WO2018072707A1 - Dérivé d'éther aromatique, son procédé de préparation, et ses applications médicales - Google Patents

Dérivé d'éther aromatique, son procédé de préparation, et ses applications médicales Download PDF

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WO2018072707A1
WO2018072707A1 PCT/CN2017/106667 CN2017106667W WO2018072707A1 WO 2018072707 A1 WO2018072707 A1 WO 2018072707A1 CN 2017106667 W CN2017106667 W CN 2017106667W WO 2018072707 A1 WO2018072707 A1 WO 2018072707A1
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alkyl
methyl
compound
group
mmol
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PCT/CN2017/106667
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Chinese (zh)
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邵宁
袁宏斌
王丁
周莹
江立群
张伟
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保诺科技（北京）有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • 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

Definitions

  • the present invention relates to a novel aromatic ether derivative or a pharmaceutically acceptable salt, tautomer, racemate, enantiomer, diastereomer, prodrug, hydrate thereof Or a solvate, and mixtures thereof, or a pharmaceutical composition containing the same, and a process for the preparation thereof.
  • the present invention also relates to a method for treating and/or preventing a FGFR4 tyrosine kinase-mediated disease using the aromatic ether derivative, and the preparation of the FGFR4 tyrosine kinase inhibitor and the medicament by the aromatic ether derivative Use in.
  • Fibroblast growth factor is a polypeptide secreted by the pituitary and hypothalamus. It promotes mitosis of fibroblasts, growth of mesoderm cells, stimulates angiogenesis, and plays an important role in wound healing and limb regeneration.
  • the FGF receptor (FGFR) signaling system is critical for normal development and physiological processes.
  • FGFR has four subtypes of FGFR1-4, and the amino acid sequences of these four subtypes are highly conserved.
  • FGFR1-4 has different binding forces for different growth factors, and its distribution in tissues is also different.
  • a complete FGFR receptor protein includes an extracellular portion, a hydrophobic single-stranded cell membrane portion, and an intracellular tyrosine kinase portion.
  • FGFR4 is a protein encoded by the FGFR-4 gene.
  • the FGFR4 gene has 18 exons.
  • FGF-FGFR signal imbalance is associated with tumorigenesis and evolution. It has been found that in mice, the FGFR4–FGF19 signal axis is closely related to hepatocellular carcinoma (HCCs). In several types of cancers such as liver cancer, FGFR4 expression is significantly increased. At the same time, the occurrence of liver cancer requires FGFR4.
  • the progeny of FGF19 transgenic mice can develop into liver cancer, however, the offspring proliferated with FGFR4 knockout mice do not develop into liver cancer.
  • FGF19 is neutralized by FGF19-specific antibodies, tumor growth is inhibited.
  • FGFR4 overexpression also occurs in other types of tumors, including breast cancer, colorectal cancer, pancreatic cancer, prostate cancer, lung cancer, and thyroid cancer.
  • FGFR4 mutations occur in rhabdomyosarcoma. Small score for FGFR4 Sub-targeted inhibition can be used in the treatment of cancer.
  • mice were treated with FGFR-1 inhibitors they were found to cause side effects such as calcium phosphate deposition in soft tissues (Brown, AP et al. (2005), Toxicol. Pathol., p. 449-455). These indicate that selective inhibition of the FGFR4 receptor, rather than extensive inhibition of the FGFR1-4 receptor, would avoid such side effects.
  • the present invention provides a compound of the formula (I) or a pharmaceutically acceptable salt, tautomer, racemate, enantiomer or diastereomer thereof , prodrugs, hydrates or solvates, and mixtures thereof:
  • W is selected from CR 1 or N;
  • Ring A is selected from a 6-14 membered arylene group, a 5-10 membered heteroarylene group, a C 3 -C 8 cycloalkylene group or a 3-10 membered heterocyclylene group;
  • R 1 and R 2 are independently selected from H, halogen, cyano, NO 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 olefin , C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, -OR 8 , -NR 6 R 7 , -C(O)R 8 , -C(O)OR 8 , -C(O) NR 6 R 7 , -NR 6 C(O)R 8 , -NR 6 C(O)OR 8 , -NR 6 C(O)NR 6 R 7 , -OC(O)R 8 , -OC(O) OR 8 , -OC(O)NR 6 R 7 , -S(O) p R 8 , -S(O) p OR 8 , -S(O) p NR 6 R 7 ,
  • L is selected from -C 1 -C 6 alkylene-, -C 2 -C 6 alkenylene-, -C 2 -C 6 alkynylene-, -OC 1 -C 6 alkylene-, -C 1 -C 6 alkylene-O-, -NR 6 C(O)-, -C(O)NR 6 -, -OC(O)-, -C(O)O-, -NR 6 -C 1 - C 6 alkylene- or -C 1 -C 6 alkylene-NR 6 -;
  • X is selected from -O-, -NH- or -CH 2 -;
  • Y is selected from -C(O)-, -S(O) p - or -CH 2 -;
  • Y may also be -NH- or -O-;
  • R 3 , R 4 and R 5 are each independently selected from H, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 3 -C 8 a cycloalkyl group or a 3-10 membered heterocyclic group;
  • R 3 and R 4 may form a chemical bond
  • R 6 , R 7 and R 8 are each independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, 3-10 membered heterocyclyl, 5 -10 membered heteroaryl or 6-14 membered aryl;
  • n 0, 1, 2, 3 or 4;
  • n 0, 1, 2, 3, 4 or 5;
  • p 1 or 2.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt, tautomer, racemate, enantiomer, diastereomer thereof , prodrugs, hydrates or solvates, and mixtures thereof, and pharmaceutically acceptable excipients.
  • a compound of the invention is provided in the pharmaceutical composition in an effective amount.
  • the compounds of the invention are provided in a therapeutically effective amount.
  • the compounds of the invention are provided in a prophylactically effective amount.
  • the pharmaceutical compositions of the invention also contain other therapeutic agents.
  • the invention provides a kit comprising: a first container comprising a compound of the invention or a pharmaceutically acceptable salt, tautomer, racemate, enantiomer thereof a diastereomer, a prodrug, a hydrate or a solvate, and mixtures thereof; and, optionally, a second container containing other therapeutic agents; and optionally, a third container containing A pharmaceutically acceptable excipient that dilutes or suspends the compound and/or other therapeutic agent.
  • the invention provides a compound of the invention, or a pharmaceutically acceptable salt, tautomer, racemate, enantiomer, diastereomer, prodrug, hydrate thereof, or a pharmaceutically acceptable salt thereof Or a solvate, and mixtures thereof, or the use of a pharmaceutical composition of the invention in the preparation of a FGFR4 tyrosine kinase inhibitor.
  • the invention provides a compound of the invention, or a pharmaceutically acceptable salt, tautomer, racemate, enantiomer, diastereomer, prodrug, hydrate thereof, or a pharmaceutically acceptable salt thereof Or a solvate, and mixtures thereof, or a pharmaceutical composition of the invention, for use in the manufacture and/or prevention of FGFR4 tyrosine Use in drugs for kinase-mediated diseases.
  • the invention provides a compound of the invention, or a pharmaceutically acceptable salt, tautomer, racemate, enantiomer, diastereomer, prodrug, hydrate thereof, or a pharmaceutically acceptable salt thereof Or a solvate, and mixtures thereof, or a pharmaceutical composition of the invention for use in the treatment and/or prevention of a FGFR4 tyrosine kinase mediated disease.
  • the invention provides a method of treating and/or preventing a FGFR4 tyrosine kinase mediated disease in a subject, comprising administering to the subject a compound of the invention or Pharmaceutically acceptable salts, tautomers, racemates, enantiomers, diastereomers, prodrugs, hydrates or solvates, and mixtures thereof, or pharmaceutical compositions of the invention .
  • the disease is a tumor, such as gastric cancer, thyroid cancer, prostate cancer, breast cancer, sarcoma (such as rhabdomyosarcoma), skin cancer (such as melanoma), liver cancer (such as hepatocellular carcinoma and bile duct).
  • Epithelial cancer eg, pancreatic intraepithelial neoplasia and pancreatic ductal adenocarcinoma
  • lung cancer eg, non-small cell lung cancer and lung adenocarcinoma
  • renal cancer eg, renal cell carcinoma
  • colorectal cancer ovarian cancer.
  • C 1 -C 6 alkyl includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1 -C 6 , C 1 -C 5 , C 1 -C 4 , C 1 - C 3 , C 1 -C 2 , C 2 -C 6 , C 2 -C 5 , C 2 -C 4 , C 2 -C 3 , C 3 -C 6 , C 3 -C 5 , C 3 -C 4 C 4 -C 6 , C 4 -C 5 and C 5 -C 6 alkyl.
  • C 1 -C 6 alkyl group means a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms, which is also referred to as "lower alkyl group”. In some embodiments, a C 1 -C 4 alkyl group is particularly preferred.
  • alkenyl group examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, 1,1-di Methylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1 -ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 1,3-dimethylbutyl, 2-ethylbutyl, and various branched isomers thereof.
  • the alkyl group can be optionally substituted or unsubstituted.
  • C 2 -C 6 alkenyl refers to a straight or branched chain hydrocarbon radical having from 2 to 6 carbon atoms and one or more carbon-carbon double bonds (eg, 1, 2 or 3 carbon-carbon double bonds) group.
  • One or more carbon-carbon double bonds may be internal (eg, in 2-butenyl) or end (eg, in 1-butenyl).
  • C 2 -C 4 alkenyl is particularly preferred.
  • alkenyl group examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, butadienyl, pentenyl, pentadienyl, Hexenyl, its various branched isomers, and the like.
  • the alkenyl group can be optionally substituted or unsubstituted.
  • C 2 -C 6 alkynyl means having from 2 to 6 carbon atoms, one or more carbon-carbon triple bonds (eg, 1, 2 or 3 carbon-carbon triple bonds), and optionally one or more A linear or branched hydrocarbon group of a carbon-carbon double bond (for example, 1, 2 or 3 carbon-carbon double bonds).
  • a C 2 -C 4 alkynyl group is particularly preferred.
  • an alkynyl group does not contain any double bonds.
  • the one or more carbon oxime bonds may be internal (eg, in 2-butynyl) or end (eg, in 1-butynyl).
  • alkynyl group examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, pentynyl, hexynyl, and various Branched isomers, etc.
  • An alkynyl group can be optionally substituted or unsubstituted.
  • C 1 -C 6 heteroalkyl refers to an alkyl group, as defined herein, which further contains one or more (eg, 1, 2, 3 or 4) heteroatoms (eg, oxygen, in the parent chain). Sulfur, nitrogen, boron, silicon, phosphorus), wherein one or more heteroatoms are between adjacent carbon atoms in the parent carbon chain, and/or one or more heteroatoms are in the carbon atom and the parent molecule Between, that is, between the connection points. Heteroalkyl groups can be optionally substituted or unsubstituted.
  • the C 1 -C 6 heteroalkyl group includes a C 1 -C 6 alkoxy group, a C 1 -C 6 alkylthio group, a C 1 -C 6 alkylamino group, and the like, which are defined in detail as follows .
  • C 1 -C 6 alkoxy refers to the group -OR wherein R is a substituted or unsubstituted C 1 -C 6 alkyl group. In some embodiments, a C 1 -C 4 alkoxy group is particularly preferred. Specific alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentyloxy, n-Hexyloxy and 1,2-dimethylbutoxy, and various branched isomers thereof and the like. The alkoxy group can be optionally substituted or unsubstituted.
  • C 1 -C 6 alkylthio refers to the group -SR wherein R is optionally substituted C 1 -C 6 alkyl.
  • a C 1 -C 4 alkylthio group is particularly preferred.
  • the C 1 -C 6 alkylthio group includes, but is not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, tert-butylthio, sec-butylthio, N-pentylthio, n-hexylthio and 1,2-dimethylbutylthio, and various branched isomers thereof.
  • the alkylthio group can be optionally substituted or unsubstituted.
  • C 1 -C 6 alkylamino refers to the group -NHR or -NR 2 wherein R is optionally substituted C 1 -C 6 alkyl.
  • a C 1 -C 4 alkylamino group is particularly preferred.
  • the C 1 -C 6 alkylamino group includes, but is not limited to, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, t-butylamino, dimethylamino, methylethylamino and diethylamino, and Its various branched isomers and the like.
  • the alkylamino group can be optionally substituted or unsubstituted.
  • Halogen means fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).
  • C 1 -C 6 haloalkyl and “C 1 -C 6 haloalkoxy” mean the above-mentioned "C 1 -C 6 alkyl” and "C 1 -C 6 alkoxy", which are one or more Halogen group substitution.
  • a C 1 -C 4 haloalkyl group is particularly preferred, more preferably a C 1 -C 2 haloalkyl group.
  • a C 1 -C 4 haloalkoxy group is particularly preferred, more preferably a C 1 -C 2 haloalkoxy group.
  • haloalkyl groups include, but the are not limited to: -CF 3, -CH 2 F, -CHF 2, -CHFCH 2 F, -CH 2 CHF 2, -CF 2 CF 3, -CCl 3, -CH 2 Cl , -CHCl 2 , 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like.
  • exemplary haloalkoxy groups include, but are not limited to, -OCH 2 F, -OCHF 2 , -OCF 3, and the like.
  • the haloalkyl and haloalkoxy groups can be optionally substituted or unsubstituted.
  • C 3 -C 8 cycloalkyl refers to a non-aromatic cyclic hydrocarbon group having from 3 to 8 ring carbon atoms and zero heteroatoms. In some embodiments, a C 3 -C 6 cycloalkyl group is particularly preferred, more preferably a C 5 -C 6 cycloalkyl group.
  • Cycloalkyl also includes ring systems wherein the cycloalkyl group is fused, bridged or spirocyclic to one or more cycloalkyl, heterocyclyl, aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring And in such cases, the number of carbons continues to indicate the number of carbons in the cycloalkyl system.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexane Alkenyl, cycloheptyl, cycloheptenyl, cycloheptadienyl, cycloheptatrienyl, cyclooctyl, cyclooctenyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2] Octyl, its various branched isomers, and the like.
  • the cycloalkyl group can be optionally substituted or unsubstituted.
  • heterocyclic group or a group of a 3 to 10 membered non-aromatic ring system having a ring carbon atom and 1 to 4 ring hetero atoms, wherein each hetero atom is independently selected from nitrogen and oxygen. , sulfur, boron, phosphorus and silicon.
  • the point of attachment may be a carbon or nitrogen atom as long as the valence permits.
  • a 3-8 membered heterocyclyl is preferred, which is a 3 to 8 membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms; in some embodiments, 4-7 A heterocyclic group is particularly preferred, which is a 4- to 7-membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring hetero atoms; more preferably a 5-6 membered heterocyclic group having a ring carbon atom and A 5- to 6-membered non-aromatic ring system of 1 to 3 ring heteroatoms.
  • Exemplary 3-membered heterocyclic groups containing one hetero atom include, but are not limited to, aziridine, oxacyclopropane, thicyclopropyl.
  • An exemplary 4 element containing a hetero atom Heterocyclyl groups include, but are not limited to, azetidinyl, oxetane and thietane.
  • Exemplary 5-membered heterocyclic groups containing one hetero atom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2, 5-dione.
  • Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolyl, oxathiolan, dithiolane, and oxazolidin-2-one .
  • Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 6-membered heterocyclic groups containing one hetero atom include, but are not limited to, piperidinyl, dihydropyranyl, tetrahydropyranyl, dihydropyridyl and thiacyclohexane.
  • Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, dioxoalkyl.
  • Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, hexahydrotriazinyl.
  • Exemplary 7-membered heterocyclic groups containing one hetero atom include, but are not limited to, azepanyl, oxaheptyl, and thiaheptanyl.
  • Exemplary 8-membered heterocyclic groups containing one hetero atom include, but are not limited to, azacyclooctyl, oxacyclooctyl, and thicyclooctyl.
  • Exemplary 5-membered heterocyclic groups (also referred to herein as 5,6-bicyclic heterocyclyl) fused to a 6-membered aryl ring include, but are not limited to, indanyl, isoindoline , dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinone, and the like.
  • Exemplary 6-membered heterocyclic groups fused to a 6-membered aryl ring include, but are not limited to, tetrahydroquinolyl, tetrahydroisoquinolinyl, and many more.
  • the heterocyclic group includes a spiro ring, a fused ring, and a heterocyclic group of a bridged ring.
  • “Spiroheterocyclyl” means a polycyclic heterocyclic group of 5 to 20 members in which one atom (referred to as a spiro atom) is shared between monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m
  • the hetero atom (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings are aromatic. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spirocycloalkyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspirocyclic group according to the number of common spiro atoms between the ring and the ring, and is preferably a monospirocycloalkyl group and a bispirocycloalkyl group. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6-membered monospirocycloalkyl group.
  • Non-limiting examples of spirocycloalkyl groups include:
  • “Fused heterocyclyl” refers to 5 to 20 members, each ring of the system sharing an adjacent pair of atoms of a polycyclic heterocyclic group with other rings in the system, and one or more rings may contain one or more A bond, but none of the rings are aromatic in which one or more ring atoms are selected from the group consisting of nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • fused heterocyclic groups include:
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heterocyclic group, non-limiting examples include:
  • the heterocyclic group may be optionally substituted or unsubstituted.
  • 6-14 membered aryl refers to a monocyclic or polycyclic (eg, bicyclic or tricyclic) 4n+2 aromatic ring system having 6 to 14 ring carbon atoms and zero heteroatoms (eg, having A group of 6, 10 or 14 ⁇ electrons shared in a ring.
  • an aryl group has six ring carbon atoms ("6-membered aryl”; for example, phenyl).
  • an aryl group has ten ring carbon atoms ("10 membered aryl”; for example, naphthyl, for example, 1-naphthyl and 2-naphthyl).
  • an aryl group has fourteen ring carbon atoms ("14-membered aryl"; for example, fluorenyl).
  • 14-membered aryl for example, fluorenyl
  • a 6-10 membered aryl group is particularly preferred, more preferably a 6 membered aryl group.
  • the aryl group may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples include:
  • the aryl group can be substituted or unsubstituted.
  • 5-10 membered heteroaryl means a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms (eg, having a ring-like arrangement) a group of 6 or 10 ⁇ electrons, wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen and sulfur.
  • a heteroaryl group containing one or more nitrogen atoms the point of attachment may be a carbon or nitrogen atom as long as the valence permits.
  • a 5-6 membered heteroaryl group is particularly preferred, which is a 5-6 membered monocyclic 4n+2 aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms.
  • Exemplary 5-membered heteroaryl groups containing one hetero atom include, but are not limited to, pyrrolyl, furyl and thienyl.
  • Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Example sexual 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl.
  • Exemplary 6-membered heteroaryl groups containing one hetero atom include, but are not limited to, pyridyl.
  • Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively.
  • Exemplary 7-membered heteroaryl groups containing one hetero atom include, but are not limited to, azepandinyl, oxepanethylene, and thiephenylene.
  • Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, mercapto, isodecyl, oxazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl , benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzooxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, Pyridazinyl and fluorenyl.
  • Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, acridinyl, quinolyl, isoquinolinyl, fluorenyl, quinoxalinyl, pyridazinyl and quinazolinyl .
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples include:
  • the heteroaryl group can be optionally substituted or unsubstituted.
  • alkylene alkenylene, alkynylene, arylene, “heteroarylene”, “cycloalkylene” and “heterocyclylene” refer to It is a divalent group of the above alkyl group, alkenyl group, alkynyl group, aryl group, heteroaryl group, cycloalkyl group and heterocyclic group. The group may be optionally substituted or unsubstituted.
  • C 1 -C 6 alkylene group means a divalent alkylene group formed by removing one hydrogen of a C 1 -C 6 alkyl group, and may be a substituted or unsubstituted alkylene group. In some embodiments, a C 1 -C 4 alkylene group is particularly preferred.
  • the unsubstituted alkylene group includes, but is not limited to, methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), arylene (-CH 2 CH 2 CH 2 CH 2 -), pentylene (-CH 2 CH 2 CH 2 CH 2 CH 2 -), hexylene (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -) ,and many more.
  • alkylene groups substituted with one or more alkyl groups (methyl groups) include, but are not limited to, substituted methylene groups (-CH(CH 3 )- , -C(CH 3 ) 2 -), substituted ethylene (-CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, -C(CH 3 ) 2 CH 2 -, -CH 2 C(CH 3 ) 2- ), substituted propylene (-CH(CH 3 )CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, -CH 2 CH 2 CH(CH 3 ) -, -C(CH 3 ) 2 CH 2 CH 2 -, -CH 2 C(CH 3 ) 2 CH 2 -, -CH 2 CH 2 C(CH 3 ) 2 -), and the like.
  • substituted methylene groups -CH(CH 3 )- , -C(CH 3 ) 2 -
  • substituted ethylene -CH(CH
  • C 2 -C 6 alkenylene group means a divalent alkenylene group formed by removing one hydrogen of a C 2 -C 6 alkenyl group, and may be a substituted or unsubstituted alkenylene group. In some embodiments, C 2 -C 4 alkenylene is particularly preferred.
  • C 2 -C 6 alkynylene group means a divalent alkynylene group formed by removing one hydrogen of a C 2 -C 6 alkynyl group, and may be a substituted or unsubstituted alkynylene group. In some embodiments, a C 2 -C 4 alkynylene group is particularly preferred. Exemplary such alkynylene groups include, but are not limited to, ethynylene (-C ⁇ C-), substituted or unsubstituted propynylene (-C ⁇ CCH 2 -), and the like.
  • 6-14 membered arylene means the removal of the above 6 a divalent group formed by a hydrogen of a 14-membered aryl group, a 5-10 membered heteroaryl group, a C 3 -C 8 cycloalkyl group, and a 3-10 membered heterocyclic group.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group.
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • Each of R aa is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R aa groups are bonded to form a heterocyclic group or a heteroaryl ring wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently 0, 1, 2, 3, 4 or 5 R dd groups Substitute
  • Each of R cc is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R cc groups are bonded to form a heterocyclic ring a hetero or heteroaryl ring wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently 0, 1, 2, 3, 4 or 5 R Substituting dd group;
  • Each of R ee is independently selected from the group consisting of alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, ring
  • An alkyl group, a heterocyclic group, an aryl group and a heteroaryl group are independently substituted by 0, 1, 2, 3, 4 or 5 R gg groups;
  • Each of R ff is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R ff groups are bonded to form a heterocyclic group Or a heteroaryl ring wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently 0, 1, 2, 3, 4 or 5 R gg Group substitution
  • pharmaceutically acceptable salt means that, within the scope of sound medical judgment, it is suitable for contact with tissues of humans and lower animals without excessive toxicity, irritation, allergies, etc., and with reasonable benefits/risk ratios. Proportionate of those salts.
  • Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts as described in detail by Berge et al., J. Pharmaceutical Sciences (1977) 66: 1-19.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and inorganic and organic bases.
  • non-toxic acid addition salts examples include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or salts with organic acids such as acetic acid, oxalic acid, Maleic acid, tartaric acid, citric acid, succinic acid or malonic acid. Also included are salts formed using conventional methods in the art, for example, ion exchange methods.
  • adipic acid salts alginate, ascorbate, aspartate, besylate, benzoate, disulfate, borate, butyrate, camphoric acid Salt, camphor sulfonate, citrate, cyclopentanoate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, gluconate, glycerophosphate Salt, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, Malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate , pectic acid ester
  • Pharmaceutically acceptable salts derived from suitable bases include the alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium salts, and the like.
  • other pharmaceutically acceptable salts include non-toxic ammonium salts, quaternary ammonium salts and amine cations formed with counterions, counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitric acid Root, lower alkyl sulfonate and aryl sulfonate.
  • Subjects for administration include, but are not limited to, humans (ie, males or females of any age group, eg, pediatric subjects (eg, infants, children, adolescents) or adult subjects (eg, young Adults, middle-aged adults or older adults) and/or non-human animals, for example, mammals, for example, primates (eg, cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep , goats, rodents, cats and/or dogs.
  • the subject is a human.
  • the subject is a non-human animal.
  • treatment includes the effect of a subject having a particular disease, disorder, or condition that reduces the severity of the disease, disorder, or condition, or delays or slows the disease, disorder. Or the development of a condition ("therapeutic treatment"), which also includes the effect that occurs before the subject begins to have a particular disease, disorder or condition (“prophylactic treatment").
  • an "effective amount" of a compound refers to an amount sufficient to cause a target biological response.
  • an effective amount of a compound of the invention can vary depending on, for example, the biological target, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the subject's Age health conditions and symptoms. Effective amounts include therapeutically effective amounts and prophylactically effective amounts.
  • a "therapeutically effective amount" of a compound as used herein is an amount sufficient to provide a therapeutic benefit in the course of treating a disease, disorder or condition, or one or more symptoms associated with a disease, disorder or condition. The amount of delay or minimization.
  • a therapeutically effective amount of a compound refers to the amount of a therapeutic agent that, when used alone or in combination with other therapies, provides a therapeutic benefit in the treatment of a disease, disorder or condition.
  • the term "therapeutically effective amount” can include an amount that improves overall treatment, reduces or avoids the symptoms or causes of the disease or condition, or enhances the therapeutic effect of other therapeutic agents.
  • a “prophylactically effective amount” of a compound is an amount sufficient to prevent a disease, disorder or condition, or an amount sufficient to prevent one or more symptoms associated with a disease, disorder or condition, or to prevent disease, unless otherwise stated. The amount of recurrence of a disorder or condition.
  • a prophylactically effective amount of a compound refers to the amount of a therapeutic agent that, when used alone or in combination with other agents, provides a prophylactic benefit in the prevention of a disease, disorder or condition.
  • the term “prophylactically effective amount” can include an amount that improves the overall prevention, or an amount that enhances the prophylactic effect of other prophylactic agents.
  • Combination and related terms mean the simultaneous or sequential administration of a compound of the invention and other therapeutic agents.
  • a compound of the invention may be administered simultaneously or sequentially with other therapeutic agents in separate unit dosage forms. Or concurrently with other therapeutic agents in a single unit dosage form.
  • Prodrug means a compound that is converted in vivo to an active form thereof having a medical effect by, for example, hydrolysis in blood.
  • Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, ACSSymposium Series, Vol. 14, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon, and H. Barbra "Improved oral drug delivery: Solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19(2) 115-130, each This article is incorporated herein by reference.
  • a prodrug is any covalently bonded carrier which, when administered to a patient, releases the compound of the invention in vivo.
  • Prodrugs are typically prepared by modifying functional groups that cleave the prodrug in vivo to yield the parent compound.
  • Prodrugs include, for example, a compound of the invention wherein a hydroxy, amino or thiol group is bonded to any group which, when administered to a patient, can be cleaved to form a hydroxy, amino or thiol group.
  • representative examples of prodrugs include, but are not limited to, covalent derivatives of the compounds of the invention formed by the hydroxyl, amino or thiol functional groups thereof with acetic acid, formic acid or benzoic acid.
  • an ester such as a methyl ester, an ethyl ester or the like can be used.
  • the ester itself may be active and/or may hydrolyze under conditions in humans.
  • Suitable pharmaceutically acceptable in vivo hydrolysable esters include those which readily decompose in the human body to release the parent acid or its salt.
  • the compounds of the invention may include one or more asymmetric centers, and thus may exist in a variety of stereoisomeric forms, for example, enantiomers, diastereomers, and racemate forms.
  • the compounds of the invention may be in the form of individual enantiomers, diastereomers or geometric isomers (e.g., cis and trans isomers), or may be in the form of a mixture of stereoisomers, A racemic mixture and a mixture rich in one or more stereoisomers are included.
  • the isomers can be separated from the mixture by methods known to those skilled in the art, including: chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of a chiral salt; or preferred isomers can be passed Prepared by asymmetric synthesis.
  • HPLC high pressure liquid chromatography
  • the compounds of the invention may also exist as "tautomers".
  • “Tautomer” means that the structure of an organic compound is produced by the phenomenon of equilibrium conversion between two functional groups. Isomers.
  • the present invention provides a compound of the formula (I) or a pharmaceutically acceptable salt, tautomer, racemate, enantiomer, diastereomer thereof, or a diastereomer thereof Constructs, prodrugs, hydrates or solvates, and mixtures thereof:
  • W is selected from CR 1 or N;
  • Ring A is selected from a 6-14 membered arylene group, a 5-10 membered heteroarylene group, a C 3 -C 8 cycloalkylene group or a 3-10 membered heterocyclylene group;
  • R 1 and R 2 are independently selected from H, halogen, cyano, NO 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 olefin , C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, -OR 8 , -NR 6 R 7 , -C(O)R 8 , -C(O)OR 8 , -C(O) NR 6 R 7 , -NR 6 C(O)R 8 , -NR 6 C(O)OR 8 , -NR 6 C(O)NR 6 R 7 , -OC(O)R 8 , -OC(O) OR 8 , -OC(O)NR 6 R 7 , -S(O) p R 8 , -S(O) p OR 8 , -S(O) p NR 6 R 7 ,
  • L is selected from -C 1 -C 6 alkylene-, -C 2 -C 6 alkenylene-, -C 2 -C 6 alkynylene-, -OC 1 -C 6 alkylene-, -C 1 -C 6 alkylene-O-, -NR 6 C(O)-, -C(O)NR 6 -, -OC(O)-, -C(O)O-, -NR 6 -C 1 - C 6 alkylene- or -C 1 -C 6 alkylene-NR 6 -;
  • X is selected from -O-, -NH- or -CH 2 -;
  • Y is selected from -C(O)-, -S(O) p - or -CH 2 -;
  • Y may also be -NH- or -O-;
  • R 3 , R 4 and R 5 are each independently selected from H, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 3 -C 8 a cycloalkyl group or a 3-10 membered heterocyclic group;
  • R 3 and R 4 may form a chemical bond
  • R 6 , R 7 and R 8 are each independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, 3-10 membered heterocyclyl, 5 -10 membered heteroaryl or 6-14 membered aryl;
  • n 0, 1, 2, 3 or 4;
  • n 0, 1, 2, 3, 4 or 5;
  • p 1 or 2.
  • W is CR 1 ; preferably, W is CH; preferably, W is CF. In another embodiment, W is N.
  • Ring A is a 6-14 membered arylene; preferably, Ring A is a 6-10 membered arylene; preferably, Ring A is a phenylene group.
  • Ring A is a 5-10 membered heteroarylene; preferably, Ring A is a 5-6 membered heteroarylene; preferably, Ring A is a 6 membered heteroarylene.
  • Ring A is a C 3 -C 8 cycloalkylene group; preferably, Ring A is a C 3 -C 6 cycloalkylene group; preferably, Ring A is a C 5 -C 6 hypocycloalkane base.
  • Ring A is a 3-10 membered heterocyclylene; preferably, Ring A is a 4-7 membered heterocyclylene; preferably, Ring A is a 5-6 membered heterocyclylene.
  • ring A is among them
  • E 1 , E 2 , E 3 and E 4 are each independently selected from CR 1 or N;
  • E 5 , E 6 , E 7 and E 8 are each independently selected from O, S, C(R 1 ) 2 or NR 1 .
  • ring A is selected from the group consisting of
  • R 1 is selected from the group consisting of H, halogen, cyano, NO 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy or -OR 8 ;
  • R 8 is selected from H or C 1 -C 6 alkyl
  • n 0, 1, 2 or 3.
  • R 1 is independently selected from H, halo, cyano, NO 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, -OR 8 , -NR 6 R 7 , -C(O)R 8 , -C(O)OR 8 , -C (O)NR 6 R 7 , -NR 6 C(O)R 8 , -OC(O)R 8 , -S(O) p R 8 , -S(O) p OR 8 , -S(O) p NR 6 R 7 , -OS(O) p R 8 or -NR 6 S(O) p R 8 ; preferably, R 1 is independently selected from H, halogen, cyano, NO 2 , C 1 -C 6
  • R 2 is independently selected from H, halo, cyano, NO 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, -OR 8 , -NR 6 R 7 , -C(O)R 8 , -C(O)OR 8 , -C (O)NR 6 R 7 , -NR 6 C(O)R 8 , -OC(O)R 8 , -S(O) p R 8 , -S(O) p OR 8 , -S(O) p NR 6 R 7 , -OS(O) p R 8 or -NR 6 S(O) p R 8 ; preferably, R 2 is independently selected from H, halogen, cyano, NO 2 , C 1 -C 6 al
  • L is selected from the group consisting of -C 1 -C 6 alkylene-, -C 2 -C 6 alkenylene-, -C 2 -C 6 alkynylene-, -OC 1 -C 6 -alkylene Base-, -C 1 -C 6 alkylene-O-, -NR 6 C(O)-, -C(O)NR 6 -, -OC(O)-, -C(O)O-, - NR 6 -C 1 -C 6 alkylene- or -C 1 -C 6 alkylene-NR 6 -; preferably, L is selected from -C 1 -C 6 alkylene-, -C 2 -C 6 Alkenylene-, -OC 1 -C 6 alkylene-, -C 1 -C 6 alkylene-O-, -NR 6 C(O)-, -C(O)NR 6 -, -OC ( O)-, -C
  • X is selected from -O- or -NH-; Y is selected from -C(O)- or -S(O) p- ; preferably, X is -NH- and Y is -C(O )-.
  • R 3 , R 4 and R 5 are each independently selected from H, halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 haloalkoxy Or, R 3 and R 4 may form a chemical bond; preferably, R 3 , R 4 and R 5 are each independently selected from H, halogen, cyano or C 1 -C 6 alkyl; or, R 3 and R 4 A chemical bond may be formed; preferably, R 3 , R 4 and R 5 are each independently selected from H or a C 1 -C 6 alkyl group; or, R 3 and R 4 may form a chemical bond.
  • R 6 , R 7 and R 8 are each independently selected from H, C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl; preferably R 6 , R 7 and R 8 are each independently It is selected from H or C 1 -C 6 alkyl.
  • the present invention provides a compound of the formula (II) or a pharmaceutically acceptable salt, tautomer, racemate, enantiomer, diastereomer thereof Body, prodrug, hydrate or solvate, and mixtures thereof:
  • R a and R c are independently selected from H, halogen, cyano, NO 2 , C 1 -C 6 alkyl or C 1 -C 6 haloalkyl;
  • R b is independently selected from H, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl;
  • R 3 and R 4 are each independently selected from H, cyano, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl;
  • R 3 and R 4 may form a chemical bond
  • A, R 1 and m are as defined above.
  • the present invention provides a compound of the formula (III) or a pharmaceutically acceptable salt, tautomer, racemate, enantiomer, diastereomer thereof Body, prodrug, hydrate or solvate, and mixtures thereof:
  • W is selected from CR 1 or N;
  • Ring A-(R 1 )m is selected from
  • R 1 is independently selected from H, halogen, cyano, NO 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy or -OR 8 ;
  • R 2 is independently selected from the group consisting of H, halogen, cyano, NO 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, -OR 8 , -NR 6 R 7 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 or -NR 6 C(O)R 8 ;
  • R 3 , R 4 and R 5 are each independently selected from H, halogen, cyano or C 1 -C 6 alkyl;
  • R 3 and R 4 may form a chemical bond
  • R 6 , R 7 and R 8 are each independently selected from H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl or 3-10 membered heterocyclyl;
  • n 0, 1, 2, 3 or 4.
  • W is selected from CF or N;
  • Ring A-(R 1 )m is selected from
  • R 1 is independently selected from H, halogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl;
  • R 2 is independently selected from H, halogen, -OR 8 , -NR 6 R 7 or -C(O)NR 6 R 7 ;
  • R 3 , R 4 and R 5 are each independently selected from H or C 1 -C 6 alkyl
  • R 3 and R 4 may form a chemical bond
  • R 6 , R 7 and R 8 are each independently selected from H, C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl;
  • n 0, 1, 2, 3 or 4.
  • the present invention provides a compound of the formula (IV): or a pharmaceutically acceptable salt, tautomer, racemate, enantiomer, diastereomer thereof Body, prodrug, hydrate or solvate, and mixtures thereof:
  • Ring A-(R 1 )m is selected from:
  • R 1 is independently selected from H, halogen, cyano, NO 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy or -OR 8 ;
  • R 2 is independently selected from the group consisting of H, halogen, cyano, NO 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, -OR 8 , -NR 6 R 7 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 6 R 7 or -NR 6 C(O)R 8 ;
  • R 3 , R 4 and R 5 are each independently selected from H, halogen, cyano or C 1 -C 6 alkyl;
  • R 3 and R 4 may form a chemical bond
  • R 6 , R 7 and R 8 are each independently selected from H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl or 3-10 membered heterocyclyl;
  • n 0, 1, 2, 3 or 4.
  • Ring A-(R 1 )m is selected from:
  • R 1 is independently selected from H, halogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl;
  • R 2 is independently selected from H, halogen, -OR 8 , -NR 6 R 7 or -C(O)NR 6 R 7 ;
  • R 3 , R 4 and R 5 are each independently selected from H or C 1 -C 6 alkyl
  • R 3 and R 4 may form a chemical bond
  • R 6 , R 7 and R 8 are each independently selected from H, C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl;
  • n 0, 1, 2, 3 or 4.
  • the present invention provides a compound of the formula (V) or a pharmaceutically acceptable salt, tautomer, racemate, enantiomer, diastereomer thereof Body, prodrug, hydrate or solvate, and mixtures thereof:
  • Ring A-(R 1 )m is selected from:
  • R 1 is independently selected from H, halogen, cyano, NO 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy or -OR 8 ;
  • R 3 , R 4 and R 5 are each independently selected from H, halogen, cyano or C 1 -C 6 alkyl;
  • R 3 and R 4 may form a chemical bond
  • R 8 is selected from H or C 1 -C 6 alkyl
  • n 0, 1, 2 or 3.
  • Ring A-(R 1 )m is selected from:
  • R 1 is independently selected from H, halogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl;
  • R 3 , R 4 and R 5 are each independently selected from H or C 1 -C 6 alkyl
  • R 3 and R 4 may form a chemical bond
  • n 0, 1, 2 or 3.
  • the present invention provides a compound of the formula (VII): or a pharmaceutically acceptable salt, tautomer, racemate, enantiomer, diastereomer thereof Body, prodrug, hydrate or solvate, and mixtures thereof:
  • Ring A-(R 1 )m is selected from:
  • R 1 is independently selected from H or C 1 -C 6 alkyl
  • R 2 is independently selected from H, halogen, -OR 8 or -C(O)NR 6 R 7 ;
  • R 6 , R 7 and R 8 are each independently selected from H, C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl;
  • n 0, 1, or 2.
  • Ring A-(R 1 )m is
  • R 1 is independently selected from C 1 -C 6 alkyl
  • R 2 is independently selected from H, halogen, -OR 8 or -C(O)NR 6 R 7 ;
  • R 6 , R 7 and R 8 are each independently selected from H, C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl;
  • n 0, 1, or 2.
  • the present invention provides a compound of the formula (VIII) or a pharmaceutically acceptable salt, tautomer, racemate, enantiomer, diastereomer thereof Body, prodrug, hydrate or solvate, and mixtures thereof:
  • W is selected from CR 1 or N;
  • Ring A is selected from a 6-14 membered arylene group, a 5-10 membered heteroarylene group, a C 3 -C 8 cycloalkylene group or a 3-10 membered heterocyclylene group;
  • R 2a and R 2c are each independently selected from H, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl or -OR 8 ;
  • R 2b is selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl or -OR 8 ;
  • R 6 and R 7 are each independently selected from H, C 1 -C 6 alkyl, -NHR 8 , -OR 8 , C 3 -C 8 cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered hetero Aryl or 6-14 membered aryl;
  • R 8 are each independently selected from H or C 1 -C 6 alkyl
  • R 9 and R 10 are each independently selected from H or C 1 -C 6 alkyl
  • n 0, 1, 2, 3 or 4;
  • R 1 is selected from the group consisting of H, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR 8 , 3-10 membered heterocyclic group , -O(CH 2 ) n NR 9 R 10 or -NR 8 (CH 2 ) n NR 9 R 10 .
  • E 1 , E 2 , E 3 and E 4 are each independently selected from CR 1 or N;
  • E 5 , E 6 , E 7 and E 8 are each independently selected from O, S, C(R 1 ) 2 or NR 1 ;
  • R 1 is as defined above.
  • Ring A-(R 1 )m is selected from:
  • R 1 and m are as defined above.
  • R 1 is selected from the group consisting of H, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR 8 , 5-6 membered heterocyclic group -O(CH 2 ) n NR 9 R 10 , -NR 8 (CH 2 ) n NR 9 R 10 .
  • R 1 is selected from the group consisting of H, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OR 8 , morpholinyl, -O(CH 2 ) n NMe 2 , -NR 8 (CH 2 ) n NMe 2 .
  • W is selected from CR 1 or N;
  • Ring A-(R 1 )m is selected from:
  • R 1 is selected from the group consisting of H, C 1 -C 6 alkyl, -OR 8 , morpholinyl, -O(CH 2 ) n NMe 2 , -NR 8 (CH 2 ) n NMe 2 ;
  • R 2a and R 2c are each independently selected from H, halogen, cyano, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl or -OR 8 ;
  • R 2b is selected from H, halogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl or -OR 8 ;
  • R 6 and R 7 are each independently selected from H, C 1 -C 6 alkyl, -NHR 8 , -OR 8 , C 3 -C 8 cycloalkyl, 3-8 membered heterocyclic, 5-6 membered hetero Aryl or 6-10 membered aryl;
  • R 8 are each independently selected from H or C 1 -C 6 alkyl
  • n 0, 1 or 2;
  • n 0, 1, 2, 3, 4, 5 or 6.
  • W is selected from N;
  • Ring A-(R 1 )m is selected from:
  • R 1 is selected from the group consisting of H, C 1 -C 6 alkyl, -OR 8 , morpholinyl, -O(CH 2 ) n NMe 2 , -NR 8 (CH 2 ) n NMe 2 ;
  • R 2a and R 2c are each independently selected from H or halogen
  • R 2b is selected from H, C 1 -C 6 alkyl or -OR 8 ;
  • R 6 and R 7 are each independently selected from H, C 1 -C 6 alkyl, -NHR 8 , -OR 8 or C 3 -C 8 cycloalkyl;
  • R 8 are each independently selected from H or C 1 -C 6 alkyl
  • n 0, 1 or 2;
  • n 0, 1, 2, 3 or 4.
  • W is selected from N.
  • the ring A is selected from a 6-14 membered arylene group, a 5-10 membered heteroarylene group or a 3-10 membered heterocyclic group.
  • the ring A is selected from the group consisting of phenyl, pyrazolyl, tetrahydropyranyl or tetrahydrofuranyl.
  • R 2a is selected from H or halogen.
  • R 2a is selected from halogen.
  • R 2a is selected from Cl.
  • R 2b is selected from H or -OR 8 .
  • R 2b is selected from H or -OCH 3 .
  • R 2c is selected from H
  • R 6 and R 7 are each independently selected from H, C 1 -C 6 alkyl, -OR 8 or C 3 -C 8 cycloalkyl.
  • R 6 and R 7 are each independently selected from the group consisting of H, methyl, methoxy, ethoxy, and cyclopropyl.
  • R 8 is independently selected from H or C 1 -C 6 alkyl.
  • R 8 is selected from a methyl group or an ethyl group.
  • n 1, 2, 3 or 4.
  • n 2.
  • any one of the above specific embodiments, or any combination thereof, may be combined with any of the other specific embodiments or any combination thereof.
  • any of the embodiments of the ring A, or any combination thereof may be combined with any of the technical solutions of W, R 1 to R 8 , m, n, and p, or the like, or any combination thereof.
  • the present invention is intended to include a combination of all such technical solutions, which are limited in scope and are not listed one by one.
  • compositions, formulations and kits are provided.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention (also referred to as "active ingredient") and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises an effective amount of the active component.
  • the pharmaceutical composition comprises a therapeutically effective amount of the active component.
  • the pharmaceutical composition comprises a prophylactically effective amount of the active component.
  • a pharmaceutically acceptable excipient for use in the present invention refers to a non-toxic carrier, adjuvant or vehicle which does not destroy the pharmacological activity of the compound formulated together.
  • Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (eg, human serum white) Protein), buffer substances (such as phosphate), glycine, sorbic acid, potassium sorbate, a mixture of partial glycerides of saturated plant fatty acids, water, salt or electrolyte (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate , sodium chloride, zinc salt, silica gel, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based materials, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax, polyethylene-polyoxypropylene - Block
  • kits e.g., pharmaceutical packs.
  • Kits provided may include a compound of the invention, other therapeutic agents, and first and second containers (eg, vials, ampoules, bottles, syringes, and/or dispersible packages or other materials containing the compounds of the invention, other therapeutic agents) Suitable container).
  • first and second containers eg, vials, ampoules, bottles, syringes, and/or dispersible packages or other materials containing the compounds of the invention, other therapeutic agents
  • kits can also optionally include a third container containing a pharmaceutically acceptable excipient for diluting or suspending a compound of the invention and/or other therapeutic agent.
  • a compound of the invention provided in a first container and a second container is combined with other therapeutic agents to form a unit dosage form.
  • the pharmaceutical composition provided by the present invention can be administered by a variety of routes including, but not limited to, oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration.
  • Drug administration by implant or other means of administration.
  • parenteral administration as used herein Including subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intra-articular administration, intra-arterial administration, intrasynovial administration, intrathoracic administration, intracranial administration, and lesions Internal administration, and intracranial injection or infusion techniques.
  • an effective amount of a compound provided herein is administered.
  • the amount of compound actually administered can be determined by the physician. .
  • the compound provided herein is administered to a subject at risk of developing the condition, typically based on a physician's recommendation and administered under the supervision of a physician, at the dosage level as described above.
  • Subjects at risk of developing a particular condition typically include subjects with a family history of the condition, or those subjects that are particularly susceptible to developing the condition by genetic testing or screening.
  • long-term administration can also be administered chronically.
  • Long-term administration refers to administration of a compound or a pharmaceutical composition thereof for a long period of time, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or can be continuously administered indefinitely, For example, the rest of the subject.
  • chronic administration is intended to provide a constant level of the compound in the blood over a prolonged period of time, for example, within a therapeutic window.
  • a pharmaceutical composition of the present invention can be further delivered using various methods of administration.
  • a pharmaceutical composition can be administered by bolus injection, for example, to increase the concentration of the compound in the blood to an effective level.
  • the bolus dose depends on the target systemic level of the active ingredient through the body, for example, an intramuscular or subcutaneous bolus dose that causes a slow release of the active ingredient, while a bolus that is delivered directly to the vein (eg, via IV IV drip) ) can be delivered more quickly, so that the concentration of the active ingredient in the blood is rapidly increased to an effective level.
  • the pharmaceutical composition can be administered in a continuous infusion form, for example, by IV intravenous drip to provide a steady state concentration of the active ingredient in the subject's body.
  • a bolus dose of the pharmaceutical composition can be administered first, followed by continued infusion.
  • Oral compositions can be in the form of a bulk liquid solution or suspension or bulk powder. More generally, however, the composition is provided in unit dosage form for ease of precise dosing.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human patients and other mammals, each unit containing a predetermined quantity of active ingredient suitable to produce the desired therapeutic effect with a suitable pharmaceutical excipient.
  • Typical unit dosage forms include prefilled, pre-measured ampoules or syringes of the liquid compositions, or pills, tablets, capsules and the like in the case of solid compositions.
  • the compound is usually a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the balance being various carriers useful for forming the desired administration form. Or excipients and processing aids.
  • a representative regimen is one to five oral doses per day, especially two to four oral doses, typically three oral doses.
  • each dose provides from about 0.01 to about 20 mg/kg of a compound of the invention, each preferably providing from about 0.1 to about 10 mg/kg, especially from about 1 to about 5 mg/kg.
  • a transdermal dose is generally selected in an amount of from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably about 0.1. To about 10% by weight, and more preferably from about 0.5 to about 15% by weight.
  • the injection dose level ranges from about 1 mg/kg/hr to at least 10 mg/kg/hr from about 1 to about 120 hours, especially 24 to 96 hours.
  • a preload bolus of about 0.1 mg/kg to about 10 mg/kg or more can also be administered.
  • the maximum total dose cannot exceed about 2 g/day.
  • Liquid forms suitable for oral administration may include suitable aqueous or nonaqueous vehicles as well as buffers, suspending and dispersing agents, coloring agents, flavoring agents, and the like.
  • the solid form may include, for example, any of the following components, or a compound having similar properties: a binder, for example, microcrystalline cellulose, tragacanth or gelatin; an excipient such as starch or lactose, a disintegrant, For example, alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silica; a sweetener such as sucrose or saccharin; or a flavoring agent such as mint, water Methyl salicylate or orange flavoring.
  • a binder for example, microcrystalline cellulose, tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrant, For example, alginic acid, Primogel or corn star
  • Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art.
  • the active compound will typically be a minor component, often from about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.
  • transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient.
  • the active component When formulated as an ointment, the active component is typically combined with a paraffin or water miscible ointment base.
  • the active ingredient can be formulated as a cream with, for example, an oil-in-water cream base.
  • Such transdermal formulations are well known in the art and generally include other ingredients for enhancing stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope of the invention.
  • transdermal administration can use a reservoir (reservoir) or porous membrane type, or a variety of solid matrix patch implementation.
  • compositions for oral administration, injection or topical administration are merely representative.
  • Other materials and processing techniques, etc. are set forth in Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, part 8 of which is incorporated herein by reference.
  • the compounds of the invention may also be administered in sustained release form or from a sustained release delivery system.
  • sustained release materials can be found in Remington's Pharmaceutical Sciences.
  • the invention further relates to pharmaceutically acceptable formulations of the compounds of the invention.
  • the formulation comprises water.
  • the formulation comprises a cyclodextrin derivative.
  • the most common cyclodextrins are alpha-, beta- and gamma-cyclodextrins consisting of 6, 7 and 8 alpha-1,4-linked glucose units, respectively, optionally including one on the attached sugar moiety. Or a plurality of substituents including, but not limited to, methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substituted.
  • the cyclodextrin is a sulfoalkyl ether beta-cyclodextrin, eg, sulfobutylether beta-cyclodextrin, also known as Captisol. See, for example, U.S. 5,376,645.
  • the formulation comprises hexapropyl- ⁇ -cyclodextrin (eg, 10-50% in water).
  • the compounds of the invention or compositions thereof may be administered in combination with other therapeutic agents to treat the disease.
  • therapeutic agents include, but are not limited to, Adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan ( Topotecan), taxol, interferon, platinum derivatives, taxanes (eg, paclitaxel), vinca alkaloids (eg, vinblastine), anthracycline ( Anthracycline) (eg, doxorubicin), epipodophyllotoxin (eg, etoposide), cisplatin, mTOR inhibitor (eg, rapamycin), Methotrexate, actinomycin D, dolastatin 10, colchicine, emetine, trimetrexate, chlorobenzene Metoprine, cyclosporine, daunorubicin, teniposide, amphotericin, alkylating agent (eg chlorambucil
  • a compound of the invention or a composition thereof can be administered in combination with any one or more anti-proliferative or chemotherapeutic agents selected from the group consisting of: abarelix, aldileukin (aldesleukin), alemtuzumab, alitretinoin, allopurinol, altretamine, amifostine, anastrozole, arsenic trioxide, day Asparaginase, azacitidine, BCG Live, bevacuzimab, fluorouracil, bexarotene, bleomycin, bortezomib, white Busulfan, calbuterone, capecitabine, camptothecin, carboplatin, carmustine, celecoxib, cetuximab Antibiotic (cetuximab), chlorambucil, cladribine, clofarabine, cyclophosphamide, cytarabine, actinomycin D, darbepo
  • therapeutic agents to which the compounds of the invention may also be combined include, but are not limited to, therapeutic agents for Alzheimer's Disease, such as donepezil hydrochloride and rivastigmine. ; therapeutic agents for Parkinson's Disease, such as L-DOPA/carbidopa, entacapone, ropinrole, pramipexole ( Pramipexole), bromocriptine, pergolide, trihexephendyl, and amantadine; a therapeutic agent for multiple sclerosis (MS), Such as beta interferon, glatiramer acetate and mitoxantrone; therapeutic agents for asthma, such as albuterol and montelukast; therapeutic agents for schizophrenia, such as Zyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1RA, azathioprine , cyclophosphamide and sulfasala
  • those other active agents can be administered separately from the compositions containing the compounds of the invention as part of a multiple dosing regimen.
  • those active agents may be part of a single dosage form, mixed with a compound of the invention in a single composition. If administered as part of a multiple dosing regimen, the two active agents can be provided simultaneously, sequentially, or at intervals from one another (usually within 5 hours of each other).
  • FGFR-4 regulates proliferation, survival, and alpha-fetoprotein secretion during progression of hepatocellular carcinoma (HCC); FGFR-4 inhibitors are therefore promising potential therapeutic agents for this unmet medical need (Ho et al., Journal Of Hepatology, 2009, 50: 118-27). HCC afflicts more than 550,000 people worldwide each year and is one of the worst 1-year survival rates of any cancer type.
  • FGF19 a member of the fibroblast growth factor (FGF) family, which is composed of hormones
  • FGF19 a member of the fibroblast growth factor (FGF) family, which is composed of hormones
  • Increased hepatocyte proliferation and liver tumor formation have been observed in FGF19 gene-transferred mice.
  • FGF19 activates FGFR-4, its major receptor in the liver, and FGFR-4 activation is thought to be a mechanism by which FGF19 can increase hepatocyte proliferation and induce hepatocellular carcinoma formation (Wu et al., J Biol Chem (2010) 285 ( 8): 5165-5170).
  • FGF19 has also been recognized by others as a driver gene in HCC (Sawey et al., Cancer Cell (2011) 19:347-358).
  • the compounds disclosed herein which are potential and selective inhibitors of FGFR-4, are believed to be useful in the treatment of HCC and other liver cancers.
  • FGFR-4 activated fibroblast growth factor receptor 4
  • MDA-MB-453 human breast cancer cell line MDA-MB-453.
  • FGFR-4 may be a driver of tumor growth in breast cancer (Roid et al, Oncogene (2010) 29(10): 1543-1552).
  • the compounds disclosed herein, which are potent and selective inhibitors of FGFR-4 are believed to be useful in the treatment of FGFR-4 regulated breast cancer.
  • FGFR-4 activation/overexpression results in overexpression of FGFR-4.
  • FGFR-4 overexpression by the mechanism is associated with rhabdomyosarcoma (RMS) (Cao et al, Cancer Res (2010) 70(16): 6497-6508).
  • RMS rhabdomyosarcoma
  • Mutations in FGFR-4 itself result in protein overactivation; this mechanism has been associated with the RMS subpopulation (Taylor et al, J Clin Invest (2009) 119: 3395-3407).
  • RMS rhabdomyosarcoma
  • the compounds disclosed herein, which are potent and selective inhibitors of FGFR-4 are believed to be useful in the treatment of FGFR-4 regulated RMS and other sarcomas.
  • FGFR-4 upstream gene Other diseases are associated with changes in the FGFR-4 upstream gene or with mutations in FGFR-4 itself.
  • mutations in the kinase domain of FGFR-4 result in overactivation, which is associated with lung adenocarcinoma (Ding et al, Nature (2008) 455 (7216): 1069-1075).
  • Amplification of FGFR-4 is associated with conditions such as renal cell carcinoma (TCGA interim data).
  • silencing FGFR4 and inhibiting ligand-receptor binding significantly slowed ovarian tumor growth, indicating that inhibitors of FGFR4 can be used to treat ovarian cancer (Zaid et al, Clin. Cancer Res. (2013) 809).
  • FGF19 Increased pathogenicity of bile acid levels is associated with changes in FGF19 levels (Vergnes et al, Cell Metabolism (2013) 17, 916-28). Thus, a decrease in the level of FGF19 may be beneficial in promoting the synthesis of bile acids and thus in the treatment of hyperlipidemia.
  • the compounds of the invention may be used to treat a variety of FGFR-related diseases, including but not limited to: gastric cancer, thyroid cancer, prostate cancer, breast cancer, sarcoma (eg, rhabdomyosarcoma), skin cancer (eg, melanoma) ), liver cancer (such as hepatocellular carcinoma and cholangiocarcinoma), pancreatic cancer (such as pancreatic intraepithelial neoplasia and pancreatic ductal adenocarcinoma), lung cancer (such as non-small cell lung cancer and lung adenocarcinoma), kidney cancer (such as kidney cells) Cancer), colorectal cancer and ovarian cancer.
  • gastric cancer thyroid cancer
  • prostate cancer breast cancer
  • sarcoma eg, rhabdomyosarcoma
  • skin cancer eg, melanoma
  • liver cancer such as hepatocellular carcinoma and cholangiocarcinoma
  • pancreatic cancer such as pancre
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR was measured using a Bruker AVANCE-400 or Varian Oxford-300 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDC1 3 ), deuterated methanol (CD 3 OD). The internal standard is tetramethylsilane (TMS) and the chemical shift is given in units of 10 -6 (ppm).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the MS was measured using an Agilent SQD (ESI) mass spectrometer (manufacturer: Agilent, model: 6110) or a Shimadzu SQD (ESI) mass spectrometer (manufacturer: Shimadzu, model: 2020).
  • ESI Agilent SQD
  • ESI Shimadzu SQD
  • the HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18, 150 x 4.6 mm, 5 ⁇ m, column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm, 5 ⁇ m column).
  • the thin-layer chromatography silica gel plate uses Qingdao Ocean GF254 silica gel plate, and the silica gel plate used for thin-layer chromatography (TLC) has a specification of 0.15 mm to 0.2 mm.
  • the specification for separation and purification of thin layer chromatography is 0.4 mm to 0.5 mm. silicone board.
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Beijing Coupling Companies such as chemicals.
  • An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
  • the pressurized hydrogenation reaction was carried out using a GCD-500G high purity hydrogen generator and a BLT-2000 medium pressure hydrogenator from Beijing Jiawei Kechuang Technology Co., Ltd.
  • the hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
  • the microwave reaction used a CEM Discover-SP type microwave reactor.
  • the temperature of the reaction is room temperature, and the temperature range is from 20 ° C to 30 ° C.
  • reaction progress in the examples was monitored by thin layer chromatography (TLC), and the system used for the reaction was A: dichloromethane and methanol system; B: petroleum ether and ethyl acetate system, the volume ratio of the solvent was based on The polarity of the compound is adjusted to adjust.
  • TLC thin layer chromatography
  • the system for purifying the compound using the column chromatography eluent and the system for developing the thin layer chromatography include A: dichloromethane and methanol systems; B: petroleum ether and ethyl acetate system, the volume ratio of the solvent according to the compound Adjustments can be made with different polarities and can also be adjusted by adding a small amount of an acidic or alkaline reagent such as triethylamine.
  • Example 3 was synthesized by following the procedure of Example 2, but in the sixth step, ammonia was replaced with methylamine hydrochloride, and directly condensed with compound 119f to prepare 4-chloro-N-methyl-3-(((2-(( 2-methyl-6-nitrophenyl)amino)pyrimidin-5-yl)oxy)methyl)benzamide 127 g.
  • Example 5 was synthesized by following the procedure of Example 4, but in the seventh step, 4-fluoro-N-cyclopropyl-3-methoxy-5-(((2-(( 2-Methyl-6-nitrophenyl)amino)pyrimidin-5-yl)oxy)methyl)benzamide 139i.
  • the desired product is finally obtained 3-(((2-(2-acrylamido-6-methylphenyl)amino)pyrimidin-5-yl)oxy)methyl)-4-fluoro-N-cyclopropyl -5-Methoxybenzamide (Compound 139).
  • Example 7 was synthesized by following the procedure of Example 6, but in the seventh step, 4-chloro-N-cyclopropyl-3-methoxy-5-(((2-(( 2-Methyl-6-nitrophenyl)amino)pyrimidin-5-yl)oxy)methyl)benzamide 142i.
  • the desired product is finally obtained 3-(((2-(2-acrylamido-6-methylphenyl)amino)pyrimidin-5-yl)oxy)methyl)-4-chloro-N-cyclopropyl -5-Methoxybenzamide (Compound 142).
  • Compound 150 was synthesized by reference to compound 141, but in the seventh step, methylamine hydrochloride was substituted for methylamine hydrochloride to prepare 4-chloro-N,3-dimethoxy-5-(((2-((2) -Methyl-6-nitrophenyl)amino)pyrimidin-5-yl)oxy)methyl)benzamide 150i.
  • the target product 3-(((2-(2-acrylamido-6-methylphenyl)amino)pyrimidin-5-yl)oxy)methyl)-4-chloro-N,5-di Methoxybenzamide 150.
  • Compound 155 was synthesized according to the procedure of Compound 158, but 4-chloro-3-(((2-chloropyrimidin-5-yl)oxy)methyl)-N,5-dimethoxybenzamide was used in the first step. Instead of 4-chloro-3-((2-chloropyrimidin-5-oxy)methyl)-N-cyclopropylbenzamide.
  • the target product is obtained 3-((2-((3S,4S)-4-Amino-tetrahydro-2H-pyran-3-ylamino)pyrimidin-5-oxy)methyl)-4-chloro-N-cyclopropane Benz-5-methoxybenzamide 156e (172 mg, brown oil), yield 100%.
  • EtOAc EtOAc N-(2-((5-((2-chloro-5-cyanobenzyl)oxy)pyrimidin-2-yl)amino)-3-methylphenyl)-2,2,2-tri Fluoroacetamide 157f (650 mg), yield 88%.
  • P1 The short-lived named P1 is reserved on the SFC machine, and the long-lasting named P2 is retained.
  • EtOAc EtOAc
  • Compound 162 was synthesized by reference to the procedure of Compound 143, but in the eighth step, 1-methyl-4-nitro-1H-pyrazole-5-amine was substituted for 1-methyl-4-nitro-1H-pyrazole- 3-amine.
  • Compound 164 was synthesized according to the procedure of Compound 143, but in the eighth step, 1-methyl-4-nitro-1H-pyrazol-3-amine was replaced with 5-methyl-2-nitroaniline.
  • Compound 165 was synthesized by reference to the procedure of Compound 143, but in the eighth step, 1-methyl-4-nitro-1H-pyrazol-3-amine was replaced with 5-methyl-2-aminonitrobenzene.
  • Example 168 was synthesized by reference to the procedure of Example 143, but in the eighth step, N 1 ,N 1 ,3-trimethyl-5-nitrobenzene-1,4-diamine was substituted for 1-methyl-4-nitro -1H-pyrazol-3-amine.
  • the title product 3-(((2-(2-acrylamido-4-(dimethylamino))-6-methylphenyl)amino)pyrimidin-5-yl)oxy)methyl)-4 was finally obtained.
  • -Chloro-N-cyclopropyl-5-methoxybenzamide 168 was finally obtained.
  • Compound 173 was synthesized by reference to the procedure of Compound 143, but the propylamine was replaced with methoxyamine in the eighth step.
  • Compound 176 was synthesized by reference to the compound 158 step.
  • Compound 178 was synthesized by reference to the procedure of compound 156, but in the second step, O-ethylhydroxylamine was used in place of cyclopropylamine, and in the third step, (3R,4S)-tetrahydrofuran-3,4-diamine was substituted (3S,4S). tert-Butyl -3-amino-tetrahydro-2H-pyran-4-ylcarbamate.
  • Compound 180 was synthesized by the reference compound 179 step, but in the first step, 1-methylpiperazine was substituted with morpholine to finally obtain the target product 3-(((2-((2-acrylamido-6-methyl-4-))). Morpholinophenyl)amino)pyrimidin-5-yl)oxy)methyl)-4-chloro-N,5-dimethoxybenzamide 180.
  • Example 183 was synthesized by reference to the procedure of Example 181, but in the eighth step, (N-amino-3-methyl-5-nitrophenyl) dimethylphosphine oxide 183b was substituted for N1,N1,3-trimethyl- 5-nitrobenzene-1,4-diamine. Finally, the target product 3-(((2-(2-acrylamido-4-(dimethylphosphino)-6-methylphenyl)amino)pyrimidin-5-yl)oxy)methyl))) 4-chloro-N,5-dimethoxybenzamide 183.
  • Compound 184 was synthesized according to the procedure of Compound 179, but in the first step, 1-ethylpiperazine was substituted for 1-methylpiperazine to finally give 3-(((2-((2-acrylamido-4-)-4-) Ethyl piperazin-1-yl)-6-methylphenyl)amino)pyrimidin-5-yl)oxy)methyl)-4-chloro-N,5-dimethoxybenzamide 184.
  • kinase assay kit the kit having a biotin-labeled substrate phosphorylation site-specific Eu-labeled antibody, and XL665 labeled avidin and associated buffers.
  • FGFR4 phosphorylates the substrate
  • Eu-Ab recognizes the phosphorylated substrate
  • XL665-SA binds to biotin on the substrate, resulting in the proximity of Eu to XL665 to produce an HTRF signal.
  • the change in activity of the kinase is detected by reading the strength of the HTRF signal.
  • the two main reactions are the kinase reaction and the detection reaction.
  • the kinase consumes ATP to phosphorylate the substrate while producing a substrate containing a phosphate group.
  • a detection reagent is added to terminate the kinase reaction, and at the same time, the specific antibody in the detection reagent and the XL665-labeled avidin are combined with the phosphate group and the biotin on the substrate to generate an HTRF signal, and the intensity of the signal is
  • the phosphorylation level of the substrate is proportional to the ability to quantitatively detect the activity of the kinase FGFR4.
  • kinase human FGFR4 protein (460-802 amino acids) was purchased from Carna Corporation (Cat. No. 08-136), and the kinase substrates were TK (purchased from Cisbio) and ATP (Sigma) using the enzyme label.
  • the TECAN Spark 10M plate reader (TECAN) reads the optical signal.
  • the kinase reaction buffer includes 1X Enzymatic buffer (CISBIO) 5 mM MgCl 2 (Sigma), 1 mM DTT (Sigma); the kinase FGFR4 was prepared using a buffer to a concentration of 0.25 ug/mL of the kinase reaction solution; the substrate reaction solution included 0.75 uM. Substrate and 500 ⁇ m ATP.
  • the compound IC 50 was calculated from the 10 concentration points by the following formula.
  • the compound was first diluted with 100% DMSO in a 96-well plate to dilute 3 concentrations: 4 mM, 40 uM, 0.4 uM, and 8 ul of the compound was transferred to a 384 LDV Echo Source plate, and the compound was transferred to the Assay plate with Echo 550 to obtain 10 concentration points. Two duplicate wells were set at each concentration point (starting point 10 uM, 3 fold dilution).
  • the percent inhibition is calculated based on the following formula:
  • Inhibition % [1-(RLU compound -RLU min )/(RLU max -RLU min )]X100
  • RLU compounds are cold light readings at a given compound concentration
  • RLU min is a cold light reading without the addition of a kinase
  • RLU max is a cold light reading without the addition of a compound.
  • the compounds of the present invention have a significant inhibitory effect on the activity of the tyrosine kinase FGFR4.

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Abstract

La présente invention concerne un dérivé d'éther aromatique, un procédé de préparation correspondant et des applications médicales correspondantes. Plus particulièrement, la présente invention concerne un nouveau composé représenté par la formule générale (VIII), un sel pharmaceutiquement acceptable, une composition pharmaceutique le comprenant et un procédé de préparation associé. La présente invention concerne également des applications du dérivé, du sel pharmaceutiquement acceptable et de la composition pharmaceutique le comprenant dans la préparation d'agents thérapeutiques, en particulier dans la préparation d'inhibiteurs de la tyrosine kinase FGFR4, et dans la préparation de médicaments pour le traitement et/ou la prévention de tumeurs ou d'inflammations. Les définitions de groupes substituants représentés par la formule générale (VIII) sont les mêmes définitions dans les spécifications.
PCT/CN2017/106667 2016-10-18 2017-10-18 Dérivé d'éther aromatique, son procédé de préparation, et ses applications médicales WO2018072707A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019242689A1 (fr) * 2018-06-22 2019-12-26 北京赛特明强医药科技有限公司 Composé de pyridine à substitution cyano et composé de pyrimidine à substitution cyano, procédé de préparation correspondant et utilisation associée
WO2021129561A1 (fr) * 2019-12-23 2021-07-01 北京赛特明强医药科技有限公司 Composé de pyridine à substitution cyano et composé de pyrimidine à substitution cyano, et leur procédé de préparation et leur utilisation
CN114835729A (zh) * 2018-05-30 2022-08-02 江苏豪森药业集团有限公司 含三并环类衍生物抑制剂、其制备方法和应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080027070A1 (en) * 2006-07-07 2008-01-31 Targegen, Inc. 2-amino--5-substituted pyrimidine inhibitors
CN104540809A (zh) * 2012-07-11 2015-04-22 蓝印药品公司 成纤维细胞生长因子受体的抑制剂
CN105143185A (zh) * 2013-03-15 2015-12-09 和记黄埔医药（上海）有限公司 新的嘧啶和吡啶化合物以及它们的用途

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080027070A1 (en) * 2006-07-07 2008-01-31 Targegen, Inc. 2-amino--5-substituted pyrimidine inhibitors
CN104540809A (zh) * 2012-07-11 2015-04-22 蓝印药品公司 成纤维细胞生长因子受体的抑制剂
CN105143185A (zh) * 2013-03-15 2015-12-09 和记黄埔医药（上海）有限公司 新的嘧啶和吡啶化合物以及它们的用途

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114835729A (zh) * 2018-05-30 2022-08-02 江苏豪森药业集团有限公司 含三并环类衍生物抑制剂、其制备方法和应用
CN114835729B (zh) * 2018-05-30 2024-05-31 江苏豪森药业集团有限公司 含三并环类衍生物抑制剂、其制备方法和应用
WO2019242689A1 (fr) * 2018-06-22 2019-12-26 北京赛特明强医药科技有限公司 Composé de pyridine à substitution cyano et composé de pyrimidine à substitution cyano, procédé de préparation correspondant et utilisation associée
CN112313207A (zh) * 2018-06-22 2021-02-02 北京赛特明强医药科技有限公司 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
CN112313207B (zh) * 2018-06-22 2023-02-14 北京赛特明强医药科技有限公司 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
WO2021129561A1 (fr) * 2019-12-23 2021-07-01 北京赛特明强医药科技有限公司 Composé de pyridine à substitution cyano et composé de pyrimidine à substitution cyano, et leur procédé de préparation et leur utilisation
JP2023508376A (ja) * 2019-12-23 2023-03-02 北京賽特明強医薬科技有限公司 シアノ置換ピリジンおよびシアノ置換ピリミジン系化合物、製造方法およびそれらの使用
JP7491612B2 (ja) 2019-12-23 2024-05-28 北京賽特明強医薬科技有限公司 シアノ置換ピリジンおよびシアノ置換ピリミジン系化合物、製造方法およびそれらの使用

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