WO2021037219A1 - 用于fgfr抑制剂的吡唑类衍生物及其制备方法 - Google Patents

用于fgfr抑制剂的吡唑类衍生物及其制备方法 Download PDF

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WO2021037219A1
WO2021037219A1 PCT/CN2020/112173 CN2020112173W WO2021037219A1 WO 2021037219 A1 WO2021037219 A1 WO 2021037219A1 CN 2020112173 W CN2020112173 W CN 2020112173W WO 2021037219 A1 WO2021037219 A1 WO 2021037219A1
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alkyl
halogenated
group
unsubstituted
substituted
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PCT/CN2020/112173
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English (en)
French (fr)
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郑乾刚
陆继廷
姚佳奇
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上海奕拓医药科技有限责任公司
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Priority claimed from CN202010451000.9A external-priority patent/CN112441980A/zh
Application filed by 上海奕拓医药科技有限责任公司 filed Critical 上海奕拓医药科技有限责任公司
Priority to EP20857639.7A priority Critical patent/EP4023639A1/en
Priority to CA3152674A priority patent/CA3152674A1/en
Priority to KR1020227010195A priority patent/KR20220054840A/ko
Priority to AU2020335054A priority patent/AU2020335054A1/en
Priority to JP2022513305A priority patent/JP2022545930A/ja
Priority to US17/638,352 priority patent/US20220298143A1/en
Priority to CN202080059510.XA priority patent/CN114728910B/zh
Publication of WO2021037219A1 publication Critical patent/WO2021037219A1/zh

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    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/38—Nitrogen atoms
    • C07D231/40—Acylated on said nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention discloses a pyrazole derivative and a preparation method thereof, a pharmaceutical composition containing them, a method for preparing the pharmaceutical composition, and their use in the treatment of diseases.
  • Fibroblast growth factor is considered to be an important mediator of many physiological processes (such as morphogenesis during development and angiogenesis).
  • the fibroblast growth factor receptor (FGFR) family includes four members: FGFR1, FGFR2, FGFR3, and FGFR4, which are composed of an extracellular ligand binding domain, a single transmembrane domain, and an intracellular cytoplasmic protein tyrosine kinase domain. composition. Under FGF stimulation, FGFR undergoes dimerization and transphosphorylation, which leads to receptor activation. The activation of the receptor is sufficient to restore and activate specific downstream signal ligands, which are involved in various processes such as the regulation of cell growth, cell metabolism and cell survival. The result is that FGF and FGFR may cause and/or promote tumor formation.
  • FGF signaling is directly related to human cancer.
  • the expression of various FGFs is increased in different ranges of tumor types, such as bladder, kidney cells and prostate tumors.
  • FGF has also been described as a powerful angiogenic factor.
  • the FGFR4 signaling pathway one of its receptor members, is strictly controlled, but FGFR4 signaling dysregulation leads to the occurrence, development, survival and metastasis of cancer. Therefore, the fibroblast growth factor receptor FGFR is widely regarded as an important anti-tumor drug target.
  • AZD4547 disclosed in PCT/GB2007/004917 is an inhibitor that targets FGFR1, 2 and 3, and is used to treat breast cancer and non-small cell lung cancer. Its structure is as follows:
  • AZD4547 is known to have a strong inhibitory effect on the biological activities of FGFR1, FGFR2 and FGFR3, but its inhibitory effect on FGFR4 is weak, so its inhibitory effect on tumors that depend on the activity of FGFR4 is not significant, such as primary liver cancer. .
  • AZD4547 is a reversible FGFR inhibitor, therefore, it has the shortcomings of insufficient long-lasting and strong efficacy, and easy to induce drug resistance.
  • Fairhurst et al. in Medchemcomm. 2017; 8:1604-1613 disclosed compound a, which can be used as a pan-FGFR irreversible inhibitor, but this inhibitor has disadvantages such as poor physical and chemical properties and poor oral pharmacokinetic properties, so it is not easy to develop into Oral drugs.
  • pan-FGFR irreversible inhibitor that can take effect orally.
  • the purpose of the present invention is to provide a class of pan-FGFR irreversible inhibitors, especially for FGFR4 irreversible inhibitors.
  • the pan-FGFR irreversible inhibitor of the present invention has good activity on tumor cells dependent on different subtypes of FGFR, especially on tumor cell lines with strong heterogeneity such as liver cancer/cholangiocarcinoma, and exhibits excellent inhibitory activity. It shows good physical and chemical properties, pharmacokinetic properties and excellent tumor inhibitory activity.
  • the first aspect of the present invention provides a compound represented by Formula I, or a pharmaceutically acceptable salt, or a solvate, isotope substitution, prodrug or metabolite thereof:
  • R 6 is selected from H or none, and when When it represents a double bond, R 6 is H, when When it is a triple bond, R 6 is none;
  • X, Y, and Z are independently selected from C or N;
  • R 1 is 1-3, and is independently selected from H, halogen, -OH, -CN, -NO 2 ,
  • R 2 is selected from halogen (such as F),
  • the heterocyclic group or heteroaromatic ring group contains 1-4 heteroatoms selected from the group consisting of N, O or S; and the above-mentioned groups may be optionally substituted by one or more substituents selected from the following Substitution: halogen (such as F), C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C1-C6 alkylthio, -N(C1-C6 alkyl) 2 , -NH( C1-C6 alkyl), C1-C8 al
  • R 3 is selected from H
  • R 5 is selected from H, C1-C6 alkyl group, C1-C6 alkoxy group; the above group may be optionally substituted by one or more substituents selected from the following: -D, halogen,- OH, -CN, -NO 2 , substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C6 alkylthio, -N (substituted Or unsubstituted C1-C6 alkyl) 2 , -NH (substituted or unsubstituted C1-C6 alkyl), substituted or unsubstituted C1-C8 alkoxy-C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl-C1-C8 alkyl, substituted or unsubstituted C1-C6 al
  • R 1-1 represents H, unsubstituted or halogenated C1-C6 alkyl, or unsubstituted or halogenated C3-C6 cycloalkyl;
  • R 1-2 and R 1-3 each independently represent H, unsubstituted or halogenated C1-C6 alkyl, unsubstituted or halogenated C3-C6 cycloalkyl, or R 1-2 and R 1-3 and The nitrogen atoms to which they are connected together form an unsubstituted or halogenated 4-6 membered saturated heterocyclic ring;
  • R 1-4 and R 1-5 each independently represent H, unsubstituted or halogenated C1-C6 alkyl, unsubstituted or halogenated C3-C6 cycloalkyl, or R 1-4 and R 1-5 and The nitrogen atoms to which they are connected together form an unsubstituted or halogenated 4-6 membered saturated heterocyclic ring;
  • R 1-6 and R 1-7 each independently represent H, unsubstituted or halogenated C1-C6 alkyl, unsubstituted or halogenated C3-C6 cycloalkyl, or R 1-6 and R 1-7 and Together with the nitrogen atom to which they are attached, an unsubstituted or halogenated 4- to 6-membered saturated heterocyclic ring is formed;
  • R 1-8 and R 1-9 each independently represent H, unsubstituted or halogenated C1-C6 alkyl, unsubstituted or halogenated C3-C6 cycloalkyl, or R 1-8 and R 1-9 and Together with the nitrogen atom to which they are attached, an unsubstituted or halogenated 4-6 membered saturated heterocyclic ring is formed;
  • R 1-10 represents H, unsubstituted or halogenated C1-C6 alkyl, unsubstituted or halogenated C3-C6 cycloalkyl;
  • R 1-11 and R 1-12 each independently represent H, C1-C6 alkyl, or C3-C6 cycloalkyl, or R 1-11 and R 1-12 and the nitrogen atom to which they are attached together form 4-6
  • the membered saturated heterocyclic ring, and the group may be optionally substituted by one or more substituents selected from the group consisting of halogen, unsubstituted or halogenated C1-C6 alkyl, unsubstituted or halogenated C1-C6 alkane Oxygen, unsubstituted or halogenated C1-C6 alkylthio, -NH 2 , (unsubstituted or halogenated C1-C4 alkyl) 2 N-, (unsubstituted or halogenated C1-C4 alkyl )NH-, -OH;
  • R 1-13 and R 1-14 each independently represent C1-C6 alkyl, C1-C6 cycloalkyl, or R 1-13 and R 1-14 together with the nitrogen atom to which they are connected form a 4-6 membered saturated hetero Ring, and the group may be optionally substituted by one or more substituents selected from the group consisting of halogen, unsubstituted or halogenated C1-C6 alkyl, unsubstituted or halogenated C1-C6 alkoxy, Unsubstituted or halogenated C1-C6 alkylthio, -NH 2 , (unsubstituted or halogenated C1-C4 alkyl) 2 N-, (unsubstituted or halogenated C1-C4 alkyl) NH- , -OH;
  • R 2-1 represents a halogenated C1-C6 alkyl group or a halogenated C3-C6 cycloalkyl group, preferably the halogen is fluorinated;
  • R 2-2 and R 2-3 each independently represent a halogenated C1-C6 alkyl group, a halogenated C3-C6 cycloalkyl group, or R 2-2 and R 2-3 together with the nitrogen atom to which they are attached form a halogenated group A 4-6 membered saturated heterocyclic ring; preferably, the halogen is fluorinated;
  • R 2-4 and R 2-5 each independently represent a halogenated C1-C6 alkyl group, a halogenated C3-C6 cycloalkyl group, or R 2-4 and R 2-5 together with the nitrogen atom to which they are attached form a halogenated group A 4-6 membered saturated heterocyclic ring; preferably, the halogen is fluorinated;
  • R 2-6 and R 2-7 each independently represent a halogenated C1-C6 alkyl group, a halogenated C3-C6 cycloalkyl group, or R 2-6 and R 2-7 together with the nitrogen atom to which they are attached form a halogenated group A 4-6 membered saturated heterocyclic ring; preferably, the halogen is fluorinated;
  • R 2-8 and R 2-9 each independently represent a halogenated C1-C6 alkyl group, a halogenated C3-C6 cycloalkyl group, or R 2-8 and R 2-9 together with the nitrogen atom to which they are attached form a halogenated group
  • the 4-6 membered saturated heterocyclic ring, or R 2-8 and R 2-9 together with the nitrogen atom to which they are attached form a halogenated 5-10 membered unsaturated heteroaromatic ring, or R 2-8 and R 2-9 Together with the nitrogen atom to which they are attached, a halogenated 5-10 membered heteroaromatic ring is formed; preferably, the halogen is fluorinated;
  • R 2-10 represents a halogenated C1-C6 alkyl group or a halogenated C3-C6 cycloalkyl group; preferably, the halogen is fluorinated;
  • R 2-11 and R 2-12 each independently represent a halogenated C1-C6 alkyl group, a halogenated C3-C6 cycloalkyl group, or R 2-8 and R 2-9 together with the nitrogen atom to which they are attached form a halogenated group A 4-6 membered saturated heterocyclic ring; preferably, the halogen is fluorinated;
  • R 2-13 and R 2-14 each independently represent a halogenated C1-C6 alkyl group, a halogenated C3-C6 cycloalkyl group, or R 2-8 and R 2-9 together with the nitrogen atom to which they are attached form a halogenated group A 4-6 membered saturated heterocyclic ring; preferably, the halogen is fluorinated;
  • R 3-1 represents H, unsubstituted or halogenated C1-C6 alkyl, or unsubstituted or halogenated C3-C6 cycloalkyl;
  • R 3-2 and R 3-3 each independently represent H, unsubstituted or halogenated C1-C6 alkyl, unsubstituted or halogenated C3-C6 cycloalkyl, or R 3-2 and R 3-3 and The nitrogen atoms to which they are connected together form an unsubstituted or halogenated 4-6 membered saturated heterocyclic ring;
  • R 3-4 and R 3-5 each independently represent H, unsubstituted or halogenated C1-C6 alkyl, unsubstituted or halogenated C3-C6 cycloalkyl, or R 3-4 and R 3-5 and The nitrogen atoms to which they are connected together form an unsubstituted or halogenated 4-6 membered saturated heterocyclic ring;
  • R 3-6 and R 3-7 each independently represent H, unsubstituted or halogenated C1-C6 alkyl, unsubstituted or halogenated C3-C6 cycloalkyl, or R 3-6 and R 3-7 and Together with the nitrogen atom to which they are attached, an unsubstituted or halogenated 4- to 6-membered saturated heterocyclic ring is formed;
  • R 3-8 and R 3-9 each independently represent H, unsubstituted or halogenated C1-C6 alkyl, unsubstituted or halogenated C3-C6 cycloalkyl, or R 3-8 and R 3-9 and Together with the nitrogen atom to which they are attached, an unsubstituted or halogenated 4-6 membered saturated heterocyclic ring is formed;
  • R 3-10 represents H, unsubstituted or halogenated C1-C6 alkyl, unsubstituted or halogenated C3-C6 cycloalkyl;
  • R 3-11 and R 3-12 each independently represent H, C1-C6 alkyl, or C3-C6 cycloalkyl, or R 3-11 and R 3-12 together with the nitrogen atom to which they are attached form 4-6
  • the membered saturated heterocyclic ring, and the group may be optionally substituted by one or more substituents selected from the group consisting of halogen, unsubstituted or halogenated C1-C6 alkyl, unsubstituted or halogenated C1-C6 alkane Oxygen, unsubstituted or halogenated C1-C6 alkylthio, -NH 2 , (unsubstituted or halogenated C1-C4 alkyl) 2 N-, (unsubstituted or halogenated C1-C4 alkyl )NH-, -OH;
  • R 3-13 and R 3-14 each independently represent a C1-C6 alkyl group, a C1-C6 cycloalkyl group, or R 3-13 and R 3-14 together with the nitrogen atom to which they are connected form a 4-6 membered saturated hetero Ring, and the group may be optionally substituted by one or more substituents selected from the group consisting of halogen, unsubstituted or halogenated C1-C6 alkyl, unsubstituted or halogenated C1-C6 alkoxy, Unsubstituted or halogenated C1-C6 alkylthio, -NH 2 , (unsubstituted or halogenated C1-C4 alkyl) 2 N-, (unsubstituted or halogenated C1-C4 alkyl) NH- , -OH.
  • X is selected from C or N; preferably, Y is C; preferably, Z is C.
  • X is selected from C or N, Y is C, and Z is C.
  • X, Y, and X are all C.
  • the number of R 1 is 1-3, and is independently selected from halogen, C1-C4 alkyl and C1-C3 alkoxy.
  • R 2 is selected from halogen (such as F),
  • the heterocyclic group or heteroaromatic ring group contains 1-4 heteroatoms selected from the group consisting of N, O or S; and the above-mentioned groups may be optionally substituted by one or more substituents selected from the following Substitution: halogen (such as F), C1-C6 alkoxy, C3-C8 cycloalkyl, C1-C6 alkylthio, -N(C1-C6 alkyl) 2 , -NH(C1-C6 alkyl) , C1-C8 alkoxy-C1-C
  • R 2 can be selected from: halogen (such as F); -NR 2-8 R 2-9 group, wherein R 2-8 and R 2-9 are each independently H, C1-C6 alkyl and halogenated C1-C6 alkyl; and C1-C8 alkyl group, C2-C8 alkenyl group, C1-C6 alkoxy group, 3-8 membered carbocyclic group , 3-8 membered heterocyclic group, 5-10 membered aromatic ring group and 5-10 membered heteroaromatic ring group, wherein these groups may be optionally substituted by one or more substituents selected from the following Substituted: halogen, halogenated C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, -N(C1-C6 alkyl) 2 , -NH(C1-C6 Alkyl), C1-C8 alkyl
  • R 2 is halogen or a group in which at least halogen is included in its substituent.
  • the group includes but is not limited to -NR 2-8 R 2-9 group, C1-C6 alkyl, C2-C8 alkenyl, C1-C6 alkoxy, optionally C1-C6 alkyl Substituted 5-10 membered aryl, 5-10 membered heteroaryl optionally substituted by C1-C6 alkyl, 3-8 membered heterocyclyl optionally substituted by C1-C6 alkyl, and optionally C1-C6 C6 alkyl substituted 3-8 membered carbocyclic group; said "including at least halogen" means that halogen substitution can occur on the ring of said aryl, heteroaryl, heterocyclyl and carbocyclyl, and/or, When the ring is substituted with other groups, such as C1-C6 alkyl, halogen substitution can also occur on the substituor
  • R 2 is selected from: -NR 2-8 R 2-9 group, wherein R 2-8 and R 2-9 are each independently H, C1-C6 alkyl and halo C1-C6 alkyl, and at least one of R 2-8 and R 2-9 is a halogenated C1-C6 alkyl; C1-C8 alkyl group, C2-C8 alkenyl group, C1-C6 alkoxy Group, 3-8 membered carbocyclic group, 3-8 membered heterocyclic group, 5-10 membered aromatic ring group, 5-10 membered heteroaromatic ring group, and these groups are at least Halogen and/or C1-C6 haloalkyl substituted, optionally further substituted by one or more substituents selected from the following: C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, -N (C1-C6 alkyl) 2 , -NH (C1-C6-
  • R 3 is selected from 5-10 membered aromatic ring groups, 5-10 membered heteroaromatic ring groups, and the heterocyclic group or heteroaromatic ring group contains 1 -4 heteroatoms selected from the following group: N, O or S; and the above groups may be optionally substituted by one or more substituents selected from the following: -D, halogen, -OH, -CN, -NO 2 , halogenated or unsubstituted C1-C6 alkoxy, halogenated or unsubstituted C3-C8 cycloalkyl, halogenated or unsubstituted C1-C6 alkylthio, -N (halo or Unsubstituted C1-C6 alkyl) 2 , -NH (halogenated or unsubstituted C1-C6 alkyl), halogenated or unsubstituted C1-C8 alkoxy-C1-C8 alkyl
  • R 3 is selected from: 5-10 membered aromatic ring group and 5-10 membered heteroaromatic ring group, said heteroaromatic ring group contains 1-4 selected Heteroatoms from the following group: N, O or S; and the above-mentioned groups may be optionally substituted by one or more substituents selected from the group consisting of -D, halogen, -OH, halogenated or unsubstituted C1 -C6 alkoxy, halogenated or unsubstituted C3-C8 cycloalkyl, halogenated or unsubstituted C1-C8 alkoxy-C1-C8 alkyl, halogenated or unsubstituted C3-C8 cycloalkyl -C1-C8 alkyl, halogenated or unsubstituted C1-C6 alkylcarbonyl, halogenated or unsubstituted C1-C6 alkoxy
  • R 5 is selected from: H, C1-C6 alkyl group and C1-C6 alkoxy group; the group C1-C6 alkyl group and C1-C6
  • the alkoxy groups are each optionally substituted by one or more substituents selected from the group consisting of -D, halogen, -OH, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 Cycloalkyl, -N (substituted or unsubstituted C1-C6 alkyl) 2 , -NH (substituted or unsubstituted C1-C6 alkyl).
  • R 6 is H.
  • the compound, or a pharmaceutically acceptable salt thereof, or a solvate, isotope substitution, prodrug or metabolite thereof has the structure shown in Formula II as follows:
  • R 4 is 1-5, and each independently represents H, halogen, -OH, -CN, -NO 2 ,
  • R 4-1 represents H, unsubstituted or halogenated C1-C6 alkyl, or unsubstituted or halogenated C3-C6 cycloalkyl;
  • R 4-2 and R 4-3 each independently represent H, unsubstituted or halogenated C1-C6 alkyl, unsubstituted or halogenated C3-C6 cycloalkyl, or R 4-2 and R 4-3 and The nitrogen atoms to which they are connected together form an unsubstituted or halogenated 4-6 membered saturated heterocyclic ring;
  • R 4-4 and R 4-5 each independently represent H, unsubstituted or halogenated C1-C6 alkyl, unsubstituted or halogenated C3-C6 cycloalkyl, or R 4-4 and R 4-5 and The nitrogen atoms to which they are connected together form an unsubstituted or halogenated 4-6 membered saturated heterocyclic ring;
  • R 4-6 and R 4-7 each independently represent H, unsubstituted or halogenated C1-C6 alkyl, unsubstituted or halogenated C3-C6 cycloalkyl, or R 4-6 and R 4-7 and Together with the nitrogen atom to which they are attached, an unsubstituted or halogenated 4- to 6-membered saturated heterocyclic ring is formed;
  • R 4-8 and R 4-9 each independently represent H, unsubstituted or halogenated C1-C6 alkyl, unsubstituted or halogenated C3-C6 cycloalkyl, or R 4-8 and R 4-9 and Together with the nitrogen atom to which they are attached, an unsubstituted or halogenated 4-6 membered saturated heterocyclic ring is formed;
  • R 4-10 represents H, unsubstituted or halogenated C1-C6 alkyl, unsubstituted or halogenated C3-C6 cycloalkyl;
  • R 4-11 and R 4-12 each independently represent H, C1-C6 alkyl, or C3-C6 cycloalkyl, or R 4-11 and R 4-12 together with the nitrogen atom to which they are attached form 4-6
  • the membered saturated heterocyclic ring, and the group may be optionally substituted by one or more substituents selected from the group consisting of halogen, unsubstituted or halogenated C1-C6 alkyl, unsubstituted or halogenated C1-C6 alkane Oxygen, unsubstituted or halogenated C1-C6 alkylthio, -NH 2 , (unsubstituted or halogenated C1-C4 alkyl) 2 N-, (unsubstituted or halogenated C1-C4 alkyl )NH-, -OH;
  • R 4-13 and R 4-14 each independently represent C1-C6 alkyl, C1-C6 cycloalkyl, or R 4-13 and R 4-14 together with the nitrogen atom to which they are connected form a 4-6 membered saturated hetero Ring, and the group may be optionally substituted by one or more substituents selected from the group consisting of halogen, unsubstituted or halogenated C1-C6 alkyl, unsubstituted or halogenated C1-C6 alkoxy, Unsubstituted or halogenated C1-C6 alkylthio, -NH 2 , (unsubstituted or halogenated C1-C4 alkyl) 2 N-, (unsubstituted or halogenated C1-C4 alkyl) NH- , -OH;
  • R 4 is selected from: C1-C8 alkyl group, C2-C8 alkenyl group, C1-C6 alkoxy group; wherein, these groups are optionally One or more substituents selected from the group consisting of -D, halogen, -OH, and substituted or unsubstituted C1-C6 alkoxy.
  • the number of R 4 is 1-3, and each R 4 may be the same or different.
  • R 4 is two, all located in the meta position.
  • R 4 is 2 C1-C6 alkoxy groups.
  • R 2 is halogen or a group including halogen in its substituent at least.
  • the group includes but is not limited to -NR 2-8 R 2-9 group, C1-C6 alkyl, C2-C8 alkenyl, C1-C6 alkoxy, optionally C1-C6 alkyl Substituted 5-10 membered aryl, 5-10 membered heteroaryl optionally substituted by C1-C6 alkyl, 3-8 membered heterocyclyl optionally substituted by C1-C6 alkyl, and optionally C1-C6 C6 alkyl substituted 3-8 membered carbocyclic group; said "including at least halogen" means that halogen substitution can occur on the ring of said aryl, heteroaryl, heterocyclyl and carbocyclyl, and/or, When the ring is substituted with other groups, such as C1-C6 alkyl, halogen substitution can also occur on the substituent.
  • R 2 is selected from: -NR 2-8 R 2-9 group, wherein R 2-8 and R 2-9 are each independently H, C1-C6 alkyl and halo C1-C6 alkyl, and at least one of R 2-8 and R 2-9 is a halogenated C1-C6 alkyl; and C1-C8 alkyl group, C2-C8 alkenyl group, C1-C6 alkane Oxy group, 3-8 membered carbocyclic group, 3-8 membered heterocyclic group, 5-10 membered aromatic ring group and 5-10 membered heteroaromatic ring group, among which these groups It is substituted by at least halogen and/or C1-C6 haloalkyl, optionally further substituted by one or more substituents selected from the following: C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkane Group, -N (C1-C6 alkyl) 2
  • R 1 is selected from the following group: H, halogen (including Cl, F, Br), -OH, -CN, C1-C4 alkyl, C1-C4 alkylhydroxyl , -(C1-C3 alkyl)N(C1-C3 alkyl) 2 , -(C1-C3 alkyl)NH 2 , C1-C3 alkoxy, -O-(C1-C3 alkyl)-OH, -O(C1-C3 alkyl) O(C1-C3 alkyl), -N(C1-C3 alkyl) 2 , -NHPh, -NH(C1-C3 alkyl), -NH(C1-C3 alkyl) ) N (C1-C3 alkyl) 2 , -CONH 2 , -NHCO (C1-C3 alkyl), -NHCOH, -NHCOPh, -CO 2
  • R 1 is H, halogen, C1-C3 alkyl or C1-C3 alkoxy, preferably H, halogen or C1-C3 alkoxy, more Preferably it is H.
  • R 2 is selected from the following group: -F, fluorinated C1-C4 alkyl, fluorinated C1-C4 alkylhydroxyl, -(fluorinated C1-C3 Alkyl) N (C1-C3 alkyl) 2 ,-(fluoro C1-C3 alkyl) NH (C1-C3 alkyl),-(C1-C3 alkyl) N (fluoro C1-C3 alkane Group) 2 , -(C1-C3 alkyl) NH (fluorinated C1-C3 alkyl), -(fluorinated C1-C3 alkyl) NH 2 , fluorinated C1-C3 alkoxy, -O -(Fluorinated C1-C3 alkyl) -OH, -O (fluorinated C1-C3 alkyl) O (C1-C3 alkyl), -O
  • R 5 is selected from the following group: H, C1-C6 alkyl group, C1-C6 alkoxy group; the above-mentioned groups may be optionally combined with one or more groups.
  • R 1 is selected from the following group: H, Cl, F, Br, -OH, C1-C3 alkyl, C1-C3 alkylhydroxyl, -(C1-C3 alkyl )N(C1-C3 alkyl) 2 , -(C1-C3 alkyl)NH 2 , C1-C3 alkoxy, -O-(C1-C3 alkyl)-OH, -O(C1-C3 alkyl) ) O(C1-C3 alkyl), -N(C1-C3 alkyl) 2 , -NHPh, -NH(C1-C3 alkyl).
  • the number of R 1 is one, which is Cl, F, Br, C1-C4 alkyl, or C1-C3 alkoxy.
  • R 1 is H.
  • R 2 is selected from: halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -N (halogenated C1-C6 alkyl) (C1-C6 alkane Group), -NH(halogenated C1-C6 alkyl), -N(halogenated C1-C6 alkyl) 2 , -(C1-C3 alkyl)N(halogenated C1-C3 alkyl) 2 , -( C1-C3 alkyl) NH (halogenated C1-C3 alkyl), halogenated 3-8 membered heterocyclic group, halogenated C1-C6 alkyl substituted 3-8 membered heterocyclic group, wherein the heterocyclic ring
  • the group may be optionally further substituted with 1 or 2 groups (such as C1-C6 alkyl, C1-C6 alkoxy, etc.) other than the halogen and hal
  • R 2 is selected from the following group: -F, fluorinated C1-C3 alkyl, fluorinated C1-C3 alkoxy, -N (fluorinated C1-C3 Alkyl) (C1-C3 alkyl), -(fluorinated C1-C3 alkyl) N(C1-C3 alkyl) 2 , -(fluorinated C1-C3 alkyl) NH(C1-C3 alkyl) ), -(C1-C3 alkyl) N (fluorinated C1-C3 alkyl) 2 , -(C1-C3 alkyl) NH (fluorinated C1-C3 alkyl),-(fluorinated C1- C3 alkyl) NH 2 , -O-(fluorinated C1-C3 alkyl) -OH, -O (fluorinated C1-C3 alkyl)
  • R 2 is selected from the following group: -F, fluorinated C1-C3 alkyl, fluorinated C1-C3 alkoxy, -N (fluorinated C1-C3 alkyl) (C1-C3 alkane Group), -(fluorinated C1-C3 alkyl) N(C1-C3 alkyl) 2 , -(fluorinated C1-C3 alkyl) NH(C1-C3 alkyl), -(C1-C3 alkyl) Group) N (fluorinated C1-C3 alkyl) 2 , -(C1-C3 alkyl) NH (fluorinated C1-C3 alkyl),-(fluorinated C1-C3 alkyl) NH 2 ,- N (fluorinated C1-C3 alkyl) 2 , -NH (fluorinated C1-C3 alkyl),-(fluorinated C1-C3 alky
  • R 5 is selected from the following group: H, C1-C4 alkyl group, C1-C4 alkoxy group; the above-mentioned groups may optionally be one or Substituted by a plurality of substituents selected from the following: -D, halogen, -OH, -CN, -NO 2 , substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl, -N (substituted or unsubstituted C1-C3 alkyl) 2 , -NH (substituted or unsubstituted C1-C3 alkyl), substituted or unsubstituted 5-6 membered aryl, substituted or unsubstituted 5- 6-membered heteroaryl group, substituted or unsubstituted 3-6 membered heterocyclic group, substituted or unsubstituted
  • R 5 is selected from: H, C1-C4 alkyl group and C1-C4 alkoxy group; the groups C1-C4 alkyl group and C1-C4 alkoxy group are each any Optionally substituted by one or more substituents selected from the group consisting of -D, halogen, -OH, substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, -N( Substituted or unsubstituted C1-C3 alkyl) 2 , -NH (substituted or unsubstituted C1-C3 alkyl); more preferably, R 5 is H or unsubstituted or halogenated C1-C3 alkyl.
  • R 2 is selected from the following group: -F, fluorinated C1-C3 alkyl, fluorinated C1-C3 alkoxy, -N(C1-C3 alkyl ) (Fluorinated C1-C3 alkyl),
  • R 1 is selected from the following group: H, Cl, F, Br, -OH, -CN, C1-C4 alkyl, C1-C4 alkylhydroxyl, -(C1-C3 alkyl)N(C1-C3 alkyl) 2 , -(C1-C3 alkyl)NH 2 , C1-C3 alkoxy, -O-(C1-C3 alkyl)-OH, -O(C1-C3 alkyl) O(C1-C3 alkyl) , -N (C1-C3 alkyl) 2 , -NHPh, -NH (C1-C3 alkyl), -NH (C1-C3 alkyl) N (C1-C3 alkyl) 2 , -CONH 2 , -NHCO (C1-C3 alkyl), -NHCOH, -NHCOPh, -CO 2 H, -CO 2 (C1-C3 alkyl),
  • R 2 is selected from: halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -N (halogenated C1-C6 alkyl) (C1-C6 alkyl), halogenated 3-8 membered heterocyclic group , A 3-8 membered heterocyclic group substituted with a halogenated C1-C6 alkyl group, wherein the heterocyclic group may optionally be further selected from 1 or 2 other than the halogen and the halogenated C1-C6 alkyl group Group (such as C1-C6 alkyl, C1-C6 alkoxy, etc.); preferably, the heterocyclic group is a heterocyclic group containing 1 or 2 nitrogens, including but not limited to piperazinyl, piperazine Ridinyl, pyrrolidinyl and azetidinyl etc.
  • R 3 is selected from: 5-10 membered aromatic ring group and 5-10 membered heteroaromatic ring group, said heteroaromatic ring group contains 1-4 heteroatoms selected from the group consisting of N, O or S; and the above-mentioned groups may be optionally substituted by one or more substituents selected from the group consisting of -D, halogen, -OH, halogenated or unsubstituted C1-C6 alkoxy, halogenated or unsubstituted C3-C8 cycloalkyl, halogenated or unsubstituted C1-C8 alkoxy-C1-C8 alkyl, halogenated or unsubstituted C3-C8 cycloalkyl-C1-C8 alkyl, halogenated or unsubstituted A substituted C1-C6 alkylcarbonyl group, a halogenated or unsubstituted C1-C6 alkoxycarbonyl group,
  • R 5 is selected from: H, C1-C6 alkyl group and C1-C6 alkoxy group; the groups C1-C6 alkyl group and C1-C6 alkoxy group are each optionally selected by one or Substituted by a plurality of substituents selected from the following: -D, halogen, -OH, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, -N (substituted or unsubstituted C1-C6 alkyl) 2 , -NH (substituted or unsubstituted C1-C6 alkyl), the preferred substituent is one or more substituents selected from the group consisting of halogen and substituted or unsubstituted C1-C4 Alkoxy;
  • R 6 is H
  • X is selected from C or N; Y is C; Z is C.
  • R 1 is selected from the group consisting of H, Cl, F, Br, C1-C4 alkyl and C1-C3 alkoxy;
  • R 2 is selected from the following group: -F, fluoro C1-C3 alkyl, fluoro C1-C3 alkoxy, -N (fluoro C1-C3 alkyl) (C1-C3 alkyl),-(fluoro C1-C3 alkyl) N(C1-C3 alkyl) 2 , -(fluoroC1-C3 alkyl)NH(C1-C3 alkyl), -(C1-C3 alkyl)N(fluoroC1-C3 Alkyl) 2 ,-(C1-C3 alkyl) NH (fluoro C1-C3 alkyl),-(fluoro C1-C3 alkyl) NH 2 , -N (fluoro C1-C3 alkyl) 2 , -NH (fluoro C1-C3 alkyl), -NH (fluoro C1-C3 alkyl) N (C1-C3 alkyl) 2
  • R 3 is selected from: 5-10 membered aromatic ring group and 5-10 membered heteroaromatic ring group, said heteroaromatic ring group contains 1-4 heteroatoms selected from the group consisting of N, O or S; and the above-mentioned groups may be optionally substituted by one or more substituents selected from the group consisting of -D, halogen, -OH, halogenated or unsubstituted C1-C6 alkoxy, halogenated or unsubstituted C3-C8 cycloalkyl, halogenated or unsubstituted C1-C8 alkoxy-C1-C8 alkyl, halogenated or unsubstituted C3-C8 cycloalkyl-C1-C8 alkyl, halogenated or unsubstituted A substituted C1-C6 alkylcarbonyl group, a halogenated or unsubstituted C1-C6 alkoxycarbonyl group,
  • R 5 is selected from: H, C1-C6 alkyl group and C1-C6 alkoxy group; the groups C1-C6 alkyl group and C1-C6 alkoxy group are each optionally selected by one or Substituted by a plurality of substituents selected from the following: -D, halogen, -OH, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, -N (substituted or unsubstituted C1-C6 alkyl) 2 , -NH (substituted or unsubstituted C1-C6 alkyl), the preferred substituent is one or more substituents selected from the group consisting of halogen and substituted or unsubstituted C1-C4 Alkoxy;
  • R 6 is H
  • X is selected from C or N; Y is C; Z is C.
  • R 1 is selected from H, halogen and C1-C3 alkoxy;
  • R 3 is a phenyl group substituted with one or more substituents selected from halogenated or unsubstituted C1-C6 alkoxy.
  • X is selected from C or N; Y is C; Z is C; R 1 is selected from H, halogen, C1-C4 alkyl and C1-C3 alkoxy; R 2 is selected from halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -N (halogenated C1-C3 alkyl) (C1-C3 alkyl), -NH (halogenated C1-C3 alkyl) ), -N (halogenated C1-C3 alkyl) 2 ,-(C1-C3 alkyl) N (halogenated C1-C3 alkyl) 2 ,-(C1-C3 alkyl) NH (halogenated C1-C3 Alkyl), halogenated 3-8 membered heterocyclic group and halogenated C1-C6 alkyl substituted 3-8 membered heterocyclic group, wherein the heterocyclic
  • the compound of the present invention or a pharmaceutically acceptable salt thereof, or a solvate, isotope substitution, prodrug or metabolite thereof, are selected from the following structures:
  • the second aspect of the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, or a solvate, isotope substitution, prodrug or metabolite thereof as described in the first aspect of the present invention for use in treatment or Prevent diseases related to the activity or expression of FGFR.
  • the disease is selected from the following group: bladder cancer, liver cancer, brain cancer, breast cancer, colon cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer, cervical cancer , Colon cancer, thyroid cancer, skin cancer, cholangiocarcinoma, acute lymphoblastic leukemia, B-cell lymphoma, Burketts lymphoma, acute myeloid leukemia, chronic myelogenous leukemia, promyelocytic leukemia, fibrosarcoma, rhabdomyomas, Melanoma, seminoma, teratoma, neuroblastoma, glioma.
  • bladder cancer liver cancer, brain cancer, breast cancer, colon cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer, cervical cancer , Colon cancer, thyroid cancer, skin cancer, cholangiocarcinoma, acute lymphoblastic leukemia, B-cell lymphoma, Burketts lymphoma, acute myeloid le
  • the third aspect of the present invention provides a pharmaceutical composition, the pharmaceutical composition comprising:
  • the pharmaceutical composition further includes (iii) a second active ingredient.
  • the pharmaceutical composition is used to treat or prevent diseases related to the activity or expression of FGFR.
  • the disease is selected from the following group: bladder cancer, liver cancer, brain cancer, Breast cancer, colon cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer, cervical cancer, colon cancer, thyroid cancer, skin cancer, cholangiocarcinoma, acute lymphoblastic leukemia, B-cell lymphoma, Burketts Lymphoma, acute myeloid leukemia, chronic myeloid leukemia, promyelocytic leukemia, fibrosarcoma, rhabdomyomas, melanoma, seminoma, teratoma, neuroblastoma, glioma.
  • the fourth aspect of the present invention provides a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, or a solvate, isotope substitution, prodrug, metabolite, or a mixture thereof selected from the group consisting of The purpose of the group:
  • the FGFR kinase is selected from the group consisting of FGFR1, FGFR2, FGFR3, and FGFR4.
  • the disease is selected from the following group: bladder cancer, liver cancer, brain cancer, breast cancer, colon cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer, cervical cancer , Colon cancer, thyroid cancer, skin cancer, cholangiocarcinoma, acute lymphoblastic leukemia, B-cell lymphoma, Burketts lymphoma, acute myeloid leukemia, chronic myelogenous leukemia, promyelocytic leukemia, fibrosarcoma, rhabdomyomas, Melanoma, seminoma, teratoma, neuroblastoma, glioma.
  • bladder cancer liver cancer, brain cancer, breast cancer, colon cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer, cervical cancer , Colon cancer, thyroid cancer, skin cancer, cholangiocarcinoma, acute lymphoblastic leukemia, B-cell lymphoma, Burketts lymphoma, acute myeloid le
  • the inventors unexpectedly discovered that the compound represented by Formula I, or a pharmaceutically acceptable salt, or a solvate, isotope substitution, prodrug or metabolite thereof, has excellent FGFR kinases.
  • the inhibitory activity especially the inhibitory activity for FGFR4, can be used to treat or prevent FGFR kinase-related diseases. Based on the above findings, the inventor completed the present invention.
  • the manufacturer's instructions for the use of the kit can be used, or the reaction and purification can be carried out in a manner known in the art or the instructions of the present invention.
  • the above-mentioned techniques and methods can be implemented according to the descriptions in a number of summary and more specific documents cited and discussed in this specification according to conventional methods well-known in the art.
  • groups and their substituents can be selected by those skilled in the art to provide stable structural parts and compounds.
  • substituent When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent obtained when the structural formula is written from right to left.
  • substituent -CH 2 O- is equivalent to -OCH 2 -.
  • C1-C6 alkyl refers to an alkyl group as defined below having a total of 1 to 6 carbon atoms.
  • the total number of carbon atoms in the simplified notation does not include the carbons that may be present in the substituents of the group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • Hydroalkyl refers to an alkyl group as defined below that is substituted with a hydroxyl group (-OH).
  • Niro refers to -NO 2 .
  • Cyano refers to -CN.
  • Amino refers to -NH 2 .
  • Substituted amino refers to an amino group substituted with one or two alkyl, alkylcarbonyl, aralkyl, heteroaralkyl groups as defined below, for example, monoalkylamino, dialkylamino, alkyl Amido, aralkylamino, heteroaralkylamino.
  • Carboxy refers to -COOH.
  • alkyl refers to a fully saturated linear or branched hydrocarbon chain group, It consists of only carbon atoms and hydrogen atoms, has, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms, and is connected to the rest of the molecule through a single bond, such as including but not limited to Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl , N-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl and decyl, etc.
  • the term “alkyl” refers to a fully saturated linear or branched hydrocarbon chain group, It consists of only carbon atoms and hydrogen atoms, has, for example, 1 to 12 (preferably
  • alkenyl means consisting only of carbon atoms and hydrogen atoms, containing at least one double bond, having, for example, 2 to 20 (preferably 2 to 10 One, more preferably 2 to 6) carbon atoms and a straight or branched hydrocarbon chain group connected to the rest of the molecule through a single bond, such as but not limited to vinyl, propenyl, allyl, but- 1-alkenyl, but-2-enyl, pent-1-enyl, pent-1,4-dienyl, etc.
  • cycloalkyl means a stable non-aromatic monocyclic or polycyclic hydrocarbon group composed of only carbon atoms and hydrogen atoms, which may include fused rings System, bridged ring system or spiro ring system, having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms, and it is saturated or unsaturated and can be passed through any suitable
  • the carbon atom is connected to the rest of the molecule by a single bond.
  • the carbon atoms in the cyclic hydrocarbon group may be optionally oxidized.
  • the cycloalkyl group is a cycloalkyl group, such as a C3-C8 alkoxy group.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H-indene Group, 2,3-indanyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzo Cyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctenyl,
  • heterocyclic group means a group consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur Stable 3- to 20-membered non-aromatic cyclic group.
  • the heterocyclic group may be a monocyclic, bicyclic, tricyclic or more ring system, which may include a fused ring system, a bridged ring system or a spiro ring system; in the heterocyclic group
  • the nitrogen, carbon, or sulfur atoms of may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclic group may be partially or fully saturated.
  • the heterocyclic group can be connected to the rest of the molecule via a carbon atom or a heteroatom and through a single bond.
  • one or more rings may be aryl or heteroaryl groups as defined below, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom.
  • the heterocyclic group is preferably a stable 4- to 11-membered non-aromatic monocyclic, bicyclic, bridged ring or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur.
  • the group is more preferably a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged ring or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur.
  • heterocyclic groups include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3.5]non Alkyl-7-yl, 2-oxa-6-aza-spiro[3.3]heptane-6-yl, 2,5-diaza-bicyclo[2.2.1]heptan-2-yl, aza Cyclobutanyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxopentyl, tetrahydroisoquinolinyl, decahydro
  • aryl means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms (preferably having 6 to 10 carbon atoms).
  • the aryl group can be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and can also be fused with the above-defined cycloalkyl or heterocyclic group, provided that the aryl group passes through The atoms on the aromatic ring are connected to the rest of the molecule by a single bond.
  • aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4-Benzoxazine-3(4H)-one-7-yl and the like.
  • arylalkyl refers to the above-defined alkyl group substituted by the above-defined aryl group.
  • heteroaryl means having 1 to 15 carbon atoms (preferably having 1 to 10 carbon atoms) and 1 to 6 selected from nitrogen in the ring A 5- to 16-membered conjugated ring system group of heteroatoms of, oxygen and sulfur.
  • heteroaryl groups can be monocyclic, bicyclic, tricyclic or more cyclic ring systems, and can also be fused with cycloalkyl or heterocyclic groups as defined above, provided that the hetero The aryl group is connected to the rest of the molecule via a single bond through an atom on the aromatic ring.
  • the nitrogen, carbon or sulfur atoms in the heteroaryl group can be optionally oxidized; the nitrogen atom can be optionally quaternized.
  • the heteroaryl group is preferably a stable 5- to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, and more preferably contains 1 to 4 selected heteroatoms.
  • heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, Benzimidazolyl, benzopyrazolyl, indolyl, furyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indazinyl, isoindolyl, indazolyl, isoindazolyl , Purinyl, quinolinyl, isoquinolinyl, naphthyl, naphthyridinyl, quinoxalinyl, pterridinyl, carbazolyl, carboline, phenanthridinyl, phenanthrolinyl, acridine Group, phena
  • heteroarylalkyl refers to the above-defined alkyl group substituted by the above-defined heteroaryl group.
  • “optionally” or “optionally” means that the event or condition described later may or may not occur, and the description includes both occurrence and non-occurrence of the event or condition.
  • “optionally substituted aryl group” means that the aryl group is substituted or unsubstituted, and the description includes both substituted aryl groups and unsubstituted aryl groups.
  • substituents described in the claims and specification of the present invention are selected from alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, cyano, nitro , Optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclic alkyl.
  • the number of substituents can be one or more, such as 1-6 or 1-3. It should be understood that the number of substituents is affected by the molecular structure of the compound.
  • the number of substituents is usually one; when the substituent is halogen, it depends on the chain length or ring carbon atom of the substituted group.
  • the number of halogen atoms can be 2-6; if the substituted group is a chain group, there can be more halogen atoms, such as a pentafluoro-substituted propyl group (such as -CH 2 CF 2 CF 3 ).
  • the fibroblast growth factor receptor (FGFR) family includes four members: FGFR1, FGFR2, FGFR3, and FGFR4, which are composed of an extracellular ligand binding domain, a single transmembrane domain, and an intracellular cytoplasmic protein tyrosine kinase domain. composition.
  • the present invention also includes all suitable isotopic variants of the compounds of the present invention or pharmaceutically acceptable salts thereof.
  • Isotopic variants of the compound of the present invention or a pharmaceutically acceptable salt thereof are defined as those in which at least one atom is replaced by an atom having the same atomic number but having an atomic mass different from the atomic mass often found in nature.
  • the isotopes that can be incorporated into the compounds of the present invention and their pharmaceutically acceptable salts include, but are not limited to, isotopes of H, C, N, and O, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 35 S, 18 F, 36 Cl and 125 I.
  • Isotopic variants of the compounds of the present invention or pharmaceutically acceptable salts thereof can be prepared by conventional techniques using appropriate isotopic variants of appropriate reagents.
  • pharmaceutically acceptable salt includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to a salt formed with an inorganic acid or an organic acid that can retain the biological effectiveness of the free base without other side effects.
  • Inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc.
  • organic acid salts include, but are not limited to, formate, acetate, and 2,2-dichloroacetate , Trifluoroacetate, propionate, caproate, caprylate, caprate, undecylenate, glycolate, gluconate, lactate, sebacate, hexanoate Acid salt, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate , Cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate,
  • “Pharmaceutically acceptable base addition salt” refers to a salt formed with an inorganic base or an organic base that can maintain the biological effectiveness of the free acid without other side effects.
  • Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
  • Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts.
  • Salts derived from organic bases include but are not limited to the following salts: primary amines, secondary amines and tertiary amines, substituted amines, including natural substituted amines, cyclic amines and basic ion exchange resins , Such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, bicyclic Hexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperazine Pyridine, N-ethylpiperidine, polyamine resin, etc.
  • Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethyl
  • pharmaceutical composition refers to a preparation of the compound of the present invention and a medium generally accepted in the art for the delivery of a biologically active compound to a mammal (such as a human).
  • the medium includes a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, facilitate the absorption of the active ingredients and then exert the biological activity.
  • the term "pharmaceutically acceptable” refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compound of the present invention, and is relatively non-toxic, that is, the substance can be administered to an individual without causing undesirable biological activity. Reacts or interacts in an undesirable manner with any components included in the composition.
  • pharmaceutically acceptable excipients include, but are not limited to, any adjuvants, carriers, excipients, glidants, enhancers that are approved by relevant government authorities as acceptable for use by humans or livestock.
  • the "tumor” in the present invention includes but is not limited to Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, sarcoma, melanoma, articular chondroma, cholangiomas, leukemia, breast cancer, stomach Intestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, esophageal cancer, pancreatic cancer, lung squamous cell carcinoma, lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, cervix Cancer, ovarian cancer, bowel cancer, nasopharyngeal cancer, brain cancer, bone cancer, kidney cancer, oral cancer/head cancer, neuroblastoma, squamous cell carcinoma of the head and neck, anaplastic large cell lymphoma, or glioblast Tumors and other diseases.
  • preventive include reducing the likelihood of the occurrence or exacerbation of a disease or condition in a patient.
  • treatment and other similar synonyms include the following meanings:
  • an effective amount refers to at least one agent or compound that is sufficient to relieve one or more symptoms of the disease or condition being treated after administration ⁇ The amount.
  • the result can be a reduction and/or alleviation of signs, symptoms or causes, or any other desired changes in the biological system.
  • the "effective amount” for treatment is the amount of the composition containing the compound disclosed herein that is required to provide significant disease relief clinically. Techniques such as dose escalation tests can be used to determine the effective amount suitable for any individual case.
  • administration refers to methods capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral route, transduodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration.
  • parenteral injection including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion
  • topical administration and rectal administration.
  • Those skilled in the art are familiar with the application techniques that can be used for the compounds and methods described herein, for example in Goodman and Gilman, The Pharmaceutical Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceuticals (current edition), Mack Publishing Co., Those discussed in Easton, Pa.
  • the compounds and compositions discussed herein are administered orally.
  • drug combination refers to drug treatments obtained by mixing or combining more than one active ingredient. It includes fixed and non-fixed combinations of active ingredients.
  • fixed combination refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient in the form of a single entity or a single dosage form.
  • non-fixed combination refers to the simultaneous administration, combination or sequential administration of at least one compound described herein and at least one synergistic agent to a patient in the form of separate entities. These also apply to cocktail therapy, such as the administration of three or more active ingredients.
  • the functional group of the intermediate compound may need to be protected by an appropriate protecting group.
  • Such functional groups include hydroxyl, amino, mercapto and carboxylic acid.
  • Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl (e.g. tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , Tetrahydropyranyl, benzyl, etc.
  • Suitable protecting groups for amino, amidino and guanidino include tert-butoxycarbonyl, benzyloxycarbonyl and the like.
  • Suitable sulfhydryl protecting groups include -C(O)-R" (wherein R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like.
  • Suitable carboxy protecting groups include alkyl, aryl or aralkyl esters.
  • Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protective groups is detailed in Greene, T.W. and P.G.M. Wuts, Protective Groups in Organi Synthesis, (1999), 4th Ed., Wiley.
  • the protecting group can also be a polymer resin.
  • the present invention provides a compound represented by formula I:
  • the compound of formula I can be converted into a pharmaceutically acceptable salt, such as an acid addition salt: for example, hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate , Citrate, oxalate, methanesulfonate, p-toluenesulfonate or alkali metal salt: such as sodium or potassium salt;
  • a pharmaceutically acceptable salt such as an acid addition salt: for example, hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate , Citrate, oxalate, methanesulfonate, p-toluenesulfonate or alkali metal salt: such as sodium or potassium salt;
  • the compounds of formula I can also exist in the form of stereoisomers, such as tautomers, geometric isomers, mesoisomers, racemates, enantiomers, and diastereomers at room temperature. Body, or a mixture thereof;
  • the hydrogen atom in the compound of formula I can exist in the form of its isotope deuterium, for example, -CH 3 can exist in the form of -CD 3 , and -CH 2 -can exist in the form of -CD 2 -.
  • the compound defined in the present invention or a pharmaceutically acceptable salt thereof is an effective anticancer drug, the properties of which are believed to result from the regulation or inhibition of FGFR activity. Therefore, the compounds of the present invention are expected to be used in the treatment of diseases or medical conditions that are completely or partly induced by FGFR, that is, the compounds can be used to produce FGFR inhibitory effects in warm-blooded animals in need of such treatment.
  • the FGFR includes: FGFR1, FGFR2, FGFR3 and FGFR4.
  • the compounds of the present invention are expected to have broad-spectrum anti-cancer properties because uncontrolled expression or abnormal activation of FGFR has been observed in many human cancers, including but not limited to bladder, liver, stomach, breast, prostate, and multiple myeloma. It is therefore expected that the compounds of the present invention will have anticancer activity against these cancers. In addition, it is expected that the compounds of the present invention will have activity against leukemia, lymphoid malignancies and solid tumors such as cancers and sarcomas in tissues such as liver, kidney, bladder, prostate, breast, and pancreas. In one embodiment, the compounds of the invention are expected to advantageously delay the growth of primary and recurrent solid tumors such as skin, colon, thyroid, lung, and ovary.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof is expected to inhibit the growth of tumors associated with FGFR, especially those tumors whose growth and spread are significantly dependent on FGFR, including, for example, certain bladder, liver, stomach, and breast. And prostate tumors and multiple myeloma.
  • the compounds of the present invention can be used to treat or prevent diseases that benefit from inhibition of FGFR kinase activity or expression, especially diseases that benefit from inhibition of FGFR4 kinase activity or expression.
  • diseases can be solid tumors or hematological tumors, including but not limited to: bladder cancer, liver cancer, brain cancer, breast cancer, colon cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer, cervical cancer, Colon cancer, thyroid cancer, skin cancer, cholangiocarcinoma, acute lymphoblastic leukemia, B-cell lymphoma, Burketts lymphoma, acute myeloid leukemia, chronic myelogenous leukemia, promyelocytic leukemia, fibrosarcoma, rhabdomyomas, melanin Tumor, seminoma, teratoma, neuroblastoma, glioma.
  • a compound of formula I as defined herein or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of the following diseases: melanoma, papillary thyroid cancer, cholangiocarcinoma, colon cancer , Ovarian cancer, lung cancer, leukemia, lymphoid malignancies, multiple myeloma; cancers and sarcomas in the liver, kidney, bladder, prostate, breast, and pancreas; and primary and recurrent skin, colon, thyroid, lung, and ovarian cancers Primary solid tumors.
  • the present invention also provides a pharmaceutical composition, which comprises a compound of formula I as defined in the text or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, diluent or carrier.
  • the pharmaceutical composition is used to produce FGFR inhibitory effect or anti-cancer effect in warm-blooded animals such as humans.
  • the present invention provides a pharmaceutical composition for treating the following diseases in warm-blooded animals such as humans: melanoma, papillary thyroid cancer, cholangiocarcinoma, colon cancer, ovarian cancer, lung cancer, leukemia, lymphoid malignancies, Multiple myeloma; cancers and sarcomas in the liver, kidney, bladder, prostate, breast, and political glands; and primary and recurrent solid tumors of the skin, colon, thyroid, and lung.
  • the composition includes a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.
  • the compound of formula I and its pharmaceutically acceptable salt itself can be used alone, but are usually administered in the form of a pharmaceutical composition, wherein the compound or salt (active ingredient) of formula (I) is combined with pharmaceutically acceptable excipients, diluents or carriers .
  • the pharmaceutical composition may contain 0.01-99%w (weight percentage), 0.05-80%w, 0.10-70%w, and/or even 0.10-50%w of the active ingredient of the total composition weight, depending on the mode of administration .
  • the present invention further provides a method for preparing a pharmaceutical composition of the present invention, which comprises combining a compound of formula I as defined herein or a pharmaceutically acceptable salt thereof with pharmaceutically acceptable excipients, diluents or carriers mixing.
  • the pharmaceutical composition can be administered locally (for example, skin or lung and/or airway), for example, in the form of creams, solutions, suspensions, hexafluoroalkane aerosols, and dry powder formulations; or systemically administered, for example, in the form of tablets Oral administration in the form of tablets, capsules, syrups, powders or granules; or gastrointestinal administration in the form of solutions or suspensions; or subcutaneous administration; or rectal administration in the form of suppositories; or transdermal administration .
  • composition of the present invention can be obtained by conventional methods using conventional pharmaceutical excipients well known in the art. Therefore, a composition intended for oral use may contain, for example, one or more coloring agents, sweetening agents, flavoring agents and/or preservatives.
  • Suitable pharmaceutically acceptable excipients for tablet preparation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate; granulating and disintegrating agents such as corn starch or alkaline acid; binding agents Such as starch; lubricants such as magnesium stearate, stearic acid or talc; preservatives such as ethyl or propyl paraben, and antioxidants such as ascorbic acid.
  • the tablets can be uncoated or coated with conventional coating materials and methods well known in the art to improve their disintegration and subsequent absorption of the active ingredient in the gastrointestinal tract, or to improve their stability and/or appearance.
  • composition for oral administration can be in the form of a hard gelatin capsule, in which the active ingredient is mixed with an inert bulk diluent such as calcium carbonate, calcium phosphate or kaolin; or can be in the form of a soft gelatin capsule, in which the active ingredient can be combined with water, or oil: such as Mix peanut oil, liquid paraffin or olive oil.
  • the aqueous suspension solution usually contains the active ingredient in fine powder form and one or more suspending agents such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, western yellow Achilles gum and gum arabic; dispersing or wetting agents such as lecithin or 1,2-alkylene oxide condensation products with fatty acids (such as polyoxyethylene stearate), or condensation of ethylene oxide with long-chain fatty alcohols Products (such as seventeen-carbon ethyleneoxy cetyl alcohol), or condensation products of ethylene oxide and partial esters derived from fatty acids and hexitols (such as polyoxyethylene sorbitol monooleate), or ethylene oxide and Condensation products of fatty acids and partial esters derived from hexitol acid liver (such as polyoxyethylene sorbitan monooleate (Polyethylenesorbitanmonooleate)).
  • suspending agents such as sodium carboxymethyl cellulose, methyl cellulose
  • the aqueous suspension may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, antioxidants (such as ascorbic acid), coloring agents, flavoring agents and/or sweetening agents (such as sucrose, saccharin) Or aspartame)).
  • preservatives such as ethyl or propyl p-hydroxybenzoate, antioxidants (such as ascorbic acid), coloring agents, flavoring agents and/or sweetening agents (such as sucrose, saccharin) Or aspartame)).
  • Oily suspensions can be prepared by suspending the active ingredient in vegetable oil (such as peanut oil, olive oil, sesame oil, or coconut oil) or mineral oil (such as liquid paraffin). Oily suspensions may also contain thickeners such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents and flavoring agents as listed above can be added to obtain a palatable oral preparation. These compositions can be preserved by adding antioxidants such as ascorbic acid.
  • Dispersible powders and granules suitable for the preparation of aqueous suspensions by adding water are generally prepared by containing the active ingredient and a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents have been exemplified by those mentioned above. Other excipients such as sweeteners, flavoring agents and coloring agents may also be present.
  • the pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion.
  • the oil phase can be vegetable oils such as olive oil or peanut oil, or mineral oils such as liquid paraffin, or a mixture of any of these.
  • Suitable emulsifiers can be, for example, naturally occurring gums such as gum arabic or tragacanth, naturally occurring phospholipids such as soybean phospholipids, lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides (such as sorbitan mono-oil Acid ester) and the condensation product of the partial ester and ethylene oxide such as polyoxyethylene sorbitan monooleate.
  • the emulsion may also contain sweetening agents, flavoring agents and preservatives.
  • Syrups and elixirs can be formulated with sweeteners such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and can also contain analgesics, preservatives, flavoring agents and/or coloring agents.
  • sweeteners such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and can also contain analgesics, preservatives, flavoring agents and/or coloring agents.
  • the pharmaceutical composition can also be in the form of a sterile injectable aqueous or oily suspension, which can use one or more of the above-mentioned suitable dispersing or wetting agents and suspending agents according to known methods.
  • the sterile injectable preparation can also be a sterile injectable solution or suspension in a toxic, parenterally acceptable diluent or solvent (for example, a solution in 1,3-butanediol).
  • Suppositories can be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at normal temperature but liquid at the rectal temperature and therefore melts in the rectum to release the drug.
  • suitable excipients include, for example, cocoa butter and polyethylene glycol.
  • topical preparations such as creams, ointments, gels, or aqueous or oily solutions or suspensions
  • conventional methods well known in the art can usually be used by using active ingredients with conventional, topical acceptable excipients or The diluent is formulated.
  • composition for insufflation administration may contain, for example, a finely divided powder with an average particle size of 30 ⁇ or less, which powder contains only the active ingredient itself or is diluted with one or more physiologically acceptable carriers such as lactose. Subsequently, the powder for insufflation is placed in a capsule containing, for example, 1-50 mg of active ingredient, and used with a turbo-inhaler device, for example, for insufflation of a known drug sodium cromoglycate.
  • composition to be administered by inhalation may be in the form of a conventional pressurized aerosol that distributes the active ingredients into an aerosol containing finely dispersed solids or liquid droplets.
  • Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons can be used and the aerosol device can conveniently determine the amount of active ingredient.
  • the dosage of the compound of the present invention for therapeutic purposes will naturally vary according to the nature and severity of the disorder, the age and sex of the animal or patient, and the route of administration.
  • the compound of the present invention is administered so as to obtain a daily dose of the active ingredient/kg body weight in the range of, for example, 0.1 mg to 1000 mg, and it can also be administered in divided doses if necessary.
  • the daily dose must vary according to the host to be treated, the specific route of administration, and the severity of the disease to be treated. Therefore, the optimal dosage can be determined by the physician treating any particular patient. Generally speaking, lower doses are given when using parenteral routes. Therefore, for intravenous administration, for example, a dose of, for example, 0.1 mg to 30 mg active ingredient/kg body weight will usually be used. Similarly, for inhaled administration, a dose of, for example, 0.1 mg to 25 mg active ingredient/kg body weight will be used.
  • oral administration is preferred.
  • a formulation intended for oral administration to humans will generally contain 0.1 mg to 2 g of active ingredient.
  • the anti-cancer treatment defined above can be used as a monotherapy or as a combination therapy, that is, in addition to the treatment with the compound of the present invention, conventional surgery or radiotherapy or chemotherapy is also used at the same time.
  • Such chemotherapy may include one or more of the following types of anti-tumor agents:
  • alkylating agents such as cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, phenylbutyric acid
  • Nitrogen mustard, busulfan, temozolomide and nitrourea Nitrogen mustard, busulfan, temozolomide and nitrourea
  • antimetabolites such as gemcitabine and antifolates such as fluoropyrimidines such as 5-fluorouracil and tegafur, raltitrexed, methotrine, cytarabine
  • anti-tumor antibiotics such as anthracyclines such as doxorubicin, bleomycin, doxorubicin, daunorubicin, epirubicin, idarubicin, mitomycin-C, Dactinomycin and Mithomycin
  • antimitotic agents vinca alkaloids such as vincristine, vinblastine,
  • anti-estrogens such as tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene
  • anti-androgens such as bica Lutamide, flutamide, nilutamide and cyproterone acetate
  • LHRH antagonists or LHRH agonists such as goserelin, leuprolide, and buserelin
  • progestogens such as Megestrol acetate
  • aromatase inhibitors such as anastrozole, letrozole, fluclozole and exemestane
  • 5*-reductase inhibitors such as finasteride
  • c-Src kinase family inhibitors such as 4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methyl Piperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline (AZD0530; International Patent Application WO01194341) and N-(2-chloro-6-methylbenzene) Yl)-2- ⁇ 6-[4-(2-hydroxyethyl)piperidin-1-yl]-2-methylimididine-4-ylamino ⁇ thiazole-5-carboxamide (dasatinib, BMS-354825 , J. Med. Chem., 2004, 47, 6658-6661), and metalloproteinase inhibitors such as marimastat, and inhibitors of urokinase plasminogen activator receptor function or antibodies to Heparanase;
  • Growth factor function inhibitors including growth factor antibodies and growth factor receptor antibodies (such as anti-erbB2 antibody trastuzumab [HerceptinTM], anti-EGFR antibody panitumumab, anti-erbB1 antibody cetuximab [ Erbitux, C225]) and any growth factor or growth factor receptor antibody disclosed by Stem et al.
  • growth factor antibodies and growth factor receptor antibodies such as anti-erbB2 antibody trastuzumab [HerceptinTM], anti-EGFR antibody panitumumab, anti-erbB1 antibody cetuximab [ Erbitux, C225]
  • growth factor receptor antibodies such as anti-erbB2 antibody trastuzumab [HerceptinTM], anti-EGFR antibody panitumumab, anti-erbB1 antibody cetuximab [ Erbitux, C225]
  • any growth factor or growth factor receptor antibody disclosed by Stem et al.
  • these inhibitors also include tyrosine Kinase inhibitors such as epidermal growth factor family inhibitors (such as EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholino) Propoxy)quinazolin-4-amine (gefitinib, AZD1839), N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4- Methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide (AZD9291), N-(3-ethyl block Phenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acyla
  • epidermal growth factor family inhibitors such as EGFR family tyrosine
  • Ras/Raf signaling inhibitors such as farnesyl transferase inhibitors, such as sorafenib (BAY43-9006)), via MEK and/or Cell signaling inhibitors of AKT kinase, hepatocyte growth factor family inhibitors, c-kit inhibitors, abl kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors, aurora kinase inhibitors (such as AZD1152, PH739358 , VX-680, MLN8054, R763, MP235, MP529, VX-528 and AX39459) and cyclin kinase inhibitors such as CDK2 and/or CDK4 and/or CDK6 inhibitors;
  • Anti-angiogenic agents for example, anti-angiogenic agents that inhibit the effect of vascular endothelial growth factor (such as anti-vascular endothelial cell growth factor antibody Bevac anti-[AvastinTM] and VEGF receptor tyrosine kinase inhibitors such as 4-( 4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (AZD6474; Example 2 in WO 01132651), 4 -(4-Fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (AZD2171; WO 00/ Example 240 in 47212), Vataranib (PTK787; WO98/35985) and SU11248 (Sunitinib; WO 01160814), as disclosed in international patent applications WO 97/22596, WO
  • Vascular injury agents such as combstatin A4 and compounds disclosed in international patent applications WO99/02166, WO00/40529, WO00/41669, WO01192224, WO02/04434 and WO02/08213;
  • Antisense therapy such as the therapy aimed at the above targets, such as ISIS 2503 (anti-ras antisense);
  • Gene therapy including, for example, methods of replacing aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, and GDEPT (gene-directed enzyme prodrug therapy) methods such as cytidine deaminase, thymidine kinase or bacterial nitro reduction Enzyme methods and methods to improve the tolerance of patients to chemotherapy or radiotherapy such as multidrug resistance gene therapy; and
  • Immunotherapy Including immune checkpoint blocking methods such as PD-1 antibodies such as Opdivo and Keytruda and PD-L1 antibodies such as Tecentriq, chimeric antigen receptor T-cell immunotherapy, increase The immunogenicity of patient tumor cells ex vivo and in vivo therapy, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor to reduce T-cell anergy, use Methods of transfecting immune cells such as cytokine-transfected dendritic cells, methods of transfecting tumor cell lines with cytokines, and methods of using anti-idiotypic antibodies.
  • cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor to reduce T-cell anergy
  • Methods of transfecting immune cells such as cytokine-transfected dendritic cells, methods of transfecting tumor cell lines with cytokines, and methods of
  • the compound of formula I can be prepared by the following route: starting material I-A-1, through nucleophilic substitution reaction to obtain I-A-1. Next, the nitro group of I-A-2 is reduced with a reducing agent to obtain the amino compound I-A-3. Then, I-A-3 is acylated with substituted (unsubstituted) acryloyl chloride or substituted (unsubstituted) propioyl chloride to obtain I-A-4. Finally, I-A-4 and I-B undergo a urethane exchange reaction to obtain the final product formula I compound.
  • a novel FGFR inhibitor and its preparation and application are provided.
  • the inhibitor can inhibit the activity of various FGFR kinases at a very low concentration, and the inhibitor has better oral drug abuse the amount.
  • a pharmaceutical composition for treating diseases related to FGFR kinase activity is provided.
  • reaction solution was stirred at -78°C for 3 hours, slowly warmed to room temperature, and quenched by adding saturated aqueous ammonium chloride solution.
  • intermediate C refers to the route of intermediate B.
  • Step 1 Add potassium carbonate (667g, 4.83mol) and trifluoroiodopropane (1.0Kg, 4.46mol) to a solution of N-tert-butoxycarbonylpiperazine (E-1,300g, 1.61mol) in acetonitrile (2.5L) ). Under the protection of argon, it was heated to 80°C and reacted for 16h. TLC detected that the reaction was complete.
  • Step 2 Add hydrochloric acid/1 dropwise to 4-(3,3,3-trifluoropropyl)piperazine-1-carboxylic acid tert-butyl ester (E-2,382g, 1.35mol) in methanol (2L) solution , 4-Dioxane (4M, 2.0L). Heat to 40°C for 16h. LCMS detected that the reaction was complete. The reaction solution was concentrated under reduced pressure to dryness to obtain 1-(3,3,3-trifluoropropyl)piperazine hydrochloride (E, 375g) as a white solid. The crude product was used directly in the next step.
  • Step 1 Dissolve 2-nitro-4-trifluoromethylbenzoic acid (4-1, 3.0g, 12.2mmol) and DMF (0.3mL) in dichloromethane (50mL), replace with argon three times, Under argon protection, the temperature was lowered to 0°C, oxalyl chloride (4.05g, 31.90mmol) was added and the temperature was raised to room temperature after the addition, and the reaction was carried out overnight, and the reaction was completed. The solvent and excess oxalyl chloride were spun off under reduced pressure, toluene (20 mL) was taken once, and the mixture was dissolved in dichloromethane (50 mL) after rotary drying.
  • Step 2 Dissolve methyl 2-nitro-4-trifluoromethylbenzoate (4-2, 3.14 g, 12.6 mmol) in methanol (60 mL). Palladium on carbon (310 mg) was added under hydrogen conditions, and the reaction was carried out at room temperature overnight. It was filtered and concentrated to obtain methyl 2-amino-4-trifluoromethylbenzoate (4-3, 2.6 g, yield: 94%) as a white solid.
  • Step 3 Dissolve the compound methyl 2-amino-4-trifluoromethylbenzoate (4-3, 1.5g, 6.8mmol) and triethylamine (1.05g, 10.3mmol) in dichloromethane (30mL) . After the temperature was lowered to 0 degree under argon protection, acryloyl chloride (807 mg, 8.9 mmol) was added dropwise, the temperature was raised to room temperature, and the mixture was stirred for 3 hours.
  • Step 4 The compound 3-(3,5-dimethoxyphenethyl)-1H-pyrazol-5-amine (A, 305mg, 1.23mmol) was suspended in xylene (25mL) and protected by argon. After the temperature was lowered to 0 degrees, 2M trimethylaluminum (0.62 mL, 1.23 mmol) was added dropwise, and after the addition, the reaction was incubated for 1 hour. Methyl 2-acrylamido-4-trifluoromethyl benzoate (4-4,330mg, 1.23mmol) was dissolved in xylene (5mL) and then added dropwise to the above reaction system. The temperature was raised to 100°C and reacted for 3 hours. , The reaction is over.
  • Step 1 Dissolve 2,2,2-trifluoroethane-1-ol (188mg, 1.880mmol) in DMF (5mL). Under the protection of argon, the ice water is cooled to 0 degrees. Slowly add 60% sodium hydrogen (45mg, 1.125mmol) and stir for 1 hour. A solution of ethyl 4-fluoro-2-nitrobenzoate (B1, 200 mg, 0.938 mmol) in DMF (2 mL) was added dropwise at 0 degrees. The temperature was naturally raised to room temperature, and the reaction was stirred overnight. The reaction solution was poured into ice ammonium chloride aqueous solution (100 mL), and extracted with ethyl acetate 3 times.
  • Step 3 Combine the crude product (2-amino-4-(2,2,2-trifluoroethoxy)phenyl)(ethoxy)methanol (5-2,146mg, 0.587mmol) and triethylamine (95mg , 0.939 mmol) was dissolved in dichloromethane (5 mL). Under argon protection, acryloyl chloride (69mg, 0.762mmol) was added dropwise at 0°C. Stir at room temperature overnight. The reaction solution was poured into ice water and extracted with dichloromethane three times. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step 1 The compound ethyl 4-fluoro-2-nitrobenzoate (B1, 300 mg, 1.407 mmol) was dissolved in DMF (6 mL). 3,3-Difluoroazetidine (230 mg, 1.776 mmol) and anhydrous potassium carbonate (777 mg, 5.626 mmol) were added sequentially. Under the protection of argon, the reaction was stirred overnight at 50°C. The reaction solution was poured into ice water (50 mL). It was extracted with ethyl acetate 3 times, the organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step 3 The crude compound ethyl 2-amino-4-(3,3-difluoroazetidine-1-yl)benzoate (6-2, 121mg, 0.486mmol) was dissolved in dichloromethane (5mL )in. Triethylamine (79 mg, 0.781 mmol) was added. Under argon protection, acryloyl chloride (57mg, 0.630mmol) was added dropwise at 0°C. Stir at room temperature overnight. The reaction solution was poured into ice water, extracted with dichloromethane three times, the organic phases were combined, washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step 1 The compound ethyl 4-fluoro-2-nitrobenzoate (B1, 300 mg, 1.407 mmol) was dissolved in DMF (6 mL). Add 4,4-difluoropiperidine (179mg, 1.478mmol) and anhydrous potassium carbonate (389mg, 2.817mmol) in sequence, and stir overnight at 50°C under argon protection. The reaction solution was poured into ice water (50 mL). It was extracted with ethyl acetate 3 times, the organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step 3 Dissolve the crude ethyl 2-amino-4-(4,4-difluoropiperidin-1-yl)benzoate (7-2, 0.697 mmol) in dichloromethane (5 mL). Add triethylamine (113 mg, 1.117 mmol). Under argon protection, acryloyl chloride (90mg, 0.994mmol) was added dropwise at 0°C. Stir at room temperature overnight. The reaction solution was poured into ice water, extracted with dichloromethane three times, the organic phases were combined, washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step 4 The compound 3-(3,5-dimethoxyphenethyl)-1H-pyrazol-5-amine (A, 134 mg, 0.542 mmol) was dissolved in xylene (5 mL). Under argon protection, trimethylaluminum (0.8mL, 1.6mmol) was added dropwise at 0°C. After incubating at 0 degrees for 1 hour, add ethyl 2-acrylamido-4-(4,4-difluoropiperidin-1-yl)benzoate (7-3, 183mg, 0.541mmol) in xylene (5mL). ) Solution.
  • Step 1 Dissolve ethyl 4-fluoro-2-nitrobenzoate (B1, 300 mg, 1.407 mmol) in DMF (6 mL). 3,3-Difluoropyrrolidine (218mg, 2.035mmol) and anhydrous potassium carbonate (389mg, 2.817mmol) were added sequentially. Under the protection of argon, stir overnight at 50°C. The reaction solution was poured into ice water (50 mL). It was extracted with ethyl acetate 3 times, the organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step 3 Dissolve the crude ethyl 2-amino-4-(3,3-difluoropyrrolidin-1-yl)benzoate (8-2, 0.589 mmol) in dichloromethane (5 mL). Triethylamine (96mg, 0.949mmol) was added. Under argon protection, acryloyl chloride (80mg, 0.884mmol) was added dropwise at 0°C. Stir at room temperature overnight. The reaction solution was poured into ice water, extracted with dichloromethane three times, the organic phases were combined, washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step 4 Dissolve 3-(3,5-dimethoxyphenethyl)-1H-pyrazol-5-amine (A, 85mg, 0.344mmol) in xylene (5mL). Under argon protection, trimethylaluminum (0.5mL, 1.0mmol) was added dropwise at 0°C. After incubating at 0 degrees for 1 hour, add ethyl 2-acrylamido-4-(3,3-difluoropyrrolidin-1-yl)benzoate (8-3, 112mg, 0.345mmol) in xylene (5mL). ) Solution.
  • Step 1 Add sodium hydrogen (60% dispersed in oil, 80 mg, 2.0) to 3,3,3-trifluoropropan-1-ol (228 mg, 2.0 mmol) in DMF (8 mL) at 0°C under the protection of Ar. mmol), stirring at 0°C for 1 h. A solution of ethyl 4-fluoro-2-nitrobenzoate (B1, 213 mg, 1.0 mmol) in DMF (4 mL) was added dropwise. The reaction was stirred at room temperature overnight.
  • Step 2 Add palladium on carbon to a solution of ethyl 2-nitro-4-(3,3,3-trifluoropropoxy)benzoate (9-1, 117mg, 0.38mmol) in anhydrous methanol (15mL) (10%, 13mg). Vacuum hydrogen replacement three times. Stir overnight under a hydrogen balloon at room temperature. Filter and concentrate the filtrate to dryness under reduced pressure to obtain crude ethyl 2-amino-4-(3,3,3-trifluoropropoxy)benzoate (9-2,110mg, 100% yield). The crude product is directly Used in the next step.
  • Step 3 At 0°C, the crude product of ethyl 2-amino-4-(3,3,3-trifluoropropoxy)benzoate (9-2,110mg, 0.397mmol) and triethylamine (64mg , 0.635mmol) in dichloromethane (10mL) was added dropwise acryloyl chloride (47mg, 0.516mmol). It was naturally warmed to room temperature and stirred overnight. The reaction solution was poured into ice water (50 mL), and extracted with dichloromethane (3 ⁇ 20 mL). The organic phase was washed with saturated brine (50 mL).
  • Step 4 Add 3-(3,5-dimethoxyphenethyl)-1H-pyrazol-5-amine (A, 20mg, 0.08mmol) in xylene (5mL) under the protection of Ar at 0°C Add trimethyl aluminum (0.2 mL, 0.288 mmol). After stirring at 0°C for 1 h, a solution of ethyl 2-acrylamido-4-(3,3,3-trifluoropropoxy)benzoate (9-3, 33 mg, 0.1 mmol) in xylene (5 mL) was added dropwise. The temperature was raised to 110°C and stirred for 3h.
  • Step 1 Add H 2 SO 4 (98%, 5 mL) to a solution of 4-fluoro-3-methoxybenzoic acid (10-1, 11 g, 64.65 mmol) in MeOH (100 mL). The reaction was heated to 70°C for 16h. TLC showed that the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure to remove most of the solvent. Add ethyl acetate (100 mL) to dilute and pour into ice water (200 mL), stir for 5 min, separate the layers, and extract the aqueous phase with ethyl acetate (100 mL).
  • Step 2 Dissolve methyl 4-fluoro-3-methoxybenzoate (10-2, 5.0 g, 27.15 mmol) in a mixed solvent of H 2 SO 4 (98%, 40 mL) and AcOH (80 mL). HNO 3 (65%, 2.6g, 27.15mmol) was added dropwise below 10°C. After the addition, react at room temperature for 3h. LCMS monitors that the reaction is basically complete. The reaction solution was poured into ice water (300 mL), and ethyl acetate (2 ⁇ 150 mL) was added for extraction.
  • Step 3 Add 1-(3,3,3-trifluoropropyl)piperazine (Intermediate E, 1.4g, 6.24mmol), Cs 2 CO 3 (5.5g, 17.02mmol) into DMF (40mL), Stir for 10min. Methyl 4-fluoro-5-methoxy-2-nitrobenzoate (10-3, 1.3 g, 5.67 mmol) was added, and the reaction was stirred at 80° C. for 4 h under the protection of Ar. LCMS monitoring started to produce by-products, and the reaction was stopped. The reaction solution was cooled to room temperature.
  • Step 4 To methyl 5-methoxy-2-nitro-4-(4-(3,3,3-trifluoropropyl)piperazin-1-yl)benzoate (10-4,730mg, Pd/C (10%, 100 mg) was added to a solution of 2.44 mmol) in MeOH (15 mL). The reaction was carried out in H 2 environment at 40°C for 4 hours. TLC monitors that the reaction is complete. The reaction solution was cooled to room temperature and filtered.
  • Step 5 At 0°C, under the protection of Ar, methyl 2-amino-5-methoxy-4-(4-(3,3,3-trifluoropropyl)piperazin-1-yl)benzoate (10 -5,580mg, 1.61mmol) and triethylamine (1.3g, 12.84mmol) in dichloromethane (10mL) solution was added dropwise acryloyl chloride (290mg, 3.21mmol) in dichloromethane (5mL) solution. After the addition, it will naturally rise to RT and react for 1.5h. TLC monitors that the reaction is complete. The reaction solution was poured into ice water (50 mL), and extracted with dichloromethane (3 ⁇ 40 mL).
  • Step 6 Suspend in xylene (3mL) of 3-(3,5-dimethoxyphenethyl)-1H-pyrazol-5-amine (A, 66mg, 0.26mmol) under the protection of Ar at 0°C AlMe 3 (2M in THF, 0.4 mL, 0.72 mmol) was added dropwise to the solution. After stirring for 30 min at 0°C, methyl 2-acrylamido-5-methoxy-4-(4-(3,3,3-trifluoropropyl)piperazin-1-yl)benzoate (10-6 , 100mg, 0.24mmol) in xylene (3mL). After stirring at room temperature for 30 minutes, the temperature was raised to 100°C to react for 4 hours.
  • TLC monitored the completion of the reaction.
  • the reaction solution was cooled to room temperature and poured into ice water (50 mL). Ethyl acetate (30 mL) was added and the mixture was stirred for 5 min. The flocs were filtered off and the layers were separated. The aqueous phase was extracted with ethyl acetate (2 ⁇ 20 mL), the organic phases were combined, washed with water (2 ⁇ 50 mL), saturated brine (2 ⁇ 50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. TLC purification yielded 125 mg of light yellow solid.
  • Step 1 Add CuCN (313 mg, 3.5 mmol) to a solution of 1-bromo-2-nitro-4-(trifluoromethoxy)benzene (11-1, 1.00 g, 3.50 mmol) in DMF (2 mL). React at 150°C for 1h. Toluene (5 mL) was added, and reflux was continued for 1 h. The reaction solution was poured into ice water (50 mL), extracted with ethyl acetate (3 ⁇ 50 mL), and the organic phase was washed with saturated brine (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure.
  • Step 2 Dissolve 2-nitro-4-(trifluoromethoxy)benzonitrile (11-2, 400 mg, 1.72 mmol) with aq. 55% sulfuric acid (10 mL) and heat to 120° C. for reaction for 16 hours.
  • the reaction solution was cooled to room temperature, poured into ice water (50 mL), extracted with ethyl acetate (3 ⁇ 50 mL), and the organic phase was washed with aq. 10% NaOH solution (50 mL).
  • the aqueous phase was adjusted to pH 2 with dilute hydrochloric acid and extracted with ethyl acetate (3 ⁇ 50 mL).
  • Step 3 Add dropwise to a solution of 2-nitro-4-(trifluoromethoxy)benzoic acid (11-3, 250mg, 0.99mmol) in methanol (2mL) and acetonitrile (16mL) under the protection of Ar at 0°C Trimethylsilanated diazomethane (2.0M in hexanes, 1.0mL, 2.0mmol). React at room temperature for 2h.
  • Step 4 Add Pd/C (10%, 30 mg) to a methanol (20 mL) solution of methyl 2-nitro-4-(trifluoromethoxy)benzoate (11-4, 188 mg, 0.66 mmol). Vacuum hydrogen replacement 3 times. Stir for 16h at room temperature under hydrogen (balloon) atmosphere. The reaction solution was filtered through Celite, and the filtrate was concentrated to dryness to obtain methyl 2-amino-4-(trifluoromethoxy)benzoate (11-5, 146 mg, yield: 94.1%) as a light brown oil.
  • Step 5 At 0°C, under the protection of Ar, to a solution of crude methyl 2-amino-4-(trifluoromethoxy)benzoate (11-5, 146mg, 0.62mmol) in dichloromethane (5mL) was added three successively Ethylamine (101 mg, 1.00 mmol) and acryloyl chloride (73 mg, 0.81 mmol). Stir at room temperature for 3h. The reaction solution was poured into ice water (50 mL), extracted with dichloromethane (3 ⁇ 50 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure.
  • Step 6 Suspend 3-(3,5-dimethoxyphenethyl)-1H-pyrazol-5-amine (A, 155mg, 0.63mmol) with xylene (5mL) under the protection of Ar at 0°C AlMe3 (2.0M, 0.9mL, 1.84mmol) was slowly added to the solution. After dripping, continue stirring at 0°C for 1 hour. A solution of methyl 2-acrylamido-4-(trifluoromethoxy)benzoate (11-6, 178 mg, 0.62 mmol) in xylene (5 mL) was added dropwise. The temperature was raised to 110°C and stirred for 3h.
  • Step 1 Combine methyl 4-fluoro-2-nitrobenzoate (B1, 2.00g, 10.04mmol), 2-methyl-1-tert-butoxycarbonylpiperazine (2.41g, 12.05mmol) and K 2 CO 3 (2.78 g, 20.08 mmol) was dissolved in DMF (20 mL). Heat to 100 °C and stir to react for 16h. The reaction solution was diluted with ethyl acetate (50 mL), washed with saturated brine (2 ⁇ 150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was subjected to silica gel chromatography (0 to 50% gradient of acetic acid).
  • Step 2 Add 4-(4-(methoxycarbonyl)-3-nitrophenyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (12-1, 1.6g, 4.21mmol) to CH TFA (4 mL) was added dropwise to 2 Cl 2 (20 mL). Stir at room temperature for 60 min.
  • Step 3 To 4-(3-methylpiperazin-1-yl)-2-nitrobenzoic acid methyl ester (12-2, 600mg, 2.15mmol) and DIPEA (1388mg, 10.74mmol) in DMF (20mL) Add 1,1,1-trifluoro-3-iodopropane (2406mg, 10.74mmol). The reaction was heated to 120 °C and stirred for 3 hours. The reaction solution was diluted with ethyl acetate (30 mL), washed with saturated brine (2 ⁇ 100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was subjected to silica gel chromatography (0 to 50% gradient of acetic acid). Ethyl: petroleum ether) was purified to obtain methyl 4-(3-methyl-4-(3,3,3-trifluoropropyl)piperazin-1-yl)-2-nitrobenzoate (12 -3,380mg, yield: 47%).
  • Step 4 To 4-(3-methyl-4-(3,3,3-trifluoropropyl)piperazin-1-yl)-2-nitrobenzoic acid methyl ester (12-3, 380mg, 1.01 Pd/C (10%, 50 mg) was added to MeOH (10 mL) in mmol). The reaction liquid was replaced with H 2 three times and then heated to 40° C. and stirred for 3 hours. The reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain white solid methyl 2-amino-4-(3-methyl-4-(3,3,3-trifluoropropyl)piperazin-1-yl)benzoate (12-4, 290 mg, yield: 83%).
  • Step 5 At 0°C, under the protection of Ar, methyl 2-amino-4-(3-methyl-4-(3,3,3-trifluoropropyl)piperazin-1-yl)benzoate (12- 4,290 mg, 0.84 mmol) and Et 3 N (255 mg, 2.52 mmol) in CH 2 Cl 2 (10 mL) were added to acryloyl chloride (114 mg, 1.26 mmol). The reaction was stirred at room temperature for 3h.
  • reaction solution was poured into ice water (30 mL), extracted with CH 2 Cl 2 (2 ⁇ 20 mL), combined the extracts, washed with saturated brine (2 ⁇ 50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain The residue was purified by silica gel chromatography (0 to 50% gradient ethyl acetate: petroleum ether) to obtain a yellow solid 2-acrylamido-4-(3-methyl-4-(3,3,3-trifluoro (Propyl)piperazin-1-yl)methyl benzoate (12-5, 300 mg, yield: 89%).
  • Step 6 Add 3-(3,5-dimethoxyphenethyl)-1H-pyrazol-5-amine (A, 223mg, 0.90mmol) in xylene (5mL) system under the protection of Ar at 0°C AlMe 3 (2M in THF, 3.00 mmol) was added dropwise. Stir at 0°C for 60 min. Add dropwise methyl 2-acrylamido-4-(3-methyl-4-(3,3,3-trifluoropropyl)piperazin-1-yl)benzoate (12-5, 300mg, 0.75mmol ) In xylene (3mL). The reaction was heated to 110°C and stirred for 3 hours.
  • Step 1 Heat the mixed solution of methyl 4-fluoro-2-nitrobenzoate (B1, 2.00g, 10.04mmol) and methylamine (2M, THF solution, 20mL) in a sealed tube to 100°C and stir for 16h .
  • the reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel chromatography (gradient ethyl acetate: petroleum ether from 0 to 40%) to obtain methyl 4-(methylamino)-2-nitrobenzoate (13 -1,1.2g, yield: 57%).
  • Step 2 Add methyl 4-(methylamino)-2-nitrobenzoate (13-1, 1.10g, 5.23mmol) and Cs 2 CO 3 (8.53g, 26.17mmol) in DMF (15mL) 1,1,1-Trifluoro-3-iodopropane (5.86 g, 26.17 mmol). The reaction was heated to 120°C and stirred for 16 hours. The reaction solution was diluted with ethyl acetate (40 mL), washed with saturated brine (2 ⁇ 100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was subjected to silica gel chromatography (0 to 50% gradient of acetic acid).
  • Step 3 Add Pd to methyl 4-(methyl(3,3,3-trifluoropropyl)amino)-2-nitrobenzoate (13-2,90mg, 1.01mmol) in MeOH (5mL) /C (10%, 20mg). The reaction liquid was replaced with H 2 three times and then heated to 40° C. and stirred for 3 hours. The reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain white solid methyl 2-amino-4-(methyl(3,3,3-trifluoropropyl)amino)benzoate (13-3,75mg, yield: 92%).
  • Step 4 At 0 °C , under the protection of Ar, methyl 2-amino-4-(methyl(3,3,3-trifluoropropyl)amino)benzoate (13-3,75mg, 0.27mmol) and Et 3 N (82 mg, 0.81 mmol) in CH 2 Cl 2 (5 mL) was added to acryloyl chloride (37 mg, 0.41 mmol). The reaction was stirred at room temperature for 3h.
  • reaction solution was poured into ice water (20 mL), extracted with CH 2 Cl 2 (2 ⁇ 20 mL), the extracts were combined, washed with saturated brine (2 ⁇ 50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain The residue was purified by silica gel chromatography (0 to 50% gradient ethyl acetate: petroleum ether) to obtain a pale yellow solid 2-acrylamido-4-((3,3,3-trifluoropropyl)amino)benzene Methyl formate (13-4, 32 mg, yield: 36%).
  • Step 5 Add 3-(3,5-dimethoxyphenethyl)-1H-pyrazol-5-amine (A, 36mg, 0.15mmol) in xylene (2mL) system under the protection of Ar at 0°C AlMe 3 (2M in THF, 0.3 mL) was added dropwise. Stir at 0°C for 60 min. A solution of methyl 2-acrylamido-4-((3,3,3-trifluoropropyl)amino)benzoate (13-4, 32 mg, 0.10 mmol) in xylene (2 mL) was added dropwise. The reaction was heated to 110°C and stirred for 3 hours.
  • Step 1 Add 4-(4-(methoxycarbonyl)-3-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester (B2, 4.6g, 12.59mmol) in dichloromethane (40mL ) TFA (20 mL) was added dropwise to the solution. The temperature was gradually raised to 25°C and reacted for 1 hour. TLC monitors that the reaction is complete.
  • Step 2 Under Ar protection, add methyl 2-nitro-4-(piperazin-1-yl)benzoate (14-1, 1.7g, 6.41mmol) and triethylamine (8mL) in dichloromethane (30mL ) Add 2,2,3,3,3-pentafluoropropionic anhydride (2.4g, 7.69mmol) to the solution. The reaction was stirred at room temperature under Ar protection for 20h. TLC monitors that the reaction is basically complete.
  • Step 3 At 0°C, under the protection of Ar, to methyl 2-nitro-4-(4-(2-(2,2,3,3,3-pentafluoropropionyl)piperazin-1-yl)benzoate (14-2, 1.6g, 3.89mmol) in THF (30mL) solution was added dropwise BH 3 ⁇ Me 2 S (10M in THF, 1.95mL, 19.45mmol). After stirring at room temperature for 5 minutes, the temperature was raised to 70 °C for 3.5 hours The reaction was completed by TLC monitoring. The reaction solution was cooled to 0°C and then slowly added dropwise MeOH (15mL) to quench.
  • Step 4 To methyl 2-nitro-4-(4-(2-(2,2,3,3,3-pentafluoropropyl)piperazin-1-yl)benzoate (14-3, 1.17 g, 2.94mmol) in MeOH (50mL) was added Pd/C (10%, 200mg) . The reaction was carried out at 40°C for 6 hours under H 2 environment. TLC monitored the completion of the reaction. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the crude product was chromatographed on silica gel.
  • Step 5 At 0°C, under the protection of Ar, methyl 2-amino-4-(4-(2-(2,2,3,3,3-pentafluoropropyl)piperazin-1-yl)benzoate ( 14-4, 1.0 g, 2.72 mmol) and triethylamine (2.2 g, 21.78 mmol) in dichloromethane (15 mL) was added dropwise with acryloyl chloride (740 mg, 8.17 mmol) in dichloromethane (5 mL). 30 The reaction was stirred at °C for 2h, and TLC monitored the reaction to be complete.
  • Step 6 Suspend 3-(3,5-dimethoxyphenethyl)-1H-pyrazol-5-amine (A, 65mg, 0.26mmol) in xylene (5mL) under the protection of Ar at 0°C AlMe 3 (2M, THF solution, 0.36 mL, 0.71 mmol) was added dropwise to the solution. After stirring for 30 min at 0°C, methyl 2-acrylamido-4-(4-(4-(2,2,3,3,3-pentafluoropropyl)piperazin-1-yl)benzoate ( 14-5, 100mg, 0.24mmol) in xylene (2mL). Stir at room temperature for 30 minutes and then heat to 100°C for 4 hours.
  • Step 1 Add potassium carbonate (11.2g, 82.94mmol) and methyl iodide (8.8g, 82.94mmol) to 3-amino-5-bromopicolinic acid (15-1, 9.0g, 41.47mmol) in DMA (150mL) solution ). The reaction was stirred at 25°C for 12h under the protection of Ar. TLC monitors that the reaction is complete.
  • Step 2 To a solution of methyl 3-amino-5-bromopicolinate (15-2, 1.2g, 5.19mmol) in acetonitrile (30mL) was added DMAP (1.27g, 10.39mmol) and di-tert-butyl dicarbonate ( 2.27g, 10.39mmol). Under Ar environment, the temperature was gradually raised to 60°C and the reaction was stirred for 0.5h. TLC monitors that the reaction is complete. The reaction solution was cooled to room temperature.
  • Step 3 To methyl 5-bromo-3-(bis(tert-butoxycarbonyl)amino)picolinate (15-3, 1.25g, 2.90mmol), 1-(3,3,3-trifluoropropyl) Piperazine (Intermediate E, 634mg, 3.48mmol), Xantphos (670mg, 1.16mmol), Cs 2 CO 3 (4.72g, 14.49mmol) in 1,4-dioxane (30mL) solution was added Pd 2 ( dba) 3 (530 mg, 0.58 mmol). The reaction was stirred at 100°C for 3.5h under Ar environment. TLC monitors that the reaction is complete.
  • Step 4 Add methyl 3-(bis(tert-butoxycarbonyl)amino)-5-(4-(3,3,3-trifluoropropyl)piperazin-1-yl)picolinate (15-4, 1.3g, 2.44mmol) was dissolved in TFA (15mL). The reaction was stirred at room temperature for 2h. TLC monitors that the reaction is complete. The reaction solution was poured into a saturated NaHCO 3 (50 mL) solution on ice.
  • Extract with ethyl acetate (3 ⁇ 50 mL), combine the organic phases, wash with saturated NaHCO 3 (50 mL), wash with saturated brine (100 mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and chromatograph on silica gel (dichloromethane) :Methanol 70:1 ⁇ 40:1) was purified to give a pale yellow solid methyl 3-amino-5-(4-(3,3,3-trifluoropropyl)piperazin-1-yl)picolinate (15 -5,710mg, yield: 87%).
  • Step 5 At 0°C, under the protection of Ar, methyl 3-amino-5-(4-(3,3,3-trifluoropropyl)piperazin-1-yl)picolinate (15-5, 710mg, 2.14)
  • a solution of acryloyl chloride (580 mg, 6.41 mmol) in dichloromethane (5 mL) was added dropwise to a dichloromethane (10 mL) solution of triethylamine (1.8 g, 17.09 mmol). After the addition, it was naturally raised to room temperature and reacted for 1.5h. TLC monitors that the reaction is complete.
  • Step 6 Suspend 3-(3,5-dimethoxyphenethyl)-1H-pyrazol-5-amine (A, 218mg, 0.883mmol) in xylene (8mL) under the protection of Ar at 0°C AlMe 3 (1.2 mL, 2M in THF, 2.407 mmol) was added dropwise to the solution. The reaction was stirred at 0°C for 30 minutes and then 3-acrylamido-5-(4-(4-(3,3,3-trifluoropropyl)piperazin-1-yl)picolinate methyl ester (15-6, 310mg, 0.802mmol) in xylene (7mL).
  • Step 1 To 4,6-difluoroindole-2,3-dione (16-1, 2.0g, 10.92mmol) in acetonitrile (40mL) was added piperazine-1-carboxylic acid tert-butyl ester (2.0 g, 10.92 mmol) and triethylamine (2 mL). Reaction at room temperature under argon atmosphere for 16h. TLC showed that the reaction was basically complete.
  • Step 3 At 0°C, under the protection of argon, to 2-amino-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-fluorobenzoic acid (16-3, 400mg, 77%, 1.18mmol), triphenylphosphorus (340mg, 1.30mmol) and methanol (1mL) in dichloromethane (10mL) solution was added dropwise diethyl azodicarboxylate (226mg, 1.30mmol). After adding, continue to react for 1h. TLC monitors that the reaction is complete.
  • Step 4 Add 4-(3-amino-5-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (16-4, 140mg, 0.40mmol) in dichloromethane ( 10mL) Trifluoroacetic acid (2mL) was added dropwise to the solution. The reaction was stirred at room temperature for 2h. TLC monitors that the reaction is complete.
  • reaction solution was diluted with dichloromethane (20mL), washed with saturated sodium bicarbonate solution (2 ⁇ 30mL), dried over anhydrous sodium sulfate and concentrated to obtain a pale yellow solid 2-amino-6-fluoro-4-(piperazine-1- Methyl) benzoate (16-5, 136 mg).
  • the crude product was used directly in the next step.
  • Step 5 Combine methyl 2-amino-6-fluoro-4-(piperazin-1-yl)benzoate (16-5, 136mg, 0.40mmol), 1,1,1-trifluoro-3-iodopropane (445mg, 1.98mmol) and triethylamine (200mg, 1.98mmol) were dissolved in DMF (10mL) solution. Under nitrogen protection, react at 95°C for 5 hours.
  • Step 6 Add methyl 2-amino-6-fluoro-4-(4-(3,3,3-trifluoropropyl)piperazin-1-yl)benzoate (16-6, 94mg) under the protection of argon. , 0.27mmol) and triethylamine (218mg, 2.15mmol) were dissolved in dichloromethane (9mL) and added dropwise a solution of acryloyl chloride (73mg, 0.81mmol) in dichloromethane (1mL). React at 30°C for 2.5h. The TLC monitoring response is complete.
  • Step 7 Add 3-(3,5-dimethoxyphenethyl)-1H-pyrazol-5-amine (16-7, 67mg, 0.27mmol) in xylene (4mL) at 0°C under the protection of argon. ) Trimethyl aluminum (2M in THF, 0.37mL, 0.74mmol) was added dropwise to the system. After stirring for 20 min at 0°C, methyl 2-acrylamido-6-fluoro-4-(4-(3,3,3-trifluoropropyl)piperazin-1-yl)benzoate (16-7, 100 mg, 0.25 mmol) in xylene (4 mL). After the addition, the temperature was gradually raised to 100°C and reacted for 4 hours.
  • TLC monitors that the reaction is complete.
  • the obtained solid was purified by Prep-HPLC to obtain an off-white solid (18 mg, TFA salt).
  • Step 1 Add methyl 2-aminobenzoate (a-1, 1.0g, 6.6mmol) and triethylamine (2.0g, 19.8mmol) dissolved in dichloromethane (20mL) dropwise at 0°C under the protection of Ar A solution of acryloyl chloride (778 mg, 8.6 mmol) in dichloromethane (5 mL). Slowly warm up to room temperature and react for 3h. LCMS showed that the reaction was complete.
  • Step 2 Add trimethylaluminum (0.75mL, 1.5 mL) to the xylene (15mL) suspension of methyl 2-acrylamidobenzoate (a-2, 130mg, 0.53mmol) under the protection of Ar at 0°C. mmol). React at 0°C for 1h. 3-(3,5-Dimethoxyphenethyl)-1H-pyrazol-5-amine (A, 103 mg, 0.53 mmol) was added to the reaction solution, the temperature was raised to 110° C., and the reaction was carried out for 4 h. LCMS showed that the reaction was complete. The reaction solution was quenched with ice water.
  • the purified FGFR1 (456-763) kinase domain protein is diluted with 20mM Tris-HCL pH8.0, 150mM Nacl protein buffer to a final concentration of about 20 ⁇ M (800ng/ ⁇ l).
  • the experimental group and the control group were incubated on ice at the same time for 2 hours, and then diluted with 4 times volume of acetone at -20 overnight. After centrifugation at 16000 ⁇ g for 10 minutes, the pellet was resuspended in 0.1% formic acid and loaded for mass spectrometry data collection.
  • FGFR4 Invitrogen, Cat. No PR4380A, Lot. No. 1856505A
  • FGFR1 Carrier-Bene-Bene-Bene-Bene-Bene-Bene-Bene-Bene-Bene-Bene-Bene-Bene-Bene-Bene-Bene-Bene-Bene-Bene-Bene-Bene (Ben, B-B-B-B-B-B-B-L112393); ATP (Sigma, Cat. No. A7699-1G, CAS No. 987-65-5); 96-well plate (Corning, Cat. No. 3365, Lot. No. 22008026); 384-well plate (Corning, Cat. No. 3573, Lot. No. 12608008).
  • the specific operations are as follows:
  • the compound is first serially diluted in a 5% DMSO solution, and 5 ⁇ L of the compound solution is added to a 384-well plate. The maximum final concentration of the compound is 1 ⁇ M. The compound is diluted three times and has 10 concentrations.
  • control substance inhibit FGFR1, FGFR2, FGFR3, FGFR4 in vitro experiments and the results are shown in the following table:
  • the human liver cancer Hep3B cell line is derived from ATCC.
  • the cells were cultured in DMEM liquid medium, and fetal bovine serum (10% FBS) and penicillin-streptomycin (100,000 U/L) were added.
  • the cells are maintained at 37°C, 95% humidity and 5% carbon dioxide in the culture medium.
  • Hep3B cells were seeded in a 96-well plate at a density of 3000 cells per well, and the cell suspension volume was 100 ⁇ L per well, and the cells were cultured overnight to allow the cells to attach.
  • each compound was diluted with DMSO in a three-fold gradient, and 1 ⁇ L of the compound DMSO solution was added to the cell culture medium.
  • the pharmacokinetics of the compounds of this invention are determined. This application uses the following methods to determine the pharmacokinetic parameters of the compounds of this application.
  • the healthy male adult mice used in the study were given a single intragastric administration of 5-100 mg/Kg for each group of animals. Fasting is from 10 hours before administration to 4 hours after administration. Blood was collected at different time points after administration, and the plasma content of the compound was determined (LC-MS/MS). The plasma concentration-time relationship is analyzed with professional software (winnonlin) to calculate the pharmacokinetic parameters of the compound. The results show that, compared with the control compound a, the compound of the present invention has a significant increase in peak oral drug concentration or oral drug exposure.
  • the compound of the present invention exhibits excellent anti-tumor activity on transplanted tumors in mice.
  • Cell culture Human liver cancer Hep3B cells are cultured in a monolayer in vitro. The culture conditions are 1640 medium with 10% fetal bovine serum, 100U/mL penicillin and 100 ⁇ g/mL streptomycin, 37°C and 5% CO 2 incubator. Use pancreatin-EDTA for routine digestion and passage twice a week. When the cell saturation is 80%-90% and the number reaches the requirement, the cells are collected, counted, and inoculated.
  • mice Balb/c nude mice, female, 6-8 weeks old, weighing 18-22 grams. Provided by Shanghai Slack Laboratory Animal Co., Ltd. or other qualified suppliers.
  • Tumor inoculation 0.2 mL (10 ⁇ 10 6 +Matrixgel) Hep3B cells were subcutaneously inoculated on the right back of each mouse, and group administration was started when the average tumor volume reached about 140-200 mm 3.
  • TGI tumor growth inhibition rate

Abstract

本发明提供了一种用作FGFR不可逆抑制剂的酰胺基吡唑类化合物、其制备方法和用途。具体地，本发明提供了式I化合物、或其药学上可接受的盐、或其溶剂化物、同位素取代物、前药或代谢产物。所述通式I的化合物具有FGFR抑制活性，能预防或治疗与FGFR活性或表达量相关的病症，优选比如癌症。

Description

用于FGFR抑制剂的吡唑类衍生物及其制备方法 技术领域
本发明公开了一种吡唑类衍生物及其制备方法，以及包含它们的药物组合物，和制备该药物组合物的方法，以及它们在治疗疾病中的用途。
背景技术
成纤维细胞生长因子(FGF)被认为是许多生理过程(如发育和血管发生过程中形态发生)的重要介质。目前存在超过25种已知的FGF家族成员。成纤维细胞生长因子受体(FGFR)家族则包括4个成员：FGFR1、FGFR2、FGFR3和FGFR4，它们分别由胞外配体结合区、单跨膜区和细胞内胞质蛋白酪氨酸激酶区组成。在FGF刺激下，FGFR发生二聚作用和转磷酸作用，这导致受体活化。而受体的活化足以恢复和激活特定的下游信号配体，所述下游信号配体参与各种过程如细胞生长、细胞代谢和细胞存活的调节。结果就是FGF和FGFR有可能引起和/或促进肿瘤的生成。
目前已知很多证据表明FGF信号传导与人类癌症直接相关，有报道称在不同范围的肿瘤类型如膀胱、肾细胞和***肿瘤中各种FGF的表达增加。FGF还被描述为强有力的血管生成因子。而在生理状态下，其受体成员之一FGFR4信号通路被严格控制，但FGFR4信号失调导致癌症的发生、发展、存活和转移。因此，成纤维细胞生长因子受体FGFR被广泛认为是一类抗肿瘤的重要药物靶点。比如，在PCT/GB2007/004917中公开的AZD4547就是靶向FGFR1、2和3的抑制剂，用于治疗乳腺癌和非小细胞肺癌。其结构如下所示：
Figure PCTCN2020112173-appb-000001
上述的AZD4547已知对FGFR1、FGFR2和FGFR3的生物活性具有较强的抑制作用，但其对FGFR4的抑制作用较弱，因此其对依赖FGFR4活性的肿瘤抑制效果不显著，比如原发性肝癌等。而且，AZD4547属于可逆性FGFR抑制剂，因此，其具有药效不够持久和强烈、容易引发耐药等缺点。Fairhurst等人在Medchemcomm.2017；8:1604–1613公开了 化合物a，可以做为泛FGFR不可逆抑制剂，但是该抑制剂存在着理化性质差、口服药代动力学性质差等缺点，不易开发成口服药物。
Figure PCTCN2020112173-appb-000002
因此，本领域迫切需要开发能够口服起效的泛FGFR不可逆抑制剂。
发明内容
本发明的目的在于提供一类泛FGFR不可逆性抑制剂，尤其是对于FGFR4不可逆的抑制剂。本发明的泛FGFR不可逆抑制剂对FGFR不同亚型依赖的肿瘤细胞均有较好活性，特别是对肝癌/胆管癌等异质性很强的肿瘤细胞株展现出了优异的抑制活性，并且展示出了良好的理化性质、药代动力学性质和优异的移植瘤抑制活性。
本发明第一方面，提供了一种式I所示的化合物、或其药学上可接受的盐、或其溶剂化物、同位素取代物、前药或代谢产物：
Figure PCTCN2020112173-appb-000003
其中，
Figure PCTCN2020112173-appb-000004
表示双键或三键；
R 6选自H或无，且当
Figure PCTCN2020112173-appb-000005
表示双键时，R 6为H,当
Figure PCTCN2020112173-appb-000006
为三键时，R 6为无；
X、Y、Z分别独立的选自C或N；
R 1的个数为1-3个，且独立地选自H、卤素，-OH，-CN，-NO 2，
-CO 2R 1-1基团，
-CONR 1-20R 1-3基团，
-NR 1-4COR 1-5基团，
-NR 1-6CO 2R 1-7基团，
-NR 1-8R 1-9基团，
-SO 2R 1-10基团，
-SO 2NR 1-11R 1-12基团，
-NR 1-13SO 2R 1-14基团，
C1-C8烷基基团，C3-C8环烷基基团，C2-C8链烯基基团，3-8元杂环基基团，C1-C6烷氧基基团，5-10元芳环基基团，5-10元杂芳环基团，或者两个相邻的R 1基团与和它们连接的原子一起形成3-8元碳环基团或杂环基团，或者两个相邻的R 1基团与和它们连接的原子一起形成5-10元芳环基团或杂芳环基团，所述的杂环基团或杂芳环基团包含1-4个选自下组的杂原子：N、O或S；且上述的基团可任选被一个或多个选自以下的取代基所取代：-D、卤素、-OH、-CN、-NO 2、取代或未取代的C1-C6烷氧基、取代或未取代的C3-C8环烷基、取代或未取代的C1-C6烷基硫基、-N(取代或未取代的C1-C6烷基) 2、-NH(取代或未取代的C1-C6烷基)、取代或未取代的C1-C8烷氧基-C1-C8烷基、取代或未取代的C3-C8环烷基-C1-C8烷基、取代或未取代的C1-C6烷基羰基、取代或未取代的C1-C6烷氧基羰基、异羟肟酸基、-S(O) 2N(取代或未取代的C1-C6烷基) 2、-S(O) 2(取代或未取代的C1-C6烷基)、-N(取代或未取代的C1-C6烷基)S(O) 2N(取代或未取代的C1-C6烷基) 2、-S(O)N(取代或未取代C1-C6烷基) 2、-S(O)(取代或未取代的C1-C6烷基)、-N(取代或未取代的C1-C6烷基)S(O)N(取代或未取代的C1-C6烷基) 2、-N(取代或未取代的C1-C6烷基)S(O)(取代或未取代的C1-C6烷基)、取代或未取代的5-10元芳基、取代或未取代的5-10元杂芳基、取代或未取代的3-8元杂环基，取代或未取代的3-8元碳环基，其中，所述杂环基或杂芳基包含1-4个选自下组的杂原子：N、O或S，且所述取代基被取代，其可任选被一个或多个选自以下的取代基取代：卤素、-OH、-CN、未取代或卤代的C1-C6烷基、未取代或卤代的C1-C6烷氧基、未取代或卤代的C3-C6环烷基、未取代或卤代的C1-C6烷基硫基、氨基(-NH 2)、-N(未取代或卤代的C1-C6烷基) 2、-NH(未取代或卤代的C1-C6烷基)、-CO 2(未取代或卤代的C1-C6烷基)、-CF 3；
R 2选自卤素(如F)，
-CO 2R 2-1基团，
-CONR 2-20R 2-3基团，
-NR 2-4COR 2-5基团，
-NR 2-6CO 2R 2-7基团，
-NR 2-8R 2-9基团，
-SO 2R 2-10基团，
-SO 2NR 2-11R 2-12基团，
-NR 2-13SO 2R 2-14基团，
C1-C8烷基基团，C2-C8链烯基基团，C1-C6烷氧基基团，3-8元碳环基基团，3-8元杂环基基团，5-10元芳环基基团，5-10元杂芳环基团，或者两个相邻的R 2基团与和它们连接的原子一起形成3-8元碳环基团或杂环基团，所述的杂环基团或杂芳环基团包含1-4个选自下组的杂原子：N、O或S；且上述的基团可任选被一个或多个选自以下的取代基所取代：卤素(如F)、C1-C6烷基、C1-C6烷氧基、C3-C8环烷基、C1-C6烷基硫基、-N(C1-C6烷基) 2、-NH(C1-C6烷基)、C1-C8烷氧基-C1-C8烷基、C3-C8环烷基-C1-C8烷基、C1-C6烷基羰基、C1-C6烷氧基羰基、-S(O) 2N(C1-C6烷基) 2、-S(O) 2(C1-C6烷基)、-N(C1-C6烷基)S(O) 2N(C1-C6烷基) 2、-S(O)N(C1-C6烷基) 2、-S(O)(C1-C6烷基)、-N(C1-C6烷基)S(O)N(C1-C6烷基) 2、-N(C1-C6烷基)S(O)(C1-C6烷基)、5-10元芳基、5-10元杂芳基、3-8元杂环基，3-8元碳环基，其中，所述杂环基或杂芳基包含1-4个选自下组的杂原子：N、O或S，且所述取代基被取代时，其可任选被一个或多个选自以下的取代基取代：卤素、卤代C1-C6烷基、卤代C1-C6烷氧基、卤代C3-C8环烷基、卤代C1-C6烷基硫基、(卤代C1-C6烷基)NH-、(卤代C1-C6烷基) 2N-、-CO 2(卤代C1-C6烷基)，优选所述卤素为F，所述卤代为氟代；优选地，条件是，R 2须为含有卤素的基团，如为卤素或其取代基中至少包括卤素的基团；
R 3选自H，
-CO 2R 3-1基团，
-CONR 3-2OR 3-3基团，
-NR 3-4COR 3-5基团，
-NR 3-6CO 2R 3-7基团，
-NR 3-8R 3-9基团，
-SO 2R 3-10基团，
-SO 2NR 3-11R 3-12基团，
-NR 3-13SO 2R 3-14基团，
C1-C8烷基基团，C3-C8环烷基基团，C2-C8链烯基基团，3-8元杂环基基团，C1-C6烷氧基基团，5-10元芳环基基团，5-10元杂芳环基团，所述的杂环基团或杂芳环基团包含1-4个选自下组的杂原子：N、O或S；且上述的基团可任选被一个或多个选自以下的取代基所取代：-D、卤素、-OH、-CN、-NO 2、取代或未取代的C1-C6烷氧基、取代或未取代的C3-C8环烷基、取代或未取代的C1-C6烷基硫基、-N(取代或未取代的C1-C6烷基) 2、-NH(取代或未取代的C1-C6烷基)、取代或未取代的C1-C8烷氧基-C1-C8烷基、取代或未取代的C3-C8环烷基-C1-C8烷基、取代或未取代的C1-C6烷基羰基、取代或未取代的 C1-C6烷氧基羰基、异羟肟酸基、-S(O) 2N(取代或未取代的C1-C6烷基) 2、-S(O) 2(取代或未取代的C1-C6烷基)、-N(取代或未取代的C1-C6烷基)S(O) 2N(取代或未取代的C1-C6烷基) 2、-S(O)N(取代或未取代C1-C6烷基) 2、-S(O)(取代或未取代的C1-C6烷基)、-N(取代或未取代的C1-C6烷基)S(O)N(取代或未取代的C1-C6烷基) 2、-N(取代或未取代的C1-C6烷基)S(O)(取代或未取代的C1-C6烷基)、取代或未取代的5-10元芳基、取代或未取代的5-10元杂芳基、取代或未取代的3-8元杂环基，取代或未取代的3-8元碳环基，其中，所述杂环基或杂芳基包含1-4个选自下组的杂原子：N、O或S，且所述取代基被取代时，其可任选被一个或多个选自以下的取代基取代：卤素、-OH、-CN、未取代或卤代的C1-C6烷基、未取代或卤代的C1-C6烷氧基、未取代或卤代的C3-C6环烷基、未取代或卤代的C1-C6烷基硫基、氨基(-NH 2)、-N(未取代或卤代的C1-C6烷基) 2、-NH(未取代或卤代的C1-C6烷基)、-CO 2(未取代或卤代的C1-C6烷基)、-CF 3；
R 5选自H、C1-C6烷基基团，C1-C6烷氧基基团；上述的基团可任选被一个或多个选自以下的取代基所取代：-D、卤素、-OH、-CN、-NO 2、取代或未取代的C1-C6烷氧基、取代或未取代的C3-C8环烷基、取代或未取代的C1-C6烷基硫基、-N(取代或未取代的C1-C6烷基) 2、-NH(取代或未取代的C1-C6烷基)、取代或未取代的C1-C8烷氧基-C1-C8烷基、取代或未取代的C3-C8环烷基-C1-C8烷基、取代或未取代的C1-C6烷基羰基、取代或未取代的C1-C6烷氧基羰基、异羟肟酸基、-S(O) 2N(取代或未取代的C1-C6烷基) 2、-S(O) 2(取代或未取代的C1-C6烷基)、-N(取代或未取代的C1-C6烷基)S(O) 2N(取代或未取代的C1-C6烷基) 2、-S(O)N(取代或未取代C1-C6烷基) 2、-S(O)(取代或未取代的C1-C6烷基)、-N(取代或未取代的C1-C6烷基)S(O)N(取代或未取代的C1-C6烷基) 2、-N(取代或未取代的C1-C6烷基)S(O)(取代或未取代的C1-C6烷基)、取代或未取代的5-10元芳基、取代或未取代的5-10元杂芳基、取代或未取代的3-8元杂环基，取代或未取代的3-8元碳环基，其中，所述杂环基或杂芳基包含1-4个选自下组的杂原子：N、O或S，且所述取代基被取代基时，其可任选被一个或多个选自以下的取代基取代：卤素、-OH、-CN、未取代或卤代的C1-C6烷基、未取代或卤代的C1-C6烷氧基、氨基(-NH 2)、-N(未取代或卤代的C1-C6烷基) 2、-NH(未取代或卤代的C1-C6烷基)、-CO 2(未取代或卤代的C1-C6烷基)、-CF 3；
R 1-1代表H、未取代或卤代的C1-C6烷基、或未取代或卤代的C3-C6环烷基；
R 1-2和R 1-3各自独立代表H、未取代或卤代的C1-C6烷基、未取代或卤代的C3-C6环烷基，或R 1-2和R 1-3与它们连接的氮原子一起形成未取代或卤代的4-6元饱和杂环；
R 1-4和R 1-5各自独立代表H、未取代或卤代的C1-C6烷基、未取代或卤代的C3-C6环烷基，或R 1-4和R 1-5与它们连接的氮原子一起形成未取代或卤代的4-6元饱和杂环；
R 1-6和R 1-7各自独立代表H、未取代或卤代的C1-C6烷基、未取代或卤代的C3-C6环烷基，或R 1-6和R 1-7和与它们连接的氮原子一起形成未取代或卤代的4至6-元饱和杂环；
R 1-8和R 1-9各自独立代表H、未取代或卤代的C1-C6烷基、未取代或卤代的C3-C6环烷基，或R 1-8和R 1-9和与它们连接的氮原子一起形成未取代或卤代的4-6元饱和杂环；
R 1-10代表H、未取代或卤代的C1-C6烷基、未取代或卤代的C3-C6环烷基；
R 1-11和R 1-12各自独立代表H、C1-C6烷基、或C3-C6环烷基，或R 1-11和R 1-12和与它们连接的氮原子一起形成4-6元饱和杂环，且所述基团可任选被一个或多个选自以下的取代基取代：卤素、未取代或卤代的C1-C6烷基、未取代或卤代的C1-C6烷氧基、未取代或卤代的C1-C6烷基硫基、-NH 2、(未取代或卤代的C1-C4烷基) 2N-、(未取代或卤代的C1-C4烷基)NH-、-OH；
R 1-13和R 1-14各自独立代表C1-C6烷基、C1-C6环烷基，或R 1-13和R 1-14和与它们连接的氮原子一起形成4-6元饱和杂环，且所述基团可任选被一个或多个选自以下的取代基取代：卤素、未取代或卤代的C1-C6烷基、未取代或卤代的C1-C6烷氧基、未取代或卤代的C1-C6烷基硫基、-NH 2、(未取代或卤代的C1-C4烷基) 2N-、(未取代或卤代的C1-C4烷基)NH-、-OH；
R 2-1代表卤代C1-C6烷基或卤代C3-C6环烷基，优选所述卤代为氟代；
R 2-2和R 2-3分别独立代表卤代C1-C6烷基，卤代的C3-C6环烷基，或R 2-2和R 2-3与它们连接的氮原子一起形成卤代的4-6元饱和杂环；优选地，所述卤代为氟代；
R 2-4和R 2-5分别独立代表卤代C1-C6烷基，卤代的C3-C6环烷基，或R 2-4和R 2-5与它们连接的氮原子一起形成卤代的4-6元饱和杂环；优选地，所述卤代为氟代；
R 2-6和R 2-7分别独立代表卤代C1-C6烷基，卤代的C3-C6环烷基，或R 2-6和R 2-7与它们连接的氮原子一起形成卤代的4-6元饱和杂环；优选地，所述卤代为氟代；
R 2-8和R 2-9分别独立代表卤代C1-C6烷基，卤代的C3-C6环烷基，或R 2-8和R 2-9与它们连接的氮原子一起形成卤代的4-6元饱和杂环，或R 2-8和R 2-9与它们连接的氮原子一起形成卤代的5-10元不饱和杂芳环，或R 2-8和R 2-9与它们连接的氮原子一起形成卤代的5-10元杂芳环；优选地，所述卤代为氟代；
R 2-10代表卤代的C1-C6烷基或卤代的C3-C6环烷基；优选地，所述卤代为氟代；
R 2-11和R 2-12分别独立代表卤代C1-C6烷基，卤代的C3-C6环烷基，或R 2-8和R 2-9与它们连接的氮原子一起形成卤代的4-6元饱和杂环；优选地，所述卤代为氟代；
R 2-13和R 2-14分别独立代表卤代C1-C6烷基，卤代的C3-C6环烷基，或R 2-8和R 2-9与它们连接的氮原子一起形成卤代的4-6元饱和杂环；优选地，所述卤代为氟代；
R 3-1代表H、未取代或卤代的C1-C6烷基、或未取代或卤代的C3-C6环烷基；
R 3-2和R 3-3各自独立代表H、未取代或卤代的C1-C6烷基、未取代或卤代的C3-C6环烷基，或R 3-2和R 3-3与它们连接的氮原子一起形成未取代或卤代的4-6元饱和杂环；
R 3-4和R 3-5各自独立代表H、未取代或卤代的C1-C6烷基、未取代或卤代的C3-C6环烷基，或R 3-4和R 3-5与它们连接的氮原子一起形成未取代或卤代的4-6元饱和杂环；
R 3-6和R 3-7各自独立代表H、未取代或卤代的C1-C6烷基、未取代或卤代的C3-C6环烷基，或R 3-6和R 3-7和与它们连接的氮原子一起形成未取代或卤代的4至6-元饱和杂环；
R 3-8和R 3-9各自独立代表H、未取代或卤代的C1-C6烷基、未取代或卤代的C3-C6环烷基，或R 3-8和R 3-9和与它们连接的氮原子一起形成未取代或卤代的4-6元饱和杂环；
R 3-10代表H、未取代或卤代的C1-C6烷基、未取代或卤代的C3-C6环烷基；
R 3-11和R 3-12各自独立代表H、C1-C6烷基、或C3-C6环烷基，或R 3-11和R 3-12和与它们连接的氮原子一起形成4-6元饱和杂环，且所述基团可任选被一个或多个选自以下的取代基取代：卤素、未取代或卤代的C1-C6烷基、未取代或卤代的C1-C6烷氧基、未取代或卤代的C1-C6烷基硫基、-NH 2、(未取代或卤代的C1-C4烷基) 2N-、(未取代或卤代的C1-C4烷基)NH-、-OH；
R 3-13和R 3-14各自独立代表C1-C6烷基、C1-C6环烷基，或R 3-13和R 3-14和与它们连接的氮原子一起形成4-6元饱和杂环，且所述基团可任选被一个或多个选自以下的取代基取代：卤素、未取代或卤代的C1-C6烷基、未取代或卤代的C1-C6烷氧基、未取代或卤代的C1-C6烷基硫基、-NH 2、(未取代或卤代的C1-C4烷基) 2N-、(未取代或卤代的C1-C4烷基)NH-、-OH。
应理解，对于X、Y和Z，当为C时，该C可被R 1取代，或未被R 1取代时，则应为CH，以满足键价理论。
作为式I的一种优选的实施方式，X选自C或N；优选地，Y为C；优选地，Z为C。优选地，X选自C或N，Y为C，且Z为C。在一些实施方式中，X、Y和X都为C。
作为式I的一种优选的实施方式，R 1的个数为1-3个，且独立地选自卤素、C1-C4烷基和C1-C3烷氧基。
在式I的一些实施方案中，R 2选自卤素(如F)，
-CO 2R 2-1基团，
-CONR 2-20R 2-3基团，
-NR 2-4COR 2-5基团，
-NR 2-6CO 2R 2-7基团，
-NR 2-8R 2-9基团，
-SO 2R 2-10基团，
-SO 2NR 2-11R 2-12基团，
-NR 2-13SO 2R 2-14基团，
C1-C8烷基基团，C2-C8链烯基基团，C1-C6烷氧基基团，3-8元碳环基基团，3-8元杂环基基团，5-10元芳环基基团，5-10元杂芳环基团，或者两个相邻的R 2基团与和它们连接的原子一起形成3-8元碳环基团或杂环基团，所述的杂环基团或杂芳环基团包含1-4个选自下组的杂原子：N、O或S；且上述的基团可任选被一个或多个选自以下的取代基所取代：卤素(如F)、C1-C6烷氧基、C3-C8环烷基、C1-C6烷基硫基、-N(C1-C6烷基) 2、-NH(C1-C6烷基)、C1-C8烷氧基-C1-C8烷基、C3-C8环烷基-C1-C8烷基、C1-C6烷基羰基、C1-C6烷氧基羰基、-S(O) 2N(C1-C6烷基) 2、-S(O) 2(C1-C6烷基)、-N(C1-C6烷基)S(O) 2N(C1-C6烷基) 2、-S(O)N(C1-C6烷基) 2、-S(O)(C1-C6烷基)、-N(C1-C6烷基)S(O)N(C1-C6烷基) 2、-N(C1-C6烷基)S(O)(C1-C6烷基)、5-10元芳基、5-10元杂芳基、3-8元杂环基，3-8元碳环基，其中，所述杂环基或杂芳基包含1-4个选自下组的杂原子：N、O或S，且所述取代基被取代时，其可任选被一个或多个选自以下的取代基取代：卤素、卤代C1-C6烷基、卤代C1-C6烷氧基、卤代C3-C8环烷基、卤代C1-C6烷基硫基、(卤代C1-C6烷基)NH-、(卤代C1-C6烷基) 2N-、-CO 2(卤代C1-C6烷基)，优选所述卤素为F，所述卤代为氟代；优选地，条件是，R 2须为含有卤素的基团，如为卤素或其取代基中至少包括卤素的基团。
作为式I的一种优选的实施方式，R 2可选自：卤素(如F)；-NR 2-8R 2-9基团，其中R 2-8和R 2-9各自独立为H、C1-C6烷基和卤代C1-C6烷基；和C1-C8烷基基团，C2-C8链烯基基团，C1-C6烷氧基基团，3-8元碳环基基团，3-8元杂环基基团，5-10元芳环基基团和5-10元杂芳环基团，其中，这些基团可任选被一个或多个选自以下的取代基所取代：卤素、卤代C1-C6烷基、C1-C6烷基、C1-C6烷氧基、C3-C8环烷基、-N(C1-C6烷基) 2、-NH(C1-C6烷基)、C1-C8烷氧基-C1-C8烷基、C3-C8环烷基-C1-C8烷基、C1-C6烷基羰基、C1-C6烷氧基羰基、5-10元芳基、5-10元杂芳基、3-8元杂环基和3-8元碳环基；其中，所述杂环基或杂芳基包含1-4个选自下组的杂原子：N、O或S。
作为式I的一种优选的实施方式，R 2为卤素或其取代基中至少包括卤素的基团。优选地，该基团包括但不限于-NR 2-8R 2-9基团、C1-C6烷基、C2-C8链烯基、C1-C6烷氧基、任选被C1-C6烷基取代的5-10元芳基、任选被C1-C6烷基取代的5-10元杂芳基、任选被C1-C6烷基取代的3-8元杂环基和任选被C1-C6烷基取代的3-8元碳环基；所述“至少包括卤素”指卤素取代可发生在所述芳基、杂芳基、杂环基和碳环基的环上，和/或，当所 述环被其它基团取代时，如被C1-C6烷基取代时，卤素取代也可发生在该取代基上。在一个或多个实施方案中，R 2选自：-NR 2-8R 2-9基团，其中，R 2-8和R 2-9各自独立为H、C1-C6烷基和卤代C1-C6烷基，且R 2-8和R 2-9中至少一个为卤代C1-C6烷基；C1-C8烷基基团，C2-C8链烯基基团，C1-C6烷氧基基团，3-8元碳环基基团，3-8元杂环基基团，5-10元芳环基基团，5-10元杂芳环基团，且这些基团至少被卤素和/或C1-C6卤代烷基取代，可任选地进一步被一个或多个选自以下的取代基所取代：C1-C6烷基、C1-C6烷氧基、C3-C8环烷基、-N(C1-C6烷基) 2、-NH(C1-C6烷基)、C1-C8烷氧基-C1-C8烷基、C3-C8环烷基-C1-C8烷基、C1-C6烷基羰基、C1-C6烷氧基羰基、5-10元芳基、5-10元杂芳基、3-8元杂环基和3-8元碳环基，其中，所述杂环基或杂芳基包含1-4个选自下组的杂原子：N、O或S。在一些实施方案中，当R 2为其取代基中至少包括卤素的基团时，R 2上的卤素原子的数量在2个以上，如2-6个。优选的卤素取代为氟代。
作为式I的一种优选的实施方式，R 3选自5-10元芳环基基团，5-10元杂芳环基团，所述的杂环基团或杂芳环基团包含1-4个选自下组的杂原子：N、O或S；且上述的基团可任选被一个或多个选自以下的取代基所取代：-D、卤素、-OH、-CN、-NO 2、卤代或未取代的C1-C6烷氧基、卤代或未取代的C3-C8环烷基、卤代或未取代的C1-C6烷基硫基、-N(卤代或未取代的C1-C6烷基) 2、-NH(卤代或未取代的C1-C6烷基)、卤代或未取代的C1-C8烷氧基-C1-C8烷基、卤代或未取代的C3-C8环烷基-C1-C8烷基、卤代或未取代的C1-C6烷基羰基、卤代或未取代的C1-C6烷氧基羰基、异羟肟酸基、-S(O) 2N(卤代或未取代的C1-C6烷基) 2、-S(O) 2(卤代或未取代的C1-C6烷基)、-N(卤代或未取代的C1-C6烷基)S(O) 2N(卤代或未取代的C1-C6烷基) 2、-S(O)N(卤代或未取代C1-C6烷基) 2、-S(O)(卤代或未取代的C1-C6烷基)、-N(卤代或未取代的C1-C6烷基)S(O)N(卤代或未取代的C1-C6烷基) 2、-N(卤代或未取代的C1-C6烷基)S(O)(卤代或未取代的C1-C6烷基)、卤代或未取代的5-10元芳基、卤代或未取代的5-10元杂芳基、卤代或未取代的3-8元杂环基，卤代或未取代的3-8元碳环基，其中，所述杂环基或杂芳基包含1-4个选自下组的杂原子：N、O或S。
作为式I的一种优选的实施方式，R 3选自：5-10元芳环基基团和5-10元杂芳环基团，所述的杂芳环基团包含1-4个选自下组的杂原子：N、O或S；且上述的基团可任选被一个或多个选自以下的取代基所取代：-D、卤素、-OH、卤代或未取代的C1-C6烷氧基、卤代或未取代的C3-C8环烷基、卤代或未取代的C1-C8烷氧基-C1-C8烷基、卤代或未取代的C3-C8环烷基-C1-C8烷基、卤代或未取代的C1-C6烷基羰基、卤代或未取代的C1-C6烷氧基羰基。
作为式I的一种优选的实施方式，
Figure PCTCN2020112173-appb-000007
表示双键。
作为式I的一种优选的实施方式，R 5选自：H、C1-C6烷基基团和C1-C6烷氧基基团；所述基团C1-C6烷基基团和C1-C6烷氧基基团各自任选被一个或多个选自以下的取代基所取代：-D、卤素、-OH、取代或未取代的C1-C6烷氧基、取代或未取代的C3-C8环烷基、-N(取代或未取代的C1-C6烷基) 2、-NH(取代或未取代的C1-C6烷基)。
作为式I的一种优选的实施方式，R 6为H。
作为式I的一种优选的实施方式，所述的化合物、或其药学上可接受的盐、或其溶剂化物、同位素取代物、前药或代谢产物具有如下式II所示的结构：
Figure PCTCN2020112173-appb-000008
其中，R 4为1-5个，且各自独立表示H、卤素，-OH，-CN，-NO 2，
-CO 2R 4-1基团，
-CONR 4-20R 4-3基团，
-NR 4-4COR 4-5基团，
-NR 4-6CO 2R 4-7基团，
-NR 4-8R 4-9基团，
-SO 2R 4-10基团，
-SO 2NR 4-11R 4-12基团，
-NR 4-13SO 2R 4-14基团，
C1-C8烷基基团，C3-C8环烷基基团，C2-C8链烯基基团，3-8元杂环基基团，C1-C6烷氧基基团，5-10元芳环基基团，5-10元杂芳环基团，或者两个相邻的R 1基团与和它们连接的原子一起形成3-8元碳环基团或杂环基团，或者两个相邻的R 1基团与和它们连接的原子一起形成5-10元芳环基团或杂芳环基团，所述的杂环基团或杂芳环基团包含1-4个选自下组的杂原子：N、O或S；且上述的基团可任选被一个或多个选自以下的取代基所取代：-D、卤素、-OH、-CN、-NO 2、取代或未取代的C1-C6烷氧基、取代或未取代的C3-C8环烷基、取代或未取代的C1-C6烷基硫基、-N(取代或未取代的C1-C6烷基) 2、-NH(取代或未取代的C1-C6烷基)、取代或未取代的C1-C8烷氧基-C1-C8烷基、取代或未取代的 C3-C8环烷基-C1-C8烷基、取代或未取代的C1-C6烷基羰基、取代或未取代的C1-C6烷氧基羰基、异羟肟酸基、-S(O) 2N(取代或未取代的C1-C6烷基) 2、-S(O) 2(取代或未取代的C1-C6烷基)、-N(取代或未取代的C1-C6烷基)S(O) 2N(取代或未取代的C1-C6烷基) 2、-S(O)N(取代或未取代C1-C6烷基) 2、-S(O)(取代或未取代的C1-C6烷基)、-N(取代或未取代的C1-C6烷基)S(O)N(取代或未取代的C1-C6烷基) 2、-N(取代或未取代的C1-C6烷基)S(O)(取代或未取代的C1-C6烷基)、取代或未取代的5-10元芳基、取代或未取代的5-10元杂芳基、取代或未取代的3-8元杂环基，取代或未取代的3-8元碳环基，其中，所述杂环基或杂芳基包含1-4个选自下组的杂原子：N、O或S，且所述取代基被取代时，其可任选被一个或多个选自以下的取代基取代：卤素、-OH、-CN、未取代或卤代的C1-C6烷基、未取代或卤代的C1-C6烷氧基、未取代或卤代的C3-C6环烷基、未取代或卤代的C1-C6烷基硫基、氨基(-NH 2)、-N(未取代或卤代的C1-C6烷基) 2、-NH(未取代或卤代的C1-C6烷基)、-CO 2(未取代或卤代的C1-C6烷基)、-CF 3；
R 4-1代表H、未取代或卤代的C1-C6烷基、或未取代或卤代的C3-C6环烷基；
R 4-2和R 4-3各自独立代表H、未取代或卤代的C1-C6烷基、未取代或卤代的C3-C6环烷基，或R 4-2和R 4-3与它们连接的氮原子一起形成未取代或卤代的4-6元饱和杂环；
R 4-4和R 4-5各自独立代表H、未取代或卤代的C1-C6烷基、未取代或卤代的C3-C6环烷基，或R 4-4和R 4-5与它们连接的氮原子一起形成未取代或卤代的4-6元饱和杂环；
R 4-6和R 4-7各自独立代表H、未取代或卤代的C1-C6烷基、未取代或卤代的C3-C6环烷基，或R 4-6和R 4-7和与它们连接的氮原子一起形成未取代或卤代的4至6-元饱和杂环；
R 4-8和R 4-9各自独立代表H、未取代或卤代的C1-C6烷基、未取代或卤代的C3-C6环烷基，或R 4-8和R 4-9和与它们连接的氮原子一起形成未取代或卤代的4-6元饱和杂环；
R 4-10代表H、未取代或卤代的C1-C6烷基、未取代或卤代的C3-C6环烷基；
R 4-11和R 4-12各自独立代表H、C1-C6烷基、或C3-C6环烷基，或R 4-11和R 4-12和与它们连接的氮原子一起形成4-6元饱和杂环，且所述基团可任选被一个或多个选自以下的取代基取代：卤素、未取代或卤代的C1-C6烷基、未取代或卤代的C1-C6烷氧基、未取代或卤代的C1-C6烷基硫基、-NH 2、(未取代或卤代的C1-C4烷基) 2N-、(未取代或卤代的C1-C4烷基)NH-、-OH；
R 4-13和R 4-14各自独立代表C1-C6烷基、C1-C6环烷基，或R 4-13和R 4-14和与它们连接的氮原子一起形成4-6元饱和杂环，且所述基团可任选被一个或多个选自以下的取代基取代：卤素、未取代或卤代的C1-C6烷基、未取代或卤代的C1-C6烷氧基、未取代或卤代的C1-C6烷基硫基、-NH 2、(未取代或卤代的C1-C4烷基) 2N-、(未取代或卤代的C1-C4 烷基)NH-、-OH；
其他如前述任一实施方式所定义。
作为式II的一种优选的实施方式，R 4选自：C1-C8烷基基团，C2-C8链烯基基团，C1-C6烷氧基基团；其中，这些基团任选被一个或多个选自以下的取代基所取代：-D、卤素、-OH和取代或未取代的C1-C6烷氧基。优选地，R 4的数量为1-3个，各R 4可相同或不同。在一些实施方案中，R 4为2个，均位于间位。在优选的实施方案中，R 4为2个C1-C6烷氧基。
作为式II的一种优选的实施方式，R 2为卤素或其取代基中至少包括卤素的基团。优选地，该基团包括但不限于-NR 2-8R 2-9基团、C1-C6烷基、C2-C8链烯基、C1-C6烷氧基、任选被C1-C6烷基取代的5-10元芳基、任选被C1-C6烷基取代的5-10元杂芳基、任选被C1-C6烷基取代的3-8元杂环基和任选被C1-C6烷基取代的3-8元碳环基；所述“至少包括卤素”指卤素取代可发生在所述芳基、杂芳基、杂环基和碳环基的环上，和/或，当所述环被其它基团取代时，如被C1-C6烷基取代时，卤素取代也可发生在该取代基上。在一个或多个实施方案中，R 2选自：-NR 2-8R 2-9基团，其中，R 2-8和R 2-9各自独立为H、C1-C6烷基和卤代C1-C6烷基，且R 2-8和R 2-9中至少一个为卤代C1-C6烷基；和C1-C8烷基基团，C2-C8链烯基基团，C1-C6烷氧基基团，3-8元碳环基基团，3-8元杂环基基团，5-10元芳环基基团和5-10元杂芳环基团，其中，这些基团至少被卤素和/或C1-C6卤代烷基取代，可任选地进一步被一个或多个选自以下的取代基所取代：C1-C6烷基、C1-C6烷氧基、C3-C8环烷基、-N(C1-C6烷基) 2、-NH(C1-C6烷基)、C1-C8烷氧基-C1-C8烷基、C3-C8环烷基-C1-C8烷基、C1-C6烷基羰基、C1-C6烷氧基羰基、5-10元芳基、5-10元杂芳基、3-8元杂环基和3-8元碳环基，其中，所述杂环基或杂芳基包含1-4个选自下组的杂原子：N、O或S。在一些实施方案中，当R 2为卤素取代的基团时，R 2上的卤素原子的数量在2个以上，如2-6个。优选的卤素取代为氟代。
作为式I和II的一种优选的实施方式，R 1选自下组：H、卤素(包括Cl、F、Br)、-OH、-CN、C1-C4烷基、C1-C4烷基羟基、-(C1-C3烷基)N(C1-C3烷基) 2、-(C1-C3烷基)NH 2、C1-C3烷氧基、-O-(C1-C3烷基)-OH、-O(C1-C3烷基)O(C1-C3烷基)、-N(C1-C3烷基) 2、-NHPh、-NH(C1-C3烷基)、-NH(C1-C3烷基)N(C1-C3烷基) 2、-CONH 2、-NHCO(C1-C3烷基)、-NHCOH、-NHCOPh、-CO 2H、-CO 2(C1-C3烷基)、-SO 2(C1-C3烷基)、-NHSO 2(C1-C3烷基)、-SO 2N(C1-C3烷基) 2。进一步地，作为式I和II的一种优选的实施方式，R 1为H、卤素、C1-C3烷基或C1-C3烷氧基，优选为H、卤素或C1-C3烷氧基，更优选为H。
作为式I和II的一种优选的实施方式，R 2选自下组：-F、氟代的C1-C4烷基、氟代的C1-C4烷基羟基、-(氟代的C1-C3烷基)N(C1-C3烷基) 2、-(氟代的C1-C3烷基)NH(C1-C3 烷基)、-(C1-C3烷基)N(氟代的C1-C3烷基) 2、-(C1-C3烷基)NH(氟代的C1-C3烷基)、-(氟代的C1-C3烷基)NH 2、氟代的C1-C3烷氧基、-O-(氟代的C1-C3烷基)-OH、-O(氟代的C1-C3烷基)O(C1-C3烷基)、-O(C1-C3烷基)O(氟代的C1-C3烷基)、-N(氟代的C1-C3烷基) 2、-NH(氟代的C1-C3烷基)、氟代苯基氨基、-NH(氟代的C1-C3烷基)N(C1-C3烷基) 2、-NH(C1-C3烷基)N(氟代的C1-C3烷基) 2、-NH(C1-C3烷基)NH(氟代的C1-C3烷基)、-NH(氟代的C1-C3烷基)NH(C1-C3烷基)、-NHCO(氟代的C1-C3烷基)、氟代苯酰胺、-CO 2(氟代的C1-C3烷基)、-SO 2(氟代的C1-C3烷基)、-NHSO 2(氟代的C1-C3烷基)、-SO 2N(氟代的C1-C3烷基) 2、3-7元碳环基基团，3-7元杂环基基团，5-6元芳环基基团，5-6元杂芳环基团，所述的杂环基团或杂芳环基团包含1-4个选自下组的杂原子：N、O或S；且上述的环基基团可任选被一个或多个选自以下的取代基所取代：F、氟代的C1-C4烷基、氟代的C1-C4烷氧基、氟代的C3-C8环烷基、氟代的C1-C4烷基硫基、-N(氟代的C1-C6烷基) 2、-NH(氟代的C1-C6烷基)、氟代的C1-C3烷基-O-C1-C3烷基、C1-C3烷基-O-氟代的C1-C3烷基、氟代的C3-C6环烷基-C1-C4烷基、C3-C6环烷基-氟代的C1-C4烷基、氟代的C1-C4烷基羰基、氟代的C1-C4烷氧基羰基、-S(O) 2N(氟代的C1-C4烷基) 2、-S(O) 2(氟代的C1-C4烷基)、-N(氟代的C1-C4烷基)S(O) 2N(C1-C6烷基) 2、-N(C1-C4烷基)S(O) 2N(氟代的C1-C4烷基) 2、-S(O)N(氟代的C1-C4烷基) 2、-S(O)(氟代的C1-C4烷基)、-N(氟代的C1-C4烷基)S(O)N(C1-C4烷基) 2、-N(C1-C4烷基)S(O)N(氟代的C1-C4烷基) 2、-N(氟代的C1-C4烷基)S(O)(C1-C6烷基)、-N(C1-C4烷基)S(O)(氟代的C1-C6烷基)、氟代的5-6元芳基、氟代的5-6元杂芳基、氟代的3-7元杂环基，氟代的3-7元碳环基，其中，所述杂环基或杂芳基包含1-4个选自下组的杂原子：N、O或S。
作为式I和II的一种优选的实施方式，R 5选自下组：H、C1-C6烷基基团，C1-C6烷氧基基团；上述的基团可任选被一个或多个选自以下的取代基所取代：-D、卤素、-OH、-CN、-NO 2、取代或未取代的C1-C6烷氧基、取代或未取代的C3-C8环烷基、-N(取代或未取代的C1-C6烷基) 2、-NH(取代或未取代的C1-C6烷基)、取代或未取代的5-10元芳基、取代或未取代的5-10元杂芳基、取代或未取代的3-8元杂环基，取代或未取代的3-8元碳环基，其中，所述杂环基或杂芳基包含1-4个选自下组的杂原子：N、O或S，且所述取代基可任选被一个或多个选自以下的取代基取代：卤素、-OH、-CN、未取代或卤代的C1-C6烷基、未取代或卤代的C1-C6烷氧基、氨基(-NH 2)、-N(未取代或卤代的C1-C6烷基) 2、-NH(未取代或卤代的C1-C6烷基)、-CF 3。
作为式I和II的进一步优选的实施方式，R 1选自下组：H、Cl、F、Br、-OH、C1-C3烷基、C1-C3烷基羟基、-(C1-C3烷基)N(C1-C3烷基) 2、-(C1-C3烷基)NH 2、C1-C3烷氧基、-O-(C1-C3烷基)-OH、-O(C1-C3烷基)O(C1-C3烷基)、-N(C1-C3烷基) 2、-NHPh、 -NH(C1-C3烷基)。在一些实施方式中，R 1的数量为1个，为Cl、F、Br、C1-C4烷基或C1-C3烷氧基。在一些实施方案中，R 1为H。
作为式I和II的进一步优选的实施方式，R 2选自：卤代C1-C6烷基，卤代C1-C6烷氧基，-N(卤代C1-C6烷基)(C1-C6烷基)，-NH(卤代C1-C6烷基)，-N(卤代C1-C6烷基) 2，-(C1-C3烷基)N(卤代C1-C3烷基) 2，-(C1-C3烷基)NH(卤代C1-C3烷基)，卤代3-8元杂环基，卤代C1-C6烷基取代的3-8元杂环基，其中，所述杂环基可任选地被1或2个选自除所述卤素和卤代C1-C6烷基以外的基团(如C1-C6烷基、C1-C6烷氧基等)进一步取代；优选地，所述杂环基为含1或2个氮的杂环基，包括但不限于哌嗪基、哌啶基、吡咯烷基和氮杂环丁烷基等。
作为式I和II的进一步优选的实施方式，R 2选自下组：-F、氟代的C1-C3烷基、氟代的C1-C3烷氧基、-N(氟代的C1-C3烷基)(C1-C3烷基)、-(氟代的C1-C3烷基)N(C1-C3烷基) 2、-(氟代的C1-C3烷基)NH(C1-C3烷基)、-(C1-C3烷基)N(氟代的C1-C3烷基) 2、-(C1-C3烷基)NH(氟代的C1-C3烷基)、-(氟代的C1-C3烷基)NH 2、-O-(氟代的C1-C3烷基)-OH、-O(氟代的C1-C3烷基)O(C1-C3烷基)、-O(C1-C3烷基)O(氟代的C1-C3烷基)、-N(氟代的C1-C3烷基) 2、-NH(氟代的C1-C3烷基)、-NH(氟代的C1-C3烷基)N(C1-C3烷基) 2、-NH(C1-C3烷基)N(氟代的C1-C3烷基) 2、-NH(C1-C3烷基)NH(氟代的C1-C3烷基)、-NH(氟代的C1-C3烷基)NH(C1-C3烷基)、-NHCO(氟代的C1-C3烷基)、-CO 2(氟代的C1-C3烷基)、-SO 2(氟代的C1-C3烷基)、-NHSO 2(氟代的C1-C3烷基)、-SO 2N(氟代的C1-C3烷基) 2、
Figure PCTCN2020112173-appb-000009
其中这些环基中的H可被至少一个选自以下的基团的取代基取代：F、-CF 3、-CHF 2、-CH 2CF 3、-CH 2CHF 2、-CH 2CH 2CF 3、CH 2CH 2CHF 2、CH 2CF 2CF 3。进一步优选地，R 2选自下组：-F、氟代的C1-C3烷基、氟代的C1-C3烷氧基、-N(氟代的C1-C3烷基)(C1-C3烷基)、-(氟代的C1-C3烷基)N(C1-C3烷基) 2、-(氟代的C1-C3烷基)NH(C1-C3烷基)、-(C1-C3烷基)N(氟代的C1-C3烷基) 2、-(C1-C3烷基)NH(氟代的C1-C3烷基)、-(氟代的C1-C3烷基)NH 2、-N(氟代的C1-C3烷基) 2、-NH(氟代的C1-C3烷基)、-NH(氟代的C1-C3烷基)N(C1-C3烷基) 2、-NH(C1-C3烷基)N(氟代的C1-C3烷基) 2、-NH(C1-C3烷基)NH(氟代的C1-C3烷基)、-NH(氟代的C1-C3烷基)NH(C1-C3烷基)、
Figure PCTCN2020112173-appb-000010
Figure PCTCN2020112173-appb-000011
其中这些环基中的H可被至少一个选自以下的基团的取代基取代：F、-CF 3、-CHF 2、-CH 2CF 3、-CH 2CHF 2、-CH 2CH 2CF 3、CH 2CH 2CHF 2、CH 2CF 2CF 3。
作为式I和II的进一种优选的实施方式，R 5选自下组：H、C1-C4烷基基团，C1-C4烷氧基基团；上述的基团可任选被一个或多个选自以下的取代基所取代：-D、卤素、-OH、-CN、-NO 2、取代或未取代的C1-C3烷氧基、取代或未取代的C3-C6环烷基、-N(取代或未取代的C1-C3烷基) 2、-NH(取代或未取代的C1-C3烷基)、取代或未取代的5-6元芳基、取代或未取代的5-6元杂芳基、取代或未取代的3-6元杂环基，取代或未取代的3-7元碳环基，其中，所述杂环基或杂芳基包含1-4个选自下组的杂原子：N、O或S，且所述取代基可任选被一个或多个选自以下的取代基取代：卤素、-OH、-CN、未取代或卤代的C1-C3烷基、未取代或卤代的C1-C3烷氧基、氨基(-NH 2)、-N(未取代或卤代的C1-C3烷基) 2、-NH(未取代或卤代的C1-C3烷基)、-CF 3。更优选地，R 5选自：H、C1-C4烷基基团和C1-C4烷氧基基团；所述基团C1-C4烷基基团和C1-C4烷氧基基团各自任选被一个或多个选自以下的取代基所取代：-D、卤素、-OH、取代或未取代的C1-C3烷氧基、取代或未取代的C3-C8环烷基、-N(取代或未取代的C1-C3烷基) 2、-NH(取代或未取代的C1-C3烷基)；更优选地，R 5为H或未取代或卤代C1-C3烷基。
作为式I和II的更进一步的优选实施方式，R 2选自下组：-F、氟代的C1-C3烷基、氟代的C1-C3烷氧基、-N(C1-C3烷基)(氟代C1-C3烷基)、
Figure PCTCN2020112173-appb-000012
应理解，前述实施方式中的任意一个可与任意其它一个或多个实施方式组合，形成本申请的其它实施方式，所有这些实施方式都包括在本申请所披露的范围之内。因此，举例 而言，在一些实施方式中，本申请的式I和II化合物中：
R 1选自下组：H、Cl、F、Br、-OH、-CN、C1-C4烷基、C1-C4烷基羟基、-(C1-C3烷基)N(C1-C3烷基) 2、-(C1-C3烷基)NH 2、C1-C3烷氧基、-O-(C1-C3烷基)-OH、-O(C1-C3烷基)O(C1-C3烷基)、-N(C1-C3烷基) 2、-NHPh、-NH(C1-C3烷基)、-NH(C1-C3烷基)N(C1-C3烷基) 2、-CONH 2、-NHCO(C1-C3烷基)、-NHCOH、-NHCOPh、-CO 2H、-CO 2(C1-C3烷基)、-SO 2(C1-C3烷基)、-NHSO 2(C1-C3烷基)、-SO 2N(C1-C3烷基) 2；
R 2选自：卤代C1-C6烷基，卤代C1-C6烷氧基，-N(卤代C1-C6烷基)(C1-C6烷基)，卤代3-8元杂环基，卤代C1-C6烷基取代的3-8元杂环基，其中，所述杂环基可任选地进一步被1或2个选自除所述卤素和卤代C1-C6烷基以外的基团(如C1-C6烷基、C1-C6烷氧基等)取代；优选地，所述杂环基为含1或2个氮的杂环基，包括但不限于哌嗪基、哌啶基、吡咯烷基和氮杂环丁烷基等；
R 3选自：5-10元芳环基基团和5-10元杂芳环基团，所述的杂芳环基团包含1-4个选自下组的杂原子：N、O或S；且上述的基团可任选被一个或多个选自以下的取代基所取代：-D、卤素、-OH、卤代或未取代的C1-C6烷氧基、卤代或未取代的C3-C8环烷基、卤代或未取代的C1-C8烷氧基-C1-C8烷基、卤代或未取代的C3-C8环烷基-C1-C8烷基、卤代或未取代的C1-C6烷基羰基、卤代或未取代的C1-C6烷氧基羰基，优选的取代基为选自以下的一个或多个取代基：卤素、卤代或未取代的C1-C4烷氧基、卤代或未取代的C1-C8烷氧基-C1-C8烷基；或R 4为1-3个，如2个，分别选自：C1-C8烷基基团，C2-C8链烯基基团，C1-C6烷氧基基团；其中，这些基团任选被一个或多个选自以下的取代基所取代：-D、卤素、-OH和取代或未取代的C1-C6烷氧基；
Figure PCTCN2020112173-appb-000013
表示双键；
R 5选自：H、C1-C6烷基基团和C1-C6烷氧基基团；所述基团C1-C6烷基基团和C1-C6烷氧基基团各自任选被一个或多个选自以下的取代基所取代：-D、卤素、-OH、取代或未取代的C1-C6烷氧基、取代或未取代的C3-C8环烷基、-N(取代或未取代的C1-C6烷基) 2、-NH(取代或未取代的C1-C6烷基)，优选的取代基为一个或多个选自以下的取代基：卤素和取代或未取代的C1-C4烷氧基；
R 6为H；
优选地，在这些实施方案中，X选自C或N；Y为C；Z为C。
在一些实施方式中，本发明式I和II的化合物中：
R 1选自下组：H、Cl、F、Br、C1-C4烷基和C1-C3烷氧基；
R 2选自下组：-F、氟代C1-C3烷基、氟代C1-C3烷氧基、-N(氟代C1-C3烷基)(C1-C3烷基)、-(氟代C1-C3烷基)N(C1-C3烷基) 2、-(氟代C1-C3烷基)NH(C1-C3烷基)、-(C1-C3 烷基)N(氟代C1-C3烷基) 2、-(C1-C3烷基)NH(氟代C1-C3烷基)、-(氟代C1-C3烷基)NH 2、-N(氟代C1-C3烷基) 2、-NH(氟代C1-C3烷基)、-NH(氟代C1-C3烷基)N(C1-C3烷基) 2、-NH(C1-C3烷基)N(氟代C1-C3烷基) 2、-NH(C1-C3烷基)NH(氟代C1-C3烷基)、-NH(氟代的C1-C3烷基)NH(C1-C3烷基)、
Figure PCTCN2020112173-appb-000014
其中这些环基中的H可被至少一个选自以下的基团的取代基取代：F、-CF 3、-CHF 2、-CH 2CF 3、-CH 2CHF 2、-CH 2CH 2CF 3、CH 2CH 2CHF 2、CH 2CF 2CF 3；
R 3选自：5-10元芳环基基团和5-10元杂芳环基团，所述的杂芳环基团包含1-4个选自下组的杂原子：N、O或S；且上述的基团可任选被一个或多个选自以下的取代基所取代：-D、卤素、-OH、卤代或未取代的C1-C6烷氧基、卤代或未取代的C3-C8环烷基、卤代或未取代的C1-C8烷氧基-C1-C8烷基、卤代或未取代的C3-C8环烷基-C1-C8烷基、卤代或未取代的C1-C6烷基羰基、卤代或未取代的C1-C6烷氧基羰基，优选的取代基为选自以下的一个或多个取代基：卤素、卤代或未取代的C1-C4烷氧基、卤代或未取代的C1-C8烷氧基-C1-C8烷基；或R 4为1-3个，如2个，分别选自：C1-C8烷基基团，C2-C8链烯基基团，C1-C6烷氧基基团；其中，这些基团任选被一个或多个选自以下的取代基所取代：-D、卤素、-OH和取代或未取代的C1-C6烷氧基；
Figure PCTCN2020112173-appb-000015
表示双键；
R 5选自：H、C1-C6烷基基团和C1-C6烷氧基基团；所述基团C1-C6烷基基团和C1-C6烷氧基基团各自任选被一个或多个选自以下的取代基所取代：-D、卤素、-OH、取代或未取代的C1-C6烷氧基、取代或未取代的C3-C8环烷基、-N(取代或未取代的C1-C6烷基) 2、-NH(取代或未取代的C1-C6烷基)，优选的取代基为一个或多个选自以下的取代基：卤素和取代或未取代的C1-C4烷氧基；
R 6为H；
优选地，在这些实施方案中，X选自C或N；Y为C；Z为C。
在一些实施方式中，本发明式I的化合物中：X选自C或N；Y为C；Z为C；R 1选自H、卤素、C1-C4烷基和C1-C3烷氧基；R 2选自卤代C1-C6烷基、卤代C1-C6烷氧基、-N(卤代C1-C3烷基)(C1-C3烷基)、-NH(卤代C1-C3烷基)、-N(卤代C1-C3烷基) 2、-(C1-C3烷基)N(卤代C1-C3烷基) 2、-(C1-C3烷基)NH(卤代C1-C3烷基)、卤代3-8元杂环基和卤代C1-C6烷基取代的3-8元杂环基，其中，所述杂环基可任选地进一步被1或2 个选自除所述卤素和卤代C1-C6烷基以外的基团(如C1-C6烷基、C1-C6烷氧基等)取代，优选地，所述杂环基为含1或2个氮的杂环基，包括但不限于哌嗪基、哌啶基、吡咯烷基和氮杂环丁烷基等；R 3为任选被一个或多个选自卤代或未取代的C1-C6烷氧基的取代基取代的5-10元芳环基；
Figure PCTCN2020112173-appb-000016
表示双键；R 5为H或C1-C3烷基；和R 6为H。进一步优选地，R 1选自H、卤素和C1-C3烷氧基；R 3为被一个或多个选自卤代或未取代的C1-C6烷氧基的取代基取代的苯基。
在一些实施方式中，本发明式II的化合物中：X选自C或N；Y为C；Z为C；R 1选自H、卤素、C1-C4烷基和C1-C3烷氧基；R 2选自卤代C1-C6烷基、卤代C1-C6烷氧基、-N(卤代C1-C3烷基)(C1-C3烷基)、-NH(卤代C1-C3烷基)、-N(卤代C1-C3烷基) 2、-(C1-C3烷基)N(卤代C1-C3烷基) 2、-(C1-C3烷基)NH(卤代C1-C3烷基)、卤代3-8元杂环基和卤代C1-C6烷基取代的3-8元杂环基，其中，所述杂环基可任选地进一步被1或2个选自除所述卤素和卤代C1-C6烷基以外的基团(如C1-C6烷基、C1-C6烷氧基等)取代，优选地，所述杂环基为含1或2个氮的杂环基，包括但不限于哌嗪基、哌啶基、吡咯烷基和氮杂环丁烷基等；R 4的数量为1-3个，如2个，分别选自：C1-C8烷基基团，C2-C8链烯基基团，C1-C6烷氧基基团；其中，这些基团任选被一个或多个选自以下的取代基所取代：-D、卤素、-OH和取代或未取代的C1-C6烷氧基；
Figure PCTCN2020112173-appb-000017
表示双键；R 5为H或C1-C3烷基；和R 6为H。进一步优选地，R 1选自H、卤素和C1-C3烷氧基；R 4为未取代的C1-C6烷氧基。
作为再进一步的优选方式，本发明所述的化合物、或其药学上可接受的盐、或其溶剂化物、同位素取代物、前药或代谢产物，选自以下的结构：
Figure PCTCN2020112173-appb-000018
Figure PCTCN2020112173-appb-000019
本发明的第二方面，提供了一种如本发明第一方面所述的式I化合物或其药学上可接受的盐、或其溶剂化物、同位素取代物、前药或代谢产物用于治疗或预防与FGFR的活性或表达量相关的疾病。
在一个优选的实施方式中，所述的疾病选自下组：膀胱癌、肝癌、脑癌、乳腺癌、结肠癌、肾癌、肺癌、卵巢癌、胰腺癌、***癌、胃癌、子***、结肠癌、甲状腺癌、皮肤癌、胆管癌、急性淋巴细胞白血病、B-细胞淋巴瘤、Burketts淋巴瘤、急性髓性白血病、慢性髓性白血病、早幼粒细胞白血病、纤维肉瘤、横纹肌瘤、黑色素瘤、***瘤、畸胎瘤、成神经细胞瘤、神经胶状瘤。
本发明的第三方面，提供了一种药物组合物，所述的药物组合物包括：
(i)作为活性成分的如本发明第一方面所述的有效量的式I化合物，或其药学上可接受的盐、或其溶剂化物、同位素取代物、前药或代谢产物；和
(ii)药学上可接受的载体。
在一个优选实施方式中，所述的药物组合物还包括(iii)第二活性成分。
在另一个优选实施方式中，所述的药物组合物用于治疗或预防与FGFR的活性或表达量相关的疾病，优选地，所述的疾病选自下组：膀胱癌、肝癌、脑癌、乳腺癌、结肠癌、肾癌、肺癌、卵巢癌、胰腺癌、***癌、胃癌、子***、结肠癌、甲状腺癌、皮肤癌、胆管癌、急性淋巴细胞白血病、B-细胞淋巴瘤、Burketts淋巴瘤、急性髓性白血病、慢性髓性白血病、早幼粒细胞白血病、纤维肉瘤、横纹肌瘤、黑色素瘤、***瘤、畸胎瘤、成神经细胞瘤、神经胶状瘤。
本发明的第四方面，提供了一种如式I或式II化合物，或其药学上可接受的盐、或其 溶剂化物、同位素取代物、前药、代谢产物或它们混合物用于选自下组的用途：
(1)制备治疗或预防与FGFR激酶活性或表达量相关的疾病的药物组合物；
(2)制备FGFR激酶抑制剂。
在一个优选的实施方式中，所述的FGFR激酶选自下组：FGFR1、FGFR2、FGFR3，和FGFR4。
在一个优选的实施方式中，所述的疾病选自下组：膀胱癌、肝癌、脑癌、乳腺癌、结肠癌、肾癌、肺癌、卵巢癌、胰腺癌、***癌、胃癌、子***、结肠癌、甲状腺癌、皮肤癌、胆管癌、急性淋巴细胞白血病、B-细胞淋巴瘤、Burketts淋巴瘤、急性髓性白血病、慢性髓性白血病、早幼粒细胞白血病、纤维肉瘤、横纹肌瘤、黑色素瘤、***瘤、畸胎瘤、成神经细胞瘤、神经胶状瘤。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过长期而深入的研究，意外地发现，如式I所示的化合物、或其药学上可接受的盐、或其溶剂化物、同位素取代物、前药或代谢产物具有优异的FGFR激酶抑制活性，特别是对于FGFR4的抑制活性，因此可以用于治疗或预防FGFR激酶相关的疾病。基于上述发现，发明人完成了本发明。
术语
除非另有定义，否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。除非另有说明，本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。
应理解，上述简述和下文的详述为示例性且仅用于解释，而不对本发明主题作任何限制。在本申请中，除非另有具体说明，否则使用单数时也包括复数。必须注意，除非文中另有清楚的说明，否则在本说明书和权利要求书中所用的单数形式包括所指事物的复数形式。还应注意，除非另有说明，否则所用“或”、“或者”表示“和/或”。此外，所用术语“包括”以及其它形式，例如“包含”、“含”和“含有”并非限制性，其可以是开放式、半封闭式和封闭式的。换言之，所述术语也包括“基本上由…构成”、或“由…构成”之义。
可在参考文献(包括Carey and Sundberg"ADVANCED ORGANIC CHEMISTRY 4TH  ED."Vols.A(2000)and B(2001),Plenum Press,New York)中找到对标准化学术语的定义。除非另有说明，否则采用本领域技术范围内的常规方法，如质谱、NMR、IR和UV/VIS光谱法和药理学方法。除非提出具体定义，否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送，以及对患者的治疗中使用标准技术。例如，可利用厂商对试剂盒的使用说明，或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述，按照本领域熟知的常规方法实施上述技术和方法。在本说明书中，可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。
当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言，-CH 2O-等同于-OCH 2-。
本文所用的章节标题仅用于组织文章的目的，而不应被解释为对所述主题的限制。本申请中引用的所有文献或文献部分包括但不限于专利、专利申请、文章、书籍、操作手册和论文，均通过引用方式整体并入本文。
在本文中定义的某些化学基团前面通过简化符号来表示该基团中存在的碳原子总数。例如，C1-C6烷基是指具有总共1至6个碳原子的如下文所定义的烷基。简化符号中的碳原子总数不包括可能存在于所述基团的取代基中的碳。
除前述以外，当用于本申请的说明书及权利要求书中时，除非另外特别指明，否则以下术语具有如下所示的含义。
在本申请中，术语“卤素”是指氟、氯、溴或碘。
“羟基”是指-OH基团。
“羟基烷基”是指被羟基(-OH)取代的如下文所定义的烷基。
“羰基”是指-C(＝O)-基团。
“硝基”是指-NO 2。
“氰基”是指-CN。
“氨基”是指-NH 2。
“取代的氨基”是指被一个或两个如下文所定义的烷基、烷基羰基、芳烷基、杂芳烷基取代的氨基，例如，单烷基氨基、二烷基氨基、烷基酰氨基、芳烷基氨基、杂芳烷基氨基。
“羧基”是指-COOH。
在本申请中，作为基团或是其它基团的一部分(例如用在卤素取代的烷基等基团中)，术语“烷基”是指完全饱和的直链或支链的烃链基，仅由碳原子和氢原子组成、具有例如 1至12个(优选为1至8个，更优选为1至6个)碳原子，且通过单键与分子的其余部分连接，例如包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、2-甲基丁基、2,2-二甲基丙基、正己基、庚基、2-甲基己基、3-甲基己基、辛基、壬基和癸基等。就本发明而言，术语“烷基”指含有1至8个碳原子的烷基。
在本申请中，作为基团或是其它基团的一部分，术语“烯基”意指仅由碳原子和氢原子组成、含有至少一个双键、具有例如2至20个(优选为2至10个，更优选为2至6个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团，例如但不限于乙烯基、丙烯基、烯丙基、丁-1-烯基、丁-2-烯基、戊-1-烯基、戊-1,4-二烯基等。
在本申请中，作为基团或是其它基团的一部分，术语“环烃基”意指仅由碳原子和氢原子组成的稳定的非芳香族单环或多环烃基，其可包括稠合环体系、桥环体系或螺环体系，具有3至15个碳原子，优选具有3至10个碳原子，更优选具有3至8个碳原子，且其为饱和或不饱和并可经由任何适宜的碳原子通过单键与分子的其余部分连接。除非本说明书中另外特别指明，环烃基中的碳原子可以任选地被氧化。优选的实施方案中，环烃基为环烷基，如C3-C8烷氧基。环烃基的实例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环辛基、1H-茚基、2,3-二氢化茚基、1,2,3,4-四氢-萘基、5,6,7,8-四氢-萘基、8,9-二氢-7H-苯并环庚烯-6-基、6,7,8,9-四氢-5H-苯并环庚烯基、5,6,7,8,9,10-六氢-苯并环辛烯基、芴基、二环[2.2.1]庚基、7,7-二甲基-二环[2.2.1]庚基、二环[2.2.1]庚烯基、二环[2.2.2]辛基、二环[3.1.1]庚基、二环[3.2.1]辛基、二环[2.2.2]辛烯基、二环[3.2.1]辛烯基、金刚烷基、八氢-4,7-亚甲基-1H-茚基和八氢-2,5-亚甲基-并环戊二烯基等。
在本申请中，作为基团或是其它基团的一部分，术语“杂环基”意指由2至14个碳原子以及1至6个选自氮、磷、氧和硫的杂原子组成的稳定的3元至20元非芳香族环状基团。除非本说明书中另外特别指明，否则杂环基可以为单环、双环、三环或更多环的环体系，其可包括稠合环体系、桥环体系或螺环体系；其杂环基中的氮、碳或硫原子可任选地被氧化；氮原子可任选地被季铵化；且杂环基可为部分或完全饱和。杂环基可以经由碳原子或者杂原子并通过单键与分子其余部分连接。在包含稠环的杂环基中，一个或多个环可以是下文所定义的芳基或杂芳基，条件是与分子其余部分的连接点为非芳香族环原子。就本发明的目的而言，杂环基优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至11元非芳香性单环、双环、桥环或螺环基团，更优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至8元非芳香性单环、双环、桥环或螺环基团。杂环基的实例包括但不限于：吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、硫代吗啉基、2,7-二氮杂-螺[3.5]壬烷-7-基、2-氧杂-6-氮杂-螺[3.3]庚烷-6-基、2,5-二氮杂-双环[2.2.1]庚烷-2-基、氮 杂环丁烷基、吡喃基、四氢吡喃基、噻喃基、四氢呋喃基、噁嗪基、二氧环戊基、四氢异喹啉基、十氢异喹啉基、咪唑啉基、咪唑烷基、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、邻苯二甲酰亚氨基等。
在本申请中，作为基团或是其它基团的一部分，术语“芳基”意指具有6至18个碳原子(优选具有6至10个碳原子)的共轭烃环体系基团。就本发明的目的而言，芳基可以为单环、双环、三环或更多环的环体系，还可以与上文所定义的环烷基或杂环基稠合，条件是芳基经由芳香环上的原子通过单键与分子的其余部分连接。芳基的实例包括但不限于苯基、萘基、蒽基、菲基、芴基、2,3-二氢-1H-异吲哚基、2-苯并噁唑啉酮、2H-1,4-苯并噁嗪-3(4H)-酮-7-基等。
在本申请中，术语“芳基烷基”是指被上文所定义的芳基所取代的上文所定义的烷基。
在本申请中，作为基团或是其它基团的一部分，术语“杂芳基”意指环内具有1至15个碳原子(优选具有1至10个碳原子)和1至6个选自氮、氧和硫的杂原子的5元至16元共轭环系基团。除非本说明书中另外特别指明，否则杂芳基可为单环、双环、三环或更多环的环体系，还可以与上文所定义的环烷基或杂环基稠合，条件是杂芳基经由芳香环上的原子通过单键与分子的其余部分连接。杂芳基中的氮、碳或硫原子可任选地被氧化；氮原子可任选地被季铵化。就本发明的目的而言，杂芳基优选为包含1至5个选自氮、氧和硫的杂原子的稳定的5元至12元芳香性基团，更优选为包含1至4个选自氮、氧和硫的杂原子的稳定的5元至10元芳香性基团或者包含1至3个选自氮、氧和硫的杂原子的5元至6元芳香性基团。杂芳基的实例包括但不限于噻吩基、咪唑基、吡唑基、噻唑基、噁唑基、噁二唑基、异噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并咪唑基、苯并吡唑基、吲哚基、呋喃基、吡咯基、***基、四唑基、三嗪基、吲嗪基、异吲哚基、吲唑基、异吲唑基、嘌呤基、喹啉基、异喹啉基、二氮萘基、萘啶基、喹噁啉基、蝶啶基、咔唑基、咔啉基、菲啶基、菲咯啉基、吖啶基、吩嗪基、异噻唑基、苯并噻唑基、苯并噻吩基、噁***基、噌啉基、喹唑啉基、苯硫基、中氮茚基、邻二氮杂菲基、异噁唑基、吩噁嗪基、吩噻嗪基、4,5,6,7-四氢苯并[b]噻吩基、萘并吡啶基、[1,2,4]***并[4,3-b]哒嗪、[1,2,4]***并[4,3-a]吡嗪、[1,2,4]***并[4,3-c]嘧啶、[1,2,4]***并[4,3-a]吡啶、咪唑并[1,2-a]吡啶、咪唑并[1,2-b]哒嗪、咪唑并[1,2-a]吡嗪等。
在本申请中，术语“杂芳基烷基”是指被上文所定义的杂芳基所取代的上文所定义的烷基。
在本申请中，“任选地”或“任选地”表示随后描述的事件或状况可能发生也可能不发生，且该描述同时包括该事件或状况发生和不发生的情况。例如，“任选地被取代的芳 基”表示芳基被取代或未被取代，且该描述同时包括被取代的芳基与未被取代的芳基。本发明权利要求书和说明书部分所述的“任选地”的取代基选自烷基、烯基、炔基、卤素、卤代烷基、卤代烯基、卤代炔基、氰基、硝基、任选取代的芳基、任选取代的杂芳基、任选取代的环烃基、任选取代的杂环烃基。在本申请中，取代基的数量可以是一个或多个，如1-6个或1-3个。应理解，取代基的数量受化合物的分子结构的影响。例如，当取代基为芳基、杂芳基、环烃基或杂环烃基时，取代基的数量通常为1个；当取代基为卤素时，根据被取代的基团的链长或环碳原子的数量，卤素原子的数量可以为2-6个；被取代的基团如果为链状基团，卤素原子可以更多，例如五氟取代的丙基(如-CH 2CF 2CF 3)。
成纤维细胞生长因子受体(FGFR)家族则包括4个成员：FGFR1、FGFR2、FGFR3和FGFR4，它们分别由胞外配体结合区、单跨膜区和细胞内胞质蛋白酪氨酸激酶区组成。
制备/分离个别异构体的常规技术包括由合适的光学纯前体的手性合成，或者使用例如手性高效液相色谱法拆分外消旋体(或盐或衍生物的外消旋体)，例如可参见Gerald Gübitz and Martin G.Schmid(Eds.),Chiral Separations,Methods and Protocols,Methods in Molecular Biology,Vol.243,2004；A.M.Stalcup,Chiral Separations,Annu.Rev.Anal.Chem.3:341-63,2010；Fumiss et al.(eds.),VOGEL’S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED.,Longman Scientific and Technical Ltd.,Essex,1991,809-816；Heller,Acc.Chem.Res.1990,23,128。
本发明还包括本发明所述的化合物或其药学上可接受的盐的所有适宜的同位素变体。本发明的化合物或其药学上可接受的盐的同位素变体被定义为其中至少一个原子被具有相同原子数、但原子质量与自然界经常发现的原子质量不同的原子所替换的那些。可以掺入到本发明的化合物及其药学上可接受的盐中的同位素包括但不限于H、C、N和O的同位素，例如 2H、 3H、 11C、 13C、 14C、 15N、 17O、 18O、 35S、 18F、 36Cl和 125I。本发明所述化合物或其药学上可接受的盐的同位素变体可以通过常规技术、采用适宜试剂的适当同位素变体来制备。
在本申请中，术语“药学上可接受的盐”包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的，与无机酸或有机酸所形成的盐。无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐等；有机酸盐包括但不限于甲酸盐、乙酸盐、2,2-二氯乙酸盐、三氟乙酸盐、丙酸盐、己酸盐、辛酸盐、癸酸盐、十一碳烯酸盐、乙醇酸盐、葡糖酸盐、乳酸盐、癸二酸盐、己二酸盐、戊二酸盐、丙二酸盐、草酸盐、马来酸盐、琥珀酸盐、富马酸盐、酒石酸盐、柠檬酸盐、棕榈酸盐、硬脂酸盐、油酸盐、肉桂酸盐、月桂酸盐、苹果酸盐、谷氨 酸盐、焦谷氨酸盐、天冬氨酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、海藻酸盐、抗坏血酸盐、水杨酸盐、4-氨基水杨酸盐、萘二磺酸盐等。这些盐可通过本专业已知的方法制备。
“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐及镁盐。衍生自有机碱的盐包括但不限于以下的盐：伯胺类、仲胺类及叔胺类，被取代的胺类，包括天然的被取代胺类、环状胺类及碱性离子交换树脂，例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、三乙醇胺、二甲基乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、胆碱、甜菜碱、乙二胺、葡萄糖胺、甲基葡萄糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。优选的有机碱包括异丙胺、二乙胺、乙醇胺、三甲胺、二环己基胺、胆碱及咖啡因。这些盐可通过本专业已知的方法制备。
在本申请中，“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药，利于活性成分的吸收进而发挥生物活性。
本文所用术语“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质(如载体或稀释剂)，并且相对无毒，即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
在本申请中，“药学上可接受的赋形剂”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
本发明所述“肿瘤”包括但不限于努南综合症、豹综合症、青少年髓单核细胞白血病、成神经细胞瘤、肉瘤、黑色素瘤、关节软骨瘤、胆管瘤、白血病、乳腺癌、胃肠间质瘤、组织细胞性淋巴瘤、非小细胞肺癌、小细胞肺癌、食道癌、胰腺癌、肺鳞癌、肺腺癌、乳腺癌、***癌、肝癌、皮肤癌、上皮细胞癌、***、卵巢癌、肠癌、鼻咽癌、脑癌、骨癌、肾癌、口腔癌/头癌、成神经细胞瘤、头颈的鳞状细胞癌、间变性大细胞淋巴瘤或成胶质细胞瘤等疾病。
本文所用术语“预防的”、“预防”和“防止”包括使病患减少疾病或病症的发生或恶化的可能性。
本文所用的术语“治疗”和其它类似的同义词包括以下含义：
(i)预防疾病或病症在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病或病症，但尚未被诊断为已患有该疾病或病症时；
(ii)抑制疾病或病症，即遏制其发展；
(iii)缓解疾病或病症，即，使该疾病或病症的状态消退；或者
(iv)减轻该疾病或病症所造成的症状。
本文所使用术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解，或生物***的任何其它所需变化。例如，用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。
本文所用术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法。这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、局部给药和经直肠给药。本领域技术人员熟知可用于本文所述化合物和方法的施用技术，例如在Goodman and Gilman,The Pharmacological Basis of Therapeutics,current ed.；Pergamon；and Remington’s,Pharmaceutical Sciences(current edition),Mack Publishing Co.,Easton,Pa中讨论的那些。在优选的实施方案中，本文讨论的化合物和组合物通过口服施用。
本文所使用术语“药物组合”、“药物联用”、“联合用药”、“施用其它治疗”、“施用其它治疗剂”等是指通过混合或组合不止一种活性成分而获得的药物治疗，其包括活性成分的固定和不固定组合。术语“固定组合”是指以单个实体或单个剂型的形式向患者同时施用至少一种本文所述的化合物和至少一种协同药剂。术语“不固定组合”是指以单独实体的形式向患者同时施用、合用或以可变的间隔时间顺次施用至少一种本文所述的化合物和至少一种协同制剂。这些也应用到鸡尾酒疗法中，例如施用三种或更多种活性成分。
本领域技术人员还应当理解，在下文所述的方法中，中间体化合物官能团可能需要由适当的保护基保护。这样的官能团包括羟基、氨基、巯基及羧酸。合适的羟基保护基包括三烷基甲硅烷基或二芳基烷基甲硅烷基(例如叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基或三甲基甲硅烷基)、四氢吡喃基、苄基等。合适的氨基、脒基及胍基的保护基包括叔丁氧羰基、苄氧羰基等。合适的巯基保护基包括-C(O)-R”(其中R”为烷基、芳基或芳烷基)、对甲氧基苄基、三苯甲基等。合适的羧基保护基包括烷基、芳基或芳烷基酯类。
保护基可根据本领域技术人员已知的和如本文所述的标准技术来引入和除去。保护基的使用详述于Greene,T.W.与P.G.M.Wuts,Protective Groups in Organi Synthesis,(1999),4th Ed.,Wiley中。保护基还可为聚合物树脂。
式I化合物
本发明提供了一种式I所示的化合物：
Figure PCTCN2020112173-appb-000020
其中，式I化合物可转化为药学上可接受的盐，例如酸加成盐：例如盐酸盐、氢溴酸盐、磷酸盐、乙酸盐、富马酸盐、马来酸盐、酒石酸盐、柠檬酸盐、草酸盐、甲磺酸盐、对甲苯磺酸盐或碱金属盐：例如钠盐或钾盐；
式I化合物还可以以立体异构体等形式存在，如常温下的互变异构体、几何异构体、内消旋体、外消旋体、对映异构体、非对映异构体，或其混合物；
式I化合物中的氢原子可以以其同位素氘的形式而存在，例如-CH 3可以以-CD 3形式存在，-CH 2-可以以-CD 2-形式存在。
我们已发现本发明中定义的化合物或其药学上可接受的盐为有效的抗癌药，其性质被认为由FGFR活性的调节或抑制产生。因此本发明化合物被期望用于治疗完全由或部分由FGFR诱导的疾病或医学病症，即所述化合物可用于在需要此等治疗的温血动物中产生FGFR抑制作用。优选地，所述的FGFR包括：FGFR1、FGFR2、FGFR3和FGFR4。
本发明化合物被期望具有广谱抗癌特性，因为在众多人类癌症中己经观察到FGFR的非控表达或异常激活，包括但不限于膀胱、肝、胃、乳腺、***和多发性骨髓瘤。因此期望本发明化合物将具有对抗这些癌症的抗癌活性。此外，期望本发明化合物将具有抗白血病、淋巴恶性肿瘤和实体瘤例如在组织：如肝、肾、膀胱、***、乳腺和胰腺中的癌和肉瘤的活性。在一个实施方案中，本发明化合物被期望有利地延缓例如皮肤、结肠、甲状腺、肺和卵巢的原发性和再发性实体瘤的生长。更具体地，本发明化合物或其药学上可接受的盐被期望抑制与FGFR有关的肿瘤的生长，特别是生长和扩散显著依赖于FGFR的那些肿瘤，包括例如某些膀胱、肝、胃、乳腺和***肿瘤和多发性骨髓瘤。
更进一步地，本发明的化合物可用于治疗或预防受益于FGFR激酶活性或表达量被抑制的疾病，尤其是受益于FGFR4激酶活性或表达量被抑制的疾病。这类疾病可以是实体瘤或血液肿瘤，包括但不限于：膀胱癌、肝癌、脑癌、乳腺癌、结肠癌、肾癌、肺癌、卵 巢癌、胰腺癌、***癌、胃癌、子***、结肠癌、甲状腺癌、皮肤癌、胆管癌、急性淋巴细胞白血病、B-细胞淋巴瘤、Burketts淋巴瘤、急性髓性白血病、慢性髓性白血病、早幼粒细胞白血病、纤维肉瘤、横纹肌瘤、黑色素瘤、***瘤、畸胎瘤、成神经细胞瘤、神经胶状瘤。
药物组合物
本发明另一方面，提供了如文中定义的式I化合物或其药学上可接受的盐在制备用于治疗以下疾病的药物中的用途：黑素瘤、***状甲状腺癌、胆管癌、结肠癌、卵巢癌、肺癌、白血病、淋巴恶性肿瘤、多发性骨髓瘤；肝、肾、膀胱、***、乳腺和胰腺中的癌和肉瘤；和皮肤、结肠、甲状腺、肺和卵巢的原发性和再发性的实体瘤。
本发明还提供了药物组合物，所述药物组合物包括如文中定义的式I化合物或其药学上可接受的盐，以及药学上可接受的辅料、稀释剂或载体。所述的药物组合物用于在温血动物如人中产生FGFR抑制作用或抗癌作用。
本发明提供了一种用于治疗温血动物如人中所患以下疾病的药物组合物：黑素瘤、***状甲状腺癌、胆管癌、结肠癌、卵巢癌、肺癌、白血病、淋巴恶性肿瘤、多发性骨髓瘤；肝、肾、膀胱、***、乳腺和政腺中的癌和肉瘤；和皮肤、结肠、甲状腺、肺的原发性和再发性的实体瘤。所述组合物包括如文中定义的式(I)化合物或其药学上可接受的盐和药学上可接受的稀释剂或载体。
可仅使用式I化合物及其药学上可接受的盐本身，但通常以药物组合物的形式给予，其中式(I)化合物或盐(活性成分)结合药学上可接受的辅料、稀释剂或载体。药物组合物可包含总组合物重量的0.01-99％w(重量百分比)、0.05-80％w、0.10-70％w，和/或甚至0.10-50％w的活性成分，这取决于给予方式。
本发明进一步提供了一种制备本发明药物组合物的方法，所述药物组合物包括将如文中定义的式I化合物或其药学上可接受的盐与药学上可接受的辅料、稀释剂或载体混合。
药物组合物可以局部(例如，皮肤或肺和/或气道)给予，例如以乳膏剂、溶液剂、混悬剂、六氟烷气雾剂和干粉制剂的形式；或全身给予，例如以片剂、胶囊剂、糖浆剂、粉剂或颗粒剂形式的口服给药；或以溶液剂或混悬剂形式的胃肠道给予；或皮下给予；或以栓剂形式的直肠给药；或经皮给予。
使用本领域熟知的常规药物赋形剂通过常规方法可得到本发明组合物。因此，意欲用于口服使用的组合物可包含例如一种或多种着色剂、甜味剂、矫味剂和/或防腐剂。
用于片剂制备的合适的药学上可接受的赋形剂，包括例如惰性稀释剂如乳糖、碳酸钠、磷酸钙或碳酸钙；成粒剂和崩解剂如玉米淀粉或algenic acid；粘合齐如淀粉；润滑剂如 硬脂酸镁、硬脂酸或滑石粉；防腐剂如对羟基苯甲酸乙酯或丙脂，和抗氧剂如抗坏血酸。片剂可不包衣或使用本领域熟知的常规包衣料和方法包衣来改善其崩解和随后活性成分在胃肠道的吸收，或改善其稳定性和/或外观。
用于口服的组合物可为硬明胶胶囊形式，其中活性成分与惰性团体稀释剂例如碳酸钙、磷酸钙或高岭土混合；或可为软明胶胶囊形式，其中活性成分可与水，或油：如花生油、液体石蜡或橄榄油混合。
混悬水溶液通常包含细小粉末形式的活性成分和一种或多种助悬剂如羧甲基纤维素纳、甲基纤维素、羟丙甲基纤维素、海藻酸纳、聚乙烯吡咯烷酮、西黄蓍胶和***胶；分散或润湿剂如卵磷脂或1，2-环氧烷烃与脂肪酸的缩合产物(如聚氧乙烯硬脂酸酯)，或环氧乙烷与长链脂肪醇的缩合产物(例如十七碳乙烯氧基鲸蜡醇)，或环氧乙烷与脂肪酸和己糖醇衍生的偏酯的缩合产物(如聚氧乙烯山梨醇单油酸酯)，或环氧乙烷与脂肪酸和己糖醇酸肝衍生的偏酯的缩合产物(如聚氧化乙烯脱水山梨醇单油酸酯(Polyethylenesorbitanmonooleate))。混悬水溶液还可包含一种或多种防腐剂(如对羟基苯甲酸乙酯或丙酯、抗氧剂(如抗坏血酸)、着色剂、矫味剂和/或甜味剂(如蔗糖、糖精或阿司帕坦))。
油性混悬剂可通过将活性成分悬浮在植物油(如花生油、橄榄油、芝麻油或椰子油)或矿物油(如液体石蜡)中来制备。油性混悬剂还可包含增稠剂如蜂蜡、硬石蜡或十六烷基醇。可加入如前所列的那些甜味剂和矫味剂来获得可口的口服制剂。这些组合物可通过加入抗氧剂如抗坏血酸来保存。
适合于通过加水来制备水性混悬剂的可分散的粉剂和颗粒剂通常通过包含活性成分和分散或润湿剂、助悬剂和一种或多种防腐剂。合适的分散剂或润湿剂和助悬剂已通过以上提及的那些举例说明。还可存在其他赋形剂如甜味剂、矫味剂和着色剂。
本发明药物组合物还可为水包油型乳剂的形式。油相可为植物油如橄榄油或花生油，或矿物油如液体石蜡，或任何这些的混合物。合适的乳化剂可为例如天然存在的树胶如***胶或西黄蓍胶，天然存在的磷脂如大豆磷脂、卵磷脂，衍生自脂肪酸和己糖醇酸酐的酯或偏酯(例如脱水山梨醇单油酸酯)和所述偏酯与环氧乙烷的缩合产物如聚氧乙烯脱水山梨糖醇单油酸酯。乳剂还可包含甜味剂、矫味剂和防腐剂。
糖浆剂和酏剂可与甜味剂如丙三醇、丙二醇、山梨醇、阿司帕坦或蔗糖配制，同时还可包含镇痛剂、防腐剂、矫味剂和/或着色剂。
药物组合物还可为无菌注射水性或油性混悬剂的形式，其可根据已知方法使用一种或多种以上已提及的适宜的分散剂或润湿剂和助悬剂。无菌注射制剂还可为在毒、在胃肠外可接受的稀释剂或溶剂(例如在1,3-丁二醇中的溶液)中的无菌注射溶液或混悬剂。
栓剂可通过将活性成分与合适的无刺激性的赋形剂混合来制备，该赋形剂在常温下为固体但在直肠温度下为液体并因此在直肠中熔化释放药物。合适的赋形剂包括例如可可脂和聚乙二醇。
局部用制剂如乳膏剂、软膏剂、凝胶剂或水性或油性的溶液剂或混悬剂，通常可使用本领域熟知的常规方法通过用活性成分与常规的、局部可接受的赋形剂或稀释剂配制得到。
吹入给药的组合物可以含,例如平均粒径30μ或更小的细小分散的粉末给予，该粉末仅含活性成分本身或用一种或多种生理学可接受的载体如乳糖稀释。随后方使地将用于吹入的粉末置于含，例如1-50mg活性成分的胶囊剂中，与涡轮吸入装置(turbo-inhaler device)使用，例如用于吹入已知药物色甘酸纳。
经吸入给予的组合物可为常规加压气雾剂的形式，该加压气雾剂将活性成分配制成含细小分散固体或液滴的气雾剂。可使用常规气雾剂推进剂如挥发性氟化烃类或烃类并且该气雾剂装置能方便地测定活性成分的量。
根据众所周知的医学原则，用于治疗目的的本发明化合物的剂量大小将自然地根据病症的性质和严重程度、动物或病人的年龄和性别以及给药途径而变化。
一般而言，给予的本发明化合物以便获得例如0.1mg至1000mg范围的活性成分/kg体重的日剂量，如果需要也可以用分剂量形式给予。但是，日剂量必须根据所治疗的宿主、具体的给药途径、所治疾病的严重程度而变化。因此，最佳剂量可由治疗任何具体患者的医师决定。一般而言，当使用非胃肠道途径时给予剂量较低。因此，例如对于静脉内给药，通常将使用在例如0.1mg至30mg活性成分/kg体重的剂量。类似地，对于吸入给予，通常将使用在例如0.1mg至25mg活性成分/kg体重的剂量。但是优选口服给药。例如意欲人口服给药的制剂通常将包含0.1mg至2g活性成分。
对于其他制剂、给药途径和剂量方案的信息，可参考Comprehensive Medicinal Chemistry(Corwin Hansch；Chairman ofEditorial Board)的公开。
组合疗法
前文定义的抗癌治疗可用作单一疗法，也可用作组合疗法,即采用本发明化合物进行治疗外，还同时采用常规手术或放疗或化疗。此类化疗可包括一种或多种以下种类的抗肿瘤剂：
(1)用于肿瘤内科的其他抗增殖/抗肿瘤药及其组合：例如烷化剂(如顺铂、奥沙利铂、卡铂、环磷酰胺、氮芥、美法仑、苯丁酸氮芥、白消安、替莫唑胺和硝基脲)，抗代谢药(如吉西他滨和抗叶酸剂如氟嘧啶如5-氟尿嘧啶和替加氟、雷替曲塞、甲氨蝶吟、阿糖胞苷和羟基脲)，抗肿瘤抗生素(如蒽环类如阿霉素、博来霉素、多柔比星、柔红霉素、表柔比 星、伊达比星、丝裂霉素-C、更生霉素和光辉霉素)，抗有丝***剂(长春花生物碱如长春新碱、长春碱、长春地辛和长春瑞滨，紫杉烷如紫杉醇和多西紫杉醇和polokinase抑制剂)，和拓扑异构酶抑制剂(鬼臼素如依托泊苷和替尼泊苷、安丫啶、托泊替康和喜树碱)；
(2)细胞生长抑制剂：抗***药(如他莫昔芬、氟维司群、托瑞米芬、雷洛昔芬、屈洛昔芬和iodoxyfene)、抗雄激素药(如比卡鲁胺、氟他胺、尼鲁米特和乙酸环丙氯地孕酮)、LHRH拮抗剂或LHRH激动剂(如戈舍瑞林、亮丙瑞林和布舍瑞林)、孕激素类(如乙酸甲地孕酮)、芳香酶抑制剂(如阿那曲唑、来曲唑、氟氯唑和依西美坦)和5*-还原酶抑制剂如非那雄胺；
(3)抑制癌细胞入侵的药物：例如c-Src激酶家族抑制剂如4-(6-氯代-2，3-亚甲二氧基苯胺基)-7-[2-(4-甲基哌嗪-1-基)乙氧基]-5-四氢吡喃-4-基氧基喹唑啉(AZD0530；国际专利申请WO 01194341)和N-(2-氯代-6-甲基苯基)-2-{6-[4-(2-羟乙基)哌啶-1-基]-2-甲基咪啶-4-基氨基}噻唑-5-甲酰胺(dasatinib，BMS-354825，J.Med.Chem.,2004,47,6658-6661)，和金属蛋白酶抑制剂例如马立马司他，和尿激酶纤溶酶原激活剂受体功能的抑制剂或Heparanase的抗体；
(4)生长因子功能抑制剂：包括生长因子抗体和生长因子受体抗体(如抗erbB2抗体曲妥单抗[HerceptinTM]、抗-EGFR抗体帕尼单抗、抗erbB1抗体西妥昔单抗[Erbitux，C225])和由Stem等在Critical reviews in oncology/hematology，2005，第54卷，第11-29页中公开的任何生长因子或生长因子受体抗体)，这些抑制剂还包括酪氨酸激酶抑制剂例如表皮生长因子家族抑制剂(如EGFR家族酪氨酸激酶抑制剂如N-(3-氯代-4-氟苯基)-7-甲氧基-6-(3-吗琳代丙氧基)喹唑啉-4-胺(吉非替尼gefitinib，AZD1839)、N-(2-((2-(二甲基胺基)乙基)(甲基)胺基)-4-甲氧基-5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)胺基)苯基)丙烯酰胺(AZD9291)、N-(3-乙块基苯基)-6,7-双(2-甲氧基乙氧基)喹唑啉-4-胺(erlotinib，OSI-774)和6-酰基酰氨基-N-(3-氯代-4-氟苯基)-7-(3-吗琳代丙氧基)喹唑啉-4-胺(CI 1033))、erbB2酪氨酸激酶抑制剂如拉帕替尼、血小板衍生生长因子家族抑制剂如伊马替尼、丝氨酸/苏氨酸激酶抑制剂(例如Ras/Raf信号传导抑制剂如法尼基转移酶抑制剂，例如索拉非尼(BAY43-9006))、通过MEK和/或AKT激酶的细胞信号传导抑制剂、肝细胞生长因子家族抑制剂、c-kit抑制剂、abl激酶抑制剂、IGF受体(***)激酶抑制剂，aurora激酶抑制剂(例如AZD1152、PH739358、VX-680、MLN8054、R763、MP235、MP529、VX-528和AX39459)和细胞周期蛋白激酶抑制剂如CDK2和/或CDK4和/或CDK6抑制剂；
(5)抗血管生成剂：例如抑制血管内皮生长因子作用的抗血管生成剂(如抗血管内皮细胞生长因子抗体贝伐羊抗[AvastinTM]和VEGF受体酪氨酸激酶抑制剂如4-(4-溴-2-氟苯胺基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉(AZD6474；WO 01132651中的实施例2)、 4-(4-氟-2-甲基吲哚-5-基氧基)-6-甲氧基-7-(3-吡咯烷-1-基丙氧基)喹唑啉(AZD2171；WO 00/47212中的实施例240)、伐他拉尼(PTK787；WO98/35985)和SU11248(舒尼替尼；WO 01160814)，如公开于国际专利申请WO 97/22596、WO 97/30035、WO 97/32856和WO 98/13354的化合物和通过其它机制作用的化合物(如利诺胶、整合素αvb3功能抑制剂和血管生长抑素)；
(6)血管损伤剂：例如考布他汀A4和公开于国际专利申请WO99/02166、WO 00/40529、WO 00/41669、WO 01192224、WO 02/04434和WO 02/08213的化合物；
(7)反义疗法：如针对上述目标的疗法，如ISIS 2503(抗ras反义)；
(8)基因疗法：包括例如替代畸变基因如畸变p53或畸变BRCA1或BRCA2的方法、GDEPT(基因导向性酶前药疗法)法例如用胞咪啶脱氨酶、胸苷激酶或细菌硝基还原酶的方法以及提高患者对化疗或放疗耐受性的方法例如多药耐药基因疗法；和
(9)免疫疗法：包括如免疫检查点封锁方法例如PD-1抗体如Opdivo和Keytruda和PD-L1抗体如Tecentriq,嵌合抗原受体T细胞免疫疗法(Chimeric antigen receptor T-cell immunotherapy)，增加患者肿瘤细胞免疫原性的先体外后体内疗法和体内疗法，例如用细胞因子如白介素2、白介素4或粒细胞-巨噬细胞集落刺激因子转染，降低T-细胞无反应性的方法，用转染免疫细胞例如细胞因子转染的树突状细胞的方法，用细胞因子转染肿瘤细胞系的方法和用抗独特型抗体的方法。
式I化合物的制备
式I化合物可由如下路线制备得到：由起始原料I-A-1，经亲核取代反应得到I-A-1。接着用还原剂还原I-A-2的硝基，得到氨基化合物I-A-3。然后用取代(未取代)的丙烯酰氯或者取代(未取代)的丙炔酰氯对I-A-3进行酰基化得到I-A-4。最后I-A-4与I-B进行氨酯交换反应得到终产物式I化合物。
Figure PCTCN2020112173-appb-000021
本发明的主要优点包括：
1.提供了一种如式I所示的化合物。
2.提供了一种结构新颖的FGFR抑制剂及其制备和应用，所述的抑制剂在极低浓度下即可抑制各类FGFR激酶的活性，所述的抑制剂有着较好的口服暴药量。
3.提供了一类治疗与FGFR激酶活性相关疾病的药物组合物。
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。除非另外说明，否则百分比和份数按重量计算。
中间体A：3-(3,5-二甲氧基苯乙基)-1H-吡唑基-5-胺
Figure PCTCN2020112173-appb-000022
冰浴下，在圆底烧瓶中放入3-(3,5-二甲氧基苯基)丙酸(A1，21g，100mmol)，加入200mL乙醇溶解之后滴加14.6mL(200mmol)氯化亚砜，反应液于室温搅拌反应12h之后，将反应液在减压下旋干，加入乙酸乙酯溶解之后用饱和NaHCO 3溶液洗涤，饱和NaCl溶液洗涤，无水Na 2SO 4干燥。硅胶柱层析分离纯化(梯度洗脱，石油醚：乙酸乙酯＝30:1至10:1)得到无色液体3-(3,5-二甲氧基苯基)丙酸乙酯(23.2g，收率：97.4％)。
在圆底烧瓶中放入搅拌子，N 2保护下加入100mL THF，将圆底烧瓶置于-78℃搅拌10min后加入74.4mL的n-BuLi(2.5M,185mmol)，将乙腈(8.64mL，201.6mmol)溶于 100mL THF后滴加到反应液中，搅拌1h之后再把化合物3-(3,5-二甲氧基苯基)丙酸乙酯(20g，84mmol)溶于48mL THF中然后缓慢滴入反应液中。反应液在-78℃搅拌3h，缓慢升至室温，加饱和氯化铵水溶液淬灭反应。反应液用乙酸乙酯萃取，所得有机层用饱和NaCl洗涤，无水Na 2SO 4干燥再旋干。硅胶柱层析分离纯化(梯度洗脱，石油醚:乙酸乙酯＝20:1至5:1)得到5-(3,5-二甲氧基苯基)-3-氧代戊腈(A2，14.2g,收率：73％)。
在圆底烧瓶中放入5-(3,5-二甲氧基苯基)-3-氧代戊腈(A2，10.2g，43.78mmol)，加入280mL乙醇溶解，然后缓慢滴加水合肼(12.86mL，218.9mmol)，升温至80℃反应24h。将反应液在减压下旋干，加入乙酸乙酯萃取，所得溶液用H 2O洗涤，饱和NaCl溶液洗涤，无水Na 2SO 4干燥。硅胶柱层析分离纯化(梯度洗脱，二氯甲烷:甲醇＝200:1至40:1)得到浅黄色固体的中间体3-(3,5-二甲氧基苯乙基)-1H-吡唑基-5-胺(A，9.34g，收率：86.35％)。
1H NMR(400MHz,Chloroform-d)δ6.26(m,3H),5.39(s,1H),4.72(brs,3H),3.70(s,6H),2.78(s,4H)；LCMS:m/z＝248.1[M+H] +。
中间体B：2-丙烯酰胺-4-(4-(3,3,3-三氟丙基)哌嗪-1-基)苯甲酸乙酯
Figure PCTCN2020112173-appb-000023
在一圆底烧瓶中加入4-氟-2-硝基苯甲酸乙酯(B1，5g，25.8mmol)，哌嗪-1-羧酸叔丁酯(6.5g，38.7mmol)和三乙胺(10mL，77.4mmol)，并加入DMSO(55mL)，后加热至70度，搅拌5小时。LCMS监控原料反应完全，之后加入30mL冰水淬灭，乙酸乙酯萃取(100mL×2)，合并有机相，饱和食盐水洗涤(100mL×2)，无水硫酸钠干燥。硅胶柱层析分离纯化(梯度洗脱，石油醚:乙酸乙酯＝30:1至2:1)得到黄色固体2-丙烯酰胺-4-(4-(3,3,3-三氟丙基)哌嗪-1-基)苯甲酸乙酯(B2，9.0g，收率：92％)。
LCMS：m/z＝325.0(M+H) +.
Figure PCTCN2020112173-appb-000024
将化合物2-丙烯酰胺-4-(4-(3,3,3-三氟丙基)哌嗪-1-基)苯甲酸乙酯(B2，2.5g， 6.6mmol)用30mL DCM溶解，加入12M盐酸乙醇7mL(84mmol)，室温条件下反应2小时。LCMS检测反应完全，旋干得到浅黄色固体2-硝基-4-(哌嗪-1-基)苯甲酸乙酯二盐酸盐(B3，2.32g，收率：100％)。
LCMS：m/z＝280.1[M+H] +.
Figure PCTCN2020112173-appb-000025
将化合物2-硝基-4-(哌嗪-1-基)苯甲酸乙酯二盐酸盐(B3，2.3g，6.6mmol)用30mL DMF溶解，然后加入三乙胺(3.2mL，23.1mmol)和三氟碘丙烷(3.25g，14.5mmol)，反应于90℃下搅拌过夜16小时。LCMS监控原料反应完全，之后加入60mL水，乙酸乙酯萃取(100mL×3)，合并有机相，饱和食盐水洗涤(100mL×2)，无水硫酸钠干燥。硅胶柱层析分离纯化(梯度洗脱，石油醚:乙酸乙酯＝30:1至3:1)得到黄色固体2-硝基-4-(4-(3,3,3-三氟丙基)哌嗪-1-基)苯甲酸乙酯(B4，1.42g，收率：57％)。
1H NMR(400MHz,Chloroform-d)δ7.76(d,J＝8.8Hz,1H),7.04(d,J＝2.5Hz,1H),6.96(dd,J＝8.9,2.6Hz,1H),4.31(q,J＝7.1Hz,2H),3.36(t,J＝5.0Hz,4H),2.64(dt,J＝19.8,6.4Hz,6H),2.35(s,2H),1.32(t,J＝7.1Hz,3H)；LCMS:m/z＝376.1(M+H) +.
Figure PCTCN2020112173-appb-000026
在一圆底烧瓶中加入2-硝基-4-(4-(3,3,3-三氟丙基)哌嗪-1-基)苯甲酸乙酯(B4，1.42g，3.79mmol)，还原铁粉(1.06g，19mmol)和氯化铵(1.26g，19mmol)，并加入30mL乙醇和3mL水，后加热至80度，搅拌2小时。LCMS监控原料反应完全，反应液用硅藻土过滤，用乙酸乙酯(20mL×2)洗两次，合并旋干得到浅黄色固体2-氨基-4-(4-(3,3,3-三氟丙基)哌嗪-1-基)苯甲酸乙酯(B5，1.25g，收率：96％)。
1H NMR(400MHz,DMSO-d 6)δ7.53(d,J＝9.1Hz,1H),6.48(s,2H),6.22(dd,J＝9.1,2.5Hz,1H),6.13(d,J＝2.4Hz,1H),4.17(q,J＝7.1Hz,2H),3.18(dd,J＝6.3,3.8Hz,4H),2.53(dd,J＝10.8,4.3Hz,8H),1.26(t,J＝7.0Hz,3H)；LCMS:m/z＝346.1[M+H] +.
Figure PCTCN2020112173-appb-000027
将化合物2-氨基-4-(4-(3,3,3-三氟丙基)哌嗪-1-基)苯甲酸乙酯(B5，1.25g，3.62mmol)溶于15mL二氯甲烷中，冰水浴冷却至0～5℃。加入三乙胺(0.80mL，5.80mmol)，丙烯酰氯(0.38mL，4.70mmol)，室温搅拌12小时，LCMS检测反应完全，加入50mL冰水淬灭，乙酸乙酯萃取(100mL×3)，饱和食盐水洗涤，有机相无水硫酸钠干燥。硅胶柱层析分离纯化(梯度洗脱，石油醚:乙酸乙酯＝30:1至2:1)得到黄色固体2-丙烯酰胺-4-(4-(3,3,3-三氟丙基)哌嗪-1-基)苯甲酸乙酯(B，1.16g，收率：80％)。
1H NMR(400MHz,Chloroform-d)δ11.58(s,1H),8.47(d,J＝2.6Hz,1H),7.92(d,J＝9.0Hz,1H),6.54(dd,J＝9.1,2.6Hz,1H),6.45–6.28(m,2H),5.77(dd,J＝10.0,1.5Hz,1H),4.33(q,J＝7.1Hz,2H),3.42(t,J＝5.2Hz,4H),2.71–2.54(m,6H),2.42–2.28(m,2H),1.39(t,J＝7.1Hz,3H)；LCMS:m/z＝400.1[M+H] +。
中间体C：2-丙烯酰胺-4-(4-(2,2,2-三氟甲基)哌嗪-1-基)苯甲酸乙酯
Figure PCTCN2020112173-appb-000028
中间体C的合成参照中间体B路线。
1H NMR(400MHz,DMSO-d6)δ11.21(s,1H),8.16(d,J＝2.6Hz,1H),7.82(d,J＝9.1Hz,1H),6.74(dd,J＝9.2,2.6Hz,1H),6.44–6.22(m,2H),5.89–5.73(m,1H),4.28(q,J＝7.1Hz,2H),3.38–3.17(m,6H),2.75(t,J＝5.0Hz,4H),1.31(t,J＝7.1Hz,3H)；LCMS:m/z＝386.1[M+H] +.
中间体D：2-丙烯酰胺-4-(4-(2,2-二氟乙基)哌嗪-1-基)苯甲酸乙酯
Figure PCTCN2020112173-appb-000029
中间体D的合成参照中间体B路线。
LCMS:m/z＝368.1[M+H] +.
中间体E：1-(3,3,3-三氟丙基)哌嗪盐酸盐
Figure PCTCN2020112173-appb-000030
步骤一：向N-叔丁氧羰基哌嗪(E-1，300g,1.61mol)的乙腈(2.5L)溶液中加入碳酸钾(667g,4.83mol)和三氟碘丙烷(1.0Kg,4.46mol)。氩气保护下加热到80℃反应16h。TLC检测反应完全。反应液加水(2L)稀释，乙酸乙酯(3×1.0L)萃取，合并萃取液，无水硫酸钠干燥，过滤，滤液减压浓缩至干，硅胶色谱纯化(石油醚：乙酸乙酯＝3:1)得白色固体4-(3,3,3-三氟丙基)哌嗪-1-羧酸叔丁酯(E-2，430g，收率：94.5％)。
1H NMR(400MHz,CDCl3):δppm 3.43(t,J＝5.2Hz,4H),2.63～2.59(m,2H),2.40(t,J＝5.2Hz,4H),2.34～2.29(m,2H),1.46(s,9H).
步骤二：向4-(3,3,3-三氟丙基)哌嗪-1-羧酸叔丁酯(E-2，382g，1.35mol)的甲醇(2L)溶液中滴加盐酸/1,4-二氧六环(4M,2.0L)。加热到40℃反应16h。LCMS检测反应完全。反应液减压浓缩至干得白色固体1-(3,3,3-三氟丙基)哌嗪盐酸盐(E，375g)。粗品直接用于下一步。
1H NMR(400MHz,MeOD-d4):δppm 3.68～3.56(m,9H),3.32～3.30(m,1H),2.97～2.90(m,2H).
实施例1：化合物1的合成
2-丙烯酰胺-N-(3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-基)-4-(4-(3,3,3-三氟丙基)哌嗪-1-基)苯甲酰胺
Figure PCTCN2020112173-appb-000031
在三颈烧瓶中加入中间体3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-胺(A，310mg，1.25mmol)，N 2保护下加入3mL超干的二甲苯溶解，在冰浴下搅拌10min后滴加2M的三甲基铝(1.9mL，3.75mmol)溶液，反应1h之后加入2-丙烯酰胺-4-(4-(3,3,3-三氟丙基)哌嗪-1-基)苯甲酸乙酯(B，500mg，1.25mmol)，搅拌10min后移去冰浴，115℃反应3h之后，降温，滴加H 2O将反应淬灭，乙酸乙酯萃取，所得溶液用饱和NaCl溶液洗涤， 无水Na 2SO 4干燥。硅胶柱层析分离纯化(梯度洗脱，二氯甲烷:甲醇＝200:1至10:1)得到白色粉末状固体2-丙烯酰胺-N-(3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-基)-4-(4-(3,3,3-三氟丙基)哌嗪-1-基)苯甲酰胺(化合物1,157mg,收率：21％)。
1H NMR(400MHz,DMSO-d 6)δ12.21(s,1H),12.04(s,1H),10.59(s,1H),8.22(d,J＝2.5Hz,1H),7.90(d,J＝9.0Hz,1H),6.71(d,J＝8.6Hz,1H),6.42(d,J＝2.3Hz,3H),6.39–6.18(m,3H),5.85–5.73(m,1H),3.71(s,6H),3.28(s,4H),2.87(s,4H),2.56(m,8H)；LCMS：m/z＝601.2[M+H] +.
实施例2：化合物2的合成
2-丙烯酰胺-N-(3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-基)-4-(4-(2,2,2-三氟乙基)哌嗪-1-基)苯甲酰胺
Figure PCTCN2020112173-appb-000032
在二颈瓶中加入3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-胺(A，963mg，3.9mmol)，N 2保护下加入30mL超干二甲苯溶解之后，冰浴下搅拌片刻，然后再缓慢加入2M三甲基铝溶液(5.85mL，11.69mmol)，冰浴下继续搅拌一个小时。一小时后，加入2-丙烯酰胺-4-(4-(2,2,2-三氟甲基)哌嗪-1-基)苯甲酸乙酯(C，1.5g，3.9mmol)，然后将反应体系移到115℃油浴下继续搅拌。反应3小时后点板，反应结束。往反应液中加入10mL水将反应液淬灭，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥。加入硅胶制砂，硅胶柱分离纯化(从DCM：MeOH＝100:1开始梯度洗脱至DCM：MeOH＝10:1)得乳白色粉末2-丙烯酰胺-N-(3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-基)-4-(4-(2,2,2-三氟乙基)哌嗪-1-基)苯甲酰胺(化合物2，535mg，收率：23.4％)。
1H NMR(400MHz,DMSO-d 6)δ12.22(s,1H),12.02(s,1H),10.61(s,1H),8.21(d,J＝2.6Hz,1H),7.90(d,J＝9.0Hz,1H),6.71(dd,J＝9.2,2.6Hz,1H),6.43–6.21(m,6H),5.81(dd,J＝9.9,1.8Hz,1H),3.71(s,6H),3.30(t,J＝5.2Hz,4H),3.27–3.21(m,2H),2.86(s,4H),2.76(t,J＝5.1Hz,4H)；LCMS:m/z＝587.3(M+H) +.
实施例3：化合物3的合成
2-丙烯酰胺-4-(4-(2,2-二氟乙基)哌嗪-1-基)-N-(3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-基)苯甲酰胺
Figure PCTCN2020112173-appb-000033
将化合物3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-胺(A，114mg，0.463mmol)在氮气保护下加入到5mL超干二甲苯中，冰水浴下搅拌片刻，缓慢加入三甲基铝的2M甲苯溶液(0.7mL，1.4mmol)，保持冰水浴搅拌1小时，加入2-丙烯酰胺-4-(4-(2,2-二氟乙基)哌嗪-1-基)苯甲酸乙酯(D，117mg，0.463mmol)，反应体系转移至油浴下加热回流(115℃)，反应3小时，LCMS检测反应结束，反应液倒入30mL水中淬灭，乙酸乙酯萃取，饱和食盐水洗涤有机相，无水硫酸钠干燥后，旋干溶剂，后制备，冻干，得白色固体2-丙烯酰胺-4-(4-(2,2-二氟乙基)哌嗪-1-基)-N-(3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-基)苯甲酰胺(化合物3，60mg，收率：23％)。
1H NMR(400MHz,DMSO-d 6)δ12.22(s,1H),12.03(s,1H),10.60(s,1H),8.21(d,J＝2.6Hz,1H),7.90(d,J＝9.0Hz,1H),6.71(d,J＝8.5Hz,1H),6.42(m,3H),6.39–6.16(m,4H),5.81(dd,J＝9.9,1.9Hz,1H),3.71(s,6H),3.29(m,4H),2.87(s,4H),2.78(dd,J＝15.7,4.3Hz,2H),2.67(dd,J＝6.8,3.1Hz,4H)；LCMS:m/z＝569.2[M+H] +.
实施例4：化合物4的合成
2-丙烯酰氨基-N-(3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-基)-4-(三氟甲基)苯甲酰胺
Figure PCTCN2020112173-appb-000034
步骤一：将2-硝基-4-三氟甲基苯甲酸(4-1，3.0g，12.2mmol)和DMF(0.3mL)溶于二氯甲烷(50mL)中，置换三次氩气，在氩气保护下降温到0度，加入草酰氯(4.05g，31.90mmol)加完升温到室温，反应过夜，反应完毕。减压旋掉溶剂及过量的草酰氯，甲苯(20mL)带一次，旋干后溶于二氯甲烷(50mL)，将混合物加入到甲醇(50mL)中，室温搅拌3小时，反应完毕。浓缩过柱(PE:EA＝20/1)得到浅绿色液体2-硝基-4-三氟甲基 苯甲酸甲酯(4-2，3.14g，收率：98.7％)。
1H NMR(400MHz,CDCl 3)δ8.22(s,1H),7.96(d,J＝8.0Hz,1H),7.89(d,J＝8.0Hz,1H),3.97(s,3H).
步骤二：将2-硝基-4-三氟甲基苯甲酸甲酯(4-2，3.14g,12.6mmol)溶于甲醇(60mL)中。氢气条件下加入钯炭(310mg)，室温反应过夜，反应完毕。过滤浓缩得到类白色固体2-氨基-4-三氟甲基苯甲酸甲酯(4-3，2.6g，收率：94％)。
LCMS:m/z 220.2[M+H] +.
步骤三：将化合物2-氨基-4-三氟甲基苯甲酸甲酯(4-3，1.5g，6.8mmol)和三乙胺(1.05g，10.3mmol)溶于二氯甲烷(30mL)中。在氩气保护下降温到0度后滴加丙烯酰氯(807mg，8.9mmol)，升温到室温，搅拌3小时，反应完毕。加水淬灭，二氯甲烷(50mL)萃取三次，合并有机相，以饱和食盐水洗，无水硫酸钠干燥，过滤浓缩过柱(PE:EA＝8/1)得到白色固体2-丙烯酰氨基-4-三氟甲基苯甲酸甲酯(4-4，750mg，收率：40％)。
LCMS:m/z 274.2[M+H] +.
步骤四：将化合物3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-胺(A，305mg，1.23mmol)悬浮于二甲苯(25mL)中，在氩气保护下降温到0度后滴加2M三甲基铝(0.62mL，1.23mmol)，加完后保温反应1小时。将2-丙烯酰氨基-4-三氟甲基苯甲酸甲酯(4-4，330mg，1.23mmol)溶于二甲苯(5mL)后滴加到上述反应体系中，升温到100度反应3小时，反应完毕。反应液冰水淬灭，乙酸乙酯(50mL)萃取三次，合并有机相，以饱和食盐水洗，无水硫酸钠干燥，过滤浓缩后经过柱和Prep-TLC纯化得到白色固体2-丙烯酰氨基-N-(3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-基)-4-(三氟甲基)苯甲酰胺(化合物4，100mg，收率：17％)。
1H NMR(400MHz,CDCl3)δ11.17(s,1H),9.45(s，1H)，9.30(brs，1H)，9.09(s，1H)，7.71(d,J＝8.0Hz,1H),7.33(d,J＝8.4Hz,1H),6.69(s,1H),6.47(d,J＝16.8Hz,1H)，6.32(s,3H),6.30(d,J＝16.8Hz,1H),5.83(d,J＝10.4Hz,1H)，3.77(s，6H)，2.97-2.91(m,4H)；LCMS:m/z 489.3[M+H] +.
实施例5：化合物5的合成
2-丙烯酰氨基-N-(3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-基)-4-(2,2,2-三氟乙氧基)苯甲酰胺
Figure PCTCN2020112173-appb-000035
步骤一：将2,2,2-三氟乙-1-醇(188mg,1.880mmol)溶解到DMF(5mL)中。氩气保护下，冰水降温到0度。缓慢加入60％钠氢(45mg，1.125mmol)后搅拌1小时。0度下滴加4-氟-2-硝基苯甲酸乙酯(B1，200mg，0.938mmol)的DMF(2mL)溶液。自然升温到室温，搅拌反应过夜。将反应液倒入冰氯化铵水溶液(100mL)中，乙酸乙酯萃取3次。合并萃取液，饱和盐水洗一次，无水硫酸钠干燥，过滤，浓缩。将得到的残留物通过硅胶色谱法纯化(0至3％梯度的乙酸乙酯：石油醚)纯化得到2-硝基-4-(2,2,2-三氟乙氧基)苯甲酸乙酯(5-1，172mg，收率：62.5％)。
步骤二：将2-硝基-4-(2,2,2-三氟乙氧基)苯甲酸乙酯(5-1，172mg，0.587mmol)溶于无水甲醇(10mL)中。加入钯碳(10％，28mg)，真空氢气置换5次。氢气下室温搅拌过夜，TLC(PE/EA＝10/1)检测反应完毕。滤除钯碳，滤液浓缩，得粗品(2-氨基-4-(2,2,2-三氟乙氧基)苯基)(乙氧基)甲醇(5-2，146mg，收率按100％计)，直接用于下一步。
LCMS:m/z 264.4[M+H] +.
步骤三：将粗品(2-氨基-4-(2,2,2-三氟乙氧基)苯基)(乙氧基)甲醇(5-2，146mg，0.587mmol)和三乙胺(95mg，0.939mmol)溶于二氯甲烷(5mL)中。氩气保护，0度下滴加丙烯酰氯(69mg，0.762mmol)。室温搅拌过夜。将反应液倒至冰水中，二氯甲烷萃取3次。合并有机相，饱和盐水洗一次，无水硫酸钠干燥，过滤，浓缩。将得到的残留物通过硅胶色谱法纯化(0至20％梯度的乙酸乙酯：石油醚)纯化得2-丙烯酰氨基-4-(2,2,2-三氟乙氧基)苯甲酸乙酯(5-3，133mg,收率：71.4％)。
LCMS:m/z 318.0[M+H] +.
步骤四：将化合物3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-胺(A，106mg,0.334mmol)溶于二甲苯(5mL)中。氩气保护，0度下滴加三甲基铝(0.6mL，1.2mmol)。0度保温 1小时后滴加2-丙烯酰氨基-4-(2,2,2-三氟乙氧基)苯甲酸乙酯(5-3，133mg,0.419mmol)的二甲苯溶液(5mL)。110度搅拌3小时，TLC(DCM/MeOH＝50/1)检测反应完全。将反应液倒入冰水(100mL)中。乙酸乙酯萃取3次，合并有机相，饱和盐水洗一次，无水硫酸钠干燥，过滤，浓缩，prep-HPLC纯化得白色固体2-丙烯酰氨基-N-(3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-基)-4-(2,2,2-三氟乙氧基)苯甲酰胺(化合物5，110mg，收率：50.6％)。
1H NMR(400MHz,DMSO-d6)δ12.26(s,1H),11.69(s,1H),10.84(s,1H),8.22(d,J＝2.4Hz,1H),7.80(d,J＝8.8Hz,1H),6.92-6.89(m,1H),6.42-6.28(m,6H),5.86-5.83(m,1H),4.89-4.82(m,2H),3.72(s,6H),2.88(s,4H)；LCMS:m/z 519.4[M+H] +.
实施例6：化合物6的合成
2-丙烯酰氨基-4-(3,3-二氟氮杂环丁烷-1-基)-N-(3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-基)苯甲酰胺
Figure PCTCN2020112173-appb-000036
步骤一：将化合物4-氟-2-硝基苯甲酸乙酯(B1，300mg,1.407mmol)溶解到DMF(6mL)中。依次加入3,3-二氟氮杂环丁烷(230mg,1.776mmol)和无水碳酸钾(777mg，5.626mmol)。氩气保护下，50度搅拌反应过夜。将反应液倒入冰水(50mL)中。乙酸乙酯萃取3次，合并有机相，饱和盐水洗一次，无水硫酸钠干燥，过滤，浓缩。将得到的残留物通过硅胶色谱法纯化(0至3％梯度的乙酸乙酯：石油醚)纯化得4-(3,3-二氟氮杂环丁烷-1-基)-2-硝基苯甲酸乙酯(6-1，139mg，收率：34.5％)。
LCMS:m/z 287.3[M+H] +.
步骤二：将化合物4-(3,3-二氟氮杂环丁烷-1-基)-2-硝基苯甲酸乙酯(6-1，139mg，0.4857mmol)溶于无水甲醇(10mL)中。加入钯碳(10％，20mg)，氢气置换5次。氢 气下室温搅拌过夜。TLC(PE/EA＝10/1)检测反应完毕。滤除钯碳，滤液浓缩得粗品2-氨基-4-(3,3-二氟氮杂环丁烷-1-基)苯甲酸乙酯(6-2，121mg，收率按100％计)，直接用于下一步。
LCMS:m/z 257.4[M+H] +.
步骤三：将粗品化合物2-氨基-4-(3,3-二氟氮杂环丁烷-1-基)苯甲酸乙酯(6-2，121mg，0.486mmol)溶于二氯甲烷(5mL)中。加入三乙胺(79mg，0.781mmol)。氩气保护，0度下滴加丙烯酰氯(57mg，0.630mmol)。室温搅拌过夜。将反应液倒至冰水中，二氯甲烷萃取3次，合并有机相，饱和盐水洗一次，无水硫酸钠干燥，过滤，浓缩。将得到的残留物通过硅胶色谱法(0至20％梯度的乙酸乙酯：石油醚)纯化得2-丙烯酰氨基-4-(3,3-二氟氮杂环丁烷-1-基)苯甲酸乙酯(6-3，108mg,收率：71.6％)。
LCMS:m/z 311.4[M+H] +.
步骤四：将3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-胺(A，88mg,0.356mmol)溶于二甲苯(5mL)中。氩气保护，0度下滴加三甲基铝(0.5mL,1.0mmol)。0度保温1小时后滴加2-丙烯酰氨基-4-(3,3-二氟氮杂环丁烷-1-基)苯甲酸乙酯(6-3，108mg,0.348mmol)的二甲苯(5mL)溶液。110度搅拌3小时，TLC(DCM/MeOH＝50/1)检测反应完全。将反应液倒入冰水(100mL)中，乙酸乙酯萃取3次，合并有机相，饱和盐水洗一次，无水硫酸钠干燥，过滤，浓缩。将得到的残留物通过硅胶色谱法纯化(0至5％梯度的甲醇：二氯甲烷)纯化得2-丙烯酰氨基-4-(3,3-二氟氮杂环丁烷-1-基)-N-(3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-基)苯甲酰胺(化合物6，63mg，收率：35.4％)。
1H NMR(400MHz,DMSO-d6)δ12.22(s,1H),12.04(s,1H),10.63(s,1H),7.94(d,J＝9.2Hz,1H),7.79(s,1H),6.42-6.22(m,7H),5.83(d,J＝10Hz,1H),4.41-4.35(m,4H),3.71(s,6H),2.87(s,4H)；LCMS:m/z 512.4[M+H] +.
实施例7：化合物7的合成
2-丙烯酰氨基-4-(4,4-二氟哌啶-1-基)-N-(3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-基)苯甲酰胺
Figure PCTCN2020112173-appb-000037
步骤一：将化合物4-氟-2-硝基苯甲酸乙酯(B1，300mg，1.407mmol)溶解到DMF(6mL)中。依次加入4,4-二氟哌啶(179mg,1.478mmol)和无水碳酸钾(389mg,2.817mmol)，氩气保护下，50度搅拌过夜。将反应液倒入冰水(50mL)中。乙酸乙酯萃取3次，合并有机相，饱和盐水洗一次，无水硫酸钠干燥，过滤，浓缩。将得到的残留物通过硅胶色谱法(0至3％梯度的乙酸乙酯：石油醚)纯化得4-(4,4-二氟哌啶-1-基)-2-硝基苯甲酸乙酯(7-1，219mg，收率：49.5％)。
步骤二：将4-(4,4-二氟哌啶-1-基)-2-硝基苯甲酸乙酯(7-1，219mg，0.697mmol)溶于无水甲醇(10mL)中。加入钯碳(10％，23mg)。真空氢气置换5次。室温搅拌过夜，TLC(石油醚/丙酮＝10/1)检测反应完毕。滤除钯碳，滤液浓缩干，得粗品2-氨基-4-(4,4-二氟哌啶-1-基)苯甲酸乙酯(7-2，收率按100％计)，直接用于下一步。
LCMS:m/z 285.1[M+H] +.
步骤三：将粗品2-氨基-4-(4,4-二氟哌啶-1-基)苯甲酸乙酯(7-2，0.697mmol)溶于二氯甲烷(5mL)中。加入三乙胺(113mg，1.117mmol)。氩气保护，0度下滴加丙烯酰氯(90mg，0.994mmol)。室温搅拌过夜。将反应液倒至冰水中，二氯甲烷萃取3次，合并有机相，饱和盐水洗一次，无水硫酸钠干燥，过滤，浓缩。将得到的残留物通过硅胶色谱法(0至20％梯度的乙酸乙酯：石油醚)纯化得无色油状物2-丙烯酰氨基-4-(4,4-二氟哌啶-1-基)苯甲酸乙酯(7-3，183mg,收率：77.6％)。
LCMS:m/z 339.4[M+H] +.
步骤四：将化合物3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-胺(A，134mg,0.542mmol)溶于二甲苯(5mL)中。氩气保护，0度下滴加三甲基铝(0.8mL，1.6mmol)。0度保温1小时后再滴加2-丙烯酰氨基-4-(4,4-二氟哌啶-1-基)苯甲酸乙酯(7-3，183mg,0.541mmol)的二甲苯(5mL)溶液。110度搅拌3小时，TLC(DCM/MeOH＝20/1+2d氨水)检测反应完全。将反应液倒入冰水(100mL)中，乙酸乙酯萃取3次，合并有机相，饱和盐水 洗一次，无水硫酸钠干燥，过滤，浓缩，将得到的残留物通过硅胶色谱法(0至5％梯度的甲醇：二氯甲烷)纯化后再prep-TLC(DCM/MeOH＝20/1+2d氨水)纯化得2-丙烯酰氨基-4-(4,4-二氟哌啶-1-基)-N-(3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-基)苯甲酰胺(化合物7，137mg，收率：46.9％)。
1H NMR(400MHz,DMSO-d6)δ12.31(s,1H),12.06(s,1H),10.67(s,1H),8.33(d,J＝2.8Hz,1H),7.99(d,J＝8.8Hz,1H),6.86-6.84(m,1H),6.48(s,3H),6.42-6.37(m,2H),6.33-6.28(m,1H),5.90-5.87(m,1H),3.78(s,6H),3.56–3.54(m,4H),2.93-2.95(m,4H),2.16–2.07(m,4H)；LCMS:m/z 540.5[M+H] +.
实施例8：化合物8的合成
2-丙烯酰氨基-4-(3,3-二氟吡咯烷-1-基)-N-(3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-基)苯甲酰胺
Figure PCTCN2020112173-appb-000038
步骤一：将4-氟-2-硝基苯甲酸乙酯(B1，300mg,1.407mmol)溶解到DMF(6mL)中。依次加入3,3-二氟吡咯烷(218mg,2.035mmol)和无水碳酸钾(389mg,2.817mmol)。氩气保护下，50度搅拌过夜。将反应液倒入冰水(50mL)中。乙酸乙酯萃取3次，合并有机相，饱和盐水洗一次，无水硫酸钠干燥，过滤，浓缩。将得到的残留物通过硅胶色谱法(0至3％梯度的乙酸乙酯：石油醚)纯化得4-(4,4-二氟哌啶-1-基)-2-硝基苯甲酸乙酯(8-1，177mg，收率：41.8％)。
步骤二：将4-(4,4-二氟哌啶-1-基)-2-硝基苯甲酸乙酯(8-1，177mg，0.589mmol)溶于无水甲醇(10mL)中，加入钯碳(10％，25mg)。真空氢气置换5次。室温搅拌过夜，TLC(石油醚/丙酮＝10/1)检测反应完毕。滤除钯碳，滤液浓缩得粗品2-氨基-4-(3,3-二氟吡咯烷-1-基)苯甲酸乙酯(8-2，收率按100％计)，直接用于下一步。
LCMS:m/z 271.0[M+H] +.
步骤三：将粗品2-氨基-4-(3,3-二氟吡咯烷-1-基)苯甲酸乙酯(8-2，0.589mmol)溶于二氯甲烷(5mL)中。加入三乙胺(96mg，0.949mmol)。氩气保护，0度下滴加丙烯酰氯(80mg，0.884mmol)。室温搅拌过夜。将反应液倒至冰水中，二氯甲烷萃取3次，合并有机相，饱和盐水洗一次，无水硫酸钠干燥，过滤，浓缩。将得到的残留物通过硅胶色谱法(0至20％梯度的乙酸乙酯：石油醚)纯化得淡黄色固体2-丙烯酰氨基-4-(3,3-二氟吡咯烷-1-基)苯甲酸乙酯(8-3，112mg,收率：58.6％)。
LCMS:m/z 325.4[M+H] +.
步骤四：将3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-胺(A，85mg,0.344mmol)溶于二甲苯(5mL)中。氩气保护，0度下滴加三甲基铝(0.5mL,1.0mmol)。0度保温1小时后再滴加2-丙烯酰氨基-4-(3,3-二氟吡咯烷-1-基)苯甲酸乙酯(8-3，112mg,0.345mmol)的二甲苯(5mL)溶液。110度搅拌3小时，TLC(DCM/MeOH＝20/1+2d氨水)检测反应完全。将反应液倒入冰水(100mL)中，乙酸乙酯萃取3次，合并有机相，饱和盐水洗一次，无水硫酸钠干燥，过滤，浓缩。将得到的残留物通过硅胶色谱法纯化(0至5％梯度的甲醇：二氯甲烷)纯化后所得固体再用甲醇洗得2-丙烯酰氨基-4-(3,3-二氟吡咯烷-1-基)-N-(3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-基)苯甲酰胺(化合物8，54mg，收率：29.7％)。
1H NMR(400MHz,DMSO-d6)δ12.19(d,J＝11.6Hz,2H),10.55(s,1H),7.95-7.92(m,2H),6.43-6.22(m,7H),5.84-5.81(m,1H),3.81-3.75(m,2H),3.72(s,6H),3.58-3.55(m,2H),2.88(s,4H),2.62-2.55(m,2H)；LCMS:m/z 526.5[M+H] +.
实施例9：化合物9的合成
2-丙烯酰氨基-N-(3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-基)-4-(3,3,3-三氟丙氧基)苯甲酰胺
Figure PCTCN2020112173-appb-000039
步骤一：0℃，Ar保护下向3,3,3-三氟丙-1-醇(228mg，2.0mmol)的DMF(8mL)中缓慢加入钠氢(60％分散于油中，80mg，2.0mmol)，0℃搅拌1h。滴加4-氟-2-硝基苯甲酸乙酯(B1，213mg，1.0mmol)的DMF(4mL)溶液。反应室温搅拌过夜。将反应液倒入冰的饱和氯化铵水溶液(100mL)中，乙酸乙酯萃取(3×30mL)，有机相合并，饱和盐水洗(100mL)，无水硫酸钠干燥，过滤，浓缩，粗品硅胶色谱法纯化(石油醚：乙酸乙酯＝30:1)得2-硝基-4-(3,3,3-三氟丙氧基)苯甲酸乙酯(9-1，117mg，收率：38.1％)。
步骤二：向2-硝基-4-(3,3,3-三氟丙氧基)苯甲酸乙酯(9-1，117mg，0.38mmol)的无水甲醇(15mL)溶液中加入钯碳(10％，13mg)。真空氢气置换三次。室温氢气球下搅拌过夜。过滤，滤液减压浓缩至干得2-氨基-4-(3,3,3-三氟丙氧基)苯甲酸乙酯粗品(9-2，110mg，收率按100％计)，粗品直接用于下一步。
LCMS:m/z 278[M+H] +.
步骤三：0℃，Ar保护下向2-氨基-4-(3,3,3-三氟丙氧基)苯甲酸乙酯粗品(9-2，110mg，0.397mmol)和三乙胺(64mg，0.635mmol)的二氯甲烷(10mL)溶液中加入滴加丙烯酰氯(47mg，0.516mmol)。自然升温至室温搅拌过夜。将反应液倒至入冰水(50mL)中，二氯甲烷萃取(3×20mL)。有机相饱和盐水洗(50mL)。合并有机相，无水硫酸钠干燥，过滤，浓缩，硅胶色谱法纯化得2-丙烯酰氨基-4-(3,3,3-三氟丙氧基)苯甲酸乙酯(9-3，33mg,收率：25.2％)。
LCMS:m/z 332.0[M+H] +.
步骤四：0℃，Ar保护下向3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-胺(A，20mg，0.08mmol)的二甲苯(5mL)中滴加三甲基铝(0.2mL，0.288mmol)。0℃搅拌1h后滴加2-丙烯酰氨基-4-(3,3,3-三氟丙氧基)苯甲酸乙酯(9-3，33mg,0.1mmol)的二甲苯(5mL)溶液。升温到110℃搅拌3h。将反应液倒入冰水(100mL)中，乙酸乙酯萃取(3×20mL)，有机相饱和盐水洗(20mL)，合并有机相，无水硫酸钠干燥，过滤，浓缩，Prep-TLC纯化得白色固体2-丙烯酰氨基-N-(3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-基)-4-(3,3,3-三氟丙氧基)苯甲酰胺(化合物9，15.46mg，收率：36.3％)。
1H NMR(400MHz,DMSO-d6)δppm 12.25(s,1H),11.75(s,1H),10.79(s,1H),8.19(s,1H),7.97(d,J＝8.9Hz,1H),6.79(d,J＝9.3Hz,1H),6.42-6.23(m,6H),5.83(d,J＝10.5Hz,1H),4.28(s,2H),3.72(s,6H),2.93-2.79(m,6H)；LCMS:m/z 533[M+H] +.
实施例10：化合物10的合成
2-丙烯酰胺基-N-(3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-基)-5-甲氧基-4-(4-(3,3,3-三氟丙基)哌嗪-1-基)苯甲酰胺
Figure PCTCN2020112173-appb-000040
步骤一：向4-氟-3-甲氧基苯甲酸(10-1，11g，64.65mmol)的MeOH(100mL)溶液中加入H 2SO 4(98％，5mL)。反应加热至70℃反应16h。TLC显示反应完全。反应液冷却至室温后减压浓缩除去大部分溶剂。加乙酸乙酯(100mL)稀释后倒入冰水(200mL)中，搅拌5min，分液，水相再用乙酸乙酯(100mL)萃取。合并有机相，水(2×100mL)洗，饱和盐水(2×100mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩得淡黄色固体4-氟-3-甲氧基苯甲酸甲酯(10-2，11.8g，收率：99％)。
1H NMR(400MHz,CDCl3)δppm 7.66-7.64(m,2H),7.14-7.09(m,1H),3.94(s,3H),3.91(s,3H).
步骤二：将4-氟-3-甲氧基苯甲酸甲酯(10-2，5.0g，27.15mmol)溶于H 2SO 4(98％，40mL)和AcOH(80mL)的混合溶剂中。10℃以下滴加HNO 3(65％，2.6g，27.15mmol)。加毕，室温反应3h。LCMS监测基本反应完全。反应液倒入冰水(300mL)中，加乙酸乙酯(2×150mL)萃取。合并有机相，饱和盐水(2×100mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩，经硅胶色谱(石油醚：二氯甲烷＝5:2)纯化得淡黄色固体4-氟-5-甲氧基-2-硝基苯甲酸甲酯(10-3，3.3g，收率：53％)。
1H NMR(400MHz,CDCl 3)δ7.81(d，J＝10.0Hz，1H)，7.18(d，J＝7.6Hz，1H)，4.01(s,3H)，3.94(s，3H).
步骤三：将1-(3,3,3-三氟丙基)哌嗪(中间体E，1.4g，6.24mmol)，Cs 2CO 3(5.5g，17.02mmol)加入DMF(40mL)中，搅拌10min。加入4-氟-5-甲氧基-2-硝基苯甲酸甲酯(10-3，1.3g，5.67mmol)，Ar保护下80℃搅拌反应4h。LCMS监测开始有副产物产生，停止反应。反应液冷却至室温。加乙酸乙酯(200mL)稀释，水洗(3×150mL)，饱和盐水(2×100mL)洗，无水硫酸钠干燥浓缩，经硅胶色谱纯化(石油醚：乙酸乙酯＝5:1)得棕黄色固体5-甲氧基-2-硝基-4-(4-(3,3,3-三氟丙基)哌嗪-1-基)苯甲酸甲酯(10-4， 610mg，收率：34％)。
LCMS:m/z 392.1[M+H] +.
步骤四：向5-甲氧基-2-硝基-4-(4-(3,3,3-三氟丙基)哌嗪-1-基)苯甲酸甲酯(10-4，730mg，2.44mmol)的MeOH(15mL)溶液中加入Pd/C(10％，100mg)。H 2环境于40℃反应4h。TLC监测反应完全。反应液冷却至室温后过滤，滤液减压浓缩，经硅胶色谱纯化(石油醚：乙酸乙酯：二氯甲烷＝5:1:1)得淡黄色固体2-氨基-5-甲氧基-4-(4-(3,3,3-三氟丙基)哌嗪-1-基)苯甲酸甲酯(10-5，580mg，收率：87％)。
LCMS:m/z 362.4[M+H] +.
步骤五：0℃，Ar保护下向2-氨基-5-甲氧基-4-(4-(3,3,3-三氟丙基)哌嗪-1-基)苯甲酸甲酯(10-5，580mg，1.61mmol)和三乙胺(1.3g，12.84mmol)的二氯甲烷(10mL)溶液中滴加丙烯酰氯(290mg，3.21mmol)的二氯甲烷(5mL)溶液。加毕，自然升至RT反应1.5h。TLC监测反应完全。反应液倒入冰水(50mL)中，二氯甲烷(3×40mL)萃取。合并有机相，饱和盐水(2×50mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩，经硅胶色谱纯化(石油醚：二氯甲烷＝1:1-0:1)得淡黄色固体2-丙烯酰胺基-5-甲氧基-4-(4-(3,3,3-三氟丙基)哌嗪-1-基)苯甲酸甲酯(10-6，570mg，收率：85％)。
LCMS:m/z 416.0[M+H] +.
步骤六：0℃，Ar保护下向3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-胺(A，66mg，0.26mmol)的二甲苯(3mL)悬浊液中滴加AlMe 3(2M in THF，0.4mL，0.72mmol)。0℃搅拌30min后加入2-丙烯酰胺基-5-甲氧基-4-(4-(3,3,3-三氟丙基)哌嗪-1-基)苯甲酸甲酯(10-6，100mg，0.24mmol)的二甲苯(3mL)溶液。室温搅拌30min后升至100℃反应4h。TLC监测反应完全，反应液冷却至室温后倒入冰水(50mL)中，加乙酸乙酯(30mL)搅拌5min，滤去絮状物，分液。水相再用乙酸乙酯萃取(2×20mL)，合并有机相，水洗(2×50mL)，饱和盐水洗(2×50mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，经Prep-TLC纯化得125mg浅黄色固体。所得固体经Prep-HPLC纯化得浅黄固体2-丙烯酰胺基-N-(3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-基)-5-甲氧基-4-(4-(3,3,3-三氟丙基)哌嗪-1-基)苯甲酰胺(化合物10，20mg，收率：13％)。
1H NMR(400MHz,DMSO-d6)δppm 12.25(s,1H),11.60(s,1H),10.83(s,1H),8.13(s,1H),7.47(s,1H),6.45-6.19(m,6H),5.79(d,J＝10.0Hz,1H),3.88(s,3H),3.72(s,6H),3.09(s,4H),2.88(s,4H),2.58-2.50(m,8H).
19F NMR(376MHz,DMSO-d6)δppm-63.55.
LCMS:m/z 631.7[M+H] +.
实施例11：化合物11的合成
2-丙烯酰胺基-N-(3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-基)-4-(三氟甲氧基)苯甲酰胺
Figure PCTCN2020112173-appb-000041
步骤一：向1-溴-2-硝基-4-(三氟甲氧基)苯(11-1，1.00g,3.50mmol)的DMF(2mL)溶液中加入CuCN(313mg,3.5mmol)。150℃反应1h。加入甲苯(5mL)，继续回流1h。反应液倒至冰水(50mL)中，乙酸乙酯(3×50mL)萃取，有机相用饱和盐水(50mL)洗涤。合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩干，粗品用硅胶色谱法(石油醚：乙酸乙酯＝1：0-15：1)纯化得黄色油状物2-硝基-4-(三氟甲氧基)苯甲腈(11-2，710mg，收率：87.9％)。
1H NMR(400MHz,DMSO-d6)δppm 8.40～8.35(m,2H),8.06～8.04(m,1H).
步骤二：将2-硝基-4-(三氟甲氧基)苯甲腈(11-2，400mg,1.72mmol)用aq.55％硫酸(10mL)溶解后加热至120℃反应16h。反应液降至室温，倒至冰水(50mL)中，乙酸乙酯(3×50mL)萃取，有机相用aq.10％NaOH溶液(50mL)洗。水相用稀盐酸调pH～2后乙酸乙酯(3×50mL)萃取，合并萃取液，无水硫酸钠干燥，过滤，滤液减压浓缩得白色固体2-硝基-4-(三氟甲氧基)苯甲酸(11-3，374mg,收率：86.4％)。
LCMS:m/z 250.1[M-H] -.
步骤三：0℃，Ar保护下向2-硝基-4-(三氟甲氧基)苯甲酸(11-3，250mg,0.99mmol)的甲醇(2mL)和乙腈(16mL)溶液中滴加三甲基硅烷化重氮甲烷(2.0M in hexanes,1.0mL,2.0mmol)。室温反应2h。反应液减压浓缩近干，加入乙酸乙酯(50mL)稀释，饱和盐水(100mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩，通过Prep-TLC(乙酸乙酯：石油醚＝1：16)纯化无色透明液体得2-硝基-4-(三氟甲氧基)苯甲酸甲酯(11-4，226mg,收率：85.6％)。
1H NMR(400MHz,CDCl 3)δppm 7.86(d,J＝8.4Hz,1H),7.74(d,J＝0.8Hz,1H),7.54(d,J＝8.4Hz,1H),3.05(s,3H).
步骤四：向2-硝基-4-(三氟甲氧基)苯甲酸甲酯(11-4，188mg,0.66mmol)的甲醇(20mL)溶液中加入Pd/C(10％，30mg)。真空氢气置换3次。氢气(气球)氛围下室温搅拌16h。反应液硅藻土过滤，滤液浓缩至干得浅棕色油状物2-氨基-4-(三氟甲氧基)苯甲酸甲酯(11-5，146mg，收率：94.1％)。
LCMS:m/z 236.3[M+H] +.
步骤五：0℃，Ar保护下向2-氨基-4-(三氟甲氧基)苯甲酸甲酯粗品(11-5，146mg,0.62mmol)的二氯甲烷(5mL)溶液中依次加入三乙胺(101mg,1.00mmol)和丙烯酰氯(73mg,0.81mmol)。室温搅拌3h。反应液倒至冰水(50mL)中，二氯甲烷(3×50mL)萃取，饱和盐水(50mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩至干，硅胶色谱法(乙酸乙酯：石油醚＝1：80-1：15)纯化得2-丙烯酰胺基-4-(三氟甲氧基)苯甲酸甲酯(11-6，178mg,收率：99.3％)。
LCMS:m/z N/A[M+H] +.
步骤六：0℃，Ar保护下向3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-胺(A，155mg,0.63mmol)用二甲苯(5mL)悬浊液中缓慢加入AlMe3(2.0M，0.9mL，1.84mmol)。滴毕，0℃继续搅拌1h。滴加2-丙烯酰胺基-4-(三氟甲氧基)苯甲酸甲酯(11-6，178mg，0.62mmol)的二甲苯(5mL)溶液。升至110℃搅拌反应3h。反应液倒至冰水(50mL)中，乙酸乙酯(3×50mL)萃取，饱和盐水(50mL)洗。合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩至干，硅胶色谱法(乙酸乙酯：石油醚＝1：50～1：15)纯化后Prep-TLC(乙酸乙酯：石油醚＝1：1)纯化得2-丙烯酰胺基-N-(3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-基)-4-(三氟甲氧基)苯甲酰胺(化合物11，34mg,收率：10.9％)。
1H NMR(400MHz,CDCl3)δppm 11.41(s,1H),9.09(s,1H),8.78(d,J＝1.6Hz,1H),7.66(d,J＝8.8Hz,1H),7.26(s,1H),6.93(d,J＝1.2Hz,1H),6.67(s,1H),6.44(s,1H),6.35-6.3(m,4H),5.84-5.81(m,1H),3.78(s,6H),2.98-2.91(m,4H).
LCMS:m/z 505.6[M+H] +.
实施例12：化合物12的合成
2-丙烯酰胺基-N-(3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-基)-4-(3-甲基-4-(3,3,3-三氟丙基)哌嗪-1-基)苯甲酰胺
Figure PCTCN2020112173-appb-000042
步骤一：将4-氟-2-硝基苯甲酸甲酯(B1，2.00g,10.04mmol)，2-甲基-1-叔丁氧羰基哌嗪(2.41g,12.05mmol)和K 2CO 3(2.78g,20.08mmol)溶解在DMF(20mL)中。加热到100 ℃搅拌反应16h。反应液加乙酸乙酯(50mL)稀释，饱和盐水洗(2×150mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，将得到的残留物通过硅胶色谱法(0至50％梯度的乙酸乙酯：石油醚)纯化得黄色固体4-(4-(甲氧基羰基)-3-硝基苯基)-2-甲基哌嗪-1-甲酸叔丁酯(12-1，1.6g，收率：42％)。
1H NMR(400MHz,CDCl3):δppm 7.78(d,J＝8.8Hz,1H),6.97(d,J＝2.4Hz,1H),6.91(dd,J＝8.8,2.4Hz,1H),4.38-4.31(m,1H),3.97-3.92(m,1H),3.85(s,3H),3.69-3.64(m,1H),3.54-3.51(m,1H),3.36-3.25(m,2H),3.10-3.03(m,1H),1.49(s,9H),1.24(d,J＝6.8Hz,3H).
步骤二：向4-(4-(甲氧基羰基)-3-硝基苯基)-2-甲基哌嗪-1-甲酸叔丁酯(12-1，1.6g，4.21mmol)的CH 2Cl 2(20mL)中滴加TFA(4mL)。室温搅拌60min。反应液减压浓缩至干，加CH 2Cl 2(50mL)稀释，饱和碳酸氢钠(50mL)洗，饱和盐水洗(2×50mL)，无水硫酸钠干燥，过滤，滤液减压浓缩得黄色固体4-(3-甲基哌嗪-1-基)-2-硝基苯甲酸甲酯(12-2，1.2g，收率：100％)。
1H NMR(400MHz,CDCl3):δppm 7.77(d,J＝8.8Hz,1H),7.04(d,J＝2.4Hz,1H),6.97(dd,J＝8.8,2.4Hz,1H),3.85(s,3H),3.70～3.65(m,2H),3.21-3.18(m,1H),3.04-2.98(m,3H),2.66(dd,J＝12.0,10.4Hz,1H),1.22(d,J＝6.4Hz,3H).
步骤三：向4-(3-甲基哌嗪-1-基)-2-硝基苯甲酸甲酯(12-2，600mg,2.15mmol)和DIPEA(1388mg，10.74mmol)的DMF(20mL)中加入1,1,1-三氟-3-碘丙烷(2406mg，10.74mmol)。反应加热到120 ℃搅拌3h。反应液加乙酸乙酯(30mL)稀释，饱和盐水洗(2×100mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，将得到的残留物通过硅胶 色谱法(0至50％梯度的乙酸乙酯：石油醚)纯化得黄色固体4-(3-甲基-4-(3,3,3-三氟丙基)哌嗪-1-基)-2-硝基苯甲酸甲酯(12-3，380mg，收率：47％)。
1H NMR(400MHz,CDCl 3):δppm 7.76(d,J＝8.8Hz,1H),7.02(d,J＝2.8Hz,1H),6.95(dd,J＝8.8,2.4Hz,1H),3.85(s,3H),3.61-3.51(m,2H),3.16-3.10(m,1H),3.05-2.97(m,1H),2.91(dt,J＝11.2,3.6Hz,1H),2.86-2.79(m,1H),2.68-2.51(m,2H),2.50-2.44(m,1H),2.36-2.23(m,2H),1.16(d,J＝6.0Hz,3H).
步骤四：向4-(3-甲基-4-(3,3,3-三氟丙基)哌嗪-1-基)-2-硝基苯甲酸甲酯(12-3，380mg,1.01mmol)的MeOH(10mL)中加入Pd/C(10％,50mg)。反应液H 2置换三次后加热到40℃搅拌3h。反应液过滤，滤液减压浓缩至干得白色固体2-氨基-4-(3-甲基-4-(3,3,3-三氟丙基)哌嗪-1-基)苯甲酸甲酯(12-4，290mg，收率：83％)。
1H NMR(400MHz,CDCl3):δppm 7.73(d,J＝9.2Hz,1H),6.24(dd,J＝9.2,2.4Hz,1H),6.00(d,J＝2.4Hz,1H),5.68(br,2H),3.82(s,3H),3.56-3.46(m,2H),3.04-2.96(m,2H),2.86(dt,J＝11.2,3.6Hz,1H),2.72-2.61(m,2H),2.58-2.52(m,1H),2.45(td,J＝11.2,3.2Hz,1H),2.33-2.24(m,2H),1.14(d,J＝6.0Hz,3H).
步骤五：0℃，Ar保护下向2-氨基-4-(3-甲基-4-(3,3,3-三氟丙基)哌嗪-1-基)苯甲酸甲酯(12-4，290mg，0.84mmol)和Et 3N(255mg，2.52mmol)的CH 2Cl 2(10mL)加入丙烯酰氯(114mg，1.26mmol)。室温搅拌反应3h。反应液倒入冰水(30mL)中，CH 2Cl 2(2×20mL)萃取，合并萃取液，饱和盐水洗(2×50mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，将得到的残留物通过硅胶色谱法(0至50％梯度的乙酸乙酯：石油醚)纯化得黄色固体2-丙烯酰胺基-4-(3-甲基-4-(3,3,3-三氟丙基)哌嗪-1-基)苯甲酸甲酯(12-5，300mg，收率：89％)。
1H NMR(400MHz,CDCl3):δppm 11.53(s,1H),8.44(d,J＝2.4Hz,1H),7.90(d,J＝8.8Hz,1H),6.54(dd,J＝8.8,2.4Hz,1H),6.40(d,J＝1.2Hz,1H),6.35(d,J＝10.0Hz,1H),5.79(dd,J＝9.2,1.6Hz,1H),3.87(s,3H),3.71-3.61(m,2H),3.16-3.10(m,1H),3.04-2.96(m,1H),2.89-2.79(m,2H)，2.69-2.54(m,2H),2.46(td,J＝11.2,3.2Hz,1H),2.33-2.25(m,2H),1.15(d,J＝6.4Hz,3H).
步骤六：0℃，Ar保护下向3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-胺(A，223mg，0.90mmol)的二甲苯(5mL)体系中滴加AlMe 3(2M in THF，3.00mmol)。0℃搅拌60min。滴加2-丙烯酰胺基-4-(3-甲基-4-(3,3,3-三氟丙基)哌嗪-1-基)苯甲酸甲酯(12-5，300mg，0.75mmol)的二甲苯(3mL)溶液。反应加热到110℃搅拌3h。反应液倒入冰水(30mL)中，CH 2Cl 2(2×20mL)萃取，合并萃取液，饱和盐水洗(2×50mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，将得到的残留物Prep-HPLC纯化得白色固体2- 丙烯酰胺基-N-(3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-基)-4-(3-甲基-4-(3,3,3-三氟丙基)哌嗪-1-基)苯甲酰胺(化合物12，62.45mg，收率：14％)。
1H NMR(400MHz,DMSO-d6):δppm 12.20(s,1H),12.05(s,1H),10.58(s,1H),8.20(d,J＝2.4Hz,1H),7.91(d,J＝9.2Hz,1H),6.73(dd,J＝10.8,2.4Hz,1H),6.42-6.21(m,6H),5.83(dd,J＝9.6,1.6Hz,1H),3.71(s,6H),3.71-3.68(m,1H),3.60(d,J＝12.0Hz,1H),2.99-2.87(m,7H),2.70-2.64(m,1H),2.58-2.36(m,5H),1.08(d,J＝6.0Hz,3H).
19F NMR(376MHz,CDCl3):δppm-63.52.
LCMS:m/z 615.4[M+H] +.
实施例13：化合物13的合成
2-丙烯酰胺基-N-(3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-基)-4-(甲基(3,3,3-三氟丙基)氨基)苯甲酰胺
Figure PCTCN2020112173-appb-000043
步骤一：将4-氟-2-硝基苯甲酸甲酯(B1，2.00g，10.04mmol)和甲胺(2M，THF溶液，20mL)的混合溶液在封管中加热到100℃搅拌反应16h。反应液减压浓缩至干，残留物通过硅胶色谱法(0至40％梯度的乙酸乙酯：石油醚)纯化得黄色固体4-(甲基氨基)-2-硝基苯甲酸甲酯(13-1,1.2g，收率：57％)。
1H NMR(400MHz,CDCl 3):δppm 7.69(d,J＝8.8Hz,1H),7.13-7.11(m,1H),6.84(d,J＝2.4Hz,1H),6.75(dd,J＝8.8,2.4Hz,1H),3.73(s,3H),2.77(d,J＝5.2Hz,3H).
步骤二：向4-(甲基氨基)-2-硝基苯甲酸甲酯(13-1,1.10g,5.23mmol)和Cs 2CO 3(8.53g，26.17mmol)的DMF(15mL)中加入1,1,1-三氟-3-碘丙烷(5.86g，26.17mmol)。反应加热到120℃搅拌16h。反应液加乙酸乙酯(40mL)稀释，饱和盐水洗(2×100mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，将得到的残留物通过硅胶色谱法(0至50％梯度 的乙酸乙酯：石油醚)纯化后再Prep-TLC(石油醚:乙酸乙酯)得黄色固体4-(甲基(3,3,3-三氟丙基)氨基)-2-硝基苯甲酸甲酯(13-2，90mg，收率：5.6％)。
1H NMR(400MHz,CDCl 3):δppm 7.81(d,J＝8.8Hz,1H),6.80(d,J＝2.4Hz,1H),6.76(dd,J＝8.8,2.4Hz,1H),3.85(s,3H),3.71(t,J＝7.2Hz,2H),3.07(s,3H),2.43-2.37(m,2H).
19F NMR(376MHz,CDCl 3):δppm-65.15.
步骤三：向4-(甲基(3,3,3-三氟丙基)氨基)-2-硝基苯甲酸甲酯(13-2,90mg,1.01mmol)的MeOH(5mL)中加入Pd/C(10％,20mg)。反应液H 2置换三次后加热到40℃搅拌3h。反应液过滤，滤液减压浓缩至干得白色固体2-氨基-4-(甲基(3,3,3-三氟丙基)氨基)苯甲酸甲酯(13-3,75mg，收率：92％)。
LCMS:m/z 277.0[M+H] +.
步骤四：0 ℃，Ar保护下向2-氨基-4-(甲基(3,3,3-三氟丙基)氨基)苯甲酸甲酯(13-3,75mg，0.27mmol)和Et 3N(82mg，0.81mmol)的CH 2Cl 2(5mL)加入丙烯酰氯(37mg，0.41mmol)。室温搅拌反应3h。反应液倒入冰水(20mL)中，CH 2Cl 2(2×20mL)萃取，合并萃取液，饱和盐水洗(2×50mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，将得到的残留物通过硅胶色谱法(0至50％梯度的乙酸乙酯：石油醚)纯化得淡黄色固体2-丙烯酸酰胺基-4-((3,3,3-三氟丙基)氨基)苯甲酸甲酯(13-4,32mg，收率：36％)。
1H NMR(400MHz,CDCl 3):δppm 11.58(s,1H),8.28(d,J＝2.8Hz,1H),7.92(d,J＝9.2Hz,1H),6.44-6.29(m,3H),5.79(dd,J＝10.0,1.6Hz,1H),3.87(s,3H),3.71(t,J＝7.2Hz,2H),3.08(s,3H),2.50-2.38(m,2H).
19F NMR(376MHz,CDCl 3):δppm-65.13.
步骤五：0℃，Ar保护下向3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-胺(A,36mg，0.15mmol)的二甲苯(2mL)体系中滴加AlMe 3(2M in THF，0.3mL)。0℃搅拌60min。滴加2-丙烯酸酰胺基-4-((3,3,3-三氟丙基)氨基)苯甲酸甲酯(13-4，32mg，0.10mmol)的二甲苯(2mL)溶液。反应加热到110℃搅拌3h。反应液倒入冰水(30mL)中，EtOAc(2×20mL)萃取，合并萃取液，饱和盐水洗(2×50mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，将得到的残留物Prep-HPLC纯化得白色固体2-丙烯酰胺基-N-(3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-基)-4-(甲基(3,3,3-三氟丙基)氨基)苯甲酰胺甲酸盐(化合物13,10.31mg，收率：20％)。
1H NMR(400MHz,MeOD-d4):δppm 8.12(d,J＝2.0Hz,1H),7.78(d,J＝8.8Hz,1H),6.56(dd,J＝8.8,2.4Hz,1H),6.37-6.30(m,7H),5.84-5.80(m,1H),3.76-3.74(m,8H),3.07(s,3H),2.95-2.89(m,4H),2.55-2.49(m,2H).
19F NMR(376MHz,MeOD-d4):δppm-66.64.
LCMS:m/z 546.2[M+H] +.
实施例14：化合物14的合成
2-丙烯酰胺基-N-(3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-基)-4-(4-(2,2,3,3,3-五氟丙基)哌嗪-1-基)苯甲酰胺
Figure PCTCN2020112173-appb-000044
步骤一：0℃下向4-(4-(甲氧基羰基)-3-硝基苯基)哌嗪-1-甲酸叔丁酯(B2，4.6g，12.59mmol)的二氯甲烷(40mL)溶液中滴加TFA(20mL)。逐渐升至25℃反应1h。TLC监测反应完全。反应液减压浓缩至干，残留物加乙酸乙酯(200mL)溶解，饱和NaHCO 3(3×300mL)洗，饱和盐水(300mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩，粗品用石油醚：乙酸乙酯＝10:1打浆得黄色固体2-硝基-4-(哌嗪-1-基)苯甲酸甲酯(14-1，3.0g，收率：91％)。
LCMS:m/z 266.4[M+H] +.
步骤二：Ar保护下向2-硝基-4-(哌嗪-1-基)苯甲酸甲酯(14-1，1.7g，6.41mmol)和三乙胺(8mL)的二氯甲烷(30mL)溶液中加入2,2,3,3,3-五氟丙酸酐(2.4g，7.69mmol)。Ar保护下室温搅拌反应20h。TLC监测基本反应完全。向反应液中加二氯甲烷(150mL)稀释，饱和盐水(2×150mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩，经硅胶色谱法(石油醚：乙酸乙酯＝10:1-5:1)纯化得黄色固体2-硝基-4-(4-(2-(2,2,3,3,3-五氟丙酰基)哌嗪-1-基)苯甲酸甲酯(14-2，2.4g，收率：92％)。
LCMS:m/z 412.4[M+H] +.
步骤三：0℃，Ar保护下向2-硝基-4-(4-(2-(2,2,3,3,3-五氟丙酰基)哌嗪-1-基)苯甲酸甲酯(14-2，1.6g，3.89mmol)的THF(30mL)溶液中滴加BH 3·Me 2S(10M in THF， 1.95mL，19.45mmol)。室温搅拌5min后升温至70℃中反应3.5h。TLC监测反应完全。反应液降温至0℃后缓慢滴加MeOH(15mL)淬灭。搅拌10min后浓缩除去溶剂大部分溶剂，加二氯甲烷(150mL)稀释，水洗(3×100mL)、饱和盐水洗(150mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，经硅胶色谱法(石油醚：乙酸乙酯＝10:1)纯化得黄色固体2-硝基-4-(4-(2-(2,2,3,3,3-五氟丙基)哌嗪-1-基)苯甲酸甲酯(14-3，1.17g，收率：76％)。
LCMS:m/z 398.1[M+H] +.
步骤四：向2-硝基-4-(4-(2-(2,2,3,3,3-五氟丙基)哌嗪-1-基)苯甲酸甲酯(14-3，1.17g，2.94mmol)的MeOH(50mL)溶液中加入Pd/C(10％，200mg)。H 2环境下40℃反应6h。TLC监测反应完全。反应液过滤，滤液减压浓缩，粗品经硅胶色谱法纯化(石油醚：乙酸乙酯＝10:1～5:1)得淡黄色固体2-氨基-4-(4-(2-(2,2,3,3,3-五氟丙基)哌嗪-1-基)苯甲酸甲酯(14-4，1.0g，收率：92％)。
LCMS:m/z 368.4[M+H] +.
步骤五：0℃，Ar保护下向2-氨基-4-(4-(2-(2,2,3,3,3-五氟丙基)哌嗪-1-基)苯甲酸甲酯(14-4，1.0g，2.72mmol)和三乙胺(2.2g，21.78mmol)的二氯甲烷(15mL)溶液中滴加丙烯酰氯(740mg，8.17mmol)的二氯甲烷(5mL)溶液。30℃搅拌反应2h，TLC监测反应完全。反应液倒入冰水(100mL)中，二氯甲烷萃取(2×50mL)，合并有机相，饱和盐水洗(2×50mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，经硅胶色谱法(二氯甲烷：甲醇＝100:1-50:1)纯化得淡黄色固体2-丙烯酰胺基-4-(4-(4-(2,2,3,3,3-五氟丙基)哌嗪-1-基)苯甲酸甲酯(14-5，550mg，收率：48％)。
LCMS:m/z 422.4[M+H] +.
步骤六：0℃，Ar保护下向3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-胺(A，65mg，0.26mmol)的二甲苯(5mL)悬浊液中滴加AlMe 3(2M，THF溶液，0.36mL，0.71mmol)。0℃下搅拌30min后再加入2-丙烯酰胺基-4-(4-(4-(2,2,3,3,3-五氟丙基)哌嗪-1-基)苯甲酸甲酯(14-5，100mg，0.24mmol)的二甲苯(2mL)溶液。室温搅拌30min后加热至100℃反应4h。LC-MS和TLC监测反应完全。反应液冷却至室温后倒入冰水(50mL)中，加乙酸乙酯(3×30mL)萃取，合并有机相，水洗(2×50mL)，饱和盐水洗(2×50mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，经硅胶色谱法(二氯甲烷：甲醇＝40:1)纯化得110mg黄色固体。所得固体再经Prep-HPLC纯化得白色固体2-丙烯酰胺基-N-(3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-基)-4-(4-(2,2,3,3,3-五氟丙基)哌嗪-1-基)苯甲酰胺(化合物14，20mg，收率：13％)。
1H NMR(400MHz,DMSO-d6)δppm 12.22(s,1H),12.02(s,1H),10.59(s,1H),8.22(s, 1H),7.92(d,J＝9.2Hz,1H),6.72(d,J＝9.2Hz,1H),6.42-6.22(m,6H),5.84(d,J＝10.6Hz,1H),3.72(s,6H),3.36-3.29(m,6H),2.88(s,4H),2.76(s,4H).
19F NMR(376MHz,DMSO-d6):δppm-82.82,-117.79.
LCMS:m/z 637.6[M+H] +.
实施例15：化合物15的合成
3-丙烯酰胺基-N-(3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-基)-5-(4-(3,3,3-三氟丙基)哌嗪-1-基)吡啶啉酰胺
Figure PCTCN2020112173-appb-000045
步骤一：向3-氨基-5-溴吡啶甲酸(15-1，9.0g，41.47mmol)的DMA(150mL)溶液中加入碳酸钾(11.2g，82.94mmol)和碘甲烷(8.8g，82.94mmol)。Ar保护下于25℃搅拌反应12h。TLC监测反应完全。反应液加乙酸乙酯(400mL)稀释，水(3×500mL)洗，饱和盐水(2×400mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩，经硅胶色谱法(石油醚：乙酸乙酯＝10:1-3:1)纯化得淡黄色固体3-氨基-5-溴吡啶甲酸甲酯(15-2，8.9g，收率：93％)。
LCMS:m/z 231.3[M+H] +.
步骤二：向3-氨基-5-溴吡啶甲酸甲酯(15-2，1.2g，5.19mmol)的乙腈(30mL)溶液中加入DMAP(1.27g，10.39mmol)和二碳酸二叔丁酯(2.27g，10.39mmol)。Ar环境下逐渐升温至60℃搅拌反应0.5h。TLC监测反应完全。反应液冷却至室温。加乙酸乙酯(200mL)稀释，水洗(3×150mL)，饱和盐水(2×150mL)洗，无水硫酸钠干燥浓缩，经柱层析分离纯化(石油醚：乙酸乙酯＝10:1)得类白色固体5-溴-3-(二(叔丁氧羰基)氨基)吡啶甲酸甲酯(15-3，1.6g，收率：71％)。
LCMS:m/z 433.3[M+H] +.
步骤三：向5-溴-3-(二(叔丁氧羰基)氨基)吡啶甲酸甲酯(15-3，1.25g，2.90mmol)， 1-(3,3,3-三氟丙基)哌嗪(中间体E,634mg，3.48mmol)，Xantphos(670mg，1.16mmol)，Cs 2CO 3(4.72g，14.49mmol)的1,4-二氧六环(30mL)溶液中加入Pd 2(dba) 3(530mg，0.58mmol)。Ar环境下100℃搅拌反应3.5h。TLC监测反应完全。反应液冷却至室温，加乙酸乙酯(300mL)稀释，水洗(3×150mL)，饱和盐水(2×150mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩浓缩，经硅胶色谱发(二氯甲烷：甲醇＝50:1)纯化得棕黄色固体3-(二(叔丁氧羰基)氨基)-5-(4-(3,3,3-三氟丙基)哌嗪-1-基)吡啶甲酸甲酯(15-4，1.3g，收率：84％)。
LCMS:m/z 533.5[M+H] +.
步骤四：将3-(二(叔丁氧羰基)氨基)-5-(4-(3,3,3-三氟丙基)哌嗪-1-基)吡啶甲酸甲酯(15-4，1.3g，2.44mmol)溶于TFA(15mL)中。室温搅拌反应2h。TLC监测反应完全。反应液倒入冰的饱和NaHCO 3(50mL)溶液中。乙酸乙酯(3×50mL)萃取，合并有机相，饱和NaHCO 3(50mL)洗，饱和盐水(100mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩，经硅胶色谱法(二氯甲烷：甲醇＝70:1～40:1)纯化得淡黄色固体3-氨基-5-(4-(3,3,3-三氟丙基)哌嗪-1-基)吡啶甲酸甲酯(15-5，710mg，收率：87％)。
LCMS:m/z 333.5[M+H] +.
步骤五：0℃，Ar保护下向3-氨基-5-(4-(3,3,3-三氟丙基)哌嗪-1-基)吡啶甲酸甲酯(15-5，710mg，2.14mmol)和三乙胺(1.8g，17.09mmol)的二氯甲烷(10mL)溶液中滴加丙烯酰氯(580mg，6.41mmol)的二氯甲烷(5mL)溶液。加毕，自然升至室温反应1.5h。TLC监测反应完全。反应液倒入冰水(50mL)中，二氯甲烷(3×40mL)萃取，合并有机相，饱和盐水洗(2×50mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，经硅胶色谱法纯化(二氯甲烷：甲醇＝50:1)得淡黄色固体3-丙烯酰胺基-5-(4-(4-(3,3,3-三氟丙基)哌嗪-1-基)吡啶甲酸甲酯(15-6，580mg，收率：70％)。
LCMS:m/z 387.0[M+H] +.
步骤六：0℃，Ar保护下向3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-胺(A，218mg，0.883mmol)的二甲苯(8mL)悬浊液中滴加AlMe 3(1.2mL，2M in THF，2.407mmol)。0℃搅拌反应30min后再加入3-丙烯酰胺基-5-(4-(4-(3,3,3-三氟丙基)哌嗪-1-基)吡啶甲酸甲酯(15-6，310mg，0.802mmol)的二甲苯(7mL)溶液。加毕，自然升至室温搅拌30min，再升温至100℃反应4h。LC-MS和TLC监测反应完全。冷却至室温后将反应液倒入冰水(50mL)中，加乙酸乙酯(50mL)，搅拌5min，滤去絮状物，分液，水相用乙酸乙酯萃取(2×25mL)，合并有机相，水洗(2×50mL)，饱和盐水洗(2×50mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，经硅胶色谱法(二氯甲烷：甲醇＝50:1)纯化得170mg黄色固体。所得固体再经Prep-HPLC纯化得白色固体3-丙烯酰胺基-N-(3-(3,5-二甲氧 基苯乙基)-1H-吡唑-5-基)-5-(4-(3,3,3-三氟丙基)哌嗪-1-基)吡啶啉酰胺(化合物15，45mg，收率：9％)。
1H NMR(400MHz,DMSO-d6)δppm 12.29(s,1H),12.13(s,1H),10.23(s,1H),8.55(s,1H),8.17(s,1H),6.48-6.27(m,6H),5.91(d,J＝10.0Hz,1H),3.71(s,6H),3.77-3.33(m,4H),2.88(s,4H),2.58-2.50(m,8H).
19F NMR(376MHz,DMSO-d6)δppm-63.55.
LCMS:m/z 602.7[M+H] +.
实施例16：化合物16的合成
2-丙烯酰胺基-N-(3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-基)-6-氟-4-(4-(3,3,3-三氟丙基)哌嗪-1-基)苯甲酰胺
Figure PCTCN2020112173-appb-000046
步骤一：向4,6-二氟吲哚-2,3-二酮(16-1，2.0g，10.92mmol)的乙腈(40mL)溶液中加入哌嗪-1-羧酸叔丁酯(2.0g，10.92mmol)和三乙胺(2mL)。氩气环境下室温反应16h。TLC显示基本反应完全。过滤，滤饼乙酸乙酯淋洗得黄色固体4-(4-氟-2,3-二氧吲哚-6-基)哌嗪-1-羧酸叔丁酯(16-2，850mg，收率：22％)。
1H NMR(400MHz,DMSO-d6)δppm 6.34(dd,J＝9.6Hz,1.6Hz,1H),6.08(d,J＝1.6 Hz,1H),3.56～3.54(m,4H),3.47～3.46(m,4H),1.40(s,9H).
19F NMR(376MHz,DMSO-d6)δppm 108.62.
LCMS:m/z 350.0[M+H] +.
步骤二：将4-(4-氟-2,3-二氧吲哚-6-基)哌嗪-1-羧酸叔丁酯(16-2，500mg，1.43mmol)溶于氢氧化钠(687mg，17.17mmol)的水(15mL)溶液中。升温至70℃，缓慢滴加双氧水(30％，406mg，3.58mmol)。加毕，继续反应1h。TLC显示基本反应完全。加乙酸乙酯(20mL)和少许冰块，用aq.2N盐酸调pH＝4。分液，水相乙酸乙酯萃取(2×20mL)，合并有机相，饱和盐水(40mL)洗，无水硫酸钠干燥，过滤浓缩得黄色固体2-氨基-4-(4-(叔丁氧基羰基)哌嗪-1-基)-6-氟苯甲酸(16-3，480mg，收率：98％)。
LCMS:m/z 284.1(M+H-56) +.
步骤三：0℃，氩气保护下向2-氨基-4-(4-(叔丁氧基羰基)哌嗪-1-基)-6-氟苯甲酸(16-3，400mg，77％，1.18mmol)，三苯基磷(340mg，1.30mmol)和甲醇(1mL)的二氯甲烷(10mL)溶液中滴加偶氮二甲酸二乙酯(226mg,1.30mmol)，。加毕继续反应1h。TLC监测反应完全。反应液加二氯甲烷(50mL)稀释后用饱和盐水(2×50mL)洗，无水硫酸钠干燥，浓缩，经柱层析纯化(石油醚：乙酸乙酯＝5：1)得类白色固体4-(3-氨基-5-氟-4-(甲氧羰基)苯基)哌嗪-1-羧酸叔丁酯(16-4，140mg，收率33％)。
步骤四：向4-(3-氨基-5-氟-4-(甲氧羰基)苯基)哌嗪-1-羧酸叔丁酯(16-4，140mg，0.40mmol)的二氯甲烷(10mL)溶液中滴加三氟乙酸(2mL)。室温搅拌反应2h。TLC监测反应完全。反应液加二氯甲烷(20mL)稀释后用饱和碳酸氢钠溶液(2×30mL)洗，无水硫酸钠干燥浓缩得淡黄色固体2-氨基-6-氟-4-(哌嗪-1-基)苯甲酸甲酯(16-5，136mg)。粗品直接用于下一步。
LCMS:m/z 254.5[M+H] +.
步骤五：将2-氨基-6-氟-4-(哌嗪-1-基)苯甲酸甲酯(16-5，136mg，0.40mmol)，1,1,1-三氟-3-碘丙烷(445mg，1.98mmol)以及三乙胺(200mg，1.98mmol)溶于DMF(10mL)溶液中。氮气保护，95℃反应5h。反应液用乙酸乙酯(50mL)稀释，水(2×40mL)洗，饱和盐水(2×40mL)洗，无水硫酸钠干燥，浓缩，经柱层析纯化(石油醚:乙酸乙酯＝3:1)得淡黄色固体2-氨基-6-氟-4-(4-(3,3,3-三氟丙基)哌嗪-1-基)苯甲酸甲酯(16-6，94mg，两步收率：68％)。
LCMS:m/z 350.4[M+H] +.
步骤六：氩气保护下向2-氨基-6-氟-4-(4-(3,3,3-三氟丙基)哌嗪-1-基)苯甲酸甲酯(16-6，94mg，0.27mmol)和三乙胺(218mg，2.15mmol)溶于二氯甲烷(9mL)溶液中滴加丙烯酰氯(73mg，0.81mmol)的二氯甲烷(1mL)溶液。30℃反应2.5h。TLC监测反 应完全。反应液倒入冰水(20mL)中，二氯甲烷(3×30mL)萃取，合并有机相，饱和盐水(40mL)洗，无水硫酸钠干燥，浓缩，经柱层析纯化(二氯甲烷:乙酸乙酯＝5:1)得黄色固体2-丙烯酸酰胺基-6-氟-4-(4-(3,3,3-三氟丙基)哌嗪-1-基)苯甲酸甲酯(16-7，100mg，收率：92％)。
1H NMR(400Hz,CDCl 3):ppm 11.54(s,1H),8.29(d,J＝1.6Hz,1H),6.44～6.23(m,3H),5.80(dd,J＝10.0Hz,1.2Hz,1H),3.91(s,3H),3.41～3.39(m,4H),2.67～2.56(m,6H),2.36(m,2H).
19F NMR(376Hz,CDCl 3):ppm 65.29,101.98.
LCMS:m/z 404.4[M+H] +.
步骤七：0℃，氩气保护下向3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-胺(16-7，67mg，0.27mmol)的二甲苯(4mL)体系中滴加三甲基铝(2M in THF,0.37mL,0.74mmol)。0℃搅拌20min后滴加2-丙烯酸酰胺基-6-氟-4-(4-(3,3,3-三氟丙基)哌嗪-1-基)苯甲酸甲酯(16-7，100mg，0.25mmol)的二甲苯(4mL)溶液。加毕，逐渐升温至100℃反应4h。TLC监测反应完全。反应液加入二氯甲烷和甲醇(v/v＝10/1，50mL)的混合溶剂稀释，冰水(3×30mL)洗，饱和盐水(30mL)洗，无水硫酸钠干燥，浓缩，经柱层析纯化(二氯甲烷:甲醇＝50:1)得浅黄色固体(78mg)。所得固体再经过Prep-HPLC纯化得类白色固体(18mg,TFA盐)。氨水游离后再用C18纯化得白色固体2-丙烯酰胺基-N-(3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-基)-6-氟-4-(4-(3,3,3-三氟丙基)哌嗪-1-基)苯甲酰胺(化合物16，8.1mg,收率：5％)。
1H NMR(400Hz,DMSO-d6):ppm 12.14(brs,1H),10.54(m,2H),7.69(s,1H),6.63-6.61(m,1H),6.41-6.19(m,6H),5.79(d,J＝10.0Hz,1H),3.71(s,6H),3.25(brs,4H),2.85(s,4H),2.56-2.54(m,8H).
19F NMR(376Hz,DMSO-d6):ppm 63.55,109.29.
LCMS:m/z 619.7[M+H] +.
对照化合物a的合成
2-丙烯酰胺基-N-(3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-基)苯甲酰胺
Figure PCTCN2020112173-appb-000047
参考公开的合成方法，得到对照化合物a。
步骤一：0℃，Ar保护下向2-氨基苯甲酸甲酯(a-1，1.0g，6.6mmol)和三乙胺(2.0g，19.8mmol)溶于二氯甲烷(20mL)中滴加的丙烯酰氯(778mg，8.6mmol)的二氯甲烷(5mL)溶液。缓慢升温到室温反应3h。LCMS显示反应完全。反应液加二氯甲烷(50mL)稀释，用饱和碳酸氢钠和饱和氯化钠洗涤，干燥，过滤，减压浓缩至干，通过硅胶色谱法(石油醚：乙酸乙酯＝20：1)得2-丙烯酰氨基苯甲酸甲酯(a-2，940mg，收率：69.3％)。
LCMS:m/z 206.2[M+H] +.
步骤二：0℃，Ar保护下向2-丙烯酰氨基苯甲酸甲酯(a-2，130mg，0.53mmol)的二甲苯(15mL)悬浊液中滴加三甲基铝(0.75mL，1.5mmol)。0℃下反应1h。将3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-胺(A，103mg，0.53mmol)加入到反应液中，升温到110℃，反应4h。LCMS显示反应完全。反应液用冰水淬灭。乙酸乙酯(3×50mL)萃取，合并有机相，用饱和氯化钠洗，干燥，过滤，减压浓缩至干，通过硅胶色谱法(二氯甲烷：甲醇＝10：1)和prep-HPLC得2-丙烯酰胺基-N-(3-(3,5-二甲氧基苯乙基)-1H-吡唑-5-基)苯甲酰胺(化合物a，48mg，收率：22.7％)。
1H NMR(400MHz,DMSO-d6)δ11.11(s,1H),9.75(s,1H),9.46(brs,1H),8.69(d,J＝8.4Hz,1H),7.59(d,J＝7.6Hz,1H),7.50-7.46(m,1H),7.07-7.03(m,1H),6.68(s,1H),6.46-6.41(m,1H),6.35(s,3H),6.32-6.28(m,1H),5.80-5.77(m,1H),3.78(s,6H),2.97-2.90(m,4H).
LCMS:m/z 421.0[M+H] +.
FGFR不可逆抑制剂与FGFR形成共价键的质谱确认
以化合物1为例，与FGFR1孵育，用质谱检测蛋白与化合物复合物的分子量。
操作步骤：纯化的FGFR1(456-763)激酶结构域蛋白，用20mM Tris-HCL pH8.0，150mM Nacl的蛋白缓冲液稀释蛋白至终浓度约为20μM(800ng/μl)。采用100ul的孵育体系，按照蛋白与化合物摩尔比1：5的比例，在实验组中加入终浓度为100μM的化合物1；对照组中加入DMSO，两组中控制DMSO的量为体系体积的1％。将实验组和对照组同时在冰上孵育2小时，随后用4倍体积丙酮在-20稀释过夜，16000×g离心10min后，沉淀用0.1％的甲酸重悬上样，进行质谱数据的采集。
Figure PCTCN2020112173-appb-000048
Figure PCTCN2020112173-appb-000049
以上数据表明，FGFR1蛋白的平均分子量为35747.8；化合物1与FGFR1形成复合物的分子量为36345.5，分子量增加了598，这与化合物1的分子量(600)非常相近，在测量误差范围之内。该实验表明，化合物1与FGFR1蛋白形成了不可逆共价结合。
FGFR抑制剂的酶学活性测试-Caliper模型
化合物对FGFR酶活的抑制是通过Caliper技术来检测的。模型中所采用试剂如下：FGFR4(Invitrogen,Cat.No PR4380A,Lot.No.1856505A)；FGFR1(Carna,Cat.No 08-133,Lot.No.12CBS-0123K)；P22peptide(GL Biochem,Cat.No.112393,Lot.No.P170622-SL112393)；ATP(Sigma,Cat.No.A7699-1G,CAS No.987-65-5)；96-well plate(Corning,Cat.No.3365,Lot.No.22008026)；384-well plate(Corning,Cat.No.3573,Lot.No.12608008)。具体操作如下：
1.准备1X激酶缓冲液(20mM HEPES,pH 7.5,0.0015％Brij-35)和反应终止缓冲液(100mM HEPES，pH 7.5,0.015％Brij-35,0.2％Coating Reagent#3,50mM EDTA)
2.化合物首先被系列稀释在5％的DMSO溶液中，在384孔板中加入5μL化合物溶液，化合物最高终浓度为1μM，三倍稀释，10个浓度。
3.在384孔板中加入10μL激酶溶液，室温孵育10分钟。
4.在384孔板中加入10μL P22多肽和ATP溶液，在28℃反应特定时间后，加入25μL反应终止缓冲液。
5.用Caliper读值采集数据，并计算抑制率：抑制率＝(max-conversion)/(max-min)*100。其中max是DMSO参照，conversion是化合物处理读值，min是最大抑制参照。采用XLfit excel add-in version 5.4.0.8软件计算化合物IC 50值
部分实施例和对照物(AZD4547)对FGFR1，FGFR2,FGFR3，FGFR4体外实验抑制试验结果如下表所示：
化合物编号 FGFR1(nM) FGFR2(nM) FGFR3(nM) FGFR4(nM)
AZD4547 1.2 2.5 1.8 165
对照物a 4.5 2.2 1.7 1.5
化合物1 1.9 1.8 3.3 1.2
化合物2 3.3 3.7 2.8 3.3
化合物3 3.6 5.3 4.6 5.7
化合物5 2.7 2.7 2.4 2.5
化合物6 2.4 2.3 1.7 2.0
化合物7 2.1 3.4 2.3 3.2
化合物8 2.7 2.8 2.3 2.7
化合物9 3.1 4.4 4.4 3.6
化合物10 5.7 6.1 7.4 4.4
化合物12 2.7 4.1 3.0 3.9
化合物13 3.4 4.9 3.1 3.8
化合物14 6.1 5.9 5.8 5.9
化合物15 4.8 4.5 3.9 4.4
以上结果显示，AZD4547对于FGFR4的抑制活性很差，本系列化合物对于FGFR4的抑制活性非常强。
人肝癌细胞Hep3B存活试验
人肝癌Hep3B细胞株来源于ATCC。细胞用DMEM液体培养基培养，另外加入胎牛血清(10％FBS)、青霉素-链霉素(100,000U/L)。细胞在培养基中保持37℃、95％的湿度和5％的二氧化碳。实验时将Hep3B细胞以每孔3000个细胞的密度铺种于96孔板中，细胞悬液体积为每孔100μL，并培养细胞过夜，使细胞附着。次日，将各化合物以三倍梯度用DMSO稀释，将1μL化合物DMSO溶液加入细胞培养基中，同时以1μL DMSO作为对照，每个化合物的各浓度均设三个平行副孔。之后将细胞置于37℃培养箱，经连续72小时化合物处理后，向细胞培养基中添加50μL CellTiter-Glo(Promega,Madison WI)，并确定各孔的相对发光单位(RLU)并计算细胞存活率和化合物活性(IC50)。
实施例Hep3B细胞抑制活性结果如下表所示：
化合物编号 Hep3B(nM) 化合物编号 Hep3B(nM)
AZD4547 263 对照化合物a 5
化合物1 1.4 化合物9 2
化合物2 0.8 化合物10 3
化合物3 3 化合物12 0.5
化合物5 9 化合物13 12
化合物6 3 化合物14 7
化合物7 6 化合物15 12
化合物8 8 化合物16 0.3
化合物药代动力学实验
本发明化合物对药代动力学测定。本申请采用以下方法测定本申请的化合物药代动力学参数。
研究使用的健康雄性成年小鼠，每组动物单次灌胃给药5-100mg/Kg。禁食从给药前10小时至给药后4小时。给药后不同时间点后采血，并测定化合物血浆含量(LC-MS/MS)。血浆浓度----时间关系用专业软件分析(winnonlin)，计算化合物的药代动力学参数。结果显示，相对于对照化合物a，本发明化合物在口服药物峰浓度或者口服暴药量得到了显著提高。
Figure PCTCN2020112173-appb-000050
Hep3B移植瘤模型
本发明化合物在小鼠移植瘤上展示出了优秀的抑瘤活性。
细胞培养：人肝癌Hep3B细胞体外单层培养，培养条件为1640培养基中加10％胎牛血清，100U/mL青霉素和100μg/mL链霉素，37℃ 5％CO 2孵箱培养。一周两次用胰酶-EDTA进行常规消化处理传代。当细胞饱和度为80％-90％，数量到达要求时，收取细胞，计数，接种。
动物：Balb/c nude小鼠，雌性，6-8周龄，体重18-22克。由上海斯莱克实验动物有限公司或其它合格供应商提供。
肿瘤接种：将0.2mL(10×10 6个+Matrixgel)Hep3B细胞皮下接种于每只小鼠的右后背，肿瘤平均体积达到约140～200mm 3时开始分组给药。
给药：配置化合物处方(0.5％MC+0.5％Tween 80)，给药剂量为0.3mg/Kg、1mg/Kg、 2mg/Kg、3mg/Kg，灌胃给药每天两次，连续21天。
实验指标：考察肿瘤生长是否被抑制、延缓或治愈。每周三次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为：V＝0.5a×b2，a和b分别表示肿瘤的长径和短径。化合物的抑瘤疗效用TGI(％)评价。TGI(％)反映肿瘤生长抑制率。TGI(％)的计算：TGI(％)＝[(1-(某处理组给药结束时平均瘤体积－该处理组开始给药时平均瘤体积))/(溶媒对照组治疗结束时平均瘤体积－溶剂对照组开始治疗时平均瘤体积)]×100％。本发明化合物的抑瘤活性TGI如下表所示：
Figure PCTCN2020112173-appb-000051
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (17)

  1. 一种式I所示的化合物、或其药学上可接受的盐、或其溶剂化物、同位素取代物、前药或代谢产物：
    Figure PCTCN2020112173-appb-100001
    其中，
    Figure PCTCN2020112173-appb-100002
    表示双键或三键；
    R 6选自H或无，且当
    Figure PCTCN2020112173-appb-100003
    表示双键时，R 6为H，当
    Figure PCTCN2020112173-appb-100004
    为三键时，R 6为无；
    X、Y、Z分别独立的选自C或N；
    R 1的个数为1-3个，且独立地选自H、卤素，-OH，-CN，-NO 2，
    -CO 2R 1-1基团，
    -CONR 1-2OR 1-3基团，
    -NR 1-4COR 1-5基团，
    -NR 1-6CO 2R 1-7基团，
    -NR 1-8R 1-9基团，
    -SO 2R 1-10基团，
    -SO 2NR 1-11R 1-12基团，
    -NR 1-13SO 2R 1-14基团，
    C1-C8烷基基团，C3-C8环烷基基团，C2-C8链烯基基团，3-8元杂环基基团，C1-C6烷氧基基团，5-10元芳环基基团，5-10元杂芳环基团，或者两个相邻的R 1基团与和它们连接的原子一起形成3-8元碳环基团或杂环基团，或者两个相邻的R 1基团与和它们连接的原子一起形成5-10元芳环基团或杂芳环基团，所述的杂环基团或杂芳环基团包含1-4个选自下组的杂原子：N、O或S；且上述的基团可任选被一个或多个选自以下的取代基所取代：-D、卤素、-OH、-CN、-NO 2、取代或未取代的C1-C6烷氧基、取代或未取代的C3-C8环烷基、取代或未取代的C1-C6烷基硫基、-N(取代或未取代的C1-C6烷基) 2、-NH(取代或未取代的C1-C6烷基)、取代或未取代的C1-C8烷氧基-C1-C8烷基、取代或未取代的 C3-C8环烷基-C1-C8烷基、取代或未取代的C1-C6烷基羰基、取代或未取代的C1-C6烷氧基羰基、异羟肟酸基、-S(O) 2N(取代或未取代的C1-C6烷基) 2、-S(O) 2(取代或未取代的C1-C6烷基)、-N(取代或未取代的C1-C6烷基)S(O) 2N(取代或未取代的C1-C6烷基) 2、-S(O)N(取代或未取代C1-C6烷基) 2、-S(O)(取代或未取代的C1-C6烷基)、-N(取代或未取代的C1-C6烷基)S(O)N(取代或未取代的C1-C6烷基) 2、-N(取代或未取代的C1-C6烷基)S(O)(取代或未取代的C1-C6烷基)、取代或未取代的5-10元芳基、取代或未取代的5-10元杂芳基、取代或未取代的3-8元杂环基，取代或未取代的3-8元碳环基，其中，所述杂环基或杂芳基包含1-4个选自下组的杂原子：N、O或S，且所述取代基可任选被一个或多个选自以下的取代基取代：卤素、-OH、-CN、未取代或卤代的C1-C6烷基、未取代或卤代的C1-C6烷氧基、未取代或卤代的C3-C6环烷基、未取代或卤代的C1-C6烷基硫基、氨基(-NH 2)、-N(未取代或卤代的C1-C6烷基) 2、-NH(未取代或卤代的C1-C6烷基)和-CO 2(未取代或卤代的C1-C6烷基)；
    R 2选自卤素，
    -CO 2R 2-1基团，
    -CONR 2-2OR 2-3基团，
    -NR 2-4COR 2-5基团，
    -NR 2-6CO 2R 2-7基团，
    -NR 2-8R 2-9基团，
    -SO 2R 2-10基团，
    -SO 2NR 2-11R 2-12基团，
    -NR 2-13SO 2R 2-14基团，
    C1-C8烷基基团，C2-C8链烯基基团，C1-C6烷氧基基团，3-8元碳环基基团，3-8元杂环基基团，5-10元芳环基基团，5-10元杂芳环基团；且上述的基团可任选被一个或多个选自以下的取代基所取代：卤素、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C3-C8环烷基、C1-C6烷基硫基、-N(C1-C6烷基) 2、-NH(C1-C6烷基)、C1-C8烷氧基-C1-C8烷基、C3-C8环烷基-C1-C8烷基、C1-C6烷基羰基、C1-C6烷氧基羰基、-S(O) 2N(C1-C6烷基) 2、-S(O) 2(C1-C6烷基)、-N(C1-C6烷基)S(O) 2N(C1-C6烷基) 2、-S(O)N(C1-C6烷基) 2、-S(O)(C1-C6烷基)、-N(C1-C6烷基)S(O)N(C1-C6烷基) 2、-N(C1-C6烷基)S(O)(C1-C6烷基)、5-10元芳基、5-10元杂芳基、3-8元杂环基和3-8元碳环基，其中，所述杂环基或杂芳基包含1-4个选自下组的杂原子：N、O或S，且所述取代基可任选被一个或多个选自以下的取代基取代：卤素、卤代C1-C6烷基、卤代C1-C6烷氧基、卤代C3-C8环烷基、卤代C1-C6烷基硫基、(卤代C1-C6烷基)NH-、(卤代C1-C6烷基) 2N-、-CO 2(卤代C1-C6 烷基)；
    R 3选自H，
    -CO 2R 3-1基团，
    -CONR 3-20R 3-3基团，
    -NR 3-4COR 3-5基团，
    -NR 3-6CO 2R 3-7基团，
    -NR 3-8R 3-9基团，
    -SO 2R 3-10基团，
    -SO 2NR 3-11R 3-12基团，
    -NR 3-13SO 2R 3-14基团，
    C1-C8烷基基团，C3-C8环烷基基团，C2-C8链烯基基团，3-8元杂环基基团，C1-C6烷氧基基团，5-10元芳环基基团，5-10元杂芳环基团，所述的杂环基团或杂芳环基团包含1-4个选自下组的杂原子：N、O或S；且上述的基团可任选被一个或多个选自以下的取代基所取代：-D、卤素、-OH、-CN、-NO 2、取代或未取代的C1-C6烷氧基、取代或未取代的C3-C8环烷基、取代或未取代的C1-C6烷基硫基、-N(取代或未取代的C1-C6烷基) 2、-NH(取代或未取代的C1-C6烷基)、取代或未取代的C1-C8烷氧基-C1-C8烷基、取代或未取代的C3-C8环烷基-C1-C8烷基、取代或未取代的C1-C6烷基羰基、取代或未取代的C1-C6烷氧基羰基、异羟肟酸基、-S(O) 2N(取代或未取代的C1-C6烷基) 2、-S(O) 2(取代或未取代的C1-C6烷基)、-N(取代或未取代的C1-C6烷基)S(O) 2N(取代或未取代的C1-C6烷基) 2、-S(O)N(取代或未取代C1-C6烷基) 2、-S(O)(取代或未取代的C1-C6烷基)、-N(取代或未取代的C1-C6烷基)S(O)N(取代或未取代的C1-C6烷基) 2、-N(取代或未取代的C1-C6烷基)S(O)(取代或未取代的C1-C6烷基)、取代或未取代的5-10元芳基、取代或未取代的5-10元杂芳基、取代或未取代的3-8元杂环基，取代或未取代的3-8元碳环基，其中，所述杂环基或杂芳基包含1-4个选自下组的杂原子：N、O或S，且所述取代基可任选被一个或多个选自以下的取代基取代：卤素、-OH、-CN、未取代或卤代的C1-C6烷基、未取代或卤代的C1-C6烷氧基、未取代或卤代的C3-C6环烷基、未取代或卤代的C1-C6烷基硫基、氨基(-NH 2)、-N(未取代或卤代的C1-C6烷基) 2、-NH(未取代或卤代的C1-C6烷基)、-CO 2(未取代或卤代的C1-C6烷基)；
    R 5选自H、C1-C6烷基基团，C1-C6烷氧基基团；上述的基团可任选被一个或多个选自以下的取代基所取代：-D、卤素、-OH、-CN、-NO 2、取代或未取代的C1-C6烷氧基、取代或未取代的C3-C8环烷基、取代或未取代的C1-C6烷基硫基、-N(取代或未取代的C1-C6烷基) 2、-NH(取代或未取代的C1-C6烷基)、取代或未取代的C1-C8烷氧基-C1-C8 烷基、取代或未取代的C3-C8环烷基-C1-C8烷基、取代或未取代的C1-C6烷基羰基、取代或未取代的C1-C6烷氧基羰基、异羟肟酸基、-S(O) 2N(取代或未取代的C1-C6烷基) 2、-S(O) 2(取代或未取代的C1-C6烷基)、-N(取代或未取代的C1-C6烷基)S(O) 2N(取代或未取代的C1-C6烷基) 2、-S(O)N(取代或未取代C1-C6烷基) 2、-S(O)(取代或未取代的C1-C6烷基)、-N(取代或未取代的C1-C6烷基)S(O)N(取代或未取代的C1-C6烷基) 2、-N(取代或未取代的C1-C6烷基)S(O)(取代或未取代的C1-C6烷基)、取代或未取代的5-10元芳基、取代或未取代的5-10元杂芳基、取代或未取代的3-8元杂环基，取代或未取代的3-8元碳环基，其中，所述杂环基或杂芳基包含1-4个选自下组的杂原子：N、O或S，且所述取代基可任选被一个或多个选自以下的取代基取代：卤素、-OH、-CN、未取代或卤代的C1-C6烷基、未取代或卤代的C1-C6烷氧基、氨基(-NH 2)、-N(未取代或卤代的C1-C6烷基) 2、-NH(未取代或卤代的C1-C6烷基)、-CO 2(未取代或卤代的C1-C6烷基)；
    R 1-1代表H、未取代或卤代的C1-C6烷基、或未取代或卤代的C3-C6环烷基；
    R 1-2和R 1-3各自独立代表H、未取代或卤代的C1-C6烷基、未取代或卤代的C3-C6环烷基，或R 1-2和R 1-3与它们连接的氮原子一起形成未取代或卤代的4-6元饱和杂环；
    R 1-4和R 1-5各自独立代表H、未取代或卤代的C1-C6烷基、未取代或卤代的C3-C6环烷基，或R 1-4和R 1-5与它们连接的氮原子一起形成未取代或卤代的4-6元饱和杂环；
    R 1-6和R 1-7各自独立代表H、未取代或卤代的C1-C6烷基、未取代或卤代的C3-C6环烷基，或R 1-6和R 1-7和与它们连接的氮原子一起形成未取代或卤代的4至6-元饱和杂环；
    R 1-8和R 1-9各自独立代表H、未取代或卤代的C1-C6烷基、未取代或卤代的C3-C6环烷基，或R 1-8和R 1-9和与它们连接的氮原子一起形成未取代或卤代的4-6元饱和杂环；
    R 1-10代表H、未取代或卤代的C1-C6烷基、未取代或卤代的C3-C6环烷基；
    R 1-11和R 1-12各自独立代表H、C1-C6烷基、或C3-C6环烷基，或R 1-11和R 1-12和与它们连接的氮原子一起形成4-6元饱和杂环，且所述基团可任选被一个或多个选自以下的取代基取代：卤素、未取代或卤代的C1-C6烷基、未取代或卤代的C1-C6烷氧基、未取代或卤代的C1-C6烷基硫基、-NH 2、(未取代或卤代的C1-C4烷基) 2N-、(未取代或卤代的C1-C4烷基)NH-、-OH；
    R 1-13和R 1-14各自独立代表C1-C6烷基、C1-C6环烷基，或R 1-13和R 1-14和与它们连接的氮原子一起形成4-6元饱和杂环，且所述基团可任选被一个或多个选自以下的取代基取代：卤素、未取代或卤代的C1-C6烷基、未取代或卤代的C1-C6烷氧基、未取代或卤代的C1-C6烷基硫基、-NH 2、(未取代或卤代的C1-C4烷基) 2N-、(未取代或卤代的C1-C4烷基)NH-、-OH；
    R 2-1代表卤代的C1-C6烷基或卤代的C3-C6环烷基；
    R 2-2和R 2-3分别独立代表卤代C1-C6烷基，卤代的C3-C6环烷基，或R 2-2和R 2-3与它们连接的氮原子一起形成卤代的4-6元饱和杂环；
    R 2-4和R 2-5分别独立代表卤代C1-C6烷基，卤代的C3-C6环烷基，或R 2-4和R 2-5与它们连接的氮原子一起形成卤代的4-6元饱和杂环；
    R 2-6和R 2-7分别独立代表卤代C1-C6烷基，卤代的C3-C6环烷基，或R 2-6和R 2-7与它们连接的氮原子一起形成卤代的4-6元饱和杂环；
    R 2-8和R 2-9分别独立代表C1-C6烷基、卤代C1-C6烷基或卤代的C3-C6环烷基，或R 2-8和R 2-9与它们连接的氮原子一起形成卤代的4-6元饱和杂环，或R 2-8和R 2-9与它们连接的氮原子一起形成卤代的5-10元不饱和杂芳环，或R 2-8和R 2-9与它们连接的氮原子一起形成卤代的5-10元杂芳环；
    R 2-10代表卤代的C1-C6烷基或卤代的C3-C6环烷基；
    R 2-11和R 2-12分别独立代表卤代C1-C6烷基，卤代的C3-C6环烷基，或R 2-8和R 2-9与它们连接的氮原子一起形成卤代的4-6元饱和杂环；
    R 2-13和R 2-14分别独立代表卤代C1-C6烷基，卤代的C3-C6环烷基，或R 2-8和R 2-9与它们连接的氮原子一起形成卤代的4-6元饱和杂环；
    -CO 2R 3-1基团，
    -CONR 3-20R 3-3基团，
    -NR 3-4COR 3-5基团，
    -NR 3-6CO 2R 3-7基团，
    -NR 3-8R 3-9基团，
    -SO 2R 3-10基团，
    -SO 2NR 3-11R 3-12基团，
    -NR 3-13SO 2R 3-14基团，
    R 3-1代表H、未取代或卤代的C1-C6烷基、或未取代或卤代的C3-C6环烷基；
    R 3-2和R 3-3各自独立代表H、未取代或卤代的C1-C6烷基、未取代或卤代的C3-C6环烷基，或R 3-2和R 3-3与它们连接的氮原子一起形成未取代或卤代的4-6元饱和杂环；
    R 3-4和R 3-5各自独立代表H、未取代或卤代的C1-C6烷基、未取代或卤代的C3-C6环烷基，或R 3-4和R 3-5与它们连接的氮原子一起形成未取代或卤代的4-6元饱和杂环；
    R 3-6和R 3-7各自独立代表H、未取代或卤代的C1-C6烷基、未取代或卤代的C3-C6环烷基，或R 3-6和R 3-7和与它们连接的氮原子一起形成未取代或卤代的4至6-元饱和杂环；
    R 3-8和R 3-9各自独立代表H、未取代或卤代的C1-C6烷基、未取代或卤代的C3-C6环烷基，或R 3-8和R 3-9和与它们连接的氮原子一起形成未取代或卤代的4-6元饱和杂环；
    R 3-10代表H、未取代或卤代的C1-C6烷基、未取代或卤代的C3-C6环烷基；
    R 3-11和R 3-12各自独立代表H、C1-C6烷基、或C3-C6环烷基，或R 3-11和R 3-12和与它们连接的氮原子一起形成4-6元饱和杂环，且所述基团可任选被一个或多个选自以下的取代基取代：卤素、未取代或卤代的C1-C6烷基、未取代或卤代的C1-C6烷氧基、未取代或卤代的C1-C6烷基硫基、-NH 2、(未取代或卤代的C1-C4烷基) 2N-、(未取代或卤代的C1-C4烷基)NH-、-OH；
    R 3-13和R 3-14各自独立代表C1-C6烷基、C1-C6环烷基，或R 3-13和R 3-14和与它们连接的氮原子一起形成4-6元饱和杂环，且所述基团可任选被一个或多个选自以下的取代基取代：卤素、未取代或卤代的C1-C6烷基、未取代或卤代的C1-C6烷氧基、未取代或卤代的C1-C6烷基硫基、-NH 2、(未取代或卤代的C1-C4烷基) 2N-、(未取代或卤代的C1-C4烷基)NH-、-OH。
  2. 如权利要求1所述的化合物、或其药学上可接受的盐、或其溶剂化物、同位素取代物、前药或代谢产物，其特征在于，R 3选自：5-10元芳环基基团和5-10元杂芳环基团，所述的杂芳环基团包含1-4个选自下组的杂原子：N、O或S；且上述的基团可任选被一个或多个选自以下的取代基所取代：-D、卤素、-OH、-CN、-NO 2、卤代或未取代的C1-C6烷氧基、卤代或未取代的C3-C8环烷基、卤代或未取代的C1-C6烷基硫基、-N(卤代或未取代的C1-C6烷基) 2、-NH(卤代或未取代的C1-C6烷基)、卤代或未取代的C1-C8烷氧基-C1-C8烷基、卤代或未取代的C3-C8环烷基-C1-C8烷基、卤代或未取代的C1-C6烷基羰基、卤代或未取代的C1-C6烷氧基羰基、异羟肟酸基、-S(O) 2N(卤代或未取代的C1-C6烷基) 2、-S(O) 2(卤代或未取代的C1-C6烷基)、-N(卤代或未取代的C1-C6烷基)S(O) 2N(卤代或未取代的C1-C6烷基) 2、-S(O)N(卤代或未取代C1-C6烷基) 2、-S(O)(卤代或未取代的C1-C6烷基)、-N(卤代或未取代的C1-C6烷基)S(O)N(卤代或未取代的C1-C6烷基) 2、-N(卤代或未取代的C1-C6烷基)S(O)(卤代或未取代的C1-C6烷基)、卤代或未取代的5-10元芳基、卤代或未取代的5-10元杂芳基、卤代或未取代的3-8元杂环基，卤代或未取代的3-8元碳环基，其中，所述杂环基或杂芳基包含1-4个选自下组的杂原子：N、O或S；
    优选地，R 3选自：5-10元芳环基基团和5-10元杂芳环基团，所述的杂芳环基团包含1-4个选自下组的杂原子：N、O或S；且上述的基团可任选被一个或多个选自以下的取代基所取代：-D、卤素、-OH、卤代或未取代的C1-C6烷氧基、卤代或未取代的C3-C8环烷基、卤代或未取代的C1-C8烷氧基-C1-C8烷基、卤代或未取代的C3-C8环烷基-C1-C8烷基、卤代或未取代的C1-C6烷基羰基、卤代或未取代的C1-C6烷氧基羰基。
  3. 如权利要求2所述的化合物、或其药学上可接受的盐、或其溶剂化物、同位素取代物、前药或代谢产物，其特征在于，具有如下式II所示的结构：
    Figure PCTCN2020112173-appb-100005
    其中，R 4为1-5个，且各自独立表示H、卤素，-OH，-CN，-NO 2，
    -CO 2R 4-1基团，
    -CONR 4-20R 4-3基团，
    -NR 4-4COR 4-5基团，
    -NR 4-6CO 2R 4-7基团，
    -NR 4-8R 4-9基团，
    -SO 2R 4-10基团，
    -SO 2NR 4-11R 4-12基团，
    -NR 4-13SO 2R 4-14基团，
    C1-C8烷基基团，C3-C8环烷基基团，C2-C8链烯基基团，3-8元杂环基基团，C1-C6烷氧基基团，5-10元芳环基基团，5-10元杂芳环基团，或者两个相邻的R 4基团与和它们连接的原子一起形成3-8元碳环基团或杂环基团，或者两个相邻的R 4基团与和它们连接的原子一起形成5-10元芳环基团或杂芳环基团，所述的杂环基团或杂芳环基团包含1-4个选自下组的杂原子：N、O或S；且上述的基团可任选被一个或多个选自以下的取代基所取代：-D、卤素、-OH、-CN、-NO 2、取代或未取代的C1-C6烷氧基、取代或未取代的C3-C8环烷基、取代或未取代的C1-C6烷基硫基、-N(取代或未取代的C1-C6烷基) 2、-NH(取代或未取代的C1-C6烷基)、取代或未取代的C1-C8烷氧基-C1-C8烷基、取代或未取代的C3-C8环烷基-C1-C8烷基、取代或未取代的C1-C6烷基羰基、取代或未取代的C1-C6烷氧基羰基、异羟肟酸基、-S(O) 2N(取代或未取代的C1-C6烷基) 2、-S(O) 2(取代或未取代的C1-C6烷基)、-N(取代或未取代的C1-C6烷基)S(O) 2N(取代或未取代的C1-C6烷基) 2、-S(O)N(取代或未取代C1-C6烷基) 2、-S(O)(取代或未取代的C1-C6烷基)、-N(取代或未取代的C1-C6烷基)S(O)N(取代或未取代的C1-C6烷基) 2、-N(取代或未取代的C1-C6烷 基)S(O)(取代或未取代的C1-C6烷基)、取代或未取代的5-10元芳基、取代或未取代的5-10元杂芳基、取代或未取代的3-8元杂环基，取代或未取代的3-8元碳环基，其中，所述杂环基或杂芳基包含1-4个选自下组的杂原子：N、O或S，且所述取代基可任选被一个或多个选自以下的取代基取代：卤素、-OH、-CN、未取代或卤代的C1-C6烷基、未取代或卤代的C1-C6烷氧基、未取代或卤代的C3-C6环烷基、未取代或卤代的C1-C6烷基硫基、氨基(-NH 2)、-N(未取代或卤代的C1-C6烷基) 2、-NH(未取代或卤代的C1-C6烷基)、-CO 2(未取代或卤代的C1-C6烷基)；
    R 4-1代表H、未取代或卤代的C1-C6烷基、或未取代或卤代的C3-C6环烷基；
    R 4-2和R 4-3各自独立代表H、未取代或卤代的C1-C6烷基、未取代或卤代的C3-C6环烷基，或R 4-2和R 4-3与它们连接的氮原子一起形成未取代或卤代的4-6元饱和杂环；
    R 4-4和R 4-5各自独立代表H、未取代或卤代的C1-C6烷基、未取代或卤代的C3-C6环烷基，或R 4-4和R 4-5与它们连接的氮原子一起形成未取代或卤代的4-6元饱和杂环；
    R 4-6和R 4-7各自独立代表H、未取代或卤代的C1-C6烷基、未取代或卤代的C3-C6环烷基，或R 4-6和R 4-7和与它们连接的氮原子一起形成未取代或卤代的4至6-元饱和杂环；
    R 4-8和R 4-9各自独立代表H、未取代或卤代的C1-C6烷基、未取代或卤代的C3-C6环烷基，或R 4-8和R 4-9和与它们连接的氮原子一起形成未取代或卤代的4-6元饱和杂环；
    R 4-10代表H、未取代或卤代的C1-C6烷基、未取代或卤代的C3-C6环烷基；
    R 4-11和R 4-12各自独立代表H、C1-C6烷基、或C3-C6环烷基，或R 4-11和R 4-12和与它们连接的氮原子一起形成4-6元饱和杂环，且所述基团可任选被一个或多个选自以下的取代基取代：卤素、未取代或卤代的C1-C6烷基、未取代或卤代的C1-C6烷氧基、未取代或卤代的C1-C6烷基硫基、-NH 2、(未取代或卤代的C1-C4烷基) 2N-、(未取代或卤代的C1-C4烷基)NH-、-OH；
    R 4-13和R 4-14各自独立代表C1-C6烷基、C1-C6环烷基，或R 4-13和R 4-14和与它们连接的氮原子一起形成4-6元饱和杂环，且所述基团可任选被一个或多个选自以下的取代基取代：卤素、未取代或卤代的C1-C6烷基、未取代或卤代的C1-C6烷氧基、未取代或卤代的C1-C6烷基硫基、-NH 2、(未取代或卤代的C1-C4烷基) 2N-、(未取代或卤代的C1-C4烷基)NH-、-OH；
    Figure PCTCN2020112173-appb-100006
    X、Y、X、R 1、R 2、R 5和R 6的定义如权利要求1所述。
  4. 如权利要求1-3任一项所述的化合物、或其药学上可接受的盐、或其溶剂化物、同位素取代物、前药或代谢产物，其特征在于，R 1选自下组：H、Cl、F、Br、-OH、-CN、C1-C4烷基、C1-C4烷基羟基、-(C1-C3烷基)N(C1-C3烷基) 2、-(C1-C3烷基)NH 2、C1-C3 烷氧基、-O-(C1-C3烷基)-OH、-O(C1-C3烷基)O(C1-C3烷基)、-N(C1-C3烷基) 2、-NHPh、-NH(C1-C3烷基)、-NH(C1-C3烷基)N(C1-C3烷基) 2、-CONH 2、-NHCO(C1-C3烷基)、-NHCOH、-NHCOPh、-CO 2H、-CO 2(C1-C3烷基)、-SO 2(C1-C3烷基)、-NHSO 2(C1-C3烷基)、-SO 2N(C1-C3烷基) 2；优选地，R 1选自H、Cl、F、Br、C1-C4烷基和C1-C3烷氧基。
  5. 如权利要求1-3任一项所述的化合物、或其药学上可接受的盐、或其溶剂化物、同位素取代物、前药或代谢产物，其特征在于，R 2选自下组：卤素、卤代C1-C4烷基、卤代C1-C4烷基羟基、-(卤代C1-C3烷基)N(C1-C3烷基) 2、-(卤代C1-C3烷基)NH(C1-C3烷基)、-(C1-C3烷基)N(卤代C1-C3烷基) 2、-(C1-C3烷基)NH(卤代C1-C3烷基)、-(卤代C1-C3烷基)NH 2、卤代C1-C3烷氧基、-O-(卤代C1-C3烷基)-OH、-O(卤代C1-C3烷基)O(C1-C3烷基)、-O(C1-C3烷基)O(卤代C1-C3烷基)、-N(C1-C3烷基)(卤代C1-C3烷基)、-N(卤代C1-C3烷基) 2、-NH(卤代C1-C3烷基)、卤代苯基氨基、-NH(卤代C1-C3烷基)N(C1-C3烷基) 2、-NH(C1-C3烷基)N(卤代C1-C3烷基) 2、-NH(C1-C3烷基)NH(卤代C1-C3烷基)、-NH(卤代C1-C3烷基)NH(C1-C3烷基)、-NHCO(卤代C1-C3烷基)、卤代苯酰胺、-CO 2(卤代C1-C3烷基)、-SO 2(卤代C1-C3烷基)、-NHSO 2(卤代C1-C3烷基)、-SO 2N(卤代C1-C3烷基) 2、3-7元碳环基基团、3-7元杂环基基团、5-6元芳环基基团和5-6元杂芳环基团，所述的杂环基团或杂芳环基团包含1-4个选自下组的杂原子：N、O或S；且上述的环基基团可任选被一个或多个选自以下的取代基所取代：卤素、卤代C1-C4烷基、卤代C1-C4烷氧基、卤代C3-C8环烷基、卤代C1-C4烷基硫基、-N(卤代C1-C6烷基) 2、-NH(卤代C1-C6烷基)、卤代C1-C3烷基-O-C1-C3烷基、C1-C3烷基-O-卤代C1-C3烷基、卤代C3-C6环烷基-C1-C4烷基、C3-C6环烷基-卤代C1-C4烷基、卤代C1-C4烷基羰基、卤代C1-C4烷氧基羰基、-S(O) 2N(卤代C1-C4烷基) 2、-S(O) 2(卤代C1-C4烷基)、-N(卤代C1-C4烷基)S(O) 2N(C1-C6烷基) 2、-N(C1-C4烷基)S(O) 2N(卤代C1-C4烷基) 2、-S(O)N(卤代C1-C4烷基) 2、-S(O)(卤代C1-C4烷基)、-N(卤代C1-C4烷基)S(O)N(C1-C4烷基) 2、-N(C1-C4烷基)S(O)N(卤代C1-C4烷基) 2、-N(卤代C1-C4烷基)S(O)(C1-C6烷基)、-N(C1-C4烷基)S(O)(卤代C1-C6烷基)、卤代5-6元芳基、卤代5-6元杂芳基、卤代3-7元杂环基，卤代3-7元碳环基，其中，所述杂环基或杂芳基包含1-4个选自下组的杂原子：N、O或S；
    优选地，R 2选自-NR 2-8R 2-9基团，其中，R 2-8和R 2-9各自独立为H、C1-C6烷基和卤代C1-C6烷基，且R 2-8和R 2-9中至少一个为卤代C1-C6烷基；和C1-C8烷基基团，C2-C8链烯基基团，C1-C6烷氧基基团，3-8元碳环基基团，3-8元杂环基基团，5-10元芳环基基团和5-10元杂芳环基团，其中，这些基团至少被卤素和/或C1-C6卤代烷基取代，可任选地进一步被一个或多个选自以下的取代基所取代：C1-C6烷基、C1-C6烷氧基、C3-C8 环烷基、-N(C1-C6烷基) 2、-NH(C1-C6烷基)、C1-C8烷氧基-C1-C8烷基、C3-C8环烷基-C1-C8烷基、C1-C6烷基羰基、C1-C6烷氧基羰基、5-10元芳基、5-10元杂芳基、3-8元杂环基和3-8元碳环基，其中，所述杂环基或杂芳基包含1-4个选自下组的杂原子：N、O或S。
  6. 如权利要求1-3任一项所述的化合物、或其药学上可接受的盐、或其溶剂化物、同位素取代物、前药或代谢产物，其特征在于，R 5选自下组：H、C1-C6烷基基团，C1-C6烷氧基基团；上述的基团可任选被一个或多个选自以下的取代基所取代：-D、卤素、-OH、-CN、-NO 2、取代或未取代的C1-C6烷氧基、取代或未取代的C3-C8环烷基、-N(取代或未取代的C1-C6烷基) 2、-NH(取代或未取代的C1-C6烷基)、取代或未取代的5-10元芳基、取代或未取代的5-10元杂芳基、取代或未取代的3-8元杂环基，取代或未取代的3-8元碳环基，其中，所述杂环基或杂芳基包含1-4个选自下组的杂原子：N、O或S，且所述取代基可任选被一个或多个选自以下的取代基取代：卤素、-OH、-CN、未取代或卤代的C1-C6烷基、未取代或卤代的C1-C6烷氧基、氨基(-NH 2)、-N(未取代或卤代的C1-C6烷基) 2、-NH(未取代或卤代的C1-C6烷基)；
    优选地，R 5选自：H、C1-C6烷基基团和C1-C6烷氧基基团；所述基团C1-C6烷基基团和C1-C6烷氧基基团各自任选被一个或多个选自以下的取代基所取代：-D、卤素、-OH、取代或未取代的C1-C6烷氧基、取代或未取代的C3-C8环烷基、-N(取代或未取代的C1-C6烷基) 2、-NH(取代或未取代的C1-C6烷基)。
  7. 如权利要求1所述的化合物、或其药学上可接受的盐、或其溶剂化物、同位素取代物、前药或代谢产物，其特征在于，
    R 1选自H、卤素、C1-C4烷基和C1-C3烷氧基，优选为H、卤素或C1-C3烷氧基，更优选为H；
    R 2选自：-NR 2-8R 2-9基团，其中，R 2-8和R 2-9各自独立为H、C1-C6烷基和卤代C1-C6烷基，且R 2-8和R 2-9中至少一个为卤代C1-C6烷基；和C1-C8烷基基团，C2-C8链烯基基团，C1-C6烷氧基基团，3-8元碳环基基团，3-8元杂环基基团，5-10元芳环基基团和5-10元杂芳环基团，其中，这些基团至少被卤素和/或C1-C6卤代烷基取代，可任选地进一步被一个或多个选自以下的取代基所取代：C1-C6烷基、C1-C6烷氧基、C3-C8环烷基、-N(C1-C6烷基) 2、-NH(C1-C6烷基)、C1-C8烷氧基-C1-C8烷基、C3-C8环烷基-C1-C8烷基、C1-C6烷基羰基、C1-C6烷氧基羰基、5-10元芳基、5-10元杂芳基、3-8元杂环基和3-8元碳环基，其中，所述杂环基或杂芳基包含1-4个选自下组的杂原子：N、O或S；
    R 3选自：5-10元芳环基基团和5-10元杂芳环基团，所述的杂芳环基团包含1-4个选自下组的杂原子：N、O或S；且上述的基团可任选被一个或多个选自以下的取代基所取 代：-D、卤素、-OH、卤代或未取代的C1-C6烷氧基、卤代或未取代的C3-C8环烷基、卤代或未取代的C1-C8烷氧基-C1-C8烷基、卤代或未取代的C3-C8环烷基-C1-C8烷基、卤代或未取代的C1-C6烷基羰基、卤代或未取代的C1-C6烷氧基羰基；
    Figure PCTCN2020112173-appb-100007
    表示双键；
    R 5选自：H、C1-C6烷基基团和C1-C6烷氧基基团；所述基团C1-C6烷基基团和C1-C6烷氧基基团各自任选被一个或多个选自以下的取代基所取代：-D、卤素、-OH、取代或未取代的C1-C6烷氧基、取代或未取代的C3-C8环烷基、-N(取代或未取代的C1-C6烷基) 2、-NH(取代或未取代的C1-C6烷基)；
    R 6为H。
  8. 如权利要求3所述的化合物、或其药学上可接受的盐、或其溶剂化物、同位素取代物、前药或代谢产物，其特征在于，
    R 1选自H、卤素、C1-C4烷基和C1-C3烷氧基，优选为H、卤素或C1-C3烷氧基，更优选为H；
    R 2选自：-NR 2-8R 2-9基团，其中，R 2-8和R 2-9各自独立为H、C1-C6烷基和卤代C1-C6烷基，且R 2-8和R 2-9中至少一个为卤代C1-C6烷基；和C1-C8烷基基团，C2-C8链烯基基团，C1-C6烷氧基基团，3-8元碳环基基团，3-8元杂环基基团，5-10元芳环基基团和5-10元杂芳环基团，其中，这些基团至少被卤素和/或C1-C6卤代烷基取代，可任选地进一步被一个或多个选自以下的取代基所取代：C1-C6烷基、C1-C6烷氧基、C3-C8环烷基、-N(C1-C6烷基) 2、-NH(C1-C6烷基)、C1-C8烷氧基-C1-C8烷基、C3-C8环烷基-C1-C8烷基、C1-C6烷基羰基、C1-C6烷氧基羰基、5-10元芳基、5-10元杂芳基、3-8元杂环基和3-8元碳环基，其中，所述杂环基或杂芳基包含1-4个选自下组的杂原子：N、O或S；
    R 4选自：C1-C8烷基基团，C2-C8链烯基基团，C1-C6烷氧基基团；其中，这些基团任选被一个或多个选自以下的取代基所取代：-D、卤素、-OH和取代或未取代的C1-C6烷氧基；
    Figure PCTCN2020112173-appb-100008
    表示双键；
    R 5选自：H、C1-C6烷基基团和C1-C6烷氧基基团；所述基团C1-C6烷基基团和C1-C6烷氧基基团各自任选被一个或多个选自以下的取代基所取代：-D、卤素、-OH、取代或未取代的C1-C6烷氧基、取代或未取代的C3-C8环烷基、-N(取代或未取代的C1-C6烷基) 2、-NH(取代或未取代的C1-C6烷基)；
    R 6为H。
  9. 如权利要求1-6中任一项所述的化合物、或其药学上可接受的盐、或其溶剂化物、同位素取代物、前药或代谢产物，其特征在于，R 2选自下组：卤代C1-C3烷基、卤代C1-C3 烷氧基、-N(卤代C1-C3烷基)(C1-C3烷基)、-(卤代C1-C3烷基)N(C1-C3烷基) 2、-(卤代C1-C3烷基)NH(C1-C3烷基)、-(C1-C3烷基)N(卤代C1-C3烷基) 2、-(C1-C3烷基)NH(卤代C1-C3烷基)、-(卤代C1-C3烷基)NH 2、-O-(卤代C1-C3烷基)-OH、-O(卤代C1-C3烷基)O(C1-C3烷基)、-O(C1-C3烷基)O(卤代C1-C3烷基)、-N(卤代C1-C3烷基) 2、-NH(卤代C1-C3烷基)、-NH(卤代C1-C3烷基)N(C1-C3烷基) 2、-NH(C1-C3烷基)N(卤代C1-C3烷基) 2、-NH(C1-C3烷基)NH(卤代C1-C3烷基)、-NH(卤代C1-C3烷基)NH(C1-C3烷基)、-NHCO(卤代C1-C3烷基)、-CO 2(卤代C1-C3烷基)、-SO 2(卤代C1-C3烷基)、-NHSO 2(卤代C1-C3烷基)、-SO 2N(卤代C1-C3烷基) 2、
    Figure PCTCN2020112173-appb-100009
    其中，这些环基被至少一个选自以下的基团的取代基取代：卤素、C1-C4烷基和卤代C1-4烷基，且取代基中至少一个是卤素或卤代C1-C4烷基。
  10. 如权利要求1或3所述的化合物、或其药学上可接受的盐、或其溶剂化物、同位素取代物、前药或代谢产物，其特征在于，
    X选自C或N；
    Y为C；
    Z为C；
    R 1选自H、卤素、C1-C4烷基和C1-C3烷氧基，优选为H、卤素或C1-C3烷氧基，更优选为H；
    R 2选自下组：卤代C1-C3烷基、卤代C1-C3烷氧基、-N(卤代C1-C3烷基)(C1-C3烷基)、-(卤代C1-C3烷基)N(C1-C3烷基) 2、-(卤代C1-C3烷基)NH(C1-C3烷基)、-(C1-C3烷基)N(卤代C1-C3烷基) 2、-(C1-C3烷基)NH(卤代C1-C3烷基)、-(卤代C1-C3烷基)NH 2、-N(卤代C1-C3烷基) 2、-NH(卤代C1-C3烷基)、-NH(卤代C1-C3烷基)N(C1-C3烷基) 2、-NH(C1-C3烷基)N(卤代C1-C3烷基) 2、-NH(C1-C3烷基)NH(卤代C1-C3烷基)、-NH(卤代C1-C3烷基)NH(C1-C3烷基)、和
    Figure PCTCN2020112173-appb-100010
    其中，这些环基被至少一个选自以下的基团的取代基取代：卤素、C1-C4烷基和卤代C1-4烷基，且取代基中至少一个是卤素或卤代C1-C4烷基；
    R 3为任选被一个或多个选自卤代或未取代的C1-C6烷氧基取代的5-10元芳环基；或R 4为卤代或未取代的C1-C6烷氧基；
    Figure PCTCN2020112173-appb-100011
    表示双键；
    R 5选自：H、C1-C3烷基基团和C1-C3烷氧基基团；
    R 6为H。
  11. 如权利要求1所述的化合物、或其药学上可接受的盐、或其溶剂化物、同位素取代物、前药或代谢产物，其特征在于，
    X选自C或N；
    Y为C；
    Z为C；
    R 1选自H、卤素、C1-C4烷基和C1-C3烷氧基，优选为H、卤素或C1-C3烷氧基，更优选为H；
    R 2选自卤代C1-C6烷基、卤代C1-C6烷氧基、-N(卤代C1-C3烷基)(C1-C3烷基)、-NH(卤代C1-C3烷基)、-N(卤代C1-C3烷基) 2、-(C1-C3烷基)N(卤代C1-C3烷基) 2、-(C1-C3烷基)NH(卤代C1-C3烷基)、卤代3-8元杂环基和卤代C1-C6烷基取代的3-8元杂环基，其中，所述杂环基任选地被1或2个选自除所述卤素和卤代C1-C6烷基以外的C1-C6烷基和C1-C6烷氧基的取代基进一步地取代；优选地，所述杂环基为含1或2个氮的杂环基，更优选地，所述杂环基选自哌嗪基、哌啶基、吡咯烷基和氮杂环丁烷基；
    R 3为任选被一个或多个选自卤代或未取代的C1-C6烷氧基的取代基取代的5-10元芳环基，优选为被一个或多个选自卤代或未取代的C1-C6烷氧基的取代基取代的苯基；
    Figure PCTCN2020112173-appb-100012
    表示双键；
    R 5为H或C1-C3烷基；和
    R 6为H。
  12. 如权利要求1所述的化合物、或其药学上可接受的盐、或其溶剂化物、同位素取代物、前药或代谢产物，其特征在于，所述化合物选自以下：
    Figure PCTCN2020112173-appb-100013
    Figure PCTCN2020112173-appb-100014
    Figure PCTCN2020112173-appb-100015
  13. 一种药物组合物，其特征在于，所述的药物组合物包括：
    (i)作为活性成分的如权利要求1-12所述的有效量的式I化合物，或其药学上可接受的盐、或其溶剂化物、同位素取代物、前药或代谢产物；和
    (ii)药学上可接受的载体。
  14. 如权利要求13所述的药物组合物，其特征在于，所述的药物组合物用于治疗或预防与FGFR的活性或表达量相关的疾病，优选地，所述的疾病选自下组：膀胱癌、肝癌、脑癌、乳腺癌、结肠癌、肾癌、肺癌、卵巢癌、胰腺癌、***癌、胃癌、子***、结肠癌、甲状腺癌、皮肤癌、胆管癌、急性淋巴细胞白血病、B-细胞淋巴瘤、Burketts淋巴瘤、急性髓性白血病、慢性髓性白血病、早幼粒细胞白血病、纤维肉瘤、横纹肌瘤、黑色素瘤、***瘤、畸胎瘤、成神经细胞瘤、神经胶状瘤。
  15. 权利要求1-12中任一项所述的化合物，或其药学上可接受的盐、或其溶剂化物、同位素取代物、前药、代谢产物，或它们混合物的用途，其特征在于，用于：
    (1)制备治疗或预防与FGFR激酶活性或表达量相关的疾病的药物组合物；
    (2)制备FGFR激酶抑制剂。
  16. 如权利要求15所述的用途，其特征在于，所述的FGFR激酶选自下组：FGFR1、FGFR2、FGFR3，和FGFR4。
  17. 如权利要求15所述的用途，其特征在于，所述的疾病选自下组：膀胱癌、肝癌、脑癌、乳腺癌、结肠癌、肾癌、肺癌、卵巢癌、胰腺癌、***癌、胃癌、子***、结肠癌、甲状腺癌、皮肤癌、胆管癌、急性淋巴细胞白血病、B-细胞淋巴瘤、Burketts淋巴瘤、急性髓性白血病、慢性髓性白血病、早幼粒细胞白血病、纤维肉瘤、横纹肌瘤、黑色素瘤、***瘤、畸胎瘤、成神经细胞瘤、神经胶状瘤。
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