WO2016029839A1 - Dérivé aminé (subtitué phényle) (substitué pyrimidine), son procédé de préparation, et utilisation comme médicament - Google Patents

Dérivé aminé (subtitué phényle) (substitué pyrimidine), son procédé de préparation, et utilisation comme médicament Download PDF

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WO2016029839A1
WO2016029839A1 PCT/CN2015/088015 CN2015088015W WO2016029839A1 WO 2016029839 A1 WO2016029839 A1 WO 2016029839A1 CN 2015088015 W CN2015088015 W CN 2015088015W WO 2016029839 A1 WO2016029839 A1 WO 2016029839A1
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alkyl
methyl
group
amino
heterocyclic ring
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PCT/CN2015/088015
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English (en)
Chinese (zh)
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魏用刚
李瑶
张国彪
邱关鹏
胡仕红
陈雷
李升�
张黔
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四川海思科制药有限公司
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Priority to CN201580023470.2A priority Critical patent/CN106458969A/zh
Publication of WO2016029839A1 publication Critical patent/WO2016029839A1/fr

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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a (substituted phenyl) (substituted pyrimidine) amino derivative of the formula (I), and optical isomers, pharmaceutically acceptable salts or cocrystals thereof, and a process for the preparation thereof Use in the preparation of oncology drugs.
  • the receptor tyrosine kinase superfamily in cell surface receptors plays an important role in the regulation of cellular signaling by extracellular growth factors.
  • the receptor tyrosine kinase is capable of catalyzing the transfer of a phosphate group from ATP to the tyrosine group of the substrate.
  • these kinases are in an unphosphorylated monomer state, and their kinase domain is in an inactive structure.
  • the receptor When the ligand binds to the extracellular domain of the receptor tyrosine kinase, the receptor undergoes oligomerization, and autophosphorylation increases the catalytic activity of the kinase and forms a binding site for the signaling protein, and the signal protein binds thereto. Thereby a plurality of signal paths are activated. These signaling pathways are linked to each other to regulate cell proliferation, survival, differentiation, function, migration and apoptosis.
  • the ErbB family belongs to the receptor tyrosine kinase and contains four members: epidermal growth factor receptor (EGFR/HER1/ErbB1), HER2 (neu/ErbB2), HER3 (ErbB3), and HER4 (ErbB4) (Olayioye, Neve et al. 2000, EMBO J, 19, 3159-3167; Yarden and Sliwkowski, 2001, Nat Rev Mol Cell Biol, 2, 127-137). They all contain an extracellular ligand binding domain, a single transmembrane domain, and an intracellular tyrosine kinase and regulatory domain.
  • Ligand-dependent receptor oligomerization results in autophosphorylation of the regulatory domain of the receptor, resulting in intracellular signal transduction, which ultimately leads to cell proliferation.
  • This signaling pathway is closely related to the occurrence and development of tumors.
  • hyperactivated ErbB receptors particularly EGFR
  • Activation of EGFR is usually due to continuous activation or self-division of ligands due to overexpression or mutation Secret expression.
  • the first generation of EGFR kinase inhibitors such as gefitinib and erlotinib are clinically effective in the treatment of non-small cell lung cancer, especially those with activating mutations in the EGFR kinase domain (Mok, Wu et al. 2009, N Engl J Med, 361, 947-957; Rosell, Moran et al, 2009, N Engl J Med, 361, 958-967).
  • the most common EGFR activating mutations are L858R and delE746_A750, which increase the affinity of the receptor for gefitinib and erlotinib compared to wild-type EGFR, while reducing the affinity of the receptor for ATP (Carey, Garton et al.
  • EGFR T790M Engelman, Zejnullahu et al, 2007, Cancer Res, 67, 11924-11932; Li, Ambrogio et al, 2008, Oncogene, 27, 4702-4711.
  • existing irreversible inhibitors have a lower ability to inhibit EGFR T790M mutations in cell line models than to inhibit EGFR-only activating mutations, and at clinically available concentrations, such compounds are unable to inhibit EGFR in vitro.
  • T790M Yamamoto, Glatt et al, 2007, Cancer Biol Ther, 6, 661-667; Godin-Heymann, Ulkus et al, 2008, Mol Cancer Ther, 7, 874-879).
  • quinazoline EGFR inhibitors also inhibit wild-type EGFR while inhibiting EGFR T790M.
  • simultaneous inhibition of wild-type EGFR can lead to rash and diarrhea in patients, which limits the dose of second-generation EGFR inhibitors, so that the plasma concentration of the drug is not sufficient to inhibit T790M, making the clinical effectiveness of such drugs Subject to greater restrictions.
  • CI-1033, HKI-272, and PF00299804 are clinically very limited in the treatment of gefitinib and erlotinib-resistant non-small cell lung cancer, and dose-dependent diarrhea and rash occur. (Janne, von Pawel et al, 2007, J Clin Oncol, 25, 3936-3944; Advani, Coiffier et al, 2010, J Clin Oncol, 28, 2085-2093).
  • a third-generation EGFR mutation selective inhibitor was introduced.
  • Such irreversible inhibitors have higher selectivity for EGFR T790M than the second-generation quinoline compounds, and may have higher activity and better tolerance in clinic.
  • the covalent pyrimidine EGFR inhibitor WZ4002 in vitro, is 30-100 fold more selective for EGFR T790M than the quinoline compound, and 100 times less resistant to wild-type EGFR. It also exhibited good pharmacodynamics in the EGFR T790M-derived animal lung cancer model (Zhou, Ercan et al, 2009, Nature, 462, 1070-1074).
  • Another mutant selective inhibitor, co-1686 is 10-25 fold more selective for EGFR T790M than wild-type EGFR in vitro. It can selectively inhibit EGFR mutations, including the resistant mutant T790M and activating mutations (L858R, del19), but not the wild-type EGFR. In vitro, oral co-1686 can cause tumor regression in the T790M mutation and does not mediate further drug-resistant mutations in tumor cells (Walter, Sjin et al, 2013, Cancer Discov, 3, 1404-1415). In order to meet clinical needs, it is necessary to continue to develop EGFR inhibitors that do not produce significant toxic side effects at concentrations that are effective in overcoming T790M mutations.
  • WO2009051822 discloses pyrimidine derivatives which are useful as EGFR inhibitors and their use in the treatment of cancer.
  • a and B are selected from carbocyclic or heterocyclic rings, and the structure is as follows:
  • WO2011140338 describes heterocyclic derivatives which are useful as EGFR inhibitors, and as antitumor drugs.
  • B is selected from 6 to 10 members of a monoaryl or diheteroaryl group containing at least one N atom
  • X1 is selected from O, S or N
  • R 29 , R 29a and R29b are each independently selected from H, 5 to 6 A non-heteroaryl group, a 5 to 6 membered non-heteroarylmethylene group or a 5 to 6 membered non-heteroarylcarbonyl group, the structure is as follows:
  • R 3 is H, C 2-4 alkenyl, C 3-4 cycloalkyl, C 1-4 alkyl or C 1-4 alkoxy, preferably H, C 1-4 alkyl or C 1-4 alkane An alkoxy group; optionally the alkoxy group is further substituted with 0 to 4 substituents selected from F, Cl or Br;
  • R 4a is selected from a C 3-4 carbocyclic ring or a 5-membered heterocyclic ring containing from 1 to 4 heteroatoms selected from N, O, S, optionally further from 0 to 4 a substituent selected from the group consisting of F, Cl, Br, I, amino, hydroxy, -NHCH 3 , -N(CH 3 ) 2 , methyl or ethyl;
  • R 4b is selected from a C 3-4 carbocyclic ring or a 4 to 6 membered heterocyclic ring containing from 1 to 4 heteroatoms selected from N, O, S, which are optionally further Substituted to four substituents selected from the group consisting of F, Cl, Br, I, amino, hydroxy, -NH(CH 3 ), -N(CH 3 ) 2 , -CH 2 CH 2 F, methyl or ethyl;
  • n is selected from 0, 1, 2 or 3.
  • R 3 is selected from H, methyl, ethyl, vinyl, cyclopropyl, methoxy, fluoromethoxy, difluoromethoxy or trifluoromethoxy, preferably H, ethyl, methoxy Or difluoromethoxy;
  • R 4 is selected from the group consisting of H, F, Cl, 7 to 11 membered spiro ring, 3 to 6 membered heterocyclic ring, -Z-(CH 2 ) n R 4a , -O-(CH 2 ) n R 4b , -Z-( CH 2 ) n NR 4c R 4d or -O-(CH 2 ) n NR 4c R 4d , preferably F, 7 to 11 membered spiro ring, 3 to 6 membered heterocyclic ring, -Z-(CH 2 ) n R 4a , -O-(CH 2 ) n R 4b , -Z-(CH 2 ) n NR 4c R 4d or -O-(CH 2 ) n NR 4c R 4d ; the heterocyclic ring contains 1 to 4 selected from N, a hetero atom of O or S, said CH 2 , spiro or heterocyclic ring optionally further
  • Z is selected from -NH- or -N(CH 3 )-;
  • R 4c and R 4d are selected from H, methyl or ethyl, preferably H or methyl;
  • R 5 is selected from H, F, Cl or morpholinyl, preferably H, F or morpholinyl;
  • R 5 is selected from H, F, Cl or morpholinyl, preferably H, F or morpholinyl;
  • R 1a and R 1b are selected from H or C 1-4 alkyl
  • R 2 is selected from H, F, Cl, Br, I, C 1-4 alkyl or C 1-4 alkoxy, said alkyl or alkoxy optionally further being 0, 1, 2, 3 or Substituted by four substituents selected from H, F, Cl, Br, I, C 1-4 alkyl or C 1-4 alkoxy;
  • R 3 is H, C 2-6 alkenyl, C 3 cycloalkyl, C 4 cycloalkyl, C 5 cycloalkyl, C 6 cycloalkyl, C 1-4 alkyl or C 1-4 alkoxy
  • the alkenyl, cycloalkyl, alkyl or alkoxy group optionally further 0, 1, 2, 3 or 4 is selected from H, F, Cl, Br, I, C 1-4 alkyl or C Substituted by a substituent of 1-4 alkoxy;
  • R 4 is selected from the group consisting of H, F, Cl, Br, I, 9-membered spiro, Z-(CH 2 ) n R 4a , O-(CH 2 ) n R 4b or O-(CH 2 ) n NR 4c R 4d
  • the spiro ring contains 1, 2, 3 or 4 heteroatoms selected from N, O, S, optionally further 0, 1, 2, 3 or 4 selected from H, F, Cl Substituted with a substituent of Br, I, C 1-4 alkyl or C 1-4 alkoxy;
  • R 4 is selected from Z-(CH 2 ) n -6 membered heterocyclic ring, 3-membered heterocyclic ring, 4-membered heterocyclic ring, 5-membered heterocyclic ring, 6-membered heterocyclic ring or N(CH 3 )-(CH 2 )
  • the heterocyclic ring contains 1 to 4 hetero atoms selected from N, O, S, and the heterocyclic ring is optionally further further further 0 to 4 H, F, Cl, Br, I, Substituted by an amino group, a C 1-4 alkyl group or a substituent of an amino group substituted by 1 to 2 C 1-4 alkyl groups, the other groups are defined by one of the following conditions:
  • R 3 is selected from ethyl or C 1-4 alkyl substituted by 1, 2 or 3 F, Cl, Br or I,
  • R 2 is selected from C 1-4 alkoxy or substituted with 1,2 or 3 F, Cl, Br or I substituted C 1-4 alkoxy,
  • Z is selected from NH or NC 1-4 alkyl
  • R 4b is selected from a C 3 carbocyclic ring, a C 4 carbocyclic ring, a C 5 carbocyclic ring, a C 6 carbocyclic ring, a 3-membered heterocyclic ring, a 4-membered heterocyclic ring, a 5-membered heterocyclic ring or a 6-membered heterocyclic ring containing 1 , 2, 3 or 4 heteroatoms selected from N, O, S, optionally further 0, 1, 2, 3 or 4 selected from H, F, Cl, Br, I Substituted with an amino group, a C 1-4 alkyl group or a substituent of an amino group substituted with 1 to 2 C 1-4 alkyl groups;
  • R 4c and R 4d are selected from H or C 1-4 alkyl
  • n is selected from 0, 1, or 2.
  • B is selected from an 8-membered heterocyclic ring, a 9-membered heterocyclic ring or a 10-membered heterocyclic ring, preferably a 9-membered heterocyclic ring, further preferably a pyridopyrazolyl group or a benzopyrrolyl group, which is optionally further further further 0, 1, 2 , 3 or 4 R 1 substituted, the heterocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from N, O, S;
  • R 1a and R 1b are selected from H or C 1-4 alkyl
  • a preferred embodiment of the invention is a compound of the formula (II) and an optical isomer, a pharmaceutically acceptable salt or a eutectic thereof, wherein:
  • R 4 is selected from the group consisting of H, F, Cl, 9-membered spiro, Z-(CH 2 ) n R 4a , O-(CH 2 ) n R 4b or O-(CH 2 ) n NR 4c R 4d , the snail
  • the ring contains 1, 2, 3 or 4 heteroatoms selected from N, O, S, optionally further 0, 1, 2, 3 or 4 selected from H, F, Cl, Br, I Substituted by a methyl or ethyl substituent;
  • the heterocyclic ring contains 1 to 4 hetero atoms selected from N, O, S, optionally further 0 to 4 selected from H, F, Cl Substituted by a substituent of Br, I, amino, NHCH 3 , N(CH 3 ) 2 , methyl or ethyl, the other groups are defined by one of the following conditions:
  • R 3 is selected from ethyl or C 1-4 alkyl substituted by 1, 2 or 3 F, Cl, Br or I, preferably methyl substituted by 1, 2 or 3 F,
  • R 2 is selected from C 1-4 alkoxy or substituted with 1,2 or 3 F, Cl, Br or I substituted C 1-4 alkoxy, preferably methoxy, fluoromethoxy, Difluoromethoxy or trifluoromethoxy,
  • Z is selected from NH or NC 1-4 alkyl
  • R 4b is selected from a C 3 carbocyclic ring, a C 4 carbocyclic ring, a 5-membered heterocyclic ring or a 6-membered heterocyclic ring, preferably a cyclopropyl group, a tetrahydropyrrolyl group or a piperazinyl group, the heterocyclic ring containing 1, 2, 3 or 4 a hetero atom selected from N, O, S, optionally further 0, 1, 2, 3 or 4 selected from the group consisting of H, F, Cl, Br, I, amino, NHCH 3 , Substituted by a substituent of N(CH 3 ) 2 , methyl or ethyl;
  • R 4c and R 4d are selected from H, methyl or ethyl.
  • a preferred embodiment of the invention is a compound of the formula (II) and an optical isomer, a pharmaceutically acceptable salt or a eutectic thereof, wherein:
  • B is selected from an 8-membered heterocyclic ring, a 9-membered heterocyclic ring or a 10-membered heterocyclic ring, which is optionally further substituted by 0, 1, 2, 3 or 4 R 1 , which contains 1, 2, 3 Or 4 heteroatoms selected from N, O, S;
  • R 1a and R 1b are selected from H or C 1-4 alkyl
  • R 2 is selected from H, F, Cl, C 1-4 alkyl or C 1-4 alkoxy;
  • R 3 is H, C 2-4 alkenyl, C 3-4 cycloalkyl, C 1-4 alkyl or C 1-4 alkoxy, said alkoxy optionally further 0, 1, 2, 3 Or 4 substituted with a substituent selected from H, F, Cl or Br;
  • R 4 is selected from the group consisting of H, F, Cl, 9-membered spiro, Z-(CH 2 ) n R 4a , O-(CH 2 ) n R 4b or O-(CH 2 ) n NR 4c R 4d , the snail
  • the ring contains 1, 2, 3 or 4 heteroatoms selected from N, O, S, optionally further 0, 1, 2, 3 or 4 selected from H, F, Cl, Br, I Substituted by a methyl or ethyl substituent;
  • the heterocyclic ring contains 1 to 4 hetero atoms selected from N, O, S, optionally further 0 to 4 selected from H, F, Cl Substituted by a substituent of Br, I, amino, NHCH 3 , N(CH 3 ) 2 , methyl or ethyl, the other groups are defined by one of the following conditions:
  • R 3 is selected from ethyl or C 1-4 alkyl substituted by 1, 2 or 3 F, Cl, Br or I,
  • R 2 is selected from C 1-4 alkoxy or substituted with 1,2 or 3 F, Cl, Br or I substituted C 1-4 alkoxy,
  • B is selected from a 9-membered heterocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, optionally further 1, 2, 3 or 4 Substituted by a substituent selected from H, F, Cl, Br, I, SO 2 CH 3 , methyl, isopropyl or cyclopropyl;
  • Z is selected from NH or NC 1-4 alkyl
  • R 4a is selected from a C 3 carbocyclic ring, a C 4 carbocyclic ring or a 5-membered heterocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from N, O, S, said carbocyclic or heterocyclic ring Optionally further taken by 0, 1, 2, 3 or 4 substituents selected from H, F, Cl, Br, I, amino, NHCH 3 , N(CH 3 ) 2 , methyl or ethyl;
  • R 4b is selected from a C 3 carbocyclic ring, a C 4 carbocyclic ring, a 5-membered heterocyclic ring or a 6-membered heterocyclic ring containing 1, 2, 3 or 4 hetero atoms selected from N, O, S,
  • the carbocyclic or heterocyclic ring is optionally further substituted by 0, 1, 2, 3 or 4 selected from H, F, Cl, Br, I, amino, NHCH 3 , N(CH 3 ) 2 , methyl or ethyl.
  • R 4c and R 4d are selected from H, methyl or ethyl
  • R 5 is a 5- to 6-membered heterocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from N, O, S
  • a preferred embodiment of the invention is a compound of the formula (II) and an optical isomer, a pharmaceutically acceptable salt or a eutectic thereof, wherein:
  • B is selected from a 9-membered heterocyclic ring, preferably a pyridopyrazolyl or a benzopyrrolyl group, which is optionally further substituted by 0, 1, 2, 3 or 4 R 1 , which contains 1, 2 , 3 or 4 heteroatoms selected from N, O, S;
  • R 2 is selected from H, F, Cl, methyl or methoxy
  • R 3 is selected from H, methyl, ethyl, vinyl, cyclopropyl, methoxy, fluoromethoxy, difluoromethoxy or trifluoromethoxy, preferably H, methoxy, cyclopropane Or difluoromethoxy;
  • R 4 is selected from the group consisting of H, F, Cl, 9-membered spiro, Z-(CH 2 ) n R 4a , O-(CH 2 ) n R 4b or O-(CH 2 ) n NR 4c R 4d , the snail
  • the ring contains 1, 2, 3 or 4 heteroatoms selected from N, O, S, optionally further 0, 1, 2, 3 or 4 selected from H, F, Cl, Br, I Substituted by a methyl or ethyl substituent;
  • the heterocyclic ring contains 1 to 4 hetero atoms selected from N, O, S, optionally further 0 to 4 selected from H, F, Cl
  • the substituents of Br, I, amino, NHCH 3 , N(CH 3 ) 2 , methyl or ethyl are taken, and other groups are defined by one of the following conditions:
  • R 3 is selected from ethyl or methyl substituted by 1, 2 or 3 F, preferably difluoromethoxy,
  • B is selected from a 9-membered heterocyclic ring, preferably a pyridopyrazolyl or a benzopyrrolyl group, the heterocyclic ring containing 1, 2, 3 or 4 hetero atoms selected from N, O, S, the hetero
  • the ring, pyridopyrazolyl or benzopyrrolyl group is optionally further 1, 2, 3 or 4 selected from H, F, Cl, Br, I, SO 2 CH 3 , methyl, isopropyl or cyclopropane. Substituted by a substituent of the group;
  • Z is selected from NH or NCH 3 ;
  • R 4a is selected from substituted or unsubstituted cyclopropyl or tetrahydropyrrolyl, and when substituted, optionally further 0, 1, 2, 3 or 4 selected from H, F, Cl, Br, I, Substituted by a substituent of an amino group, NHCH 3 , N(CH 3 ) 2 , methyl or ethyl;
  • R 4b is selected from substituted or unsubstituted cyclopropyl, tetrahydropyrrolyl or piperazinyl, and when substituted, optionally further selected from 0, 1, 2, 3 or 4 selected from H, F, Cl, Br Substituted with a substituent of I, amino, NHCH 3 , N(CH 3 ) 2 , methyl or ethyl;
  • R 4c and R 4d are selected from H, methyl or ethyl
  • R 5 is morpholinyl, piperazinyl, piperidinyl or tetrahydropyrrolyl, preferably morpholinyl or piperazinyl, said morpholine
  • a preferred embodiment of the invention a compound of the formula (II), and an optical isomer, a pharmaceutically acceptable salt or a eutectic thereof, wherein
  • R 2 is selected from H, F, Cl, methyl or methoxy
  • R 4 is selected from H, F, Cl or one of the following structures:
  • R 4 when other groups are defined, one of the following conditions may be selected:
  • R 3 is selected from ethyl or methyl substituted by 1, 2 or 3 F.
  • R 2 is a methoxy group
  • B is selected from Or one of the following structures replaced by 1 F:
  • R 5 is selected from the group consisting of H, F, Cl, morpholinyl, piperazinyl, piperidinyl or tetrahydropyrrolyl;
  • R 5 is morpholinyl, piperazinyl, piperidinyl or tetrahydropyrrolyl.
  • a preferred embodiment of the invention is a compound of the formula (I) or formula (II), wherein the compound is selected from one of the following structures:
  • the present invention relates to a compound represented by the formula (I) or the formula (II), and an optical isomer, a pharmaceutically acceptable salt or a cocrystal thereof, wherein the salt is selected from the group consisting of a hydrochloride, a sulfate, and a phosphoric acid. Salt, acetate, trifluoroacetate, fumarate, benzoate, besylate, methanesulfonate, triflate or combinations thereof.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of the inventions described in the invention and an optical isomer, pharmaceutically acceptable salt or co-crystal thereof, and A pharmaceutically acceptable carrier or excipient.
  • the invention further relates to the use of a compound of the invention and an optical isomer, pharmaceutically acceptable salt or co-crystal thereof, or a pharmaceutical composition as described above, in the manufacture of a medicament for the treatment of cancer.
  • the cancer includes head and neck cancer, ovarian cancer, bladder cancer, cervical cancer, esophageal cancer, gastric cancer, breast cancer, endometrial cancer, colon cancer, lung cancer, brain tumor, non-small cell lung cancer, pancreatic cancer, Solid tumor, colorectal tumor or malignant glioma.
  • the invention further relates to a method of treating cancer comprising administering a compound of the invention as indicated above, or an optical isomer, a pharmaceutically acceptable salt or co-crystal thereof, or a pharmaceutical composition according to the invention .
  • R 6 is selected from H, F, Cl, Br, I or OH
  • R 6 is H in the compound of the formula (IA) and is reacted with a format reagent or an alkyllithium reagent or the like to give a compound of the formula (IB'), and the nitro group of the compound of the formula (IB') is Reduction to give a compound of the formula (IB);
  • R a and R d are each independently selected from the group consisting of an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group or a cyclo group.
  • Halogen means fluorine, chlorine, bromine, or iodine.
  • Niro means -NO 2 .
  • R a and R d are each independently selected from the group consisting of an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group or a cyclo group.
  • Heterocycle means a substituted or unsubstituted saturated or unsaturated aromatic ring, a non-aromatic ring, and comprises at least one heteroatom selected from N, O, P or S, optionally substituted in a heterocyclic ring N, S, and P can be oxidized to various oxidation states.
  • the aromatic ring, non-aromatic ring may be a monocyclic, bicyclic, tricyclic or polycyclic ring system, non-limiting examples include, ethylene oxide, azacyclopropyl, oxetanyl, azetidine Base, 1,3-dioxolan, 1,4-dioxolane, 1,3-dioxane, azepanyl, pyridyl, furyl, thienyl, pyranyl, N- Alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithiane, dihydrofuran, Hydropyran, dithiapentane, tetrahydrofuran, tetrahydropyrrole, tetrahydroimidazole, tetrahydrothi
  • R a and R d are each independently selected from the group consisting of an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group or a cyclo group.
  • R a and R d are each independently selected from the group consisting of an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group or a cyclo group.
  • R a and R d are each independently selected from the group consisting of an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group or a cyclo group.
  • the ring atom contains 5 to 20 atoms, preferably 5 to 14 atoms, further preferably 5 to 12, and further preferably 5 to 10.
  • Non-limiting examples include And adamantane.
  • R a and R d are each independently selected from the group consisting of an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group or a cyclo group.
  • Benzyl refers to -CH 2 - phenyl, substituted or unsubstituted of substituted, non-limiting examples include -CH 2 - phenyl, -CH 2 - p-methylphenyl and the like.
  • R a and R d are each independently selected from the group consisting of an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group, and a cyclo group.
  • heteroaryl groups include, but are not limited to, pyridinyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, Piperidinyl, morpholine, thiomorpholine, 1,3-dithiane, benzimidazole, piperidinyl, benzimidazole, benzopyridine, pyrrolopyridine and the like.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples include
  • R a and R d are each independently selected from the group consisting of an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group or a cyclo group.
  • silica refers to a group formed by the substitution of one or more hydrogen atoms in a silicon methane with an alkyl group, examples including, but not limited to, trimethylsilyl, triethylsilyl, tert-butyldimethyl Silyl and tert-butyldiphenylsilyl and the like.
  • alkyl group optionally substituted by F means that the alkyl group may, but need not, be substituted by F, indicating a case where the alkyl group is substituted by F and a case where the alkyl group is not substituted by F.
  • “Pharmaceutically acceptable salt” or “pharmaceutically acceptable salt thereof” refers to maintaining the biological effectiveness and properties of the free acid or free base, and the free acid is passed through a non-toxic inorganic or organic base. Or the free acid obtained by reacting with a non-toxic inorganic or organic acid, including alkali metal salts such as sodium salts, potassium salts, lithium salts, etc.; alkaline earth metal salts such as calcium salts, magnesium salts, etc.
  • metal salts such as iron salts, copper salts, cobalt salts, etc.
  • organic alkali salts such as ammonium salts, triethylamine salts, pyridinium salts, methylpyridine salts, 2,6-dimethylpyridine salts, ethanolamine salts, Diethanolamine salt, triethanolamine salt, cyclohexylamine salt, ethylenediamine salt, phosphonium salt, isopropylamine salt, trimethylamine salt, tripropylamine salt, triethanolamine salt, diethanolamine salt, ethanolamine salt, Dimethylethanolamine salt, dicyclohexylamine salt, caffeine salt, procaine salt, choline salt, betaine salt, phenicillin salt, glucosamine salt, N-methylglucamine salt, theobromine salt , tromethamine salt, sulfonium salt, piperazine salt, morpholine salt, piperidine salt, N-ethyl piperidine salt, tetramethyl Salt
  • Carrier refers to a carrier or diluent that does not cause significant irritation to the organism and does not abrogate the biological activity and properties of the administered compound.
  • Excipient refers to an inert substance that is added to a pharmaceutical composition to further depend on the administration of the compound.
  • excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and different types of starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, Granules, lubricants, binders, disintegrators, and the like.
  • Co-crystal or “eutectic” refers to a crystal in which an active pharmaceutical ingredient (API) and a cocrystal former (CCF) are combined by hydrogen bonding or other non-covalent bonds.
  • API active pharmaceutical ingredient
  • CCF cocrystal former
  • the pure state of API and CCF is solid at room temperature and there is a fixed stoichiometric ratio between the components.
  • Eutectic is a multi-component crystal that contains both a binary eutectic formed between two neutral solids and a multi-component eutectic formed by a neutral solid with a salt or solvate.
  • the "eutectic former” includes, but is not limited to, various pharmaceutically acceptable acids, bases, nonionic compounds, water, amino acids, alcohols, or other solvents, non-limiting examples of which include alanine (Ala), hydrazine Acid (Val), leucine (Leu), isoleucine (Ile), proline (Pro), phenylalanine (Phe), tryptophan (Trp), methionine (Met), glycine ( Gly), serine (Ser), threonine (Thr), cysteine (Cys), tyrosine (Tyr), asparagine (Asn), glutamine (Gln), lysine (Lys) , arginine (Arg), histidine (His), aspartic acid (Asp), glutamic acid (Glu), pyroglutamic acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydrochloric acid, formic acid, acetic acid ,
  • Effective dose refers to an amount of a compound that causes a physiological or medical translation of a tissue, system or subject, which amount is sought, and includes one or more of the conditions or conditions sufficient to prevent treatment when administered to a subject. The amount of a compound that occurs or reduces it to some extent.
  • Solvate means a compound of the invention or a salt thereof, which also includes a stoichiometric or non-stoichiometric amount of solvent bound by intermolecular non-covalent forces.
  • solvent is water, it is a hydrate.
  • IC 50 refers to the half-inhibitory concentration, which is the concentration at which half of the maximum inhibitory effect is achieved.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • the NMR was measured using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD). ), the internal standard is tetramethylsilane (TMS).
  • the HPLC was measured using an Agilent 1260 DAD high pressure liquid chromatograph (Zorbax SB-C18 100 x 4.6 mm).
  • Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.20mm.
  • the specification for thin layer chromatography separation and purification is 0.4mm. ⁇ 0.5mm.
  • 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 Titan Technology, Anheji Chemical, Shanghai Demer, Chengdu Kelon Chemical, Suiyuan Chemical Technology, and Belling Technology. And other companies.
  • the nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon having a volume of about 1 L.
  • the hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
  • the solution means an aqueous solution.
  • reaction temperature is room temperature.
  • the room temperature is an optimum reaction temperature of 20 ° C to 30 ° C.
  • Boc tert-butoxycarbonyl
  • n-Bu n-butyl
  • TBS tert-butyldimethylsilyl
  • TIPS triisopropylsilyl
  • ⁇ 4a (12.78g, 109mmol) was dissolved in tetrahydrofuran (60mL), cooled under nitrogen, cooled to 0 ° C, methyl magnesium bromide (36.4mL, 109mmol) was added dropwise, stirring was continued for 0.5 hour, trichloropyrimidine was added (10 g, 54.5 mmol), reacted at room temperature for 1 hour, and further reacted at 60 ° C for 1.5 hours.
  • 2,4-Dichloro-5-methoxypyrimidine (9a) (10.74 g, 60 mmol) was weighed and placed in a 500 mL round bottom flask, and polyethylene glycol 400 (150 mL) and triethylbenzene were sequentially added to the reaction flask.
  • Amine (12.5 mL, 90.00 mmol), vinyl n-butyl ether (11.6 mL, 90.00 mmol) and palladium acetate (0.67 g, 3 mmol), warmed to 80 ° C and stirred for 16 hours.
  • the reaction mixture was cooled to room temperature, water (200 mL) was added, and ethyl acetate (250 mL ⁇ 2) was evaporated.
  • Embodiment 2 The resolution methods of Embodiment 2 and Embodiment 3 are as follows:
  • the third step (1-((2-acrylamido-4-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino) -5-Methoxyphenoxy)methyl)cyclopropyl)carbamic acid tert-butyl ester (5D)
  • the third step N-(2-((1-(tert-butoxycarbonyl)aminocyclopropyl)methyl)(methyl)amino)-5-((5-chloro-4-(1H- ⁇ ) Ind-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (6D)
  • N 1 -(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-6-methoxy-4-(2-(4-methylpiperidine) Pyrazin-1-yl)ethoxy)phenyl-1,3-diamine (150 mg, 0.288 mmol) was dissolved in tetrahydrofuran (10 mL) and N,N-diisopropylethylamine (0.057 mL) After cooling to 0 ° C, a solution of acryloyl chloride (0.028 mL, 0.345 mmol) in tetrahydrofuran (5 mL) was added dropwise, and the mixture was allowed to react at room temperature for 1 hour.
  • N 1 -(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-4-(2-(dimethylamino)ethoxy)-6 -Methoxyphenyl-1,3-diamine (350 mg, 0.75 mmol) was dissolved in tetrahydrofuran (28 mL). N,N-diisopropylethylamine (ie DIPEA) (0.15 mL, 0.9 The mixture was cooled to 0 ° C, and a solution of acryloyl chloride (0.073 mL, 0.9 mmol) in THF (5 mL) was evaporated.
  • 6-Nitroindole (16A) (16.2 g, 0.1 mol) was dissolved in pyridine (40 mL), and acetic anhydride (40.8 g, 0.4 mol) was added and allowed to react at room temperature overnight. The reaction mixture was concentrated. EtOAc (EtOAc) (EtOAc) ⁇ -1-base) Ethyl ketone (16B), yellow solid (6 g, yield 30%).
  • Step 5 4-(3-(2,5-Dichloropyrimidin-4-yl)-1-methyl-1H-indol-6-yl)morpholine (16F)
  • Step 6 5-Chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-6-morpholine-1H-indol-3-yl Pyrimidine-2-amine (16G)
  • reaction solution was cooled to room temperature, acetonitrile (50 mL) was added and filtered, and the filter cake was washed with water (50mL) and dried to give -chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)- 4-(1-Methyl-6-morpholine-1H-indol-3-yl)pyrimidin-2-amine (16G), m.p.
  • Step 7 N 1 -(5-chloro-4-(1-methyl-6-morpholine-1H-indol-3-yl)pyrimidin-2-yl)-4-fluoro-6-methoxy Benzene-1,3-diamine (16H)
  • Step 8 N-(5-((5-chloro-4-(1-methyl-6-morpholin-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-fluoro- 4-methoxyphenyl)acrylamide (Compound 16)
  • N 1 -(5-chloro-4-(1-methyl-6-morpholine-1H-indol-3-yl)pyrimidin-2-yl)-4-fluoro-6-methoxybenzene-1 , 3-diamine (16H) (150 mg, 0.31 mmol) was dissolved in THF (10 mL), N,N-diisopropylethylamine (0.06 mL, 0.37 mmol), and then cooled to 0 ° C. A solution of (0.03 mL, 0.37 mmol) in tetrahydrofuran (5 mL).
  • reaction mixture was concentrated to dryness EtOAc mjjjjjjjjjjj -(3-(Dimethylamino)tetrahydropyrrol-1-yl)-2-methoxy-5-nitrophenyl)-4-(4-fluoro-1H-indol-3-yl)pyrimidine- 2-Amine (17B) (0.5 g, yield 38%).
  • N 1 -(5-chloro-4-(4-fluoro-1H-indol-3-yl)pyrimidin-2-yl)-N 4 -(2-(dimethylamino)ethyl) 2-methoxy-N 4 -methyl-5-nitrobenzene-1,4-diamine (18B) (0.52 g, 1 mmol), iron powder (0.34 g, 6.1 mmol), ammonium chloride (54 mg) 1 mmol) and ethanol/water (28 mL/10 mL) were heated to reflux for 2 hours.
  • the third step 4-(1-methyl-1H-indol-3-yl)-N-(3-morpholinyl-5-nitrophenyl)pyrimidin-2-amine (24D)
  • N 1 -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-5-morpholinium-1,3-diamine (24E) 250 mg, 0.625 mmol
  • Dissolved in 5 mL of pyridine added with acrylic acid (90 mg, 1.25 mmol), and added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.5 mmol, 478 mg).
  • Step 5 N-(5-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethyl) Base amino)ethyl)(methyl)amino)-4-ethylphenyl)acrylamide (compound 25)
  • Tetrahydrofuran 250 mL was added to a 2 L round bottom flask.
  • 6-bromoindole 100.0 g, A solution of 0.510 mol
  • the mixture was stirred at 0 ° C for 30 minutes, and a solution of triisopropylchlorosilane (100 g, 0.518 mol) in tetrahydrofuran (250 mL) was added dropwise.

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Abstract

L'invention concerne un dérivé aminé (substitué phényle) (substitué pyrimidine) tel que décrit dans la formule (I), un isomère optique, un sel pharmaceutiquement acceptable ou un produit eutectique de ce dernier, ainsi que son procédé de préparation et son utilisation dans la préparation de médicaments contre des tumeurs. Le composé de formule (I) est : <formule 1>.
PCT/CN2015/088015 2014-08-25 2015-08-25 Dérivé aminé (subtitué phényle) (substitué pyrimidine), son procédé de préparation, et utilisation comme médicament WO2016029839A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106117185A (zh) * 2015-08-31 2016-11-16 广州科擎新药开发有限公司 2,4‑二含氮基团取代嘧啶类化合物及其制备方法和应用
CN106432231A (zh) * 2016-09-09 2017-02-22 无锡佰翱得生物科学有限公司 Azd9291的药用盐、及其晶型和制备方法
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JP2017533266A (ja) * 2014-11-05 2017-11-09 インベンティスバイオ シャンハイ リミテッド ピリミジン又はピリジン系化合物、それらの製造方法及び医薬使用
CN107344934A (zh) * 2016-05-04 2017-11-14 江苏正大丰海制药有限公司 药物活性物质的固体形式
WO2017197062A1 (fr) 2016-05-11 2017-11-16 Beta Pharma, Inc. Dérivés de 2-anilinopyrimidine utilisés en tant qu'agents thérapeutiques pour le traitement de cancers du cerveau
WO2017218892A1 (fr) * 2016-06-17 2017-12-21 Beta Pharma, Inc. Sels pharmaceutiques de n-(2-(2-(diméthylamino)éthoxy)-4-méthoxy-5-((4-(1-méthyl-1h-indol-3-yl)pyrimidin-2-yl)amino)phényl)acrylamide et leurs formes cristallines
WO2018050052A1 (fr) * 2016-09-19 2018-03-22 郑州泰基鸿诺医药股份有限公司 Composé contenant un noyau pyrimidine, inhibiteur d'egfr et son application
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AU2018211880B2 (en) * 2017-01-26 2019-04-11 Hanmi Pharm. Co., Ltd. Pyrimidine compound and pharmaceutical use thereof
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US20190225610A1 (en) * 2016-09-19 2019-07-25 Nanling Chuangte Pharmaceutical Technology Co., Ltd. Deuterated 3-(4,5-substituted aminopyrimidine)phenyl derivatives and use thereof
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US10513509B2 (en) 2016-05-26 2019-12-24 Recurium Ip Holdings, Llc EGFR inhibitor compounds
US10590111B2 (en) 2014-12-11 2020-03-17 Beta Pharma, Inc. Substituted 2-anilinopyrimidine derivatives as EGFR modulators
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Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101503402A (zh) * 2009-03-10 2009-08-12 沈阳药科大学 2-苯胺嘧啶衍生物及其制备和用途
CN101902911A (zh) * 2007-10-19 2010-12-01 阿维拉制药公司 杂芳基化合物和其用途
CN102083800A (zh) * 2008-06-27 2011-06-01 阿维拉制药公司 杂芳基化合物和其用途
CN103702990A (zh) * 2011-07-27 2014-04-02 阿斯利康(瑞典)有限公司 2-(2,4,5-取代苯胺)嘧啶衍生物作为egfr调谐子用于治疗癌症
CN104761585A (zh) * 2014-01-03 2015-07-08 南京波尔泰药业科技有限公司 作为egfr酪氨酸激酶的抑制剂的取代氨基嘧啶
CN104860941A (zh) * 2014-02-25 2015-08-26 上海海雁医药科技有限公司 2,4-二取代苯-1,5-二胺衍生物及其应用以及由其制备的药物组合物和药用组合物

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2060565A1 (fr) * 2007-11-16 2009-05-20 4Sc Ag Nouveaux composés bifonctionnels inhibiteurs de protéine kinases et d'histone deacetylases
TWI385174B (zh) * 2008-11-10 2013-02-11 Nat Health Research Institutes 作為酪胺酸激酶抑制劑之稠合雙環及多環嘧啶化合物
BR112016029662B1 (pt) * 2014-06-19 2023-10-24 Takeda Pharmaceutical Company Limited COMPOSTO DE FÓRMULA Bf OU UMA FORMA FARMACEUTICAMENTE ACEITÁVEL DO MESMO, COMPOSIÇÃO FARMACÊUTICA COMPREENDENDO O MESMO E SEU USO
CN105085489B (zh) * 2014-11-05 2019-03-01 益方生物科技（上海）有限公司 嘧啶或吡啶类化合物、其制备方法和医药用途

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101902911A (zh) * 2007-10-19 2010-12-01 阿维拉制药公司 杂芳基化合物和其用途
CN102083800A (zh) * 2008-06-27 2011-06-01 阿维拉制药公司 杂芳基化合物和其用途
CN101503402A (zh) * 2009-03-10 2009-08-12 沈阳药科大学 2-苯胺嘧啶衍生物及其制备和用途
CN103702990A (zh) * 2011-07-27 2014-04-02 阿斯利康(瑞典)有限公司 2-(2,4,5-取代苯胺)嘧啶衍生物作为egfr调谐子用于治疗癌症
CN104761585A (zh) * 2014-01-03 2015-07-08 南京波尔泰药业科技有限公司 作为egfr酪氨酸激酶的抑制剂的取代氨基嘧啶
CN104860941A (zh) * 2014-02-25 2015-08-26 上海海雁医药科技有限公司 2,4-二取代苯-1,5-二胺衍生物及其应用以及由其制备的药物组合物和药用组合物

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2015330506B2 (en) * 2014-10-11 2020-01-30 Jiangsu Hansoh Pharmaceutical Group Co., Ltd. EGFR inhibitor, and preparation and application thereof
US10428081B2 (en) 2014-10-11 2019-10-01 Shanghai Hansoh Biomedical Co., Ltd. EGFR inhibitor, preparation method and use thereof
US10259820B2 (en) * 2014-10-11 2019-04-16 Shanghai Hansoh Biomedical Co., Ltd. EGFR inhibitor, preparation method and use thereof
EP3216786A4 (fr) * 2014-11-05 2018-07-04 InventisBio Shanghai Ltd. Composés pyrimidine ou pyridine, leur procédé de préparation et leurs utilisations pharmaceutiques
IL286165B2 (en) * 2014-11-05 2023-07-01 Inventisbio Co Ltd Pyrimidine or pyridine compounds, a method for their preparation and pharmaceutical uses thereof
IL286165B1 (en) * 2014-11-05 2023-03-01 Inventisbio Co Ltd Pyrimidine or pyridine compounds, a method for their preparation and pharmaceutical uses thereof
US11498921B1 (en) 2014-11-05 2022-11-15 InventisBio Co., Ltd. Pyrimidine or pyridine compounds, preparation method therefor and pharmaceutical uses thereof
US11203589B2 (en) 2014-11-05 2021-12-21 InventisBio Co., Ltd. Pyrimidine or pyridine compounds, preparation method therefor and pharmaceutical uses thereof
JP2017533266A (ja) * 2014-11-05 2017-11-09 インベンティスバイオ シャンハイ リミテッド ピリミジン又はピリジン系化合物、それらの製造方法及び医薬使用
EP3885344A3 (fr) * 2014-11-05 2021-12-08 InventisBio Co., Ltd. Composés de pyrimidine, leur procédé de préparation et leurs utilisations pharmaceutiques
US10179784B2 (en) 2014-11-05 2019-01-15 Inventisbio Shanghai Ltd. Pyrimidine or pyridine compounds, preparation method therefor and pharmaceutical uses thereof
US10590111B2 (en) 2014-12-11 2020-03-17 Beta Pharma, Inc. Substituted 2-anilinopyrimidine derivatives as EGFR modulators
US11414401B2 (en) 2014-12-11 2022-08-16 Beta Pharma Inc. Substituted 2-anilinopyrimidine derivatives as EGFR modulators
AU2016314898B2 (en) * 2015-08-31 2019-06-27 Bebetter Med Inc. 2,4-bis(nitrogen-containing group)-substituted pyrimidine compound, preparation method and use thereof
CN106117185B (zh) * 2015-08-31 2017-11-07 广州必贝特医药技术有限公司 2,4‑二含氮基团取代嘧啶类化合物及其制备方法和应用
US11267802B2 (en) 2015-08-31 2022-03-08 Bebetter Med Inc. 2,4-bis(nitrogen-containing group)-substituted pyrimidine compound, preparation method and use thereof
WO2017036263A1 (fr) * 2015-08-31 2017-03-09 广州科擎新药开发有限公司 Composé pyrimidine à substitution 2,4-di-(groupe azoté), son procédé de préparation et son utilisation
CN106117185A (zh) * 2015-08-31 2016-11-16 广州科擎新药开发有限公司 2,4‑二含氮基团取代嘧啶类化合物及其制备方法和应用
US10435388B2 (en) 2016-01-07 2019-10-08 Cs Pharmatech Limited Selective inhibitors of clinically important mutants of the EGFR tyrosine kinase
CN107344934A (zh) * 2016-05-04 2017-11-14 江苏正大丰海制药有限公司 药物活性物质的固体形式
WO2017197062A1 (fr) 2016-05-11 2017-11-16 Beta Pharma, Inc. Dérivés de 2-anilinopyrimidine utilisés en tant qu'agents thérapeutiques pour le traitement de cancers du cerveau
CN109715164A (zh) * 2016-05-11 2019-05-03 贝达医药公司 作为用于治疗脑癌之治疗剂的2-苯胺基嘧啶衍生物
AU2017264839B2 (en) * 2016-05-11 2021-08-05 Beta Pharma, Inc. 2-Anilinopyrimidine derivatives as therapeutic agents for treatment of brain cancers
US11052086B2 (en) 2016-05-11 2021-07-06 Beta Pharma, Inc. 2-anilinopyrimidine derivatives as therapeutic agents for treatment of brain cancers
JP2019514996A (ja) * 2016-05-11 2019-06-06 ベータ ファーマ，インコーポレイテッド 脳腫瘍の処置のための治療剤としての２−アミノピリミジン誘導体
EP3454860A4 (fr) * 2016-05-11 2020-01-15 Beta Pharma, Inc. Dérivés de 2-anilinopyrimidine utilisés en tant qu'agents thérapeutiques pour le traitement de cancers du cerveau
US10513509B2 (en) 2016-05-26 2019-12-24 Recurium Ip Holdings, Llc EGFR inhibitor compounds
US11098030B2 (en) 2016-05-26 2021-08-24 Recurium Ip Holdings, Llc EGFR inhibitor compounds
WO2017218892A1 (fr) * 2016-06-17 2017-12-21 Beta Pharma, Inc. Sels pharmaceutiques de n-(2-(2-(diméthylamino)éthoxy)-4-méthoxy-5-((4-(1-méthyl-1h-indol-3-yl)pyrimidin-2-yl)amino)phényl)acrylamide et leurs formes cristallines
CN109937043A (zh) * 2016-06-17 2019-06-25 贝达医药公司 N-(2-(2-(二甲基氨基)乙氧基)-4-甲氧基-5-((4-(1-甲基-1h-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺的药物盐及其晶型
AU2017285448B2 (en) * 2016-06-17 2021-02-04 Beta Pharma, Inc. Pharmaceutical salts of N-(2-(2-(dimethylamino)ethoxy)-4-methoxy-5-((4-(1-methyl-1h-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide and crystalline forms thereof
US10844045B2 (en) 2016-06-17 2020-11-24 Beta Pharma, Inc. Pharmaceutical salts N-(2-(2-(dimethylamino)ethoxy)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide and crystalline forms thereof
CN106432231A (zh) * 2016-09-09 2017-02-22 无锡佰翱得生物科学有限公司 Azd9291的药用盐、及其晶型和制备方法
US20190225610A1 (en) * 2016-09-19 2019-07-25 Nanling Chuangte Pharmaceutical Technology Co., Ltd. Deuterated 3-(4,5-substituted aminopyrimidine)phenyl derivatives and use thereof
WO2018050052A1 (fr) * 2016-09-19 2018-03-22 郑州泰基鸿诺医药股份有限公司 Composé contenant un noyau pyrimidine, inhibiteur d'egfr et son application
US10654851B2 (en) * 2016-09-19 2020-05-19 Nanjing Chuangte Pharmaceutical Technology Co., Ltd. Deuterated 3-(4,5-substituted aminopyrimidine)phenyl derivatives and use thereof
CN107840846B (zh) * 2016-09-19 2020-11-24 郑州泰基鸿诺医药股份有限公司 一种含嘧啶环的化合物、egfr抑制剂及其应用
CN107840846A (zh) * 2016-09-19 2018-03-27 郑州泰基鸿诺医药股份有限公司 一种含嘧啶环的化合物、egfr抑制剂及其应用
CN106674203A (zh) * 2016-11-25 2017-05-17 山东轩德医药科技有限公司 一种3‑(2‑氯嘧啶‑4‑基)‑1‑甲基吲哚的制备方法
KR20180085701A (ko) * 2017-01-19 2018-07-27 부산대학교 산학협력단 신규한 2-아닐리노피리미딘 유도체 및 이를 포함하는 조성물
KR102011356B1 (ko) 2017-01-19 2019-08-16 부산대학교 산학협력단 신규한 2-아닐리노피리미딘 유도체 및 이를 포함하는 조성물
US10519141B2 (en) 2017-01-26 2019-12-31 Hanmi Pharm. Co., Ltd. Pyrimidine compound and pharmaceutical use thereof
AU2018211880B2 (en) * 2017-01-26 2019-04-11 Hanmi Pharm. Co., Ltd. Pyrimidine compound and pharmaceutical use thereof
US10280154B2 (en) 2017-01-26 2019-05-07 Hanmi Pharm. Co., Ltd. Pyrimidine compound and pharmaceutical use thereof
US10633367B2 (en) * 2017-10-03 2020-04-28 X-Cutag Therapeutics, Inc. Fluorine- and/or deuterium-containing compounds for treating non-small cell lung cancer and related diseases
CN111825658A (zh) * 2019-04-18 2020-10-27 华东理工大学 新型egfr三突变抑制剂及其应用
WO2020211853A1 (fr) * 2019-04-18 2020-10-22 华东理工大学 Nouvel inhibiteur de la mutation triple de l'egfr et utilisation associée
CN113179640A (zh) * 2019-11-26 2021-07-27 上海翰森生物医药科技有限公司 含氮多环类衍生物抑制剂、其制备方法和应用
WO2021104305A1 (fr) * 2019-11-26 2021-06-03 上海翰森生物医药科技有限公司 Inhibiteur d'un dérivé polycyclique contenant de l'azote, son procédé de préparation et son utilisation
CN111303123B (zh) * 2020-03-31 2021-08-31 南京雷正医药科技有限公司 2-(2,4,5-取代苯胺基)嘧啶化合物及其应用
CN111303123A (zh) * 2020-03-31 2020-06-19 南京雷正医药科技有限公司 2-(2,4,5-取代苯胺基)嘧啶化合物及其应用
CN112159392B (zh) * 2020-09-15 2021-11-23 南京雷正医药科技有限公司 取代嘧啶化合物及其药物组合物和该化合物的用途
CN112159392A (zh) * 2020-09-15 2021-01-01 南京雷正医药科技有限公司 取代嘧啶化合物及其药物组合物和该化合物的用途
WO2022116995A1 (fr) * 2020-12-02 2022-06-09 上海和誉生物医药科技有限公司 Dérivé de 2,3-dihydro-1h-pyrrolo[3,2-b]pyridine, son procédé de préparation et son utilisation
WO2023011505A1 (fr) * 2021-08-06 2023-02-09 上海和誉生物医药科技有限公司 Dérivé de pyrimidine ou de pyridine, son procédé de préparation et son application en pharmacie
CN115785134A (zh) * 2022-10-28 2023-03-14 浙大城市学院 一种含氮杂环的硼酸化合物及制备方法和应用
CN115785134B (zh) * 2022-10-28 2023-08-29 浙大城市学院 一种含氮杂环的硼酸化合物及制备方法和应用

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