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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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Publication number
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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Prior art keywords
alkyl
methyl
group
amino
heterocyclic ring
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PCT/CN2015/088015
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English (en)
Chinese (zh)
Inventor
魏用刚
李瑶
张国彪
邱关鹏
胡仕红
陈雷
李升�
张黔
Original Assignee
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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