WO2021164697A1 - Substituted amide derivative and composition thereof and use thereof - Google Patents

Substituted amide derivative and composition thereof and use thereof 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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PCT/CN2021/076684
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French (fr)
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.

Abstract

Provided are a substituted amide derivative and a composition containing the compound and a use thereof. The substituted amide derivative is a compound as represented by formula (I) or a tautomer, a stereoisomer, a prodrug, a crystal form, a pharmaceutically acceptable salt, a hydrate, or a solvate. The compound and the composition thereof can be used for treating and/or preventing wild and/or mutant EGFR and/or HER2 kinase mediated tumor.

Description

取代的酰胺衍生物及其组合物及用途Substituted amide derivatives and their compositions and uses 技术领域Technical field
本发明属于医药技术领域，尤其涉及对野生的和/或突变的EGFR和/或HER2具有抑制作用的取代的酰胺衍生物，包含它们的药物组合物，以及它们的制备方法和用途。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.
背景技术Background technique
EGFR是一种受体酪氨酸激酶，通过与作为配体的表皮生长因子(以下也称为EGF)结合而在正常组织中发挥其生理功能，并有助于上皮组织的生长和凋亡抑制。已知EGFR基因的体细胞突变是致癌原因：例如，缺失外显子19区域中第746至750位氨基酸(下文中也称为“外显子19缺失突变”)的EGFR和外显子21区域中第858位氨基酸从亮氨酸突变为精氨酸(下文中也称为“L858R突变”)的EGFR不断诱导EGF非依赖性激酶活性，并导致癌细胞的生长和存活。例如，在东亚约30％-50％的非小细胞肺癌中观察到这些突变，在欧洲和美国约10％的非小细胞肺癌中也观察到这些突变，因而其被认为是癌症的原因之一。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 . 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. .
因此，已经积极地进行EGFR抑制剂作为抗肿瘤剂的研究和开发，并运用于EGFR突变阳性肺癌的治疗中。例如，吉非替尼、埃罗替尼和阿法替尼对外显子19缺失突变的和L858R突变的EGFR阳性肺癌具有很高的抗肿瘤作用，但是它们以其治疗剂量使用会引起消化道疾病和皮肤病等副作用。Therefore, research and development of EGFR inhibitors as antitumor agents have been actively carried out and used in the treatment of EGFR mutation-positive lung cancer. For example, 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.
最近的研究发现，一些癌症的EGFR具有新的突变，其中一个或多个氨基酸***外显子20区域(下文中也称为“外显子20***突变”)，并且这些癌症相对先前已知的EGFR抑制剂具有低敏感性。Recent studies have found that some cancers have new mutations in EGFR, in which one or more amino acids are inserted into the exon 20 region (hereinafter also referred to as "exon 20 insertion mutations"), and these cancers are relatively EGFR inhibitors have low sensitivity.
另一方面，已有报告指出外显子18的点突变或缺失突变以及外显子21的点突变等数种较稀少的EGFR突变。例如，已经发现了新的EGFR点突变的肺癌，其中外显子18区域中第719位甘氨酸被任意氨基酸取代(以下简称G719X突变)、以及外显子21区域中第861位亮氨酸被谷氨酰胺取代(以下简称L861Q突变)。On the other hand, there have been reports that point mutations or deletion mutations in exon 18 and point mutations in exon 21 are several rarer EGFR mutations. For example, 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(也称为ErbB2)是属于ErbB2家族的受体酪氨酸激酶。HER2被认为是原癌基因，在各种各样的癌中报道了HER2的基因扩增或突变、过量表达等。在这些伴有HER2的基因异常、过量表达的癌细胞中，由于HER2和下游通路的信号活化，使得癌细胞的生存、增殖信号等增强。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突变是肺癌的常见驱动突变基因之一，主要表现为基因扩增、点突变、20号外显子***突变以及其它突变类型(如缺失***突变、移码突变等)，其中以外显子20的***突变最为常见。例如，HER2突变体包含一个YVMA***到外显子20(以下简称ex20insYVMA)。突变型HER2比野生型HER2更有效地激活信号传导、磷酸化EGFR、诱导肿瘤的形成和扩散。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. For example, 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.
因此，可以推测能够控制HER2的激酶活性的抑制剂通过抑制癌细胞中的HER2和下游通路的信号传导来发挥抗肿瘤效果，因而可以认为能够有效用作癌症治疗药。Therefore, it can be presumed that 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.
因此，有必要进一步研发新的EGFR抑制剂和HER2抑制剂，以期望可以有效抑制野生的EGFR和/或外显子20***突变的EGFR、外显子18点突变的EGFR、外显子21点突变的EGFR、野生的HER2和/或突变的HER2。Therefore, it is necessary to further develop new EGFR inhibitors and HER2 inhibitors in order to effectively inhibit wild EGFR and/or exon 20 insertion mutation EGFR, exon 18 point mutation EGFR, and exon 21 point. Mutant EGFR, wild HER2 and/or mutant HER2.
发明概述Summary of the invention
本发明提供了一种新的酰胺衍生物及包含该化合物的组合物及其用途，其对外显子20***(exon20ins)突变型EGFR、外显子18点突变型EGFR、外显子21点突变型EGFR、外显子19缺失(exon19del)突变型EGFR、L858R突变型EGFR、外显子19缺失/T790M突变型EGFR、L858R/T790M突变型EGFR等具有更好的抑制活性和高选择性，以及对野生的HER2和/突变的HER2具有抑制活性， 因而提供一种具有低毒副作用的抗肿瘤药物。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.
对此，本发明采用以下技术方案：In this regard, the present invention adopts the following technical solutions:
在一方面中，本发明涉及式(I)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物：In one aspect, the present invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof:
Figure PCTCN2021076684-appb-000001
Figure PCTCN2021076684-appb-000001
其中，in,
环A为芳香环；Ring A is an aromatic ring;
A 1为CR A1或N原子； A 1 is CR A1 or N atom;
A 2、A 3和A 5各自独立地为C或N原子； A 2 , A 3 and A 5 are each independently a C or N atom;
A 4为CR A4、N原子或NR A4； A 4 is CR A4 , N atom or NR A4 ;
前提是，当A 1和A 3是N，且A 2和A 5是C时，A 4不为N； The premise is that when A 1 and A 3 are N, and A 2 and A 5 are C, A 4 is not N;
R A1和R A4各自独立地为H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；且上述基团任选地被一个或多个R”取代； 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为CR B1或N； B 1 is CR B1 or N;
B 2为CR B2或N； B 2 is CR B2 or N;
B 3为CR B3或N； B 3 is CR B3 or N;
B 4为CR B4或N； B 4 is CR B4 or N;
R B1、R B2、R B3和R B4各自独立地选自H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；或者，R B1和R B2、R B3和R B4可以分别与它们所连接的C原子一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；且上述基团任选地被一个或多个R”取代； 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 and R B4 may be respectively connected to the C atom to which they are attached Together to 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″;
W选自键、O、S、NR N或CR C1R C2； W is selected from bond, O, S, NR N or CR C1 R C2 ;
R N选自H、C 1-6烷基或C 1-6卤代烷基，且上述基团任选地被一个或多个R*取代； 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和R C2各自独立地选自H、D、卤素、C 1-6烷基或C 1-6卤代烷基，且上述基团任选地被一个或多个R*取代； 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选自键、O、S、NR N或(CR C1R C2) p； L is selected from bond, O, S, NR N or (CR C1 R C2 ) p ;
p＝0、1或2；p=0, 1 or 2;
Y选自C 1-6烷基、C 3-7环烷基或3至7元杂环基，且上述基团任选地被m个R取代； 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选自-C(O)-、-C(O)NR N-*、-S(O) 2-或-S(O) 2NR N-*，其中*表示与Y相连接； Z is selected from -C(O)-, -C(O)NR N -*, -S(O) 2 -or -S(O) 2 NR N -*, where * means connected to Y;
V为-C(R 5)＝C(R 4)(R 3)； V is -C(R 5 )=C(R 4 )(R 3 );
R 3选自H、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，且上述基团任选地被一个或多个R*取代； 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和R 5各自独立地选自H、卤素、-CN、C 1-6烷基或C 1-6卤代烷基，且上述基团任选地被一个或多个R*取代；或者，R 4和R 5连同它们所连接的双键一起形成叁键； 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和R 2各自独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；或者，R 1和R 2连同它们所连接的N原子一起形成3至7元杂环基或5至10元杂芳基；且上述基团任选地被一个或多个R’取代； 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';
每个R’各自独立地选自H、D、卤素、-CN、＝O、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，或者，相同原子或相邻原子上的两个R’基团可以一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；其中R’定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R'is independently selected from H, D, halogen, -CN, =0, 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 two R'groups on the same atom or adjacent atoms can form a C 3-7 cycloalkyl group together , 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group; wherein each group in the definition of R'is optionally substituted with one or more D until fully deuterated;
每个R”各自独立地选自H、D、卤素、-CN、＝O、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，或者，相同原子或相邻原子上的两个R”基团可以一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；其中R”定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R" is independently selected from H, D, halogen, -CN, =0, 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 two R" groups on the same atom or adjacent atoms can form a C 3-7 cycloalkyl group together , 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group; wherein each group in the definition of R" is optionally substituted by one or more D until it is fully deuterated;
每个R*各自独立地选自H、D、卤素、-CN、＝O、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；或者，相同原子或相邻原子上的两个R*基团可以一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；其中R*定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R* is independently selected from H, D, halogen, -CN, =O, 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, two R* groups on the same atom or adjacent atoms can form a C 3-7 cycloalkyl group together , 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group; wherein each group in the definition of R* is optionally substituted by one or more D until fully deuterated;
每个R各自独立地选自H、D、卤素、-CN、＝O、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；或者，相同原子或相邻原子上的两个R基团可以一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；其中R定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R is independently selected from H, D, halogen, -CN, =O, 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, A 3- to 7-membered heterocyclic group, a C 6-10 aryl group or a 5- to 10-membered heteroaryl group; alternatively, two R groups on the same atom or adjacent atoms can form a C 3-7 cycloalkyl group, 3 To 7-membered heterocyclyl, C 6-10 aryl or 5 to 10-membered heteroaryl; wherein each group in the definition of R is optionally substituted with one or more D until fully deuterated;
m＝0、1、2、3、4、5、6、7、8或9；m=0, 1, 2, 3, 4, 5, 6, 7, 8 or 9;
每个R a、R b和R c各自独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，或者R b和R c连同它们所连接的N原子一起形成3至7元杂环基或5至10元杂芳基；其中R a、R b和R c定义中的每个基团任选地被一个或多个D取代，直至完全氘代。 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.
在另一方面，本发明提供了一种药物组合物，其含有本发明化合物或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，和药学上可接受的赋形剂。在具体实施方案中，本发明化合物以治疗有效量提供。在具体实施方案中，本发明化合物以预防有效量提供。In another aspect, 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. In a specific embodiment, the compound of the invention is provided in a therapeutically effective amount. In a specific embodiment, the compound of the invention is provided in a prophylactically effective amount.
在另一方面，本发明提供了一种本发明化合物或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，或本发明的药物组合物在制备用于治疗和/或预防野生型或突变型EGFR激酶介导的肿瘤的药物中的用途。In another aspect, 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 Use of the pharmaceutical composition in the preparation of a medicament for the treatment and/or prevention of wild-type or mutant EGFR kinase-mediated tumors.
在另一方面，本发明提供了一种治疗和/或预防受试者中的疾病，如野生的和/或突变的EGFR激酶介导的肿瘤的方法，包括向所述受试者给药本发明化合物或其互变异构体、立体异构体、前药、晶 型、药学上可接受的盐、水合物或溶剂合物，或本发明药物组合物。In another aspect, 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 The compound of the invention or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, or the pharmaceutical composition of the invention.
在具体实施方案中，所述的突变的EGFR选自外显子20***突变型EGFR、外显子18点突变型EGFR、外显子21点突变型EGFR、外显子19缺失突变型EGFR或L858R突变型EGFR。In a specific embodiment, 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.
在具体实施方案中，所述的外显子20***突变为其中一个或多个氨基酸***外显子20区域的突变。在具体实施方案中，所述的外显子20***突变为其中1至7个氨基酸***外显子20区域的突变。在具体实施方案中，所述的外显子20***突变为其中1至4个氨基酸***外显子20区域的突变。在具体实施方案中，所述的外显子20***突变为A763_Y764insFQEA、V769_D770insASV、D770_N771insSVD、D770_N771insNPG、D770_N771insG、D770>GY、N771_P772insN、P772_R773insPR、H773_V774insNPH、H773_V774insPH、H773_V774insAH、H773_V774insH、H774_C774insHV、A761_E762insEAFQ。在具体实施方案中，所述的外显子20***突变为V769_D770insASV、D770_N771insSVD、D770_N771insNPG、D770_N771insG、H773_V774insNPH或H773_V774insPH。In a specific embodiment, 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. In a specific embodiment, 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_H773_H774ins_V774ins, H773_H774ins, H773_H773_H774ins_V774ins, H773_VH774ins In a specific embodiment, the exon 20 insertion mutation is V769_D770insASV, D770_N771insSVD, D770_N771insNPG, D770_N771insG, H773_V774insNPH or H773_V774insPH.
在具体实施方案中，所述的外显子18点突变选自外显子18的G719X突变或外显子18的E709X突变。在具体实施方案中，所述的G719X突变选自G719A、G719S和G719C中的至少一种突变。在具体实施方案中，所述的E709X突变选自E709K和E709A中的至少一种突变。In a specific embodiment, the exon 18 point mutation is selected from the G719X mutation of exon 18 or the E709X mutation of exon 18. In a specific embodiment, the G719X mutation is selected from at least one mutation of G719A, G719S and G719C. In a specific embodiment, the E709X mutation is selected from at least one mutation of E709K and E709A.
在具体实施方案中，所述的外显子21点突变选自外显子21的L861X突变。在具体实施方案中，所述L861X突变为L861Q突变。In a specific embodiment, the exon 21 point mutation is selected from the L861X mutation of exon 21. In a specific embodiment, the L861X mutation is a L861Q mutation.
在具体实施方案中，所述的突变的EGFR具有T790M突变且具有选自外显子20***突变、外显子18点突变、外显子21点突变、外显子19缺失突变或L858R突变中的至少一种突变。In a specific embodiment, 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.
在具体实施方案中，本发明化合物或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物用于治疗表达具有外显子20***突变的EGFR的肿瘤患者。In a specific embodiment, 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.
在具体实施方案中，本发明化合物或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物用于治疗表达具有T790M突变且具有外显子20***突变的EGFR的肿瘤患者。In a specific embodiment, 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.
在具体实施方案中，本发明化合物或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物用于治疗表达具有外显子18点突变型EGFR的肿瘤患者。In a specific embodiment, 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.
在具体实施方案中，本发明化合物或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物用于治疗表达具有T790M突变且具有外显子18点突变型EGFR的肿瘤患者。In a specific embodiment, 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.
在具体实施方案中，本发明化合物或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物用于治疗表达具有外显子21点突变型EGFR的肿瘤患者。In a specific embodiment, 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.
在具体实施方案中，本发明化合物或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物用于治疗表达具有T790M突变且具有外显子21点突变型EGFR的癌症患者。In a specific embodiment, 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.
在具体实施方案中，本发明化合物或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物用于治疗表达具有外显子19缺失突变型EGFR的肿瘤患者。In a specific embodiment, 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.
在具体实施方案中，本发明化合物或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物用于治疗表达具有T790M突变且具有外显子19缺失突变型EGFR的癌症患者。In a specific embodiment, 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.
在具体实施方案中，本发明化合物或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物用于治疗表达具有L858R突变型EGFR的肿瘤患者。In a specific embodiment, 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.
在具体实施方案中，本发明化合物或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物用于治疗表达具有T790M突变且具有L858R突变型EGFR的肿瘤患者。In a specific embodiment, 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.
在具体实施方案中，本发明提供了一种本发明化合物或其互变异构体、立体异构体、前药、晶型、 药学上可接受的盐、水合物或溶剂合物，或本发明的药物组合物在制备用于治疗和/或预防以下肿瘤的药物中的用途，或者本发明提供了一种治疗和/或预防受试者中的以下肿瘤的方法，包括向所述受试者给药本发明化合物或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，或本发明药物组合物：肺癌、乳腺癌、头颈癌、脑肿瘤、子宫癌、造血***肿瘤或皮肤癌。In a specific embodiment, 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 person administers the compound of the present invention or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the pharmaceutical composition of the present invention: lung cancer, breast cancer , Head and neck cancer, brain tumor, uterine cancer, hematopoietic system tumor or skin cancer.
在另一方面，本发明提供了一种本发明化合物或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，或本发明的药物组合物在制备用于治疗和/或预防野生的和/或突变的HER2激酶介导的肿瘤的药物的用途。In another aspect, 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.
在另一方面，本发明提供了一种治疗和/或预防受试者中的疾病，如野生的和/或突变的HER2激酶介导的肿瘤的方法，包括向所述受试者给药本发明化合物或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，或本发明药物组合物。In another aspect, 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 The compound of the invention or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, or the pharmaceutical composition of the invention.
在具体实施方案中，所述突变的HER2选自G309A突变型HER2、S310F突变型HER2、R678Q突变型HER2、L775_T759缺失突变型HER2、D769H突变型HER2、V777L突变型HER2、V842I突变型HER2、R869C突变型HER2、L755S突变型HER2或ex20insYVMA突变型HER2。In a specific embodiment, 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.
在具体实施方案中，所述ex20insYVMA突变型HER2选自A775_G776insYVMA突变型HER2突变。In a specific embodiment, the ex20insYVMA mutant HER2 is selected from the group consisting of A775_G776insYVMA mutant HER2 mutations.
在具体实施方案中，本发明提供了一种本发明化合物或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，或本发明的药物组合物在制备用于治疗和/或预防以下肿瘤的药物中的用途，或者本发明提供了一种治疗和/或预防受试者中以下肿瘤的方法，包括向所述受试者给药本发明化合物或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，或本发明药物组合物：肺癌、胃癌或乳腺癌。In a specific embodiment, 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 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 providing Administration of the compound of the present invention or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the pharmaceutical composition of the present invention: lung cancer, gastric cancer or breast cancer.
由随后的具体实施方式、实施例和权利要求，本发明的其他目的和优点将对于本领域技术人员显而易见。From the following specific embodiments, examples and claims, other objects and advantages of the present invention will be apparent to those skilled in the art.
附图说明Description of the drawings
图1为在NCI-N87细胞体内模型中各组小鼠肿瘤体积的生长曲线。Figure 1 shows the growth curve of the tumor volume of each group of mice in the NCI-N87 cell in vivo model.
图2在NCI-N87细胞体内模型中各组随治疗时间的相对肿瘤体积百分比的变化曲线。Figure 2 Curves of relative tumor volume percentage changes in each group with treatment time in the NCI-N87 cell in vivo model.
图3在BT-474细胞体内模型中各组小鼠肿瘤体积的生长曲线。Figure 3 The growth curve of the tumor volume of each group of mice in the BT-474 cell in vivo model.
图4在BT-474细胞体内模型中各组随治疗时间的相对肿瘤体积百分比的变化曲线。Figure 4 Curves of relative tumor volume percentage changes in each group with treatment time in the BT-474 cell in vivo model.
图5在NCI-N87细胞体内模型中各组随治疗时间的体重的变化曲线。Figure 5 The body weight change curve of each group with treatment time in the NCI-N87 cell in vivo model.
图6在NCI-N87细胞体内模型中各组随治疗时间的体重百分比的变化曲线。Fig. 6 The change curve of body weight percentage of each group with treatment time in the NCI-N87 cell in vivo model.
图7在BT-474细胞体内模型中各组随治疗时间的体重的变化曲线。Fig. 7 The change curve of body weight of each group with treatment time in the BT-474 cell in vivo model.
图8在BT-474细胞体内模型中各组随治疗时间的体重百分比的变化曲线。Fig. 8 The change curve of body weight percentage of each group with treatment time in the BT-474 cell in vivo model.
具体实施方案Specific implementation plan
定义definition
化学定义Chemical definition
下面更详细地描述具体官能团和化学术语的定义。The definitions of specific functional groups and chemical terms are described in more detail below.
当列出数值范围时，既定包括每个值和在所述范围内的子范围。例如“C 1-6烷基”包括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和C 5-6烷基。 When listing numerical ranges, it is intended to include each value and sub-ranges within the stated range. For example, "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烷基”是指具有1至6个碳原子的直链或支链饱和烃基团，本文也称为“低级烷基”。在一些 实施方案中，C 1-4烷基是特别优选的。所述烷基的实例包括但不限于：甲基(C 1)、乙基(C 2)、正丙基(C 3)、异丙基(C 3)、正丁基(C 4)、叔丁基(C 4)、仲丁基(C 4)、异丁基(C 4)、正戊基(C 5)、3-戊基(C 5)、戊基(C 5)、新戊基(C 5)、3-甲基-2-丁基(C 5)、叔戊基(C 5)和正己基(C 6)。不论烷基前是否修饰有“取代的”，烷基的每个独立地任选被取代，例如，1至5个取代基、1至3个取代基或1个取代基，适当的取代基如下定义。 The "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. Examples of the alkyl group 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 ). Regardless of whether or not the alkyl group is modified with "substituted", 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烯基”是指具有2至6个碳原子和至少一个碳碳双键的直链或支链烃基团。在一些实施方案中，C 2-4烯基是优选的。C 2-6烯基的例子包括：乙烯基(C 2)、1-丙烯基(C 3)、2-丙烯基(C 3)、1-丁烯基(C 4)、2-丁烯基(C 4)、丁二烯基(C 4)、戊烯基(C 5)、戊二烯基(C 5)、己烯基(C 6)，等等。术语“C 2-6烯基”还包括杂烯基，其中一或多个(例如，1、2、3或4个)碳原子被杂原子(例如，氧、硫、氮、硼、硅、磷)替代。不论烯基前是否修饰有“取代的”，烯基的每个独立地任选被取代，例如，1至5个取代基、1至3个取代基或1个取代基，适当的取代基如下定义。 The "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. The term "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炔基”是指具有2至6个碳原子、至少一个碳-碳叁键以及任选地一个或多个碳-碳双键的直链或支链烃基团。在一些实施方案中，C 2-4炔基是优选的。C 2-6炔基的例子包括但不限于：乙炔基(C 2)、1-丙炔基(C 3)、2-丙炔基(C 3)、1-丁炔基(C 4)、2-丁炔基(C 4)，戊炔基(C 5)、己炔基(C 6)，等等。术语“C 2-6炔基”还包括杂炔基，其中一或多个(例如，1、2、3或4个)碳原子被杂原子(例如，氧、硫、氮、硼、硅、磷)替代。不论炔基前是否修饰有“取代的”，炔基的每个独立地任选被取代，例如，1至5个取代基、1至3个取代基或1个取代基，适当的取代基如下定义。 "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. The term "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烷氧基”是指基团-OR，其中，R为取代或未取代的C 1-6烷基。在一些实施方案中，C 1-4烷氧基是特别优选的。具体的所述烷氧基包括但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基、仲丁氧基、正戊氧基、正己氧基和1,2-二甲基丁氧基。不论烷氧基前是否修饰有“取代的”，烷氧基的每个独立地任选被取代，例如，1至5个取代基、1至3个取代基或1个取代基，适当的取代基如下定义。 "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烷氨基”是指基团-NHR或者-NR 2，其中，R为取代或未取代的C 1-6烷基。在一些实施方案中，C 1-4烷氨基是特别优选的。具体的所述烷氨基包括但不限于：甲氨基、乙氨基、正丙氨基、异丙氨基、正丁氨基、二甲氨基、甲乙氨基和二乙氨基。不论烷氨基前是否修饰有“取代的”，烷氨基的每个独立地任选被取代，例如，1至5个取代基、1至3个取代基或1个取代基，适当的取代基如下定义。 "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. Regardless of whether the alkylamino group is modified with "substituted" before it, 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.
“卤代”或“卤素”是指氟(F)、氯(Cl)、溴(Br)和碘(I)。在一些实施方案中，卤素基团是F、Cl或Br。在一些实施方案中，卤素基团是F或Cl。在一些实施方案中，卤素基团是F。"Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I). In some embodiments, the halogen group is F, Cl, or Br. In some embodiments, the halogen group is F or Cl. In some embodiments, the halogen group is F.
因此，“C 1-6卤代烷基”和“C 1-6卤代烷氧基”是指上述“C 1-6烷基”和“C 1-6烷氧基”，其被一个或多个卤素基团取代。在一些实施方案中，C 1-4卤代烷基是特别优选的，更优选C 1-2卤代烷基。在一些实施方案中，C 1-4卤代烷氧基是特别优选的，更优选C 1-2卤代烷氧基。示例性的所述卤代烷基包括但不限于：-CF 3、-CH 2F、-CHF 2、-CHFCH 2F、-CH 2CHF 2、-CF 2CF 3、-CCl 3、-CH 2Cl、-CHCl 2、2,2,2-三氟-1,1-二甲基-乙基，等等。示例性的所述卤代烷氧基包括但不限于：-OCH 2F、-OCHF 2、-OCF 3，等等。 Therefore, "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. In some embodiments, C 1-4 haloalkyl is particularly preferred, and C 1-2 haloalkyl is more preferred. In some embodiments, C 1-4 haloalkoxy is particularly preferred, and C 1-2 haloalkoxy is more preferred. Exemplary 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环烷基”是指具有3至10个环碳原子和零个杂原子的非芳香环烃基团。在一些实施方案中，C 3-7环烷基是优选的，C 3-6环烷基是特别优选的，更优选C 5-6环烷基。环烷基还包括其中上述环烷基环与一个或多个芳基或杂芳基稠合的环体系，其中连接点在环烷基环上，且在这样的情况中，碳的数目继续表示环烷基体系中的碳的数目。示例性的所述环烷基包括但不限于：环丙基(C 3)、环丙烯基(C 3)、环丁基(C 4)、环丁烯基(C 4)、环戊基(C 5)、环戊烯基(C 5)、环己基(C 6)、环己烯基(C 6)、环已二烯基(C 6)、环庚基(C 7)、环庚烯基(C 7)、环庚二烯基(C 7)、环庚三烯基(C 7)、环辛基(C 8)、环辛烯基(C 8)、二环[2.2.1] 庚基(C 7)、二环[2.2.2]辛基(C 8)、环壬基(C 9)、环壬烯基(C 9)、环癸基(C 10)、环癸烯基(C 10)、八氢-1H-茚基(C 9)、十氢萘基(C 10)、螺[4.5]癸基(C 10)，等等。不论环烷基前是否修饰有“取代的”，环烷基的每个独立地任选被取代，例如，1至5个取代基、1至3个取代基或1个取代基，适当的取代基如下定义。 "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 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C 9 ), decahydronaphthyl (C 10 ), spiro[4.5]decyl (C 10 ), and so on. Regardless of whether the cycloalkyl group is modified with "substituted", 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.
“3至10元杂环基”或是指具有环碳原子和1至4个环杂原子的3至10元非芳香环系的基团，其中，每个杂原子独立地选自氮、氧、硫、硼、磷和硅。在包含一个或多个氮原子的杂环基中，只要化合价允许，连接点可为碳或氮原子。在一些实施方案中，3至7元杂环基是优选的，其为具有环碳原子和1至3个环杂原子的3至7元非芳香环系；在一些实施方案中，3至6元杂环基是特别优选的，其为具有环碳原子和1至3个环杂原子的3至6元非芳香环系；更优选5至6元杂环基，其为具有环碳原子和1至3个环杂原子的5至6元非芳香环系。杂环基还包括其中上述杂环基环与一个或多个环烷基、芳基或杂芳基稠合的环体系，其中连接点在杂环基环上；且在这样的情况下，环成员的数目继续表示在杂环基环体系中环成员的数目。不论杂环基前是否修饰有“取代的”，杂环基的每个独立地任选被取代，例如，1至5个取代基、1至3个取代基或1个取代基，适当的取代基如下定义。"3 to 10 membered 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. In a heterocyclic group containing one or more nitrogen atoms, as long as the valence permits, the point of attachment may be a carbon or nitrogen atom. In some embodiments, 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. Regardless of whether the heterocyclic group is modified with "substituted" in front of it, 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.
示例性的包含一个杂原子的3元杂环基包括但不限于：氮杂环丙烷基、氧杂环丙烷基、硫杂环丙烷基(thiorenyl)。示例性的含有一个杂原子的4元杂环基包括但不限于：氮杂环丁烷基、氧杂环丁烷基和硫杂环丁烷基。示例性的含有一个杂原子的5元杂环基包括但不限于：四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、吡咯烷基、二氢吡咯基和吡咯基-2,5-二酮。示例性的包含两个杂原子的5元杂环基包括但不限于：二氧杂环戊烷基、氧硫杂环戊烷基(oxasulfuranyl)、二硫杂环戊烷基(disulfuranyl)和噁唑烷-2-酮。示例性的包含三个杂原子的5元杂环基包括但不限于：***啉基、噁二唑啉基和噻二唑啉基。示例性的包含一个杂原子的6元杂环基包括但不限于：哌啶基、四氢吡喃基、二氢吡啶基和硫杂环己烷基(thianyl)。示例性的包含两个杂原子的6元杂环基包括但不限于：哌嗪基、吗啉基、二硫杂环己烷基、二噁烷基。示例性的包含三个杂原子的6元杂环基包括但不限于：六氢三嗪基(triazinanyl)。示例性的含有一个杂原子的7元杂环基包括但不限于：氮杂环庚烷基、氧杂环庚烷基和硫杂环庚烷基。示例性的包含一个杂原子的8元杂环基包括但不限于：氮杂环辛烷基、氧杂环辛烷基和硫杂环辛烷基。示例性的与C 6芳基环稠合的5元杂环基(在本文中也称作5,6-双环杂环基)包括但不限于：二氢吲哚基、异二氢吲哚基、二氢苯并呋喃基、二氢苯并噻吩基、苯并噁唑啉酮基，等等。示例性的与C 6芳基环稠合的6元杂环基(本文还指的是6,6-双环杂环基)包括但不限于：四氢喹啉基、四氢异喹啉基，等等。 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 (also referred to herein as 5,6-bicyclic heterocyclic groups) include, but are not limited to: indolinyl, isoindolinyl , Dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, etc. Exemplary 6-membered heterocyclic groups fused to a C 6 aryl ring (also referred to herein as 6,6-bicyclic heterocyclic groups) include, but are not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, and many more.
“C 6-14芳基”是指具有6-14个环碳原子和零个杂原子的单环或多环的(例如，双环或三环)4n+2芳族环体系(例如，具有以环状排列共享的6、10或14个π电子)的基团。在一些实施方案中，芳基具有六个环碳原子(“C 6芳基”；例如，苯基)。在一些实施方案中，芳基具有十个环碳原子(“C 10芳基”；例如，萘基，例如，1-萘基和2-萘基)。在一些实施方案中，芳基具有十四个环碳原子(“C 14芳基”；例如，蒽基)。在一些实施方案中，C 6-10芳基是特别优选的，更优选C 6芳基。芳基还包括其中上述芳基环与一个或多个环烷基或杂环基稠合的环***，而且连接点在所述芳基环上，在这种情况下，碳原子的数目继续表示所述芳基环***中的碳原子数目。不论芳基前是否修饰有“取代的”，芳基的每个独立地任选被取代，例如，1至5个取代基、1至3个取代基或1个取代基，适当的取代基如下定义。 "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 π electrons) groups are arranged in a ring. In some embodiments, an aryl group having six ring carbon atoms ( "C 6 aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C 10 aryl"; for example, naphthyl, for example, 1-naphthyl and 2-naphthyl). In some embodiments, 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. Regardless of whether the aryl group is modified with "substituted", 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至10元杂芳基”是指具有环碳原子和1-4个环杂原子的5-10元单环或双环的4n+2芳族环体系(例如，具有以环状排列共享的6或10个π电子)的基团，其中每个杂原子独立地选自氮、氧和硫。在含有一个或多个氮原子的杂芳基中，只要化合价允许，连接点可以是碳或氮原子。杂芳基双环***在一个或两个环中可以包括一个或多个杂原子。杂芳基还包括其中上述杂芳基环与一个或多个环烷基或 杂环基稠合的环***，而且连接点在所述杂芳基环上，在这种情况下，碳原子的数目继续表示所述杂芳基环***中的碳原子数目。在一些实施方案中，5至6元杂芳基是特别优选的，其为具有环碳原子和1-4个环杂原子的5-6元单环或双环的4n+2芳族环体系。不论杂芳基前是否修饰有“取代的”，杂芳基的每个独立地任选被取代，例如，1至5个取代基、1至3个取代基或1个取代基，适当的取代基如下定义。"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 π electrons), where each heteroatom is independently selected from nitrogen, oxygen and sulfur. In heteroaryl groups containing one or more nitrogen atoms, as long as the valence allows, 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. In some embodiments, 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. Regardless of whether the heteroaryl group is modified with "substituted" in front of it, 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.
示例性的含有一个杂原子的5元杂芳基包括但不限于：吡咯基、呋喃基和噻吩基。示例性的含有两个杂原子的5元杂芳基包括但不限于：咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基和异噻唑基。示例性的含有三个杂原子的5元杂芳基包括但不限于：***基、噁二唑基和噻二唑基。示例性的含有四个杂原子的5元杂芳基包括但不限于：四唑基。示例性的含有一个杂原子的6元杂芳基包括但不限于：吡啶基。示例性的含有两个杂原子的6元杂芳基包括但不限于：哒嗪基、嘧啶基和吡嗪基。示例性的含有三个或四个杂原子的6元杂芳基分别包括但不限于：三嗪基和四嗪基。示例性的含有一个杂原子的7元杂芳基包括但不限于：氮杂环庚三烯基、氧杂环庚三烯基和硫杂环庚三烯基。示例性的5,6-双环杂芳基包括但不限于：吲哚基、异吲哚基、吲唑基、苯并***基、苯并噻吩基、异苯并噻吩基、苯并呋喃基、苯并异呋喃基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噁二唑基、苯并噻唑基、苯并异噻唑基、苯并噻二唑基、茚嗪基和嘌呤基。示例性的6,6-双环杂芳基包括但不限于：萘啶基、喋啶基、喹啉基、异喹啉基、噌琳基、喹喔啉基、酞嗪基和喹唑啉基。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 .
“羰基”是指-C(O)-基团。"Carbonyl" refers to the -C(O)- group.
示例性的碳原子上的取代基包括但不局限于：卤素、-CN、-NO 2、-N 3、-SO 2H、-SO 3H、-OH、-OR aa、-ON(R bb) 2、-N(R bb) 2、-N(R bb) 3 +X -、-N(OR cc)R bb、-SH、-SR aa、-SSR cc、-C(＝O)R aa、-CO 2H、-CHO、-C(OR cc) 2、-CO 2R aa、-OC(＝O)R aa、-OCO 2R aa、-C(＝O)N(R bb) 2、-OC(＝O)N(R bb) 2、-NR bbC(＝O)R aa、-NR bbCO 2R aa、-NR bbC(＝O)N(R bb) 2、-C(＝NR bb)R aa、-C(＝NR bb)OR aa、-OC(＝NR bb)R aa、-OC(＝NR bb)OR aa、-C(＝NR bb)N(R bb) 2、-OC(＝NR bb)N(R bb) 2、-NR bbC(＝NR bb)N(R bb) 2、-C(＝O)NR bbSO 2R aa、-NR bbSO 2R aa、-SO 2N(R bb) 2、-SO 2R aa、-SO 2OR aa、-OSO 2R aa、-S(＝O)R aa、-OS(＝O)R aa、-Si(R aa) 3、-OSi(R aa) 3、-C(＝S)N(R bb) 2、-C(＝O)SR aa、-C(＝S)SR aa、-SC(＝S)SR aa、-SC(＝O)SR aa、-OC(＝O)SR aa、-SC(＝O)OR aa、-SC(＝O)R aa、-P(＝O) 2R aa、-OP(＝O) 2R aa、-P(＝O)(R aa) 2、-OP(＝O)(R aa) 2、-OP(＝O)(OR cc) 2、-P(＝O) 2N(R bb) 2、-OP(＝O) 2N(R bb) 2、-P(＝O)(NR bb) 2、-OP(＝O)(NR bb) 2、-NR bbP(＝O)(OR cc) 2、-NR bbP(＝O)(NR bb) 2、-P(R cc) 2、-P(R cc) 3、-OP(R cc) 2、-OP(R cc) 3、-B(R aa) 2、-B(OR cc) 2、-BR aa(OR cc)、烷基、卤代烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基，其中，每个烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R dd基团取代； Exemplary substituents on carbon atoms include, but are not limited to: halogen, -CN, -NO 2 , -N 3 , -SO 2 H, -SO 3 H, -OH, -OR aa , -ON (R bb ) 2, -N (R bb) 2, -N (R bb) 3 + X -, -N (OR cc) R bb, -SH, -SR aa, -SSR cc, -C (= O) R aa , -CO 2 H, -CHO, -C(OR cc ) 2 , -CO 2 R aa , -OC(=O)R aa , -OCO 2 R aa , -C(=O)N(R bb ) 2 , -OC(=O)N(R bb ) 2 , -NR bb C(=O)R aa , -NR bb CO 2 R aa , -NR bb C(=O)N(R bb ) 2 , -C (=NR bb )R aa , -C(=NR bb )OR aa , -OC(=NR bb )R aa , -OC(=NR bb )OR aa , -C(=NR bb )N(R bb ) 2. -OC(=NR bb )N(R bb ) 2 , -NR bb C(=NR bb )N(R bb ) 2 , -C(=O)NR bb SO 2 R aa , -NR bb SO 2 R aa , -SO 2 N(R bb ) 2 , -SO 2 R aa , -SO 2 OR aa , -OSO 2 R aa , -S(=O)R aa , -OS(=O)R aa ,- Si(R aa ) 3 , -OSi(R aa ) 3 , -C(=S)N(R bb ) 2 , -C(=O)SR aa , -C(=S)SR aa , -SC(= S)SR aa , -SC(=O)SR aa , -OC(=O)SR aa , -SC(=O)OR aa , -SC(=O)R aa , -P(=O) 2 R aa , -OP(=O) 2 R aa , -P(=O)(R aa ) 2 , -OP(=O)(R aa ) 2 , -OP(=O)(OR cc ) 2 , -P( =O) 2 N(R bb ) 2 , -OP(=O) 2 N(R bb ) 2 , -P(=O)(NR bb ) 2 , -OP(=O)(NR bb ) 2 ,- NR bb P(=O)(OR cc ) 2 , -NR bb P(=O)(NR bb ) 2 , -P(R cc ) 2 , -P(R cc ) 3 , -OP(R cc ) 2 , -OP(R cc ) 3 , -B(R aa ) 2 , -B(OR cc ) 2 , -BR aa (OR cc ), alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and hetero Aryl groups, where each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclyl, aryl and heteroaryl group is independently substituted with 0, 1, 2, 3, 4 or 5 R dd groups ；
或者在碳原子上的两个偕氢被基团＝O、＝S、＝NN(R bb) 2、＝NNR bbC(＝O)R aa、＝NNR bbC(＝O)OR aa、＝NNR bbS(＝O) 2R aa、＝NR bb或＝NOR cc取代； Or the two geminal hydrogens on the carbon atom are grouped by =0, =S, =NN(R bb ) 2 , =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , = Replace with NNR bb S(=O) 2 R aa , =NR bb or =NOR cc ;
R aa的每个独立地选自烷基、卤代烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基，或者两个R aa基团结合以形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R dd基团取代； 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
R bb的每个独立地选自：氢、-OH、-OR aa、-N(R cc) 2、-CN、-C(＝O)R aa、-C(＝O)N(R cc) 2、-CO 2R aa、-SO 2R aa、-C(＝NR cc)OR aa、-C(＝NR cc)N(R cc) 2、-SO 2N(R cc) 2、-SO 2R cc、-SO 2OR cc、-SOR aa、-C(＝S)N(R cc) 2、-C(＝O)SR cc、-C(＝S)SR cc、-P(＝O) 2R aa、-P(＝O)(R aa) 2、-P(＝O) 2N(R cc) 2、-P(＝O)(NR cc) 2、烷基、卤代烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基，或者两个R bb基团结合以形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R dd基团取代； Each of R bb is independently selected from: hydrogen, -OH, -OR aa , -N(R cc ) 2 , -CN, -C(=O)R aa , -C(=O)N(R cc ) 2. -CO 2 R aa , -SO 2 R aa , -C(=NR cc )OR aa , -C(=NR cc )N(R cc ) 2 , -SO 2 N(R cc ) 2 , -SO 2 R cc , -SO 2 OR cc , -SOR aa , -C(=S)N(R cc ) 2 , -C(=O)SR cc , -C(=S)SR cc , -P(=O ) 2 R aa , -P(=O)(R aa ) 2 , -P(=O) 2 N(R cc ) 2 , -P(=O)(NR cc ) 2 , alkyl, haloalkyl, alkene Group, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R bb groups combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkyne Group, carbocyclic group, heterocyclic group, aryl group and heteroaryl group are independently substituted with 0, 1, 2, 3, 4 or 5 R dd groups;
R cc的每个独立地选自氢、烷基、卤代烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基，或者两个R cc基团结合以形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R dd基团取代； 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 dd的每个独立地选自：卤素、-CN、-NO 2、-N 3、-SO 2H、-SO 3H、-OH、-OR ee、-ON(R ff) 2、-N(R ff) 2,、-N(R ff) 3 +X -、-N(OR ee)R ff、-SH、-SR ee、-SSR ee、-C(＝O)R ee、-CO 2H、-CO 2R ee、-OC(＝O)R ee、-OCO 2R ee、-C(＝O)N(R ff) 2、-OC(＝O)N(R ff) 2、-NR ffC(＝O)R ee、-NR ffCO 2R ee、-NR ffC(＝O)N(R ff) 2、-C(＝NR ff)OR ee、-OC(＝NR ff)R ee、-OC(＝NR ff)OR ee、-C(＝NR ff)N(R ff) 2、-OC(＝NR ff)N(R ff) 2、-NR ffC(＝NR ff)N(R ff) 2、-NR ffSO 2R ee、-SO 2N(R ff) 2、-SO 2R ee、-SO 2OR ee、-OSO 2R ee、-S(＝O)R ee、-Si(R ee) 3、-OSi(R ee) 3、-C(＝S)N(R ff) 2、-C(＝O)SR ee、-C(＝S)SR ee、-SC(＝S)SR ee、-P(＝O) 2R ee、-P(＝O)(R ee) 2、-OP(＝O)(R ee) 2、-OP(＝O)(OR ee) 2、烷基、卤代烷基、烯基、炔基、碳环基、杂环基、芳基、杂芳基，其中，每个烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R gg基团取代，或者两个偕R dd取代基可结合以形成＝O或＝S； Each of R dd is independently selected from: halogen, -CN, -NO 2 , -N 3 , -SO 2 H, -SO 3 H, -OH, -OR ee , -ON(R ff ) 2 , -N (R ff) 2 ,, - N (R ff) 3 + X -, -N (OR ee) R ff, -SH, -SR ee, -SSR ee, -C (= O) R ee, -CO 2 H, -CO 2 R ee , -OC(=O)R ee , -OCO 2 R ee , -C(=O)N(R ff ) 2 , -OC(=O)N(R ff ) 2 ,- NR ff C(=O)R ee , -NR ff CO 2 R ee , -NR ff C(=O)N(R ff ) 2 , -C(=NR ff )OR ee , -OC(=NR ff ) R ee , -OC(=NR ff )OR ee , -C(=NR ff )N(R ff ) 2 , -OC(=NR ff )N(R ff ) 2 , -NR ff C(=NR ff ) N(R ff ) 2 , -NR ff SO 2 R ee , -SO 2 N(R ff ) 2 , -SO 2 R ee , -SO 2 OR ee , -OSO 2 R ee , -S(=O)R ee , -Si(R ee ) 3 , -OSi(R ee ) 3 , -C(=S)N(R ff ) 2 , -C(=O)SR ee , -C(=S)SR ee ,- SC(=S)SR ee , -P(=O) 2 R ee , -P(=O)(R ee ) 2 , -OP(=O)(R ee ) 2 , -OP(=O)(OR ee ) 2 , alkyl, haloalkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic group The group, the aryl group and the heteroaryl group are independently substituted with 0, 1, 2, 3, 4 or 5 R gg groups, or two geminal R dd substituents may be combined to form =O or =S;
R ee的每个独立地选自烷基、卤代烷基、烯基、炔基、碳环基、芳基、杂环基和杂芳基，其中，每个烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R gg基团取代； Each of 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;
R ff的每个独立地选自氢、烷基、卤代烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基，或者两个R ff基团结合形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R gg基团取代； 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
R gg的每个独立地是：卤素、-CN、-NO 2、-N 3、-SO 2H、-SO 3H、-OH、-OC 1-6烷基、-ON(C 1-6烷基) 2、-N(C 1-6烷基) 2、-N(C 1-6烷基) 3 +X -、-NH(C 1-6烷基) 2 +X -、-NH 2(C 1-6烷基) +X -、-NH 3 +X -、-N(OC 1-6烷基)(C 1-6烷基)、-N(OH)(C 1-6烷基)、-NH(OH)、-SH、-SC 1-6烷基、-SS(C 1-6烷基)、-C(＝O)(C 1-6烷基)、-CO 2H、-CO 2(C 1-6烷基)、-OC(＝O)(C 1-6烷基)、-OCO 2(C 1-6烷基)、-C(＝O)NH 2、-C(＝O)N(C 1-6烷基) 2、-OC(＝O)NH(C 1-6烷基)、-NHC(＝O)(C 1-6烷基)、-N(C 1-6烷基)C(＝O)(C 1-6烷基)、-NHCO 2(C 1-6烷基)、-NHC(＝O)N(C 1-6烷基) 2、-NHC(＝O)NH(C 1-6烷基)、-NHC(＝O)NH 2、-C(＝NH)O(C 1-6烷基)、-OC(＝NH)(C 1-6烷基)、-OC(＝NH)OC 1-6烷基、-C(＝NH)N(C 1-6烷基) 2、-C(＝NH)NH(C 1-6烷基)、-C(＝NH)NH 2、-OC(＝NH)N(C 1-6烷基) 2、-OC(NH)NH(C 1-6烷基)、-OC(NH)NH 2、-NHC(NH)N(C 1-6烷基) 2、-NHC(＝NH)NH 2、-NHSO 2(C 1-6烷基)、-SO 2N(C 1-6烷基) 2、-SO 2NH(C 1-6烷基)、-SO 2NH 2、-SO 2C 1-6烷基、-SO 2OC 1-6烷基、-OSO 2C 1-6烷基、-SOC 1-6烷基、-Si(C 1-6烷基) 3、-OSi(C 1-6烷基) 3、-C(＝S)N(C 1-6烷基) 2、C(＝S)NH(C 1-6烷基)、C(＝S)NH 2、-C(＝O)S(C 1-6烷基)、-C(＝S)SC 1-6烷基、-SC(＝S)SC 1-6烷基、-P(＝O) 2(C 1-6烷基)、-P(＝O)(C 1-6烷基) 2、-OP(＝O)(C 1-6烷基) 2、-OP(＝O)(OC 1-6烷基) 2、C 1-6烷基、C 1-6卤代烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 7碳环基、C 6-C 10芳基、C 3-C 7杂环基、C 5-C 10杂芳基；或者两个偕R gg取代基可结合形成＝O或＝S；其中，X -为反离子。 Each of R gg is independently: halogen, -CN, -NO 2 , -N 3 , -SO 2 H, -SO 3 H, -OH, -OC 1-6 alkyl, -ON (C 1-6 alkyl) 2, -N (C 1-6 alkyl) 2, -N (C 1-6 alkyl) 3 + X -, -NH ( C 1-6 alkyl) 2 + X -, -NH 2 (C 1-6 alkyl) + X -, -NH 3 + X -, -N (OC 1-6 alkyl) (C 1-6 alkyl), - N (OH) ( C 1-6 alkyl ), -NH(OH), -SH, -SC 1-6 alkyl, -SS (C 1-6 alkyl), -C(=O) (C 1-6 alkyl), -CO 2 H, -CO 2 (C 1-6 alkyl), -OC(=O) (C 1-6 alkyl), -OCO 2 (C 1-6 alkyl), -C(=O)NH 2 , -C (=O)N(C 1-6 alkyl) 2 , -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -NHCO 2 (C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl) 2 ,- NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH 2 , -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1- 6 alkyl), -OC(=NH)OC 1-6 alkyl, -C(=NH)N(C 1-6 alkyl) 2 , -C(=NH)NH(C 1-6 alkyl) , -C(=NH)NH 2 , -OC(=NH)N(C 1-6 alkyl) 2 , -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH 2 , -NHC(NH)N(C 1-6 alkyl) 2 , -NHC(=NH)NH 2 , -NHSO 2 (C 1-6 alkyl), -SO 2 N(C 1-6 alkyl) 2 , -SO 2 NH (C 1-6 alkyl), -SO 2 NH 2 , -SO 2 C 1-6 alkyl, -SO 2 OC 1-6 alkyl, -OSO 2 C 1-6 alkyl, -SOC 1-6 alkyl, -Si(C 1-6 alkyl) 3 , -OSi(C 1-6 alkyl) 3 , -C(=S)N(C 1-6 alkyl) 2 , C (=S)NH(C 1-6 alkyl), C(=S)NH 2 , -C(=O)S(C 1-6 alkyl), -C(=S)SC 1-6 alkyl , -SC(=S)SC 1-6 alkyl, -P(=O) 2 (C 1-6 alkyl), -P(=O)(C 1-6 alkyl) 2 , -OP(= O)(C 1-6 alkyl) 2 , -OP(= O) (OC 1-6 alkyl) 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 carbocyclic group , C 6 -C 10 aryl, C 3 -C 7 heterocyclyl, C 5 -C 10 heteroaryl; or two geminal R gg substituents can be combined to form =O or =S; where X - is the opposite ion.
示例性的氮原子上取代基包括但不局限于：氢、-OH、-OR aa、-N(R cc) 2、-CN、-C(＝O)R aa、-C(＝O)N(R cc) 2、-CO 2R aa、-SO 2R aa、-C(＝NR bb)R aa、-C(＝NR cc)OR aa、-C(＝NR cc)N(R cc) 2、-SO 2N(R cc) 2、-SO 2R cc、-SO 2OR cc、-SOR aa、-C(＝S)N(R cc) 2、-C(＝O)SR cc、-C(＝S)SR cc、-P(＝O) 2R aa、-P(＝O)(R aa) 2、-P(＝O) 2N(R cc) 2、-P(＝O)(NR cc) 2、烷基、卤代烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基，或者连接至氮原子的两个R cc基团结合形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R dd基团取代，且其中R aa、R bb、R cc和R dd如上所述。 Exemplary substituents on the nitrogen atom include, but are not limited to: hydrogen, -OH, -OR aa , -N(R cc ) 2 , -CN, -C(=O)R aa , -C(=O)N (R cc ) 2 , -CO 2 R aa , -SO 2 R aa , -C(=NR bb )R aa , -C(=NR cc )OR aa , -C(=NR cc )N(R cc ) 2. -SO 2 N(R cc ) 2 , -SO 2 R cc , -SO 2 OR cc , -SOR aa , -C(=S)N(R cc ) 2 , -C(=O)SR cc , -C(=S)SR cc , -P(=O) 2 R aa , -P(=O)(R aa ) 2 , -P(=O) 2 N(R cc ) 2 , -P(=O )(NR cc ) 2 , alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R cc groups connected to the nitrogen atom combine 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 The dd group is substituted, and wherein R aa , R bb , R cc and R dd are as described above.
“氘代”或“D”指化合物或基团中的一个或多个氢被氘所取代；氘代可以是一取代、二取代、多取代或全取代。术语“一个或多个氘代的”与“一次或多次氘代”可互换使用。"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. The terms "one or more deuterated" and "one or more deuterated" are used interchangeably.
“非氘代的化合物”是指含氘原子比例不高于天然氘同位素含量(0.015％)的化合物。"Non-deuterated compound" refers to a compound that contains a proportion of deuterium atoms not higher than the natural deuterium isotope content (0.015%).
氘在氘代位置的氘同位素含量至少是大于天然氘同位素含量0.015％，较佳地大于30％，更佳地大于50％，更佳地大于75％，更佳地大于95％，更佳地大于99％。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%.
术语“药学上可接受的盐”是指，在可靠的医学判断范围内，适合与人和低等动物的组织接触而没有过度毒性、刺激性、***反应等等，并且与合理的益处/危险比例相称的那些盐。药学上可接受的盐在本领域是众所周知的。例如，Berge等人在J.Pharmaceutical Sciences(1977)66:1-19中详细描述的药学上可接受的盐。本发明化合物的药学上可接受的盐包括衍生自合适的无机和有机酸和无机和有机碱的盐。药学上可接受的无毒的酸加成盐的实例是与无机酸形成的盐，例如盐酸、氢溴酸、磷酸、硫酸和高氯酸，或与有机酸形成的盐，例如乙酸、草酸、马来酸、酒石酸、枸橼酸、琥珀酸或丙二酸。也包括使用本领域常规方法形成的盐，例如，离子交换方法。其它药学上可接受的盐包括：已二酸盐、海藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、重硫酸盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡萄糖酸盐、甘油磷酸盐、葡糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、果胶酯酸盐、过硫酸盐、3-苯丙酸盐、磷酸盐、苦味酸盐、特戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐、十一烷酸盐、戊酸盐，等等。衍生自合适的碱的药学上可接受的盐包括碱金属、碱土金属、铵和N +(C 1-4烷基) 4盐。代表性的碱金属或碱土金属盐包括钠、锂、钾、钙、镁盐，等等。如果合适的话，其它的药学上可接受的盐包括与反离子形成的无毒的铵盐、季铵盐和胺阳离子，反离子例如卤离子、氢氧根、甲酸根、硫酸根、磷酸根、硝酸根、低级烷基磺酸根和芳基磺酸根。 The term "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. Examples of pharmaceutically acceptable non-toxic acid addition salts are 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. Other pharmaceutically acceptable 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, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, Thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. 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. If appropriate, 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.
给药的“受试者”包括但不限于：人(即，任何年龄组的男性或女性，例如，儿科受试者(例如，婴儿、儿童、青少年)或成人受试者(例如，年轻的成人、中年的成人或年长的成人))和/或非人的动物，例如，哺乳动物，例如，灵长类(例如，食蟹猴、恒河猴)、牛、猪、马、绵羊、山羊、啮齿动物、猫和/或狗。在一些实施方案中，受试者是人。在一些实施方案中，受试者是非人动物。本文可互换使用术语“人”、“患者”和“受试者”。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. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human", "patient" and "subject" are used interchangeably herein.
“疾病”、“障碍”和“病症”在本文中可互换地使用。"Disease", "disorder" and "condition" are used interchangeably herein.
除非另作说明，否则，本文使用的术语“治疗”包括受试者患有具体疾病、障碍或病症时所发生的作用，它降低疾病、障碍或病症的严重程度，或延迟或减缓疾病、障碍或病症的发展(“治疗性治疗”)，还包括受试者开始患有具体疾病、障碍或病症之前发生的作用(“预防性治疗”)。Unless otherwise specified, the term "treatment" as used herein 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").
“组合”以及相关术语是指同时或依次给药本发明的治疗剂。例如，本发明化合物可以与另一治疗剂以分开的单位剂型同时或依次给药，或与另一治疗剂一起呈单一单位剂型同时给药。"Combination" and related terms refer to the simultaneous or sequential administration of the therapeutic agents of the present invention. For example, 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.
具体实施方式Detailed ways
化合物Compound
本文中，“本发明化合物”指的是以下的式(I)化合物(包括各式的子集)，或其药学上可接受的盐、水合物或溶剂合物。Herein, "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.
在一个实施方案中，本发明涉及式(I)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物：In one embodiment, the present invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof:
Figure PCTCN2021076684-appb-000002
Figure PCTCN2021076684-appb-000002
其中，in,
环A为芳香环；Ring A is an aromatic ring;
A 1为CR A1或N原子； A 1 is CR A1 or N atom;
A 2、A 3和A 5各自独立地为C或N原子； A 2 , A 3 and A 5 are each independently a C or N atom;
A 4为CR A4、N原子或NR A4； A 4 is CR A4 , N atom or NR A4 ;
前提是，当A 1和A 3是N，且A 2和A 5是C时，A 4不为N； The premise is that when A 1 and A 3 are N, and A 2 and A 5 are C, A 4 is not N;
R A1和R A4各自独立地为H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；且上述基团任选地被一个或多个R”取代； 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为CR B1或N； B 1 is CR B1 or N;
B 2为CR B2或N； B 2 is CR B2 or N;
B 3为CR B3或N； B 3 is CR B3 or N;
B 4为CR B4或N； B 4 is CR B4 or N;
R B1、R B2、R B3和R B4各自独立地选自H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；或者，R B1和R B2、R B3和R B4可以分别与它们所连接的C原子一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；且上述基团任选地被一个或多个R”取代； 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 and R B4 may be respectively connected to the C atom to which they are attached Together to 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″;
W选自键、O、S、NR N或CR C1R C2； W is selected from bond, O, S, NR N or CR C1 R C2 ;
R N选自H、C 1-6烷基或C 1-6卤代烷基，且上述基团任选地被一个或多个R*取代； 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和R C2各自独立地选自H、D、卤素、C 1-6烷基或C 1-6卤代烷基，且上述基团任选地被一个或多个R*取代； 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选自键、O、S、NR N或(CR C1R C2) p； L is selected from bond, O, S, NR N or (CR C1 R C2 ) p ;
p＝0、1或2；p=0, 1 or 2;
Y选自C 1-6烷基、C 3-7环烷基或3至7元杂环基，且上述基团任选地被m个R取代； 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选自-C(O)-、-C(O)NR N-*、-S(O) 2-或-S(O) 2NR N-*，其中*表示与Y相连接； Z is selected from -C(O)-, -C(O)NR N -*, -S(O) 2 -or -S(O) 2 NR N -*, where * means connected to Y;
V为-C(R 5)＝C(R 4)(R 3)； V is -C(R 5 )=C(R 4 )(R 3 );
R 3选自H、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，且上述基团任选地被一个或多个R*取代； 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和R 5各自独立地选自H、卤素、-CN、C 1-6烷基或C 1-6卤代烷基，且上述基团任选地被一个或多个R*取代；或者，R 4和R 5连同它们所连接的双键一起形成叁键； 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和R 2各自独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；或者，R 1和R 2连同它们所连接的N原子一起形成3至7元杂环基或5至10元杂芳基；且上述基团任选地被一个或多个R’取代； 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';
每个R’各自独立地选自H、D、卤素、-CN、＝O、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，或者，相同原子或相邻原子上的两个R’基团可以一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；其中R’定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R'is independently selected from H, D, halogen, -CN, =0, 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 two R'groups on the same atom or adjacent atoms can form a C 3-7 cycloalkyl group together , 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group; wherein each group in the definition of R'is optionally substituted with one or more D until fully deuterated;
每个R”各自独立地选自H、D、卤素、-CN、＝O、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，或者，相同原子或相邻原子上的两个R”基团可以一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；其中R”定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R" is independently selected from H, D, halogen, -CN, =0, 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 two R" groups on the same atom or adjacent atoms can form a C 3-7 cycloalkyl group together , 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group; wherein each group in the definition of R" is optionally substituted by one or more D until it is fully deuterated;
每个R*各自独立地选自H、D、卤素、-CN、＝O、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；或者，相同原子或相邻原子上的两个R*基团可以一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；其中R*定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R* is independently selected from H, D, halogen, -CN, =O, 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, two R* groups on the same atom or adjacent atoms can form a C 3-7 cycloalkyl group together , 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group; wherein each group in the definition of R* is optionally substituted by one or more D until fully deuterated;
每个R各自独立地选自H、D、卤素、-CN、＝O、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；或者，相同原子或相邻原子上的两个R基团可以一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；其中R定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R is independently selected from H, D, halogen, -CN, =O, 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, A 3- to 7-membered heterocyclic group, a C 6-10 aryl group or a 5- to 10-membered heteroaryl group; alternatively, two R groups on the same atom or adjacent atoms can form a C 3-7 cycloalkyl group, 3 To 7-membered heterocyclyl, C 6-10 aryl or 5 to 10-membered heteroaryl; wherein each group in the definition of R is optionally substituted with one or more D until fully deuterated;
m＝0、1、2、3、4、5、6、7、8或9；m=0, 1, 2, 3, 4, 5, 6, 7, 8 or 9;
每个R a、R b和R c各自独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，或者R b和R c连同它们所连接的N原子一起形成3至7元杂环基或5至10元杂芳基；其中R a、R b和R c定义中的每个基团任选地被一个或多个D取代，直至完全氘代。 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、A 2、A 3、A 4和A 5 A 1 , A 2 , A 3 , A 4 and A 5
在一个实施方案中，
Figure PCTCN2021076684-appb-000003
选自以下结构： In one embodiment,
Figure PCTCN2021076684-appb-000003
Selected from the following structures:
Figure PCTCN2021076684-appb-000004
Figure PCTCN2021076684-appb-000004
在另一个实施方案中，
Figure PCTCN2021076684-appb-000005
选自以下结构： In another embodiment,
Figure PCTCN2021076684-appb-000005
Selected from the following structures:
Figure PCTCN2021076684-appb-000006
Figure PCTCN2021076684-appb-000006
在另一个实施方案中，
Figure PCTCN2021076684-appb-000007
选自以下结构： In another embodiment,
Figure PCTCN2021076684-appb-000007
Selected from the following structures:
Figure PCTCN2021076684-appb-000008
Figure PCTCN2021076684-appb-000008
在另一个实施方案中，
Figure PCTCN2021076684-appb-000009
选自以下结构： In another embodiment,
Figure PCTCN2021076684-appb-000009
Selected from the following structures:
Figure PCTCN2021076684-appb-000010
Figure PCTCN2021076684-appb-000010
在一个实施方案中，A 1选自CR A1或N；在另一个实施方案中，A 1是CR A1；在另一个实施方案中，A 1是N。 In one embodiment, A 1 is selected from CR A1 or N; in another embodiment, A 1 is CR A1 ; in another embodiment, A 1 is N.
在上述A 1的实施方案中，R A1选自H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，且上述基团任选地被一个或多个R”取代。 In the above embodiment of A 1 , 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″.
在一个实施方案中，R A1为H；在另一个实施方案中，R A1为D；在另一个实施方案中，R A1为卤素；在另一个实施方案中，R A1为-CN；在另一个实施方案中，R A1为C 1-6烷基；在另一个实施方案中，R A1为C 1-6卤代烷基；在另一个实施方案中，R A1为C 2-6烯基；在另一个实施方案中，R A1为C 2-6炔基；在另一个实施方案中，R A1为-C(O)R a；在另一个实施方案中，R A1为-C(O)OR a；在另一个实施方案中，R A1为-C(O)NR bR c；在另一个实施方案中，R A1为-NR bR c；在另一个实施方案中，R A1为-NR aC(O)R b；在另一个实施方案中，R A1为-NR aC(O)OR b；在另一个实施方案中，R A1为-NR aC(O)NR bR c；在另一个实施方案中，R A1为-OR a；在另一个实施方案中，R A1为-OC(O)R a；在另一个实施方案中，R A1为-OC(O)OR a；在另一个实施方案中，R A1为-OC(O)NR bR c；在另一个实施方案中，R A1为C 3-7环烷基；在另一个实施方案中，R A1为3至7元杂环基；在另一个实施方案中，R A1为C 6-10芳基；在另一个实 施方案中，R A1为5至10元杂芳基。 In one embodiment, 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 another embodiment, R A1 is -OR a ; in another embodiment, R A1 is -OC(O)R a ; in another embodiment, R A1 is -OC(O)OR a ; In another embodiment, R A1 is -OC(O)NR b R c ; in another embodiment, R A1 is C 3-7 cycloalkyl; in another embodiment, R A1 is 3 to 7-membered heterocyclyl; in another embodiment, R A1 is C 6-10 aryl; in another embodiment, R A1 is 5 to 10-membered heteroaryl.
在另一个实施方案中，R A1选自H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基或C 1-6烷氨基，其中所述基团任选地被一个或多个R”取代；在另一个实施方案中，R A1选自H、D、卤素、-CN、C 1-6烷基或C 1-6卤代烷基，其中所述基团任选地被一个或多个R”取代；在另一个实施方案中，R A1选自H、D、F、Cl、Br、-CN、-Me、-CD 3、-CHF 2、-CH 2F或CF 3；在另一个实施方案中，R A1选自H、D、F、-Me或-CD 3；在另一个实施方案中，R A1选自H或D；在另一个实施方案中，R A1选自H。 In another embodiment, 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.
在一个实施方案中，A 2选自C或N原子；在另一个实施方案中，A 2是C原子；在另一个实施方案中，A 2是N原子。 In one embodiment, 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.
在一个实施方案中，A 3选自C或N原子；在另一个实施方案中，A 3是C原子；在另一个实施方案中，A 3是N原子。 In one embodiment, 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.
在一个实施方案中，A 4选自CR A4、N原子或NR A4；在另一个实施方案中，A 2是CR A4；在另一个实施方案中，A 2是N原子；在另一个实施方案中，A 2是NR A4。 In one embodiment, 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 .
在上述A 4的实施方案中，R A4选自H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，且上述基团任选地被一个或多个R”取代。 In the above embodiment of A 4 , 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″.
在一个实施方案中，R A4为H；在另一个实施方案中，R A4为D；在另一个实施方案中，R A4为卤素；在另一个实施方案中，R A4为-CN；在另一个实施方案中，R A4为C 1-6烷基；在另一个实施方案中，R A4为C 1-6卤代烷基；在另一个实施方案中，R A4为C 2-6烯基；在另一个实施方案中，R A4为C 2-6炔基；在另一个实施方案中，R A4为-C(O)R a；在另一个实施方案中，R A4为-C(O)OR a；在另一个实施方案中，R A4为-C(O)NR bR c；在另一个实施方案中，R A4为-NR bR c；在另一个实施方案中，R A4为-NR aC(O)R b；在另一个实施方案中，R A4为-NR aC(O)OR b；在另一个实施方案中，R A4为-NR aC(O)NR bR c；在另一个实施方案中，R A4为-OR a；在另一个实施方案中，R A4为-OC(O)R a；在另一个实施方案中，R A4为-OC(O)OR a；在另一个实施方案中，R A4为-OC(O)NR bR c；在另一个实施方案中，R A4为C 3-7环烷基；在另一个实施方案中，R A4为3至7元杂环基；在另一个实施方案中，R A4为C 6-10芳基；在另一个实施方案中，R A4为5至10元杂芳基。 In one embodiment, 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 another embodiment, R A4 is -OR a ; in another embodiment, R A4 is -OC(O)R a ; in another embodiment, R A4 is -OC(O)OR a ; In another embodiment, R A4 is -OC(O)NR b R c ; in another embodiment, R A4 is C 3-7 cycloalkyl; in another embodiment, R A4 is 3 to 7-membered heterocyclyl; in another embodiment, R A4 is C 6-10 aryl; in another embodiment, R A4 is 5 to 10-membered heteroaryl.
在一个实施方案中，R A4选自H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基或C 1-6烷氨基，其中所述基团任选地被一个或多个R”取代；在另一个实施方案中，R A4选自H、D、卤素、-CN、C 1-6烷基或C 1-6卤代烷基，其中所述基团任选地被一个或多个R”取代；在另一个实施方案中，R A4选自H、D、F、Cl、Br、-CN、-Me、-CD 3、-CHF 2、-CH 2F或CF 3；在另一个实施方案中，R A4选自H、D、F、-Me或-CD 3；在另一个实施方案中，R A4选自H或D；在另一个实施方案中，R A4选自H。 In one embodiment, 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.
在一个实施方案中，A 5选自C或N原子；在另一个实施方案中，A 5是C原子；在另一个实施方案中，A 5是N原子。 In one embodiment, 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、B 2、B 3和B 4 B 1 , B 2 , B 3 and B 4
在一个实施方案中，B 1选自CR B1或N；在另一个实施方案中，B 1选自CR B1；在另一个实施方案中，B 1选自N。 In one embodiment, 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.
在一个实施方案中，B 2选自CR B2或N；在另一个实施方案中，B 2选自CR B2；在另一个实施方案中，B 2选自N。 In one embodiment, 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.
在一个实施方案中，B 3选自CR B1或N；在另一个实施方案中，B 3选自CR B3；在另一个实施方案中，B 3选自N。 In one embodiment, 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.
在一个实施方案中，B 4选自CR B4或N；在另一个实施方案中，B 4选自CR B4；在另一个实施方案中，B 4选自N。 In one embodiment, 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.
在一个实施方案中，R B1、R B2、R B3和R B4各自独立地选自H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；或者，R B1和R B2、R B3和R B4可以分别与它们所连接的C原子一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；且上述基团任选地被一个或多个R”取代。 In one embodiment, 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 B2 , R B3 and R B4 may be the same as The C atoms to which they are attached 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-mentioned groups are optionally substituted by one or more Replace with R”.
在一个实施方案中，R B1、R B2、R B3和R B4各自独立地为H；在另一个实施方案中，R B1、R B2、R B3和R B4各自独立地为D；在另一个实施方案中，R B1、R B2、R B3和R B4各自独立地为卤素；在另一个实施方案中，R B1、R B2、R B3和R B4各自独立地为-CN；在另一个实施方案中，R B1、R B2、R B3和R B4各自独立地为C 1-6烷基；在另一个实施方案中，R B1、R B2、R B3和R B4各自独立地为C 1-6卤代烷基；在另一个实施方案中，R B1、R B2、R B3和R B4各自独立地为C 2-6烯基；在另一个实施方案中，R B1、R B2、R B3和R B4各自独立地为C 2-6炔基；在另一个实施方案中，R B1、R B2、R B3和R B4各自独立地为-C(O)R a；在另一个实施方案中，R B1、R B2、R B3和R B4各自独立地为-C(O)OR a；在另一个实施方案中，R B1、R B2、R B3和R B4各自独立地为-C(O)NR bR c；在另一个实施方案中，R B1、R B2、R B3和R B4各自独立地为-NR bR c；在另一个实施方案中，R B1、R B2、R B3和R B4各自独立地为-NR aC(O)R b；在另一个实施方案中，R B1、R B2、R B3和R B4各自独立地为-NR aC(O)OR b；在另一个实施方案中，R B1、R B2、R B3和R B4各自独立地为-NR aC(O)NR bR c；在另一个实施方案中，R B1、R B2、R B3和R B4各自独立地为-OR a；在另一个实施方案中，R B1、R B2、R B3和R B4各自独立地为-OC(O)R a；在另一个实施方案中，R B1、R B2、R B3和R B4各自独立地为-OC(O)OR a；在另一个实施方案中，R B1、R B2、R B3和R B4各自独立地为-OC(O)NR bR c；在另一个实施方案中，R B1、R B2、R B3和R B4各自独立地为C 3-7环烷基；在另一个实施方案中，R B1、R B2、R B3和R B4各自独立地为3至7元杂环基；在另一个实施方案中，R B1、R B2、R B3和R B4各自独立地为C 6-10芳基；在另一个实施方案中，R B1、R B2、R B3和R B4各自独立地为5至10元杂芳基。 In one embodiment, 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 B2, R B3 and B4 are each independently R & lt -C (O) R a; in another embodiment, R B1 , R B2 , R B3 and R B4 are each independently -C(O)OR a ; in another embodiment, R B1 , R B2 , R B3 and R B4 are each independently -C(O)NR b R c ; in another embodiment, R B1 , R B2 , R B3 and R B4 are each independently -NR b R c ; in another embodiment, R B1 , R B2 , R B3 and R B4 Each is independently -NR a C(O)R b ; in another embodiment, R B1 , R B2 , R B3 and R B4 are each independently -NR a C(O)OR b ; in another embodiment In the scheme, R B1 , R B2 , R B3 and R B4 are each independently -NR a C(O)NR b R c ; in another embodiment, R B1 , R B2 , R B3 and R B4 are each independently for -OR a; in another embodiment, R B1, R B2, R B3 and R B4 each independently -OC (O) R a; in another embodiment, R B1, R B2, R B3 and R B4 are each independently -OC(O)OR a ; in another embodiment, R B1 , R B2 , R B3 and R B4 are each independently -OC(O)NR b R c ; In one embodiment, R B1 , R B2 , R B3 and R B4 are each independently C 3-7 cycloalkyl; in another embodiment, R B1 , R B2 , R B3 and R B4 are each independently 3- to 7-membered heterocyclyl; in another embodiment, R B1 , R B2 , R B3 and R B4 are each independently a C 6-10 aryl group; in another embodiment, R B1 , R B2 , R B3 and R B4 are each independently a 5- to 10-membered heteroaryl group.
在另一个实施方案中，R B1和R B2与它们所连接的C原子一起形成C 3-7环烷基；在另一个实施方案中，R B1和R B2与它们所连接的C原子一起形成3至7元杂环基；在另一个实施方案中，R B1和R B2与它们所连接的C原子一起形成C 6-10芳基；在另一个实施方案中，R B1和R B2与它们所连接的C原子一起形成5至10元杂芳基；在另一个实施方案中，R B3和R B4与它们所连接的C原子一起形成C 3-7环烷基；在另一个实施方案中，R B3和R B4与它们所连接的C原子一起形成3至7元杂环基；在另一个实施方案中，R B3和R B4与它们所连接的C原子一起形成C 6-10芳基；在另一个实施方案中，R B3和R B4与它们所连接的C原子一起形成5至10元杂芳基。 In another embodiment, 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 B4 together with the C atom to which they are attached form a 5- to 10-membered heteroaryl group.
在另一个实施方案中，R B1、R B2、R B3和R B4各自独立地选自H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷氨基、C 3-7环烷基、3至7元杂环基、C 2-6烯基、C 2-6炔基、C 6-10芳基或5至10元杂芳基，或者，R B1和R B2、或R B3和R B4可以分别与它们所连接的C原子一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；其中所述基团任选地被一个或多个R”取代； 在另一个实施方案中，R B1、R B2、R B3和R B4各自独立地选自H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷氨基、C 3-7环烷基、3至7元杂环基、C 2-6烯基、C 6-10芳基或5至10元杂芳基，或者，R B1和R B2、或R B3和R B4可以分别与它们所连接的C原子一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；其中所述基团任选地被一个或多个R”取代；在另一个实施方案中，R B1、R B2、R B3和R B4各自独立地选自H、D、F、Cl、Br、-CN、-CH＝CH 2、-OMe、-OCH 2F、-OCHF 2、-Me、-Et、-N(Me) 2、环丙基或呋喃基，或者R B1和R B2、或R B3和R B4分别与它们所连接的碳原子一起形成苯环、吡啶环或二氧戊环；在另一个实施方案中，R B1、R B2、R B3和R B4各自独立地选自H、D、F、Cl、Br、-CN、-CH＝CH 2、-OMe、-OCH 2F、-OCHF 2、-Me或-N(Me) 2；在另一个实施方案中，R B3和R B4是H，R B1和R B2各自独立地选自H、D、F、Cl、Br、-CN、-CH＝CH 2、-OMe、-OCH 2F、-OCHF 2、-Me或-N(Me) 2；在另一个实施方案中，R B3和R B4是氢，R B1和R B2各自独立地选自H、D、F、Cl、Br或-Me；在另一个实施方案中，R B3和R B4是氢，R B1和R B2各自独立地选自H、D或-Me；在另一个实施方案中，R B3和R B4是氢，R B1和R B2各自独立地选自H或-Me。 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, 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, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-7 cycloalkyl, 3 to 7-membered heterocyclyl, C 2-6 alkenyl, C 6-10 aryl, or 5 to 10-membered heteroaryl, or, R B1 and R B2 , or R B3 and R B4 may be respectively connected to the C to which they are connected The atoms 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; wherein the group is optionally substituted by one or more R" In another embodiment, R B1 , R B2 , R B3 and R B4 are each independently selected from H, D, F, Cl, Br, -CN, -CH=CH 2 , -OMe, -OCH 2 F , -OCHF 2 , -Me, -Et, -N(Me) 2 , cyclopropyl or furanyl, or R B1 and R B2 , or R B3 and R B4 together with the carbon atoms to which they are connected to form a benzene ring , Pyridine ring or dioxolane; in another embodiment, R B1 , R B2 , R B3 and R B4 are each independently selected from H, D, F, Cl, Br, -CN, -CH=CH 2 , -OMe, -OCH 2 F, -OCHF 2 , -Me or -N(Me) 2 ; In another embodiment, R B3 and R B4 are H, and R B1 and R B2 are each independently selected from H, D, F, Cl, Br, -CN, -CH=CH 2 , -OMe, -OCH 2 F, -OCHF 2 , -Me or -N(Me) 2 ; in another embodiment, R B3 and R B4 is hydrogen, R B1 and R B2 are each independently selected from H, D, F, Cl, Br, or -Me; in another embodiment, R B3 and R B4 are hydrogen, and R B1 and R B2 are each independently Is selected from H, D, or -Me; in another embodiment, R B3 and R B4 are hydrogen, and R B1 and R B2 are each independently selected from H or -Me.
WW
在一个实施方案中，W选自键、O、S、NR N或CR C1R C2；在另一个实施方案中，W选自键；在另一个实施方案中，W选自O；在另一个实施方案中，W选自S；在另一个实施方案中，W选自NR N；在另一个实施方案中，W选自CR C1R C2。 In one embodiment, 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 .
在一个实施方案中，W选自O或CR C1R C2。 In one embodiment, W is selected from O or CR C1 R C2 .
在一个实施方案中，R N选自H、C 1-6烷基或C 1-6卤代烷基，其中所述基团任选地被一个或多个R*取代；在另一个实施方案中，R N选自H或甲基。 In one embodiment, 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.
在一个实施方案中，R C1和R C2各自独立地选自H、D、卤素、C 1-6烷基或C 1-6卤代烷基，其中所述基团任选地被一个或多个R*取代；在另一个实施方案中，R C1和R C2各自独立地选自H、D或甲基；在另一个实施方案中，R C1和R C2各自独立地为H。 In one embodiment, 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和R 2 R 1 and R 2
在一个实施方案中，R 1和R 2各自独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；或者，R 1和R 2连同它们所连接的N原子一起形成3至7元杂环基或5至10元杂芳基；且上述基团任选地被一个或多个R’取代。 In one embodiment, 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′.
在一个实施方案中，R 1和R 2各自独立地为H；在另一个实施方案中，R 1和R 2各自独立地为C 1-6烷基；在另一个实施方案中，R 1和R 2各自独立地为C 1-6卤代烷基；在另一个实施方案中，R 1和R 2各自独立地为C 2-6烯基；在另一个实施方案中，R 1和R 2各自独立地为C 2-6炔基；在另一个实施方案中，R 1和R 2各自独立地为C 3-7环烷基；在另一个实施方案中，R 1和R 2各自独立地为3至7元杂环基；在另一个实施方案中，R 1和R 2各自独立地为C 6-10芳基；在另一个实施方案中，R 1和R 2各自独立地为5至10元杂芳基；在另一个实施方案中，R 1和R 2连同它们所连接的N原子一起形成3至7元杂环基；在另一个实施方案中，R 1和R 2连同它们所连接的N原子一起形成5至10元杂芳基。 In one embodiment, 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 5- to 10-membered heteroaryl group.
在另一个实施方案中，R 1和R 2各自独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，或者，R 1和R 2连同它们所连接的N原子一起形成3至7元杂环基；其中所述基团任选地被一个或多个R’取代；在另一个实施方案中，R 1和R 2各自独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基或C 6-10芳基，或者，R 1和R 2连同它们所连接的N原子一起形成3至7元杂环基；其中所述基团任选地被一个或多个R’取代；在另一个实施方案中，R 1和R 2各自独立地选自H、-OMe、-Me或苯基，或者R 1和R 2连同它们所连接的N原子一起 形成任选的被羟基取代的氮杂环丁烷基、吡咯烷基或哌啶基。 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, 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, -Me or phenyl, or R 1 and R 2 together with the N atom to which they are attached form an optional hydroxyl group Substituted azetidinyl, pyrrolidinyl or piperidinyl.
LL
在一个实施方案中，L选自键、O、S、NR N或(CR C1R C2) p；在另一个实施方案中，L为键；在另一个实施方案中，L为O；在另一个实施方案中，L为S；在另一个实施方案中，L为NR N；在另一个实施方案中，L为(CR C1R C2) p。 In one embodiment, 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 .
在另一个实施方案中，L选自键、O、NR N或(CR C1R C2) p；在另一个实施方案中，L选自键或(CR C1R C2) p；在另一个实施方案中，L选自键；在另一个实施方案中，L为(CR C1R C2) p。 In another embodiment, 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 In another embodiment, L is (CR C1 R C2 ) p .
在L的实施方案中，p选自1或2；在另一个实施方案中，p是1。In an embodiment of L, p is selected from 1 or 2; in another embodiment, p is 1.
在一个实施方案中，R N选自H、C 1-6烷基或C 1-6卤代烷基，其中所述基团任选地被一个或多个R*取代；在另一个实施方案中，R N选自H或甲基；在另一个实施方案中，R N为H；在另一个实施方案中，R N为C 1-6烷基；在另一个实施方案中，R N中所述的C 1-6烷基任选地被一个或多个R*取代。 In one embodiment, 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*.
在L的实施方案中，R C1和R C2各自独立地选自H、D、卤素、C 1-6烷基或C 1-6卤代烷基，其中所述基团任选地被一个或多个R*取代；在另一个实施方案中，R C1和R C2各自独立地选自H、D或甲基；在另一个实施方案中，R C1和R C2各自独立地为H；在另一个实施方案中，R C1和R C2各自独立地为D；在另一个实施方案中，R C1和R C2各自独立地为卤素；在另一个实施方案中，R C1和R C2各自独立地为C 1-6烷基；在另一个实施方案中，R L1和R L2中所述的C 1-6烷基任选地被一个或多个R取代；在另一个实施方案中，R C1和R C2各自独立地为C 1-6卤代烷基。 In the embodiment of L, 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.
在另一个实施方案中，R C1和R C2各自独立地选自H、D、卤素、C 1-6烷基或C 1-6卤代烷基，其中所述基团被一个或多个R*取代；在另一个实施方案中，R C1和R C2各自独立地选自H、D或甲基；在另一个实施方案中，R C1和R C2各自独立地为H。 In another embodiment, 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* 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.;
YY
在一个实施方案中，Y选自C 1-6烷基、C 3-7环烷基或3至7元杂环基，其中所述基团任选地被m个R取代；在另一个实施方案中，Y为C 1-6烷基；在另一个实施方案中，Y为C 3-7环烷基；在另一个实施方案中，Y为3至7元杂环基；在另一个实施方案中，Y中所述的C 1-6烷基、C 3-7环烷基或3至7元杂环基任选地被m个R取代。 In one embodiment, 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 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.
在另一实施方案中，Y选自至少含有一个N原子的3至7元杂环基，且N原子与Z相连，其中所述的3至7元杂环基任选地被m个R取代；在另一实施方案中，Y选自至少含有一个N原子的3至7元杂环基，且N原子与Z相连，其中所述的3至7元杂环基任选地被m个选自D、卤素、C 1-6烷基或C 1-6卤代烷基的取代基取代；在另一个实施方案中，Y选自吡咯烷基或哌啶基，且N原子与Z相连，其中所述的吡咯烷基或哌啶基任选地被m个选自D、卤素、C 1-6烷基或C 1-6卤代烷基的取代基取代；在另一个实施方案中，Y选自吡咯烷基、甲基吡咯烷基、哌啶基或氟代哌啶基，且N原子与Z相连。 In another embodiment, 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 In another embodiment, 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, methylpyrrolidinyl, piperidinyl or fluoropiperidinyl, and the N atom is connected to Z.
ZZ
在一个实施方案中，Z选自-C(O)-、-C(O)NR N-*、-S(O) 2-或-S(O) 2NR N-*，其中*表示与Y相连接；在另一个实施方案中，Z为-C(O)-；在另一个实施方案中，Z为-C(O)NR N-*，其中*表示与Y相连接；在另一个实施方案中，Z为-S(O) 2-；在另一个实施方案中，Z为-S(O) 2NR N-*，其中*表示与Y相连接。 In one embodiment, 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 In another embodiment, Z is -C(O)-; In another embodiment, Z is -C(O)NR N -*, where * means that it is connected to Y; in another embodiment In the scheme, Z is -S(O) 2 -; in another embodiment, Z is -S(O) 2 NR N -*, where * means that it is connected to Y.
在另一个实施方案中，Z选自-C(O)-或-C(O)NR N-*，其中*表示与Y相连接。 In another embodiment, Z is selected from -C(O)- or -C(O)NR N -*, where * means that it is connected to Y.
在Z的实施方案中，R N选自H、C 1-6烷基或C 1-6卤代烷基，且上述基团任选地被一个或多个R* 取代；在另一个实施方案中，R N为H；在另一个实施方案中，R N为C 1-6烷基；在另一个实施方案中，R N为C 1-6卤代烷基。 In the Z embodiment, 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.
在另一个实施方案中，R N选自H或C 1-6烷基，其中所述的C 1-6烷基任选地被一个或多个R*取代；在另一个实施方案中，R Z选自H或甲基。 In another embodiment, 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.
VV
在一个实施方案中，V选自-C(R 5)＝C(R 4)(R 3)。 In one embodiment, V is selected from -C(R 5 )=C(R 4 )(R 3 ).
在V的实施方案中，R 3选自H、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，其中所述基团任选地被一个或多个R*取代；在另一个实施方案中，R 3为H；在另一个实施方案中，R 3为卤素；在另一个实施方案中，R 3为CN；在另一个实施方案中，R 3为C 1-6烷基；在另一个实施方案中，R 3为C 1-6卤代烷基；在另一个实施方案中，R 3为C 3-7环烷基；在另一个实施方案中，R 3为3至7元杂环基；在另一个实施方案中，R 3为C 6-10芳基；在另一个实施方案中，R 3为5至10元杂芳基；在另一个实施方案中，R 3中所述的C 1-6烷基、C 3-7环烷基、3至7元杂环基、C 6-10芳基和5至10元杂芳基任选地被一个或多个R*取代。 In the embodiment of V, 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 heterocyclic group, the C 6-10 aryl group, and the 5 to 10-membered heteroaryl group are optionally substituted with one or more R*.
在另一个实施方案中，R 3选自H、卤素、-CN、C 1-6烷基或C 1-6卤代烷基，其中所述基团任选地被一个或多个R*取代；在另一个实施方案中，R 3选自H、C 1-6烷基或C 1-6卤代烷基，其中所述基团任选地被一个或多个R*取代；在另一个实施方案中，R 3选自H或C 1-6烷基，其中所述的C 1-6烷基任选地被一个或多个二烷基氨基取代。 In another embodiment, 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.
在V的实施方案中，R 4和R 5各自独立地选自H、卤素、-CN、C 1-6烷基或C 1-6卤代烷基，其中所述基团任选地被一个或多个R*取代；或者，R 4和R 5连同它们所连接的双键一起形成叁键；在另一个实施方案中，R 4和R 5各自独立地为H；在另一个实施方案中，R 4和R 5各自独立地为卤素；在另一个实施方案中，R 4和R 5各自独立地为CN；在另一个实施方案中，R 4和R 5各自独立地为C 1-6烷基；在另一个实施方案中，R 4和R 5各自独立地为C 1-6卤代烷基；在另一个实施方案中，R 4和R 5连同它们所连接的双键一起形成叁键。 In the embodiment of V, 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.
在另一个实施方案中，R 4和R 5各自独立地选自H、卤素或CN；在另一个实施方案中，R 4和R 5各自独立地为H。 In another embodiment, 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.
在一个实施方案中，Y-Z-V选自以下结构：In one embodiment, Y-Z-V is selected from the following structures:
Figure PCTCN2021076684-appb-000011
Figure PCTCN2021076684-appb-000011
在另一个实施方案中，Y-Z-V选自以下结构：In another embodiment, Y-Z-V is selected from the following structures:
Figure PCTCN2021076684-appb-000012
Figure PCTCN2021076684-appb-000012
以上任一具体实施方案中的任一技术方案或其任意组合，可以与其它具体实施方案中的任一技术方案或其任意组合进行组合。例如，A 1、A 2、A 3、A 4、A 5、B 1、B 2、B 3、B 4、W、L、Y、Z、V、R 1和R 2的任一技术方案或其任意组合进行组合。本发明旨在包括所有这些技术方案的组合，限于篇幅， 不再一一列出。 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. For example, any of the technical solutions of A 1 , A 2 , A 3 , A 4 , A 5 , B 1 , B 2 , B 3 , B 4 , W, L, Y, Z, V, R 1 and R 2 or Combine any combination of them. 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.
在更具体实施方案中，本发明涉及上文所述的式(I)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，In a more specific embodiment, 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,
Figure PCTCN2021076684-appb-000013
选自以下结构：
Figure PCTCN2021076684-appb-000013
Selected from the following structures:
Figure PCTCN2021076684-appb-000014
Figure PCTCN2021076684-appb-000014
优选地，Preferably,
Figure PCTCN2021076684-appb-000015
选自以下结构：
Figure PCTCN2021076684-appb-000015
Selected from the following structures:
Figure PCTCN2021076684-appb-000016
Figure PCTCN2021076684-appb-000016
优选地，Preferably,
Figure PCTCN2021076684-appb-000017
选自以下结构：
Figure PCTCN2021076684-appb-000017
Selected from the following structures:
Figure PCTCN2021076684-appb-000018
Figure PCTCN2021076684-appb-000018
优选地，Preferably,
Figure PCTCN2021076684-appb-000019
选自以下结构：
Figure PCTCN2021076684-appb-000019
Selected from the following structures:
Figure PCTCN2021076684-appb-000020
Figure PCTCN2021076684-appb-000020
在更具体实施方案中，本发明涉及上文所述的式(I)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，In a more specific embodiment, 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选自至少含有一个N原子的3至7元杂环基，且N原子与Z相连，其中所述3至7元杂环基任选地被m个R取代；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选自-C(O)-；Z is selected from -C(O)-;
V选自-CH＝CH(R 3)，其中，R 3选自H、C 1-6烷基或C 1-6卤代烷基，且上述基团任选地被一个或多个R*取代； V is selected from -CH=CH(R 3 ), wherein R 3 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*;
优选地，Preferably,
Y选自至少含有一个N原子的3至7元杂环基，且N原子与Z相连，其中所述3至7元杂环基任选地被m个选自D、卤素、C 1-6烷基或C 1-6卤代烷基的取代基取代； 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选自-C(O)-；Z is selected from -C(O)-;
V选自-CH＝CH(R 3)，其中，R 3选自H或被-NR bR c取代的C 1-6烷基或C 1-6卤代烷基； V is selected from -CH=CH(R 3 ), wherein R 3 is selected from H or C 1-6 alkyl or C 1-6 haloalkyl substituted by -NR b R c;
优选地，Preferably,
Y选自吡咯烷基或哌啶基，且N原子与Z相连，其中所述吡咯烷基和哌啶基任选地被一个或多个选自D、卤素、C 1-6烷基或C 1-6卤代烷基的取代基取代； 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选自-C(O)-；Z is selected from -C(O)-;
V选自-CH＝CH(R 3)，其中，R 3选自H或被-NR bR c取代的C 1-6烷基或C 1-6卤代烷基； V is selected from -CH=CH(R 3 ), wherein R 3 is selected from H or C 1-6 alkyl or C 1-6 haloalkyl substituted by -NR b R c;
优选地，Preferably,
Y选自吡咯烷基、甲基吡咯烷基、哌啶基或氟代哌啶基，且N原子与Z相连；Y is selected from pyrrolidinyl, methylpyrrolidinyl, piperidinyl or fluoropiperidinyl, and the N atom is connected to Z;
Z选自-C(O)-；Z is selected from -C(O)-;
V选自-CH＝CH(R 3)，其中，R 3选自H或被-NR bR c取代的C 1-6烷基或C 1-6卤代烷基； V is selected from -CH=CH(R 3 ), wherein R 3 is selected from H or C 1-6 alkyl or C 1-6 haloalkyl substituted by -NR b R c;
优选地，-Y-Z-V选自以下结构：Preferably, -Y-Z-V is selected from the following structures:
Figure PCTCN2021076684-appb-000021
Figure PCTCN2021076684-appb-000021
其中，n＝0、1或2，其他基团如上文所述；Wherein, n=0, 1 or 2, and other groups are as described above;
优选地，-Y-Z-V选自以下结构：Preferably, -Y-Z-V is selected from the following structures:
Figure PCTCN2021076684-appb-000022
Figure PCTCN2021076684-appb-000022
优选地，-Y-Z-V选自以下结构：Preferably, -Y-Z-V is selected from the following structures:
Figure PCTCN2021076684-appb-000023
Figure PCTCN2021076684-appb-000023
在更具体实施方案中，本发明涉及上文所述的式(I)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，W为CH 2、CHD或CD 2。 In a more specific embodiment, 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 .
在更具体实施方案中，本发明涉及上文所述的式(I)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R B1、R B2、R B3和R B4各自独立地选自H、D、F、Cl、Br、-CN、-CH＝CH 2、-OMe、-OCH 2F、-OCHF 2、-Me、-Et、-N(Me) 2、环丙基或呋喃基，或者R B1和R B2、或R B3和R B4分别与它们所连接的碳原子一起形成苯环、吡啶环或二氧戊环；优选地，R B1、R B2、R B3和R B4不同时为H；优选地，R B1和R B2均为非氢基团。 In a more specific embodiment, the present invention relates to the compound of formula (I) described above, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or Solvate, wherein R B1 , R B2 , R B3 and R B4 are each independently selected from H, D, F, Cl, Br, -CN, -CH=CH 2 , -OMe, -OCH 2 F,- OCHF 2 , -Me, -Et, -N(Me) 2 , cyclopropyl or furanyl, or R B1 and R B2 , or R B3 and R B4 together with the carbon atoms to which they are connected to form a benzene ring, pyridine Ring or dioxolane; preferably, R B1 , R B2 , R B3 and R B4 are not H at the same time; preferably, R B1 and R B2 are both non-hydrogen groups.
在更具体实施方案中，本发明涉及上文所述的式(I)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R 1和R 2各自独立地选自H、-OMe、-Me或苯基，或者R 1和R 2连同它们所连接的N原子一起形成任选的被羟基取代的氮杂环丁烷基、吡咯烷基或哌啶基。 In a more specific embodiment, 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.
在更具体实施方案中，本发明涉及上文所述的化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其为式(II)、式(III)或式(IV)化合物：In a more specific embodiment, 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):
Figure PCTCN2021076684-appb-000024
Figure PCTCN2021076684-appb-000024
其中，各基团如上文定义。Wherein, each group is as defined above.
在更具体实施方案中，本发明涉及上文所述的化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其为式(III-1)：In a more specific embodiment, 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):
Figure PCTCN2021076684-appb-000025
Figure PCTCN2021076684-appb-000025
其中，各基团如上文定义；Wherein, each group is as defined above;
优选地，Preferably,
A 2和A 3各自独立地为C或N原子； A 2 and A 3 are each independently a C or N atom;
R B1、R B2、R B3和R B4各自独立地选自卤素、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；或者，R B1和R B2可以与它们所连接的C原子一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；且上述基团任选地被一个或多个R”取代； 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 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 3选自H、卤素、-CN、C 1-6烷基或C 1-6卤代烷基，且上述基团任选地被一个或多个R*取代； 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和R 5各自独立地选自H、卤素、-CN、C 1-6烷基或C 1-6卤代烷基，且上述基团任选地被一个或多个R*取代；或者，R 4和R 5连同它们所连接的双键一起形成叁键； 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和R 2各自独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；或者，R 1和R 2连同它们所连接的N原子一起形成3至7元杂环基或5至10元杂芳基；且上述基团任选地被一个或多个R’取代； 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';
每个R’各自独立地选自H、D、卤素、-CN、＝O、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，或者，相同原子或相邻原子上的两个R’基团可以一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；其中R’定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R'is independently selected from H, D, halogen, -CN, =0, 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 two R'groups on the same atom or adjacent atoms can form a C 3-7 cycloalkyl group together , 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group; wherein each group in the definition of R'is optionally substituted with one or more D until fully deuterated;
每个R”各自独立地选自H、D、卤素、-CN、＝O、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，或者，相同原子或相邻原子上的两个R”基团可以一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；其中R”定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R" is independently selected from H, D, halogen, -CN, =0, 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 two R" groups on the same atom or adjacent atoms can form a C 3-7 cycloalkyl group together , 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group; wherein each group in the definition of R" is optionally substituted by one or more D until it is fully deuterated;
每个R*各自独立地选自H、D、卤素、-CN、＝O、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；或者，相同原子或相邻原子上的两个R*基团可以一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；其中R*定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R* is independently selected from H, D, halogen, -CN, =O, 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, two R* groups on the same atom or adjacent atoms can form a C 3-7 cycloalkyl group together , 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group; wherein each group in the definition of R* is optionally substituted by one or more D until fully deuterated;
每个R各自独立地选自H、D、卤素、-CN、＝O、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、 -OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；或者，相同原子或相邻原子上的两个R基团可以一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；其中R定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R is independently selected from H, D, halogen, -CN, =O, 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, A 3- to 7-membered heterocyclic group, a C 6-10 aryl group or a 5- to 10-membered heteroaryl group; alternatively, two R groups on the same atom or adjacent atoms can form a C 3-7 cycloalkyl group, 3 To 7-membered heterocyclyl, C 6-10 aryl or 5 to 10-membered heteroaryl; wherein each group in the definition of R is optionally substituted with one or more D until fully deuterated;
m＝0、1、2、3、4或5；m=0, 1, 2, 3, 4 or 5;
n＝0、1或2；n=0, 1 or 2;
每个R a、R b和R c各自独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，或者R b和R c连同它们所连接的N原子一起形成3至7元杂环基或5至10元杂芳基；其中R a、R b和R c定义中的每个基团任选地被一个或多个D取代，直至完全氘代。 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.
在更具体实施方案中，本发明涉及上文所述的化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其为式(III-2)：In a more specific embodiment, 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):
Figure PCTCN2021076684-appb-000026
Figure PCTCN2021076684-appb-000026
其中，in,
A 2和A 3各自独立地为C或N原子； A 2 and A 3 are each independently a C or N atom;
R B1和R B2各自独立地选自卤素、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；或者，R B1和R B2可以与它们所连接的C原子一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；且上述基团任选地被一个或多个R”取代； 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 to 7 membered heterocyclic group together with the C atom to which they are attached , C 6-10 aryl or 5 to 10-membered heteroaryl; and the above-mentioned groups are optionally substituted by one or more R″;
R 1和R 2各自独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；或者，R 1和R 2连同它们所连接的N原子一起形成3至7元杂环基或5至10元杂芳基；且上述基团任选地被一个或多个R’取代； 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';
每个R’各自独立地选自H、D、卤素、-CN、＝O、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，或者，相同原子或相邻原子上的两个R’基团可以一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；其中R’定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R'is independently selected from H, D, halogen, -CN, =0, 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 two R'groups on the same atom or adjacent atoms can form a C 3-7 cycloalkyl group together , 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group; wherein each group in the definition of R'is optionally substituted with one or more D until fully deuterated;
每个R”各自独立地选自H、D、卤素、-CN、＝O、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，或者，相同原子或相邻原子上的两个R”基团可以一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；其中R”定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R" is independently selected from H, D, halogen, -CN, =0, 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 two R" groups on the same atom or adjacent atoms can form a C 3-7 cycloalkyl group together , 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group; wherein each group in the definition of R" is optionally substituted by one or more D until it is fully deuterated;
每个R a、R b和R c各自独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，或者R b和R c连同它们所连接的N原子一起形成3至7元杂环基或5至10元杂芳基；其中R a、R b和R c定义中的每个基团任选地被一个或多个D取代，直至完全氘代。 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.
在更具体实施方案中，本发明涉及上文所述的(III-2)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，In a more specific embodiment, 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和A 3各自独立地为C或N原子； A 2 and A 3 are each independently a C or N atom;
R B1和R B2各自独立地选自C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基；或者，R B1和R B2可以与它们所连接的C原子一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；且上述基团任选地被一个或多个R”取代； 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和R 2各自独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基；或者，R 1和R 2连同它们所连接的N原子一起形成3至7元杂环基或5至10元杂芳基；且上述基团任选地被一个或多个R’取代； 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 The linked N atoms together form a 3- to 7-membered heterocyclic group or a 5- to 10-membered heteroaryl group; and the above-mentioned groups are optionally substituted by one or more R′;
每个R’各自独立地选自H、D、卤素、-CN、＝O、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，或者，相同原子或相邻原子上的两个R’基团可以一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；其中R’定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R'is independently selected from H, D, halogen, -CN, =0, 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 two R'groups on the same atom or adjacent atoms can form a C 3-7 cycloalkyl group together , 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group; wherein each group in the definition of R'is optionally substituted with one or more D until fully deuterated;
每个R”各自独立地选自H、D、卤素、-CN、＝O、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，或者，相同原子或相邻原子上的两个R”基团可以一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；其中R”定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R" is independently selected from H, D, halogen, -CN, =0, 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 two R" groups on the same atom or adjacent atoms can form a C 3-7 cycloalkyl group together , 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group; wherein each group in the definition of R" is optionally substituted by one or more D until it is fully deuterated;
每个R a、R b和R c各自独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，或者R b和R c连同它们所连接的N原子一起形成3至7元杂环基或5至10元杂芳基；其中R a、R b和R c定义中的每个基团任选地被一个或多个D取代，直至完全氘代。 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.
在更具体实施方案中，本发明涉及上文所述的(III-2)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，In a more specific embodiment, 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和A 3各自独立地为C或N原子； A 2 and A 3 are each independently a C or N atom;
R B1和R B2各自独立地选自C 1-6烷基或C 1-6卤代烷基；或者，R B1和R B2可以与它们所连接的C原子一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；且上述基团任选地被一个或多个R”取代； 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和R 2各自独立地选自C 1-6烷基或C 1-6卤代烷基；或者，R 1和R 2连同它们所连接的N原子一起形成3至7元杂环基或5至10元杂芳基；且上述基团任选地被一个或多个R’取代； 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';
每个R’各自独立地选自H、D、卤素、-CN、＝O、-NR bR c或-OR a；其中R’定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R'is independently selected from H, D, halogen, -CN, =O, -NR b R c or -OR a ; wherein each group in the definition of R'is optionally substituted by one or more D Replacement until fully deuterated;
每个R”各自独立地选自H、D、卤素、-CN、＝O、-NR bR c或-OR a；其中R”定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R" is independently selected from H, D, halogen, -CN, =O, -NR b R c or -OR a ; wherein each group in the definition of R "is optionally substituted by one or more D Replacement until fully deuterated;
每个R a、R b和R c各自独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基，或者R b和R c连同它们所连接的N原子一起形成3至7元杂环基或5至10元杂芳基；其中R a、R b和R c定义中的每个基团任选地被一个或多个D取代，直至完全氘代。 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.
在更具体实施方案中，本发明涉及上文所述的(III-2)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，In a more specific embodiment, 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和A 3各自独立地为C或N原子； A 2 and A 3 are each independently a C or N atom;
R B1和R B2均为甲基，且其任选地被一个或多个R”取代； R B1 and R B2 are both methyl, and they are optionally substituted with one or more R″;
R 1和R 2均为甲基，且其任选地被一个或多个R’取代； R 1 and R 2 are both methyl, and they are optionally substituted with one or more R′;
每个R’各自独立地选自H、D、卤素、-CN、＝O、-NH 2或-OH； Each R'is independently selected from H, D, halogen, -CN, =O, -NH 2 or -OH;
每个R”各自独立地选自H、D、卤素、-CN、＝O、-NH 2或-OH。 Each R" is independently selected from H, D, halogen, -CN, =O, -NH 2 or -OH.
在更具体实施方案中，本发明涉及上文所述的化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其为式(IV-1)：In a more specific embodiment, 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):
Figure PCTCN2021076684-appb-000027
Figure PCTCN2021076684-appb-000027
其中，各基团如上文定义；Wherein, each group is as defined above;
优选地，Preferably,
A 1为CR A1或N原子； A 1 is CR A1 or N atom;
A 4为CR A4或N原子； A 4 is CR A4 or N atom;
优选地，A 1和A 4不同时为N原子； Preferably, A 1 and A 4 are not N atoms at the same time;
R A1和R A4各自独立地为H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；且上述基团任选地被一个或多个R”取代； 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和R B4各自独立地选自卤素、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；或者，R B1和R B2、R B3和R B4可以分别与它们所连接的C原子一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；且上述基团任选地被一个或多个R”取代； 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 B4 can form C 3 together with the C atom to which they are attached. -7 cycloalkyl, 3 to 7 membered heterocyclyl, C 6-10 aryl or 5 to 10 membered heteroaryl; and the above groups are optionally substituted by one or more R″;
R 3选自H、卤素、-CN、C 1-6烷基或C 1-6卤代烷基，且上述基团任选地被一个或多个R*取代； 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和R 5各自独立地选自H、卤素、-CN、C 1-6烷基或C 1-6卤代烷基，且上述基团任选地被一个或多个R*取代；或者，R 4和R 5连同它们所连接的双键一起形成叁键； 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和R 2各自独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；或者，R 1和R 2连同它们所连接的N原子一起形成3至7元杂环基或5至10元杂芳基；且上述基团任选地被一个或多个R’取代； 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';
每个R’各自独立地选自H、D、卤素、-CN、＝O、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，或者，相同原子或相邻原子上的两个R’基团可以一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；其中R’定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R'is independently selected from H, D, halogen, -CN, =0, 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 two R'groups on the same atom or adjacent atoms can form a C 3-7 cycloalkyl group together , 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group; wherein each group in the definition of R'is optionally substituted with one or more D until fully deuterated;
每个R”各自独立地选自H、D、卤素、-CN、＝O、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，或者，相同原子或相邻原子上的两个R”基团可以一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；其中R”定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R" is independently selected from H, D, halogen, -CN, =0, 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 two R" groups on the same atom or adjacent atoms can form a C 3-7 cycloalkyl group together , 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group; wherein each group in the definition of R" is optionally substituted by one or more D until it is fully deuterated;
每个R*各自独立地选自H、D、卤素、-CN、＝O、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；或者，相同原子或相邻原子上的两个R*基团可以一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；其中R*定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R* is independently selected from H, D, halogen, -CN, =O, 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, two R* groups on the same atom or adjacent atoms can form a C 3-7 cycloalkyl group together , 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group; wherein each group in the definition of R* is optionally substituted by one or more D until fully deuterated;
每个R各自独立地选自H、D、卤素、-CN、＝O、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；或者，相同原子或相邻原子上的两个R基团可以一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；其中R定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R is independently selected from H, D, halogen, -CN, =O, 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, A 3- to 7-membered heterocyclic group, a C 6-10 aryl group or a 5- to 10-membered heteroaryl group; alternatively, two R groups on the same atom or adjacent atoms can form a C 3-7 cycloalkyl group, 3 To 7-membered heterocyclyl, C 6-10 aryl or 5 to 10-membered heteroaryl; wherein each group in the definition of R is optionally substituted with one or more D until fully deuterated;
m＝0、1、2、3、4或5；m=0, 1, 2, 3, 4 or 5;
n＝0、1或2；n=0, 1 or 2;
每个R a、R b和R c各自独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，或者R b和R c连同它们所连接的N原子一起形成3至7元杂环基或5至10元杂芳基；其中R a、R b和R c定义中的每个基团任选地被一个或多个D取代，直至完全氘代。 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.
在更具体实施方案中，本发明涉及上文所述的化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其为式(IV-2)：In a more specific embodiment, 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):
Figure PCTCN2021076684-appb-000028
Figure PCTCN2021076684-appb-000028
其中，in,
A 1为CR A1或N原子； A 1 is CR A1 or N atom;
A 4为CR A4或N原子； A 4 is CR A4 or N atom;
优选地，A 1和A 4不同时为N原子； Preferably, A 1 and A 4 are not N atoms at the same time;
R A1和R A4各自独立地为H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；且上述基团任选地被一个或多个R”取代； 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和R B2各自独立地选自卤素、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；或者，R B1和R B2可以与它们所连接的C原子一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；且上述基团任选地被一个或多个R”取代； 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 to 7 membered heterocyclic group together with the C atom to which they are attached , C 6-10 aryl or 5 to 10-membered heteroaryl; and the above-mentioned groups are optionally substituted by one or more R″;
R 1和R 2各自独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；或者，R 1和R 2连同它们所连接的N原子一起形成3至7元杂环基或5至10元杂芳基；且上述基团任选地被一个或多个R’取代； 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';
每个R’各自独立地选自H、D、卤素、-CN、＝O、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，或者，相同原子或相邻原子上的两个R’基团可以一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；其中R’定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R'is independently selected from H, D, halogen, -CN, =0, 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 two R'groups on the same atom or adjacent atoms can form a C 3-7 cycloalkyl group together , 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group; wherein each group in the definition of R'is optionally substituted with one or more D until fully deuterated;
每个R”各自独立地选自H、D、卤素、-CN、＝O、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，或者，相同原子或相邻原子上的两个R”基团可以一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；其中R”定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R" is independently selected from H, D, halogen, -CN, =0, 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 two R" groups on the same atom or adjacent atoms can form a C 3-7 cycloalkyl group together , 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group; wherein each group in the definition of R" is optionally substituted by one or more D until it is fully deuterated;
每个R a、R b和R c各自独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，或者R b和R c连同它们所连接的N原子一起形成3至7元杂环基或5至10元杂芳基；其中R a、R b和R c定义中的每个基团任选地被一个或多个D取代，直至完全氘代。 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.
在更具体实施方案中，本发明涉及上文所述的式(IV-2)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，In a more specific embodiment, the present invention relates to the compound of formula (IV-2) described above, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrated物 or solvate, in which,
A 1为CR A1或N原子； A 1 is CR A1 or N atom;
A 4为CR A4或N原子； A 4 is CR A4 or N atom;
R A1和R A4各自独立地为H或D； R A1 and R A4 are each independently H or D;
R B1和R B2各自独立地选自C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基；或者，R B1和R B2可以与它们所连接的C原子一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；且上述基团任选地被一个或多个R”取代； 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和R 2各自独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基；或者，R 1和R 2连同它们所连接的N原子一起形成3至7元杂环基或5至10元杂芳基；且上述基团任选地被一个或多 个R’取代； 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 The linked N atoms together form a 3- to 7-membered heterocyclic group or a 5- to 10-membered heteroaryl group; and the above-mentioned groups are optionally substituted by one or more R′;
每个R’各自独立地选自H、D、卤素、-CN、＝O、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，或者，相同原子或相邻原子上的两个R’基团可以一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；其中R’定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R'is independently selected from H, D, halogen, -CN, =0, 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 two R'groups on the same atom or adjacent atoms can form a C 3-7 cycloalkyl group together , 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group; wherein each group in the definition of R'is optionally substituted with one or more D until fully deuterated;
每个R”各自独立地选自H、D、卤素、-CN、＝O、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，或者，相同原子或相邻原子上的两个R”基团可以一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；其中R”定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R" is independently selected from H, D, halogen, -CN, =0, 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 two R" groups on the same atom or adjacent atoms can form a C 3-7 cycloalkyl group together , 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group; wherein each group in the definition of R" is optionally substituted by one or more D until it is fully deuterated;
每个R a、R b和R c各自独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，或者R b和R c连同它们所连接的N原子一起形成3至7元杂环基或5至10元杂芳基；其中R a、R b和R c定义中的每个基团任选地被一个或多个D取代，直至完全氘代。 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.
在更具体实施方案中，本发明涉及上文所述的式(IV-2)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，In a more specific embodiment, the present invention relates to the compound of formula (IV-2) described above, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrated物 or solvate, in which,
A 1为CR A1或N原子； A 1 is CR A1 or N atom;
A 4为CR A4或N原子； A 4 is CR A4 or N atom;
R A1和R A4各自独立地为H或D； R A1 and R A4 are each independently H or D;
优选地，A 1和A 4不同时为N原子； Preferably, A 1 and A 4 are not N atoms at the same time;
R B1和R B2各自独立地选自C 1-6烷基或C 1-6卤代烷基；或者，R B1和R B2可以分别与它们所连接的C原子一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；且上述基团任选地被一个或多个R”取代； 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和R 2各自独立地选自C 1-6烷基或C 1-6卤代烷基；或者，R 1和R 2连同它们所连接的N原子一起形成3至7元杂环基或5至10元杂芳基；且上述基团任选地被一个或多个R’取代； 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';
每个R’各自独立地选自H、D、卤素、-CN、＝O、-NR bR c或-OR a；其中R’定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R'is independently selected from H, D, halogen, -CN, =O, -NR b R c or -OR a ; wherein each group in the definition of R'is optionally substituted by one or more D Replacement until fully deuterated;
每个R”各自独立地选自H、D、卤素、-CN、＝O、-NR bR c或-OR a；其中R”定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R" is independently selected from H, D, halogen, -CN, =O, -NR b R c or -OR a ; wherein each group in the definition of R "is optionally substituted by one or more D Replacement until fully deuterated;
每个R a、R b和R c各自独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基，或者R b和R c连同它们所连接的N原子一起形成3至7元杂环基或5至10元杂芳基；其中R a、R b和R c定义中的每个基团任选地被一个或多个D取代，直至完全氘代。 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.
在更具体实施方案中，本发明涉及上文所述的式(IV-2)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，In a more specific embodiment, the present invention relates to the compound of formula (IV-2) described above, or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrated物 or solvate, in which,
A 1为CR A1或N原子； A 1 is CR A1 or N atom;
A 4为CR A4或N原子； A 4 is CR A4 or N atom;
优选地，A 1和A 4不同时为N原子； Preferably, A 1 and A 4 are not N atoms at the same time;
R A1和R A4均为H； R A1 and R A4 are both H;
R B1和R B2均为甲基，且其任选地被一个或多个R”取代； R B1 and R B2 are both methyl, and they are optionally substituted with one or more R″;
R 1和R 2均为甲基，且其任选地被一个或多个R’取代； R 1 and R 2 are both methyl, and they are optionally substituted with one or more R′;
每个R’各自独立地选自H、D、卤素、-CN、＝O、-NH 2或-OH； Each R'is independently selected from H, D, halogen, -CN, =O, -NH 2 or -OH;
每个R”各自独立地选自H、D、卤素、-CN、＝O、-NH 2或-OH。 Each R" is independently selected from H, D, halogen, -CN, =O, -NH 2 or -OH.
在更具体实施方案中，本发明涉及以下化合物或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，所述化合物选自：In a more specific embodiment, 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 :
Figure PCTCN2021076684-appb-000029
Figure PCTCN2021076684-appb-000029
Figure PCTCN2021076684-appb-000030
Figure PCTCN2021076684-appb-000030
本发明化合物可包括一个或多个不对称中心，且因此可以存在多种立体异构体形式，例如，对映异构体和/或非对映异构体形式。例如，本发明化合物可为单独的对映异构体、非对映异构体或几何异构体(例如顺式和反式异构体)，或者可为立体异构体的混合物的形式，包括外消旋体混合物和富含一种或多种立体异构体的混合物。异构体可通过本领域技术人员已知的方法从混合物中分离，所述方法包括：手性高压液相色谱法(HPLC)以及手性盐的形成和结晶；或者优选的异构体可通过不对称合成来制备。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. For example, 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.
“互变异构体”是指某些化合物中的一个官能团改变其结构成为另一种官能团异构体，并且能迅速地相互转换，成为两种异构体处在动态平衡中，而这两种异构体，称为互变异构体。"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.
本领域技术人员将理解，有机化合物可以与溶剂形成复合物，其在该溶剂中发生反应或从该溶剂中沉淀或结晶出来。这些复合物称为“溶剂合物”。当溶剂是水时，复合物称为“水合物”。本发明涵盖了本发明化合物的所有溶剂合物。Those skilled in the art will understand that 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.
术语“溶剂合物”是指通常由溶剂分解反应形成的与溶剂相结合的化合物或其盐的形式。这个物理缔合可包括氢键键合。常规溶剂包括包括水、甲醇、乙醇、乙酸、DMSO、THF、***等。本文所述的化合物可制备成，例如，结晶形式，且可被溶剂化。合适的溶剂合物包括药学上可接受的溶剂合物且进一步包括化学计量的溶剂合物和非化学计量的溶剂合物。在一些情况下，所述溶剂合物将能够分离，例如，当一或多个溶剂分子掺入结晶固体的晶格中时。“溶剂合物”包括溶液状态的溶剂合物和可分离的溶剂合物。代表性的溶剂合物包括水合物、乙醇合物和甲醇合物。The term "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. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, ether and the like. The compounds described herein can be prepared, for example, in crystalline form, and can be solvated. 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.
术语“水合物”是指与水相结合的化合物。通常，包含在化合物的水合物中的水分子数与该水合物中该化合物分子数的比率确定。因此，化合物的水合物可用例如通式R·x H 2O代表，其中R是该化合物，和x是大于0的数。给定化合物可形成超过一种水合物类型，包括，例如，单水合物(x为1)、低级水合物(x是大于0且小于1的数，例如，半水合物(R·0.5H 2O))和多水合物(x为大于1的数，例如，二水合物(R·2H 2O)和六水合物(R·6H 2O))。 The term "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)).
本发明化合物可以是无定形或结晶形式(晶型或多晶型)。此外，本发明化合物可以以一种或多种结晶形式存在。因此，本发明在其范围内包括本发明化合物的所有无定形或结晶形式。术语“多晶型物”是指特定晶体堆积排列的化合物的结晶形式(或其盐、水合物或溶剂合物)。所有的多晶型物具有相同的元素组成。不同的结晶形式通常具有不同的X射线衍射图、红外光谱、熔点、密度、硬度、晶体形状、光电性质、稳定性和溶解度。重结晶溶剂、结晶速率、贮存温度和其他因素可导致一种结晶形式占优。化合物的各种多晶型物可在不同的条件下通过结晶制备。The compounds of the present invention may be in amorphous or crystalline form (crystalline or polymorphic). In addition, 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.
本发明还包括同位素标记的化合物，它们等同于式(I)所述的那些，但一个或多个原子被原子质量或质量数不同于自然界常见的原子质量或质量数的原子所代替。可以引入本发明化合物中的同位素的 实例包括氢、碳、氮、氧、磷、硫、氟和氯的同位素，分别例如 2H、 3H、 13C、 11C、 14C、 15N、 18O、 17O、 31P、 32P、 35S、 18F和 36Cl。含有上述同位素和/或其它原子的其它同位素的本发明化合物、其前体药物和所述化合物或所述前体药物的药学上可接受的盐都属于本发明的范围。某些同位素标记的本发明化合物、例如引入放射性同位素(例如 3H和 14C)的那些可用于药物和/或底物组织分布测定。氚、即 3H和碳-14、即 14C同位素是特别优选的，因为它们容易制备和检测。进而，被更重的同位素取代，例如氘、即 2H，由于代谢稳定性更高可以提供治疗上的益处，例如延长体内半衰期或减少剂量需求，因而在有些情况下可能是优选的。同位素标记的本发明式(I)化合物及其前体药物一般可以这样制备，在进行下述流程和/或实施例与制备例所公开的工艺时，用容易得到的同位素标记的试剂代替非同位素标记的试剂。 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. Examples of 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. The compounds of the present invention containing the above-mentioned isotopes and/or other isotopes of other atoms, their prodrugs, and the compounds or pharmaceutically acceptable salts of the prodrugs all fall within the scope of the present invention. Certain isotope-labeled compounds of the invention, such as those incorporating radioisotopes (e.g. 3 H and 14 C), can be used for drug and/or substrate tissue distribution determination. Tritium, 3 H and carbon-14, 14 C isotopes are particularly preferred because they are easy to prepare and detect. Furthermore, substitution by heavier isotopes, such as deuterium, ie 2 H, may provide therapeutic benefits due to higher metabolic stability, such as prolonging the half-life in the body or reducing dosage requirements, and may therefore be preferable in some cases. Isotopically-labeled compounds of formula (I) of the present invention and their prodrugs can generally be prepared in this way. When performing the processes disclosed in the following procedures and/or examples and preparation examples, the non-isotope-labeled reagents are replaced with readily available isotope-labeled reagents. Labeled reagents.
此外，前药也包括在本发明的上下文内。本文所用的术语“前药”是指在体内通过例如在血液中水解转变成其具有医学效应的活性形式的化合物。药学上可接受的前药描述于T.Higuchi和V.Stella，Prodrugs as Novel Delivery Systems，A.C.S.Symposium Series的Vol.14，Edward B.Roche，ed.，Bioreversible Carriers in Drug Design，American Pharmaceutical Association and Pergamon Press，1987，以及D.Fleisher、S.Ramon和H.Barbra“Improved oral drug delivery：solubility limitations overcome by the use of prodrugs”，Advanced Drug Delivery Reviews(1996)19(2)115-130，每篇引入本文作为参考。In addition, 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.
前药为任何共价键合的本发明化合物，当将这种前药给予患者时，其在体内释放母体化合物。通常通过修饰官能团来制备前药，修饰是以使得该修饰可以通过常规操作或在体内裂解产生母体化合物的方式进行的。前药包括，例如，其中羟基、氨基或巯基与任意基团键合的本发明化合物，当将其给予患者时，可以裂解形成羟基、氨基或巯基。因此，前药的代表性实例包括(但不限于)式(I)化合物的羟基、巯基和氨基官能团的乙酸酯/酰胺、甲酸酯/酰胺和苯甲酸酯/酰胺衍生物。另外，在甲酸(-COOH)的情况下，可以使用酯，例如甲酯、乙酯等。酯本身可以是有活性的和/或可以在人体体内条件下水解。合适的药学上可接受的体内可水解的酯基包括容易在人体中分解而释放母体酸或其盐的那些基团。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. Therefore, representative examples of 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). In addition, in the case of formic acid (-COOH), 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.
治疗treatment
本发明提供了一种治疗和/或预防受试者中的疾病，如野生的和/或突变的EGFR激酶介导的癌症的方法，包括向所述受试者给药本发明化合物或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，或本发明药物组合物。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.
在具体实施方案中，所述的突变的EGFR选自外显子20***突变型EGFR、外显子18点突变型EGFR、外显子21点突变型EGFR、外显子19缺失突变型EGFR或L858R突变型EGFR。In a specific embodiment, 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.
在具体实施方案中，所述的突变的EGFR具有T790M突变且具有选自外显子20***突变、外显子18点突变、外显子21点突变、外显子19缺失突变或L858R突变中的至少一种突变。In a specific embodiment, 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.
在本文中，“EGFR”是指人表皮生长因子受体蛋白质，又称为ErbB-1或HER1。In this article, "EGFR" refers to human epidermal growth factor receptor protein, also known as ErbB-1 or HER1.
在本文中，“野生型EGFR”是指无体细胞突变的EGFR。As used herein, "wild-type EGFR" refers to EGFR without somatic cell mutation.
在本文中，“外显子20***突变”是指其中一个或多个氨基酸(优选1至7个，更优选1至4个)***EGFR的外显子20区域(如第761位至第823位氨基酸序列)的突变；优选地，突变为其中氨基酸序列FQEA(从N-端以苯丙氨酸、谷氨酰胺、谷氨酸和丙氨酸这种顺序)***外显子20区域中第763位丙氨酸和第764位酪氨酸之间的突变(A763_Y764insFQEA)；优选地，突变为其中氨基酸序列ASV(从N-端以丙氨酸、丝氨酸和缬氨酸这种顺序)***外显子20区域中第769位缬氨酸和第770位天冬氨酸之间的突变(V769_D770insASV)；优选地，突变为其中氨基酸序列SVD(从N-端以丝氨酸、缬氨酸和天冬氨酸这种顺序)***外显子20区域中第770位天冬氨酸和第771位天冬酰 胺之间的突变(D770_N771insSVD)；优选地，突变为其中氨基酸序列NPG(从N-端以天冬酰胺、脯氨酸和甘氨酸这种顺序)***外显子20区域中第770位天冬氨酸和第771位天冬酰胺之间的突变(D770_N771insNPG)；优选地，突变为其中氨基酸G(甘氨酸)***第770位天冬氨酸和第771位天冬酰胺之间的突变(D770_N771insG)；优选地，突变为其中外显子20区域中第770位天冬氨酸删除，且由此***氨基酸序列GY(从N-端以甘氨酸和酪氨酸这种顺序)的突变(D770>GY)；优选地，突变为其中氨基酸N(天冬酰胺)***外显子20区域中第771位天冬酰胺和第772位脯氨酸之间的突变(N771_P772insN)；优选地，突变为其中氨基酸序列PR(从N-端以脯氨酸和精氨酸这种顺序)***外显子20区域中第772位脯氨酸和第773位组氨酸之间的突变(P772_R773insPR)；优选地，突变为其中氨基酸序列NPH(从N-端以天冬酰胺、脯氨酸和组氨酸这种顺序)***外显子20区域中第773位组氨酸和第774位缬氨酸之间的突变(H773_V774insNPH)；优选地，突变为其中氨基酸序列PH(从N-端以脯氨酸和组氨酸这种顺序)***外显子20区域中第773位组氨酸和第774位缬氨酸之间的突变(H773_V774insPH)；优选地，突变为其中氨基酸序列AH(从N-端以丙氨酸和组氨酸这种顺序)***外显子20区域中第773位组氨酸和第774位缬氨酸之间的突变(H773_V774insAH)；优选地，突变为其中氨基酸H(组氨酸)***外显子20区域中第773位组氨酸和第774位缬氨酸之间的突变(H773_V774insH)；优选地，突变为其中氨基酸序列HV(从N-端以组氨酸和缬氨酸这种顺序)***外显子20区域中第774位缬氨酸和第775位半胱氨酸之间的突变(V774_C774insHV)；优选地，突变为其中氨基酸序列EAFQ(从N-端以谷氨酸、丙氨酸、苯丙氨酸和谷氨酰胺这种顺序)***外显子20区域中第761位丙氨酸和第762位谷氨酸之间的突变(A761_E762insEAFQ)。更优选地，突变为其中氨基酸序列ASV(从N-端以丙氨酸、丝氨酸和缬氨酸这种顺序)***外显子20区域中第769位缬氨酸和第770位天冬氨酸之间的突变(V769_D770insASV)；更优选地，突变为其中氨基酸序列SVD(从N-端以丝氨酸、缬氨酸和天冬氨酸这种顺序)***外显子20区域中第770位天冬氨酸和第771位天冬酰胺之间的突变(D770_N771insSVD)；更优选地，突变为其中氨基酸序列NPG(从N-端以天冬酰胺、脯氨酸和甘氨酸这种顺序)***外显子20区域中第770位天冬氨酸和第771位天冬酰胺之间的突变(D770_N771insNPG)；更优选地，突变为其中氨基酸G(甘氨酸)***外显子20区域中第770位天冬氨酸和第771位天冬酰胺之间的突变(D770_N771insG)；更优选地，突变为其中氨基酸序列NPH(从N-端以天冬酰胺、脯氨酸和组氨酸这种顺序)***外显子20区域中第773位组氨酸和第774位缬氨酸之间的突变(H773_V774insNPH)；更优选地，突变为其中氨基酸序列PH(从N-端以脯氨酸和组氨酸这种顺序)***外显子20区域中第773位组氨酸和第774位缬氨酸之间的突变(H773_V774insPH)；更优选地，突变为其中氨基酸序列SVD(从N-端以丝氨酸、缬氨酸和天冬氨酸这种顺序)***外显子20区域中第770位天冬氨酸和第771位天冬氨酸之间的突变(D770_N771insSVD)；更优选地，突变为其中氨基酸G(甘氨酸)***外显子20区域中第770位天冬氨酸和第771位天冬酰胺之间的突变(D770_N771insG)。As used herein, "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 serine, valine and aspartic acid) The sequence of amino acid) is inserted into the mutation between aspartic acid at position 770 and asparagine at position 771 in the region of exon 20 (D770_N771insSVD); preferably, the mutation is in which the amino acid sequence NPG (from the N-terminus The sequence of asparagine, proline and glycine) is inserted into the mutation between asparagine at position 770 and asparagine at position 771 in the region of exon 20 (D770_N771insNPG); preferably, the mutation is wherein amino acid G (Glycine) A mutation (D770_N771insG) inserted between aspartic acid at position 770 and asparagine at position 771; preferably, the mutation is in which the aspartic acid at position 770 in the exon 20 region is deleted, and thus A mutation (D770>GY) into the amino acid sequence GY (in the order of glycine and tyrosine from the N-terminus); preferably, the mutation is where the amino acid N (asparagine) is inserted at position 771 in the exon 20 region The mutation between asparagine and proline at position 772 (N771_P772insN); preferably, the mutation is in which the amino acid sequence PR (in the order of proline and arginine from the N-terminus) is inserted into the exon 20 region The mutation between proline at position 772 and histidine at position 773 (P772_R773insPR); preferably, the mutation is wherein the amino acid sequence NPH (from the N-terminus to asparagine, proline and histidine) Sequence) inserted into the mutation between histidine 773 and valine 774 in the exon 20 region (H773_V774insNPH); preferably, the mutation is the amino acid sequence PH (from the N-terminus with proline and group The sequence of amino acid) is inserted into the mutation between histidine at position 773 and valine at position 774 in the exon 20 region (H773_V774insPH); preferably, the mutation is in which the amino acid sequence AH (from the N-terminus to C The sequence of amino acid and histidine) is inserted into the mutation between histidine at position 773 and valine at position 774 in the exon 20 region (H773_V774insAH); preferably, the mutation is The amino acid H (histidine) is inserted into the mutation between the 773th histidine and the 774th valine in the exon 20 region (H773_V774insH); preferably, the mutation is wherein the amino acid sequence HV (from the N-terminal In the order of histidine and valine) insert the mutation between the 774th valine and the 775th cysteine in the exon 20 region (V774_C774insHV); preferably, the mutation is wherein the amino acid sequence EAFQ (From the N-terminus in the order of glutamic acid, alanine, phenylalanine and glutamine) Insert the mutation between the 761st alanine and the 762nd glutamate in the exon 20 region (A761_E762insEAFQ). More 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 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) is inserted into aspartic acid at position 770 in region of exon 20 The mutation between acid and asparagine at position 771 (D770_N771insG); more preferably, the mutation is in which the amino acid sequence NPH (from the N-terminus in the order of asparagine, proline and histidine) is inserted into the exon The mutation between the 773th histidine and the 774th valine in the sub20 region (H773_V774insNPH); more preferably, the mutation is wherein the amino acid sequence PH (proline and histidine from the N-terminus) Sequence) inserted into the mutation between histidine 773 and valine 774 in the exon 20 region (H773_V774insPH); more preferably, the mutation is the amino acid sequence SVD (from the N-terminus with serine, valine) Acid and aspartic acid) inserted into the mutation between aspartic acid at position 770 and aspartic acid at position 771 in the region of exon 20 (D770_N771insSVD); more preferably, the mutation is where the amino acid G ( Glycine) was inserted into the mutation between aspartic acid at position 770 and asparagine at position 771 in the region of exon 20 (D770_N771insG).
在本文中，“表达具有外显子20***突变的EGFR的癌症患者”是指表达在EGFR的外显子20区域的至少一部分具有外显子20***突变的EGFR的癌症患者。EGFR可在两个或更多不同部分具有外显子20***突变，但优选其中一个部分。而且，EGFR也可具有除外显子20***突变之外的其他突变(如外显子19缺失突变，L858R突变，或T790M突变)。As used herein, "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. Moreover, EGFR may also have mutations other than the insertion mutation in exon 20 (such as exon 19 deletion mutation, L858R mutation, or T790M mutation).
在本发明中，用于检测癌症患者中表达EGFR外显子20***突变的方法没有特别限制，只要该方法能够检测突变，并且可以使用任何已知的检测方法。检测外显子20***突变的检测靶标可以是EGFR基因的基因序列、EGFR基因的转录产物和EGFR蛋白中的任何一种。In the present invention, 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.
用于检测外显子20***突变的样品没有特别限制，只要样品是从癌症患者分离的生物样品即可， 特别是从癌症患者获得并含有恶性肿瘤细胞的样品。生物样品的实例包括体液(例如血液、尿液等)、组织、其提取物和获得组织的培养物。分离生物样品的方法可以根据生物样品的类型适当选择。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. Examples of 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.
根据检测方法通过适当处理来制备生物样品。此外，用于检测的试剂(例如，含有引物或探针的试剂)可以根据检测方法通过常规方法制备。Prepare biological samples through appropriate treatments according to the detection method. In addition, reagents used for detection (for example, reagents containing primers or probes) can be prepared by conventional methods according to the detection method.
在本发明的一个实施方案中，检测恶性肿瘤患者中表达的EGFR的外显子20***突变的存在的步骤可以在向癌症患者施用抗肿瘤剂之前进行。In one embodiment of the present invention, 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.
在本文中，“外显子18点突变”表示野生型EGFR外显子18区域中氨基酸中的点突变。优选地，突变为外显子18区域中1个氨基酸被取代的点突变或缺失突变；更优选地，突变为外显子18中密码子709所编码的谷氨酸被任意氨基酸取代的点突变(即E790X)，以及外显子18中密码子719所编码的甘氨酸被任意氨基酸取代的点突变(即G719X)。具体来说，E790X可例如：外显子18区域中密码子709所编码的谷氨酸被赖氨酸取代的点突变(即E709K)，及外显子18区域中密码子709所编码的谷氨酸被丙氨酸取代的点突变(即E709A)。G719X可例如：外显子18区域中密码子719所编码的甘氨酸被丙氨酸取代的点突变(即G719A)，外显子18区域中密码子719所编码的甘氨酸被丝氨酸取代的点突变(即G719S)，及外显子18区域中密码子719所编码的甘氨酸被半胱氨酸取代的点突变(即G719C)，其中G719A最常见。As used herein, "exon 18 point mutation" means a point mutation in an amino acid in the exon 18 region of wild-type EGFR. Preferably, 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). Specifically, 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.
在本文中，“外显子18点突变型EGFR”表示具有至少1个外显子18点突变的EGFR；优选地该EGFR具有2个以上相关外显子18点突变；更优选地，该EGFR具有1个外显子18点突变。此外，该EGFR也可具有外显子18点突变以外的其他突变(例如外显子19缺失突变、L858R突变及T790M突变等)。Herein, "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. In addition, the EGFR may also have mutations other than exon 18 point mutations (for example, exon 19 deletion mutation, L858R mutation, T790M mutation, etc.).
在本文中，“外显子21”表示野生型EGFR的氨基酸序列中824-875的区域。Here, "exon 21" represents the region 824-875 in the amino acid sequence of wild-type EGFR.
在本文中，“外显子21点突变”表示野生型EGFR外显子21区域的氨基酸中的点突变。优选地，外显子21点突变为外显子21区域中1个氨基酸被取代的点突变；更优选地，外显子21点突变为外显子21区域中密码子861所编码的亮氨酸被任意氨基酸取代的点突变(即L861X)，例如，外显子21区域中密码子861所编码的亮氨酸被谷氨酰胺取代的点突变(即L861Q)。As used herein, "exon 21 point mutation" means a point mutation in an amino acid in the exon 21 region of wild-type EGFR. Preferably, 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), for example, a point mutation in which the leucine encoded by codon 861 in the exon 21 region is replaced by glutamine (ie, L861Q).
在本文中，“外显子21点突变型EGFR”表示具有至少1个外显子21点突变的EGFR；优选地该EGFR具有2个以上相关外显子21点突变；更优选地，该EGFR具有1个外显子21点突变。此外，该EGFR也可具有外显子21点突变以外的其他突变(例如外显子19缺失突变、L858R突变及T790M突变等)。As used herein, "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. In addition, the EGFR may also have mutations other than exon 21 point mutations (for example, exon 19 deletion mutation, L858R mutation, T790M mutation, etc.).
在具体实施方案中，所述的突变的EGFR为具有T790M突变且具有选自外显子20***突变、外显子18点突变、外显子21点突变、外显子19缺失突变或L858R突变中的至少一种突变。In a specific embodiment, 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.
具体而言，本发明中具有T790M突变且具有选自外显子18点突变型EGFR、外显子21点突变型EGFR为下列中任一者：具有T790M突变且具有外显子18区域E709X和/或G719X突变型EGFR；具有T790M突变且具有外显子21区域L861X突变型EGFR。具体来说为下列中任一者：具有T790M突变且具有E709K或E709A突变型EGFR；具有T790M突变且具有G719A、G719S或G719C突变型EGFR；具有T790M突变且具有L861Q突变型EGFR；其中，具有T790M突变且具有G719A和具有T790M突变且具有L861Q突变型EGFR更为常见。Specifically, 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. Specifically, it 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.
在本文中，癌症患者所表达的EGFR具有外显子18和/或外显子21点突变的检测方法只要可检测出上述突变即可，可使用已知的检测方法。In this article, 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.
用于检测外显子18和/或外显子21点突变的样品没有特别限制，只要样品是从癌症患者分离的生物样品即可，特别是从癌症患者获得并含有恶性肿瘤细胞的样品。生物样品的实例包括体液(例如 血液、尿液等)、组织、其提取物和获得组织的培养物。分离生物样品的方法可以根据生物样品的类型适当选择。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. Examples of 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.
根据检测方法通过适当处理来制备生物样品。此外，用于检测的试剂(例如，含有引物或探针的试剂)可以根据检测方法通过常规方法制备。Prepare biological samples through appropriate treatments according to the detection method. In addition, reagents used for detection (for example, reagents containing primers or probes) can be prepared by conventional methods according to the detection method.
在本发明的一个实施方案中，检测恶性肿瘤患者中表达的外显子18和/或外显子21点突变的存在的步骤可以在向癌症患者施用抗肿瘤剂之前进行。In one embodiment of the present invention, 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.
本发明中突变的EGFR激酶介导的肿瘤具体实例包括但不限于：头颈癌、胃肠癌症(食管癌、胃癌、十二指肠癌、肝癌、胆管癌(例如，胆囊和胆管癌)、胰腺癌、结肠直肠癌(例如，结肠癌和直肠癌)等)、肺癌(例如，非小细胞肺癌、小细胞肺癌和间皮瘤)、乳腺癌、生殖器癌症(卵巢癌、子宫癌(例如，子***和子宫内膜癌)等)、泌尿道癌(例如，肾癌、膀胱癌、***癌和睾丸癌)、造血***肿瘤(例如，白血病、恶性淋巴瘤和多发性骨髓瘤)、骨肉瘤、软组织肉瘤、皮肤癌、脑肿瘤等。优选实例包括肺癌、乳腺癌、头颈癌、脑肿瘤、子宫癌、造血***肿瘤或皮肤癌。Specific examples of 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 cancer, brain tumor, uterine cancer, hematopoietic system tumor or skin cancer.
在具体实施方案中，所述的突变的EGFR选自外显子20***突变型EGFR、外显子18点突变型EGFR、外显子21点突变型EGFR、外显子19缺失突变型EGFR或L858R突变型EGFR。In a specific embodiment, 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.
在具体实施方案中，所述的突变的EGFR具有T790M突变且具有选自外显子18点突变型EGFR、外显子21点突变型EGFR、外显子19缺失突变型EGFR或L858R突变型EGFR。In a specific embodiment, 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 .
本发明还提供***患者的方法，包括向表达具有选自外显子20***突变型EGFR、外显子18点突变型EGFR、外显子21点突变型EGFR、外显子19缺失突变型EGFR或L858R突变型EGFR的肿瘤患者给药有效量的包括本发明化合物或其药学上可接受的盐的抗肿瘤剂的步骤。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 step of administering an effective amount of an antitumor agent including the compound of the present invention or a pharmaceutically acceptable salt thereof to a tumor patient with EGFR or L858R mutant EGFR.
本发明还提供本发明化合物或其药学上可接受的盐，其用于治疗表达具有选自外显子20***突变型EGFR、外显子18点突变型EGFR、外显子21点突变型EGFR、外显子19缺失突变型EGFR或L858R突变型EGFR的肿瘤患者。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.
本发明还提供本发明化合物或其药学上可接受的盐在治疗具有选自外显子20***突变型EGFR、外显子18点突变型EGFR、外显子21点突变型EGFR、外显子19缺失突变型EGFR或L858R突变型EGFR的肿瘤患者中的用途。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.
本发明还提供在肿瘤患者中预测使用抗肿瘤剂的治疗效果的方法，所述抗肿瘤剂为本发明化合物或其药学上可接受的盐作为活性成分，该方法包括以下步骤(1)和(2)：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):
(1)检测从患者获得的生物样品中包含的EGFR基因的突变的存在与否的步骤；和(1) Steps to detect the presence or absence of the mutation of the EGFR gene contained in the biological sample obtained from the patient; and
(2)当步骤(1)中的检测结果发现EGFR基因具有选自外显子20***突变、外显子18点突变、外显子21点突变、外显子19缺失突变或L858R突变时，预测化学疗法极有可能对患者表现出足够的治疗效果的步骤。(2) When the test result in 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.
本发明还提供***患者的方法，该方法包括以下步骤(1)至(2)：The present invention also provides a method for treating tumor patients, the method comprising the following steps (1) to (2):
(1)检测从患者获得的生物样品中包含的EGFR基因的突变的存在与否步骤；(1) Steps to detect the presence or absence of the mutation of the EGFR gene contained in the biological sample obtained from the patient;
(2)当步骤(1)中的检测结果发现EGFR基因具有选自外显子20***突变、外显子18点突变、外显子21点突变、外显子19缺失突变或L858R突变时，使用本发明化合物或其药学上可接受的盐治疗该患者的步骤。(2) When the test result in 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.
在另一方面，本发明提供了一种治疗和/或预防受试者中的疾病，如野生的和/或突变的HER2激酶介导的肿瘤的方法，包括向所述受试者给药本发明化合物或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，或本发明药物组合物。In another aspect, 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 The compound of the invention or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, or the pharmaceutical composition of the invention.
在具体实施方案中，所述突变的HER2选自G309A突变型HER2、S310F突变型HER2、R678Q 突变型HER2、L775_T759缺失突变型HER2、D769H突变型HER2、V777L突变型HER2、V842I突变型HER2、R869C突变型HER2、L755S突变型HER2或ex20insYVMA突变型HER2。In a specific embodiment, 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.
在具体实施方案中，所述ex20insYVMA突变型HER2选自A775_G776insYVMA突变型HER2突变。In a specific embodiment, the ex20insYVMA mutant HER2 is selected from the group consisting of A775_G776insYVMA mutant HER2 mutations.
在本文中，“HER2”包括人或非人哺乳动物的HER2。并且，术语“HER2”包括亚型。As used herein, "HER2" includes HER2 of human or non-human mammals. Also, the term "HER2" includes subtypes.
本发明中，HER2激酶介导的肿瘤优选为具有HER2过量表达、HER2基因扩增或HER2突变的肿瘤。上述“肿瘤”没有特别限制，例如可以为头颈部癌、食管癌、胃癌、结肠癌、直肠癌、肝癌、胆囊-胆管癌、胆道癌、胰腺癌、肺癌、乳腺癌、卵巢癌、***、子宫癌、肾癌、膀胱癌、***癌、睾丸肿瘤、骨-软组织肉瘤、血液癌、多发性骨髓瘤、皮肤癌、脑肿瘤、间皮癌等。优选乳腺癌、胃癌、食管癌、卵巢癌、肺癌、食管癌、胆囊-胆管癌、胆道癌、膀胱癌、结肠癌，更优选乳腺癌、胃癌、食管癌、胆道癌、卵巢癌、肺癌、食管癌，进一步优选乳腺癌、胃癌、肺癌。In the present invention, 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. Preferably 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.
在本发明的治疗方法中，“有效量”指足以在需要所述治疗的个体中产生所需治疗益处的量或剂量。本发明化合物的有效量或剂量可通过常规方法(例如模型化、剂量递增或临床试验)以及常规因素(例如药物递送的模式或途径、药剂的药代动力学、感染的严重程度和过程、个体的健康状况和体重、和治疗医师的判断)来确定。示例性剂量是在每天约0.1mg到1g、或每天约1mg到50mg、或每天约50mg到250mg或每天约250mg到1g的范围内。总剂量可以按单一剂量或分开剂量单位(例如，BID、TID、QID)给药。In the treatment method of the present invention, "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).
在患者的疾病发生改善后，可调整剂量以便预防性或维持性治疗。例如，可根据症状将给药剂量或给药频率或二者降低到维持所需治疗或预防效应的量。当然，如果症状已减轻到适当程度，那么可停止治疗。然而，任一症状复发时，患者可能需要长期间歇治疗。患者还可需要长期缓慢治疗。After the patient's disease has improved, the dosage can be adjusted for preventive or maintenance treatment. For example, 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. Of course, if the symptoms have alleviated to an appropriate level, then treatment can be stopped. However, when either symptom recurs, the patient may require long-term intermittent treatment. Patients may also require long-term slow treatment.
药物组合物、制剂和试剂盒Pharmaceutical compositions, preparations and kits
在另一方面，本发明提供了药物组合物，其包含本发明化合物(还称为“活性组分”)和药学上可接受的赋形剂。在一些实施方案中，所述药物组合物包含有效量的活性组分。在一些实施方案中，所述药物组合物包含治疗有效量的活性组分。在一些实施方案中，所述药物组合物包含预防有效量的活性组分。In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition contains an effective amount of active ingredient. In some embodiments, the pharmaceutical composition includes a therapeutically effective amount of the active ingredient. In some embodiments, the pharmaceutical composition includes a prophylactically effective amount of the active ingredient.
用于本发明的药学上可接受的赋形剂是指不会破坏一起配制的化合物的药理学活性的无毒载剂、佐剂或媒剂。可以用于本发明组合物中的药学上可接受的载剂、佐剂或媒剂包括但不限于，离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白(如人类血清白蛋白)、缓冲物质(如磷酸盐)、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质(如硫酸鱼精蛋白)、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、硅胶、三硅酸镁、聚乙烯吡咯烷酮、基于纤维素的物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段聚合物、聚乙二醇以及羊毛脂。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, polyethylene glycol and lanolin.
本发明还包括试剂盒(例如，药物包装)。所提供的试剂盒可以包括本发明化合物、其它治疗剂，以及含有本发明化合物、其它治疗剂的第一和第二容器(例如，小瓶、安瓿瓶、瓶、注射器和/或可分散包装或其它合适的容器)。在一些实施方案中，提供的试剂盒还可以任选包括第三容器，其含有用于稀释或悬浮本发明化合物和/或其它治疗剂的药用赋形剂。在一些实施方案中，提供在第一容器和第二容器中的本发明化合物和其它治疗剂组合形成一个单位剂型。The present invention also includes 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). In some embodiments, 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. In some embodiments, 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.
本发明提供的药物组合物可以通过许多途径给药，包括但不限于：口服给药、肠胃外给药、吸入给药、局部给药、直肠给药、鼻腔给药、口腔给药、***给药、通过植入剂给药或其它给药方式。例如，本文使用的肠胃外给药包括皮下给药、皮内给药、静脉内给药、肌肉内给药、关节内给药、动脉内给药、滑膜腔内给药、胸骨内给药、脑脊髓膜内给药、病灶内给药、和颅内的注射或输液技术。The pharmaceutical composition provided by the present invention can be administered by many routes, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration Drugs, administration via implants or other modes of administration. For example, 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.
通常，给予有效量的本文所提供的化合物。按照有关情况，包括所治疗的病症、选择的给药途径、实际给予的化合物、个体患者的年龄、体重和响应、患者症状的严重程度，等等，可以由医生确定实际上给予的化合物的量。Generally, an effective amount of the compound provided herein is administered. According to the relevant circumstances, including the condition being treated, the route of administration chosen, the compound actually administered, the age, weight and response of the individual patient, the severity of the patient’s symptoms, etc., the doctor can determine the amount of the compound actually administered .
当用于预防本发明所述病症时，给予处于形成所述病症危险之中的受试者本文所提供的化合物，典型地基于医生的建议并在医生监督下给药，剂量水平如上所述。处于形成具体病症的危险之中的受试者，通常包括具有所述病症的家族史的受试者，或通过遗传试验或筛选确定尤其对形成所述病症敏感的那些受试者。When used to prevent the condition of the present invention, 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.
还可以长期给予本文所提供的药物组合物(“长期给药”)。长期给药是指在长时间内给予化合物或其药物组合物，例如，3个月、6个月、1年、2年、3年、5年等等，或者可无限期地持续给药，例如，受试者的余生。在一些实施方案中，长期给药意欲在长时间内在血液中提供所述化合物的恒定水平，例如，在治疗窗内。The pharmaceutical compositions provided herein can also be administered chronically ("long-term administration"). 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. In some embodiments, 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.
可以使用各种给药方法，进一步递送本发明的药物组合物。例如，在一些实施方案中，可以推注给药药物组合物，例如，为了使化合物在血液中的浓度快速提高至有效水平。推注剂量取决于活性组分的目标全身性水平，例如，肌内或皮下的推注剂量使活性组分缓慢释放，而直接递送至静脉的推注(例如，通过IV静脉滴注)能够更加快速地递送，使得活性组分在血液中的浓度快速升高至有效水平。在其它实施方案中，可以以持续输液形式给予药物组合物，例如，通过IV静脉滴注，从而在受试者身体中提供稳态浓度的活性组分。此外，在其它实施方案中，可以首先给予推注剂量的药物组合物，而后持续输液。Various administration methods can be used to further deliver the pharmaceutical composition of the present invention. For example, in some embodiments, 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. For example, 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. In other embodiments, 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. In addition, in other embodiments, a bolus dose of the pharmaceutical composition may be administered first, followed by continuous infusion.
口服组合物可以采用散装液体溶液或混悬剂或散装粉剂形式。然而，更通常，为了便于精确地剂量给药，以单位剂量形式提供所述组合物。术语“单位剂型”是指适合作为人类患者及其它哺乳动物的单元剂量的物理离散单位，每个单位包含预定数量的、适于产生所需要的治疗效果的活性物质与合适药学赋形剂。典型的单位剂量形式包括液体组合物的预装填的、预先测量的安瓿或注射器，或者在固体组合物情况下的丸剂、片剂、胶囊剂等。在这种组合物中，所述化合物通常为较少的组分(约0.1至约50重量％，或优选约1至约40重量％)，剩余部分为对于形成所需给药形式有用的各种载体或赋形剂以及加工助剂。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. The term "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. In this composition, 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.
对于口服剂量，代表性的方案是，每天一个至五个口服剂量，尤其是两个至四个口服剂量，典型地是三个口服剂量。使用这些剂量给药模式，每个剂量提供大约0.01至大约20mg/kg的本发明化合物，优选的剂量各自提供大约0.1至大约10mg/kg，尤其是大约1至大约5mg/kg。For oral doses, the representative regimen is one to five oral doses per day, especially two to four oral doses, typically three oral doses. Using these dosing modes, 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.
为了提供与使用注射剂量类似的血液水平，或比使用注射剂量更低的血液水平，通常选择透皮剂量，数量为大约0.01至大约20％重量，优选大约0.1至大约20％重量，优选大约0.1至大约10％重量，且更优选大约0.5至大约15％重量。In order to provide a blood level similar to or lower than the injected dose, 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.
从大约1至大约120小时，尤其是24至96小时，注射剂量水平在大约0.1mg/kg/小时至至少10mg/kg/小时的范围。为了获得足够的稳定状态水平，还可以给予大约0.1mg/kg至大约10mg/kg或更多的预载推注。对于40至80kg的人类患者来说，最大总剂量不能超过大约2g/天。From about 1 to about 120 hours, especially 24 to 96 hours, the injection dose level is in the range of about 0.1 mg/kg/hour to at least 10 mg/kg/hour. In order to obtain a sufficient steady-state level, a preload bolus of about 0.1 mg/kg to about 10 mg/kg or more can also be given. For human patients of 40 to 80 kg, the maximum total dose cannot exceed approximately 2 g/day.
适于口服给药的液体形式可包括合适的水性或非水载体以及缓冲剂、悬浮剂和分散剂、着色剂、调味剂，等等。固体形式可包括，例如，任何下列组份，或具有类似性质的化合物：粘合剂，例如，微晶纤维素、黄蓍胶或明胶；赋形剂，例如，淀粉或乳糖，崩解剂，例如，褐藻酸、Primogel或玉米淀粉；润滑剂，例如，硬脂酸镁；助流剂，例如，胶体二氧化硅；甜味剂，例如，蔗糖或糖精；或调味剂，例如，薄荷、水杨酸甲酯或橙味调味剂。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.
可注射的组合物典型地基于可注射用的无菌盐水或磷酸盐缓冲盐水，或本领域中已知的其它可注 射的赋形剂。如前所述，在这种组合物中，活性化合物典型地为较少的组分，经常为约0.05至10％重量，剩余部分为可注射的赋形剂等。Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art. As mentioned earlier, in such compositions, 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.
典型地将透皮组合物配制为含有活性组分的局部软膏剂或乳膏剂。当配制为软膏剂时，活性组分典型地与石蜡或可与水混溶的软膏基质组合。或者，活性组分可与例如水包油型乳膏基质一起配制为乳膏剂。这种透皮制剂是本领域中公知的，且通常包括用于提升活性组分或制剂的稳定的皮肤渗透的其它组份。所有这种已知的透皮制剂和组份包括在本发明提供的范围内。The transdermal composition is typically formulated as a topical ointment or cream containing the active ingredients. When formulated as an ointment, the active ingredient is typically combined with paraffin or a water-miscible ointment base. Alternatively, 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.
本发明化合物还可通过经皮装置给予。因此，经皮给药可使用贮存器(reservoir)或多孔膜类型、或者多种固体基质的贴剂实现。The compounds of the invention can also be administered via transdermal devices. Therefore, transdermal administration can be achieved using a reservoir or porous membrane type, or a variety of solid matrix patches.
用于口服给予、注射或局部给予的组合物的上述组份仅仅是代表性的。其它材料以及加工技术等阐述于Remington's Pharmaceutical Sciences,17th edition,1985,Mack Publishing Company,Easton,Pennsylvania的第8部分中，本文以引用的方式引入该文献。The above-mentioned components of the composition 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.
本发明化合物还可以以持续释放形式给予，或从持续释放给药***中给予。代表性的持续释放材料的描述可在Remington's Pharmaceutical Sciences中找到。The compounds of the present invention can also be administered in a sustained release form or from a sustained release drug delivery system. A description of representative sustained-release materials can be found in Remington's Pharmaceutical Sciences.
本发明还涉及本发明化合物的药学上可接受的制剂。在一个实施方案中，所述制剂包含水。在另一个实施方案中，所述制剂包含环糊精衍生物。最常见的环糊精为分别由6、7和8个α-1,4-连接的葡萄糖单元组成的α-、β-和γ-环糊精，其在连接的糖部分上任选包括一个或多个取代基，其包括但不限于：甲基化的、羟基烷基化的、酰化的和磺烷基醚取代。在一些实施方案中，所述环糊精为磺烷基醚β-环糊精，例如，磺丁基醚β-环糊精，也称作Captisol。参见，例如，U.S.5,376,645。在一些实施方案中，所述制剂包括六丙基-β-环糊精(例如，在水中，10-50％)。The invention also relates to pharmaceutically acceptable formulations of the compounds of the invention. In one embodiment, the formulation contains water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β- and γ-cyclodextrins composed of 6, 7 and 8 α-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. In some embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, for example, sulfobutyl ether β-cyclodextrin, also known as Captisol. See, for example, U.S. 5,376,645. In some embodiments, the formulation includes hexapropyl-β-cyclodextrin (e.g., 10-50% in water).
药物组合Drug combination
本文所述的本发明化合物可与一或多种其它活性成份组合用于药物组合物或方法中以治疗本文所述的疾病和病症。其它额外活性成份包括缓和治疗针对预期疾病靶标的不利效应的其它治疗剂或药剂。所述组合可用于增加功效，改善其它疾病症状，降低一或多种副作用，或降低本发明化合物的所需剂量。额外活性成份可调配成与本发明化合物分开的药物组合物或可与本发明化合物包括在单一药物组合物中。额外活性成份可与本发明化合物的给药同时、在其之前或在其之后给药。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. Other 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.
组合药剂包括那些已知或观察到在治疗本文所述疾病和病症中有效的活性成份，包括有效针对与疾病相关的另一靶标的那些。举例来说，本发明的组合物和制剂、以及治疗方法可进一步包含其它药物，例如其它可用于治疗或缓解目标疾病或相关症状或状况的药剂。对于癌症适应症来说，所述其它药剂包括(但不限于)激酶抑制剂，例如EGFR抑制剂(例如，埃罗替尼、吉非替尼(gefitinib))；Raf抑制剂(例如，维罗非尼(vemurafenib))、VEGFR抑制剂(例如，舒尼替尼(sunitinib))；标准化学治疗剂，例如烷基化剂、抗代谢物、抗肿瘤抗生素、拓扑异构酶抑制剂、铂药物、有丝***抑制剂、抗体、激素疗法或皮质类固醇。对于疼痛适应症来说，适宜的组合药剂包括消炎剂，例如NSAID。本发明的药物组合物可另外包含一或多种所述活性剂，并且治疗方法可另外包含给药有效量的一或多种所述活性剂。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. For example, 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. For cancer indications, 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. For pain indications, 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.
实施例Example
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件或按照制造厂商所建议的条件进行。除非另外说明，否则份数和百分比为重量份和重量百分比。The present invention will be further explained below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions in the following examples are usually carried out according to conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise specified, parts and percentages are parts by weight and percentages by weight.
通常，在制备流程中，各反应在惰性溶剂中，在室温至回流温度(如0℃～100℃，优选0℃～80 ℃)下进行。反应时间通常为0.1-60小时，优选地为0.5-24小时。Generally, in the preparation process, 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.
本文所用的缩写具有以下含义：The abbreviations used in this article have the following meanings:
Pd(PPh 3) 4：四(三苯基膦)钯 Pd(PPh 3 ) 4 : Tetra(triphenylphosphine) palladium
Na 2CO 3：碳酸钠 Na 2 CO 3 : Sodium carbonate
EDCI：1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐EDCI: 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride
HOBT：1-羟基苯并***HOBT: 1-Hydroxybenzotriazole
NIS：N-碘代丁二酰亚胺NIS: N-iodosuccinimide
DMF：N,N-二甲基甲酰胺DMF: N,N-Dimethylformamide
Pd(dppf)Cl 2：[1,1'-双(二苯基膦基)二茂铁]二氯化钯 Pd(dppf)Cl 2 : [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride
MTBE：甲基叔丁基醚MTBE: methyl tert-butyl ether
DME：乙二醇二甲醚DME: Ethylene Glycol Dimethyl Ether
NBS：N-溴代丁二酰亚胺NBS: N-Bromosuccinimide
Cbz：苄氧羰基Cbz: Benzyloxycarbonyl
TEA：三乙胺TEA: Triethylamine
DCM：二氯甲烷DCM: Dichloromethane
ACN：乙腈ACN: Acetonitrile
POCl 3：三氯氧磷 POCl 3 : Phosphorus oxychloride
tert-Butyl nitrite：亚硝酸叔丁酯tert-Butyl nitrite: tert-butyl nitrite
TPP：三苯基膦TPP: Triphenylphosphine
DIAD：偶氮二甲酸二异丙酯DIAD: Diisopropyl azodicarboxylate
NH 4OAc：乙酸铵 NH 4 OAc: Ammonium acetate
DMSO：二甲亚砜DMSO: Dimethyl sulfoxide
B 2pin 2：联硼酸频哪醇酯 B 2 pin 2 : pinacol diboronic acid ester
KOAc：乙酸钾KOAc: potassium acetate
Dioxane：二氧六环Dioxane: Dioxane
NaNO 2：亚硝酸钠 NaNO 2 : Sodium nitrite
EtOH：乙醇EtOH: ethanol
NaOH：氢氧化钠NaOH: Sodium hydroxide
DIPEA：N,N-二异丙基乙胺DIPEA: N,N-Diisopropylethylamine
TFAA：三氟乙酸酐TFAA: Trifluoroacetic anhydride
H 2O 2：双氧水 H 2 O 2 : hydrogen peroxide
DBU：1,8-二氮杂二环[5.4.0]十一碳-7-烯DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene
NaH：氢化钠NaH: Sodium hydride
THF：四氢呋喃THF: Tetrahydrofuran
i-PrOH：异丙醇i-PrOH: isopropanol
PtO 2：二氧化铂 PtO 2 ：platinum dioxide
EA：乙酸乙酯EA: ethyl acetate
EtOH：乙醇EtOH: ethanol
Tosmic：对甲基苯磺酰甲基异腈Tosmic: p-toluenesulfonyl methyl isonitrile
PdCl 2：二氯化钯 PdCl 2 : Palladium dichloride
TESiH：三乙基硅烷TESiH: Triethylsilane
NaIO 4：高碘酸钠 NaIO 4 : Sodium Periodate
中间体A1(R)-4-氨基-7-(1-(叔丁氧羰基)哌啶-3-基)-7H-吡咯并[2,3-d]嘧啶-5-甲酸的制备Preparation of intermediate A1(R)-4-amino-7-(1-(tert-butoxycarbonyl)piperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid
Figure PCTCN2021076684-appb-000031
Figure PCTCN2021076684-appb-000031
采用以下合成路线：The following synthetic route is adopted:
Figure PCTCN2021076684-appb-000032
Figure PCTCN2021076684-appb-000032
步骤1(R)-4-氨基-7-(1-(叔丁氧羰基)哌啶-3-基)-7H-吡咯并[2,3-d]嘧啶-5-甲酸2-(二乙基氨基)乙酯的合成Step 1 (R)-4-amino-7-(1-(tert-butoxycarbonyl)piperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid 2-(diethyl Synthesis of ethyl amino) ethyl ester
向配有磁力搅拌和冷凝管的50mL单口瓶中加入(R)-3-(4-氨基-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)哌啶-1-甲酸叔丁酯(500mg，1.13mmol)、2-(二乙基氨基)乙醇(660mg，5.64mmol)和NMP(10mL)，搅拌溶清，氮气氛下加入Pd(dppf)Cl 2(41mg，0.056mmol)，加毕，一氧化碳气球置换三次，一氧化碳气球氛下升温到120℃，并保温搅拌反应1.5小时。冷却到室温，加入水(50mL)和乙酸乙酯(50mL)，搅拌5分钟，分出有机相，水相乙酸乙酯萃取(40mL*2)，合并有机相，水洗(100mL*3)，饱和食盐水洗(40mL)，无水硫酸钠干燥，过滤，浓缩并过硅胶柱得淡黄色固体380mg，收率53.32％。LC-MS(APCI):m/z＝461.3(M+1) +. Add (R)-3-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1 to a 50mL single-mouth flask equipped with a magnetic stirring and condenser tube -Tert-butyl formate (500mg, 1.13mmol), 2-(diethylamino)ethanol (660mg, 5.64mmol) and NMP (10mL), stir to clear, add Pd(dppf)Cl 2 (41mg, 0.056mmol). After the addition, the carbon monoxide balloon was replaced three times, and the temperature was raised to 120° C. under the atmosphere of the carbon monoxide balloon, and the reaction was kept under stirring for 1.5 hours. Cool to room temperature, add water (50mL) and ethyl acetate (50mL), stir for 5 minutes, separate the organic phase, extract the aqueous phase with ethyl acetate (40mL*2), combine the organic phases, wash with water (100mL*3), and saturate It was washed with brine (40 mL), dried with anhydrous sodium sulfate, filtered, concentrated and passed through a silica gel column to obtain 380 mg of a pale yellow solid with a yield of 53.32%. LC-MS(APCI): m/z=461.3(M+1) + .
步骤2(R)-4-氨基-7-(1-(叔丁氧羰基)哌啶-3-基)-7H-吡咯并[2,3-d]嘧啶-5-甲酸(中间体A1)的合成Step 2 (R)-4-amino-7-(1-(tert-butoxycarbonyl)piperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (Intermediate A1) Synthesis
向配有磁力搅拌的50mL单口瓶中加入(R)-4-氨基-7-(1-(叔丁氧羰基)哌啶-3-基)-7H-吡咯并[2,3-d]嘧啶-5-甲酸2-(二乙基氨基)乙酯(377mg，0.82mmol)和THF(4mL)，搅拌溶清，滴加入氢氧化钠(262mg，6.55mmol)的水溶液(2mL)，滴毕，室温搅拌反应1小时。减压蒸除THF，加入水(5mL)，乙酸乙酯洗涤(10mL*1)，水相用2M盐酸调pH～4，析出大量白色固体，过滤，水洗(6mL)，溶于DCM(20mL)，无水硫酸钠干燥，过滤，减压浓缩至干得白色固体260mg，收率87.89％。LC-MS(APCI):m/z＝362.2(M+1) +. 1H NMR(300MHz,CDCl 3)δ11.85(s,1H),11.48(s,1H),8.08(s,1H),7.76(s,1H),4.73-4.64(m,1H),4.43-4.32(m,1H),4.16-4.10(m,1H),3.20-3.03(m,1H),2.88-2.81(m,1H),2.27-2.19(m,1H),2.05-1.98(m,2H),1.86-1.66(m,1H),1.48(s,9H). Add (R)-4-amino-7-(1-(tert-butoxycarbonyl)piperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine to a 50mL single-neck flask equipped with magnetic stirring 2-(diethylamino)ethyl -5-carboxylate (377mg, 0.82mmol) and THF (4mL), stir to dissolve, and add dropwise an aqueous solution (2mL) of sodium hydroxide (262mg, 6.55mmol). The reaction was stirred at room temperature for 1 hour. Distill THF off under reduced pressure, add water (5mL), wash with ethyl acetate (10mL*1), adjust the pH to 4 of the aqueous phase with 2M hydrochloric acid, precipitate a large amount of white solid, filter, wash with water (6mL), and dissolve in DCM (20mL) , Dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain 260 mg of white solid with a yield of 87.89%. LC-MS(APCI): m/z=362.2(M+1) + . 1 H NMR(300MHz,CDCl 3 )δ11.85(s,1H),11.48(s,1H),8.08(s,1H) ,7.76(s,1H),4.73-4.64(m,1H),4.43-4.32(m,1H),4.16-4.10(m,1H),3.20-3.03(m,1H),2.88-2.81(m, 1H), 2.27-2.19 (m, 1H), 2.05-1.98 (m, 2H), 1.86-1.66 (m, 1H), 1.48 (s, 9H).
中间体A2 4-氨基-7-(1-(叔丁氧羰基)哌啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-5-甲酸的制备Intermediate A2 Preparation of 4-amino-7-(1-(tert-butoxycarbonyl)piperidin-3-yl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxylic acid
Figure PCTCN2021076684-appb-000033
Figure PCTCN2021076684-appb-000033
采用以下合成路线：The following synthetic route is adopted:
Figure PCTCN2021076684-appb-000034
Figure PCTCN2021076684-appb-000034
步骤1 3-(4-氨基吡咯并[2,1-f][1,2,4]三嗪-7-基)-5,6-二氢吡啶-1(2H)-甲酸叔丁酯的合成Step 1 3-(4-Aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester synthesis
将4-氨基-7-溴吡咯并[2,1-f][1,2,4]三嗪(4.69g，13.6mmol)，3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-5,6-二氢吡啶-1(2H)-甲酸叔丁酯(5.04g，16.3mmol)，Pd(dppf)Cl 2(0.5g，0.68mmol)和碳酸钠(4.35g，41mmol)加入到70mL DME和15mL水中，氮气置换三次，升温至90℃反应过夜。将反应液冷却至室温，加入100mL水，用乙酸乙酯(60mL*3)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，经硅胶柱分离得淡黄色固体3.21g，收率75％。ESI-MS:316[M ++1]. The 4-amino-7-bromopyrrolo[2,1-f][1,2,4]triazine (4.69g, 13.6mmol), 3-(4,4,5,5-tetramethyl-1 ,3,2-Dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (5.04g, 16.3mmol), Pd(dppf)Cl 2 (0.5g, 0.68mmol) and sodium carbonate (4.35g, 41mmol) were added to 70mL DME and 15mL water, replaced with nitrogen three times, heated to 90°C and reacted overnight. The reaction solution was cooled to room temperature, 100 mL of water was added, and it was extracted with ethyl acetate (60 mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain 3.21 g of a pale yellow solid. The rate is 75%. ESI-MS:316[M + +1].
步骤2 3-(4-氨基吡咯并[2,1-f][1,2,4]三嗪-7-基)哌啶-1-甲酸叔丁酯的合成Step 2 Synthesis of tert-butyl 3-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate
将3-(4-氨基吡咯并[2,1-f][1,2,4]三嗪-7-基)-5,6-二氢吡啶-1(2H)-甲酸叔丁酯(3.21g，10.2mmol)溶于30mL无水乙醇中，加入300mg 10％钯碳，氢气置换三次，在一个大气压的氢气氛下搅拌过夜。反应完全后滤除钯碳，滤液浓缩，经硅胶柱分离得淡黄色油状物2.9g，收率90％。ESI-MS:318[M ++1]. The 3-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (3.21 g, 10.2 mmol) was dissolved in 30 mL of absolute ethanol, 300 mg of 10% palladium on carbon was added, hydrogen was replaced three times, and the mixture was stirred overnight under a hydrogen atmosphere of one atmosphere. After the reaction was completed, the palladium-carbon was filtered off, the filtrate was concentrated, and 2.9 g of light yellow oil was obtained through silica gel column separation, with a yield of 90%. ESI-MS:318[M + +1].
步骤3 3-(4-氨基-5-溴吡咯并[2,1-f][1,2,4]三嗪-7-基)哌啶-1-甲酸叔丁酯的合成Step 3 Synthesis of tert-butyl 3-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate
将3-(4-氨基吡咯并[2,1-f][1,2,4]三嗪-7-基)哌啶-1-甲酸叔丁酯(2.9g，9.16mmol)溶于30mL DMF中，冰浴下分批加入NBS(1.78g，10mmol)，自然升至室温反应过夜。反应完全后，向反应液中加入100mL水，用乙酸乙酯(40mL*3)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，经硅胶柱分离得淡黄色固体2.54g，收率70％。ESI-MS:398[M ++2]. Dissolve tert-butyl 3-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate (2.9g, 9.16mmol) in 30mL DMF In the middle, NBS (1.78g, 10mmol) was added in batches under ice bath, and the reaction was allowed to rise to room temperature overnight. After the reaction was completed, 100 mL of water was added to the reaction solution, extracted with ethyl acetate (40 mL*3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain 2.54 g of light yellow solid. The yield was 70%. ESI-MS:398[M + +2].
步骤4 4-氨基-7-(1-(叔丁氧羰基)哌啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-5-甲酸甲酯的合成Step 4 Synthesis of 4-amino-7-(1-(tert-butoxycarbonyl)piperidin-3-yl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxylic acid methyl ester
将3-(4-氨基-5-溴吡咯并[2,1-f][1,2,4]三嗪-7-基)哌啶-1-甲酸叔丁酯(1.58g，4mmol)，Pd(PPh 3) 2Cl 2(146mg，0.2mmol)和三乙胺(2.02g，20mmol)加入到20mL甲醇中，在一个大气压的一氧化碳气体氛下60℃反应过夜。将反应液冷却至室温，加入40mL水稀释，用乙酸乙酯(30mL*3)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，经硅胶柱分离得淡黄色固体940mg，收率62.7％。ESI-MS:376[M ++1]. The 3-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylic acid tert-butyl ester (1.58g, 4mmol), Pd(PPh 3 ) 2 Cl 2 (146 mg, 0.2 mmol) and triethylamine (2.02 g, 20 mmol) were added to 20 mL of methanol, and reacted overnight at 60° C. under a carbon monoxide atmosphere at one atmospheric pressure. The reaction solution was cooled to room temperature, diluted with 40 mL of water, and extracted with ethyl acetate (30 mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain 940 mg of light yellow solid. The rate is 62.7%. ESI-MS:376[M + +1].
步骤5 4-氨基-7-(1-(叔丁氧羰基)哌啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-5-甲酸(中间体A2)的合成Step 5 4-Amino-7-(1-(tert-butoxycarbonyl)piperidin-3-yl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxylic acid (Intermediate A2 )Synthesis
将4-氨基-7-(1-(叔丁氧羰基)哌啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-5-甲酸甲酯(937mg，2.5mmol)溶于15mL乙醇和5mL水中，加入氢氧化钠(252mg，6.3mmol)，室温反应过夜。向反应液中加 入30mL水稀释，用1N盐酸调节pH＝3-4，乙酸乙酯(30mL*3)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，经硅胶柱分离得淡黄色固体722mg，收率80％。ESI-MS:362[M ++1]. 4-amino-7-(1-(tert-butoxycarbonyl)piperidin-3-yl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxylic acid methyl ester (937mg, 2.5 mmol) was dissolved in 15 mL of ethanol and 5 mL of water, sodium hydroxide (252 mg, 6.3 mmol) was added, and the reaction was carried out at room temperature overnight. Add 30mL of water to the reaction solution to dilute, adjust the pH=3-4 with 1N hydrochloric acid, extract with ethyl acetate (30mL*3), wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, concentrate, and separate on a silica gel column. Light yellow solid 722mg, yield 80%. ESI-MS:362[M + +1].
中间体A3(R)-8-氨基-3-(1-(叔丁氧羰基)哌啶-3-基)咪唑并[1,5-a]吡嗪-1-甲酸的制备Preparation of intermediate A3(R)-8-amino-3-(1-(tert-butoxycarbonyl)piperidin-3-yl)imidazo[1,5-a]pyrazine-1-carboxylic acid
Figure PCTCN2021076684-appb-000035
Figure PCTCN2021076684-appb-000035
采用以下合成路线：The following synthetic route is adopted:
Figure PCTCN2021076684-appb-000036
Figure PCTCN2021076684-appb-000036
向反应瓶中加入(R)-3-(8-氨基-1-碘代咪唑并[1,5-α]吡嗪-3-基)哌啶-1-甲酸叔丁酯(0.8g，1.8mmol)、N,N-二乙基乙醇胺(1.06g，9.0mmol)、二(三苯基膦)二氯化钯(63mg，0.09mmol)和10ml无水NMP，充一氧化碳气球，升温至120℃搅拌反应1h，TLC检测反应完毕后降至室温，加入过量水稀释，用乙酸乙酯萃取3-4次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥后过滤浓缩得中间体粗品，直接投入到下一步。Add tert-butyl (R)-3-(8-amino-1-iodoimidazo[1,5-α]pyrazin-3-yl)piperidine-1-carboxylate (0.8g, 1.8 mmol), N,N-diethylethanolamine (1.06g, 9.0mmol), bis(triphenylphosphine) palladium dichloride (63mg, 0.09mmol) and 10ml anhydrous NMP, filled with carbon monoxide balloon, heated to 120℃ The reaction was stirred for 1 hour. After the reaction was detected by TLC, it was cooled to room temperature, diluted with excess water, extracted with ethyl acetate 3-4 times, combined the organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude intermediate. Go directly to the next step.
向上述中间体中加入10ml甲醇溶解，加入一水合氢氧化锂(226mg，5.39mmol)和2ml水，室温下搅拌反应1h，TLC监测反应完毕后，冰浴下用2N稀盐酸调PH至弱酸性，析出白色固体，过滤后真空干燥得到0.35g白色固体，收率：53.7％。LC-MS(APCI):m/z＝362.3(M+1) +。 Add 10ml methanol to the above intermediate to dissolve, add lithium hydroxide monohydrate (226mg, 5.39mmol) and 2ml water, stir the reaction at room temperature for 1h, TLC monitor the reaction is completed, use 2N dilute hydrochloric acid to adjust the PH to weak acidity under ice bath , A white solid precipitated, filtered and dried under vacuum to obtain 0.35 g of white solid, yield: 53.7%. LC-MS (APCI): m/z=362.3 (M+1) + .
中间体A4(R)-4-氨基-7-(1-((苄氧基)羰基)哌啶-3-基)咪唑并[5,1-f][1,2,4]三嗪-5-甲酸的制备Intermediate A4(R)-4-amino-7-(1-((benzyloxy)carbonyl)piperidin-3-yl)imidazo[5,1-f][1,2,4]triazine- Preparation of 5-formic acid
Figure PCTCN2021076684-appb-000037
Figure PCTCN2021076684-appb-000037
采用以下合成路线：The following synthetic route is adopted:
Figure PCTCN2021076684-appb-000038
Figure PCTCN2021076684-appb-000038
步骤1(R)-哌啶-1,3-二甲酸(1-苄基)(3-琥珀酰亚胺)酯的合成Step 1. Synthesis of (R)-piperidine-1,3-dicarboxylic acid (1-benzyl)(3-succinimide) ester
将(R)-1-((苄氧基)羰基)哌啶-3-甲酸(8g，30.4mmol)，N-羟基丁二酰亚胺(4.26g，37mmol)和三乙胺(6.14g，60.8mmol)溶于50mL二氯甲烷，冰浴下加入EDCI(8.68g，45.3mmol)，室温反应过夜。反应液加入50mL DCM稀释，水洗，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，经硅胶柱分离得淡黄色油状物10.15g，收率93％。ESI-MS:361[M ++1]. (R)-1-((benzyloxy)carbonyl)piperidine-3-carboxylic acid (8g, 30.4mmol), N-hydroxysuccinimide (4.26g, 37mmol) and triethylamine (6.14g, 60.8mmol) was dissolved in 50mL of dichloromethane, EDCI (8.68g, 45.3mmol) was added under ice bath, and reacted at room temperature overnight. The reaction solution was diluted with 50 mL of DCM, washed with water, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain 10.15 g of light yellow oil, with a yield of 93%. ESI-MS:361[M + +1].
步骤2(R)-3-(((3-氨基-5-氧代-4,5-二氢-1,2,4-三嗪-6-基)甲基)氨基甲酰基)哌啶-1-甲酸苄基酯的合成Step 2 (R)-3-(((3-Amino-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)methyl)carbamoyl)piperidine- Synthesis of benzyl 1-formate
将(R)-哌啶-1,3-二甲酸(1-苄基)(3-琥珀酰亚胺)酯(10.15g，28.2mmol)和3-氨基-6-(氨基甲基)-1,2,4-三嗪-5(4H)-酮乙酸盐(5.67g，28.2mmol)溶于100mL乙腈，加入三乙胺(8.54g，84.6mmol)，升温至50℃反应过夜。反应冷却后加入150mL水稀释，用乙酸乙酯(80mL*3)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，经硅胶柱分离得淡黄色固体8.07g，收率74％。ESI-MS:387[M ++1]. Combine (R)-piperidine-1,3-dicarboxylic acid (1-benzyl)(3-succinimide) ester (10.15g, 28.2mmol) and 3-amino-6-(aminomethyl)-1 2,4-Triazine-5(4H)-one acetate (5.67g, 28.2mmol) was dissolved in 100mL of acetonitrile, triethylamine (8.54g, 84.6mmol) was added, and the temperature was raised to 50°C to react overnight. After the reaction was cooled, diluted with 150 mL of water, extracted with ethyl acetate (80 mL*3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain 8.07 g of light yellow solid, the yield was 74% . ESI-MS:387[M + +1].
步骤3(R)-3-(2-氨基-4-氧代-3,4-二氢咪唑并[5,1-f][1,2,4]三嗪-7-基)哌啶-1-甲酸苄基酯的合成Step 3 (R)-3-(2-Amino-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-7-yl)piperidine- Synthesis of benzyl 1-formate
将(R)-3-(((3-氨基-5-氧代-4,5-二氢-1,2,4-三嗪-6-基)甲基)氨基甲酰基)哌啶-1-甲酸苄基酯(8.07g，20.9mmol)溶于80mL乙腈，缓慢加入三氯氧磷(6.4g，41.8mmol)，升温至60℃反应过夜。反应液冷却后用水淬灭，2N氢氧化钠溶液调节pH＝7，用乙酸乙酯(60mL*3)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，经硅胶柱分离得淡黄色固体5.78g，收率75.2％。ESI-MS:369[M ++1]. (R)-3-(((3-Amino-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)methyl)carbamoyl)piperidine-1 -Benzyl formate (8.07 g, 20.9 mmol) was dissolved in 80 mL of acetonitrile, phosphorus oxychloride (6.4 g, 41.8 mmol) was slowly added, and the temperature was raised to 60° C. to react overnight. The reaction solution was cooled and quenched with water, adjusted to pH=7 with 2N sodium hydroxide solution, extracted with ethyl acetate (60mL*3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column. Pale yellow solid 5.78g, yield 75.2%. ESI-MS:369[M + +1].
步骤4(R)-3-(2-氨基-5-溴-4-氧代-3,4-二氢咪唑并[5,1-f][1,2,4]三嗪-7-基)哌啶-1-甲酸苄基酯的合成Step 4 (R)-3-(2-Amino-5-bromo-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-7-yl ) Synthesis of benzyl piperidine-1-carboxylate
将(R)-3-(2-氨基-4-氧代-3,4-二氢咪唑并[5,1-f][1,2,4]三嗪-7-基)哌啶-1-甲酸苄基酯(5.78g，15.7mmol)溶于40mL DMF中，冰浴下分批加入NBS(2.94g，16.5mmol)，自然升至室温反应过夜。反应完全后，向反应液中加入100mL水，用乙酸乙酯(50mL*3)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，经硅胶柱分离得淡黄色固体5.77g，收率82％。ESI-MS:449[M ++2]. (R)-3-(2-Amino-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-7-yl)piperidine-1 -Benzyl formate (5.78 g, 15.7 mmol) was dissolved in 40 mL DMF, NBS (2.94 g, 16.5 mmol) was added in batches under ice bath, and the reaction was allowed to rise to room temperature overnight. After the reaction was completed, 100 mL of water was added to the reaction solution, extracted with ethyl acetate (50 mL*3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain 5.77 g of pale yellow solid. The yield was 82%. ESI-MS:449[M + +2].
步骤5(R)-3-(5-溴-4-氧代-3,4-二氢咪唑并[5,1-f][1,2,4]三嗪-7-基)哌啶-1-甲酸苄基酯的合成Step 5 (R)-3-(5-Bromo-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-7-yl)piperidine- Synthesis of benzyl 1-formate
将(R)-3-(2-氨基-5-溴-4-氧代-3,4-二氢咪唑并[5,1-f][1,2,4]三嗪-7-基)哌啶-1-甲酸苄基酯(5.77g，12.9mmol)溶于50mL四氢呋喃，缓慢加入亚硝酸叔丁酯(2g，19.4mmol)，升温至60℃反应3 小时。反应完全后加入100mL水稀释，用乙酸乙酯(100mL*3)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，经硅胶柱分离得淡黄色固体4.79g，收率86％。ESI-MS:434[M ++2]. (R)-3-(2-Amino-5-bromo-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-7-yl) Benzyl piperidine-1-carboxylate (5.77 g, 12.9 mmol) was dissolved in 50 mL of tetrahydrofuran, tert-butyl nitrite (2 g, 19.4 mmol) was slowly added, and the temperature was raised to 60° C. to react for 3 hours. After the reaction was completed, it was diluted with 100 mL of water, extracted with ethyl acetate (100 mL*3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain 4.79 g of light yellow solid, with a yield of 86% . ESI-MS:434[M + +2].
步骤6(R)-3-(4-氨基-5-溴咪唑并[5,1-f][1,2,4]三嗪-7-基)哌啶-1-甲酸苄基酯的合成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
将(R)-3-(5-溴-4-氧代-3,4-二氢咪唑并[5,1-f][1,2,4]三嗪-7-基)哌啶-1-甲酸苄基酯(4.79g，11.1mmol)和1,2,4-三氮唑(2.3g，33.3mmol)溶于40mL吡啶中，冰浴下缓慢滴加三氯氧磷(5.1g，33.3mmol)，滴加完毕移至室温反应2小时。冰浴下向反应液中缓慢滴加氨-乙醇溶液(15mL，7mol/L)，滴加完毕室温搅拌2小时。TLC检测反应完全，反应液加水淬灭，用乙酸乙酯(80mL*3)萃取，有机相用2N盐酸洗至pH＝5-6，然后经饱和食盐水洗涤，无水硫酸钠干燥，浓缩，硅胶柱分离得淡黄色固体3.6g，收率75.5％。ESI-MS:433[M ++2]. (R)-3-(5-Bromo-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-7-yl)piperidine-1 -Benzyl formate (4.79g, 11.1mmol) and 1,2,4-triazole (2.3g, 33.3mmol) were dissolved in 40mL pyridine, and phosphorus oxychloride (5.1g, 33.3 mmol), after the addition, move to room temperature and react for 2 hours. An ammonia-ethanol solution (15 mL, 7 mol/L) was slowly added dropwise to the reaction solution under an ice bath, and the addition was completed and stirred at room temperature for 2 hours. TLC detected the completion of the reaction, the reaction solution was quenched with water, extracted with ethyl acetate (80mL*3), the organic phase was washed with 2N hydrochloric acid to pH=5-6, then washed with saturated brine, dried with anhydrous sodium sulfate, and concentrated. The silica gel column separated 3.6 g of a light yellow solid with a yield of 75.5%. ESI-MS:433[M + +2].
步骤7(R)-4-氨基-7-(1-((苄氧基)羰基)哌啶-3-基)咪唑并[5,1-f][1,2,4]三嗪-5-甲酸甲酯的合成Step 7 (R)-4-amino-7-(1-((benzyloxy)carbonyl)piperidin-3-yl)imidazo[5,1-f][1,2,4]triazine-5 -Synthesis of methyl formate
将(R)-3-(4-氨基-5-溴咪唑并[5,1-f][1,2,4]三嗪-7-基)哌啶-1-甲酸苄基酯(700mg，1.62mmol)，Pd(PPh 3) 2Cl 2(60mg，0.08mmol)和三乙胺(818mg，8.1mmol)加入到20mL甲醇中，在一个大气压的一氧化碳气体氛下60℃反应过夜。将反应液冷却至室温，加入30mL水稀释，用乙酸乙酯(20mL*3)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，经硅胶柱分离得淡黄色固体414mg，收率62％。ESI-MS:411[M ++1]. (R)-3-(4-Amino-5-bromoimidazo[5,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylic acid benzyl ester (700mg, 1.62 mmol), Pd(PPh 3 ) 2 Cl 2 (60 mg, 0.08 mmol) and triethylamine (818 mg, 8.1 mmol) were added to 20 mL of methanol, and reacted overnight at 60°C under a carbon monoxide atmosphere at one atmospheric pressure. The reaction solution was cooled to room temperature, diluted with 30 mL of water, and extracted with ethyl acetate (20 mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated on a silica gel column to obtain 414 mg of a pale yellow solid. The rate is 62%. ESI-MS:411[M + +1].
步骤8(R)-4-氨基-7-(1-((苄氧基)羰基)哌啶-3-基)咪唑并[5,1-f][1,2,4]三嗪-5-甲酸(中间体A4)的合成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)
将(R)-4-氨基-7-(1-((苄氧基)羰基)哌啶-3-基)咪唑并[5,1-f][1,2,4]三嗪-5-甲酸甲酯(414mg，1.01mmol)溶于15mL乙醇和10mL水中，加入氢氧化钠(100mg，2.5mmol)，室温反应过夜。向反应液中加入30mL水稀释，用1N盐酸调节pH＝3-4，乙酸乙酯(30mL*3)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，经硅胶柱分离得淡黄色固体325mg，收率81％。ESI-MS:397[M ++1]. (R)-4-amino-7-(1-((benzyloxy)carbonyl)piperidin-3-yl)imidazo[5,1-f][1,2,4]triazine-5- Methyl formate (414 mg, 1.01 mmol) was dissolved in 15 mL of ethanol and 10 mL of water, sodium hydroxide (100 mg, 2.5 mmol) was added, and the reaction was carried out at room temperature overnight. Add 30mL of water to the reaction solution to dilute, adjust the pH=3-4 with 1N hydrochloric acid, extract with ethyl acetate (30mL*3), wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, concentrate, and separate on a silica gel column. Light yellow solid 325mg, yield 81%. ESI-MS:397[M + +1].
中间体B1 2-(4-氨基苯基)-N,N-二甲基乙酰胺的制备Intermediate B1 Preparation of 2-(4-aminophenyl)-N,N-dimethylacetamide
Figure PCTCN2021076684-appb-000039
Figure PCTCN2021076684-appb-000039
采用以下合成路线：The following synthetic route is adopted:
Figure PCTCN2021076684-appb-000040
Figure PCTCN2021076684-appb-000040
步骤1N,N-二甲基-2-(4-硝基苯基)乙酰胺的合成Step 1 Synthesis of N,N-dimethyl-2-(4-nitrophenyl)acetamide
依次往配有磁力搅拌的50mL三口烧瓶中加入2-(4-硝基苯基)乙酸(2.0g，11.04mmol)、无水DCM(20mL)和无水DMF(0.2mL)，搅拌溶清，冷却到0℃，氮气氛下缓慢滴加入草酰氯(1.54g，12.14mmol)，滴毕，拆去冰浴，室温下搅拌反应1小时。再次冷却到0℃，缓慢滴加入二甲胺(2M四氢呋喃溶液，11.0mL，22.08mmol)，室温搅拌反应半小时。加入水(30mL)和二氯甲烷(30mL)淬灭反应，分出有机层，水相二氯甲烷萃取(30mLx2)，合并有机相，无水硫酸钠干燥，过滤，浓缩并过硅胶柱得白色固体2.1g，收率91.35％。LC-MS(APCI):m/z＝209.2(M+1) +. Add 2-(4-nitrophenyl)acetic acid (2.0g, 11.04mmol), anhydrous DCM (20mL) and anhydrous DMF (0.2mL) to a 50mL three-necked flask equipped with magnetic stirring, and stir to clear. After cooling to 0°C, oxalyl chloride (1.54 g, 12.14 mmol) was slowly added dropwise under nitrogen atmosphere, after the dropping, the ice bath was removed, and the reaction was stirred at room temperature for 1 hour. It was cooled to 0°C again, dimethylamine (2M tetrahydrofuran solution, 11.0 mL, 22.08 mmol) was slowly added dropwise, and the reaction was stirred at room temperature for half an hour. The reaction was quenched by adding water (30mL) and dichloromethane (30mL), the organic layer was separated, the aqueous phase was extracted with dichloromethane (30mLx2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated and passed through a silica gel column to obtain white Solid 2.1g, yield 91.35%. LC-MS(APCI): m/z＝209.2(M+1) + .
步骤2 2-(4-氨基苯基)-N,N-二甲基乙酰胺(中间体B1)的合成Step 2 Synthesis of 2-(4-aminophenyl)-N,N-dimethylacetamide (Intermediate B1)
向配有磁力搅拌的50mL单口烧瓶中加入N,N-二甲基-2-(4-硝基苯基)乙酰胺(2.1g，10.1mmol)和甲醇(20mL)，搅拌溶清，加入Pd/C(10％，210mg)，抽真空并氢气置换三次，氢气球氛下室 温搅拌反应过夜。加入二氯甲烷(30mL)稀释反应液，滤除催化剂，滤液浓缩至干得棕色固体1.7g，收率94.6％，LC-MS(APCI):m/z＝179.1(M+1) +. Add N,N-dimethyl-2-(4-nitrophenyl)acetamide (2.1g, 10.1mmol) and methanol (20mL) into a 50mL single-necked flask equipped with magnetic stirring. Stir to clear and add Pd /C (10%, 210mg), evacuated and replaced with hydrogen three times, stirred at room temperature under a hydrogen balloon atmosphere and reacted overnight. Dichloromethane (30mL) was added to dilute the reaction solution, the catalyst was filtered off, and the filtrate was concentrated to dryness to obtain a brown solid 1.7g. The yield was 94.6%. LC-MS (APCI): m/z=179.1(M+1) + .
中间体B2 2-(4-氨基-2,3-二甲基苯基)-N,N-二甲基乙酰胺的制备Intermediate B2 Preparation of 2-(4-amino-2,3-dimethylphenyl)-N,N-dimethylacetamide
Figure PCTCN2021076684-appb-000041
Figure PCTCN2021076684-appb-000041
采用以下合成路线：The following synthetic route is adopted:
Figure PCTCN2021076684-appb-000042
Figure PCTCN2021076684-appb-000042
步骤1 2-(2,3-二甲基-4-硝基苯基)丙二酸二乙酯的合成Step 1 Synthesis of diethyl 2-(2,3-dimethyl-4-nitrophenyl)malonate
向反应瓶中加入丙二酸二乙酯(1.89g，11.82mmol)，加入10ml无水DMSO，分批加入叔丁醇钠，室温下搅拌反应10分钟，再缓慢滴加2,3-二甲基-4-氟硝基苯(1.0g，5.91mmol)的10ml无水DMSO溶液，加毕，升温至80℃反应过夜，TLC监测反应完毕后降至室温，加入过量水稀释，用乙酸乙酯萃取3-4次，合并有机相，饱和食盐水洗涤，浓缩后硅胶柱层析纯化得到1.08g产物，收率：59.1％。LC-MS(APCI):m/z＝310.1(M+1) +。 Add diethyl malonate (1.89g, 11.82mmol) to the reaction flask, add 10ml of anhydrous DMSO, add sodium tert-butoxide in batches, stir at room temperature for 10 minutes, and then slowly add 2,3-dimethyl 4-fluoronitrobenzene (1.0g, 5.91mmol) in 10ml anhydrous DMSO solution. After the addition, the temperature was raised to 80°C and reacted overnight. After the reaction was monitored by TLC, the reaction was reduced to room temperature, and excess water was added to dilute with ethyl acetate. Extract 3-4 times, combine the organic phases, wash with saturated brine, concentrate and purify by silica gel column chromatography to obtain 1.08 g of product, yield: 59.1%. LC-MS (APCI): m/z=310.1 (M+1) + .
步骤2 2-(2,3-二甲基-4-硝基苯基)乙酸的合成Step 2 Synthesis of 2-(2,3-dimethyl-4-nitrophenyl)acetic acid
向反应瓶中加入2-(2,3-二甲基-4-硝基苯基)丙二酸二乙酯(30.93g，0.1mol)、用150ml甲醇溶解，加入氢氧化钠(14.8g，0.37mol)的74ml水溶液，加热至80℃反应3-5小时，TLC监测反应完毕，降温至0℃，浓缩除去甲醇，冰浴下用2N稀盐酸调pH至弱酸性，析出白色固体，过滤，滤饼用冰水洗涤，真空干燥得到16.23g产物，收率：77.6％。LC-MS(APCI):m/z＝210.5(M+1) +。 Add 2-(2,3-dimethyl-4-nitrophenyl) diethyl malonate (30.93g, 0.1mol) to the reaction flask, dissolve it with 150ml methanol, and add sodium hydroxide (14.8g, 0.37mol) 74ml aqueous solution, heated to 80°C and reacted for 3-5 hours, TLC monitored the reaction to complete, cooled to 0°C, concentrated to remove methanol, adjusted the pH to weak acidity with 2N dilute hydrochloric acid under ice bath, precipitated a white solid, filtered, The filter cake was washed with ice water and dried under vacuum to obtain 16.23 g of product, with a yield of 77.6%. LC-MS (APCI): m/z=210.5(M+1) + .
步骤3 2-(2,3-二甲基-4-硝基苯基)-N,N-二甲基乙酰胺的合成Step 3 Synthesis of 2-(2,3-dimethyl-4-nitrophenyl)-N,N-dimethylacetamide
向反应瓶中加入2-(2,3-二甲基-4-硝基苯基)乙酸(16.23g，77.6mmol)，加入150ml DCM，加入草酰氯(17.7g，140mmol)，再加入催化量的无水DMF(0.5ml)，氮气保护下室温搅拌反应2-3h，TLC监测反应完毕后浓缩除去溶剂和过量的草酰氯，再加入100ml无水DCM溶解，氮气保护下降温至0℃，缓慢滴加2M的二甲胺的四氢呋喃溶液(194ml，388mmol)，加毕，室温搅拌反应1小时，TLC监测反应完毕后，加入50ml二氯甲烷稀释，依次用1N稀盐酸、饱和碳酸氢钠、水和饱和食盐水洗涤，浓缩后硅胶柱层析纯化得到白色固体15.6g，收率：85.2％。LC-MS(APCI):m/z＝237.6(M+1) +。 Add 2-(2,3-dimethyl-4-nitrophenyl)acetic acid (16.23g, 77.6mmol) to the reaction flask, add 150ml DCM, add oxalyl chloride (17.7g, 140mmol), and add a catalytic amount Anhydrous DMF (0.5ml), the reaction was stirred at room temperature for 2-3h under nitrogen protection. After the reaction was monitored by TLC, the reaction was concentrated to remove the solvent and excess oxalyl chloride, and then 100ml of anhydrous DCM was added to dissolve, and the temperature was reduced to 0℃ under nitrogen protection. 2M dimethylamine in tetrahydrofuran solution (194ml, 388mmol) was added dropwise. After the addition was completed, the reaction was stirred at room temperature for 1 hour. After the reaction was monitored by TLC, 50ml of dichloromethane was added to dilute, followed by 1N dilute hydrochloric acid, saturated sodium bicarbonate, and water. It was washed with saturated brine, concentrated and purified by silica gel column chromatography to obtain 15.6 g of white solid, yield: 85.2%. LC-MS (APCI): m/z=237.6(M+1) + .
步骤4 2-(4-氨基-2,3-二甲基苯基)-N,N-二甲基乙酰胺(中间体B2)的合成Step 4 Synthesis of 2-(4-amino-2,3-dimethylphenyl)-N,N-dimethylacetamide (Intermediate B2)
向反应瓶中加入2-(2,3-二甲基-4-硝基苯基)-N,N-二甲基乙酰胺(15.6g，66mmol)，用150ml甲醇溶解，加入催化量的钯碳，充氢气球，室温下搅拌反应3-5h，TLC监测反应完毕后过滤除去钯碳，滤饼用甲醇洗涤3-4次，合并有机相，浓缩后硅胶柱层析纯化得到12.4g白色固体，收率91％。LC-MS(APCI):m/z＝207.3(M+1) +。 Add 2-(2,3-dimethyl-4-nitrophenyl)-N,N-dimethylacetamide (15.6g, 66mmol) to the reaction flask, dissolve it with 150ml methanol, and add a catalytic amount of palladium Carbon, filled with hydrogen balloon, stirred at room temperature for 3-5h, TLC monitored the reaction to remove palladium-carbon by filtration, the filter cake was washed 3-4 times with methanol, combined the organic phases, concentrated and purified by silica gel column chromatography to obtain 12.4g of white solid , The yield is 91%. LC-MS (APCI): m/z=207.3(M+1) + .
实施例1(R)-7-(1-丙烯酰基哌啶-3-基)-4-氨基-N-(4-(2-(二甲基氨基)-2-氧代乙基)苯基)-7H-吡咯并Example 1 (R)-7-(1-acryloylpiperidin-3-yl)-4-amino-N-(4-(2-(dimethylamino)-2-oxoethyl)phenyl )-7H-pyrrolo [2,3-d]嘧啶-5-甲酰胺的制备Preparation of [2,3-d]pyrimidine-5-carboxamide
Figure PCTCN2021076684-appb-000043
Figure PCTCN2021076684-appb-000043
采用以下合成路线：The following synthetic route is adopted:
Figure PCTCN2021076684-appb-000044
Figure PCTCN2021076684-appb-000044
步骤1(R)-3-(4-氨基-5-((4-(2-(二甲基氨基)-2-氧代乙基)苯基)氨基甲酰基)-7H-吡咯并[2,3-d]嘧啶-7-基)哌啶-1-甲酸叔丁酯的合成Step 1 (R)-3-(4-amino-5-((4-(2-(dimethylamino)-2-oxoethyl)phenyl)carbamoyl)-7H-pyrrolo[2 Synthesis of tert-butyl ,3-d)pyrimidin-7-yl)piperidine-1-carboxylate
向配有磁力搅拌的50mL单口瓶中加入中间体A1(140mg，0.38mmol)、中间体B1(69mg，0.38mmol)、DIPEA(150mg，1.16mmol)和无水DMF(3mL)，搅拌溶清，冷却到0℃，氮气氛下加入HATU(221mg，0.58mmol)，加毕，氮气氛下室温搅拌反应2小时。加入水(20mL)和乙酸乙酯(20mL)，分出有机相，水相乙酸乙酯萃取(20mLx2)，合并有机相，饱和食盐水洗涤(50mLx3)，无水硫酸钠干燥，过滤，浓缩并过硅胶柱得白色固体130mg，收率62.85％。LC-MS(APCI):m/z＝522.2(M+1) +. 1H NMR(400MHz,CDCl 3)δ8.38(s,1H),8.30(s,1H),7.78(s,1H),7.47(d,J＝8.4Hz,2H),7.22(d,J＝8.4Hz,2H),7.13(s,2H),4.78-4.66(m,1H),4.20-4.17(m,1H),4.05-2.88(m,1H),3.72(s,2H),3.39-3.22(m,1H),3.08-2.98(m,7H),2.23-2.15(m,2H),1.78-1.63(m,2H),1.48(s,9H). Add Intermediate A1 (140mg, 0.38mmol), Intermediate B1 (69mg, 0.38mmol), DIPEA (150mg, 1.16mmol) and anhydrous DMF (3mL) to a 50mL single-neck flask equipped with magnetic stirring, and stir to dissolve. After cooling to 0°C, HATU (221 mg, 0.58 mmol) was added under nitrogen atmosphere. After the addition, the reaction was stirred at room temperature under nitrogen atmosphere for 2 hours. Add water (20mL) and ethyl acetate (20mL), separate the organic phase, extract the aqueous phase with ethyl acetate (20mLx2), combine the organic phases, wash with saturated brine (50mLx3), dry with anhydrous sodium sulfate, filter, concentrate and After passing through a silica gel column, 130 mg of a white solid was obtained, with a yield of 62.85%. LC-MS(APCI): m/z=522.2(M+1) + . 1 H NMR(400MHz,CDCl 3 )δ8.38(s,1H),8.30(s,1H),7.78(s,1H) ,7.47(d,J=8.4Hz,2H),7.22(d,J=8.4Hz,2H),7.13(s,2H),4.78-4.66(m,1H),4.20-4.17(m,1H), 4.05-2.88 (m, 1H), 3.72 (s, 2H), 3.39-3.22 (m, 1H), 3.08-2.98 (m, 7H), 2.23-2.15 (m, 2H), 1.78-1.63 (m, 2H) ), 1.48(s, 9H).
步骤2(R)-4-氨基-N-(4-(2-(二甲基氨基)-2-氧代乙基)苯基)-7-(哌啶-3-基)-7H-吡咯并[2,3-d]嘧啶-5-甲酰胺的合成Step 2 (R)-4-amino-N-(4-(2-(dimethylamino)-2-oxoethyl)phenyl)-7-(piperidin-3-yl)-7H-pyrrole Synthesis of and [2,3-d]pyrimidine-5-carboxamide
向配有磁力搅拌的25mL单口瓶中加入(R)-3-(4-氨基-5-((4-(2-(二甲基氨基)-2-氧代乙基)苯基)氨基甲酰基)-7H-吡咯并[2,3-d]嘧啶-7-基)哌啶-1-甲酸叔丁酯(130mg，0.58mmol)和DCM(3mL)，加入三氟醋酸(1mL)，氮气氛下室温搅拌反应2小时。减压浓缩至干，加入DCM(10mL)和饱和碳酸氢钠水溶液(10mL)，分出有机相，水相DCM萃取(20mLx2)，合并有机相，无水硫酸钠干燥，过滤，浓缩至干得棕色固体102mg，收率99.4％。LC-MS(APCI):m/z＝422.2(M+1) +. Add (R)-3-(4-amino-5-((4-(2-(dimethylamino)-2-oxoethyl)phenyl)aminomethyl into a 25mL single-neck flask equipped with magnetic stirring Acyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylic acid tert-butyl ester (130mg, 0.58mmol) and DCM (3mL), add trifluoroacetic acid (1mL), nitrogen The reaction was stirred at room temperature under atmosphere for 2 hours. Concentrate to dryness under reduced pressure, add DCM (10mL) and saturated aqueous sodium bicarbonate (10mL), separate the organic phase, extract the aqueous phase with DCM (20mLx2), combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate to dryness. 102 mg of brown solid, yield 99.4%. LC-MS(APCI): m/z=422.2(M+1) + .
步骤3(R)-7-(1-丙烯酰基哌啶-3-基)-4-氨基-N-(4-(2-(二甲基氨基)-2-氧代乙基)苯基)-7H-吡咯并[2,3-d]嘧啶-5-甲酰胺的合成Step 3 (R)-7-(1-acryloylpiperidin-3-yl)-4-amino-N-(4-(2-(dimethylamino)-2-oxoethyl)phenyl) Synthesis of -7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
(R)-4-氨基-N-(4-(2-(二甲基氨基)-2-氧代乙基)苯基)-7-(哌啶-3-基)-7H-吡咯并[2,3-d]嘧啶-5-甲酰胺(102mg，0.24mmol)溶于乙腈(4mL)和水(3mL)中，加入三乙胺(60mg，0.6mmol),冷却到0℃，氮气氛下缓慢滴加丙烯酰氯(22mg，0.24mmol)的乙腈溶液(1mL)，滴毕，保温0℃ 搅拌反应1小时。加入饱和碳酸氢钠水溶液(10mL)和乙酸乙酯(20mL)，搅拌5分钟，分出有机相，水相乙酸乙酯萃取(15mLx2)，合并有机相，无水硫酸钠干燥，过滤，浓缩并过硅胶柱得淡黄色固体40mg，收率34.76％。LC-MS(APCI):m/z＝476.2(M+1) +. 1H NMR(300MHz,CDCl 3)δ8.66-8.63(m,1H),8.25(s,1H),7.90-7.77(m,1H),7.48(d,J＝8.1Hz,2H),7.25-7.18(m,4H),6.60-6.58(m,1H),6.36-6.33(m,1H),5.75-5.72(m,1H),4.62-4.55(m,2H),3.70(s,2H),3.00-2.75(m,2H),3.05(s,3H),2.98(s,3H),2.96-2.85(m,1H),2.30-2.20(m,2H),1.90-1.84(m,2H). (R)-4-amino-N-(4-(2-(dimethylamino)-2-oxoethyl)phenyl)-7-(piperidin-3-yl)-7H-pyrrolo[ 2,3-d]pyrimidine-5-carboxamide (102mg, 0.24mmol) was dissolved in acetonitrile (4mL) and water (3mL), added with triethylamine (60mg, 0.6mmol), cooled to 0℃, under nitrogen atmosphere Acrylic acid chloride (22 mg, 0.24 mmol) in acetonitrile (1 mL) was slowly added dropwise, and after the dripping was completed, the reaction was stirred at 0° C. for 1 hour. Add saturated aqueous sodium bicarbonate (10mL) and ethyl acetate (20mL), stir for 5 minutes, separate the organic phase, extract the aqueous phase with ethyl acetate (15mLx2), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate and After passing through a silica gel column, 40 mg of a pale yellow solid was obtained, with a yield of 34.76%. LC-MS(APCI): m/z=476.2(M+1) + . 1 H NMR(300MHz, CDCl 3 )δ8.66-8.63(m,1H), 8.25(s,1H), 7.90-7.77( m,1H),7.48(d,J=8.1Hz,2H),7.25-7.18(m,4H),6.60-6.58(m,1H),6.36-6.33(m,1H),5.75-5.72(m, 1H),4.62-4.55(m,2H),3.70(s,2H),3.00-2.75(m,2H),3.05(s,3H),2.98(s,3H),2.96-2.85(m,1H) , 2.30-2.20 (m, 2H), 1.90-1.84 (m, 2H).
实施例2(R)-7-(1-丙烯酰基哌啶-3-基)-4-氨基-N-(4-(2-(二甲基氨基)-2-氧代乙基)-2,3-二甲基苯Example 2 (R)-7-(1-acryloylpiperidin-3-yl)-4-amino-N-(4-(2-(dimethylamino)-2-oxoethyl)-2 ,3-Dimethylbenzene 基)-7H-吡咯并[2,3-d]嘧啶-5-甲酰胺的制备Yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
Figure PCTCN2021076684-appb-000045
Figure PCTCN2021076684-appb-000045
采用以下合成路线：The following synthetic route is adopted:
Figure PCTCN2021076684-appb-000046
Figure PCTCN2021076684-appb-000046
步骤1(R)-3-(4-氨基-5-((4-(2-(二甲基氨基)-2-氧代乙基)-2,3-二甲基苯基)氨基甲酰基)-7H-吡咯并[2,3-d]嘧啶-7-基)哌啶-1-甲酸叔丁酯的合成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
向配有磁力搅拌的50mL单口瓶中加入中间体A1(140mg，0.38mmol)、中间体B2(69mg，0.38mmol)、DIPEA(150mg，1.16mmol)和无水DMF(3mL)，搅拌溶清，冷却到0℃，氮气氛下加入HATU(221mg，0.58mmol)，加毕，氮气氛下室温搅拌反应2小时。加入水(20mL)和乙酸乙酯(20mL)，分出有机相，水相乙酸乙酯萃取(20mL*2)，合并有机相，饱和食盐水洗涤(50mL*3)，无水硫酸钠干燥，过滤，浓缩并过硅胶柱得白色固体130mg，收率62.85％。LC-MS(APCI):m/z＝550.2(M+1) +. Add Intermediate A1 (140 mg, 0.38 mmol), Intermediate B2 (69 mg, 0.38 mmol), DIPEA (150 mg, 1.16 mmol) and anhydrous DMF (3 mL) to a 50 mL single-neck flask equipped with magnetic stirring, and stir to dissolve. After cooling to 0°C, HATU (221 mg, 0.58 mmol) was added under nitrogen atmosphere. After the addition, the reaction was stirred at room temperature under nitrogen atmosphere for 2 hours. Add water (20mL) and ethyl acetate (20mL), separate the organic phase, extract the aqueous phase with ethyl acetate (20mL*2), combine the organic phases, wash with saturated brine (50mL*3), and dry with anhydrous sodium sulfate. It was filtered, concentrated and passed through a silica gel column to obtain 130 mg of white solid with a yield of 62.85%. LC-MS(APCI): m/z=550.2(M+1) + .
步骤2(R)-4-氨基-N-(4-(2-(二甲基氨基)-2-氧代乙基)-2,3-二甲基苯基)-7-(哌啶-3-基)-7H-吡咯并[2,3-d]嘧啶-5-甲酰胺的合成Step 2 (R)-4-amino-N-(4-(2-(dimethylamino)-2-oxoethyl)-2,3-dimethylphenyl)-7-(piperidine- Synthesis of 3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
向配有磁力搅拌的25mL单口瓶中加入(R)-3-(4-氨基-5-((4-(2-(二甲基氨基)-2-氧代乙基)-2,3-二甲基苯基)氨基甲酰基)-7H-吡咯并[2,3-d]嘧啶-7-基)哌啶-1-甲酸叔丁酯(130mg，0.23mmol)和DCM(3mL)，加入三氟醋酸(1mL)，氮气氛下室温搅拌反应2小时。减压浓缩至干，加入DCM(10mL)和饱和碳酸氢钠水溶液(10mL)，分出有机相，水相DCM萃取(20mLx2)，合并有机相，无水硫 酸钠干燥，过滤，浓缩至干得棕色固体102mg，收率99.4％。LC-MS(APCI):m/z＝450.2(M+1) +. Add (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 (130mg, 0.23mmol) and DCM (3mL) were added Trifluoroacetic acid (1 mL) was stirred for 2 hours at room temperature under nitrogen atmosphere. Concentrate to dryness under reduced pressure, add DCM (10mL) and saturated aqueous sodium bicarbonate (10mL), separate the organic phase, extract the aqueous phase with DCM (20mLx2), combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate to dryness. 102 mg of brown solid, yield 99.4%. LC-MS(APCI): m/z=450.2(M+1) + .
步骤3(R)-7-(1-丙烯酰基哌啶-3-基)-4-氨基-N-(4-(2-(二甲基氨基)-2-氧代乙基)-2,3-二甲基苯基)-7H-吡咯并[2,3-d]嘧啶-5-甲酰胺的合成Step 3 (R)-7-(1-acryloylpiperidin-3-yl)-4-amino-N-(4-(2-(dimethylamino)-2-oxoethyl)-2, Synthesis of 3-Dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
(R)-4-氨基-N-(4-(2-(二甲基氨基)-2-氧代乙基)-2,3-二甲基苯基)-7-(哌啶-3-基)-7H-吡咯并[2,3-d]嘧啶-5-甲酰胺(102mg，0.23mmol)溶于乙腈(4mL)和水(3mL)中，加入三乙胺(60mg，0.6mmol),冷却到0℃，氮气氛下缓慢滴加丙烯酰氯(22mg，0.24mmol)的乙腈溶液(1mL)，滴毕，保温0℃搅拌反应1小时。加入饱和碳酸氢钠水溶液(10mL)和乙酸乙酯(20mL)，搅拌5分钟，分出有机相，水相乙酸乙酯萃取(15mL*2)，合并有机相，无水硫酸钠干燥，过滤，浓缩并过硅胶柱得淡黄色固体40mg，收率33.8％。LC-MS(APCI):m/z＝504.2(M+1) +. 1H NMR(300MHz,CDCl 3)δ8.66-8.63(m,1H),8.25(s,1H),7.90-7.77(m,1H),7.48(d,J＝8.1Hz,2H),7.25-7.18(m,2H),6.60-6.58(m,1H),6.36-6.33(m,1H),5.75-5.72(m,1H),4.62-4.55(m,2H),3.70(s,2H),3.00-2.75(m,2H),3.05(s,3H),2.98(s,3H),2.96-2.85(m,1H),2.71(s,3H),2.63(s,3H),2.30-2.20(m,2H),1.90-1.84(m,2H). (R)-4-amino-N-(4-(2-(dimethylamino)-2-oxoethyl)-2,3-dimethylphenyl)-7-(piperidine-3- Base)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (102mg, 0.23mmol) was dissolved in acetonitrile (4mL) and water (3mL), and triethylamine (60mg, 0.6mmol) was added, After cooling to 0°C, slowly add acryloyl chloride (22mg, 0.24mmol) in acetonitrile solution (1mL) dropwise under nitrogen atmosphere. After dropping, keep at 0°C and stir for 1 hour. Add saturated aqueous sodium bicarbonate (10mL) and ethyl acetate (20mL), stir for 5 minutes, separate the organic phase, extract the aqueous phase with ethyl acetate (15mL*2), combine the organic phases, dry with anhydrous sodium sulfate, and filter. Concentrate and pass through a silica gel column to obtain 40 mg of pale yellow solid, with a yield of 33.8%. LC-MS(APCI): m/z=504.2(M+1) + . 1 H NMR(300MHz, CDCl 3 )δ8.66-8.63(m,1H), 8.25(s,1H), 7.90-7.77( m,1H),7.48(d,J=8.1Hz,2H),7.25-7.18(m,2H),6.60-6.58(m,1H),6.36-6.33(m,1H),5.75-5.72(m, 1H),4.62-4.55(m,2H),3.70(s,2H),3.00-2.75(m,2H),3.05(s,3H),2.98(s,3H),2.96-2.85(m,1H) , 2.71(s,3H), 2.63(s,3H), 2.30-2.20(m,2H),1.90-1.84(m,2H).
实施例37-(1-丙烯酰基哌啶-3-基)-4-氨基-N-(4-(2-(二甲基氨基)-2-氧代乙基)苯基)吡咯并Example 37-(1-Acryloylpiperidin-3-yl)-4-amino-N-(4-(2-(dimethylamino)-2-oxoethyl)phenyl)pyrrolo [2,1-f][1,2,4]三嗪-5-甲酰胺的制备Preparation of [2,1-f][1,2,4]triazine-5-carboxamide
Figure PCTCN2021076684-appb-000047
Figure PCTCN2021076684-appb-000047
采用以下合成路线：The following synthetic route is adopted:
Figure PCTCN2021076684-appb-000048
Figure PCTCN2021076684-appb-000048
步骤1 3-(4-氨基-5-((4-(2-(二甲基氨基)-2-氧代乙基)苯基)氨基甲酰基)吡咯并[2,1-f][1,2,4]三嗪-7-基)哌啶-1-甲酸叔丁酯的合成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
将中间体A2(722mg，2mmol)，中间体B1(356mg，2mmol)和三乙胺(404mg，4mmol)溶于20mL二氯甲烷，冰浴下加入HATU(1.14g，3mmol)，室温反应过夜。反应液加入20mL二氯甲烷稀释，水洗，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，经硅胶柱分离得淡黄色固体720mg，收率69.1％。ESI-MS:522[M ++1]. Intermediate A2 (722mg, 2mmol), Intermediate B1 (356mg, 2mmol) and triethylamine (404mg, 4mmol) were dissolved in 20mL of dichloromethane, HATU (1.14g, 3mmol) was added under ice bath, and reacted at room temperature overnight. The reaction solution was diluted with 20 mL of dichloromethane, washed with water, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain 720 mg of light yellow solid with a yield of 69.1%. ESI-MS:522[M + +1].
步骤2 4-氨基-N-(4-(2-(二甲基氨基)-2-氧代乙基)苯基)-7-(哌啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-5-甲酰胺的合成Step 2 4-Amino-N-(4-(2-(dimethylamino)-2-oxoethyl)phenyl)-7-(piperidin-3-yl)pyrrolo[2,1-f ][1,2,4] Triazine-5-Carboxamide Synthesis
将3-(4-氨基-5-((4-(2-(二甲基氨基)-2-氧代乙基)苯基)氨基甲酰基)吡咯并[2,1-f][1,2,4]三嗪-7-基)哌啶-1-甲酸叔丁酯(720mg，1.38mmol)溶于10mL二氯甲烷中，加入3mL三氟乙酸，室温搅拌1小时。旋蒸蒸除溶剂，残留物溶于25mL二氯甲烷，分别用饱和碳酸氢钠溶液和饱和食盐水洗涤，有机相经无水硫酸钠干燥，浓缩，经硅胶柱分离得淡黄色固体414mg，收率71.2％。ESI-MS:422[M ++1]. The 3-(4-amino-5-((4-(2-(dimethylamino)-2-oxoethyl)phenyl)carbamoyl)pyrrolo[2,1-f][1, 2,4] Triazin-7-yl)piperidine-1-carboxylic acid tert-butyl ester (720 mg, 1.38 mmol) was dissolved in 10 mL of dichloromethane, 3 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 hour. The solvent was removed by rotary evaporation. The residue was dissolved in 25 mL of dichloromethane, washed with saturated sodium bicarbonate solution and saturated brine, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain 414 mg of light yellow solid. The rate is 71.2%. ESI-MS:422[M + +1].
步骤3 7-(1-丙烯酰基哌啶-3-基)-4-氨基-N-(4-(2-(二甲基氨基)-2-氧代乙基)苯基)吡咯并[2,1-f][1,2,4]三嗪-5-甲酰胺的合成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
将4-氨基-N-(4-(2-(二甲基氨基)-2-氧代乙基)苯基)-7-(哌啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-5-甲酰胺(414mg，0.98mmol)和三乙胺(198mg，1.96mmol)溶于15mL二氯甲烷中，冰浴降温至-20℃，缓慢加入丙烯酰氯(89mg，0.98mmol)，滴加完毕撤去冰浴，室温搅拌1小时。加入30mL水稀释，用二氯甲烷(20mL*3)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，经硅胶柱分离得淡黄色固体310mg，收率66.6％。ESI-MS:476[M ++1]. 1H NMR(400MHz,CDCl 3)δ7.91(d,J＝15.4Hz,1H),7.54(d,J＝8.3Hz,2H),7.22(d,J＝8.5Hz,2H),6.93(d,J＝21.3Hz,1H),6.57(ddd,J＝46.8,16.8,10.6Hz,1H),6.24(dd,J＝53.5,16.8Hz,1H),5.66(dd,J＝59.2,10.6Hz,1H),4.38(d,J＝12.4Hz,0.5H),4.21(d,J＝13.3Hz,1H),3.79(d,J＝13.1Hz,0.5H),3.68(s,2H),3.59-3.48(m,1H),3.34–3.26(m,1H),3.24–3.15(m,1H)3.01(s,3H),2.95(s,3H),2.19(d,J＝6.8Hz,2H),1.77–1.57(m,2H). The 4-amino-N-(4-(2-(dimethylamino)-2-oxoethyl)phenyl)-7-(piperidin-3-yl)pyrrolo[2,1-f] [1,2,4]Triazine-5-carboxamide (414mg, 0.98mmol) and triethylamine (198mg, 1.96mmol) were dissolved in 15mL of dichloromethane, cooled to -20℃ in an ice bath, and slowly added acryloyl chloride (89mg, 0.98mmol), remove the ice bath after dropping, and stir at room temperature for 1 hour. Add 30mL of water to dilute, extract with dichloromethane (20mL*3), wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, concentrate, and separate on silica gel column to obtain a light yellow solid 310mg with a yield of 66.6%. ESI-MS: 476[M + +1]. 1 H NMR(400MHz,CDCl 3 )δ7.91(d,J=15.4Hz,1H),7.54(d,J=8.3Hz,2H),7.22(d ,J=8.5Hz,2H), 6.93(d,J=21.3Hz,1H), 6.57(ddd,J=46.8,16.8,10.6Hz,1H), 6.24(dd,J=53.5,16.8Hz,1H) ,5.66(dd,J＝59.2,10.6Hz,1H), 4.38(d,J＝12.4Hz,0.5H),4.21(d,J＝13.3Hz,1H),3.79(d,J＝13.1Hz,0.5 H), 3.68 (s, 2H), 3.59-3.48 (m, 1H), 3.34-3.26 (m, 1H), 3.24-3.15 (m, 1H) 3.01 (s, 3H), 2.95 (s, 3H), 2.19(d,J=6.8Hz,2H),1.77–1.57(m,2H).
实施例4(R)-7-(1-丙烯酰基哌啶-3-基)-4-氨基-N-(4-(2-(二甲基氨基)-2-氧代乙基)苯基)吡咯并Example 4 (R)-7-(1-acryloylpiperidin-3-yl)-4-amino-N-(4-(2-(dimethylamino)-2-oxoethyl)phenyl )Pyrrolo [2,1-f][1,2,4]三嗪-5-甲酰胺的制备Preparation of [2,1-f][1,2,4]triazine-5-carboxamide
Figure PCTCN2021076684-appb-000049
Figure PCTCN2021076684-appb-000049
将100mg的消旋体实施例3化合物溶解在甲醇(10mL)溶液中，在下述手性制备色谱柱和手性拆分条件下进行分离得到目标产物(保留时间：61.925min，相对含量：50.04％，命名为R构型)。100 mg of the racemate compound of Example 3 was dissolved in methanol (10 mL), and separated under the following chiral preparative chromatographic column and chiral resolution conditions to obtain the target product (retention time: 61.925min, relative content: 50.04%) , Named as R configuration).
手性制备色谱柱：CHIRALPAK IC(商品名),10mm×250mm(内径×长度)，5μm(填料粒径)Chiral preparative chromatography column: CHIRALPAK IC (trade name), 10mm×250mm (inner diameter×length), 5μm (filler particle size)
柱温：30℃Column temperature: 30℃
流速：1.0mL/minFlow rate: 1.0mL/min
紫外检测波长：254nmUV detection wavelength: 254nm
流动相：二氯甲烷:正己烷:甲醇:乙醇(0.1％二乙胺)＝45:42:5:8Mobile phase: dichloromethane: n-hexane: methanol: ethanol (0.1% diethylamine) = 45:42:5:8
实施例5(S)-7-(1-丙烯酰基哌啶-3-基)-4-氨基-N-(4-(2-(二甲基氨基)-2-氧代乙基)苯基)吡咯并Example 5 (S)-7-(1-acryloylpiperidin-3-yl)-4-amino-N-(4-(2-(dimethylamino)-2-oxoethyl)phenyl )Pyrrolo [2,1-f][1,2,4]三嗪-5-甲酰胺的制备。Preparation of [2,1-f][1,2,4]triazine-5-carboxamide.
Figure PCTCN2021076684-appb-000050
Figure PCTCN2021076684-appb-000050
将100mg的消旋体实施例3化合物溶解在甲醇(10mL)溶液中，在下述手性制备色谱柱和手性拆分条件下进行分离得到目标产物(保留时间：65.193min，相对含量：49.96％，命名为S构型)。100 mg of the racemate compound of Example 3 was dissolved in methanol (10 mL) and separated under the following chiral preparative chromatography column and chiral resolution conditions to obtain the target product (retention time: 65.193 min, relative content: 49.96%) , Named as S configuration).
手性制备色谱柱：CHIRALPAK IC(商品名),10mm×250mm(内径×长度),5μm(填料粒径)Chiral preparative chromatography column: CHIRALPAK IC (trade name), 10mm×250mm (inner diameter×length), 5μm (filler particle size)
柱温：30℃Column temperature: 30℃
流速：1.0mL/minFlow rate: 1.0mL/min
紫外检测波长：254nmUV detection wavelength: 254nm
流动相：二氯甲烷:正己烷:甲醇:乙醇(0.1％二乙胺)＝45:42:5:8Mobile phase: dichloromethane: n-hexane: methanol: ethanol (0.1% diethylamine) = 45:42:5:8
实施例6 7-(1-丙烯酰基哌啶-3-基)-4-氨基-N-(4-(2-(二甲基氨基)-2-氧代乙基)-2,3-二甲基苯基)吡Example 6 7-(1-acryloylpiperidin-3-yl)-4-amino-N-(4-(2-(dimethylamino)-2-oxoethyl)-2,3-di Methyl phenyl) pyridine 咯并[2,1-f][1,2,4]三嗪-5-甲酰胺的制备Preparation of Rolo[2,1-f][1,2,4]triazine-5-carboxamide
Figure PCTCN2021076684-appb-000051
Figure PCTCN2021076684-appb-000051
采用以下合成路线：The following synthetic route is adopted:
Figure PCTCN2021076684-appb-000052
Figure PCTCN2021076684-appb-000052
步骤1 3-(4-氨基-5-((4-(2-(二甲基氨基)-2-氧代乙基)-2,3-二甲基苯基)氨基甲酰基)吡咯并[2,1-f][1,2,4]三嗪-7-基)哌啶-1-甲酸叔丁酯的合成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
将中间体A2(722mg，2mmol)，中间体B2(412mg，2mmol)和三乙胺(404mg，4mmol) 溶于20mL DCM，冰浴下加入HATU(1.14g，3mmol)，室温反应过夜。反应液加入20mL DCM稀释，水洗，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，经硅胶柱分离得淡黄色固体720mg，收率65.5％。ESI-MS:550[M ++1]. Intermediate A2 (722mg, 2mmol), intermediate B2 (412mg, 2mmol) and triethylamine (404mg, 4mmol) were dissolved in 20mL DCM, HATU (1.14g, 3mmol) was added under ice bath, and reacted at room temperature overnight. The reaction solution was diluted with 20 mL of DCM, washed with water, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain 720 mg of light yellow solid with a yield of 65.5%. ESI-MS:550[M + +1].
步骤2 4-氨基-N-(4-(2-(二甲基氨基)-2-氧代乙基)-2,3-二甲基苯基)-7-(哌啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-5-甲酰胺的合成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
将3-(4-氨基-5-((4-(2-(二甲基氨基)-2-氧代乙基)-2,3-二甲基苯基)氨基甲酰基)吡咯并[2,1-f][1,2,4]三嗪-7-基)哌啶-1-甲酸叔丁酯(720mg，1.31mmol)溶于10mL DCM中，加入3mL三氟乙酸，室温搅拌1小时。旋蒸蒸除溶剂，残留物溶于25mL DCM，分别用饱和碳酸氢钠溶液和饱和食盐水洗涤，有机相经无水硫酸钠干燥，浓缩，经硅胶柱分离得淡黄色固体440mg，收率75％。ESI-MS:450[M ++1]. The 3-(4-amino-5-((4-(2-(dimethylamino)-2-oxoethyl)-2,3-dimethylphenyl)carbamoyl)pyrrolo[2 ,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylic acid tert-butyl ester (720mg, 1.31mmol) was dissolved in 10mL DCM, 3mL trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 hour . The solvent was evaporated by rotary evaporation, the residue was dissolved in 25mL DCM, washed with saturated sodium bicarbonate solution and saturated brine, the organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain a pale yellow solid 440mg, the yield was 75 %. ESI-MS:450[M + +1].
步骤3 7-(1-丙烯酰基哌啶-3-基)-4-氨基-N-(4-(2-(二甲基氨基)-2-氧代乙基)-2,3-二甲基苯基)吡咯并[2,1-f][1,2,4]三嗪-5-甲酰胺的合成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
将4-氨基-N-(4-(2-(二甲基氨基)-2-氧代乙基)-2,3-二甲基苯基)-7-(哌啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-5-甲酰胺(440mg，0.98mmol)和三乙胺(198mg，1.96mmol)溶于15mL DCM中，冰浴降温至-20℃，缓慢加入丙烯酰氯(89mg，0.98mmol)，滴加完毕撤去冰浴，室温搅拌1小时。加入30mL水稀释，用DCM(20mL*3)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，经硅胶柱分离得淡黄色固体320mg，收率65％。ESI-MS:504[M ++1]. 1H NMR(500MHz,CDCl 3)δ10.22(s,1H),8.07(d,J＝39.6Hz,1H),7.96(d,J＝16.8Hz,1H),6.99(d,J＝8.2Hz,1H),6.89(d,J＝12.3Hz,1H),6.73–6.56(m,1H),6.28(d,J＝16.8Hz,1H),5.69(t,J＝10.6Hz,1H),4.62(d,J＝12.9Hz,0.5H),4.50(d,J＝13.3Hz,0.5H),4.36(d,J＝13.5Hz,0.5H),3.89(d,J＝13.3Hz,0.5H),3.69(s,2H),3.45(dt,J＝10.0,6.0Hz,1H),3.34(d,J＝12.3Hz,1H),3.17(t,J＝11.6Hz,0.5H),3.04(s,3H),3.00(s,3H),2.95(d,J＝11.8Hz,0.5H),2.35–2.26(m,1H),2.24(s,3H),2.21(s,3H),1.95–1.81(m,2H).1.79–1.74(m,1H). Add 4-amino-N-(4-(2-(dimethylamino)-2-oxoethyl)-2,3-dimethylphenyl)-7-(piperidin-3-yl)pyrrole And [2,1-f][1,2,4]triazine-5-carboxamide (440mg, 0.98mmol) and triethylamine (198mg, 1.96mmol) were dissolved in 15mL DCM and cooled to -20 in an ice bath At ℃, slowly add acryloyl chloride (89mg, 0.98mmol), remove the ice bath after dripping, and stir at room temperature for 1 hour. It was diluted with 30 mL of water and extracted with DCM (20 mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain 320 mg of light yellow solid with a yield of 65%. ESI-MS:504[M + +1]. 1 H NMR(500MHz,CDCl 3 )δ10.22(s,1H), 8.07(d,J=39.6Hz,1H),7.96(d,J=16.8Hz ,1H),6.99(d,J＝8.2Hz,1H),6.89(d,J＝12.3Hz,1H),6.73-6.56(m,1H),6.28(d,J＝16.8Hz,1H),5.69 (t,J=10.6Hz,1H), 4.62(d,J=12.9Hz,0.5H), 4.50(d,J=13.3Hz,0.5H), 4.36(d,J=13.5Hz,0.5H), 3.89 (d, J = 13.3Hz, 0.5H), 3.69 (s, 2H), 3.45 (dt, J = 10.0, 6.0 Hz, 1H), 3.34 (d, J = 12.3 Hz, 1H), 3.17 (t, J = 11.6Hz, 0.5H), 3.04 (s, 3H), 3.00 (s, 3H), 2.95 (d, J = 11.8Hz, 0.5H), 2.35-2.26 (m, 1H), 2.24 (s, 3H) ),2.21(s,3H),1.95-1.81(m,2H).1.79-1.74(m,1H).
实施例7(R)-7-(1-丙烯酰胺基哌啶-3-基)-4-氨基-N-(4-(2-(二甲基氨基)-2-氧代乙基)-2,3-二甲基苯Example 7 (R)-7-(1-acrylamidopiperidin-3-yl)-4-amino-N-(4-(2-(dimethylamino)-2-oxoethyl)- 2,3-Dimethylbenzene 基)吡咯并[2,1-f][1,2,4]三嗪-5-甲酰胺的制备。Yl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide.
Figure PCTCN2021076684-appb-000053
Figure PCTCN2021076684-appb-000053
将100mg的消旋体实施例6化合物溶解在甲醇(10mL)溶液中，在下述手性制备色谱柱和手性拆分条件下进行分离得到目标产物(保留时间：25.332min，相对含量：49.54％，命名为R构型)。100 mg of the racemate compound of Example 6 was dissolved in methanol (10 mL), and separated under the following chiral preparative chromatographic column and chiral resolution conditions to obtain the target product (retention time: 25.332 min, relative content: 49.54%) , Named as R configuration).
手性制备色谱柱：CHIRALPAK IC(商品名),10mm×250mm(内径×长度),5μm(填料粒径)Chiral preparative chromatography column: CHIRALPAK IC (trade name), 10mm×250mm (inner diameter×length), 5μm (filler particle size)
柱温：30℃Column temperature: 30℃
流速：1.0mL/minFlow rate: 1.0mL/min
紫外检测波长：254nmUV detection wavelength: 254nm
流动相：二氯甲烷:正己烷:甲醇:乙醇(0.1％二乙胺)＝45:42:5:8Mobile phase: dichloromethane: n-hexane: methanol: ethanol (0.1% diethylamine) = 45:42:5:8
实施例8(S)-7-(1-丙烯酰胺基哌啶-3-基)-4-氨基-N-(4-(2-(二甲基氨基)-2-氧代乙基)-2,3-二甲基苯Example 8 (S)-7-(1-acrylamidopiperidin-3-yl)-4-amino-N-(4-(2-(dimethylamino)-2-oxoethyl)- 2,3-Dimethylbenzene 基)吡咯并[2,1-f][1,2,4]三嗪-5-甲酰胺的制备。Yl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide.
Figure PCTCN2021076684-appb-000054
Figure PCTCN2021076684-appb-000054
将100mg的消旋体实施例6化合物溶解在甲醇(10mL)溶液中，在下述手性制备色谱柱和手性拆分条件下进行分离得到目标产物(保留时间：28.760min，相对含量：50.46％，命名为S构型)。100 mg of the racemate compound of Example 6 was dissolved in methanol (10 mL), and separated under the following chiral preparative chromatographic column and chiral resolution conditions to obtain the target product (retention time: 28.760 min, relative content: 50.46%) , Named as S configuration).
手性制备色谱柱：CHIRALPAK IC(商品名),10mm×250mm(内径×长度),5μm(填料粒径)Chiral preparative chromatography column: CHIRALPAK IC (trade name), 10mm×250mm (inner diameter×length), 5μm (filler particle size)
柱温：30℃Column temperature: 30℃
流速：1.0mL/minFlow rate: 1.0mL/min
紫外检测波长：254nmUV detection wavelength: 254nm
流动相：二氯甲烷:正己烷:甲醇:乙醇(0.1％二乙胺)＝45:42:5:8Mobile phase: dichloromethane: n-hexane: methanol: ethanol (0.1% diethylamine) = 45:42:5:8
实施例9(R)-3-(1-丙烯酰基哌啶-3-基)-8-氨基-N-(4-(2-(二甲基氨基)-2-氧代乙基)苯基)咪唑并Example 9 (R)-3-(1-acryloylpiperidin-3-yl)-8-amino-N-(4-(2-(dimethylamino)-2-oxoethyl)phenyl ) Imidazo [1,5-a]吡嗪-1-甲酰胺的制备[1,5-a] Preparation of pyrazine-1-carboxamide
Figure PCTCN2021076684-appb-000055
Figure PCTCN2021076684-appb-000055
采用以下合成路线：The following synthetic route is adopted:
Figure PCTCN2021076684-appb-000056
Figure PCTCN2021076684-appb-000056
步骤1(R)-3-(8-氨基-1-((4-(2-(二甲基氨基)-2-氧代乙基)苯基)氨基甲酰基)咪唑并[1,5-a]吡嗪-3-基)哌啶-1-甲酸叔丁酯的合成Step 1 (R)-3-(8-amino-1-((4-(2-(dimethylamino)-2-oxoethyl)phenyl)carbamoyl)imidazo[1,5- a]Synthesis of tert-butyl pyrazin-3-yl)piperidine-1-carboxylate
向反应瓶中加入中间体A3(200mg，0.55mmol)和中间体B1(117.5mg，0.66mmol)，加入10ml无水DCM溶解，氮气保护下加入HATU(252mg，0.66mmol)和DIPEA(179mg，1.38mmol)，加毕，室温下反应1h，TLC监测反应完毕后，浓缩除去溶剂，粗品经硅胶柱层析纯化后得到253mg类白色固体，收率：88.3％。LC-MS(APCI):m/z＝522.4(M+1) +。 Add Intermediate A3 (200mg, 0.55mmol) and Intermediate B1 (117.5mg, 0.66mmol) to the reaction flask, add 10ml of anhydrous DCM to dissolve, add HATU (252mg, 0.66mmol) and DIPEA (179mg, 1.38) under nitrogen protection After the addition, the reaction was carried out at room temperature for 1 h. After the reaction was monitored by TLC, the solvent was removed by concentration. The crude product was purified by silica gel column chromatography to obtain 253 mg of off-white solid. Yield: 88.3%. LC-MS (APCI): m/z=522.4(M+1) + .
步骤2(R)-3-(1-丙烯酰基哌啶-3-基)-8-氨基-N-(4-(2-(二甲基氨基)-2-氧代乙基)苯基)咪唑并[1,5-a]吡嗪-1-甲酰胺的合成Step 2 (R)-3-(1-acryloylpiperidin-3-yl)-8-amino-N-(4-(2-(dimethylamino)-2-oxoethyl)phenyl) Synthesis of imidazo[1,5-a]pyrazine-1-carboxamide
向反应瓶中加入(R)-3-(8-氨基-1-((4-(2-(二甲基氨基)-2-氧代乙基)苯基)氨基甲酰基)咪唑并[1,5-a]吡嗪-3-基)哌啶-1-甲酸叔丁酯(253mg，0.48mmol)，氮气保护下加入4N的氯化氢二氧六环溶液(5ml，20mmol)，室温下搅拌反应1h，TLC监测反应完毕后浓缩至干，直接投入到下一步。Add (R)-3-(8-amino-1-((4-(2-(dimethylamino)-2-oxoethyl)phenyl)carbamoyl)imidazo[1 ,5-a]pyrazin-3-yl)piperidine-1-carboxylic acid tert-butyl ester (253mg, 0.48mmol), add 4N hydrogen chloride dioxane solution (5ml, 20mmol) under nitrogen protection, and stir the reaction at room temperature After 1h, TLC monitored the reaction and concentrated to dryness, and put it directly into the next step.
向上述中间体中加入10ml无水DCM和三乙胺(138mg，1.36mmol)，冰浴下滴加丙烯酰氯(44mg，0.48mmol)，加毕搅拌反应10分钟后TLC监测反应完毕，加入DCM稀释，依次用水和饱和食盐水洗涤，浓缩后硅胶柱层析纯化得到142mg白色固体，收率：62.4％。LC-MS(APCI):m/z＝476.8(M+1) +。 1H NMR(400MHz,DMSO-d 6)δ10.55(s,1H),8.34(d,J＝2.5Hz,1H),8.18d,J＝2.5Hz,1H),7.56(d,J＝4.4Hz,2H),7.41(d,J＝4.4Hz,2H),6.61(m,1H),6.22(d,J＝6.5Hz,1H),5.71(d,J＝6.5Hz,1H),3.81(m,2H),3.80(s,2H),3.52(m,4H),3.12(s,6H),3.02(m,1H),2.10(m,2H),1.64(m,2H). 10ml of anhydrous DCM and triethylamine (138mg, 1.36mmol) were added to the above intermediate, acryloyl chloride (44mg, 0.48mmol) was added dropwise under ice bath, after stirring for 10 minutes, TLC monitored the completion of the reaction, adding DCM to dilute , Washed with water and saturated brine successively, concentrated and purified by silica gel column chromatography to obtain 142 mg of white solid, yield: 62.4%. LC-MS (APCI): m/z=476.8(M+1) + . 1 H NMR (400MHz, DMSO-d 6 ) δ 10.55 (s, 1H), 8.34 (d, J = 2.5 Hz, 1H), 8.18d, J = 2.5 Hz, 1H), 7.56 (d, J = 4.4 Hz, 2H), 7.41 (d, J = 4.4 Hz, 2H), 6.61 (m, 1H), 6.22 (d, J = 6.5 Hz, 1H), 5.71 (d, J = 6.5 Hz, 1H), 3.81 ( m, 2H), 3.80 (s, 2H), 3.52 (m, 4H), 3.12 (s, 6H), 3.02 (m, 1H), 2.10 (m, 2H), 1.64 (m, 2H).
实施例10(R)-3-(1-丙烯酰基哌啶-3-基)-8-氨基-N-(4-(2-(二甲基氨基)-2-氧代乙基)-2,3-二甲基苯基)Example 10 (R)-3-(1-acryloylpiperidin-3-yl)-8-amino-N-(4-(2-(dimethylamino)-2-oxoethyl)-2 ,3-Dimethylphenyl) 咪唑并[1,5-a]吡嗪-1-甲酰胺的制备Preparation of imidazo[1,5-a]pyrazine-1-carboxamide
Figure PCTCN2021076684-appb-000057
Figure PCTCN2021076684-appb-000057
采用以下合成路线：The following synthetic route is adopted:
Figure PCTCN2021076684-appb-000058
Figure PCTCN2021076684-appb-000058
步骤1(R)-3-(8-氨基-1-((4-(2-(二甲基氨基)-2-氧代乙基)-2,3-二甲基苯基)氨基甲酰基)咪唑并[1,5-a]吡嗪-3-基)哌啶-1-甲酸叔丁酯的合成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
向反应瓶中加入中间体A3(200mg，0.55mmol)和中间体B2(137mg，0.66mmol)，加入10ml无水DCM溶解，氮气保护下加入HATU(252mg，0.66mmol)和DIPEA(179mg，1.38mmol)，加毕，室温下反应1h，TLC监测反应完毕后，浓缩除去溶剂，粗品经硅胶柱层析纯化后得到249mg类白色固体，收率：81.9％。LC-MS(APCI):m/z＝550.8(M+1) +。 Add Intermediate A3 (200mg, 0.55mmol) and Intermediate B2 (137mg, 0.66mmol) to the reaction flask, add 10ml of anhydrous DCM to dissolve, add HATU (252mg, 0.66mmol) and DIPEA (179mg, 1.38mmol) under nitrogen protection After the addition, the reaction was carried out at room temperature for 1 h. After the reaction was monitored by TLC, the solvent was removed by concentration. The crude product was purified by silica gel column chromatography to obtain 249 mg of off-white solid. Yield: 81.9%. LC-MS (APCI): m/z=550.8(M+1) + .
步骤2(R)-3-(1-丙烯酰基哌啶-3-基)-8-氨基-N-(4-(2-(二甲基氨基)-2-氧代乙基)-2,3-二甲基苯基)咪唑并[1,5-a]吡嗪-1-甲酰胺的合成Step 2 (R)-3-(1-acryloylpiperidin-3-yl)-8-amino-N-(4-(2-(dimethylamino)-2-oxoethyl)-2, Synthesis of 3-Dimethylphenyl)imidazo[1,5-a]pyrazine-1-carboxamide
向反应瓶中加入(R)-3-(8-氨基-1-((4-(2-(二甲基氨基)-2-氧代乙基)-2,3-二甲基苯基)氨基甲酰基)咪唑并[1,5-a]吡嗪-3-基)哌啶-1-甲酸叔丁酯(249mg，0.45mmol)，氮气保护下加入4N的氯化氢二氧六环溶液(5ml，20mmol)，室温下搅拌反应1h，TLC监测反应完毕后浓缩至干，直接投入到下一步。Add (R)-3-(8-amino-1-((4-(2-(dimethylamino)-2-oxoethyl)-2,3-dimethylphenyl) to the reaction flask Carbamoyl)imidazo[1,5-a]pyrazin-3-yl)piperidine-1-carboxylic acid tert-butyl ester (249mg, 0.45mmol), add 4N hydrogen chloride dioxane solution (5ml , 20mmol), the reaction was stirred at room temperature for 1h, TLC monitored the reaction was completed, concentrated to dryness, directly put into the next step.
向上述中间体中加入10ml无水DCM和三乙胺(138mg，1.36mmol)，冰浴下滴加丙烯酰氯(41mg，0.45mmol)，加毕搅拌反应10分钟后TLC监测反应完毕，加入DCM稀释，依次用水和饱和食盐水洗涤，浓缩后硅胶柱层析纯化得到117mg白色固体，收率：51.3％。LC-MS(APCI):m/z＝504.8(M+1) +。 1H NMR(400MHz,DMSO-d 6)δ10.53(s,1H),8.41(d,J＝2.3Hz,1H),8.18d,J＝2.3Hz,1H),7.51(d,J＝4.4Hz,1H),7.38(d,J＝4.4Hz,1H),6.64(m,1H),6.17(d,J＝5.5Hz,1H),5.69(d,J＝5.5Hz,1H),3.83(m,2H),3.80(s,2H),3.52(m,4H),3.11(s,6H),3.02(m,1H),2.54(s,3H),2.50(s,3H),2.15(m,1H),1.84(m,3H). 10ml of anhydrous DCM and triethylamine (138mg, 1.36mmol) were added to the above intermediate, acryloyl chloride (41mg, 0.45mmol) was added dropwise under ice bath, after stirring for 10 minutes, TLC monitored the completion of the reaction, adding DCM to dilute , Washed with water and saturated brine in turn, concentrated and purified by silica gel column chromatography to obtain 117 mg of white solid, yield: 51.3%. LC-MS (APCI): m/z=504.8(M+1) + . 1 H NMR(400MHz,DMSO-d 6 )δ10.53(s,1H), 8.41(d,J=2.3Hz,1H), 8.18d,J=2.3Hz,1H), 7.51(d,J=4.4 Hz, 1H), 7.38 (d, J = 4.4 Hz, 1H), 6.64 (m, 1H), 6.17 (d, J = 5.5 Hz, 1H), 5.69 (d, J = 5.5 Hz, 1H), 3.83 ( m, 2H), 3.80(s, 2H), 3.52(m, 4H), 3.11(s, 6H), 3.02(m, 1H), 2.54(s, 3H), 2.50(s, 3H), 2.15(m ,1H),1.84(m,3H).
实施例11(R)-7-(1-丙烯酰基哌啶-3-基)-4-氨基-N-(4-(2-(二甲基氨基)-2-氧代乙基)-2,3-二甲基苯基)Example 11 (R)-7-(1-acryloylpiperidin-3-yl)-4-amino-N-(4-(2-(dimethylamino)-2-oxoethyl)-2 ,3-Dimethylphenyl) 咪唑并[5,1-f][1,2,4]三嗪-5-甲酰胺的制备Preparation of imidazo[5,1-f][1,2,4]triazine-5-carboxamide
Figure PCTCN2021076684-appb-000059
Figure PCTCN2021076684-appb-000059
采用以下合成路线：The following synthetic route is adopted:
Figure PCTCN2021076684-appb-000060
Figure PCTCN2021076684-appb-000060
步骤1(R)-3-(4-氨基-5-((4-(2-(二甲基氨基)-2-氧代乙基)-2,3-二甲基苯基)氨基甲酰基)咪唑并[5,1-f][1,2,4]三嗪-7-基)哌啶-1-甲酸苄基酯的合成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
将中间体A4(325mg，0.82mmol)，中间体B2(170mg，0.82mmol)和三乙胺(166mg，1.64mmol)溶于20mL DCM，冰浴下加入HATU(443mg，1.23mmol)，室温反应过夜。反应液加入20mL DCM稀释，水洗，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，经硅胶柱分离得淡黄色固体315mg，收率66％。ESI-MS:585[M ++1]. Intermediate A4 (325mg, 0.82mmol), intermediate B2 (170mg, 0.82mmol) and triethylamine (166mg, 1.64mmol) were dissolved in 20mL DCM, HATU (443mg, 1.23mmol) was added under ice bath, and reacted at room temperature overnight . The reaction solution was diluted with 20 mL of DCM, washed with water, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain 315 mg of light yellow solid with a yield of 66%. ESI-MS:585[M + +1].
步骤2(R)-4-氨基-N-(4-(2-(二甲基氨基)-2-氧代乙基)-2,3-二甲基苯基)-7-(哌啶-3-基)咪唑并[5,1-f][1,2,4]三嗪-5-甲酰胺的合成Step 2 (R)-4-amino-N-(4-(2-(dimethylamino)-2-oxoethyl)-2,3-dimethylphenyl)-7-(piperidine- Synthesis of 3-yl)imidazo[5,1-f][1,2,4]triazine-5-carboxamide
将(R)-3-(4-氨基-5-((4-(2-(二甲基氨基)-2-氧代乙基)-2,3-二甲基苯基)氨基甲酰基)咪唑并[5,1-f][1,2,4]三嗪-7-基)哌啶-1-甲酸苄基酯(315mg，0.54mmol)溶于20mL无水乙醇中，加入40mg10％钯碳，氢气置换三次，在一个大气压的氢气氛下搅拌过夜。反应完全后滤除钯碳，滤液浓缩，经硅胶柱分离得淡黄色油状物194mg，收率80％。ESI-MS:451[M ++1]. Add (R)-3-(4-amino-5-((4-(2-(dimethylamino)-2-oxoethyl)-2,3-dimethylphenyl)carbamoyl) Imidazo[5,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylic acid benzyl ester (315mg, 0.54mmol) was dissolved in 20mL of absolute ethanol, and 40mg of 10% palladium was added The carbon and hydrogen were replaced three times, and the mixture was stirred overnight under an atmosphere of hydrogen at one atmospheric pressure. After the completion of the reaction, the palladium carbon was filtered off, the filtrate was concentrated, and 194 mg of pale yellow oil was obtained through silica gel column separation, with a yield of 80%. ESI-MS:451[M + +1].
步骤3(R)-7-(1-丙烯酰基哌啶-3-基)-4-氨基-N-(4-(2-(二甲基氨基)-2-氧代乙基)-2,3-二甲基苯基)咪唑并[5,1-f][1,2,4]三嗪-5-甲酰胺的合成Step 3 (R)-7-(1-acryloylpiperidin-3-yl)-4-amino-N-(4-(2-(dimethylamino)-2-oxoethyl)-2, Synthesis of 3-Dimethylphenyl)imidazo[5,1-f][1,2,4]triazine-5-carboxamide
将(R)-4-氨基-N-(4-(2-(二甲基氨基)-2-氧代乙基)-2,3-二甲基苯基)-7-(哌啶-3-基)咪唑并[5,1-f][1,2,4]三嗪-5-甲酰胺(194mg，0.43mmol)和三乙胺(87mg，0.86mmol)溶于15mL DCM中，冰浴降温至-20℃，缓慢加入丙烯酰氯(39mg，0.43mmol)，滴加完毕撤去冰浴，室温搅拌1小时。加入20mL水稀释，用DCM(10mL*3)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，经硅胶柱分离得淡黄色固体130mg，收率60％。ESI-MS:505[M ++1]. 1H NMR(400MHz,DMSO-d 6)δ9.97(d,J＝18.9Hz,1H),9.81(d,J＝3.5Hz,1H),8.71(s,1H),8.03(d,J＝5.2Hz,1H),7.24(d,J＝8.1Hz,1H),6.95(d,J＝8.2Hz,1H),6.81(ddd,J＝38.0,16.7,10.5Hz,1H),6.07(t,J＝16.1Hz,1H),5.64(dd,J＝31.4,10.4Hz,1H),4.58(d,J＝12.4Hz,0.5H),4.24(d,J＝13.8Hz,0.5H),4.17(d,J＝12.6Hz,0.5H),4.04(d,J＝13.7Hz,0.5H),3.71(s,2H),3.66(d,J＝10.6Hz,1H),3.45–3.37(m,1H),3.23(d,J＝10.3Hz,1H),3.05(s,3H),2.86(s,3H),2.19(s,1H),2.13(d,J＝16.1Hz,6H),2.03(d,J＝11.2Hz,1H),1.93(d,J＝17.1Hz,1H),1.54(s,1H). Add (R)-4-amino-N-(4-(2-(dimethylamino)-2-oxoethyl)-2,3-dimethylphenyl)-7-(piperidine-3 -Yl)imidazo[5,1-f][1,2,4]triazine-5-carboxamide (194mg, 0.43mmol) and triethylamine (87mg, 0.86mmol) dissolved in 15mL DCM, ice bath The temperature was lowered to -20°C, acryloyl chloride (39mg, 0.43mmol) was slowly added, the ice bath was removed after the addition, and the mixture was stirred at room temperature for 1 hour. It was diluted with 20 mL of water, extracted with DCM (10 mL*3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column to obtain 130 mg of light yellow solid with a yield of 60%. ESI-MS:505[M + +1]. 1 H NMR(400MHz,DMSO-d 6 )δ9.97(d,J=18.9Hz,1H), 9.81(d,J=3.5Hz,1H), 8.71 (s, 1H), 8.03 (d, J = 5.2 Hz, 1H), 7.24 (d, J = 8.1 Hz, 1H), 6.95 (d, J = 8.2 Hz, 1H), 6.81 (ddd, J = 38.0, 16.7, 10.5 Hz, 1H), 6.07 (t, J = 16.1 Hz, 1H), 5.64 (dd, J = 31.4, 10.4 Hz, 1H), 4.58 (d, J = 12.4 Hz, 0.5H), 4.24 (d ,J=13.8Hz,0.5H), 4.17(d,J=12.6Hz,0.5H), 4.04(d,J=13.7Hz,0.5H), 3.71(s,2H), 3.66(d,J=10.6 Hz, 1H), 3.45–3.37 (m, 1H), 3.23 (d, J = 10.3 Hz, 1H), 3.05 (s, 3H), 2.86 (s, 3H), 2.19 (s, 1H), 2.13 (d ,J=16.1Hz,6H),2.03(d,J=11.2Hz,1H),1.93(d,J=17.1Hz,1H),1.54(s,1H).
生物活性测试Biological activity test
生物实施例1：激酶抑制测试Biological Example 1: Kinase inhibition test
1)EGFR(WT)和EGFR(D770_N771insNPG)激酶活性抑制测试1) EGFR (WT) and EGFR (D770_N771insNPG) kinase activity inhibition test
使用ADP-GloTM Kinase Assay kit(Promega，V9102)试剂盒，测定待测药物对EGFR(WT)和EGFR(D770_N771insNPG)(SignalChem，E-10-132GG)的抑制活性。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).
待测药物最高浓度为1μM，3倍梯度稀释，12个浓度。384孔板(Perkin Elmer，6007290)中每孔加入0.1μL各种浓度的药物溶液，分别与5μL EGFR(WT)或5μL EGFR(D770_N771insNPG)混合，双复孔。25℃孵育15min后，加入5μL底物启动反应，25℃孵育60min。体系中最终反应浓度为： 0.5nM EGFR,10μM ATP,0.03mg/mL Poly(4:1Glu,Tyr)Peptide,HEPES 50mM,EGTA 1mM,MgCl 210mM,Brij35 0.01％。然后加入10μL ADP Glo reagent，25℃继续孵育40min。再加入20μL检测试剂，25℃孵育40min后，在Envision酶标仪(Perkin Elmer,2104)上读数，并计算不同浓度化合物对酶的抑制率。使用GraphPad Prism 6.0软件分析数据，利用非线性曲线回归来拟合数据得出剂量-效应曲线，并由此计算IC 50值。 The highest concentration of the drug to be tested is 1μM, 3 times dilution, 12 concentrations. In a 384-well plate (Perkin Elmer, 6007290), 0.1 μL of drug solutions of various concentrations were added to each well, and mixed with 5 μL of EGFR (WT) or 5 μL of EGFR (D770_N771insNPG) respectively, and double-replicated. After incubating at 25°C for 15 minutes, add 5 μL 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, 10μM ATP, 0.03mg/mL Poly(4:1Glu, Tyr) Peptide, HEPES 50mM, EGTA 1mM, MgCl 2 10mM, Brij35 0.01%. Then add 10μL ADP Glo reagent and incubate at 25℃ for 40min. Then add 20μL 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.
2)HER2(WT)和HER2(A775_G776insYVMA)激酶活性抑制测试2) HER2 (WT) and HER2 (A775_G776insYVMA) kinase activity inhibition test
使用ADP-GloTM Kinase Assay kit(Promega，V9102)试剂盒，测定待测药物对HER2(WT)和HER2(A775_G776insYVMA)(SignalChem，E27-13BG)的抑制活性。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).
待测药物最高浓度为1μM，3倍梯度稀释，12个浓度。384孔板(Perkin Elmer，6007290)中每孔加入0.1μL各种浓度的药物溶液与5μL HER2(WT)或5μL HER2(A775_G776insYVMA)混合，双复孔。25℃孵育15min后，加入5μL底物启动反应，25℃孵育60min。体系中最终反应浓度为：20nM HER2,5μM ATP,0.03mg/mL Poly(4:1Glu,Tyr)Peptide,HEPES 50mM,EGTA 1mM,MgCl 2 10mM,Brij35 0.01％。然后加入10μL ADP Glo reagent，25℃继续孵育40min。再加入20μL检测试剂，25℃孵育40min后，在Envision酶标仪(Perkin Elmer,2104)上读数，并计算不同浓度化合物对酶的抑制率。使用GraphPad Prism 6.0软件分析数据，利用非线性曲线回归来拟合数据得出剂量-效应曲线，并由此计算IC 50值。 The highest concentration of the drug to be tested is 1μM, 3 times dilution, 12 concentrations. Each well of a 384-well plate (Perkin Elmer, 6007290) was added with 0.1 μL of drug solutions of various concentrations, mixed with 5 μL of HER2 (WT) or 5 μL of HER2 (A775_G776insYVMA), and double-replicated wells. After incubating at 25°C for 15 minutes, add 5 μL of substrate to start the reaction, and incubate at 25°C for 60 minutes. The final reaction concentration in the system is: 20nM HER2, 5μM ATP, 0.03mg/mL Poly(4:1Glu, Tyr) Peptide, HEPES 50mM, EGTA 1mM, MgCl 2 10mM, Brij35 0.01%. Then add 10μL ADP Glo reagent and incubate at 25℃ for 40min. Then add 20μL 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.
在上述激酶抑制实验中测试了本发明化合物，发现本发明化合物对EGFR(WT)、EGFR(D770_N771insNPG)和HER2(WT)、HER2(A775_G776insYVMA)激酶具有强效的活性。代表性实施例化合物的结果归纳于如下表1中。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. The results of representative example compounds are summarized in Table 1 below.
表1Table 1
Figure PCTCN2021076684-appb-000061
Figure PCTCN2021076684-appb-000061
注释：其中TAS0728的化学名称为(R)-1-(1-丙烯酰基哌啶-3-基)-4-氨基-N-(4-(2-(二甲基氨基)-2-氧代乙基)-2,3-二甲基苯基)-1H-吡唑并[3,4-d]嘧啶-3-甲酰胺Note: The chemical name of 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
生物实施例2：针对表达野生型和突变型EGFR的细胞系的生长抑制活性的测试Biological Example 2: Test for growth inhibitory activity of cell lines expressing wild-type and mutant EGFR
1)A431细胞、A549细胞、H1975细胞和HCC827细胞的生长抑制活性的测试1) Test of growth inhibitory activity of A431 cells, A549 cells, H1975 cells and HCC827 cells
A431细胞和A549细胞是野生型EGFR细胞；H1975细胞是具有L858R点突变且具有T790M点突变的EGFR细胞；HCC827细胞是外显子19缺失的突变型EGFR细胞。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.
调整A431(WT EGFR)细胞、A549细胞(WT EGFR)、H1975细胞(Ex19del)和HCC827细胞(L858R/T790M EGFR)浓度，分别加50μL细胞悬液至384孔板中，37℃、5％CO 2培养过夜。设置Tecan D300E程序。用Tecan D300E仪器加药，待测药物最高浓度为10μM，3倍梯度稀释，10个浓度，双复孔，继续培养72h。取出384孔板放在室温平衡30min，每孔加入30μL的CTG(Promega,G7573)试剂，室温放置10min，信号稳定后，在EnVision(Perkin Elmer 2104)上读取Luminescence值。抑制率(％)＝(1-Lum 待测药/Lum 阴性对照)x100,阴性对照组为0.667％DMSO。IC 50的计算采用XL-fit软件。 Adjust the concentration of A431 (WT EGFR) cells, A549 cells (WT EGFR), H1975 cells (Ex19del) and HCC827 cells (L858R/T790M EGFR), and add 50μL 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 10μM, 3 times of gradient dilution, 10 concentrations, double multiple wells, and continue to incubate for 72 hours. Take out the 384-well plate and equilibrate at room temperature for 30 minutes, add 30 μL of CTG (Promega, G7573) reagent to each well, and place at room temperature for 10 minutes. After the signal is stable, read the Luminescence value on EnVision (Perkin Elmer 2104). Inhibition rate (%)=(1-Lum test drug /Lum negative control )×100, the negative control group is 0.667% DMSO. The calculation of IC 50 uses XL-fit software.
在上述细胞毒性实验中测试了本发明化合物，发现本发明化合物对野生型的EGFR的A431细胞和A549细胞不具有抑制活性，对突变型EGFR的H1975细胞和HCC827细胞具有强效的活性和高选择性，由此可知本发明化合物可高特异性地抑制外显子19缺失的突变型EGFR和L858R/T790M的突变型EGFR。代表性实施例化合物的结果归纳于如下表2中。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. The results of representative example compounds are summarized in Table 2 below.
2)Ba/F 3亲代和Ba/F 3EGFR-D770-N771ins_SVD细胞的生长抑制活性的测试 2) Ba/F 3 parental generation and Ba/F 3 EGFR-D770-N771ins_SVD cell growth inhibitory activity test
取对数生长期细胞，用台盼蓝排斥法检测细胞活力，确保细胞活力在90％以上。调整Ba/F3亲代和Ba/F3EGFR-D770-N771ins_SVD细胞的浓度，分别加90μL细胞悬液至96孔板中，37℃、5％CO 2培养过夜。待测药物最高浓度为1μM，3.16倍梯度稀释，9个浓度。96孔板中每孔加入10μL各种浓度的药物溶液，三个复孔，继续培养72h。取出96孔板放在室温平衡30min，每孔加入等体积的CTG试剂，定轨摇床上振动5min使细胞裂解，室温放置20min稳定冷光信号后，在SpectraMax多标记微孔板检测仪(MD，2104-0010A)上读取冷光值。细胞存活率(％)＝(待测药的冷光值-培养液对照的冷光值)/(细胞对照的冷光值-培养液对照的冷光值)×100％。使用GraphPad Prism 7.0软件分析数据，利用非线性S曲线回归来拟合数据得出剂量-效应曲线，并由此计算IC 50值。 Take the logarithmic growth phase cells, use the trypan blue exclusion method to detect the cell viability to ensure that the cell viability is above 90%. Adjust the concentration of Ba/F3 parental and Ba/F3EGFR-D770-N771ins_SVD cells, add 90 μL of cell suspension to 96-well plates, and incubate overnight at 37°C and 5% CO 2. The highest concentration of the drug to be tested is 1μM, 3.16-fold serial dilution, 9 concentrations. Add 10 μL of drug solutions of various concentrations to each well of the 96-well plate, three replicate wells, and continue to incubate for 72 hours. Take out the 96-well plate and equilibrate at room temperature for 30 minutes, add an equal volume of CTG reagent to each well, shake on an orbital shaker for 5 minutes to lyse the cells, and place it at room temperature for 20 minutes to stabilize the luminescence signal. -0010A) to read the luminescence value. Cell survival rate (%)=(luminescence value of the drug to be tested-luminescence value of the culture solution control)/(luminescence value of the cell control-luminescence value of the culture solution control)×100%. GraphPad Prism 7.0 software was used to analyze the data, and nonlinear S-curve regression was used to fit the data to obtain a dose-effect curve, and the IC 50 value was calculated from this.
本发明化合物对Ba/F3EGFR-D770-N771ins_SVD细胞也具有强效的活性和高选择性，由此可知本发明化合物可高特异性地抑制外显子20***的突变型EGFR。代表性实施例化合物的结果归纳于如下表2中。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. The results of representative example compounds are summarized in Table 2 below.
表2：Table 2:
Figure PCTCN2021076684-appb-000062
Figure PCTCN2021076684-appb-000062
生物实施例3：针对表达野生型HER2的细胞系的生长抑制活性的测试Biological Example 3: Test for growth inhibitory activity of cell lines expressing wild-type HER2
1)SK-BR-3细胞、NCI-N87细胞和BT-474细胞的生长抑制活性的测试1) Test of growth inhibitory activity of SK-BR-3 cells, NCI-N87 cells and BT-474 cells
SK-BR-3细胞、NCI-N87细胞和BT-474细胞是野生型HER2细胞。调整SK-BR-3细胞、NCI-N87细胞和BT-474细胞浓度，分别加50μL细胞悬液至384孔板中，37℃、5％CO 2培养过夜。设置Tecan D300E程序。用Tecan D300E仪器加药，待测药物最高浓度为10μM，3倍梯度稀释，10个浓度，双复孔，继续培养72h。取出384孔板放在室温平衡30min，每孔加入30μL的CTG(Promega,G7573)试剂，室温放置10min，信号稳定后，在EnVision(Perkin Elmer 2104)上读取Luminescence值。抑制率(％)＝(1-Lum 待测药/Lum 阴性对照)x100,阴性对照组为0.667％DMSO。IC 50的计算采用XL-fit软件。 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 50μL 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 10μM, 3 times of gradient dilution, 10 concentrations, double multiple wells, and continue to incubate for 72 hours. Take out the 384-well plate and equilibrate at room temperature for 30 minutes, add 30 μL of CTG (Promega, G7573) reagent to each well, and place at room temperature for 10 minutes. After the signal is stable, read the Luminescence value on EnVision (Perkin Elmer 2104). Inhibition rate (%)=(1-Lum test drug /Lum negative control )×100, the negative control group is 0.667% DMSO. The calculation of IC 50 uses XL-fit software.
在上述细胞毒性实验中测试了本发明化合物，发现本发明化合物对野生型的HER2的SK-BR-3细胞、NCI-N87细胞和BT-474细胞具有强效的活性，由此可知本发明化合物可高特异性地抑制野生型的HER2。代表性实施例化合物的结果归纳于如下表3和4中。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. The results of representative example compounds are summarized in Tables 3 and 4 below.
2)Ba/F 3亲代和Ba/F 3HER2-A775_G776insYVMA细胞的生长抑制活性的测试 2) Test of growth inhibitory activity of Ba/F 3 parents and Ba/F 3 HER2-A775_G776insYVMA cells
取对数生长期细胞，用台盼蓝排斥法检测细胞活力，确保细胞活力在90％以上。调整Ba/F3亲代和Ba/F3HER2-A775_G776insYVMA细胞的浓度，分别加90μL细胞悬液至96孔板中，37℃、5％CO 2 培养过夜。待测药物最高浓度为1μM，3.16倍梯度稀释，9个浓度。96孔板中每孔加入10μL药物溶液，三个复孔，继续培养72h。取出96孔板放在室温平衡30min，每孔加入等体积的CTG试剂，定轨摇床上振动5min使细胞裂解，室温放置20min稳定冷光信号后，在SpectraMax多标记微孔板检测仪(MD，2104-0010A)上读取冷光值。细胞存活率(％)＝(待测药的冷光值-培养液对照的冷光值)/(细胞对照的冷光值-培养液对照的冷光值)×100％。使用GraphPad Prism 7.0软件分析数据，利用非线性S曲线回归来拟合数据得出剂量-效应曲线，并由此计算IC 50值。 Take the logarithmic growth phase cells, use the trypan blue exclusion method to detect the cell viability to ensure that the cell viability is above 90%. Adjust the concentration of Ba/F3 parent and Ba/F3HER2-A775_G776insYVMA cells, add 90 μL of cell suspension to 96-well plates, and incubate overnight at 37°C and 5% CO 2. The highest concentration of the drug to be tested is 1μM, 3.16-fold serial dilution, 9 concentrations. Add 10μL of the drug solution to each well of the 96-well plate, three replicate wells, and continue to incubate for 72 hours. Take out the 96-well plate and equilibrate at room temperature for 30 minutes, add an equal volume of CTG reagent to each well, shake on an orbital shaker for 5 minutes to lyse the cells, and place it at room temperature for 20 minutes to stabilize the luminescence signal. -0010A) to read the luminescence value. Cell survival rate (%)=(luminescence value of test drug-luminescence value of culture solution control)/(luminescence value of cell control-luminescence value of culture solution control)×100%. GraphPad Prism 7.0 software was used to analyze the data, and nonlinear S-curve regression was used to fit the data to obtain a dose-effect curve, and the IC 50 value was calculated from this.
本发明化合物对Ba/F3HER2-A775_G776insYVMA细胞也具有强效的活性和高选择性，代表性实施例化合物的结果归纳于如下表3中。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.
表3：table 3:
Figure PCTCN2021076684-appb-000063
Figure PCTCN2021076684-appb-000063
表4：Table 4:
Figure PCTCN2021076684-appb-000064
Figure PCTCN2021076684-appb-000064
生物实施例4：大鼠药代动力学实验Biological Example 4: Rat pharmacokinetic experiment
6只雄性Sprague-Dawley大鼠，7-8周龄，体重约210g，分成2组，每组3只，经静脉或口服单个剂量的化合物(静脉1mg/kg，口服10mg/kg)，比较其药代动力学差异。Six male Sprague-Dawley rats, 7-8 weeks old, weighing about 210g, were divided into 2 groups, 3 rats in each group, and a single dose of the compound (1 mg/kg intravenously, 10 mg/kg oral) was administered intravenously or orally, and compared. Pharmacokinetic differences.
大鼠采用标准饲料饲养，给予水。试验前16小时开始禁食。药物用5％DMSO、40％PEG400和55％生理盐水溶解。眼眶采血，采血的时间点为给药后0.083小时，0.25小时、0.5小时、1小时、2小时、4小时、8小时、12小时和24小时。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.
大鼠吸入***后短暂麻醉，眼眶采集300μL血样于试管。试管内有30μL 1％肝素钠溶液。使用前，试管于60℃烘干过夜。在最后一个时间点血样采集完成之后，大鼠***麻醉后处死。The rats were briefly anesthetized after inhaling ether, and 300 μL blood samples were collected from the orbit and placed in a test tube. There is 30μL 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.
血样采集后，立即温和地颠倒试管至少5次，保证混合充分后放置于冰上。血样在4℃6000rpm离心8分钟，将血浆与红细胞分离。用移液器吸出60μL血液(产生约30μL血浆)到微型K2EDTA管中，标明化合物的名称和时间点。血浆在进行分析前保存在-20℃。用LC-MS/MS测定血浆中本发明化合物的浓度。药代动力学参数基于每只动物在不同时间点的血药浓度进计算。Immediately after the blood sample is collected, gently invert the test tube at least 5 times to ensure that it is fully mixed before placing it on ice. 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 μL of blood (to produce approximately 30 μL 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.
实验表明，本发明化合物在动物体内具有更好的药代动力学性质，因此具有更好的药效学和治疗效果。代表性实施例化合物的结果归纳于下表5中。Experiments show that the compound of the present invention has better pharmacokinetic properties in animals, and therefore has better pharmacodynamics and therapeutic effects. The results of representative example compounds are summarized in Table 5 below.
表5：table 5:
Figure PCTCN2021076684-appb-000065
Figure PCTCN2021076684-appb-000065
Figure PCTCN2021076684-appb-000066
Figure PCTCN2021076684-appb-000066
生物实施例5：对具有皮下植入NCI-N87(人胃癌细胞)和BT-474(人乳腺癌细胞)细胞的体内模型Biological Example 5: In vivo model with subcutaneous implantation of NCI-N87 (human gastric cancer cells) and BT-474 (human breast cancer cells) cells 的抗肿瘤效果的评价Evaluation of the anti-tumor effect
将NCI-N87细胞(0.1mL,10×10 6个)和BT-474细胞(0.1mL,10×10 6个)皮下接种于6-8周龄Balb/c雄性小鼠的右后背。细胞接种一周后，测量在小鼠体内发现的肿瘤的长度(mm)和宽度(mm)。计算其肿瘤体积(tumor volume：TV)后，将小鼠分组，每组6只，使得这些组具有基本相等的平均TV。将小鼠分组的日期确定为“分组日”(第0天)。 NCI-N87 cells (0.1 mL, 10×10 6 cells) and BT-474 cells (0.1 mL, 10×10 6 cells) were subcutaneously inoculated into the right back of 6-8 week-old Balb/c male mice. One week after cell inoculation, the length (mm) and width (mm) of tumors found in the mice were measured. After calculating the tumor volume (TV), 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).
制备含有本发明化合物的测试溶液，并以15mg/kg/天的剂量连续27天口服施用于皮下植入NCI-N87细胞的小鼠(第一次施用日为第1天)。对照组施用溶媒(5％DMSO、40％PEG400和55％生理盐水)。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).
制备含有本发明化合物的测试溶液，并以15mg/kg/天的剂量连续30天口服施用于皮下植入BT-474细胞的小鼠(第一次施用日为第1天)。对照组施用溶媒(5％DMSO、40％PEG400和55％生理盐水)。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).
为了确定抗肿瘤效果指标，计算最后一天测量每个药物施用组的TV，并由下列等式计算最后一天的肿瘤体积相对于分组日(第0天)的肿瘤体积(相对肿瘤体积Relative tumor volume：RTV)和TGI(％)，评估抗肿瘤作用，表6和7显示该结果。图1至图4显示出随时间测量TV和RTV。当施用本发明的任何化合物的组表现出统计学上比对照组的平均RTV显著更小的RTV(ANOVA检验，p<0.05)时，确定存在抗肿瘤效果。In order to determine the anti-tumor effect index, calculate the TV of each drug administration group on the last day and calculate the tumor volume on the last day relative to the tumor volume on the grouping day (day 0) (relative tumor volume) from the following equation: RTV) and TGI (%) to evaluate the anti-tumor effect. Tables 6 and 7 show the results. Figures 1 to 4 show the measurement of TV and RTV over time. When the group administered with any compound of the present invention shows an RTV that is statistically significantly smaller than the average RTV of the control group (ANOVA test, p<0.05), it is determined that there is an antitumor effect.
TV＝(长×宽 2)/2 TV=(length×width 2 )/2
RTV＝(第t天的TV)/(第0天的TV)，其中，t表示测量肿瘤体积的日期。RTV=(TV on day t)/(TV on day 0), where t represents the date when the tumor volume was measured.
T/C(％)＝(测试施用组的平均RTV)/(溶媒对照组的平均RTV)×100％T/C(%)=(average RTV of test administration group)/(average RTV of vehicle control group)×100%
TGI(％)＝(1-T/C)×100％TGI(%)=(1-T/C)×100%
为了确定毒性指标，随时间测量小鼠的体重(Boby weight：BW)，并由下列等式计算从分组日(第0天)至最后一天的平均体重变化(Boby weight change：BWC(％))。图5至图8显示出该结果。In order to determine the toxicity index, the weight of mice (Boby weight: BW) was measured over time, and the average weight change from the grouping day (day 0) to the last day (Boby weight change: BWC (%)) was calculated by the following equation . Figures 5 to 8 show the results.
BWC(％)＝[(第t天的BW)-(第0天的BW)]/(第0天的BW)×100％，其中，t表示测量体重的日期。BWC(%)=[(BW on day t)-(BW on day 0)]/(BW on day 0)×100%, where t represents the date when the weight was measured.
表6：在NCI-N87细胞体内模型中各组抗肿瘤效果Table 6: Anti-tumor effects of each group in the NCI-N87 cell in vivo model
Figure PCTCN2021076684-appb-000067
Figure PCTCN2021076684-appb-000067
表7：在BT-474细胞体内模型中各组抗肿瘤效果Table 7: Anti-tumor effects of each group in the BT-474 cell in vivo model
Figure PCTCN2021076684-appb-000068
Figure PCTCN2021076684-appb-000068
从图1至图4以及表6和7清楚看出，在NCI-N87和BT-474的小鼠模型中，相比于TAS0728，本发明化合物表现出更加显著的抗肿瘤效果。如图5至图8所示，本发明化合物没有观察到毒性(如体重减轻)。It is clear from Figures 1 to 4 and Tables 6 and 7 that in the mouse models of NCI-N87 and BT-474, compared to TAS0728, the compound of the present invention exhibits a more significant anti-tumor effect. As shown in Figures 5 to 8, no toxicity (such as weight loss) was observed for the compounds of the present invention.
以上内容是结合具体的优选实施方式对本发明所作的进一步详细说明，不能认定本发明的具体实施只局限于这些说明。对于本发明所属技术领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干简单推演或替换，都应当视为属于本发明的保护范围。The above content is a further detailed description of the present invention in combination with specific preferred embodiments, and it cannot be considered that the specific implementation of the present invention is limited to these descriptions. For those of ordinary skill in the technical field to which the present invention belongs, a number of simple deductions or substitutions can be made without departing from the concept of the present invention, which should be regarded as falling within the protection scope of the present invention.

Claims (31)

  1. 式(I)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物：The compound of formula (I), or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate:
    Figure PCTCN2021076684-appb-100001
    Figure PCTCN2021076684-appb-100001
    其中，in,
    环A为芳香环；Ring A is an aromatic ring;
    A 1为CR A1或N原子； A 1 is CR A1 or N atom;
    A 2、A 3和A 5各自独立地为C或N原子； A 2 , A 3 and A 5 are each independently a C or N atom;
    A 4为CR A4、N原子或NR A4； A 4 is CR A4 , N atom or NR A4 ;
    前提是，当A 1和A 3是N，且A 2和A 5是C时，A 4不为N； The premise is that when A 1 and A 3 are N, and A 2 and A 5 are C, A 4 is not N;
    R A1和R A4各自独立地为H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；且上述基团任选地被一个或多个R”取代； 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为CR B1或N； B 1 is CR B1 or N;
    B 2为CR B2或N； B 2 is CR B2 or N;
    B 3为CR B3或N； B 3 is CR B3 or N;
    B 4为CR B4或N； B 4 is CR B4 or N;
    R B1、R B2、R B3和R B4各自独立地选自H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；或者，R B1和R B2、R B3和R B4可以分别与它们所连接的C原子一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；且上述基团任选地被一个或多个R”取代； 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 and R B4 may be respectively connected to the C atom to which they are attached Together to 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″;
    W选自键、O、S、NR N或CR C1R C2； W is selected from bond, O, S, NR N or CR C1 R C2 ;
    R N选自H、C 1-6烷基或C 1-6卤代烷基，且上述基团任选地被一个或多个R*取代； 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和R C2各自独立地选自H、D、卤素、C 1-6烷基或C 1-6卤代烷基，且上述基团任选地被一个或多个R*取代； 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选自键、O、S、NR N或(CR C1R C2) p； L is selected from bond, O, S, NR N or (CR C1 R C2 ) p ;
    p＝0、1或2；p=0, 1 or 2;
    Y选自C 1-6烷基、C 3-7环烷基或3至7元杂环基，且上述基团任选地被m个R取代； 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选自-C(O)-、-C(O)NR N-*、-S(O) 2-或-S(O) 2NR N-*，其中*表示与Y相连接； Z is selected from -C(O)-, -C(O)NR N -*, -S(O) 2 -or -S(O) 2 NR N -*, where * means connected to Y;
    V为-C(R 5)＝C(R 4)(R 3)； V is -C(R 5 )=C(R 4 )(R 3 );
    R 3选自H、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，且上述基团任选地被一个或多个R*取代； 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和R 5各自独立地选自H、卤素、-CN、C 1-6烷基或C 1-6卤代烷基，且上述基团任选地被一个或多个R*取代；或者，R 4和R 5连同它们所连接的双键一起形成叁键； 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和R 2各自独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；或者，R 1和R 2连同它们所连接的N原子一起形成3至7元杂环基或5至10元杂芳基；且上述基团任选地被一个或多个R’取代； 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';
    每个R’各自独立地选自H、D、卤素、-CN、＝O、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，或者，相同原子或相邻原子上的两个R’基团可以一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；其中R’定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R'is independently selected from H, D, halogen, -CN, =0, 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 two R'groups on the same atom or adjacent atoms can form a C 3-7 cycloalkyl group together , 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group; wherein each group in the definition of R'is optionally substituted with one or more D until fully deuterated;
    每个R”各自独立地选自H、D、卤素、-CN、＝O、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，或者，相同原子或相邻原子上的两个R”基团可以一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；其中R”定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R" is independently selected from H, D, halogen, -CN, =0, 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 two R" groups on the same atom or adjacent atoms can form a C 3-7 cycloalkyl group together , 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group; wherein each group in the definition of R" is optionally substituted by one or more D until it is fully deuterated;
    每个R*各自独立地选自H、D、卤素、-CN、＝O、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；或者，相同原子或相邻原子上的两个R*基团可以一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；其中R*定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R* is independently selected from H, D, halogen, -CN, =O, 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, two R* groups on the same atom or adjacent atoms can form a C 3-7 cycloalkyl group together , 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group; wherein each group in the definition of R* is optionally substituted by one or more D until fully deuterated;
    每个R各自独立地选自H、D、卤素、-CN、＝O、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；或者，相同原子或相邻原子上的两个R基团可以一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；其中R定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R is independently selected from H, D, halogen, -CN, =O, 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, A 3- to 7-membered heterocyclic group, a C 6-10 aryl group or a 5- to 10-membered heteroaryl group; alternatively, two R groups on the same atom or adjacent atoms can form a C 3-7 cycloalkyl group, 3 To 7-membered heterocyclyl, C 6-10 aryl or 5 to 10-membered heteroaryl; wherein each group in the definition of R is optionally substituted with one or more D until fully deuterated;
    m＝0、1、2、3、4、5、6、7、8或9；m=0, 1, 2, 3, 4, 5, 6, 7, 8 or 9;
    每个R a、R b和R c各自独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，或者R b和R c连同它们所连接的N原子一起形成3至7元杂环基或5至10元杂芳基；其中R a、R b和R c定义中的每个基团任选地被一个或多个D取代，直至完全氘代。 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.
  2. 根据权利要求1所述的化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，The compound according to claim 1, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:
    Figure PCTCN2021076684-appb-100002
    选自以下结构：
    Figure PCTCN2021076684-appb-100002
    Selected from the following structures:
    Figure PCTCN2021076684-appb-100003
    Figure PCTCN2021076684-appb-100003
    优选地，Preferably,
    Figure PCTCN2021076684-appb-100004
    选自以下结构：
    Figure PCTCN2021076684-appb-100004
    Selected from the following structures:
    Figure PCTCN2021076684-appb-100005
    Figure PCTCN2021076684-appb-100005
    优选地，Preferably,
    Figure PCTCN2021076684-appb-100006
    选自以下结构：
    Figure PCTCN2021076684-appb-100006
    Selected from the following structures:
    Figure PCTCN2021076684-appb-100007
    Figure PCTCN2021076684-appb-100007
    优选地，Preferably,
    Figure PCTCN2021076684-appb-100008
    选自以下结构：
    Figure PCTCN2021076684-appb-100008
    Selected from the following structures:
    Figure PCTCN2021076684-appb-100009
    Figure PCTCN2021076684-appb-100009
  3. 根据权利要求1或2所述的化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，The compound according to claim 1 or 2, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:
    Y选自至少含有一个N原子的3至7元杂环基，且N原子与Z相连，其中所述3至7元杂环基任选地被m个R取代；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选自-C(O)-；Z is selected from -C(O)-;
    V选自-CH＝CH(R 3)，其中，R 3选自H、C 1-6烷基或C 1-6卤代烷基，且上述基团任选地被一个或多个R*取代； V is selected from -CH=CH(R 3 ), wherein R 3 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*;
    优选地，Preferably,
    Y选自至少含有一个N原子的3至7元杂环基，且N原子与Z相连，其中所述3至7元杂环基 任选地被m个选自D、卤素、C 1-6烷基或C 1-6卤代烷基的取代基取代； 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选自-C(O)-；Z is selected from -C(O)-;
    V选自-CH＝CH(R 3)，其中，R 3选自H或被-NR bR c取代的C 1-6烷基或C 1-6卤代烷基； V is selected from -CH=CH(R 3 ), wherein R 3 is selected from H or C 1-6 alkyl or C 1-6 haloalkyl substituted by -NR b R c;
    优选地，Preferably,
    Y选自吡咯烷基或哌啶基，且N原子与Z相连，其中所述吡咯烷基和哌啶基任选地被一个或多个选自D、卤素、C 1-6烷基或C 1-6卤代烷基的取代基取代； 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选自-C(O)-；Z is selected from -C(O)-;
    V选自-CH＝CH(R 3)，其中，R 3选自H或被-NR bR c取代的C 1-6烷基或C 1-6卤代烷基； V is selected from -CH=CH(R 3 ), wherein R 3 is selected from H or C 1-6 alkyl or C 1-6 haloalkyl substituted by -NR b R c;
    优选地，Preferably,
    Y选自吡咯烷基、甲基吡咯烷基、哌啶基或氟代哌啶基，且N原子与Z相连；Y is selected from pyrrolidinyl, methylpyrrolidinyl, piperidinyl or fluoropiperidinyl, and the N atom is connected to Z;
    Z选自-C(O)-；Z is selected from -C(O)-;
    V选自-CH＝CH(R 3)，其中，R 3选自H或被-NR bR c取代的C 1-6烷基或C 1-6卤代烷基； V is selected from -CH=CH(R 3 ), wherein R 3 is selected from H or C 1-6 alkyl or C 1-6 haloalkyl substituted by -NR b R c;
    优选地，-Y-Z-V选自以下结构：Preferably, -Y-Z-V is selected from the following structures:
    Figure PCTCN2021076684-appb-100010
    Figure PCTCN2021076684-appb-100010
    其中，n＝0、1或2，其他基团如权利要求1所述；Wherein, n=0, 1 or 2, and other groups are as described in claim 1;
    优选地，-Y-Z-V选自以下结构：Preferably, -Y-Z-V is selected from the following structures:
    Figure PCTCN2021076684-appb-100011
    Figure PCTCN2021076684-appb-100011
    优选地，-Y-Z-V选自以下结构：Preferably, -Y-Z-V is selected from the following structures:
    Figure PCTCN2021076684-appb-100012
    Figure PCTCN2021076684-appb-100012
  4. 根据权利要求1-3中任一项所述的化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，W为CH 2、CHD或CD 2。 The compound according to any one of claims 1 to 3, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein: W is CH 2 , CHD or CD 2 .
  5. 根据权利要求1-4中任一项所述的化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R B1、R B2、R B3和R B4各自独立地选自H、D、F、Cl、Br、-CN、-CH＝CH 2、-OMe、-OCH 2F、-OCHF 2、-Me、-Et、-N(Me) 2、环丙基或呋喃基，或者R B1和R B2、或R B3和R B4分别与它们所连接的碳原子一起形成苯环、吡啶环或二氧戊环；优选地，R B1、R B2、R B3和R B4不同时为H；优选地，R B1和R B2均为非氢基团。 The compound according to any one of claims 1 to 4, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein: R B1 , R B2 , R B3 and R B4 are each independently selected from H, D, F, Cl, Br, -CN, -CH=CH 2 , -OMe, -OCH 2 F, -OCHF 2 , -Me, -Et, -N(Me) 2 , cyclopropyl or furanyl, or R B1 and R B2 , or R B3 and R B4 together with the carbon atoms to which they are connected to form a benzene ring, a pyridine ring or a dioxolane ring ; Preferably, R B1 , R B2 , R B3 and R B4 are not H at the same time; preferably, R B1 and R B2 are both non-hydrogen groups.
  6. 根据权利要求1-5中任一项所述的化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，R 1和R 2各自独立地选自H、-OMe、-Me或苯基，或者 The compound according to any one of claims 1 to 5, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein: R 1 and R 2 are each independently selected from H, -OMe, -Me or phenyl, or
    R 1和R 2连同它们所连接的N原子一起形成任选的被羟基取代的氮杂环丁烷基、吡咯烷基或哌啶基。 R 1 and R 2 together with the N atom to which they are attached form an azetidinyl, pyrrolidinyl or piperidinyl group optionally substituted with a hydroxy group.
  7. 根据权利要求1-6中任一项所述的化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其为式(II)、式(III)或式(IV)化合物：The compound according to any one of claims 1-6, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, which is Compound of formula (II), formula (III) or formula (IV):
    Figure PCTCN2021076684-appb-100013
    Figure PCTCN2021076684-appb-100013
    其中，各基团如权利要求1-6中任一项定义。Wherein, each group is as defined in any one of claims 1-6.
  8. 根据权利要求1-6中任一项所述的化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其为式(III-1)：The compound according to any one of claims 1-6, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, which is Formula (III-1):
    Figure PCTCN2021076684-appb-100014
    Figure PCTCN2021076684-appb-100014
    其中，各基团如权利要求1-6中任一项定义；Wherein, each group is as defined in any one of claims 1-6;
    优选地，Preferably,
    A 2和A 3各自独立地为C或N原子； A 2 and A 3 are each independently a C or N atom;
    R B1、R B2、R B3和R B4各自独立地选自卤素、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；或者，R B1和R B2可以与它们所连接的C原子一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；且上述基团任选地被一个或多个R”取代； 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 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 3选自H、卤素、-CN、C 1-6烷基或C 1-6卤代烷基，且上述基团任选地被一个或多个R*取代； 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和R 5各自独立地选自H、卤素、-CN、C 1-6烷基或C 1-6卤代烷基，且上述基团任选地被一个或多个R*取代；或者，R 4和R 5连同它们所连接的双键一起形成叁键； 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和R 2各自独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；或者，R 1和R 2连同它们所连接的N原子一起形成3至7元杂环基或5至10元杂芳基；且上述基团任选地被一个或多个R’取代； 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';
    每个R’各自独立地选自H、D、卤素、-CN、＝O、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，或者，相同原子或相邻原子上的两个R’基团可以一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；其中R’定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R'is independently selected from H, D, halogen, -CN, =0, 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 two R'groups on the same atom or adjacent atoms can form a C 3-7 cycloalkyl group together , 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group; wherein each group in the definition of R'is optionally substituted with one or more D until fully deuterated;
    每个R”各自独立地选自H、D、卤素、-CN、＝O、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，或者，相同原子或相邻原子上的两个R”基团可以一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；其中R”定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R" is independently selected from H, D, halogen, -CN, =0, 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 two R" groups on the same atom or adjacent atoms can form a C 3-7 cycloalkyl group together , 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group; wherein each group in the definition of R" is optionally substituted by one or more D until it is fully deuterated;
    每个R*各自独立地选自H、D、卤素、-CN、＝O、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；或者，相同原子或相邻原子上的两个R*基团可以一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；其中R*定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R* is independently selected from H, D, halogen, -CN, =O, 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, two R* groups on the same atom or adjacent atoms can form a C 3-7 cycloalkyl group together , 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group; wherein each group in the definition of R* is optionally substituted by one or more D until fully deuterated;
    每个R各自独立地选自H、D、卤素、-CN、＝O、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；或者，相同原子或相邻原子上的两个R基团可以一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；其中R定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R is independently selected from H, D, halogen, -CN, =O, 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, A 3- to 7-membered heterocyclic group, a C 6-10 aryl group or a 5- to 10-membered heteroaryl group; alternatively, two R groups on the same atom or adjacent atoms can form a C 3-7 cycloalkyl group, 3 To 7-membered heterocyclyl, C 6-10 aryl or 5 to 10-membered heteroaryl; wherein each group in the definition of R is optionally substituted with one or more D until fully deuterated;
    m＝0、1、2、3、4或5；m=0, 1, 2, 3, 4 or 5;
    n＝0、1或2；n=0, 1 or 2;
    每个R a、R b和R c各自独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，或者R b和R c连同它们所连接的N原子一起形成3至7元杂环基或5至10元杂芳基；其中R a、R b和R c定义中的每个基团任选地被一个或多个D取代，直至完全氘代。 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.
  9. 根据权利要求8所述的化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其为式(III-2)：The compound according to claim 8, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, which is of formula (III-2) :
    Figure PCTCN2021076684-appb-100015
    Figure PCTCN2021076684-appb-100015
    其中，in,
    A 2和A 3各自独立地为C或N原子； A 2 and A 3 are each independently a C or N atom;
    R B1和R B2各自独立地选自卤素、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；或者，R B1和R B2可以与它们所连接的C原子一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；且上述基团任选地被一个或多个R”取代； 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 to 7 membered heterocyclic group together with the C atom to which they are attached , C 6-10 aryl or 5 to 10-membered heteroaryl; and the above-mentioned groups are optionally substituted by one or more R″;
    R 1和R 2各自独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；或者，R 1和R 2连同它们所连接的N原子一起形成3至7 元杂环基或5至10元杂芳基；且上述基团任选地被一个或多个R’取代； 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';
    每个R’各自独立地选自H、D、卤素、-CN、＝O、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，或者，相同原子或相邻原子上的两个R’基团可以一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；其中R’定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R'is independently selected from H, D, halogen, -CN, =0, 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 two R'groups on the same atom or adjacent atoms can form a C 3-7 cycloalkyl group together , 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group; wherein each group in the definition of R'is optionally substituted with one or more D until fully deuterated;
    每个R”各自独立地选自H、D、卤素、-CN、＝O、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，或者，相同原子或相邻原子上的两个R”基团可以一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；其中R”定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R" is independently selected from H, D, halogen, -CN, =0, 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 two R" groups on the same atom or adjacent atoms can form a C 3-7 cycloalkyl group together , 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group; wherein each group in the definition of R" is optionally substituted by one or more D until it is fully deuterated;
    每个R a、R b和R c各自独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，或者R b和R c连同它们所连接的N原子一起形成3至7元杂环基或5至10元杂芳基；其中R a、R b和R c定义中的每个基团任选地被一个或多个D取代，直至完全氘代。 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.
  10. 根据权利要求9所述的化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，The compound according to claim 9, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:
    A 2和A 3各自独立地为C或N原子； A 2 and A 3 are each independently a C or N atom;
    R B1和R B2各自独立地选自C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基；或者，R B1和R B2可以与它们所连接的C原子一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；且上述基团任选地被一个或多个R”取代； 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和R 2各自独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基；或者，R 1和R 2连同它们所连接的N原子一起形成3至7元杂环基或5至10元杂芳基；且上述基团任选地被一个或多个R’取代； 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 The linked N atoms together form a 3- to 7-membered heterocyclic group or a 5- to 10-membered heteroaryl group; and the above-mentioned groups are optionally substituted by one or more R′;
    每个R’各自独立地选自H、D、卤素、-CN、＝O、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，或者，相同原子或相邻原子上的两个R’基团可以一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；其中R’定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R'is independently selected from H, D, halogen, -CN, =0, 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 two R'groups on the same atom or adjacent atoms can form a C 3-7 cycloalkyl group together , 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group; wherein each group in the definition of R'is optionally substituted with one or more D until fully deuterated;
    每个R”各自独立地选自H、D、卤素、-CN、＝O、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，或者，相同原子或相邻原子上的两个R”基团可以一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；其中R”定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R" is independently selected from H, D, halogen, -CN, =0, 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 two R" groups on the same atom or adjacent atoms can form a C 3-7 cycloalkyl group together , 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group; wherein each group in the definition of R" is optionally substituted by one or more D until it is fully deuterated;
    每个R a、R b和R c各自独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，或者R b和R c连同它们所连接的N原子一起形成3至7元杂环基或5至10元杂芳基；其中R a、R b和R c定义中的每个基团任选地被一个或多个D取代，直至完全氘代。 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.
  11. 根据权利要求10所述的化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，The compound according to claim 10, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:
    A 2和A 3各自独立地为C或N原子； A 2 and A 3 are each independently a C or N atom;
    R B1和R B2各自独立地选自C 1-6烷基或C 1-6卤代烷基；或者，R B1和R B2可以与它们所连接的C原子一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；且上述基团任选地被一个或多个R”取代； 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和R 2各自独立地选自C 1-6烷基或C 1-6卤代烷基；或者，R 1和R 2连同它们所连接的N原子一起形成3至7元杂环基或5至10元杂芳基；且上述基团任选地被一个或多个R’取代； 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';
    每个R’各自独立地选自H、D、卤素、-CN、＝O、-NR bR c或-OR a；其中R’定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R'is independently selected from H, D, halogen, -CN, =O, -NR b R c or -OR a ; wherein each group in the definition of R'is optionally substituted by one or more D Replacement until fully deuterated;
    每个R”各自独立地选自H、D、卤素、-CN、＝O、-NR bR c或-OR a；其中R”定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R" is independently selected from H, D, halogen, -CN, =O, -NR b R c or -OR a ; wherein each group in the definition of R "is optionally substituted by one or more D Replacement until fully deuterated;
    每个R a、R b和R c各自独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基，或者R b和R c连同它们所连接的N原子一起形成3至7元杂环基或5至10元杂芳基；其中R a、R b和R c定义中的每个基团任选地被一个或多个D取代，直至完全氘代。 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.
  12. 根据权利要求11所述的化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，The compound according to claim 11, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:
    A 2和A 3各自独立地为C或N原子； A 2 and A 3 are each independently a C or N atom;
    R B1和R B2均为甲基，且其任选地被一个或多个R”取代； R B1 and R B2 are both methyl, and they are optionally substituted with one or more R″;
    R 1和R 2均为甲基，且其任选地被一个或多个R’取代； R 1 and R 2 are both methyl, and they are optionally substituted with one or more R′;
    每个R’各自独立地选自H、D、卤素、-CN、＝O、-NH 2或-OH； Each R'is independently selected from H, D, halogen, -CN, =O, -NH 2 or -OH;
    每个R”各自独立地选自H、D、卤素、-CN、＝O、-NH 2或-OH。 Each R" is independently selected from H, D, halogen, -CN, =O, -NH 2 or -OH.
  13. 根据权利要求1-6中任一项所述的化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其为式(IV-1)：The compound according to any one of claims 1-6, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, which is Formula (IV-1):
    Figure PCTCN2021076684-appb-100016
    Figure PCTCN2021076684-appb-100016
    其中，各基团如权利要求1-6中任一项定义；Wherein, each group is as defined in any one of claims 1-6;
    优选地，Preferably,
    A 1为CR A1或N原子； A 1 is CR A1 or N atom;
    A 4为CR A4或N原子； A 4 is CR A4 or N atom;
    优选地，A 1和A 4不同时为N原子； Preferably, A 1 and A 4 are not N atoms at the same time;
    R A1和R A4各自独立地为H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；且上述基团任选地被一个或多个R”取代； 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和R B4各自独立地选自卤素、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；或者，R B1和R B2、R B3和R B4可以分别与它们所连接的C原子一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；且上述基团任选地被一个或多个R”取代； 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 B4 can form C 3 together with the C atom to which they are attached. -7 cycloalkyl, 3 to 7 membered heterocyclyl, C 6-10 aryl or 5 to 10 membered heteroaryl; and the above groups are optionally substituted by one or more R″;
    R 3选自H、卤素、-CN、C 1-6烷基或C 1-6卤代烷基，且上述基团任选地被一个或多个R*取代； 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和R 5各自独立地选自H、卤素、-CN、C 1-6烷基或C 1-6卤代烷基，且上述基团任选地被一个或多个R*取代；或者，R 4和R 5连同它们所连接的双键一起形成叁键； 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和R 2各自独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；或者，R 1和R 2连同它们所连接的N原子一起形成3至7元杂环基或5至10元杂芳基；且上述基团任选地被一个或多个R’取代； 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';
    每个R’各自独立地选自H、D、卤素、-CN、＝O、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，或者，相同原子或相邻原子上的两个R’基团可以一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；其中R’定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R'is independently selected from H, D, halogen, -CN, =0, 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 two R'groups on the same atom or adjacent atoms can form a C 3-7 cycloalkyl group together , 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group; wherein each group in the definition of R'is optionally substituted with one or more D until fully deuterated;
    每个R”各自独立地选自H、D、卤素、-CN、＝O、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，或者，相同原子或相邻原子上的两个R”基团可以一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；其中R”定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R" is independently selected from H, D, halogen, -CN, =0, 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 two R" groups on the same atom or adjacent atoms can form a C 3-7 cycloalkyl group together , 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group; wherein each group in the definition of R" is optionally substituted by one or more D until it is fully deuterated;
    每个R*各自独立地选自H、D、卤素、-CN、＝O、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；或者，相同原子或相邻原子上的两个R*基团可以一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；其中R*定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R* is independently selected from H, D, halogen, -CN, =O, 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, two R* groups on the same atom or adjacent atoms can form a C 3-7 cycloalkyl group together , 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group; wherein each group in the definition of R* is optionally substituted by one or more D until fully deuterated;
    每个R各自独立地选自H、D、卤素、-CN、＝O、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；或者，相同原子或相邻原子上的两个R基团可以一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；其中R定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R is independently selected from H, D, halogen, -CN, =O, 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, A 3- to 7-membered heterocyclic group, a C 6-10 aryl group or a 5- to 10-membered heteroaryl group; alternatively, two R groups on the same atom or adjacent atoms can form a C 3-7 cycloalkyl group, 3 To 7-membered heterocyclyl, C 6-10 aryl or 5 to 10-membered heteroaryl; wherein each group in the definition of R is optionally substituted with one or more D until fully deuterated;
    m＝0、1、2、3、4或5；m=0, 1, 2, 3, 4 or 5;
    n＝0、1或2；n=0, 1 or 2;
    每个R a、R b和R c各自独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，或者R b和R c连同它们所连接的N原子一起形成3至7元杂环基或5至10元杂芳基；其中R a、R b和R c定义中的每个基团任选地被一个或多个D取代，直至完全氘代。 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.
  14. 根据权利要求13所述的化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其为式(IV-2)：The compound according to claim 13, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, which is of formula (IV-2) :
    Figure PCTCN2021076684-appb-100017
    Figure PCTCN2021076684-appb-100017
    其中，in,
    A 1为CR A1或N原子； A 1 is CR A1 or N atom;
    A 4为CR A4或N原子； A 4 is CR A4 or N atom;
    优选地，A 1和A 4不同时为N原子； Preferably, A 1 and A 4 are not N atoms at the same time;
    R A1和R A4各自独立地为H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；且上述基团任选地被一个或多个R”取代； 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和R B2各自独立地选自卤素、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；或者，R B1和R B2可以与它们所连接的C原子一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；且上述基团任选地被一个或多个R”取代； 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 to 7 membered heterocyclic group together with the C atom to which they are attached , C 6-10 aryl or 5 to 10-membered heteroaryl; and the above-mentioned groups are optionally substituted by one or more R″;
    R 1和R 2各自独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；或者，R 1和R 2连同它们所连接的N原子一起形成3至7元杂环基或5至10元杂芳基；且上述基团任选地被一个或多个R’取代； 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';
    每个R’各自独立地选自H、D、卤素、-CN、＝O、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，或者，相同原子或相邻原子上的两个R’基团可以一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；其中R’定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R'is independently selected from H, D, halogen, -CN, =0, 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 two R'groups on the same atom or adjacent atoms can form a C 3-7 cycloalkyl group together , 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group; wherein each group in the definition of R'is optionally substituted with one or more D until fully deuterated;
    每个R”各自独立地选自H、D、卤素、-CN、＝O、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，或者，相同原子或相邻原子上的两个R”基团可以一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；其中R”定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R" is independently selected from H, D, halogen, -CN, =0, 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 two R" groups on the same atom or adjacent atoms can form a C 3-7 cycloalkyl group together , 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group; wherein each group in the definition of R" is optionally substituted by one or more D until it is fully deuterated;
    每个R a、R b和R c各自独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，或者R b和R c连同它们所连接的N原子一起形成3至7元杂环基或5至10元杂芳基；其中R a、R b和R c定义中的每个基团任选地被一个或多个D取代，直至完全氘代。 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.
  15. 根据权利要求14所述的化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，The compound according to claim 14, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:
    A 1为CR A1或N原子； A 1 is CR A1 or N atom;
    A 4为CR A4或N原子； A 4 is CR A4 or N atom;
    R A1和R A4各自独立地为H或D； R A1 and R A4 are each independently H or D;
    R B1和R B2各自独立地选自C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基；或者，R B1和R B2可以与它们所连接的C原子一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；且上述基团任选地被一个或多个R”取代； 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和R 2各自独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基；或者，R 1和R 2连同它们所连接的N原子一起形成3至7元杂环基或5至10元杂芳基；且上述基团任选地被一个或多个R’取代； 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 The linked N atoms together form a 3- to 7-membered heterocyclic group or a 5- to 10-membered heteroaryl group; and the above-mentioned groups are optionally substituted by one or more R′;
    每个R’各自独立地选自H、D、卤素、-CN、＝O、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，或者，相同原子或相邻原子上的两个R’基团可以一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；其中R’定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R'is independently selected from H, D, halogen, -CN, =0, 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 two R'groups on the same atom or adjacent atoms can form a C 3-7 cycloalkyl group together , 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group; wherein each group in the definition of R'is optionally substituted with one or more D until fully deuterated;
    每个R”各自独立地选自H、D、卤素、-CN、＝O、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C(O)R a、-C(O)OR a、-C(O)NR bR c、-NR bR c、-NR aC(O)R b、-NR aC(O)OR b、-NR aC(O)NR bR c、-OR a、-OC(O)R a、-OC(O)OR a、-OC(O)NR bR c、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，或者，相同原子或相邻原子上的两个R”基团可以一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；其中R”定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R" is independently selected from H, D, halogen, -CN, =0, 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 two R" groups on the same atom or adjacent atoms can form a C 3-7 cycloalkyl group together , 3 to 7 membered heterocyclic group, C 6-10 aryl group or 5 to 10 membered heteroaryl group; wherein each group in the definition of R" is optionally substituted by one or more D until it is fully deuterated;
    每个R a、R b和R c各自独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基，或者R b和R c连同它们所连接的N原子一起形成3至7元杂环基或5至10元杂芳基；其中R a、R b和R c定义中的每个基团任选地被一个或多个D取代，直至完全氘代。 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.
  16. 根据权利要求15所述的化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，The compound according to claim 15, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:
    A 1为CR A1或N原子； A 1 is CR A1 or N atom;
    A 4为CR A4或N原子； A 4 is CR A4 or N atom;
    R A1和R A4各自独立地为H或D； R A1 and R A4 are each independently H or D;
    优选地，A 1和A 4不同时为N原子； Preferably, A 1 and A 4 are not N atoms at the same time;
    R B1和R B2各自独立地选自C 1-6烷基或C 1-6卤代烷基；或者，R B1和R B2可以分别与它们所连接的C原子一起形成C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基；且上述基团任选地被一个或多个R”取代； 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和R 2各自独立地选自C 1-6烷基或C 1-6卤代烷基；或者，R 1和R 2连同它们所连接的N原子一起形成3至7元杂环基或5至10元杂芳基；且上述基团任选地被一个或多个R’取代； 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';
    每个R’各自独立地选自H、D、卤素、-CN、＝O、-NR bR c或-OR a；其中R’定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R'is independently selected from H, D, halogen, -CN, =O, -NR b R c or -OR a ; wherein each group in the definition of R'is optionally substituted by one or more D Replacement until fully deuterated;
    每个R”各自独立地选自H、D、卤素、-CN、＝O、-NR bR c或-OR a；其中R”定义中的每个基团任选地被一个或多个D取代，直至完全氘代； Each R" is independently selected from H, D, halogen, -CN, =O, -NR b R c or -OR a ; wherein each group in the definition of R "is optionally substituted by one or more D Replacement until fully deuterated;
    每个R a、R b和R c各自独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基，或者R b和R c连同它们所连接的N原子一起形成3至7元杂环基或5至10元杂芳基；其中R a、R b和R c定义 中的每个基团任选地被一个或多个D取代，直至完全氘代。 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.
  17. 根据权利要求16所述的化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，其中，The compound according to claim 16, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:
    A 1为CR A1或N原子； A 1 is CR A1 or N atom;
    A 4为CR A4或N原子； A 4 is CR A4 or N atom;
    优选地，A 1和A 4不同时为N原子； Preferably, A 1 and A 4 are not N atoms at the same time;
    R A1和R A4均为H； R A1 and R A4 are both H;
    R B1和R B2均为甲基，且其任选地被一个或多个R”取代； R B1 and R B2 are both methyl, and they are optionally substituted with one or more R″;
    R 1和R 2均为甲基，且其任选地被一个或多个R’取代； R 1 and R 2 are both methyl, and they are optionally substituted with one or more R′;
    每个R’各自独立地选自H、D、卤素、-CN、＝O、-NH 2或-OH； Each R'is independently selected from H, D, halogen, -CN, =O, -NH 2 or -OH;
    每个R”各自独立地选自H、D、卤素、-CN、＝O、-NH 2或-OH。 Each R" is independently selected from H, D, halogen, -CN, =O, -NH 2 or -OH.
  18. 化合物或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，所述化合物选自：The compound or its tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, the compounds are selected from:
    Figure PCTCN2021076684-appb-100018
    Figure PCTCN2021076684-appb-100018
    Figure PCTCN2021076684-appb-100019
    Figure PCTCN2021076684-appb-100019
  19. 药物组合物，其含有权利要求1-18中任一项的化合物或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，和药学上可接受的赋形剂。A pharmaceutical composition containing the compound of any one of claims 1-18 or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, And pharmaceutically acceptable excipients.
  20. 权利要求1-18中任一项的化合物或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，或权利要求19的药物组合物在制备用于治疗和/或预防野生的和/或突变的EGFR激酶介导的肿瘤的药物中的用途；The compound of any one of claims 1-18 or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, or the drug of claim 19 Use of the composition in the preparation of a medicament for the treatment and/or prevention of wild and/or mutant EGFR kinase-mediated tumors;
    优选地，其中所述突变的EGFR选自外显子20***突变型EGFR、外显子18点突变型EGFR、外显子21点突变型EGFR、外显子19缺失突变型EGFR或L858R突变型EGFR；Preferably, the mutated 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;
    优选地，其中所述外显子20***突变选自V769_D770insASV、D770_N771insSVD、D770_N771insNPG、D770_N771insG、H773_V774insNPH或H773_V774insPH；Preferably, wherein the exon 20 insertion mutation is selected from V769_D770insASV, D770_N771insSVD, D770_N771insNPG, D770_N771insG, H773_V774insNPH or H773_V774insPH;
    优选地，其中所述外显子18点突变选自G719A、G719S、G719C、E709K和E709A中的至少一种突变；Preferably, wherein the exon 18 point mutation is selected from at least one mutation of G719A, G719S, G719C, E709K and E709A;
    优选地，其中所述外显子21点突变选自L861Q突变；Preferably, wherein the exon 21 point mutation is selected from the L861Q mutation;
    优选地，其中所述突变的EGFR还同时具有T790M突变。Preferably, the mutated EGFR also has a T790M mutation at the same time.
  21. 权利要求1-18中任一项的化合物或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，或权利要求19的药物组合物在制备用于治疗和/或预防以下肿瘤的药物中的用途：肺癌、乳腺癌、头颈癌、脑肿瘤、子宫癌、造血***肿瘤或皮肤癌。The compound of any one of claims 1-18 or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, or the drug of claim 19 Use of the composition in the preparation of a medicament for treating and/or preventing the following tumors: lung cancer, breast cancer, head and neck cancer, brain tumor, uterine cancer, hematopoietic system tumor or skin cancer.
  22. 权利要求1-18中任一项的化合物或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，或权利要求19的药物组合物在制备用于治疗和/或预防野生的和/或突变的HER2激酶介导的肿瘤的药物中的用途；The compound of any one of claims 1-18 or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, or the drug of claim 19 Use of the composition in the preparation of a medicament for the treatment and/or prevention of wild and/or mutant HER2 kinase-mediated tumors;
    优选地，其中所述突变的HER2选自G309A突变型HER2、S310F突变型HER2、R678Q突变型 HER2、L775_T759缺失突变型HER2、D769H突变型HER2、V777L突变型HER2、V842I突变型HER2、R869C突变型HER2、L755S突变型HER2或ex20insYVMA突变型HER2；Preferably, 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;
    优选地，其中所述ex20insYVMA突变型HER2选自A775_G776insYVMA突变型HER2突变。Preferably, the ex20insYVMA mutant HER2 is selected from the group consisting of A775_G776insYVMA mutant HER2 mutations.
  23. 权利要求1-18中任一项的化合物或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，或权利要求19的药物组合物在制备用于治疗和/或预防以下肿瘤的药物中的用途：肺癌、胃癌或乳腺癌。The compound of any one of claims 1-18 or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, or the drug of claim 19 Use of the composition in the preparation of a medicament for treating and/or preventing the following tumors: lung cancer, gastric cancer or breast cancer.
  24. 一种在受试者中治疗和/或预防野生的和/或突变的EGFR激酶介导的肿瘤的方法，包括向所述受试者给药权利要求1-18中任一项的化合物或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，或权利要求19的药物组合物；A method for treating and/or preventing wild and/or mutant EGFR kinase-mediated tumors in a subject, comprising administering to the subject the compound of any one of claims 1-18 or Tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the pharmaceutical composition of claim 19;
    优选地，其中所述突变的EGFR选自外显子20***突变型EGFR、外显子18点突变型EGFR、外显子21点突变型EGFR、外显子19缺失突变型EGFR或L858R突变型EGFR；Preferably, the mutated 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;
    优选地，其中所述外显子20***突变选自V769_D770insASV、D770_N771insSVD、D770_N771insNPG、D770_N771insG、H773_V774insNPH或H773_V774insPH；Preferably, wherein the exon 20 insertion mutation is selected from V769_D770insASV, D770_N771insSVD, D770_N771insNPG, D770_N771insG, H773_V774insNPH or H773_V774insPH;
    优选地，其中所述外显子18点突变选自G719A、G719S、G719C、E709K和E709A中的至少一种突变；Preferably, wherein the exon 18 point mutation is selected from at least one mutation of G719A, G719S, G719C, E709K and E709A;
    优选地，其中所述外显子21点突变选自L861Q突变；Preferably, wherein the exon 21 point mutation is selected from the L861Q mutation;
    优选地，其中所述突变的EGFR还同时具有T790M突变。Preferably, the mutated EGFR also has a T790M mutation at the same time.
  25. 一种在受试者中治疗和/或预防以下肿瘤的方法：肺癌、乳腺癌、头颈癌、脑肿瘤、子宫癌、造血***肿瘤或皮肤癌，包括向所述受试者给药权利要求1-18中任一项的化合物或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，或权利要求19的药物组合物。A method for treating and/or preventing the following tumors in a subject: lung cancer, breast cancer, head and neck cancer, brain tumor, uterine cancer, hematopoietic tumor or skin cancer, comprising administering to the subject claim 1 -18 The compound or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, or the pharmaceutical composition of claim 19.
  26. 一种在受试者中治疗和/或预防野生的和/或突变的HER2激酶介导的肿瘤的方法，包括向所述受试者给药权利要求1-18中任一项的化合物或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，或权利要求19的药物组合物；A method for treating and/or preventing wild and/or mutant HER2 kinase-mediated tumors in a subject, comprising administering to the subject the compound of any one of claims 1-18 or Tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the pharmaceutical composition of claim 19;
    优选地，其中所述突变的HER2选自G309A突变型HER2、S310F突变型HER2、R678Q突变型HER2、L775_T759缺失突变型HER2、D769H突变型HER2、V777L突变型HER2、V842I突变型HER2、R869C突变型HER2、L755S突变型HER2或ex20insYVMA突变型HER2；Preferably, 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;
    优选地，其中所述ex20insYVMA突变型HER2选自A775_G776insYVMA突变型HER2突变。Preferably, the ex20insYVMA mutant HER2 is selected from the group consisting of A775_G776insYVMA mutant HER2 mutations.
  27. 一种在受试者中治疗和/或预防以下肿瘤的方法：肺癌、胃癌或乳腺癌，包括向所述受试者给药权利要求1-18中任一项的化合物或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，或权利要求19的药物组合物。A method of treating and/or preventing the following tumors in a subject: lung cancer, gastric cancer or breast cancer, comprising administering to the subject the compound of any one of claims 1-18 or its tautomers Forms, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the pharmaceutical composition of claim 19.
  28. 权利要求1-18中任一项的化合物或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，或权利要求19的药物组合物，其用于治疗和/或预防野生的和/或突变的EGFR激酶介导的肿瘤；The compound of any one of claims 1-18 or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, or the drug of claim 19 A composition for the treatment and/or prevention of wild and/or mutant EGFR kinase-mediated tumors;
    优选地，其中所述突变的EGFR选自外显子20***突变型EGFR、外显子18点突变型EGFR、外显子21点突变型EGFR、外显子19缺失突变型EGFR或L858R突变型EGFR；Preferably, the mutated 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;
    优选地，其中所述外显子20***突变选自V769_D770insASV、D770_N771insSVD、D770_N771insNPG、D770_N771insG、H773_V774insNPH或H773_V774insPH；Preferably, wherein the exon 20 insertion mutation is selected from V769_D770insASV, D770_N771insSVD, D770_N771insNPG, D770_N771insG, H773_V774insNPH or H773_V774insPH;
    优选地，其中所述外显子18点突变选自G719A、G719S、G719C、E709K和E709A中的至少一种突变；Preferably, wherein the exon 18 point mutation is selected from at least one mutation of G719A, G719S, G719C, E709K and E709A;
    优选地，其中所述外显子21点突变选自L861Q突变；Preferably, wherein the exon 21 point mutation is selected from the L861Q mutation;
    优选地，其中所述突变的EGFR还同时具有T790M突变。Preferably, the mutated EGFR also has a T790M mutation at the same time.
  29. 权利要求1-18中任一项的化合物或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，或权利要求19的药物组合物，其用于治疗和/或预防以下肿瘤：肺癌、乳腺癌、头颈癌、脑肿瘤、子宫癌、造血***肿瘤或皮肤癌。The compound of any one of claims 1-18 or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, or the drug of claim 19 The composition is used to treat and/or prevent the following tumors: lung cancer, breast cancer, head and neck cancer, brain tumor, uterine cancer, hematopoietic system tumor or skin cancer.
  30. 权利要求1-18中任一项的化合物或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，或权利要求19的药物组合物，其用于治疗和/或预防野生的和/或突变的HER2激酶介导的肿瘤；The compound of any one of claims 1-18 or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, or the drug of claim 19 A composition for the treatment and/or prevention of tumors mediated by wild and/or mutant HER2 kinase;
    优选地，其中所述突变的HER2选自G309A突变型HER2、S310F突变型HER2、R678Q突变型HER2、L775_T759缺失突变型HER2、D769H突变型HER2、V777L突变型HER2、V842I突变型HER2、R869C突变型HER2、L755S突变型HER2或ex20insYVMA突变型HER2；Preferably, 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;
    优选地，其中所述ex20insYVMA突变型HER2选自A775_G776insYVMA突变型HER2突变。Preferably, the ex20insYVMA mutant HER2 is selected from the group consisting of A775_G776insYVMA mutant HER2 mutations.
  31. 权利要求1-18中任一项的化合物或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂合物，或权利要求19的药物组合物，其用于治疗和/或预防以下肿瘤：肺癌、胃癌或乳腺癌。The compound of any one of claims 1-18 or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate, or the drug of claim 19 The composition is used to treat and/or prevent the following tumors: lung cancer, gastric cancer or breast cancer.
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WO2011153553A2 (en) * 2010-06-04 2011-12-08 The Regents Of The University Of California Methods and compositions for kinase inhibition
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WO2011153553A2 (en) * 2010-06-04 2011-12-08 The Regents Of The University Of California Methods and compositions for kinase inhibition
CN103857396A (en) * 2011-07-13 2014-06-11 药品循环公司 Inhibitors of bruton's tyrosine kinase
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