US20210163478A1 - Fused ring derivative used as fgfr4 inhibitor - Google Patents

Fused ring derivative used as fgfr4 inhibitor Download PDF

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US20210163478A1
US20210163478A1 US17/263,571 US201917263571A US2021163478A1 US 20210163478 A1 US20210163478 A1 US 20210163478A1 US 201917263571 A US201917263571 A US 201917263571A US 2021163478 A1 US2021163478 A1 US 2021163478A1
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methyl
compound
formyl
naphthyridine
pyridin
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Hongwei Yang
Rui Zhou
Liang Zhou
Xin Sun
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Jacobio Pharmaceuticals Co Ltd
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Jacobio Pharmaceuticals Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention provides fused ring derivative compound, uses for inhibiting FGFR4 and methods of treating diseases using said compound thereof.
  • Fibroblast Growth Factor Receptor belongs to the family of receptor protein tyrosine kinases. Many signaling pathways, including Ras-MAPK, AKT-PI3K, and phospholipase C, can be activated through the binding of FGFR and its corresponding ligands, and these pathways play an important role in cell growth, proliferation and survival.
  • Alterations in FGFRs are associated with many human cancers, and these alterations, including overexpression of FGF ligand, FGFR or activated FGFR mutations, can lead to tumor occurrence, development and resistance to traditional cancer treatments by activating the pathway.
  • Large-scale DNA sequencing of thousands of tumor samples revealed that components of the FGFR pathway are the most common mutations in human cancers.
  • FGFR4 is a tyrosine kinase receptor in the human body encoded by the gene FGFR4 and is highly conserved in evolution, and it works by combining with its specific ligand FGF19.
  • the signaling pathway of FGFR is roughly shown as follows: activated FGFR4 causes phosphorylation of FRS2 and recruits GRB2, thus the signaling pathways of Ras-Raf-ERK1/2MAPK and PI3K-Akt are finally activated, which makes the cells proliferate and resist apoptosis. More and more researches have indicated that FGFR activation and the overexpression of FGF19 play an important role in the occurrence and development of liver cancer, and the inhibition of FGFR4 can effectively reduce the occurrence of liver cancer. FGFR4, ligand FGF19 and coreceptor KLB were highly expressed in about 1 ⁇ 3 of liver cancer patients. In addition, the changes of FGFR4-FGF19 signal axis are also related to the occurrence of colorectal cancer, breast cancer, pancreatic cancer, prostate cancer, lung cancer, and thyroid cancer.
  • fibroblast growth factor receptor 4 (FGFR4) inhibitors have great potential for the treatment of liver cancer, and have better pertinence and effectiveness than the similar drugs.
  • Liver cancer the second only to lung cancer, is the most common malignant tumor and fatal disease, and china has the most liver cancer patients in the world.
  • Sorafenib as the only approved first-line drug for the treatment of patients with advanced liver cancer, only extends average three months survival time of the patient, and it has strong side effects because it is a multi-targeted tyrosine kinase inhibitor.
  • the inhibitor of FGFR4 is a hot research direction in the field of worldwide liver cancer therapeutic research, and the world biopharmaceutical companies are competing for a market direction of FGFR4 inhibitors.
  • no one drug of FGFR4 inhibitor has been marketed currently due to the limitation of experimental methods and the period of the research and so on. China has the highest incidence of liver cancer and the most patients with liver cancer in the world, thus the breakthrough in this direction of FGFR inhibitors will have strong significance to clinical application.
  • no similar drugs of FGFR inhibitors are in clinical studies in China, and the worldwide FGFR inhibitors are all in the early clinical research stage. Therefore, the breakthrough in this direction of FGFR inhibitors will greatly enhance the international competitiveness of the new drug research and development of China.
  • the present invention relates to fused ring compound, which as an FGFR4 inhibitors use for treating diseases mediated by FGFR4.
  • the invention first provides the compound shown in structural formula I or a pharmaceutically acceptable salt thereof:
  • R 1 at each occurrence is independently
  • X at each occurrence is independently selected from absent, O, —NR X1 — or —CR X1 R X2 —; and p is 0, 1, 2 or 3;
  • R X1 and R X2 at each occurrence are independently selected from H; D; —F; —Cl; —Br; —I; —C 1-6 alkyl; —C 1-6 alkyl substituted with 1, 2, or 3 substituents; —C 1-6 alkoxy or —C 1-6 alkoxy substituted with 1, 2, or 3 substituents; each said substituent at each occurrence is independently optionally selected from D, halogen, —OH, —CN, —NH 2 , —NO 2 , —COOH, —C 1-3 alkyl or —C 1-3 alkoxy;
  • Y at each occurrence is independently selected from O or S;
  • R 7 at each occurrence is independently selected from H, D, —C 1-6 alkyl, —C 1-6 alkoxy, —C 3-8 cycloalkyl or 3-8 membered heterocyclic, and R 7 at each occurrence is independently optionally substituted or unsubstituted with one or more substituents selected from D, —F, —Cl, —Br, —I, —OH, oxo, ⁇ O, —SH, —CN, —NO 2 , —N 3 , —C 1-3 alkyl, —C 1-3 alkoxy, —C 2-4 alkenyl, —C 2-4 akynyl, —C 1-3 haloalkyl, —C 3-6 cycloalkyl, 3-6 membered heterocyclic, 3-6 membered heterocyclyloxy, 3-6 membered heterocyclylthio, C 5-8 aryl, C 5-8 aryloxy, C 5-8 arylthio
  • R 8 at each occurrence is independently selected from H, D, —C 1-6 alkyl, —C 1-6 alkoxy, —C 2-6 alkenyl, —C 2-6 akynyl, —C(O)R 11 , —C 1-6 alkyl-C(O)R 11 , —C 3-6 cycloalkyl, 3-8 membered heterocyclic, and R 8 at each occurrence is independently optionally substituted or unsubstituted with one or more substituents selected from D, —F, —Cl, —Br, —I, —OH, oxo, ⁇ O, —SH, —CN, —NO 2 , —N 3 , —C 1-3 alkyl, —C 2-4 alkenyl, —C 2-4 akynyl, —C 1-3 haloalkyl, —C 3-6 cycloalkyl, 3-6 membered heterocyclic, 3-6 membered hetero
  • R 7 and R 8 together with the carbon and nitrogen to which they are respectively attached form 5-10 membered monocyclic heterocyclic, 5-12 membered spirocyclic heterocyclic, 5-12 membered fused heterocyclic, or 5-12 membered bridged heterocyclic, and each said ring system at each occurrence is independently optionally substituted or unsubstituted with one or more substituents selected from D, —F, —Cl, —Br, —I, —OH, oxo, ⁇ O, —SH, —CN, —NO 2 , —N 3 , —C 1-3 alkyl, —C 1-3 alkoxy, —C 2-4 alkenyl, —C 2-4 alkynyl, —C 1-3 haloalkyl, —C 3-6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclic, 3-6 membered heterocyclyloxy, 3-6 membered heterocyclyl
  • R 2 and R 3 at each occurrence are independently selected from H; D; —F; —Cl; —Br; —I; —OH; —SH; —CN; —NH 2 ; —NO 2 ; —N 3 ; —C 1-6 alkyl; —C 1-6 alkyl; —C 1-6 alkyl substituted with 1, 2 or 3 substituents selected from -D, —F, —Cl, —Br, —I, —OH, —CN, —NH 2 , —NO 2 , —COOH, —C 1-3 alkyl or C 1-3 alkoxy; C 1-6 alkoxy; —C 1-6 alkoxy substituted with 1, 2 or 3 substituents selected from -D, —F, —Cl, —Br, —I, —OH, —CN, —NH 2 , —NO 2 , —COOH, —C 1-3 alkyl or —C 1-3
  • G at each occurrence is independently selected from —CR G1 R G2 —, —NR G1 —, —S—, —SO—, —SO 2 — or O; m is 0, 1, 2, 3 or 4;
  • Each R G1 and R G2 at each occurrence is independently selected from H; D; —C 1-6 alkyl; —C 1-6 alkyl substituted with 1, 2 or 3 substituents; —C 1-6 alkoxy; —C 1-6 alkoxy substituted with 1, 2 or 3 substituents; each said substituent is independently optionally selected from D, halogen, —OH, —CN, —NH 2 , —NO 2 , —COOH, —C 1-3 alkyl or C 1-3 alkoxy;
  • Q at each occurrence is independently selected from —CR 4 R 4 ′—(CR 4 R 4 ′) q — or —NR 4 —(CR 4 R 4 ′) q —, and q is selected from 0, 1, 2, 3 or 4;
  • R 4 and R 4 ′ at each occurrence are independently selected from H; D; —F; —Cl; —Br; —I; —OH; —C 1-6 alkyl; —C 1-6 alkyl substituted with 1, 2 or 3 substituents; —C 1-6 alkoxy; —C 1-6 alkoxy substituted with 1, 2 or 3 substituents; —C 3-8 cycloalkyl; C 3-8 cycloalkyl substituted with 1, 2 or 3 substituents; C 3-8 heterocyclic; 3-8 membered heterocyclic substituted with 1, 2 or 3 substituents; each said substituent at each occurrence is independently optionally selected from D, halogen, —OH, —CN, —NH 2 , —NO 2 , —COOH, —C 1-3 alkyl or C 1-3 alkoxy; or
  • R 4 and R 4 ′ together with the carbon to which they are both attached form C 3-8 carbocyclic ring, 3-8 membered heterocyclic ring or 5-10 membered heteroaryl ring, and each ring system at each occurrence is independently optionally substituted or unsubstituted with one or more substituents;
  • R 5 and R 5 ′ at each occurrence are independently selected from H; D; —F; —Cl; —Br; —I; —OH; —C 1-6 alkyl; —C 1-6 alkyl substituted with 1, 2 or 3 substituents; —C 1-6 alkoxy; —C 1-6 alkoxy substituted with 1, 2 or 3 substituents; —C 3-8 cycloalkyl; C 3-8 cycloalkyl substituted with 1, 2 or 3 substituents; 3-8 membered heterocyclic; 3-8 membered heterocyclic substituted with 1, 2 or 3 substituents; each said substituent is independently optionally selected from D, halogen, —OH, —CN, —NH 2 , —NO 2 , —COOH, —C 1-3 alkyl or C 1-3 alkoxy; or
  • R 5 and R 5 ′ together with the carbon to which they are both attached form —C 3-8 carbocyclic ring, 3-8 membered heterocyclic ring, 5-10 membered heteroaryl ring, and each said heterocyclic and each said heteroaryl at each occurrence independently optionally contains one or two heteroatoms selected from N, O or S, and each said ring system at each occurrence is independently optionally substituted or unsubstituted with one or more substituents; or
  • R 4 and R 5 together with the atom to which they are respectively attached form 5-10 membered aromatic ring, —C 3-10 carbocyclic, 4-10 membered heterocyclic ring, each said heterocyclic at each occurrence independently optionally contains one or two heteroatoms selected from N, O or S, and each said ring system at each occurrence is independently optionally substituted or unsubstituted with one or more substituents;
  • W at each occurrence is independently selected from —(CR w1 R w2 ) n —S—, —(CR w1 R w2 )—SO— or —(CR w 1 R w2 ) n —SO 2 —, n is selected from 0, 1, 2, 3 or 4;
  • R w1 and R w2 at each occurrence are independently selected from H; D; —F; —Cl; —Br; —OH; methyl; ethyl; propyl; isopropyl; —C 1-3 alkyl substituted with 1, 2 or 3 substituents; methoxy; ethoxy; propoxy; isopropoxy; —C 1-3 alkoxy substituted with 1, 2 or 3 substituents; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; —C 3-6 cycloalkyl substituted with 1, 2 or 3 substituents; 3 membered heterocyclic; 4 membered heterocyclic; 5 membered heterocyclic; 6 membered heterocyclic or 3-6 membered heterocyclic substituted with 1, 2 or 3 substituents; and each said substituent at each occurrence is independently optionally selected from D, —F, —Cl, —Br, —I, —OH,
  • R 6 at each occurrence is independently selected from H; D; —F; —Cl; —Br; —I; —C 1-3 alkyl; —C 1-3 alkyl substituted with 1, 2 or 3 substituents; —C 1-3 alkoxy; —C 1-3 alkoxy substituted with 1, 2 or 3 substituents; —C 1-3 alkyl-COO—C 1-3 alkyl; —C 3-6 cycloalkyl or —C 3-6 cycloalkyl substituted with 1, 2 or 3 substituents; and each said substituent is independently optionally selected from D, halogen, —OH, —CN, —NH 2 , —NO 2 , —COOH, —C 1-3 alkyl or C 1-3 alkoxy; or
  • the heterocyclic ring is independently optionally substituted or unsubstituted with one or more substituents, and the heterocyclic ring independently optionally contains 1, 2, or 3 heteroatoms selected from N, O or S, and each said substituent is independently optionally selected from D, halogen, —OH, —CN, —NH 2 , —NO 2 , —COOH, —C 1-3 alkyl or C 1-3 alkoxy; or
  • R 4 and R 6 together with the atom to which they are respectively attached form 5-8 membered monocyclic heterocyclic, 5-10 membered spirocyclic heterocyclic, 5-10 membered fused heterocyclic, 5-10 membered bridged heterocyclic or 5-10 membered heteroaryl ring, and each said ring system independently optionally contains 1, 2 or 3 heteroatoms selected from N, O or S, and each said ring system is independently optionally substituted or unsubstituted with 1, 2, or 3 substituents selected from D, —F, —Cl, —Br, —I, —OH, —NH 2 , —CN, —COOH, oxo, ⁇ O, —C 1-3 alkyl or C 1-3 alkoxy; or
  • each said ring system independently optionally contains 1, 2 or 3 heteroatoms selected from N, O or S, and each said ring system is independently optionally substituted or unsubstituted with 1, 2, or 3 substituents selected from D, —F, —Cl, —Br, —I, —OH, —NH 2 , —CN, —COOH, oxo, ⁇ O, —C 1-3 alkyl or C 1-3 alkoxy;
  • Each R 9 at each occurrence is independently selected from H, D, —C 1-3 alkyl, —C 1-3 alkyl C 1-3 alkoxy, —C 2-4 alkenyl, —C 3-6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclic, C 1-3 haloalkyl, phenyl, p-methyl phenyl, amino, —NH—C 1-3 alkyl, —N(C 1-3 alkyl) 2 or C 1-3 alkylamide;
  • Each R 10 at each occurrence is independently selected from H, D, —C 1-3 alkyl, —C 1-3 alkyl C 1-3 alkoxy, —C 3-6 cycloalkyl, —C 5-10 aryl, C 1-3 haloalkyl, or C 1-3 alkyl substituted with hydroxyl;
  • Each R 11 at each occurrence is independently selected from H, D, —C 1-3 alkyl, —C 1-3 alkoxy, —C 3-6 cycloalkyl, —C 3-6 cycloalkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, C 1-3 alkyl substituted with hydroxyl, or C 1-3 alkoxy substituted with hydroxyl;
  • R 12 and R 13 at each occurrence are independently selected from H, D, —C 1-3 alkyl, —C 1-3 alkyl C 1-3 alkoxy, —C 1-3 alkoxy C 1-3 alkyl, —C 3-6 cycloalkyl C 1-3 alkyl, —C 2-4 alkenyl, —C 2-4 alkynyl, —C 3-6 cycloalkyl, substituted or unsubstituted C 5-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, or C 1-3 alkanoyl;
  • t at each occurrence is independently selected from 0, 1 or 2.
  • R 1 at each occurrence is independently
  • X at each occurrence is independently selected from absent, 0, —NR X1 — or —CR X1 R X2 —; and p is 0, 1 or 2;
  • R X1 and R X2 at each occurrence are independently selected from H; D; —F; —Cl; —Br; —I; —C 1-3 alkyl; C 1-3 alkyl substituted with 1, 2 or 3 substituents; C 1-3 alkoxy or C 1-3 alkoxy substituted with 1, 2 or 3 substituents; each said substituent is independently optionally selected from D, —F, —Cl, —Br, —I, —OH, —CN, —NH 2 , —NO 2 , —COOH, —C 1-3 alkyl or C 1-3 alkoxy;
  • Y at each occurrence is independently selected from 0 or S;
  • R 7 at each occurrence is independently selected from H, D, —C 1-3 alkyl, —C 1-3 alkoxy, —C 3-5 cycloalkyl or 3-8 membered heterocyclic, and the heterocyclic independently optionally contains 1, 2 or 3 heteroatoms selected from N, O or S, and R 7 at each occurrence is independently optionally substituted or unsubstituted with one or more substituents selected from D, —F, —Cl, —Br, —I, —OH, oxo, ⁇ O, —SH, —CN, —NO 2 , —N 3 , —C 1-3 alkyl, —C 1-3 alkoxy, —C 2-4 alkenyl, —C 2-4 alkynyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, 3-6 membered heterocyclyloxy, 3-6 membered heterocyclylthio, C 5-8
  • R 8 at each occurrence is independently selected from H, D, —C 1-3 alkyl, —C 1-3 alkoxy, —C 2-4 alkenyl, —C 2-4 alkynyl, —C(O)R 11 , —C 1-3 alkyl-C(O)R, —C 3-6 cycloalkyl, or 3-8 membered heterocyclic
  • R 8 is independently optionally substituted or unsubstituted with one or more substituents selected from D, —F, —Cl, —Br, —I, —OH, oxo, ⁇ O, —SH, —CN, —NO 2 , —N 3 , —C 1-3 alkyl, —C 2-4 alkenyl, —C 2-4 alkynyl, C 1-3 haloalkyl, —C 3-6 cycloalkyl, 3-6 membered heterocyclic, 3-6 membered heterocyclyloxy, 3-6 membere
  • R 7 and R 8 together with the carbon and nitrogen to which they are respectively attached form 5-7 membered monocyclic heterocyclic, 5-10 membered spirocyclic heterocyclic, 5-10 membered fused heterocyclic or 5-10 membered bridged heterocyclic, each said ring system is independently optionally contains 1, 2 or 3 heteroatoms selected from N, O or S, and each said ring system is independently optionally substituted or unsubstituted with one or more substituents selected from D, —F, —Cl, —Br, —I, —OH, oxo, ⁇ O, —SH, —CN, —NO 2 , —N 3 , —C 1-3 alkyl, —C 1-3 alkoxy, —C 2-4 alkenyl, —C 2-4 alkynyl, C 1-3 haloalkyl, —C 3-6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclic, 3-6
  • each R 9 is independently optionally selected from H, D, —C 1-3 alkyl, —C 1-3 alkyl C 1-3 alkoxy, —C 2-4 alkenyl, —C 3-6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclic, C 1-3 haloalkyl, phenyl, p-methyl phenyl, amino, —NH—C 1-3 alkyl, —N(C 1-3 alkyl) 2 or C 1-3 alkylamide;
  • each R 10 is independently optionally selected from H, D, —C 1-3 alkyl, —C 1-3 alkyl C 1-3 alkoxy, —C 3-6 cycloalkyl, —C 5-10 aryl, C 1-3 haloalkyl or C 1-3 alkyl substituted with hydroxyl;
  • each R 11 is independently optionally selected from H, D, —C 1-3 alkyl, —C 1-3 alkoxy, —C 3-6 cycloalkyl, —C 3-6 cycloalkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, C 1-3 alkyl substituted with hydroxyl, or C 1-3 alkoxy substituted with hydroxyl;
  • R 12 and R 13 are respectively independently selected from H, D, —C 1-3 alkyl, —C 1-3 alkyl C 1-3 alkoxy, —C 1-3 alkoxy C 1-3 alkyl, —C 3-6 cycloalkyl C 1-3 alkyl, —C 2-4 alkenyl, —C 2-4 alkynyl, —C 3-6 cycloalkyl, substituted or unsubstituted —C 5-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl or —C 1-3 alkanoyl;
  • t 0, 1 or 2.
  • R 1 at each occurrence is independently
  • X at each occurrence is independently selected from absent, 0, —NR X1 — or —CR X1 R X2 —; and p is 0 or 1;
  • R X1 and R X2 at each occurrence are independently selected from H; D; —F; —Cl; —Br; —I; methyl; ethyl; propyl; isopropyl; C 1-3 alkyl substituted with 1, 2 or 3 substituents; methoxy; ethoxy; propoxy; isopropoxy or C 1-3 alkoxy substituted with 1, 2 or 3 substituents; each said substituent is independently optionally selected from D, —F, —Cl, —Br, —I, —OH, —CN, —NH 2 , —NO 2 , —COOH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, or isopropoxy;
  • Y at each occurrence is independently 0;
  • R 7 at each occurrence is independently selected from H, D, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3 membered heterocyclic, 4 membered heterocyclic, 5 membered heterocyclic, 6 membered heterocyclic, 7 membered heterocyclic, 8 membered heterocyclic, and each said heterocyclic independently optionally contains one or two heteroatoms selected from N, O or S, and R 7 at each occurrence is independently optionally substituted or unsubstituted with substituents selected from D, —F, —Cl, —Br, —I, —OH, oxo, ⁇ O, —SH, —CN, —NO 2 , —N 3 , methyl, ethyl, propyl, isopropyl, methoxy,
  • R 8 at each occurrence is independently selected from H, D, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —C 2-4 alkenyl, —C 2-4 alkynyl, —C(O)R 11 , -methyl-C(O)R 11 , -ethyl-C(O)R 11 , -propyl-C(O)R 11 , -isopropyl-C(O)R 11 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3 membered heterocyclic, 4 membered heterocyclic, 5 membered heterocyclic, 6 membered heterocyclic, 7 membered heterocyclic, 8 membered heterocyclic, and said heterocyclic independently optionally contains one or two heteroatoms selected from N, O or S, and R is independently optionally substituted or unsubstituted with
  • R 7 and R 8 together with the carbon and nitrogen to which they are respectively attached form 5 membered monocyclic heterocyclic, 6 membered monocyclic heterocyclic, 7 membered monocyclic heterocyclic, 5 membered spirocyclic heterocyclic, 6 membered spirocyclic heterocyclic, 7 membered spirocyclic heterocyclic, 8 membered spirocyclic heterocyclic, 9 membered spirocyclic heterocyclic, 10 membered spirocyclic heterocyclic, 5 membered fused heterocyclic, 6 membered fused heterocyclic, 7 membered fused heterocyclic, 8 membered fused heterocyclic, 9 membered fused heterocyclic, 10 membered fused heterocyclic, 5 membered bridged heterocyclic, 6 membered bridged heterocyclic, 7 membered bridged heterocyclic, 8 membered bridged heterocyclic, 9 membered bridged heterocyclic, or 10 membered bridged heterocycl
  • each R 9 is independently optionally selected from H, D, methyl, ethyl, propyl, isopropyl, —C 1-3 alkylC 1-3 alkoxy, —C 2-4 alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted or unsubstituted 3-6 membered heterocyclic, C 1-3 haloalkyl, phenyl, p-methyl phenyl, amino, —NH—C 1-3 alkyl, —N(C 1-3 alkyl) 2 or C 1-3 alkylamide;
  • each R 10 is independently optionally selected from H, D, methyl, ethyl, propyl, isopropyl, —C 1-3 alkylC 1-3 alkoxy, —C 3-6 cycloalkyl, —C 5-10 aryl, C 1-3 haloalkyl or C 1-3 alkyl substituted with hydroxyl;
  • each R 11 is independently optionally selected from H, D, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 3-6 membered cycloalkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, C 1-3 alkyl substituted with hydroxyl, or C 1-3 alkoxy substituted with hydroxyl;
  • R 12 and R 13 are respectively independently selected from H, D, methyl, ethyl, propyl, isopropyl, —C 1-3 alkylC 1-3 alkoxy, —C 1-3 alkoxy C 1-3 alkyl, —C 3-6 cycloalkyl C 1-3 alkyl, —C 2-4 alkenyl, —C 2-4 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted or unsubstituted C 5-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl or —C 1-3 alkylamide;
  • t 0, 1 or 2.
  • R 1 at each occurrence is independently
  • X at each occurrence is independently selected from —CH 2 —, —CHD-, —CD 2 -, —CH(CH 3 )—, —C(CH 3 ) 2 —, —CHF—, —CHBr— or —CH(OH)—; and p is 0 or 1;
  • Y at each occurrence is independently O;
  • R 7 at each occurrence is independently selected from H, D, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, dioxolane, azacyclobutyl, piperidyl, piperazinyl, oxopiperazinyl, oxypiperidyl, tetrahydrofuranyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl or oxadiazole, R 7 at each occurrence is independently optionally substituted or unsubstituted with one or more substituents selected from D, —F, —Cl, —Br, —I, —OH, oxo,
  • R 8 at each occurrence is independently selected from H, D, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —C 2-4 alkenyl, —C 2-4 alkynyl, —C(O)H, -methyl-C(O)H, -ethyl-C(O)H, -propyl-C(O)H, -isopropyl-C(O)H, —C(O)-methyl, -methyl-C(O)-methyl, -ethyl-C(O)-methyl, -propoxy-C(O)methyl, -isopropoxy-C(O)-methyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3 membered heterocyclic, 4 membered heterocyclic, 5 membered heterocyclic, 6 membered heterocyclic, 7 membered heterocycl
  • R 7 and R 8 together with the carbon and nitrogen to which they are respectively attached form dioxolane, azetidine, piperidine, piperazine, oxopiperazine, oxopiperidine, tetrahydrofuran, tetrahydroimidazole, tetrahydrothiazole, tetrahydrooxazole, tetrahydropyran, tetrahydropyrrole, azapentyl ring, morpholinyl, thiomorpholinyl, 7-membered oxazacyclo or 7-membered oxazacyclospiro, each said ring system is independently optionally substituted or unsubstituted with one or more substituents selected from D, —F; —Cl; —Br; —I; —OH; oxo; ⁇ O; —SH; —CN; —NO 2 ; —N 3 ; methyl; ethyl; propy
  • R 1 is selected from:
  • R 1 is selected from:
  • R 2 and R 3 are respectively independently selected from H; D; —F; —Cl; —Br; —I; —OH; —SH; —CN; —NH 2 ; —NO 2 ; —N 3 ; —C 1-3 alkyl; —C 1-3 alkyl substituted with 1, 2 or 3 substituents selected from -D, —F, —Cl, —Br, —I, —OH, —CN, —NH 2 , —NO 2 , —COOH, —C 1-3 alkyl or C 1-3 alkoxy; —C 1-3 alkoxy; C 1-3 alkoxy substituted with 1, 2 or 3 substituents selected from -D, —F, —Cl, —Br, —I, —OH, —CN, —NH 2 , —NO 2 , —COOH, —C 1-3 alkyl or C 1-3 alkoxy; substituted or unsubsti
  • each R 9 is independently optionally selected from H, D, —C 1-3 alkyl, —C 1-3 alkyl C 1-3 alkoxy, —C 2-4 alkenyl, —C 3-6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclic, C 1-3 haloalkyl, phenyl, p-methyl phenyl, amino, —NH—C 1-3 alkyl, —N(C 1-3 alkyl) 2 or C 1-3 alkylamide;
  • each R 10 is independently optionally selected from H, D, —C 1-3 alkyl, —C 1-3 alkyl C 1-3 alkoxy, —C 3-6 cycloalkyl, —C 5-8 aryl, C 1-3 haloalkyl or C 1-3 alkyl substituted with hydroxyl;
  • each R 1 is independently optionally selected from H, D, —C 1-3 alkyl, —C 1-3 alkoxy, —C 3-6 cycloalkyl, —C 3-6 cycloalkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, C 1-3 alkyl substituted with hydroxyl, or C 1-3 alkoxy substituted with hydroxyl;
  • each R 12 and R 13 is respectively independently optionally selected from H, D, —C 1-3 alkyl, —C 1-3 alkyl C 1-3 alkoxy, —C 1-3 alkoxy C 1-3 alkyl, —C 3-6 cycloalkyl C 1-3 alkyl, —C 2-4 alkenyl, —C 2-4 alkynyl, —C 3-6 cycloalkyl, substituted or unsubstituted C 5-8 aryl, substituted or unsubstituted 5-8 membered heteroaryl or C 1-3 alkanoyl;
  • t 0, 1 or 2.
  • R 2 and R 3 are respectively independently selected from H; D; —F; —Cl; —Br; —I; —OH; —SH; —CN; —NO 2 ; —N 3 ; methyl; ethyl; propyl; isopropyl; —C 1-3 alkyl substituted with 1, 2 or 3 substituents selected from -D, —F, —Cl, —Br, —I, —OH, —CN, —NH 2 , —NO 2 , —COOH, —C 1-3 alkyl or C 1-3 alkoxy; methoxy; ethoxy; propoxy; isopropoxy; C 1-3 alkoxy substituted with 1, 2 or 3 substituents selected from -D, —F, —Cl, —Br, —I, —OH, —CN, —NH 2 , —NO 2 , —COOH, —C 1-3 alkyl or C 1-3 alk
  • each R 9 is independently optionally selected from H, D, methyl, ethyl, propyl, isopropyl, —C 1-3 alkyl C 1-3 alkoxy, —C 2-4 alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted or unsubstituted 3-6 membered heterocyclic, C 1-3 haloalkyl, phenyl, p-methyl phenyl, amino, —NH—C 1-3 alkyl, —N(C 1-3 alkyl) 2 or C 1-3 alkylamide;
  • each R 10 is independently optionally selected from H, D, methyl, ethyl, propyl, isopropyl, —C 1-3 alkyl C 1-3 alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —C 5-8 -aryl, C 1-3 haloalkyl or C 1-3 alkyl substituted with hydroxyl;
  • each R 10 is independently optionally selected from H, D, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —C 3-6 cycloalkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, C 1-3 alkyl substituted with hydroxyl, or C 1-3 alkoxy substituted with hydroxyl;
  • each R 12 and R 13 is respectively independently optionally selected from H, D, methyl, ethyl, propyl, isopropyl, —C 1-3 alkyl C 1-3 alkoxy, —C 1-3 alkoxy C 1-3 alkyl, —C 3-6 cycloalkyl C 1-3 alkyl, —C 2-4 alkenyl, —C 2-4 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted or unsubstituted C 5-8 aryl, substituted or unsubstituted 5-8 membered heteroaryl or C 1-3 alkanoyl;
  • t 0 or 1.
  • R 2 and R 3 are respectively independently selected from H; D; —F; —Cl; —Br; —I; —OH; —SH; —CN; —NO 2 ; —N 3 ; methyl; ethyl; propyl; isopropyl; —C 1-3 alkyl substituted with 1, 2 or 3 substituents selected from -D, —F, —Cl, —Br, —I, —OH, —CN, —NH 2 , —NO 2 , —COOH, —C 1-3 alkyl or C 1-3 alkoxy; methoxy, ethoxy, propoxy, isopropoxy; C 1-3 alkoxy substituted with 1, 2 or 3 substituents selected from -D, —F, —Cl, —Br, —I, —OH, —CN, —NH 2 , —NO 2 , —COOH, —C 1-3 alkyl or C 1-3 alk
  • R 2 and R 3 are respectively independently selected from H, D, —F, —Cl, —Br, —I, —OH, —SH, —CN, —NO 2 , —N 3 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
  • R 2 and R 3 are respectively independently selected from H, D, —F or methyl.
  • G at each occurrence is independently selected from —CR G1 R G2 —, —NR G1 —, —S—, —SO—, —SO 2 — or 0; m is 0, 1, 2, 3 or 4;
  • G at each occurrence is independently selected from —CR G1 R G2 —, —NR G1 —, —S—, —SO—, —SO 2 — or 0; m is 0, 1, 2 or 3;
  • G at each occurrence is independently selected from —CR G1 R G2 —, —NR G1 —, —S—, —SO—, —SO 2 — or 0; m is 0, 1, 2, or 3;
  • each R G1 and R G2 is independently selected from H; D; methyl; ethyl; propyl; isopropyl; —C 1-3 alkyl substituted with 1, 2 or 3 substituents; methoxy, ethoxy, propoxy; isopropoxy; —C 1-3 alkoxy substituted with 1, 2 or 3 substituents; each said substituent is independently optionally selected from D, —F, —Cl, —Br, —I, —OH, —CN, —NH 2 , —NO 2 , —COOH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
  • G at each occurrence is independently selected from —CH 2 —, —CHD-, —CD 2 -, —NH—, —S—, —SO—, —SO 2 — or 0; m is 0, 1 or 2.
  • G at each occurrence is independently selected from —CH 2 —, —CHD-, —CD 2 -, —NH—, —S—, —SO—, —SO 2 — or 0; m is 0 or 1.
  • G at each occurrence is independently selected from —NH— or 0; m is 0 or 1.
  • G at each occurrence is independently selected from —NH— or 0; m is 1.
  • G at each occurrence is independently selected from —NH—; m is 0 or 1.
  • G at each occurrence is independently selected from —NH—; m is 1.
  • m is 0.
  • Q at each occurrence is independently selected from —CR 4 R 4 ′—(CR 4 R 4 ′)q-;
  • Both R 4 and R 4 ′ are independently selected from H; D; —F; —Cl; —Br; —I; —OH; —C 1-6 alkyl; C 1-6 alkyl substituted with 1, 2 or 3 substituents; —C 1-6 alkoxy; C 1-6 alkoxy substituted with 1, 2 or 3 substituents; —C 3-8 cycloalkyl; C 3-8 cycloalkyl substituted with 1, 2 or 3 substituents; 3-8 membered heterocyclic; 3-8 membered heterocyclic substituted with 1, 2 or 3 substituents; each said substituent is independently optionally selected from D, halogen, —OH, —CN, —NH 2 , —NO 2 , —COOH, —C 1-3 alkyl or C 1-3 alkoxy; or
  • R 4 and R 4 ′ together with the carbon to which they are both attached form —C 3-8 carbocyclic ring, -3-8 membered heterocyclic ring or -5-10 membered heteroaryl ring, each ring system is independently optionally substituted or unsubstituted with one or more substituents.
  • Q is —NR 4 —(CR 4 R 4 ′) q —;
  • Both R 4 and R 4 ′ are independently selected from H; D; —F; —Cl; —Br; —I; —OH; —C 1-6 alkyl; C 1-6 alkyl substituted with 1, 2 or 3 substituents; —C 1-6 alkoxy; C 1-6 alkoxy substituted with 1, 2 or 3 substituents; —C 3-8 cycloalkyl; C 3-8 cycloalkyl substituted with 1, 2 or 3 substituents; 3-8 membered heterocyclic; 3-8 membered heterocyclic substituted with 1, 2 or 3 substituents; each said substituent is independently optionally selected from D, halogen, —OH, —CN, —NH 2 , —NO 2 , —COOH, —C 1-3 alkyl or C 1-3 alkoxy; or
  • R 4 and R 4 ′ together with the carbon to which they are both attached form —C 3-8 carbocyclic ring, -3-8 membered heterocyclic ring or -5-10 membered heteroaryl ring, each ring system is independently optionally substituted or unsubstituted with one or more substituents.
  • Q is —CR 4 R 4 ′—(CR 4 R 4 ′) q — or —NR 4 —(CR 4 R 4 ′)—, and q is selected from 0, 1, 2, 3 or 4;
  • Both R 4 and R 4 ′ are independently selected from H; D; —F; —Cl; —Br; —I; —OH; —C 1-3 alkyl; C 1-3 alkyl substituted with 1, 2 or 3 substituents; —C 1-3 alkoxy; C 1-3 alkoxy substituted with 1, 2 or 3 substituents; —C 3-6 cycloalkyl; C 3-6 cycloalkyl substituted with 1, 2 or 3 substituents; 3-6 membered heterocyclic; 3-6 membered heterocyclic substituted with 1, 2 or 3 substituents; each said substituent is independently optionally selected from D, halogen, —OH, —CN, —NH 2 , —NO 2 , —COOH, —C 1-3 alkyl or C 1-3 alkoxy; or R 4 and R 4 ′ together with the carbon to which they are both attached form —C 3-6 carbocyclic ring, -3-6 membered heterocyclic ring or 5-8 membere
  • Q is —CR 4 R 4 ′—(CR 4 R 4 ′) q —;
  • Both R 4 and R 4 ′ are independently selected from H; D; —F; —Cl; —Br; —I; —OH; —C 1-3 alkyl; C 1-3 alkyl substituted with 1, 2 or 3 substituents; —C 1-3 alkoxy; C 1-3 alkoxy substituted with 1, 2 or 3 substituents; —C 3-6 cycloalkyl; C 3-6 cycloalkyl substituted with 1, 2 or 3 substituents; 3-6 membered heterocyclic; 3-6 membered heterocyclic substituted with 1, 2 or 3 substituents; each said substituent is independently optionally selected from D, halogen, —OH, —CN, —NH 2 , —NO 2 , —COOH, —C 1-3 alkyl or C 1-3 alkoxy; or
  • R 4 and R 4 ′ together with the carbon to which they are both attached form —C 3-6 carbocyclic ring, -3-6 membered heterocyclic ring or 5-8 membered heteroaryl ring, and each ring system is independently optionally substituted or unsubstituted with one or more substituents.
  • Q is —NR 4 —(CR 4 R 4 ′) q —;
  • Both R 4 and R 4 ′ are independently selected from H; D; —F; —Cl; —Br; —I; —OH; —C 1-3 alkyl; C 1-3 alkyl substituted with 1, 2 or 3 substituents; —C 1-3 alkoxy; C 1-3 alkoxy substituted with 1, 2 or 3 substituents; —C 3-6 cycloalkyl; C 3-6 cycloalkyl substituted with 1, 2 or 3 substituents; 3-6 membered heterocyclic; 3-6 membered heterocyclic substituted with 1, 2 or 3 substituents; each said substituent is independently optionally selected from D, halogen, —OH, —CN, —NH 2 , —NO 2 , —COOH, —C 1-3 alkyl or C 1-3 alkoxy; or
  • R 4 and R 4 ′ together with the carbon to which they are both attached form —C 3-6 carbocyclic ring, -3-6 membered heterocyclic ring or 5-8 membered heteroaryl ring, each ring system is independently optionally substituted or unsubstituted with one or more substituents.
  • Q is —CR 4 R 4 ′—(CR 4 R 4 ′) q — or —NR 4 —(CR 4 R 4 ′)—, and q is selected from 0, 1, 2, 3 or 4;
  • Both R 4 and R 4 ′ are independently selected from H; D; —F; —Cl; —Br; —I; —OH; —C 1-3 alkyl; C 1-3 alkyl substituted with 1, 2 or 3 substituents; —C 1-3 alkoxy; C 1-3 alkoxy substituted with 1, 2 or 3 substituents; —C 3-6 cycloalkyl; C 3-6 cycloalkyl substituted with 1, 2 or 3 substituents; 3-6 membered heterocyclic; 3-6 membered heterocyclic substituted with 1, 2 or 3 substituents; each said substituent is independently optionally selected from D, —F, —Cl, —Br, —I, —OH, —CN, —NH 2 , —NO 2 , —COOH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; or
  • R 4 and R 4 ′ together with the carbon to which they are both attached form —C 3-6 carbocyclic ring, -3-6 membered heterocyclic ring or 5-8 membered heteroaryl ring, said each heterocyclic ring and each heteroaryl ring independently optionally contains 1 or 2 heteroatoms selected from N, O or S, and each ring system is independently optionally substituted or unsubstituted with one or more substituents.
  • Q is —CR 4 R 4 ′—(CR 4 R 4 ′) q —;
  • Both R 4 and R 4 ′ are independently selected from H; D; —F; —Cl; —Br; —I; —OH; —C 1-3 alkyl; C 1-3 alkyl substituted with 1, 2 or 3 substituents; —C 1-3 alkoxy; C 1-3 alkoxy substituted with 1, 2 or 3 substituents; —C 3-6 cycloalkyl; C 3-6 cycloalkyl substituted with 1, 2 or 3 substituents; 3-6 membered heterocyclic; 3-6 membered heterocyclic substituted with 1, 2 or 3 substituents; each said substituent is independently optionally selected from D, —F, —Cl, —Br, —I, —OH, —CN, —NH 2 , —NO 2 , —COOH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; or
  • R 4 and R 4 ′ together with the carbon to which they are both attached form —C 3-6 carbocyclic ring, -3-6 membered heterocyclic ring or -5-8 membered heteroaryl ring, said each heterocyclic ring and each heteroaryl ring independently optionally contains 1 or 2 heteroatoms selected from N, O or S, and each ring system is independently optionally substituted or unsubstituted with one or more substituents.
  • Q is —NR 4 —(CR 4 R 4 ′) q —;
  • Both R 4 and R 4 ′ are independently selected from H; D; —F; —Cl; —Br; —I; —OH; —C 1-3 alkyl; C 1-3 alkyl substituted with 1, 2 or 3 substituents; —C 1-3 alkoxy; C 1-3 alkoxy substituted with 1, 2 or 3 substituents; —C 3-6 cycloalkyl; C 3-6 cycloalkyl substituted with 1, 2 or 3 substituents; 3-6 membered heterocyclic; 3-6 membered heterocyclic substituted with 1, 2 or 3 substituents; each said substituent is independently optionally selected from D, —F, —Cl, —Br, —I, —OH, —CN, —NH 2 , —NO 2 , —COOH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; or
  • R 4 and R 4 ′ together with the carbon to which they are both attached form —C 3-6 carbocyclic ring, -3-6 membered heterocyclic ring or -5-8 membered heteroaryl ring, said each heterocyclic ring and each heteroaryl ring independently optionally contains 1 or 2 heteroatoms selected from N, O or S, and each ring system is independently optionally substituted or unsubstituted with one or more substituents.
  • Q is —CR 4 R 4 ′—(CR 4 R 4 ′) q — or —NR 4 —(CR 4 R 4 ′)—, and q is selected from 0, 1, 2, 3 or 4;
  • Both R 4 and R 4 ′ are independently selected from H; D; —F; —Cl; —Br; —I; —OH; methyl; ethyl; propyl; isopropyl; —C 1-3 alkyl substituted with 1, 2 or 3 substituents; methoxy; ethoxy; propoxy; isopropoxy; or —C 1-3 alkoxy substituted with 1, 2 or 3 substituents; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; C 3-6 cycloalkyl substituted with 1, 2 or 3 substituents; 3-6 membered heterocyclic; or 3-6 membered heterocyclic substituted with 1, 2 or 3 substituents; each said substituent is independently optionally selected from D, —F, —Cl, —Br, —I, —OH, —CN, —NH 2 , —NO 2 , —COOH, methyl, ethyl
  • R 4 and R 4 ′ together with the carbon to which they are both attached form 3 membered carbocyclic ring; 4 membered carbocyclic ring; 5 membered carbocyclic ring; 6 membered carbocyclic ring; 3 membered heterocyclic ring; 4 membered heterocyclic ring; 5 membered heterocyclic ring; 6 membered heterocyclic ring; 5 membered heteroaryl ring; 6 membered heteroaryl ring; 7 membered heteroaryl ring; 8 membered heteroaryl ring; said each heterocyclic ring and each heteroaryl ring independently optionally contains 1 or 2 heteroatoms selected from N, O or S, and said each carbocyclic ring, each heterocyclic ring, and heteroaryl ring is independently optionally substituted or unsubstituted with 1, 2 or 3 substituents.
  • Q is —CR 4 R 4 ′—(CR 4 R 4 ′) q —;
  • R 4 and R 4 ′ are independently selected from H; D; —F; —Cl; —Br; —I; —OH; methyl; ethyl; propyl; isopropyl; —C 1-3 alkyl substituted with 1, 2 or 3 substituents; methoxy; ethoxy; propoxy; isopropoxy; —C 1-3 alkoxy substituted with 1, 2 or 3 substituents; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; C 3-6 cycloalkyl substituted with 1, 2 or 3 substituents; 3-6 membered heterocyclic; 3-6 membered heterocyclic substituted with 1, 2 or 3 substituents; each said substituent is independently optionally selected from D, —F, —Cl, —Br, —I, —OH, —CN
  • R 4 and R 4 ′ together with the carbon to which they are both attached form 3 membered carbocyclic ring; 4 membered carbocyclic ring; 5 membered carbocyclic ring; 6 membered carbocyclic ring; 3 membered heterocyclic ring; 4 membered heterocyclic ring; 5 membered heterocyclic ring; 6 membered heterocyclic ring; 5 membered heteroaryl ring; 6 membered heteroaryl ring; 7 membered heteroaryl ring; 8 membered heteroaryl ring; said each heterocyclic ring and each heteroaryl ring independently optionally contains 1 or 2 heteroatoms selected from N, O or S, and said each carbocyclic ring, each heterocyclic ring, each heteroaryl ring is independently optionally substituted or unsubstituted with 1, 2 or 3 substituents.
  • Q is —NR 4 —(CR 4 R 4 ′) q —;
  • Both R 4 and R 4 ′ are independently selected from H; D; —F; —Cl; —Br; —I; —OH; methyl; ethyl; propyl; isopropyl; —C 1-3 alkyl substituted with 1, 2 or 3 substituents; methoxy; ethoxy; propoxy; isopropoxy; —C 1-3 alkoxy substituted with 1, 2 or 3 substituents; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; C 3-6 cycloalkyl substituted with 1, 2 or 3 substituents; 3-6 membered heterocyclic; 3-6 membered heterocyclic substituted with 1, 2 or 3 substituents; each said substituent is independently optionally selected from D, —F, —Cl, —Br, —I, —OH, —CN, —NH 2 , —NO 2 , —COOH, methyl, ethyl, prop
  • R 4 and R 4 ′ together with the carbon to which they are both attached form 3 membered carbocyclic ring; 4 membered carbocyclic ring; 5 membered carbocyclic ring; 6 membered carbocyclic ring; 3 membered heterocyclic ring; 4 membered heterocyclic ring; 5 membered heterocyclic ring; 6 membered heterocyclic ring; 5 membered heteroaryl ring; 6 membered heteroaryl ring; 7 membered heteroaryl ring; 8 membered heteroaryl ring; said each heterocyclic ring and heteroaryl ring independently optionally contains 1 or 2 heteroatoms selected from N, O or S, and said each carbocyclic ring, each heterocyclic ring, and each heteroaryl ring is independently optionally substituted or unsubstituted with 1, 2 or 3 substituents.
  • Both R 5 and R 5 ′ are independently selected from H; D; —F; —Cl; —Br; —I; —OH; —C 1-3 alkyl; —C 1-3 alkyl substituted with 1, 2 or 3 substituents; —C 1-3 alkoxy; —C 1-3 alkoxy substituted with 1, 2 or 3 substituents; —C 3-6 cycloalkyl; —C 3-6 cycloalkyl substituted with 1, 2 or 3 substituents; 3-6 membered heterocyclic; 3-6 membered heterocyclic substituted with 1, 2 or 3 substituents; each said substituent is independently optionally selected from D, halogen, —OH, —CN, —NH 2 , —NO 2 , —COOH, —C 1-3 alkyl or C 1-3 alkoxy; or
  • R 5 and R 5 ′ together with the carbon to which they are both attached to form —C 3-6 carbocyclic ring, 3-6 membered heterocyclic ring, 5-8 membered heteroaryl ring, said each heterocyclic ring and each heteroaryl ring independently optionally contains 1 or 2 heteroatoms selected from N, O or S, and said ring system is independently optionally substituted or unsubstituted with one or more substituents; or
  • R 4 and R 5 together with the atom to which they are respectively attached form 5-10 membered aromatic ring, —C 3-8 carbocyclic ring, 4-8 membered heterocyclic ring, each said heterocyclic independently optionally contains 1 or 2 substituents selected from N, O or S, and each said ring system is dependently optionally substituted or unsubstituted with one or more substituents.
  • Both R 5 and R 5 ′ are independently selected from H; D; —F; —Cl; —Br; —I; —OH; methyl; ethyl; propyl; isopropyl; —C 1-3 alkyl substituted with 1, 2 or 3 substituents; methoxy; ethoxy; propoxy; isopropoxy; —C 1-3 alkoxy substituted with 1, 2 or 3 substituents; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; —C 3-6 cycloalkyl substituted with 1, 2 or 3 substituents; 3 membered heterocyclic; 4 membered heterocyclic; 5 membered heterocyclic; 6 membered heterocyclic; 3-6 membered heterocyclic substituted with 1, 2 or 3 substituents; each said heterocyclic dependently optionally contains 1 or 2 substituents selected from N, O or S; each said substituent is independently optionally selected from D,
  • R 5 and R 5 ′ together with the carbon to which they are both attached to form 3 membered carbocyclic ring, 4 membered carbocyclic ring, 5 membered carbocyclic ring, 6 membered carbocyclic ring, 3 membered heterocyclic ring, 4 membered heterocyclic ring, 5 membered heterocyclic ring, 6 membered heterocyclic ring, 5 membered heteroaryl ring, 6 membered heteroaryl ring, 7 membered heteroaryl ring or 8 membered heteroaryl ring, said each heterocyclic ring and each heteroaryl ring independently optionally contains 1 or 2 heteroatoms selected from N, O or S, and said each ring system is independently optionally substituted or unsubstituted with 1, 2 or 3 substituents; or
  • R 4 and R 5 together with the atom to which they are respectively attached form 5 membered aromatic ring, 6 membered aromatic ring, 7 membered aromatic ring, 8 membered aromatic ring, 9 membered aromatic ring, 10 membered aromatic ring, 4 membered carbocyclic ring, 5 membered carbocyclic ring, 6 membered carbocyclic ring, 7 membered carbocyclic ring, 8 membered carbocyclic ring, 4 membered heterocyclic ring, 5 membered heterocyclic ring, 6 membered heterocyclic ring, 7 membered heterocyclic ring, 8 membered heterocyclic ring, the each heterocyclic independently optionally contains 1 or 2 heteroatoms selected from N, O or S, and said each ring system is independently optionally substituted or unsubstituted with 1, 2 or 3 substituents.
  • Both R 5 and R 5 ′ are independently selected from H; D; —F; —Cl; —Br; —I; —OH; methyl; ethyl; propyl; isopropyl; —C 1-3 alkyl substituted with 1, 2 or 3 substituents; methoxy; ethoxy; propoxy; isopropoxy; —C 1-3 alkoxy substituted with 1, 2 or 3 substituents; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; —C 3-6 cycloalkyl substituted with 1, 2 or 3 substituents; 3 membered heterocyclic; 4 membered heterocyclic; 5 membered heterocyclic; 6 membered heterocyclic; 3-6 membered heterocyclic substituted with 1, 2 or 3 substituents; each said heterocyclic independently optionally contains 1 or 2 heteroatoms selected from N, O or S; each said substituent is independently optionally selected from D,
  • R 5 and R 5 ′ together with the carbon to which they are both attached form 3 membered carbocyclic ring, 4 membered carbocyclic ring, 5 membered carbocyclic ring, 6 membered carbocyclic ring, 3 membered heterocyclic ring, 4 membered heterocyclic ring, 5 membered heterocyclic ring, 6 membered heterocyclic ring, 5 membered heteroaryl ring, 6 membered heteroaryl ring, 7 membered heteroaryl ring, 8 membered heteroaryl ring; said each heterocyclic ring and each heteroaryl ring independently optionally contains 1 or 2 heteroatoms selected from N, O or S, and said each ring system is independently optionally substituted or unsubstituted with 1, 2 or 3 substituents selected from D, —F, —Cl, —Br, —I, —OH, oxo, ⁇ O, —NH 2 , —CN, —COOH, —NO
  • R 4 and R 5 together with the atom to which they are respectively attached form benzene, naphthalene, 3 membered carbocyclic ring, 4 membered carbocyclic ring, 5 membered carbocyclic ring, 6 membered carbocyclic ring, piperidine, piperazine, oxopiperazine, oxopiperidine, tetrahydrofuran, tetrahydroimidazole, tetrahydrothiazole, tetrahydrooxazole, tetrahydropyran, tetrahydropyrrole or azapentyl ring, and said each ring system is independently optionally substituted or unsubstituted with 1, 2 or 3 substituents selected from D, —F, —Cl, —Br, —I, —OH, NH 2 , —CN, —COOH, —NO 2 , methyl, ethyl, propyl, isoprop
  • R 6 at each occurrence is independently selected from H; D; —F; —Cl; —Br; —I; methyl; ethyl; propyl; isopropyl; —C 1-3 alkyl substituted with 1, 2 or 3 substituents; methoxy; ethoxy; propoxy; isopropoxy; —C 1-3 alkoxy substituted with 1, 2 or 3 substituents; -methyl-COO-methyl; -ethyl-COO-ethyl; -propyl-COO-propyl; -isopropyl-COO-isopropyl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; —C 3-6 carbocyclic substituted with 1, 2 or 3 substituents; each said substituent is independently optionally selected from D, —F, —Cl, —Br, —I, —OH, —NH 2 ,
  • Q and R 6 together with the carbon and W to which they are respectively attached form 4 membered heterocyclic ring, 5 membered heterocyclic ring, 6 membered heterocyclic ring or 7 membered heterocyclic ring, said heterocyclic ring is independently optionally substituted or unsubstituted with one or more substituents, said heterocyclic ring is independently optionally contains 1, 2 or 3 heteroatoms selected from N, O or S, said each substituent is independently optionally selected from D, —F, —Cl, —Br, —I, —OH, —CN, —NH 2 , —NO 2 , —COOH, —C 1-3 alkyl or C 1-3 alkoxy; or R 4 and R 6 together with the atom to which they are respectively attached form 5 membered monocyclic heterocyclic, 6 membered monocyclic heterocyclic, 7 membered monocyclic heterocyclic, 8 membered monocyclic heterocyclic, 5 membered spirocyclic hetero
  • R 5 and R 6 together with the carbon and W to which they are respectively attached form 4 membered heterocyclic ring, 5 membered heterocyclic ring, 6 membered heterocyclic ring, 5 membered heteroaryl ring, 6 membered heteroaryl ring, 7 membered heteroaryl ring, 8 membered heteroaryl ring, the each ring system independently optionally contains 1, 2 or 3 heteroatoms selected from N, O or S, and each said ring system is independently optionally substituted or unsubstituted with 1, 2 or 3 substituents selected from D, —F, —Cl, —Br, —I, —OH, —NH 2 , —CN, —COOH, oxo, ⁇ O, Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy.
  • the compound is selected from:
  • the compound is selected from:
  • the present invention provided a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of formula I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • the present invention provided a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of formula I of the invention or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • the present invention provided the use of the compound of formula I or a pharmaceutically acceptable salt thereof, or pharmaceutical composition for the manufacture of a medicament.
  • the said medicament is used for the treatment, prevention or precaution of diseases or conditions mediated by FGFR4 activity.
  • the diseases or conditions mediated by FGFR4 activity are cancer and/or cancerometastasis.
  • the diseases mediated by FGFR4 activity are selected from one or more of the following diseases: liver cancer, head and neck cancer, esophageal cancer, stomach cancer, prostate cancer, ovarian cancer, lung cancer, breast cancer, colorectal cancer, rhabdomyoma and combinations thereof.
  • the present invention provides a method for the treatment, prevention or precaution of the diseases or conditions mediated by FGFR4 activity, said method comprises administering to the subject a therapeutically effective amount of compound of formula I or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof.
  • the diseases or conditions mediated by FGFR4 activity are cancer and/or cancerometastasis.
  • the diseases mediated by FGFR4 activity are selected from one or more following diseases: liver cancer, head and neck cancer, esophageal cancer, stomach cancer, prostate cancer, ovarian cancer, lung cancer, breast cancer, colorectal cancer, rhabdomyoma and combinations thereof.
  • the present invention provides the compound of formula I or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof for use in the treatment, prevention or precaution of the diseases or conditions mediated by FGFR4 activity.
  • the diseases or conditions mediated by FGFR4 activity are cancer and/or cancerometastasis.
  • the diseases mediated by FGFR4 activity are selected from one or more following diseases: liver cancer, head and neck cancer, esophageal cancer, stomach cancer, prostate cancer, ovarian cancer, lung cancer, breast cancer, colorectal cancer, rhabdomyoma and combinations thereof.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • the preferred halogen group refers to fluorine, chlorine and bromine.
  • C 1-6 alkyl substituted with halogen refers to one or more (especially 1, 2 or 3) hydrogen atoms of them substituted by halogen atoms, especially fluorine or chlorine atoms.
  • C 1-6 alkyl substituted with fluorine, C 2-6 alkenyl substituted with fluorine, C 2-6 alkynyl substituted with fluorine and C 1-6 alkoxy substituted with fluorine are preferred, especially C 1-6 alkyl substituted with fluorine, for example —CF 3 , —CHF 2 , —CH 2 F, —CH 2 CH 2 F, —CH 2 CHF 2 , —CH 2 CF 3 ; C 1-6 alkyl substituted with fluorine, for example —OCF 3 , —OCHF 2 , —OCH 2 F, —OCH 2 CH 2 F, —OCH 2 CHF 2 or —OCH 2 CF 3 ; especially —CF 3 , —OCF 3 and —OCHF 2 .
  • alkyl includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties.
  • alkyl radicals include methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclobutyl, n-pentyl, 3-(2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclopentyl, n-hexyl, 2-hexyl and 2-methylpentyl and cyclohexyl.
  • the C 1-8 alkyl in the present invention is defined as a group with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms arranged in straight chain or branched chain.
  • alkylene means a difunctional group obtained by removal of hydrogen atom from an alkyl that is defined above.
  • methylene i.e., —CH 2 —
  • ethylene i.e., —CH 2 —CH 2 — or —CH(CH 3 )—
  • propylene i.e., —CH 2 —CH 2 — CH 2 —, —CH(—CH 2 —CH 3 )— or —CH 2 —CH(CH 3 )—).
  • alkoxy refers to straight or branched chain alkoxy group containing specific number of carbon atoms.
  • C 1-6 alkoxy refers to straight or branched chain alkoxy group containing at least one, at most six carbon atoms, including but not limited to, methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy, 2-methyl prop-1-oxy, 2-methyl prop-2-oxy, pentyloxy, hexyloxy, cyclopentyloxy or methylcyclopropoxy and so on.
  • alkenyl refers to an alkyl as defined above consisting of at least two carbons and at least one carbon-carbon double bonds
  • C 2-8 alkenyl refers to a straight or branched alkenyl containing 2-8 carbons. For example, ethyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc.
  • alkynyl refers to alkyl as defined above consisting of at least two carbons and at least one carbon-carbon triple bonds
  • C 2-8 alkynyl refers to a straight or branched alkenyl containing 2-8 carbons. For example, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, etc.
  • aryl as used in the present invention by itself or as part of another substituent refers to a monocyclic or polycyclic aromatic hydrocarbon. Phenyl and naphthyl are preferred aryl. The most preferred aryl is phenyl.
  • heterocyclic refers to a monocyclic or polycyclic non-aromatic family containing one or more heteroatoms, partially unsaturated or completely saturated ring system.
  • Preferred heteroatoms include N, O and S, including N-oxides, sulfur oxides and dioxides.
  • the ring is three to eight membered and is either fully saturated or has one or more degrees of unsaturation. Multiple degrees of substitution, preferably 1, 2 or 3, are included within the present definition.
  • heterocyclic examples include but are not limited to azacyclobutyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, azacycloheptyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholino, thiomorpholino, thiomorpholino sulfoxide, oxadiazole, nitroxanyl, pyridazinyl, indolyl, pyrimidinyl, pyrazinyl, isothiazolyl, diazanonaphthyl or indolazinyl.
  • Heterocyclic includes but is not limited to monocyclic heterocyclic and/or polycyclic heterocyclic.
  • Monocyclic heterocyclic includes but is not limited to pyrrolidinyl, tetrahydrofuranyl, piperidinyl, pyranyl, piperazinyl, morpholinyl, thiomorpholinyl or homopiperazinyl, etc., preferably pyrrolidinyl, tetrahydrofuranyl or pyranyl.
  • Polycyclic heterocyclic includes but is not limited to spirocyclic, fused ring and bridged-ring heterocyclic.
  • “Spirocyclic heterocyclic” refers to polycyclic heterocyclic atom sharing a single atom (abbreviated spiroatom) between single rings, wherein one or more ring atom selected from heteroatoms of nitrogen, oxygen, S(O)r (wherein r is an integer of 0, 1, 2), and the remaining ring atoms are carbon. These can contain one or more double bonds, but none of the rings has a fully conjugated 7-electron system.
  • Spirocycloalkyl is classified as monospiroheterocyclyl, dispiroheterocyclyl or polyspiroheterocyclyl according to the number of spiroatoms shared between the rings.
  • Spirocycloalkyl includes but is not limited to:
  • “Fused ring heterocyclic” refers to a polycyclic heterocyclic in which each ring in the system shares an adjacent pair of atoms with other rings in the system.
  • One or more rings may contain one or more double bonds, but none of the ring has a fully conjugated 7-electron system, wherein one or more ring atoms are selected from heteroatoms of nitrogen, oxygen, and S(O)r (wherein r is an integer of 0, 1, 2), and the remaining ring atoms are carbon.
  • the fused heterocyclic includes but is not limited to:
  • “Bridged heterocyclic group” refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected. These may contain one or more double bonds, but none of the rings has a fully conjugated ⁇ -electron system.
  • One or more ring atoms are selected from nitrogen, oxygen, and S(O)r (wherein r is an integer of 0, 1, 2) heteroatoms, and the remaining ring atoms are carbon. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyls. Bridged cycloalkyl includes but are not limited to:
  • heteroaryl used in the present invention by itself or as part of another substituent refers to an aromatic ring system containing carbon and at least one heteroatom.
  • the heteroaryl can be monocyclic or polycyclic, substituted or unsubstituted. Monocyclic heteroaryl can have one to four heteroatoms in the ring, while polycyclic heteroaryl can have one to ten heteroatoms.
  • the polycyclic heteroaryl ring may contain a fused spiroring or bridged ring, e.g., the cyclic heteroaryl is a polycyclic heteroaryl.
  • the bicyclic heteroaryl ring may contain 8 to 12 member atoms.
  • Monocyclic heteroaryl rings can contain 5 to 8 member atoms (number of carbon and heteroatoms).
  • heteroaryl include but are not limited to thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl adenine, quinolinyl or isoquinolinyl.
  • cycloalkyl used in the present invention by itself or 5 as part of another substituent refers to monocyclic, bicyclic or polycyclic of non-aromatic family saturated or partially unsubstituted hydrocarbyl, and optionally includes alkylene linker through which cycloalkyl can be connected.
  • exemplary “cycloalkyl” group includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and so on.
  • alkyl or “aryl” or any prefix roots thereof appears in the name of a substituent (for example, aralkyl or dialkylamino), unless otherwise specified, either by itself or as a part of another substituent should be construed as inclusion of the limitations of “alkyl” and “aryl” above mentioned.
  • the designated number of carbon atoms shall independently refer to the number of carbon atoms in the alkyl moiety or the number of carbon atoms in the alkyl moiety of a larger substituent with an alkyl group as its prefix.
  • R- or S-isomers when specifically designated as R- or S-isomers by chemical names, should be understood as the main configuration as R-isomer or S-isomer, respectively.
  • R- or S-designated isomers may be substantially free (as determined by chiral HPLC, less than 5%, less than 1%, or undetectable) of the other isomer of the chiral center.
  • the R- or S-isomer can be prepared by the methods exemplified in this application, for example, by using a chiral auxiliary such as R- or S-tert-butylsulfinamide in the synthesis process.
  • R- or S-isomers of the dominant configuration herein include, but are not limited to, chiral HPLC purification of mixtures of stereoisomers (such as racemic mixtures).
  • General methods for separating stereoisomers (e.g., enantiomers and/or diastereomers) using HPLC are known in the art.
  • the compounds described herein may exist in an isotope-labeled or enriched form, which contains one or more atoms with atomic mass or mass number different from the most abundant atomic mass or mass number in nature.
  • Isotopes can be radioactive or non-radioactive isotopes.
  • Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine, and iodine include but are not limited to 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 32 P, 35 S, 18 F, 36 Cl, and 125 I.
  • Compounds containing other isotopes of these and/or other atoms are within the scope of the present invention.
  • one or more hydrogen atoms of any compound described herein can be replaced with deuterium to provide a corresponding labeled or enriched compound.
  • the term “subject” refers to an animal that has become a subject of treatment, observation or experiment, preferably a mammal, and most preferably a human.
  • ring system (which may also be referred to as a “ring system”) as used herein includes, but is not limited to, carbon rings, heterocycles, heteroaryl rings, etc., and may include only heterocycles and/or heteroaryl rings, and includes determining which rings are needed based on the context.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. Accordingly, pharmaceutical compositions containing the compounds of the present invention as the active ingredient as well as methods of preparing the instant compounds are also part of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents and such solvates are also intended to be encompassed within the scope of this invention.
  • the compounds of the present invention may also be present in the form of pharmaceutically acceptable salts.
  • the salts of the compounds of this invention refer to non-toxic “pharmaceutically acceptable salts”.
  • the pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts.
  • the pharmaceutically acceptable acidic/anionic salt generally takes a form in which the basic nitrogen is protonated with an inorganic or organic acid.
  • organic or inorganic acids include hydrochloric, hydrobromic, hydriodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic, saccharinic or trifluoroacetic.
  • Pharmaceutically acceptable basic/cationic salts include, and are not limited to aluminum, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, lithium, magnesium, potassium, sodium and zinc.
  • the present invention includes within its scope the prodrugs of the compounds of this invention.
  • such prodrugs will be functional derivatives of the compounds that are readily converted in vivo into the required compound.
  • the term “administering” encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the subject.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.
  • the present invention includes compounds described can contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers.
  • the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof.
  • the above Formula is shown without a definitive stereochemistry at certain positions.
  • the present invention includes all stereoisomers of the compound of Formula (I) and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.
  • the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof.
  • the present invention includes any possible solvates and polymorphic forms.
  • a type of a solvent that forms the solvate is not particularly limited so long as the solvent is pharmacologically acceptable.
  • water, ethanol, propanol, acetone or the like can be used.
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
  • the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper (high and low value), trivalent iron, ferrous iron, lithium, magnesium, manganese (high and low value), potassium, sodium, zinc and the like. Salts of ammonium, calcium, magnesium, potassium, and sodium are particularly preferred.
  • Non-toxic organic bases that can be derived into pharmaceutically acceptable salts include primary, secondary, and tertiary amines, as well as cyclic amines and substituent-containing amines, such as naturally occurring and synthetic substituent-containing amines.
  • Other pharmaceutically acceptable non-toxic organic bases capable of forming salts Including ion exchange resins and arginine, betaine, caffeine, choline, N′,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorphanol, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, haemamine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethyl
  • the compound of the present invention When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • Such acids include, e.g., acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pteric acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid.
  • acetic acid e.g., acetic acid, benzenesulfonic acid, benzoic acid, camphors
  • citric acid Preferably, citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid.
  • formic acid and hydrochloric acid are preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure, especially at least 98% pure (% are on a weight for weight basis).
  • compositions of the present invention comprise a compound of formula I (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable excipient and optionally other therapeutic ingredients or adjuvants.
  • the compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
  • the pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • the compounds or prodrugs or metabolites or pharmaceutically acceptable salts thereof of this invention as the active ingredient can be admixed with a pharmaceutical carrier to form a pharmaceutical composition according to conventional pharmaceutical compounding techniques.
  • a pharmaceutical carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g. oral or parenteral (including intravenous).
  • the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient.
  • compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a water-in-oil liquid emulsion.
  • the compound or a pharmaceutically acceptable salt thereof may also be administered by controlled release means and/or delivery devices.
  • the compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients.
  • the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.
  • compositions of this invention may include a pharmaceutically acceptable carrier and a compound of formula I or a pharmaceutically acceptable salt.
  • the compounds of formula I or pharmaceutically acceptable salts thereof can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
  • the pharmaceutical carrier used in the present invention can be, for example, solid carrier, liquid carrier or gas carrier.
  • Solid carrier includes lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • Liquid carriers include sugar syrup, peanut oil, olive oil, and water.
  • Gas carrier includes carbon dioxide and nitrogen. In preparing the compositions for oral dosage form, any convenient pharmaceutical media may be used.
  • oral liquid formulations such as suspensions, elixirs and solutions
  • carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like
  • oral solid formulations such as powders, capsules and tablets.
  • tablets and capsules are preferred for oral formulations.
  • tablets may be coated by standard aqueous or nonaqueous techniques.
  • a tablet containing the compound or pharmaceutical composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, mixed with a lubricant, inert diluent, surface active or dispersing agent.
  • the powdered compound or pharmaceutical composition is wetted with an inert liquid diluent and then the molded tablets may be made by molding in a suitable machine.
  • Each tablet preferably contains from about 0.05 mg to about 5 g of the active ingredient, each cachet or capsule preferably containing from about 0.05 mg to about 5 g of the active ingredient.
  • a formulation intended for the oral administration to humans may contain from about 0.5 mg to about 5 g of active agent, compounded with an appropriate and convenient amount of supplementary materials which may vary from about 0.05 to about 95 percent of the total composition.
  • Unit dosage forms generally contain from about 1 mg to about 2 g of the active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.
  • compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water.
  • a suitable surfactant can be included, such as, hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils.
  • a preservative can be included in the pharmaceutical composition of the present invention to prevent the detrimental growth of microorganisms.
  • the present invention provides the pharmaceutical compositions suitable for injection, including sterile aqueous solutions or dispersions.
  • the pharmaceutical compositions can be prepared in the form of sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In any cases, the final injectable form must be sterile and must be easily flowable for ease of injection.
  • the pharmaceutical compositions must be stable under the conditions of manufacture and storage. Thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.
  • compositions provided by the present invention can be in a form suitable for topical use, such as, an aerosol, cream, ointment, lotion, dusting powder or other similar formulations. Further, the pharmaceutical compositions provided by the present invention can be in a form suitable for use in transdermal devices. These formulations may be prepared, via conventional processing methods, utilizing the compound of formula (I) of this invention or a pharmaceutically acceptable salt thereof. As an example, a cream or ointment is prepared by admixing hydrophilic material and water, together with about 5 wt % to about 10 wt % of the compound, to produce a cream or ointment having a desired consistency.
  • the pharmaceutical compositions provided by the present invention can be in a form suitable for rectal administration wherein the carrier is a solid.
  • the preferred dosage form is a mixture forming a unit dose of suppository. Suitable ingredients include cocoa butter and other materials commonly used in the art.
  • the suppositories may be conveniently formed by first admixing the pharmaceutical composition with the softened or melted excipients followed by chilling and shaping in molds.
  • the above-mentioned pharmaceutical formulations may also include, as appropriate, one or more additional excipients components, such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • additional excipients components such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • other adjuvants can also include penetration enhancers that regulate the isotonic pressure of the drug and blood.
  • a compound of formula (I) or a pharmaceutical composition including a pharmaceutically acceptable salts thereof may also be prepared in the form of powder or concentrated solution.
  • the dosage level of the drug is approximately 0.01 mg/kg to about 150 mg/kg of body weight per day, or 0.5 mg to 7 g per patient per day.
  • the effective dosage level of the drug for disease and discomforts such as inflammation, cancer, psoriasis, allergy/asthma, disease and discomforts of the immune system, disease and discomforts of the central nervous system (CNS), is 0.01 mg/kg to 50 mg/kg of body weight per day, or 0.5 mg to 3.5 g per patient per day.
  • the compound A1-2 (102.05 g, 0.37 mol) was dissolved in EtOAc (800 mL), and palladium on carbon (6.49 g) was added. The reaction mixture was purged with hydrogen three times, and stirred overnight at room temperature. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to afford the compound A1-3 (99.83 g, 0.36 mol).
  • the B1-2 (5.22 g, 38.07 mmol) and pyridine (15.52 g, 196.21 mmol) were dissolved in DCM (160 mL), and phenyl chloroformate (9.32 g, 59.53 mmol) was added.
  • the reaction mixture was stirred for 1.5 hrs at room temperature, and then filtered to obtain the compound B1 as a solid.
  • the filtrate was concentrated under reduced pressure, and the residue was purified by a silica gel column to afford the purified product.
  • the preparation method of compound E1-1 was according to the synthetic procedure of preparing D1-1 in intermediate D1.
  • the preparation method of compound F1-1 was according to the synthetic procedure of preparing D1-1 in intermediate D1.
  • the compound F1-1(0.30 g, 0.98 mmol) and carbonyl diimidazole (0.24 g, 1.48 mmol) were mixed with DCM (10 mL). The reaction mixture was stirred for 2 hrs at 45° C., and purified by a silica gel column to obtain the compound F1-2 (87 mg, 0.26 mmol).
  • the reaction mixture was stirred for 0.5 h at room temperature, and saturated sodium bicarbonate aqueous solution was added to adjust the pH of the reaction mixture to 8.
  • the solid was precipitated, filtered and washed with H 2 O (3 mL ⁇ 2).
  • the filter cake was dispersed in CH 3 CN (30 mL) and DCM (2 mL), filtered, and washed with acetonitrile (3 mL ⁇ 1) to obtain the compound 1 (695 mg, 1.33 mmol).
  • the compound 71-1 was synthesized according to the synthesis method of compound 1-2 of example 1.
  • the FGFR4 kinase inhibition of compounds was tested by using mobility shift assay in this experiment, and the rate of FGFR4 kinase inhibition of compounds or half inhibitory concentration IC 50 thereof was obtained.
  • the compounds to be tested were prepared to gradient concentration in 100% DMSO, and diluted with buffer solution (the pH of the buffer solution was 7.5, and the buffer solution contained 50 mM HEPES(N-(2-Hydroxyethyl)piperazine-N′-2-sulfonic acid), 0.00015% (ml/ml) Brij-35 (Dodecyl polyethylene glycol ether) and the water) to the reacting solution with 10% DMSO. The reacting solution was added into the 384-well plate.
  • buffer solution the pH of the buffer solution was 7.5, and the buffer solution contained 50 mM HEPES(N-(2-Hydroxyethyl)piperazine-N′-2-sulfonic acid), 0.00015% (ml/ml) Brij-35 (Dodecyl polyethylene glycol ether) and the water
  • 500 ⁇ M would be prepared with 100% DMSO, and diluted in gradient of 10 concentrations, and then diluted 10 times in gradient with buffer solution to prepare an intermediate dilution of the compound containing 10% DMSO. 5 ⁇ l of the intermediate dilution was transferred to 384-well plate;
  • FGFR4 enzyme (Invitrogen, Cat. No PR4380A, Lot. No 1856505A) was diluted with the buffer solution (the pH of the buffer solution was 7.5, and the buffer solution contained 50 mM HEPES, 0.00015% (ml/ml) Brij-35, 2 mM DTT (Dithiothreitol) and the water) to obtain a FGFR enzyme solution with the optimum concentration (the final concentration of the FGFR enzyme solution was 12.5 nM). 10 ⁇ l FGFR enzyme solution was transferred to 384-well plate above mentioned in step (1), and incubated with the compounds to be tested for 10-15 minutes.
  • the substrate (Peptide FAM-P22, GL Biochem, Cat. No. 112393, Lot. No. P180116-MJ112393) was diluted with buffer solution (the pH of the buffer solution was 7.5, and the buffer solution contained 50 mM HEPES, 0.00015% (ml/ml) Brij-35, 10 mM MgCl 2 , adenosine triphosphate 66 ⁇ M under Km and the water) to obtain a substrate solution with the optimum concentration of 10 nM. 10 ⁇ l the substrate solution was added into the 384-well plate above mentioned in step (2) to start the reaction, and the reaction was undergoing at 28° C. for 1 hour;
  • the reference compound in the present invention has the following structure
  • the MTS method was used to test the inhibitory effect of the compounds on the proliferation of Hepatoma cell Hep3B (high expression of FGFR4 and FGF19), and the half inhibitory concentration IC 50 of the compounds to Hep3B was obtained.
  • the Hep3B cell line was purchased from ATCC, and the complete culture medium of the Hep3B cell line was MEM+10% FBS+1% PS.
  • MEM cell culture medium, fetal bovine serum, and trypsin were purchased from Gibco
  • cell culture flasks were purchased from Greiner
  • disposable Cell Counting Plate and Taittinger Blue Solution were purchased from Bio-Rad.
  • the pharmacokinetics experiment of the compounds in rats was performed using the SD rats (Vitolihua).
  • Mode of administration single gavage administration and intravenous injection administration.
  • the mobile phase A 5% acetonitrile and 95% water (0.1% FA (formic acid));
  • the mobile phase B 95% acetonitrile and 5% water (0.1% FA);
  • Injection volume 5 ⁇ L
  • phase A (%) phase B (%) 0.00 95.0 5.00 0.20 95.0 5.00 1.00 0.00 100 2.20 0.00 100 2.21 95.0 5.00 4.00 95.0 5.00
  • the mobile phase A 5% acetonitrile and 95% water (0.1% FA);
  • the mobile phase B 95% acetonitrile and 5% water (0.1% FA);
  • Injection volume 3 ⁇ L
  • phase B (%) 0.00 95.0 5.00 0.15 95.0 5.00 1.50 0.00 100 2.50 0.00 100 2.60 95.0 5.00 3.80 95.0 5.00
  • the mobile phase A 5% acetonitrile and 95% water (0.1% FA);
  • the mobile phase B 95% acetonitrile and 5% water (0.1% FA);
  • Injection volume 10 ⁇ L
  • phase A (%) phase B (%) 0.00 95.0 5.00 0.15 95.0 5.00 1.50 0.00 100 2.50 0.00 100 2.60 95.0 5.00 3.80 95.0 5.00
  • Chromatographic column Xselect HSS T3 2.5 m (2.1 ⁇ 50 mm)(the chromatographic column using for compound 4, compound 5, compound 20, compound 56, compound 71); Phenomenex Kinetex 5 ⁇ m C 18 100A (2.1 ⁇ 50 mm)(the chromatographic column using for reference compound);
  • the mobile phase A 5% acetonitrile and 95% water (0.1% FA);
  • the mobile phase B 95% acetonitrile and 5% water (0.1% FA);
  • Injection volume 2 ⁇ L
  • phase B (%) 0.00 95.0 5.00 0.30 95.0 5.00 1.80 5.00 95.0 2.50 5.00 95.0 2.51 95.0 5.00 3.00 95.0 5.00
  • p.o. refers to oral administration.
  • This experiment conducted when the pharmacological experiment in vivo was performed by gavage administration, wherein, the blood samples and tumor samples were taken at different time points to detect drug concentration in blood and drug concentrations in tumors.
  • Sampling time point of blood samples the sampling point of compound 4 and reference compound were before administration, at 1 h, 2 h, 4 h, 6 h. Three mice were sampled at each sampling point; Sampling time point of tumor samples: the sampling point of compound 4 and reference compound were at 4 h, 6 h. Three mice were sampled at each sampling point;
  • Tumour sample collection 200-300 mg of each tumor tissue was taken. The tumor weight was marked, quickly freezed in liquid nitrogen and placed into a refrigerator at ⁇ 80° C. for waiting for testing.
  • Tumour sample processing pure water was added into the tumor sample according to a ratio of 1 mg:3 mL between the weight of the tumor sample and the volume of pure water and then it was homogenized.
  • the mobile phase A 5% acetonitrile and 95% water (0.1% FA);
  • the mobile phase B 95% acetonitrile and 5% water (0.1% FA);
  • Injection volume 2 ⁇ L
  • phase B (%) 0.00 95.0 5.00 0.30 95.0 5.00 1.80 5.00 95.0 2.50 5.00 95.0 2.51 95.0 5.00 3.00 95.0 5.00
  • Q1, Q3, DP, EP, CE and CXP in the table respectively refer that Q1: parent ion; Q3: product ion; DP: declustering voltage; EP: inlet voltage; CE: collision energy; CXP: collision cell outlet voltage.
  • p.o. refers to oral administration.
  • the Hep3B cell line was purchased from ATCC; MEM cell culture medium, fetal bovine serum, and trypsin were purchased from Gibco; cell culture flasks were purchased from Greiner; and disposable Cell Counting Plate and taittinger Blue Solution Purchased from Bio-Rad.
  • the disposable sterile syringe was purchased from Changzhou Jinlong Medical Plastic Instrument Co., Ltd, eye surgical scissors and eye surgical forceps were purchased from Shanghai Medical Instrument (Group) Co., Ltd. Surgical Instrument Factory, and 6-8 week old female NOD-SCID mice were purchased from Vitalivar.
  • the cultured cells were collected and counted using a BIO-Rad TC20 cell counter. According to the counting results, the cultured cells were resuspended with PBS and matrix gel (1:1) to obtain a cell suspension (density 5 ⁇ 10 7 /ml), and the cell suspension was placed in an ice box for later use.
  • the cells were mixed well before seeding, and 0.5 ml of cell suspension was taken with a 1 ml syringe and bubbles in the cell suspension were removed. The syringe with the cell suspension was place on an ice pack for later use.
  • NOD-SCID mice were set with the left hand, and the skin on the right back of the mice was disinfected with 75% alcohol. The inoculation was beginning after 30 seconds.
  • the tumor was measured and the tumor size was calculated on the 12-15 days after inoculation.
  • tumor volume (mm 3 ) length (mm) ⁇ width (mm) ⁇ width (mm)/2
  • mice When the tumors grew to an average volume of 100-150 mm 3 , the mice were randomly divided into two groups according to tumor size and the weight of the mouse. There were 9 mice in either group, and one was the control group and the other was the treatment group.
  • the method of administration was gavage, and the control group was administered with 10% DMSO+90% ddH 2 O and the treatment group was respectively administered with the compound 4 at a dosage of 15/30/60 mg/kg once a day, the compound 4 at a dosage of 15 mg/kg twice a day, and the reference compound at a dosage of 60 mg/kg once a day.
  • the solvent of the compound 4 was 10% DMSO+90% ddH 2 O, and the solvent of the reference compound was 100% ddH 2 O. Tumors were measured and the mice were weighed twice a week after administration.
  • the experiment was finished until the tumor volume of the control group was about 1500 mm 3 .
  • TGI Tumor growth inhibition
  • the compound 4 of the present invention has an excellent antitumor effect, and the effect of 15 mg/kg BID of the compound 4 is equivalent to the effect of 60 mg/kg QD of the reference compound in the Hep3B model.
  • the compound 4 achieved the same efficacy compared with the reference compound although the dose of the compound 4 was reduced by half, Therefore, the toxic side effects is fewer and the safety is higher.

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