 2 4-Amino-N-(4-(2-(dimethylamino)-2-oxoethyl)-2,3-dimethylphenyl)-7-(piperidin-3-yl) Synthesis of pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide
  • Step 3 7-(1-acryloylpiperidin-3-yl)-4-amino-N-(4-(2-(dimethylamino)-2-oxoethyl)-2,3-dimethyl Of phenyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide
  • Chiral preparative chromatography column CHIRALPAK IC (trade name), 10mm ⁇ 250mm (inner diameter ⁇ length), 5 ⁇ m (filler particle size)
  • UV detection wavelength 254nm
  • Chiral preparative chromatography column CHIRALPAK IC (trade name), 10mm ⁇ 250mm (inner diameter ⁇ length), 5 ⁇ m (filler particle size)
  • UV detection wavelength 254nm
  • Step 1 (R)-3-(8-amino-1-((4-(2-(dimethylamino)-2-oxoethyl)-2,3-dimethylphenyl)carbamoyl ) Synthesis of imidazo[1,5-a]pyrazin-3-yl)piperidine-1-carboxylic acid tert-butyl ester
  • Step 1 (R)-3-(4-amino-5-((4-(2-(dimethylamino)-2-oxoethyl)-2,3-dimethylphenyl)carbamoyl ) Synthesis of imidazo[5,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylic acid benzyl ester
  • the ADP-Glo Kinase Assay kit (Promega, V9102) was used to determine the inhibitory activity of the tested drug on EGFR (WT) and EGFR (D770_N771insNPG) (SignalChem, E-10-132GG).
  • the highest concentration of the drug to be tested is 1 ⁇ M, 3 times dilution, 12 concentrations.
  • a 384-well plate Perkin Elmer, 6007290
  • 0.1 ⁇ L of drug solutions of various concentrations were added to each well, and mixed with 5 ⁇ L of EGFR (WT) or 5 ⁇ L of EGFR (D770_N771insNPG) respectively, and double-replicated. After incubating at 25°C for 15 minutes, add 5 ⁇ L of substrate to start the reaction, and incubate at 25°C for 60 minutes.
  • the final reaction concentration in the system is: 0.5nM EGFR, 10 ⁇ M ATP, 0.03mg/mL Poly(4:1Glu, Tyr) Peptide, HEPES 50mM, EGTA 1mM, MgCl 2 10mM, Brij35 0.01%.
  • 10 ⁇ L ADP Glo reagent and incubate at 25°C for 40min.
  • 20 ⁇ L of detection reagent incubate at 25°C for 40min, read on Envision microplate reader (Perkin Elmer, 2104), and calculate the inhibitory rate of different concentrations of compounds on the enzyme.
  • GraphPad Prism 6.0 software was used to analyze the data, and nonlinear curve regression was used to fit the data to obtain a dose-response curve, and the IC 50 value was calculated from this.
  • the ADP-Glo Kinase Assay kit (Promega, V9102) was used to determine the inhibitory activity of the tested drug on HER2 (WT) and HER2 (A775_G776insYVMA) (SignalChem, E27-13BG).
  • the highest concentration of the drug to be tested is 1 ⁇ M, 3 times dilution, 12 concentrations.
  • Each well of a 384-well plate (Perkin Elmer, 6007290) was added with 0.1 ⁇ L of drug solutions of various concentrations, mixed with 5 ⁇ L of HER2 (WT) or 5 ⁇ L of HER2 (A775_G776insYVMA), and double-replicated wells. After incubating at 25°C for 15 minutes, add 5 ⁇ L of substrate to start the reaction, and incubate at 25°C for 60 minutes.
  • the final reaction concentration in the system is: 20nM HER2, 5 ⁇ M ATP, 0.03mg/mL Poly(4:1Glu, Tyr) Peptide, HEPES 50mM, EGTA 1mM, MgCl 2 10mM, Brij35 0.01%. Then add 10 ⁇ L ADP Glo reagent and incubate at 25°C for 40min. Then add 20 ⁇ L of detection reagent, incubate at 25°C for 40min, read on Envision microplate reader (Perkin Elmer, 2104), and calculate the inhibitory rate of different concentrations of compounds on the enzyme. GraphPad Prism 6.0 software was used to analyze the data, and nonlinear curve regression was used to fit the data to obtain a dose-response curve, and the IC 50 value was calculated from this.
  • the compound of the present invention was tested in the above-mentioned kinase inhibition experiment, and it was found that the compound of the present invention has potent activity on EGFR (WT), EGFR (D770_N771insNPG), HER2 (WT), and HER2 (A775_G776insYVMA) kinases.
  • WT EGFR
  • D770_N771insNPG HER2
  • WT HER2
  • HER2 A775_G776insYVMA
  • TAS0728 is (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-N-(4-(2-(dimethylamino)-2-oxo Ethyl)-2,3-dimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide
  • A431 cells and A549 cells are wild-type EGFR cells; H1975 cells are EGFR cells with L858R point mutation and T790M point mutation; HCC827 cells are mutant EGFR cells with exon 19 deletion.
  • A431 (WT EGFR) cells Adjust the concentration of A431 (WT EGFR) cells, A549 cells (WT EGFR), H1975 cells (Ex19del) and HCC827 cells (L858R/T790M EGFR), and add 50 ⁇ L of cell suspension to a 384-well plate at 37°C, 5% CO 2 Cultivate overnight.
  • Set up the Tecan D300E program Dosing with Tecan D300E instrument, the highest concentration of the drug to be tested is 10 ⁇ M, 3 times of gradient dilution, 10 concentrations, double multiple wells, and continue to incubate for 72 hours.
  • the compound of the present invention was tested in the above cytotoxicity experiment, and it was found that the compound of the present invention has no inhibitory activity against wild-type EGFR A431 cells and A549 cells, but has potent activity and high selectivity against H1975 cells and HCC827 cells of mutant EGFR. Therefore, it can be seen that the compound of the present invention can inhibit exon 19 deletion mutant EGFR and L858R/T790M mutant EGFR with high specificity.
  • Table 2 The results of representative example compounds are summarized in Table 2 below.
  • the compound of the present invention also has potent activity and high selectivity on Ba/F3EGFR-D770-N771ins_SVD cells. It can be seen that the compound of the present invention can inhibit the mutant EGFR inserted in exon 20 with high specificity.
  • Table 2 The results of representative example compounds are summarized in Table 2 below.
  • SK-BR-3 cells, NCI-N87 cells and BT-474 cells are wild-type HER2 cells. Adjust the concentration of SK-BR-3 cells, NCI-N87 cells and BT-474 cells, respectively add 50 ⁇ L of cell suspension to a 384-well plate, and incubate overnight at 37°C and 5% CO 2. Set up the Tecan D300E program. Dosing with Tecan D300E instrument, the highest concentration of the drug to be tested is 10 ⁇ M, 3 times of gradient dilution, 10 concentrations, double multiple wells, and continue to incubate for 72 hours.
  • the compound of the present invention was tested in the above-mentioned cytotoxicity experiment, and it was found that the compound of the present invention has potent activity against wild-type HER2 SK-BR-3 cells, NCI-N87 cells and BT-474 cells. This shows that the compound of the present invention It can inhibit wild-type HER2 with high specificity.
  • Tables 3 and 4 The results of representative example compounds are summarized in Tables 3 and 4 below.
  • the compounds of the present invention also have potent activity and high selectivity against Ba/F3HER2-A775_G776insYVMA cells.
  • the results of representative example compounds are summarized in Table 3 below.
  • the rats were fed with standard feed and given water. Fasting was started 16 hours before the test.
  • the drug was dissolved with 5% DMSO, 40% PEG400 and 55% normal saline. Blood was collected from the orbit. The time points for blood collection were 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours and 24 hours after administration.
  • the rats were briefly anesthetized after inhaling ether, and 300 ⁇ L blood samples were collected from the orbit and placed in a test tube. There is 30 ⁇ L of 1% heparin sodium solution in the test tube. Before use, the test tube was dried at 60°C overnight. After the blood sample was collected at the last time point, the rats were anesthetized with ether and sacrificed.
  • the blood sample was centrifuged at 6000 rpm at 4°C for 8 minutes to separate the plasma from the red blood cells. Aspirate 60 ⁇ L of blood (to produce approximately 30 ⁇ L of plasma) with a pipette into a miniature K2EDTA tube, and indicate the name and time point of the compound. The plasma is stored at -20°C before analysis. The concentration of the compound of the present invention in plasma was determined by LC-MS/MS. The pharmacokinetic parameters are calculated based on the blood drug concentration of each animal at different time points.
  • NCI-N87 cells 0.1 mL, 10 ⁇ 10 6 cells
  • BT-474 cells 0.1 mL, 10 ⁇ 10 6 cells
  • mice were subcutaneously inoculated into the right back of 6-8 week-old Balb/c male mice.
  • the length (mm) and width (mm) of tumors found in the mice were measured.
  • the mice are divided into groups of 6 mice, so that these groups have substantially the same average TV. The date when the mice were grouped was determined as the "group day" (day 0).
  • a test solution containing the compound of the present invention was prepared and administered orally to mice implanted with NCI-N87 cells subcutaneously at a dose of 15 mg/kg/day for 27 consecutive days (the first day of administration is the first day).
  • the control group was given vehicle (5% DMSO, 40% PEG400 and 55% normal saline).
  • a test solution containing the compound of the present invention was prepared and administered orally to mice implanted with BT-474 cells subcutaneously at a dose of 15 mg/kg/day for 30 consecutive days (the first day of administration was the first day).
  • the control group was given vehicle (5% DMSO, 40% PEG400 and 55% normal saline).
  • RTV (TV on day t)/(TV on day 0), where t represents the date when the tumor volume was measured.
  • T/C(%) (average RTV of test administration group)/(average RTV of vehicle control group) ⁇ 100%
  • TGI(%) (1-T/C) ⁇ 100%
  • BWC(%) [(BW on day t)-(BW on day 0)]/(BW on day 0) ⁇ 100%, where t represents the date when the weight was measured.

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Abstract

L'invention concerne un dérivé d'amide substitué et une composition contenant le composé et une utilisation de celui-ci. Le dérivé d'amide substitué est un composé représenté par la formule (I) ou un tautomère, un stéréoisomère, un promédicament, une forme cristalline, un sel pharmaceutiquement acceptable, un hydrate ou un solvate. Le composé et la composition de celui-ci peuvent être utilisés pour traiter et/ou prévenir une tumeur médiée par l'EGFR et/ou une kinase HER2 sauvage et/ou mutant.
PCT/CN2021/076684 2020-02-18 2021-02-18 Dérivé d'amide substitué et composition de celui-ci et son utilisation WO2021164697A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101610676A (zh) * 2006-09-22 2009-12-23 药品循环公司 布鲁顿酪氨酸激酶的抑制剂
WO2011153553A2 (fr) * 2010-06-04 2011-12-08 The Regents Of The University Of California Méthodes et compositions pour l'inhibition de kinases
CN103857396A (zh) * 2011-07-13 2014-06-11 药品循环公司 布鲁顿酪氨酸激酶抑制剂
WO2018033091A1 (fr) * 2016-08-17 2018-02-22 深圳市塔吉瑞生物医药有限公司 Composé bicyclique fusionné pour inhiber l'activité de la tyrosine kinase
WO2019013562A1 (fr) * 2017-07-12 2019-01-17 주식회사 대웅제약 Nouveau dérivé de 1h-pyrazolopyridine et composition pharmaceutique le contenant

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PL3345907T3 (pl) * 2015-09-01 2020-09-07 Taiho Pharmaceutical Co., Ltd. Związki pirazolo[3,4-d]pirymidynowe lub ich sole

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101610676A (zh) * 2006-09-22 2009-12-23 药品循环公司 布鲁顿酪氨酸激酶的抑制剂
WO2011153553A2 (fr) * 2010-06-04 2011-12-08 The Regents Of The University Of California Méthodes et compositions pour l'inhibition de kinases
CN103857396A (zh) * 2011-07-13 2014-06-11 药品循环公司 布鲁顿酪氨酸激酶抑制剂
WO2018033091A1 (fr) * 2016-08-17 2018-02-22 深圳市塔吉瑞生物医药有限公司 Composé bicyclique fusionné pour inhiber l'activité de la tyrosine kinase
WO2019013562A1 (fr) * 2017-07-12 2019-01-17 주식회사 대웅제약 Nouveau dérivé de 1h-pyrazolopyridine et composition pharmaceutique le contenant

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