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WO2018004258A1 - Nouveau dérivé hétérocyclique et son utilisation - Google Patents

Nouveau dérivé hétérocyclique et son utilisation Download PDF

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Publication number
WO2018004258A1
WO2018004258A1 PCT/KR2017/006849 KR2017006849W WO2018004258A1 WO 2018004258 A1 WO2018004258 A1 WO 2018004258A1 KR 2017006849 W KR2017006849 W KR 2017006849W WO 2018004258 A1 WO2018004258 A1 WO 2018004258A1
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WO
WIPO (PCT)
Prior art keywords
dimethoxyphenyl
imidazo
pyrido
amino
acrylamide
Prior art date
Application number
PCT/KR2017/006849
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English (en)
Korean (ko)
Inventor
이문섭
변은영
김지숙
김원정
김남두
정승현
안영길
Original Assignee
한미약품 주식회사
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Priority claimed from KR1020170081047A external-priority patent/KR20180002053A/ko
Application filed by 한미약품 주식회사 filed Critical 한미약품 주식회사
Priority to EP17820534.0A priority Critical patent/EP3476846A4/fr
Priority to US16/313,778 priority patent/US10696675B2/en
Priority to JP2018568423A priority patent/JP2019520367A/ja
Priority to CN201780040926.5A priority patent/CN109476672A/zh
Publication of WO2018004258A1 publication Critical patent/WO2018004258A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • 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
    • C07D471/12—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 three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems

Definitions

  • the present invention relates to novel heterocyclic derivative compounds and uses thereof, and more particularly to novel heterocyclic derivative compounds having selective inhibitory activity against Fibroblast growth factor receptor (FGFR) and It relates to a pharmaceutical composition for preventing or treating various diseases associated with the FGFR comprising the same.
  • FGFR Fibroblast growth factor receptor
  • FGF fibroblast growth factor
  • FGFs include a family of 22 structurally related polypeptides with a variety of biological activities. Most of these signaling molecules function by binding to and activating their cognate receptors (FGFR; called FGFR1-4), a family of receptor tyrosine kinases (Eswarakumar et al., 2005; Ornitz and Itoh, 2001). ).
  • Mitogenic signaling by these FGFRs is subsequently mediated through a number of pathways including ras / raf / MAP kinase cascade (Ozawa et al., Teratog. Carcinog. Mutagen. , 2001, 21, 27-44).
  • FGFR-FGF signaling systems play an important role in development and tissue repair by regulating cell functions / processes such as growth, differentiation, migration, morphogenesis and angiogenesis.
  • FGFR FGFR signaling networks
  • overexpression, mutations, translocations and truncations may cause myeloma, breast, stomach, colon, bladder , Pancreas and hepatocellular carcinoma, are known to be associated with numerous human cancers (Bange et al., 2002; Cappeln et al., 1999; Chesi et al., 2001; Chesi et al., 1997; Gowardhan et. al., 2005; Jaakkola et al., 1993; Jang et al., 2001; Jang et al., 2000; Jeffers et al., 2002; Xiao et al., 1998].
  • fibroblast growth factor receptor 4 FGF receptor 4 or FGFR4
  • FGF19 fibroblast growth factor 19
  • FGFR4 or FGF19 described above is expressed or overexpressed in many cancers (See, e.g., Dieci et al. 2013, Cancer Discovery, OF1-OF16).
  • many studies have predicted that expression of FGFR4 or FGF19 is a phenotype that significantly accelerates disease progression in cancer patients.
  • FGFR4 or FGF19 expression was reduced or knocked down, cell proliferation decreased and cell death increased (See, e.g., Wesche et al. 2011, Biochem J, 437; 199-213).
  • FGF19 a selective ligand of FGFR4
  • FGF19 is associated with aggressiveness in many cancers, including liver cancer, skin cancers such as melanoma, rectal cancer, and thyroid cancer.
  • FGF19 is overexpressed in 30-50% of liver cancer patients.
  • PFS progression-free survival
  • OS overall survival
  • the risk index of the overexpressed group was higher than that of the non-overexpressed group. It was 2.3-3.6 times higher (S. Miura et al., 2012, BMC Cancer, 12, 1471-2407).
  • One object of the present invention is to provide a novel heterocyclic derivative compound having excellent selective inhibitory activity against fibroblast growth factor receptor.
  • Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of the compound.
  • R 1, R 2, R 3 and R 4 is selected from each independently H, halogen, C 1- 4 group consisting of alkyl and C 1- 4 alkoxy;
  • E is CH or N
  • D is NH or a bond
  • Q is hydrogen or Is
  • W is hydrogen, halogen or-(CH 2 ) p NR'R ";
  • R 'and R " is selected from the group consisting of H or C 1- 6 alkyl, each independently, wherein R' and R" are bonded to each other may form a 3- C 6 alkylene bridge, the alkylene At least one methylene in the bridge is unsubstituted or substituted with one or more selected from the group consisting of -O-, -S (O)-, -S (O) 2-, and -N (R ')-;
  • Ring A is selected from the group consisting of aryl, heteroaryl, cycloalkyl and heterocyclyl, wherein the heteroaryl represents a 5-7 membered aromatic ring containing 1 to 3 heteroatoms selected from O, N and S Heterocyclyl means a 5 to 7 membered cyclic moiety containing 1 to 3 heteroatoms or functional groups selected from N, O, S, SO and SO 2 ;
  • R 5 When the R 5 a plurality individuals they may be the same or different and form a 3- C 6 alkylene bridge adjacent R 5 are bonded to each other to each other, at least one methylene in the alkylene bridge is -O-, - Or unsubstituted or substituted with one or more selected from the group consisting of S (O)-, -S (O) 2-, and -N (R ')-;
  • R 6 is hydrogen, halogen, hydroxy, C 1- 6 alkyl, - (CH 2) q NR'R ", - (2 CH) q OR 7, C 3- 7 cycloalkyl, heterocyclyl, - (CH 2 ) q C ( ⁇ O) R 7 , — (CH 2 ) q SR 7 and — (CH 2 ) q SO 2 R 7 ;
  • C 1- 6 alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, hydroxy, -CN, straight chained or branched C 1- 6 alkyl, halogenated C 1 - 6 alkyl, C May be unsubstituted or substituted with one or more substituents selected from the group consisting of 3-7 cycloalkyl and heterocyclyl;
  • p and q are each independently integers of 0 to 6;
  • n is an integer of 0-4.
  • a pharmaceutical composition and a pharmaceutical formulation for the prophylaxis or treatment of various diseases related to the FGFR comprising the above compound in a therapeutically effective amount.
  • the heterocyclic derivative compound represented by the formula (1) provided in the present invention may be selectively used as a prophylactic or therapeutic agent for various diseases related to the FGFR because of its excellent inhibitory activity against FGFR.
  • 'halogen means fluorine, chlorine, bromine or iodine unless otherwise noted.
  • the term 'alkyl' refers to a saturated, straight-chain or branched hydrocarbon radical represented by CnH 2n +1 , specifically between 1 and 6, each between 1 and 6 It refers to a saturated, straight or branched hydrocarbon radical comprising between, between 1 and 10, or between 1 and 20 carbon atoms.
  • these radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, neopentyl, n-hexyl, heptyl, octyl radicals.
  • C 1- 6 alkyl refers to a hydrocarbon moiety having from 1 to 6 straight-chain or branched. Examples thereof include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, and the like.
  • the term 'alkenyl' refers to monovalent groups derived from unsaturated, straight chain or branched hydrocarbon moieties having at least one carbon-carbon double bond, in particular each It refers to an unsaturated, straight or branched monovalent group comprising between 2 and 6, between 2 and 8, between 2 and 10, or between 2 and 20 carbon atoms. Examples thereof include, but are not limited to, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl radicals.
  • 'alkynyl' refers to a monovalent group derived from an unsaturated, straight or branched hydrocarbon moiety having at least one carbon-carbon triple bond.
  • alkoxy is between 1 and 6, between 1 and 8, between 1 and 10, or between 1 and 20, each represented by OC n H 2n +1 . It refers to an oxygen radical having a monovalent group derived from a saturated, straight or branched hydrocarbon moiety containing carbon atoms.
  • C 1- 6 alkoxy are unless otherwise noted, means an oxygen radical having a hydrocarbon residue having 1 to 6 straight-chain or branched. Examples thereof include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy, pentoxy, hexoxy and the like.
  • 'cycloalkyl' refers to monovalent groups derived from monocyclic or polycyclic saturated or partially unsaturated carbocyclic ring compounds.
  • C 3- 7 cycloalkyl refers to a hydrocarbon moiety having 3 to 7 ring-shaped. Examples thereof include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • the term 'heterocyclyl' means a 3-7 membered cyclic moiety containing 1 to 3 heteroatoms or functional groups selected from N, O, S, SO and SO 2 . do. Examples thereof include oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydro-2 H -pyran-4-yl, tetrahydro-2 H -pyran-3-yl, oxepan-4-yl, ox Cefpan-3-yl, piperidin-1-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, morpholin-4-yl, thiomorpholin-4- 1,1,1-dioxide thiomorpholin-4-yl, pyrrolidin-1-yl, pyrrolidin-3-yl, azetidin-1-yl, azetidin-3-yl, aziridine-1
  • 'aryl' refers to a mono- or polycyclic carbocyclic ring system having 6 to 14 carbon atoms having one or more aromatic rings fused or non-fused, aryl Examples of include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indenyl, andracenyl, and the like.
  • heteroaryl' refers to five to five, containing one or more, for example one to four, preferably one to three heteroatoms selected from O, N and S. 12-membered, preferably 5-7 membered monocyclic or bicyclic or higher aromatic group.
  • Examples of monocyclic heteroaryl include thiazolyl, oxazolyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, isoxazolyl, pyrazolyl, triazolyl, thiadiazoleyl, tetrazoyl, oxadiazoleyl, pyridine 1, pyridazinyl, pyrimidinyl, pyrazinyl and the like, but are not limited to these.
  • bicyclic heteroaryl examples include indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, benztriazolyl, quinolinyl, iso Quinolinyl, purinyl, puropyridinyl, and the like, but are not limited to these.
  • 'alkylene bridge' as used in the present invention connects two different carbons of the same ring structure, may consist of carbon and hydrogen, contains no unsaturation, preferably has 3 to 6 carbon atoms Straight or branched chain divalent hydrocarbon bridges such as propylene, n -butylene and the like.
  • the alkylene bridge may connect any two carbons in the ring structure.
  • at least one methylene in the alkylene bridge is one or more selected from the group consisting of -O-, -S-, -S (O)-, -S (O) 2-, and -N (R ')-. to be substituted and, where, R 'is hydrogen, C 1- 6 alkyl, C 3- 7 cycloalkyl or aryl.
  • the present invention relates to a novel heterocyclic derivative compound of Formula 1 and its use, and more particularly to novel novel Formula 1 having selective inhibitory activity against Fibroblast growth factor receptor (FGFR).
  • FGFR Fibroblast growth factor receptor
  • a compound selected from a heterocyclic derivative compound of Formula 1, a pharmaceutically acceptable salt thereof, an optical isomer, a hydrate, and a solvate thereof is provided.
  • R 1, R 2, R 3 and R 4 is selected from each independently H, halogen, C 1- 4 group consisting of alkyl and C 1- 4 alkoxy;
  • E is CH or N
  • D is NH or a bond
  • Q is hydrogen or Is
  • W is hydrogen, halogen or-(CH 2 ) p NR'R ";
  • R 'and R " is selected from the group consisting of H or C 1- 6 alkyl, each independently, wherein R' and R" are bonded to each other may form a 3- C 6 alkylene bridge, the alkylene At least one methylene in the bridge is unsubstituted or substituted with one or more selected from the group consisting of -O-, -S (O)-, -S (O) 2-, and -N (R ')-;
  • Ring A is selected from the group consisting of aryl, heteroaryl, cycloalkyl and heterocyclyl, wherein the heteroaryl represents a 5-7 membered aromatic ring containing 1 to 3 heteroatoms selected from O, N and S Heterocyclyl means a 5 to 7 membered cyclic moiety containing 1 to 3 heteroatoms or functional groups selected from N, O, S, SO and SO 2 ;
  • R 5 When the R 5 a plurality individuals they may be the same or different and form a 3- C 6 alkylene bridge adjacent R 5 are bonded to each other to each other, at least one methylene in the alkylene bridge is -O-, - Or unsubstituted or substituted with one or more selected from the group consisting of S (O)-, -S (O) 2-, and -N (R ')-;
  • R 6 is hydrogen, halogen, hydroxy, C 1- 6 alkyl, - (CH 2) q NR'R ", - (CH 2) q OR 7, C 3- 7 cycloalkyl, heterocyclyl, - (CH 2 ) q C ( ⁇ O) R 7 , — (CH 2 ) q SR 7 and — (CH 2 ) q SO 2 R 7 ;
  • C 1- 6 alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, hydroxy, -CN, straight chained or branched C 1- 6 alkyl, halogenated C 1 - 6 alkyl, C May be unsubstituted or substituted with one or more substituents selected from the group consisting of 3-7 cycloalkyl and heterocyclyl;
  • p and q are each independently integers of 0 to 6;
  • n is an integer of 0-4.
  • E is N.
  • the compound represented by Chemical Formula 1 may be represented by the following Chemical Formula 2 to Chemical Formula 5:
  • X is selected from the group consisting of O, S, NH, and CH 2 ;
  • n is an integer from 0 to 2;
  • At least one of Z 1 to Z 4 is N and the others are each independently N or C (R 5 );
  • Y is selected from the group consisting of O, S and N (R 5 );
  • R 1 to R 5 , D, E, W, and n are as defined in the formula (1).
  • any one of Z 1 to Z 4 is N and the other compound is C (R 5 ).
  • Y is N (R 5 ), and any one of Z 1 and Z 2 provides a compound.
  • Preferred examples of the compound of Formula 1 according to the present invention include, but are not limited to:
  • a method for preparing the compound represented by Chemical Formula 1 is not particularly limited, but may be synthesized by, for example, a method of preparing the following Reaction Schemes 1, 2, 3, 4 or 5:
  • R 1 , R 2 , R 3 and R 4 are each as defined in Formula 1.
  • a compound represented by Chemical Formula 5 ' is synthesized by conducting a compound of Chemical Formula 4 and 2-phenylacetonitrile having four substituents at 2,3,4,5 positions in the presence of a base such as NaH. , And reacted with 1,2-dichloroethyl ethyl ether or chloroacetaldehyde to synthesize the imidazole ring to synthesize a compound represented by the formula (7) consisting of three rings.
  • the compound represented by Chemical Formula 8 was synthesized by oxidizing sulfide of the compound represented by Chemical Formula 7 using mCPBA or oxone.
  • R 1, R 2, R 3 and R 4 are as defined in formula (I).
  • E1 in Scheme 5 is hydrogen, NO 2 , N 3 , NH-Boc;
  • the compound represented by the formula (8), (9) and (14) in the scheme 5 is reacted with an amine or aniline in which the amine group is protected under a base or palladium catalyst to synthesize the compound represented by the formula (15), represented by the formula (15)
  • the compound represented by the formula (16) was synthesized by deprotecting the amine protecting group from the compound under reduced or acid catalyst, and the compound represented by the formula (1) was synthesized by introducing an acrylic group into the compound represented by the formula (16).
  • the compounds according to the invention can also form pharmaceutically acceptable salts.
  • Such pharmaceutically acceptable salts are not particularly limited as long as they form acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions.
  • inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, etc .
  • Organic carbon acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, and the like
  • acid addition salts formed by sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid and the like.
  • the compounds according to the invention may have an asymmetric carbon center and therefore may exist as R or S isomers, racemic compounds, diastereomeric mixtures, or individual diastereomers, all of these isomers and mixtures being within the scope of the invention. Included.
  • a pharmaceutical composition containing a therapeutically effective amount of a compound selected from the compound of Formula 1 and a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the present invention is useful for preventing or treating various diseases related thereto by inhibiting the activity of the fibroblast growth factor receptor (FGFR) compound represented by Formula 1 included therein.
  • FGFR fibroblast growth factor receptor
  • the pharmaceutical composition is a pharmaceutical composition for preventing or treating cancer or a tumor
  • the cancer is liver cancer, liver cell carcinoma, hepatocellular carcinoma, thyroid cancer , Colorectal cancer, testicular cancer, testicular cancer, bone cancer, oral cancer, basal cell carcinoma, ovarian cancer, brain tumor, gallbladder carcinoma, biliary tract cancer, head and neck cancer, colorectal cancer, bladder cancer, vesical carcinoma, tongue cancer, esophageal cancer, glioma , Glioblastoma, renal cancer, malignant melanoma, gastric cancer, breast cancer, sarcoma, pharynx carcinoma, uterine cancer ), Cervical cancer, prostate cancer, rectal cancer cancer, pancreatic cancer, lung cancer, skin cancer and other solid cancers, but are not limited to these.
  • a pharmaceutical formulation comprising the pharmaceutical composition described above.
  • the pharmaceutical preparations of the invention may be in various oral dosage forms, such as tablets, pills, powders, capsules, syrups or emulsions, or parenteral dosage forms such as intramuscular, intravenous or subcutaneous administration, such as injections, preferably oral Dosage forms.
  • the pharmaceutical preparation is a conventional non-toxic pharmaceutically acceptable additive in addition to the active ingredient, and may be formulated according to a conventional method by adding one or more selected from the group consisting of, for example, a carrier, an adjuvant, and an excipient. have.
  • Excipients that may be used in the pharmaceutical formulations of the present invention may include sweeteners, binders, solubilizers, solubilizers, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, fragrances, and the like.
  • the present invention is not limited thereto.
  • lactose lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, magnesium aluminum silicate, starch, gelatin, tragacanth gum, alginate, sodium alginate, methylcellulose, sodium carboxymethyl Cellulose, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor and the like can be used.
  • examples of the carrier used include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin , Talc, and the like, but are not limited thereto.
  • the carrier may include water, saline solution, aqueous glucose solution, pseudoglucose solution, alcohol, glycol, ether, oil, fatty acid, fatty acid ester, glyceride, and the like. Does not.
  • the compounds according to the invention are prepared in the form of pharmaceutical preparations, which are suitable for use in addition to the active ingredient for oral or parenteral administration, for example, pharmaceutically organic or inorganic inert carrier materials such as water, gelatin, Gum arabic, lactose, starch, vegetable oil, polyalkylene glycol and the like.
  • Pharmaceutical formulations may be in solid form, eg, tablets, dragees, suppositories or capsules, or in liquid form, eg, solutions, suspensions or emulsions. In addition, they may optionally contain auxiliaries such as preservatives, stabilizers, wetting agents or emulsifiers; It contains an osmotic pressure modifying salt or buffer.
  • injectable solutions or suspensions are particularly preferred.
  • surfactant aids such as bile salts or animal or plant phospholipids, also mixtures thereof, and liposomes or components thereof.
  • tablets, dragees or capsules containing talc and / or hydrocarbon vehicles or binders for example lactose, corn or potato starch, are particularly suitable. It may also be administered in liquid form, such as juice with added sweeteners.
  • the dose of the compound of Formula 1 according to the present invention to the human body is generally in the range of 0.1 mg / day to 2,000 mg / day based on an adult patient weighing 70 kg.
  • the compounds according to the invention can be administered once daily to divided doses.
  • the dosage may vary depending on the patient's state of health, age, weight and sex, dosage form and degree of disease, and thus the scope of the present invention is not limited to the above-described dosage.
  • Step 7 N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3- d ] pyridine Preparation of midin-2-yl) amino) cyclopentyl) acrylamide
  • Step 3 N -((3S, 4S) -3-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2 Preparation of, 3- d ] pyrimidin-2-yl) amino) tetrahydro-2H-pyran-4-yl) acrylamide
  • Step 3 N- (2-((6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrid Preparation of midin-2-yl) amino) phenyl) acrylamide
  • Step 3 6- (2,6-Difluoro-3,5-dimethoxyphenyl) -2- (methylsulfonyl) imidazo [1 ', 2': 1,6] pyrido [2,3- d] preparation of pyrimidine
  • Step 2 4- (3- (6- (2,6-dichloro-3,5-dimethoxyphenyl) imidazo [1 ', 2': 1,6] pyrido [2,3-d] pyrimidine Preparation of -2-yl) phenyl) morpholine
  • Inhibitory activity against FGFR1, 2, 3, 4 kinases was measured for the synthetic compounds. Activity measurements were conducted by the Commission Invitrogen Corporation SelectScreen ® Biochemical Kinase Profiling Service. Z'-LYTE ® biochemical assays were used and ATP concentrations were set based on Km values. The results are shown in Table 1 in percent inhibition of kinase activity of the control group.
  • HUH7 cell lines After counting HUH7 cell lines, 96 well plates were inoculated with 5.0 X 10 3 cells per well. After inoculation, the cells were incubated for 24 hours in 37, 5% carbon dioxide (CO 2 ) incubator. The next day, the synthetic compounds were prepared by diluting each. Diluted compounds were added to the cell lines inoculated the day before by concentration, and reacted in 37, 5% carbon dioxide (CO 2 ) incubator for 72 hours. However, in the positive control without compound, 0.1% DMSO (DMSO, dimethyl sulfoxide) diluted with medium was added.
  • DMSO dimethyl sulfoxide
  • Negative control plate was fixed at 4 and put trichloroacetic acid (TCA, Trichloroacetic acid) solution. After the reaction for 72 hours, the medium containing the compound was removed, then the TS solution was added, and the cells were fixed at 4 to 30 to 60 minutes. The TS solution was discarded and the plate was washed with distilled water and then dried in air. 0.4% ESB (SRB, Sulforhodamin B) solution was added to the plate and stained at room temperature for 10 minutes. The plates were washed with tap water containing 1% acetic acid solution and then dried in air. 10 mM Trisma base solution was added to dissolve the solid SALB. Absorbance (OD value) was measured at 540 nm with a Microplate Reader. GI 50 values of each compound were calculated using GraphPad Prism V6.0 Software. The results are shown in Table 1 below.

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Abstract

La présente invention concerne un nouveau dérivé hétérocyclique et son utilisation et plus particulièrement, un nouveau dérivé hétérocyclique ayant une activité inhibitrice sélective contre un récepteur du facteur de croissance des fibroblastes (FGFR), et une composition pharmaceutique comprenant celui-ci, pour prévenir ou traiter diverses maladies associées au FGFR.
PCT/KR2017/006849 2016-06-28 2017-06-28 Nouveau dérivé hétérocyclique et son utilisation WO2018004258A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP17820534.0A EP3476846A4 (fr) 2016-06-28 2017-06-28 Nouveau dérivé hétérocyclique et son utilisation
US16/313,778 US10696675B2 (en) 2016-06-28 2017-06-28 Imidazopyridopyrimidine derivative compound and use thereof
JP2018568423A JP2019520367A (ja) 2016-06-28 2017-06-28 新規なヘテロサイクリック誘導体化合物およびその用途
CN201780040926.5A CN109476672A (zh) 2016-06-28 2017-06-28 新型杂环衍生物化合物及其用途

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KR10-2016-0080785 2016-06-28
KR20160080785 2016-06-28
KR1020170081047A KR20180002053A (ko) 2016-06-28 2017-06-27 신규한 헤테로시클릭 유도체 화합물 및 이의 용도
KR10-2017-0081047 2017-06-27

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JP2020509089A (ja) * 2017-02-27 2020-03-26 ▲貝▼▲達▼▲薬▼▲業▼股▲フン▼有限公司Ｂｅｔｔａ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｃｏ．， Ｌｔｄ． Ｆｇｆｒ阻害剤およびその使用
CN109721600B (zh) * 2017-10-30 2021-04-27 上海凌达生物医药有限公司 一类含氮稠环化合物及其制备方法和用途
WO2019085894A1 (fr) * 2017-10-30 2019-05-09 如东凌达生物医药科技有限公司 Composé cyclique fusionné contenant de l'azote, son procédé de préparation et son utilisation
CN109721600A (zh) * 2017-10-30 2019-05-07 如东凌达生物医药科技有限公司 一类含氮稠环化合物及其制备方法和用途
WO2020038458A1 (fr) * 2018-08-23 2020-02-27 如东凌达生物医药科技有限公司 Classe de composé de triazole cyclique fusionné, procédé de préparation et utilisation
CN110857300A (zh) * 2018-08-23 2020-03-03 如东凌达生物医药科技有限公司 一类稠环三氮唑类化合物、制备方法和用途
CN110857300B (zh) * 2018-08-23 2021-11-05 上海凌达生物医药有限公司 一类稠环三氮唑类化合物、制备方法和用途
JP2022502438A (ja) * 2018-09-27 2022-01-11 貝達薬業股▲ふん▼有限公司Betta Pharmaceuticals Co., Ltd Ｆｇｆｒ４阻害剤及びその使用
CN112771049B (zh) * 2018-09-27 2024-01-26 贝达药业股份有限公司 Fgfr4抑制剂及其应用
CN112771049A (zh) * 2018-09-27 2021-05-07 贝达药业股份有限公司 Fgfr4抑制剂及其应用
CN110950867A (zh) * 2018-09-27 2020-04-03 首药控股(北京)有限公司 一种fgfr4激酶抑制剂及其制备方法和用途
JP7446287B2 (ja) 2018-09-27 2024-03-08 貝達薬業股▲ふん▼有限公司 Ｆｇｆｒ４阻害剤及びその使用
WO2020063788A1 (fr) * 2018-09-27 2020-04-02 贝达药业股份有限公司 Inhibiteur de fgfr4 et son utilisation
TWI822868B (zh) * 2018-09-27 2023-11-21 大陸商貝達藥業股份有限公司 Ｆｇｆｒ４抑制劑、包含其的藥物組合物及其用途
EP3848377A4 (fr) * 2018-09-27 2022-06-15 Betta Pharmaceuticals Co., Ltd Inhibiteur de fgfr4 et son utilisation
JP2022523448A (ja) * 2019-03-08 2022-04-22 ショウヤオ ホールディングス（ベイジン） カンパニー， リミテッド Ｆｇｆｒ４キナーゼ阻害剤、その製造方法及び用途
JP7378488B2 (ja) 2019-03-08 2023-11-13 ショウヤオ ホールディングス（ベイジン） カンパニー， リミテッド Ｆｇｆｒ４キナーゼ阻害剤、その製造方法及び用途
EP3936509A4 (fr) * 2019-03-08 2022-03-30 Shouyao Holdings (Beijing) Co., Ltd. Inhibiteur de fgfr4 kinase, son procédé de préparation et son utilisation
CN113646314B (zh) * 2019-03-08 2023-12-08 首药控股(北京)股份有限公司 Fgfr4激酶抑制剂及其制备方法和用途
WO2020182062A1 (fr) * 2019-03-08 2020-09-17 首药控股(北京)有限公司 Inhibiteur de fgfr4 kinase, son procédé de préparation et son utilisation
CN113646314A (zh) * 2019-03-08 2021-11-12 首药控股(北京)股份有限公司 Fgfr4激酶抑制剂及其制备方法和用途
CN115397827A (zh) * 2020-03-27 2022-11-25 贝达药业股份有限公司 Fgfr4抑制剂的盐型、晶型及其用途
CN115397827B (zh) * 2020-03-27 2024-03-15 贝达药业股份有限公司 Fgfr4抑制剂的盐型、晶型及其用途
EP4130004A4 (fr) * 2020-03-27 2024-04-10 Betta Pharmaceuticals Co., Ltd Sel et formes cristallines d'inhibiteur de fgfr4 et leurs utilisations

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