WO2018113584A1 - Fgfr4抑制剂、其制备方法与药学上的应用 - Google Patents

Fgfr4抑制剂、其制备方法与药学上的应用 Download PDF

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Publication number
WO2018113584A1
WO2018113584A1 PCT/CN2017/116186 CN2017116186W WO2018113584A1 WO 2018113584 A1 WO2018113584 A1 WO 2018113584A1 CN 2017116186 W CN2017116186 W CN 2017116186W WO 2018113584 A1 WO2018113584 A1 WO 2018113584A1
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Prior art keywords
group
alkyl
hydrazine
cycloalkyl
halogen
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PCT/CN2017/116186
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English (en)
French (fr)
Inventor
杨飞
邓海兵
应海燕
喻红平
陈椎
徐耀昌
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Abbisko Therapeutics Co Ltd
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Abbisko Therapeutics Co Ltd
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Priority to DK17883905.6T priority Critical patent/DK3524603T3/da
Priority to EP17883905.6A priority patent/EP3524603B1/en
Priority to JP2019525831A priority patent/JP6919922B2/ja
Priority to CN201780051138.6A priority patent/CN109661394B/zh
Priority to ES17883905T priority patent/ES2926124T3/es
Priority to AU2017378943A priority patent/AU2017378943B2/en
Priority to US16/348,957 priority patent/US10968220B2/en
Priority to CA3042960A priority patent/CA3042960C/en
Application filed by Abbisko Therapeutics Co Ltd filed Critical Abbisko Therapeutics Co Ltd
Priority to RU2019122913A priority patent/RU2747260C2/ru
Priority to KR1020197013213A priority patent/KR102288281B1/ko
Publication of WO2018113584A1 publication Critical patent/WO2018113584A1/zh
Priority to PH12019501029A priority patent/PH12019501029A1/en
Anticipated expiration legal-status Critical
Priority to US17/139,552 priority patent/US11555036B2/en
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
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    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
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    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of drug synthesis, and in particular relates to a FGFR4 inhibitor, a preparation method thereof and a pharmaceutical application.
  • Fibroblast growth factor is a family of 22 structurally related polypeptides with diverse biological activities that regulate cell proliferation, differentiation, migration, and in limb development, angiogenesis, tissue repair, and tumor formation. It plays a major role in the process (Eswarakumar et al., 2005 Cytokine Growth Factor Rev 16: 139-149; Ornitz and Itoh, 2001 Genome Bio 12: Reviews 3005).
  • the corresponding receptor for FGF belongs to a family of RPTKs of receptor tyrosine kinases.
  • Four receptors for FGFR1, FGFR2, FGFR3 and FGFR4 have been discovered (Ullrich and Schlessinger, 1990 Cell 61: 203). Their interaction with the corresponding ligand FGF leads to receptor dimerization and autophosphorylation, which initiates multiple signaling cascades downstream including MAPK and AKT (Powers et al., 2000 Endocr Relat Cancer 7: 165- 197).
  • FGFR1-3 has been found to be overexpressed, mutated, translocated, and considered to be in a variety of tumors including myeloma, breast, gastric, colon, bladder, mesenteric, and hepatocellular carcinomas.
  • Genes driving cancer (Chesi et al., 2001 Blood 97: 729-726; Gowardhan et al., 2005 Br J Cancer 92: 320-327; Jaakkola et al., 1993 Int J Cancer 54: 378-282; Jang et al., 2001 Cancer Res 61:3541-3543), there have also been some FGFR inhibitors in the clinical and preclinical development process.
  • FGFR1 can regulate the level of intracellular phosphorylation, so pan-FGFR inhibitors pose safety concerns.
  • Hepatocellular carcinoma is one of the leading causes of cancer-related deaths in China and one of the fastest growing cancers per year (Shariff et al., 2009 Expert Rev Gastroenterol Hepato 13: 353-367).
  • the current first-line treatment option is sorafenni, and there are no approved second-line drugs, and there is still a need for targeted drugs with anti-tumor agents.
  • FGFR4 is a dominant FGFR present in human hepatocytes, and its high expression in hepatocytes is thought to be associated with the aggressiveness of hepatocellular tumors. Therefore, FGFR4 plays a very important role in liver cancer.
  • FGF19 and FGFR4 are also thought to be related to the aggressiveness of other cancer types (such as gastric cancer, prostate cancer, lung cancer, colorectal cancer, pancreatic cancer, ovarian cancer) (Ye et al, 2011 Cancer 5304-5313; Xu et Al, 2011 BMC Cancer 11:84; Fawdar et al, 2013 PNAS 110: 12426-12431).
  • FGFR inhibitors have entered the clinical research stage as anti-tumor drugs, but these are mainly inhibitors of FGFR1, 2 and 3, and the inhibition of FGFR4 activity is weak, and the inhibition of FGFR1-3 has hyperphosphatemia.
  • target related side effects Highly selective inhibitor of FGFR4 can effectively treat cancer diseases caused by abnormal FGFR4 signaling pathway, and can avoid the side effects of hyperphosphatemia caused by FGFR1-3 inhibition.
  • Highly selective small molecule inhibitors against FGFR4 in tumor targeted therapy The field has significant application prospects. Therefore, the development of a novel anti-tumor agent that can selectively target FGFR4 as a good drug candidate will meet the needs of domestic liver cancer and other tumor-targeted drugs, and bring the advantages of better safety and specificity.
  • a first aspect of the invention provides a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
  • X 1 is selected from -C(R 7 )- or N;
  • X 2 , X 3 , X 5 are each independently selected from -(CR 8 ) n -, -C(O)-, -N(R 9 )-, N, O or S;
  • X 4 is selected from C or N;
  • Z is selected from C 1-8 alkylene, C 2-8 alkenylene, C 2-8 metaalkynyl , C 3-8 cycloalkyl, 3-10 membered heterocyclic, C 5-10 Or a 5-10 membered heteroaryl group, the above group optionally further selected from one or more selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C 1-8 alkyl, C 2-8 olefin , C 2-8 alkynyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, -C 0-8 -S(O r R 10 , -C 0-8 -OR 11 , -C 0-8 -C(O)OR 11 , -C 0-8 -C(O)R 12 , -C 0-8 -OC(O) R 12 , -C 0-8 -NR 13 R 14
  • R 1 is selected from the group consisting of hydrogen, hydrazine, C 1-8 alkyl, C 1-8 alkoxy C 1-8 alkyl, C 3-8 cycloalkoxy C 1-8 alkyl, C 3-8 cycloalkyl C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-10 membered heterocyclic, C 5-10 aryl, 5-10 a heteroaryl group or a C 1-8 alkanoyl group;
  • R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are each independently selected from the group consisting of hydrogen, hydrazine, halogen, cyano, nitro, azide, C 1-8 alkyl, C 2-8 chain.
  • the above groups are optionally further further selected from one or more selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, Halogen substituted C 1-8 alkyl, C 3-8 cycloalkyl, 3-10 membered heterocyclic, C 5-10 aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 10 , -C 0-8 -OR 11 , -C 0-8 -C(O)OR 11 , -C 0-8 -C(O)R 12 , -C 0-8 -OC(O)R 12 , -C 0-8 -NR 13 R 14 , -C 0-8 -C(O)NR 13 R 14 , -C 0-8 -N(R 13 )-C(O)R 12 or -C 0 Substituted by
  • R 8 is selected from the group consisting of hydrogen, hydrazine, halogen, cyano, nitro, azide, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl 3-10 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, -C 0-8 -S(O) r R 10 , -C 0-8 -S(O)(NR 9 ) R 10 , -C 0-8 -P(O)(R 10 ) 2 , -C 0-8 -OR 11 , -C 0-8 -C(O)OR 11 , -C 0-8 -C (O)R 12 , -C 0-8 -OC(O)R 12 , -C 0-8 -NR 13 R 14 , -C 0-8 -C(O)NR 13 R 14 , -C 0-8 -N(
  • the above groups are optionally further further selected from one or more selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, Halogen substituted C 1-8 alkyl, C 3-8 cycloalkyl, 3-10 membered heterocyclic, C 5-10 aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 10 , -C 0-8 -OR 11 , -C 0-8 -C(O)OR 11 , -C 0-8 -C(O)R 12 , -C 0-8 -OC(O)R 12 , -C 0-8 -NR 13 R 14 , -C 0-8 -C(O)NR 13 R 14 , -C 0-8 -N(R 13 )-C(O)R 12 or -C 0 Substituted by
  • R 9 is selected from the group consisting of hydrogen, hydrazine, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-10 membered heterocyclic, C 5 - a 10 aryl group, a 5-10 membered heteroaryl group or a C 1-8 alkanoyl group, the above group optionally further selected from one or more selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halo substituted C 1-8 alkyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl 5-10 membered heteroaryl, -C 0-8 -S(O) r R 10 , -C 0-8 -OR 11 , -C 0-8 -C(O)OR 11 , -
  • R 10 is selected from the group consisting of hydrogen, hydrazine, C 1-8 alkyl, C 2-8 alkenyl, C 3-8 cycloalkyl, 3-10 membered heterocyclic, halo-substituted C 1-8 alkyl, C 5 a -10 aryl group, a 5-10 membered heteroaryl group, an amino group, a mono C 1-8 alkylamino group, a di C 1-8 alkylamino group or a C 1-8 alkanoylamino group;
  • R 12 is selected from the group consisting of hydrogen, hydrazine, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 alkoxy, C 3-8 cycloalkyl, C 3- 8- cycloalkoxy, 3-10 membered heterocyclic, 3-10 membered heterocyclooxy, C 5-10 aryl, 5-10 membered heteroaryl, C 5-10 aryloxy or 5-10 member Heteroaryloxy, the above groups are optionally mono- or polysubstituted by hydrazine, halogen, cyano, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkylthio , C 3-8 cycloalkyl, 3-10 membered heterocyclic, C 5-10 aryl, 5-10 membered heteroaryl, C 1-8 alkylsulfonyl, C 1-8 alkylsulfonylamino , amino, mono C 1-8 alkylamino, di
  • R 13 and R 14 are each independently selected from the group consisting of hydrogen, hydrazine, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-10 membered hetero a cyclic group, a C 5-10 aryl group, a 5-10 membered heteroaryl group, a C 1-8 alkylsulfonyl group or a C 1-8 alkanoyl group, or alternatively, R 13 , R 14 and a directly attached nitrogen atom thereof 4-10 membered heterocyclic group,
  • n 0 or 1
  • n 0, 1 or 2;
  • r 0, 1 or 2;
  • X 3 is selected from -(CR 8 ) n -
  • X 2 is selected from -C(O)-
  • X 4 is selected from C
  • X 5 is selected from -N(R 9 )-, N, O or S
  • X 3 is selected from -C(O)-
  • X 2 is selected from -N(R 9 )-
  • Z is selected from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 Alkenyl or phenyl.
  • the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, Z is selected from the group consisting of C 1-4 alkylene, C 2-4 alkenylene, C 2 a 4 -alkynylene group, a C 3-6 cycloalkyl group, a 3-8 membered heterocyclic group, a C 5-8 aryl group or a 5-8 membered heteroaryl group, the above group optionally further selected by one or more From hydrazine, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-8 Heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, -C 0-4 -S(O) r R 10 , -C 0-4 -OR 11 , -C 0-4 -C( O) OR 11 ,
  • R 1 is selected from the group consisting of hydrogen, hydrazine, C 1-4 alkyl, C 1-4 alkoxy C 1-4 alkyl, C 3-6 cycloalkoxy C 1-4 alkyl, C 3-6 cycloalkyl C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-8 membered heterocyclic, C 5-8 aryl, 5-8 a heteroaryl group or a C 1-4 alkanoyl group;
  • R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are each independently selected from the group consisting of hydrogen, hydrazine, halogen, cyano, nitro, azide, C 1-4 alkyl, C 2-4 chain Alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, -C 0-4 -S(O) r R 10 , -C 0-4 -S(O (NR 9 )R 10 , -C 0-4 -P(O)(R 10 ) 2 , -C 0-4 -OR 11 , -C 0-4 -C(O)OR 11 , -C 0- 4 -C(O)R 12 , -C 0-4 -OC(O)R 12 , -C 0-4 -NR 13 R 14 , -C 0-4 -C(O)NR 13 R 14 , -C
  • the above groups are optionally further further selected from one or more selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, Halogen substituted C 1-4 alkyl, C 3-4 cycloalkyl, 3-8 membered heterocyclic, C 5-8 aryl, 5-8 membered heteroaryl, -C 0-4 -S(O) r R 10 , -C 0-4 -OR 11 , -C 0-4 -C(O)OR 11 , -C 0-4 -C(O)R 12 , -C 0-4 -OC(O)R 12 , -C 0-4 -NR 13 R 14 , -C 0-4 -C(O)NR 13 R 14 , -C 0-4 -N(R 13 )-C(O)R 12 or -C 0 Substituted by
  • the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, Z is selected from a C 1-2 alkylene group or the following structure:
  • the above groups are optionally further further selected from one or more selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-8 membered heterocyclic, C 5-8 aryl, 5-8 membered heteroaryl, -C 0-4 -S(O) r R 10 , -C 0-4 -OR 11 , -C 0-4 -C(O)OR 11 , -C 0-4 -C(O)R 12 , -C 0-4 -OC(O)R 12 , -C 0-4 -NR 13 R 14 , -C 0-4 -C(O)NR 13 R 14 , -C 0-4 -N(R 13 )-C(O)R 12 or -C 0-4 -N(R 13 )- Substituted by a
  • the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, R 1 is selected from the group consisting of hydrogen, hydrazine, methyl, isopropyl, methoxyethyl, and a ring. Propoxymethyl, cyclopropylmethyl, allyl, cyclopropyl or acetyl;
  • R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen, hydrazine, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 ring
  • the atoms together form a C 5-8 cycloalkyl, a 5-8 membered heterocyclyl, a 5-8 membered aryl or a 5-8 membered heteroaryl group, the above group optionally further selected from one or more selected from the group consisting of hydrazine and halogen.
  • R 6 is selected from hydrogen or hydrazine.
  • R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen, hydrazine, chlorine, fluorine, methyl, isopropyl, allyl, ethynyl, cyclopropyl, 3-oxetanyl, Trifluoromethyl, trimethylmethyl, -C 0-4 -OR 11 or -C 0-4 -NR 13 R 14 , or R 2 and R 4 , R 3 and R 5 and the carbon atom directly attached thereto Forming together a 5-8 membered heterocyclic group selected from oxygen or nitrogen, the 5-8 membered heterocyclic group optionally further selected from one or more selected from the group consisting of hydrazine, halogen, cyano, nitro, and Nitro, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo substituted C 1-4 alkyl, C 3-4 cycloalkyl, 3-8 membered heterocyclic , C 5-8
  • R 6 is selected from hydrogen or hydrazine.
  • the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of the following compounds of the formula (IIa):
  • X 3 is selected from -N(R 9 )-, N, O or S;
  • Z is selected from C 1-2 alkylene or the following structure:
  • the above groups are optionally further further selected from one or more selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-8 membered heterocyclic group, C 5-8 aryl, 5-8 membered heteroaryl, -C 0-4 -S(O) r R 10 , -C 0-4 -OR 11 , -C 0-4 -C(O)OR 11 , -C 0-4 -C(O)R 12 , -C 0-4 -OC(O)R 12 , -C 0-4 -NR 13 R 14 , -C 0-4 -C(O)NR 13 R 14 , -C 0-4 -N(R 13 )-C(O)R 12 or -C 0-4 -N(R 13 )- Substituted by
  • R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen, hydrazine, chlorine, fluorine, methyl, isopropyl, allyl, ethynyl, cyclopropyl, 3-oxetanyl, Trifluoromethyl, trimethylmethyl, -C 0-4 -OR 11 or -C 0-4 -NR 13 R 14 , or R 2 and R 4 , R 3 and R 5 and the carbon atom directly attached thereto Forming together a 5-8 membered heterocyclic group selected from oxygen or nitrogen, the 5-8 membered heterocyclic group optionally further selected from one or more selected from the group consisting of hydrazine, halogen, cyano, nitro, and Nitro, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo substituted C 1-4 alkyl, C 3-4 cycloalkyl, 3-8 membered heterocyclic , C 5-8
  • R 7 is selected from the group consisting of hydrogen, hydrazine, chlorine, fluorine, hydroxy, allyl, ethynyl, cyclopropyl, 3-oxetanyl, trifluoromethyl, trimethyl, -C 0-4 -OR 11 or -C 0-4 -NR 13 R 14 ;
  • R 9 is selected from hydrogen, hydrazine, C 1-4 alkyl, C 3-6 cycloalkyl or 3-8 membered heterocyclic group, and the above group is further further selected from one or more selected from the group consisting of hydrazine, halogen, and cyano.
  • X 1 , X 2 , X 5 , R 8 , R 10 , R 11 , R 12 , R 13 , R 14 , m, n, r are as defined above.
  • the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the following formula (IIIa-1), (IIIa-2), (IIIa-3) or (IIIa-4) compound:
  • Z is selected from C 1-2 alkylene or the following structure:
  • the above groups are optionally further further selected from one or more selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-8 membered heterocyclic, C 5-8 aryl, 5-8 membered heteroaryl, -C 0-4 -S(O) r R 10 , -C 0-4 -OR 11 , -C 0-4 -C(O)OR 11 , -C 0-4 -C(O)R 12 , -C 0-4 -OC(O)R 12 , -C 0-4 -NR 13 R 14 , -C 0-4 -C(O)NR 13 R 14 , -C 0-4 -N(R 13 )-C(O)R 12 or -C 0-4 -N(R 13 )- Substituted by a
  • R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen, hydrazine, chlorine, fluorine, hydroxy, methyl, isopropyl, cyclopropyl, 3-oxetanyl, trifluoromethyl, Tris-methyl or -OR 11 , or R 2 and R 4 , R 3 and R 5 together with the carbon atom to which they are directly bonded form a 5-8 membered heterocyclic group selected from oxygen or nitrogen;
  • R 7 is selected from the group consisting of hydrogen, hydrazine, chlorine, fluorine, hydroxyl, cyclopropyl or -OR 11 ;
  • R 9 is selected from hydrogen, hydrazine, C 1-4 alkyl, C 3-6 cycloalkyl or 3-8 membered heterocyclic group, and the above group is further further selected from one or more selected from the group consisting of hydrazine, halogen, C 1 -4 alkyl, halo substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, -C 0-4 -OR 11 , -C 0-4 -NR 13 R 14 or Substituted by a substituent of -C 0-4 -C(O)NR 13 R 14 ;
  • X 1 , X 5 , R 8 , R 10 , R 11 , R 12 , R 13 , R 14 , m, n, r are as defined in claim 1.
  • the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of the compound of the formula (IVa-1):
  • X 5 is selected from -CH- or N;
  • Z is selected from C 1-2 alkylene or the following structure:
  • the above groups are optionally further further selected from one or more selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-8 membered heterocyclic, C 5-8 aryl, 5-8 membered heteroaryl, -C 0-4 -S(O) r R 10 , -C 0-4 -OR 11 , -C 0-4 -C(O)OR 11 , -C 0-4 -C(O)R 12 , -C 0-4 -OC(O)R 12 , -C 0-4 -NR 13 R 14 , -C 0-4 -C(O)NR 13 R 14 , -C 0-4 -N(R 13 )-C(O)R 12 or -C 0-4 -N(R 13 )- Substituted by a
  • R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen, hydrazine, chlorine, fluorine, hydroxy, methyl, isopropyl, cyclopropyl, 3-oxetanyl, trifluoromethyl, Tris-methyl or -OR 11 , or R 2 and R 4 , R 3 and R 5 together with the carbon atom to which they are directly bonded form a 5-8 membered heterocyclic group selected from oxygen or nitrogen;
  • R 7 is selected from the group consisting of hydrogen, hydrazine, chlorine, fluorine, hydroxyl, cyclopropyl or -OR 11 ;
  • R 8 is selected from the group consisting of hydrogen, hydrazine, halogen, cyano, nitro, azide, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl 3-10 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, -C 0-8 -S(O) r R 10 , -C 0-8 -S(O)(NR 9 ) R 10 , -C 0-8 -P(O)(R 10 ) 2 , -C 0-8 -OR 11 , -C 0-8 -C(O)OR 11 , -C 0-8 -C (O)R 12 , -C 0-8 -OC(O)R 12 , -C 0-8 -NR 13 R 14 , -C 0-8 -C(O)NR 13 R 14 , -C 0-8 -N(
  • the above groups are optionally further further selected from one or more selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, Halogen substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclic, C 5-8 aryl, 5-8 membered heteroaryl, -C 0-4 -S(O) r R 10 , -C 0-4 -OR 11 , -C 0-4 -C(O)OR 11 , -C 0-4 -C(O)R 12 , -C 0-4 -OC(O)R 12 , -C 0-4 -NR 13 R 14 , -C 0-4 -C(O)NR 13 R 14 , -C 0-4 -N(R 13 )-C(O)R 12 or -C 0 Substituted by
  • X 1 , R 10 , R 11 , R 12 , R 13 , R 14 , m, n, and r are as defined above.
  • the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, R 8 is selected from the group consisting of hydrogen, hydrazine, halogen, cyano, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-10 membered heterocyclic, C 5-10 aryl, 5-10 membered heteroaryl, -C 0- 8 -OR 11 , -C 0-8 -NR 13 R 14 , -C 0-8 -N(R 13 )-C(O)R 12 or -C 0-8 -N(R 13 )-C(O ) OR 11 ,
  • the above groups are optionally further further selected from one or more selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, Halogen substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclic, C 5-8 aryl, 5-8 membered heteroaryl, -C 0-4 -S(O) r R 10 , -C 0-4 -OR 11 , -C 0-4 -C(O)OR 11 , -C 0-4 -C(O)R 12 , -C 0-4 -OC(O)R 12 , -C 0-4 -NR 13 R 14 , -C 0-4 -C(O)NR 13 R 14 , -C 0-4 -N(R 13 )-C(O)R 12 or -C 0 Substituted by
  • the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of the following compound of the formula (IIb):
  • X 3 is selected from -(CR 8 ) n - or -C(O)-;
  • Z is selected from C 1-2 alkylene or the following structure:
  • the above groups are optionally further further selected from one or more selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-8 membered heterocyclic, C 5-8 aryl, 5-8 membered heteroaryl, -C 0-4 -S(O) r R 10 , -C 0-4 -OR 11 , -C 0-4 -C(O)OR 11 , -C 0-4 -C(O)R 12 , -C 0-4 -OC(O)R 12 , -C 0-4 -NR 13 R 14 , -C 0-4 -C(O)NR 13 R 14 , -C 0-4 -N(R 13 )-C(O)R 12 or -C 0-4 -N(R 13 )- Substituted by a
  • R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen, hydrazine, chlorine, fluorine, methyl, isopropyl, allyl, ethynyl, cyclopropyl, 3-oxetanyl, Trifluoromethyl, trimethylmethyl, -C 0-4 -OR 11 or -C 0-4 -NR 13 R 14 , or R 2 and R 4 , R 3 and R 5 and the carbon atom directly attached thereto Forming together a 5-8 membered heterocyclic group selected from oxygen or nitrogen, the 5-8 membered heterocyclic group optionally further selected from one or more selected from the group consisting of hydrazine, halogen, cyano, nitro, and Nitro, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo substituted C 1-4 alkyl, C 3-4 cycloalkyl, 3-8 membered heterocyclic , C 5-8
  • R 7 is selected from the group consisting of hydrogen, hydrazine, chlorine, fluorine, hydroxy, allyl, ethynyl, cyclopropyl, 3-oxetanyl, trifluoromethyl, trimethyl, -C 0-4 -OR 11 or -C 0-4 -NR 13 R 14 ;
  • R 9 is selected from hydrogen, hydrazine, C 1-4 alkyl, C 3-6 cycloalkyl or 3-8 membered heterocyclic group, and the above group is further further selected from one or more selected from the group consisting of hydrazine, halogen, and cyano.
  • X 1 , X 2 , X 5 , R 8 , R 10 , R 11 , R 12 , R 13 , R 14 , m, n, r are as defined above;
  • X 3 is selected from -(CR 8 ) n -, X 2 is selected from -C(O)-, and X 5 is selected from -N(R 9 )-, N, O or S; when X 3 is selected From -C(O)-, X 2 is selected from -N(R 9 )-, and Z is selected from C 1-4 alkyl or phenyl.
  • the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of the following compounds of the formula (IIIb-1) or (IIIb-2):
  • Z is selected from C 1-2 alkylene or the following structure:
  • the above groups are optionally further further selected from one or more selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-8 membered heterocyclic, C 5-8 aryl, 5-8 membered heteroaryl, -C 0-4 -S(O) r R 10 , -C 0-4 -OR 11 , -C 0-4 -C(O)OR 11 , -C 0-4 -C(O)R 12 , -C 0-4 -OC(O)R 12 , -C 0-4 -NR 13 R 14 , -C 0-4 -C(O)NR 13 R 14 , -C 0-4 -N(R 13 )-C(O)R 12 or -C 0-4 -N(R 13 )- Substituted by a
  • R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen, hydrazine, chlorine, fluorine, hydroxy, methyl, isopropyl, cyclopropyl, 3-oxetanyl, trifluoromethyl, Tris-methyl or -OR 11 , or R 2 and R 4 , R 3 and R 5 together with the carbon atom to which they are directly bonded form a 5-8 membered heterocyclic group selected from oxygen or nitrogen;
  • R 7 is selected from the group consisting of hydrogen, hydrazine, chlorine, fluorine, hydroxyl, cyclopropyl or -OR 11 ;
  • X 1 , R 10 , R 11 , R 12 , R 13 , R 14 , m, r are as defined above.
  • the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of the following compounds of the formula (IIIb-3):
  • R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen, hydrazine, chlorine, fluorine, hydroxyl, methyl, isopropyl, cyclopropyl, 3-oxetanyl, and trifluoromethyl.
  • R 7 is selected from the group consisting of hydrogen, hydrazine, chlorine, fluorine, hydroxyl, cyclopropyl or -OR 11 ;
  • R 9 is selected from hydrogen, hydrazine, C 1-4 alkyl, C 3-6 cycloalkyl or 3-8 membered heterocyclic group, and the above group is further further selected from one or more selected from the group consisting of hydrazine, halogen, C 1 -4 alkyl, halo substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, -C 0-4 -OR 11 , -C 0-4 -NR 13 R 14 or Substituted by a substituent of -C 0-4 -C(O)NR 13 R 14 ;
  • X 1 , R 8 , R 10 , R 11 , R 13 , R 14 and n are as defined above.
  • the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof includes, but is not limited to, the following compounds:
  • X is a leaving group, preferably from chlorine, bromine, methylthio, methylsulfonyl or methoxy; R is selected from nitro, cyano or azide; Pg is an amino protecting group, preferably from tert-butyl Oxycarbonyl, benzyloxycarbonyl, 2-biphenyl-2-propoxycarbonyl or p-toluenesulfonyl; X 1 , X 2 , X 3 , X 4 , X 5 , R 1 , R 2 , R 3 , R 4 R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , m, n and r are as defined above.
  • the corresponding compound when X is selected from the group consisting of a methylsulfonyl group, the corresponding compound can be obtained by an oxidation reaction with an oxidizing agent such as m-CPBA (m-chloroperoxybenzoic acid) when R is a methylthio group.
  • an oxidizing agent such as m-CPBA (m-chloroperoxybenzoic acid) when R is a methylthio group.
  • the optional conversion reaction between different substituents depending on the substituent means that, if necessary, after the condensation reaction, according to X 1 , X 2 , X 3 , X 4 , X 5 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 Substituent conversion is carried out by routine experimentation in the art under the conditions of chemical synthesis under the conditions of the substituent definition.
  • a third aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the above formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a fourth aspect of the invention provides a compound of the above formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or the use of the aforementioned pharmaceutical composition for the preparation of a medicament for FGFR4 inhibitor.
  • the fifth aspect of the present invention provides a compound represented by the above formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or the use of the aforementioned pharmaceutical composition for the preparation of a medicament for treating cancer.
  • the cancer is prostate cancer, liver cancer, pancreatic cancer, esophageal cancer, gastric cancer, lung cancer, breast cancer, ovarian cancer, colon cancer, skin cancer, glioblastoma or rhabdomyosarcoma.
  • a sixth aspect of the invention provides a compound represented by the above formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition, which is used as an FGFR4 inhibitor.
  • the cancer is prostate cancer, liver cancer, pancreatic cancer, esophageal cancer, gastric cancer, lung cancer, breast cancer, ovarian cancer, colon cancer, skin cancer, glioblastoma or rhabdomyosarcoma.
  • the eighth aspect of the present invention provides a method for inhibiting FGFR4, which comprises administering to a patient in need of treatment a therapeutically effective amount of the compound of the above formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, Or the aforementioned pharmaceutical composition.
  • a ninth aspect of the invention provides a method of treating cancer, which comprises administering to a patient in need of treatment a therapeutically effective amount of a compound of the above formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, Or the aforementioned pharmaceutical composition.
  • the cancer is prostate cancer, liver cancer, pancreatic cancer, esophageal cancer, gastric cancer, lung cancer, breast cancer, ovarian cancer, colon cancer, skin cancer, glioblastoma or rhabdomyosarcoma.
  • the series of compounds developed by the invention have strong inhibitory effect on FGFR4 kinase activity and have very high selectivity, and can be widely applied for the preparation of cancer, especially prostate cancer, liver cancer, pancreatic cancer, esophageal cancer, gastric cancer, lung cancer, Drugs for breast cancer, ovarian cancer, colon cancer, skin cancer, glioblastoma or rhabdomyosarcoma are expected to be developed into a new generation of FGFR4 inhibitor drugs.
  • Can be widely used in the preparation of drugs for the treatment of cancer especially prostate cancer, liver cancer, pancreatic cancer, esophageal cancer, stomach cancer, lung cancer, breast cancer, ovarian cancer, colon cancer, skin cancer, glioblastoma or rhabdomyosarcoma, is expected to develop Into a new generation of FGFR4 inhibitor drugs. . On the basis of this, the present invention has been completed.
  • Alkyl means a straight-chain or branched-chain saturated aliphatic hydrocarbon group, for example, "C 1-8 alkyl” means a straight-chain alkyl group having from 1 to 8 carbon atoms and a branched alkyl group, including but Not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2- Dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropane 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethyl Butyl, 2-ethylbutyl, 2-methyl
  • Alkyl group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more groups independently selected from deuterium, halogen, cyano, nitro, azido group, C 1 -8 alkyl, halo substituted C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 10 , -C 0-8 -OR 11 , -C 0-8 -C(O)OR 11 , -C 0 -8 -C(O)R 12 , -C 0-8 -OC(O)R 12 , -C 0-8 -NR 13 R 14 , -C 0-8 -C(O)NR 13 R 14 ,-Substituents of C 0-8 -N(R
  • Cycloalkyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, for example, "C 3-8 cycloalkyl” refers to a cycloalkyl group of 3 to 8 carbon atoms, which is divided into a single ring. a cycloalkyl, polycyclic cycloalkyl group, wherein:
  • Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, Cyclooctyl and the like.
  • Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups.
  • “Spirocycloalkyl” refers to a polycyclic group that shares a carbon atom (called a spiro atom) between the monocyclic rings. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system.
  • the spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group depending on the number of common spiro atoms between the ring and the ring, and the spirocycloalkyl group includes, but is not limited to:
  • fused cycloalkyl refers to an all-carbon polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but None of the rings have a fully conjugated ⁇ -electron system. Depending on the number of constituent rings, it may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl groups, and fused cycloalkyl groups include, but are not limited to:
  • Bridge cycloalkyl refers to an all-carbon polycyclic group in which two rings share two carbon atoms that are not directly bonded, which may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system . According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, and bridged cycloalkyl groups include but are not limited to:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group including, but not limited to, indanyl, tetrahydronaphthyl , benzocycloheptyl and the like.
  • the cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C.
  • Heterocyclyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent wherein one or more of the ring atoms are selected from nitrogen, oxygen or S(O) r (where r is an integer 0, 1, 2 a hetero atom, but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • r is an integer 0, 1, 2 a hetero atom, but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • r is an integer 0, 1, 2 a hetero atom, but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • r is an integer 0, 1, 2 a hetero atom, but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • Monocyclic heterocyclic groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like.
  • Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • “Spiroheterocyclyl” refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between a single ring, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) r (where r is an integer) The heteroatoms of 0, 1, 2), and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system.
  • the spiroheterocyclyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspiroheterocyclic group depending on the number of common spiro atoms between the ring and the ring.
  • Spiroheterocyclyl includes, but is not limited to:
  • “Fused heterocyclyl” refers to a polycyclic heterocyclic group in which each ring of the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more double bonds, but none
  • the ring has a fully conjugated pi-electron system in which one or more ring atoms are selected from the group consisting of nitrogen, oxygen or S(O) r (wherein r is an integer of 0, 1, 2) heteroatoms, the remaining ring atoms being carbon.
  • the bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl group may be classified according to the number of constituent rings, and the fused heterocyclic group includes but is not limited to:
  • Bridge heterocyclyl refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly bonded, and these may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system, One or more of the ring atoms are selected from the group consisting of nitrogen, oxygen or S(O) r (wherein r is an integer of 0, 1, 2) heteroatoms, and the remaining ring atoms are carbon.
  • the bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group may be classified according to the number of constituent rings, and the bridged heterocyclic group includes but is not limited to:
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heterocyclic group including, but not limited to:
  • the heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C.
  • Aryl means an all-carbon monocyclic or fused polycyclic (ie, a ring that shares a pair of adjacent carbon atoms) groups having a polycyclic ring of a conjugated ⁇ -electron system (ie, having a ring adjacent to a carbon atom) a group, for example, "C 5-10 aryl” means an all-carbon aryl group having 5 to 10 carbons, and "5-10 membered aryl group” means an all-carbon aryl group having 5 to 10 carbons, including It is not limited to phenyl and naphthyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl ring including, but not limited to:
  • the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from halogen, cyano, nitro, azide, C 1-8 alkyl. , C 2-8 alkenyl, C 2-8 alkynyl, halogen substituted C 1-8 alkyl, C 3-8 cycloalkyl, 3-10 membered heterocyclic, C 5-10 aryl, 5 -10-membered heteroaryl, -C 0-8 -S(O) r R 10 , -C 0-8 -OR 11 , -C 0-8 -C(O)OR 11 , -C 0-8 -C (O)R 12 , -C 0-8 -OC(O)R 12 , -C 0-8 -NR 13 R 14 , -C 0-8 -C(O)NR 13 R 14 , -C 0-8 Substituted by a substituent of
  • Heteroaryl refers to a heteroaromatic system containing from 1 to 4 heteroatoms including nitrogen, oxygen and a hetero atom of S(O)r (wherein r is an integer of 0, 1, 2), for example, 5-7 membered heteroaryl refers to a heteroaromatic system containing 5 to 7 ring atoms, and 5-10 membered heteroaryl refers to a heteroaromatic system containing 5 to 10 ring atoms, including but not limited to furyl, thiophene.
  • Base pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring including, but not limited to:
  • the heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C.
  • Alkenyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, for example, C 2-8 alkenyl refers to a straight or branched chain containing from 2 to 8 carbons. Alkenyl. These include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like.
  • the alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C 1-8.
  • Alkynyl means an alkyl radical as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, for example, C2-8 alkynyl refers to a straight or branched chain containing from 2 to 8 carbons. Alkynyl. These include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like.
  • the alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C 1-8.
  • Alkoxy means -O-(alkyl) wherein alkyl is as defined above, for example, "C 1-8 alkoxy” refers to an alkyloxy group containing from 1 to 8 carbons, including but not It is limited to methoxy, ethoxy, propoxy, butoxy and the like.
  • the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent, preferably one or more of the following groups, independently selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C 1-8 alkyl, halo substituted C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 5 -10 aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 10 , -C 0-8 -OR 11 , -C 0-8 -C(O)OR 11 ,- C 0-8 -C(O)R 12 , -C 0-8 -OC(O)R 12 , -C 0-8 -NR 13 R 14 , -C 0-8 -C(O)NR 13 R 14 Substituted by a
  • Cycloalkoxy refers to and -O-(unsubstituted cycloalkyl), wherein cycloalkyl is as defined above, for example, “C 3-8 cycloalkoxy” refers to 3-8 carbons. Cycloalkyloxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.
  • the cycloalkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C 1-8 alkyl, halo substituted C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 5 -10 aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 10 , -C 0-8 -OR 11 , -C 0-8 -C(O)OR 11 ,- C 0-8 -C(O)R 12 , -C 0-8 -OC(O)R 12 , -C 0-8 -NR 13 R 14 , -C 0-8 -C(O)NR 13 R 14 Substituted
  • 3-10 membered heterocyclic oxy refers to -O-(unsubstituted 3-10 membered heterocyclic group) wherein 3-10 membered heterocyclic group is as defined above, 3-10 membered heterocyclic oxy group.
  • the substituent is preferably one or more of the following groups, independently selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C 1-8 Alkyl, halogen substituted C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl 5-10 membered heteroaryl, -C 0-8 -S(O) r R 10 , -C 0-8 -OR 11 , -C 0-8 -C(O)OR 11 , -C 0-8 -C(O)R 12 , -C 0-8 -OC(O)R 12 , -C 0-8 -NR 13 R 14 , -C 0-8 -C(O)NR 13 R 14 , -C 0-10 -C(O)NR 13 R 14 , -C 0 Substituted by hydr
  • C 5-10 aryloxy means both -O-(unsubstituted C 5-10 aryl) wherein the C 5-10 aryl group is as defined above, and the C 5-10 aryloxy group may be optionally Substituted or unsubstituted, when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C 1-8 alkyl, halo Substituted C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 N-heteroaryl, -C 0-8 -S(O) r R 10 , -C 0-8 -OR 11 , -C 0-8 -C(O)OR 11 , -C 0-8 -C(O R 12 ,
  • 5-10 membered heteroaryloxy means -O-(unsubstituted 5-10 membered heteroaryl) wherein 5-10 membered heteroaryl is as defined above, 5-10 membered heteroaryloxy It may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C 1-8 Alkyl, halogen substituted C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl 5-10 membered heteroaryl, -C 0-8 -S(O) r R 10 , -C 0-8 -OR 11 , -C 0-8 -C(O)OR 11 , -C 0-8 -C(O)R 12 , -C —
  • C 1-8 alkanoyl refers to a monovalent atomic group remaining after the C 1-8 alkyl acid has been removed from the hydroxy group, and is also generally referred to as "C 0-7 -C(O)-", for example, “C 1 -C"(O)-” means acetyl; “C 2 -C(O)-” means propionyl; “C 3 -C(O)-” means butyryl or isobutyryl.
  • -C 0-8 -OR 11 means that the oxygen atom in -OR 11 is attached to a C 0-8 alkyl group, wherein the C 0 alkyl group means a bond, and the C 1-8 alkyl group is as defined above.
  • -C 0-8 -NR 13 R 14 means that the nitrogen atom in -NR 13 R 14 is bonded to a C 0-8 alkyl group, wherein the C 0 alkyl group means a bond, and the C 1-8 alkyl group is as defined above. Said.
  • Halo-substituted C 1-8 alkyl refers to a hydrogen on the alkyl group optionally substituted with a fluorine, chlorine, bromine or iodine atom, including 1 to 8 carbon alkyl groups, including but not limited to difluoromethyl, Chloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, and the like.
  • the hydrogen on the "halo-substituted C 1-8 alkoxy" alkyl group is optionally a 1-8 carbon alkoxy group substituted with a fluorine, chlorine, bromine or iodine atom.
  • fluorine chlorine, bromine or iodine atom.
  • these include, but are not limited to, difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, and the like.
  • Halogen means fluoro, chloro, bromo or iodo.
  • THF refers to tetrahydrofuran.
  • EA/EtOAc refers to ethyl acetate.
  • MeOH refers to methanol.
  • EtOH refers to ethanol.
  • PivOH refers to trimethylacetic acid.
  • DMSO dimethyl sulfoxide.
  • DMF means N,N-dimethylformamide.
  • DIPEA refers to diisopropylethylamine.
  • CH 3 CN means ⁇ .
  • PE means petroleum ether.
  • DCM/CH 2 Cl 2 means dichloromethane.
  • DCE dichloroethane
  • DMA dimethylacetamide
  • Et 3 N triethylamine
  • NH 4 Cl ammonium chloride
  • NMP N-methylpyrrolidone
  • HOAc acetic acid
  • TFA trifluoroacetic acid
  • MeI means methyl iodide.
  • KI means potassium iodide.
  • MsCl nail sulfonyl chloride.
  • SO 2 Cl 2 means sulfonyl chloride.
  • POCl 3 refers to phosphorus oxychloride.
  • MeONa means sodium methoxide.
  • NaHCO 3 refers to sodium bicarbonate.
  • Na 2 SO 4 refers to sodium sulfate.
  • K 2 CO 3 refers to potassium carbonate.
  • NaN 3 refers to sodium azide.
  • NaH refers to sodium hydride.
  • CuI refers to cuprous iodide.
  • PPA polyphosphoric acid.
  • m-CPBA refers to m-chloroperoxybenzoic acid.
  • MnO 2 refers to manganese dioxide.
  • LiAlH 4 refers to lithium aluminum hydride.
  • LiOH refers to lithium hydroxide.
  • NaOAc refers to sodium acetate.
  • NaNO 2 refers to sodium nitrite.
  • AgNO 3 refers to silver nitrate.
  • Boc 2 O refers to di-tert-butyl dicarbonate.
  • LiCl means lithium chloride.
  • Zn(CN) 2 refers to zinc cyanide.
  • IBX means 2-iodobenzoic acid.
  • Pd/C means palladium carbon.
  • Pd(OAc) 2 refers to palladium acetate.
  • PPh 3 refers to triphenylphosphine.
  • Pd(PPh 3 ) 2 Cl 2 refers to bistriphenylphosphine palladium dichloride.
  • Pd 2 (dba) 3 refers to tris(dibenzylideneacetone) dipalladium.
  • Pd(dppf)Cl 2 means [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride.
  • Pd(PPh 3 ) 4 refers to tetrakis(triphenylphosphine)palladium.
  • brett-phos refers to dicyclohexyl [3,6-dimethoxy-2',4',6'-triisopropyl[1,1'-biphenyl]-2-yl]phosphine.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group.
  • Substituted means that one or more hydrogen atoms in the group are each independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond such as an olefin.
  • “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
  • the structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS).
  • NMR chemical shift ( ⁇ ) is given in parts per million (ppm).
  • NMR was measured using a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ).
  • the internal standard was four.
  • Methyl silane (TMS) Methyl silane
  • LC-MS was determined by LC-MS using an Agilent 6120 mass spectrometer.
  • the HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).
  • the thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification for TLC is 0.15mm ⁇ 0.20mm, and the specification for separation and purification of thin layer chromatography is 0.4mm ⁇ 0.5mm.
  • Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.
  • the third step preparation of 6-chloro-4-methoxy nicotine aldehyde
  • the fourth step preparation of 6-chloro-4-hydroxy nicotine aldehyde
  • Step 6 Preparation of 7-chloro-3-(2,6-dichloro-3,5-dimethoxyphenyl)-2H-pyrano[3,2-c]pyridin-2-one
  • Oxalyl chloride (12.7 g, 100 mmol) was added to a suspension of 2-chloro-5-nitroiso-nicotonic acid (16 g, 80 mmol) in dichloromethane (150 mL). After the addition was completed, the reaction solution was stirred at room temperature for 3 hours. Methanol (100 mL) was added, and the reaction mixture was stirred at room temperature for further 4 hr and dried. The crude product was dissolved with EtOAc (EtOAc) (EtOAcjjjjjjjj Yield: 98%).
  • the third step preparation of methyl 2-(3,5-dimethoxyphenyl)-5-nitroisonicotine
  • Step 4 Preparation of methyl 5-amino-2-(3,5-dimethoxyphenyl)isonigubutanoate
  • 6-(3,5-Dimethoxyphenyl)pyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione 5.0 g, 16.7 mmol
  • phosphorus oxychloride 50 mL
  • N,N-diethylaniline 3 mL
  • Step 8 Preparation of 2-chloro-6-(3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidine
  • Step 9 Preparation of 2-chloro-6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidine
  • Second step Preparation of methyl 2-chloro-5-((3,5-dimethoxyphenyl)ethynyl)iso-n-butyric acid
  • Methyl 5-bromo-2-chloroisoglutamate (30 g, 120 mmol) was dissolved in 1,4-dioxane (300 mL), then 3,5-dimethoxyphenylacetylene (20.4 g, 120 mmol).
  • CuI (2.28 g, 12 mmol)
  • Pd(dppf)Cl 2 (4.2 g, 6 mmol)
  • Et 3 N (12.0 g, 120 mmol) were taken up in vacuo, N 2 protected and heated to 60 ° C for 6 hours. The reaction was complete, filtered and concentrated.
  • the third step preparation of 7-chloro-3-(3,5-dimethoxyphenyl)-1H-pyrano[4,3-c]pyridin-1-one
  • Second step Preparation of 7-chloro-3-(3,5-dimethoxyphenyl)-2-methyl-2,6-naphthyridin-1(2H)-one
  • the third step 7-chloro-3-(2,6-dichloro-3,5-dimethoxyphenyl)-2-methyl-2,6-naphthyridin-1(2H)-one preparation
  • 5-Amino-2-chloroisoglutamic acid (4.0 g, 23 mmol) was added to SOCl 2 (50 mL), heated to 80 ° C, and stirred for 4 hr. The reaction was completed and cooled to room temperature. Concentration, the obtained crude product was dissolved in anhydrous THF (20 mL), cooled in ice water, and concentrated aqueous ammonia (100 mL). CH 2 Cl 2 (100mL) and extracted five times, and the combined organic phases were dried over anhydrous Na 2 SO 4. Filtration and concentration gave the compound 5-amino-2-chloroisocarbamide (3.5 g, yield: 88%).
  • the third step preparation of 6-chloro-4-((2,2,2-trifluoroethyl)amino)nicotine
  • 6-Chloro-4-((2,2,2-trifluoroethyl)amino)nicotinaldehyde (0.86 g, 3.61 mmol) was dissolved in DMF (20 mL), then 3,5-dimethoxyphenylacetate The ester (760 mg, 3.61 mmol) and K 2 CO 3 (1.5 g, 10.84 mmol) were heated to 110 ° C for 3 hours.
  • Step 5 7-Chloro-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(2,2,2-trifluoroethyl)-1,6-diaza Preparation of naphthalene-2(1H)-one
  • the first step preparation of 5-bromo-2-chloroiso-nicotine
  • Second step Preparation of 2-chloro-5-((3,5-dimethoxyphenyl)ethynyl)iso-n-butyraldehyde
  • the third step preparation of 2-chloro-5-((3,5-dimethoxyphenyl)ethynyl)iso-n-butyraldehyde oxime
  • the fourth step preparation of 7-chloro-3-(3,5-dimethoxyphenyl)-2,6-naphthyridine-2-oxidation
  • Second step Preparation of 7-chloro-N-(cyclopropylmethyl)-3-(3,5-dimethoxyphenyl)-2,6-naphthyridin-1-amine
  • the third step 7-chloro-N-(cyclopropylmethyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-2,6-naphthyridine-1- Preparation of amine
  • Methyl 5-bromo-2-(methylthio)pyrimidine-4-carboxylate (2631 mg, 10.0 mmol), 1-ethynyl-3,5-dimethoxybenzene (1622 mg, 10.0 mmol) dissolved in dry THF (50mL), pumping gas, nitrogen protection. Then, Et 3 N (2.8 mL, 20.0 mmol), Pd(PPh 3 ) 2 Cl 2 (702 mg, 1.0 mmol), PPh 3 (525 mg, 2.0 mmol) and CuI (190 mg, 1.0 mmol) were added. Heat to 90 ° C and stir the reaction overnight.
  • Step 5 Preparation of 6-(3,5-dimethoxyphenyl)-8-methoxy-2-(methylthio)pyrido[3,4-d]pyrimidine
  • 6-(3,5-Dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidin-8(7H)-one 100 mg, 0.304 mmol
  • silver carbonate 109 mg, Toluene (3 mL)
  • iodomethane 431 mg, 3.036 mmol
  • Step 6 Preparation of 6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-methoxy-2-(methylthio)pyrido[3,4-d]pyrimidine
  • 6-(3,5-Dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidin-8(7H)-one (20.0 mg, 0.061 mmol) and N,N- diisopropylethylamine (78mg, 0.610mmol) was added acetonitrile (2mL), was added POCl 3 (0.8mL). Heat to 90 ° C and stir the reaction overnight. Evaporate under reduced pressure to remove the solvent. It was diluted with EtOAc (10 mL) and washed with aq. The organic phase was separated, washed with brine and dried over anhydrous sodium sulfate.
  • the compound 2,6-difluoro-3,5-dimethoxyaniline (27.0 g, 143 mmol) was added to a 6.0 M hydrochloric acid solution (240 mL), and an aqueous NaNO 2 solution (10.35 g, 150 mmol) was slowly added dropwise under ice-cooling. 30 mL water). After the completion of the dropwise addition for 25 minutes, the reaction was continued for 15 minutes to give an orange-brown suspension which was then added to aqueous KI (94.9 g, 570 mmol, 150 mL of water). The temperature was raised to room temperature, and the reaction was stirred for 30 minutes to precipitate a solid. Filtered, washed with water to obtain a crude product.
  • Second step Preparation of (2,6-difluoro-3,5-dimethoxyphenylacetylene)-based trimethylsilane
  • the third step preparation of 3-ethynyl-2,4-difluoro-1,5-dimethoxybenzene
  • Step 5 Preparation of 5-((2,6-difluoro-3,5-dimethoxyphenyl)ethynyl)-2-(methylthio)pyrimidine-4-carboxylic acid
  • Step 7 6-(2,6-Difluoro-3,5-dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidin-8(7H)-one preparation
  • Step 8 Preparation of 8-chloro-6-(2,6-difluoro-3,5-dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidine
  • Step 9 N-(cyclopropylmethyl)-6-(2,6-difluoro-3,5-dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d Preparation of pyrimidine-8-amine
  • Second step Preparation of 8-cyclopropyl-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidine
  • Step 3 Preparation of tert-butyl((3S,4S)-4-azidotetrahydro-2H-pyran-3-yl)carbamate
  • Second step Preparation of tert-butyl ((3R,4S)-4-(1,3-dicarbonylisoindoline-2-yl)tetrahydrofuran-3-yl)carbamate
  • reaction solution was then directly concentrated and subjected to column chromatography (eluent: PE/EA 15-30%) to give the compound tert-butyl((3R,4S)-4-(1,3-dicarbonylisoindoline). -2-yl)tetrahydrofuran-3-yl)carbamate (950 mg) crude.
  • Second step 7-((2-Amino-6-methylphenyl)amino)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-2-methyl-2, Preparation of 6-naphthyridin-1(2H)-one
  • the third step N-(2-((7-(2,6-dichloro-3,5-dimethoxyphenyl)-6-methyl-5-carbonyl-5,6-dihydro-2, Preparation of 6-naphthyridin-3-yl)amino)-3-methylphenyl)acrylamide
  • Example 2-75 was prepared by referring to the synthesis method of Example 1:
  • N-(cyclopropylmethyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidine-8 The amine (210 mg, 0.465 mmol) was dissolved in dichloromethane (6 mL) and then m-chloroperoxybenzoic acid (200 mg, 1.. The reaction was stirred at room temperature for 18 hours. The reaction was completed, saturated sodium sulfite solution (5 mL) was added and stirred for 5 min. The organic layer was washed with saturated sodium hydrogen carbonate and brine and dried over anhydrous sodium sulfate.
  • N 8 -(cyclopropylmethyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-N 2 -(1-methyl-4-nitro-1H-pyrazole -3-yl)pyrido[3,4-d]pyrimidine-2,8-diamine (40 mg, 0.074 mmol) was dissolved in methanol (10 mL), followed by triethylamine (3 drops) and Pd/C (20 mg) , 10% content), stirred under a hydrogen balloon at room temperature for 45 minutes.
  • N 2 -(4-Amino-1-methyl-1H-pyrazol-3-yl)-N 8 -(cyclopropylmethyl)-6-(2,6-dichloro-3,5-dimethyl oxyphenyl) pyrido [3,4-d] pyrimidine-2,8-diamine (30mg, 0.058mmol) was dissolved in THF / H 2 O (8mL / 2mL), was added NaHCO 3 (33mg, 0.39mmol), Acetyl chloride (7 mg, 0.078 mmol, dissolved in 1 mL of THF) was added dropwise under ice bath.
  • Second step ( ⁇ )-N-((3R,4S)-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d] Preparation of pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acrylamide
  • the third step N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2- Of amino)amino)tetrahydro-2H-pyran-4-yl)acrylamide
  • N-(cyclopropylmethyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylthio)pyrido[3,4-d]pyrimidine-8 The amine (210 mg, 0.465 mmol) was dissolved in dichloromethane (6 mL) and then m-chloroperoxybenzoic acid (200 mg, 1.. The reaction was stirred at room temperature for 18 hours. The reaction was completed, saturated sodium sulfite solution (5 mL) was added and stirred for 5 min. The organic layer was washed with saturated sodium hydrogen carbonate and brine and dried over anhydrous sodium sulfate.
  • the third step ( ⁇ )-N-((3R,4S)-4-((8-((cyclopropylmethyl)amino)-6-(2,6-dichloro-3,5-dimethyl) Preparation of oxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acrylamide
  • Second step tert-butyl ((3R,4S)-4-((8-chloro-6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d Preparation of pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)carbamate
  • Step 5 N-((3R,4S)-4-((6-(2,6-Dichloro-3,5-dimethoxyphenyl)-8-(methylamino)pyridin[3, Preparation of 4-d]pyrimidin-2-yl)amino)tetrahydrofuran-3-yl)acrylamide
  • the third step N-((3S,4S)-4-azidotetrahydro-2H-pyran-3-yl)-6-(2,6-difluoro-3,5-dimethoxyphenyl) 8-(3-methoxyazetidin-1-yl)pyrido[3,4-d]pyrimidin-2-amine
  • N-((3S,4S)-4-azidotetrahydro-2H-pyran-3-yl)-6-(2,6-difluoro-3,5-dimethoxyphenyl)-8-( 3-methoxyazetidin-1-yl)pyrido[3,4-d]pyrimidin-2-amine (350 mg, 0.662 mmol) was dissolved in THF (10 mL) and water (1 mL). Phosphorus (521 mg, 1.99 mmol) was heated to 80 degrees and stirred for 16 hours.
  • Step 5 N-((3S,4S)-3-((6-(2,6-Difluoro-3,5-dimethoxyphenyl)-8-(3-methoxyazetidine- Preparation of 1-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide
  • the third step N-(5-(6-(2,6-dichloro-3,5-dimethoxyphenyl)pyrido[3,4-d]pyrimidin-2-yl)-1-(2) Of -methoxyethyl)-1H-pyrazol-4-yl)acrylamide
  • the present invention uses the FGFR4 Caliper Assay to determine the properties of a compound against FGFR4 inhibitory activity.
  • the specific experimental process is as follows:
  • the kinase reaction carried out in the present invention was carried out in a 384-well plate, and 12.5 ⁇ M of FGFR4 and 65 ⁇ M of ATP and 1 ⁇ M of peptide (5Fluo Ahx KKKKEEIYFFFG NH2) were respectively taken;
  • Stop the reaction by adding a stop solution 100 mM HEPES, pH 7.5, 5% DMSO, 0.1% Caliper coating reagent, 10 mM EDTA and 0.015% Brij35;
  • the present invention employs (Cell Titer Glo (CTG) experiment) to evaluate the functional effects of compounds on cell proliferation.
  • Huh7 hepatocellular carcinoma cells (Catalog No. TChU182) from the Chinese Academy of Sciences cell bank were used in DMEM high glucose (Gibco, cat. No. 1773536), 10% fetal bovine serum (Gibco, 10099-141) at 37 ° C, 5% Culture in a CO 2 incubator.
  • Compound-mediated inhibition of cell proliferation/survival was assessed by quantification of cellular ATP levels using CTG reagent (Promega, #G7573).
  • the specific experimental process is as follows:
  • the dose effect was evaluated by 5-fold serial dilution of the test compound, starting from 10 ⁇ M;
  • the series of compounds of the present invention have a strong inhibitory effect on FGFR4 kinase activity.
  • the series of compounds of the present invention have a strong inhibitory effect on the proliferation activity of HuH-7 cells highly expressed by FGFR4.

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Abstract

提供一种具有式(Ⅰ)结构的FGFR4抑制剂及其制备方法和应用，该化合物对FGFR4激酶活性具有很强的抑制作用，并具有非常高的选择性，可广泛应用于制备治疗癌症特别是前列腺癌、肝癌、胰腺癌、食管癌、胃癌、肺癌、乳腺癌、卵巢癌、结肠癌、皮肤癌、神经胶质母细胞瘤或横纹肌肉瘤的药物，有望开发成新一代FGFR4抑制剂药物。

Description

FGFR4抑制剂、其制备方法与药学上的应用 技术领域
本发明属于药物合成领域，具体涉及一种FGFR4抑制剂、其制备方法与药学上的应用。
技术背景
成纤维细胞生长因子(FGF)是一个有22种具有不同生物学活性的结构相关多肽的一个家族，它们能调节细胞增殖，分化，迁移，并在肢体发育，血管生成，组织修复，以及肿瘤形成等过程中发挥主要作用(Eswarakumar et al.,2005Cytokine Growth Factor Rev16:139-149；Ornitz and Itoh,2001Genome Bio12:Reviews3005)。
FGF的相应受体(FGFR)属于受体酪氨酸激酶的一个家族RPTK。目前已经有FGFR1，FGFR2，FGFR3以及FGFR4四种受体被发现(Ullrich and Schlessinger,1990Cell 61:203)。它们与相应的配体FGF的相互作用会导致受体二聚化和自我磷酸化，从而启动下游包括MAPK和AKT在内多种信号传导级联反应(Powers et al.,2000Endocr Relat Cancer7:165-197)。
FGFR1-3已经被发现在多种肿瘤(包括骨髓瘤、乳腺癌、胃癌、结肠癌、膀胱癌、膜腺癌、和肝细胞癌等)中有过表达，突变，转位，并且被认为是驱动癌症的基因(Chesi et al.,2001Blood 97:729-726；Gowardhan et al.,2005Br J Cancer92:320-327；Jaakkola et al.,1993Int J Cancer54:378-282；Jang et al.,2001Cancer Res 61:3541-3543)，也已经有一些FGFR抑制剂在临床及临床前的研发过程中。但之前有研究表明FGFR1能调节细胞内磷酸化水平，因此泛FGFR抑制剂会带来安全性上的担忧。
肝细胞癌(HCC)是导致中国癌症相关死亡的主要起因之一，也是每年发病人数增长最快的癌症之一(Shariff et al.,2009Expert Rev Gastroenterol Hepato13:353-367)。目前的一线治疗方案是索拉芬妮，且没有被批准的二线药物，仍然需要具有抗肿瘤剂的靶向药物。
在5～10％的肝细胞癌病人中带有FGF19的过表达，而FGFR4是人肝细胞中存在的优势FGFR,并且其在肝细胞中的高表达被认为与肝细胞肿瘤的侵袭性相关。因此FGFR4在肝癌中有非常重要的作用。另外，FGF19以及FGFR4的相互作用也被认为与其他癌症类型(比如胃癌，前列腺癌，肺癌，结肠直肠癌，胰腺癌，卵巢癌)的侵袭性有关(Ye et al,2011Cancer 5304-5313；Xu et al,2011BMC Cancer 11:84；Fawdar et al,2013PNAS110:12426-12431)。
目前已有一些FGFR抑制剂作为抗肿瘤药物进入临床研究阶段，但这些都主要是针对FGFR1、2和3的抑制剂，对FGFR4的活性抑制较弱，且FGFR1-3的抑制具有高血磷症等靶点相关副作用。FGFR4高选择性抑制剂能有效治疗FGFR4信号通路异常导致的癌症疾病，并可避免FGFR1-3抑制导致的高血磷症等相关副作用，针对FGFR4的高选择性小分子抑制剂在肿瘤靶向治疗领域具有重大应用前景。因此，研发选择性靶向FGFR4的可以作为良好药物候选物的新型抗肿瘤试剂将可以满足国内肝癌及其他肿瘤靶向药物的需求，并带来安全性好和特异性更强的优点。
发明内容
本发明的目的在于提供一种FGFR4抑制剂、其制备方法与药学上的应用。
本发明第一方面提供一种式(I)化合物、其立体异构体或其药学上可接受盐：
Figure PCTCN2017116186-appb-000001
其中，
X1选自-C(R7)-或N；
X2、X3、X5各自独立的选自-(CR8)n-、-C(O)-、-N(R9)-、N、O或S；
X4选自C或N；
Z选自C1-8亚烷基、C2-8亚链烯基、C2-8亚链炔基、C3-8环烷基、3-10元杂环基、C5-10芳基或5-10元杂芳基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-10元杂环基、C5-10芳基、5-10元杂芳基、-C0-8-S(O)rR10、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-C0-8-N(R13)-C(O)R12或-C0-8-N(R13)-C(O)OR11的取代基所取代，上述基团再任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-10元杂环基、C5-10芳基、5-10元杂芳基、-C0-8-S(O)rR10、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-C0-8-N(R13)-C(O)R12或-C0-8-N(R13)-C(O)OR11的取代基所取代；
R1选自氢、氘、C1-8烷基、C1-8烷氧C1-8烷基、C3-8环烷氧基C1-8烷基、C3-8环烷基C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-10元杂环基、C5-10芳基、5-10元杂芳基或C1-8烷酰基；
R2、R3、R4、R5、R6、R7各自独立的选自氢、氘、卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-10元杂环基、-C0-8-S(O)rR10、-C0-8-S(O)(NR9)R10、-C0-8-P(O)(R10)2、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-C0-8-N(R13)-C(O)R12或-C0-8-N(R13)-C(O)OR11，或者，R2与R4、R3与R5、R4与R6、R5与R6和其直接相连的碳原子一起形成C5-10环烷基、5-10元杂环基、5-10元芳基或5-10元杂芳基，
上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-10元杂环基、C5-10芳基、5-10元杂芳基、-C0-8-S(O)rR10、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-C0-8-N(R13)-C(O)R12或-C0-8-N(R13)-C(O)OR11的取代基所取代；
R8选自氢、氘、卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-10元杂环基、C5-10芳基、5-10元杂芳基、-C0-8-S(O)rR10、-C0-8-S(O)(NR9)R10、-C0-8-P(O)(R10)2、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-C0-8-N(R13)-C(O)R12或-C0-8-N(R13)-C(O)OR11，
上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-10元杂环基、C5-10芳基、5-10元杂芳基、-C0-8-S(O)rR10、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-C0-8-N(R13)-C(O)R12或-C0-8-N(R13)-C(O)OR11的取代基所取代，上述基团再任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-10元杂环基、C5-10芳基、5-10元杂芳基、-C0-8-S(O)rR10、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-C0-8-N(R13)-C(O)R12或-C0-8-N(R13)-C(O)OR11的取代基所取代；
R9选自氢、氘、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-10元杂环基、C5-10芳基、5-10元杂芳基或C1-8烷酰基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-10元杂环基、C5-10芳基、5-10元杂芳基、-C0-8-S(O)rR10、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-C0-8-N(R13)-C(O)R12或-C0-8-N(R13)-C(O)OR11的取代基所取代；
R10选自氢、氘、C1-8烷基、C2-8链烯基、C3-8环烷基、3-10元杂环基、卤取代C1-8烷基、C5-10芳基、5-10元杂芳基、氨基、单C1-8烷基氨基、二C1-8烷基氨基或C1-8烷酰氨基；
R11选自氢、氘、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-10元杂环基、C5-10芳基或5-10元杂芳基，上述基团任选地被以下基团单取代或多取代：氘、卤素、氰基、C1-8烷基、C1-8烷氧基、C1-8烷硫基、C3-8环烷基、3-10元杂环基、C5-10芳基、5-10元杂芳基、C1-8烷基磺酰基、C1-8烷基磺酰胺基、氨基、单C1-8烷基氨基、二C1-8烷基氨基、＝O或羟基；
R12选自氢、氘、C1-8烷基、C2-8链烯基、C2-8链炔基、C1-8烷氧基、C3-8环烷基、C3-8环烷氧基、3-10元杂环基、3-10元杂环氧基、C5-10芳基、5-10元杂芳基、C5-10芳氧基或5-10元杂芳氧基，上述基团任选地被以下基团单取代或多取代：氘、卤素、氰基、C1-8烷基、C1-8烷氧基、C1-8烷硫基、C3-8环烷基、3-10元杂环基、C5-10芳基、5-10元杂芳基、C1-8烷基磺酰基、C1-8烷基磺酰胺基、氨基、单C1-8烷基氨基、二C1-8烷基氨基、＝O或羟基；
R13、R14各自独立的选自氢、氘、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-10元杂环基、C5-10芳基、5-10元杂芳基、C1-8烷基磺酰基或C1-8烷酰基，或者，R13、R14和其直接相连的氮原子一起形成4-10元杂环基，
上述基团任选地被以下基团单取代或多取代：氘、卤素、C1-8烷基、C1-8烷氧基、C1-8烷硫基、C3-8环烷基、3-10元杂环基、C5-10芳基、5-10元杂芳基、C1-8烷基磺酰基、C1-8烷基磺酰胺基、氨基、单C1-8烷基氨基、二C1-8烷基氨基、＝O或羟基；
m为0或1；
n为0、1或2；
r为0、1或2；
条件是，当X3选自-(CR8)n-时，X2选自-C(O)-，X4选自C，X5选自-N(R9)-、N、O或S；当X3选自-C(O)-时，X2选自-N(R9)-，且Z选自C1-8烷基、C2-8链烯基、C2-8链炔基或苯基。
作为进一步优选的方案，所述的式(I)化合物、其立体异构体或其药学上可接受盐，Z选自C1-4亚烷基、C2-4亚链烯基、C2-4亚链炔基、C3-6环烷基、3-8元杂环基、C5-8芳基或5-8元杂芳基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-8元杂环基、C5-8芳基、5-8元杂芳基、-C0-4-S(O)rR10、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0-4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-C0-4-N(R13)-C(O)R12或-C0-4-N(R13)-C(O)OR11的取代基所取代，上述基团再任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、卤取代C1-4烷基、C3-6环烷基、3-8元杂环基、C5-8芳基、5-8元杂芳基、-C0-4-S(O)rR10、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0-4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-C0-4-N(R13)-C(O)R12或-C0-4-N(R13)-C(O)OR11的取代基所取代；
R1选自氢、氘、C1-4烷基、C1-4烷氧C1-4烷基、C3-6环烷氧基C1-4烷基、C3-6环烷基C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-8元杂环基、C5-8芳基、5-8元杂芳基或C1-4烷酰基；
R2、R3、R4、R5、R6、R7各自独立的选自氢、氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-8元杂环基、-C0-4-S(O)rR10、-C0-4-S(O)(NR9)R10、-C0-4-P(O)(R10)2、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0-4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-C0-4-N(R13)-C(O)R12或-C0-4-N(R13)-C(O)OR11，或者，R2与R4、R3与R5、R4与R6、R5与R6和其直接相连的碳原子一起形成C5-8环烷基、5-8元杂环基、5-8元芳基或5-8元杂芳基，
上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、卤取代C1-4烷基、C3-4环烷基、3-8元杂环基、C5-8芳基、5-8元杂芳基、-C0-4-S(O)rR10、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0-4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-C0-4-N(R13)-C(O)R12或-C0-4-N(R13)-C(O)OR11的取代基所取代。
作为更进一步优选的方案，所述的式(I)化合物、其立体异构体或其药学上可接受盐，Z选自C1-2亚烷基或如下结构：
Figure PCTCN2017116186-appb-000002
上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-8元杂环基、C5-8芳基、5-8元杂芳基、-C0-4-S(O)rR10、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0-4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-C0-4-N(R13)-C(O)R12或-C0-4-N(R13)-C(O)OR11的取代基所取代，上述基团再任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、卤取代C1-4烷基、C3-6环烷基、3-8元杂环基、C5-8芳基、5-8元杂芳基、 -C0-4-S(O)rR10、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0-4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-C0-4-N(R13)-C(O)R12或-C0-4-N(R13)-C(O)OR11的取代基所取代。
作为更进一步优选的方案，所述的式(I)化合物、其立体异构体或其药学上可接受盐，R1选自氢、氘、甲基、异丙基、甲氧乙基、环丙氧甲基、环丙甲基、烯丙基、环丙基或乙酰基；
R2、R3、R4、R5各自独立的选自氢、氘、卤素、C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-8元杂环基、-C0-4-O-R11或-C0-4-NR13R14，或者，R2与R4、R3与R5和其直接相连的碳原子一起形成C5-8环烷基、5-8元杂环基、5-8元芳基或5-8元杂芳基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、卤取代C1-4烷基、C3-4环烷基、3-8元杂环基、C5-8芳基、5-8元杂芳基、-C0-4-S(O)rR10、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0-4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-C0-4-N(R13)-C(O)R12或-C0-4-N(R13)-C(O)OR11的取代基所取代；
R6选自氢或氘。
作为更进一步优选的方案，所述的式(I)化合物、其立体异构体或其药学上可接受盐，R1选自氢、氘、甲基或环丙甲基；
R2、R3、R4、R5各自独立的选自氢、氘、氯、氟、甲基、异丙基、烯丙基、乙炔基、环丙基、3-氧杂环丁基、三氟甲基、三氘甲基、-C0-4-O-R11或-C0-4-NR13R14，或者，R2与R4、R3与R5和其直接相连的碳原子一起形成5-8元杂环基，所述杂原子选自氧或氮，所述5-8元杂环基任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、卤取代C1-4烷基、C3-4环烷基、3-8元杂环基、C5-8芳基、5-8元杂芳基、-C0-4-S(O)rR10、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0-4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-C0-4-N(R13)-C(O)R12或-C0-4-N(R13)-C(O)OR11的取代基所取代；
R6选自氢或氘。
作为更进一步优选的方案，所述的式(I)化合物、其立体异构体或其药学上可接受盐选自如下式(Ⅱa)化合物：
Figure PCTCN2017116186-appb-000003
其中，X3选自-N(R9)-、N、O或S；
Z选自C1-2亚烷基或如下结构：
Figure PCTCN2017116186-appb-000004
上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-8元杂环基、C5-8芳基、5-8元杂芳基、-C0-4-S(O)rR10、 -C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0-4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-C0-4-N(R13)-C(O)R12或-C0-4-N(R13)-C(O)OR11的取代基所取代，上述基团再任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、卤取代C1-4烷基、C3-6环烷基、3-8元杂环基、C5-8芳基、5-8元杂芳基、-C0-4-S(O)rR10、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0-4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-C0-4-N(R13)-C(O)R12或-C0-4-N(R13)-C(O)OR11的取代基所取代；
R2、R3、R4、R5各自独立的选自氢、氘、氯、氟、甲基、异丙基、烯丙基、乙炔基、环丙基、3-氧杂环丁基、三氟甲基、三氘甲基、-C0-4-O-R11或-C0-4-NR13R14，或者，R2与R4、R3与R5和其直接相连的碳原子一起形成5-8元杂环基，所述杂原子选自氧或氮，所述5-8元杂环基任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、卤取代C1-4烷基、C3-4环烷基、3-8元杂环基、C5-8芳基、5-8元杂芳基、-C0-4-S(O)rR10、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0-4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-C0-4-N(R13)-C(O)R12或-C0-4-N(R13)-C(O)OR11的取代基所取代；
R7选自氢、氘、氯、氟、羟基、烯丙基、乙炔基、环丙基、3-氧杂环丁基、三氟甲基、三氘甲基、-C0-4-O-R11或-C0-4-NR13R14；
R9选自氢、氘、C1-4烷基、C3-6环烷基或3-8元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、卤取代C1-4烷基、C3-6环烷基、3-8元杂环基、C5-8芳基、5-8元杂芳基、-C0-4-S(O)rR10、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0-4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-C0-4-N(R13)-C(O)R12或-C0-4-N(R13)-C(O)OR11的取代基所取代；
X1、X2、X5、R8、R10、R11、R12、R13、R14、m、n、r如前所述。
作为更进一步优选的方案，所述的式(I)化合物、其立体异构体或其药学上可接受盐选自如下式(Ⅲa-1)、(Ⅲa-2)、(Ⅲa-3)或(Ⅲa-4)化合物：
Figure PCTCN2017116186-appb-000005
其中，Z选自C1-2亚烷基或如下结构：
Figure PCTCN2017116186-appb-000006
上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-8元杂环基、C5-8芳基、5-8元杂芳基、-C0-4-S(O)rR10、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0-4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-C0-4-N(R13)-C(O)R12或-C0-4-N(R13)-C(O)OR11的取代基所取代，上述基团再任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、卤取代C1-4烷基、C3-6环烷基、3-8元杂环基、C5-8芳基、5-8元杂芳基、-C0-4-S(O)rR10、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0-4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-C0-4-N(R13)-C(O)R12或-C0-4-N(R13)-C(O)OR11的取代基所取代；
R2、R3、R4、R5各自独立的选自氢、氘、氯、氟、羟基、甲基、异丙基、环丙基、3-氧杂环丁基、三氟甲基、三氘甲基或-O-R11，或者，R2与R4、R3与R5和其直接相连的碳原子一起形成5-8元杂环基，所述杂原子选自氧或氮；
R7选自氢、氘、氯、氟、羟基、环丙基或-O-R11；
R9选自氢、氘、C1-4烷基、C3-6环烷基或3-8元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、C1-4烷基、卤取代C1-4烷基、C3-6环烷基、3-8元杂环基、-C0-4-O-R11、-C0-4-NR13R14或-C0-4-C(O)NR13R14的取代基所取代；
X1、X5、R8、R10、R11、R12、R13、R14、m、n、r如权利要求1所述。
作为更进一步优选的方案，所述的式(I)化合物、其立体异构体或其药学上可接受盐，选自式(Ⅳa-1)化合物：
Figure PCTCN2017116186-appb-000007
其中，X5选自-CH-或N；
Z选自C1-2亚烷基或如下结构：
Figure PCTCN2017116186-appb-000008
上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-8元杂环基、C5-8芳基、5-8元杂芳基、-C0-4-S(O)rR10、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0-4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-C0-4-N(R13)-C(O)R12或-C0-4-N(R13)-C(O)OR11的取代基所取代，上述基团再任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、卤取代C1-4烷基、C3-6环烷基、3-8元杂环基、C5-8芳基、5-8元杂芳基、-C0-4-S(O)rR10、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0-4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-C0-4-N(R13)-C(O)R12或-C0-4-N(R13)-C(O)OR11的取代基所取代；
R2、R3、R4、R5各自独立的选自氢、氘、氯、氟、羟基、甲基、异丙基、环丙基、3-氧杂环丁基、三氟甲基、三氘甲基或-O-R11，或者，R2与R4、R3与R5和其直接相连的碳原子一起形成5-8元杂环基，所述杂原子选自氧或氮；
R7选自氢、氘、氯、氟、羟基、环丙基或-O-R11；
R8选自氢、氘、卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-10元杂环基、C5-10芳基、5-10元杂芳基、-C0-8-S(O)rR10、-C0-8-S(O)(NR9)R10、-C0-8-P(O)(R10)2、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-C0-8-N(R13)-C(O)R12或-C0-8-N(R13)-C(O)OR11，
上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、卤取代C1-4烷基、C3-6环烷基、3-8元杂环基、C5-8芳基、5-8元杂芳基、-C0-4-S(O)rR10、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0-4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-C0-4-N(R13)-C(O)R12或-C0-4-N(R13)-C(O)OR11的取代基所取代，上述基团再任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、卤取代C1-4烷基、C3-6环烷基、3-8元杂环基、C5-8芳基、5-8元杂芳基、-C0-4-S(O)rR10、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0-4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-C0-4-N(R13)-C(O)R12或-C0-4-N(R13)-C(O)OR11的取代基所取代；
X1、R10、R11、R12、R13、R14、m、n、r如前所述。
作为更进一步优选的方案，所述的式(I)化合物、其立体异构体或其药学上可接受盐，R8选自氢、氘、卤素、氰基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-10元杂环基、C5-10芳基、5-10元杂芳基、-C0-8-O-R11、-C0-8-NR13R14、-C0-8-N(R13)-C(O)R12或-C0-8-N(R13)-C(O)OR11，
上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、卤取代C1-4烷基、C3-6环烷基、3-8元杂环基、C5-8芳基、5-8元杂芳基、-C0-4-S(O)rR10、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0-4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-C0-4-N(R13)-C(O)R12或-C0-4-N(R13)-C(O)OR11的取代基所取代，上述基团再任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、卤取代C1-4烷基、C3-6环烷基、3-8元杂环基、C5-8芳基、5-8元杂芳基、-C0-4-S(O)rR10、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0-4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-C0-4-N(R13)-C(O)R12或-C0-4-N(R13)-C(O)OR11的取代基所取代。
作为更进一步优选的方案，所述的式(I)化合物、其立体异构体或其药学上可接受盐，选自如下式(Ⅱb)化合物：
Figure PCTCN2017116186-appb-000009
其中，X3选自-(CR8)n-或-C(O)-；
Z选自C1-2亚烷基或如下结构：
Figure PCTCN2017116186-appb-000010
上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-8元杂环基、C5-8芳基、5-8元杂芳基、-C0-4-S(O)rR10、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0-4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-C0-4-N(R13)-C(O)R12或-C0-4-N(R13)-C(O)OR11的取代基所取代；
R2、R3、R4、R5各自独立的选自氢、氘、氯、氟、甲基、异丙基、烯丙基、乙炔基、环丙基、3-氧杂环丁基、三氟甲基、三氘甲基、-C0-4-O-R11或-C0-4-NR13R14，或者，R2与R4、R3与R5和其直接相连的碳原子一起形成5-8元杂环基，所述杂原子选自氧或氮，所述5-8元杂环基任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、卤取代C1-4烷基、C3-4环烷基、3-8元杂环基、C5-8芳基、5-8元杂芳基、-C0-4-S(O)rR10、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0-4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-C0-4-N(R13)-C(O)R12或-C0-4-N(R13)-C(O)OR11的取代基所取代；
R7选自氢、氘、氯、氟、羟基、烯丙基、乙炔基、环丙基、3-氧杂环丁基、三氟甲基、三氘甲基、-C0-4-O-R11或-C0-4-NR13R14；
R9选自氢、氘、C1-4烷基、C3-6环烷基或3-8元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、卤取代C1-4烷基、C3-6环烷基、3-8元杂环基、C5-8芳基、5-8元杂芳基、-C0-4-S(O)rR10、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0-4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-C0-4-N(R13)-C(O)R12或-C0-4-N(R13)-C(O)OR11的取代基所取代；
X1、X2、X5、R8、R10、R11、R12、R13、R14、m、n、r如前所述；
条件是，当X3选自-(CR8)n-时，X2选自-C(O)-，X5选自-N(R9)-、N、O或S；当X3选自-C(O)-时，X2选自-N(R9)-，且Z选自C1-4烷基或苯基。
作为更进一步优选的方案，所述的式(I)化合物、其立体异构体或其药学上可接受盐选自如下式(Ⅲb-1)或(Ⅲb-2)化合物：
Figure PCTCN2017116186-appb-000011
其中，Z选自C1-2亚烷基或如下结构：
Figure PCTCN2017116186-appb-000012
上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-8元杂环基、C5-8芳基、5-8元杂芳基、-C0-4-S(O)rR10、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0-4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-C0-4-N(R13)-C(O)R12或-C0-4-N(R13)-C(O)OR11的取代基所取代；
R2、R3、R4、R5各自独立的选自氢、氘、氯、氟、羟基、甲基、异丙基、环丙基、3-氧杂环丁基、三氟甲基、三氘甲基或-O-R11，或者，R2与R4、R3与R5和其直接相连的碳原子一起形成5-8元杂环基，所述杂原子选自氧或氮；
R7选自氢、氘、氯、氟、羟基、环丙基或-O-R11；
X1、R10、R11、R12、R13、R14、m、r如前所述。
作为更进一步优选的方案，所述的式(I)化合物、其立体异构体或其药学上可接受盐选自如下式(Ⅲb-3)化合物：
Figure PCTCN2017116186-appb-000013
其中，R2、R3、R4、R5各自独立的选自氢、氘、氯、氟、羟基、甲基、异丙基、环丙基、3-氧杂环丁基、三氟甲基、三氘甲基或‐O‐R11，或者，R2与R4、R3与R5和其直接相连的碳原子一起形成5-8元杂环基，所述杂原子选自氧或氮；
R7选自氢、氘、氯、氟、羟基、环丙基或-O-R11；
R9选自氢、氘、C1-4烷基、C3-6环烷基或3-8元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、C1-4烷基、卤取代C1-4烷基、C3-6环烷基、3-8元杂环基、-C0-4-O-R11、-C0-4-NR13R14或-C0-4-C(O)NR13R14的取代基所取代；
X1、R8、R10、R11、R13、R14、n如前所述。
作为最优选的方案，所述的式(I)化合物、其立体异构体或其药学上可接受盐包括但不限于如下化合物：
Figure PCTCN2017116186-appb-000014
Figure PCTCN2017116186-appb-000015
Figure PCTCN2017116186-appb-000016
Figure PCTCN2017116186-appb-000017
Figure PCTCN2017116186-appb-000018
Figure PCTCN2017116186-appb-000019
Figure PCTCN2017116186-appb-000020
Figure PCTCN2017116186-appb-000021
Figure PCTCN2017116186-appb-000022
Figure PCTCN2017116186-appb-000023
Figure PCTCN2017116186-appb-000024
Figure PCTCN2017116186-appb-000025
Figure PCTCN2017116186-appb-000026
Figure PCTCN2017116186-appb-000027
Figure PCTCN2017116186-appb-000028
Figure PCTCN2017116186-appb-000029
Figure PCTCN2017116186-appb-000030
Figure PCTCN2017116186-appb-000031
Figure PCTCN2017116186-appb-000032
Figure PCTCN2017116186-appb-000033
Figure PCTCN2017116186-appb-000034
Figure PCTCN2017116186-appb-000035
Figure PCTCN2017116186-appb-000036
Figure PCTCN2017116186-appb-000037
Figure PCTCN2017116186-appb-000038
Figure PCTCN2017116186-appb-000039
Figure PCTCN2017116186-appb-000040
Figure PCTCN2017116186-appb-000041
Figure PCTCN2017116186-appb-000042
Figure PCTCN2017116186-appb-000043
Figure PCTCN2017116186-appb-000044
Figure PCTCN2017116186-appb-000045
Figure PCTCN2017116186-appb-000046
Figure PCTCN2017116186-appb-000047
Figure PCTCN2017116186-appb-000048
Figure PCTCN2017116186-appb-000049
Figure PCTCN2017116186-appb-000050
Figure PCTCN2017116186-appb-000051
Figure PCTCN2017116186-appb-000052
Figure PCTCN2017116186-appb-000053
Figure PCTCN2017116186-appb-000054
Figure PCTCN2017116186-appb-000055
Figure PCTCN2017116186-appb-000056
Figure PCTCN2017116186-appb-000057
Figure PCTCN2017116186-appb-000058
Figure PCTCN2017116186-appb-000059
Figure PCTCN2017116186-appb-000060
Figure PCTCN2017116186-appb-000061
本发明第二方面提供一种前述式(I)化合物、其立体异构体或其药学上可接受盐的制备方法，当m＝1时，根据烯丙酰胺基的反应顺序，可按如下方式进行制备：
Figure PCTCN2017116186-appb-000062
或者，
Figure PCTCN2017116186-appb-000063
或者，
Figure PCTCN2017116186-appb-000064
或者，
Figure PCTCN2017116186-appb-000065
或者，当m＝0时，可按如下方式进行制备：
Figure PCTCN2017116186-appb-000066
任选的，根据取代基的不同，在不同的取代基之间进行转换反应；
其中：X为离去基团，优选自氯、溴、甲硫基、甲磺酰基或甲氧基；R选自硝基、氰基或叠氮基；Pg为氨基保护基，优选自叔丁氧羰基、苄氧羰基、2-联苯基-2-丙氧羰基或对甲苯磺酰基；X1、X2、X3、X4、X5、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、m、n、r如前所述。
作为更进一步优选的方案，当X选自甲磺酰基时，其相应化合物可通过R为甲硫基时与氧化剂，例如m-CPBA(间氯过氧苯甲酸)氧化反应制备得到。
作为更进一步优选的方案，所述任选的根据取代基的不同，在不同的取代基之间进行转换反应是指，在需要时，也可以在前述缩合反应之后，根据X1、X2、X3、X4、X5、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14取代基定义的不同，在符合化学合成原理的条件下，通过本领域常规实验进行取代基的转换。
本发明第三方面提供一种药物组合物，其包括治疗有效剂量的前述式(I)化合物、其立体异构体或其药学上可接受盐及可药用的载体。
本发明第四方面提供一种前述式(I)化合物、其立体异构体或其药学上可接受盐，或前述药物组合物在制备FGFR4抑制剂药物中的应用。
本发明第五方面提供一种前述式(I)所示的化合物、其立体异构体或其药学上可接受的盐，或前述药物组合物在制备治疗癌症的药物中的应用。
优选的，所述癌症是前列腺癌、肝癌、胰腺癌、食管癌、胃癌、肺癌、乳腺癌、卵巢癌、结肠癌、皮肤癌、神经胶质母细胞瘤或横纹肌肉瘤。
本发明第六方面提供一种前述式(I)所示的化合物、其立体异构体或其药学上可接受的盐，或前述药物组合物，其用作FGFR4抑制剂。
本发明第七方面提供一种前述式(I)所示的化合物、其立体异构体或其药学上可接受的盐，或前述药物组合物，其用于治疗癌症。
优选的，所述癌症是前列腺癌、肝癌、胰腺癌、食管癌、胃癌、肺癌、乳腺癌、卵巢癌、结肠癌、皮肤癌、神经胶质母细胞瘤或横纹肌肉瘤。
本发明第八方面提供一种抑制FGFR4的方法，所述方法包括给予需要治疗的患者有效治疗量的前述式(I)所示的化合物、其立体异构体或其药学上可接受的盐，或前述药物组合物。
本发明第九方面提供一种治疗癌症的方法，所述方法包括给予需要治疗的患者有效治疗量的前述式(I)所示的化合物、其立体异构体或其药学上可接受的盐，或前述药物组合物。
优选的，所述癌症是前列腺癌、肝癌、胰腺癌、食管癌、胃癌、肺癌、乳腺癌、卵巢癌、结肠癌、皮肤癌、神经胶质母细胞瘤或横纹肌肉瘤。
本发明所开发的系列化合物对FGFR4激酶活性具有很强的抑制作用，并具有非常高的选择性，可广泛应用于制备治疗癌症特别是前列腺癌、肝癌、胰腺癌、食管癌、胃癌、肺癌、乳腺癌、卵巢癌、结肠癌、皮肤癌、神经胶质母细胞瘤或横纹肌肉瘤的药物，有望开发成新一代FGFR4抑制剂药物。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本申请的发明人经过广泛而深入地研究，首次研发出一种具有式(Ⅰ)结构的FGFR4抑制剂，该系列化合物对FGFR4激酶活性具有很强的抑制作用，并具有非常高的选择性，可广泛应用于制备治疗癌症特别是前列腺癌、肝癌、胰腺癌、食管癌、胃癌、肺癌、乳腺癌、卵巢癌、结肠癌、皮肤癌、神经胶质母细胞瘤或横纹肌肉瘤的药物，有望开发成新一代FGFR4抑制剂药物。。在此基础上，完成了本发明。
详细说明：除非有相反陈述，下列用在说明书和权利要求书中的术语具有下述含义。
“烷基”指直链或含支链的饱和脂族烃基团，例如，“C1-8烷基”指包括1至8个碳原子的直链烷基和含支链烷基，包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1，1-二甲基丙基、1，2-二甲基丙基、2，2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1，1，2-三甲基丙基、1，1-二甲基丁基、1，2-二甲基丁基、2，2-二甲基丁基、1，3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2，3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2，3-二甲基戊基、2，4-二甲基戊基、2，2-二甲基戊基、3，3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2，3-二甲基己基、2，4-二甲基己基、2，5-二甲基己基、2，2-二甲基己基、3，3-二甲基己基、4，4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基或其各种支链异构体等。
烷基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C1-8烷基、卤取代C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-10元杂环基、C5-10芳基、5-10元杂芳基、-C0-8-S(O)rR10、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-C0-8-N(R13)-C(O)R12或-C0-8-N(R13)-C(O)OR11的取代基所取代。
“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，例如，“C3-8环烷基”指包括3至8个碳原子的环烷基，分为单环环烷基、多环环烷基，其中：
单环环烷基包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等。
多环环烷基包括螺环、稠环和桥环的环烷基。“螺环烷基”指单环之间共用一个碳原子(称螺原子)的多环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，螺环烷基包括但不限于：
Figure PCTCN2017116186-appb-000067
“稠环烷基”指系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，稠环烷基包括但不限于：
Figure PCTCN2017116186-appb-000068
“桥环烷基”指任意两个环共用两个不直接连接的碳原子的全碳多环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，桥环烷基包括但不限于：
Figure PCTCN2017116186-appb-000069
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，包括但不限于茚满基、四氢萘基、苯并环庚烷基等。
环烷基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C1-8烷基、卤取代C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-10元杂环基、C5-10芳基、5-10元杂芳基、-C0-8-S(O)rR10、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-C0-8-N(R13)-C(O)R12或-C0-8-N(R13)-C(O)OR11的取代基所取代。
“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其中一个或多个环原子选自氮、氧或S(O)r(其中r是整数0、1、2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。例如，“5-10元杂环基”指包含5至10个环原子的环基，“3-10元杂环基”指包含3至10个环原子的环基。
单环杂环基包括但不限于吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。
多环杂环基包括螺环、稠环和桥环的杂环基。“螺杂环基”指单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子选自氮、氧或S(O)r(其中r是整数0、1、2)的杂原子，其余环原子为碳。这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基。螺杂环基包括但不限于：
Figure PCTCN2017116186-appb-000070
“稠杂环基”指系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子选自氮、氧或S(O)r(其中r是整数0、1、2)的杂原子，其余环原子为碳。根据组成环的数目可以分为双环、三环、四环或多环稠杂环烷基，稠杂环基包括但不限于：
Figure PCTCN2017116186-appb-000071
“桥杂环基”指任意两个环共用两个不直接连接的原子的多环杂环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子选自氮、氧或S(O)r(其中r是整数0、1、2)的杂原子，其余环原子为碳。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，桥杂环基包括但不限于：
Figure PCTCN2017116186-appb-000072
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，包括但不限于：
Figure PCTCN2017116186-appb-000073
杂环基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C1-8烷基、卤取代C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-10元杂环基、C5-10芳基、5-10元杂芳基、-C0-8-S(O)rR10、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-C0-8-N(R13)-C(O)R12或-C0-8-N(R13)-C(O)OR11的取代基所取代。
“芳基”指全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，具有共轭的π电子体系的多环(即其带有相邻对碳原子的环)基团，例如，“C5-10芳基”指含有5-10个碳的全碳芳基，“5-10元芳基”指含有5-10个碳的全碳芳基，包括但不限于苯基和萘基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，包括但不限于：
Figure PCTCN2017116186-appb-000074
芳基可以是取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-10元杂环基、C5-10芳基、5-10元杂芳基、-C0-8-S(O)rR10、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-C0-8-N(R13)-C(O)R12或-C0-8-N(R13)-C(O)OR11的取代基所取代。
“杂芳基”指包含1至4个杂原子的杂芳族体系，所述杂原子包括氮、氧和S(O)r(其中r是整数0、1、2)的杂原子，例如，5-7元杂芳基指含有5-7个环原子的杂芳族体系，5-10元杂芳基指含有5-10个环原子的杂芳族体系，包括但不限于呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，包括但不限于：
Figure PCTCN2017116186-appb-000075
杂芳基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C1-8烷基、卤取代C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-10元杂环基、C5-10芳基、5-10元杂芳基、-C0-8-S(O)rR10、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-C0-8-N(R13)-C(O)R12或-C0-8-N(R13)-C(O)OR11的取代基所取代。
“烯基”指由至少两个碳原子和至少一个碳-碳双键组成的如上述定义的烷基，例如，C2-8链烯基指含有2-8个碳的直链或含支链烯基。包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-，2-或3-丁烯基等。
烯基可以是取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C1-8烷基、卤取代C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-10元杂环基、C5-10芳基、5-10元杂芳基、-C0-8-S(O)rR10、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-C0-8-N(R13)-C(O)R12或-C0-8-N(R13)-C(O)OR11的取代基所取代。
“炔基”指至少两个碳原子和至少一个碳-碳三键组成的如上所定义的烷基，例如，C2-8链炔基指含有2-8个碳的直链或含支链炔基。包括但不限于乙炔基、1-丙炔基、2-丙炔基、1-，2-或3-丁炔基等。
炔基可以是取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C1-8烷基、卤取代C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-10元杂环基、C5-10芳基、5-10元杂芳基、-C0-8-S(O)rR10、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-C0-8-N(R13)-C(O)R12或-C0-8-N(R13)-C(O)OR11的取代基所取代。
“烷氧基”指-O-(烷基)，其中烷基的定义如上所述，例如，“C1-8烷氧基”指含1-8个碳的烷基氧基，包括但不限于甲氧基、乙氧基、丙氧基、丁氧基等。
烷氧基可以是任选取代的或未取代的，当被取代时，取代基，优选为一个或多个以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C1-8烷基、卤取代C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-10元杂环基、C5-10芳基、5-10元杂芳基、-C0-8-S(O)rR10、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-C0-8-N(R13)-C(O)R12或-C0-8-N(R13)-C(O)OR11的取代基所取代。
“环烷氧基”指和-O-(未取代的环烷基)，其中环烷基的定义如上所述，例如，“C3-8环烷氧基”指含3-8个碳的环烷基氧基，包括但不限于环丙氧基、环丁氧基、环戊氧基、环己氧基等。
环烷氧基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C1-8烷基、卤取代C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-10元杂环基、C5-10芳基、5-10元杂芳基、-C0-8-S(O)rR10、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-C0-8-N(R13)-C(O)R12或-C0-8-N(R13)-C(O)OR11的取代基所取代。
“3-10元杂环氧基”指和-O-(未取代的3-10元杂环基)，其中3-10元杂环基的定义如上所述，3-10元杂环氧基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C1-8烷基、卤取代C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-10元杂环基、C5-10芳基、5-10元杂芳基、-C0-8-S(O)rR10、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-C0-8-N(R13)-C(O)R12或-C0-8-N(R13)-C(O)OR11的取代基所取代。
“C5-10芳氧基”指和-O-(未取代的C5-10芳基)，其中C5-10芳基的定义如上所述，C5-10芳氧基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C1-8烷基、卤取代C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-10元杂环基、C5-10芳基、5-10元杂芳基、-C0-8-S(O)rR10、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-C0-8-N(R13)-C(O)R12或-C0-8-N(R13)-C(O)OR11的取代基所取代。
“5-10元杂芳氧基”指和-O-(未取代的5-10元杂芳基)，其中5-10元杂芳基的定义如上所述，5-10元杂芳氧基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C1-8烷基、卤取代C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-10元杂环基、C5-10芳基、5-10元杂芳基、-C0-8-S(O)rR10、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-C0-8-N(R13)-C(O)R12或-C0-8-N(R13)-C(O)OR11的取代基所取代。
“C1-8烷酰基”指C1-8烷基酸去掉羟基后剩下的一价原子团，通常也表示为“C0-7-C(O)-”，例如，“C1-C(O)-”是指乙酰基；“C2-C(O)-”是指丙酰基；“C3-C(O)-”是指丁酰基或异丁酰基。
“-C0-8-S(O)rR10”指-S(O)rR10中的硫原子连接在C0-8烷基上，其中C0烷基是指键，C1-8烷基的定义如上所述。
“-C0-8-O-R11”指-O-R11中的氧原子连接在C0-8烷基上，其中C0烷基是指键，C1-8烷基的定义如上所述。
“-C0-8-C(O)OR11”指-C(O)OR11中的羰基连接在C0-8烷基上，其中C0烷基是指键，C1-8烷基的定义如上所述。
“-C0-8-C(O)R12”指-C(O)R12中的羰基连接在C0-8烷基上，其中C0烷基是指键，C1-8烷基的定义如上所述。
“-C0-8-O-C(O)R12”指-O-C(O)R12中的氧原子连接在C0-8烷基上，其中C0烷基是指键，C1-8烷基的定义如上所述。
“-C0-8-NR13R14”指-NR13R14中的氮原子连接在C0-8烷基上，其中C0烷基是指键，C1-8烷基的定义如上所述。
“-C0-8-C(O)NR13R14”指-C(O)NR13R14中的羰基连接在C0-8烷基上，其中C0烷基是指键，C1-8烷基的定义如上所述。
“-C0-8-N(R13)-C(O)R12”指-N(R13)-C(O)R12中的氮原子连接在C0-8烷基上，其中C0烷基是指键，C1-8烷基的定义如上所述。
“-C0-8-N(R13)-C(O)OR11”指-N(R13)-C(O)OR11中的氮原子连接在C0-8烷基上，其中C0烷基是指键，C1-8烷基的定义如上所述。
“卤取代C1-8烷基”指烷基上的氢任选的被氟、氯、溴、碘原子取代的1-8个碳烷基基团，包括但不限于二氟甲基、二氯甲基、二溴甲基、三氟甲基、三氯甲基、三溴甲基等。
“卤取代C1-8烷氧基”烷基上的氢任选的被氟、氯、溴、碘原子取代的1-8个碳烷氧基基团。包括但不限于二氟甲氧基、二氯甲氧基、二溴甲氧基、三氟甲氧基、三氯甲氧基、三溴甲氧基等。
“卤素”指氟、氯、溴或碘。“THF”指四氢呋喃。“EA/EtOAc”指乙酸乙酯。“MeOH”指甲醇。“EtOH”指乙醇。“PivOH”指三甲基乙酸。“DMSO”指二甲亚砜。“DMF”指N、N-二甲基甲酰胺。“DIPEA”指二异丙基乙胺。“CH3CN”指乙晴。“PE”指石油醚。“DCM/CH2Cl2”指二氯甲烷。“DCE”指二氯乙烷。“DMA”指二甲基乙酰胺。“Et3N”指三乙胺。“NH4Cl”指氯化铵。“NMP”指N-甲基吡咯烷酮。“HOAc”指乙酸。“TFA”指三氟乙酸。“MeI”指碘甲烷。“KI”指碘化钾。“MsCl”指甲磺酰氯。“SO2Cl2”指磺酰氯。“POCl3”指三氯氧磷。“MeONa”指甲醇钠。“NaHCO3”指碳酸氢钠。“Na2SO4”指硫酸钠。“K2CO3”指碳酸钾。“NaN3”指叠氮化钠。“NaH”指氢化钠。“CuI”指碘化亚铜。“PPA”指多聚磷酸。“m-CPBA”指间氯过氧苯甲酸。“MnO2”指二氧化锰。“LiAlH4”指氢化铝锂。“LiOH”指氢氧化锂。“NaOAc”指乙酸钠。“NaNO2”指亚硝酸钠。“AgNO3”指硝酸银。“Boc2O”指二碳酸二叔丁酯。“LiCl”指氯化锂。“Zn(CN)2”指氰化锌。“IBX”指2-碘酰苯甲酸。“Pd/C”指钯碳。“Pd(OAc)2”指醋酸钯。“PPh3”指三苯基磷。“Pd(PPh3)2Cl2”指双三苯基磷二氯化钯。“Pd2(dba)3”指三(二亚苄基丙酮)二钯。“Pd(dppf)Cl2”指[1,1'-双(二苯基膦基)二茂铁]二氯化钯。“Pd(PPh3)4”指四(三苯基膦)钯。“brett-phos”指二环己基[3,6-二甲氧基-2',4',6'-三异丙基[1,1'-联苯]-2-基]膦。
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和键的碳原子(如烯烃)结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
下面结合实施例对本发明做进一步详细、完整地说明，但决非限制本发明，本发明也并非仅局限于实施例的内容。
本发明的化合物结构是通过核磁共振(NMR)或/和液质联用色谱(LC-MS)来确定的。NMR化学位移(δ)以百万分之一(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代甲醇(CD3OD)和氘代氯仿(CDCl3)，内标为四甲基硅烷(TMS)。
液质联用色谱LC-MS的测定用Agilent 6120质谱仪。HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C18 150×4.6mm色谱柱)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，TLC采用的规格是0.15mm～0.20mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。
本发明实施例中的起始原料是已知的并且可以在市场上买到，或者可以采用或按照本领域已知的方法来合成。
在无特殊说明的情况下，本发明的所有反应均在连续的磁力搅拌下，在干燥氮气或氩气氛下进行，溶剂为干燥溶剂，反应温度单位为摄氏度。
中间体的制备
中间体1 7-氯-3-(2,6-二氯-3,5-二甲氧苯基)-2H-吡喃并[3,2-c]吡啶-2-酮的制备
Figure PCTCN2017116186-appb-000076
第一步：6-氯-4-甲氧基尼古丁酸乙酯的制备
Figure PCTCN2017116186-appb-000077
化合物4,6-二氯尼古丁酸乙酯(10.0g，45.4mmol)加入无水THF(100mL)，冰水浴冷却至0℃，再加入MeONa(2.8g，51.8mmol)。加完后室温搅拌，反应过夜。反应完全后浓缩，除去THF，粗产品溶于乙酸乙酯(100mL)，水洗2次，无水Na2SO4干燥。过滤，浓缩，得化合物6-氯-4-甲氧基尼古丁酸乙酯(8.2g，收率：84％)。MS(ESI):m/z 216.3[M+1]+.
第二步：(6-氯-4-甲氧基吡啶-3-基)甲醇的制备
Figure PCTCN2017116186-appb-000078
化合物6-氯-4-甲氧基尼古丁酸乙酯(8.2g，38.1mmol)溶于无水THF(200mL)，冰水浴冷却下加入LiAH4(3.0g，81.1mmol)，加完后室温反应2小时。反应完全，加入2N NaOH水溶液(25mL)萃取。过滤除去固体残渣，滤液经浓缩得化合物6-氯-4-甲氧基吡啶-3-基)甲醇(6.0g，收率：91％)。MS(ESI):m/z 174.2[M+1]+.
第三步：6-氯-4-甲氧基尼古丁醛的制备
Figure PCTCN2017116186-appb-000079
化合物6-氯-4-甲氧基吡啶-3-基)甲醇(6.0g，34.6mmol)溶于丙酮(100mL)，再加入IBX(12.0g，42.9mmol)，加热至回流，反应18小时。反应完全，过滤，浓缩，得化合物6-氯-4-甲氧基尼古丁醛(4.2g，收率：71％)。MS(ESI):m/z 172.2[M+1]+.
第四步：6-氯-4-羟基尼古丁醛的制备
Figure PCTCN2017116186-appb-000080
化合物6-氯-4-甲氧基尼古丁醛(4.2g，24.5mmol)溶于1,4-二氧六环(30ml)，再加入浓盐酸(10mL)，加热至90℃，反应16小时。反应完全后浓缩，粗产品经硅胶柱层析分离(PE：EA＝2:1)，得化合物6-氯-4-羟基尼古丁醛(1.5g，收率：39％)。
1H NMR(400MHz,CDCl3):δppm 11.37(s,1H),9.99(s,1H),8.57(s,1H),6.99(s,1H).
第五步：7-氯-3-(3,5-二甲氧苯基)-2H-吡喃并[3,2-c]吡啶-2-酮的制备
Figure PCTCN2017116186-appb-000081
化合物6-氯-4-羟基尼古丁醛(0.60g，3.82mmol)加入乙酸酐(10mL)，再加入2-(3,5-二甲氧苯基)乙酸(0.80g，4.08mmol)和三乙胺(1.5g，10.7mmol)，加热至110℃，反应40分钟。反应完全，冷却至室温，浓缩，所得固体用石油醚/乙酸乙酯(3:1)洗涤，得化合物7-氯-3-(3,5-二甲氧苯基)-2H-吡喃并[3,2-c]吡啶-2-酮(0.35g，收率：29％)。MS(ESI):m/z 318.3[M+1]+.
第六步：7-氯-3-(2,6-二氯-3,5-二甲氧苯基)-2H-吡喃并[3,2-c]吡啶-2-酮的制备
Figure PCTCN2017116186-appb-000082
化合物7-氯-3-(3,5-二甲氧苯基)-2H-吡喃并[3,2-c]吡啶-2-酮(0.35g，1.1mmol)溶于无水乙腈(10mL)。冷却至-30℃，滴加SO2Cl2(1.0g，7.4mmol)，维持低温反应1小时。加入饱和NaHCO3水溶液淬灭，浓缩除去乙腈。过滤，固体再依次水洗和石油醚/乙酸乙酯(3:1)洗涤，得化合物7-氯-3-(2,6-二氯-3,5-二甲氧苯基)-2H-吡喃并[3,2-c]吡啶-2-酮(0.21g，收率：49％)。MS(ESI):m/z 386.3[M+1]+.
中间体2 2-氯-6-(2,6-二氯-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶的制备
Figure PCTCN2017116186-appb-000083
第一步：2-氯-5-硝基异尼古丁酸的制备
Figure PCTCN2017116186-appb-000084
0℃下，在2-氯-4-甲基-5-硝基吡啶(20.0g,11.6mmol)的硫酸(200mL)溶液中加入三氧化铬(40.0g,40mmol)。加完后，混合物在0℃下搅拌1小时，慢慢变到室温搅拌过夜，然后泼到冰水(1L)中。过滤得到2-氯-5-硝基异尼古丁酸(18g,收率:77％)。MS(ESI):m/z201.1[M-1]-.
第二步：2-氯-5-硝基异尼古丁酸甲酯的制备
Figure PCTCN2017116186-appb-000085
0℃下，在2-氯-5-硝基异尼古丁酸(16g,80mmol)的二氯甲烷(150mL)混悬液中加入草酰氯(12.7g,100mmol)。加完后，反应液在室温下搅拌3小时。加入甲醇(100mL)，然后反应液在室温继续搅拌4小时，旋干。粗产品用二氯甲烷(200mL)溶解，用碳酸氢钠溶液(100mL*2)洗涤，并用无水硫酸钠干燥，浓缩得到化合物2-氯-5-硝基异尼古丁酸甲酯(17.2g,收率:98％)。
第三步：2-(3,5-二甲氧苯基)-5-硝基异尼古丁酸甲酯的制备
Figure PCTCN2017116186-appb-000086
在2-氯-5-硝基异尼古丁酸甲酯(10.0g,46.0mmol)的二氧六环(200mL)和水(50mL)溶液中加入3,5-二甲氧基苯硼酸(8.47g,46mmol)，四(三苯基膦)钯(5g,4.6mmol)和碳酸钠(5g,16mmol)。加完料后，混合物在110℃氮气环境下搅拌直到原料反应完。反应液浓缩后柱层析(洗脱剂:CH2Cl2/PE 20:1)分离，得到化合物2-(3,5-二甲氧苯基)-5-硝基异尼古丁酸甲酯(6g,收率:41％)。MS(ESI):m/z 318.9[M+1]+.
第四步：5-氨基-2-(3,5-二甲氧苯基)异尼古丁酸甲酯的制备
Figure PCTCN2017116186-appb-000087
在2-(3,5-二甲氧苯基)-5-硝基异尼古丁酸甲酯(6g,18.8mmol)的甲醇(100mL)溶液中加入钯/碳(10％,500mg)，然后混合物在室温氢气环境下搅拌4小时。过滤并旋干，得到5-氨基-2-(3,5-二甲氧苯基)异尼古丁酸甲酯(5g,收率:92.3％)。MS(ESI):m/z 289.3[M+1]+.
第五步：6-(3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-2,4(1H,3H)-二酮的制备
Figure PCTCN2017116186-appb-000088
5-氨基-2-(3,5-二甲氧苯基)异尼古丁酸甲酯(5g,17.4mmol)和脲(12g,200mmol)的混合物加热到160℃，搅拌4小时。然后泼到冰水(100mL)中，过滤，得到6-(3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-2,4(1H,3H)-二酮(6g,收率:99％)。MS(ESI):m/z 300.3[M+1]+.
第六步：2,4-二氯-6-(3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶的制备
Figure PCTCN2017116186-appb-000089
在6-(3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-2,4(1H,3H)-二酮(5.0g,16.7mmol)的三氯氧磷(50mL)混悬液中加入N,N-二乙基苯胺(3mL)。然后混合物在110℃下搅拌过夜。溶剂旋干，加入冰水(200mL)，用碳酸氢钠水溶液调节pH到7，水溶液用EtOAc(50mL)萃取3次。有机层用无水硫酸钠干燥，过滤，浓缩，柱层析分离[洗脱剂:(EA:PE＝1:5)]得到化合物2,4-二氯-6-(3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶(2.5g,收率:44.5％)。MS(ESI):m/z336.2[M+1]+.
第七步：2-氯-6-(3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-4-胺的制备
Figure PCTCN2017116186-appb-000090
在2,4-二氯-6-(3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶(2.5g,7.5mmol)的甲醇(100mL)溶液中加入浓氨水(2g)。然后混合物在25℃下搅拌4小时。用盐酸(1N)调节pH值到7，甲醇在真空下旋掉，过滤得到2-氯-6-(3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-4-胺(2g,收率:84％)。MS(ESI):m/z 317.1[M+1]+.
第八步：2-氯-6-(3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶的制备
Figure PCTCN2017116186-appb-000091
在2-氯-6-(3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-4-胺(1g,3.1mmol)的四氢呋喃(100mL)溶液中加入叔丁基亚硝酸酯(720mg,6.2mmol)。然后混合物加热到回流，搅拌48小时。反应液浓缩后柱层析[洗脱剂:(EA:PE＝1:5-1:2)]得到化合物2-氯-6-(3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶(400mg，收率:41％)。
1H NMR(400MHz,DMSO-d6):δ9.7(s,1H),9.53(s,1H),8.74(s,1H),7.4(s,2H),6.64(s,1H),3.88(S,6H)；
MS(ESI):m/z 302.0[M+1]+.
第九步：2-氯-6-(2,6-二氯-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶的制备
Figure PCTCN2017116186-appb-000092
参照中间体1第六步的合成方法制备。
中间体3 2-氯-6-(2,6-二氟-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶和
中间体4 2-氯-6-(2-氟-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶的制备
Figure PCTCN2017116186-appb-000093
2-氯-6-(3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶(120mg,0.4mmol)溶于干燥乙腈(20mL)，冰水浴冷却至0℃，慢慢滴加1-氯甲基-4-氟-1,4-重氮化二环2.2.2辛烷双(四氟硼酸盐)(select-fluor，283mg,0.8mmol)。加完后升至室温反应6小时。TLC监测，基本反应完全。用饱和NaHCO3淬灭，除去大部分乙腈，乙酸乙酯萃取。浓缩，硅胶柱层析(PE/EA＝10/11，加10％DCM调节)，得到2-氯-6-(2,6-二氟-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶(20mg，产率：15％)，MS m/z(ESI):338[M+H]+。同时得到2-氯-6-(2-氟-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶(70mg，产率55％)，MS m/z(ESI):320[M+H]+.
以下中间体5-10参照中间体2的合成方法制备：
Figure PCTCN2017116186-appb-000094
中间体11 7-氯-3-(2,6-二氯-3,5-二甲氧苯基)-1H-吡喃并[4,3-c]吡啶-1-酮的制备
Figure PCTCN2017116186-appb-000095
第一步：5-溴-2-氯异尼古丁酸甲酯的制备
Figure PCTCN2017116186-appb-000096
5-溴-2-氯异尼古丁酸(30.0g，12.6mmol)溶于甲醇(300mL)，再加入SOCl2(18.0g，15mmol)，加热至75℃，反应8小时，LCMS监测反应完全。冷却至室温，减压浓缩。所 得粗品加入EtOAc(300mL)，再用饱和NaHCO3水溶液洗涤，无水Na2SO4干燥。过滤，浓缩，得到5-溴-2-氯异尼古丁酸甲酯(32.0g，收率：99％)。MS(ESI):m/z 251.9[M+1]+.
第二步：2-氯-5-((3,5-二甲氧苯基)乙炔基)异尼古丁酸甲酯的制备
Figure PCTCN2017116186-appb-000097
5-溴-2-氯异尼古丁酸甲酯(30g,120mmol)溶于1,4-二氧六环(300mL)，再加入3,5-二甲氧基苯乙炔(20.4g,120mmol)，CuI(2.28g,12mmol)，Pd(dppf)Cl2(4.2g,6mmol)以及Et3N(12.0g,120mmol)，抽换气，N2保护,加热至60℃，反应6小时。反应完全，过滤，浓缩。粗品经硅胶柱层析分离(DCM:PE＝20:1)，得化合物2-氯-5-((3,5-二甲氧苯基)乙炔基)异尼古丁酸甲酯(22g,收率：55％)。MS(ESI):m/z 332.1[M+1]+.
第三步：7-氯-3-(3,5-二甲氧苯基)-1H-吡喃并[4,3-c]吡啶-1-酮的制备
Figure PCTCN2017116186-appb-000098
2-氯-5-((3,5-二甲氧苯基)乙炔基)异尼古丁酸甲酯(21.0g，63mmol)加入PPA(200mL)，加热至80℃，反应8小时。LCMS监测反应完全，反应混合物倒入冰水(1000mL)。过滤，得到固体化合物7-氯-3-(3,5-二甲氧苯基)-1H-吡喃并[4,3-c]吡啶-1-酮(15.0g，收率：75％)。MS(ESI):m/z 318.2[M+1]+.
第四步：7-氯-3-(2,6-二氯-3,5-二甲氧苯基)-1H-吡喃并[4,3-c]吡啶-1-酮的制备
Figure PCTCN2017116186-appb-000099
参照中间体1第六步的合成方法制备。
中间体12 7-氯-3-(2,6-二氯-3,5-二甲氧苯基)-2-甲基-2,6-二氮杂萘-1(2H)-酮的制备
Figure PCTCN2017116186-appb-000100
第一步：7-氯-3-(3,5-二甲氧苯基)-2,6-二氮杂萘-1(2H)-酮的制备
Figure PCTCN2017116186-appb-000101
化合物7-氯-3-(3,5-二甲氧苯基)-1H-吡喃并[4,3-c]吡啶-1-酮(15g,47.3mmol)溶于DMF(200mL)，加入浓氨水(150mL)。反应混合物加热至80℃反应48小时。LCMS监测反应完全，过滤，得到固体化合物7-氯-3-(3,5-二甲氧苯基)-2,6-二氮杂萘-1(2H)-酮(7.5g，收率：50.5％)。
1H NMR(400MHz,DMSO-d6):δppm11.7(m,1H),8.97(s,1H),8.01(s,1H),7.14(s,1H),6.97(s,2H),6.61(s,1H),3.86(s,6H)；
MS(ESI):m/z 317.2[M+1]+.
第二步：7-氯-3-(3,5-二甲氧苯基)-2-甲基-2,6-二氮杂萘-1(2H)-酮的制备
Figure PCTCN2017116186-appb-000102
7-氯-3-(3,5-二甲氧苯基)-2,6-二氮杂萘-1(2H)-酮(2g,6.32mmol)溶于DMF(30mL)，冰水浴冷却下加入NaH(758mg,18.95mmol)。混合物在0℃下搅拌15分钟，然后滴入MeI(8.967g,63.151mmol)，室温下搅拌反应1小时。反应完毕后，加水淬灭。乙酸乙酯萃取三次，合并有机相，水洗，饱和食盐水洗，无水硫酸钠干燥。过滤，浓缩后柱层析分离(洗脱剂:PE/EtOAc＝2:1)，得到化合物7-氯-3-(3,5-二甲氧苯基)-2-甲基-2,6-二氮杂萘-1(2H)-酮(1.35g,收率：65％)。
MS m/z(ESI):331.0[M+H]+.
第三步：7-氯-3-(2,6-二氯-3,5-二甲氧苯基)-2-甲基-2,6-二氮杂萘-1(2H)-酮的制备
Figure PCTCN2017116186-appb-000103
参照中间体1第六步的合成方法制备。MS m/z(ESI):399.2[M+H]+.
以下中间体13-19参照中间体12的合成方法制备：
Figure PCTCN2017116186-appb-000104
Figure PCTCN2017116186-appb-000105
中间体20 6-氯-2-(2,6-二氯-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-4(3H)-酮的制备
Figure PCTCN2017116186-appb-000106
第一步：5-氨基-2-氯异尼克酰胺的制备
Figure PCTCN2017116186-appb-000107
5-氨基-2-氯异尼古丁酸(4.0g，23mmol)加入SOCl2(50mL)，加热至80℃，搅拌反应4小时。反应完全，冷却至室温。浓缩，所得粗产品溶于无水THF(20mL)，冰水浴冷却，加入浓氨水(100mL)，反应完全。CH2Cl2(100mL)萃取5次，合并有机相，无水Na2SO4干燥。过滤，浓缩，得化合物5-氨基-2-氯异尼克酰胺(3.5g,收率：88％)。
第二步：6-氯-2-(3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-4(3H)-酮的制备
Figure PCTCN2017116186-appb-000108
化合物5-氨基-2-氯异尼克酰胺(3.5g，20.4mmol)和3,5-二甲氧基苯甲醛(3.7g，22.3mmol)溶于EtOH(50mL)，加入HOAc(10mL)，加热至80℃，反应2天。反应液浓缩，粗产品溶于CH2Cl2(100mL)和THF(100mL)混合溶液，再加入MnO2(17.0g，87.0mmol)，室温搅拌4天。反应完全，过滤，浓缩，粗品再加入EtOAc(100mL)打浆。过滤，得化合物6-氯-2-(3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-4(3H)-酮(4.0g，收率：63％)。
1H NMR(400MHz,DMSO-d6):δppm 12.78(s,1H),8.91(s,1H),7.95(s,1H),7.44(s,1H),7.43(s,1H),3.84(s,6H).
第三步：6-氯-2-(2,6-二氯-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-4(3H)-酮的制备
Figure PCTCN2017116186-appb-000109
6-氯-2-(3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-4(3H)-酮(1.0g，3.2mmol)溶于CH3CN(50mL)，冷却至-20℃，再加入SO2Cl2(0.85g，6.3mmol)，维持低温反应3小时。反应完全，加入饱和NaHCO3水溶液淬灭。过滤，得化合物6-氯-2-(2,6-二氯-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-4(3H)-酮(1.1g，92％)。MS(ESI):m/z 386[M+H]+.
中间体21 6-氯-2-(2,6-二氯-3,5-二甲氧苯基)-3-甲基吡啶并[3,4-d]嘧啶-4(3H)-酮的制备
Figure PCTCN2017116186-appb-000110
6-氯-2-(2,6-二氯-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-4(3H)-酮(0.65g,1.68mmol)溶于DMF(20mL)，冰水浴冷却至0℃，加入NaH(134mg,3.36mmol)。室温下搅拌反应2小时。反应完全，加入水(50mL)淬灭。过滤，清水洗涤，干燥，得到化合物6-氯-2-(2,6-二氯-3,5-二甲氧苯基)-3-甲基吡啶并[3,4-d]嘧啶-4(3H)-酮(0.65g,产率96％)。MS m/z(ESI):400[M+H]+.
中间体22 7-氯-3-(2,6-二氯-3,5-二甲氧苯基)-1-(2,2,2-三氟乙基)-1,6-二氮杂萘-2(1H)-酮的制备
Figure PCTCN2017116186-appb-000111
第一步：6-氯-4-((2,2,2-三氟乙基)氨基)尼古丁酸乙酯的制备
Figure PCTCN2017116186-appb-000112
4,6-二氯尼古丁酸乙酯(4.0g，18.18mmol)和三氟乙氨(2.7g，27.27mmol)溶于DMSO(50mL)，再加入Et3N(5.5g，54.55mmol)。加热至120℃，反应12小时。反应完全，冷却至室温，加入水(200mL)，再用EtOAc(50mL)萃取3次，有机相用无水Na2SO4干燥。过滤，浓缩，粗品经硅胶柱层析分离(PE:EA＝3:1)，得化合物6-氯-4-((2,2,2-三氟乙基)氨基)尼古丁酸乙酯(1.5g，收率：29.1％)。MS(ESI):m/z 283.0[M+1]+.
第二步：(6-氯-4-((2,2,2-三氟乙基)氨基)吡啶-3-基)甲醇的制备
Figure PCTCN2017116186-appb-000113
化合物6-氯-4-((2,2,2-三氟乙基)氨基)尼古丁酸乙酯(1.5g，5.32mmol)溶于干燥THF(30mL)，冰水浴冷却。缓慢加入LiAlH4(0.39g，10.64mmol)，0℃下反应2小时。反应完全，加入Na2SO4 .10H2O淬灭。过滤，滤液浓缩，得化合物(6-氯-4-((2,2,2-三氟乙基)氨基)吡啶-3-基)甲醇(1.1g，收率：86％)。
第三步：6-氯-4-((2,2,2-三氟乙基)氨基)尼古丁醛的制备
Figure PCTCN2017116186-appb-000114
化合物(6-氯-4-((2,2,2-三氟乙基)氨基)吡啶-3-基)甲醇(1.1g,4.58mmol)溶于CH2Cl2/THF(30mL/10mL)，再加入MnO2(4.78g,54.9mmol)，室温搅拌反应12小时。反应完全，过滤，滤液浓缩，得粗产品6-氯-4-((2,2,2-三氟乙基)氨基)尼古丁醛(0.86g，收率：79％)。
第四步：7-氯-3-(3,5-二甲氧苯基)-1-(2,2,2-三氟乙基)-1,6-二氮杂萘-2(1H)-酮的制备
Figure PCTCN2017116186-appb-000115
6-氯-4-((2,2,2-三氟乙基)氨基)尼古丁醛(0.86g，3.61mmol)溶于DMF(20mL)，再加入3,5-二甲氧基苯乙酸甲酯(760mg，3.61mmol)和K2CO3(1.5g，10.84mmol)，加热至110℃，反应3小时。反应完全，浓缩，粗产品经硅胶柱层析分离(PE:EA＝10:1)，得7-氯-3-(3,5-二甲氧苯基)-1-(2,2,2-三氟乙基)-1,6-二氮杂萘-2(1H)-酮(960mg，收率：67％)。MS(ESI):m/z 399.0[M+1]+.
第五步：7-氯-3-(2,6-二氯-3,5-二甲氧苯基)-1-(2,2,2-三氟乙基)-1,6-二氮杂萘-2(1H)-酮的制备
Figure PCTCN2017116186-appb-000116
参照中间体1第六步的合成方法制备。
以下中间体23-25参照中间体22的合成方法制备：
Figure PCTCN2017116186-appb-000117
Figure PCTCN2017116186-appb-000118
中间体26 3-氯-7-(2,6-二氯-3,5-二甲氧苯基)-2,6-二氮杂萘的制备
Figure PCTCN2017116186-appb-000119
第一步：5-溴-2-氯异尼古丁醛的制备
Figure PCTCN2017116186-appb-000120
二异丙胺(8.95g，88mmol)溶于干燥THF(100mL)，氮气保护，冷却至-78℃，滴加正丁基锂(50mL，78mmol)，加完后在0℃下搅拌反应10分钟。再冷却至-78℃，然后加入2-氯-5-溴吡啶(10.0g，52mmol)，在此温度下搅拌反应1小时，最后滴加干燥DMF(11.4g，0.16mol)，继续低温搅拌反应1小时。加入氯化铵溶液粹灭，然后用EtOAc(300mL)稀释，用水(50mL)洗涤3次，再用饱和食盐水(100mL)洗涤，无水硫酸钠干燥。过滤，浓缩后柱层析(洗脱剂:PE/EtOAc 9:1)分离，得到化合物5-溴-2-氯异尼古丁醛(7.0g,产率：61％)。
1H NMR(400MHz,CDCl3):δ10.3(s,1H),8.69(s,1H),7.73(s,1H).
MS m/z(ESI):252.0,254.0,256.0[M+MeOH+H]+。
第二步：2-氯-5-((3,5-二甲氧苯基)乙炔基)异尼古丁醛的制备
Figure PCTCN2017116186-appb-000121
氮气保护下将5-溴-2-氯异尼古丁醛(2.5g，11.3mmol)，1-乙炔基-3,5-二甲氧基苯(1.93g，11.9mmol)，DIPEA(3.66g，28.4mmol)，CuI(108mg，0.6mmol)，Pd(PPh3)2Cl2(398mg,0.6mmol)加入1,4-二氧六环(50mL)中，加热50℃，搅拌反应1小时。反应完全，用EtOAc(300mL)稀释，依次用水(50mL*3)和饱和食盐水(100mL)洗涤，并用无水硫酸钠干燥，浓缩后柱层析(洗脱剂:PE/EtOAc 9:1)分离，得到化合物2-氯-5-((3,5-二甲氧苯基)乙炔基)异尼古丁醛(3.0g,产率：75％)。MS m/z(ESI):302.2,304.2[M+H]+.
第三步：2-氯-5-((3,5-二甲氧苯基)乙炔基)异尼古丁醛肟的制备
Figure PCTCN2017116186-appb-000122
在氮气保护下2-氯-5-((3,5-二甲氧苯基)乙炔基)异尼古丁醛(0.6g,2mmol)，NaOAc(245mg,3.0mmol)以及盐酸羟胺(207mg,3.0mmol)溶于乙醇/1,2-二氯乙烷(20mL/11.2mL)，加热50℃，搅拌反应50分钟。反应完全，加入EtOAc(200mL)稀释，依次用水(50mL*2)和饱和食盐水(80mL)洗涤，并用无水硫酸钠干燥。过滤，浓缩，得到化合物2-氯-5-((3,5-二甲氧苯基)乙炔基)异尼古丁醛肟(612mg,产率：100％)。
第四步：7-氯-3-(3,5-二甲氧苯基)-2,6-二氮杂萘-2-氧化的制备
Figure PCTCN2017116186-appb-000123
2-氯-5-((3,5-二甲氧苯基)乙炔基)异尼古丁醛肟(612mg，1.9mmol)，AgNO3(66mg，0.38mmol)加入氯仿(20mL)，加热至60℃，搅拌反应1小时。反应完全，浓缩，柱层析(洗脱剂:CH2Cl2/MeOH 35:1)分离，得到化合物7-氯-3-(3,5-二甲氧苯基)-2,6-二氮杂萘-2-氧化(580mg，产率：95％)。
MS m/z(ESI):317.2,319.2[M+H]+.
第五步：3-氯-7-(3,5-二甲氧苯基)-2,6-二氮杂萘的制备
Figure PCTCN2017116186-appb-000124
7-氯-3-(3,5-二甲氧苯基)-2,6-二氮杂萘-2-氧化(200mg,0.63mmol)溶于二氯甲烷(10mL)，冰水浴冷却，再加入三氯化磷(0.7mL,1.4mmol)。室温下搅拌反应过夜。反应完全，加入饱和NaHCO3水溶液(20ml)，DCM(80mL)萃取。饱和食盐水(50mL)洗涤，无水硫酸钠干燥。过滤，浓缩，柱层析(洗脱剂：CH2Cl2/MeOH 50:1)分离，得化合物3-氯-7-(3,5-二甲氧苯基)-2,6-二氮杂萘(60mg,产率：32％)。MS m/z(ESI):301.2,303.2[M+H]+.
第六步：3-氯-7-(2,6-二氯-3,5-二甲氧苯基)-2,6-二氮杂萘的制备
Figure PCTCN2017116186-appb-000125
参照中间体1的合成方法制备。
以下中间体27-32参照中间体26的合成方法制备：
Figure PCTCN2017116186-appb-000126
中间体33 7-氯-N-(环丙基甲基)-3-(2,6-二氯-3,5-二甲氧苯基)-2,6-二氮杂萘-1-胺的制备
Figure PCTCN2017116186-appb-000127
第一步：7-氯-1-((环丙基甲基)氨基)-3-(3,5-二甲氧苯基)-2,6-二氮杂萘2-氧化的制备
Figure PCTCN2017116186-appb-000128
将7-氯-3-(3,5-二甲氧苯基)-2,6-二氮杂萘2-氧化(4.0g，12.6mmol)溶于甲苯(80mL)，依次加入环丙基甲胺(7.19g，0.1mol)和CuI(241mg,1.26mmol)。在氧气氛围下加热50度反应过夜。反应完全，反应液过滤后浓缩。残留物柱层析(洗脱剂:二氯甲烷/甲醇25:1)分离，得到化合物7-氯-1-((环丙基甲基)氨基)-3-(3,5-二甲氧苯基)-2,6-二氮杂萘2-氧化(2.8g，57％)。
MS m/z(ESI):386.4[M+H]+.
第二步：7-氯-N-(环丙基甲基)-3-(3,5-二甲氧苯基)-2,6-二氮杂萘-1-胺的制备
Figure PCTCN2017116186-appb-000129
将7-氯-1-((环丙基甲基)氨基)-3-(3,5-二甲氧苯基)-2,6-二氮杂萘2-氧化(2.8g,5.1mmol)溶于二氯甲烷(40mL)，冰水浴冷却下滴加PCl3(3mL，6.1mmol)，室温搅拌反应1小时。将碳酸氢钠饱和溶液(50mL)加入反应中，然后用二氯甲烷(100mL*3)萃取，合并有机相，用无水硫酸钠干燥浓缩。残留物柱层析(洗脱剂:二氯甲烷/甲醇50:1)分离，得到化合物7-氯-N-(环丙基甲基)-3-(3,5-二甲氧苯基)-2,6-二氮杂萘-1-胺(570mg，21％)。
MS m/z(ESI):370.4[M+H]+.
第三步：7-氯-N-(环丙基甲基)-3-(2,6-二氯-3,5-二甲氧苯基)-2,6-二氮杂萘-1-胺的制备
Figure PCTCN2017116186-appb-000130
将7-氯-N-(环丙基甲基)-3-(3,5-二甲氧苯基)-2,6-二氮杂萘-1-胺(550mg，0.27mmol)加入乙腈(20mL)，然后在-30度下滴加磺酰氯(73mg，0.54mmol)，维持低温搅拌反应1小时。将碳酸氢钠饱和溶液(30mL)加入反应液中，然后用乙酸乙酯(50mL*3)萃取。合并有机相，用无水硫酸钠干燥，过滤，浓缩。残留物柱层析(洗脱剂:石油醚/ 乙酸乙酯10:1)分离，得到化合物7-氯-N-(环丙基甲基)-3-(2,6-二氯-3,5-二甲氧苯基)-2,6-二氮杂萘-1-胺(337mg，52％)。
MS m/z(ESI+APCI):438.2/440.2[M+H]+.
以下中间体34-131参照中间体33的合成方法制备：
Figure PCTCN2017116186-appb-000131
Figure PCTCN2017116186-appb-000132
Figure PCTCN2017116186-appb-000133
Figure PCTCN2017116186-appb-000134
Figure PCTCN2017116186-appb-000135
Figure PCTCN2017116186-appb-000136
Figure PCTCN2017116186-appb-000137
Figure PCTCN2017116186-appb-000138
Figure PCTCN2017116186-appb-000139
Figure PCTCN2017116186-appb-000140
Figure PCTCN2017116186-appb-000141
Figure PCTCN2017116186-appb-000142
Figure PCTCN2017116186-appb-000143
中间体132 6-(2,6-二氯-3,5-二甲氧苯基)-8-甲氧基-2-(甲硫基)吡啶并[3,4-d]嘧啶的制备
Figure PCTCN2017116186-appb-000144
第一步：5-((3,5-二甲氧苯基)乙炔基)-2-(甲硫基)嘧啶-4-羧酸甲酯的制备
Figure PCTCN2017116186-appb-000145
5-溴-2-(甲硫基)嘧啶-4-羧酸甲酯(2631mg，10.0mmol)，1-乙炔基-3,5-二甲氧基苯(1622mg，10.0mmol)溶于干燥THF(50mL)，抽换气，氮气保护。再依次加入Et3N(2.8mL，20.0mmol)，Pd(PPh3)2Cl2(702mg，1.0mmol)，PPh3(525mg，2.0mmol)以及CuI(190mg，1.0mmol)。加热至90℃，搅拌反应过夜。反应完全，冷却至室温，加入饱和NaHCO3水溶液(100mL)，EtOAc(100mL)萃取2次。饱和食盐水洗涤，无水Na2SO4干燥。过滤，浓缩，硅胶柱层析(PE:EA4:1)分离，得化合物5-((3,5-二甲氧苯基)乙炔基)-2-(甲硫基)嘧啶-4-羧酸甲酯(2.5g，收率：73％)。MS m/z(ESI):345.2[M+H]+.
第二步：5-((3,5-二甲氧苯基)乙炔基)-2-(甲硫基)嘧啶-4-羧酸的制备
Figure PCTCN2017116186-appb-000146
5-((3,5-二甲氧苯基)乙炔基)-2-(甲硫基)嘧啶-4-羧酸甲酯(600mg，1.742mmol)溶于甲醇(15mL)，加入一水合氢氧化锂(366mg，8.711mmol)的水溶液(5mL)。室温搅拌过夜，反应完全。减压蒸发除去有机溶剂，水相中加入EtOAc(30mL)，用1N盐酸溶液调 节pH值到3～4。有机相分离后用饱和食盐水洗涤，无水硫酸钠干燥。过滤，浓缩，得到化合物5-((3,5-二甲氧苯基)乙炔基)-2-(甲硫基)嘧啶-4-羧酸(584mg,定量收率)。MS m/z(ESI):331.2[M+H]+.
第三步：6-(3,5-二甲氧苯基)-2-(甲硫基)-8H-吡喃并[3,4-d]嘧啶-8-酮的制备
Figure PCTCN2017116186-appb-000147
5-((3,5-二甲氧苯基)乙炔基)-2-(甲硫基)嘧啶-4-羧酸(584mg,1.768mmol)加入丙酮(25mL)，再向此悬浊液中加入AgNO3(180mg,1.059mmol)。室温搅拌反应4小时，并有绿色固体析出。过滤，得到化合物6-(3,5-二甲氧苯基)-2-(甲硫基)-8H-吡喃并[3,4-d]嘧啶-8-酮(600mg,粗品)。MS m/z(ESI):331.2[M+H]+.
第四步：6-(3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶-8(7H)-酮的制备
Figure PCTCN2017116186-appb-000148
6-(3,5-二甲氧苯基)-2-(甲硫基)-8H-吡喃并[3,4-d]嘧啶-8-酮(600mg，粗品)加入冰醋酸(50mL)，再加入醋酸铵(2.1g，27.243mmol)。加热至115℃反应16小时。反应完全，冷却至室温，缓慢倒入饱和碳酸氢钠水溶液。EtOAc(100mL)萃取。有机相分液后用饱和食盐水洗涤，无水硫酸钠干燥，浓缩后柱层析(洗脱剂:CH2Cl2/MeOH 0～6％)分离，得到化合物6-(3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶-8(7H)-酮(298mg，两步收率：50％)。MS m/z(ESI):330.2[M+H]+.
第五步：6-(3,5-二甲氧苯基)-8-甲氧基-2-(甲硫基)吡啶并[3,4-d]嘧啶的制备
Figure PCTCN2017116186-appb-000149
6-(3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶-8(7H)-酮(100mg，0.304mmol)和碳酸银(109mg，0.395mmol)加入甲苯(3mL)，再加入碘甲烷(431mg，3.036mmol)。混合物在封管内加热至100℃反应3小时。反应完全，冷却至室温，加入EtOAc稀释。过滤除去盐，滤液浓缩后柱层析(洗脱剂：PE/EtOAc 10～80％)分离，得到化合物6-(3,5-二甲氧苯基)-8-甲氧基-2-(甲硫基)吡啶并[3,4-d]嘧啶(47mg，收率：45％)。MS m/z(ESI):344.3[M+H]+.
第六步：6-(2,6-二氯-3,5-二甲氧苯基)-8-甲氧基-2-(甲硫基)吡啶并[3,4-d]嘧啶的制备
Figure PCTCN2017116186-appb-000150
参照中间体1的合成方法制备。
以下中间体133-134参照实施例132合成方法制备得到：
Figure PCTCN2017116186-appb-000151
中间体135 6-(2,6-二氯-3,5-二甲氧苯基)-N-(2-甲氧基乙基)-2-(甲硫基)吡啶并[3,4-d]嘧啶-8-胺的制备
Figure PCTCN2017116186-appb-000152
第一步：8-氯-6-(3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶的制备
Figure PCTCN2017116186-appb-000153
6-(3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶-8(7H)-酮(20.0mg，0.061mmol)和N,N-二异丙基乙胺(78mg，0.610mmol)加入乙腈(2mL)，再加入POCl3(0.8mL)。加热至90℃，搅拌反应过夜。减压蒸发，除去溶剂。加入EtOAc(10mL)稀释，用饱和碳酸氢钠溶液洗涤。有机相分离后用饱和食盐水洗涤，无水硫酸钠干燥。过滤，浓缩后柱层析(洗脱剂：PE/EtOAc 0～40％)分离，得到化合物8-氯-6-(3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶(6mg，收率：28％)。
MS m/z(ESI):348.2[M+H]+.
第二步：6-(3,5-二甲氧苯基)-N-(2-甲氧基乙基)-2-(甲硫基)吡啶并[3,4-d]嘧啶-8-胺的制备
Figure PCTCN2017116186-appb-000154
8-氯-6-(3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶(6mg，0.017mmol)和N,N-二异丙基乙胺(6.5mg，0.052mmol)溶于乙腈(1.5mL)，再加入2-甲氧基乙烷-1-胺(4mg，0.052mmol)。加热至90℃，搅拌反应过夜。反应完全，冷却至室温，加入EtOAc(5mL)稀释，用饱和食盐水洗涤，无水硫酸钠干燥。过滤，浓缩，柱层析(洗脱剂：PE/EtOAc 0～50％)分离，得到化合物6-(3,5-二甲氧苯基)-N-(2-甲氧基乙基)-2-(甲硫基)吡啶并[3,4-d]嘧啶-8-胺(4mg，收率：61％)。
MS m/z(ESI):387.4[M+H]+.
第三步：6-(2,6-二氯-3,5-二甲氧苯基)-N-(2-甲氧基乙基)-2-(甲硫基)吡啶并[3,4-d]嘧啶-8-胺的制备
Figure PCTCN2017116186-appb-000155
参照中间体1的合成方法制备。
中间体139 4-(6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶-8-基)吗啉的制备
Figure PCTCN2017116186-appb-000156
第一步：2,4-二氟-3-碘-1,5-二甲氧基苯的制备
Figure PCTCN2017116186-appb-000157
将化合物2,6-二氟-3,5-二甲氧基苯胺(27.0g，143mmol)加入6.0M盐酸溶液(240mL)中，冰水浴冷却下缓慢滴加NaNO2水溶液(10.35g，150mmol，30mL水)。25分钟滴加完，继续反应15分钟，产生桔红色悬浊液，将其加入KI水溶液(94.9g，570mmol，150mL水)。升至室温，搅拌反应30分钟，析出固体。过滤，水洗，得粗产品。将粗产 品加入MeOH(60mL)，室温搅拌30分钟。过滤，干燥，得2,4-二氟-3-碘-1,5-二甲氧基苯(29.3g，收率：68％)。
第二步：(2,6-二氟-3,5-二甲氧基苯乙炔)基三甲基硅烷的制备
Figure PCTCN2017116186-appb-000158
2,4-二氟-3-碘-1,5-二甲氧基苯(25.8g，86.0mmol)、三甲基硅基乙炔(36.5mL，258mmol)CuI(817mg，4.3mmol)以及三乙胺(35.8mL，258mmol)加入DMF(250mL)。抽换气，氮气保护，然后加入Pd(PPh3)2Cl2(3.15g，4.3mmol)。加热50度，反应2小时。反应完全，加入饱和NH4Cl水溶液淬灭，再入二氯甲烷萃取3次。合并有机相，Na2SO4干燥。过滤，浓缩，得粗产品(27.0g)，直接用于下步反应。
第三步：3-乙炔基-2,4-二氟-1,5-二甲氧基苯的制备
Figure PCTCN2017116186-appb-000159
(2,6-二氟-3,5-二甲氧基苯乙炔)基三甲基硅烷(27.0g，粗品)加入THF/MeOH(200/200mL)，再加入NaOH水溶液(8.6mL，8.6mmol，1.0N)。室温搅拌15分钟。反应完全，加入饱和NH4Cl水溶液淬灭，二氯甲烷萃取3次。合并有机相，无水Na2SO4干燥。过滤，浓缩，粗品加入MeOH(50mL)打浆，室温搅拌30分钟。过滤，得到目标产物(15.0g，2步收率：88％)。
第四步：5-((2,6-二氟-3,5-二甲氧苯基)乙炔基)-2-(甲硫基)嘧啶-4-羧酸甲酯的制备
Figure PCTCN2017116186-appb-000160
3-乙炔基-2,4-二氟-1,5-二甲氧基苯(10.0g，50.5mmol)和5-溴-2-甲硫基-嘧啶-4-羧酸甲酯(13.0g，49.5mmol)溶于DMF(100mL)，再加入CuI(479mg，2.52mmol)、Pd(PPh3)4(2.91g，2.52mmol)以及Et3N(35.0mL，252.5mmol)，氮气保护。加热100度，反应1.5小时。反应完全，冷却至室温，加入饱和NH4Cl水溶液淬灭，二氯甲烷萃取3次。合并有机相，无水Na2SO4干燥，过滤，浓缩。粗品经硅胶柱层析分离(PE:EA:DCM＝10:2:1)，纯化得目标产物(15.4g，收率：82％)。1H NMR(400MHz,CDCl3)δ8.82(s,1H),6.69(t,J＝8.0Hz,1H),4.03(s,3H),3.90(s,6H),2.63(s,3H).
第五步：5-((2,6-二氟-3,5-二甲氧苯基)乙炔基)-2-(甲硫基)嘧啶-4-羧酸的制备
Figure PCTCN2017116186-appb-000161
5-((2,6-二氟-3,5-二甲氧苯基)乙炔基)-2-(甲硫基)嘧啶-4-羧酸甲酯(30.0g，78.9mmol)溶于THF(300mL)，再加入LiOH/H2O(236.8mL，236.8mmol，1M)。室温搅拌反应2小时。反应完全，浓缩除去THF，再用稀盐酸酸化至pH约为3，析出固体。过滤，水洗，干燥，得目标产物(28.5g，收率：99％)。
第六步：6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲硫基)-8H-吡喃并[3,4-d]嘧啶-8-酮的制备
Figure PCTCN2017116186-appb-000162
5-((2,6-二氟-3,5-二甲氧苯基)乙炔基)-2-(甲硫基)嘧啶-4-羧酸(2.5g，6.83mmol)溶于DCE(50mL)，再加入TFA(0.5mL)。加热回流，反应过夜。反应完全，浓缩，再加入MeOH(50mL)打浆，室温搅拌30分钟。过滤，固体再用MeOH(10mL)洗涤，得目标产物(2.0g，收率：80％)。1H NMR(400MHz,DMSO-d6)δ9.23(s,1H),7.22(t,J＝8.4Hz,1H),7.17(s,1H),3.93(s,6H),2.63(s,3H).
第七步：6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶-8(7H)-酮的制备
Figure PCTCN2017116186-appb-000163
参照中间体132第四步操作。
第八步：8-氯-6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶的制备
Figure PCTCN2017116186-appb-000164
6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶-8(7H)-酮(1g,2.74mmol)溶于DCE(80mL)，加热至90度，然后加入苯膦酰二氯(3.0mL，21.92mmol)，加热搅拌16小时，冷却，在冰浴下调节pH至中性，DCM提取，硅胶柱层析分离(MeOH/DCM 1/20)，纯化得到化合物8-氯-6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶(930mg，产率88％)。MS m/z(ESI):384[M+H]+。
第九步：N-(环丙基甲基)-6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶-8-胺的制备
Figure PCTCN2017116186-appb-000165
参照中间体135第二步操作。
以下中间体136-330参照中间体135或139合成方法制备得到：
Figure PCTCN2017116186-appb-000166
Figure PCTCN2017116186-appb-000167
Figure PCTCN2017116186-appb-000168
Figure PCTCN2017116186-appb-000169
Figure PCTCN2017116186-appb-000170
Figure PCTCN2017116186-appb-000171
Figure PCTCN2017116186-appb-000172
Figure PCTCN2017116186-appb-000173
Figure PCTCN2017116186-appb-000174
Figure PCTCN2017116186-appb-000175
Figure PCTCN2017116186-appb-000176
Figure PCTCN2017116186-appb-000177
Figure PCTCN2017116186-appb-000178
Figure PCTCN2017116186-appb-000179
Figure PCTCN2017116186-appb-000180
Figure PCTCN2017116186-appb-000181
Figure PCTCN2017116186-appb-000182
Figure PCTCN2017116186-appb-000183
Figure PCTCN2017116186-appb-000184
Figure PCTCN2017116186-appb-000185
Figure PCTCN2017116186-appb-000186
Figure PCTCN2017116186-appb-000187
Figure PCTCN2017116186-appb-000188
Figure PCTCN2017116186-appb-000189
Figure PCTCN2017116186-appb-000190
中间体331 8-环丙基-6-(2,6-二氯-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶的制备
Figure PCTCN2017116186-appb-000191
第一步：8-氯-6-(2,6-二氯-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶的制备
Figure PCTCN2017116186-appb-000192
8-氯-6-(3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶(500mg,1.43mmol)加入二氯甲烷(30mL)，冷却至零下30度。SO2Cl2(0.35mL,4.31mmol)溶于二氯甲烷(30mL)，搅拌下，缓慢滴加入反应液中，加完继续搅拌反应半小时。反应完全，加入饱和碳酸氢钠水溶液(50mL)淬灭。萃取，再依次用水洗涤，饱和食盐水洗涤，无水硫酸钠干燥。过滤，浓缩，柱层析分离，纯化得8-氯-6-(2,6-二氯-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶(620mg，88％)。MS m/z(ESI):416.2[M+H]+.
第二步：8-环丙基-6-(2,6-二氯-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶的制备
Figure PCTCN2017116186-appb-000193
8-氯-6-(2,6-二氯-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶(83mg，0.20mmol)、环丙基硼酸(26mg，0.30mmol)、Pd(OAc)2(5mg，0.02mmol)、PCy3(11mg，0.04mmol)以及K3PO4(127mg，0.60mmol)加入甲苯/水(6:1，5mL)，加热至100度，搅拌反应过夜。反应完全，冷却至室温。EtOAc稀释，饱和食盐水洗涤，无水Na2SO4干燥。过滤，浓缩，柱层析分离，得8-环丙基-6-(2,6-二氯-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶(60mg，71％)。MS m/z(ESI):422.2[M+H]+.
以下中间体332-364参照331的合成方法制备得到：
Figure PCTCN2017116186-appb-000194
Figure PCTCN2017116186-appb-000195
Figure PCTCN2017116186-appb-000196
Figure PCTCN2017116186-appb-000197
Figure PCTCN2017116186-appb-000198
Figure PCTCN2017116186-appb-000199
中间体365(3S,4S)-4-叠氮四氢-2H-吡喃-3-胺盐酸的制备
Figure PCTCN2017116186-appb-000200
第一步：叔-丁基((3S,4S)-4-羟基四氢-2H-吡喃-3-基)氨基甲酸酯的制备
Figure PCTCN2017116186-appb-000201
(3R,4R)-3-氨基四氢-2H-吡喃-4-醇(5.00g，42.7mmol)溶于MeOH(100mL)，再依次加入Et3N(4.75g，47.0mmol)和Boc2O(10.25g，47.0mmol)，室温搅拌反应过夜。LCMS监测，反应完全。浓缩除去甲醇，粗产品用石油醚(100mL)洗涤，过滤，得化合物叔-丁基((3S,4S)-4-羟基四氢-2H-吡喃-3-基)氨基甲酸酯(8.50g，收率：92％)。
1H NMR(400MHz,CDCl3):δppm 4.68(m,1H),4.03(m,1H).3.93(m,1H),3.63(m,1H),3.45(m,2H),3.19(m,1H),2.81(m,1H),2.04(m,1H),1.68(m,1H),1.61(s,9H).
第二步：(3R,4R)-3-((叔-丁氧基羰基)氨基)四氢-2H-吡喃-4-基甲磺酸酯的制备
Figure PCTCN2017116186-appb-000202
化合物叔-丁基((3S,4S)-4-羟基四氢-2H-吡喃-3-基)氨基甲酸酯(8.5g,39.2mmol)溶于CH2Cl2(100mL)，冰水浴冷却，依次加入Et3N(4.30g，43.0mmol)和MsCl(4.98g，43.0mmol)。维持0℃反应6小时，反应完全。加水(20mL)洗涤，有机相用无水Na2SO4干燥。过滤，浓缩，得化合物(3R,4R)-3-((叔-丁氧基羰基)氨基)四氢-2H-吡喃-4-基甲磺酸酯(10.2g，收率：88％)。
1H NMR(400MHz,CDCl3):δppm 4.90(m,1H),4.76(m,1H).4.03(m,1H),3.98(m,1H),3.67(m,2H),3.47(m,1H),3.14(s,3H),2.18(m,1H),1.92(m,1H),1.44(s,9H).
第三步：叔-丁基((3S,4S)-4-叠氮四氢-2H-吡喃-3-基)氨基甲酸酯的制备
Figure PCTCN2017116186-appb-000203
(3R,4R)-3-((叔-丁氧基羰基)氨基)四氢-2H-吡喃-4-基甲磺酸酯(10.2g，34.6mmol)溶于干燥DMF(100mL)，再依次加入NaOAc(9.38g，69.0mmol)和NaN3(4.49g,69.0mmol)，加热至90℃，反应过夜。反应完全，化合物倒入水(200mL)，再用EtOAc(50mL)萃取2次。合并有机相，用LiCl水溶液(50mL)洗涤2次，无水Na2SO4干燥，过滤，浓缩，得化合物叔-丁基((3S,4S)-4-叠氮四氢-2H-吡喃-3-基)氨基甲酸酯(6.8g，收率：81％)。
1H NMR(400MHz,CDCl3):δppm 4.85(m,1H),3.89(m,2H).3.77(m,1H),3.63(m,2H),3.51(m,1H),1.93(m,2H),1.45(s,9H).
第四步：(3S,4S)-4-叠氮四氢-2H-吡喃-3-胺盐酸的制备
Figure PCTCN2017116186-appb-000204
叔-丁基((3S,4S)-4-叠氮四氢-2H-吡喃-3-基)氨基甲酸酯(6.8g，28.0mmol)加入HCl/EtOAc(100mL)，室温搅拌反应8小时。LCMS监测，反应完全。浓缩，得到化合物(3S,4S)-4-叠氮四氢-2H-吡喃-3-胺盐酸(4.0g，收率：80％)。
1H NMR(400MHz,DMSO-d6):δppm 8.47(m,3H),4.36(m,1H),3.80(m,2H),3.63(m,3H),2.0(m,2H).
中间体366(3S,4R)-4-叠氮四氢呋喃-3-胺盐酸的制备
Figure PCTCN2017116186-appb-000205
中间体366 参照中间体365的合成方法由(3S,4R)-4-氨基四氢呋喃-3-醇制备。
中间体367 叔-丁基((3R,4S)-4-氨基四氢呋喃-3-基)氨基甲酸酯
Figure PCTCN2017116186-appb-000206
第一步：叔-丁基((3S,4R)-4-羟基四氢呋喃-3-基)氨基甲酸酯的制备
Figure PCTCN2017116186-appb-000207
(3R,4S)-4-氨基四氢呋喃-3-醇(5.00g，48.487mmol)溶于甲醇(100mL)，加入三乙胺(12.24g,121.2mmol)，冰水浴冷却，再加入Boc2O(11.64g,53.34mmol)。加完后，室温下搅拌反应24小时。反应完全，有机相浓缩，除去大部分，加入水(100mL)搅拌，析出大量白色固体，过滤并用水洗涤，得到化合物叔-丁基((3S,4R)-4-羟基四氢呋喃-3-基)氨基甲酸酯(8.00g，收率：81％)。
1H NMR(400MHz,Chloroform-d)δ4.72(s,1H),4.29(m,1H),4.09(m,1H),4.08–4.02(m,1H),3.95(s,1H),3.69(m,1H),3.61(m,1H),1.45(s,9H).
第二步：叔-丁基((3R,4S)-4-(1,3-二羰基异二氢吲哚-2-基)四氢呋喃-3-基)氨基甲酸酯的制备
Figure PCTCN2017116186-appb-000208
叔-丁基((3S,4R)-4-羟基四氢呋喃-3-基)氨基甲酸酯(200mg,0.984mmol)，三苯基磷(620mg,2.364mmol)和异二氢吲哚-1,3-二酮(173mg,1.181mmol)溶于四氢呋喃(10mL)，冰水浴冷却，再缓慢滴加偶氮二羧酸二异丙酯(717mg,3.546mmol)。加完后，继续在冰水浴下搅拌反应1小时。然后反应液直接浓缩后柱层析(洗脱剂：PE/EA15-30％)分离，得到化合物叔-丁基((3R,4S)-4-(1,3-二羰基异二氢吲哚-2-基)四氢呋喃-3-基)氨基甲酸酯(950mg)粗品。
1H NMR(400MHz,Chloroform-d)δ7.87(m,2H),7.75(m,2H),4.84(d,J＝9.5Hz,1H),4.51(t,J＝8.0Hz,1H),4.37(t,J＝8.3Hz,1H),4.21–4.15(m,1H),4.09(t,J＝8.8Hz,1H),3.85(m,J＝9.2,6.4Hz,1H),1.11(s,9H).
MS m/z(ESI):559.5[M+H]+.
第三步：叔-丁基((3R,4S)-4-氨基四氢呋喃-3-基)氨基甲酸酯的制备
Figure PCTCN2017116186-appb-000209
叔-丁基((3R,4S)-4-(1,3-二羰基异二氢吲哚-2-基)四氢呋喃-3-基)氨基甲酸酯(950mg,21％,0.600mmol)溶于乙醇(6mL)，再加入水合肼(45mg,0.900mmol)。加热至75度，搅拌反应2小时。反应完全，浓缩，柱层析(洗脱剂：DCM/MeOH 0～5％)分离，得到化合物叔-丁基((3R,4S)-4-氨基四氢呋喃-3-基)氨基甲酸酯(120mg,两步收率：60％)。
1H NMR(400MHz,Chloroform-d)δ5.24(s,1H),4.11(s,1H),4.05(m,1H),4.00(m,1H),3.63–3.52(m,2H),3.49(m,1H),1.46(s,9H).
以下中间体368-375参照中间体367合成方法制备：
Figure PCTCN2017116186-appb-000210
Figure PCTCN2017116186-appb-000211
具体实施例化合物的制备
实施例1N-(2-((7-(2,6-二氯-3,5-二甲氧苯基)-6-甲基-5-羰基-5,6-二氢-2,6-二氮杂萘-3-基)氨基)-3-甲基苯基)丙烯酰基酰胺的制备
Figure PCTCN2017116186-appb-000212
第一步：3-(2,6-二氯-3,5-二甲氧苯基)-2-甲基-7-((2-甲基-6-硝基苯基)氨基)-2,6-二氮杂萘-1(2H)-酮的制备
Figure PCTCN2017116186-appb-000213
7-氯-3-(2,6-二氯-3,5-二甲氧苯基)-2-甲基-2,6-二氮杂萘-1(2H)-酮(150mg,0.375mmol)溶于1,4-二氧六环(20mL)，然后加入2-甲基-6-硝基苯胺(114mg,0.751mmol)，碳酸铯(367mg,1.126mmol)，brett-phos(161mg,0.3mmol)和Pd2(dba)3(172mg,0.188mmol)。抽换气，氮气保护。加热至120℃，反应2小时。反应完全，浓缩，硅胶柱层析分离(洗脱剂：PE/EtOAc＝2:1)，得到化合物3-(2,6-二氯-3,5-二甲氧苯基)-2-甲基-7-((2-甲基-6-硝基苯基)氨基)-2,6-二氮杂萘-1(2H)-酮(40mg,产率21％)。MS m/z(ESI):516[M+H]+.
第二步：7-((2-氨基-6-甲基苯基)氨基)-3-(2,6-二氯-3,5-二甲氧苯基)-2-甲基-2,6-二氮杂萘-1(2H)-酮的制备
Figure PCTCN2017116186-appb-000214
将3-(2,6-二氯-3,5-二甲氧苯基)-2-甲基-7-((2-甲基-6-硝基苯基)氨基)-2,6-二氮杂萘-1(2H)-酮(40mg,0.078mmol)溶于10毫升甲醇，然后加入10毫克Pd-C，反应在氢气下室温搅拌30分钟。反应结束后，浓缩，硅胶柱层析分离(洗脱剂：CH2Cl2/MeOH＝10:1)，得到化合物7-((2-氨基-6-甲基苯基)氨基)-3-(2,6-二氯-3,5-二甲氧苯基)-2-甲基-2,6-二氮杂萘-1(2H)-酮(9.5mg,产率25％)。
MS m/z(ESI):486.4[M+H]+.
第三步：N-(2-((7-(2,6-二氯-3,5-二甲氧苯基)-6-甲基-5-羰基-5,6-二氢-2,6-二氮杂萘-3-基)氨基)-3-甲基苯基)丙烯酰基酰胺的制备
Figure PCTCN2017116186-appb-000215
将7-((2-氨基-6-甲基苯基)氨基)-3-(2,6-二氯-3,5-二甲氧苯基)-2-甲基-2,6-二氮杂萘-1(2H)-酮(9.5mg，0.02mmol)溶于THF/H2O(4mL/1mL)，然后加入碳酸氢钠(9mg,0.104mmol)，冰水浴冷却，滴加丙烯酰氯/THF溶液(2mg/2mL，0.02mmol)。0℃下搅拌反应10分钟。反应完全，二氯甲烷萃取3次。合并有机相，再用饱和氯化钠水溶液洗涤，无水硫酸钠干燥。过滤，浓缩，粗品经硅胶柱层析分离，得到化合物N-(2-((7-(2,6-二氯-3,5-二甲氧苯基)-6-甲基-5-羰基-5,6-二氢-2,6-二氮杂萘-3-基)氨基)-3-甲基苯基)丙烯酰基酰胺(1mg，收率：9％)。
1H NMR(400MHz,CDCl3)δ8.60(s,1H),8.30(d,J＝8.1Hz,1H),7.31(s,1H),7.10–7.05(m,2H),6.68(s,1H),6.52–6.48(m,1H),6.44(s,1H),6.39(s,1H),6.33(d,J＝1.4Hz,1H),6.19(d,J＝10.2Hz,1H),5.68(dd,J＝10.2,1.4Hz,1H),3.99(s,6H),3.25(s,3H),2.21(s,3H).
MS m/z(ESI):541.4[M+H]+.
以下实施例2-75参照实施例1合成方法制备得到：
Figure PCTCN2017116186-appb-000216
Figure PCTCN2017116186-appb-000217
Figure PCTCN2017116186-appb-000218
Figure PCTCN2017116186-appb-000219
Figure PCTCN2017116186-appb-000220
Figure PCTCN2017116186-appb-000221
Figure PCTCN2017116186-appb-000222
Figure PCTCN2017116186-appb-000223
Figure PCTCN2017116186-appb-000224
Figure PCTCN2017116186-appb-000225
Figure PCTCN2017116186-appb-000226
实施例76 N-(3-((8-((环丙基甲基)氨基)-6-(2,6-二氯-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-2-基)氨基)-1-甲基-1H-吡唑-4-基)丙烯酰基酰胺的制备
Figure PCTCN2017116186-appb-000227
第一步：N-(环丙基甲基)-6-(2,6-二氯-3,5-二甲氧苯基)-2-(甲磺酰)吡啶并[3,4-d]嘧啶-8-胺的制备
Figure PCTCN2017116186-appb-000228
N-(环丙基甲基)-6-(2,6-二氯-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶-8-胺(210mg,0.465mmol)溶于二氯甲烷(6mL)，再加入间氯过氧苯甲酸(200mg,1.163mmol)。室温下搅拌反应18小时。反应完全，加入饱和亚硫酸钠溶液(5mL)，搅拌5分钟。二氯甲烷萃取，有机相再分别用饱和碳酸氢钠和饱和食盐水洗涤，并用无水硫酸钠干燥。过滤，浓缩，柱层析(洗脱剂:PE/EA＝2/1)分离，得到化合物N-(环丙基甲基)-6-(2,6-二氯-3,5-二甲氧苯基)-2-(甲磺酰)吡啶并[3,4-d]嘧啶-8-胺(186mg，收率：82.7％)。
MS m/z(ESI):483.4[M+H]+.
第二步：N8-(环丙基甲基)-6-(2,6-二氯-3,5-二甲氧苯基)-N2-(1-甲基-4-硝基-1H-吡唑-3-基)吡啶并[3,4-d]嘧啶-2,8-二胺
Figure PCTCN2017116186-appb-000229
N-(环丙基甲基)-6-(2,6-二氯-3,5-二甲氧苯基)-2-(甲磺酰)吡啶并[3,4-d]嘧啶-8-胺(90mg,0.186mmol)溶于干燥DMF(5mL)，零度下加入NaH(15mg,0.372mmol)，室温搅拌10分钟，然后加入1-甲基-4-硝基-1H-吡唑-3-胺(32mg，0.223mmol)，室温搅拌3小时。饱和氯化铵水溶液淬灭，乙酸乙酯萃取，硅胶柱层析(PE/EA＝1/1)分离，得到化合物N8-(环丙基甲基)-6-(2,6-二氯-3,5-二甲氧苯基)-N2-(1-甲基-4-硝基-1H-吡唑-3-基)吡啶并[3,4-d]嘧啶-2,8-二胺(100mg,产率98％)。MS m/z(ESI):545[M+H]+。
第三步：N2-(4-氨基-1-甲基-1H-吡唑-3-基)-N8-(环丙基甲基)-6-(2,6-二氯-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-2,8-二胺
Figure PCTCN2017116186-appb-000230
N8-(环丙基甲基)-6-(2,6-二氯-3,5-二甲氧苯基)-N2-(1-甲基-4-硝基-1H-吡唑-3-基)吡啶并[3,4-d]嘧啶-2,8-二胺(40mg，0.074mmol)溶于甲醇(10mL)，依次加入三乙胺(3滴)和Pd/C(20mg，10％含量)，氢气球下于室温搅拌45分钟。反应完全，过滤，硅胶柱层析(DCM/MeOH)，得到化合物N2-(4-氨基-1-甲基-1H-吡唑-3-基)-N8-(环丙基甲基)-6-(2,6- 二氯-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-2,8-二胺(30mg，产率80％)。MS m/z(ESI):515[M+H]+。
第四步：N-(3-((8-((环丙基甲基)氨基)-6-(2,6-二氯-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-2-基)氨基)-1-甲基-1H-吡唑-4-基)丙烯酰基酰胺
Figure PCTCN2017116186-appb-000231
N2-(4-氨基-1-甲基-1H-吡唑-3-基)-N8-(环丙基甲基)-6-(2,6-二氯-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-2,8-二胺(30mg，0.058mmol)溶于THF/H2O(8mL/2mL)，加入NaHCO3(33mg，0.39mmol)，冰浴下滴加烯丙酰氯(7mg，0.078mmol，溶于1mL THF中)。搅拌10分钟，加入20mL饱和碳酸氢钠水溶液，乙酸乙酯提取，硅胶柱层析(PE/EA＝1/1)分离，得到化合物N-(3-((8-((环丙基甲基)氨基)-6-(2,6-二氯-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-2-基)氨基)-1-甲基-1H-吡唑-4-基)丙烯酰基酰胺(10mg，产率22％)。MS m/z(ESI):569[M+H]+。
1H NMR(400MHz,CDCl3)δ9.03(s,1H),8.17(s,1H),6.77(s,1H),6.63(s,1H),6.38(d,J＝16.6Hz,2H),6.33–6.24(m,1H),5.70(d,J＝10.1Hz,1H),3.95(s,6H),3.87(s,3H),3.53-3.36(m,2H),1.19-1.10(m,1H),0.55-0.41(m,2H),0.42-0.29(m,2H).
以下实施例77-117参照实施例76合成方法制备得到：
Figure PCTCN2017116186-appb-000232
Figure PCTCN2017116186-appb-000233
Figure PCTCN2017116186-appb-000234
Figure PCTCN2017116186-appb-000235
Figure PCTCN2017116186-appb-000236
Figure PCTCN2017116186-appb-000237
Figure PCTCN2017116186-appb-000238
实施例118 (±)-N-((3R,4S)-4-((6-(2,6-二氯-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-2-基)氨基)四氢呋喃-3-基)丙烯酰基酰胺的制备
Figure PCTCN2017116186-appb-000239
第一步：(±)-(3S,4R)-N3-(6-(2,6-二氯-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-2-基)四氢呋喃-3,4-二胺的制备
Figure PCTCN2017116186-appb-000240
2-氯-6-(2,6-二氯-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶(40.0mg,0.108mmol)和反式-四氢呋喃-3,4-二胺二盐酸(28.3mg，0.162mmol)溶于乙腈(2mL)，再加入N,N-二异丙基乙胺(70mg,0.543mmol)。加热至回流，反应16小时。冷却，反应液加入EtOAc(10mL)稀释，饱和食盐水洗涤，并用无水硫酸钠干燥。过滤，浓缩，PTLC分离(展开剂:CH2Cl2/MeOH＝10:1)，得到化合物(3S,4R)-N3-(6-(2,6-二氯-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-2-基)四氢呋喃-3,4-二胺(30mg,收率：64％)。MS m/z(ESI):436.1[M+H]+.
第二步：(±)-N-((3R,4S)-4-((6-(2,6-二氯-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-2-基)氨基)四氢呋喃-3-基)丙烯酰基酰胺的制备
Figure PCTCN2017116186-appb-000241
(±)-(3S,4R)-N3-(6-(2,6-二氯-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-2-基)四氢呋喃-3,4-二胺(30.0mg,0.069mmol)溶于THF/H2O(1.2/0.3mL)，加入NaHCO3(23.0mg，0.276mmol)。冰水浴冷却，加入丙烯酰氯(6.8mg,0.076mmol)，加完后混合物在0℃下搅拌10分钟。反应液加入EtOAc(5mL)稀释，饱和食盐水洗涤，并用无水硫酸钠干燥。过滤，浓缩，粗品经PTLC分离纯化(展开剂:CH2Cl2/MeOH＝10:1)，得到化合物N-((3R,4S)-4-((6-(2,6-二氯-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-2-基)氨基)四氢呋喃-3-基)丙烯酰基酰胺(17.4mg,收率:52％)。
1H NMR(400MHz,CDCl3)δ9.21(s,1H),9.16(s,1H),7.55(s,1H),6.68(s,1H),6.45(d,J＝7.3Hz,1H),6.27(dd,J＝17.0,1.4Hz,1H),6.07(dd,J＝16.9,10.3Hz,1H),5.63(dd,J＝10.2,1.4Hz,1H),4.94(dd,J＝11.6,4.9Hz,1H),4.90–4.79(m,1H),4.34–4.19(m,2H),3.98(s,6H),3.90–3.79(m,2H).MS m/z(ESI):490.1[M+H]+.
实施例119 N-((3S,4S)-3-((6-(2,6-二氯-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-2-基)氨基)四氢-2H-吡喃-4-基)丙烯酰基酰胺的制备
Figure PCTCN2017116186-appb-000242
第一步：N-((3S,4S)-4-叠氮四氢-2H-吡喃-3-基)-6-(2,6-二氯-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-2-胺的制备
Figure PCTCN2017116186-appb-000243
2-氯-6-(2,6-二氯-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶(100mg,0.27mmol)溶于NMP(3mL)，然后加入Na2CO3(143mg,1.349mmol)和(3S,4S)-4-叠氮四氢-2H-吡喃-3-胺的盐酸盐(72mg,0.405mmol)。加热至120℃反应2小时。反应完全，冷却至室温，加水，乙酸乙酯萃取三次，合并有机相，无水Na2SO4干燥。过滤，浓缩，柱层析(洗脱剂：石油醚/乙酸乙酯2:1)分离，得到化合物N-((3S,4S)-4-叠氮四氢-2H-吡喃-3-基)-6-(2,6-二氯-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-2-胺(38mg,产率：29％)。MS m/z(ESI):478.4[M+H]+.
第二步：(3S,4S)-N3-(6-(2,6-二氯-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-2-基)四氢-2H-吡喃-3,4-二胺的制备
Figure PCTCN2017116186-appb-000244
N-((3S,4S)-4-叠氮四氢-2H-吡喃-3-基)-6-(2,6-二氯-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-2-胺(38mg,0.08mmol)溶于MeOH(8mL)，然后加入Pd/C(10mg)，氢气球下室温搅拌30分钟。反应结束后，浓缩，柱层析(洗脱剂：二氯甲烷/甲醇10:1)分离，得到化合物(3S,4S)-N3-(6-(2,6-二氯-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-2-基)四氢-2H-吡喃-3,4-二胺(12mg,产率：33％)。MS m/z(ESI):451.2[M+H]+.
第三步：N-((3S,4S)-3-((6-(2,6-二氯-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-2-基)氨基)四氢-2H-吡喃-4-基)丙烯酰基酰胺的制备
Figure PCTCN2017116186-appb-000245
(3S,4S)-N3-(6-(2,6-二氯-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-2-基)四氢-2H-吡喃-3,4-二胺(12mg，0.027mmol)溶于THF/H2O(4mL/1mL)，然后加入NaHCO3(12mg,0.141mmol)，冰水浴冷却，滴加丙烯酰氯(3mg,0.027mmol)的THF(2mL)溶液。低温搅拌反应10分钟，反应完全。二氯甲烷萃取三次，合并有机相，饱和氯化钠洗，无水硫酸钠干燥，浓缩，柱层析[洗脱剂:二氯甲烷/石油醚(10:1)]得到化合物N-((3S,4S)-3-((6-(2,6-二氯-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-2-基)氨基)四氢-2H-吡喃-4-基)丙烯酰基酰胺(6.3mg，产率：47％)。
1H NMR(400MHz,CDCl3)δ9.17(s,2H),7.56(s,1H),6.68(s,1H),6.25(dd,J＝16.9,1.4Hz,1H),6.01(dd,J＝17.0,10.3Hz,1H),5.60(dd,J＝10.3,1.4Hz,1H),4.55(s,1H),4.35(s,1H),4.11–4.00(m,2H),3.98(s,6H),3.78(d,J＝12.1Hz,1H),3.64(dd,J＝13.4,10.9Hz,1H),2.24-2.20(m,2H),2.02-1.99(m,2H).MS m/z(ESI):505.4[M+H]+.
以下实施例120-420、752参照实施例118或119的合成方法制备得到：
Figure PCTCN2017116186-appb-000246
Figure PCTCN2017116186-appb-000247
Figure PCTCN2017116186-appb-000248
Figure PCTCN2017116186-appb-000249
Figure PCTCN2017116186-appb-000250
Figure PCTCN2017116186-appb-000251
Figure PCTCN2017116186-appb-000252
Figure PCTCN2017116186-appb-000253
Figure PCTCN2017116186-appb-000254
Figure PCTCN2017116186-appb-000255
Figure PCTCN2017116186-appb-000256
Figure PCTCN2017116186-appb-000257
Figure PCTCN2017116186-appb-000258
Figure PCTCN2017116186-appb-000259
Figure PCTCN2017116186-appb-000260
Figure PCTCN2017116186-appb-000261
Figure PCTCN2017116186-appb-000262
Figure PCTCN2017116186-appb-000263
Figure PCTCN2017116186-appb-000264
Figure PCTCN2017116186-appb-000265
Figure PCTCN2017116186-appb-000266
Figure PCTCN2017116186-appb-000267
Figure PCTCN2017116186-appb-000268
Figure PCTCN2017116186-appb-000269
Figure PCTCN2017116186-appb-000270
Figure PCTCN2017116186-appb-000271
Figure PCTCN2017116186-appb-000272
Figure PCTCN2017116186-appb-000273
Figure PCTCN2017116186-appb-000274
Figure PCTCN2017116186-appb-000275
Figure PCTCN2017116186-appb-000276
Figure PCTCN2017116186-appb-000277
Figure PCTCN2017116186-appb-000278
Figure PCTCN2017116186-appb-000279
Figure PCTCN2017116186-appb-000280
Figure PCTCN2017116186-appb-000281
Figure PCTCN2017116186-appb-000282
Figure PCTCN2017116186-appb-000283
Figure PCTCN2017116186-appb-000284
Figure PCTCN2017116186-appb-000285
Figure PCTCN2017116186-appb-000286
Figure PCTCN2017116186-appb-000287
Figure PCTCN2017116186-appb-000288
实施例421 N-((3R,4S)-4-((8-((环丙基甲基)氨基)-6-(2,6-二氯-3,5-二甲氧苯基)吡啶并
[3,4-d]嘧啶-2-基)氨基)四氢呋喃-3-基)丙烯酰基酰胺的制备
Figure PCTCN2017116186-appb-000289
第一步：N-(环丙基甲基)-6-(2,6-二氯-3,5-二甲氧苯基)-2-(甲磺酰)吡啶并[3,4-d]嘧啶-8-胺的制备
Figure PCTCN2017116186-appb-000290
N-(环丙基甲基)-6-(2,6-二氯-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶-8-胺(210mg,0.465mmol)溶于二氯甲烷(6mL)，再加入间氯过氧苯甲酸(200mg,1.163mmol)。室温下搅拌反应18小时。反应完全，加入饱和亚硫酸钠溶液(5mL)，搅拌5分钟。二氯甲烷萃取，有机相再分别用饱和碳酸氢钠和饱和食盐水洗涤，并用无水硫酸钠干燥。过滤，浓缩，柱层析(洗脱剂:PE/EA＝2/1)分离，得到化合物N-(环丙基甲基)-6-(2,6-二氯-3,5-二甲氧苯基)-2-(甲磺酰)吡啶并[3,4-d]嘧啶-8-胺(186mg，收率：82.7％)。
MS m/z(ESI):483.4[M+H]+.
第二步：(±)-N2-((3S,4R)-4-氨基四氢呋喃-3-基)-N8-(环丙基甲基)-6-(2,6-二氯-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-2,8-二胺的制备
Figure PCTCN2017116186-appb-000291
N-(环丙基甲基)-6-(2,6-二氯-3,5-二甲氧苯基)-2-(甲磺酰)吡啶并[3,4-d]嘧啶-8-胺(190mg,0.393mmol)和(3R,4S)-四氢呋喃-3,4-二胺二盐酸(206mg，1.179mmol)溶于乙腈(6mL)，再加入N,N-二异丙基乙胺(507mg,3.93mmol)。加热至回流，搅拌反应20小时。反应完全，冷却至室温，反应液用EtOAc(20mL)稀释，饱和食盐水洗涤，并用无水硫酸钠干燥。过滤，浓缩，制备板(展开剂：CH2Cl2/MeOH 10/1)分离，得到化合物(±)-N2-((3S,4R)-4-氨基四氢呋喃-3-基)-N8-(环丙基甲基)-6-(2,6-二氯-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-2,8-二胺(120mg,收率：60％)。
MS m/z(ESI):505.4[M+H]+.
第三步：(±)-N-((3R,4S)-4-((8-((环丙基甲基)氨基)-6-(2,6-二氯-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-2-基)氨基)四氢呋喃-3-基)丙烯酰基酰胺的制备
Figure PCTCN2017116186-appb-000292
零度下,在(±)-N2-((3S,4R)-4-氨基四氢呋喃-3-基)-N8-(环丙基甲基)-6-(2,6-二氯-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-2,8-二胺(120mg,0.237mmol)和碳酸氢钠(79.6mg,0.948mmol)的四氢呋喃(6.4mL)和水(1.6mL)的溶液中加入丙烯酰氯(22.6mg,0.249mmol)。加完后，混合物在零度下搅拌5分钟。反应液用EtOAc(10mL)稀释，饱和食盐水洗涤，并用无水硫酸钠干燥。过滤，浓缩，制备板(展开剂:CH2Cl2/MeOH＝20/1)分离，得到化合物(±)-N-((3R,4S)-4-((8-((环丙基甲基)氨基)-6-(2,6-二氯-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-2-基)氨基)四氢呋喃-3-基)丙烯酰基酰胺(93mg,收率:70％)。
1H NMR(400MHz,CDCl3)δ8.89(s,1H),6.80(brs,1H),6.68(s,1H),6.62(s,1H),6.38(brs,1H),6.21(dd,J＝17.0,1.5Hz,1H),6.02(dd,J＝17.0,10.2Hz,1H),5.56(dd,J＝10.1,1.5Hz,1H),4.93–4.83(m,2H),4.30–4.18(m,2H),3.96(s,6H),3.90(dd,J＝9.7,3.2Hz,1H),3.79(dd,J＝9.2,5.2Hz,1H),3.52–3.37(m,2H),0.88(t,J＝6.0Hz,1H),0.57–0.48(m,2H),0.36–0.26(m,2H).MS m/z(ESI):559.5[M+H]+.
第四步：N-((3R,4S)-4-((8-((环丙基甲基)氨基)-6-(2,6-二氯-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-2-基)氨基)四氢呋喃-3-基)丙烯酰基酰胺的制备
Figure PCTCN2017116186-appb-000293
(±)-N-((3R,4S)-4-((8-((环丙基甲基)氨基)-6-(2,6-二氯-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-2-基)氨基)四氢呋喃-3-基)丙烯酰基酰胺(93mg,0.166mmol)经手性HPLC分离，得到N-((3R,4S)-4-((8-((环丙基甲基)氨基)-6-(2,6-二氯-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-2-基)氨基)四氢呋喃-3-基)丙烯酰基酰胺(43.5mg,ee值>98％,收率:46.8％)和N-((3S,4R)-4-((8-((环丙基甲基)氨基)-6-(2,6-二氯-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-2-基)氨基)四氢呋喃-3-基)丙烯酰基酰胺(39mg,ee值>98％,收率:41.9％)。
实施例433 N-((3R,4S)-4-((6-(2,6-二氯-3,5-二甲氧苯基)-8-(甲基氨基)吡啶并[3,4-d]嘧啶-2-基)氨基)四氢呋喃-3-基)丙烯酰基酰胺的制备
Figure PCTCN2017116186-appb-000294
第一步：8-氯-6-(2,6-二氯-3,5-二甲氧苯基)-2-(甲磺酰)吡啶并[3,4-d]嘧啶的制备
Figure PCTCN2017116186-appb-000295
参照实施例421第一步操作。
第二步：叔丁基((3R,4S)-4-((8-氯-6-(2,6-二氯-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-2-基)氨基)四氢呋喃-3-基)氨基甲酸酯的制备
Figure PCTCN2017116186-appb-000296
8-氯-6-(2,6-二氯-3,5-二甲氧苯基)-2-(甲磺酰)吡啶并[3,4-d]嘧啶(409mg,0.912mmol)和叔丁基((3R,4S)-4-氨基四氢呋喃-3-基)氨基甲酸酯(553mg,2.736mmol)溶于乙腈(50mL)，再加入三氟乙酸(31mg，0.274mmol)。反应液在95度下搅拌4小时。冷却后，加入乙酸乙酯(50mL)稀释,用饱和碳酸氢钠和饱和食盐水洗涤，并用无水硫酸钠干燥，浓缩后柱层析分离(CH2Cl2/MeOH 0～4％),纯化得到化合物叔丁基((3R,4S)-4-((8-氯-6-(2,6- 二氯-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-2-基)氨基)四氢呋喃-3-基)氨基甲酸酯(414mg，收率：79.6％)。MS m/z(ESI):570.4,572.4[M+H]+。
第三步：叔丁基((3R,4S)-4-((6-(2,6-二氯-3,5-二甲氧苯基)-8-(甲基氨基)吡啶并[3,4-d]嘧啶-2-基)氨基)四氢呋喃-3-基)氨基甲酸酯的制备
Figure PCTCN2017116186-appb-000297
叔丁基((3R,4S)-4-((8-氯-6-(2,6-二氯-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-2-基)氨基)四氢呋喃-3-基)氨基甲酸酯(60mg,0.105mmol)和甲胺(1.5mL,33％乙醇溶液)的N-甲基吡咯烷酮(1mL)溶液在110度加热18h。反应液用乙酸乙酯(5mL)稀释，饱和食盐水洗涤，并用无水硫酸钠干燥，浓缩后用制备板分离(PE/EA＝1:1)，纯化得到化合物叔丁基((3R,4S)-4-((6-(2,6-二氯-3,5-二甲氧苯基)-8-(甲基氨基)吡啶并[3,4-d]嘧啶-2-基)氨基)四氢呋喃-3-基)氨基甲酸酯(32mg,收率：54％)。MS m/z(ESI):565.4,567.4[M+H]+。
第四步：N2-((3S,4R)-4-氨基四氢呋喃-3-基)-6-(2,6-二氯-3,5-二甲氧苯基)-N8-甲基吡啶并[3,4-d]嘧啶-2,8-二胺的三氟乙酸盐的制备
Figure PCTCN2017116186-appb-000298
叔丁基((3R,4S)-4-((6-(2,6-二氯-3,5-二甲氧苯基)-8-(甲基氨基)吡啶并[3,4-d]嘧啶-2-基)氨基)四氢呋喃-3-基)氨基甲酸酯(32mg,0.057mmol)的三氟乙酸的二氯甲烷(2mL,20％)溶液在室温下搅拌1h。浓缩后的油状物直接用于下步反应。MS m/z(ESI):465.4，467.4[M+H]+。
第五步：N-((3R,4S)-4-((6-(2,6-二氯-3,5-二甲氧苯基)-8-(甲基氨基)吡啶并[3,4-d]嘧啶-2-基)氨基)四氢呋喃-3-基)丙烯酰基酰胺的制备
Figure PCTCN2017116186-appb-000299
零度下,在N2-((3S,4R)-4-氨基四氢呋喃-3-基)-6-(2,6-二氯-3,5-二甲氧苯基)-N8-甲基吡啶并[3,4-d]嘧啶-2,8-二胺的三氟乙酸盐(粗品)和NaHCO3(57mg，0.684mmol)的四氢呋喃(3.2mL)和水(0.8mL)溶液中加入丙烯酰氯(5.7mg，0.063mmol)。加完后，混合物在零度下搅拌5分钟。反应液用EtOAc(mL)稀释，饱和碳酸氢钠和饱和食盐水洗涤，并用无水硫酸钠干燥，浓缩后用制备板分离(CH2Cl2/MeOH 20:1)，纯化得到化合物 N-((3R,4S)-4-((6-(2,6-二氯-3,5-二甲氧苯基)-8-(甲基氨基)吡啶并[3,4-d]嘧啶-2-基)氨基)四氢呋喃-3-基)丙烯酰基酰胺(17.6mg,收率:59.5％)。
1H NMR(400MHz,CDCl3)δ8.88(s,1H),6.67(s,1H),6.62(s,1H),6.30(brs,1H),6.19(d,J＝16.9Hz,1H),5.97(dd,J＝17.0,10.3Hz,1H),5.88(brs,1H),5.54(d,J＝10.4Hz,1H),4.95–4.83(m,2H),4.29–4.18(m,2H),3.95(s,6H),3.89(dd,J＝9.7,3.0Hz,1H),3.77(dd,J＝9.3,5.5Hz,1H),3.14(d,J＝4.4Hz,3H).MS m/z(ESI):519.4,521.4[M+H]+。
实施例775 N-((3S,4S)-3-((6-(2,6-二氟-3,5-二甲氧苯基)-8-(3-甲氧基吖丁啶-1-基)吡啶并[3,4-d]嘧啶-2-基)氨基)四氢-2H-吡喃-4-基)丙烯酰基酰胺的制备
Figure PCTCN2017116186-appb-000300
第一步：8-氯-6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲磺酰)吡啶并[3,4-d]嘧啶的制备
Figure PCTCN2017116186-appb-000301
8-氯-6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲硫基)吡啶并[3,4-d]嘧啶(930mg，2.42mmol)溶于DCM(50mL)，加入m-CPBA(1.23g，6.05mmol)，室温下搅拌2小时。反应完全，加入硫代硫酸钠淬灭，DCM提取，硅胶柱层析分离，纯化得到化合物8-氯-6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲磺酰)吡啶并[3,4-d]嘧啶(800mg，产率79％)。MS m/z(ESI):416[M+H]+。
第二步：N-((3S,4S)-4-叠氮四氢-2H-吡喃-3-基)-8-氯-6-(2,6-二氟-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-2-胺的制备
Figure PCTCN2017116186-appb-000302
8-氯-6-(2,6-二氟-3,5-二甲氧苯基)-2-(甲磺酰)吡啶并[3,4-d]嘧啶(1g，2.41mmol)溶于叔丁醇(80mL)和DCE(20mL)，再加入DIPEA(1.55g，12.05mmol)，加热至90度，搅拌反应过夜。DCM提取，硅胶柱层析分离，得到化合物N-((3S,4S)-4-叠氮四氢-2H-吡喃-3-基)-8-氯-6-(2,6-二氟-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-2-胺(650mg，产率56％)。MS m/z(ESI):478[M+H]+。
第三步：N-((3S,4S)-4-叠氮四氢-2H-吡喃-3-基)-6-(2,6-二氟-3,5-二甲氧苯基)-8-(3-甲氧基吖丁啶-1-基)吡啶并[3,4-d]嘧啶-2-胺
Figure PCTCN2017116186-appb-000303
N-((3S,4S)-4-叠氮四氢-2H-吡喃-3-基)-8-氯-6-(2,6-二氟-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-2-胺(325mg，0.68mmol)，3-甲氧基吖丁啶盐酸(252mg，2.04mmol)和DIPEA(439mg，3.4mmol)溶于正丁醇(15mL)，加热至100度，反应4小时。浓缩，乙酸乙酯提取，硅胶柱层析分离，得到化合物N-((3S,4S)-4-叠氮四氢-2H-吡喃-3-基)-6-(2,6-二氟-3,5-二甲氧苯基)-8-(3-甲氧基吖丁啶-1-基)吡啶并[3,4-d]嘧啶-2-胺(350mg，产率：97％)。MS m/z(ESI):529[M+H]+。
第四步：(3S,4S)-N3-(6-(2,6-二氟-3,5-二甲氧苯基)-8-(3-甲氧基吖丁啶-1-基)吡啶并[3,4-d]嘧啶-2-基)四氢-2H-吡喃-3,4-二胺的制备
Figure PCTCN2017116186-appb-000304
N-((3S,4S)-4-叠氮四氢-2H-吡喃-3-基)-6-(2,6-二氟-3,5-二甲氧苯基)-8-(3-甲氧基吖丁啶-1-基)吡啶并[3,4-d]嘧啶-2-胺(350mg，0.662mmol)溶于THF(10mL)和水(1mL)中，加入三苯基磷(521mg，1.99mmol)，加热至80度，搅拌反应16小时。冷却，直接加入无水硫酸钠干燥，浓缩，硅胶柱层析分离，得到化合物(3S,4S)-N3-(6-(2,6-二氟-3,5-二甲氧苯基)-8-(3-甲氧基吖丁啶-1-基)吡啶并[3,4-d]嘧啶-2-基)四氢-2H-吡喃-3,4-二胺(290mg，产率87％)。MS m/z(ESI):503[M+H]+。
第五步：N-((3S,4S)-3-((6-(2,6-二氟-3,5-二甲氧苯基)-8-(3-甲氧基吖丁啶-1-基)吡啶并[3,4-d]嘧啶-2-基)氨基)四氢-2H-吡喃-4-基)丙烯酰基酰胺的制备
Figure PCTCN2017116186-appb-000305
(3S,4S)-N3-(6-(2,6-二氟-3,5-二甲氧苯基)-8-(3-甲氧基吖丁啶-1-基)吡啶并[3,4-d]嘧啶-2-基)四氢-2H-吡喃-3,4-二胺(290mg，0.58mmol)溶于THF(20mL)和水(5mL)，加入NaHCO3(243mg，2.89mmol)，室温下滴加丙烯酰氯溶液(63mg，0.69mmol，溶于1mL THF中)，室温搅拌10分钟，TLC检测，反应完全。加入饱和NaHCO3水溶液淬灭，乙酸乙酯提取，浓缩，硅胶柱层析分离，得到化合物N-((3S,4S)-3-((6-(2,6-二氟-3,5-二甲氧苯基)-8-(3-甲氧基吖丁啶-1-基)吡啶并[3,4-d]嘧啶-2-基)氨基)四氢-2H-吡喃-4-基)丙烯酰基酰胺(204mg，产率63％)。MS m/z(ESI):557[M+H]+。
1H NMR(400MHz,CDCl3)δ8.92(s,1H),6.96(s,1H),6.69(t,J＝8.0Hz,1H),6.65(s,1H),6.25(dd,J＝17.0,1.4Hz,1H),6.08(s,1H),6.02(dd,J＝16.9,10.3Hz,1H),5.60(dd,J＝10.3,1.4Hz,1H),4.73(brs,1H),4.56(brs,1H),4.42(d,J＝8.5Hz,1H),4.39–4.22(m,4H),4.05(dd,J＝12.0,4.5Hz,1H),3.99(d,J＝11.7Hz,1H),3.92(s,6H),3.75(dd,J＝11.9,1.6Hz,1H),3.65–3.57(m,1H),3.33(s,3H),2.09–2.02(m,1H),1.91–1.81(m,1H).
以下实施例422-714、753-806参照实施例433、421或775的合成方法制备得到：
Figure PCTCN2017116186-appb-000306
Figure PCTCN2017116186-appb-000307
Figure PCTCN2017116186-appb-000308
Figure PCTCN2017116186-appb-000309
Figure PCTCN2017116186-appb-000310
Figure PCTCN2017116186-appb-000311
Figure PCTCN2017116186-appb-000312
Figure PCTCN2017116186-appb-000313
Figure PCTCN2017116186-appb-000314
Figure PCTCN2017116186-appb-000315
Figure PCTCN2017116186-appb-000316
Figure PCTCN2017116186-appb-000317
Figure PCTCN2017116186-appb-000318
Figure PCTCN2017116186-appb-000319
Figure PCTCN2017116186-appb-000320
Figure PCTCN2017116186-appb-000321
Figure PCTCN2017116186-appb-000322
Figure PCTCN2017116186-appb-000323
Figure PCTCN2017116186-appb-000324
Figure PCTCN2017116186-appb-000325
Figure PCTCN2017116186-appb-000326
Figure PCTCN2017116186-appb-000327
Figure PCTCN2017116186-appb-000328
Figure PCTCN2017116186-appb-000329
Figure PCTCN2017116186-appb-000330
Figure PCTCN2017116186-appb-000331
Figure PCTCN2017116186-appb-000332
Figure PCTCN2017116186-appb-000333
Figure PCTCN2017116186-appb-000334
Figure PCTCN2017116186-appb-000335
Figure PCTCN2017116186-appb-000336
Figure PCTCN2017116186-appb-000337
Figure PCTCN2017116186-appb-000338
Figure PCTCN2017116186-appb-000339
Figure PCTCN2017116186-appb-000340
Figure PCTCN2017116186-appb-000341
Figure PCTCN2017116186-appb-000342
Figure PCTCN2017116186-appb-000343
Figure PCTCN2017116186-appb-000344
Figure PCTCN2017116186-appb-000345
Figure PCTCN2017116186-appb-000346
Figure PCTCN2017116186-appb-000347
Figure PCTCN2017116186-appb-000348
Figure PCTCN2017116186-appb-000349
Figure PCTCN2017116186-appb-000350
Figure PCTCN2017116186-appb-000351
Figure PCTCN2017116186-appb-000352
Figure PCTCN2017116186-appb-000353
Figure PCTCN2017116186-appb-000354
Figure PCTCN2017116186-appb-000355
Figure PCTCN2017116186-appb-000356
实施例715 N-(5-(6-(2,6-二氯-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-2-基)-1-(2-甲氧基乙基)-1H-吡唑-4-基)丙烯酰基酰胺的制备
Figure PCTCN2017116186-appb-000357
第一步：6-(2,6-二氯-3,5-二甲氧苯基)-2-(1-(2-甲氧基乙基)-4-硝基-1H-吡唑-5-基)吡啶并 [3,4-d]嘧啶的制备
Figure PCTCN2017116186-appb-000358
将化合物1-(2-甲氧基乙基)-4-硝基-1H-吡唑(84mg，0.49mmol)和化合物2-氯-6-(2,6-二氯-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶(200mg，0.54mmol)溶入DMA(15mL)，然后加入CuI(112mg，0.59mmol)，PivOH(15mg，0.15mmol)，K2CO3(88mg，0.64mmol)和Pd(PPh3)2Cl2(34mg，0.05mmol)。氮气保护下，加热至140度反应1小时。反应完全，减压浓缩，除去溶剂。快速硅胶柱分离(PE/EA 2:1)，纯化得产品6-(2,6-二氯-3,5-二甲氧苯基)-2-(1-(2-甲氧基乙基)-4-硝基-1H-吡唑-5-基)吡啶并[3,4-d]嘧啶(103mg，收率42％)。MS m/z(ESI):505[M+1]+.
第二步：5-(6-(2,6-二氯-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-2-基)-1-(2-甲氧基乙基)-1H-吡唑-4-胺的制备
Figure PCTCN2017116186-appb-000359
化合物6-(2,6-二氯-3,5-二甲氧苯基)-2-(1-(2-甲氧基乙基)-4-硝基-1H-吡唑-5-基)吡啶并[3,4-d]嘧啶(103mg，0.20mmol)溶于EtOH/H2O(10/3mL)混合液，然后加入Fe粉(114mg，2.04mmol)和NH4Cl(109mg，2.04mmol)。加热回流反应2小时。反应结束后，反应液用二氯甲烷萃取三次，合并有机相依次用水，饱和氯化钠水溶液洗涤。无水硫酸钠干燥，过滤、浓缩。粗产品用快速硅胶柱层析分离(CH2Cl2/MeOH 10:1)，纯化得产品5-(6-(2,6-二氯-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-2-基)-1-(2-甲氧基乙基)-1H-吡唑-4-胺(12mg，收率12％)。MS m/z(ESI):476[M+1]+.
第三步：N-(5-(6-(2,6-二氯-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-2-基)-1-(2-甲氧基乙基)-1H-吡唑-4-基)丙烯酰基酰胺的制备
Figure PCTCN2017116186-appb-000360
将化合物5-(6-(2,6-二氯-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-2-基)-1-(2-甲氧基乙基)-1H-吡唑-4-胺(12mg，0.025mmol)溶于THF/H2O(4:1，4mL)混合液中，然后加入NaHCO3(11mg，0.13mmol)。冰水浴冷却，加入丙烯酰氯(2.3mg，0.025mmol)，0度下搅拌反应10分钟。反应结束后，反应液在减压下浓缩，硅胶柱层析分离(CH2Cl2/MeOH10:1)，纯化得产品N-(5-(6-(2,6-二氯-3,5-二甲氧苯基)吡啶并[3,4-d]嘧啶-2-基)-1-(2-甲氧基乙基)-1H-吡唑-4-基)丙烯酰基酰胺(4.8mg，收率36％)。MS m/z(ESI):529[M+1]+.
1H NMR(400MHz,CDCl3)δ10.71(s,1H),9.63(s,1H),9.60(s,1H),8.61(s,1H),7.80(s,1H),6.72(s,1H),6.49(d,J＝16.7Hz,1H),6.40(dd,J＝16.9,9.7Hz,1H),5.84(d,J＝9.7Hz,1H),5.21(t,J＝6.0Hz,2H),4.00(s,7H),3.89(t,J＝5.9Hz,2H),3.35(s,3H).
以下实施例716-729参照实施例715的合成方法制备。
Figure PCTCN2017116186-appb-000361
Figure PCTCN2017116186-appb-000362
Figure PCTCN2017116186-appb-000363
实施例730 N-((3-(2,6-二氯-3,5-二甲氧苯基)-1-甲基-2-羰基-1,2-二氢-1,6-二氮杂萘-7-基)甲基)丙烯酰基酰胺的制备
Figure PCTCN2017116186-appb-000364
第一步：3-(2,6-二氯-3,5-二甲氧苯基)-1-甲基-2-羰基-1,2-二氢-1,6-二氮杂萘-7-甲腈的制备
Figure PCTCN2017116186-appb-000365
7-氯-3-(2,6-二氯-3,5-二甲氧苯基)-1-甲基-1,6-二氮杂萘-2(1H)-酮(250.0mg，0.626mmol)，Zn(CN)2(110mg，0.938mmol)和1,1'-双(二苯基膦)二茂铁(34.7mg,0.063mmol)加入DMF/H2O(5mL，100:1)，再加入Pd2(dba)3(28.7mg，0.031mmol)，氮气保护。加热至120℃，搅拌反应20小时。反应完全，冷却至室温，用水稀释并用EtOAc萃取，有机相用饱和食盐水洗涤，并用无水硫酸钠干燥。过滤，浓缩，硅胶柱层析(展开剂：PE/EtOAc＝10～25％)分离，得到化合物3-(2,6-二氯-3,5-二甲氧苯基)-1-甲基-2-羰基-1,2-二氢-1,6-二氮杂萘-7-甲腈(75mg,收率：28％)。MS m/z(ESI):390.0[M+H]+.
第二步：7-(氨基甲基)-3-(2,6-二氯-3,5-二甲氧苯基)-1-甲基-1,6-二氮杂萘-2(1H)-酮的制备
Figure PCTCN2017116186-appb-000366
3-(2,6-二氯-3,5-二甲氧苯基)-1-甲基-2-羰基-1,2-二氢-1,6-二氮杂萘-7-甲腈(15mg，0.038mmol)溶于甲醇(3mL)，加入浓盐酸(15L)和10％的Pd/C(催化量)。氢气球下室温搅拌反应2小时，反应完全。过滤，旋干，得到粗品7-(氨基甲基)-3-(2,6-二氯-3,5-二甲氧苯基)-1-甲基-1,6-二氮杂萘-2(1H)-酮，直接用于下步反应。MS m/z(ESI):394.0[M+H]+.
第三步：N-((3-(2,6-二氯-3,5-二甲氧苯基)-1-甲基-2-羰基-1,2-二氢-1,6-二氮杂萘-7-基)甲 基)丙烯酰基酰胺的制备
Figure PCTCN2017116186-appb-000367
0℃下,在7-(氨基甲基)-3-(2,6-二氯-3,5-二甲氧苯基)-1-甲基-1,6-二氮杂萘-2(1H)-酮(粗品，0.038mmol)和NaHCO3(19.0mg，0.230mmol)的THF/H2O(0.8mL/0.2mL)溶液中加入丙烯酰氯(3.8mg，0.042mmol)。0℃下搅拌反应10分钟。反应液用EtOAc(5mL)稀释，饱和食盐水洗涤，并用无水硫酸钠干燥。过滤，浓缩后用制备板(展开剂：CH2Cl2/MeOH＝10:1)分离，得到化合物N-((3-(2,6-二氯-3,5-二甲氧苯基)-1-甲基-2-羰基-1,2-二氢-1,6-二氮杂萘-7-基)甲基)丙烯酰基酰胺(1.1mg，两步收率：6％)。
1H NMR(400MHz,Chloroform-d)δ8.75(s,1H),7.68(s,1H),7.40(s,1H),6.65(s,1H),6.38–6.32(m,1H),6.27–6.21(m,1H),5.73–5.69(m,1H),5.30(s,1H),4.81(d,J＝5.6Hz,2H),3.96(s,6H),3.78(s,3H)；
MS m/z(ESI):448.0[M+H]+.
以下实施例731-751参照实施例730的合成方法制备得到：
Figure PCTCN2017116186-appb-000368
Figure PCTCN2017116186-appb-000369
Figure PCTCN2017116186-appb-000370
生物学测试评价
一、FGFR4体外生物化学激酶分析
本发明采用FGFR4Caliper Assay测定化合物对FGFR4抑制活性的特性。具体实验过程如下：
1、本发明所进行的激酶反应是在384孔板中进行，分别取12.5μM的FGFR4和65μM的ATP以及1μM的肽(5Fluo Ahx KKKKEEIYFFFG NH2)；
2、加入50mM HEPES,pH 7.5,1mM DTT,0.02％Tween20,0.02％BSA,0.6％DMSO,10mM beta甘油磷酸盐及10μM原钒酸纳，16mM MgCl2的反应体系中；
3、在30℃下孵育反应40分钟；
4、添加停止溶液(100mM HEPES,pH7.5,5％DMSO,0.1％Caliper涂布试剂，10mM EDTA及0.015％Brij35)来终止反应；
5、取已终止激酶反应的培养盘转移至Caliper LC 3000工作站读取数据，使用Caliper微流体迁移偏移技术分离磷酸化与未磷酸化的肽，并通过恒定缓冲液流经芯片来转 移分析物，且通过其标记的荧光信号监控底物肽的迁移，利用所形成的磷酸基肽的量计算激酶活性。
6、最后，通过非线性回归分析不同化合物浓度下的抑制百分比来测定IC50值。具体实施例化合物酶学活性检测结果见表1。
二、FGFR4细胞增殖实验
本发明采用(Cell Titer Glo(CTG)实验)来评价化合物对细胞增殖的功能性作用。使用来自于中科院细胞库的Huh7肝细胞癌细胞(目录号TChU182)在DMEM高葡萄糖(Gibco,cat.No.1773536)，10％胎牛血清(Gibco,10099-141)中在37℃，5％CO2培养箱中培养。细胞增殖/存活的化合物介导的抑制通过对细胞ATP水平的定量来评价，使用CTG试剂(Promega,#G7573)。具体实验过程如下：
1、将细胞以3500细胞/孔/90μL新鲜培养基接种到组织培养基处理的96孔板(Costar#3904)；
2、加入10μL包含以10倍其最终所需浓度的化合物稀释液的培养基；
3、通过测试化合物5倍系列稀释来评价剂量效应作用，从10μM开始；
4、在细胞于37℃5％CO2下孵育3天后，加入50μL CTG和发光测定后对抑制剂对于细胞存活的影响进行定量；
5、使用读板器(M1000，Tecan)使用Graphpad Prism中四参数曲线拟合来测定导致半数最大生长抑制的化合物浓度(EC50)以及导致绝对半数生长抑制的化合物浓度(Absolute IC50)。具体实施例化合物细胞活性检测结果见表1：
表1 酶学及细胞活性检测结果
Figure PCTCN2017116186-appb-000371
Figure PCTCN2017116186-appb-000372
Figure PCTCN2017116186-appb-000373
Figure PCTCN2017116186-appb-000374
Figure PCTCN2017116186-appb-000375
Figure PCTCN2017116186-appb-000376
Figure PCTCN2017116186-appb-000377
Figure PCTCN2017116186-appb-000378
Figure PCTCN2017116186-appb-000379
Figure PCTCN2017116186-appb-000380
Figure PCTCN2017116186-appb-000381
Figure PCTCN2017116186-appb-000382
从具体实施例化合物酶学活性数据来看，本发明系列化合物对FGFR4激酶活性具有很强的抑制作用。从具体实施例化合物细胞活性数据来看，本发明系列化合物对FGFR4高表达的HuH-7细胞增殖活性具有很强的抑制作用。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (22)

  1. 式(I)化合物、其立体异构体或其药学上可接受盐：
    Figure PCTCN2017116186-appb-100001
    其中，
    X1选自-C(R7)-或N；
    X2、X3、X5各自独立的选自-(CR8)n-、-C(O)-、-N(R9)-、N、O或S；
    X4选自C或N；
    Z选自C1-8亚烷基、C2-8亚链烯基、C2-8亚链炔基、C3-8环烷基、3-10元杂环基、C5-10芳基或5-10元杂芳基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-10元杂环基、C5-10芳基、5-10元杂芳基、-C0-8-S(O)rR10、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-C0-8-N(R13)-C(O)R12或-C0-8-N(R13)-C(O)OR11的取代基所取代，上述基团再任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-10元杂环基、C5-10芳基、5-10元杂芳基、-C0-8-S(O)rR10、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-C0-8-N(R13)-C(O)R12或-C0-8-N(R13)-C(O)OR11的取代基所取代；
    R1选自氢、氘、C1-8烷基、C1-8烷氧C1-8烷基、C3-8环烷氧基C1-8烷基、C3-8环烷基C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-10元杂环基、C5-10芳基、5-10元杂芳基或C1-8烷酰基；
    R2、R3、R4、R5、R6、R7各自独立的选自氢、氘、卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-10元杂环基、-C0-8-S(O)rR10、-C0-8-S(O)(NR9)R10、-C0-8-P(O)(R10)2、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-C0-8-N(R13)-C(O)R12或-C0-8-N(R13)-C(O)OR11，或者，R2与R4、R3与R5、R4与R6、R5与R6和其直接相连的碳原子一起形成C5-10环烷基、5-10元杂环基、5-10元芳基或5-10元杂芳基，
    上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-10元杂环基、C5-10芳基、5-10元杂芳基、-C0-8-S(O)rR10、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、- C0-8-NR13R14、-C0-8-C(O)NR13R14、-C0-8-N(R13)-C(O)R12或-C0-8-N(R13)-C(O)OR11的取代基所取代；
    R8选自氢、氘、卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3 -8环烷基、3-10元杂环基、C5-10芳基、5-10元杂芳基、-C0-8-S(O)rR10、-C0-8-S(O)(NR9)R10、-C0-8-P(O)(R10)2、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-C0-8-N(R13)-C(O)R12或-C0-8-N(R13)-C(O)OR11，
    上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-10元杂环基、C5-10芳基、5-10元杂芳基、-C0-8-S(O)rR10、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-C0-8-N(R13)-C(O)R12或-C0-8-N(R13)-C(O)OR11的取代基所取代，上述基团再任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-10元杂环基、C5-10芳基、5-10元杂芳基、-C0-8-S(O)rR10、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-C0-8-N(R13)-C(O)R12或-C0-8-N(R13)-C(O)OR11的取代基所取代；
    R9选自氢、氘、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-10元杂环基、C5-10芳基、5-10元杂芳基或C1-8烷酰基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、卤取代C1-8烷基、C3-8环烷基、3-10元杂环基、C5-10芳基、5-10元杂芳基、-C0-8-S(O)rR10、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-C0-8-N(R13)-C(O)R12或-C0-8-N(R13)-C(O)OR11的取代基所取代；
    R10选自氢、氘、C1-8烷基、C2-8链烯基、C3-8环烷基、3-10元杂环基、卤取代C1-8烷基、C5-10芳基、5-10元杂芳基、氨基、单C1-8烷基氨基、二C1-8烷基氨基或C1-8烷酰氨基；
    R11选自氢、氘、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-10元杂环基、C5-10芳基或5-10元杂芳基，上述基团任选地被以下基团单取代或多取代：氘、卤素、氰基、C1-8烷基、C1-8烷氧基、C1-8烷硫基、C3-8环烷基、3-10元杂环基、C5-10芳基、5-10元杂芳基、C1-8烷基磺酰基、C1-8烷基磺酰胺基、氨基、单C1-8烷基氨基、二C1-8烷基氨基、＝O或羟基；
    R12选自氢、氘、C1-8烷基、C2-8链烯基、C2-8链炔基、C1-8烷氧基、C3-8环烷基、C3-8环烷氧基、3-10元杂环基、3-10元杂环氧基、C5-10芳基、5-10元杂芳基、C5-10芳氧基或5-10元杂芳氧基，上述基团任选地被以下基团单取代或多取代：氘、卤素、氰基、C1-8烷基、C1-8烷氧基、C1-8烷硫基、C3-8环烷基、3-10元杂环基、C5-10芳基、5-10元杂芳基、C1-8烷基磺酰基、C1-8烷基磺酰胺基、氨基、单C1-8烷基氨基、二C1-8烷基氨基、＝O或羟基；
    R13、R14各自独立的选自氢、氘、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-10元杂环基、C5-10芳基、5-10元杂芳基、C1-8烷基磺酰基或C1-8烷酰基，或者，R13、R14和其直接相连的氮原子一起形成4-10元杂环基，
    上述基团任选地被以下基团单取代或多取代：氘、卤素、C1-8烷基、C1-8烷氧基、C1-8烷硫基、C3-8环烷基、3-10元杂环基、C5-10芳基、5-10元杂芳基、C1-8烷基磺酰基、C1-8烷基磺酰胺基、氨基、单C1-8烷基氨基、二C1-8烷基氨基、＝O或羟基；
    m为0或1；
    n为0、1或2；
    r为0、1或2；
    条件是，当X3选自-(CR8)n-时，X2选自-C(O)-，X4选自C，X5选自-N(R9)-、N、O或S；当X3选自-C(O)-时，X2选自-N(R9)-，且Z选自C1-8烷基、C2-8链烯基、C2-8链炔基或苯基。
  2. 根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，Z选自C1-4亚烷基、C2-4亚链烯基、C2-4亚链炔基、C3-6环烷基、3-8元杂环基、C5-8芳基或5-8元杂芳基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-8元杂环基、C5-8芳基、5-8元杂芳基、-C0-4-S(O)rR10、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0-4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-C0-4-N(R13)-C(O)R12或-C0-4-N(R13)-C(O)OR11的取代基所取代，上述基团再任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、卤取代C1-4烷基、C3-6环烷基、3-8元杂环基、C5-8芳基、5-8元杂芳基、-C0-4-S(O)rR10、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0-4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-C0-4-N(R13)-C(O)R12或-C0-4-N(R13)-C(O)OR11的取代基所取代；
    R1选自氢、氘、C1-4烷基、C1-4烷氧C1-4烷基、C3-6环烷氧基C1-4烷基、C3-6环烷基C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-8元杂环基、C5-8芳基、5-8元杂芳基或C1-4烷酰基；
    R2、R3、R4、R5、R6、R7各自独立的选自氢、氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-8元杂环基、-C0-4-S(O)rR10、-C0-4-S(O)(NR9)R10、-C0-4-P(O)(R10)2、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0-4-O-C(O)R12、-C0 -4-NR13R14、-C0-4-C(O)NR13R14、-C0-4-N(R13)-C(O)R12或-C0-4-N(R13)-C(O)OR11，或者，R2与R4、R3与R5、R4与R6、R5与R6和其直接相连的碳原子一起形成C5-8环烷基、5-8元杂环基、5-8元芳基或5-8元杂芳基，
    上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、卤取代C1-4烷基、C3-4环烷基、3-8元杂环基、C5-8芳基、5-8元杂芳基、-C0-4-S(O)rR10、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0-4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-C0-4-N(R13)-C(O)R12或-C0-4-N(R13)-C(O)OR11的取代基所取代。
  3. 根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，Z选自C1-2亚烷基或如下结构：
    Figure PCTCN2017116186-appb-100002
    上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-8元杂环基、C5-8芳基、5-8元杂芳基、-C0-4-S(O)rR10、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0-4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-C0-4-N(R13)-C(O)R12或-C0-4-N(R13)-C(O)OR11的取代基所取代，上述基团再任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、卤取代C1-4烷基、C3-6环烷基、3-8元杂环基、C5-8芳基、5-8元杂芳基、-C0-4-S(O)rR10、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0-4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-C0-4-N(R13)-C(O)R12或-C0-4-N(R13)-C(O)OR11的取代基所取代。
  4. 根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，
    R1选自氢、氘、甲基、异丙基、甲氧乙基、环丙氧甲基、环丙甲基、烯丙基、环丙基或乙酰基；
    R2、R3、R4、R5各自独立的选自氢、氘、卤素、C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-8元杂环基、-C0-4-O-R11或-C0-4-NR13R14，或者，R2与R4、R3与R5和其直接相连的碳原子一起形成C5-8环烷基、5-8元杂环基、5-8元芳基或5-8元杂芳基，
    上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、卤取代C1-4烷基、C3-4环烷基、3-8元杂环基、C5-8芳基、5-8元杂芳基、-C0-4-S(O)rR10、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0-4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-C0-4-N(R13)-C(O)R12或-C0-4-N(R13)-C(O)OR11的取代基所取代；
    R6选自氢或氘。
  5. 根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，R1选自氢、氘、甲基或环丙甲基；
    R2、R3、R4、R5各自独立的选自氢、氘、氯、氟、甲基、异丙基、烯丙基、乙炔基、环丙基、3-氧杂环丁基、三氟甲基、三氘甲基、-C0-4-O-R11或-C0-4-NR13R14，
    或者，R2与R4、R3与R5和其直接相连的碳原子一起形成5-8元杂环基，所述杂原子选自氧或氮，所述5-8元杂环基任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、卤取代C1-4烷基、C3-4环烷基、3-8元杂环基、C5-8芳基、5-8元杂芳基、-C0-4-S(O)rR10、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0- 4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-C0-4-N(R13)-C(O)R12或-C0-4-N(R13)-C(O)OR11的取代基所取代；
    R6选自氢或氘。
  6. 根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，选自如下式(Ⅱa)化合物：
    Figure PCTCN2017116186-appb-100003
    其中，X3选自-N(R9)-、N、O或S；
    Z选自C1-2亚烷基或如下结构：
    Figure PCTCN2017116186-appb-100004
    上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-8元杂环基、C5-8芳基、5-8元杂芳基、-C0-4-S(O)rR10、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0-4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-C0-4-N(R13)-C(O)R12或-C0-4-N(R13)-C(O)OR11的取代基所取代，上述基团再任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、卤取代C1-4烷基、C3-6环烷基、3-8元杂环基、C5-8芳基、5-8元杂芳基、-C0-4-S(O)rR10、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0-4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-C0-4-N(R13)-C(O)R12或-C0-4-N(R13)-C(O)OR11的取代基所取代；
    R2、R3、R4、R5各自独立的选自氢、氘、氯、氟、甲基、异丙基、烯丙基、乙炔基、环丙基、3-氧杂环丁基、三氟甲基、三氘甲基、-C0-4-O-R11或-C0-4-NR13R14，
    或者，R2与R4、R3与R5和其直接相连的碳原子一起形成5-8元杂环基，所述杂原子选自氧或氮，所述5-8元杂环基任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠 氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、卤取代C1-4烷基、C3-4环烷基、3-8元杂环基、C5-8芳基、5-8元杂芳基、-C0-4-S(O)rR10、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0- 4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-C0-4-N(R13)-C(O)R12或-C0-4-N(R13)-C(O)OR11的取代基所取代；
    R7选自氢、氘、氯、氟、羟基、烯丙基、乙炔基、环丙基、3-氧杂环丁基、三氟甲基、三氘甲基、-C0-4-O-R11或-C0-4-NR13R14；
    R9选自氢、氘、C1-4烷基、C3-6环烷基或3-8元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、卤取代C1-4烷基、C3-6环烷基、3-8元杂环基、C5-8芳基、5-8元杂芳基、-C0-4-S(O)rR10、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0-4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-C0-4-N(R13)-C(O)R12或-C0-4-N(R13)-C(O)OR11的取代基所取代；
    X1、X2、X5、R8、R10、R11、R12、R13、R14、m、n、r如权利要求1所述。
  7. 根据权利要求6所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，选自如下式(Ⅲa-1)、(Ⅲa-2)、(Ⅲa-3)或(Ⅲa-4)化合物：
    Figure PCTCN2017116186-appb-100005
    其中，Z选自C1-2亚烷基或如下结构：
    Figure PCTCN2017116186-appb-100006
    上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-8元杂环基、C5-8芳基、5-8元杂芳基、-C0-4-S(O)rR10、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0-4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-C0-4-N(R13)-C(O)R12或-C0-4-N(R13)-C(O)OR11的取代基所取代，上述基团再任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、卤取代C1-4烷基、C3-6环烷基、3-8元杂环基、C5-8芳基、5-8元杂芳基、 -C0-4-S(O)rR10、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0-4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-C0-4-N(R13)-C(O)R12或-C0-4-N(R13)-C(O)OR11的取代基所取代；
    R2、R3、R4、R5各自独立的选自氢、氘、氯、氟、羟基、甲基、异丙基、环丙基、3-氧杂环丁基、三氟甲基、三氘甲基或-O-R11，
    或者，R2与R4、R3与R5和其直接相连的碳原子一起形成5-8元杂环基，所述杂原子选自氧或氮；
    R7选自氢、氘、氯、氟、羟基、环丙基或-O-R11；
    R9选自氢、氘、C1-4烷基、C3-6环烷基或3-8元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、C1-4烷基、卤取代C1-4烷基、C3-6环烷基、3-8元杂环基、-C0-4-O-R11、-C0-4-NR13R14或-C0-4-C(O)NR13R14的取代基所取代；
    X1、X5、R8、R10、R11、R12、R13、R14、m、n、r如权利要求1所述。
  8. 根据权利要求7所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，选自式(Ⅳa-1)化合物：
    Figure PCTCN2017116186-appb-100007
    其中，X5选自-CH-或N；
    Z选自C1-2亚烷基或如下结构：
    Figure PCTCN2017116186-appb-100008
    上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-8元杂环基、C5-8芳基、5-8元杂芳基、-C0-4-S(O)rR10、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0-4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-C0-4-N(R13)-C(O)R12或-C0-4-N(R13)-C(O)OR11的取代基所取代，上述基团再任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、卤取代C1-4烷基、C3-6环烷基、3-8元杂环基、C5-8芳基、5-8元杂芳基、-C0-4-S(O)rR10、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0-4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-C0-4-N(R13)-C(O)R12或-C0-4-N(R13)-C(O)OR11的取代基所取代；
    R2、R3、R4、R5各自独立的选自氢、氘、氯、氟、羟基、甲基、异丙基、环丙基、3-氧杂环丁基、三氟甲基、三氘甲基或-O-R11，
    或者，R2与R4、R3与R5和其直接相连的碳原子一起形成5-8元杂环基，所述杂原子选自氧或氮；
    R7选自氢、氘、氯、氟、羟基、环丙基或-O-R11；
    R8选自氢、氘、卤素、氰基、硝基、叠氮基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3 -8环烷基、3-10元杂环基、C5-10芳基、5-10元杂芳基、-C0-8-S(O)rR10、-C0-4-S(O)(NR9)R10、-C0-8-P(O)(R10)2、-C0-8-O-R11、-C0-8-C(O)OR11、-C0-8-C(O)R12、-C0-8-O-C(O)R12、-C0-8-NR13R14、-C0-8-C(O)NR13R14、-C0-8-N(R13)-C(O)R12或-C0-8-N(R13)-C(O)OR11，
    上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、卤取代C1-4烷基、C3-6环烷基、3-8元杂环基、C5-8芳基、5-8元杂芳基、-C0-4-S(O)rR10、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0-4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-C0-4-N(R13)-C(O)R12或-C0-4-N(R13)-C(O)OR11的取代基所取代，上述基团再任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2- 4链烯基、C2-4链炔基、卤取代C1-4烷基、C3-6环烷基、3-8元杂环基、C5-8芳基、5-8元杂芳基、-C0-4-S(O)rR10、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0-4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-C0-4-N(R13)-C(O)R12或-C0-4-N(R13)-C(O)OR11的取代基所取代；
    X1、R10、R11、R12、R13、R14、m、n、r如权利要求1所述。
  9. 根据权利要求8所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，
    R8选自氢、氘、卤素、氰基、C1-8烷基、C2-8链烯基、C2-8链炔基、C3-8环烷基、3-10元杂环基、C5-10芳基、5-10元杂芳基、-C0-8-O-R11、-C0-8-NR13R14、-C0-8-N(R13)-C(O)R12或-C0-8-N(R13)-C(O)OR11，
    上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、卤取代C1-4烷基、C3-6环烷基、3-8元杂环基、C5-8芳基、5-8元杂芳基、-C0-4-S(O)rR10、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0-4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-C0-4-N(R13)-C(O)R12或-C0-4-N(R13)-C(O)OR11的取代基所取代，上述基团再任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2- 4链烯基、C2-4链炔基、卤取代C1-4烷基、C3-6环烷基、3-8元杂环基、C5-8芳基、5-8元杂芳基、-C0-4-S(O)rR10、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0-4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-C0-4-N(R13)-C(O)R12或-C0-4-N(R13)-C(O)OR11的取代基所取代。
  10. 根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，选自如下式(Ⅱb)化合物：
    Figure PCTCN2017116186-appb-100009
    其中，X3选自-(CR8)n-或-C(O)-；
    Z选自C1-2亚烷基或如下结构：
    Figure PCTCN2017116186-appb-100010
    上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-8元杂环基、C5-8芳基、5-8元杂芳基、-C0-4-S(O)rR10、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0-4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-C0-4-N(R13)-C(O)R12或-C0-4-N(R13)-C(O)OR11的取代基所取代；
    R2、R3、R4、R5各自独立的选自氢、氘、氯、氟、甲基、异丙基、烯丙基、乙炔基、环丙基、3-氧杂环丁基、三氟甲基、三氘甲基、-C0-4-O-R11或-C0-4-NR13R14，
    或者，R2与R4、R3与R5和其直接相连的碳原子一起形成5-8元杂环基，所述杂原子选自氧或氮，所述5-8元杂环基任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、卤取代C1-4烷基、C3-4环烷基、3-8元杂环基、C5-8芳基、5-8元杂芳基、-C0-4-S(O)rR10、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0- 4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-C0-4-N(R13)-C(O)R12或-C0-4-N(R13)-C(O)OR11的取代基所取代；
    R7选自氢、氘、氯、氟、羟基、烯丙基、乙炔基、环丙基、3-氧杂环丁基、三氟甲基、三氘甲基、-C0-4-O-R11或-C0-4-NR13R14；
    R9选自氢、氘、C1-4烷基、C3-6环烷基或3-8元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、卤取代C1-4烷基、C3-6环烷基、3-8元杂环基、C5-8芳基、5-8元杂芳基、-C0-4-S(O)rR10、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0-4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-C0-4-N(R13)-C(O)R12或-C0-4-N(R13)-C(O)OR11的取代基所取代；
    X1、X2、X5、R8、R10、R11、R12、R13、R14、m、n、r如权利要求1所述；
    条件是，当X3选自-(CR8)n-时，X2选自-C(O)-，X5选自-N(R9)-、N、O或S；当X3选自-C(O)-时，X2选自-N(R9)-，且Z选自C1-4烷基或苯基。
  11. 根据权利要求10所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，选自如下式(Ⅲb-1)或(Ⅲb-2)化合物：
    Figure PCTCN2017116186-appb-100011
    其中，Z选自C1-2亚烷基或如下结构：
    Figure PCTCN2017116186-appb-100012
    上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C1-4烷基、C2-4链烯基、C2-4链炔基、C3-6环烷基、3-8元杂环基、C5-8芳基、5-8元杂芳基、-C0-4-S(O)rR10、-C0-4-O-R11、-C0-4-C(O)OR11、-C0-4-C(O)R12、-C0-4-O-C(O)R12、-C0-4-NR13R14、-C0-4-C(O)NR13R14、-C0-4-N(R13)-C(O)R12或-C0-4-N(R13)-C(O)OR11的取代基所取代；
    R2、R3、R4、R5各自独立的选自氢、氘、氯、氟、羟基、甲基、异丙基、环丙基、3-氧杂环丁基、三氟甲基、三氘甲基或-O-R11，
    或者，R2与R4、R3与R5和其直接相连的碳原子一起形成5-8元杂环基，所述杂原子选自氧或氮；
    R7选自氢、氘、氯、氟、羟基、环丙基或-O-R11；
    X1、R10、R11、R12、R13、R14、m、r如权利要求1所述。
  12. 根据权利要求10所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，选自如下式(Ⅲb-3)化合物：
    Figure PCTCN2017116186-appb-100013
    其中，R2、R3、R4、R5各自独立的选自氢、氘、氯、氟、羟基、甲基、异丙基、环丙基、3-氧杂环丁基、三氟甲基、三氘甲基或-O-R11，
    或者，R2与R4、R3与R5和其直接相连的碳原子一起形成5-8元杂环基，所述杂原子选自氧或氮；
    R7选自氢、氘、氯、氟、羟基、环丙基或-O-R11；
    R9选自氢、氘、C1-4烷基、C3-6环烷基或3-8元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、C1-4烷基、卤取代C1-4烷基、C3-6环烷基、3-8元杂环基、-C0-4-O-R11、-C0-4-NR13R14或-C0-4-C(O)NR13R14的取代基所取代；
    X1、R8、R10、R11、R13、R14、n如权利要求1所述。
  13. 根据权利要求1-12任一所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，选自如下化合物：
    Figure PCTCN2017116186-appb-100014
    Figure PCTCN2017116186-appb-100015
    Figure PCTCN2017116186-appb-100016
    Figure PCTCN2017116186-appb-100017
    Figure PCTCN2017116186-appb-100018
    Figure PCTCN2017116186-appb-100019
    Figure PCTCN2017116186-appb-100020
    Figure PCTCN2017116186-appb-100021
    Figure PCTCN2017116186-appb-100022
    Figure PCTCN2017116186-appb-100023
    Figure PCTCN2017116186-appb-100024
    Figure PCTCN2017116186-appb-100025
    Figure PCTCN2017116186-appb-100026
    Figure PCTCN2017116186-appb-100027
    Figure PCTCN2017116186-appb-100028
    Figure PCTCN2017116186-appb-100029
    Figure PCTCN2017116186-appb-100030
    Figure PCTCN2017116186-appb-100031
    Figure PCTCN2017116186-appb-100032
    Figure PCTCN2017116186-appb-100033
    Figure PCTCN2017116186-appb-100034
    Figure PCTCN2017116186-appb-100035
    Figure PCTCN2017116186-appb-100036
    Figure PCTCN2017116186-appb-100037
    Figure PCTCN2017116186-appb-100038
    Figure PCTCN2017116186-appb-100039
    Figure PCTCN2017116186-appb-100040
    Figure PCTCN2017116186-appb-100041
    Figure PCTCN2017116186-appb-100042
    Figure PCTCN2017116186-appb-100043
    Figure PCTCN2017116186-appb-100044
    Figure PCTCN2017116186-appb-100045
    Figure PCTCN2017116186-appb-100046
    Figure PCTCN2017116186-appb-100047
    Figure PCTCN2017116186-appb-100048
    Figure PCTCN2017116186-appb-100049
    Figure PCTCN2017116186-appb-100050
    Figure PCTCN2017116186-appb-100051
    Figure PCTCN2017116186-appb-100052
    Figure PCTCN2017116186-appb-100053
    Figure PCTCN2017116186-appb-100054
    Figure PCTCN2017116186-appb-100055
    Figure PCTCN2017116186-appb-100056
    Figure PCTCN2017116186-appb-100057
    Figure PCTCN2017116186-appb-100058
    Figure PCTCN2017116186-appb-100059
    Figure PCTCN2017116186-appb-100060
  14. 权利要求1-13任一所述的式(I)化合物、其立体异构体或其药学上可接受盐的制备方法，当m＝1时，包括如下步骤：
    Figure PCTCN2017116186-appb-100061
    或者，
    Figure PCTCN2017116186-appb-100062
    或者，
    Figure PCTCN2017116186-appb-100063
    或者，
    Figure PCTCN2017116186-appb-100064
    或者，当m＝0时，包括如下步骤：
    Figure PCTCN2017116186-appb-100065
    任选的，根据取代基的不同，在不同的取代基之间进行转换反应；
    其中：X为离去基团，优选自氯、溴、甲硫基、甲磺酰基或甲氧基；R选自硝基、氰基或叠氮基；Pg为氨基保护基，优选自叔丁氧羰基、苄氧羰基、2-联苯基-2-丙氧羰基或对甲苯磺酰基；X1、X2、X3、X4、X5、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、m、n、r如权利要求1所定义。
  15. 一种药物组合物，其包括治疗有效剂量的权利要求1-13任一所述的式(I)化合物、其立体异构体或其药学上可接受盐及可药用的载体。
  16. 权利要求1-13任一所述的式(I)化合物、其立体异构体或其药学上可接受盐，或权利要求15所述的药物组合物在制备FGFR4抑制剂药物中的应用。
  17. 根据权利要求1-13任一所述的式(I)所示的化合物、其立体异构体或其药学上可接受的盐，或权利要求15所述的药物组合物在制备治疗癌症的药物中的应用；优选的，所述癌症是前列腺癌、肝癌、胰腺癌、食管癌、胃癌、肺癌、乳腺癌、卵巢癌、结肠癌、皮肤癌、神经胶质母细胞瘤或横纹肌肉瘤。
  18. 根据权利要求1-13任一所述的式(I)化合物、其立体异构体或其药学上可接受盐，或权利要求15所述的药物组合物，其用作FGFR4抑制剂。
  19. 根据权利要求1-13任一所述的式(I)所示的化合物、其立体异构体或其药学上可接受的盐，或权利要求15所述的药物组合物，其用于治疗癌症；优选的，所述癌症是前列腺癌、肝癌、胰腺癌、食管癌、胃癌、肺癌、乳腺癌、卵巢癌、结肠癌、皮肤癌、神经胶质母细胞瘤或横纹肌肉瘤。
  20. 一种抑制FGFR4的方法，所述方法包括给予需要治疗的患者有效治疗量的权利要求1-13任一所述的式(I)化合物、其立体异构体或其药学上可接受盐，或权利要求15所述的药物组合物。
  21. 一种治疗癌症的方法，所述方法包括给予需要治疗的患者有效治疗量的权利要求1-13任一所述的式(I)所示的化合物、其立体异构体或其药学上可接受的盐，或权利要求15所述的药物组合物。
  22. 根据权利要求21所述的方法，其特征在于，所述癌症是前列腺癌、肝癌、胰腺癌、食管癌、胃癌、肺癌、乳腺癌、卵巢癌、结肠癌、皮肤癌、神经胶质母细胞瘤或横纹肌肉瘤。
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