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 PDFInfo
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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
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- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 1
- 229960005026 toremifene Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000005740 tumor formation Effects 0.000 description 1
- 230000001875 tumorinhibitory effect Effects 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 229940075466 undecylenate Drugs 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N urethane group Chemical group NC(=O)OCC JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- UHTHHESEBZOYNR-UHFFFAOYSA-N vandetanib Chemical compound COC1=CC(C(/N=CN2)=N/C=3C(=CC(Br)=CC=3)F)=C2C=C1OCC1CCN(C)CC1 UHTHHESEBZOYNR-UHFFFAOYSA-N 0.000 description 1
- 229950000578 vatalanib Drugs 0.000 description 1
- YCOYDOIWSSHVCK-UHFFFAOYSA-N vatalanib Chemical compound C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 YCOYDOIWSSHVCK-UHFFFAOYSA-N 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- 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 or sparfloxacin
-
- 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
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Abstract
Description
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 |
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 |
Claims (17)
- 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:其中,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。
- 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。
- 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: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;
- 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。
- 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。
- 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)。
- 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;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。
- 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;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。
- 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、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。
- 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;R 5选自:H、C1-C3烷基基团和C1-C3烷氧基基团;R 6为H。
- 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;R 5为H或C1-C3烷基;和R 6为H。
- 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。
- 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、前列腺癌、胃癌、子宫颈癌、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、精原细胞瘤、畸胎瘤、成神经细胞瘤、神经胶状瘤。
- 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。
- 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。
- 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、前列腺癌、胃癌、子宫颈癌、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、精原细胞瘤、畸胎瘤、成神经细胞瘤、神经胶状瘤。
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CA3152674A CA3152674A1 (en) | 2019-08-31 | 2020-08-28 | Pyrazole derivatives for fgfr inhibitor and preparation method thereof |
US17/638,352 US20220298143A1 (en) | 2019-08-31 | 2020-08-28 | Pyrazole Derivatives for FGFR Inhibitor and Preparation Method Thereof |
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