WO2021129561A1 - 一种氰基取代吡啶及氰基取代嘧啶类化合物、制备方法及其应用 - Google Patents

一种氰基取代吡啶及氰基取代嘧啶类化合物、制备方法及其应用 Download PDF

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WO2021129561A1
WO2021129561A1 PCT/CN2020/137938 CN2020137938W WO2021129561A1 WO 2021129561 A1 WO2021129561 A1 WO 2021129561A1 CN 2020137938 W CN2020137938 W CN 2020137938W WO 2021129561 A1 WO2021129561 A1 WO 2021129561A1
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ethyl
methyl
alkyl
propyl
cyano
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PCT/CN2020/137938
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English (en)
French (fr)
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张强
杨磊夫
郑南桥
于善楠
孙月明
郭振科
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北京赛特明强医药科技有限公司
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Priority to US17/788,663 priority Critical patent/US20230125046A1/en
Priority to KR1020227024785A priority patent/KR20220114643A/ko
Priority to AU2020414132A priority patent/AU2020414132B2/en
Priority to CA3162851A priority patent/CA3162851A1/en
Priority to JP2022538861A priority patent/JP2023508376A/ja
Priority to EP20907599.3A priority patent/EP4083021A4/en
Publication of WO2021129561A1 publication Critical patent/WO2021129561A1/zh

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    • A—HUMAN NECESSITIES
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
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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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C—CHEMISTRY; METALLURGY
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    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • 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
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • 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 relates to a cyano-substituted pyridine and cyano-substituted pyrimidine compound, a pharmaceutically acceptable salt, isomer, hydrate, solvate, or prodrug thereof, and a preparation method and application thereof.
  • FGFR is mainly divided into 4 subtypes, namely FGFR1, FGFR2, FGFR3 and FGFR4. Each subtype has the general structural characteristics of receptor tyrosine kinases: the extracellular domain that binds to the ligand, the transmembrane domain, and the intracellular domain of receptor phosphorylation.
  • the ligand When the ligand binds specifically to the receptor, it induces FGFR autophosphorylation, and then dimerizes, so that its domain changes from an inactive state to an active state.
  • the activated FGFR and intracellular kinases are close to each other and phosphorylate each other, thereby activating a series of downstream related signal pathways, and finally stimulating cell proliferation and differentiation, and inhibiting cell apoptosis. Because FGFR plays an important role in the occurrence and development of tumors, targeted therapy for FGFR has become a hot area of clinical research.
  • the first category is chemical small molecule inhibitors, which can competitively or non-competitively bind to the intracellular kinase domain of FGFR to inhibit FGFR itself Phosphorylation, dimerization and the ability to catalyze the phosphorylation of downstream proteins, thereby inhibiting the FGFR signaling pathway.
  • the second category is biological monoclonal antibodies or peptide inhibitors, which can bind to the extracellular domain of FGFR and prevent the binding of FGF and FGFR, thereby inhibiting the activation of FGFR and blocking the transduction of FGFR signals (Seiji Mori, Yoshikazu Takada, Med .Sci.2013,1,20-36).
  • Small molecule tyrosine kinase inhibitors block cell proliferation signals by blocking the activity of intracellular kinases in combination with ATP. Due to the similar structure of the FGFR1, FGFR2, and FGFR3 kinase domains, the inhibitors developed at this stage for these three kinases have similar effects. However, there are certain differences between the FGFR4 kinase domain and the FGFR1-3 kinase domain, so many can effectively inhibit FGFR1 -3 inhibitors are not effective against FGFR4.
  • FGFR inhibitors can be divided into: 1) ATP competitive reversible inhibitor, 2) covalent binding irreversible inhibitor, 3) ATP non-competitive inhibitor (Wu Daichao et al., Cancer Research 2017, 44(1): 61-65).
  • AZD-4547 is a small molecule selective ATP competitive reversible inhibitor that acts linearly with FGFR. From the protein-ligand complex co-crystal structure of FGFR1/AZD-4547, it can be seen that the 3-aminopyrazole mother ring of AZD-4547 has 3 hydrogen bonds with Ala564 and Glu562 in the hinge region, 3,5-di The methoxyphenyl side chain extends into the inward hydrophobic pocket of the hinge region, and the para-chiral piperazine-substituted benzoyl group has hydrophilic or hydrophobic interaction with the solvent-proximal domain extending outside the hinge region.
  • JNJ-42756493 interacts with FGFR as a T-shaped small molecule selective ATP competitive reversible inhibitor. From the JNJ-42756493/FGFR1 co-crystal structure, it can be seen that the position N of the quinoxaline parent ring 1 of JNJ-42756493 and the hinge Ala564 forms a hydrogen bond.
  • the 3,5-dimethoxyphenyl side chain occupies the inward hydrophobic pocket of the hinge region, while the isopropylamine side chain and the downward pocket of the hinge region have a hydrophilic or hydrophobic effect.
  • NH also has a hydrogen bond with Asp641.
  • FGFR1, 2 and 3 at this site are tyrosine residues.
  • PD173074 a selective FGFR inhibitor with nanomolar inhibitory activity, was discovered.
  • 2-aminoquinazoline derivatives that specifically inhibit FGFR4 were discovered, as amino ⁇
  • the compound BLU-9931 was obtained. It was found that its acrylamide could bind irreversibly with Cys552 of FGFR4, and its inhibitory activity against FGFR4 had an IC 50 of 3 nmol/L, which was more selective than FGFR1.
  • BLU-554 is a selective FGFR4 covalent irreversible inhibitor, and in September 2015, it was approved by the FDA for clinical trials for the treatment of hepatocellular carcinoma.
  • TAS-120 and PRN-1371 are also covalent inhibitors of FGFR, and the enzyme inhibitory activity of each subtype of FGFR can reach the nanomolar level.
  • ARQ-087 is a non-ATP competitive inhibitor, and its selectivity to FGFR1, 2 and 3 is more than 8 times superior to FGFR4.
  • FGFR4 Changes in FGFR have been associated with a variety of human cancers, including myeloma, breast cancer, gastric cancer, colon cancer, bladder cancer, pancreatic cancer, and hepatocellular carcinoma.
  • Small molecule inhibitors of FGFR can be divided into pan-FGFR and FGFR4-specific small molecule inhibitors. Due to the similar structure of the kinase domains of FGFR1, FGFR2, and FGFR3, the inhibitors developed at this stage for these three kinases have similar effects. It is reported that FGFR4 plays an important role especially in liver cancer (PLoS One, 2012, Vol. 7, 36713). There are certain differences between the FGFR4 kinase domain and the FGFR1-3 kinase domain, so many inhibitors that can effectively inhibit FGFR1-3 have poor effects on FGFR4.
  • H3 Biopharmaceuticals has published patent WO 2015057938 A1 (publication date 20150423) Pyrimidines as FGFR4 inhibitors and their preparation and WO 2015057963 A1 (publication date 20150423) N- Aryl-heteroarylamines as FGFR4 inhibitors and their preparation discloses specific FGFR4 inhibitors.
  • H3B-6527 has entered the FDA phase I clinical stage and obtained orphan drug qualification. Its structure is as follows:
  • H3B6527 has strong anti-tumor activity on cells amplified by FGF19 gene, and there is no adverse reaction related to bile acid in mouse and monkey animal models.
  • a single administration of H3B-6527 only controls the growth of cancer cells but cannot eliminate them (Cancer Res; 77(24) December 15, 2017).
  • the resistance of H3B-6527 to the key sites V550L or V550 mutations can reduce or invalidate the efficacy. How to break through the limitations of these gene mutations that cause resistance will become the focus of the next phase of FGFR4 inhibitor research.
  • Inhibitors targeting FGFR4 have many advantages, especially their excellent selectivity and resistance to mutations. There are few drugs currently on the market. Therefore, it is found that such small molecule inhibitors targeting FGFR4 will have better therapeutic effects and application prospects. The development of new, highly selective and potent inhibitors of FGFR4 has become an urgent clinical problem.
  • the compound represented by formula (I) provided by the present invention can be used to treat or prevent diseases caused by tyrosine kinase FGFR4 , Including certain variants of the tyrosine kinase FGFR4 receptor.
  • X is N or CH
  • L is -O-, -S-, Or -NR 5 -, wherein R 5 and R 6 are each independently hydrogen, methyl, ethyl, propyl or isopropyl;
  • R 2 is hydrogen, halogen, C 1 -C 3 alkoxy, C 1 -C 3 alkyl
  • R 3 is selected from hydrogen, halogen, hydroxyl, amino, cyano, carboxyl, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, halo C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 3 alkynyl, C 2 -C 3 alkenyl, C 1 -C 3 alkoxy, C 1 -C 3 alkylthio, mono or double C 1 -C 3 alkylamino , C 3 -C 4 cycloalkyloxy, C 3 -C 4 cycloalkyl substituted C 1 -C 3 alkyl, cyano substituted C 1 -C 3 alkyl, carbamoyl substituted C 1- C 3 alkyl group, or the following groups:
  • q is an integer of 1-3
  • R s is selected from -H, C 1 -C 3 alkyl
  • R p is selected from -H, C 1 -C 3 alkyl
  • R'and R" are each independently -H, C 1 -C 3 alkyl, C 3 -C 4 cycloalkyl,
  • R 7 is selected from -H, halogen, hydroxy, cyano, amino, carboxy, C 1 -C 3 alkyl, C 3 -C 4 cycloalkyl, C 1 -C 3 alkoxy, mono or double C 1- C 3 alkyl substituted amino group;
  • R 4 is -T 1 -R 8 or -T 2 -R 9 ,
  • T 1 is:
  • T 2 is:
  • p1 is an integer of 0-4, p2 is an integer of 2-4, p3 is an integer of 0-1,
  • R p is -H or C 1 -C 3 alkyl
  • R 8 is selected from -H, halogen, hydroxyl, amino, cyano, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, halo C 1 -C 3 alkoxy, C 3 -C 6 Cycloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkylthio, mono or double C 1 -C 3 alkylamino, or 1-2 selected from hydroxyl, C 1 -C 6 alkane Group, C 1 -C 3 alkoxy, formyl, acetyl, propionyl, isopropyl, hydroxy substituted C 1 -C 3 alkyl, carboxy substituted C 1 -C 3 alkyl, oxo, C 1- C 3 alkyl substituted or unsubstituted 4-6 membered heteroalicyclic group, or -NR 10 R 11 substituted or unsubstituted 4-6 membered heteroalicyclic group with the same or different substituents,
  • R 10 and R 11 are each independently selected from -H, C 1 -C 6 alkyl, C 3 -C 4 cycloalkyl, hydroxy substituted C 2 -C 6 alkyl, cyano substituted C 1 -C 2 Alkyl, C 1 -C 3 alkyl substituted with C 1 -C 3 alkoxy, C 1 -C 3 alkyl substituted with C 1 -C 3 alkylthio, halogenated C 1 -C 3 alkyl, methyl Sulfone group substituted C 1 -C 3 alkyl, mono or double C 1 -C 3 alkylamino substituted C 1 -C 3 alkyl, C 1 -C 3 alkyl substituted or unsubstituted 4-6 membered heteroalicyclic group , Or R 10 , R 11 and the nitrogen atom to which they are connected are composed of 1-2 selected from -H, hydroxyl, oxo, halogen, C 1 -C 3 alkoxy substituted C
  • the 4-6 membered heteroalicyclic group contains 1-2 heteroatoms selected from N, O or S;
  • R 9 is selected from -H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 1-2 selected from hydroxyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, A 4-6 membered heteroalicyclic group substituted or unsubstituted by the same or different substituents in formyl, acetyl, propionyl, and isopropionyl,
  • the 4-6 membered heteroalicyclic group in R 9 contains 1-2 heteroatoms selected from N, O or S;
  • R 1 is R 4 is 4-ethyl-piperazin-1-yl and L is -O- or At the same time, R 2 and R 3 are not hydrogen at the same time.
  • R 2 is -H, -F, -Cl, methyl or methoxy.
  • R 3 is selected from -H, -F, -Cl, -Br, hydroxyl, carboxyl, cyano, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, Ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, methylthio, ethylthio, propylthio, isopropylthio, fluoromethyl, difluoromethyl , Trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, ethynyl, vinyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclobutylmethyl, amino, methyl Amino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, or the following groups:
  • q is an integer of 2-3
  • R s is selected from -H, methyl, ethyl
  • R p is selected from -H, methyl, ethyl
  • R'and R" are independently selected from -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl,
  • R 7 is selected from -H, -F, hydroxyl, cyano, carboxy, amino, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methyl Amino, ethylamino, dimethylamino.
  • R 3 is selected from -H, -F, -Cl, hydroxyl, carboxyl, cyano, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy Group, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, methylthio, ethylthio, propylthio, isopropylthio, fluoromethyl, difluoromethyl, three Fluoromethyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclobutylmethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, methyl Oxyethoxy, ethoxyethoxy, carbamoyl (NH 2 CO-), methylsulfone.
  • R 4 is -T 1 -R 8 ,
  • T 1 is selected from:
  • p1 is an integer of 0-3, and p2 is an integer of 2-3;
  • R p is selected from -H, methyl, ethyl
  • R 8 is selected from -H, F, -Cl, hydroxyl, amino, cyano, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl, ethyl, propyl, butyl, hexyl, Isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, butoxy, iso Propoxy, methylthio, ethylthio, propylthio, isopropylthio, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino or less Group:
  • R 12 is -H, -F, methyl, ethyl,
  • R 13 is -H, -F, hydroxyl, hydroxymethyl, cyano, methyl, ethyl, methoxy, or -NR 15 R 16 ,
  • R 14 is -H, -F, methyl, ethyl, propyl, isopropyl
  • R 17 is -H, -F, methyl, ethyl, propyl, isopropyl
  • R s1 and R s2 are each independently selected from H and methyl;
  • R 15 and R 16 are each independently -H, methyl, ethyl, propyl, isopropyl, hydroxyethyl, hydroxypropyl, cyanomethyl, cyanoethyl, methoxyethyl, methyl Oxypropyl, ethoxyethyl, ethoxypropyl, isopropoxyethyl, isopropoxypropyl, cyclopropyl, cyclobutyl, dimethylaminoethyl, dimethylaminopropyl , Diethylaminoethyl, diethylaminopropyl, methylethylaminoethyl, methylethylaminopropyl, fluoroethyl, fluoropropyl, methylthioethyl, methylthiopropyl, ethyl Thioethyl, ethylthiopropyl, isopropylthioethyl,
  • R 18 is selected from -H, methyl, ethyl, formyl, acetyl, hydroxyethyl, hydroxypropyl, fluoroethyl, fluoropropyl, methoxyethyl, methoxypropyl, ethoxy Ethyl, ethoxypropyl, methylsulfone, ethylsulfone,
  • R 19 and R 20 are each independently selected from -H, methyl, ethyl, hydroxy, cyano, fluorine, formyl, acetyl, hydroxyethyl, hydroxypropyl, fluoroethyl, fluoropropyl, methoxy Ethylethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, methylsulfone, ethylsulfone, amino, methylamino, dimethylamino, methoxy, ethoxy.
  • R 4 is -T 1 -R 8 .
  • T 1 is selected from:
  • p1 is 0, p2 is an integer of 2-3;
  • R p is selected from -H, methyl, ethyl
  • R 8 is selected from methylamino, ethylamino, propylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino or the following groups:
  • R 12 is -H, -F, methyl, ethyl,
  • R 13 is -H, -NR 15 R 16 ,
  • R 14 is -H, methyl, ethyl, propyl, isopropyl
  • R 17 is methyl, ethyl, propyl, isopropyl
  • R s1 and R s2 are each independently selected from H and methyl;
  • R 15 and R 16 are each independently -H, methyl, ethyl, propyl, isopropyl, hydroxyethyl, hydroxypropyl, cyanomethyl, cyanoethyl, methoxyethyl, methyl Oxypropyl, ethoxyethyl, ethoxypropyl, isopropoxyethyl, isopropoxypropyl, cyclopropyl, cyclobutyl, dimethylaminoethyl, dimethylaminopropyl , Diethylaminoethyl, diethylaminopropyl, methylethylaminoethyl, methylethylaminopropyl, fluoroethyl, fluoropropyl, methylthioethyl, methylthiopropyl, ethyl Thioethyl, ethylthiopropyl, isopropylthioethyl,
  • R 18 is selected from -H, methyl, ethyl, formyl, acetyl, hydroxyethyl, hydroxypropyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxypropyl , Methylsulfone, ethylsulfone,
  • R 19 and R 20 are each independently selected from -H, methyl, ethyl, hydroxy, cyano, fluoro, hydroxyethyl, hydroxypropyl, fluoroethyl, fluoropropyl, methoxyethyl, methoxy Group propyl, ethoxyethyl, ethoxypropyl, methylsulfone, ethylsulfone, amino, methylamino, dimethylamino, methoxy, ethoxy.
  • R 4 is
  • R 12 is -H, -F, methyl, ethyl,
  • R 13 is -H, -NR 15 R 16 ,
  • R s1 and R s2 are H
  • R 15 and R 16 are each independently -H, methyl, ethyl, propyl, isopropyl, hydroxyethyl, hydroxypropyl, cyanomethyl, cyanoethyl, methoxyethyl, methyl Oxypropyl, ethoxyethyl, ethoxypropyl, isopropoxyethyl, isopropoxypropyl, cyclopropyl, cyclobutyl, dimethylaminoethyl, dimethylaminopropyl , Diethylaminoethyl, diethylaminopropyl, methylethylaminoethyl, methylethylaminopropyl, fluoroethyl, fluoropropyl, methylthioethyl, methylthiopropyl, ethyl Thioethyl, ethylthiopropyl, isopropylthioethyl,
  • R 18 is selected from -H, methyl, ethyl, formyl, acetyl, hydroxyethyl, hydroxypropyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxypropyl , Methylsulfone, ethylsulfone,
  • R 19 and R 20 are each independently selected from -H, methyl, ethyl, hydroxyl, cyano, and fluorine.
  • X is N or CH
  • L is -O-, -S-, Or -NR 5 -, wherein R 5 and R 6 are each independently hydrogen, methyl, ethyl, propyl or isopropyl;
  • R 2 is -H, -F, -Cl, methyl or methoxy
  • R 3 is selected from -H, -F, -Cl, -Br, hydroxyl, carboxyl, cyano, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, propoxy Group, isopropoxy, cyclopropyloxy, cyclobutyloxy, methylthio, ethylthio, propylthio, isopropylthio, fluoromethyl, difluoromethyl, trifluoromethyl, Fluoromethoxy, difluoromethoxy, trifluoromethoxy, ethynyl, vinyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclobutylmethyl, amino, methylamino, ethylamino, two Methylamino, diethylamino, N-methyl-N-ethylamino, or the following groups:
  • q is an integer of 2-3
  • R s is selected from -H, methyl, ethyl
  • R p is selected from -H, methyl, ethyl
  • R'and R" are independently selected from -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl,
  • R 7 is selected from -H, -F, hydroxyl, cyano, carboxy, amino, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methyl Amino, ethylamino, dimethylamino;
  • R 4 is -T 1 -R 8 ,
  • T 1 is selected from:
  • p1 is an integer of 0-3, and p2 is an integer of 2-3;
  • R p is selected from -H, methyl, ethyl
  • R 8 is selected from -H, F, -Cl, hydroxyl, amino, cyano, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl, ethyl, propyl, butyl, hexyl, Isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, butoxy, iso Propoxy, methylthio, ethylthio, propylthio, isopropylthio, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino or less Group:
  • R 12 is -H, -F, methyl, ethyl,
  • R 13 is -H, -F, hydroxyl, hydroxymethyl, cyano, methyl, ethyl, methoxy, or -NR 15 R 16 ,
  • R 14 is -H, -F, methyl, ethyl, propyl, isopropyl
  • R 17 is -H, -F, methyl, ethyl, propyl, isopropyl
  • R s1 and R s2 are each independently selected from -H and methyl;
  • R 15 and R 16 are each independently -H, methyl, ethyl, propyl, isopropyl, hydroxyethyl, hydroxypropyl, cyanomethyl, cyanoethyl, methoxyethyl, methyl Oxypropyl, ethoxyethyl, ethoxypropyl, isopropoxyethyl, isopropoxypropyl, cyclopropyl, cyclobutyl, dimethylaminoethyl, dimethylaminopropyl , Diethylaminoethyl, diethylaminopropyl, methylethylaminoethyl, methylethylaminopropyl, fluoroethyl, fluoropropyl, methylthioethyl, methylthiopropyl, ethyl Thioethyl, ethylthiopropyl, isopropylthioethyl,
  • R 18 is selected from -H, methyl, ethyl, formyl, acetyl, hydroxyethyl, hydroxypropyl, fluoroethyl, fluoropropyl, methoxyethyl, methoxypropyl, ethoxy Ethyl, ethoxypropyl, methylsulfone, ethylsulfone,
  • R 19 and R 20 are each independently selected from -H, methyl, ethyl, hydroxy, cyano, fluorine, formyl, acetyl, hydroxyethyl, hydroxypropyl, fluoroethyl, fluoropropyl, methoxy Ethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, methylsulfone, ethylsulfone, amino, methylamino, dimethylamino, methoxy, ethoxy,
  • R 4 is 4-ethyl-piperazin-1-yl
  • L is -O- or
  • R 2 and R 3 are not hydrogen at the same time.
  • L is -O-, and when R 4 is 4-ethyl-piperazin-1-yl, R 2 and R 3 are not hydrogen at the same time.
  • X is N
  • L is -O-
  • R 2 is -H, -F, -Cl, methyl or methoxy
  • R 3 is selected from -H, -F, -Cl, hydroxyl, carboxyl, cyano, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, propoxy, iso Propoxy, cyclopropyloxy, cyclobutyloxy, methylthio, ethylthio, propylthio, isopropylthio, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl , Cyclobutyl, cyclopropylmethyl, cyclobutylmethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, methoxyethoxy, ethyl Oxyethoxy, carbamoyl (NH 2 CO-), methylsulfone;
  • R 4 is -T 1 -R 8 ,
  • T 1 is selected from:
  • p1 is 0, p2 is an integer of 2-3;
  • R p is selected from -H, methyl, ethyl
  • R 8 is selected from methylamino, ethylamino, propylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino or the following groups:
  • R 12 is -H, -F, methyl, ethyl,
  • R 13 is -H, -NR 15 R 16 ,
  • R 14 is -H, methyl, ethyl, propyl, isopropyl
  • R 17 is methyl, ethyl, propyl, isopropyl
  • R s1 and R s2 are each independently selected from H and methyl;
  • R 15 and R 16 are each independently -H, methyl, ethyl, propyl, isopropyl, hydroxyethyl, hydroxypropyl, cyanomethyl, cyanoethyl, methoxyethyl, methyl Oxypropyl, ethoxyethyl, ethoxypropyl, isopropoxyethyl, isopropoxypropyl, cyclopropyl, cyclobutyl, dimethylaminoethyl, dimethylaminopropyl , Diethylaminoethyl, diethylaminopropyl, methylethylaminoethyl, methylethylaminopropyl, fluoroethyl, fluoropropyl, methylthioethyl, methylthiopropyl, ethyl Thioethyl, ethylthiopropyl, isopropylthioethyl,
  • R 18 is selected from -H, methyl, ethyl, formyl, acetyl, hydroxyethyl, hydroxypropyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxypropyl , Methylsulfone, ethylsulfone,
  • R 19 and R 20 are each independently selected from -H, methyl, ethyl, hydroxy, cyano, fluoro, hydroxyethyl, hydroxypropyl, fluoroethyl, fluoropropyl, methoxyethyl, methoxy Propyl, ethoxyethyl, ethoxypropyl, methylsulfone, ethylsulfone, amino, methylamino, dimethylamino, methoxy, ethoxy;
  • R 4 is 4-ethyl-piperazin-1-yl
  • L is -O- or
  • R 2 and R 3 are not hydrogen at the same time.
  • X is N
  • L is -O-
  • R 2 is -H, -F, -Cl, methyl or methoxy
  • R 3 is selected from -H, -F, -Cl, hydroxyl, carboxyl, cyano, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, propoxy, iso Propoxy, cyclopropyloxy, cyclobutyloxy, methylthio, ethylthio, propylthio, isopropylthio, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl , Cyclobutyl, cyclopropylmethyl, cyclobutylmethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, methoxyethoxy, ethyl Oxyethoxy, carbamoyl (NH 2 CO-), methylsulfone;
  • R 12 is -H, -F, methyl, ethyl,
  • R 13 is -H, -NR 15 R 16 ,
  • R s1 and R s2 are H
  • R 15 and R 16 are each independently -H, methyl, ethyl, propyl, isopropyl, hydroxyethyl, hydroxypropyl, cyanomethyl, cyanoethyl, methoxyethyl, methyl Oxypropyl, ethoxyethyl, ethoxypropyl, isopropoxyethyl, isopropoxypropyl, cyclopropyl, cyclobutyl, dimethylaminoethyl, dimethylaminopropyl , Diethylaminoethyl, diethylaminopropyl, methylethylaminoethyl, methylethylaminopropyl, fluoroethyl, fluoropropyl, methylthioethyl, methylthiopropyl, ethyl Thioethyl, ethylthiopropyl, isopropylthioethyl,
  • R 18 is selected from -H, methyl, ethyl, formyl, acetyl, hydroxyethyl, hydroxypropyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxypropyl , Methylsulfone, ethylsulfone,
  • R 19 and R 20 are each independently selected from -H, methyl, ethyl, hydroxyl, cyano, and fluorine.
  • the pharmaceutically acceptable salt of the compound is selected from the hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate, nitrate, Phosphate, formate, acetate, propionate, glycolate, lactate, succinate, maleate, tartrate, malate, citrate, fumarate, glucose Acid salt, benzoate, mandelate, methanesulfonate, isethionate, benzenesulfonate, oxalate, palmitate, 2-naphthalenesulfonate, p-toluenesulfonate, cyclic Hexsulfamate, salicylate, hexonate, trifluoroacetate, aluminum salt, calcium salt, chloroprocaine salt, choline salt, diethanolamine salt, ethylenediamine salt, lithium salt , One or more of magnesium salt, potassium salt, sodium salt and zinc salt.
  • Another aspect of the present invention relates to the preparation and treatment of the compound of formula (I), its isomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs for the treatment of diseases related to tyrosine kinase FGFR4 and itself Application in drugs for immune diseases, wherein the diseases and autoimmune diseases related to tyrosine kinase FGFR4 include fundus diseases, dry eye, psoriasis, vitiligo, dermatitis, alopecia areata, rheumatoid arthritis, colon Inflammation, multiple sclerosis, systemic lupus erythematosus, Crohn's disease, atheroma, pulmonary fibrosis, liver fibrosis, bone marrow fibrosis, non-small cell lung cancer, small cell lung cancer, breast cancer, pancreatic cancer, glial Tumor, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, end
  • compositions comprising the compound represented by formula (I) of the present application, its isomers, hydrates, solvates, pharmaceutically acceptable salts or pro Medicine, and one or more pharmaceutically acceptable carriers or excipients.
  • the pharmaceutical composition may also include one or more other therapeutic agents.
  • the present invention also relates to a method for treating diseases or disorders mediated by tyrosine kinase FGFR4, which comprises administering a therapeutically effective amount of a compound of formula (I) to a patient (human or other mammals, especially human) in need Or a salt thereof, the diseases or disorders mediated by the tyrosine kinase FGFR4 include those mentioned above.
  • alkyl refers to a saturated linear and branched hydrocarbon group with the specified number of carbon atoms.
  • the term C 1 -C 6 alkyl refers to an alkyl moiety containing 1 to 6 carbon atoms
  • C 1 -C 3 Alkyl refers to an alkyl moiety containing 1 to 3 carbon atoms, for example, C 1 -C 6 alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl Base, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methyl Basepentyl and so on.
  • substituent terms such as “alkyl” are used in combination with other substituent terms, for example, in the terms “C 1 -C 3 alkoxy substituted C 1 -C 3 alkyl” or "hydroxy substituted C 2 -C 6 alkane”
  • this linking substituent term e.g., alkyl
  • C 1 -C 3 alkoxy substituted C 1 -C 3 alkyl include, but are not limited to, methoxymethyl, methoxyethyl, ethoxypropyl, and the like.
  • hydroxyl substituted C 2 -C 6 alkyl include, but are not limited to, hydroxyethyl, hydroxypropyl, hydroxyisopropyl and the like.
  • the alkoxy group is an alkyl-O- group formed by the previously described linear or branched alkyl group and -O-, for example, a methoxy group, an ethoxy group, and the like.
  • the alkylthio group is an alkyl-S- group formed by the previously described linear or branched alkyl group and -S-, for example, methylthio, ethylthio and the like.
  • Alkenyl and alkynyl include straight chain, branched chain alkenyl or alkynyl, the term C 2 -C 3 alkenyl or C 2 -C 3 alkynyl means a straight chain or branched C 2 having at least one alkenyl or alkynyl group -C 3 hydrocarbon group.
  • halo C 1 -C 6 alkyl refers to a group having one or more halogen atoms, which may be the same or different, on one or more carbon atoms of an alkyl moiety including 1 to 6 carbon atoms.
  • halo C 1 -C 6 alkyl may include, but are not limited to, -CF 3 (trifluoromethyl), -CCl 3 (trichloromethyl), 1,1-difluoroethyl, 2,2 , 2-Trifluoroethyl and hexafluoroisopropyl, etc.
  • halo C 1 -C 6 alkoxy means a haloalkyl-O- group formed by the halogenated C 1 -C 6 alkyl group and -O-, which can be, for example, trifluoromethyl Oxy, trichloromethoxy and so on.
  • C 1 -C 3 acyl group includes formyl (-CHO), acetyl (CH 3 CO-), and propionyl (C 2 H 5 CO-).
  • Cycloalkyl means a non-aromatic, saturated, cyclic hydrocarbon group containing the specified number of carbon atoms.
  • the term “(C 3 -C 6 )cycloalkyl” refers to a non-aromatic cyclic hydrocarbon ring having 3-6 ring carbon atoms.
  • Exemplary "(C 3 -C 6 )cycloalkyl” includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • aryl means a group or part containing an aromatic monocyclic or bicyclic hydrocarbon atom group, which contains 6 to 12 carbon ring atoms and has at least one aromatic ring.
  • aryl are phenyl, naphthyl, indenyl and dihydroindenyl (indanyl).
  • the aryl group is preferably a phenyl group.
  • 4-6 membered heteroalicyclic group represents an unsubstituted or substituted stable 4- to 6-membered non-aromatic monocyclic saturated ring system, which consists of carbon atoms And it is composed of 1 to 2 heteroatoms selected from N, O, S, among which N, S heteroatoms can be oxidized at will, and N heteroatoms can also be quaternized at will.
  • heterocycles include, but are not limited to, azetidinyl, oxetanyl, thietane, pyrrolidinyl, pyrrolinyl, pyrazolidinyl, pyrazolinyl, imidazole Alkyl, imidazolinyl, oxazolinyl, thiazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, 1,3-dioxolane, piperidinyl, piperazinyl, tetrahydrofuranyl Hydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-oxathiolanyl, 1,3 -Oxythiolanyl, 1,3-dithianyl, 1,4-oxathiolanyl, 1,4-oxa
  • carbonyl refers to a -C(O)- group.
  • halogen and halo refer to chlorine, fluorine, bromine or iodine substituents.
  • Hydroxo is intended to mean the -OH radical.
  • cyano as used herein refers to the group -CN.
  • each independently means that when more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.
  • the compounds, isomers, crystalline forms or prodrugs of formula I and their pharmaceutically acceptable salts can exist in solvated and unsolvated forms.
  • the solvated form may be a water-soluble form.
  • the present invention includes all of these solvated and unsolvated forms.
  • isomers in this application refers to different compounds with the same molecular formula, which may include various isomeric forms such as stereoisomers and tautomers.
  • “Stereoisomers” are isomers that differ only in the arrangement of their atoms in space. Certain compounds described herein contain one or more asymmetric centers, and therefore can produce enantiomers, diastereomers, and other stereoisomers that can be defined as (R)- or (S)- based on absolute stereochemistry form.
  • the chemical entities, pharmaceutical compositions, and methods of the present invention are intended to include all these possible isomers, including racemic mixtures, optically pure forms, and intermediate mixtures.
  • optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the optical activity of the compound can be analyzed by any suitable method, including but not limited to chiral chromatography and optical rotation determination, and the degree of advantage of one stereoisomer over other isomers can be determined.
  • the individual isomers (or isomer-enriched mixtures) of the present invention can be resolved using methods known to those skilled in the art.
  • the resolution can be carried out as follows: (1) by forming diastereomeric salts, complexes or other derivatives; (2) by selective reaction with stereoisomer-specific reagents, such as by enzymes Promote oxidation or reduction; or (3) by gas-liquid chromatography or liquid chromatography in a chiral environment, such as on a chiral carrier (such as silica gel bound with a chiral ligand) or in hand In the presence of sexual solvents.
  • a chiral carrier such as silica gel bound with a chiral ligand
  • stereoisomers can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts, or solvents, or one enantiomer can be converted into another isomer by asymmetric transformation .
  • Tautomers are structurally different isomers that can be converted into each other through tautomerization.
  • Tautomerization is a form of isomerization and includes proton transfer or proton transfer tautomerization, which can be considered a subset of acid-base chemistry.
  • Proton transfer tautomerization or “proton transfer tautomerization” involves the transfer of protons with bond-level changes, often the exchange of single bonds with adjacent double bonds. When tautomerization is possible (for example, in solution), a chemical equilibrium of tautomers can be reached.
  • An example of tautomerization is keto-enol tautomerization.
  • the compound of the present invention as the active ingredient and the method for preparing the compound are the content of the present invention.
  • the crystalline forms of some compounds can exist as polycrystals, and this form can also be included in the current invention.
  • some compounds can form solvates with water (ie, hydrates) or common organic solvents, and such solvates are also included in the scope of this invention.
  • the compounds of the present invention can be used for therapy in free form, or in the form of pharmaceutically acceptable salts or other derivatives where appropriate.
  • pharmaceutically acceptable salt refers to the organic and inorganic salts of the compound of the present invention. This salt is suitable for humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and has reasonable Benefit/risk ratio.
  • Pharmaceutically acceptable salts of amines, carboxylic acids, phosphonates, and other types of compounds are well known in the art.
  • the salt can be formed by reacting the compound of the present invention with a suitable free base or acid.
  • salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, and malonic acid, Or by using methods well known in the art, such as ion exchange methods, these salts can be obtained.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphoric acid Salt, camphorsulfonate, citrate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconic acid Salt, hemisulfate, caproate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, methane Sulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, per-3-phenylpropionate, Phosphate, picrate, propionate
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like.
  • Other pharmaceutically acceptable salts include appropriate non-toxic ammonium, quaternary ammonium, and use such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and arylsulfonate. Amine cation formed by acid salt.
  • prodrug as used herein means that a compound can be converted into the compound represented by formula (I) of the present invention in vivo. This conversion is affected by the hydrolysis of the prodrug in the blood or the enzymatic conversion of the prodrug into the parent compound in the blood or tissues.
  • the pharmaceutical composition of the present invention includes the compound of structural formula (I) described herein or a pharmaceutically acceptable salt thereof, kinase inhibitors (small molecules, polypeptides, antibodies, etc.), immunosuppressants, anticancer drugs, antiviral agents, and Inflammation, antifungal, antibiotic or anti-vascular hyperproliferative compound; and any pharmaceutically acceptable carrier, adjuvant or excipient.
  • kinase inhibitors small molecules, polypeptides, antibodies, etc.
  • immunosuppressants anticancer drugs, antiviral agents, and Inflammation, antifungal, antibiotic or anti-vascular hyperproliferative compound
  • any pharmaceutically acceptable carrier, adjuvant or excipient any pharmaceutically acceptable carrier, adjuvant or excipient.
  • the compound of the present invention can be used alone, or in combination with one or more other compounds of the present invention or with one or more other agents.
  • the therapeutic agents can be formulated to be administered simultaneously or sequentially at different times, or the therapeutic agents can be administered as a single composition.
  • the so-called "combination therapy” refers to the use of the compound of the present invention together with another agent.
  • the mode of administration is simultaneous co-administration of each agent or sequential administration of each agent. In either case, the purpose is to To achieve the best effect of the drug.
  • Co-administration includes simultaneous delivery of dosage forms, as well as separate separate dosage forms for each compound.
  • the administration of the compound of the present invention can be used simultaneously with other therapies known in the art, for example, the use of radiotherapy or cytostatic agents, cytotoxic agents, other anti-cancer agents and other additional therapies in cancer treatment to improve Cancer symptoms.
  • the present invention is not limited to the order of administration; the compounds of the present invention may be administered previously, concurrently, or after other anticancer agents or cytotoxic agents.
  • one or more compounds or salts of formula (I) as its active ingredient can be tightly mixed with the pharmaceutical carrier, which is carried out according to the traditional pharmaceutical ingredient technology.
  • the carrier can take various forms according to the preparation form designed according to different administration methods (for example, oral or parenteral administration).
  • Appropriate pharmaceutically acceptable carriers are well known in the art. A description of some of these pharmaceutically acceptable carriers can be found in the "Handbook of Pharmaceutical Excipients", which is jointly published by the American Pharmaceutical Association and the British Pharmaceutical Society.
  • the pharmaceutical composition of the present invention may have the following forms, for example, suitable for oral administration, such as tablets, capsules, pills, powders, sustained release forms, solutions or suspensions; for parenteral injections such as clear liquids, suspensions, Emulsion; or for topical medications such as ointments and creams; or as suppositories for rectal administration.
  • the pharmaceutical ingredients can also be used in unit dose form suitable for single-time administration of precise doses.
  • the pharmaceutical ingredient will include a traditional pharmaceutical carrier or excipient and a compound made according to the current invention as an active ingredient. In addition, it may also include other medical or pharmaceutical preparations, carriers, adjuvants, and the like.
  • Therapeutic compounds can also be given to mammals instead of humans.
  • the dose of drug given to a mammal will depend on the species of the animal and its disease or disorder.
  • Therapeutic compounds can be given to animals in the form of capsules, boluses, or tablet potions.
  • the therapeutic compound can also be injected or infused into the animal's body. We prepare these drug forms in a traditional way that meets the standards of veterinary practice.
  • the pharmacological compound can be mixed with animal feed and fed to animals. Therefore, concentrated feed additives or premixes can be prepared to mix with ordinary animal feed.
  • Another object of the present invention is to provide a method for treating cancer in a subject in need, which comprises a method of administering to the subject a therapeutically effective amount of a composition containing the compound of the present invention.
  • the compound of the present invention has better selectivity for FGFR4 than other receptors, especially better than other FGF receptors, such as FGFR1, FGFR2 and FGFR3. Therefore, the present invention relates to compounds that are selective FGFR4 inhibitors.
  • the compound of formula (I) in free or pharmaceutically acceptable salt form is suitable for the treatment of conditions (such as cancer) mediated by the activity of the FGFR4 protein and/or responsive to FGFR4 inhibition (In particular, it refers to a condition in a therapeutically beneficial manner), most particularly a disease or disorder as mentioned below in this article.
  • the compounds of the present invention can be used to treat cancer. Specifically, the compounds of the present invention can be used to treat indications selected from liver cancer, breast cancer, glioblastoma, prostate cancer, rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer, and colon cancer.
  • the compounds of the present invention can also be used to treat solid malignant tumors characterized by positive FGFR4 expression.
  • the compounds of the present invention can also be used to treat solid malignant tumors characterized by positive KLB ( ⁇ -klotho) expression.
  • the compounds of the present invention can also be used to treat solid malignant tumors characterized by positive FGF19 expression.
  • the compounds of the present invention can also be used to treat solid malignant tumors characterized by positive FGFR4 and positive KLB expression.
  • the compounds of the present invention can also be used to treat solid malignant tumors characterized by positive FGFR4 and positive FGF19 expression.
  • the compounds of the present invention can also be used to treat solid malignant tumors characterized by positive FGFR4, positive KLB, and positive FGF19 expression.
  • any positive expression in FGFR4, KLB and/or FGF19 can be evaluated by methods known to the skilled person, such as RT-qPCR, Western immunoblotting, ELISA, immunohistochemistry.
  • the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in therapy.
  • the treatment is selected from diseases that can be treated by inhibiting FGFR4.
  • the disease is selected from the list mentioned above, suitably liver cancer.
  • the present invention provides a method of treating diseases treated by inhibiting FGFR4, comprising administering a therapeutically acceptable amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the disease is selected from the list mentioned above, suitably liver cancer.
  • the present invention provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of medicines.
  • the drug is used to treat diseases that can be treated by inhibiting FGFR4.
  • the disease is selected from the list mentioned above, suitably liver cancer.
  • the present invention also provides a method for preparing the corresponding compound.
  • a variety of synthetic methods can be used to prepare the compound described herein, including the method involved in the following examples, the compound of the present invention or its pharmaceutically acceptable salt, isomer
  • the body or hydrate can be synthesized using the following methods and synthetic methods known in the field of organic chemistry synthesis, or by those skilled in the art understanding variations on these methods. Preferred methods include but are not limited to the following methods.
  • the final product of the present invention can be prepared by the following scheme, wherein R 1 , R 2 , R 3 , R 4 , X, and L are as defined above,
  • Q in intermediate A can be halogen (preferably chlorine) or methylsulfone group (sulfoxide group).
  • the reaction in step 1 can be under acid catalysis, neutral conditions or The substitution reaction is carried out by heating under alkaline conditions to synthesize compound (I').
  • Q in intermediate A is chlorine
  • compound (I') can also be synthesized by Buchwald coupling reaction; afterwards, the protective group of tert-butyloxycarbonyl is removed under acidic conditions, and the final product (I) is further synthesized with acryloyl chloride. .
  • the preparation method of the compound of the present invention includes the preparation of the above intermediates,
  • Step 1 Compound (B 2 ) is reacted with (Boc) 2 O to obtain compound (B 3 ), X'can be Cl, F, Br or I;
  • Step 2 Compound (B 3 ) is reacted with R 4 -H (amine or alcohol) under alkaline or neutral conditions to obtain compound (B 4 ).
  • R 4 -H amine or alcohol
  • compound (B 4 ) can also be obtained by Buchwald coupling reaction;
  • Step 3 The compound (B 4 ) reacts with a reducing agent to form an intermediate (B).
  • the base mentioned in step 2 is selected from inorganic bases such as cesium carbonate, triethylamine, sodium hydride, sodium bis(trimethylsilyl)amide, or a combination of two or more of organic bases.
  • the Buchwald condition is preferably Pd 2 (dba) 3 , a combination of XantPhos and cesium carbonate;
  • the reducing agent in step 3 is selected from stannous chloride, hydrogen and palladium carbon combination, hydrogen and Raney nickel combination, zinc powder and acid combination, iron powder and acid combination and other reducing agent systems;
  • a preparation method of intermediate (A) is as follows,
  • Step 1 Compound (A 2 ) undergoes substitution reaction with A 1 in the presence of a base to obtain (A 3 );
  • Step 2 Compound (A 3 ) is dehydrated into compound (A) by amide dehydration under the conditions of a dehydrating agent.
  • the present invention provides a preferred embodiment of the above reaction, preferably,
  • the base is selected from organic or inorganic bases, such as triethylamine, N'N-diisopropylethylamine, sodium hydride, sodium bis(trimethylsilyl)amide, n-butyl lithium One or a combination of two or more;
  • the dehydrating agent is selected from phosphorus oxychloride, aluminum trichloride, phosphorus pentoxide, phosphorus chloride (phosphorus pentachloride or phosphorus trichloride) and the like.
  • the reaction solvent is provided by Sinopharm Reagent
  • Thin layer chromatography silica gel plate (thickness 0.5mm, 1mm, 200X200mm) is provided by Yantai Xinnuo Chemical Co., Ltd.
  • N,N-di-tert-butoxycarbonyl-2-nitro-5-fluoroaniline (3.3g, 9.2mmol) and ethylpiperazine (3mL) were added to DMF, heated to 120°C for 8 hours, and cooled. Concentrate and purify by column chromatography to obtain 3.1 g of yellow solid, MS: 351[M+H] + ;
  • Step 1 (2-((5-cyano-4-((2-isopropoxyphenyl)amino)pyrimidin-2-yl)amino)-5-(4-methylpiperazin-1-yl )Phenyl) Synthesis of tert-butyl carbamate
  • Step 2 N-(2-((5-cyano-4-((2-isopropoxyphenyl)amino)pyrimidin-2-yl)amino)-5-(4-methylpiperazine-1 -(Yl)phenyl)acrylamide synthesis
  • Example 2 The compounds in the following table refer to the preparation method of Example 1 and were prepared by the corresponding intermediate reaction.
  • Table 3 lists the structure, name and characterization data of the compound prepared in Example 2-81.
  • Example 82 N-(2-((5-cyano-4-((2-isopropoxyphenyl)amino)pyridin-2-yl)amino)-5-(4-(dimethylamino) )Piperidin-1-yl)phenyl)acrylamide
  • HMDSNa (2N, 1mL) was slowly added dropwise to a solution of 2-isopropoxyaniline (300mg, 2mmol) in tetrahydrofuran (5mL), and the reaction was stirred for half an hour, and then 2,4-bis was added dropwise.
  • a solution of chloro-5-nicotinamide (190mg, 1mmol) in tetrahydrofuran (1mL) was stirred overnight in an ice-water bath, quenched by adding water to make the slurry, filtered to obtain a light yellow solid 230mg, yield 75%, MS: 306[M+ H] + .
  • Step 3 (2-((5-cyano-4-((2-isopropoxyphenyl)amino)pyridin-2-yl)amino)-5-(4-(dimethylamino)piperidine -1-yl) phenyl) t-butyl carbamate
  • Example 84 N-(2-((5-cyano-4-((2-isopropoxyphenyl)amino)pyridin-2-yl)amino)-5-(4-ethylpiperazine- 1-yl)phenyl)acrylamide
  • test method is as follows:
  • a the compound is diluted with DMSO solution in a 3-fold ratio to form 11 gradients, the 12th gradient is pure DMSO solution (as a positive control); take a new 96-well plate b and use the above solution 25 times diluted with ultrapure water (DMSO concentration is 4%)
  • Add 2 ⁇ substrate/ATP mixture Take 5 ⁇ l of the above 2 ⁇ substrate/ATP mixture into the corresponding reaction wells of a 384-well plate with a discharge gun.
  • Negative control set a negative control well in a 384-well plate, add 2.5 ⁇ l 4 ⁇ substrate, 2.5 ⁇ l 4 ⁇ enzyme solution, 2.5 ⁇ l 1 ⁇ Kinase Assay Buffer and 2.5 ⁇ l ultrapure water containing 4% DMSO to each well .
  • Inhibition rate (reading value of positive control well-reading value of experimental well)/(reading value of positive control well-reading value of negative control well)*100%
  • the final concentration of FGFR4 kinase was 3.85 nM
  • the final concentration of ATP was 100 ⁇ M
  • the final concentration of substrate ULight TM -labeled JAK-1 (Tyr1023) Peptide was 100 nM
  • the enzymatic reaction time was 2 hours.
  • the highest final concentration of the compound in the reaction system was 2.5 ⁇ M, and there were 11 concentrations after 3-fold gradient dilution, and the lowest final concentration was 0.042 nM.
  • the final concentration of DMSO is 1%.
  • the final concentration of FGFR4 V550L kinase is 1 nM
  • the final concentration of ATP is 10 ⁇ M
  • the final concentration of substrate ULight TM -labeled PolyGT is 100 nM
  • the enzymatic reaction time is 2 hours.
  • the highest final concentration of the compound in the reaction system was 2.5 ⁇ M, and there were 11 concentrations after 3-fold serial dilution, and the lowest final concentration was 0.042 nM.
  • the final concentration of DMSO is 1%.
  • Table 4 lists the results of the determination of the inhibitory activity of some compounds in this patent on the tyrosine kinase FGFR4 and the V550L mutant tyrosine kinase FGFR4, where A means IC 50 is less than or equal to 10 nM, B means IC 50 is greater than 10 nM but less than or equal to 50nM, C represents the IC 50 is greater than or equal to but less than 50nM 100nM, D represents the IC 50 of greater than 100nM, and D is smaller than or equal to 1000nM, NT indicates No correlation value.
  • test of compound inhibiting cell proliferation is as follows:
  • Table 6 lists the results of the determination of the proliferation inhibitory activity of some compounds in the application on Ba/F3ETV6-FGFR4 cells and Ba/F3ETV6-FGFR4-V550L cells, where A means IC 50 is less than or equal to 10 nM, B means IC 50 is greater than 10 nM but less than or equal to 50nM, C represents the IC 50 is greater than or equal to but less than 50nM 100nM, D represents the IC 50 of greater than 100nM, and D is smaller than or equal to 1000nM, NT indicates No correlation value.
  • Table 6 Results of the determination of the proliferation inhibitory activity of the compounds of the present invention on Ba/F3ETV6-FGFR4 cells and Ba/F3ETV6-FGFR4-V550L cells
  • the biological data provided by the present invention shows that the compounds of the present invention are beneficial to the treatment or prevention of diseases caused by FGFR4 kinase abnormalities, including diseases caused by FGFR4 gene mutations (V550L, V550M, etc.), including primary and metastatic cancers , Including solid tumors.
  • Such cancers include, but are not limited to: non-small cell lung cancer, small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, intrauterine cancer Membranous cancer, prostate cancer, bladder cancer, leukemia, stomach cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic myeloid leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, nasopharyngeal cancer, esophageal cancer, brain Tumor, B-cell and T-cell lymphoma, lymphoma, multiple myeloma, biliary carcinosarcoma, cholangiocarcinoma.
  • the compounds of the present invention also include the treatment of cancers resistant to one or more other treatment methods.
  • the compounds of the present invention can also be used in other diseases related to FGFR4 kinase besides cancer, including but not limited to fundus diseases, psoriasis, rheumatoid arthritis, atheroma, pulmonary fibrosis, and liver fibrosis.
  • the compound of the present invention can be used as monotherapy or combination therapy, and can be used in combination with multiple compounds of the present invention or in combination with other drugs other than the present invention.

Abstract

一种氰基取代吡啶及氰基取代嘧啶类化合物、制备方法及其应用，具体涉及式（I）所示化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药，其制备方法及其在制备作为激酶抑制剂的药物中的应用。该化合物对FGFR4及突变型FGFR4V550L等激酶均具有良好的抑制活性。

Description

一种氰基取代吡啶及氰基取代嘧啶类化合物、制备方法及其应用 技术领域
本发明涉及一种氰基取代吡啶及氰基取代嘧啶类化合物，其药学上可接受的盐，异构体，水合物，溶剂化物，或前药，及其制备方法和用途。
背景技术
细胞中FGFR的激活突变或扩增可导致FGF-FGFR信号通路的过度激活，使得细胞获得过度增殖、逃避凋亡、容易迁移等致癌特性，所以FGFRs可作为直接或间接肿瘤治疗的靶标。FGFR主要分为4种亚型，分别为FGFR1、FGFR2、FGFR3和FGFR4。各亚型均具有受体酪氨酸激酶的一般结构特点：与配体结合的胞外区、跨膜区和受体磷酸化的胞内区。当配体与受体特异性结合后，诱导FGFR自身磷酸化，进而二聚化，使得其结构域从非活性状态转变为活性状态。活化的FGFR又与胞内的激酶互相靠近，相互磷酸化，从而激活下游一系列的相关信号通路，最终刺激细胞的增殖、分化，抑制细胞凋亡。由于FGFR在肿瘤的发生发展中有重要的作用，针对FGFR的靶向治疗成为临床研究的热点领域。已有的靶向FGFR的药物，按照其来源可分为两类：第一类是化学小分子抑制剂，它可以竞争性或非竞争性的与FGFR胞内激酶结构域结合，抑制FGFR的自身磷酸化、二聚化和催化下游蛋白磷酸化的能力，从而抑制FGFR信号通路。第二类是生物单抗或多肽抑制剂，它可以与FGFR的胞外区结合，阻止FGF与FGFR的结合，从而抑制FGFR的活化，阻断FGFR信号的转导(Seiji Mori,Yoshikazu Takada,Med.Sci.2013,1,20-36)。
小分子酪氨酸激酶抑制剂通过阻断胞内激酶与ATP结合的活性，阻断细胞增殖信号。由于FGFR1、FGFR2、FGFR3激酶域的结构相似，现阶段研发的针对这三个激酶的抑制剂效果相差不大，然而，FGFR4激酶域与FGFR1-3激酶域存在一定差异，因此许多能有效抑制FGFR1-3的抑制剂对FGFR4效果不佳。如近几年处于临床试验阶段的AZD-4547、Infigratinib、CH-5183284、E-7090、BAY-1163877、INCB-54828等针对的是FGFR1/2/3靶标，FGF-401、BLU-554针对的是FGFR4靶标。小分子FGFR抑制剂可分为：1)ATP竞争性可逆抑制剂、2)共价结合不可逆抑制剂、3)ATP非竞争性抑制剂(伍代朝等,肿瘤防治研究2017,44(1):61-65)。
AZD-4547是与FGFR作用呈直线型的小分子选择性ATP竞争性可逆抑制剂。从FGFR1/AZD-4547的蛋白-配体复合物共晶结构可以看出，AZD-4547的3-氨基吡唑母环与铰链区的Ala564和Glu562有3个氢键作用，3,5-二甲氧基苯基侧链伸入铰链区向内的疏水口袋，对位手性哌嗪取代的苯甲酰基，与伸向铰链区外的近溶剂端结构域发生亲水或疏水的相互作用。在这些作用下，整个分子呈一种直线形式***FGFR1的ATP结合区域，与FGFR1蛋白紧密结合。具有类似直线型作用的化合物还包括BGJ-398、CH-5183284和ASP-5878。
JNJ-42756493与FGFR作用呈T型的小分子选择性ATP竞争性可逆抑制剂，从JNJ-42756493/FGFR1共晶结构可以看出，JNJ-42756493的喹喔啉母环1位N与铰链区的Ala564形成一个氢键，3,5-二甲氧基苯基侧链占据铰链区向里的疏水口袋，而异丙胺侧链与铰链区向下的口袋有亲水或疏水的作用，异丙胺的NH 与Asp641也有一个氢键作用。
由于蛋白ATP结合位点的铰链区与FGFR1、2和3有1个不同的半胱氨酸残基，而此位点FGFR1、2和3为酪氨酸残基。从这个结构上的微小差异出发，发现具有纳摩尔级抑制活性的FGFR选择性抑制剂PD173074，在此基础上发现了可特异性抑制FGFR4的2-氨基喹唑啉类衍生物，当氨基的β位上引入1个丙烯酰胺的取代基时获得化合物BLU-9931,发现其丙烯酰胺可与FGFR4的Cys552产生不可逆的共价结合，其对FGFR4抑制活性IC 50为3nmol/L，其选择性比FGFR1/2/3分别高297、184和50倍。通过对BLU-9931的进一步结构优化，发现BLU-554是选择性FGFR4共价不可逆抑制剂，并于2015年9月获得了FDA批准用于治疗肝细胞癌的临床试验。TAS-120和PRN-1371也是FGFR共价抑制剂，对FGFR各亚型的酶抑制活性均可达到纳摩尔水平。
ARQ-087为非ATP竞争性的抑制剂，其对FGFR1、2和3的选择性比FGFR4有8倍以上的优势。
FGFR的改变已与多种人类癌症相关联，包括骨髓瘤、乳腺癌、胃癌、结肠癌、膀胱癌、胰腺癌及肝细胞癌。FGFR的小分子抑制剂可分为泛FGFR和FGFR4特异性小分子抑制剂。由于FGFR1、FGFR2、FGFR3激酶域的结构相似，现阶段研发的针对这三个激酶的抑制剂效果相差不大。据报导FGFR4尤其在肝癌中起重要作用(PLoS One,2012，第7卷,36713)。FGFR4激酶域与FGFR1-3激酶域存在一定差异，因此许多能有效抑制FGFR1-3的抑制剂对FGFR4效果不佳。
为了提高小分子抑制剂对FGFR4激酶域的选择性并减少不良反应，H3生物医药公司在专利WO 2015057938 A1(公开日20150423)Pyrimidines as FGFR4 inhibitors and their preparation和WO 2015057963 A1(公开日20150423)N-Aryl-heteroarylamines as FGFR4 inhibitors and their preparation中公开了FGFR4特异性抑制剂，其中H3B-6527已进入FDA一期临床阶段，并获得孤儿药资格，其结构如下：
Figure PCTCN2020137938-appb-000001
H3B6527对FGF19基因扩增的细胞具有强抗肿瘤活性，且在小鼠和猴的动物模型中没有胆汁酸相关的不良反应。但是H3B-6527单一给药仅控制癌细胞生长而无法清除癌细胞(Cancer Res；77(24)December 15,2017)。H3B-6527对关键位点V550L或V550突变导致的耐药性使疗效降低或失效，如何突破这些导致耐药的基因突变的限制将成为下一阶段FGFR4抑制剂研究的重点。
针对FGFR4靶标的抑制剂有许多优点，尤其是其优异的选择性和抗突变性。目前上市的药物很少，因此，发现这类以FGFR4为靶标的小分子抑制剂会有更好的治疗效果和应用前景。研发出全新的、对FGFR4高选择性的、药效强的抑制剂成为临床中亟待解决的问题。
发明内容
本发明所提供式(I)表示的化合物，其药学上可接受的盐，异构体，水合物，溶剂化物，或前药，其 可用作治疗或预防由酪氨酸激酶FGFR4引起的疾病，包括酪氨酸激酶FGFR4受体的某些变种。
Figure PCTCN2020137938-appb-000002
式(I)中，
X为N或CH；
L为-O-、-S-、
Figure PCTCN2020137938-appb-000003
或者-NR 5-，其中，R 5和R 6各自独立地为氢、甲基、乙基、丙基或者异丙基；
R 1为
Figure PCTCN2020137938-appb-000004
R 2为氢、卤素、C 1-C 3烷氧基、C 1-C 3烷基；
R 3选自氢、卤素、羟基、氨基、氰基、羧基、C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 3烷氧基、C 3-C 6环烷基、C 2-C 3炔基、C 2-C 3烯基、C 1-C 3烷氧基、C 1-C 3烷硫基、单或双C 1-C 3烷基氨基、C 3-C 4环烷基氧基、C 3-C 4环烷基取代的C 1-C 3烷基、氰基取代的C 1-C 3烷基、氨基甲酰基取代的C 1-C 3烷基、或以下基团：
Figure PCTCN2020137938-appb-000005
q为1-3的整数，
R s选自-H、C 1-C 3烷基，R p选自-H、C 1-C 3烷基，
R'、R”分别独立地为-H、C 1-C 3烷基、C 3-C 4环烷基，
R 7选自-H、卤素、羟基、氰基、氨基、羧基、C 1-C 3烷基、C 3-C 4环烷基、C 1-C 3烷氧基、单或双C 1-C 3烷基取代的氨基；
R 4为-T 1-R 8或-T 2-R 9，
T 1为：
Figure PCTCN2020137938-appb-000006
T 2为：
Figure PCTCN2020137938-appb-000007
p1为0-4的整数，p2为2-4的整数，p3为0-1的整数，
R p为-H或C 1-C 3烷基，
R 8选自-H、卤素、羟基、氨基、氰基、C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 3烷氧基、C 3-C 6环烷基、C 1-C 3烷氧基、C 1-C 3烷硫基、单或双C 1-C 3烷基氨基、或者被1-2个选自羟基、C 1-C 6烷基、C 1-C 3烷氧基、甲酰基、乙酰基、丙酰基、异丙酰基、羟基取代的C 1-C 3烷基、羧基取代的C 1-C 3烷基、氧代、C 1-C 3烷基取代或非取代的4-6元杂脂环基、或-NR 10R 11中的相同或不同的取代基所取代或非取代的4-6元杂脂环基，
R 10、R 11各自独立地选自-H、C 1-C 6烷基、C 3-C 4环烷基、羟基取代的C 2-C 6烷基、氰基取代的C 1-C 2烷基、C 1-C 3烷氧基取代的C 1-C 3烷基、C 1-C 3烷硫基取代的C 1-C 3烷基、卤代C 1-C 3烷基、甲砜基取代C 1-C 3烷基、单或双C 1-C 3烷氨基取代C 1-C 3烷基、C 1-C 3烷基取代或非取代的4-6元杂脂环基，或者R 10、R 11与其相连的氮原子构成被1-2个选自-H、羟基、氧代、卤素、C 1-C 3烷氧基取代C 1-C 3烷基、C 1-C 3烷基砜基、氰基、氨基、C 1-C 3酰基、C 1-C 3烷基、单或双C 1-C 3烷氨基、羟基取代的C 2-C 3烷基、C 1-C 3烷氧基中的相同或不同的取代基所取代或非取代的4-6元杂脂环基，
所述4-6元杂脂环基含1-2个选自N、O或S的杂原子；
R 9选自-H、C 1-C 6烷基、C 3-C 6环烷基、被1-2个选自羟基、C 1-C 3烷基、C 1-C 3烷氧基、甲酰基、乙酰基、丙酰基、异丙酰基中的相同或不同的取代基所取代或者非取代的4-6元杂脂环基，
R 9中所述4-6元杂脂环基中含1-2个选自N、O或S的杂原子；
且，当R 1为
Figure PCTCN2020137938-appb-000008
R 4为4-乙基-哌嗪-1-基且L为-O-或者
Figure PCTCN2020137938-appb-000009
时，R 2和R 3不同时为氢。
在优选的方案中，R 2为-H、-F、-Cl、甲基或甲氧基。
在优选的方案中，R 3选自-H、-F、-Cl、-Br、羟基、羧基、氰基、甲基、乙基、丙基、异丙基、叔丁基、甲氧基、乙氧基、丙氧基、异丙氧基、环丙基氧基、环丁基氧基、甲硫基、乙硫基、丙硫基、异丙硫基、氟甲基、二氟甲基、三氟甲基、氟甲氧基、二氟甲氧基、三氟甲氧基、乙炔基、乙烯基、环丙基、环丁基、环丙基甲基、环丁基甲基、氨基、甲氨基、乙氨基、二甲氨基、二乙氨基、N-甲基-N-乙基氨基、或以下基团：
Figure PCTCN2020137938-appb-000010
q为2-3的整数，
R s选自-H、甲基、乙基，R p选自-H、甲基、乙基，
R'、R”分别独立的选自-H、甲基、乙基、丙基、异丙基、环丙基、环丁基，
R 7选自-H、-F、羟基、氰基、羧基、氨基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、甲氨基、乙氨基、二甲氨基。
在进一步的优选方案中，R 3选自-H、-F、-Cl、羟基、羧基、氰基、甲基、乙基、丙基、异丙基、叔丁基、甲氧基、乙氧基、丙氧基、异丙氧基、环丙基氧基、环丁基氧基、甲硫基、乙硫基、丙硫基、异丙硫基、氟甲基、二氟甲基、三氟甲基、环丙基、环丁基、环丙基甲基、环丁基甲基、氨基、甲氨基、乙氨基、 二甲氨基、二乙氨基、N-甲基-N-乙基氨基、甲氧基乙氧基、乙氧基乙氧基、氨基甲酰基(NH 2CO-)、甲砜基。
在优选的方案中，R 4为-T 1-R 8，
T 1选自：
Figure PCTCN2020137938-appb-000011
p1为0-3的整数，p2为2-3的整数；
R p选自-H、甲基、乙基；
R 8选自-H、F、-Cl、羟基、氨基、氰基、氟甲氧基、二氟甲氧基、三氟甲氧基、甲基、乙基、丙基、丁基、己基、异丙基、氟甲基、二氟甲基、三氟甲基、环丙基、环丁基、环戊基、环己基、甲氧基、乙氧基、丙氧基、丁氧基、异丙氧基、甲硫基、乙硫基、丙硫基、异丙硫基、甲氨基、乙氨基、丙氨基、二甲氨基、二乙氨基、N-甲基-N-乙基氨基或以下基团：
Figure PCTCN2020137938-appb-000012
R 12为-H、-F、甲基、乙基，
R 13为-H、-F、羟基、羟甲基、氰基、甲基、乙基、甲氧基、或–NR 15R 16，
R 14为-H、-F、甲基、乙基、丙基、异丙基、
Figure PCTCN2020137938-appb-000013
其中，R 17为-H、-F、甲基、乙基、丙基、异丙基，
R s1、R s2分别独立地选自H、甲基；
R 15、R 16分别独立地为-H、甲基、乙基、丙基、异丙基、羟乙基、羟丙基、氰基甲基、氰基乙基、甲氧基乙基、甲氧基丙基、乙氧基乙基、乙氧基丙基、异丙氧基乙基、异丙氧基丙基、环丙基、环丁基、二甲氨基乙基、二甲氨基丙基、二乙氨基乙基、二乙氨基丙基、甲基乙基氨基乙基、甲基乙基氨基丙基、氟乙基、氟丙基、甲硫基乙基、甲硫基丙基、乙硫基乙基、乙硫基丙基、异丙硫基乙基、异丙硫基丙基、甲砜基乙基、甲砜基丙基、乙砜基乙基、乙砜基丙基、2-羟基-2-甲基丙基、3-羟基-3-甲基丁基、氧杂环丁基、四氢呋喃基、四氢吡喃基，或者R 15、R 16与其相连的氮原子构成取代或非取代的4-6元杂脂环基，选自以下基团：
Figure PCTCN2020137938-appb-000014
R 18选自-H、甲基、乙基、甲酰基、乙酰基、羟乙基、羟丙基、氟乙基、氟丙基、甲氧基乙基、甲氧基丙基、乙氧基乙基、乙氧基丙基、甲砜基、乙砜基，
R 19和R 20各自独立地选自-H、甲基、乙基、羟基、氰基、氟、甲酰基、乙酰基、羟乙基、羟丙基、氟乙基、氟丙基、甲氧基乙基、甲氧基丙基、乙氧基乙基、乙氧基丙基、甲砜基、乙砜基、氨基、甲氨基、 二甲氨基、甲氧基、乙氧基。
在进一步的优选方案中，R 4为-T 1-R 8，
T 1选自：
Figure PCTCN2020137938-appb-000015
p1为0，p2为2-3的整数；
R p选自-H、甲基、乙基；
R 8选自甲氨基、乙氨基、丙氨基、二甲氨基、二乙氨基、N-甲基-N-乙基氨基或以下基团：
Figure PCTCN2020137938-appb-000016
R 12为-H、-F、甲基、乙基，
R 13为-H、-NR 15R 16，
R 14为-H、甲基、乙基、丙基、异丙基、
Figure PCTCN2020137938-appb-000017
其中，R 17为甲基、乙基、丙基、异丙基，
R s1、R s2分别独立地选自H、甲基；
R 15、R 16分别独立地为-H、甲基、乙基、丙基、异丙基、羟乙基、羟丙基、氰基甲基、氰基乙基、甲氧基乙基、甲氧基丙基、乙氧基乙基、乙氧基丙基、异丙氧基乙基、异丙氧基丙基、环丙基、环丁基、二甲氨基乙基、二甲氨基丙基、二乙氨基乙基、二乙氨基丙基、甲基乙基氨基乙基、甲基乙基氨基丙基、氟乙基、氟丙基、甲硫基乙基、甲硫基丙基、乙硫基乙基、乙硫基丙基、异丙硫基乙基、异丙硫基丙基、甲砜基乙基、甲砜基丙基、乙砜基乙基、乙砜基丙基、2-羟基-2-甲基丙基、3-羟基-3-甲基丁基、氧杂环丁-3-基、四氢呋喃-3-基、四氢-2H-吡喃-4-基，或者R 15、R 16与其相连的氮原子构成取代或非取代的4-6元杂脂环基，选自以下基团：
Figure PCTCN2020137938-appb-000018
R 18选自-H、甲基、乙基、甲酰基、乙酰基、羟乙基、羟丙基、甲氧基乙基、甲氧基丙基、乙氧基乙基、乙氧基丙基、甲砜基、乙砜基，
R 19和R 20各自独立地选自-H、甲基、乙基、羟基、氰基、氟、羟乙基、羟丙基、氟乙基、氟丙基、甲氧基乙基、甲氧基丙基、乙氧基乙基、乙氧基丙基、甲砜基、乙砜基、氨基、甲氨基、二甲氨基、甲氧基、乙氧基。
在进一步的优选方案中，R 4为
Figure PCTCN2020137938-appb-000019
R 12为-H、-F、甲基、乙基，
R 13为-H、-NR 15R 16，
R s1、R s2为H，
R 15、R 16分别独立地为-H、甲基、乙基、丙基、异丙基、羟乙基、羟丙基、氰基甲基、氰基乙基、甲氧基乙基、甲氧基丙基、乙氧基乙基、乙氧基丙基、异丙氧基乙基、异丙氧基丙基、环丙基、环丁基、二甲氨基乙基、二甲氨基丙基、二乙氨基乙基、二乙氨基丙基、甲基乙基氨基乙基、甲基乙基氨基丙基、氟乙基、氟丙基、甲硫基乙基、甲硫基丙基、乙硫基乙基、乙硫基丙基、异丙硫基乙基、异丙硫基丙基、甲砜基乙基、甲砜基丙基、乙砜基乙基、乙砜基丙基、2-羟基-2-甲基丙基、3-羟基-3-甲基丁基、氧杂环丁-3-基、四氢呋喃-3-基、四氢-2H-吡喃-4-基，或者R 15、R 16与其相连的氮原子构成取代或非取代的4-6元杂脂环基，选自以下基团：
Figure PCTCN2020137938-appb-000020
R 18选自-H、甲基、乙基、甲酰基、乙酰基、羟乙基、羟丙基、甲氧基乙基、甲氧基丙基、乙氧基乙基、乙氧基丙基、甲砜基、乙砜基，
R 19和R 20各自独立地选自-H、甲基、乙基、羟基、氰基、氟。
根据本发明的一个方面，提供一种式(I)所示化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药，
Figure PCTCN2020137938-appb-000021
式(I)中，
X为N或CH；
L为-O-、-S-、
Figure PCTCN2020137938-appb-000022
或者-NR 5-，其中，R 5和R 6各自独立地为氢、甲基、乙基、丙基或者异丙基；
R 1为
Figure PCTCN2020137938-appb-000023
R 2为-H、-F、-Cl、甲基或甲氧基；
R 3选自-H、-F、-Cl、-Br、羟基、羧基、氰基、甲基、乙基、丙基、异丙基、叔丁基、甲氧基、乙氧基、丙氧基、异丙氧基、环丙基氧基、环丁基氧基、甲硫基、乙硫基、丙硫基、异丙硫基、氟甲基、二氟甲基、三氟甲基、氟甲氧基、二氟甲氧基、三氟甲氧基、乙炔基、乙烯基、环丙基、环丁基、环丙基甲基、环丁 基甲基、氨基、甲氨基、乙氨基、二甲氨基、二乙氨基、N-甲基-N-乙基氨基、或以下基团：
Figure PCTCN2020137938-appb-000024
q为2-3的整数，
R s选自-H、甲基、乙基，R p选自-H、甲基、乙基，
R'、R”分别独立的选自-H、甲基、乙基、丙基、异丙基、环丙基、环丁基，
R 7选自-H、-F、羟基、氰基、羧基、氨基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、甲氨基、乙氨基、二甲氨基；
R 4为-T 1-R 8，
T 1选自：
Figure PCTCN2020137938-appb-000025
p1为0-3的整数，p2为2-3的整数；
R p选自-H、甲基、乙基；
R 8选自-H、F、-Cl、羟基、氨基、氰基、氟甲氧基、二氟甲氧基、三氟甲氧基、甲基、乙基、丙基、丁基、己基、异丙基、氟甲基、二氟甲基、三氟甲基、环丙基、环丁基、环戊基、环己基、甲氧基、乙氧基、丙氧基、丁氧基、异丙氧基、甲硫基、乙硫基、丙硫基、异丙硫基、甲氨基、乙氨基、丙氨基、二甲氨基、二乙氨基、N-甲基-N-乙基氨基或以下基团：
Figure PCTCN2020137938-appb-000026
R 12为-H、-F、甲基、乙基，
R 13为-H、-F、羟基、羟甲基、氰基、甲基、乙基、甲氧基、或–NR 15R 16，
R 14为-H、-F、甲基、乙基、丙基、异丙基、
Figure PCTCN2020137938-appb-000027
其中，R 17为-H、-F、甲基、乙基、丙基、异丙基，
R s1、R s2分别独立地选自-H、甲基；
R 15、R 16分别独立地为-H、甲基、乙基、丙基、异丙基、羟乙基、羟丙基、氰基甲基、氰基乙基、甲氧基乙基、甲氧基丙基、乙氧基乙基、乙氧基丙基、异丙氧基乙基、异丙氧基丙基、环丙基、环丁基、二甲氨基乙基、二甲氨基丙基、二乙氨基乙基、二乙氨基丙基、甲基乙基氨基乙基、甲基乙基氨基丙基、氟乙基、氟丙基、甲硫基乙基、甲硫基丙基、乙硫基乙基、乙硫基丙基、异丙硫基乙基、异丙硫基丙基、甲砜基乙基、甲砜基丙基、乙砜基乙基、乙砜基丙基、2-羟基-2-甲基丙基、3-羟基-3-甲基丁基、氧杂环丁基、四氢呋喃基、四氢吡喃基，或者R 15、R 16与其相连的氮原子构成取代或非取代的4-6元杂脂环基，选自以下基团：
Figure PCTCN2020137938-appb-000028
R 18选自-H、甲基、乙基、甲酰基、乙酰基、羟乙基、羟丙基、氟乙基、氟丙基、甲氧基乙基、甲氧基丙基、乙氧基乙基、乙氧基丙基、甲砜基、乙砜基，
R 19和R 20各自独立地选自-H、甲基、乙基、羟基、氰基、氟、甲酰基、乙酰基、羟乙基、羟丙基、氟乙基、氟丙基、甲氧基乙基、甲氧基丙基、乙氧基乙基、乙氧基丙基、甲砜基、乙砜基、氨基、甲氨基、二甲氨基、甲氧基、乙氧基，
且，当R 4为4-乙基-哌嗪-1-基、L为-O-或者
Figure PCTCN2020137938-appb-000029
时，R 2和R 3不同时为氢。
在优选的方案中，L为-O-，且，当R 4为4-乙基-哌嗪-1-基时，R 2和R 3不同时为氢。
在进一步优选的方案中，X为N；
L为-O-；
R 1为
Figure PCTCN2020137938-appb-000030
R 2为-H、-F、-Cl、甲基或甲氧基；
R 3选自-H、-F、-Cl、羟基、羧基、氰基、甲基、乙基、丙基、异丙基、叔丁基、甲氧基、乙氧基、丙氧基、异丙氧基、环丙基氧基、环丁基氧基、甲硫基、乙硫基、丙硫基、异丙硫基、氟甲基、二氟甲基、三氟甲基、环丙基、环丁基、环丙基甲基、环丁基甲基、氨基、甲氨基、乙氨基、二甲氨基、二乙氨基、N-甲基-N-乙基氨基、甲氧基乙氧基、乙氧基乙氧基、氨基甲酰基(NH 2CO-)、甲砜基；
R 4为-T 1-R 8，
T 1选自：
Figure PCTCN2020137938-appb-000031
p1为0，p2为2-3的整数；
R p选自-H、甲基、乙基；
R 8选自甲氨基、乙氨基、丙氨基、二甲氨基、二乙氨基、N-甲基-N-乙基氨基或以下基团：
Figure PCTCN2020137938-appb-000032
R 12为-H、-F、甲基、乙基，
R 13为-H、-NR 15R 16，
R 14为-H、甲基、乙基、丙基、异丙基、
Figure PCTCN2020137938-appb-000033
其中，R 17为甲基、乙基、丙基、异丙基，
R s1、R s2分别独立地选自H、甲基；
R 15、R 16分别独立地为-H、甲基、乙基、丙基、异丙基、羟乙基、羟丙基、氰基甲基、氰基乙基、甲氧基乙基、甲氧基丙基、乙氧基乙基、乙氧基丙基、异丙氧基乙基、异丙氧基丙基、环丙基、环丁基、二甲氨基乙基、二甲氨基丙基、二乙氨基乙基、二乙氨基丙基、甲基乙基氨基乙基、甲基乙基氨基丙基、氟乙基、氟丙基、甲硫基乙基、甲硫基丙基、乙硫基乙基、乙硫基丙基、异丙硫基乙基、异丙硫基丙基、甲砜基乙基、甲砜基丙基、乙砜基乙基、乙砜基丙基、2-羟基-2-甲基丙基、3-羟基-3-甲基丁基、氧杂环丁-3-基、四氢呋喃-3-基、四氢-2H-吡喃-4-基，或者R 15、R 16与其相连的氮原子构成取代或非取代的4-6元杂脂环基，选自以下基团：
Figure PCTCN2020137938-appb-000034
R 18选自-H、甲基、乙基、甲酰基、乙酰基、羟乙基、羟丙基、甲氧基乙基、甲氧基丙基、乙氧基乙基、乙氧基丙基、甲砜基、乙砜基，
R 19和R 20各自独立地选自-H、甲基、乙基、羟基、氰基、氟、羟乙基、羟丙基、氟乙基、氟丙基、甲氧基乙基、甲氧基丙基、乙氧基乙基、乙氧基丙基、甲砜基、乙砜基、氨基、甲氨基、二甲氨基、甲氧基、乙氧基；
且，当R 4为4-乙基-哌嗪-1-基、L为-O-或者
Figure PCTCN2020137938-appb-000035
时，R 2和R 3不同时为氢。
在进一步优选的方案中，X为N；
L为-O-；
R 1为
Figure PCTCN2020137938-appb-000036
R 2为-H、-F、-Cl、甲基或甲氧基；
R 3选自-H、-F、-Cl、羟基、羧基、氰基、甲基、乙基、丙基、异丙基、叔丁基、甲氧基、乙氧基、丙氧基、异丙氧基、环丙基氧基、环丁基氧基、甲硫基、乙硫基、丙硫基、异丙硫基、氟甲基、二氟甲基、三氟甲基、环丙基、环丁基、环丙基甲基、环丁基甲基、氨基、甲氨基、乙氨基、二甲氨基、二乙氨基、N-甲基-N-乙基氨基、甲氧基乙氧基、乙氧基乙氧基、氨基甲酰基(NH 2CO-)、甲砜基；
R 4为
Figure PCTCN2020137938-appb-000037
R 12为-H、-F、甲基、乙基，
R 13为-H、-NR 15R 16，
R s1、R s2为H，
R 15、R 16分别独立地为-H、甲基、乙基、丙基、异丙基、羟乙基、羟丙基、氰基甲基、氰基乙基、甲氧 基乙基、甲氧基丙基、乙氧基乙基、乙氧基丙基、异丙氧基乙基、异丙氧基丙基、环丙基、环丁基、二甲氨基乙基、二甲氨基丙基、二乙氨基乙基、二乙氨基丙基、甲基乙基氨基乙基、甲基乙基氨基丙基、氟乙基、氟丙基、甲硫基乙基、甲硫基丙基、乙硫基乙基、乙硫基丙基、异丙硫基乙基、异丙硫基丙基、甲砜基乙基、甲砜基丙基、乙砜基乙基、乙砜基丙基、2-羟基-2-甲基丙基、3-羟基-3-甲基丁基、氧杂环丁-3-基、四氢呋喃-3-基、四氢-2H-吡喃-4-基，或者R 15、R 16与其相连的氮原子构成取代或非取代的4-6元杂脂环基，选自以下基团：
Figure PCTCN2020137938-appb-000038
R 18选自-H、甲基、乙基、甲酰基、乙酰基、羟乙基、羟丙基、甲氧基乙基、甲氧基丙基、乙氧基乙基、乙氧基丙基、甲砜基、乙砜基，
R 19和R 20各自独立地选自-H、甲基、乙基、羟基、氰基、氟。
根据本申请的一些实施方案，所述化合物的药学上可接受的盐为选自所述化合物的盐酸盐、氢溴酸盐、氢碘酸盐、高氯酸盐、硫酸盐、硝酸盐、磷酸盐、甲酸盐、乙酸盐、丙酸盐、羟基乙酸盐、乳酸盐、琥珀酸盐、马来酸盐、酒石酸盐、苹果酸盐、柠檬酸盐、富马酸盐、葡萄糖酸盐、安息香酸盐、扁桃酸盐、甲磺酸盐、羟乙基磺酸盐、苯磺酸盐、草酸盐、棕榈酸盐、2-萘磺酸盐、对甲苯磺酸盐、环己氨基磺酸盐、水杨酸盐、己糖酸盐、三氟乙酸盐、铝盐、钙盐、氯普鲁卡因盐、胆碱盐、二乙醇胺盐、乙二胺盐、锂盐、镁盐、钾盐、钠盐和锌盐中的一种或多种。
本发明的另一方面涉及所述式(I)的化合物、其异构体、水合物、溶剂化物、药学上可接受的盐或前药在制备治疗与酪氨酸激酶FGFR4相关的疾病及自身免疫疾病的药物中的应用，其中，所述与酪氨酸激酶FGFR4相关的疾病及自身免疫疾病包括眼底疾病、干眼症、银屑病、白癜风、皮炎、斑秃、类风湿性关节炎、结肠炎、多重硬化、***性红斑狼疮、克罗恩病、动脉粥样化、肺纤维化、肝纤维化、骨髓纤维化、非小细胞肺癌、小细胞肺癌、乳腺癌、胰腺癌、神经胶质瘤、胶质母细胞瘤、卵巢癌、子***、结肠直肠癌、黑色素瘤、子宫内膜癌、***癌、膀胱癌、白血病、胃癌、肝癌、胃肠间质瘤、甲状腺癌、慢性粒细胞白血病、急性髓细胞性白血病、非霍奇金淋巴瘤、鼻咽癌、食道癌、脑瘤、B细胞和T细胞淋巴瘤、淋巴瘤、多发性骨髓瘤、胆道癌肉瘤、胆管癌。
本发明的又一方面提供了一种药物组合物，该药物组合物包括本申请的式(I)所示的化合物、其异构体、水合物、溶剂化物、药学上可接受的盐或前药，以及一种或多种药学上可接受的载体或赋形剂。
根据本申请的一些实施方案，该药物组合物还可以包括一种或多种其他治疗剂。
本发明还涉及一种治疗酪氨酸激酶FGFR4介导的疾病或病症的方法，其包括对有需要的患者(人或其他哺乳动物，尤其是人)给药治疗有效量的式(I)化合物或其盐，所述酪氨酸激酶FGFR4介导的疾病或病症包括前述提及的那些。
发明详述
除非另有说明，在本申请(包括说明书和权利要求书)中使用的以下术语具有下面给出的定义。在本申请中，除非另外说明，使用“或”或“和”意味着“和/或”。此外，术语“包括”以及其它形式的使用，例如“包含”、“含有”和“具有”，不是限制性的。本文使用的章节标题仅仅是为了组织的目的，而不应解释为对所述的主题的限制。
除非有特殊说明，烷基表示具有指定数目碳原子的饱和直链、支链烃基，术语C 1-C 6烷基表示含有1至6个碳原子的烷基部分，同理C 1-C 3烷基表示含有1至3个碳原子的烷基部分，比如，C 1-C 6烷基包括甲基、乙基、丙基、异丙基、n-丁基、异丁基、仲-丁基、叔-丁基、n-戊基、3-(2-甲基)丁基、2-戊基、2-甲基丁基、新戊基、n-己基、2-己基和2-甲基戊基等。
当取代基术语例如“烷基”与其它取代基术语组合使用时，例如在术语“C 1-C 3烷氧基取代的C 1-C 3烷基”或“羟基取代C 2-C 6烷基”中，该连接取代基术语(例如烷基)旨在包含二价的部分，其中连接点通过所述连接取代基。“C 1-C 3烷氧基取代的C 1-C 3烷基”的实例包括但不限于甲氧基甲基、甲氧基乙基和乙氧基丙基等。“羟基取代C 2-C 6烷基”的实例包括但不限于羟基乙基、羟基丙基和羟基异丙基等。
烷氧基为由先前描述的直链或支链烷基与-O-形成的烷基-O-基团，例如，甲氧基、乙氧基等等。类似的，烷硫基由先前描述的直链或支链烷基与-S-形成的烷基-S-基团，例如，甲硫基，乙硫基等等。
烯基和炔基包括直链、支链烯基或炔基，术语C 2-C 3烯基或者C 2-C 3炔基表示具有至少一个烯基或炔基的直链或支链C 2-C 3烃基。
术语“卤代C 1-C 6烷基”表示在包括1到6个碳原子的烷基部分的一个或多个碳原子上具有一个或多个可以相同或不同的卤素原子的基团。“卤代C 1-C 6烷基”的实例可以包括但不限于-CF 3(三氟甲基)、-CCl 3(三氯甲基)、1,1-二氟乙基、2,2,2-三氟乙基和六氟异丙基等。类似的，术语“卤代C 1-C 6烷氧基”表示由所述的卤代C 1-C 6烷基与-O-形成的卤代烷基-O-基团，可以为例如三氟甲氧基、三氯甲氧基等等。
术语“C 1-C 3酰基”包括甲酰基(-CHO)、乙酰基(CH 3CO-)、丙酰基(C 2H 5CO-)。
“环烷基”表示含有指定数目碳原子的非芳香的、饱和的、环状的烃基。例如，术语“(C 3-C 6)环烷基”指的是具有3-6个环碳原子的非芳香的环状烃环。示例性的“(C 3-C 6)环烷基”包括环丙基、环丁基、环戊基和环己基。
术语“芳基”表示包含芳香的单环或双环烃原子团的基团或部分，其含有6到12个碳环原子且具有至少一个芳香环。“芳基”的实例为苯基、萘基、茚基和二氢茚基(茚满基)。通常，在本发明化合物中，芳基优选为苯基。
在这里使用的术语“4-6元杂脂环基”，除非有特殊说明，代表未被取代的或已被取代的稳定的4至6元非芳香的单环饱和环体系，它们由碳原子以及从N，O，S中选的1至2个杂原子组成，其中N，S杂原子可以被随意氧化，N杂原子还可以被随意季铵化。这类杂环的例子包括但不限于氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、吡咯烷基、吡咯啉基、吡唑烷基、吡唑啉基、咪唑烷基、咪唑啉基、噁唑啉基、噻唑啉基、四氢呋喃基、二氢呋喃基、四氢噻吩基、1,3-二氧杂环戊烷基、哌啶基、哌嗪基、四氢吡喃基、二氢吡喃基、四氢噻喃基、1,3-二噁烷基、1,4-二噁烷基、1,3-氧硫杂环戊烷基、1,3-氧硫杂环己烷基、1,3-二 噻烷基、1,4-氧硫杂环戊烷基、1,4-氧硫杂环己烷基、1,4-二噻烷基、吗啉基、硫吗啉基。
术语“羰基”指的是-C(O)-基。术语“卤素”和“卤”表示氯、氟、溴或碘取代基。“氧代”表示双键的氧部分；例如，直接连接到碳原子上形成一个羰基部分(C＝O)。“羟基”旨在表示-OH原子团。本文所用术语“氰基”是指基团-CN。
术语“各自独立地”是指当一个以上的取代基选自许多可能的取代基时，那些取代基可以相同或不同。
很清楚，式I的化合物、异构体、晶型或前药及其可药用盐可以存在溶剂化形式和非溶剂化形式。例如溶剂化形式可以是水溶形式。本发明包括所有这些溶剂化的和未溶剂化的形式。
本申请中术语“异构体”为具有相同分子式的不同化合物，可以包括立体异构、互变异构等各种异构形式。“立体异构体”是仅原子在空间的排列方式不同的异构体。本文描述的某些化合物含有一个或多个不对称中心，且因此可以产生对映体、非对映体和其他依据绝对立体化学可以被定义为(R)-或(S)-的立体异构形式。本发明的化学实体、药物组合物和方法旨在包括所有这些可能的异构体，包括外消旋混合物、光学纯形式和中间的混合物。旋光(R)-和(S)-异构体可以使用手性合成子或手性试剂来制备，或使用常规技术来拆分。化合物的光学活性可以通过任何合适的方法进行分析，包括但不限于手性色谱法和旋光测定法，且可确定一种立体异构体超越其他异构体的优势程度。
可使用本领域技术人员已知的方法拆分本发明单独的异构体(或异构体富集的混合物)。例如，可如下进行所述拆分：(1)通过形成非对映异构体盐、复合物或其他衍生物；(2)通过与立体异构体特异性试剂的选择性反应，例如通过酶促氧化或还原；或(3)通过在手性环境中的气-液色谱或液相色谱，所述手性环境例如在手性载体上(例如结合有手性配体的硅胶)或在手性溶剂存在下。本领域技术人员将会理解，当将所需立体异构体通过上述分离方法之一转化成另一化学实体时，需要其他步骤来释放所需形式。或者，特异性立体异构体可通过使用光学活性试剂、底物、催化剂或溶剂的不对称合成法来合成，或通过不对称转化将一种对映异构体转化成另一种异构体。
当本文所述的化合物含有烯烃双键时，除非另有说明，其意指该化合物包括各种顺反异构体。
“互变异构体”是可通过互变异构化互相转换的结构上不同的异构体。“互变异构化”是异构化的一种形式，且包括质子移变或质子转移互变异构化，可认为它是酸碱化学的子集。“质子移变互变异构化”或“质子转移互变异构化”涉及伴有键级变换的质子迁移，往往是单键与相邻的双键的互换。当可能发生互变异构化时(例如，在溶液中)，可达到互变异构体的化学平衡。互变异构化的一个实例为酮-烯醇互变异构化。
作为活性成分的本发明的化合物，以及制备该化合物的方法，都是本发明的内容。而且，一些化合物的晶型形式可以作为多晶体存在，这种形式也可以被包括在目前的发明里。另外，一些化合物可以和水(即水合物)或普通的有机溶剂一起形成溶剂化物，这种溶剂化物也被包括在此项发明的范畴内。
本发明的化合物可以以游离的形式用于治疗，或者在适当情况下以药学上可接受的盐或其它衍生物的形式用于治疗。如本文所用，术语“药学上可接受的盐”是指本发明的化合物的有机盐及无机盐，此盐适用于人类和低等动物，无过度毒性、刺激性、过敏反应等，具有合理的利益/风险比。胺，羧酸，膦酸盐，和其它类型的化合物的药学上可接受的盐在所属领域中是众所周知的。该盐可以由本发明的化合物与合适的游离碱或酸反应而成。包括但不限于，与无机酸如盐酸、氢溴酸、磷酸、硫酸、高氯酸或与有机酸如乙酸、 草酸、马来酸、酒石酸、柠檬酸、琥珀酸、丙二酸形成的盐，或通过使用本领域熟知的方法，例如离子交换法，来得到这些盐。其他药学上可接受的盐包括己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、半硫酸盐、己酸盐、氢碘酸盐、2-羟基乙磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、甲烷磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、棕榈酸盐、双羟萘酸盐、果胶酸盐、过硫酸盐、过3-苯基丙酸盐、磷酸盐、苦味酸盐、丙酸盐、硬脂酸盐、硫酸盐、硫氰酸盐、对甲苯磺酸盐、十一烷酸盐等。代表性的碱或碱土金属盐包括钠、锂、钾、钙、镁等。其他药学上可接受的盐包括适当的无毒的铵、季铵，和使用诸如卤离子、氢氧根、羧酸根、硫酸根、磷酸根、硝酸根，低级烷基磺酸盐和芳基磺酸盐形成的胺基阳离子。
另外，本文所用术语“前药”是指一个化合物在体内可以转化为本发明式(I)所示的化合物。此转化受前体药物在血液中水解或在血液或组织中经酶转化为母体化合物的影响。
本发明的药物组合物包含本文所述结构式(I)化合物或其药学上可接受的盐、激酶抑制剂(小分子，多肽，抗体等)、免疫抑制剂、抗癌药、抗病毒剂、抗炎剂、抗真菌剂、抗生素或抗血管过度增生化合物的另外的活性剂；以及任何药学上可接受的载体、佐剂或赋形剂。
本发明的化合物可以作为单独使用，也可以与一种或多种其它本发明的化合物或与一种或多种其它药剂联合使用。当联合给药时，治疗剂可以配制成同时给药或顺序地在不同的时间给药，或者所述治疗剂可以作为单一组合物给药。所谓“组合疗法”，指的是使用本发明的化合物与另一种药剂一起使用，给药方式为每种药剂同时共同给药或每种药剂顺序给药，无论哪种情况，目的都是要达到药物的最佳效果。共同给药包括同时递送剂型，以及每种化合物分别的单独剂型。因此，本发明的化合物的给药可以与已知的本领域的其他疗法同时使用，例如，在癌症治疗中使用放射治疗或细胞生长抑制剂、细胞毒性剂、其它抗癌剂等附加疗法来改善癌症状。本发明并不限于给药的顺序；本发明的化合物可以先前施用，同时施用，或在其他抗癌剂或细胞毒性剂之后施用。
为了制备这一发明的药学成分，作为其活性成分的分子式(I)的一种或多种化合物或盐类可紧密的与药学载体混合在一起，这是根据传统的制药配料技术而进行的，其中的载体可根据按不同的给药方式(例如，口服或肠外给药)设计好的制备形式而采用多种多样的形式。适当的药学上可接受的载体在技术上是众所周知的。对一些这类药学可接受的载体的描述可以在《药学赋形剂手册》里找到，该书由美国药学会和英国药学社联合出版。
本发明药物组合物可以有以下形式，比如说，适合口服给药，例如药片，胶囊，药丸，药粉，持续释放的形式，溶液或悬浮液；用于胃肠外注射如透明液，悬浮液，乳状液；或者用于局部用药如膏，霜；亦或作为栓剂用于直肠给药。药学成分也可以单位剂量的形式适合用于精确剂量的一次性给药。该药学成分将包括一种传统的药学载体或赋形剂以及根据目前的发明制成的作为活性成分的化合物，另外，也可以包括其他的医学或药学制剂，载体，辅助剂，等等。
治疗性化合物也可给于哺乳动物而非人类。给一个哺乳动物所用的药物剂量将取决于该动物的种类以 及它的疾病状况或其所处的失调状态。治疗性化合物可以以胶囊，大丸药，药片药水的形式喂给动物。也可以通过注射或灌输的方式让治疗性化合物进入动物体内。我们根据符合兽医实践标准的传统的方式制备好这些药物形式。作为一种可选择的方式，药学合成药可以同动物饲料混合在一起喂给动物，因此，浓缩的饲料添加剂或预拌和料可以备以混合普通的动物饲料。
本发明的又一目的是在于提供一种用于治疗有需要的受试者中癌症的方法，其包括给受试者施用含本发明的化合物的组合物的治疗有效量的一种方法。
本发明的化合物对于FGFR4具有优于其他受体的选择性，特别是优于其他FGF受体，例如FGFR1、FGFR2和FGFR3。因此，本发明涉及作为选择性的FGFR4抑制剂的化合物。
考虑其作为FGFR4抑制剂的活性，以游离或可药用盐形式的式(I)化合物适用于治疗通过FGFR4蛋白质的活性介导的病状(诸如癌症)和/或对FGFR4的抑制具有反应性(特别是指以治疗上有益的方式)的病状，最特别的是如本文下文所提及的疾病或病症。
本发明的化合物可用于治疗癌症。具体而言，本发明的化合物可用于治疗选自肝癌、乳腺癌、神经胶母细胞瘤、***癌、横纹肌肉瘤、胃癌、卵巢癌、肺癌、结肠癌的适应症。
本发明的化合物还可以用于治疗特征为阳性FGFR4表达的实体恶性肿瘤。
本发明的化合物还可以用于治疗特征为阳性KLB(β-klotho)表达的实体恶性肿瘤。
本发明的化合物还可以用于治疗特征为阳性FGF19表达的实体恶性肿瘤。
本发明的化合物还可以用于治疗特征为阳性FGFR4和阳性KLB表达的实体恶性肿瘤。
本发明的化合物还可以用于治疗特征为阳性FGFR4和阳性FGF19表达的实体恶性肿瘤。
本发明的化合物还可以用于治疗特征为阳性FGFR4、阳性KLB和阳性FGF19表达的实体恶性肿瘤。
如上文所述在FGFR4、KLB和/或FGF19中的任何阳性表达都可以通过技术人员已知的方法进行评价，例如RT-qPCR、Western免疫印迹法、ELISA、免疫组织化学。
因此，作为其它实施方案，本发明提供了式(I)化合物或其可药用盐在治疗中的用途。在其它实施方案中，该治疗是选自可以通过抑制FGFR4来治疗的疾病。在另一项实施方案中，该疾病是选自上文所提及的清单，合适地是肝癌。
在另一项实施方案中，本发明提供了治疗通过抑制FGFR4来治疗的疾病的方法，包括施用治疗上可接受量的式(I)化合物或其可药用盐。在其它实施方案中，该疾病是选自上文所提及的清单，合适地是肝癌。
因此，作为其它实施方案，本发明提供了式(I)化合物或其可药用盐在制备药物中的用途。在其它实施方案中，该药物是用于治疗可以通过抑制FGFR4来治疗的疾病。在另一项实施方案中，该疾病是选自上文所提及的清单，合适地是肝癌。
本发明还提供了制备相应化合物的方法，可以使用多种合成方法制备本文所述的化合物，包括下述实施例中所涉及的方法，本发明的化合物或者其药学上可接受的盐，异构体或水合物可以使用下述方法与有机化学合成领域已知的合成方法，或通过本领域技术人员理解对这些方法的变化方法合成，优选方法包括但不限于下述方法。
本发明终产物可通过以下方案制备，其中R 1，R 2，R 3，R 4，X，L如前文所定义，
Figure PCTCN2020137938-appb-000039
中间体A中Q可以为卤素(优选为氯)或甲基砜基(亚砜基)，当采用M为BocNH-的B类中间体时，步骤1的反应可在酸催化、中性条件或碱性条件下加热进行取代反应合成化合物(I’)。当中间体A中Q为氯时，也可通过Buchwald偶联反应合成化合物(I’)；之后在酸性条件下脱去叔丁基氧羰基保护基，并进一步与丙烯酰氯合成终产物(I)。
本发明化合物的制备方法包含上面各中间体的制备，
其中中间体(B)制备方法如下，
Figure PCTCN2020137938-appb-000040
第1步：化合物(B 2)与(Boc) 2O反应得到化合物(B 3)，X’可以为Cl、F、Br或I；
第2步：化合物(B 3)与R 4-H(胺或者醇)在碱性或中性条件下进行反应得到化合物(B 4)。当X’为Cl、Br或I时，也可通过Buchwald偶联反应得到化合物(B 4)；
第3步：化合物(B 4)与还原剂反应生成中间体(B)。
第2步所述的碱选自碳酸铯，三乙胺，氢化钠，双(三甲基硅基)氨基钠等无机碱或者有机碱中一种或两种以上的组合，Buchwald条件优选Pd 2(dba) 3，XantPhos和碳酸铯的组合；
第3步所述的还原剂选自氯化亚锡，氢气与钯碳组合，氢气与雷尼镍组合，锌粉与酸组合，铁粉与酸组合等还原剂体系；
中间体(A)的一种制备方法如下，
Figure PCTCN2020137938-appb-000041
第1步：化合物(A 2)在碱存在的条件下与A 1进行取代反应得到(A 3)；
第2步：化合物(A 3)在脱水剂的条件下酰胺脱水成为化合物(A)。
本发明提供了上述反应的优先实施方案，优选地，
第1步，所述的碱选自有机或无机碱，例如三乙胺，N’N-二异丙基乙基胺，氢化钠，双(三甲基硅基)氨基钠，正丁基锂中一种或两种以上的组合；
优选地，所述脱水剂选自三氯氧磷，三氯化铝，五氧化二磷，氯化磷(五氯化磷或三氯化磷)等。
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合具体实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅用以解释本发明，并不用于限定本发明。实施例中未注明具体技术或条件的，按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。本文所使用的术语“和/或”包括一个或多个相关的所列项目的任意的和所有的组合。本申请中部分化合物的命名通过chemdraw产生后翻译为中文。
具体实施方式
一.化学试剂来源
反应溶剂由中国国药试剂提供
普通反应化学原料由伊诺凯、安耐吉、麦克林、百灵威、药石等公司提供
薄层层析硅胶板(厚度0.5mm,1mm，200X200mm)由烟台新诺化工有限公司提供
硅胶(200-300目)由中国国药试剂公司提供
二.化学简称
DMF：N’N-二甲基甲酰胺
DIEA：N’N-二异丙基乙基胺
NMP：N-甲基吡咯烷酮
Pd(OAc) 2：醋酸钯
Pd 2(dba) 3：三(二亚苄基茚丙酮)二钯
Xantphos：4,5-双二苯基膦-9,9-二甲基氧杂蒽
Binap：1,1'-联萘-2,2'-双二苯膦
(Boc) 2O：二碳酸二叔丁酯
三.中间体的制备
A系列中间体
中间体A1.2-氯-4-((2-异丙氧基苯基)氨基)嘧啶-5-甲腈
Figure PCTCN2020137938-appb-000042
步骤1).2-氯-4-((2-异丙氧基苯基)氨基)嘧啶-5-甲酰胺的合成
分别将2,4-二氯嘧啶-5-甲酰胺(1.9g,10mmol)，2-异丙氧基苯胺(1.65g,11mmol)和三乙胺(2g,20mmol)加入DMF(10mL)，室温搅拌反应2小时，加水打浆，过滤，干燥得白色固体产物2.5g，收率82％，MS:307[M+H] +；
步骤2).2-氯-4-((2-异丙氧基苯基)氨基)嘧啶-5-甲腈的合成
将2-氯-4-((2-异丙氧基苯基)氨基)嘧啶-5-甲酰胺(307mg，1mmol)加入到三氯氧磷(2mL)中,加热至120摄氏度，搅拌反应5小时，浓缩，用饱和碳酸氢钠溶液洗涤得微黄色固体产物220mg，收率76％，MS：289[M+H] +。
同中间体A1的反应步骤，由带有不同取代基的苯胺类化合物代替以上步骤1中的2-异丙氧基苯胺进行反应得到如下中间体A2-A23。以下表1示出了中间体A2-A23的结构、名称和质谱数据。
Figure PCTCN2020137938-appb-000043
Figure PCTCN2020137938-appb-000044
Figure PCTCN2020137938-appb-000045
表1中间体A2-A23的结构、名称和质谱数据
B系列中间体
中间体B1.(2-氨基-5-(4-乙基哌嗪-1-基)苯基)氨基甲酸叔丁酯的制备
Figure PCTCN2020137938-appb-000046
步骤1)N,N-二叔丁氧羰基-2-硝基-5-氟苯胺的制备
分别将5-氟-2-硝基苯胺(1.6g,10mmol)，(Boc) 2O(4.7g,22mmol)和DMAP(0.37g,3mmol)加入二氯甲烷溶液中，室温搅拌过夜，浓缩，柱层析(硅胶，流动相为石油醚/乙酸乙酯＝10/1)纯化得到亮黄色固体产物3.3g， MS:357[M+H] +；
步骤2)(5-(4-乙基哌嗪-1-基)-2-硝基苯基)氨基甲酸叔丁酯的制备
N,N-二叔丁氧羰基-2-硝基-5-氟苯胺(3.3g,9.2mmol)和乙基哌嗪(3mL)分别加入到DMF中，加热至120℃反应8小时，冷却，浓缩，柱层析纯化得到黄色固体3.1g，MS:351[M+H] +；
步骤3)(2-氨基-5-(4-乙基哌嗪-1-基)苯基)氨基甲酸叔丁酯的制备
(5-(4-乙基哌嗪-1-基)-2-硝基苯基)氨基甲酸叔丁酯(3.1g，8.9mmol)加入Pd/C的甲醇溶液中，氢气置换2次，室温搅拌反应3小时，过滤，浓缩，由二氯甲烷打浆，过滤得白色固体2.5g，MS:321[M+H] +。
采用与中间体B1的合成类似的反应步骤，由带有不同取代基的5-氟2-硝基苯胺类化合物代替以上步骤1中的5-氟2-硝基苯胺、和由不同的碱取代步骤2中的乙基哌嗪进行反应得到如下中间体B2-B56。以下表2示出了中间体B2-B56的结构、名称和质谱数据。
Figure PCTCN2020137938-appb-000047
Figure PCTCN2020137938-appb-000048
Figure PCTCN2020137938-appb-000049
Figure PCTCN2020137938-appb-000050
Figure PCTCN2020137938-appb-000051
Figure PCTCN2020137938-appb-000052
表2.中间体B2-B56的结构、名称和质谱数据
四.具体实施例的制备
实施例1：N-(2-((5-氰基-4-((2-异丙氧基苯基)氨基)嘧啶-2-基)氨基)-5-(4-甲基哌嗪-1-基)苯基)丙烯酰胺
Figure PCTCN2020137938-appb-000053
步骤1：(2-((5-氰基-4-((2-异丙氧基苯基)氨基)嘧啶-2-基)氨基)-5-(4-甲基哌嗪-1-基)苯基)氨基甲酸叔丁酯的合成
将中间体2-氯-4-((2-异丙氧基苯基)氨基)嘧啶-5-甲腈(160mg,0.55mmol)，(2-氨基-5-(4-甲基哌嗪-1-基)苯基)氨基甲酸叔丁酯(155mg,0.5mmol)和三氟乙酸(催化量，20微升)，加入仲丁醇中加热反应12小时，冷却，浓缩，使用饱和碳酸钠溶液洗涤，有机相浓缩并使用硅胶柱层析得到白色固体产物240mg，收率86％，MS:559[M+H] +；
步骤2：N-(2-((5-氰基-4-((2-异丙氧基苯基)氨基)嘧啶-2-基)氨基)-5-(4-甲基哌嗪-1-基)苯基)丙烯酰胺的合成
(2-((5-氰基-4-((2-异丙氧基苯基)氨基)嘧啶-2-基)氨基)-5-(4-甲基哌嗪-1-基)苯基)氨基甲酸叔丁酯(120mg,0.2mmol)加入到三氟乙酸(1mL)和二氯甲烷(2mL)的溶剂中，室温搅拌反应3小时，浓缩得灰色油状物溶于干燥四氢呋喃(1mL)中，在冰水浴条件下缓慢滴加丙烯酰氯(28mg,0.3mmol)，并继续搅拌反应0.5小时，加水淬灭，饱和碳酸氢钠溶液洗涤，二氯甲烷萃取，有机相干燥，浓缩，由制备硅胶薄板(流动相甲醇/二氯甲烷体积比8/100)纯化得白色固体产物45mg。 1H NMR(400MHz,DMSO-d 6)δ9.66(s,1H),8.97(s,1H),8.47(s,1H),8.24(s,1H),7.94(s,1H),7.33(d,J＝25.8Hz,2H),7.08(s,2H),6.82(d,J＝9.1Hz,1H),6.72(s,1H),6.50(dd,J＝16.9,10.2Hz,1H),6.24(dd,J＝17.0,2.0Hz,1H),5.78–5.70(m,1H),4.74–4.47(m,1H),3.14(s,4H),2.47(d,J＝5.2Hz,4H),2.24(s,3H),1.33–1.21(m,6H).MS:513[M+H] +。
下表中化合物参照实施例1的制备方法，采用相应的中间体反应制备得到，下表3列出了实施例2-81制备的化合物的结构、名称及其核磁氢谱和质谱表征数据。
Figure PCTCN2020137938-appb-000054
Figure PCTCN2020137938-appb-000055
Figure PCTCN2020137938-appb-000056
Figure PCTCN2020137938-appb-000057
Figure PCTCN2020137938-appb-000058
Figure PCTCN2020137938-appb-000059
Figure PCTCN2020137938-appb-000060
Figure PCTCN2020137938-appb-000061
Figure PCTCN2020137938-appb-000062
Figure PCTCN2020137938-appb-000063
Figure PCTCN2020137938-appb-000064
Figure PCTCN2020137938-appb-000065
Figure PCTCN2020137938-appb-000066
Figure PCTCN2020137938-appb-000067
Figure PCTCN2020137938-appb-000068
表3.实施例2-81制备的化合物的结构、名称及其核磁氢谱和质谱表征数据
实施例82：N-(2-((5-氰基-4-((2-异丙氧基苯基)氨基)吡啶-2-基)氨基)-5-(4-(二甲基氨基)哌啶-1-基)苯基)丙烯酰胺
Figure PCTCN2020137938-appb-000069
步骤1)6-氯-4-((2-异丙氧基苯基)氨基)烟酰胺的制备
在冰盐浴条件下向2-异丙氧基苯胺(300mg,2mmol)的四氢呋喃(5mL)溶液中缓慢滴加HMDSNa(2N,1mL)，继续搅拌反应半小时，随后滴加入2,4-二氯-5-烟酰胺(190mg,1mmol)的四氢呋喃(1mL)溶液，在冰水浴条件下搅拌反应过夜，加水淬灭打浆，过滤得浅黄色固体230mg,收率75％，MS:306[M+H] +。
步骤2)6-氯-4-((2-异丙氧基苯基)氨基)烟腈的制备
6-氯-4-((2-异丙氧基苯基)氨基)烟酰胺(220mg,0.8mmol)的三氯氧磷(2mL)溶液加热至回流反应3小时，冷却，浓缩，饱和碳酸氢钠洗涤，二氯甲烷萃取，取有机相干燥，浓缩得黄色固体160mg，MS:288[M+H] +。
步骤3)(2-((5-氰基-4-((2-异丙氧基苯基)氨基)吡啶-2-基)氨基)-5-(4-(二甲基氨基)哌啶-1-基)苯基)氨基甲酸叔丁酯的制备
将6-氯-4-((2-异丙氧基苯基)氨基)烟腈(120mg,0.4mmol)，(2-氨基-5-(4-(二甲基氨基)哌啶-1-基)苯基)氨基甲酸叔丁酯(135mg,0.4mmol)，Pd 2(dba) 3(10mg)，Xantphos(10mg)以及碳酸钠(110mg,1mmol)分别溶于装有二氧六环(5mL)和水(0.5mL)的封管中，反应体系由氩气置换后在120℃加热反应10小时，冷却，过滤，滤液浓缩后直接由制备薄层板(1mm,硅胶)纯化得到浅黄色固体产物104mg，MS:586[M+H] +。
步骤4)：(2-((5-氰基-4-((2-异丙氧基苯基)氨基)吡啶-2-基)氨基)-5-(4-(二甲基氨基)哌啶-1-基)苯基)氨基甲酸叔丁酯(88mg,0.15mmol)加入含有三氟乙酸(1mL)的二氯甲烷(3mL)溶液中，室温搅拌1小时，浓缩，加入无水四氢呋喃(2mL)，随后在冰水浴条件下滴加丙烯酰氯(40微升)并继续搅拌半小时，加水淬灭，二氯甲烷萃取，饱和碳酸氢钠洗涤，有机相干燥，浓缩并经制备型薄板(0.5mm,负载硅胶)纯化(展开体系V 二氯甲烷/甲醇＝11/1)得到白色固体产物33mg。 1H NMR(400MHz,DMSO-d 6)δ9.53(s,1H),8.23(s,1H),8.18(s,1H),7.80(s,1H),7.30(d,J＝2.7Hz,1H),7.26–7.05(m,4H),6.93(td,J＝7.5,1.5Hz,1H),6.74(dd,J＝8.9,2.8Hz,1H),6.45(dd,J＝17.0,10.1Hz,1H),6.20(dd,J＝17.0,2.0Hz,1H),5.85(s,1H),5.72(dd,J＝10.1,2.0Hz,1H),4.56(p,J＝6.1Hz,1H),3.66(d,J＝12.4Hz,2H),2.71–2.60(m,2H),2.53(s,1H),2.37(s,6H),1.89(d,J＝11.1Hz, 2H),1.54(dd,J＝13.8,10.0Hz,2H),1.20(d,J＝6.0Hz,6H).MS:540[M+H] +。
实施例83：N-(2-((5-氰基-4-((2-异丙氧基苯基)氨基)吡啶-2-基)氨基)-5-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)丙烯酰胺
Figure PCTCN2020137938-appb-000070
同实施例82操作，由(2-氨基-5-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基甲酸叔丁酯代替步骤实施例82步骤3)的(2-氨基-5-(4-(二甲基氨基)哌啶-1-基)苯基)氨基甲酸叔丁酯进行反应得到目标产物； 1H NMR(400MHz,DMSO-d 6)δ9.53(s,1H),8.21(s,1H),8.16(s,1H),7.80(s,1H),7.29(d,J＝2.8Hz,1H),7.25–7.05(m,4H),6.93(td,J＝7.5,1.5Hz,1H),6.72(dd,J＝8.9,2.8Hz,1H),6.45(dd,J＝16.9,10.2Hz,1H),6.20(dd,J＝17.0,2.1Hz,1H),5.83(s,1H),5.72(dd,J＝10.1,2.0Hz,1H),4.61–4.50(m,1H),3.63(d,J＝12.3Hz,2H),3.35(br,4H),2.65(td,J＝12.2,2.2Hz,2H),2.55-2.50(m,1H),2.41–2.21(m,4H),2.16(s,3H),1.83(d,J＝12.3Hz,2H),1.47(dd,J＝11.7,3.6Hz,2H),1.20(d,J＝6.1Hz,6H).MS:595[M+H] +。
实施例84：N-(2-((5-氰基-4-((2-异丙氧基苯基)氨基)吡啶-2-基)氨基)-5-(4-乙基哌嗪-1-基)苯基)丙烯酰胺
Figure PCTCN2020137938-appb-000071
同实施例82操作，由(2-氨基-5-(4-乙基哌嗪-1-基)苯基)氨基甲酸叔丁酯代替步骤实施例82步骤3)的(2-氨基-5-(4-(二甲基氨基)哌啶-1-基)苯基)氨基甲酸叔丁酯进行反应得到目标产物； 1H NMR(400MHz,DMSO-d 6)δ9.55(s,1H),8.22-8.14(m,2H),7.80(s,1H),7.31–7.05(m,5H),6.93(td,J＝7.5,1.5Hz,1H),6.74(dd,J＝8.9,2.8Hz,1H),6.45(dd,J＝17.0,10.1Hz,1H),6.20(dd,J＝17.0,2.0Hz,1H),5.85(s,1H),5.72(dd,J＝10.1,2.0Hz,1H),4.56(p,J＝6.0Hz,1H),3.08(t,J＝5.0Hz,4H),2.50(br,4H),2.38(q,J＝7.2Hz,2H),1.20(d,J＝6.0Hz,6H),1.04(t,J＝7.2Hz,3H).MS:526[M+H] +。
实验例1.
小分子化合物抑制FGFR4激酶活性和FGFR4 V550L突变激酶活性的测试，测试方法如下：
1)化合物的稀释:
在96孔板a中，将化合物用DMSO溶液按3倍比例稀释，形成11个梯度，第12个梯度为纯DMSO 溶液(作为阳性对照)；取一块新的96孔板b，将上述溶液用超纯水稀释25倍(DMSO浓度为4％)
2)将化合物转盘到384孔板：
将上述96孔板b中用超纯水稀释过的化合物溶液转盘到384孔板相应的孔中。
3)加4×激酶溶液：用排枪取2.5μl上述4×激酶溶液加入到384孔板相应的反应孔中，混匀室温预反应5分钟。
4)加2×底物/ATP混合液:用排枪取5μl上述2×底物/ATP混合液到384孔板相应的反应孔中。
5)阴性对照：在384孔板中设置阴性对照孔，每孔加入2.5μl 4×底物、2.5μl 4×酶溶液、2.5μl 1×Kinase Assay Buffer和2.5μl含4％DMSO的超纯水。
6)离心混匀，避光室温反应2小时。
7)终止酶促反应：
吸取5μl上述4×终止液到384孔板相应孔，离心混匀，室温反应5分钟。
8)显色反应：
吸取5μl上述4×检测液加入到384孔板相应孔，离心混匀，室温反应1小时。
9)将384孔板放入读板仪，调取相应的程序检测信号。
10)IC 50分析：
孔读值＝10000*EU665值/EU615值
抑制率＝(阳性对照孔读值-实验孔读值)/(阳性对照孔读值-阴性对照孔读值)*100％
将药物浓度和相应抑制率输入GraphPad Prism 5处理可计算出相应的IC 50。
FGFR4激酶活性抑制分子筛选实验条件：
反应体系中FGFR4激酶终浓度3.85nM，ATP的终浓度为100μM，底物ULight TM-labeled JAK-1(Tyr1023)Peptide的终浓度100nM，酶促反应时间为2小时。
反应体系中化合物最高终浓度为2.5μM，经3倍梯度稀释后共11个浓度，最低终浓度为0.042nM。DMSO终浓度为1％。
FGFR4 V550L激酶活性抑制分子筛选实验条件：
反应体系中FGFR4 V550L激酶终浓度1nM，ATP的终浓度为10μM，底物ULight TM-labeled PolyGT的终浓度100nM，酶促反应时间为2小时。
反应体系中化合物最高终浓度为2.5μM，经3倍梯度稀释后共11个浓度，最低终浓度为0.042nM。DMSO终浓度为1％。
表4列出了本专利中部分化合物对酪氨酸激酶FGFR4和对V550L突变的酪氨酸激酶FGFR4抑制活性的测定结果，其中A表示IC 50小于或等于10nM，B表示IC 50大于10nM但小于或等于50nM，C表示IC 50大于50nM但小于或等于100nM，D表示IC 50大于100nM，且D小于或等于1000nM，NT表示未有相关值。
表4:本发明化合物对FGFR4激酶和V550L突变的酪氨酸激酶FGFR4抑制活性测定结果
Figure PCTCN2020137938-appb-000072
Figure PCTCN2020137938-appb-000073
实验例2.
化合物抑制细胞增殖的测试，具体方法如下：
1.取培养至对数生长期的细胞，吹打均匀，转移至15mL离心管中，按照1000rpm的条件室温离心4分钟；
2.弃去上清液，加入5mL完全培养液，吹打均匀，取10μL细胞悬浮液和10μL 0.4％胎盼蓝混匀，在细胞计数仪下进行计数并确保活细胞比例在90％以上；
3.按照表5所示条件每孔接种80μL的细胞混悬液到96孔板中，96孔板外周36孔不加细胞仅加无菌水，仅里面60孔用于细胞实验和对照；
4. 5×化合物稀释：将化合物以4倍比例进行浓度梯度稀释，共9个浓度，用完全培养基完成80倍整体稀释，该浓度为最终药物浓度的5倍，DMSO浓度为1.25％；
5.在96孔板中实验孔每孔加入20μL对应的不同浓度梯度的化合物，阳性和阴性对照孔加入20μL完全培养液摇匀，每孔中DMSO的终浓度为0.25％；
6.培养72h后每孔加入10μL CCK-8试剂，37℃培养1-2h；于450nm处读其OD值；
7.细胞存活率(％)＝[(As-Ab)/(Ac-Ab)]*100％
As：实验孔(含有细胞的培养基、CCK-8、化合物)
Ac：对照孔(含有细胞的培养基、CCK-8)
Ab：空白孔(不含细胞和化合物的培养基、CCK-8)
8.将数值导入Graphpad Prism5软件进行IC 50计算。
表5.细胞基本信息和接种条件
Figure PCTCN2020137938-appb-000074
表6列出了本申请中部分化合物对Ba/F3ETV6-FGFR4细胞和Ba/F3ETV6-FGFR4-V550L细胞增殖抑制活性的测定结果，其中A表示IC 50小于或等于10nM，B表示IC 50大于10nM但小于或等于50nM，C表示IC 50大于50nM但小于或等于100nM，D表示IC 50大于100nM，且D小于或等于1000nM，NT表示未有相关值。
表6:本发明化合物对Ba/F3ETV6-FGFR4细胞和Ba/F3ETV6-FGFR4-V550L细胞增殖抑制活性测定结果
Figure PCTCN2020137938-appb-000075
Figure PCTCN2020137938-appb-000076
本发明所提供的生物学数据表明，本发明的化合物有利于治疗或预防由于FGFR4激酶异常而引起的疾病，包括FGFR4基因突变(V550L，V550M等)引起的疾病，包括原发性和转移性癌症，包括实体瘤。此类癌症包括但不限于:非小细胞肺癌、小细胞肺癌、乳腺癌、胰腺癌、神经胶质瘤、胶质母细胞瘤、卵巢癌、子***、结肠直肠癌、黑色素瘤、子宫内膜癌、***癌、膀胱癌、白血病、胃癌、肝癌、胃肠间质瘤、甲状腺癌、慢性粒细胞白血病、急性髓细胞性白血病、非霍奇金淋巴瘤、鼻咽癌、食道癌、脑瘤、B细胞和T细胞淋巴瘤、淋巴瘤、多发性骨髓瘤、胆道癌肉瘤、胆管癌。本发明的化合物也包括治疗耐一种或多种其它治疗方法的癌症。本发明的化合物还可用于与FGFR4激酶有关的除了癌症以外的其他疾病，包括但不限于眼底疾病，银屑病、风湿性关节炎、动脉粥样化、肺纤维化、肝纤维化。本发明的化合物可以作为单一疗法或联合疗法，可以与多个本发明的化合物联合用药或与本发明以外的其他药物联合用药。
以上所述是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明所述原则的前提下，本发明的实施方式还可以作出若干改进和修饰，这些改进和修饰也应视为本发明的保护范围。

Claims (13)

  1. 一种式(I)所示化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药，
    Figure PCTCN2020137938-appb-100001
    式(I)中，
    X为N或CH；
    L为-O-、-S-、
    Figure PCTCN2020137938-appb-100002
    或者-NR 5-，其中，R 5和R 6各自独立地为氢、甲基、乙基、丙基或者异丙基；
    R 1为
    Figure PCTCN2020137938-appb-100003
    R 2为氢、卤素、C 1-C 3烷氧基、C 1-C 3烷基；
    R 3选自氢、卤素、羟基、氨基、氰基、羧基、C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 3烷氧基、C 3-C 6环烷基、C 2-C 3炔基、C 2-C 3烯基、C 1-C 3烷氧基、C 1-C 3烷硫基、单或双C 1-C 3烷基氨基、C 3-C 4环烷基氧基、C 3-C 4环烷基取代的C 1-C 3烷基、氰基取代的C 1-C 3烷基、氨基甲酰基取代的C 1-C 3烷基、或以下基团：
    Figure PCTCN2020137938-appb-100004
    q为1-3的整数，
    R s选自-H、C 1-C 3烷基，R p选自-H、C 1-C 3烷基，
    R'、R”分别独立地为-H、C 1-C 3烷基、C 3-C 4环烷基，
    R 7选自-H、卤素、羟基、氰基、氨基、羧基、C 1-C 3烷基、C 3-C 4环烷基、C 1-C 3烷氧基、单或双C 1-C 3烷基取代的氨基；
    R 4为-T 1-R 8或-T 2-R 9，
    T 1为：
    Figure PCTCN2020137938-appb-100005
    T 2为：
    Figure PCTCN2020137938-appb-100006
    p1为0-4的整数，p2为2-4的整数，p3为0-1的整数，
    R p为-H或C 1-C 3烷基，
    R 8选自-H、卤素、羟基、氨基、氰基、C 1-C 6烷基、卤代C 1-C 6烷基、卤代C 1-C 3烷氧基、C 3-C 6环烷基、C 1-C 3烷氧基、C 1-C 3烷硫基、单或双C 1-C 3烷基氨基、或者被1-2个选自羟基、C 1-C 6烷基、C 1-C 3烷氧基、甲酰基、乙酰基、丙酰基、异丙酰基、羟基取代的C 1-C 3烷基、羧基取代的C 1-C 3烷基、氧代、C 1-C 3烷基取代或非取代的4-6元杂脂环基、或-NR 10R 11中的相同或不同的取代基所取代或非取代的4-6元杂脂环基，
    R 10、R 11各自独立地选自-H、C 1-C 6烷基、C 3-C 4环烷基、羟基取代的C 2-C 6烷基、氰基取代的C 1-C 2烷基、C 1-C 3烷氧基取代的C 1-C 3烷基、C 1-C 3烷硫基取代的C 1-C 3烷基、卤代C 1-C 3烷基、甲砜基取代C 1-C 3烷基、单或双C 1-C 3烷氨基取代C 1-C 3烷基、C 1-C 3烷基取代或非取代的4-6元杂脂环基，或者R 10、R 11与其相连的氮原子构成被1-2个选自-H、羟基、氧代、卤素、C 1-C 3烷氧基取代C 1-C 3烷基、C 1-C 3烷基砜基、氰基、氨基、C 1-C 3酰基、C 1-C 3烷基、单或双C 1-C 3烷氨基、羟基取代的C 2-C 3烷基、C 1-C 3烷氧基中的相同或不同的取代基所取代或非取代的4-6元杂脂环基，
    所述4-6元杂脂环基含1-2个选自N、O或S的杂原子；
    R 9选自-H、C 1-C 6烷基、C 3-C 6环烷基、被1-2个选自羟基、C 1-C 3烷基、C 1-C 3烷氧基、甲酰基、乙酰基、丙酰基、异丙酰基中的相同或不同的取代基所取代或者非取代的4-6元杂脂环基，
    R 9中所述4-6元杂脂环基中含1-2个选自N、O或S的杂原子；
    且，当R 1为
    Figure PCTCN2020137938-appb-100007
    R 4为4-乙基-哌嗪-1-基且L为-O-或者
    Figure PCTCN2020137938-appb-100008
    时，R 2和R 3不同时为氢。
  2. 根据权利要求1所述的式(I)的化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药，其中，R 2为-H、-F、-Cl、甲基或甲氧基。
  3. 根据权利要求1-2中任一项所述的式(I)的化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药，其中，
    R 3选自-H、-F、-Cl、-Br、羟基、羧基、氰基、甲基、乙基、丙基、异丙基、叔丁基、甲氧基、乙氧基、丙氧基、异丙氧基、环丙基氧基、环丁基氧基、甲硫基、乙硫基、丙硫基、异丙硫基、氟甲基、二氟甲基、三氟甲基、氟甲氧基、二氟甲氧基、三氟甲氧基、乙炔基、乙烯基、环丙基、环丁基、环丙基甲基、环丁基甲基、氨基、甲氨基、乙氨基、二甲氨基、二乙氨基、N-甲基-N-乙基氨基、或以下基团：
    Figure PCTCN2020137938-appb-100009
    q为2-3的整数，
    R s选自-H、甲基、乙基，R p选自-H、甲基、乙基，
    R'、R”分别独立的选自-H、甲基、乙基、丙基、异丙基、环丙基、环丁基，
    R 7选自-H、-F、羟基、氰基、羧基、氨基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、甲氨基、乙氨基、二甲氨基。
  4. 根据权利要求1-3中任一项所述的式(I)的化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药，其中，
    R 4为-T 1-R 8，
    T 1选自：
    Figure PCTCN2020137938-appb-100010
    p1为0-3的整数，p2为2-3的整数；
    R p选自-H、甲基、乙基；
    R 8选自-H、F、-Cl、羟基、氨基、氰基、氟甲氧基、二氟甲氧基、三氟甲氧基、甲基、乙基、丙基、丁基、己基、异丙基、氟甲基、二氟甲基、三氟甲基、环丙基、环丁基、环戊基、环己基、甲氧基、乙氧基、丙氧基、丁氧基、异丙氧基、甲硫基、乙硫基、丙硫基、异丙硫基、甲氨基、乙氨基、丙氨基、二甲氨基、二乙氨基、N-甲基-N-乙基氨基或以下基团：
    Figure PCTCN2020137938-appb-100011
    R 12为-H、-F、甲基、乙基，
    R 13为-H、-F、羟基、羟甲基、氰基、甲基、乙基、甲氧基、或–NR 15R 16，
    R 14为-H、-F、甲基、乙基、丙基、异丙基、
    Figure PCTCN2020137938-appb-100012
    其中，R 17为-H、-F、甲基、乙基、丙基、异丙基，
    R s1、R s2分别独立地选自H、甲基；
    R 15、R 16分别独立地为-H、甲基、乙基、丙基、异丙基、羟乙基、羟丙基、氰基甲基、氰基乙基、甲氧基乙基、甲氧基丙基、乙氧基乙基、乙氧基丙基、异丙氧基乙基、异丙氧基丙基、环丙基、环丁基、二甲氨基乙基、二甲氨基丙基、二乙氨基乙基、二乙氨基丙基、甲基乙基氨基乙基、甲基乙基氨基丙基、氟乙基、氟丙基、甲硫基乙基、甲硫基丙基、乙硫基乙基、乙硫基丙基、异丙硫基乙基、异丙硫基丙基、甲砜基乙基、甲砜基丙基、乙砜基乙基、乙砜基丙基、2-羟基-2-甲基丙基、3-羟基-3-甲基丁基、氧杂环丁基、四氢呋喃基、四氢吡喃基，或者R 15、R 16与其相连的氮原子构成取代或非取代的4-6元杂脂环基，选自以下基团：
    Figure PCTCN2020137938-appb-100013
    R 18选自-H、甲基、乙基、甲酰基、乙酰基、羟乙基、羟丙基、氟乙基、氟丙基、甲氧基乙基、甲氧基丙基、乙氧基乙基、乙氧基丙基、甲砜基、乙砜基，
    R 19和R 20各自独立地选自-H、甲基、乙基、羟基、氰基、氟、甲酰基、乙酰基、羟乙基、羟丙基、氟乙基、氟丙基、甲氧基乙基、甲氧基丙基、乙氧基乙基、乙氧基丙基、甲砜基、乙砜基、氨基、甲氨基、二甲氨基、甲氧基、乙氧基。
  5. 根据权利要求4所述的式(I)的化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药，其中，R 4为-T 1-R 8，
    T 1选自：
    Figure PCTCN2020137938-appb-100014
    p1为0，p2为2-3的整数；
    R p选自-H、甲基、乙基；
    R 8选自甲氨基、乙氨基、丙氨基、二甲氨基、二乙氨基、N-甲基-N-乙基氨基或以下基团：
    Figure PCTCN2020137938-appb-100015
    R 12为-H、-F、甲基、乙基，
    R 13为-H、-NR 15R 16，
    R 14为-H、甲基、乙基、丙基、异丙基、
    Figure PCTCN2020137938-appb-100016
    其中，R 17为甲基、乙基、丙基、异丙基，
    R s1、R s2分别独立地选自H、甲基；
    R 15、R 16分别独立地为-H、甲基、乙基、丙基、异丙基、羟乙基、羟丙基、氰基甲基、氰基乙基、甲氧基乙基、甲氧基丙基、乙氧基乙基、乙氧基丙基、异丙氧基乙基、异丙氧基丙基、环丙基、环丁基、二甲氨基乙基、二甲氨基丙基、二乙氨基乙基、二乙氨基丙基、甲基乙基氨基乙基、甲基乙基氨基丙基、氟乙基、氟丙基、甲硫基乙基、甲硫基丙基、乙硫基乙基、乙硫基丙基、异丙硫基乙基、异丙硫基丙基、甲砜基乙基、甲砜基丙基、乙砜基乙基、乙砜基丙基、2-羟基-2-甲基丙基、3-羟基-3-甲基丁基、氧杂环丁-3-基、四氢呋喃-3-基、四氢-2H-吡喃-4-基，或者R 15、R 16与其相连的氮原子构成取代或非取代的4-6元杂脂环基，选自以下基团：
    Figure PCTCN2020137938-appb-100017
    R 18选自-H、甲基、乙基、甲酰基、乙酰基、羟乙基、羟丙基、甲氧基乙基、甲氧基丙基、乙氧基乙基、乙氧基丙基、甲砜基、乙砜基，
    R 19和R 20各自独立地选自-H、甲基、乙基、羟基、氰基、氟、羟乙基、羟丙基、氟乙基、氟丙基、甲氧基乙基、甲氧基丙基、乙氧基乙基、乙氧基丙基、甲砜基、乙砜基、氨基、甲氨基、二甲氨基、甲氧基、乙氧基。
  6. 根据权利要求4所述的式(I)的化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药，其中，
    R 4为
    Figure PCTCN2020137938-appb-100018
    R 12为-H、-F、甲基、乙基，
    R 13为-H、-NR 15R 16，
    R s1、R s2为H，
    R 15、R 16分别独立地为-H、甲基、乙基、丙基、异丙基、羟乙基、羟丙基、氰基甲基、氰基乙基、甲氧基乙基、甲氧基丙基、乙氧基乙基、乙氧基丙基、异丙氧基乙基、异丙氧基丙基、环丙基、环丁基、二甲氨基乙基、二甲氨基丙基、二乙氨基乙基、二乙氨基丙基、甲基乙基氨基乙基、甲基乙基氨基丙基、氟乙基、氟丙基、甲硫基乙基、甲硫基丙基、乙硫基乙基、乙硫基丙基、异丙硫基乙基、异丙硫基丙基、甲砜基乙基、甲砜基丙基、乙砜基乙基、乙砜基丙基、2-羟基-2-甲基丙基、3-羟基-3-甲基丁基、氧杂环丁-3-基、四氢呋喃-3-基、四氢-2H-吡喃-4-基，或者R 15、R 16与其相连的氮原子构成取代或非取代的4-6元杂脂环基，选自以下基团：
    Figure PCTCN2020137938-appb-100019
    R 18选自-H、甲基、乙基、甲酰基、乙酰基、羟乙基、羟丙基、甲氧基乙基、甲氧基丙基、乙氧基乙基、乙氧基丙基、甲砜基、乙砜基，
    R 19和R 20各自独立地选自-H、甲基、乙基、羟基、氰基、氟。
  7. 根据权利要求1所述的式(I)的化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药，其中，X为N或CH；
    L为-O-、-S-、
    Figure PCTCN2020137938-appb-100020
    或者-NR 5-，其中，R 5和R 6各自独立地为氢、甲基、乙基、丙基或者异丙基；
    R 1为
    Figure PCTCN2020137938-appb-100021
    R 2为-H、-F、-Cl、甲基或甲氧基；
    R 3选自-H、-F、-Cl、-Br、羟基、羧基、氰基、甲基、乙基、丙基、异丙基、叔丁基、甲氧基、乙氧基、丙氧基、异丙氧基、环丙基氧基、环丁基氧基、甲硫基、乙硫基、丙硫基、异丙硫基、氟甲基、二氟甲基、三氟甲基、氟甲氧基、二氟甲氧基、三氟甲氧基、乙炔基、乙烯基、环丙基、环丁基、环丙基甲基、环丁基甲基、氨基、甲氨基、乙氨基、二甲氨基、二乙氨基、N-甲基-N-乙基氨基、或以下基团：
    Figure PCTCN2020137938-appb-100022
    q为2-3的整数，
    R s选自-H、甲基、乙基，R p选自-H、甲基、乙基，
    R'、R”分别独立的选自-H、甲基、乙基、丙基、异丙基、环丙基、环丁基，
    R 7选自-H、-F、羟基、氰基、羧基、氨基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、甲氨基、乙氨基、二甲氨基；
    R 4为-T 1-R 8，
    T 1选自：
    Figure PCTCN2020137938-appb-100023
    p1为0-3的整数，p2为2-3的整数；
    R p选自-H、甲基、乙基；
    R 8选自-H、F、-Cl、羟基、氨基、氰基、氟甲氧基、二氟甲氧基、三氟甲氧基、甲基、乙基、丙基、丁基、己基、异丙基、氟甲基、二氟甲基、三氟甲基、环丙基、环丁基、环戊基、环己基、甲氧基、乙氧基、丙氧基、丁氧基、异丙氧基、甲硫基、乙硫基、丙硫基、异丙硫基、甲氨基、乙氨基、丙氨基、二甲氨基、二乙氨基、N-甲基-N-乙基氨基或以下基团：
    Figure PCTCN2020137938-appb-100024
    R 12为-H、-F、甲基、乙基，
    R 13为-H、-F、羟基、羟甲基、氰基、甲基、乙基、甲氧基、或-NR 15R 16，
    R 14为-H、-F、甲基、乙基、丙基、异丙基、
    Figure PCTCN2020137938-appb-100025
    其中，R 17为-H、-F、甲基、乙基、丙基、异丙基，
    R s1、R s2分别独立地选自-H、甲基；
    R 15、R 16分别独立地为-H、甲基、乙基、丙基、异丙基、羟乙基、羟丙基、氰基甲基、氰基乙基、甲氧基乙基、甲氧基丙基、乙氧基乙基、乙氧基丙基、异丙氧基乙基、异丙氧基丙基、环丙基、环丁基、二甲氨基乙基、二甲氨基丙基、二乙氨基乙基、二乙氨基丙基、甲基乙基氨基乙基、甲基乙基氨基丙基、氟乙基、氟丙基、甲硫基乙基、甲硫基丙基、乙硫基乙基、乙硫基丙基、异丙硫基乙基、异丙硫基丙基、甲砜基乙基、甲砜基丙基、乙砜基乙基、乙砜基丙基、2-羟基-2-甲基丙基、3-羟基-3-甲基丁基、氧杂环丁基、四氢呋喃基、四氢吡喃基，或者R 15、R 16与其相连的氮原子构成取代或非取代的4-6元杂脂环基，选自以下基团：
    Figure PCTCN2020137938-appb-100026
    R 18选自-H、甲基、乙基、甲酰基、乙酰基、羟乙基、羟丙基、氟乙基、氟丙基、甲氧基乙基、甲氧基丙基、乙氧基乙基、乙氧基丙基、甲砜基、乙砜基，
    R 19和R 20各自独立地选自-H、甲基、乙基、羟基、氰基、氟、甲酰基、乙酰基、羟乙基、羟丙基、氟乙基、氟丙基、甲氧基乙基、甲氧基丙基、乙氧基乙基、乙氧基丙基、甲砜基、乙砜基、氨基、甲氨基、二甲氨基、甲氧基、乙氧基，
    且，当R 4为4-乙基-哌嗪-1-基、L为-O-或者
    Figure PCTCN2020137938-appb-100027
    时，R 2和R 3不同时为氢。
  8. 根据权利要求7所述的式(I)的化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药，其中，L为-O-，且，当R 4为4-乙基-哌嗪-1-基时，R 2和R 3不同时为氢。
  9. 权利要求1所述的化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药，所述化合物选自：
    Figure PCTCN2020137938-appb-100028
    Figure PCTCN2020137938-appb-100029
    Figure PCTCN2020137938-appb-100030
    Figure PCTCN2020137938-appb-100031
  10. 一种药用组合物，包括权利要求1-9中任一项所述的化合物或其药学上可接受的盐或其水合物或其溶剂化物或其前药，与药学上可接受的载体或赋形剂。
  11. 如权利要求10所述的药用组合物，其中，所述药用组合物还包含一种或多种其它治疗剂。
  12. 根据权利要求1-9中任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物或其前药在制备治疗与酪氨酸激酶FGFR4相关的疾病及自身免疫疾病的药物中的应用。
  13. 根据权利要求12所述的应用，其中所述与酪氨酸激酶FGFR4相关的疾病及自身免疫疾病包括眼底疾病、干眼症、银屑病、白癜风、皮炎、斑秃、类风湿性关节炎、结肠炎、多重硬化、***性红斑狼疮、克罗恩病、动脉粥样化、肺纤维化、肝纤维化、骨髓纤维化、非小细胞肺癌、小细胞肺癌、乳腺癌、胰腺癌、神经胶质瘤、胶质母细胞瘤、卵巢癌、子***、结肠直肠癌、黑色素瘤、子宫内膜癌、***癌、膀胱癌、白血病、胃癌、肝癌、胃肠间质瘤、甲状腺癌、慢性粒细胞白血病、急性髓细胞性白血病、非霍奇金淋巴瘤、鼻咽癌、食道癌、脑瘤、B细胞和T细胞淋巴瘤、淋巴瘤、多发性骨髓瘤、胆道癌肉瘤、胆管癌。
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