WO2020108619A1 - Mnk抑制剂 - Google Patents

Mnk抑制剂 Download PDF

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WO2020108619A1
WO2020108619A1 PCT/CN2019/121976 CN2019121976W WO2020108619A1 WO 2020108619 A1 WO2020108619 A1 WO 2020108619A1 CN 2019121976 W CN2019121976 W CN 2019121976W WO 2020108619 A1 WO2020108619 A1 WO 2020108619A1
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alkyl
compound
unsubstituted
pharmaceutically acceptable
formula
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PCT/CN2019/121976
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French (fr)
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杨和平
高大新
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上海迪诺医药科技有限公司
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic 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
    • C07D471/02Heterocyclic 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
    • C07D471/10Spiro-condensed systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic 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
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic 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
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52Purines, e.g. adenine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic 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
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/527Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim spiro-condensed
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • A61P35/02Antineoplastic agents specific for leukemia
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D403/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic 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
    • C07D471/02Heterocyclic 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
    • C07D471/04Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic 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
    • C07D471/12Heterocyclic 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
    • C07D471/14Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic 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 two hetero rings
    • C07D487/04Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic 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 two hetero rings
    • C07D487/10Spiro-condensed systems
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D491/00Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
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Definitions

  • the present invention relates to a novel MNK inhibitor, its pharmaceutical composition and its use as a cancer therapeutic agent.
  • MAP interacting kinases 1 and 2 are a class of serine/threonine protein kinases that can be activated by ERK or p38 and can phosphorylate eukaryotic initiation factor 4E (eIF4E) during protein synthesis and It is essential in the stability of cell function.
  • eIF4E involves cap-dependent translation initiation.
  • the eIF4E protein binds to the 5'cap structure of mRNA, which is necessary for cap-dependent translation initiation. Multiple evidences indicate that eIF4E exhibits a real carcinogenic effect in vivo.
  • eIF4E is overexpressed in many types of human cancer and is related to the poor prognosis of tumor patients (Mamane Y, et al. Oncogene, 2004 23:3172-79; Graff JR, et al., Cancer Res, 2009 69: 3866 -73; Ruggero D, et al. Nat Med, 2004 10:484-6), including colon cancer and breast cancer (Chrestensen, CA, et al., J. Biol.
  • transgenic mice overexpressing eIF4E have greatly increased tumor incidence in multiple organs.
  • Clinical results show that not only the overexpression of eIF4E contributes to tumor progression, even the hyperphosphorylation of eIF4E can also contribute to tumor progression.
  • Increased phosphorylation of eIF4E has been observed in a variety of solid tumors and lymphomas and is associated with poor prognosis in patients, especially in non-small cell lung cancer.
  • MNK1 is highly expressed in hematological malignancies (Worch J., et al., Oncogene, 2004 23:9162-72). Both MNK1 and MNK2 are up-regulated in solid tumors such as glioma and ovarian cancer.
  • MNK/eIF4E axis is involved in pro-angiogenesis, anti-apoptotic expression, cell cycle and motor proteins, and phosphorylation of eIF4E at the Ser209 site promotes its carcinogenic potential (Topisirovic, I., et al., Cancer Res., 2004 64 (23): 8639-42), and MNK1/2 is the only kinase known to drive this process.
  • Phosphorylation of eIF4E by MNK1/2 can promote the expression of a variety of oncogene proteins, including MCL-1 (Wendel, HG, et al., Genes Dev., 2007 21(24):3232-37), FGF2, c -Myc, VEGF, MMP3, CCL2, BIRC2, cyclin D1 (De Benedetti, A., et.al., Cell Biol., 1999, 31(1): 59-72), cyclin D3 (Graff, JR, et al., Cancer Res., 200868(3):631-34) and ODC. And it is necessary in the transformation process induced by Ras and c-Myc. Plays a key role in multiple intracellular signaling pathways. These include the rapamycin complex 1 (mTORC1) and ERK (classical MAP kinase) pathways. Both signaling pathways are often activated in cancer.
  • mTORC1 rapamycin complex 1
  • ERK classical
  • MNK1 and/or MNK2 inhibitors for example: WO2015/200481, WO2017/075394, WO2017/075412, WO2017/087808 disclose a series of isoindol-1-ones and 2,3- Dihydroimidazo[1,5-a]pyridine-1,5-dione compounds; WO2017/085484, WO2017/085483, WO2014/044691, WO2014/048894 disclose a series of thiazolopyrimidine and pyrrolopyrimidine compounds ; WO2015/050505, WO2013/147711 disclose a series of imidazopyridazine compounds.
  • MNK inhibitor has good MNK1 and MNK2 inhibitory effect.
  • the technical problem to be solved by the present invention is to provide a novel compound represented by formula I or I', its pharmaceutical composition and application.
  • the compound of formula I or I'of the present invention has good MNK1 and/or MNK2 inhibition, and can effectively treat and/or alleviate various related diseases mediated by MNK1 and/or MNK2, such as cancer.
  • the present invention provides a compound represented by Formula I, its isomer, prodrug, stable isotope derivative or pharmaceutically acceptable salt;
  • R is -NH-Cy or Cy
  • R 1 is H, -OH, -NH 2 , R A , -NH-R A , -NH-C(O)-R A or -OR A ;
  • R 2 is H, CN, deuterated C 1-4 alkyl or R B ;
  • R 3 is H, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl; the R 3 is unsubstituted or optionally substituted with 1 to 3 R 9 at any position;
  • R 4 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, 5-6 membered heteroaryl, C 3-8 cycloalkyl, 3 -8 membered heterocycloalkyl, C 6-10 aryl C 1-6 alkyl, 5-6 membered heteroaryl C 1-6 alkyl, C 3-8 cycloalkyl C 1-6 alkyl or 3 -8 membered heterocycloalkyl C 1-6 alkyl; said R 4 is unsubstituted or optionally substituted with 1 to 3 R 9 at any position;
  • R 1 , R 2 , R 3 and R 4 is an independent substituent, or
  • R 1 and R 3 are connected to each other to form a 3-10 membered heterocycloalkyl; the 3-10 membered heterocycloalkyl is unsubstituted or optionally substituted with 1 to 3 R 9 at any position;
  • R 2 and R 3 are connected to each other to form a 3-10 membered heterocycloalkyl group; the 3-10 membered heterocycloalkyl group is unsubstituted or optionally substituted with 1 to 3 R 9 at any position;
  • R 3 and R 4 together with the carbon atom to which they are connected together form C 3-10 cycloalkyl or 3-10 membered heterocycloalkyl; the C 3-10 cycloalkyl or 3-10 membered heterocycloalkyl Is unsubstituted, or optionally substituted with 1 to 3 R 9 in any position; or
  • R 2 and R 3 are connected to each other to form a double bond with the ⁇ bond;
  • R 5 and R 5a are independently hydrogen, halogen, cyano, C 1-4 alkyl, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy or C 1-4 alkylamino;
  • Cy is a 5-10 membered heteroaromatic ring; the Cy is unsubstituted, or is optionally selected from 1 to 3 selected from halogen, -CN, -NH 2 , -NHOH, -OH, -R C , -OR C , -NHR C , -NH-OR C , -NHC(O)R C , -C(O)R C and -C(O)N(R C ) 2 substituents are substituted in any position;
  • Each R A is independently C 1-8 alkyl, C 2-8 alkenyl or C 2-8 alkynyl; the R A is unsubstituted, or is optionally selected from 1 to 3 selected from halogen, -OH , -NH 2 , oxo, C 1-3 alkoxy and C 1-3 alkylamino substituents are substituted at any position;
  • Each R B is independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, 5-6 membered heteroaryl, C 3-8 cycloalkyl, 3-8 Member heterocycloalkyl, -(CH 2 ) n -phenyl, -(CH 2 ) n -(5-6 membered heteroaryl), -(CH 2 ) n -C 3-8 cycloalkyl or -( CH 2 ) n -(3-8 membered heterocycloalkyl); the R B is unsubstituted or optionally substituted with 1 to 3 R 9 at any position;
  • Each R C is independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, 5-6 membered heteroaryl, C 3-8 cycloalkyl, 3-8 Heterocyclic heterocyclic alkyl, -(CH 2 ) n -OC 1-6 alkyl, -(CH 2 ) n -phenyl, -(CH 2 ) n -(5-6 membered heteroaryl), -(CH 2 ) n -C 3-8 cycloalkyl, -(CH 2 ) n -(3-8 membered heterocycloalkyl) or -(3-8 membered heterocycloalkyl)-C 1-6 alkyl; Said R C is unsubstituted, or optionally substituted with 1 to 3 R 10 at any position;
  • Each R 9 and each R 10 are independently H, -CN, -NO 2 , -SH, -NH 2 , -OH, -C(O)OH, -NHC(O)R a , -NHS ( O) 2 R a , -C(O)R a , halogen, oxo, ester, amide, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1- 4 alkoxy, C 1-4 alkylamino, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, -(CH 2 ) n -NH 2 , -(CH 2 ) n -OH, -(CH 2 ) n -(C 1-4 alkylamino) or -(CH 2 ) n -(C 1-4 alkoxy);
  • Each R a is independently C 1-6 alkyl or C 2-6 alkenyl
  • n 1, 2, 3 or 4.
  • the present invention provides a compound represented by formula I', its isomers, prodrugs, stable isotope derivatives or pharmaceutically acceptable salts;
  • a 1 is N or CR 5 ;
  • a 2 is N or CR 5a ;
  • a 3 is N or CR 5b ;
  • R is -NH-Cy or Cy
  • R 1 is H, -OH, -NH 2 , R A , -NH-R A , -NH-C(O)-R A or -OR A ;
  • R 2 is H, CN, deuterated C 1-4 alkyl or R B ;
  • R 3 is H, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl; the R 3 is unsubstituted or optionally substituted with 1 to 3 R 9 at any position;
  • R 4 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, 5-6 membered heteroaryl, C 3-8 cycloalkyl, 3 -8 membered heterocycloalkyl, C 6-10 aryl C 1-6 alkyl, 5-6 membered heteroaryl C 1-6 alkyl, C 3-8 cycloalkyl C 1-6 alkyl or 3 -8 membered heterocycloalkyl C 1-6 alkyl; said R 4 is unsubstituted or optionally substituted with 1 to 3 R 9 at any position;
  • R 1 , R 2 , R 3 and R 4 is an independent substituent, or
  • R 1 and R 3 are connected to each other to form a 3-10 membered heterocycloalkyl; the 3-10 membered heterocycloalkyl is unsubstituted or optionally substituted with 1 to 3 R 9 at any position;
  • R 2 and R 3 are connected to each other to form a 3-10 membered heterocycloalkyl group; the 3-10 membered heterocycloalkyl group is unsubstituted or optionally substituted with 1 to 3 R 9 at any position;
  • R 3 and R 4 together with the carbon atom to which they are connected together form C 3-10 cycloalkyl or 3-10 membered heterocycloalkyl; the C 3-10 cycloalkyl or 3-10 membered heterocycloalkyl Is unsubstituted, or optionally substituted with 1 to 3 R 9 in any position; or
  • R 2 and R 3 are connected to each other to form a double bond with the ⁇ bond;
  • R 5 , R 5a and R 5b are independently hydrogen, halogen, cyano, C 1-4 alkyl, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy or C 1-4 alkyl Amino
  • Cy is a 5-10 membered heteroaromatic ring; the Cy is unsubstituted, or is optionally selected from 1 to 3 selected from halogen, -CN, -NH 2 , -NHOH, -OH, -R C , -OR C , -NHR C , -NH-OR C , -NHC(O)R C , -C(O)R C and -C(O)N(R C ) 2 substituents are substituted in any position;
  • Each R A is independently C 1-8 alkyl, C 2-8 alkenyl or C 2-8 alkynyl; the R A is unsubstituted, or is optionally selected from 1 to 3 selected from halogen, -OH , -NH 2 , oxo, C 1-3 alkoxy and C 1-3 alkylamino substituents are substituted at any position;
  • Each R B is independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, 5-6 membered heteroaryl, C 3-8 cycloalkyl, 3-8 Member heterocycloalkyl, -(CH 2 ) n -phenyl, -(CH 2 ) n -(5-6 membered heteroaryl), -(CH 2 ) n -C 3-8 cycloalkyl or -( CH 2 ) n -(3-8 membered heterocycloalkyl); the R B is unsubstituted or optionally substituted with 1 to 3 R 9 at any position;
  • Each R C is independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, 5-6 membered heteroaryl, C 3-8 cycloalkyl, 3-8 Heterocyclic heterocyclic alkyl, -(CH 2 ) n -OC 1-6 alkyl, -(CH 2 ) n -phenyl, -(CH 2 ) n -(5-6 membered heteroaryl), -(CH 2 ) n -C 3-8 cycloalkyl, -(CH 2 ) n -(3-8 membered heterocycloalkyl) or -(3-8 membered heterocycloalkyl)-C 1-6 alkyl; Said R C is unsubstituted, or optionally substituted with 1 to 3 R 10 at any position;
  • Each R 9 and each R 10 are independently H, -CN, -NO 2 , -SH, -NH 2 , -OH, -C(O)OH, -NHC(O)R a , -NHS ( O) 2 R a , -C(O)R a , halogen, oxo, ester, amide, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1- 4 alkoxy, C 1-4 alkylamino, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, -(CH 2 ) n -NH 2 , -(CH 2 ) n -OH, -(CH 2 ) n -(C 1-4 alkylamino) or -(CH 2 ) n -(C 1-4 alkoxy);
  • Each R a is independently C 1-6 alkyl or C 2-6 alkenyl
  • n 1, 2, 3 or 4.
  • the definition of certain groups in the compound of formula I, its isomers, prodrugs, stable isotope derivatives or pharmaceutically acceptable salts may be as follows, without The described group can be as described in any of the above schemes:
  • W 1 is O
  • W 2 is O
  • R is -NH-Cy
  • R 1 is H, -OH, -NH 2 , R A , -NH-R A , -NH-C(O)-R A or -OR A ;
  • R 2 and R 3 are connected to each other to form a 3-10 membered heterocycloalkyl group; the 3-10 membered heterocycloalkyl group is unsubstituted or optionally substituted with 1 to 3 R 9 at any position;
  • R 4 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, 5-6 membered heteroaryl, C 3-8 cycloalkyl, 3 -8 membered heterocycloalkyl, C 6-10 aryl C 1-6 alkyl, 5-6 membered heteroaryl C 1-6 alkyl, C 3-8 cycloalkyl C 1-6 alkyl or 3 -8 membered heterocycloalkyl C 1-6 alkyl; said R 4 is unsubstituted or optionally substituted with 1 to 3 R 9 at any position;
  • R 5 is hydrogen, halogen, cyano or C 1-4 alkyl
  • R 5a is hydrogen
  • Cy is a 5-10 membered heteroaromatic ring; the Cy is unsubstituted, or is optionally selected from 1 to 3 selected from halogen, -CN, -NH 2 , -NHOH, -OH, -R C , -OR C , -NHR C , -NH-OR C , -NHC(O)R C , -C(O)R C and -C(O)N(R C ) 2 substituents are substituted in any position;
  • Each R A is independently C 1-8 alkyl, C 2-8 alkenyl or C 2-8 alkynyl; the R A is unsubstituted, or is optionally selected from 1 to 3 selected from halogen, -OH , -NH 2 , oxo, C 1-3 alkoxy and C 1-3 alkylamino substituents are substituted at any position;
  • Each R B is independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, 5-6 membered heteroaryl, C 3-8 cycloalkyl, 3-8 Member heterocycloalkyl, -(CH 2 ) n -phenyl, -(CH 2 ) n -(5-6 membered heteroaryl), -(CH 2 ) n -C 3-8 cycloalkyl or -( CH 2 ) n -(3-8 membered heterocycloalkyl); the R B is unsubstituted or optionally substituted with 1 to 3 R 9 at any position;
  • Each R C is independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, 5-6 membered heteroaryl, C 3-8 cycloalkyl, 3-8 Heterocyclic heterocyclic alkyl, -(CH 2 ) n -OC 1-6 alkyl, -(CH 2 ) n -phenyl, -(CH 2 ) n -(5-6 membered heteroaryl), -(CH 2 ) n -C 3-8 cycloalkyl, -(CH 2 ) n -(3-8 membered heterocycloalkyl) or -(3-8 membered heterocycloalkyl)-C 1-6 alkyl; Said R C is unsubstituted, or optionally substituted with 1 to 3 R 10 at any position;
  • Each R 9 and each R 10 are independently H, -CN, -NO 2 , -SH, -NH 2 , -OH, -C(O)OH, -NHC(O)R a , -NHS ( O) 2 R a , -C(O)R a , halogen, oxo, ester, amide, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1- 4 alkoxy, C 1-4 alkylamino, halogenated C 1-4 alkyl or halogenated C 1-4 alkoxy;
  • Each R a is independently C 1-6 alkyl or C 2-6 alkenyl
  • n 1, 2, 3 or 4.
  • each R 9 and each R 10 are independently H, -CN, -NO 2 , -SH, -NH 2 , -OH, -C(O)OH, -NHC(O) R a , -NHS(O) 2 R a , halogen, oxo, ester, amide, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkyl Oxy, C 1-4 alkylamino, halogenated C 1-4 alkyl or halogenated C 1-4 alkoxy.
  • each R 9 and each R 10 are independently H, -CN, -NO 2 , -SH, -NH 2 , -OH, -C(O)OH, -NHC(O) R a , -NHS(O) 2 R a , -C(O)R a , halogen, oxo, ester, amide, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, C 1-4 alkoxy, C 1-4 alkylamino, halogenated C 1-4 alkyl or halogenated C 1-4 alkoxy.
  • R 9 is H, —NH 2 , —OH, F, Cl, ⁇ O, —NHC(O)—C 2-6 alkenyl, —NHS(O) 2 —C 2- 6 alkenyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, halogenated C 1-4 alkyl or halogenated C 1-4 alkoxy.
  • R 10 is H, —CN, —NH 2 , —OH, F, Cl, ⁇ O, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl , C 1-4 alkoxy, C 1-4 alkylamino, halogenated C 1-4 alkyl or halogenated C 1-4 alkoxy.
  • R 10 is H, —NH 2 or C 1-4 alkylamino.
  • R 10 is H.
  • R A is C 1-6 alkyl or C 2-6 alkenyl; the R A is unsubstituted, or is optionally selected from 1 to 3 selected from F, Cl, -OH,
  • the R B is C 1-6 alkyl (eg, methyl, ethyl, n-propyl, isopropyl), C 2-6 alkenyl (eg: allyl), C 3-6 cycloalkyl (for example: cyclopropyl or cyclobutyl), phenyl or 5-6 membered heteroaryl; the R B is unsubstituted or optionally substituted by 1 to 3 R 9 in any Position; R 9 is as defined above.
  • the R C is independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, 5-6 membered heteroaryl, C 3-8 ring Alkyl, 3-8 membered heterocycloalkyl, -(CH 2 ) n -OC 1-6 alkyl, -(CH 2 ) n -phenyl, -(CH 2 ) n -(5-6 membered heteroaryl Group), -(CH 2 ) n -C 3-8 cycloalkyl or -(CH 2 ) n -(3-8 membered heterocycloalkyl); the R C is unsubstituted, or optionally 1 ⁇ 3 R 10 substitutions at arbitrary positions;
  • the R C is independently C 1-6 alkyl, C 2-6 alkenyl, phenyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl, 3-6 membered Heterocycloalkyl, -(CH 2 ) n -OC 1-6 alkyl, -(CH 2 ) n -phenyl, -(CH 2 ) n -(5-6 membered heteroaryl), -(CH 2 ) n -C 3-6 cycloalkyl or -(CH 2 ) n -(3-6 membered heterocycloalkyl); the R C is unsubstituted or optionally substituted by 1 to 3 R 10 in any Position; where n is preferably 1, 2, or 3; R 10 is as defined above.
  • the R C is independently C 1-6 alkyl or C 3-6 cycloalkyl; the R C is unsubstituted or optionally substituted with 1 to 3 R 10 at any position ; Where R 10 is as defined above.
  • the R C is independently C 1-6 alkyl (eg, methyl, ethyl, n-propyl, isopropyl, or tert-butyl) or C 3-6 cycloalkyl (eg : Cyclopropyl).
  • the R 1 is H, -OH, -NH 2, -NH (CH 3) or -NH (CH 2 CH 3).
  • R 1 is H.
  • R 2 is H, CD 3, or R B , wherein R B is as defined above.
  • R 2 is H or R B , wherein R B is as defined above. .
  • R 2 is H, deuterated methyl, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, —C(O)CH ⁇ CH 2 or
  • the R 3 is H or C 1-6 alkyl; the R 3 is unsubstituted, or optionally substituted with 1 to 3, 1 to 2, or 1 R 9 at any position;
  • the definition of R 9 is as described above.
  • R 3 is H or C 1-6 alkyl.
  • R 3 is H, methyl, or ethyl.
  • R 4 is H, C 1-6 alkyl, phenyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl, or 3-6 membered heterocycloalkyl; R 4 is unsubstituted or optionally substituted with 1 to 3, 1 to 2 or 1 R 9 at any position; the definition of R 9 is as described above.
  • the R 4 is methyl, ethyl, n-propyl, isopropyl, phenyl, pyridyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; the R 4 It is unsubstituted or optionally substituted with 1 to 3, 1 to 2 or 1 fluorine, chlorine and methyl substituents at any position.
  • each of R 3 and R 4 is an independent substituent.
  • the R 3 and R 4 together with the carbon atom to which they are connected together form a C 3-10 cycloalkyl or 3-10 membered heterocycloalkyl; the C 3-10 cycloalkyl or 3-
  • the 10-membered heterocycloalkyl group is unsubstituted, or is optionally substituted with 1 to 3 R 9 at any position; the definition of R 9 is as described above.
  • the R 3 and R 4 together with the carbon atom to which they are connected together form a C 3-10 cycloalkyl group, more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,3- Dihydro-1H-indenyl, 2,3-dihydro-1H-indenyl-1-one, spiro[3,2]hexyl or spiro[3.3]heptyl.
  • the R 3 and R 4 together with the carbon atom to which they are connected together form a 3-10 membered heterocycloalkyl group, more preferably a 3-8 membered heterocycloalkyl group, for example: tetrahydrofuranyl, pyrrolidinyl, Azetidinyl, piperidinyl or thietane 1-oxide.
  • the R 3 and R 4 together with the carbon atom to which they are connected together form a 3-10 membered heterocycloalkyl group, more preferably a 3-8 membered heterocycloalkyl group, for example: tetrahydrofuranyl, pyrrolidinyl, Azetidinyl, piperidinyl, or 1-oxo-thietanyl.
  • each of R 1 and R 3 is an independent substituent.
  • the R 1 and R 3 are connected to each other to form a 3-10 membered heterocycloalkyl; the 3-10 membered heterocycloalkyl is unsubstituted or optionally substituted with 1 to 3 R 9 In any position.
  • R 1 and R 3 are interconnected to form a 4-8 membered heterocycloalkyl.
  • R 1 and R 3 are interconnected to form a 5-6 membered heterocycloalkyl.
  • R 2 and R 3 are each independent substituents.
  • the R 2 and R 3 are connected to each other to form a 3-10 membered heterocycloalkyl; the 3-10 membered heterocycloalkyl is unsubstituted or optionally substituted with 1 to 3 R 9 In any position.
  • the R 2 and R 3 are connected to each other to form a 4-8 membered heterocycloalkyl; the 4-8 membered heterocycloalkyl is unsubstituted or optionally substituted with 1 to 3 R 9 In any position.
  • the R 2 and R 3 are interconnected with an ⁇ bond (single bond) to form a double bond.
  • R 5 is hydrogen, halogen, cyano, C 1-4 alkoxy, halogenated C 1-4 alkyl, or halogenated C 1-4 alkoxy.
  • R 5 is hydrogen, halogen, or C 1-4 alkyl.
  • R 5 is H, F, Cl, or —CH 3 .
  • R 5a is hydrogen, halogen, cyano, C 1-4 alkoxy, halogenated C 1-4 alkyl, or halogenated C 1-4 alkoxy.
  • R 5a is hydrogen
  • R 5b is hydrogen, halogen, cyano, C 1-4 alkoxy, halogenated C 1-4 alkyl, or halogenated C 1-4 alkoxy.
  • R 5b is hydrogen, halogen, C 1-4 alkoxy, or C 1-4 alkyl.
  • R 5b is H, F, Cl, -CH 3 or -OCH 3 .
  • a 1 is CR 5
  • a 2 is CH
  • a 3 is N or CR 5b .
  • R is Where R 6 , R 7 and R 8 are independently H, halogen, -CN, -NH 2 , -NHOH, -OH, -R C , -OR C , -NHR C , -NH-OR C ,- NHC(O)R C or -NHS(O) 2 R C ; R 6 and R 7 are independent substituents, or R 6 and R 7 are connected to each other to form a heteroaryl or heterocycloalkyl; the heteroaryl Or heterocycloalkyl is unsubstituted, or is optionally selected from 1 to 3 selected from halogen, -CN, -NH 2 , -NHOH, -OH, -R C , -OR C , -NHR C , -NH-OR The substituents of C , -NHC(O)R C , -C(O)R C and -C(O)N(R C ) 2 are substituted at any position; the
  • R is Where R 6 , R 7 and R 8 are independently H, halogen, -CN, -NH 2 , -NHOH, -OH, -R C , -OR C , -NHR C , -NH-OR C ,- NHC(O)R C or -NHS(O) 2 R C ; R 6 and R 7 are independent substituents, or R 6 and R 7 together with the atoms to which they are attached form a heteroaryl or heterocycloalkyl group; Heteroaryl or heterocycloalkyl is unsubstituted, or is optionally selected from 1 to 3 selected from halogen, -CN, -NH 2 , -NHOH, -OH, -R C , -OR C , -NHR C ,- The substituents of NH-OR C , -NHC(O)R C , -C(O)R C and -C(O)N(R C ) 2 are
  • R is Where R 6 , R 7 and R 8 are independently H, halogen, -CN, -NH 2 , -NHOH, -OH, -R C , -OR C , -NHR C , -NH-OR C ,- NHC(O)R C or -NHS(O) 2 R C ; R C is as defined above.
  • R 8 is H.
  • the R 6 is H, F, Cl, -CN, -NH 2 , -CH 3 , -CF 3 , -CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , -OCF 3. -O-n-propyl, -O-isopropyl, cyclopropyl or 1-methyl-1H-pyrazolyl.
  • R 7 is H, —NH 2 , —NHR C , —NH—OR C, or —NHC(O)R C ; R C is as defined above.
  • R 7 is H, —NH 2 , —NHR C, or —NHC(O)R C ; R C is as defined above.
  • R 6 and R 7 together with the atoms to which they are attached form a 5-6 membered heteroaryl or 5-6 membered heterocycloalkyl; the 5-6 membered heteroaryl or 5-6 membered Heterocycloalkyl is unsubstituted, or is optionally selected from 1-2 or 1 selected from halogen, -CN, -NH 2 , -NHOH, -OH, -R C , -OR C , -NHR C , -NH-
  • the substituents of OR C and -NHC(O)R C are substituted at arbitrary positions; the definition of R C is as described above.
  • the R 6 and R 7 together with the atoms to which they are attached form a 5-6 membered heteroaryl or heterocycloalkyl; the 5-6 membered heteroaryl or heterocycloalkyl is unsubstituted,
  • 1-2 or 1 are selected from F, Cl, -CN, -NH 2 , -CH 3 , -CF 3 , -CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , -OCF 3 , -O-n-propyl, -O-isopropyl, cyclopropyl, -NHR C , -NH-OR C and -NHC(O)R C substituents are substituted at any position; the definition of R C As mentioned earlier.
  • the R is any of the following structures:
  • R 11 and R 12 are independently H, halogen, -CN, -NH 2 , -NHOH, -OH, -R C , -OR C , -NHR C , -NH-OR C, or -NHC(O ) R C ;
  • R C and R 8 are as defined above.
  • the R 11 is H, F, Cl, -CN, -NH 2 , -CH 3 , -CF 3 , -CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , -OCF 3. -O-n-propyl, -O-isopropyl, cyclopropyl, -NHR C , -NH-OR C or -NHC(O)R C ; the definition of R C is as described above.
  • R 11 is H.
  • the R 12 is H, F, Cl, -CN, -NH 2, -CH 3, -CF 3, -CH 2 CH 3, -OCH 3, -OCH 2 CH 3, -OCF 3. -O-n-propyl, -O-isopropyl, cyclopropyl, -NHR C , -NH-OR C or -NHC(O)R C ; the definition of R C is as described above.
  • R 12 is H.
  • W 1 is O.
  • W 2 is O.
  • the compound of formula I, its isomer, prodrug, stable isotope derivative or pharmaceutically acceptable salt is the compound of formula II, its isomer, Prodrug, stable isotope derivative or pharmaceutically acceptable salt:
  • R 1 is H, -OH, -NH 2 , R A , -NH-R A , -NH-C(O)-R A or -OR A ;
  • R 2 is H, CN or R B ;
  • R 3 is H, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl; the R 3 is unsubstituted or optionally substituted with 1 to 3 R 9 at any position;
  • R 4 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, 5-6 membered heteroaryl, C 3-8 cycloalkyl, 3 -8 membered heterocycloalkyl; said R 4 is unsubstituted or optionally substituted with 1 to 3 R 9 at any position;
  • R 3 and R 4 are independent substituents, or R 3 and R 4 together with the carbon atom to which they are connected together form a C 3-10 cycloalkyl or 3-10 membered heterocycloalkyl; the C 3-10 ring
  • the alkyl group or 3-10 membered heterocycloalkyl group is unsubstituted, or optionally substituted with 1 to 3 R 9 at any position;
  • R 5 is hydrogen, halogen, cyano or C 1-4 alkyl
  • R 6 , R 7 and R 8 are independently H, halogen, -CN, -NH 2 , -NHOH, -OH, -R C , -OR C , -NHR C , -NH-OR C , -NHC ( O)R C or -NHS(O) 2 R C ;
  • R 6 and R 7 are independent substituents, or R 6 and R 7 together with the atoms to which they are attached form a heteroaryl or heterocycloalkyl group; the heteroaryl or heterocycloalkyl group is unsubstituted or is optionally substituted 1 to 3 are selected from halogen, -CN, -NH 2 , -NHOH, -OH, -R C , -OR C , -NHR C , -NH-OR C , -NHC(O)R C , -C( O)R C and -C(O)N(R C ) 2 substituents are substituted at any positions;
  • Each R A is independently C 1-8 alkyl, C 2-8 alkenyl or C 2-8 alkynyl; the R A is unsubstituted, or is optionally selected from 1 to 3 selected from halogen, -OH , -NH 2 , oxo, C 1-3 alkoxy and C 1-3 alkylamino substituents are substituted at any position;
  • Each R B is independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, 5-6 membered heteroaryl, C 3-8 cycloalkyl, 3-8 Member heterocycloalkyl, -(CH 2 ) n -phenyl, -(CH 2 ) n -(5-6 membered heteroaryl), -(CH 2 ) n -C 3-8 cycloalkyl or -( CH 2 ) n -(3-8 membered heterocycloalkyl); the R B is unsubstituted or optionally substituted with 1 to 3 R 9 at any position;
  • Each R C is independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, 5-6 membered heteroaryl, C 3-8 cycloalkyl, 3-8 Heterocyclic heterocyclic alkyl, -(CH 2 ) n -OC 1-6 alkyl, -(CH 2 ) n -phenyl, -(CH 2 ) n -(5-6 membered heteroaryl), -(CH 2 ) n -C 3-8 cycloalkyl or -(CH 2 ) n -(3-8 membered heterocycloalkyl); the R C is unsubstituted or optionally substituted by 1 to 3 R 10 in Anywhere
  • Each R 9 and each R 10 are independently H, -CN, -NO 2 , -SH, -NH 2 , -OH, -C(O)OH, -NHC(O)R a , -NHS ( O) 2 R a , -C(O)R a , halogen, oxo, ester, amide, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1- 4 alkoxy, C 1-4 alkylamino, halogenated C 1-4 alkyl or halogenated C 1-4 alkoxy;
  • Each R a is independently C 1-6 alkyl or C 2-6 alkenyl
  • n 1, 2, 3 or 4.
  • the definition of certain groups in the compound of formula II, its isomers, prodrugs, stable isotope derivatives or pharmaceutically acceptable salts can be as follows, without The described group can be as described in any of the above schemes:
  • R 2 is H or R B ;
  • Each R 9 and each R 10 are independently H, -CN, -NO 2 , -SH, -NH 2 , -OH, -C(O)OH, -NHC(O)R a , -NHS ( O) 2 R a , halogen, oxo, ester, amide, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1- 4 alkylamino, halogenated C 1-4 alkyl or halogenated C 1-4 alkoxy.
  • R A is C 1-6 alkyl or C 2-6 alkenyl; the R A is unsubstituted, or is optionally selected from 1 to 3 selected from F, Cl, -OH,
  • the R B is C 1-6 alkyl (eg, methyl, ethyl, n-propyl, isopropyl), C 2-6 alkenyl (eg: allyl), C 3-6 cycloalkyl (for example: cyclopropyl), phenyl or 5-6 membered heteroaryl; the R B is unsubstituted or optionally substituted with 1 to 3 R 9 at any position; R 9
  • the definition is as described above.
  • the R C is independently C 1-6 alkyl, C 2-6 alkenyl, phenyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl, 3-6 membered Heterocycloalkyl, -(CH 2 ) n -OC 1-6 alkyl, -(CH 2 ) n -phenyl, -(CH 2 ) n -(5-6 membered heteroaryl), -(CH 2 ) n -C 3-6 cycloalkyl or -(CH 2 ) n -(3-6 membered heterocycloalkyl); the R C is unsubstituted or optionally substituted by 1 to 3 R 10 in any Position; where n is preferably 1, 2, or 3; R 10 is as defined above.
  • the R C is independently C 1-6 alkyl or C 3-6 cycloalkyl; the R C is unsubstituted or optionally substituted with 1 to 3 R 10 at any position ; Where R 10 is as defined above.
  • the R C is independently C 1-6 alkyl (eg, methyl, ethyl, n-propyl, isopropyl, or tert-butyl) or C 3-6 cycloalkyl (eg : Cyclopropyl).
  • each R 9 and each R 10 are independently H, -CN, -NO 2 , -SH, -NH 2 , -OH, -C(O)OH, -NHC(O) R a , -NHS(O) 2 R a , halogen, oxo, ester, amide, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkyl Oxygen, C 1-4 alkylamino, halogenated C 1-4 alkyl or halogenated C 1-4 alkoxy;
  • R 9 is H, —NH 2 , —OH, F, Cl, ⁇ O, —NHC(O)—C 2-6 alkenyl, —NHS(O) 2 —C 2- 6 alkenyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, halogenated C 1-4 alkyl or halogenated C 1-4 alkoxy.
  • R 10 is H, —CN, —NH 2 , —OH, F, Cl, ⁇ O, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl , C 1-4 alkoxy, C 1-4 alkylamino, halogenated C 1-4 alkyl or halogenated C 1-4 alkoxy.
  • R 10 is H.
  • the R 1 is H, -OH, -NH 2, -NH (CH 3) or -NH (CH 2 CH 3).
  • R 1 is H.
  • R 2 is H or R B.
  • R 2 is H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, —C(O)CH ⁇ CH 2 or
  • the R 3 is H or C 1-6 alkyl; the R 3 is unsubstituted, or optionally substituted with 1 to 3, 1 to 2, or 1 R 9 at any position;
  • the definition of R 9 is as described above.
  • R 3 is H or C 1-6 alkyl.
  • R 3 is H, methyl, or ethyl.
  • R 4 is H, C 1-6 alkyl, phenyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl, or 3-6 membered heterocycloalkyl; R 4 is unsubstituted or optionally substituted with 1 to 3, 1 to 2 or 1 R 9 at any position; the definition of R 9 is as described above.
  • the R 4 is methyl, ethyl, n-propyl, isopropyl, phenyl, pyridyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; the R 4 It is unsubstituted or optionally substituted with 1 to 3, 1 to 2 or 1 fluorine, chlorine and methyl substituents at any position.
  • the R 3 and R 4 together with the carbon atom to which they are connected together form a C 3-10 cycloalkyl or 3-10 membered heterocycloalkyl; the C 3-10 cycloalkyl or 3-
  • the 10-membered heterocycloalkyl group is unsubstituted, or is optionally substituted with 1 to 3 R 9 at any position; the definition of R 9 is as described above.
  • the R 3 and R 4 together with the carbon atom to which they are connected together form a C 3-10 cycloalkyl group, more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,3 -Dihydro-1H-indenyl, 2,3-dihydro-1H-indenyl-1-one, spiro[3,2]hexyl or spiro[3.3]heptyl.
  • the R 3 and R 4 together with the carbon atom to which they are connected together form a 3-10 membered heterocycloalkyl group, more preferably a 3-8 membered heterocycloalkyl group, for example: tetrahydrofuranyl, pyrrolidinyl, Azetidinyl, piperidinyl or thietane 1-oxide.
  • the R 3 and R 4 together with the carbon atom to which they are connected together form a 3-10 membered heterocycloalkyl group, more preferably a 3-8 membered heterocycloalkyl group, for example: tetrahydrofuranyl, pyrrolidinyl, Azetidinyl, piperidinyl, or 1-oxo-thietanyl.
  • the R 5 is F, Cl, -CN, -CH 3 or -CH 2 CH 3 .
  • R 5 is F.
  • the R 5 is Cl.
  • R 5 is —CH 3 .
  • R 8 is H.
  • the R 6 is H, F, Cl, -CN, -NH 2 , -CH 3 , -CF 3 , -CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , -OCF 3. -O-n-propyl, -O-isopropyl, cyclopropyl or 1-methyl-1H-pyrazolyl.
  • R 7 is H, —NH 2 , —NHR C , —NH—OR C, or —NHC(O)R C ; R C is as defined above.
  • the R 6 and R 7 together with the atoms to which they are attached form a 5-6 membered heteroaryl or heterocycloalkyl; the 5-6 membered heteroaryl or heterocycloalkyl is unsubstituted, Alternatively, it can be selected from 1-3, 1-2 or 1 selected from halogen, -CN, -NH 2 , -NHOH, -OH, -R C , -OR C , -NHR C , -NH-OR C and-
  • the substituent of NHC(O)R C is substituted at any position; the definition of R C is as described above.
  • the R 6 and R 7 together with the atoms to which they are attached form a 5-6 membered heteroaryl or heterocycloalkyl; the 5-6 membered heteroaryl or heterocycloalkyl is unsubstituted,
  • 1-2 or 1 are selected from F, Cl, -CN, -NH 2 , -CH 3 , -CF 3 , -CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , -OCF 3 , -O-n-propyl, -O-isopropyl, cyclopropyl, -NHR C , -NH-OR C and -NHC(O)R C substituents are substituted at any position; the definition of R C As mentioned earlier.
  • R 11 and R 12 are independently H, halogen, -CN, -NH 2 , -NHOH, -OH, -R C , -OR C , -NHR C , -NH-OR C, or -NHC(O ) R C ;
  • R C and R 8 are as defined above.
  • R 11 and R 12 are independently H, halogen, -CN, -NH 2 , -NHOH, -OH, -R C , -OR C , -NHR C , -NH-OR C, or -NHC(O ) R C ;
  • R C and R 8 are as defined above.
  • the R 11 is H, F, Cl, -CN, -NH 2 , -CH 3 , -CF 3 , -CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , -OCF 3. -O-n-propyl, -O-isopropyl, cyclopropyl, -NHR C , -NH-OR C or -NHC(O)R C ; the definition of R C is as described above.
  • R 11 is H.
  • the R 12 is H, F, Cl, -CN, -NH 2, -CH 3, -CF 3, -CH 2 CH 3, -OCH 3, -OCH 2 CH 3, -OCF 3. -O-n-propyl, -O-isopropyl, cyclopropyl, -NHR C , -NH-OR C or -NHC(O)R C ; the definition of R C is as described above.
  • R 12 is H.
  • the compound of formula I, its isomer, prodrug, stable isotopic derivative or pharmaceutically acceptable salt is the compound of formula III, its isomer, Prodrug, stable isotope derivative or pharmaceutically acceptable salt:
  • n 0, 1, 2 or 3
  • t 0, 1, 2 or 3
  • X and Y are independently O, NH or CH 2 ;
  • R 1 , R 2 , R 5 , R 6 , R 7 , R 8 and R 9 are as described above.
  • the compound of formula I, its isomer, prodrug, stable isotopic derivative or pharmaceutically acceptable salt is the compound of formula IV, its isomer, Prodrug, stable isotope derivative or pharmaceutically acceptable salt:
  • n 0, 1, 2 or 3
  • t 0, 1, 2 or 3
  • R 1 , R 2 , R 5 , R 6 , R 7 , R 8 and R 9 are as described above.
  • the compound of formula I, its isomer, prodrug, stable isotope derivative or pharmaceutically acceptable salt is the compound of formula V, its isomer, Prodrug, stable isotope derivative or pharmaceutically acceptable salt:
  • n 0, 1, 2 or 3
  • t 0, 1, 2 or 3
  • R 1 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are as described above.
  • the compound of formula I, its isomer, prodrug, stable isotope derivative or pharmaceutically acceptable salt is a compound of formula VI, its isomer, Prodrug, stable isotope derivative or pharmaceutically acceptable salt:
  • R 1 , R 4 , R 5 , R 6 , R 7 and R 8 are as described above.
  • the compound of formula I', its isomer, prodrug, stable isotopic derivative or pharmaceutically acceptable salt is the compound of formula VII, its isomer , Prodrugs, stable isotope derivatives or pharmaceutically acceptable salts:
  • n 0, 1, 2 or 3
  • t 0, 1, 2 or 3
  • R 1 , R 2 , R 5 , R 6 , R 7 , R 8 , R 9 and A 3 are as described above.
  • the compound of formula I′, its isomer, prodrug, stable isotopic derivative or pharmaceutically acceptable salt is the compound of formula VIII, its isomer , Prodrugs, stable isotope derivatives or pharmaceutically acceptable salts:
  • n 0, 1, 2 or 3
  • t 0, 1, 2 or 3
  • R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and A 3 are as described above.
  • the compound of Formula I, the isomer, prodrug, stable isotopic derivative or pharmaceutically acceptable salt is optionally the following compound:
  • the compound of Formula I, the isomer, prodrug, stable isotopic derivative or pharmaceutically acceptable salt is optionally the following compound:
  • the compound of Formula I, the isomer, prodrug, stable isotopic derivative or pharmaceutically acceptable salt is optionally the following compound:
  • the compound of Formula I, the isomer, prodrug, stable isotopic derivative or pharmaceutically acceptable salt is optionally the following compound:
  • the compound represented by formula I', the isomer, prodrug, stable isotopic derivative or pharmaceutically acceptable salt thereof are optionally the following compounds:
  • the compound represented by formula I' isomers, prodrugs, stable isotope derivatives or pharmaceutically acceptable salts thereof are optionally the following compounds:
  • the present invention also provides a method for preparing a compound represented by Formula I or I', which is any of the following methods:
  • Method 1 In a solvent, under basic conditions, X or X'and RH are subjected to Buchwald-hartwig coupling or Ullmann coupling reaction to obtain the compound represented by formula I or I';
  • L is a halogen or other leaving group, such as -OTf, -OTs or -OMs, L is preferably chlorine, bromine or iodine; R, R 1 , R 2 , R 3 , R 4 , R 5 , R 5a , A 1 , A 2 , A 3 , W 1 and W 2 are as defined above.
  • Method 2 In a solvent, under basic conditions, X or X'and RH are subjected to a Buchwald-hartwig coupling reaction to obtain a compound represented by Formula I or I';
  • L is halogen or other leaving group, such as -OTf, -OTs or -OMs, L is preferably chlorine, bromine or iodine; R 1 , R 2 , R 3 , R 4 , R 5 , R 5a , A 1 , A 2 , A 3 , W 1 , W 2 and Cy are as defined above.
  • the R is preferably
  • the conditions and steps of the Buchwald-hartwig coupling reaction may be the conditions and steps of a conventional coupling reaction in the art, and the following reaction conditions are particularly preferred in the present invention: the solvent is preferred 1,4-dioxane or tert-butanol; the amount of the solvent is preferably 5 to 80 mL/mmol compound X, X', XI or XI'; the base used under the alkaline conditions is preferably cesium carbonate or Sodium tert-butoxide; the molar ratio of the base to the compound X, X', XI or XI' is preferably 1.05:1 to 3:1; the coupling reagent is preferably Pd 2 (dba) 3 , Xantphos and/or XPhos system Or Pd 2 (dba) 3 and Ru-phos system; the temperature of the reaction is preferably 50-120°C; the reaction can be detected by TLC or LCMS, and generally disappears as
  • the organic phase is dried, the organic solvent is removed under reduced pressure, and the residue is purified by conventional purification means, for example, silica gel column chromatography, Flash column chromatography, or prep-HPLC.
  • the purification steps and conditions of silica gel column chromatography, Flash column chromatography or prep-HPLC can be conventional purification steps and conditions in the art.
  • the R is preferably
  • the conditions and steps of the Ullmann coupling reaction can be the conditions and steps of conventional coupling reactions in the art, and the following reaction conditions are particularly preferred in the present invention:
  • the solvent is preferably 1,4-dioxane
  • the base Preferably, potassium phosphate and trans-1,2-cyclohexanediamine are reacted in the presence of cuprous iodide to obtain I or I'.
  • the -NH 2 in Cy when -NH 2 in Cy does not participate in the reaction, the -NH 2 is preferably protected by a protecting group to avoid any side reactions. If the above amino protecting group is present, it is necessary to go through a subsequent deprotection step to obtain the compound represented by formula I, I', I-1 or I'-1. Any suitable amino protecting group, for example: tert-butoxycarbonyl (Boc) group, acetyl, cyclopropionyl, Both can be used to protect amino groups.
  • a protecting group for example: tert-butoxycarbonyl (Boc) group, acetyl, cyclopropionyl, Both can be used to protect amino groups.
  • the subsequent deprotection reaction can be performed under standard conditions, for example, p-toluenesulfonic acid/methanol system, methylene chloride/trifluoroacetic acid system, saturated hydrogen chloride ether solution, or trifluoromethanesulfonic acid trimethylsulfonate Carboxymethyl ester/2,6-lutidine/dichloromethane system; acetyl, cyclopropionyl as protective groups, subsequent deprotection reaction can be under standard conditions, such as potassium hydroxide (sodium)/ethanol /Tetrahydrofuran/water system; As a protecting group, the subsequent deprotection reaction can be carried out under standard conditions, for example, an ethylenediamine/ethanol system.
  • X including X, X-1, and X-2) or X'(including X', X'-1, and X'-2) can be synthesized by the methods shown in the following reaction formulas 3 to 4:
  • R t is H or C 1-6 alkyl
  • R 1 is H
  • R 2 , R 3 , R 4 , R 5 , R 5a , L, W 1 and W 2 are as defined above;
  • reaction temperature is preferably 70 to 110°C, and the reaction time is preferably 2 to 24 hours.
  • Equation 3 when R 2 is H, When R 3 is a substituted C 1-6 alkyl (the substituent includes at least one halogen or ester group), a compound represented by formula X-1 or X′-1 is obtained:
  • R 2 is C 1-6 alkyl or deuterated C 1-4 alkyl (preferably methyl, ethyl or deuterated methyl); R 1 , R 3 , R 4 , R 5 , R 5a ,
  • L, W 1 and W 2 are as described above;
  • L′ is a halogen or other leaving group, such as -OTf, -OTs or -OMs, and L is preferably bromine or iodine;
  • compound X-2 or X'-2 is reacted with R 2 -L' to obtain compound X or X'.
  • the reaction temperature is preferably 70 to 110°C, and the reaction time is preferably 5 to 48 hours.
  • the pharmaceutically acceptable salt of the compound represented by formula I or I' can be synthesized by a general chemical method.
  • the salt can be prepared by reacting a free base or acid with an equivalent stoichiometric amount or an excess of acid (inorganic acid or organic acid) or base (inorganic base or organic base) in a suitable solvent or solvent composition.
  • the present invention also provides a pharmaceutical composition, which includes an active component and a pharmaceutically acceptable excipient; the active component includes a compound represented by formula I or I', its isomer, prodrug, stable One or more of isotope derivatives and pharmaceutically acceptable salts.
  • the present invention also provides a pharmaceutical composition, which includes a therapeutically effective amount of an active component and a pharmaceutically acceptable excipient;
  • the active component includes a compound represented by formula I or I', isomers thereof, pro One or more of medicines, stable isotope derivatives and pharmaceutically acceptable salts.
  • the active component may further include other kinds of therapeutic agents for treating related diseases caused by abnormal levels of MNK1 and/or MNK2; the related diseases caused by abnormal levels of MNK1 and/or MNK2 It is preferably cancer.
  • the active component may further include other therapeutic agents for cancer.
  • the pharmaceutically acceptable excipient may include a pharmaceutically acceptable carrier, diluent and/or excipient.
  • the pharmaceutical composition can be made into various types of unit dosage forms, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories and injections (solutions and suspensions), etc. , Liquids, suspensions, emulsions, suppositories and injections (solutions and suspensions) are preferred.
  • any excipient known and widely used in the art may be used.
  • carriers such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc.
  • binders such as water, ethanol, propanol, ordinary syrup, glucose solution, starch Solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose and potassium phosphate, polyvinylpyrrolidone, etc.
  • disintegrants such as dry starch, sodium alginate, agar powder and kelp powder, sodium bicarbonate, carbonic acid Calcium, fatty acid esters of polyethylene sorbitan, sodium lauryl sulfate, monoglyceryl stearate, starch and lactose, etc.
  • disintegration inhibitors such as white sugar, glycerol tristearate, coconut oil and hydrogenation Oil
  • Adsorption accelerators such as quaternary ammonium base and
  • any known and widely used excipients in the art can be used, for example, carriers such as lactose, starch, coconut oil, hardened vegetable oil, kaolin and talc, etc.; , Such as gum arabic powder, tragacanth powder, gelatin and ethanol; disintegrants, such as agar and kelp powder.
  • any excipient known and widely used in the art may be used, for example, polyethylene glycol, coconut oil, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic glycerides .
  • the solution or suspension can be sterilized (preferably with an appropriate amount of sodium chloride, glucose or glycerin, etc.) to make an injection that is isotonic with blood.
  • any carrier commonly used in the art may also be used.
  • common dissolving agents, buffering agents and analgesics can also be added.
  • the content of the composition in the pharmaceutical composition is not particularly limited, and can be selected within a wide range, usually 5 to 95% by mass, preferably 30 to 80 by mass %.
  • the administration method of the pharmaceutical composition is not particularly limited.
  • various formulations can be selected for administration.
  • tablets, pills, solutions, suspensions, emulsions, granules, or capsules are administered orally; injections can be administered alone or mixed with injection delivery fluids (such as glucose solution and amino acid solution) for intravenous injection; suppositories are given Medicine to the rectum.
  • injection delivery fluids such as glucose solution and amino acid solution
  • the present invention also provides the compound of formula I or I', its isomer, prodrug, solvate, hydrate, stable isotope derivative or pharmaceutically acceptable salt, or the pharmaceutical composition Application in the preparation of MNK1 and/or MNK2 inhibitors.
  • the MNK1 and/or MNK2 inhibitor means that it can inhibit the activity or expression of MNK1 and/or MNK2 (including the abnormal activity or overexpression of MNK1 and/or MNK2).
  • the present invention also provides the compound of formula I or I', its isomer, prodrug, solvate, hydrate, stable isotope derivative or pharmaceutically acceptable salt, or the pharmaceutical composition It has the treatment or reduction of tumor cell growth, proliferation and/or survival, uncomfortable cellular immune response and its related disorders, or uncomfortable cell inflammatory response and its related disorders.
  • the tumor cell growth, proliferation and/or survival, uncomfortable cellular immune response and its related disorders, or uncomfortable cell inflammatory response and its related disorders are mediated by MNK1 and/or MNK2.
  • the present invention also provides the compound of formula I or I', its isomer, prodrug, solvate, hydrate, stable isotope derivative or pharmaceutically acceptable salt, or the pharmaceutical composition Use in the preparation of a medicament for the treatment, alleviation and/or prevention of related diseases mediated by MNK1 and/or MNK2.
  • the related diseases mediated by MNK1 and/or MNK2 are value-added diseases, preferably cancer.
  • the present invention also provides the compound of formula I or I', its isomer, prodrug, solvate, hydrate, stable isotope derivative or pharmaceutically acceptable salt, or the pharmaceutical composition Use in the preparation of therapeutic and/or cancer alleviating drugs.
  • the present invention also provides the compound of formula I or I', its isomer, prodrug, solvate, hydrate, stable isotope derivative or pharmaceutically acceptable salt, or the pharmaceutical composition Use in the treatment and/or alleviation of cancer, which includes administering to a mammal a therapeutically effective dose of a compound represented by formula (I), its isomers, prodrugs, solvates, hydrates, stable isotope derivatives or A pharmaceutically acceptable salt, or a pharmaceutical composition containing the same.
  • the present invention also provides the compound of formula I or I', its isomer, prodrug, solvate, hydrate, stable isotope derivative or pharmaceutically acceptable salt, or the pharmaceutical composition It is used in combination with one or more other kinds of therapeutic agents and/or treatment methods for the treatment of cancer to treat, alleviate and/or prevent related diseases mediated by MNK1 and/or MNK2.
  • the related diseases mediated by MNK1 and/or MNK2 are proliferative diseases, preferably cancer.
  • the present invention further provides a combined preparation comprising a compound represented by formula I or I', its isomer, prodrug, stable isotope derivative or pharmaceutically acceptable salt, or the pharmaceutical composition and other Various kinds of therapeutic agents and/or treatment methods for treating cancer are used in combination.
  • the other kinds of therapeutic agents for treating cancer may be combined with the above-mentioned compounds of formula I or I'into a single-dose therapeutic dosage form, or separately administered sequentially.
  • the other kinds of therapeutic agents and/or treatment methods for treating cancer may include but are not limited to: alkylating agents, topozyme I/II inhibitors, antimitotic agents, antimetabolites, hormones and One or more of hormone analogues, antitumor antibiotics, small molecule kinase inhibitors, small molecule immunomodulators, interferons, monoclonal antibodies, and radiotherapy.
  • the alkylating agent may be selected from but not limited to: cisplatin, carboplatin, oxaliplatin, nedaplatin, nitrogen mustard, N-oxide-nitrogen mustard hydrochloride, chlorambucil, uracil Nitrogen mustard, cyclophosphamide, ifosfamide, thiotepa, carboquinone, triiminoquinone, inprosulfan tosylate, mannosulfan, trioxifan, busulan, nimustine hydrochloride , Dibromomannitol, melphalan, dacarbazine, ramustine, carmustine, lomustine, streptozotocin, temozolomide, procarbazine, ethyleneimine derivatives, methanesulfonate One or more of the class, nitrosourea, triazene.
  • the topozyme I/II inhibitor may be selected from but not limited to: doxorubicin, daunorubicin, epirubicin, idarubicin, irinotecan, topotecan, lubi One or more of tecan, belotecan, etoposide, teniposide, doxorubicin and dexrazoxane, camptothecin.
  • the anti-mitotic agents include but are not limited to: paclitaxel, docetaxel, polyglutamic acid paclitaxel, isovinblastine, vincristine, vinblastine, vindesine, vinpodine, etoposide, and One or more of nipatoside, ixabepilone, raloxatose, ortataxel, tesetaxel, tocosal, and ispins.
  • the antimetabolite drugs may be selected from but not limited to: folic acid antagonists, pyrimidine analogs, purine analogs, adenosine deaminase inhibitors, such as: methotrexate, 5-fluorouracil, fluorourea One or more of glycosides, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin and gemcitabine.
  • the hormone therapeutic agent may be selected from, but not limited to: phosphoestrol, diethylstilbestrol, chlorostilbestrol, medroxyprogesterone acetate, megestrol acetate, chlorgesterone acetate, cyproterone acetate , Danazol, dienogest, allyl estradiol, gestrinone, nomegestrol, tonazepam, mepatricin, raloxifene, omemexifen, zomeloxifen, an Lumit, testosterone, anti-estrogen, LH-RH derivatives, aromatase inhibitors, anti-androgens, adrenocortical hormones, androgen synthesis inhibitors, retinoic acid and drugs that delay retinoic acid metabolism One or more.
  • the anti-tumor antibiotics include but are not limited to: actinomycin D, doxorubicin, daunorubicin, bleomycin, pelopromycin, mitomycin C, arubicin , One or more of pirarubicin, epirubicin, netastatin, idarubicin, sirolimus and penrorubicin.
  • the small molecule kinase inhibitors include but are not limited to: erlotinib, imatinib, apatinib, nilotinib, crizotinib, dasatinib, pazopanib , Regefenib, rusolitinib, sorafenib, sunitinib, vandetanib, verofenib, bosutinib, gefitinib, afatinib, axitinib Nigra, dalapini, dacomitinib, nidanib, lovastinib, marcetinib, middoturin, lenatinib, panatinib, redotinib, trametinib , Alanine brinibub, sildenibu, carbotinib malate, ibrutinib, icotinib, cipatinib, cobin
  • the monoclonal antibodies include but are not limited to: alemtuzumab, bentuximab, cetuximab, rituximab, denosumab, epilimumab, ofatumumab MAb, panitumumab, tositumomab, trastuzumab, bevacizumab, pertuzumab, catumaxomab, elotuzumab, epalizumab, One of the resistance to rituximab, nimotuzumab, tocilizumab, matuzumab, zalutumumab, atuzumab, ramucirumab, and nivolumab Or more.
  • the small molecule immunomodulators include but are not limited to: TLR7 agonists, TLR8 agonists, TLR9 agonists, IDO inhibitors, CD73 inhibitors, STING inhibitors, A2AR antagonists, PD-L1 inhibitors One or more.
  • the interferon used for cancer treatment includes but is not limited to: interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon beta, interferon gamma-1a or interferon gamma-n1, etc. .
  • the radiotherapy is well known in the art and includes X-ray therapy, such as gamma radiation, radiopharmaceutical therapy, and the like.
  • the cancer includes metastatic and non-metastatic cancers, and also includes family inherited and sporadic cancers, and may also include solid tumors and non-solid tumors.
  • specific examples of the solid tumor may include but are not limited to: eye cancer, bone cancer, lung cancer, gastric cancer, pancreatic cancer, islet cell cancer, breast cancer, triple negative breast cancer, prostate cancer, trend-resistant prostate cancer , Brain cancer (including malignant glioma, medulloblastoma), CNS cancer, glioblastoma, ovarian cancer, bladder cancer, urothelial cancer, cervical cancer, testicular cancer, kidney cancer (including glands Cancer and Wilms Cancer), oral cancer (including squamous cell carcinoma), tongue cancer, laryngeal cancer, nasopharyngeal cancer, head and neck cancer, colon cancer, small intestine cancer, rectal cancer, colorectal cancer, parathyroid cancer, thyroid Cancer, esophageal cancer, gallbladder cancer, cholangiocarcinoma, cervical cancer, liver cancer, hepatocellular carcinoma, lung cancer, non-small cell lung cancer, sarcoma, leiomyosarcoma,
  • non-solid tumors may include, but are not limited to: B-cell lymphoma, T-cell lymphoma, diffuse large B-cell lymphoma, Hodgkin lymphoma, non-Hodgkin Chikin lymphoma, Burkitt lymphoma, myelodysplastic syndrome, lymphocytic leukemia (including lymphoblastic leukemia, lymphoma, myeloma, multiple myeloma, chronic lymphocytic leukemia (T cell chronic lymphocytic leukemia, One or more of B-cell chronic lymphocytic leukemia) and myeloid-related leukemia (including acute myeloid leukemia, chronic myelogenous leukemia).
  • the therapeutically effective dose of the compound represented by formula I or I′ or a pharmaceutically acceptable salt is given, and the therapeutically effective dose varies according to various factors, including, for example, the activity of the specific compound used, the Factors such as the metabolic stability and duration of action of the compound, the patient's age, weight, health status, gender, mode and time of administration, absorption metabolic properties, severity of specific diseases or conditions, and other factors.
  • “Therapeutically effective amount” refers to an amount sufficient to provide an effective treatment for a MNK1 and/or MNK2 related disorder or disease in the mammal when administered to the mammal.
  • the amount of the compound of the present invention constituting a therapeutically effective amount needs to vary according to the compound, the condition and its severity, the mode of administration, and the age of the mammal to be treated, but it can be determined by those skilled in the art based on the knowledge and the present invention The content is determined routinely.
  • the mammal is preferably a human.
  • substituted by 1 to 3 groups at any position refers to any 1, 2 or 3 of the 1, 2, or 3 atoms specified on the group
  • the hydrogen atom is substituted with the specified group, provided that the normal valence of the specified atom is not exceeded, and the substitutions are all reasonable substitutions common in the art.
  • alkyl refers to a saturated linear or branched hydrocarbon group containing 1-20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1-8, 1-6, 1-4, 1-3 carbons
  • Representative examples of atoms, alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, pentyl, hexyl, heptyl , Octyl, nonyl, decyl, 4,4-dimethylpentyl, 2,2,4-trimethylpentyl, undecyl, dodecyl, and their various isomers Wait.
  • deuterated alkyl refers to an alkyl group optionally substituted with a deuterium atom.
  • the deuterated alkyl group described in the present invention is preferably an alkyl group completely substituted with a deuterium atom, for example, -CD 3 , -C 2 D 5 .
  • cycloalkyl refers to a saturated or partially unsaturated (containing 1 or 2 double bonds) monocyclic or polycyclic group containing 3-20 carbon atoms.
  • Cycloalkyl is preferably C 3-10 cycloalkyl, more preferably C 3-8 monocycloalkyl, C 3-6 monocycloalkyl, and representative examples of the “monocycloalkyl” include but are not limited to : Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, cyclohexenyl.
  • Polycyclic cycloalkyl includes “bridged cycloalkyl”, “fused cycloalkyl” and “spirocycloalkyl”.
  • Representative examples of “bridged cycloalkyl” include but are not limited to: norbornyl, bicyclic [2.2. 1] Heptenyl, bicyclic [3.1.1] heptyl, bicyclic [2.2.1] heptyl, bicyclic [2.2.2] octyl, bicyclic [3.2.2] nonyl, bicyclic [3.3. 1] Nonyl, bicyclo[4.2.1] nonyl, adamantyl, etc.
  • “Fused cycloalkyl” includes cycloalkyl rings fused to phenyl, cycloalkyl or heteroaryl groups.
  • Condensed cycloalkyl groups include but are not limited to: benzocyclobutenyl, 2,3-di Hydrogen-1H-indenyl, 5,6-dihydro-4H-cyclopentyl[B]thienyl, decahydronaphthyl, etc.
  • “Spirocycloalkyl” refers to a bicyclic group formed by two monocyclic cycloalkyls sharing one carbon atom.
  • Spirocycloalkyl includes but is not limited to: spiro[3,3]heptyl, spiro[3,2]hexyl , Spiro[2,5]octyl, spiro[2,4]heptyl, spiro[4,5]decyl, etc.
  • C 3-10 cycloalkyl refers to a cycloalkyl group containing 3-10 carbon atoms
  • C 3-8 cycloalkyl refers to a cycloalkyl group containing 3-8 carbon atoms.
  • C 3-6 cycloalkyl refers to a cycloalkyl group containing 3 to 6 carbon atoms.
  • the monocyclic cycloalkyl or polycyclic cycloalkyl can be linked to the parent molecule through any one or two carbon atoms in the ring.
  • heterocycloalkyl refers to a saturated or partially unsaturated (including 1 or 2 double bonds) non-aromatic cyclic group composed of carbon atoms and heteroatoms selected from nitrogen, oxygen, or sulfur.
  • the group may be a monocyclic or polycyclic group.
  • the number of hetero atoms in the heterocycloalkyl group is preferably 1, 2, 3 or 4, and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl group may be optionally Oxidized.
  • the nitrogen atom may optionally be further substituted with other groups to form a tertiary amine or quaternary ammonium salt.
  • the "monocyclic heterocycloalkyl group” is preferably a 3-10 membered monocyclic heterocycloalkyl group, and more preferably a 3-8 membered monocyclic heterocycloalkyl group.
  • monocyclic heterocycloalkyl group preferably a 3-10 membered monocyclic heterocycloalkyl group, and more preferably a 3-8 membered monocyclic heterocycloalkyl group.
  • Polycyclic heterocycloalkyl includes “fused heterocycloalkyl”, “spiro heterocyclyl” and “bridged heterocycloalkyl”. "Fused heterocycloalkyl” includes monocyclic heterocycloalkyl rings fused to phenyl, cycloalkyl, heterocycloalkyl, or heteroaryl.
  • Condensed heterocycloalkyl includes, but is not limited to: 2,3 -Dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, dihydroindolyl, 2,3-dihydrobenzo[b]thienyl, dihydrobenzopiperanyl, 1, 2,3,4-tetrahydroquinolinyl, 6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidinyl, etc.
  • Spiroheterocyclyl refers to a bicyclic group formed by two heterocycloalkyl groups or a cycloalkyl group and a heterocycloalkyl group sharing a carbon atom.
  • Spiroheterocyclic groups include, but are not limited to: 5-aza[2.5 ] Octyl, 4-aza[2.5]octyl, 4-aza[2.4]heptyl, etc.
  • the 9-10 membered heterocycloalkyl group is preferably a 9-10 membered fused heterocycloalkyl group.
  • Monocyclic heterocycloalkyl and polycyclic heterocycloalkyl can be linked to the parent molecule through any one or two ring atoms on the ring.
  • the above ring atoms specifically refer to carbon atoms and/or nitrogen atoms constituting the ring skeleton.
  • cycloalkylalkyl refers to the connection between the cycloalkyl group and the parent core structure through an alkyl group.
  • cycloalkylalkyl includes the above definitions of alkyl and cycloalkyl.
  • heterocycloalkylalkyl refers to the connection between the heterocycloalkyl group and the parent core structure through an alkyl group.
  • heterocycloalkylalkyl includes the above definitions of alkyl and heterocycloalkyl.
  • alkoxy refers to a cyclic or acyclic alkyl group having the number of carbon atoms connected through an oxygen bridge, and includes alkyloxy, cycloalkyloxy, and heterocycloalkyloxy groups. Thus, “alkoxy” includes the above definitions of alkyl, heterocycloalkyl, and cycloalkyl.
  • alkenyl refers to a linear, branched or cyclic non-aromatic hydrocarbon group containing at least one carbon-carbon double bond. There may be 1-3 carbon-carbon double bonds, preferably one carbon-carbon double bond.
  • C 2-4 alkenyl refers to an alkenyl group having 2-4 carbon atoms
  • C 2-6 alkenyl refers to an alkenyl group having 2-6 carbon atoms, including vinyl, propenyl , Butenyl, 2-methylbutenyl and cyclohexenyl.
  • alkynyl refers to a linear, branched, or cyclic hydrocarbon group containing at least one carbon-carbon triple bond. There may be 1-3 carbon-carbon triple bonds, preferably one carbon-carbon triple bond.
  • C 2-6 alkynyl refers to an alkynyl group having 2 to 6 carbon atoms, including ethynyl, propynyl, butynyl, and 3-methylbutynyl.
  • aryl refers to any stable 6-20 membered monocyclic or polycyclic aromatic group, such as: phenyl, naphthyl, tetrahydronaphthyl, indanyl or biphenyl, etc. .
  • heteroaryl refers to an aromatic ring group formed by replacing at least one ring carbon atom with a heteroatom selected from nitrogen, oxygen, or sulfur, which may be a 5-7 membered monocyclic heteroaryl or 7 -20 fused heteroaryl. At least one ring in the "fused heteroaryl group” is a heteroaromatic ring, and the “heteroaryl ring” is preferably a 5-6 membered monocyclic heteroaryl group and a 9-12 or 9-10 membered fused heteroaryl group .
  • the number of hetero atoms is preferably 1, 2, or 3, 5-6 membered heteroaryl groups include but are not limited to: pyridyl, pyrimidinyl, piperazinyl, pyridazin-3(2H)-keto , Furanyl, thienyl, thiazolyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl , 1,3,4-oxadiazolyl, 1,3,4-thiadiazole, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, etc.;
  • 9-10 membered fused heteroaryl groups include, but are not limited to: indazolyl, isoindazolyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzo
  • arylalkyl refers to the connection between the aryl group and the parent core structure through an alkyl group.
  • arylalkyl includes the above definitions of alkyl and aryl.
  • heteroarylalkyl refers to the connection between the heterocycloalkyl group and the parent core structure through an alkyl group.
  • heteroarylalkyl includes the above definitions of alkyl and heteroaryl.
  • halogen means fluorine, chlorine, bromine or iodine.
  • haloalkyl refers to an alkyl group optionally substituted with halogen.
  • haloalkyl includes the above definitions of halogen and alkyl.
  • haloalkoxy refers to an alkoxy group optionally substituted with halogen.
  • haloalkoxy includes the above definitions of halogen and alkoxy.
  • ester group means -C(O)OR', and R'is C 1-6 alkyl.
  • amido means -C(O)N(R") 2 , R" is hydrogen, C 1-6 alkyl or C 2-6 alkenyl.
  • acyl refers to -C(O)R"', R"' is C 1-6 alkyl, C 2-6 alkenyl or C 3-8 cycloalkyl.
  • nitro refers to -NO 2 .
  • cyano refers to -CN.
  • hydroxyl refers to -OH.
  • mercapto refers to -SH.
  • amino refers to -NH 2.
  • alkylamino means that at least one hydrogen atom on the amino group is replaced by an alkyl group, including but not limited to: -NHCH 3 , -N(CH 3 ) 2 , -N(CH 3 )(CH 2 CH 3 ),- N(CH 2 CH 3 ) 2 .
  • alkylamino includes the above definitions of alkyl and amino.
  • room temperature in the present invention refers to 15-30°C.
  • the stable isotope derivatives include: isotope substituted derivatives obtained by replacing any hydrogen atom in formula I with 1-5 deuterium atoms (for example: R 2 is CD 3 ), and any carbon atom in formula I is replaced by 1 -Isotope substituted derivatives obtained by substitution of 3 carbon 14 atoms or isotope substituted derivatives obtained by substitution of any oxygen atom in formula I or I'with 1-3 oxygen 18 atoms.
  • prodrug refers to the conversion of the compound into the original active compound after metabolism in the body.
  • the prodrug is an inactive substance, or less active than the active parent compound, but can provide convenient handling, administration, or improved metabolic properties.
  • the “pharmaceutically acceptable salts” of the present invention are discussed in Berge, et al., “Pharmaceutically Acceptable Salts", J. Pharm. Sci., 66, 1-19 (1977), It is obvious that the salts are essentially non-toxic and can provide the required pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion.
  • the compound of the present invention may have an acidic group, a basic group or an amphoteric group.
  • Typical pharmaceutically acceptable salts include salts prepared by reacting the compound of the present invention with an acid, for example: hydrochloride, hydrobromic acid Salt, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, nitrate, acetate, Propionate, caprate, caprylate, formate, acrylate, isobutyrate, caproate, enanthate, oxalate, malonate, succinate, suberate, Benzoate, methylbenzoate, phthalate, maleate, mesylate, p-toluenesulfonate, (D,L)-tartrate, citrate, male Acid salt, (D,L)-malate, fumarate, lactate, triflate, naphthalene-1-sulfonate, mandelate, pyruvate,
  • its pharmaceutically acceptable salts may also include: alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; organic alkali salts, such as ammonia and alkyl Salts formed by base aminos, hydroxyalkyl aminos, amino acids (lysine, arginine), N-methylglucamine, etc.
  • alkali metal salts such as sodium or potassium salts
  • alkaline earth metal salts such as calcium or magnesium salts
  • organic alkali salts such as ammonia and alkyl Salts formed by base aminos, hydroxyalkyl aminos, amino acids (lysine, arginine), N-methylglucamine, etc.
  • the “isomer” in the present invention means that the compound of formula I or I'of the present invention may have an asymmetric center and a racemate, a racemic mixture and a single diastereomer, all of these isomers,
  • the stereoisomers, geometric isomers, atropisomers, and tautomers are included in the present invention.
  • the compound of formula I or I'or its salt exists in stereoisomeric form (for example, it contains one or more asymmetric carbon atoms)
  • the individual stereoisomer (enantiomer and Diastereomers) and mixtures thereof are included within the scope of the present invention.
  • the present invention also includes individual isomers of compounds or salts represented by formula I or I', and mixtures of isomers in which one or more chiral centers are inverted.
  • the scope of the present invention includes mixtures of stereoisomers, as well as purified enantiomers or enantiomer/diastereomer-enriched mixtures.
  • the present invention includes all enantiomers and mixtures of stereoisomers of all possible different combinations of diastereomers.
  • the present invention includes all combinations and subsets of the stereoisomers of all specific groups defined above.
  • the invention also includes geometric isomers of compounds of formula I or I'or salts thereof, said geometric isomers including cis-trans isomers.
  • the present invention also includes tautomers of compounds of formula I or I'or salts thereof, where tautomers refer to the migration of protons from one atom of a molecule to another atom of the same molecule.
  • tautomers refer to the migration of protons from one atom of a molecule to another atom of the same molecule.
  • the reagents and raw materials used in the present invention are commercially available.
  • the structures of all compounds of the present invention can be identified by nuclear magnetic resonance ( 1 H NMR) and/or mass spectrometry (MS).
  • MS Low-resolution mass spectrometry
  • the purification of the compounds and intermediates of the present invention can use conventional preparation of silica gel plates or the use of rapid separators for separation and purification.
  • the elution system can be ethyl acetate/petroleum ether system or dichloromethane/methanol system.
  • Preparative HPLC can also be used for separation.
  • High-performance liquid chromatograph uses GilsonGX-281 to prepare liquid chromatography.
  • the column is xtimate C18, 10um, 21.2 ⁇ 250mm.
  • Separation conditions 1 Elution gradient, mobile phase B from 10% to 25%, elution time 5 minutes, mobile phase B from 25% to 45%, elution time 15 minutes, mobile phase A: 10 mM ammonium bicarbonate aqueous solution, Mobile phase B: Acetonitrile;
  • Separation conditions 2 Elution gradient, mobile phase B from 15% to 30%, elution time 5 minutes, mobile phase B from 30% to 50%, elution time 15 minutes, mobile phase A: 0.05% aqueous hydrochloric acid, mobile phase B: acetonitrile;
  • separation conditions 3 mobile phase B from 15% to 20%, elution time 5 minutes, mobile phase B from 20% to 40%, elution time 15 minutes, mobile phase A: 0.05% aqueous hydrochloric acid, mobile phase B: acetonitrile; separation
  • the thin-layer silicone board is Yantai Huanghai HSGF254 or Qingdao GF254 silicone board.
  • Flash column chromatography Flash system/Cheetah TM
  • Agela Technologies MP200 Flash system/Cheetah TM
  • the supporting separation column is Flashcolumm Silica-CS (80g), Cat No. CS140080-0.
  • All compounds of the present invention can be analyzed by an ultra-high performance liquid chromatograph (UPLC) using the Waters ACQUITY Hclass platform, the chromatography column is: Waters ACQUITY UPLC BEH Shield RP18 2.1mm*100mm, 1.7 ⁇ m, mobile phase A: acetonitrile, mobile phase B: 5mm potassium dihydrogen phosphate aqueous solution (adjust pH to 2.5 with phosphoric acid). Gradient elution time 15 minutes, flow rate: 0.4mL/min, detection wavelength: 214nm &254nm; column temperature: 40°C; injection volume 1 ⁇ L; gradient elution conditions are as follows in Table 1:
  • the chiral compounds or intermediates involved in the present invention can be separated and analyzed by supercritical fluid chromatography (SFC).
  • a supercritical fluid chromatograph SFC-80 (Thar, Waters) was used with a flow rate of 80 g/min and a column temperature of 35°C.
  • the detection wavelength is 214 and/or 254 nM.
  • the chiral analysis of the compound of the present invention uses a supercritical fluid chromatography analyzer SFC Method Station (Thar, Waters) with a flow rate of 4 mL/min, a column temperature of 40° C. and a detection wavelength of 214 and/or 254 nM.
  • Step 1 To a solution of 5-bromo-3-methylpyridine-2-carboxylic acid (50 g, 231 mmol) in ethanol (250 mL), concentrated sulfuric acid (12.5 mL) was added dropwise. The reaction solution was stirred at 95°C overnight and concentrated under reduced pressure. The residue was dissolved with DCM (500 mL), and the pH was adjusted to 7 with saturated aqueous sodium carbonate solution. The organic phase was separated and the aqueous phase was extracted with DCM. The organic phases were combined and washed with water and saturated saline, respectively.
  • Step 2 Under ice bath conditions, to the DCM (280 mL) solution of the product obtained in Step 1 (55 g, 225 mmol) was added urea peroxide (37.1 g, 394 mmol) in portions, and then trifluoroacetic anhydride (55.6 mL, 394mmol). After the addition, the reaction system was raised to room temperature and stirred for 5 hours. The reaction solution was poured into ice water, and extracted with DCM (2 ⁇ 200 mL).
  • Step 3 To the DMF (200 mL) solution of the product (58 g, 223 mmol) obtained in step 2, trifluoroacetic anhydride (55 mL, 390 mmol) was slowly added dropwise. After the addition, the reaction system was heated to 40°C and stirred for 1 hour. The reaction solution was poured into ice water, a large amount of white solid was generated, and filtered. The filter cake was washed sequentially with water and MTBE. The filter cake was dried in vacuo to give ethyl 5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxylate (25 g) as a white solid. m/z:[M+H] + 260.0,262.0.
  • Step 4 Stir the product obtained in Step 3 (5.6g, 21.5mmol) and Cs 2 CO 3 (28.1g, 86.1mmol) in DMF (50mL) for 15 minutes, then add O-(diphenylphosphine oxide Base) hydroxylamine (10 g, 43.1 mmol). After the addition, the reaction system was stirred at room temperature for 2 hours. Water (150 mL) was added to the reaction solution, and extracted with EtOAc (50 mL ⁇ 4).
  • Step 5 The product obtained in Step 4 (500 mg, crude product) and ammonia methanol solution (7 mol/L, 10 mL) were added to a sealed tube, heated to 85° C., and stirred for 2 days. Then, the reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain 1-amino-5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (500 mg, crude product) as yellow. solid.
  • Step 6 The product obtained in Step 5 (400 mg, crude product) and cyclohexanone (1.6 g, 16.3 mmol) were added to 1,4-dioxane (10 mL), and the reaction solution was stirred at 95° C. for 2 hours, slowly After cooling to room temperature, concentrated sulfuric acid (0.1 mL) was added thereto with vigorous stirring, and stirring was continued for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered.
  • Step 1 Combine ethyl 1-amino-5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxylate (300 mg, 1.09 mmol) in acetone (5 mL) and 1,4 -Dioxane (10 mL) solution was added to the sealed tube, and the reaction system was stirred at 110°C for 2 days. After cooling, the reaction solution was directly concentrated to obtain ethyl 5-bromo-3-methyl-6-oxo-1-(prop-2-ylideneamino)-1,6-dihydropyridine-2-carboxylate (370 mg) It is a yellow liquid. m/z:[M+H] + 315.0,317.0.
  • Step 2 Sodium borohydride (126 mg, 3.33 mmol) was added to the MeOH (10 mL) solution of the product (350 mg, crude) obtained in Step 1. The reaction system was stirred at room temperature for 3 days. The reaction solution was poured into water and extracted with ethyl acetate (3 ⁇ 30 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain 5-bromo-1-(isopropylamino)-3-methyl Ethyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid ethyl ester (70 mg) is a yellow liquid. m/z:[M+H] + 317.0,319.0.
  • Step 4 The product obtained in Step 3 (45 mg, 0.16 mmol) was added to sulfoxide chloride (5 mL) and DCM (5 mL). The reaction system was heated to 50° C. and stirred for 8 hours. The reaction solution was concentrated and ammonia methanol (5 mL) was added. , 7M), the reaction system was stirred at room temperature for 2 hours and concentrated to give 5-bromo-1-(isopropylamino)-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (40mg) is a brown solid. m/z:[M+H] + 288.0,290.0.
  • Step 5 Add concentrated sulfuric acid (2 drops) to a solution of the product obtained in Step 4 (40 mg, crude) and cyclohexanone (136 mg, 1.39 mmol) in 1,4-dioxane (10 mL). The reaction solution was heated to 95°C and stirred for 16 hours.
  • Step 1 Add copper acetate (1.98g, 10.9mmol) and pyridine (1.15g, 15.5mmol) to 1-amino-5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-
  • ethyl 2-formate 2.0 g, 7.27 mmol
  • 3-nitrophenylboronic acid (2.43 g, 14.5 mmol)
  • DCM 10 mL
  • the reaction system was stirred at 45° C. for 16 hours.
  • the reaction system was cooled to room temperature and poured into water.
  • the aqueous phase was extracted with DCM (3 ⁇ 30 mL).
  • the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 3 The product obtained in Step 2 (650 mg, 1.77 mmol) was added to sulfoxide chloride (5 mL) and DCM (5 mL), and the reaction system was stirred at 50°C for 4 hours. After the reaction solution was concentrated, an ammonia methanol solution (7M, 5 mL) was added, the reaction system was stirred at room temperature for 1 hour, and concentrated under reduced pressure to obtain 5-bromo-3-methyl-1-((3-nitrophenyl)amino )-6-oxo-1,6-dihydropyridine-2-carboxamide (800 mg) is a yellow solid. m/z:[M+H] + 366.8.
  • Step 4 Add concentrated sulfuric acid (0.1 mL) dropwise to the 1,4-dioxane (10 mL) solution of the product (400 mg, 1.09 mmol) and cyclobutanone (611 mg, 8.72 mmol) obtained in step 3, the reaction system Stir at 50°C for 4 hours.
  • Step 1 Compound 1.4 (200 mg, 0.6 mmol), methyl iodide (445 mg, 3 mmol) and DMF (2 mL) were added to a sealed tube, and the reaction system was stirred at 105°C for 16 hours. Then the reaction solution was concentrated under reduced pressure, and the residue was purified by prep-TLC (EtOAc) to obtain 7'-bromo-5'-chloro-1'-methylspiro[cyclobutane-1,2'-pyrido[2, 1-f][1,2,4]triazine]-4',8'(1'H,3'H)-dione (200mg) is a yellow solid. m/z:[M+H] + 331.9.
  • Step 2 Under nitrogen protection, the product obtained in Step 1 (60mg, 0.18mmol), tert-butyl carbamate (42mg, 0.36mmol), Pd 2 (dba) 3 (3mg), Xantphos (3mg), XPhos (3mg) , A mixture of Cs 2 CO 3 (118 mg, 0.36 mmol) and tert-butanol (1.6 mL) was stirred at 85° C. for 24 hours.
  • Step 3 Under ice bath conditions, TFA (0.3 mL) was added dropwise to a solution of the product (40 mg, 0.11 mmol) obtained in Step 2 in DCM (0.3 mL). After the addition, the reaction solution was stirred at room temperature for 16 hours.
  • Step 1 Under ice bath, add a solution of 2-methyl-3-nitro-5-bromoaniline (5g, 21.6mmol) in acetonitrile (40mL) dropwise to cuprous chloride (3.3g, 33.5mmol) and In a suspension of tert-butyl nitrite (3.5 g, 33.5 mmol) in acetonitrile (40 mL), the reaction system was stirred at 30° C. overnight. The reaction solution was poured into hydrochloric acid (0.5N) and extracted with EtOAc (3 ⁇ 150 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 2 At 80°C, add potassium permanganate (15.8g, 100mmol) in batches to the mixed solution of the product (5g, 20mmol) obtained in step 1 in pyridine (75mL) and water (50mL) within 6 hours. Stir at 80°C overnight. Ethanol (100 mL) was added to the reaction solution, and after refluxing for 30 minutes, it was filtered while hot, and the filter cake was washed with THF (3 ⁇ 50 mL). The combined filtrate was concentrated, 10% aqueous sodium hydroxide solution was added to the residue, and the impurities were extracted with EtOAc (3 ⁇ 80 mL).
  • Step 3 To the product obtained in Step 2 (1.96g, 7mmol), aqueous sodium hydroxide solution (0.88N, 9.8mL), ferric chloride (0.12g, 0.77mmol) and isopropanol (1.0mL) were added successively. The reaction system was heated to 75°C, and 80% hydrazine hydrate (2.2 g, 35.2 mmol) was slowly added dropwise thereto with stirring, and the reaction system was stirred at 75°C for 2 hours.
  • Step 1 To a mixture of trichloroacetaldehyde (9g, 61mmol), anhydrous sodium sulfate (35g, 243mmol) and water (165mL) was added 3-bromo-5-chloro-2-methoxyaniline (7.2g, 30.4 mmol) of DMF (75 mL) followed by concentrated hydrochloric acid (3.8 mL) and the reaction system was stirred at 90°C for 25 minutes. Hydroxylamine hydrochloride (12.7 g, 182 mmol) was added to the above reaction system and stirred at 90°C for 5 hours.
  • Step 2 Preheat concentrated sulfuric acid (60 mL) to 30°C, add the product obtained in step 1 (7.4g, 23.9mmol) in batches with stirring and keep the internal temperature at 30-50°C, after addition, the reaction system is at 70°C Stir for 15 minutes.
  • Step 2 The ethanol/water (3/1,200mL) solution of the product (4.8g, 19.7mmol) and ammonium chloride (10.5g, 196.7mmol) obtained in Step 1 was heated to 60°C, and then iron powder (11g) was added in portions , 197mmol), the resulting mixture was stirred for 2 hours. After filtration, the filter cake was washed with EtOAc until no product remained, and the filtrate was extracted with EtOAc. The organic phases were combined, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 2-amino-4-bromo-6-methylbenzaldehyde (4.1 g) as a light brown solid.
  • Step 1 2-amino-4-bromo-3-methoxy-6-methylbenzoic acid (synthesis method refers to US2009143353A1) (2.6g, 10mmol), HOBT (1.6g, 12mmol) and EDCI (2.1g, 11mmol) ) Dissolved in DMF (25mL), stirred at room temperature for 15 minutes, cooled to 0°C, 30% ammonia water (25mL) was added dropwise, and stirred at room temperature for 16 hours. It was extracted with ethyl acetate (50 mL ⁇ 3), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 2 The product obtained in Step 1 (200 mg, 0.77 mmol) and cyclopentanone (324 mg, 3.86 mmol) were suspended in ethanol (5 mL), concentrated sulfuric acid (75 mg, 0.77 mmol) was added, and the reaction solution was refluxed at 95°C for 3 hours , Cooled to room temperature, filtered to obtain 7'-bromo-8'-methoxy-5'-methyl-1'H-spiro[cyclopentane-1,2'-quinazoline]-4'(3' H)-one (intermediate 8.0, 250 mg) is a gray solid. m/z:[M+H] + 259.0.
  • Step 3 DMF (3mL) solution of Intermediate 8.0 (150mg, 0.46mmol) and methyl iodide (0.5mL) was stirred at 105°C in a sealed tube overnight, the reaction solution was cooled to room temperature, diluted with ethyl acetate, and the organic phase was used The aqueous solution of sodium thiosulfate was washed, the organic phase was separated and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 1 Add Xantphos (18 mg, 30.2 ⁇ mol) and Pd 2 (dba) 3 (14 mg, 15.2 mmol) to N,N-dimethyl-3-(piperazin-1-yl)propan-1-amine in this order (100 mg, 0.302 mmol), N,N-di-Boc-2-amino-6-chloropyrimidine (156 mg, 0.30 mmol) and cesium carbonate (494 mg, 1.52 mmol) in 1,4-dioxane (10 mL) In the solution, the reaction system was replaced with nitrogen three times and stirred at 95°C for 3 hours. After cooling, the reaction was quenched by adding water (15 mL).
  • Step 2 TFA (2mL) was added to the DCM (5mL) solution of the product (80mg, 0.172mmol) obtained in Step 1, the reaction system was stirred at room temperature for 4 hours, and the reaction solution was concentrated to obtain 6-(4-(3-(two Methylamino)propyl)piperazin-1-yl)pyrimidine-4-amine (Intermediate 9.1, 80 mg) is a yellow oil. m/z:[M+H] + 264.0.
  • Step 1 Intermediate 1.1 (100 mg, 0.3 mmol), tert-butyl 6-aminopyrimidine-4-carbamate (77.3 mg, 0.37 mmol), Pd 2 (dba) 3 (15 mg), Xantphos (15 mg), Cs A mixture of 2 CO 3 (200 mg, 0.61 mmol) and 1,4-dioxane (2.5 mL) was replaced with nitrogen three times, and then the reaction system was heated to 85° C. and stirred for 3 hours. The reaction solution was concentrated under reduced pressure. The residue was slurried with ethanol (2.5 mL) and filtered. The filter cake was rinsed with a small amount of cold ethanol.
  • Step 1 Intermediate 1.1 (50 mg, 0.15 mmol) and iodomethane (44 mg, 0.31 mmol) were added to DMF (5 mL), and the reaction system was heated to 70° C. in a sealed tube and stirred for 2 days.
  • Step 2 Add XPhos (4mg, 8.82 ⁇ mol), Xantphos (5mg, 8.82 ⁇ mol) and Pd 2 (dba) 3 (4mg, 4.41 ⁇ mol) to the product obtained in Step 1 (30mg, 88.2 ⁇ mol), 7H-pyrrolo [2,3-d]pyrimidine-4-amine (13 mg, 97.0 ⁇ mol) and Cs 2 CO 3 (37 mg, 0.12 mmol) in 1,4-dioxane (4 mL) solution, the reaction system was replaced with nitrogen three times Then, microwave reaction was carried out at 110°C for 3 hours, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 1 Acryloyl chloride (1.2 mL, 14.8 mmol) was added dropwise to a solution of intermediate 1.1 (0.30 g, 0.9 mmol) in DMF (9 mL), and the reaction system was stirred at 85°C for 20 minutes. Under an ice bath, the reaction solution was poured into saturated aqueous sodium bicarbonate solution (30 mL) to quench the reaction. The aqueous phase was extracted with EtOAc (3 ⁇ 15 mL). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate.
  • Step 2 Add Ru-phos (6 mg, 13.2 ⁇ mol) and Pd 2 (dba) 3 (6.0 mg, 6.6 mmol) to the product obtained in Step 1 (50 mg, 0.13 mmol), 7H-pyrrolo[2,3- d) A solution of pyrimidine-4-amine (27 mg, 0.20 mmol) and sodium tert-butoxide (16 mg, 0.17 mmol) in toluene (3 mL). The reaction system was replaced with nitrogen three times, and stirred at 105° C. for 3 hours.
  • Example 7 7'-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5'-chlorospiro[cyclopentane-1,2'-pyrido[2,1 -f][1,2,4]Triazine]-4',8'(1'H,3'H)-Dione Hydrochloride (Compound 1-7)
  • Example 8 7'-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-1'-ethyl-5'-methylspiro[cyclohexane-1,2' -Synthesis of pyrido[2,1-f][1,2,4]triazine]-4',8'(1'H,3'H)-dione hydrochloride (Compound 1-8)
  • Example 12 7'-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5'-chloro-1'-methylspiro[cyclopentane-1,2'- Synthesis of pyrido[2,1-f][1,2,4]triazine]-4',8'(1'H,3'H)-dione hydrochloride (Compound 1-12)
  • Example 17 7'-((6-amino-5-chloropyrimidin-4-yl)amino)-5'-chlorospiro[cyclopentane-1,2'-pyrido[2,1-f][ Synthesis of 1,2,4]triazine]-4',8'(1'H,3'H)-dione hydrochloride (Compound 1-17)
  • Example 18 7'-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-1',5'-dimethylspiro[cyclobutane-1,2'-pyridine Of [2,1-f][1,2,4]triazine]-4',8'(1'H,3'H)-dione hydrochloride (Compound 1-18)
  • Step 2 Acryloyl chloride (15 mg, 170 ⁇ mol) was added dropwise to a solution of compound Z-2 (50 mg, 113 ⁇ mol) in DMF (2 mL) at 0° C. The reaction system was stirred at room temperature for 20 minutes. The reaction solution was poured into saturated aqueous sodium bicarbonate solution (15 mL) at 0°C to quench the reaction. The aqueous phase was extracted with ethyl acetate (3 ⁇ 15 mL), the organic phases were combined and concentrated under reduced pressure, and the residue was subjected to prep-HPLC ( Isolation condition 2) Purification gave compound 1-19 (0.62 mg, yield: 1%) as a light yellow solid.
  • Example 22 7'-((1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)-5'-chloro-1'-methylspiro[cyclobutane-1,2' -Synthesis of pyrido[2,1-f][1,2,4]triazine]-4',8'(1'H,3'H)-dione hydrochloride (Compound 1-22)
  • Example 25 7'-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5'-chloro-1',3,3-trimethylspiro[cyclobutane- 1,2'-pyrido[2,1-f][1,2,4]triazine]-4',8'(1'H,3'H)-dione hydrochloride (Compound 1-25 )Synthesis
  • Example 26 7-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5-chloro-2-(3-fluorophenyl)-2-methyl-2,3 -Dihydro-1H-pyrido[2,1-f][1,2,4]triazine]-4,8-dione hydrochloride (Compound 1-26)
  • Example 27 7'-((6-amino-5-fluoropyrimidin-4-yl)amino)-5'-chlorospiro[cyclobutane-1,2'-pyrido[2,1-f][ Synthesis of 1,2,4]triazine]-4',8'(1'H,3'H)-dione hydrochloride (Compound 1-27)
  • Example 28 8-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-6-chloro-3a-methyl-2,3,3a,4-tetrahydro-1H- Synthesis and Example 29 of pyrido[2,1-f]pyrrolo[1,2-b][1,2,4]triazine-5,9-dione hydrochloride (Compound 1-28): 7-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-9-chloro-3a-methyl-2,3,3a,4-tetrahydro-1H-pyrido[2 Of 1,1-f]pyrrolo[2,1-c][1,2,4]triazine-6,10-dione hydrochloride (Compound 1-29)
  • Example 32 7'-((6-amino-5-methoxypyrimidin-4-yl)amino)-5'-chlorospiro[cyclobutane-1,2'-pyrido[2,1-f ][1,2,4]Triazine]-4',8'(1'H,3'H)-Dione Hydrochloride (Compound 1-32)
  • Example 35 5′′-chloro-1′′-methyl-7′′-[(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-1′′H,3′′H-dispiro [Cyclobutane-1,1'-cyclobutane-3',2′′-pyrido[2,1-f][1,2,4]triazine]-4′′,8′′-dione hydrochloride Synthesis of Salt (Compound 1-35)
  • Example 36 7'-((9H-purin-6-yl)amino)-5'-chlorospiro[cyclobutane-1,2'-pyrido[2,1-f][1,2,4 ]Triazine]-4',8'(1'H,3'H)-Dione Hydrochloride (Compound 1-36)
  • Example 37 5'-chloro-1'-( 2 H 3 )methyl-7'-[(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-1'H,3 'H-spiro[cyclopentane-1,2'-pyrido[2,1-f][1,2,4]triazine]-4',8'-dione hydrochloride (Compound 1-37 )Synthesis
  • Example 38 9-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-7-chloro-4a-methyl-1,2,3,4,4a,5-hexa Synthesis of hydrodipyrido[1,2-b:2',1'-f][1,2,4]triazine-6,10-dione hydrochloride (compound 1-38)
  • Example 44 7'-((4-amino-1,3,5-triazin-2-yl)amino)-5'-chlorospiro[cyclobutane-1,2'-pyrido[2,1 -f][1,2,4]Triazine]-4',8'(1'H,3'H)-Dione Hydrochloride (Compound 1-44)
  • Example 45 9-((6-aminopyrimidin-4-yl)amino)-7-chloro-4a-methyl-1,2,3,4,4a,5-hexahydrodipyrido[1,2 -b: Synthesis of 2',1'-f][1,2,4]triazine-6,10-dione hydrochloride (Compound 1-45)
  • Example 46 5′′-chloro-7′′-[(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-1′′H,3′′H-dispiro[cyclopropane-1, 1'-cyclobutane-3',2′′-pyrido[2,1-f][1,2,4]triazine]-4′′,8′′-dione hydrochloride (Compound 1-46) Synthesis
  • Example 48 8-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-6-methyl-3a-phenyl-2,3,3a,4-tetrahydro-1H -Synthesis of pyrido[2,1-f]pyrrolidine[1,2-b][1,2,4]triazine-5,9-dione hydrochloride (Compound 1-48)
  • Example 50 7'-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5'-chloro-1'-methylspiro[cyclobutane-1,2' -Synthesis of pyrido[2,1-f][1,2,4]triazine]-4',8'(1'H,3'H)-dione hydrochloride (Compound 1-50)
  • Step 1 Under nitrogen protection, to 7'-bromo-5'-chloro-1'-methyl spiro[cyclobutane-1,2'-pyrido[2,1-f][1,2,4] Triazine]-4',8'(1'H,3'H)-dione (100mg, 301 ⁇ mol) and N,N-dimethyl-N'-(7H-pyrrolo[2,3-d] To a solution of pyrimidin-4-yl)formamidine (74mg, 391 ⁇ mol) in 1,4-dioxane (5mL) was added trans-1,2-cyclohexanediamine (17mg, 150 ⁇ mol) and cuprous iodide successively (27 mg, 150 ⁇ mol) and potassium phosphate (192 mg, 902 ⁇ mol), the reaction system was replaced with nitrogen three times and stirred at 90° C.
  • Step 2 To a solution of compound Y-1 (125 mg, 284 ⁇ mol) in ethanol (3 mL) was added ethylenediamine (34 mg, 567 ⁇ mol), and the reaction system was stirred at 80° C. overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by prep-HPLC (separation condition 5) to obtain compound 1-50 (49.2 mg, yield: 45%) as a pale yellow solid.
  • Example 51 5'-chloro-7'-((6-(4-(3-(dimethylamino)propyl)piperazin-1-yl)pyrimidin-4-yl)amino)-1'- Methylspiro[cyclobutane-1,2'-pyrido[2,1-f][1,2,4]triazine]-4',8'(1'H,3'H)-dione Synthesis of Hydrochloride (Compound 1-51)
  • 1-28B was used to obtain 1-28B hydrochloride.
  • 1-38A is used to prepare 1-38A hydrochloride.
  • 1-38B was used to prepare 1-38B hydrochloride.
  • Example 58 7'-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-1'H-spiro[cyclobutane-1,2'-pyrido[2,3 -d]Pyrimidine]-4'(3'H)-one hydrochloride (Compound 2-5)
  • Example 62 7'-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5'-chloro-8'-methoxy-1'-methyl-1'H Of -spiro[cyclobutane-1,2'-quinazoline]-4'(3'H)-one hydrochloride (compound 2-9)
  • Example 65 7'-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-1',5'-dimethyl-1'H-spiro[cyclobutane-1 Of 2,2'-pyridine[2,3-d]pyrimidine]-4'(3'H)-one hydrochloride (Compound 2-12)
  • Example 66 2-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-6a-methyl-6a,7,8,9-tetrahydropyrido[3,2- e] Synthesis and Example 67 of pyrrolo[1,2-a]pyrimidin-5(6H)-one hydrochloride (Compound 2-13): 2-(4-amino-7H-pyrrolo[2,3 -d]pyrimidin-7-yl)-6a-methyl-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrimidin-5(6H)- Synthesis of Ketone Hydrochloride (Compound 2-14)
  • Step 1 Heat an absolute ethanol solution (5mL) of 2-amino-6-chloronicotinamide (70mg, 0.4mmol) and 5-chloro-2-pentanone (150mg, 1.22mmol) to 95°C, then slowly drop Add concentrated sulfuric acid (3 drops). After the addition, the reaction system was stirred at 95°C overnight. The reaction solution was poured into ice water, and a solid precipitated, stirred for 5 minutes, and filtered.
  • 2-amino-6-chloronicotinamide 70mg, 0.4mmol
  • 5-chloro-2-pentanone 150mg, 1.22mmol
  • Step 2 Combine the product obtained in Step 1 (60 mg, 0.25 mmol), 7H-pyrrolo[2,3-d]pyrimidin-4-amine (37 mg, 0.28 mmol), Cs 2 CO 3 (99 mg, 0.3 mmol), Pd A mixture of 2 (dba) 3 (23 mg, 0.025 mmol), XPhos (12 mg, 0.025 mmol), XantPhos (15 mg, 0.025 mmol) and 1,4-dioxane (3 mL) was purged with nitrogen and microwaved at 100°C React for 2 hours. After cooling to room temperature, filtering, the filter cake was washed with DCM/MeOH (10/1). The organic phases were combined and concentrated under reduced pressure.
  • Example 68 8-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-6-chloro-3a-methyl-2,3,3a,4-tetrahydropyrrolo[ Synthesis of 1,2-a]quinazoline-5(1H)-one hydrochloride (Compound 2-15)
  • Example 70 8-((7H-pyrrole[2,3-d]pyrimidin-4-yl)amino)-9-methoxy-3a,6-dimethyl-2,3,3a,4-tetra Synthesis of Hydropyrrolo[1,2-a]quinazoline-5(1H)-one hydrochloride (Compound 2-17)
  • Example 1 MNK1 and MNK2 in vitro enzyme inhibition level test
  • the ADP-Glo TM Max Assay Kit (Promega, V9101) was used to detect the amount of ADP produced to calculate the inhibition rate of the compound on the enzyme.
  • the components of the buffer used in the experiment were: 15 mM HEPES, 10 mM MgCl 2 , 20 mM NaCl, 1 mM EGTA, 0.1 mg/ml bovine serum protein, 0.02% Tween-20.
  • MNK1 reaction system includes 20nM MNK1 (Thermo, PR9138A), 100uM polypeptide (Gill Biochemical, sequence: Ac-TATKSGSTTKNR-NH2), 200uM ATP and different concentrations of the test compound, the final concentration of DMSO is 0.33%, the reaction system is at room temperature Incubate for 60 minutes.
  • the MNK2 reaction system includes 5nM MNK2 (Thermo, PR8046A), 100uM polypeptide (Gill Biochemical, sequence: Ac-TATKSGSTTKNR-NH2), 100uM ATP and different concentrations of the test compound. The final concentration of DMSO is 0.33%.
  • the reaction system was incubated at room temperature for 45 minutes. After the incubation, the ADP-Glo TM Max Assay Kit was used to detect the generated ADP and TECAN M1000-pro. The experimental data was analyzed and processed by GraphPad Prism 5 software to obtain the IC 50 value. Table 6
  • kinases MNK1 and MNK2 integrate several oncogenic factors and immune signaling pathways, thereby selectively regulating cellular mRNA stability and transcription.
  • Phospho-EIF4E (Ser209) cellular kit (Cisibo) was used to determine the endogenous phosphorylation level of EIF4E in OCI-LY7B cell non-Hodgkin's lymphoma cells. The experiment was conducted according to the manufacturer's experimental protocol. In short, OCI-LY7 cells were plated on a 96-well cell culture plate with 50 uL of 2 ⁇ 106 cells/ml of serum-free IMDM medium and incubated at 37°C overnight. The next day, the concentration range of the test compound was created by diluting 100% DMSO and then further diluting it with serum-free medium. Cells were added with diluted compounds and incubated at 37°C for 3h.
  • Numbering IC 50 (nM) Numbering IC 50 (nM) 1-3 5.132 1-38B 1.250 1-4 3.610 2-2 2.321 1-6 2.179 2-9 1.600 1-9 2.600 2-11 0.479 1-12 1.556 2-15 0.731 1-16 1.588 2-19 3.195 1-28 1.574 2-20 4.822 1-28B 0.690 2-21 0.682 1-38 1.410 2-22 0.934 .

Abstract

本发明公开了一种如式I或I'所示结构的新型MNK抑制剂。本发明的MNK抑制剂在体内和体外均具有良好的抑制MNK1和/或MNK2水平的作用,进一步本发明的MNK抑制剂还可以有效治疗MNK1和/或MNK2介导的疾病,例如:癌症。

Description

MNK抑制剂
本申请要求申请日为2018年11月30日的中国专利申请CN201811454361.8、申请日为2019年1月9日的中国专利申请CN201910018886.5、申请日为2019年1月30日的中国专利申请CN201910089611.0、申请日为2019年4月4日的中国专利申请CN201910270657.2的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及一种新型MNK抑制剂、其药物组合物及其作为癌症治疗剂的用途。
背景技术
MAP相互作用性激酶1和2(MNK1和MNK2)是一类丝氨酸/苏氨酸蛋白激酶,可以被ERK或p38激活并且能够使真核起始因子4E(eIF4E)磷酸化,在蛋白质的合成和细胞功能稳定中至关重要。eIF4E涉及到帽(cap)-依赖性翻译启动。eIF4E蛋白于mRNA的5'帽结构相互结合,对于帽依赖性翻译启动是必需的。多项证据表明eIF4E在体内表现出真正的致癌促进作用。eIF4E在多种类型的人类癌症中过度表达,并且与肿瘤患者的预后不良有关(Mamane Y,et al.Oncogene,2004 23:3172-79;Graff JR,et al.,Cancer Res,2009 69:3866-73;Ruggero D,et al.Nat Med,2004 10:484-6),包括结肠癌、乳腺癌(Chrestensen,C.A.,et al.,J.Biol.Chem.,2007 282(7):4243-52)、膀胱癌、肺癌、***癌(Tomlins,S.A.,et al.,Nat.Genet.,2007 39(1):41-51)、胃肠道癌、头颈癌、霍奇金氏淋巴瘤、成神经细胞瘤、胶质瘤(Bredel,M.,et al,Cancer Res.,2005 65(10):4088-96)、卵巢癌(Hendrix,N.D.,et al.,Cancer Res.,2006 66(3):1354-62)、胰腺癌(Lapointe,J.,et al.,Proc.Natl.Acad.Sci.USA,2004,101(3):811-16)等。同样的,过表达eIF4E的转基因小鼠在多个器官中的肿瘤发生率大大提高。临床结果显示,不仅仅eIF4E的过表达有助于肿瘤的进展,即使是eIF4E的过磷酸化也可以有助于肿瘤的进展。已经在多种实体瘤和淋巴瘤中观察到eIF4E磷酸化的增强与患者的预后不良相关,特别是在非小细胞肺癌中。MNK1在血液***恶性肿瘤中高表达(Worch J.,et al.,Oncogene,2004 23:9162-72),MNK1和MNK2在实体肿瘤如胶质瘤和卵巢癌中表达均上调。
MNK/eIF4E轴参与促血管生成、抗细胞凋亡的表达、细胞周期和运动蛋白,Ser209位点上eIF4E的磷酸化促进其致癌潜力(Topisirovic,I.,et al.,Cancer Res.,2004 64(23):8639-42),而MNK1/2是已知驱动该过程的唯一激酶。MNK1/2对eIF4E的磷酸化可以促进多种促癌基因蛋白的表达,包括MCL-1(Wendel,H.G.,et al.,Genes Dev.,2007 21(24):3232-37),FGF2,c-Myc,VEGF,MMP3,CCL2,BIRC2,cyclin D1(De Benedetti,A., et al.,Cell Biol.,1999,31(1):59-72),细胞周期蛋白D3(Graff,J.R.,et al.,Cancer Res.,200868(3):631-34)和ODC。并且在Ras和c-Myc诱导的转化过程中是必需的。在多条细胞内信号传导途径中起到关键作用。包括雷帕霉素复合物1(mTORC1)和ERK(经典MAP激酶)途径。这两条信号传导途径都经常在癌症中被激活。
目前,有多份关于MNK1和/或MNK2抑制剂的专利公开,例如:WO2015/200481,WO2017/075394,WO2017/075412,WO2017/087808公开了一系列异吲哚-1-酮和2,3-二氢咪唑并[1,5-a]吡啶-1,5-二酮类化合物;WO2017/085484,WO2017/085483,WO2014/044691,WO2014/048894公开了一系列噻唑并嘧啶和吡咯并嘧啶类化合物;WO2015/050505,WO2013/147711公开了一系列咪唑并哒嗪类化合物。
尽管对MNKs研究在不断深入,也有小分子实体进入临床研究阶段,但是还没有真正的进入市场的MNK抑制剂,随着对MNK抑制剂构效关系的不断深入研究,本发明公开了一类新型的MNK抑制剂,具有良好的MNK1和MNK2抑制效果。
发明内容
本发明所要解决的技术问题在于,提供了一种新型如式I或I’所示化合物、其药物组合物及应用。本发明的如式I或I’所示化合物具有良好的MNK1和/或MNK2抑制作用,可以有效治疗和/或缓解由MNK1和/或MNK2介导的各种相关疾病,例如癌症。
本发明提供了一种如式I所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐;
Figure PCTCN2019121976-appb-000001
其中,W 1和W 2分别独立地为=O、=S、=NH、=N-OH或=N-O(C 1-6烷基);
R为-NH-Cy或Cy;
R 1为H、-OH、-NH 2、R A、-NH-R A、-NH-C(O)-R A或-O-R A
R 2为H、CN、氘代C 1-4烷基或R B
R 3为H、C 1-6烷基、C 2-6烯基或C 2-6炔基;所述R 3为未取代,或者选择性被1~3个R 9取代在任意位置;
R 4为H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 6-10芳基、5-6元杂芳基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基C 1-6烷基、5-6元杂芳基C 1-6烷基、C 3-8环烷基C 1-6烷基或3-8元杂环烷基C 1-6烷基;所述R 4为未取代,或者选择性被1~3个R 9取代在任意位置;
所述R 1、R 2、R 3和R 4分别为独立取代基,或者
1)R 1和R 3相互连接形成3-10元杂环烷基;所述3-10元杂环烷基为未取代,或者选择性被1~3个R 9取代在任意位置;
2)R 2和R 3相互连接形成3-10元杂环烷基;所述3-10元杂环烷基为未取代,或者选择性被1~3个R 9取代在任意位置;
3)R 3和R 4与其共同连接的碳原子一起形成C 3-10环烷基或3-10元杂环烷基;所述C 3-10环烷基或3-10元杂环烷基为未取代,或者选择性被1~3个R 9取代在任意位置;或
4)R 2和R 3相互连接与α键共同形成双键;
R 5和R 5a分别独立地为氢、卤素、氰基、C 1-4烷基、卤代C 1-4烷基、卤代C 1-4烷氧基或C 1-4烷氨基;
Cy为5-10元杂芳环;所述Cy为未取代,或者选择性被1~3个选自卤素、-CN、-NH 2、-NHOH、-OH、-R C、-OR C、-NHR C、-NH-OR C、-NHC(O)R C、-C(O)R C和-C(O)N(R C) 2的取代基取代在任意位置;
每个R A独立地为C 1-8烷基、C 2-8烯基或C 2-8炔基;所述R A为未取代,或者选择性被1~3个选自卤素、-OH、-NH 2、氧代基、C 1-3烷氧基和C 1-3烷氨基的取代基取代在任意位置;
每个R B独立地为C 1-6烷基、C 2-6烯基、C 2-6炔基、苯基、5-6元杂芳基、C 3-8环烷基、3-8元杂环烷基、-(CH 2) n-苯基、-(CH 2) n-(5-6元杂芳基)、-(CH 2) n-C 3-8环烷基或-(CH 2) n-(3-8元杂环烷基);所述R B为未取代,或者选择性被1~3个R 9取代在任意位置;
每个R C独立地为C 1-6烷基、C 2-6烯基、C 2-6炔基、苯基、5-6元杂芳基、C 3-8环烷基、3-8元杂环烷基、-(CH 2) n-OC 1-6烷基、-(CH 2) n-苯基、-(CH 2) n-(5-6元杂芳基)、-(CH 2) n-C 3-8环烷基、-(CH 2) n-(3-8元杂环烷基)或-(3-8元杂环烷基)-C 1-6烷基;所述R C为未取代,或者选择性被1~3个R 10取代在任意位置;
每个R 9和每个R 10分别独立地为H、-CN、-NO 2、-SH、-NH 2、-OH、-C(O)OH、-NHC(O)R a、-NHS(O) 2R a、-C(O)R a、卤素、氧代基、酯基、酰胺基、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、C 1-4烷氨基、卤代C 1-4烷基、卤代C 1-4烷氧基、-(CH 2) n-NH 2、-(CH 2) n-OH、-(CH 2) n-(C 1-4烷氨基)或-(CH 2) n-(C 1-4烷氧基);
每个R a独立地为C 1-6烷基或C 2-6烯基;
n为1、2、3或4。
本发明提供了一种如式I’所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐;
Figure PCTCN2019121976-appb-000002
其中,W 2为=O、=S、=NH、=N-OH或=N-O(C 1-6烷基);
A 1为N或CR 5
A 2为N或CR 5a
A 3为N或CR 5b
R为-NH-Cy或Cy;
R 1为H、-OH、-NH 2、R A、-NH-R A、-NH-C(O)-R A或-O-R A
R 2为H、CN、氘代C 1-4烷基或R B
R 3为H、C 1-6烷基、C 2-6烯基或C 2-6炔基;所述R 3为未取代,或者选择性被1~3个R 9取代在任意位置;
R 4为H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 6-10芳基、5-6元杂芳基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基C 1-6烷基、5-6元杂芳基C 1-6烷基、C 3-8环烷基C 1-6烷基或3-8元杂环烷基C 1-6烷基;所述R 4为未取代,或者选择性被1~3个R 9取代在任意位置;
所述R 1、R 2、R 3和R 4分别为独立取代基,或者
1)R 1和R 3相互连接形成3-10元杂环烷基;所述3-10元杂环烷基为未取代,或者选择性被1~3个R 9取代在任意位置;
2)R 2和R 3相互连接形成3-10元杂环烷基;所述3-10元杂环烷基为未取代,或者选择性被1~3个R 9取代在任意位置;
3)R 3和R 4与其共同连接的碳原子一起形成C 3-10环烷基或3-10元杂环烷基;所述C 3-10环烷基或3-10元杂环烷基为未取代,或者选择性被1~3个R 9取代在任意位置;或
4)R 2和R 3相互连接与α键共同形成双键;
R 5、R 5a和R 5b分别独立地为氢、卤素、氰基、C 1-4烷基、卤代C 1-4烷基、卤代C 1-4烷氧基或C 1-4烷氨基;
Cy为5-10元杂芳环;所述Cy为未取代,或者选择性被1~3个选自卤素、-CN、-NH 2、-NHOH、-OH、-R C、-OR C、-NHR C、-NH-OR C、-NHC(O)R C、-C(O)R C和-C(O)N(R C) 2的取代基取代在任意位置;
每个R A独立地为C 1-8烷基、C 2-8烯基或C 2-8炔基;所述R A为未取代,或者选择性被1~3个选自卤素、-OH、-NH 2、氧代基、C 1-3烷氧基和C 1-3烷氨基的取代基取代在任意位置;
每个R B独立地为C 1-6烷基、C 2-6烯基、C 2-6炔基、苯基、5-6元杂芳基、C 3-8环烷基、3-8元杂环烷基、-(CH 2) n-苯基、-(CH 2) n-(5-6元杂芳基)、-(CH 2) n-C 3-8环烷基或-(CH 2) n-(3-8元杂环烷基);所述R B为未取代,或者选择性被1~3个R 9取代在任意位置;
每个R C独立地为C 1-6烷基、C 2-6烯基、C 2-6炔基、苯基、5-6元杂芳基、C 3-8环烷基、3-8元杂环烷基、-(CH 2) n-OC 1-6烷基、-(CH 2) n-苯基、-(CH 2) n-(5-6元杂芳基)、-(CH 2) n-C 3-8环烷基、-(CH 2) n-(3-8元杂环烷基)或-(3-8元杂环烷基)-C 1-6烷基;所述R C为未取代,或者选择性被1~3个R 10取代在任意位置;
每个R 9和每个R 10分别独立地为H、-CN、-NO 2、-SH、-NH 2、-OH、-C(O)OH、-NHC(O)R a、-NHS(O) 2R a、-C(O)R a、卤素、氧代基、酯基、酰胺基、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、C 1-4烷氨基、卤代C 1-4烷基、卤代C 1-4烷氧基、-(CH 2) n-NH 2、-(CH 2) n-OH、-(CH 2) n-(C 1-4烷氨基)或-(CH 2) n-(C 1-4烷氧基);
每个R a独立地为C 1-6烷基或C 2-6烯基;
n为1、2、3或4。
以下所述的如式I或I’所述的所有实施方案、及任意实施方案的组合均包含在本发明如式I或I’所示的结构式的范围中。
在一些实施方案中,所述的如式I所述的化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐里某些基团的定义可如下所述,未描述的基团可如上任一方案所述:
其中,W 1为O;W 2为O;
R为-NH-Cy;
R 1为H、-OH、-NH 2、R A、-NH-R A、-NH-C(O)-R A或-O-R A
R 2和R 3相互连接形成3-10元杂环烷基;所述3-10元杂环烷基为未取代,或者选择性被1~3个R 9取代在任意位置;
R 4为H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 6-10芳基、5-6元杂芳基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基C 1-6烷基、5-6元杂芳基C 1-6烷基、C 3-8环烷基C 1-6烷基或3-8元杂环烷基C 1-6烷基;所述R 4为未取代,或者选择性被1~3个R 9取代在任意位置;
R 5为氢、卤素、氰基或C 1-4烷基;
R 5a为氢;
Cy为5-10元杂芳环;所述Cy为未取代,或者选择性被1~3个选自卤素、-CN、-NH 2、-NHOH、-OH、-R C、-OR C、-NHR C、-NH-OR C、-NHC(O)R C、-C(O)R C和-C(O)N(R C) 2的取代基取代在任意位置;
每个R A独立地为C 1-8烷基、C 2-8烯基或C 2-8炔基;所述R A为未取代,或者选择性 被1~3个选自卤素、-OH、-NH 2、氧代基、C 1-3烷氧基和C 1-3烷氨基的取代基取代在任意位置;
每个R B独立地为C 1-6烷基、C 2-6烯基、C 2-6炔基、苯基、5-6元杂芳基、C 3-8环烷基、3-8元杂环烷基、-(CH 2) n-苯基、-(CH 2) n-(5-6元杂芳基)、-(CH 2) n-C 3-8环烷基或-(CH 2) n-(3-8元杂环烷基);所述R B为未取代,或者选择性被1~3个R 9取代在任意位置;
每个R C独立地为C 1-6烷基、C 2-6烯基、C 2-6炔基、苯基、5-6元杂芳基、C 3-8环烷基、3-8元杂环烷基、-(CH 2) n-OC 1-6烷基、-(CH 2) n-苯基、-(CH 2) n-(5-6元杂芳基)、-(CH 2) n-C 3-8环烷基、-(CH 2) n-(3-8元杂环烷基)或-(3-8元杂环烷基)-C 1-6烷基;所述R C为未取代,或者选择性被1~3个R 10取代在任意位置;
每个R 9和每个R 10分别独立地为H、-CN、-NO 2、-SH、-NH 2、-OH、-C(O)OH、-NHC(O)R a、-NHS(O) 2R a、-C(O)R a、卤素、氧代基、酯基、酰胺基、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、C 1-4烷氨基、卤代C 1-4烷基或卤代C 1-4烷氧基;
每个R a独立地为C 1-6烷基或C 2-6烯基;
n为1、2、3或4。
在一些实施方案中,每个R 9和每个R 10分别独立地为H、-CN、-NO 2、-SH、-NH 2、-OH、-C(O)OH、-NHC(O)R a、-NHS(O) 2R a、卤素、氧代基、酯基、酰胺基、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、C 1-4烷氨基、卤代C 1-4烷基或卤代C 1-4烷氧基。
在一些实施方案中,每个R 9和每个R 10分别独立地为H、-CN、-NO 2、-SH、-NH 2、-OH、-C(O)OH、-NHC(O)R a、-NHS(O) 2R a、-C(O)R a、卤素、氧代基、酯基、酰胺基、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、C 1-4烷氨基、卤代C 1-4烷基或卤代C 1-4烷氧基。
在一些实施方案中,所述R 9为H、-NH 2、-OH、F、Cl、=O、-NHC(O)-C 2-6烯基、-C(O)-C 2-6烯基、-NHS(O) 2-C 2-6烯基、C 1-4烷基、C 1-4烷氧基、C 1-4烷氨基、卤代C 1-4烷基或卤代C 1-4烷氧基。
在一些实施方案中,所述R 9为H、-NH 2、-OH、F、Cl、=O、-NHC(O)-C 2-6烯基、-NHS(O) 2-C 2-6烯基、C 1-4烷基、C 1-4烷氧基、C 1-4烷氨基、卤代C 1-4烷基或卤代C 1-4烷氧基。
在一些实施方案中,所述R 9为H、F、Cl、=O、-NHC(O)-C 2-6烯基或C 1-4烷基。
在一些实施方案中,所述R 10为H、-CN、-NH 2、-OH、F、Cl、=O、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、C 1-4烷氨基、卤代C 1-4烷基或卤代C 1-4烷氧基。
在一些实施方案中,所述R 10为H、-NH 2或C 1-4烷氨基。
在一些实施方案中,所述R 10为H。
在一些实施方案中,所述R A为C 1-6烷基或C 2-6烯基;所述R A为未取代,或者选择性被1~3个选自F、Cl、-OH、-NH 2、=O、-OCH 3和-N(CH 3) 2的取代基取代在任意位置。
在一些实施方案中,所述R B为C 1-6烷基(例如:甲基、乙基、正丙基、异丙基)、C 2-6烯基(例如:烯丙基)、C 3-6环烷基(例如:环丙基或环丁基)、苯基或5-6元杂芳基;所述R B为未取代,或者选择性被1~3个R 9取代在任意位置;R 9的定义如前所述。
在一些实施方案中,所述R C独立地为C 1-6烷基、C 2-6烯基、C 2-6炔基、苯基、5-6元杂芳基、C 3-8环烷基、3-8元杂环烷基、-(CH 2) n-OC 1-6烷基、-(CH 2) n-苯基、-(CH 2) n-(5-6元杂芳基)、-(CH 2) n-C 3-8环烷基或-(CH 2) n-(3-8元杂环烷基);所述R C为未取代,或者选择性被1~3个R 10取代在任意位置;
在一些实施方案中,所述R C独立地为C 1-6烷基、C 2-6烯基、苯基、5-6元杂芳基、C 3-6环烷基、3-6元杂环烷基、-(CH 2) n-OC 1-6烷基、-(CH 2) n-苯基、-(CH 2) n-(5-6元杂芳基)、-(CH 2) n-C 3-6环烷基或-(CH 2) n-(3-6元杂环烷基);所述R C为未取代,或者选择性被1~3个R 10取代在任意位置;其中n优选为1、2或3;R 10的定义如前所述。
在一些实施方案中,所述R C独立地为C 1-6烷基或C 3-6环烷基;所述R C为未取代,或者选择性被1~3个R 10取代在任意位置;其中R 10的定义如前所述。
在一些实施方案中,所述R C独立地为C 1-6烷基(例如:甲基、乙基、正丙基、异丙基或叔丁基)或C 3-6环烷基(例如:环丙基)。
在一些实施方案中,所述R 1为H、-OH、-OCH 3、-NH 2、-NH(CH 3)、-NH(CH 2CH 3)或-NH(CH 2CH=CH 2)。
在一些实施方案中,所述R 1为H、-OH、-NH 2、-NH(CH 3)或-NH(CH 2CH 3)。
在一些实施方案中,所述R 1为H。
在一些实施方案中,R 2为H、CD 3或R B,其中,R B的定义如前所述。
在一些实施方案中,R 2为H或R B,其中,R B的定义如前所述。。
在一些实施方案中,所述R 2为H、C 1-6烷基、C 2-6烯基、C 3-6环烷基、苯基或5-6元杂芳基;所述R 2为未取代,或者选择性被1~3、1~2个或1个选自F、Cl、=O、-NHC(O)-C 2-6烯基和C 1-4烷基的取代基取代在任意位置。
在一些实施方案中,所述R 2为H、CD 3、C 1-6烷基、C 2-6烯基、C 3-6环烷基、苯基或5-6元杂芳基;所述R 2为未取代,或者选择性被1~3、1~2个或1个选自F、Cl、=O、-NHC(O)-C 2-6烯基和C 1-4烷基的取代基取代在任意位置。
在一些实施方案中,所述R 2为H、氘代甲基、甲基、乙基、正丙基、异丙基、环丙 基、-C(O)CH=CH 2
Figure PCTCN2019121976-appb-000003
在一些实施方案中,所述R 3为H或C 1-6烷基;所述R 3为未取代,或者选择性被1~3、1~2或1个R 9取代在任意位置;所述R 9的定义如前所述。
在一些实施方案中,所述R 3为H或C 1-6烷基。
在一些实施方案中,所述R 3为H、甲基或乙基。
在一些实施方案中,所述R 4为H、C 1-6烷基、苯基、5-6元杂芳基、C 3-6环烷基或3-6元杂环烷基;所述R 4为未取代,或者选择性被1~3、1~2或1个R 9取代在任意位置;所述R 9的定义如前所述。
在一些实施方案中,所述R 4为甲基、乙基、正丙基、异丙基、苯基、吡啶基、环丙基、环丁基、环戊基或环己基;所述R 4为未取代,或者选择性被1~3、1~2或1个氟、氯和甲基的取代基取代在任意位置。
在一些实施方案中,所述R 3和R 4分别为独立取代基。
在一些实施方案中,所述R 3和R 4与其共同连接的碳原子一起形成C 3-10环烷基或3-10元杂环烷基;所述C 3-10环烷基或3-10元杂环烷基为未取代,或者选择性被1~3个R 9取代在任意位置;所述R 9的定义如前所述。
在一些实施方案中,所述R 3和R 4与其共同连接的碳原子一起形成C 3-10环烷基更优选为环丙基、环丁基、环戊基、环己基、2,3-二氢-1H-茚基、2,3-二氢-1H-茚基-1-酮、螺[3,2]己基或螺[3.3]庚基。
在一些实施方案中,所述R 3和R 4与其共同连接的碳原子一起形成3-10元杂环烷基更优选为3-8元杂环烷基,例如:四氢呋喃基、吡咯烷基、氮杂环丁基、哌啶基或硫杂环丁烷1-氧化物。
在一些实施方案中,所述R 3和R 4与其共同连接的碳原子一起形成3-10元杂环烷基更优选为3-8元杂环烷基,例如:四氢呋喃基、吡咯烷基、氮杂环丁基、哌啶基或1-氧代-硫杂环丁基。
在一些实施方案中,所述R 1和R 3分别为独立取代基。
在一些实施方案中,所述R 1和R 3相互连接形成3-10元杂环烷基;所述3-10元杂环烷基为未取代,或者选择性被1~3个R 9取代在任意位置。
在一些实施方案中,所述R 1和R 3相互连接形成4-8元杂环烷基。
在一些实施方案中,所述R 1和R 3相互连接形成5-6元杂环烷基。
在一些实施方案中,所述R 2和R 3分别为独立取代基。
在一些实施方案中,所述R 2和R 3相互连接形成3-10元杂环烷基;所述3-10元杂环烷基为未取代,或者选择性被1~3个R 9取代在任意位置。
在一些实施方案中,所述R 2和R 3相互连接形成4-8元杂环烷基;所述4-8元杂环烷基为未取代,或者选择性被1~3个R 9取代在任意位置。
在一些实施方案中,所述R 2和R 3相互连接形成5-6元杂环烷基;所述5-6元杂环烷基为未取代,或者选择性被1个=O取代在任意位置。
在一些实施方案中,所述R 2和R 3相互连接与α键(单键)共同形成双键。
在一些实施方案中,R 5为氢、卤素、氰基、C 1-4烷氧基、卤代C 1-4烷基或卤代C 1-4烷氧基。
在一些实施方案中,R 5为氢、卤素或C 1-4烷基。
在一些实施方案中,所述R 5为H、F、Cl或-CH 3
在一些实施方案中,R 5a为氢、卤素、氰基、C 1-4烷氧基、卤代C 1-4烷基或卤代C 1-4烷氧基。
在一些实施方案中,R 5a为氢。
在一些实施方案中,R 5b为氢、卤素、氰基、C 1-4烷氧基、卤代C 1-4烷基或卤代C 1-4烷氧基。
在一些实施方案中,R 5b为氢、卤素、C 1-4烷氧基或C 1-4烷基。
在一些实施方案中,R 5b为H、F、Cl、-CH 3或-OCH 3
在一些实施方案中,A 1为CR 5,A 2为CH,A 3为N或CR 5b
在一些实施方案中,所述R为
Figure PCTCN2019121976-appb-000004
Figure PCTCN2019121976-appb-000005
其中,R 6、R 7和R 8分别独立地为H、卤素、-CN、-NH 2、-NHOH、-OH、-R C、-OR C、-NHR C、-NH-OR C、-NHC(O)R C或-NHS(O) 2R C;R 6和R 7分别为独立取代基,或者R 6和R 7相互连接形成杂芳基或杂环烷基;所述杂芳基或杂环烷基为未取代,或者选择性被1~3个选自卤素、-CN、-NH 2、-NHOH、-OH、-R C、-OR C、-NHR C、-NH-OR C、-NHC(O)R C、-C(O)R C和-C(O)N(R C) 2的取代基取代在任意位置;R C的定义如前所述。
在一些实施方案中,所述R为
Figure PCTCN2019121976-appb-000006
其中,R 6、R 7和R 8分别独立地为H、卤素、-CN、-NH 2、-NHOH、-OH、-R C、-OR C、-NHR C、-NH-OR C、-NHC(O)R C或-NHS(O) 2R C;R 6和R 7分别为独立取代基,或者R 6和R 7与其连接的原子一起形成杂芳基或杂环烷基;所述杂芳基或杂环烷基为未取代,或者选择性被1~3个选自卤素、-CN、-NH 2、-NHOH、-OH、-R C、-OR C、-NHR C、-NH-OR C、-NHC(O)R C、-C(O)R C和-C(O)N(R C) 2的取代基取代在任意位置;R C的定义如前所述。
在一些实施方案中,所述R为
Figure PCTCN2019121976-appb-000007
Figure PCTCN2019121976-appb-000008
其中,R 6、R 7和R 8分别独立地为H、卤素、-CN、-NH 2、-NHOH、-OH、-R C、-OR C、-NHR C、-NH-OR C、-NHC(O)R C或-NHS(O) 2R C;R C的定义如前所述。
在一些实施方案中,所述R 8为H。
在一些实施方案中,所述R 6为H、F、Cl、-CN、-NH 2、-CH 3、-CF 3、-CH 2CH 3、-OCH 3、-OCH 2CH 3、-OCF 3、-O-正丙基、-O-异丙基、环丙基或1-甲基-1H-吡唑基。
在一些实施方案中,所述R 7为H、-NH 2、-NHR C、-NH-OR C或-NHC(O)R C;R C的定义如前所述。
在一些实施方案中,所述R 7为H、-NH 2、-NHR C或-NHC(O)R C;R C的定义如前所述。
在一些实施方案中,所述R 6和R 7与其连接的原子一起形成5-6元杂芳基或5-6元杂环烷基;所述5-6元杂芳基或5-6元杂环烷基为未取代,或者选择性被1-2或1个选自卤素、-CN、-NH 2、-NHOH、-OH、-R C、-OR C、-NHR C、-NH-OR C和-NHC(O)R C的取代基取代在任意位置;所述R C的定义如前所述。
在一些实施方案中,所述R 6和R 7与其连接的原子一起形成5-6元杂芳基或杂环烷基;所述5-6元杂芳基或杂环烷基为未取代,或者选择性被1-2或1个选自F、Cl、-CN、-NH 2、-CH 3、-CF 3、-CH 2CH 3、-OCH 3、-OCH 2CH 3、-OCF 3、-O-正丙基、-O-异丙基、环丙基、-NHR C、-NH-OR C和-NHC(O)R C的取代基取代在任意位置;所述R C的定义如前所述。
在一些实施方案中,所述R为如下任一结构:
Figure PCTCN2019121976-appb-000009
Figure PCTCN2019121976-appb-000010
其中,R 11和R 12分别独立地为H、卤素、-CN、-NH 2、-NHOH、-OH、-R C、-OR C、-NHR C、-NH-OR C或-NHC(O)R C;R C和R 8的定义如前所述。
在一些实施方案中,所述R 11为H、F、Cl、-CN、-NH 2、-CH 3、-CF 3、-CH 2CH 3、-OCH 3、-OCH 2CH 3、-OCF 3、-O-正丙基、-O-异丙基、环丙基、-NHR C、-NH-OR C或-NHC(O)R C;所述R C的定义如前所述。
在一些实施方案中,所述R 11为H。
在一些实施方案中,所述R 12为H、F、Cl、-CN、-NH 2、-CH 3、-CF 3、-CH 2CH 3、-OCH 3、-OCH 2CH 3、-OCF 3、-O-正丙基、-O-异丙基、环丙基、-NHR C、-NH-OR C或-NHC(O)R C;所述R C的定义如前所述。
在一些实施方案中,所述R 12为H。
在一些实施方案中,所述W 1为O。
在一些实施方案中,所述W 2为O。
在一些实施方案中,所述的如式I所述的化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐为式II所述的化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐:
Figure PCTCN2019121976-appb-000011
其中,R 1为H、-OH、-NH 2、R A、-NH-R A、-NH-C(O)-R A或-O-R A
R 2为H、CN或R B
R 3为H、C 1-6烷基、C 2-6烯基或C 2-6炔基;所述R 3为未取代,或者选择性被1~3个R 9取代在任意位置;
R 4为H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 6-10芳基、5-6元杂芳基、C 3-8环烷基、3-8元杂环烷基;所述R 4为未取代,或者选择性被1~3个R 9取代在任意位置;
所述R 3和R 4为独立取代基,或者R 3和R 4与其共同连接的碳原子一起形成C 3-10环烷基或3-10元杂环烷基;所述C 3-10环烷基或3-10元杂环烷基为未取代,或者选择性被1~3个R 9取代在任意位置;
R 5为氢、卤素、氰基或C 1-4烷基;
R 6、R 7和R 8分别独立地为H、卤素、-CN、-NH 2、-NHOH、-OH、-R C、-OR C、-NHR C、-NH-OR C、-NHC(O)R C或-NHS(O) 2R C
R 6和R 7分别为独立取代基,或者R 6和R 7与其连接的原子一起形成杂芳基或杂环烷基;所述杂芳基或杂环烷基为未取代,或者选择性被1~3个选自卤素、-CN、-NH 2、-NHOH、-OH、-R C、-OR C、-NHR C、-NH-OR C、-NHC(O)R C、-C(O)R C和-C(O)N(R C) 2的取代基取代在任意位置;
每个R A独立地为C 1-8烷基、C 2-8烯基或C 2-8炔基;所述R A为未取代,或者选择性被1~3个选自卤素、-OH、-NH 2、氧代基、C 1-3烷氧基和C 1-3烷氨基的取代基取代在任意位置;
每个R B独立地为C 1-6烷基、C 2-6烯基、C 2-6炔基、苯基、5-6元杂芳基、C 3-8环烷基、3-8元杂环烷基、-(CH 2) n-苯基、-(CH 2) n-(5-6元杂芳基)、-(CH 2) n-C 3-8环烷基或-(CH 2) n-(3-8元杂环烷基);所述R B为未取代,或者选择性被1~3个R 9取代在任意位置;
每个R C独立地为C 1-6烷基、C 2-6烯基、C 2-6炔基、苯基、5-6元杂芳基、C 3-8环烷基、3-8元杂环烷基、-(CH 2) n-OC 1-6烷基、-(CH 2) n-苯基、-(CH 2) n-(5-6元杂芳基)、-(CH 2) n-C 3-8环烷基或-(CH 2) n-(3-8元杂环烷基);所述R C为未取代,或者选择性被1~3个R 10取代在任意位置;
每个R 9和每个R 10分别独立地为H、-CN、-NO 2、-SH、-NH 2、-OH、-C(O)OH、-NHC(O)R a、-NHS(O) 2R a、-C(O)R a、卤素、氧代基、酯基、酰胺基、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、C 1-4烷氨基、卤代C 1-4烷基或卤代C 1-4烷氧基;
每个R a独立地为C 1-6烷基或C 2-6烯基;
n为1、2、3或4。
以下所述的如式II所述的所有实施方案、及任意实施方案的组合均包含在本发明如式II所示的结构式的范围中。
在一些实施方案中,所述的如式II所述的化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐里某些基团的定义可如下所述,未描述的基团可如上任一方案所述:
其中,R 2为H或R B
每个R 9和每个R 10分别独立地为H、-CN、-NO 2、-SH、-NH 2、-OH、-C(O)OH、-NHC(O)R a、-NHS(O) 2R a、卤素、氧代基、酯基、酰胺基、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、C 1-4烷氨基、卤代C 1-4烷基或卤代C 1-4烷氧基。
在一些实施方案中,所述R A为C 1-6烷基或C 2-6烯基;所述R A为未取代,或者选择性被1~3个选自F、Cl、-OH、-NH 2、=O、-OCH 3和-N(CH 3) 2的取代基取代在任意位置。
在一些实施方案中,所述R B为C 1-6烷基(例如:甲基、乙基、正丙基、异丙基)、C 2-6烯基(例如:烯丙基)、C 3-6环烷基(例如:环丙基)、苯基或5-6元杂芳基;所述R B为未取代,或者选择性被1~3个R 9取代在任意位置;R 9的定义如前所述。
在一些实施方案中,所述R C独立地为C 1-6烷基、C 2-6烯基、苯基、5-6元杂芳基、C 3-6环烷基、3-6元杂环烷基、-(CH 2) n-OC 1-6烷基、-(CH 2) n-苯基、-(CH 2) n-(5-6元杂芳基)、-(CH 2) n-C 3-6环烷基或-(CH 2) n-(3-6元杂环烷基);所述R C为未取代,或者选择性被1~3个R 10取代在任意位置;其中n优选为1、2或3;R 10的定义如前所述。
在一些实施方案中,所述R C独立地为C 1-6烷基或C 3-6环烷基;所述R C为未取代,或者选择性被1~3个R 10取代在任意位置;其中R 10的定义如前所述。
在一些实施方案中,所述R C独立地为C 1-6烷基(例如:甲基、乙基、正丙基、异丙基或叔丁基)或C 3-6环烷基(例如:环丙基)。
在一些实施方案中,每个R 9和每个R 10分别独立地为H、-CN、-NO 2、-SH、-NH 2、-OH、-C(O)OH、-NHC(O)R a、-NHS(O) 2R a、卤素、氧代基、酯基、酰胺基、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、C 1-4烷氨基、卤代C 1-4烷基或卤代C 1-4烷氧基;
在一些实施方案中,所述R 9为H、-NH 2、-OH、F、Cl、=O、-NHC(O)-C 2-6烯基、-C(O)-C 2-6烯基、-NHS(O) 2-C 2-6烯基、C 1-4烷基、C 1-4烷氧基、C 1-4烷氨基、卤代C 1-4烷基或卤代C 1-4烷氧基。
在一些实施方案中,所述R 9为H、-NH 2、-OH、F、Cl、=O、-NHC(O)-C 2-6烯基、-NHS(O) 2-C 2-6烯基、C 1-4烷基、C 1-4烷氧基、C 1-4烷氨基、卤代C 1-4烷基或卤代C 1-4烷氧基。
在一些实施方案中,所述R 9为H、F、Cl、=O、-NHC(O)-C 2-6烯基或C 1-4烷基。
在一些实施方案中,所述R 10为H、-CN、-NH 2、-OH、F、Cl、=O、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、C 1-4烷氨基、卤代C 1-4烷基或卤代C 1-4烷氧基。
在一些实施方案中,所述R 10为H。
在一些实施方案中,所述R 1为H、-OH、-OCH 3、-NH 2、-NH(CH 3)、-NH(CH 2CH 3)或-NH(CH 2CH=CH 2)。
在一些实施方案中,所述R 1为H、-OH、-NH 2、-NH(CH 3)或-NH(CH 2CH 3)。
在一些实施方案中,所述R 1为H。
在一些实施方案中,R 2为H或R B
在一些实施方案中,所述R 2为H、C 1-6烷基、C 2-6烯基、C 3-6环烷基、苯基或5-6元杂芳基;所述R 2为未取代,或者选择性被1~3、1~2个或1个选自F、Cl、=O、NHC(O)-C 2-6烯基和C 1-4烷基的取代基取代在任意位置。
在一些实施方案中,所述R 2为H、甲基、乙基、正丙基、异丙基、环丙基、-C(O)CH=CH 2
Figure PCTCN2019121976-appb-000012
在一些实施方案中,所述R 3为H或C 1-6烷基;所述R 3为未取代,或者选择性被1~3、1~2或1个R 9取代在任意位置;所述R 9的定义如前所述。
在一些实施方案中,所述R 3为H或C 1-6烷基。
在一些实施方案中,所述R 3为H、甲基或乙基。
在一些实施方案中,所述R 4为H、C 1-6烷基、苯基、5-6元杂芳基、C 3-6环烷基或3-6元杂环烷基;所述R 4为未取代,或者选择性被1~3、1~2或1个R 9取代在任意位置;所述R 9的定义如前所述。
在一些实施方案中,所述R 4为甲基、乙基、正丙基、异丙基、苯基、吡啶基、环丙基、环丁基、环戊基或环己基;所述R 4为未取代,或者选择性被1~3、1~2或1个氟、氯和甲基的取代基取代在任意位置。
在一些实施方案中,所述R 3和R 4与其共同连接的碳原子一起形成C 3-10环烷基或3-10元杂环烷基;所述C 3-10环烷基或3-10元杂环烷基为未取代,或者选择性被1~3个R 9取代在任意位置;所述R 9的定义如前所述。
在一些实施方案中,所述R 3和R 4与其共同连接的碳原子一起形成C 3-10环烷基,更优选为环丙基、环丁基、环戊基、环己基、2,3-二氢-1H-茚基、2,3-二氢-1H-茚基-1-酮、螺[3,2]己基或螺[3.3]庚基。
在一些实施方案中,所述R 3和R 4与其共同连接的碳原子一起形成3-10元杂环烷基更优选为3-8元杂环烷基,例如:四氢呋喃基、吡咯烷基、氮杂环丁基、哌啶基或硫杂环丁烷1-氧化物。
在一些实施方案中,所述R 3和R 4与其共同连接的碳原子一起形成3-10元杂环烷基更优选为3-8元杂环烷基,例如:四氢呋喃基、吡咯烷基、氮杂环丁基、哌啶基或1-氧代-硫杂环丁基。
在一些实施方案中,所述R 5为F、Cl、-CN、-CH 3或-CH 2CH 3
在一些实施方案中,所述R 5为F。
在一些实施方案中,所述R 5为Cl。
在一些实施方案中,所述R 5为-CH 3
在一些实施方案中,所述R 8为H。
在一些实施方案中,所述R 6为H、F、Cl、-CN、-NH 2、-CH 3、-CF 3、-CH 2CH 3、-OCH 3、-OCH 2CH 3、-OCF 3、-O-正丙基、-O-异丙基、环丙基或1-甲基-1H-吡唑基。
在一些实施方案中,所述R 7为H、-NH 2、-NHR C、-NH-OR C或-NHC(O)R C;R C的定义如前所述。
在一些实施方案中,所述R 6和R 7与其连接的原子一起形成5-6元杂芳基或杂环烷基;所述5-6元杂芳基或杂环烷基为未取代,或者选择性被1~3、1-2或1个选自卤素、-CN、-NH 2、-NHOH、-OH、-R C、-OR C、-NHR C、-NH-OR C和-NHC(O)R C的取代基取代在任意位置;所述R C的定义如前所述。
在一些实施方案中,所述R 6和R 7与其连接的原子一起形成5-6元杂芳基或杂环烷基;所述5-6元杂芳基或杂环烷基为未取代,或者选择性被1-2或1个选自F、Cl、-CN、-NH 2、-CH 3、-CF 3、-CH 2CH 3、-OCH 3、-OCH 2CH 3、-OCF 3、-O-正丙基、-O-异丙基、环丙基、-NHR C、-NH-OR C和-NHC(O)R C的取代基取代在任意位置;所述R C的定义如前所述。
在一些实施方案中,基团
Figure PCTCN2019121976-appb-000013
为如下任一结构:
Figure PCTCN2019121976-appb-000014
其中,R 11和R 12分别独立地为H、卤素、-CN、-NH 2、-NHOH、-OH、-R C、-OR C、-NHR C、-NH-OR C或-NHC(O)R C;R C和R 8的定义如前所述。
在一些实施方案中,基团
Figure PCTCN2019121976-appb-000015
为如下任一结构:
Figure PCTCN2019121976-appb-000016
其中,R 11和R 12分别独立地为H、卤素、-CN、-NH 2、-NHOH、-OH、-R C、-OR C、-NHR C、-NH-OR C或-NHC(O)R C;R C和R 8的定义如前所述。
在一些实施方案中,所述R 11为H、F、Cl、-CN、-NH 2、-CH 3、-CF 3、-CH 2CH 3、-OCH 3、-OCH 2CH 3、-OCF 3、-O-正丙基、-O-异丙基、环丙基、-NHR C、-NH-OR C或-NHC(O)R C;所述R C的定义如前所述。
在一些实施方案中,所述R 11为H。
在一些实施方案中,所述R 12为H、F、Cl、-CN、-NH 2、-CH 3、-CF 3、-CH 2CH 3、-OCH 3、-OCH 2CH 3、-OCF 3、-O-正丙基、-O-异丙基、环丙基、-NHR C、-NH-OR C或-NHC(O)R C;所述R C的定义如前所述。
在一些实施方案中,所述R 12为H。
在一些实施方案中,所述如式I所述的化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐,为如式III所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐:
Figure PCTCN2019121976-appb-000017
其中,m为0、1、2或3;t为0、1、2或3;
X和Y分别独立地为O、NH或CH 2
R 1、R 2、R 5、R 6、R 7、R 8和R 9的定义均如前所述。
在一些实施方案中,所述如式I所述的化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐,为如式IV所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐:
Figure PCTCN2019121976-appb-000018
其中,m为0、1、2或3;t为0、1、2或3;
R 1、R 2、R 5、R 6、R 7、R 8和R 9的定义均如前所述。
在一些实施方案中,所述如式I所述的化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐,为如式V所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐:
Figure PCTCN2019121976-appb-000019
其中,m为0、1、2或3;t为0、1、2或3;
R 1、R 4、R 5、R 6、R 7、R 8和R 9的定义均如前所述。
在一些实施方案中,所述如式I所述的化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐,为如式VI所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐:
Figure PCTCN2019121976-appb-000020
其中,R 1、R 4、R 5、R 6、R 7和R 8的定义均如前所述。
在一些实施方案中,所述如式I’所述的化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐,为如式VII所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐:
Figure PCTCN2019121976-appb-000021
其中,m为0、1、2或3;t为0、1、2或3;
R 1、R 2、R 5、R 6、R 7、R 8、R 9和A 3的定义均如前所述。
在一些实施方案中,所述如式I’所述的化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐,为如式VIII所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐:
Figure PCTCN2019121976-appb-000022
其中,m为0、1、2或3;t为0、1、2或3;
R 1、R 4、R 5、R 6、R 7、R 8、R 9和A 3的定义均如前所述。
在一些实施方案中,如式I所示的化合物,其异构体、前药、稳定的同位素衍生物或药学上可接受的盐任选为以下化合物:
Figure PCTCN2019121976-appb-000023
Figure PCTCN2019121976-appb-000024
在一些实施方案中,如式I所示的化合物,其异构体、前药、稳定的同位素衍生物或药学上可接受的盐任选为以下化合物:
Figure PCTCN2019121976-appb-000025
Figure PCTCN2019121976-appb-000026
Figure PCTCN2019121976-appb-000027
在一些实施方案中,如式I所示的化合物,其异构体、前药、稳定的同位素衍生物或药学上可接受的盐任选为以下化合物:
Figure PCTCN2019121976-appb-000028
Figure PCTCN2019121976-appb-000029
在一些实施方案中,如式I所示的化合物,其异构体、前药、稳定的同位素衍生物或药学上可接受的盐任选为以下化合物:
Figure PCTCN2019121976-appb-000030
在一些实施方案中,如式I’所示的化合物,其异构体、前药、稳定的同位素衍生物或药学上可接受的盐任选为以下化合物:
Figure PCTCN2019121976-appb-000031
在一些实施方案中,如式I’所示的化合物,其异构体、前药、稳定的同位素衍生物 或药学上可接受的盐任选为以下化合物:
Figure PCTCN2019121976-appb-000032
Figure PCTCN2019121976-appb-000033
本发明还提供了如式I或I’所示的化合物制备方法,其为如下任一方法:
方法1:溶剂中,碱性条件下,将X或X’和RH通过Buchwald-hartwig偶联或Ullmann偶联反应得到如式I或I’所示化合物;
Figure PCTCN2019121976-appb-000034
其中,L为卤素或其它离去基团,例如-OTf、-OTs或-OMs,所示L优选为氯、溴或碘;R、R 1、R 2、R 3、R 4、R 5、R 5a、A 1、A 2、A 3、W 1和W 2的定义如前所述。
方法2:溶剂中,碱性条件下,将X或X’和RH通过Buchwald-hartwig偶联反应得到如式I或I’所示化合物;
Figure PCTCN2019121976-appb-000035
其中,L为卤素或其它离去基团,例如-OTf、-OTs或-OMs,所示L优选为氯、溴或碘;R 1、R 2、R 3、R 4、R 5、R 5a、A 1、A 2、A 3、W 1、W 2和Cy的定义如前所述。
如反应式1所示方法中,使用Buchwald-hartwig偶联反应时,所述R优选为
Figure PCTCN2019121976-appb-000036
如方法1或2所示方法中,所述的Buchwald-hartwig偶联反应的条件和步骤可为本领域常规的偶联反应的条件和步骤,本发明特别优选以下反应条件:所述的溶剂优选1,4-二氧六环或叔丁醇;所述溶剂的用量优选5~80mL/mmol化合物X、X’、XI或XI’;所述的碱性条件下使用的碱优选为碳酸铯或叔丁醇钠;所述的碱与化合物X、X’、XI或XI’的摩尔比优选1.05:1~3:1;偶联试剂优选为Pd 2(dba) 3、Xantphos和/或XPhos体系或Pd 2(dba) 3和Ru-phos体系;所述的反应的温度优选50~120℃;所述的反应可通过TLC或LCMS进行检测,一般以化合物X、X’、XI或XI’消失时作为反应的终点,优选1~24小时;所述的反应结束后,还可通过后处理进一步纯化产物,优选包括如下步骤:将反 应体系用冰水淬灭后,用溶剂稀释,分离有机相,有机相干燥,减压除去有机溶剂,残留物用常规纯化手段,例如,硅胶柱层析、Flash柱层析或prep-HPLC纯化。所述的硅胶柱层析、Flash柱层析或prep-HPLC纯化的步骤和条件可为本领域中常规纯化的步骤和条件。
如方法1所示方法中,使用Ullmann偶联反应时,所述R优选为
Figure PCTCN2019121976-appb-000037
所述的Ullmann偶联反应的条件和步骤可为本领域常规的偶联反应的条件和步骤,本发明特别优选以下反应条件:所述的溶剂优选1,4-二氧六环,所述碱优选为磷酸钾和反式-1,2-环己二胺,在碘化亚铜存在下反应得到I或I’。
所述方法1或2中,Cy中存在不参与反应的-NH 2时,该-NH 2优选通过保护基保护,避免有任何副反应发生。如果存在上述氨基保护基团则需要经过后续的脱保护步骤后,得到如式I、I’、I-1或I’-1所示化合物。任何合适的氨基保护基团,例如:叔丁氧羰基(Boc)基团、乙酰基、环丙酰基、
Figure PCTCN2019121976-appb-000038
均可以用于保护氨基基团。如果使用Boc作为保护基,后续的脱保护反应可以在标准条件,例如,对甲苯磺酸/甲醇体系,二氯甲烷/三氟乙酸体系、饱和的氯化氢***溶液、或三氟甲磺酸三甲基硅酯/2,6-二甲基吡啶/二氯甲烷体系中进行;乙酰基、环丙酰基作为保护基,后续的脱保护反应可以在标准条件,例如,氢氧化钾(钠)/乙醇/四氢呋喃/水体系中进行;
Figure PCTCN2019121976-appb-000039
作为保护基,后续的脱保护反应可以在标准条件,例如,乙二胺/乙醇体系中进行。
方法1中,X(包括X、X-1和X-2)或X’(包括X’、X’-1和X’-2)可通过如下反应式3~4所示方法合成:
Figure PCTCN2019121976-appb-000040
其中,R t为H或C 1-6烷基;R 1为H;R 2、R 3、R 4、R 5、R 5a、L、W 1和W 2的定义如前所述;
溶剂中(例如:乙醇,1,4-二氧六环),酸性条件下(例如:浓硫酸),将化合物XII或XII’与相应的酮、醛、缩酮后缩醛反应得到化合物X或X’。反应温度优选为70~110℃,反应时间优选为2~24小时。
反应式3中,当所述R 2为H,
Figure PCTCN2019121976-appb-000041
中,所述R 3为取代的C 1-6烷基时(所述取代基包括至少1个卤素或酯基),得到如式X-1或X’-1所示化合物:
Figure PCTCN2019121976-appb-000042
Figure PCTCN2019121976-appb-000043
Figure PCTCN2019121976-appb-000044
其中,R 2为C 1-6烷基或氘代C 1-4烷基(优选为甲基、乙基或氘代甲基);R 1、R 3、R 4、R 5、R 5a、L、W 1和W 2的定义如前所述;L’为卤素或其它离去基团,例如-OTf、-OTs或-OMs,所示L优选为溴或碘;
溶剂中(例如:DMF),将化合物X-2或X’-2与R 2-L’反应得到化合物X或X’。反应温度优选为70~110℃,反应时间优选为5~48小时。
所述如式I或I’所示化合物的药学上可接受的盐可通过一般的化学方法合成。
一般情况下,盐的制备可以通过游离碱或酸与等化学当量或者过量酸(无机酸或有机酸)或碱(无机碱或有机碱)在合适的溶剂或溶剂组合物中反应制得。
本发明还提供了一种药物组合物,其包括活性组分以及药学上可接受的辅料;所述活性组分包括如式I或I’所示化合物、其异构体、前药、稳定的同位素衍生物和药学上可接受的盐中的一种或多种。
本发明还提供了一种药物组合物,其包括治疗有效量的活性组分以及药学上可接受的辅料;所述活性组分包括如式I或I’所示化合物、其异构体、前药、稳定的同位素衍生物和药学上可接受的盐中的一种或多种。
所述药物组合物中,所述活性组分还可包括其它种类用于治疗由于MNK1和/或MNK2水平失常引起的相关疾病的治疗剂;所述由于MNK1和/或MNK2水平失常引起的相关疾病优选为癌症。
所述药物组合物中,所述活性组分还可包括癌症的其它治疗剂。
所述药物组合物中,所述药学上可接受的辅料可包括药学上可接受的载体、稀释剂和/或赋形剂。
根据治疗目的,可将药物组合物制成各种类型的给药单位剂型,如片剂、丸剂、粉剂、液体、悬浮液、乳液、颗粒剂、胶囊、栓剂和针剂(溶液及悬浮液)等,优选液体、悬浮液、乳液、栓剂和针剂(溶液及悬浮液)等。
为了使片剂形式的药物组合物成形,可使用本领域任何已知并广泛使用的赋形剂。例如,载体,如乳糖、白糖、氯化钠、葡萄糖、尿素、淀粉、碳酸钙、高岭土、结晶纤维素和硅酸等;粘合剂,如水、乙醇、丙醇、普通糖浆、葡萄糖溶液、淀粉溶液、明胶溶液,羧甲基纤维素、紫胶、甲基纤维素和磷酸钾、聚乙烯吡咯烷酮等;崩解剂,如干淀粉、藻酸钠、琼脂粉和海带粉,碳酸氢钠、碳酸钙、聚乙烯脱水山梨醇的脂肪酸酯、十二烷基硫酸钠、硬脂酸单甘酯、淀粉和乳糖等;崩解抑制剂,如白糖、甘油三硬脂酸酯、椰子油和氢化油;吸附促进剂,如季胺碱和十二烷基硫酸钠等;润湿剂,如甘油、淀粉等;吸附剂,如淀粉、乳糖、高岭土、膨润土和胶体硅酸等;以及润滑剂,如纯净的滑石,硬脂酸盐、硼酸粉和聚乙二醇等。还可以根据需要选用通常的涂渍材料制成糖衣片剂、涂明胶膜片剂、肠衣片剂、涂膜片剂、双层膜片剂及多层片剂。
为了使丸剂形式的药物组合物成形,可使用本领域任何已知的并广泛使用的赋形剂,例如,载体,如乳糖,淀粉,椰子油,硬化植物油,高岭土和滑石粉等;粘合剂,如***树胶粉,黄蓍胶粉,明胶和乙醇等;崩解剂,如琼脂和海带粉等。
为了使栓剂形式的药物组合物成形,可使用本领域任何已知并广泛使用的赋性剂,例如,聚乙二醇,椰子油,高级醇,高级醇的酯,明胶和半合成的甘油酯等。
为了制备针剂形式的药物组合物,可将溶液或悬浮液消毒后(最好加入适量的氯化钠,葡萄糖或甘油等),制成与血液等渗压的针剂。在制备针剂时,也可使用本领域内任何常用的载体。例如,水,乙醇,丙二醇,乙氧基化的异硬脂醇,聚氧基化的异硬脂醇和聚乙烯脱水山梨醇的脂肪酸酯等。此外,还可加入通常的溶解剂、缓冲剂和止痛剂等。
本发明中,所述的组合物在药物组合物中的含量无特殊限制,可在很宽的范围内进行选择,通常可为质量百分比的5~95%,较佳的为质量百分比30~80%。
本发明中,所述药物组合物的给药方法没有特殊限制。可根据病人年龄、性别和其它条件及症状,选择各种剂型的制剂给药。例如,片剂、丸剂、溶液、悬浮液、乳液、颗粒剂或胶囊口服给药;针剂可以单独给药,或者和注射用输送液(如葡萄糖溶液及氨基酸溶液)混合进行静脉注射;栓剂为给药到直肠。
本发明还提供了所述如式I或I’所示化合物、其异构体、前药、溶剂化物、水合物、稳定的同位素衍生物或药学上可接受的盐,或所述药物组合物在制备MNK1和/或MNK2 抑制剂中的应用。所述的MNK1和/或MNK2抑制剂是指可以抑制MNK1和/或MNK2活性或表达(包括MNK1和/或MNK2的异常活动或过表达)。
本发明还提供了所述如式I或I’所示化合物、其异构体、前药、溶剂化物、水合物、稳定的同位素衍生物或药学上可接受的盐,或所述药物组合物具有治疗或减轻肿瘤细胞生长、增殖和/或存活,不适的细胞免疫反应及其相关病症,或不适的细胞炎性反应及其相关病症。所述肿瘤细胞生长、增殖和/或存活,不适的细胞免疫反应及其相关病症,或不适的细胞炎性反应及其相关病症是由MNK1和/或MNK2介导的。
本发明还提供了所述如式I或I’所示化合物、其异构体、前药、溶剂化物、水合物、稳定的同位素衍生物或药学上可接受的盐,或所述药物组合物在制备治疗、缓解和/或预防由MNK1和/或MNK2介导的相关疾病的药物中的应用。所述MNK1和/或MNK2介导的相关疾病为增值性疾病,优选为癌症。
本发明还提供了所述如式I或I’所示化合物、其异构体、前药、溶剂化物、水合物、稳定的同位素衍生物或药学上可接受的盐,或所述药物组合物在制备治疗和/或缓解癌症药物中的应用。
本发明还提供了所述如式I或I’所示化合物、其异构体、前药、溶剂化物、水合物、稳定的同位素衍生物或药学上可接受的盐,或所述药物组合物在治疗和/或缓解癌症中的应用,其包括给与哺乳动物治疗有效剂量的如式(I)所示化合物、其异构体、前药、溶剂化物、水合物、稳定的同位素衍生物或药学上可接受的盐,或包含其的药物组合物。
本发明还提供了所述如式I或I’所示化合物、其异构体、前药、溶剂化物、水合物、稳定的同位素衍生物或药学上可接受的盐,或所述药物组合物和一种或多种其它种类的用于治疗癌症的治疗剂和/或治疗方法联合用于治疗、缓解和/或预防由MNK1和/或MNK2介导的相关疾病。所述MNK1和/或MNK2介导的相关疾病为增殖性疾病,优选为癌症。
本发明还进一步提供一种联合制剂,包括如式I或I’所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐,或所述药物组合物和其它种类的用于治疗癌症的治疗剂和/或治疗方法合用。
本发明中,所述其它种类的用于治疗癌症的治疗剂可以和所述的如式I或I’所示化合物做成单一给药的治疗剂型,或者分别先后给药的治疗剂型。
本发明中,所述其它种类的用于治疗癌症的治疗剂和/或治疗方法可包括但不限于:烷化剂、拓扑酶I/II抑制剂、抗有丝***剂、抗代谢类药物、激素和激素类似物、抗肿瘤抗生素、小分子激酶抑制剂、小分子免疫调节剂、干扰素、单克隆抗体和放疗中的一种或多种。
本发明中,所述烷化剂可选自但不限于:顺铂、卡铂、奥沙利铂、奈达铂、氮芥、盐酸N-氧化-氮芥、环丁酸氮芥、尿嘧啶氮芥、环磷酰胺、异环磷酰胺、噻替派、卡波醌、三亚胺醌、甲苯磺酸英丙舒凡、甘露舒凡、曲奥舒凡、白消安、盐酸尼莫司汀、二溴甘露醇、美法仑、达卡巴嗪、雷莫司汀、卡莫司汀、洛莫司汀、链脲霉素、替莫唑胺、丙卡巴肼、乙烯亚胺衍生物、甲烷磺酸酯类、亚硝脲类、三氮烯类中的一种或多种。
本发明中,所述拓扑酶I/II抑制剂可选自但不限于:多柔比星、柔红霉素、表柔比星、依达比星、伊立替康、拓扑替康、鲁比替康、贝洛替康、依托泊苷、提尼泊苷、阿霉素和右雷佐生、喜树碱中的一种或多种。
本发明中,所述抗有丝***剂包括但不限于:紫杉醇、多西紫杉醇、聚谷氨酸紫杉醇、异长春碱、长春新碱、长春碱、长春地辛、长春利定、依托泊苷、替尼泊苷、伊沙匹隆、拉洛他塞、ortataxel、tesetaxel、tocosal和伊斯平斯中的一种或多种。
本发明中,所述抗代谢类药物可选自但不限于:叶酸拮抗剂、嘧啶类似物、嘌呤类似物、腺苷脱氨酶抑制剂,例如:甲氨蝶呤、5-氟尿嘧啶、氟脲苷、阿糖胞苷、6-巯基嘌呤、6-硫鸟嘌呤、磷酸氟达拉滨、喷司他丁和吉西他滨中的一种或多种。
本发明中,所述激素治疗剂可选自但不限于:磷雌酚、己烯雌酚、氯烯雌酚、醋酸甲羟孕酮、醋酸甲地孕酮、醋酸氯地孕酮、醋酸环丙孕酮、达那唑、地诺孕素、烯丙雌醇、孕三烯酮、诺美孕酮、通尿灵、美帕曲星、雷洛昔芬、奥美昔芬、佐美洛昔芬、安鲁米特、睾内酯、抗***类、LH-RH衍生物、芳香酶抑制剂、抗雄激素类、肾上腺皮质激素类、雄激素合成抑制剂、维甲酸和延迟维甲酸代谢的药物中的一种或多种。
本发明中,所述抗肿瘤抗生素包括但不限于:放线菌素D、多柔比星、柔红霉素、博来霉素、培洛霉素、丝裂霉素C、阿柔比星、吡柔比星、表柔比星、净司他丁斯酯、伊达比星、西罗莫司和戊柔比星中的一种或多种。
本发明中,所述小分子激酶抑制剂包括但不限于:厄洛替尼、伊马替尼、阿帕替尼、尼洛替尼、克唑替尼、达沙替尼、帕唑帕尼、瑞格菲尼、鲁索利替尼、索拉菲尼、苏尼替尼、凡德他尼、维罗非尼、博舒替尼、吉非替尼、阿法替尼、阿昔替尼、达拉菲尼、达克替尼、尼达尼布、乐伐替尼、马赛替尼、米哚妥林、来那替尼、帕纳替尼、雷多替尼、曲美替尼、丙氨酸布立尼布、西地尼布、苹果酸卡博替尼、依鲁替尼、埃克替尼、西帕替尼、考比替尼和艾代拉利司中的一种或多种。
本发明中,所述单克隆抗体包括但不限于:阿伦单抗、本妥昔单抗、西妥昔单抗、利妥昔单抗、地诺单抗、依匹单抗、奥法木单抗、帕尼单抗、托西莫单抗、曲妥单抗、贝伐珠单抗、帕妥珠单抗、卡妥索单抗、埃洛妥珠单抗、依帕珠单抗、耐昔妥珠单抗、尼妥珠单抗、托珠单抗、马托珠单抗、扎鲁木单抗、阿托珠单抗、雷莫芦单抗和纳武单 抗中的一种或多种。
本发明中,所述小分子免疫调节剂包括但不限于:TLR7激动剂、TLR8激动剂、TLR9激动剂、IDO抑制剂、CD73抑制剂、STING抑制剂、A2AR拮抗剂、PD-L1抑制剂中的一种或多种。
本发明中,所述用于癌症治疗的干扰素包括但不限于:干扰素α、干扰素α-2a、干扰素α-2b、干扰素β、干扰素γ-1a或干扰素γ-n1等。
本发明中,所述放疗是本领域熟知的并且包括X射线的治疗,例如伽马放射、放射药物治疗等。
本发明中,所述癌症包括转移性的和非转移性的癌症,也包括家族遗传性的和偶发性的癌症,还可包括固体肿瘤和非固体肿瘤。
本发明中,所述固体肿瘤的具体例子可包括但不限于:眼癌、骨癌、肺癌、胃癌、胰腺癌、胰岛细胞癌、乳腺癌、三阴性乳腺癌、***癌、趋势抵抗性***癌、脑癌(包括噁性胶质瘤、成神经管细胞瘤)、CNS癌、成胶质细胞瘤、卵巢癌、膀胱癌、尿路上皮癌、子***、睾丸癌、肾癌(包括腺癌和肾母细胞癌)、口腔癌(包括鳞状细胞癌)、舌癌、喉癌、鼻咽癌、头颈癌、结肠癌、小肠癌、直肠癌、结直肠癌、甲状旁腺癌、甲状腺癌、食管癌、胆囊癌、胆管癌、***、肝癌、肝细胞癌、肺癌、非小细胞肺癌、肉瘤、平滑肌肉瘤、成肌细胞瘤、肌瘤、横纹肌瘤、神经节瘤、神经上皮瘤、神经母细胞瘤、皮肤癌、黑色素瘤、恶性类癌综合症、类癌心脏病中的一种或多种。
本发明中,所述非固体肿瘤(包括血液学肿瘤)的具体例子可包括但不限于:B细胞淋巴瘤、T细胞淋巴瘤、弥漫性大B细胞淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、伯基特淋巴瘤、骨髓增生异常综合症、淋巴性白血病(包括成淋巴细胞白血病、淋巴瘤、骨髓瘤、多发性骨髓瘤、慢性淋巴性白血病(T细胞慢性淋巴性白血病、B细胞慢性淋巴性白血病)和髓性相关的白血病(包括急性髓性白血病、慢性髓性白血病)中的一种或多种。
本发明中,所述给与治疗有效剂量的如式I或I’所示化合物或药学上可接受的盐,所述治疗有效剂量根据各种因素而变化,例如包括所用特定化合物的活性、该化合物的代谢稳定性和作用时长、患者年龄、体重、健康状况、性别、给药方式和时间、吸收代谢特性、具体疾病或病症的严重程度等因素。“治疗有效量”是指当给与哺乳动物足以提供对于该哺乳动物中MNK1和/或MNK2相关病症或疾病的有效治疗的量。构成治疗有效量的本发明化合物的量需要根据化合物、病症以及其严重性、给药方式、待治疗哺乳动物的年龄的变化而变化,但可以由本领域技术人员根据其所掌握的知识和本发明内容来常规地确定。
本发明中,所述哺乳动物优选为人。
本发明中,除非另有说明,术语“被1~3个基团取代在任意位置”是指基团上所指定的1个、2个或3个原子的任何1个、2个或3个氢原子用所指定的基团取代,条件是不超过指定原子的正常化合价,所述取代均为本领域常见的合理取代。
本发明中,当与取代基的键合显示与连接环中两个原子的键合相交时,那么这样的取代基可键合在环上的任何可键合的环原子。
除非另有说明,在本发明说明书和权利要求书中出现的以下术语具有下述含义:
术语“烷基”是指包含1-20个碳原子的饱和直链或支链烃基,优选1-10个碳原子,更优选1-8,1-6,1-4,1-3个碳原子,烷基的代表性例子包括但不限于:甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、异丁基、戊基、己基、庚基、辛基、壬基、癸基、4,4-二甲基戊基、2,2,4-三甲基戊基、十一烷基、十二烷基,及它们的各种异构体等。
术语“氘代烷基”是指氘原子任意取代的烷基,本发明所述氘代烷基优选被氘原子全取代的烷基,例如-CD 3、-C 2D 5
术语“环烷基”是指包含3-20个碳原子的饱和或部分不饱和(包含1或2个双键)的单环或多环基团。“环烷基”优选C 3-10环烷基,更优选C 3-8单环烷基、C 3-6单环烷基,所述“单环烷基”的代表性例子包括但不限于:环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环癸基、环十二烷基、环己烯基。“多环环烷基”包括“桥环基”、“稠合环烷基”和“螺环烷基”,“桥环基”的代表性例子包括但不限于:冰片基、双环[2.2.1]庚烯基、双环[3.1.1]庚烷基、双环[2.2.1]庚烷基、双环[2.2.2]辛烷基、双环[3.2.2]壬烷基、双环[3.3.1]壬烷基、双环[4.2.1]壬烷基和金刚烷基等。“稠合环烷基”包含稠合到苯基、环烷基或杂芳基上的环烷基环,稠合环烷基包括但不限于:苯并环丁烯基、2,3-二氢-1H-茚基、5,6-二氢-4H-环戊基[B]噻吩基、十氢萘基等。“螺环烷基”是指两个单环环烷基共用一个碳原子形成的双环基团,螺环烷基包括但不限于:螺[3,3]庚基、螺[3,2]己基、螺[2,5]辛基、螺[2,4]庚基、螺[4,5]癸基等。“C 3-10环烷基”是指包含3-10个碳原子的环烷基;“C 3-8环烷基”是指包含3-8个碳原子的环烷基。“C 3-6环烷基”是指包含3-6个碳原子的环烷基。单环环烷基或多环环烷基可以通过环上任意的1个或2个碳原子链接到母体分子上。
术语“杂环烷基”指由碳原子以及选自氮、氧或硫等杂原子组成的饱和或部分不饱和(包含1或2个双键)的非芳香环状基团,此环状基团可为单环或多环基团,在本发明中,杂环烷基中杂原子个数优选1、2、3或4,杂环烷基中的氮、碳或硫原子可任选地被氧化。氮原子可任选进一步被其他基团取代而形成叔胺或季铵盐。“单环杂环烷基”优选3-10元单环杂环烷基,更优选3-8元单环杂环烷基。例如:氮丙啶基、四氢呋喃基、 吗啉-4-基、硫代吗啉基、硫代吗啉-S-氧化物-4-基、哌啶基、吡咯烷基、哌嗪基、硫杂环丁烷1-氧化物、1-氧代-硫杂环丁基等。“多环杂环烷基”包括“稠合杂环烷基”、“螺杂环基”和“桥杂环烷基”。“稠合杂环烷基”包含稠合到苯基、环烷基、杂环烷基或杂芳基的单环杂环烷基环,稠合杂环烷基包括但不限于:2,3-二氢苯并呋喃基、1,3-二氢异苯并呋喃基、二氢吲哚基、2,3-二氢苯并[b]噻吩基、二氢苯并哌喃基、1,2,3,4-四氢喹啉基、6,7-二氢-5H-吡咯并[2,3-d]嘧啶基、等。“螺杂环基”是指两个杂环烷基或一个环烷基和一个杂环烷基共用一个碳原子形成的双环基团,螺杂环基包括但不限于:5-氮杂[2.5]辛基、4-氮杂[2.5]辛基、4-氮杂[2.4]庚基等。所述9-10元杂环烷基优选为9-10元稠合杂环烷基。单环杂环烷基和多环杂环烷基可以通过环上任意的1个或2个环原子链接到母体分子上。上述环原子特指组成环骨架的碳原子和/或氮原子。
术语“环烷基烷基”是指环烷基与母核结构之间通过烷基连接。由此,“环烷基烷基”包含上述烷基和环烷基的定义。
术语“杂环烷基烷基”是指杂环烷基与母核结构之间通过烷基连接。由此,“杂环烷基烷基”包含上述烷基和杂环烷基的定义。
术语“烷氧基”指通过氧桥连接的具有所述碳原子数目的环状或者非环状烷基,包含烷基氧基、环烷基氧基和杂环烷基氧基。由此,“烷氧基”包含上述烷基、杂环烷基和环烷基的定义。
术语“烯基”指含有至少1个碳碳双键的直链、支链或者环状非芳香烃基。其中可以存在1-3个碳碳双键,优选存在1个碳碳双键。术语“C 2-4烯基”是指具有2-4个碳原子的烯基,术语“C 2-6烯基”是指具有2-6个碳原子的烯基,包括乙烯基、丙烯基、丁烯基、2-甲基丁烯基和环己烯基。
术语“炔基”是指含有至少1个碳碳三键的直链、支链或者环状烃基。其中可以存在1-3个碳碳三键,优选存在1个碳碳三键。术语“C 2-6炔基”是指具有2-6个碳原子的炔基,包括乙炔基、丙炔基、丁炔基和3-甲基丁炔基。
术语“芳基”是指任何稳定的6-20元单环或多环芳香族基团,例如:苯基、萘基、四氢萘基、2,3-二氢化茚基或联苯基等。
术语“杂芳基”是指至少1个环上的碳原子被选自氮、氧或硫的杂原子置换所形成的芳香环基团,其可为5-7元单环杂芳基或7-20稠合杂芳基。所述“稠合杂芳基”中至少有一个环为杂芳环,所述“杂芳环”优选5-6元单环杂芳基和9-12或9-10元稠合杂芳基。在本发明中,杂原子个数优选1、2或3,5-6元杂芳基的例子包括但不限于:吡啶基、嘧啶基、哌嗪基、哒嗪-3(2H)-酮基、呋喃基、噻吩基、噻唑基、吡咯基、咪唑基、吡唑基、噁唑基、异噁唑基、1,2,5-噁二唑基、1,2,4-噁二唑基、1,3,4-噁二唑基、1,3,4-噻 二唑、1,2,4-三氮唑基、1,2,3-三氮唑基、四氮唑基等;9-10元稠合杂芳基的例子包括但不限于:吲唑基、异吲唑基、吲哚基、异吲哚基、苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并噁唑基、喹啉基、异喹啉基、异喹啉酮基、喹唑啉基、7H-吡咯并[2,3-d]嘧啶基、1H-吡唑并[3,4-d]嘧啶、噻唑并[5,4-d]嘧啶、9H-嘌呤、噻唑并[4,5-d]嘧啶-2(3H)-酮基、3H-[1,2,3]三氮唑并[4,5-d]嘧啶基、5,6,7,8-四氢苯并[4,5]噻唑并[2,3-d]嘧啶基、6,7-二氢-5H-环戊烷并[4,5]噻唑并[2,3-d]嘧啶基等。
术语“芳基烷基”是指芳基与母核结构之间通过烷基连接。由此,“芳基烷基”包含上述烷基和芳基的定义。
术语“杂芳基烷基”是指杂环烷基与母核结构之间通过烷基连接。由此,“杂芳基烷基”包含上述烷基和杂芳基的定义。术语“卤素”表示氟、氯、溴或碘。
术语“卤代烷基”是指被卤素任意取代的烷基。由此,“卤代烷基”包含以上卤素和烷基的定义。
术语“卤代烷氧基”是指被卤素任意取代的烷氧基。由此,“卤代烷氧基”包含以上卤素和烷氧基的定义。
术语“酯基”是指-C(O)OR’,R’为C 1-6烷基。
术语“酰胺基”是指-C(O)N(R”) 2,R”为氢、C 1-6烷基或C 2-6烯基。
术语“羧基”是指-C(O)OH。
术语“酰基”是指-C(O)R”’,R”’为C 1-6烷基、C 2-6烯基或C 3-8环烷基。
术语“硝基”是指-NO 2
术语“氧代基”是指=O。
术语“氰基”是指-CN。
术语“羟基”是指-OH。
术语“巯基”是指-SH。
术语“氨基”是指-NH 2
术语“烷氨基”是指氨基上至少一个氢原子被烷基所取代,包括但不限于:-NHCH 3、-N(CH 3) 2、-N(CH 3)(CH 2CH 3)、-N(CH 2CH 3) 2。由此,“烷氨基”包含上述烷基和氨基的定义。
符号“=”表示双键;
本发明所述“室温”是指15-30℃。
所述的稳定的同位素衍生物包括:式I中任意的氢原子被1-5个氘原子取代得到的同位素取代衍生物(例如:R 2为CD 3)、式I中任意的碳原子被1-3个碳14原子取代得到的同位素取代衍生物或式I或I’中任意的氧原子被1-3个氧18原子取代得到的同位素取代衍生物。
所述的“前药”是指化合物在体内代谢后转换成原始活性化合物。代表性地讲,前药为非活性物质,或者比活性母体化合物活性小,但可以提供方便的操作、给药或者改善代谢特性。
本发明所述的“药学上可接受的盐”在Berge,et al.,“Pharmaceutically acceptable salts”,J.Pharm.Sci.,66,1-19(1977)中有讨论,并对药物化学家来说是显而易见,所述的盐是基本上无毒性的,并能提供所需的药代动力学性质、适口性、吸收、分布、代谢或***等。本发明所述化合物可以具有酸性基团、碱性基团或两性基团,典型的药学上可接受的盐包括通过本发明化合物和酸反应制备得到的盐,例如:盐酸盐、氢溴酸盐、硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、硝酸盐、乙酸盐、丙酸盐、癸酸盐、辛酸盐、甲酸盐、丙烯酸盐、异丁酸盐、己酸盐、庚酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、苯甲酸盐、甲基苯甲酸盐、邻苯二甲酸盐、马来酸盐、甲磺酸盐、对甲苯磺酸盐、(D,L)-酒石酸盐,柠檬酸盐,马来酸盐,(D,L)-苹果酸盐,富马酸盐,乳酸盐、三氟甲磺酸盐、萘-1-磺酸盐、扁桃酸盐、丙酮酸盐、硬脂酸盐、抗坏血酸盐、水杨酸盐。当本发明化合物含有酸性基团时,其药学上可接受的盐还可以包括:碱金属盐,例如钠或钾盐;碱土金属盐,例如钙或镁盐;有机碱盐,例如和氨、烷基氨类、羟基烷基氨类、氨基酸(赖氨酸、精氨酸)、N-甲基葡糖胺等形成的盐。
本发明所述“异构体”是指本发明的式I或I’化合物可以有不对称中心和外消旋体、外消旋混合物和单个非对映异构体,所有这些异构体,包括立体异构体、几何异构体、阻转异构体、互变异构体均包含在本发明中。在本发明中,式I或I’化合物或其盐以立体异构的形式(例如,其含有一个或多个不对称碳原子)存在时,单独的立体异构体(对映异构体和非对映异构体)以及它们的混合物包括在本发明的范围内。本发明还包括式I或I’表示的化合物或盐的单独异构体,以及与其中一个或多个手性中心反转的异构体的混合物。本发明的范围包括:立体异构体的混合物,以及纯化的对映异构体或对映异构体/非对映异构体富集的混合物。本发明包括所有对映异构体及非对应异构体所有可能的不同组合的立体异构体的混合物。本发明包括上文定义的所有具体基团的立体异构体的全部组合和子集。本发明还包括式I或I’化合物或其盐的几何异构体,所述几何异构体包括顺反异构体。本发明还包括式I或I’化合物或其盐的互变异构体,所述互变异构体是指从分子的一个原子到同一个分子的另一个原子的质子迁移。例如,当W 1为=O且R 1为H时,本发明提供如式I或I’所示化合物的互变异构体,如下所示:
Figure PCTCN2019121976-appb-000045
在不违背本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
具体实施方式
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
本发明所有化合物的结构可通过核磁共振( 1H NMR)和/或质谱检测(MS)鉴定。
1H NMR化学位移(δ)以ppm记录(10 -6)。NMR通过Bruker AVANCE-400光谱仪进行。合适的溶剂是氘代氯仿(CDCl 3),氘代甲醇(CD 3OD),氘代二甲亚砜(DMSO-d 6),四甲基硅烷作为内标(TMS)。
低分辨率质谱(MS)由Utimate 3000 HPLC-MSQ Plus MS质谱仪测定,使用Kinetex 2.6u C18 100A(50×4.6mm)LCMS-02-001,ESI源,梯度洗脱条件:95%溶剂A和5%溶剂B(小于1.5分钟或大于3分钟),然后5%溶剂A和95%溶剂B(1.5分钟到3分钟),百分数为某一溶剂占总溶剂体积的体积百分数。溶剂A:10mM的碳酸氢铵水溶液;溶剂B:乙腈。
本发明化合物及中间体的纯化可以使用常规的制备硅胶板或使用快速分离机进行分离纯化,洗脱体系可以是乙酸乙酯/石油醚体系或二氯甲烷/甲醇体系。还可以使用制备HPLC进行分离。
高效液相色谱仪(prep-HPLC)使用GilsonGX-281制备液相色谱,色谱柱为xtimate C18,10um,21.2×250mm。分离条件1:洗脱梯度,流动相B从10%到25%,洗脱时间5分钟,流动相B从25%到45%,洗脱时间15分钟,流动相A:10mM碳酸氢铵水溶液,流动相B:乙腈;分离条件2:洗脱梯度,流动相B从15%到30%,洗脱时间5分钟,流动相B从30%到50%,洗脱时间15分钟,流动相A:0.05%的盐酸水溶液,流动相B: 乙腈;分离条件3:流动相B从15%到20%,洗脱时间5分钟,流动相B从20%到40%,洗脱时间15分钟,流动相A:0.05%的盐酸水溶液,流动相B:乙腈;分离条件4:流动相B从10%到20%,洗脱时间5分钟,流动相B从20%到45%,洗脱时间15分钟,流动相A:0.05%的盐酸水溶液,流动相B:乙腈;分离条件5:流动相B从5%到10%,洗脱时间5分钟,流动相B从10%到30%,洗脱时间15分钟,流动相A:0.05%的盐酸水溶液,流动相B:乙腈;分离条件6:流动相B从10%到10%,洗脱时间5分钟,流动相B从10%到35%,洗脱时间15分钟,流动相A:0.05%的盐酸水溶液,流动相B:乙腈。检测波长:214nm、254nm和/或262nm;流速:15.0mL/分钟。
薄层硅胶板(prep-TLC)是烟台黄海HSGF254或青岛GF254硅胶板。
快速分离机(Flash柱层析)(Flash system/Cheetah TM)使用的是Agela Technologies MP200,配套使用的分离柱为Flashcolumm Silica-CS(80g),Cat No.CS140080-0。
本发明所有化合物可通过超高效液相色谱仪进行分析,超高效液相色谱仪(UPLC)使用Waters ACQUITY Hclass平台,色谱柱为:Waters ACQUITY UPLC BEH Shield RP18 2.1mm*100mm,1.7μm,流动相A:乙腈,流动相B:5mm磷酸二氢钾水溶液(用磷酸调pH值至2.5)。梯度洗脱时间15分钟,流速:0.4mL/min,检测波长:214nm&254nm;柱温:40℃;进样量1μL;梯度洗脱条件如下表1:
表1
时间(分钟) 流速相A(%) 流速相B(%)
0.00 10 90
5.00 40 60
7.00 90 10
13.00 90 10
13.10 10 90
15.00 10 90
本发明所涉及的手性化合物或中间体可通过超临界流体色谱仪(SFC)进行分离和分析。
手性拆分使用超临界流体色谱仪SFC-80(Thar,Waters),流速为80g/min,柱温为35℃。检测波长为214和/或254nM。手性拆分条件:手性柱IC 20×250mm,10um(Daicel),流动相为二氧化碳/甲醇(含有0.2%的氨甲醇溶液)=50/50,样品浓度:5mg/mL(甲醇),进样量:4mL。
本发明化合物的手性分析使用超临界流体色谱分析仪SFC Method Station(Thar,Waters),流速为4mL/min,柱温为40℃;检测波长为214和/或254nM。手性分析条件: 手性柱Cellulose-SC 4.6×100mm,5um(YMC),流动相为二氧化碳/甲醇(含有0.2%的氨甲醇溶液)=65/35。
本发明实施例中所述微波反应使用
Figure PCTCN2019121976-appb-000046
Initiator+Microwave System EU(356006)型微波反应器。本发明无特殊注明外,所有实施例中的反应均在氮气或氩气保护下进行。
本发明实施例中使用的缩写含义如下:
NaBH 4:硼氢化钠、TFA:三氟乙酸、Cs 2CO 3:碳酸铯、Boc 2O:二叔丁基二碳酸酯、DMAP:4-二甲氨基吡啶、Xantphos:4,5-双二苯基膦-9,9-二甲基氧杂蒽、Ruphos:2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯、XPhos:2-二环己基磷-2,4,6-三异丙基联苯、Pd 2(dba) 3:三(二亚苄基丙酮)二钯、THF:四氢呋喃、PE:石油醚、EtOAc:乙酸乙酯、DCM:二氯甲烷、DMF:N,N-二甲基甲酰胺、MeOH:甲醇、EtOH:乙醇、MTBE:甲基叔丁基醚、DMSO:二甲亚砜、HOBT:1-羟基苯并***、EDCI:1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐。
中间体的合成:
中间体1.1的合成
Figure PCTCN2019121976-appb-000047
步骤1:向5-溴-3-甲基吡啶-2-羧酸(50g,231mmol)的乙醇(250mL)溶液中,滴加浓硫酸(12.5mL)。反应液于95℃下搅拌过夜,减压浓缩。残留物用DCM(500mL)溶解,并用饱和碳酸钠水溶液调节pH为7。分离有机相,水相用DCM萃取。合并有机相,分别用水,饱和食盐水洗涤。无水硫酸钠干燥,过滤,滤液减压浓缩得到5-溴-3-甲基吡啶-2-甲酸乙酯(55.1g)为浅黄色油状物。m/z:[M+H] +276.0; 1H NMR(400MHz,DMSO-d 6):δ8.61(s,1H),8.12(s,1H),4.33(q,J=7.2Hz,2H),2.44(s,3H),1.31(t,J=7.2Hz,3H).
步骤2:冰浴条件下,向步骤1所得产物(55g,225mmol)的DCM(280mL)溶液中分批加入过氧化脲(37.1g,394mmol),然后缓慢滴加三氟乙酸酐(55.6mL,394mmol)。加毕,反应体系升至室温搅拌5小时。将反应液倒入冰水中,用DCM(2×200mL)萃取。合并有机相,用饱和食盐水洗涤、无水硫酸钠干燥,过滤、滤液减压浓缩得到5-溴-2-(乙氧羰基)-3-甲基吡啶1-氧化物(58g)为黄褐色油状物。m/z:[M+H] +260.0,262.0.
步骤3:向步骤2所得产物(58g,223mmol)的DMF(200mL)溶液中缓慢滴加三氟乙酸酐(55mL,390mmol)。加毕,反应体系加热至40℃搅拌1小时。将反应液倒入冰水中,有大量白色固体产生,过滤。滤饼依次用水和MTBE洗涤。滤饼真空干燥得到5-溴-3-甲基-6-氧代-1,6-二氢吡啶-2-甲酸乙酯(25g)为白色固体。m/z:[M+H] +260.0,262.0.
步骤4:将步骤3所得产物(5.6g,21.5mmol)和Cs 2CO 3(28.1g,86.1mmol)的DMF(50mL)溶液先搅拌15分钟,再向其中加入O-(二苯基氧膦基)羟胺(10g,43.1mmol)。加毕,反应体系室温搅拌2小时。向反应液中加入水(150mL),用EtOAc(50mL×4)萃取,合并有机相后依次用水和饱和食盐水洗涤、无水硫酸钠干燥,过滤,滤液减压浓缩得到1-氨基-5-溴-3-甲基-6-氧代-1,6-二氢吡啶-2-甲酸乙酯(6g,粗品)为黄色油状液体。m/z:[M+H] +275.0.
步骤5:将步骤4所得产物(500mg,粗品)和氨甲醇溶液(7mol/L,10mL)加入封管中,加热至85℃,搅拌2天。然后将反应液冷却至室温并减压浓缩,得到1-氨基-5-溴-3-甲基-6-氧代-1,6-二氢吡啶-2-甲酰胺(500mg,粗品)为黄色固体。m/z:[M+H] +246.0; 1H NMR(400MHz,DMSO-d 6):δ7.96(s,1H),7.91(s,1H),7.86(s,1H),5.85(s,2H),2.02(s,3H).
步骤6:将步骤5所得产物(400mg,粗品)和环己酮(1.6g,16.3mmol)加入至1,4-二氧六环(10mL)中,反应液在95℃下搅拌2小时,缓慢冷却至室温,反应液剧烈搅拌下向其中加入浓硫酸(0.1mL),继续搅拌1.5小时。将反应液减压浓缩,残留物用乙酸乙酯稀释,有机相分别用水和饱和食盐水洗涤、无水硫酸钠干燥,过滤,滤液减压浓缩,残留物用prep-TLC(DCM/MeOH=20/1)纯化得到7'-溴-5'-甲基螺[环己烷-1,2'-吡啶并[2,1-f][1,2,4]三嗪-4',8'(1'H,3'H)-二酮(中间体1.1,400mg)为类白色固体。m/z:[M+H] +326.0; 1H NMR(400MHz,DMSO-d 6):δ9.17(s,1H),7.92(s,1H),3.57(s,1H),2.38(s,3H),1.70-1.40(m,10H).
中间体1.2-1.6的合成
利用中间体1.1的合成方法,将步骤1中5-溴-3-甲基吡啶-2-羧酸替换为相应的取代的3,5-二溴吡啶-2-羧酸、步骤6中的环己酮替换为相应的酮得到中间体1.2-1.6:
表2
Figure PCTCN2019121976-appb-000048
Figure PCTCN2019121976-appb-000049
中间体1.8的合成
Figure PCTCN2019121976-appb-000050
步骤1:将1-氨基-5-溴-3-甲基-6-氧代-1,6-二氢吡啶-2-甲酸乙酯(300mg,1.09mmol)的丙酮(5mL)和1,4-二氧六环(10mL)溶液加入到封管中,反应体系在110℃下搅拌2天。冷却后将反应液直接浓缩得到5-溴-3-甲基-6-氧代-1-(丙-2-亚基氨基)-1,6-二氢吡啶-2-甲酸乙酯(370mg)为黄色液体。m/z:[M+H] +315.0,317.0.
步骤2:将硼氢化钠(126mg,3.33mmol)加入到步骤1所得产物(350mg,粗品)的MeOH(10mL)溶液中。反应体系室温搅拌3天。将反应液倒入水中,用乙酸乙酯(3×30mL)萃取,有机相用无水硫酸钠干燥、过滤,滤液减压浓缩得到5-溴-1-(异丙基氨基)-3-甲基-6-氧代-1,6-二氢吡啶-2-甲酸乙酯(70mg)为黄色液体。m/z:[M+H] +317.0,319.0.
步骤3:将一水合氢氧化锂(26mg,0.63mmol)加入到步骤2所得产物(50mg,0.16mmol)的MeOH/THF/水(5mL/5mL/5mL)混合溶液中。反应体系加热到50℃搅拌16小时。将反应液浓缩后倒入水中,用1N HCl调pH=5,水相用乙酸乙酯(3×30mL)萃取,有机相用无水硫酸钠干燥、过滤,滤液减压浓缩得到5-溴-1-(异丙基氨基)-3-甲基-6-氧代-1,6-二氢吡啶-2-羧酸(45mg)为黄色固体。m/z:[M+H] +289.0,291.0.
步骤4:将步骤3所得产物(45mg,0.16mmol)加到氯化亚砜(5mL)和DCM(5mL)中,反应体系加热到50℃搅拌8小时,将反应液浓缩后加入氨甲醇(5mL,7M),反应体系在室温下搅拌2小时后浓缩得到5-溴-1-(异丙基氨基)-3-甲基-6-氧代-1,6-二氢吡啶-2-甲酰胺(40mg)为棕色固体。m/z:[M+H] +288.0,290.0.
步骤5:将浓硫酸(2滴)加入到步骤4所得产物(40mg,粗品)和环己酮(136mg,1.39mmol)的1,4-二氧六环(10mL)溶液中。反应液加热到95℃搅拌16小时。冷却后将反应液浓缩,向残留物中加入水和石油醚打浆,过滤、滤饼真空干燥得到7'-溴-1'-异丙基-5'-甲基螺[环己烷-1,2'-吡啶并[2,1-f][1,2,4]三嗪-4',8'(1'H,3'H)-二酮(中间体1.8,50mg)为棕色固体。m/z:[M+H] +368.0,370.0.
中间体1.9的合成
Figure PCTCN2019121976-appb-000051
步骤1:将醋酸铜(1.98g,10.9mmol)和吡啶(1.15g,15.5mmol)加入到1-氨基-5-溴-3-甲基-6-氧代-1,6-二氢吡啶-2-甲酸乙酯(2.0g,7.27mmol)、3-硝基苯硼酸(2.43g,14.5mmol)的DCM(10mL)溶液中,反应体系在45℃下搅拌16小时。将反应体系冷却至室温后倒入水中,水相用DCM(3×30mL)萃取,合并有机相后用无水硫酸钠干燥,过滤、滤液减压浓缩,残留物用Flash柱层析(PE/EtOAc=1/1)纯化得到5-溴-3-甲基-1-((3-硝基苯基)氨基)-6-氧代-1,6-二氢吡啶-2-甲酸乙酯(700mg)为黄色固体。m/z:[M+H] +395.8.
步骤2:将一水合氢氧化锂(297mg,7.07mmol)加入到步骤1所得产物(700mg,1.77mmol)的MeOH/THF/水(3mL/3mL/3mL)混合溶液中,反应体系室温下搅拌4小时。将反应液浓缩后倒入水中,用1N盐酸调pH=3,水相用EtOAc(3×10mL)萃取,合并有机相后用无水硫酸钠干燥,过滤、滤液减压浓缩得到5-溴-3-甲基-1-((3-硝基苯基)氨基)-6-氧代-1,6-二氢吡啶-2-羧酸(650mg)为黄色固体。m/z:[M+H] +367.8.
步骤3:将步骤2所得产物(650mg,1.77mmol)加到氯化亚砜(5mL)和DCM (5mL)中,反应体系在50℃下搅拌4小时。将反应液浓缩后,加入氨甲醇溶液(7M,5mL),反应体系在室温下搅拌1小时,减压浓缩得到5-溴-3-甲基-1-((3-硝基苯基)氨基)-6-氧代-1,6-二氢吡啶-2-甲酰胺(800mg)为黄色固体。m/z:[M+H] +366.8.
步骤4:将浓硫酸(0.1mL)滴加到步骤3所得产物(400mg,1.09mmol)和环丁酮(611mg,8.72mmol)的1,4-二氧六环(10mL)溶液中,反应体系在50℃下搅拌4小时。冷却后将反应液浓缩,加入水中过滤得到固体,再用乙醇(5mL)打浆、过滤、滤饼真空干燥得到7'-溴-5'-甲基-1'-(3-硝基苯基)螺[环丁烷-1,2'-吡啶并[2,1-f][1,2,4]三嗪]-4',8'(1'H,3'H)-二酮(中间体1.9,294mg)为黄色固体。m/z:[M+H] +418.8.
中间体1.10的合成
Figure PCTCN2019121976-appb-000052
将1-氨基-5-溴-3-氯-6-氧代-1,6-二氢吡啶-2-甲酰胺(200mg,0.75mmol)和3,3-二甲基环丁酮(295mg,3.0mmol)加入到无水乙醇(5mL)中,反应体系加热至90℃,缓慢滴加浓硫酸(6滴)。该混合溶液加热搅拌4小时,有白色固体析出。减压浓缩,将固体分散到饱和碳酸氢钠水溶液中,过滤。滤饼分别用水和石油醚洗涤。滤饼真空干燥得到7'-溴-5'-氯-3,3-二甲基螺[环丁烷-1,2'-吡啶并[2,1-f][1,2,4]三嗪]-4',8'(1'H,3'H)-二酮(中间体1.10,240mg)为浅黄色固体。m/z:[M+H] +346.0,348.0; 1H NMR(400MHz,DMSO-d 6):δ9.76(s,1H),8.15(s,1H),7.33(s,1H),2.12-1.94(m,4H),1.22(s,3H),1.14(s,3H).
中间体1.11-1.14的合成
利用中间体1.10的合成方法,将3,3-二甲基环丁酮替换为相应的酮得到中间体1.11-1.14:
表3
Figure PCTCN2019121976-appb-000053
Figure PCTCN2019121976-appb-000054
中间体2.1的合成
Figure PCTCN2019121976-appb-000055
步骤1:将化合物1.4(200mg,0.6mmol),碘甲烷(445mg,3mmol)和DMF(2mL)加入封管中,反应体系在105℃下搅拌16小时。然后将反应液减压浓缩,残留物用prep-TLC(EtOAc)纯化得到7'-溴-5'-氯-1'-甲基螺[环丁烷-1,2'-吡啶并[2,1-f][1,2,4]三嗪]-4',8'(1'H,3'H)-二酮(200mg)为黄色固体。m/z:[M+H] +331.9.
步骤2:氮气保护下,将步骤1所得产物(60mg,0.18mmol),氨基甲酸叔丁酯(42mg,0.36mmol),Pd 2(dba) 3(3mg),Xantphos(3mg),XPhos(3mg),Cs 2CO 3(118mg,0.36mmol)和叔丁醇(1.6mL)的混合物在85℃下搅拌24小时。将反应液减压浓缩,残留物用prep-TLC(PE/EtOAc=1/1)纯化得到(5'-氯-1'-甲基-4',8'-二氧代-1',3',4',8'-四氢螺[环丁烷-1,2'-吡啶并[2,1-f][1,2,4]三嗪]-7'-基)氨基甲酸叔丁酯(40mg)为白色固体。m/z:[M+H] +368.9.
步骤3:冰浴条件下,向步骤2所得产物(40mg,0.11mmol)的DCM(0.3mL)溶液中滴加TFA(0.3mL),加毕,反应液室温搅拌16小时。将反应液减压浓缩,残留物用DCM稀释,加入碳酸氢钠固体调节pH=7,搅拌约20分钟,过滤,滤液减压浓缩得到7'-氨基-5'-氯-1'-甲基螺[环丁烷-1,2'-吡啶并[2,1-f][1,2,4]三嗪]-4',8'(1'H,3'H)-二酮(中间体2.1,40mg)为黄色固体。m/z:[M+H] +269.0.
中间体3.1和3.2的合成
Figure PCTCN2019121976-appb-000056
将1-氨基-5-溴-3-氯-6-氧代-1,6-二氢吡啶-2-甲酰胺(100mg,0.4mmol)、5-氯-2-戊酮(113mg,0.9mmol)和浓硫酸(1滴)加入至乙醇(1mL)中,80℃下搅拌8小时。 缓慢冷却至室温,过滤,滤饼真空干燥得到7-溴-5-氯-2-(3-氯丙基)-2-甲基-2,3-二氢-1H-吡啶并[2,1-f][1,2,4]三嗪-4,8-二酮(中间体3.1)和8-溴-6-氯-3a-甲基-2,3,3a,4-四氢-1H-吡啶并[2,1-f]吡咯并[1,2-b][1,2,4]三嗪-5,9-二酮(中间体3.2)的混合物(85mg,3.1/3.2=1/2.7)为白色固体。m/z:[M+H] +368.0,332.0.
中间体3.3的合成
Figure PCTCN2019121976-appb-000057
将1-氨基-5-溴-3-氯-6-氧代-1,6-二氢吡啶-2-甲酰胺(150mg,0.56mmol)和6-氯-2-己酮(227mg,1.69mmol)的乙醇(6mL)溶液在封管中110℃下搅拌16小时。反应液冷却至室温后浓缩,残留物用乙酸乙酯溶解,有机相用水洗,分离有机相并用无水硫酸钠干燥,过滤,滤液减压浓缩得到9-溴-7-氯-4a-甲基-1,2,3,4,4a,5-六氢二吡啶并[1,2-b:2',1'-f][1,2,4]三嗪-6,10-二酮(中间体3.3,150mg)棕色固体。m/z:[M+H] +345.8.
中间体3.4-3.6的合成
利用中间体3.3的合成方法,用1-氨基-5-溴-3-甲基-6-氧代-1,6-二氢吡啶-2-甲酰胺和相应的氯代酮反应得到中间体3.4-3.6:
表4
Figure PCTCN2019121976-appb-000058
中间体4.1的合成
Figure PCTCN2019121976-appb-000059
将1-氨基-5-溴-3-甲基-6-氧代-1,6-二氢吡啶-2-甲酰胺(100mg,0.4mmol)、乙酰丙 酸甲酯(264mg,2mmol)和浓硫酸(1滴)加入至1,4-二氧六环(1mL)中,95℃下搅拌4小时。缓慢冷却至室温,过滤,滤液减压浓缩得到8-溴-3a,6-二甲基-2,3,3a,4-四氢-1H-吡啶并[2,1-f]吡咯并[1,2-b][1,2,4]三嗪-1,5,9-三酮(中间体4.1,80mg)为黄色油状物。m/z:[M+H] +326.0.
中间体5.1的合成
Figure PCTCN2019121976-appb-000060
将1-氨基-5-溴-3-甲基-6-氧代-1,6-二氢吡啶-2-甲酰胺(60mg,0.2mmol),三氯化锑(6mg)和原乙酸三乙酯(0.6mL)置于微波管中100℃反应10分钟。将反应液冷却至室温后减压浓缩,残留物用无水乙醇(2mL)打浆,过滤,滤饼真空干燥得到7-溴-5-氯-2-甲基-3H-吡啶并[2,1-f][1,2,4]三嗪-4,8-二酮(中间体5.1,50mg)为白色固体。m/z:[M+H] +289.8.
中间体6.1的合成
Figure PCTCN2019121976-appb-000061
步骤1:冰浴条件下,将2-甲基-3-硝基-5-溴苯胺(5g,21.6mmol)的乙腈(40mL)溶液滴加到氯化亚铜(3.3g,33.5mmol)和亚硝酸叔丁酯(3.5g,33.5mmol)的乙腈(40mL)混悬液中,反应体系在30℃下搅拌过夜。将反应液倒入盐酸(0.5N)中,用EtOAc(3×150mL)萃取,合并有机相后用无水硫酸钠干燥,过滤、滤液减压浓缩,残留物用Flash柱层析(PE/EtOAc=1/1)纯化得到5-溴-1-氯-2-甲基-3-硝基苯(3.23g)为黄白色固体。 1H NMR(400MHz,DMSO-d 6):δ8.15(d,J=8.8Hz,2H),2.37(s,3H).
步骤2:80℃下,6小时内往步骤1所得产物(5g,20mmol)的吡啶(75mL)和水(50mL)的混合溶液中分批加入高锰酸钾(15.8g,100mmol),反应体系在80℃下搅拌过夜。向反应液中加入乙醇(100mL),回流30分钟后趁热过滤,滤饼用THF(3×50mL)洗涤。将合并的滤液浓缩,残留物中加入10%氢氧化钠水溶液,用EtOAc(3×80mL)萃取除去杂质。水相用1N盐酸调节pH=2后用DCM/MeOH=10/1(3×80mL)萃取,合并有机相后用无水硫酸钠干燥,过滤、减压浓缩得到4-溴-2-氯-6-硝基苯甲酸(1.56g)为类白色固体。 1H NMR(400MHz,DMSO-d 6):δ14.55(br.s,1H),8.39(d,J=5.6Hz,2H).
步骤3:往步骤2所得产物(1.96g,7mmol)中依次加入氢氧化钠水溶液(0.88N,9.8mL)、三氯化铁(0.12g,0.77mmol)和异丙醇(1.0mL),将反应体系加热至75℃,搅拌下缓慢向其中滴加80%水合肼(2.2g,35.2mmol),反应体系在75℃下搅拌2小时。冷却至室温后过滤,滤液浓缩后倒入水(10mL)中,用1N盐酸调pH=2,过滤、滤饼真空干燥后得到2-氨基-4-溴-6-氯苯甲酸(中间体6.1,1.5g)为类白色固体。m/z:[M+H] +249.8.
中间体6.2的合成
Figure PCTCN2019121976-appb-000062
步骤1:向三氯乙醛(9g,61mmol)、无水硫酸钠(35g,243mmol)和水(165mL)混合物中加入3-溴-5-氯-2-甲氧基苯胺(7.2g,30.4mmol)的DMF(75mL)溶液,随后加入浓盐酸(3.8mL),反应体系在90℃下搅拌25分钟。将盐酸羟胺(12.7g,182mmol)加入上述反应体系中并在90℃下搅拌5小时。将反应混合物冷却至室温,加水(1L)剧烈搅拌,过滤、滤饼真空干燥后得到N-(3-溴-5-氯-2-甲氧基苯基)-2-(肟基)乙酰胺(7.56g)为黄白色固体。m/z:[M+H] +307.0; 1H NMR(400MHz,DMSO-d 6):δ12.52(s,1H),9.54(s,1H),8.23(s,1H),7.81(s,1H),7.54(s,1H),3.78(s,3H).
步骤2:将浓硫酸(60mL)预热至30℃,搅拌下分批加入步骤1所得产物(7.4g,23.9mmol)并保持内温在30~50℃,加毕,反应体系在70℃下搅拌15分钟。将反应混合物缓慢倒入剧烈搅拌的碎冰(160g)和冰水(320mL)中。过滤收集析出的固体,并用冰水洗涤pH=7后真空干燥,干燥后固体用乙醇(20mL)打浆,过滤、滤饼真空干燥后得到6-溴-4-氯-7-甲氧基吲哚啉-2,3-二酮(5.59g)为橙色固体。m/z:[M+H] +289.8; 1H NMR(400MHz,DMSO-d 6):δ11.63(s,1H),7.43(s,1H),3.75(s,3H).
步骤3:冰浴条件下,向步骤2所得产物(5.6g,19.2mmol)的1,4-二氧六环溶液(84mL)中加入30%双氧水(9.8mL),然后滴加氢氧化钠水溶液(0.67N,360mL),得到的混合物缓慢升到室温并搅拌3小时。用乙酸乙酯(3×80mL)萃取除去杂质,水相用1N盐酸调节pH=2后,用乙酸乙酯(3×80mL)萃取,合并有机相后用无水硫酸钠干燥,过滤、滤液减压浓缩得到2-氨基-4-溴-6-氯-3-甲氧基苯甲酸(中间体6.2,4.58g)为黄色固体。m/z:[M+H] +279.8.
中间体6.3的合成
利用中间体6.2的合成方法,用3-溴-5-氯-2-氟苯胺(合成方法参考US20110052578A1)反应得到2-氨基-4-溴-6-氯-3-氟苯甲酸(中间体6.3)。m/z:[M+H] +267.8.
中间体6.4的合成
Figure PCTCN2019121976-appb-000063
步骤1:将2,3-二甲基-5-溴硝基苯(31.2g,132mmol)溶于DMF(150mL)中,溶液加热至100℃搅拌过夜。待冷至室温,将反应液迅速加入到预先冷却的高碘酸钠(113.2g,529mmol)溶液(DMF/水=1/1,300mL)中。反应液室温搅拌5小时,过滤。滤饼用PE/EtOAc(10/1)洗涤至无产物,滤液用PE/EtOAc(10/1)萃取。合并有机相,无水硫酸钠干燥。过滤,减压浓缩。残留物用Flash柱层析(PE/EtOAc=10/1)纯化得到4-溴-2-甲基-6-硝基苯甲醛(5.8g)为浅褐色固体。 1H NMR(400MHz,CDCl 3):δ10.28(s,1H),8.11(s,1H),7.75(s,1H),2.50(s,3H).
步骤2:将步骤1所得产物(4.8g,19.7mmol)和氯化铵(10.5g,196.7mmol)的乙醇/水(3/1,200mL)溶液加热至60℃,然后分批加入铁粉(11g,197mmol),得到的混合物搅拌2小时。过滤,滤饼用EtOAc洗涤至无产物残留,滤液用EtOAc萃取。合并有机相,分别用水,饱和食盐水洗涤,无水硫酸钠干燥。过滤,滤液减压浓缩得到2-氨基-4-溴-6-甲基苯甲醛(4.1g)为浅褐色固体。m/z:[M+H] +216.0; 1H NMR(400MHz,DMSO-d 6):δ10.24(s,1H),7.58(br.s,2H),6.91(s,1H),6.61(s,1H),2.54(s,3H).
步骤3:将亚氯酸钠(5.2g,57.46mmol)和磷酸二氢钠(6.89g,57.5mmol)溶解于水(50mL)中,然后将该溶液滴加到步骤2所得产物(4.1g,19.2mmol)和2-甲基-2-丁烯(6.72g,95.8mmol)的叔丁醇/THF(1/1,100mL)溶液中,室温搅拌过夜。用氢氧化钠水溶液(0.5M)淬灭反应,EtOAc萃取。水相再用稀盐酸(1N)调pH=6,用DCM萃取。合并DCM相,用饱和食盐水洗涤,无水硫酸钠干燥,过滤、滤液减压浓缩。残留物用DCM/PE(1/100)洗涤,过滤,滤饼真空干燥得到2-氨基-4-溴-6-甲基苯甲酸(化合物6.4,2.15g)为浅褐色固体。m/z:[M+H] +230.0.
中间体7.1的合成
Figure PCTCN2019121976-appb-000064
向2,6-二氯-4-甲基烟酰胺(2.6g,12.7mmol)和1,4-二氧六环(25mL)的混合物中加入氨水(10mL)。将反应体系密封,加热到135℃搅拌24小时。减压浓缩,残留物经Flash柱层析纯化(DCM/MeOH=50/1~20/1)得到2-氨基-6-氯-4-甲基烟酰胺(中间体7.1,660mg)为浅黄色固体。m/z:[M+H] +186.0; 1H NMR(400MHz,DMSO-d 6):δ7.80(s, 1H),7.64(s,1H),6.50(s,1H),6.17(s,2H),2.20(s,3H).
中间体8.1的合成
Figure PCTCN2019121976-appb-000065
步骤1:2-氨基-4-溴-3-甲氧基-6-甲基苯甲酸(合成方法参考US2009143353A1)(2.6g,10mmol)、HOBT(1.6g,12mmol)和EDCI(2.1g,11mmol)溶解于DMF(25mL)中,室温搅拌15分钟,冷却至0℃,滴加30%氨水(25mL),室温搅拌16小时。用乙酸乙酯萃取(50mL×3),合并有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤、滤液减压浓缩,残留物用EtOAc/PE(9/1)溶液打浆,过滤,滤饼真空干燥得到2-氨基-4-溴-3-甲氧基-6-甲基苯甲酰胺(1.2g)为淡黄色固体。m/z:[M+H] +259.0, 1H NMR(400MHz,DMSO-d 6):δ7.75(s,1H),7.59(s,1H),6.66(s,1H),4.99(br.s,2H),3.66(s,3H),2.17(s,3H).
步骤2:将步骤1所得产物(200mg,0.77mmol)和环戊酮(324mg,3.86mmol)混悬于乙醇(5mL)中,加入浓硫酸(75mg,0.77mmol),反应液95℃回流3小时,冷却至室温,过滤得到7'-溴-8'-甲氧基-5'-甲基-1'H-螺[环戊烷-1,2'-喹唑啉]-4'(3'H)-酮(中间体8.0,250mg)为灰色固体。m/z:[M+H] +259.0.
步骤3:将中间体8.0(150mg,0.46mmol)和碘甲烷(0.5mL)的DMF(3mL)溶液在封管中105℃搅拌过夜,反应液冷却至室温,加乙酸乙酯稀释,有机相用硫代硫酸钠水溶液洗涤,分离有机相并用无水硫酸钠干燥,过滤、滤液减压浓缩,残留物用Flash柱层析(PE/EtOAc=3/1)纯化得到7'-溴-8'-甲氧基-1',5'-二甲基-1'H-螺[环戊烷-1,2'-喹唑啉]-4'(3'H)-酮(中间体8.1,75mg)为白色固体。m/z:[M+H] +339.0.
中间体8.2-8.16的合成
利用中间体8.0的合成方法,用相应的取代的苯甲酸或苯甲酰胺和相应的环烷基酮或杂环烷基酮反应得到中间体8.2-8.14:
利用中间体8.1的合成方法,用相应的取代的苯甲酸或苯甲酰胺和环丁酮反应得到中间体8.15-8.16:
表5
Figure PCTCN2019121976-appb-000066
Figure PCTCN2019121976-appb-000067
Figure PCTCN2019121976-appb-000068
中间体9.1的合成
Figure PCTCN2019121976-appb-000069
步骤1:依次将Xantphos(18mg,30.2μmol)和Pd 2(dba) 3(14mg,15.2mmol)加入到N,N-二甲基-3-(哌嗪-1-基)丙-1-胺(100mg,0.302mmol)、N,N-二-Boc-2-氨基-6-氯嘧啶(156mg,0.30mmol)和碳酸铯(494mg,1.52mmol)的1,4-二氧六环(10mL)溶液中,反应体系用氮气置换三次后在95℃下搅拌3小时,冷却后加水(15mL)淬灭反应,水相用乙酸乙酯(3×10mL)萃取,合并有机相减压浓缩,残留物用prep-TLC(PE/EtOAc=1/1)纯化得N,N-二-Boc-2-氨基-6-(4-(3-(二甲基氨基)丙基)哌嗪-1-基)嘧啶(80mg)为淡棕色液体。m/z:[M+H] +465.2.
步骤2:将TFA(2mL)加入步骤1所得产物(80mg,0.172mmol)的DCM(5mL) 溶液中,反应体系室温搅拌4小时,将反应液浓缩后得6-(4-(3-(二甲基氨基)丙基)哌嗪-1-基)嘧啶-4-胺(中间体9.1,80mg)为黄色油状物。m/z:[M+H] +264.0.
化合物的合成:
实施例1:7'-((6-氨基嘧啶-4-基)氨基)-5'-甲基螺[环己烷-1,2'-吡啶并[2,1-f][1,2,4]三嗪]-4',8'(1'H,3'H)-二酮盐酸盐(化合物1-1)的合成
Figure PCTCN2019121976-appb-000070
步骤1:将中间体1.1(100mg,0.3mmol),6-氨基嘧啶-4-氨基甲酸叔丁酯(77.3mg,0.37mmol),Pd 2(dba) 3(15mg),Xantphos(15mg),Cs 2CO 3(200mg,0.61mmol)和1,4-二氧六环(2.5mL)的混合物用氮气置换3次,然后将反应体系升温至85℃搅拌3小时。将反应液减压浓缩,残留物用乙醇(2.5mL)打浆,过滤,滤饼用少量冷乙醇淋洗,滤饼真空干燥后得到(6-((5'-甲基-4',8'-二羰基-1',3',4',8'-四氢螺[环己烷-1,2'-吡啶[2,1-f][1,2,4]三嗪]-7'-基)氨基)嘧啶-4-基)氨基甲酸叔丁酯(200mg,粗品)为黄色固体。m/z:[M+H] +456.0.
步骤2:冰浴条件下,向步骤1所得产物(200mg,粗品)的DCM(1.5mL)溶液中滴加TFA(1.8mL),加毕,将反应体系缓慢升至室温并搅拌1.5小时。将反应液减压浓缩,残留物中加入饱和碳酸氢钠水溶液调节pH=7,有气泡产生并有灰色固体析出,过滤,收集固体并用prep-HPLC(分离条件2)纯化得化合物1-1(27.5mg,两步产率:26%)为淡黄色固体。m/z:[M+H] +356.0; 1H NMR(400MHz,DMSO-d 6):δ9.81(s,1H),8.98(s,1H),8.47(s,1H),7.98(br.s,3H),6.42(s,1H),2.43(s,3H),1.73-1.20(m,10H).
实施例2:7'-((7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-5'-甲基螺[环己烷-1,2'-吡啶并[2,1-f][1,2,4]三嗪]-4',8'(1'H,3'H)-二酮盐酸盐(化合物1-2)的合成
Figure PCTCN2019121976-appb-000071
将中间体1.1(50mg,0.15mmol),7H-吡咯并[2,3-d]嘧啶-4-胺(25mg,0.18mmol),Pd 2(dba) 3(10mg),Xantphos(10mg),Cs 2CO 3(100mg,0.3mmol)和1,4-二氧六环(1.2mL)的混合物用氮气置换3次,然后将反应体系升温至95℃搅拌6小时。将反应液减压浓缩,残留物用prep-HPLC(分离条件2)纯化得到化合物1-2(20mg,产率:34%)为黄色固体。m/z:[M+H] +380.0; 1H NMR(400MHz,DMSO-d 6):δ12.42(s,1H),9.75(br.s, 1H),9.03(s,1H),8.45(s,1H),8.21(s,1H),7.46(s,1H),6.89(s,1H),2.49(s,3H),1.75-1.25(m,10H).
实施例3:7'-((7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-5'-氯螺[环己烷-1,2'-吡啶并[2,1-f][1,2,4]三嗪]-4',8'(1'H,3'H)-二酮盐酸盐(化合物1-3)的合成
Figure PCTCN2019121976-appb-000072
利用化合物1-2的合成方法,将中间体1.1替换为1.2得到化合物1-3为白色固体。m/z:[M+H] +400.0; 1H NMR(400MHz,DMSO-d 6):δ12.27(s,1H),9.25(br.s,1H),9.12(s,1H),8.64(s,1H),8.51(s,1H),7.44(s,1H),6.89(s,1H),1.84-1.16(m,10H).
实施例4:7'-((7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-1',5'-二甲基螺[环己烷-1,2'-吡啶并[2,1-f][1,2,4]三嗪]-4',8'(1'H,3'H)-二酮盐酸盐(化合物1-4)的合成
Figure PCTCN2019121976-appb-000073
步骤1:将中间体1.1(50mg,0.15mmol)和碘甲烷(44mg,0.31mmol)加入到DMF(5mL)中,反应体系在封管中加热到70℃搅拌2天。将反应液倒入到EtOAc中,分别用水和饱和食盐水洗涤,分离有机相并用无水硫酸钠干燥、过滤,滤液减压浓缩,残留物用prep-TLC(DCM/MeOH=20/1)纯化得7'-溴-1',5'-二甲基螺[环己烷-1,2'-吡啶并[2,1-f][1,2,4]三嗪]-4',8'(1'H,3'H)-二酮(30mg,产率:58%)为黄色液体。m/z:[M+H] +340.0,342.0.
步骤2:依次将XPhos(4mg,8.82μmol)、Xantphos(5mg,8.82μmol)和Pd 2(dba) 3(4mg,4.41μmol)加入到步骤1所得产物(30mg,88.2μmol)、7H-吡咯并[2,3-d]嘧啶-4-胺(13mg,97.0μmol)和Cs 2CO 3(37mg,0.12mmol)的1,4-二氧六环(4mL)溶液中,反应体系用氮气置换三次,然后在110℃微波反应3小时,过滤,滤液减压浓缩,残留物用prep-HPLC(分离条件2)纯化得化合物1-4(11.3mg,产率:33%)为淡黄色固体。m/z:[M+H] +394.0; 1H NMR(400MHz,DMSO-d 6):δ12.16(br.s,1H),8.74(s,1H),8.46(s,2H),7.42(s,1H),6.79(s,1H),2.58(s,3H),2.50(3H,overlapping with solvent),2.20-1.23(m,10H).
实施例5:7'-((7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-1'-丙烯酰-5'-甲基螺[环己烷-1,2'-吡啶并[2,1-f][1,2,4]三嗪]-4',8'(1'H,3'H)-二酮盐酸盐(化合物1-5)的合成
Figure PCTCN2019121976-appb-000074
步骤1:将丙烯酰氯(1.2mL,14.8mmol)滴加到中间体1.1(0.30g,0.9mmol)的DMF(9mL)溶液中,反应体系在85℃下搅拌20分钟。冰浴下,将反应液倒入到饱和碳酸氢钠水溶液(30mL)中淬灭反应,水相用EtOAc萃取(3×15mL),合并有机相后用饱和食盐水洗涤、无水硫酸钠干燥,过滤,滤液减压浓缩,残留物用prep-TLC(PE/EtOAc=1/2)纯化得到1'-丙烯酰-7'-溴-5'-甲基螺[环己烷-1,2'-吡啶并[2,1-f][1,2,4]三嗪]-4',8'(1'H,3'H)-二酮(250mg,产率:71%)为淡黄色固体。m/z:[M+H] +380.0.
步骤2:依次将Ru-phos(6mg,13.2μmol)和Pd 2(dba) 3(6.0mg,6.6mmol)加入到步骤1所得产物(50mg,0.13mmol)、7H-吡咯并[2,3-d]嘧啶-4-胺(27mg,0.20mmol)和叔丁醇钠(16mg,0.17mmol)的甲苯(3mL)溶液中,反应体系用氮气置换三次后在105℃下搅拌3小时,冷却后加水(15mL)淬灭反应,水相用乙酸乙酯(3×10mL)萃取,合并有机相减压浓缩,残留物用prep-HPLC(分离条件2)纯化得化合物1-5(0.65mg,产率:1%)为淡黄色固体。m/z:[M+H] +434.1; 1H NMR(400MHz,DMSO-d 6):δ12.06(br.s,1H),9.31(s,1H),8.77(s,1H),8.73(s,1H),8.49(s,1H),7.39(s,1H),6.86(s,1H),6.29-6.21(m,1H),6.10-6.01(m,1H),5.79-5.73(m,1H),3.03-2.97(m,1H),2.50(overlapping with solvent,3H),1.89-1.27(m,9H)。
实施例6:7'-((7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-5'-氯-1'-甲基螺[环己烷-1,2'-吡啶并[2,1-f][1,2,4]三嗪]-4',8'(1'H,3'H)-二酮盐酸盐(化合物1-6)的合成
Figure PCTCN2019121976-appb-000075
利用化合物1-4的合成方法,将中间体1.1替换为1.2得到化合物1-6为淡黄色固体。m/z:[M+H] +414.0; 1H NMR(400MHz,DMSO-d 6):δ12.18(s,1H),9.02(s,1H),8.93(s,1H),8.72(s,1H),8.51(s,1H),7.43(s,1H),6.85(s,1H),2.61(s,3H),1.65-1.27(m,10H).
实施例7:7'-((7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-5'-氯螺[环戊烷-1,2'-吡啶并[2,1-f][1,2,4]三嗪]-4',8'(1'H,3'H)-二酮盐酸盐(化合物1-7)的合成
Figure PCTCN2019121976-appb-000076
利用化合物1-2的合成方法,将中间体1.1替换为1.3得到化合物1-7为淡黄色固体。m/z:[M+H] +386.0; 1H NMR(400MHz,DMSO-d 6):δ12.24(s,1H),9.30(s,1H),9.20(br.s,1H),8.66(s,1H),8.51(s,1H),7.43(s,1H),6.88(s,1H),1.84-1.70(m,8H).
实施例8:7'-((7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-1'-乙基-5'-甲基螺[环己烷-1,2'-吡啶并[2,1-f][1,2,4]三嗪]-4',8'(1'H,3'H)-二酮盐酸盐(化合物1-8)的合成
Figure PCTCN2019121976-appb-000077
利用化合物1-4的合成方法,将碘甲烷替换为碘乙烷得到化合物1-8为淡黄色固体。m/z:[M+H] +408.0; 1H NMR(400MHz,DMSO-d 6):δ12.49(br.s,1H),9.83(br.s,1H),8.81(s,1H),8.47(s,1H),8.23(br.s,1H),7.47(s,1H),6.91(s,1H),3.31-3.17(m,1H),2.90-2.78(m,1H),2.48(s,3H),2.00-1.89(m,1H),1.79-1.44(m,6H),1.38-1.20(m,3H),0.97(t,J=7.2Hz,3H).
实施例9:7'-((7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-5'-氯螺[环丁烷-1,2'-吡啶并[2,1-f][1,2,4]三嗪]-4',8'(1'H,3'H)-二酮盐酸盐(化合物1-9)的合成
Figure PCTCN2019121976-appb-000078
利用化合物1-2的合成方法,将中间体1.1替换为1.4得到化合物1-9为淡黄色固体。m/z:[M+H] +372.0; 1H NMR(400MHz,DMSO-d 6):δ12.28(s,1H),9.58(s,1H),9.31(br.s,1H),8.62(s,1H),8.51(s,1H),7.45(s,1H),6.90(s,1H),2.24-2.16(m,4H),1.90-1.75(m,2H).
实施例10:7-((7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-5-氯-2,2-二甲基-2,3-二氢-1H-吡啶并[2,1-f][1,2,4]三嗪-4,8-二酮盐酸盐(化合物1-10)的合成
Figure PCTCN2019121976-appb-000079
利用化合物1-2的合成方法,将中间体1.1替换为1.5得到化合物1-10为白色固体。m/z:[M+H] +360.0; 1H NMR(400MHz,DMSO-d 6):δ12.29(br.s,1H),9.40(br.s,1H),9.17(s,1H),8.64(s,1H),8.51(s,1H),7.44(s,1H),6.90(s,1H),1.36(s,6H).
实施例11:7'-((6-氨基-5-氟嘧啶-4-基)氨基)-5'-氯螺[环丁烷-1,2'-吡啶并[2,1-f][1,2,4]三嗪]-4',8'(1'H,3'H)-二酮盐酸盐(化合物1-11)的合成
Figure PCTCN2019121976-appb-000080
利用化合物1-1的合成方法,用中间体1.4和(6-氨基-5-氟嘧啶-4-基)氨基甲酸叔丁酯反应得到化合物1-11为淡黄色固体。m/z:[M+H] +366.0; 1H NMR(400MHz,DMSO-d 6):δ9.51(s,1H),8.42(s,1H),8.20(s,1H),8.09(s,1H),7.35-7.05(m,3H),2.25-2.10(m,3H),2.05-1.95(m,1H),1.88-1.70(m,2H).
实施例12:7'-((7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-5'-氯-1'-甲基螺[环戊烷-1,2'-吡啶并[2,1-f][1,2,4]三嗪]-4',8'(1'H,3'H)-二酮盐酸盐(化合物1-12)的合成
Figure PCTCN2019121976-appb-000081
利用化合物1-4的合成方法,将中间体1.1替换为1.3得到化合物1-12为淡黄色固体。m/z:[M+H] +400.0; 1H NMR(400MHz,DMSO-d 6):δ12.37(br.s,1H),9.58(br.s,1H),9.25(s,1H),8.64-8.45(m,2H),7.46(s,1H),6.92(s,1H),2.66(s,3H),2.01-1.55(m,8H).
实施例13:7'-((7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-1'-异丙基-5'-甲基螺[环己烷-1,2'-吡啶并[2,1-f][1,2,4]三嗪]-4',8'(1'H,3'H)-二酮盐酸盐(化合物1-13)的合成
Figure PCTCN2019121976-appb-000082
依次将XPhos(6mg,13.6μmol)、Xantphos(8mg,13.6μmol)和Pd 2(dba) 3(6mg,6.80μmol)加入到中间体1.8(50mg,136μmol)、7H-吡咯并[2,3-d]嘧啶-4-胺(22mg,163μmol)和Cs 2CO 3(66mg,0.20mmol)的1,4-二氧六环(10mL)溶液中,反应体系用氮气置换三次,然后在95℃下搅拌16小时,过滤,滤液浓缩后用prep-HPLC(分离条件2)纯化得化合物1-13(19.8mg,产率:29%)为淡黄色固体。m/z:[M+H] +422.0; 1H NMR(400MHz,DMSO-d 6):δ12.42(br.s,1H),9.45(br.s,1H),8.80(s,1H),8.47(s,1H),8.45(s,1H),7.44(t,J=2.8Hz,1H),6.88(t,J=2.4Hz,1H),2.47(overlapping with solvent,3H),2.05-1.85(m,1H),1.60-1.84(m,4H),1.45-1.55(m,2H),1.44-1.20(m,4H),1.18(d,J=6.4Hz,3H),0.90(d,J=6.4Hz,3H)。
实施例14:N-(5-氯-6-((5'-氯-4',8'-二氧代-1',3',4',8'-四氢螺[环戊烷-1,2'-吡啶并[2,1-f][1,2,4]三嗪]-7'-基)氨基)嘧啶-4-基)环丙酰胺盐酸盐(化合物1-14)的合成
Figure PCTCN2019121976-appb-000083
利用化合物1-2的合成方法,用中间体1.3和N-(6-氨基-5-氯嘧啶-4-基)环丙酰胺反应得到化合物1-14为淡黄色固体。m/z:[M+H] +464.0; 1H NMR(400MHz,DMSO-d 6):δ10.77(s,1H),9.33(s,1H),8.90(s,1H),8.69(s,1H),8.58(s,1H),7.06(br.s,1H),2.05-1.85(m,1H),1.84-1.60(m,8H),0.90-0.80(m,4H).
实施例15:7'-((7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-5'-甲基螺[环丁烷-1,2'-吡啶并[2,1-f][1,2,4]三嗪]-4',8'(1'H,3'H)-二酮盐酸盐(化合物1-15)的合成
Figure PCTCN2019121976-appb-000084
利用化合物1-2的合成方法,将中间体1.1替换为1.6得到化合物1-15为黄色固体。m/z:[M+H] +352.0; 1H NMR(400MHz,DMSO-d 6):δ12.75(br.s,1H),10.87(br.s,1H),9.60 (s,1H),8.44(s,1H),7.90(br.s,1H),7.52(s,1H),7.05(s,1H),2.44(s,3H),2.30-2.18(m,4H),1.85-1.74(m,2H).
实施例16:7'-((7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-5'-氯-1'-甲基螺[环丁烷-1,2'-吡啶并[2,1-f][1,2,4]三嗪]-4',8'(1'H,3'H)-二酮盐酸盐(化合物1-16)的合成
Figure PCTCN2019121976-appb-000085
利用化合物1-4的合成方法,将中间体1.1替换为1.4得到化合物1-16为黄色固体。m/z:[M+H] +386.0; 1H NMR(400MHz,DMSO-d 6):δ12.27(s,1H),9.46(s,1H),9.32(s,1H),8.64(s,1H),8.51(s,1H),7.45(s,1H),6.90(s,1H),2.60(s,3H),2.32(dd,J=15.0,7.6Hz,2H),2.05-1.92(m,2H),1.81(dd,J=15.2,7.6Hz,2H).
实施例17:7'-((6-氨基-5-氯嘧啶-4-基)氨基)-5'-氯螺[环戊烷-1,2'-吡啶并[2,1-f][1,2,4]三嗪]-4',8'(1'H,3'H)-二酮盐酸盐(化合物1-17)的合成
Figure PCTCN2019121976-appb-000086
将氢氧化钾(145mg,2.58mmol)加入到化合物1-14(120mg,0.26mmol)的乙醇(5mL),THF(5mL)和水(5mL)的混合溶液中,将反应体系加热到50℃搅拌16小时。将反应液减压浓缩,残留物用水打浆、过滤,得到固体用prep-HPLC(分离条件2)纯化得化合物1-17(7.8mg,产率:8%)为淡黄色固体。m/z:[M+H] +396.0; 1H NMR(400MHz,DMSO-d 6):δ9.26(s,1H),8.54(s,2H),8.23(s,1H),7.25(br.s,2H),1.81-1.23(m,6H).
实施例18:7'-((7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-1',5'-二甲基螺[环丁烷-1,2'-吡啶并[2,1-f][1,2,4]三嗪]-4',8'(1'H,3'H)-二酮盐酸盐(化合物1-18)的合成
Figure PCTCN2019121976-appb-000087
利用化合物1-4的合成方法,将中间体1.1替换为1.6得到化合物1-18为黄色固体。m/z:[M+H] +366.0; 1H NMR(400MHz,DMSO-d 6):δ12.59(s,1H),10.32(s,1H),9.37(s,1H),8.44(s,1H),8.08(s,1H),7.49(s,1H),6.98(s,1H),2.57(s,3H),2.45(s,3H),2.38-2.29 (m,2H),2.02-1.91(m,2H),1.82-1.75(m,2H).
实施例19:N-(3-(7'-((7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-5'-甲基-4',8'-二氧代-3',4'-二氢螺[环丁烷-1,2'-吡啶并[2,1-f][1,2,4]三嗪]-1'(8'H)-基)苯基)丙烯酰胺盐酸盐(化合物1-19)的合成
Figure PCTCN2019121976-appb-000088
步骤1:将铁粉(75mg,1.33mmol)加入到化合物Z-1(利用化合物2的合成方法,将中间体1.1替换为1.9得到化合物Z-1)(90mg,0.19mmol)的醋酸溶液(5mL)中,反应体系在50℃下搅拌16小时。冷却后过滤,滤液浓缩后倒入水中,用饱和碳酸氢钠水溶液调pH=7,过滤、滤饼真空干燥后得到化合物Z-2(80mg,产率:95%)为黄色固体。m/z:[M+H] +443.0.
步骤2:0℃下将丙烯酰氯(15mg,170μmol)滴加到化合物Z-2(50mg,113μmol)的DMF(2mL)溶液中,反应体系在室温下搅拌20分钟。0℃下将反应液倒入到饱和碳酸氢钠水溶液(15mL)中淬灭反应,水相用乙酸乙酯萃取(3×15mL),合并有机相并减压浓缩,残留物用prep-HPLC(分离条件2)纯化得化合物1-19(0.62mg,产率:1%)为淡黄色固体。m/z:[M+H] +497.0; 1H NMR(400MHz,DMSO-d 6):δ12.15(br.s,1H),10.24(s,1H),9.53(s,1H),9.02(br.s,1H),8.59(s,1H),8.47(s,1H),7.50-7.44(m,1H),7.39(s,2H),7.29-7.21(m,1H),6.80(s,1H),6.64-6.56(m,1H),6.45-6.34(m,1H),6.28-6.18(m,1H),5.77-5.68(m,1H),2.89-2.79(m,1H),2.54(s,3H),2.39-2.14(m,2H),2.05-1.85(m,3H).
实施例20:5'-氯-1'-甲基-7'-(噻吩并[2,3-d]嘧啶-4-基氨基)螺[环丁烷-1,2'-吡啶并[2,1-f][1,2,4]三嗪]-4',8'(1'H,3'H)-二酮盐酸盐(化合物1-20)的合成
Figure PCTCN2019121976-appb-000089
利用化合物1-4的合成方法,用中间体1.4和噻吩并[2,3-d]嘧啶-4-胺反应得到化合物1-20为黄色固体。m/z:[M+H] +403.0; 1H NMR(400MHz,DMSO-d 6):δ9.47(s,1H),9.27(s,1H),8.76(s,1H),8.72(s,1H),7.90-7.82(m,2H),2.61(s,3H),2.50-2.33(m,2H),2.00-1.95(m,2H),1.85-1.75(m,2H).
实施例21:5'-氯-7'-(噻吩并[2,3-d]嘧啶-4-基氨基)螺[环戊烷-1,2'-吡啶并[2,1-f][1,2,4]三嗪]-4',8'(1'H,3'H)-二酮盐酸盐(化合物1-21)的合成
Figure PCTCN2019121976-appb-000090
利用化合物1-2的合成方法,用中间体1.3和噻吩并[2,3-d]嘧啶-4-胺反应得到化合物1-21为淡黄色固体。m/z:[M+H] +403.0; 1H NMR(400MHz,DMSO-d 6):δ9.32(s,1H),9.24(s,1H),8.76(s,1H),8.70(s,1H),7.90-7.83(m,2H),7.55-7.33(m,1H),1.90-1.79(m,2H),1.78-1.64(m,6H).
实施例22:7'-((1H-吡唑并[3,4-d]嘧啶-4-基)氨基)-5'-氯-1'-甲基螺[环丁烷-1,2'-吡啶并[2,1-f][1,2,4]三嗪]-4',8'(1'H,3'H)-二酮盐酸盐(化合物1-22)的合成
Figure PCTCN2019121976-appb-000091
利用化合物1-4的合成方法,用中间体1.4和1H-吡唑并[3,4-d]嘧啶-4-胺反应得到化合物1-22为淡黄色固体。m/z:[M+H] +387.2; 1H NMR(400MHz,DMSO-d 6):δ13.83(br.s,1H),9.77(s,1H),9.46(s,1H),8.83(s,1H),8.63(s,1H),8.62(s,1H),2.61(s,3H),2.45-2.23(m,2H),2.03-1.92(m,2H),1.86-1.75(m,2H).
实施例23:7'-((6-氨基嘧啶-4-基)氨基)-5'-氯-1'-甲基螺[环丁烷-1,2'-吡啶并[2,1-f][1,2,4]三嗪]-4',8'(1'H,3'H)-二酮盐酸盐(化合物1-23)的合成
Figure PCTCN2019121976-appb-000092
步骤1:氮气保护下,将中间体2.1(40mg,0.15mmol),N,N-二-Boc-2-氨基-6-氯嘧啶(59mg,0.18mmol),Pd 2(dba) 3(5mg),Xantphos(5mg),XPhos(5mg),Cs 2CO 3(73mg,0.22mmol)和叔丁醇(1.5mL)的混合物在85℃下搅拌8小时。将反应液减压浓缩,残留物用prep-TLC(PE/EtOAc=1/1)纯化得到化合物X-1(60mg,产率:73%)为淡黄色固体。m/z:[M+H] +562.0.
步骤2:冰浴条件下,向化合物X-1(60mg,0.11mmol)的DCM(0.4mL)溶液中滴加TFA(0.4mL),加毕,反应液室温搅拌12小时。将反应液减压浓缩,残留物用 DCM稀释,加入碳酸氢钠固体调节pH=7,搅拌约20分钟,过滤,滤液减压浓缩,残留物用prep-HPLC(分离条件2)纯化得到化合物1-23(1.67mg,产率:4%)为黄色固体。m/z:[M+H] +362.2; 1H NMR(400MHz,DMSO-d 6):δ9.97(s,1H),9.45(s,1H),8.53(s,1H),8.32(s,1H),7.98(s,2H),6.56(s,1H),2.56(s,3H),2.40-2.27(m,2H),2.00-1.90(m,2H),1.84-1.76(m,2H).
实施例24:7'-((7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-5'-氯-3,3-二甲基螺[环丁烷-1,2'-吡啶并[2,1-f][1,2,4]三嗪]-4',8'(1'H,3'H)-二酮盐酸盐(化合物1-24)的合成
Figure PCTCN2019121976-appb-000093
利用化合物1-2的合成方法,用将中间体1.1替换为1.10得到化合物1-24为淡黄色固体。m/z:[M+H] +400.2; 1H NMR(400MHz,DMSO-d 6):δ12.18(s,1H),9.48(s,1H),9.08(br.s,1H),8.73(s,1H),8.51(s,1H),7.42(s,1H),6.92(s,1H),2.04(s,4H),1.28(s,3H),1.15(s,3H).
实施例25:7'-((7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-5'-氯-1',3,3-三甲基螺[环丁烷-1,2'-吡啶并[2,1-f][1,2,4]三嗪]-4',8'(1'H,3'H)-二酮盐酸盐(化合物1-25)的合成
Figure PCTCN2019121976-appb-000094
利用化合物1-4的合成方法,用将中间体1.1替换为1.10得到化合物1-25为淡黄色固体。m/z:[M+H] +414.2; 1H NMR(400MHz,DMSO-d 6):δ12.24(s,1H),9.39(s,1H),9.23(br.s,1H),8.69(s,1H),8.51(s,1H),7.44(s,1H),6.92(s,1H),2.59(s,3H),2.26-2.13(m,2H),1.91-1.76(m,2H),1.22(s,3H),1.15(s,3H).
实施例26:7-((7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-5-氯-2-(3-氟苯基)-2-甲基-2,3-二氢-1H-吡啶并[2,1-f][1,2,4]三嗪]-4,8-二酮盐酸盐(化合物1-26)的合成
Figure PCTCN2019121976-appb-000095
利用化合物1-2的合成方法,用将中间体1.1替换为1.11得到化合物1-26为淡黄色固体。m/z:[M+H] +440.2; 1H NMR(400MHz,DMSO-d 6):δ12.28(s,1H),9.95(s,1H),9.32(br.s,1H),8.55-8.40(m,2H),7.81(br.s,1H),7.45-7.30(m,4H),7.09(t,J=8.4Hz,1H), 6.92(s,1H),1.65(s,3H).
实施例27:7'-((6-氨基-5-氟嘧啶-4-基)氨基)-5'-氯螺[环丁烷-1,2'-吡啶并[2,1-f][1,2,4]三嗪]-4',8'(1'H,3'H)-二酮盐酸盐(化合物1-27)的合成
Figure PCTCN2019121976-appb-000096
利用化合物1-1的合成方法,用化合物1.4和(6-氨基-5-氯嘧啶-4-基)氨基甲酸叔丁酯反应得到化合物1-27为淡黄色固体。m/z:[M+H] +382.1; 1H NMR(400MHz,DMSO-d 6):δ9.54(s,1H),8.56(s,1H),8.53(s,1H),8.25(s,1H),7.36(br.s,2H),2.17(t,J=8.0Hz,4H),1.86-1.72(m,2H).
实施例28:8-((7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-6-氯-3a-甲基-2,3,3a,4-四氢-1H-吡啶并[2,1-f]吡咯并[1,2-b][1,2,4]三嗪-5,9-二酮盐酸盐(化合物1-28)的合成和实施例29:7-((7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-9-氯-3a-甲基-2,3,3a,4-四氢-1H-吡啶并[2,1-f]吡咯并[2,1-c][1,2,4]三嗪-6,10-二酮盐酸盐(化合物1-29)的合成
Figure PCTCN2019121976-appb-000097
利用化合物1-2的合成方法,用将中间体1.1替换为3.1和3.2的混合物得到化合物1-28和1-29均为淡黄色固体(prep-HPLC分离条件:3)。化合物1-28,UPLC RT=4.508min,m/z:[M+H] +386.2; 1H NMR(400MHz,DMSO-d 6):δ12.24(s,1H),9.20(br.s,1H),8.95(s,1H),8.68(s,1H),8.51(s,1H),7.44(s,1H),6.88(s,1H),3.71-3.62(m,2H),2.00-1.86(m,4H),1.31(s,3H);化合物1-29,UPLC RT=4.550min,m/z:[M+H] +386.2; 1H NMR(400MHz,DMSO-d 6):δ12.20(s,1H),9.09(br.s,1H),8.72(s,1H),8.51(s,1H),7.42(s,1H),6.89(s,1H),3.63-3.53(m,2H),2.09-1.90(m,4H),1.26(s,3H).
实施例30:8-((7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-3a,6-二甲基-2,3,3a,4-四氢-1H-吡啶并[2,1-f]吡咯并[1,2-b][1,2,4]三嗪-1,5,9-三酮(化合物1-30)的合成
Figure PCTCN2019121976-appb-000098
利用化合物1-2的合成方法,用将中间体1.1替换为4.1得到化合物1-30为淡黄色固体(prep-HPLC分离条件:1)。m/z:[M+H] +380.1; 1H NMR(400MHz,DMSO-d 6):δ12.05(s,1H),9.11(s,1H),8.78(s,1H),8.66(s,1H),8.48(s,1H),7.38(s,1H),6.85(s,1H),2.78-2.64(m,2H),2.50(overlapping,3H),2.40-2.26(m,2H),1.49(s,3H).
实施例31:7'-((6-氨基-5-(1-甲基-1H-吡唑-4-基)嘧啶-4-基)氨基)-5'-氯螺[环丁烷-1,2'-吡啶并[2,1-f][1,2,4]三嗪]-4',8'(1'H,3'H)-二酮盐酸盐(化合物1-31)的合成
Figure PCTCN2019121976-appb-000099
利用化合物1-1的合成方法,用中间体1.4和(6-氨基-5-(1-甲基-1H-吡唑-4-基)嘧啶-4-基)氨基甲酸叔丁酯反应得到化合物1-31为淡黄色固体。m/z:[M+H] +428.2; 1H NMR(400MHz,DMSO-d 6):δ12.09(s,1H),9.58(s,1H),8.61(s,1H),8.44(d,J=8.0Hz,2H),8.01(s,1H),7.64(br.s,3H),3.96(s,3H),2.22-2.00(m,4H),1.87-1.67(m,2H).
实施例32:7'-((6-氨基-5-甲氧基嘧啶-4-基)氨基)-5'-氯螺[环丁烷-1,2'-吡啶并[2,1-f][1,2,4]三嗪]-4',8'(1'H,3'H)-二酮盐酸盐(化合物1-32)的合成
Figure PCTCN2019121976-appb-000100
利用化合物1-1的合成方法,用中间体1.4和(6-氨基-5-甲氧基嘧啶-4-基)氨基甲酸叔丁酯反应得到化合物1-32为淡黄色固体。m/z:[M+H] +378.2; 1H NMR(400MHz,DMSO-d 6):δ9.56(s,1H),8.57(s,1H),8.37(s,1H),8.29(s,1H),7.70(br.s,2H),3.75(s,3H),2.54(s,1H),2.25-2.08(m,4H),1.92-1.63(m,2H).
实施例33:5'-氯-1'-( 2H 3)甲基-7'-[(7H-吡咯并[2,3-d]嘧啶-4-基)氨基]-1'H,3'H-螺[环丁烷-1,2'-吡啶并[2,1-f][1,2,4]三嗪]-4',8'-二酮盐酸盐(化合物1-33)的合成
Figure PCTCN2019121976-appb-000101
利用化合物1-4的合成方法,用中间体1.4和氘代碘甲烷为起始原料反应得到化合物1-33为黄色固体。m/z:[M+H] +389.0; 1H NMR(400MHz,DMSO-d 6):δ12.29(s,1H),9.61-9.13(m,2H),8.64(s,1H),8.51(s,1H),7.45(s,1H),6.91(s,1H),2.41-2.26(m,2H),2.09-1.91(m,2H),1.87-1.72(m,2H).
实施例34:5″-氯-7″-[(7H-吡咯并[2,3-d]嘧啶-4-基)氨基]-1″H,3″H-二螺[环丁烷-1,1'-环丁烷-3',2″-吡啶并[2,1-f][1,2,4]三嗪]-4″,8″-二酮盐酸盐(化合物1-34)的合成
Figure PCTCN2019121976-appb-000102
利用化合物1-2的合成方法,用将中间体1.1替换为1.13得到化合物1-34为淡黄色固体。m/z:[M+H] +412.2; 1H NMR(400MHz,DMSO-d 6):δ12.15(s,1H),9.44(s,1H),8.99(br.s,1H),8.76(s,1H),8.51(s,1H),7.42(s,1H),6.90(s,1H),2.27(d,J=12Hz,2H),2.20(d,J=12.4Hz,2H),2.12(t,J=7.2Hz,2H),1.98(t,J=7.2Hz,2H),1.82-1.72(m,2H).
实施例35:5″-氯-1″-甲基-7″-[(7H-吡咯并[2,3-d]嘧啶-4-基)氨基]-1″H,3″H-二螺[环丁烷-1,1'-环丁烷-3',2″-吡啶并[2,1-f][1,2,4]三嗪]-4″,8″-二酮盐酸盐(化合物1-35)的合成
Figure PCTCN2019121976-appb-000103
利用化合物1-4的合成方法,将中间体1.1替换为1.13得到化合物1-35为淡黄色固体。m/z:[M+H] +426.2; 1H NMR(400MHz,DMSO-d 6):δ12.38(s,1H),9.61(br.s,1H),9.41(s,1H),8.55(s,1H),8.52(s,1H),7.46(s,1H),6.95(s,1H),2.57(s,3H),2.44-2.30(m,2H),2.15-1.90(m,6H),1.82-1.70(m,2H).
实施例36:7'-((9H-嘌呤-6-基)氨基)-5'-氯螺[环丁烷-1,2'-吡啶并[2,1-f][1,2,4]三嗪]-4',8'(1'H,3'H)-二酮盐酸盐(化合物1-36)的合成
Figure PCTCN2019121976-appb-000104
利用化合物1-2的合成方法,用中间体1.4和9H-嘌呤-6-胺反应得到化合物1-36为淡黄色固体。m/z:[M+H] +373.0; 1H NMR(400MHz,DMSO-d 6):δ9.59(s,1H),9.14(s,1H),8.78(s,1H),8.69(s,1H),8.56(s,1H),2.32-2.09(m,4H),1.93-1.66(m,2H).
实施例37:5'-氯-1'-( 2H 3)甲基-7'-[(7H-吡咯并[2,3-d]嘧啶-4-基)氨基]-1'H,3'H-螺[环戊烷-1,2'-吡啶并[2,1-f][1,2,4]三嗪]-4',8'-二酮盐酸盐(化合物1-37)的合成
Figure PCTCN2019121976-appb-000105
利用化合物1-4的合成方法,用中间体1.3和氘代碘甲烷为起始原料反应得到化合物1-37为黄色固体。m/z:[M+H] +403.0; 1H NMR(400MHz,DMSO-d 6):δ12.41(br.s,1H),9.70(br.s,1H),9.26(s,1H),8.61-8.41(m,2H),7.46(s,1H),6.93(s,1H),2.03-1.52(m,8H).
实施例38:9-((7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-7-氯-4a-甲基-1,2,3,4,4a,5-六氢二吡啶并[1,2-b:2',1'-f][1,2,4]三嗪-6,10-二酮盐酸盐(化合物1-38)的合成
Figure PCTCN2019121976-appb-000106
利用化合物1-2的合成方法,将中间体1.1替换为3.3得到化合物1-38为黄色固体。m/z:[M+H] +400.0; 1H NMR(400MHz,DMSO-d 6):δ12.18(s,1H),9.11-8.87(m,2H),8.75(s,1H),8.52(s,1H),7.43(t,J=2.8Hz,1H),6.83(t,J=2.8Hz,1H),3.05(d,J=10.4Hz,1H)2.73-2.61(m,1H),1.94(d,J=13.6Hz,1H),1.80-1.46(m,5H),1.22(s,3H).
实施例39:5'-氯-7'-(嘧啶-4-基氨基)螺[环丁烷-1,2'-吡啶并[2,1-f][1,2,4]三嗪]-4',8'(1'H,3'H)-二酮盐酸盐(化合物1-39)的合成
Figure PCTCN2019121976-appb-000107
利用化合物1-2的合成方法,用中间体1.4和嘧啶-4-胺反应得到化合物1-39为黄色固体。m/z:[M+H] +333.0; 1H NMR(400MHz,DMSO-d 6):δ10.40(brs,1H),9.63(s,1H),9.04(s,1H),8.64(s,1H),8.53(d,J=6.4Hz,1H),7.58(d,J=6.4Hz,1H),2.19(t,J=8.0Hz,3H),2.06-1.92(m,1H),1.90-1.72(m,2H).
实施例40:5'-氯-7'-(7H-吡咯并[2,3-d]嘧啶-7-基)螺[环丁烷-1,2'-吡啶并[2,1-f][1,2,4]三嗪]-4',8'(1'H,3'H)-二酮盐酸盐(化合物1-40)的合成
Figure PCTCN2019121976-appb-000108
利用化合物1-2的合成方法,用中间体1.4和7H-吡咯并[2,3-d]嘧啶反应得到化合物1-40为黄色固体。m/z:[M+H] +357.0; 1H NMR(400MHz,DMSO-d 6):δ9.95(s,1H),9.44(s,1H),9.19(s,1H),8.28-8.18(m,2H),7.10(d,J=3.6Hz,1H),2.26(t,J=8.0Hz,4H),1.91-1.67(m,2H).
实施例41:8-((7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-3a,6-二甲基-2,3,3a,4-四氢-1H-吡啶并[2,1-f]吡咯并[1,2-b][1,2,4]三嗪-5,9-二酮盐酸盐(化合物1-41)的合成
Figure PCTCN2019121976-appb-000109
利用化合物1-2的合成方法,将中间体1.1替换为3.4得到化合物1-41为淡黄色固体。m/z:[M+H] +366.0; 1H NMR(400MHz,DMSO-d 6):δ12.54(s,1H),10.12(br.s,1H),8.85(s,1H),8.45(s,1H),8.14(s,1H),7.48(s,1H),6.94(s,1H),3.64(overlapping with the solvent,1H),2.80-2.70(m,1H),2.50(overlapping with the solvent,3H),2.26-2.11(m,1H),1.93(br.s,3H),1.29(s,3H).
实施例42:7-((7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-5-氯-2-环丁基-2-甲基-2,3-二氢-1H-吡啶并[2,1-f][1,2,4]三嗪]-4,8-二酮盐酸盐(化合物1-42)的合成
Figure PCTCN2019121976-appb-000110
利用化合物1-2的合成方法,将中间体1.1替换为1.12得到化合物1-42为淡黄色固 体。m/z:[M+H] +400.0; 1H NMR(400MHz,DMSO-d 6):δ12.12(s,1H),9.12(s,1H),8.85(s,1H),8.75(s,1H),8.50(s,1H),7.40(s,2H),6.85(s,1H),2.54(s,3H),1.88-1.54(m,8H).
实施例43:7-((7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-5-氯-2-甲基-3H-吡啶并[2,1-f][1,2,4]三嗪]-4,8-二酮盐酸盐(化合物1-43)的合成
Figure PCTCN2019121976-appb-000111
利用化合物1-2的合成方法,将中间体1.1替换为5.1得到化合物1-43为淡黄色固体。m/z:[M+H] +344.0; 1H NMR(400MHz,DMSO-d 6+CD 3OD):δ8.97(s,1H),8.50(s,1H),7.39(s,1H),6.80(s,1H),2.17(s,3H).
实施例44:7'-((4-氨基-1,3,5-三嗪-2-基)氨基)-5'-氯螺[环丁烷-1,2'-吡啶并[2,1-f][1,2,4]三嗪]-4',8'(1'H,3'H)-二酮盐酸盐(化合物1-44)的合成
Figure PCTCN2019121976-appb-000112
利用化合物1-2的合成方法,用中间体1.4和2,4-二氨基-1,3,5-三嗪反应得到化合物1-44为淡黄色固体。m/z:[M+H] +349.0; 1H NMR(400MHz,DMSO-d 6):δ9.57(br.s,1H),8.68-8.47(m,2H),8.44(s,1H),8.39(s,1H),8.07(br.s,1H),7.95(br.s,1H),7.84(s,1H),2.18(t,J=8.4Hz,4H),1.89-1.69(m,2H).
实施例45:9-((6-氨基嘧啶-4-基)氨基)-7-氯-4a-甲基-1,2,3,4,4a,5-六氢二吡啶并[1,2-b:2',1'-f][1,2,4]三嗪-6,10-二酮盐酸盐(化合物1-45)的合成
Figure PCTCN2019121976-appb-000113
利用化合物1-1的合成方法,将中间体1.1替换为3.3得到化合物1-45为黄色固体。m/z:[M+H] +376.0, 1H NMR(400MHz,DMSO-d 6)δ9.98(s,1H),9.06(s,1H),8.56(s,1H),8.32(s,2H),8.09(br.s,2H),6.58(s,1H),3.01(d,J=10.0Hz,1H),2.64(t,J=11.2Hz,1H),1.93(d,J=14.0Hz,1H),1.77-1.44(m,5H),1.19(s,3H).
实施例46:5″-氯-7″-[(7H-吡咯并[2,3-d]嘧啶-4-基)氨基]-1″H,3″H-二螺[环丙烷-1,1'-环丁烷-3',2″-吡啶并[2,1-f][1,2,4]三嗪]-4″,8″-二酮盐酸盐(化合物1-46)的合成
Figure PCTCN2019121976-appb-000114
利用化合物1-2的合成方法,用将中间体1.1替换为1.14得到化合物1-46为淡黄色固体。m/z:[M+H] +398.0; 1H NMR(400MHz,DMSO-d 6):δ12.14(s,1H),9.67(s,1H),8.97(s,1H),8.78(s,1H),8.50(s,1H),7.42(s,1H),6.89(s,1H),2.47-2.23(m,4H),0.58-0.44(m,4H).
实施例47:8-((6-氨基嘧啶-4-基)氨基)-6-氯-3a-甲基-2,3,3a,4-四氢-1H-吡啶并[2,1-f]吡咯烷[1,2-b][1,2,4]三嗪-5,9-二酮盐酸盐(化合物1-47)的合成
Figure PCTCN2019121976-appb-000115
利用化合物1-1的合成方法,将中间体1.1替换为3.2得到化合物1-47为黄色固体。m/z:[M+H] +362.0; 1H NMR(400MHz,DMSO-d 6):δ10.00(s,1H),8.96(s,1H),8.55(s,1H),8.33(s,1H),8.03(s,2H),6.58(s,1H),1.93(s,4H),1.28(s,2H).
实施例48:8-((7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-6-甲基-3a-苯基-2,3,3a,4-四氢-1H-吡啶并[2,1-f]吡咯烷[1,2-b][1,2,4]三嗪-5,9-二酮盐酸盐(化合物1-48)的合成
Figure PCTCN2019121976-appb-000116
利用化合物1-2的合成方法,用将中间体1.1替换为3.6得到化合物1-48为淡黄色固体。m/z:[M+H] +428.0; 1H NMR(400MHz,DMSO-d 6):δ12.51(br.s,1H),9.99(s,1H),9.68(s,1H),8.41(s,1H),8.05(br.s,1H),7.49(t,J=8.0Hz,3H),7.32(t,J=7.6Hz,2H),7.24(t,J=7.2Hz,1H),6.93(s,1H),3.89(d,J=7.6Hz,1H),2.99(q,J=8.4Hz,1H),2.37(s,4H),2.15-2.04(m,2H),2.02-1.90(m,1H).
实施例49:9-((7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-4a,7-二甲基-1,2,3,4,4a,5-六氢二吡啶并[1,2-b:2',1'-f][1,2,4]三嗪-6,10-二酮盐酸盐(化合物1-49)的合成
Figure PCTCN2019121976-appb-000117
利用化合物1-2的合成方法,用将中间体1.1替换为3.5得到化合物1-49为淡黄色固体。m/z:[M+H] +380.0; 1H NMR(400MHz,DMSO-d 6):δ12.61(br.s,1H),10.31(br.s,1H),8.96(s,1H),8.44(d,J=1.6Hz,1H),8.07(s,1H),7.50(q,J=2.4Hz,1H),6.95(s,1H),3.08(d,J=10.8Hz,1H),2.64(t,J=10.8Hz,1H),2.49(s,3H),1.94(d,J=13.6Hz,1H),1.77-1.50(m,5H),1.19(s,3H).
实施例50:7'-(4-氨基-7H-吡咯并[2,3-d]嘧啶-7-基)-5'-氯-1'-甲基螺[环丁烷-1,2'-吡啶并[2,1-f][1,2,4]三嗪]-4',8'(1'H,3'H)-二酮盐酸盐(化合物1-50)的合成
Figure PCTCN2019121976-appb-000118
N,N-二甲基-N'-(7H-吡咯并[2,3-d]嘧啶-4-基)甲脒的合成:向4-氨基-7H-吡咯[2,3-d]嘧啶(1g,7.45mmol)的DMF(10mL)溶液中加入N,N-二甲基甲酰胺二甲基缩醛(1.07g,8.95mmol),反应体系在室温下搅拌过夜。反应混合物减压浓缩,加入DCM(30mL),用饱和食盐水洗涤、无水硫酸钠干燥,过滤、滤液减压浓缩。残留物用异丙醚打浆、过滤,滤饼干燥得到产物(0.57g)为黄色固体。m/z:[M+H] +190.0; 1H NMR(400MHz,DMSO-d 6):δ11.64(br.s,1H),8.79(s,1H),8.29(s,1H),7.22(d,J=1.6Hz,1H),6.45(d,J=1.6Hz,1H),3.16(s,3H),3.10(s,3H).
步骤1:氮气保护下,向7'-溴-5'-氯-1'-甲基螺[环丁烷-1,2'-吡啶并[2,1-f][1,2,4]三嗪]-4',8'(1'H,3'H)-二酮(100mg,301μmol)和N,N-二甲基-N'-(7H-吡咯并[2,3-d]嘧啶-4-基)甲脒(74mg,391μmol)的1,4-二氧六环(5mL)溶液中依次加入反式-1,2-环己二胺(17mg,150μmol)、碘化亚铜(27mg,150μmol)和磷酸钾(192mg,902μmol),反应体系用氮气置换三次后在90℃下搅拌过夜。反应冷却后减压浓缩,加水(15mL),用乙酸乙酯(3×15mL)萃取,合并有机相后用饱和食盐水洗涤、用无水硫酸钠干燥,过滤、滤液减压浓缩得到化合物Y-1(125mg,产率98%)为黄色固体。m/z:[M+H] +441.0.
步骤2:向化合物Y-1(125mg,284μmol)的乙醇(3mL)溶液中加入乙二胺(34mg,567μmol),反应体系在80℃下搅拌过夜。反应液减压浓缩,残留物用prep-HPLC(分离条件5)纯化得化合物1-50(49.2mg,产率:45%)为淡黄色固体。m/z:[M+H] +386.0; 1H NMR(400MHz,DMSO-d 6):δ9.77(s,1H),9.25(br.s,1H),8.55(br.s,1H),8.42(s,1H),8.08(s,1H),7.80-7.74(m,1H),7.10-7.04(m,1H),2.60(s,3H),2.40-2.27(m,2H),2.11-1.96(m,2H),1.88-1.74(m,2H).
实施例51:5'-氯-7'-((6-(4-(3-(二甲基氨基)丙基)哌嗪-1-基)嘧啶-4-基)氨基)-1'-甲基螺 [环丁烷-1,2'-吡啶并[2,1-f][1,2,4]三嗪]-4',8'(1'H,3'H)-二酮盐酸盐(化合物1-51)的合成
Figure PCTCN2019121976-appb-000119
利用化合物1-4的合成方法,将步骤1中的中间体1.1替换为1.4,步骤2中的7H-吡咯并[2,3-d]嘧啶-4-胺替换为中间体9.1反应得到化合物1-51为黄色固体。m/z:[M+H] +516.0; 1H NMR(400MHz,DMSO-d 6):δ11.59(br.s,1H),10.76(br.s,1H),9.39(s,1H),9.18(s,1H),8.56(s,1H),8.47(s,1H),6.89(s,1H),4.37(d,J=13.6Hz,2H),3.61(d,J=13.6Hz,2H),3.49(t,J=13.2Hz,2H),3.28-3.14(m,4H),3.08(d,J=10.8Hz,2H),2.76(d,J=4.8Hz,6H),2.56(s,3H),2.40-2.28(m,2H),2.25-2.13(m,2H),2.02-1.88(m,2H),1.86-1.72(m,2H).
实施例52:化合物1-28A和1-28B的制备
Figure PCTCN2019121976-appb-000120
将1g的化合物1-28通过SFC手性拆分得到化合物1-28A(430mg,手性分析RT=1.9分钟,e.e%=99.1%)和化合物1-28B(444mg,手性分析RT=2.5分钟,e.e%=98.2%),均为黄色固体。
将化合物1-28A(430mg)加入至DCM(50mL)和MeOH(5mL)的混合物溶液中,然后再加入盐酸甲醇溶液(4N,0.3mL),得到的混合物室温搅拌1小时后直接减压浓缩得到1-28A盐酸盐(428mg)为黄色固体。m/z:[M+H] +428.0; 1H NMR(400MHz,DMSO-d 6):δ12.24(s,1H),9.20(br.s,1H),8.95(s,1H),8.68(s,1H),8.51(s,1H),7.44(s,1H),6.88(s,1H),3.71-3.62(m,2H),2.00-1.86(m,4H),1.31(s,3H).
利用1-28A的盐酸盐的制备方法,用1-28B制备得到1-28B盐酸盐。m/z:[M+H] +428.0; 1H NMR(400MHz,DMSO-d 6):δ12.24(s,1H),9.20(br.s,1H),8.95(s,1H),8.68(s,1H),8.51(s,1H),7.44(s,1H),6.88(s,1H),3.71-3.62(m,2H),2.00-1.86(m,4H),1.31(s,3H).
实施例53:化合物1-38A和1-38B的制备
Figure PCTCN2019121976-appb-000121
将640mg的化合物1-38通过SFC手性拆分得到化合物1-38A(245mg,手性分析RT=1.96分钟,e.e%=100%)和化合物1-38B(244mg,手性分析RT=2.92分钟,e.e%=99.3%),均为黄色固体。
利用1-28A的盐酸盐的制备方法,用1-38A制备得到1-38A盐酸盐。m/z:[M+H] +400.0, 1H NMR(400MHz,DMSO-d 6):δ12.18(s,1H),9.11-8.87(m,2H),8.75(s,1H),8.52(s,1H),7.43(t,J=2.8Hz,1H),6.83(t,J=2.8Hz,1H),3.05(d,J=10.4Hz,1H)2.73-2.61(m,1H),1.94(d,J=13.6Hz,1H),1.80-1.46(m,5H),1.22(s,3H).
利用1-28A的盐酸盐的制备方法,用1-38B制备得到1-38B盐酸盐。m/z:[M+H] +400.0, 1H NMR(400MHz,DMSO-d 6):δ12.18(s,1H),9.11-8.87(m,2H),8.75(s,1H),8.52(s,1H),7.43(t,J=2.8Hz,1H),6.83(t,J=2.8Hz,1H),3.05(d,J=10.4Hz,1H)2.73-2.61(m,1H),1.94(d,J=13.6Hz,1H),1.80-1.46(m,5H),1.22(s,3H).
实施例54:7'-((7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-8'-甲氧基-5'-甲基-1'H-螺[环戊烷-1,2'-喹唑啉]-4'(3'H)-酮盐酸盐(化合物2-1)的合成
Figure PCTCN2019121976-appb-000122
将中间体8.7(80mg,0.25mmol),7H-吡咯并[2,3-d]嘧啶-4-胺(41mg,0.30mmol),Pd 2(dba) 3(20mg),Pd(OAc) 3(10mg),Xantphos(20mg),Xphos(20mg),Cs 2CO 3(165mg,0.51mmol)和1,4-二氧六环(3mL)的混合物置于微波反应管中,鼓吹氮气5分钟,然后微波条件下120℃搅拌8小时。将反应液减压浓缩,残留物用prep-HPLC(分离条件4)纯化,得到化合物2-1(7mg,产率:8%)为黄色固体。m/z:[M+H] +380.0; 1H NMR(400MHz,DMSO-d 6):δ12.42(s,1H),9.75(br.s,1H),9.03(s,1H),8.45(s,1H),8.21(s,1H),7.46(s,1H),6.89(s,1H),2.49(s,3H),1.75-1.25(m,10H).
实施例55:7'-((7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-5'-氯-1'H-螺[环丁烷-1,2'-喹唑啉]-4'(3'H)-酮盐酸盐(化合物2-2)的合成
Figure PCTCN2019121976-appb-000123
利用化合物2-1的合成方法,将中间体8.7替换为8.8得到化合物2-2为黄色固体。m/z:[M+H] +355.0; 1H NMR(400MHz,DMSO-d 6):δ12.08(br.s,1H),9.72(br.s,1H),8.53-8.36(m,2H),7.64-7.30(m,3H),7.17(s,1H),6.92-6.85(m,1H),2.32-2.16(m,4H),1.81-1.69(m,2H).
实施例56:7'-((7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-5'-氯-1'H-螺[环己烷-1,2'-喹唑啉]-4'(3'H)-酮盐酸盐(化合物2-3)的合成
Figure PCTCN2019121976-appb-000124
利用化合物2-1的合成方法,将中间体8.7替换为8.9得到化合物2-3为淡黄色固体。m/z:[M+H] +383.0; 1H NMR(400MHz,DMSO-d 6):δ12.10(br.s,1H),9.76(br.s,1H),8.39(s,1H),7.88(s,1H),7.51(s,1H),7.35(s,1H),7.12(s,1H),7.01(s,1H),6.87(s,1H),1.77-1.49(m,8H),1.43-1.25(m,2H).
实施例57:7'-((7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-1'H-螺[环丁烷-1,2'-吡啶并[2,3-d]嘧啶]-4'(3'H)-酮盐酸盐(化合物2-4)的合成
Figure PCTCN2019121976-appb-000125
利用化合物2-1的合成方法,将中间体8.7替换为8.10得到化合物2-4为淡黄色固体。m/z:[M+H] +322.0.
实施例58:7'-((7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-1'H-螺[环丁烷-1,2'-吡啶并[2,3-d]嘧啶]-4'(3'H)-酮盐酸盐(化合物2-5)的合成
Figure PCTCN2019121976-appb-000126
利用化合物2-1的合成方法,将中间体8.7替换为8.11得到化合物2-5为淡黄色固体。m/z:[M+H] +385.0; 1H NMR(400MHz,DMSO-d 6):δ12.20(br.s,1H),9.97(br.s,1H),8.41 (s,1H),8.16(s,1H),7.51(s,1H),7.37(s,1H),7.24(s,1H),7.15(s,1H),6.90(s,1H),3.70(overlapping with solvent,4H),1.91-1.66(m,4H).
实施例59:7'-((7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-8'-甲氧基-1',5'-二甲基-1'H-螺[环戊烷-1,2'-喹唑啉]-4'(3'H)-酮盐酸盐(化合物2-6)的合成
Figure PCTCN2019121976-appb-000127
将中间体8.1(75mg,0.22mmol),7H-吡咯并[2,3-d]嘧啶-4-胺(44mg,0.33mmol)、Pd 2(dba) 3(20mg)、Xantphos(20mg)、Xphos(20mg)、Cs 2CO 3(86mg,0.26mmol)和1,4-二氧六环(3mL)的混合物置于微波反应管中,鼓吹氮气5分钟,然后微波120℃下反应8小时。将反应液减压浓缩,残留物用prep-HPLC(分离条件3)纯化得到化合物2-6(15mg,产率:17%)为类白色固体。m/z:[M+H] +393.0; 1H NMR(400MHz,DMSO-d 6):δ12.97(s,1H),11.63(br.s,1H),8.37(s,1H),8.32(s,1H),7.50(s,1H),7.09(s,1H),6.96(br.s,1H),3.69(s,3H),2.66(s,3H),2.57(s,3H),2.00-1.60(m,8H).
实施例60:7'-((7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-8'-甲氧基-1',5'-二甲基-1'H-螺[环丁烷-1,2'-喹唑啉]-4'(3'H)-酮盐酸盐(化合物2-7)的合成
Figure PCTCN2019121976-appb-000128
利用化合物2-6的合成方法,将中间体8.0替换为8.2得到化合物2-7为棕色固体。m/z:[M+H] +379.0; 1H NMR(400MHz,DMSO-d 6):δ12.97(s,1H),11.66(s,1H),8.70(s,1H),8.33(s,1H),7.51(s,1H),7.11(s,1H),6.98(s,1H),3.75(s,3H),2.61(s,3H),2.57(s,3H),2.29-2.21(m,2H),2.14-2.05(m,2H),1.88-1.65(m,2H).
实施例61:7'-((7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-8'-甲氧基-1',5'-二甲基-1'H-螺[环己烷-1,2'-喹唑啉]-4'(3'H)-酮盐酸盐(化合物2-8)的合成
Figure PCTCN2019121976-appb-000129
利用化合物2-6的合成方法,将中间体8.0替换为8.3得到化合物2-8为类棕色固体。 m/z:[M+H] +407.0; 1H NMR(400MHz,DMSO-d 6):δ12.92(s,1H),11.45(s,1H),8.32(s,1H),8.11(s,1H),7.51(s,1H),7.10(s,1H),6.92(s,1H),3.73(s,3H),2.64(s,3H),2.58(s,3H),1.83(s,2H),1.65-1.30(m,8H).
实施例62:7'-((7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-5'-氯-8'-甲氧基-1'-甲基-1'H-螺[环丁烷-1,2'-喹唑啉]-4'(3'H)-酮盐酸盐(化合物2-9)的合成
Figure PCTCN2019121976-appb-000130
利用化合物2-6的合成方法,将中间体8.0替换为8.5得到化合物2-9为类白色固体。m/z:[M+H] +399.0; 1H NMR(400MHz,DMSO-d 6):δ12.62(br.s,1H),10.67(br.s,1H),8.84(s,1H),8.38(s,1H),7.75(br.s,1H),7.48(s,1H),6.96(s,1H),3.81(s,3H),2.63(s,3H),2.30-2.20(m,2H),2.16-2.04(m,2H),1.90-1.69(m,2H).
实施例63:7'-((7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-5'-氯-1'-甲基-1'H-螺[环戊烷-1,2'-喹唑啉]-4'(3'H)-酮盐酸盐(化合物2-10)的合成
Figure PCTCN2019121976-appb-000131
利用化合物2-6的合成方法,将中间体8.0替换为8.7得到化合物2-10为淡黄色固体。m/z:[M+H] +383.0; 1H NMR(400MHz,DMSO-d 6):δ12.20(br.s,1H),10.03(br.s,1H),8.41(s,1H),8.32(s,1H),7.59(s,1H),7.41-7.31(m,2H),6.90(s,1H),2.81(s,3H),2.00-1.90(m,2H),1.88-1.77(m,2H),1.76-1.55(m,4H).
实施例64:7'-((7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-5'-氯-1'-甲基-1'H-螺[环丁烷-1,2'-喹唑啉]-4'(3'H)-酮盐酸盐(化合物2-11)的合成
Figure PCTCN2019121976-appb-000132
利用化合物2-6的合成方法,将中间体8.0替换为8.8得到化合物2-11为黄色固体。m/z:[M+H] +369.0; 1H NMR(400MHz,DMSO-d 6):δ12.15(br.s,1H),9.91(br.s,1H),8.79(s,1H),8.42(s,1H),7.65(s,1H),7.47-7.32(m,2H),6.88(s,1H),2.94(s,3H),2.48-2.43(m,2H),2.21-2.10(m,2H),1.85-1.60(m,2H).
实施例65:7'-((7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-1',5'-二甲基-1'H-螺[环丁烷-1,2'-吡 啶[2,3-d]嘧啶]-4'(3'H)-酮盐酸盐(化合物2-12)的合成
Figure PCTCN2019121976-appb-000133
利用化合物2-6的合成方法,将中间体8.0替换为8.12得到化合物2-12为黄色固体。m/z:[M+H] +350.0.
实施例66:2-((7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-6a-甲基-6a,7,8,9-四氢吡啶并[3,2-e]吡咯并[1,2-a]嘧啶-5(6H)-酮盐酸盐(化合物2-13)的合成和实施例67:2-(4-氨基-7H-吡咯并[2,3-d]嘧啶-7-基)-6a-甲基-6a,7,8,9-四氢吡啶并[3,2-e]吡咯并[1,2-a]嘧啶-5(6H)-酮盐酸盐(化合物2-14)的合成
Figure PCTCN2019121976-appb-000134
步骤1:将2-氨基-6-氯烟酰胺(70mg,0.4mmol)和5-氯-2-戊酮(150mg,1.22mmol)的无水乙醇溶液(5mL)加热至95℃,然后缓慢滴加浓硫酸(3滴)。加毕,反应体系在95℃下搅拌过夜。将反应液倒入冰水中,有固体析出,搅拌5分钟,过滤。滤饼用石油醚洗涤,真空干燥后得到2-氯-6a-甲基-6a,7,8,9-四氢吡啶并[3,2-e]吡咯并[1,2-a]嘧啶-5(6H)-酮(60mg,产率:62%)为浅黄色固体。m/z:[M+H] +238.0; 1H NMR(400MHz,DMSO-d 6):δ8.66(s,1H),7.89(d,J=8.0Hz,1H),6.71(d,J=8.0Hz,1H),3.61-3.50(m,2H),2.15-1.92(m,4H),1.32(s,3H).
步骤2:将步骤1所得产物(60mg,0.25mmol),7H-吡咯并[2,3-d]嘧啶-4-胺(37mg,0.28mmol)、Cs 2CO 3(99mg,0.3mmol),Pd 2(dba) 3(23mg,0.025mmol),XPhos(12mg,0.025mmol)、XantPhos(15mg,0.025mmol)和1,4-二氧六环(3mL)的混合物用氮气吹扫后于100℃微波反应2小时。待冷至室温,过滤,滤饼用DCM/MeOH(10/1)洗涤。合并有机相,减压浓缩。残留物经prep-HPLC(分离条件6)纯化得到化合物2-13(12.8mg,产率:15%)和2-14(5.8mg,产率:7%),均为浅黄色固体。化合物2-13:UPLCRT=2.970min;m/z:[M+H] +336.0; 1H NMR(400MHz,DMSO-d 6):δ13.10(s,1H),12.39(br.s,1H),8.84(s,1H),8.61(s,1H),8.08(d,J=8.0Hz,1H),7.68(s,1H),7.39(s,1H),6.91(s,1H),3.97-3.87(m,1H),3.87-3.75(m,1H),2.23-2.02(m,4H),1.39(s,3H).化合物2-14:UPLCRT=3.501min;m/z:[M+H] +336.0; 1H NMR(400MHz,DMSO-d 6):δ9.37(br.s,2H),8.65(s,1H),8.52(s,1H),8.25(s,1H),8.15(d,J=8.0Hz,1H),7.84(d,J=8.0Hz,1H), 7.16(s,1H),3.73-3.64(m,2H),2.20-1.96(m,4H),1.37(s,3H).
实施例68:8-((7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-6-氯-3a-甲基-2,3,3a,4-四氢吡咯并[1,2-a]喹唑啉-5(1H)-酮盐酸盐(化合物2-15)的合成
Figure PCTCN2019121976-appb-000135
利用化合物2-13的合成方法,将2-氨基-6-氯烟酰胺替换为2-氨基-4-溴-6-氯苯甲酰胺得到化合物2-15为黄色固体。m/z:[M+H] +369.0; 1H NMR(400MHz,DMSO-d 6):δ12.08(br.s,1H),9.77(br.s,1H),8.39(s,1H),8.29(s,1H),7.42(s,1H),7.35(s,1H),7.23(s,1H),6.87(s,1H),3.46-3.41(m,2H),2.14-1.95(m,4H),1.27(s,3H).
实施例69:9-((7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-7-氯-4a-甲基-3,4,4a,5-四氢-1H-吡啶并[1,2-a]喹唑啉-6(2H)-酮盐酸盐(化合物2-16)的合成
Figure PCTCN2019121976-appb-000136
利用化合物2-13的合成方法,用2-氨基-4-溴-6-氯苯甲酰胺和6-氯-2-己酮反应得到化合物2-16为黄色固体。m/z:[M+H] +383.0; 1H NMR(400MHz,DMSO-d 6):δ12.10(br.s,1H),9.82(br.s,1H),8.40(s,1H),8.23(s,1H),7.66(s,1H),7.41-7.32(m,2H),6.86(s,1H),2.77-2.69(m,1H),2.57-2.53(m,1H),1.91-1.79(m,2H),1.76-1.44(m,4H),1.24(s,3H).
实施例70:8-((7H-吡咯[2,3-d]嘧啶-4-基)氨基)-9-甲氧基-3a,6-二甲基-2,3,3a,4-四氢吡咯并[1,2-a]喹唑啉-5(1H)-酮盐酸盐(化合物2-17)的合成
Figure PCTCN2019121976-appb-000137
利用化合物2-13的合成方法,将2-氨基-6-氯烟酰胺替换为2-氨基-4-溴-3-甲氧基-6-甲基苯甲酰胺得到化合物2-17为黄色固体。m/z:[M+H] +379.0; 1H NMR(400MHz,DMSO-d 6):δ12.91(s,1H),11.50(br.s,1H),8.30(s,1H),8.12(s,1H),7.51(s,1H),6.97(s,1H),6.88(s,1H),3.73-3.68(m,1H),3.50(overlapping with the solvent,3H),3.36-3.29(m,1H),2.59(s,3H),2.29-2.18(m,1H),2.03-1.84(m,3H),1.37(s,3H).
实施例71:9-((7H-吡咯[2,3-d]嘧啶-4-基)氨基)-10-甲氧基-4a,7-二甲基-3,4,4a,5-四氢 -1H-吡啶并[1,2-a]喹唑啉-6(2H)-酮盐酸盐(化合物2-18)的合成
Figure PCTCN2019121976-appb-000138
利用化合物2-13的合成方法,用2-氨基-4-溴-3-甲氧基-6-甲基苯甲酰胺和6-氯-2-己酮反应得到化合物2-18为黄色固体。m/z:[M+H] +393.0; 1H NMR(400MHz,DMSO-d 6):δ12.91(s,1H),11.33(s,1H),8.33(s,1H),8.23(s,1H),7.51(s,1H),7.19(s,1H),6.85(s,1H),3.76(s,3H),3.70-3.65(m,1H),3.15-3.05(m,1H),2.60(s,3H),2.02-1.91(m,1H),1.74-1.45(m,5H),1.25(s,3H).
实施例72:7'-((6-氨基嘧啶-4-基)氨基)-5'-氯-1'-甲基-1'H-螺[环丁烷-1,2'-喹唑啉]-4'(3'H)-酮盐酸盐(化合物2-19)的合成
Figure PCTCN2019121976-appb-000139
利用化合物1-1的合成方法,将中间体1.1替换为8.15得到化合物2-19为黄色固体。m/z:[M+H] +345.0; 1H NMR(400MHz,DMSO-d 6):δ10.69(s,1H),8.82(s,1H),8.50(s,1H),8.12(br.s,2H),7.22(s,1H),7.02(s,1H),6.24(s,1H),2.91(s,3H),2.46(overlapping with the solvent,2H),2.22-2.04(m,2H),1.84-1.61(m,2H).
实施例73:7'-((7H-吡咯[2,3-d]嘧啶-4-基)氨基)-1',5'-二甲基-1'H-螺[环丁烷-1,2'-喹唑啉]-4'(3'H)-酮盐酸盐(化合物2-20)的合成
Figure PCTCN2019121976-appb-000140
利用化合物2-6的合成方法,将中间体8.0替换为8.13得到化合物2-20为淡黄色固体。m/z:[M+H] +349.0; 1H NMR(400MHz,DMSO-d 6):δ12.79(s,1H),11.20(br.s,1H),8.72(s,1H),8.38(s,1H),7.49(s,1H),7.06(s,1H),7.01(s,1H),6.92(s,1H),3.93-3.83(m,1H),2.90(s,3H),2.81(d,J=8.0Hz,1H),2.60(s,3H),2.23-2.10(br.s,2H),1.86-1.73(m,1H),1.74-1.61(m,1H).
实施例74:7'-((7H-吡咯[2,3-d]嘧啶-4-基)氨基)-5'-氯-8'-氟-1'-甲基-1'H-螺[环丁烷-1,2'-喹唑啉]-4'(3'H)-酮盐酸盐(化合物2-21)的合成
Figure PCTCN2019121976-appb-000141
利用化合物2-6的合成方法,将中间体8.0替换为8.14得到化合物2-21为黄色固体。m/z:[M+H] +387.0; 1H NMR(400MHz,DMSO-d 6):δ12.30(br.s,1H),10.16(br.s,1H),8.91(s,1H),8.37(s,1H),7.86(d,J=5.6Hz,1H),7.41(s,1H),6.89(s,1H),2.63(s,3H),2.29-2.17(m,2H),2.15-2.04(m,2H),1.91-1.68(m,2H).
实施例75:7'-((6-氨基嘧啶-4-基)氨基)-5'-氯-8'-氟-1'-甲基-1'H-螺[环丁烷-1,2'-喹唑啉]-4'(3'H)-酮盐酸盐(化合物2-22)的合成
Figure PCTCN2019121976-appb-000142
利用化合物1-1的合成方法,将中间体1.1替换为8.16得到化合物2-22为黄色固体。m/z:[M+H] +362.8; 1H NMR(400MHz,DMSO-d 6):δ10.07(br.s,1H),8.85(s,1H),8.38(s,1H),8.07-7.35(m,3H),6.08(s,1H),2.61(s,3H),2.26-2.16(m,2H),2.12-2.02(m,2H),1.90-1.67(m,2H).
生物实施例
实施例1:MNK1和MNK2体外酶抑制水平测试
本实验使用ADP-Glo TM Max Assay Kit(Promega,V9101)检测反应ADP的生成量以计算化合物对酶的抑制率。实验使用的缓冲液成分为:15mM HEPES,10mM MgCl 2,20mM NaCl,1mM EGTA,0.1mg/ml牛血清蛋白,0.02%Tween-20。MNK1反应体系包括20nM MNK1(Thermo,PR9138A),100uM多肽(吉尔生化,序列:Ac-TATKSGSTTKNR-NH2),200uM ATP和不同浓度的待测化合物,DMSO的终浓度为0.33%,反应体系在室温条件下孵育60分钟。MNK2反应体系包括5nM MNK2(Thermo,PR8046A),100uM多肽(吉尔生化,序列:Ac-TATKSGSTTKNR-NH2),100uM ATP和不同浓度的待测化合物,DMSO的终浓度为0.33%。反应体系在室温条件下孵育45分钟。孵育完成后使用ADP-Glo TM Max Assay Kit检测产生的ADP并使用TECAN M1000-pro检测。实验数据通过GraphPad Prism 5软件进行分析处理以得出IC 50值。 表6
编号 MNK1IC 50(nM) MNK2IC 50(nM) 编号 MNK1IC 50(nM) MNK2IC 50(nM)
1-1 5.750 6.205 1-37 2.033 1.155
1-2 3.349 3.162 1-38 2.147 1.346
1-3 1.870 1.306 1-39 8.505 6.623
1-4 1.368 1.194 1-40 192.6 462.5
1-5 150.3 21.03 1-41 3.127 2.307
1-6 2.476 1.112 1-42 8.353 7.672
1-7 1.759 1.035 1-43 10.56 20.10
1-8 2.179 1.582 1-44 8.096 9.288
1-9 1.803 0.897 1-45 4.766 2.209
1-10 3.817 2.175 1-46 2.930 3.252
1-11 2.399 2.860 1-47 3.373 1.788
1-12 1.818 1.129 1-48 5.713 4.764
1-13 7.832 3.836 1-49 2.834 1.614
1-14 19.58 25.95 1-50 21.24 26.82
1-15 2.800 1.393 1-51 462.3 88.30
1-16 1.548 0.702 2-1 3.996 2.048
1-17 2.266 1.852 2-2 2.212 0.968
1-18 2.146 1.813 2-3 2.106 0.809
1-19 48.18 19.63 2-4 3.873 4.246
1-20 1.705 2.372 2-5 1.861 1.070
1-21 2.863 4.126 2-6 3.817 1.611
1-22 2.435 1.424 2-7 2.706 1.501
1-23 2.649 1.649 2-8 1.293 0.941
1-24 3.323 1.718 2-9 1.934 0.733
1-25 2.201 1.130 2-10 2.556 1.010
1-26 4.237 6.138 2-11 3.213 1.110
1-27 2.223 1.818 2-13 5.271 3.152
1-28 2.926 1.620 2-14 4.981 2.872
1-29 13.92 14.14 2-15 3.509 1.336
1-30 6.187 4.311 2-16 2.811 1.590
1-31 4.109 8.430 2-17 2.803 1.900
1-32 2.629 1.626 2-18 8.732 4.026
1-33 2.457 0.966 2-19 1.586 0.653
1-34 2.952 2.721 2-20 1.523 0.890
1-35 2.885 1.615 2-21 0.949 0.384
1-36 4.382 6.087 2-22 2.775 1.058
实施例2:pEIF4E细胞水平检测
通过磷酸化真核起始因子eIF4E及其他关键效应蛋白,激酶MNK1和MNK2整合了几种致癌因子和免疫信号通路,从而选择性调控细胞mRNA的稳定性和转录。
Phospho-EIF4E(Ser209)cellular assay试剂盒(Cisibo)用于测定OCI-LY7B细胞非霍奇淋巴瘤细胞中内源性EIF4E的磷酸化水平。该实验是根据制造商的实验方案进行的。简单来说,OCI-LY7细胞用50uL的2×106细胞/毫升的无血清IMDM培养基铺在96孔细胞培养板上,并在37℃培养过夜。次日,待测化合物的浓度范围是通过稀释100%DMSO,然后进一步用无血清培养基稀释来创建的。细胞加入稀释的化合物并在37℃培养3h。然后向细胞中加入4X的细胞裂解液,室温振荡30分钟。取16uL的裂解液转移至384白色浅孔板,然后加入4uL预配制的抗体混合溶液,1000rpm离心30s。用封板膜封板,室温孵育过夜。然后在TECAN M1000 Pro读板仪上使用HTRF设置进行测试。结果如下表7:
表7
编号 IC 50(nM) 编号 IC 50(nM)
1-3 5.132 1-38B 1.250
1-4 3.610 2-2 2.321
1-6 2.179 2-9 1.600
1-9 2.600 2-11 0.479
1-12 1.556 2-15 0.731
1-16 1.588 2-19 3.195
1-28 1.574 2-20 4.822
1-28B 0.690 2-21 0.682
1-38 1.410 2-22 0.934

Claims (17)

  1. 一种如式I或I’所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐;
    Figure PCTCN2019121976-appb-100001
    其中,W 1和W 2分别独立地为=O、=S、=NH、=N-OH或=N-O(C 1-6烷基);
    A 1为N或CR 5
    A 2为N或CR 5a
    A 3为N或CR 5b
    R为-NH-Cy或Cy;
    R 1为H、-OH、-NH 2、R A、-NH-R A、-NH-C(O)-R A或-O-R A
    R 2为H、CN、氘代C 1-4烷基或R B
    R 3为H、C 1-6烷基、C 2-6烯基或C 2-6炔基;所述R 3为未取代,或者选择性被1~3个R 9取代在任意位置;
    R 4为H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 6-10芳基、5-6元杂芳基、C 3-8环烷基、3-8元杂环烷基、C 6-10芳基C 1-6烷基、5-6元杂芳基C 1-6烷基、C 3-8环烷基C 1-6烷基或3-8元杂环烷基C 1-6烷基;所述R 4为未取代,或者选择性被1~3个R 9取代在任意位置;
    所述R 1、R 2、R 3和R 4分别为独立取代基,或者
    1)R 1和R 3相互连接形成3-10元杂环烷基;所述3-10元杂环烷基为未取代,或者选择性被1~3个R 9取代在任意位置;
    2)R 2和R 3相互连接形成3-10元杂环烷基;所述3-10元杂环烷基为未取代,或者选择性被1~3个R 9取代在任意位置;
    3)R 3和R 4与其共同连接的碳原子一起形成C 3-10环烷基或3-10元杂环烷基;所述C 3-10环烷基或3-10元杂环烷基为未取代,或者选择性被1~3个R 9取代在任意位置;或
    4)R 2和R 3相互连接与α键共同形成双键;
    R 5、R 5a和R 5b分别独立地为氢、卤素、氰基、C 1-4烷基、卤代C 1-4烷基、卤代C 1-4烷氧基或C 1-4烷氨基;
    Cy为5-10元杂芳环;所述Cy为未取代,或者选择性被1~3个选自卤素、-CN、-NH 2、-NHOH、-OH、-R C、-OR C、-NHR C、-NH-OR C、-NHC(O)R C、-C(O)R C和-C(O)N(R C) 2的 取代基取代在任意位置;
    每个R A独立地为C 1-8烷基、C 2-8烯基或C 2-8炔基;所述R A为未取代,或者选择性被1~3个选自卤素、-OH、-NH 2、氧代基、C 1-3烷氧基和C 1-3烷氨基的取代基取代在任意位置;
    每个R B独立地为C 1-6烷基、C 2-6烯基、C 2-6炔基、苯基、5-6元杂芳基、C 3-8环烷基、3-8元杂环烷基、-(CH 2) n-苯基、-(CH 2) n-(5-6元杂芳基)、-(CH 2) n-C 3-8环烷基或-(CH 2) n-(3-8元杂环烷基);所述R B为未取代,或者选择性被1~3个R 9取代在任意位置;
    每个R C独立地为C 1-6烷基、C 2-6烯基、C 2-6炔基、苯基、5-6元杂芳基、C 3-8环烷基、3-8元杂环烷基、-(CH 2) n-OC 1-6烷基、-(CH 2) n-苯基、-(CH 2) n-(5-6元杂芳基)、-(CH 2) n-C 3-8环烷基、-(CH 2) n-(3-8元杂环烷基)或-(3-8元杂环烷基)-C 1-6烷基;所述R C为未取代,或者选择性被1~3个R 10取代在任意位置;
    每个R 9和每个R 10分别独立地为H、-CN、-NO 2、-SH、-NH 2、-OH、-C(O)OH、-NHC(O)R a、-NHS(O) 2R a、-C(O)R a、卤素、氧代基、酯基、酰胺基、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、C 1-4烷氨基、卤代C 1-4烷基、卤代C 1-4烷氧基、-(CH 2) n-NH 2、-(CH 2) n-OH、-(CH 2) n-(C 1-4烷氨基)或-(CH 2) n-(C 1-4烷氧基);
    每个R a独立地为C 1-6烷基或C 2-6烯基;
    n为1、2、3或4。
  2. 如权利要求1所述的如式I或I’所示的化合物,其异构体、前药、稳定的同位素衍生物或药学上可接受的盐,其特征在于,R为
    Figure PCTCN2019121976-appb-100002
    Figure PCTCN2019121976-appb-100003
    其中,R 6、R 7和R 8分别独立地为H、卤素、-CN、-NH 2、-NHOH、-OH、-R C、-OR C、-NHR C、-NH-OR C、-NHC(O)R C或-NHS(O) 2R C;R 6和R 7分别为独立取代基,或者R 6和R 7相互连接形成杂芳基或杂环烷基;所述杂芳基或杂环烷基为未取代,或者选择性被1~3个选自卤素、-CN、-NH 2、-NHOH、-OH、-R C、-OR C、-NHR C、-NH-OR C、-NHC(O)R C、-C(O)R C和-C(O)N(R C) 2的取代基取代在任意位置。
  3. 如权利要求2所述的如式I或I’所示的化合物,其异构体、前药、稳定的同位素衍生物或药学上可接受的盐,其特征在于,R 6为H、F、Cl、-CN、-NH 2、-CH 3、-CF 3、-CH 2CH 3、-OCH 3、-OCH 2CH 3、-OCF 3、-O-正丙基、-O-异丙基、环丙基或1-甲基-1H-吡唑基;
    和/或,R 7为H、-NH 2、-NHR C、-NH-OR C或-NHC(O)R C
    和/或,R 8为H。
  4. 如权利要求2所述的如式I或I’所示的化合物,其异构体、前药、稳定的同位素衍生物或药学上可接受的盐,其特征在于,R为
    Figure PCTCN2019121976-appb-100004
    Figure PCTCN2019121976-appb-100005
    Figure PCTCN2019121976-appb-100006
    其中,R 11和R 12分别独立地为H、卤素、-CN、-NH 2、-NHOH、-OH、-R C、-OR C、-NHR C、-NH-OR C或-NHC(O)R C
  5. 如权利要求4所述的如式I或I’所示的化合物,其异构体、前药、稳定的同位素衍生物或药学上可接受的盐,其特征在于,R 8为H;
    和/或,R 11为H;
    和/或,R 12为H。
  6. 如权利要求1所述的如式I或I’所示的化合物,其异构体、前药、稳定的同位素衍生物或药学上可接受的盐,其特征在于,R 9为H、-NH 2、-OH、F、Cl、=O、-NHC(O)-C 2-6烯基、-C(O)-C 2-6烯基、-NHS(O) 2-C 2-6烯基、C 1-4烷基、C 1-4烷氧基、C 1-4烷氨基、卤代C 1-4烷基或卤代C 1-4烷氧基。
  7. 如权利要求1所述的如式I或I’所示的化合物,其异构体、前药、稳定的同位素衍生物或药学上可接受的盐,其特征在于,W 1为O;W 2为O;
    和/或,R 1为H、-OH、-OCH 3、-NH 2、-NH(CH 3)、-NH(CH 2CH 3)或-NH(CH 2CH=CH 2);
    和/或,R 2为H、CD 3、C 1-6烷基、C 2-6烯基、苯基、或5-6元杂芳基;所述R 2为未取代,或者选择性被1~3个选自F、Cl、-OH、-NH 2、=O、-OCH 3、-N(CH 3) 2和-NHC(O)CH=CH 2的取代基取代在任意位置;
    和/或,R 3为H、甲基或乙基;
    和/或,R 4为甲基、乙基、正丙基、异丙基、苯基、吡啶基、环丙基、环丁基、环戊基或环己基;所述R 4为未取代,或者选择性被1~2个或1个选自氟、氯、甲基和三氟甲基的取代基取代在任意位置;
    和/或,R 5为氢、卤素或C 1-4烷基;
    和/或,R 5a为H;
    和/或,R 5b为氢、卤素、C 1-4烷氧基或C 1-4烷基。
  8. 如权利要求1所述的如式I或I’所示的化合物,其异构体、前药、稳定的同位素衍生物或药学上可接受的盐,其特征在于,R 3和R 4与其共同连接的碳原子一起形成环丙基、环丁基、环戊基、环己基、2,3-二氢-1H-茚基、2,3-二氢-1H-茚基-1-酮、螺[3,2]己基、螺[3.3]庚基、四氢呋喃基、吡咯烷基、氮杂环丁基、哌啶基或1-氧代-硫杂环丁基;
    或,R 2和R 3相互连接形成5-6元杂环烷基;所述5-6元杂环烷基为未取代,或者选择性被1个=O取代在任意位置。
  9. 如权利要求1所述的如式I或I’所示的化合物,其异构体、前药、稳定的同位素衍生物或药学上可接受的盐,其特征在于,所述如式I或I’所示的化合物为式II所示的化合物,其异构体、前药、稳定的同位素衍生物或药学上可接受的盐,
    Figure PCTCN2019121976-appb-100007
    其中,R 1为H、-OH、-NH 2、R A、-NH-R A、-NH-C(O)-R A或-O-R A
    R 2为H、CN或R B
    R 3为H、C 1-6烷基、C 2-6烯基或C 2-6炔基;所述R 3为未取代,或者选择性被1~3个R 9取代在任意位置;
    R 4为H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 6-10芳基、5-6元杂芳基、C 3-8环烷基或3-8元杂环烷基;所述R 4为未取代,或者选择性被1~3个R 9取代在任意位置;
    所述R 3和R 4为独立取代基,或者R 3和R 4与其共同连接的碳原子一起形成C 3-10环烷基或3-10元杂环烷基;所述C 3-10环烷基或3-10元杂环烷基为未取代,或者选择性被1~3个R 9取代在任意位置;
    R 5为氢、卤素、氰基或C 1-4烷基;
    R 6、R 7和R 8分别独立地为H、卤素、-CN、-NH 2、-NHOH、-OH、-R C、-OR C、-NHR C、-NH-OR C、-NHC(O)R C或-NHS(O) 2R C
    R 6和R 7分别为独立取代基,或者R 6和R 7与其连接的原子一起形成杂芳基或杂环烷 基;所述杂芳基或杂环烷基为未取代,或者选择性被1~3个选自卤素、-CN、-NH 2、-NHOH、-OH、-R C、-OR C、-NHR C、-NH-OR C、-NHC(O)R C、-C(O)R C和-C(O)N(R C) 2的取代基取代在任意位置;
    每个R A独立地为C 1-8烷基、C 2-8烯基或C 2-8炔基;所述R A为未取代,或者选择性被1~3个选自卤素、-OH、-NH 2、氧代基、C 1-3烷氧基和C 1-3烷氨基的取代基取代在任意位置;
    每个R B独立地为C 1-6烷基、C 2-6烯基、C 2-6炔基、苯基、5-6元杂芳基、C 3-8环烷基、3-8元杂环烷基、-(CH 2) n-苯基、-(CH 2) n-(5-6元杂芳基)、-(CH 2) n-C 3-8环烷基或-(CH 2) n-(3-8元杂环烷基);所述R B为未取代,或者选择性被1~3个R 9取代在任意位置;
    每个R C独立地为C 1-6烷基、C 2-6烯基、C 2-6炔基、苯基、5-6元杂芳基、C 3-8环烷基、3-8元杂环烷基、-(CH 2) n-OC 1-6烷基、-(CH 2) n-苯基、-(CH 2) n-(5-6元杂芳基)、-(CH 2) n-C 3-8环烷基、-(CH 2) n-(3-8元杂环烷基)或-(3-8元杂环烷基)-C 1-6烷基;所述R C为未取代,或者选择性被1~3个R 10取代在任意位置;
    每个R 9和每个R 10分别独立地为H、-CN、-NO 2、-SH、-NH 2、-OH、-C(O)OH、-NHC(O)R a、-NHS(O) 2R a、-C(O)R a、卤素、氧代基、酯基、酰胺基、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、C 1-4烷氨基、卤代C 1-4烷基或卤代C 1-4烷氧基;
    每个R a独立地为C 1-6烷基或C 2-6烯基;
    n为1、2、3或4。
  10. 如权利要求1~6任一项所述的如式I或I’所示的化合物,其异构体、前药、稳定的同位素衍生物或药学上可接受的盐,其特征在于,所述如式I或I’所示的化合物为式IV、V、VI、VII或VIII所示的化合物,其异构体、前药、稳定的同位素衍生物或药学上可接受的盐,
    通式IV所示的化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐:
    Figure PCTCN2019121976-appb-100008
    其中,m为0、1、2或3;t为0、1、2或3;
    R 1、R 2、R 5、R 6、R 7、R 8和R 9的定义如权利要求1~6任一项所述;
    通式V所示的化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐:
    Figure PCTCN2019121976-appb-100009
    其中,m为0、1、2或3;t为0、1、2或3;
    R 1、R 4、R 5、R 6、R 7、R 8和R 9的定义如权利要求1~6任一项所述;
    通式VI所示的化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐:
    Figure PCTCN2019121976-appb-100010
    其中,R 1、R 4、R 5、R 6、R 7和R 8的定义如权利要求1~6任一项所述;
    通式VII所示的化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐:
    Figure PCTCN2019121976-appb-100011
    其中,m为0、1、2或3;t为0、1、2或3;
    R 1、R 2、R 5、R 6、R 7、R 8、R 9和A 3的定义如权利要求1~6任一项所述;
    通式VIII所示的化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐:
    Figure PCTCN2019121976-appb-100012
    其中,m为0、1、2或3;t为0、1、2或3;
    R 1、R 4、R 5、R 6、R 7、R 8、R 9和A 3的定义如权利要求1~6任一项所述。
  11. 如权利要求1所述的如式I或I’所示的化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐,为以下任一化合物:
    Figure PCTCN2019121976-appb-100013
    Figure PCTCN2019121976-appb-100014
    Figure PCTCN2019121976-appb-100015
    Figure PCTCN2019121976-appb-100016
    Figure PCTCN2019121976-appb-100017
    Figure PCTCN2019121976-appb-100018
  12. 一种药物组合物,其包括活性组分以及药学上可接受的辅料;所述活性组分包括如权利要求1~11任一项所述的如式I或I’所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐。
  13. 如权利要求12所述的药物组合物,其进一步还包含其它种类的用于治疗由于MNK1和/或MNK2水平失常引起的相关疾病的治疗剂。
  14. 如权利要求13所述的药物组合物,其特征在于,所述的由MNK1和/或MNK2水平失常引起的相关疾病为癌症。
  15. 一种如权利要求1~11任一项所述的如式I或I’所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐,或如权利要求12所述药物组合物在制备MNK1和/或MNK2抑制剂药物中的应用。
  16. 一种如权利要求1~11任一项所述的如式I或I’所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐,或如权利要求12和13所述药物组合物在制备治疗和/或缓解由MNK1和/或MNK2水平失常引起的相关疾病的药物中的应用。
  17. 如权利要求16所述的应用,其特征在于,所述的由MNK1和/或MNK2水平失常引起的相关疾病为癌症。
PCT/CN2019/121976 2018-11-30 2019-11-29 Mnk抑制剂 WO2020108619A1 (zh)

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