WO2021043322A1 - Azepino pyrimidine derivatives and medical use thereof - Google Patents

Azepino pyrimidine derivatives and medical use thereof Download PDF

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Publication number
WO2021043322A1
WO2021043322A1 PCT/CN2020/119633 CN2020119633W WO2021043322A1 WO 2021043322 A1 WO2021043322 A1 WO 2021043322A1 CN 2020119633 W CN2020119633 W CN 2020119633W WO 2021043322 A1 WO2021043322 A1 WO 2021043322A1
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compound
alkyl
product
raw material
synthesis
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PCT/CN2020/119633
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French (fr)
Chinese (zh)
Inventor
魏国平
杨玲
王含建
杨霞
阳华
麦克劳德卡卢姆
付宁
李志伟
邴铁军
赵谈封
麦克莱恩约翰
Original Assignee
正大天晴药业集团南京顺欣制药有限公司
正大天晴药业集团股份有限公司
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Priority to CN202080057947.XA priority Critical patent/CN114616232A/en
Publication of WO2021043322A1 publication Critical patent/WO2021043322A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • This application relates to azepanopyrimidine derivatives, their preparation methods, pharmaceutical compositions containing the compounds, and their use as KRas G12C inhibitors in the treatment of cancer.
  • Ras gene is an important proto-oncogene, named after it is found in rat sarcoma virus.
  • the Ras protein encoded by it is located on the inner side of the cell membrane and can bind to GTP/GDP and can be hydrolyzed with the assistance of GTPase activating protein (GAP) GTP.
  • GAP GTPase activating protein
  • Ras protein controls the "on” and "off” in the signal transmission process of growth factors and cytokines, and promotes cell proliferation and differentiation. Life processes such as aging, aging and apoptosis play an important role (Bos J L et al., Cell, 2007,129(5):865-877).
  • the human Ras gene family has three members: Harvey rat sarcoma virus carcinogenic homolog (HRas), neuroblastoma rat sarcoma virus oncogene homolog (NRas) and Kirsten rat sarcoma virus oncogene Source material (KRas), of which KRas is mainly expressed in the intestine, lung and thymus (Rajalingam K et al., Biochim Biophys Acta, 2007, 1773(8): 1177-1195).
  • HRas Harvey rat sarcoma virus carcinogenic homolog
  • NRas neuroblastoma rat sarcoma virus oncogene homolog
  • KRas Kirsten rat sarcoma virus oncogene Source material
  • KRas G12C inhibitors under development include ARS-1620, MRTX-1257, AMG-510 and MRTX-849, of which AMG-510 and MRTX-849 have entered clinical trials.
  • This application relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof,
  • R 4 and/or R 6 are not present;
  • Part A is selected from or Wherein, R is selected from H or C 1-6 alkyl;
  • the AR 2 part is jointly selected from
  • Each R 1 is substituted on the ring, which is independently selected from halogen, oxo, -OH, -NH 2 , -CN, or the following groups optionally substituted with 1, 2 or 3 R 0 : C 1 -6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, or di-C 1-6 alkylamino;
  • Each R 0 is independently selected from halogen, -OH, -NH 2 , -CN, C 1-4 alkoxy, C 1-4 alkylamino, or di-C 1-4 alkylamino;
  • n 0, 1, 2, 3, 4, 5 or 6;
  • Each R a is independently selected from H, halo, or C 1-4 alkyl
  • Each R b is independently selected from H or the following groups optionally substituted with 1, 2 or 3 R c : C 1-6 alkyl, C 1-4 alkoxy C 1-3 alkyl, C 1-4 alkylamino C 1-3 alkyl, di-C 1-4 alkylamino C 1-3 alkyl, 3-7 membered cycloalkyl C 1-3 alkyl, or 4-7 membered heterocycloalkane Group C 1-3 alkyl;
  • Each R c is independently selected from halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 alkoxy, or halo C 1-6 alkyl;
  • X is selected from a single bond, -S-, -O-, -NH-, or -N(C 1-3 alkyl)-;
  • R 3 is selected from H or the following groups optionally substituted with 1, 2, 3 or 4 R d : C 1-6 alkyl, 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, benzo 4-6 membered heterocyclic group, 4-7 membered heterocycloalkyl C 1-3 alkyl, or 5-6 membered heteroaryl C 1-3 alkyl ;
  • Each R d is independently selected from halogen, -OH, oxo, -NH 2 , -CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, di-C 1- 4 -alkylamino, 3-7-membered cycloalkyl, 4-7-membered heterocycloalkyl, or 4-7-membered heterocycloalkyl C 1-3 alkyl, wherein the C 1-4 alkylamino, The di-C 1-4 alkylamino group is optionally substituted with a substituent selected from 1 or 2 cyano groups or 5-6 membered heteroaryl groups;
  • Y is selected from a single bond, -CH 2 -, or a carbonyl group
  • B is selected from phenyl, naphthyl, 5-6 membered heteroaryl, benzo5-6 membered cycloalkenyl, benzo5 optionally substituted with 1, 2, 3, 4, 5 or 6 R e -6 membered heterocyclic group, or benzo 5-6 membered heteroaryl group;
  • Each R e is independently selected from halogen, -CN, -OH, -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino , Two C 1-6 alkylamino, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, halogenated C 1-6 alkylthio, halogenated C 1-6 alkylamino, two (Halo C 1-6 alkyl) amino group, or optionally substituted with 1, 2 or 3 R e1 as follows: 3-7 membered cycloalkyl, 3-7 membered cycloalkyl C 1-3 Alkyl, 4-7 membered heterocycloalkyl, or 4-7 membered heterocycloalkyl C 1-3 alkyl;
  • Each R e1 is independently selected from halogen, -CN, -OH, -NH 2 , C 1-4 alkyl, halo C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkyl Amino, or di-C 1-4 alkylamino;
  • R 4 and R 5 are independently selected from H, halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 alkoxy, or halogenated C 1-6 alkyl, or, R 4 and R 5 together form a carbonyl group, a 3-6 membered cycloalkyl group or a 4-6 membered heterocycloalkyl group;
  • R 6 and R 7 are independently selected from H, halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 alkoxy, or halogenated C 1-6 alkyl, or, R 6 and R 7 together form a carbonyl group, a 3-6 membered cycloalkyl group or a 4-6 membered heterocycloalkyl group.
  • Is a 4-10 membered or 4-9 membered heterocycloalkyl containing two Ns; in some embodiments, It is a 4-7 membered or 4-6 heterocycloalkyl group containing one N; in some embodiments, the heterocycloalkyl group is a monocyclic heterocyclic ring or a spiro heterocyclic ring.
  • Part A is selected from Wherein, R is selected from H or C 1-6 alkyl.
  • the AR 2 moiety is collectively selected from
  • Part A is selected from Wherein, R is selected from H or C 1-6 alkyl. In some embodiments, Part A is selected from
  • the AR 2 moiety is collectively selected from Wherein, R is selected from H or C 1-6 alkyl.
  • R is selected from H. In some embodiments, R is selected from C 1-4 alkyl. In some embodiments, R is selected from methyl or ethyl.
  • R 1 is independently selected from halogen, oxo, -OH, -NH 2 , -CN, or the following groups optionally substituted with 1, 2, or 3 R 0 : C 1-4 Alkyl, C 1-4 alkoxy, C 1-4 alkylamino, or di-C 1-4 alkylamino. In some embodiments, R 1 is independently selected from C 1-4 alkyl optionally substituted with 1, 2, or 3 R 0.
  • R 0 is independently selected from halogen, -OH, -NH 2 , -CN, C 1-3 alkoxy, C 1-3 alkylamino, or di-C 1-3 alkylamino. In some embodiments, R 0 is independently selected from -CN, or C 1-3 alkoxy.
  • R 1 is independently selected from C 1-4 alkyl, cyano C 1-3 alkyl, or C 1-3 alkoxy C 1-3 alkyl. In some embodiments, R 1 is independently selected from methyl, cyanomethyl, or methoxymethyl. In some embodiments, R 1 is independently selected from cyanomethyl.
  • n is 0, 1, 2, 3, or 4. In some embodiments, m is 0, 1, or 2.
  • the AR 2 moiety is collectively selected from In some embodiments, the AR 2 moiety is collectively selected from In some embodiments, the AR 2 moiety is collectively selected from In some embodiments, the AR 2 moiety is collectively selected from In some embodiments, the AR 2 moiety is collectively selected from In some embodiments, the AR 2 moiety is collectively selected from In some embodiments, the AR 2 moiety is collectively selected from
  • R 2 is independently selected from C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl, or C 1-4 alkylsulfonyl.
  • R 2 is independently selected from halo C 1-4 alkylcarbonyl. In some embodiments, R 2 is independently selected from fluoro C 1-4 alkylcarbonyl or chloro C 1-4 alkylcarbonyl.
  • R a is independently selected from H, fluoro, chloro, methyl or ethyl. In some embodiments, R a is independently selected from H.
  • R b is independently selected from H or the following groups optionally substituted with 1, 2, or 3 R c : C 1-4 alkyl, di-C 1-3 alkylamino C 1- 2- alkyl, or 4-6 membered heterocycloalkyl C 1-2 alkyl.
  • R b is independently selected from H or the following groups optionally substituted with 1, 2, or 3 R c : methyl, dimethylaminomethyl, morpholinomethyl, piperidine Alkylmethyl, tetrahydropyrrolylmethyl, or azetidinylmethyl.
  • R b is independently selected from H.
  • R c is independently selected from fluorine, chlorine, -OH, -NH 2 , -CN, C 1-3 alkyl, C 1-3 alkoxy, or fluoro C 1-3 alkyl . In some embodiments, R c is independently selected from fluorine, chlorine, methyl, ethyl, or trifluoromethyl.
  • the R 2 is selected from the following groups: In some embodiments, the R 2 is selected from the following groups: In some embodiments, the R 2 is selected from the following groups: In some embodiments, the R 2 is selected from the following groups:
  • X is selected from a single bond, -O-, or -NH-. In some embodiments, X is selected from -O-, or -NH-. In some embodiments, X is selected from -O-.
  • R 3 is selected from H or the following groups optionally substituted with 1, 2, 3, or 4 Rd : C 1-4 alkyl, 4-7 membered heterocycloalkyl, 5- 6-membered heteroaryl, phenyl, benzo 5-6 membered heterocyclyl, 4-7 membered heterocycloalkyl C 1-3 alkyl, or 5-6 membered heteroaryl C 1-3 alkyl.
  • R 3 is selected from the following groups optionally substituted with 1, 2, 3, or 4 R d : 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, 4-7 A membered heterocycloalkyl C 1-3 alkyl group, or a 5-6 membered heteroaryl C 1-3 alkyl group. In some embodiments, R 3 is selected from the following groups optionally substituted with 1, 2, 3, or 4 Rd : 4-7 membered heterocycloalkyl C 1-3 alkyl.
  • R 3 is selected from H or the following groups optionally substituted with 1, 2, 3, or 4 Rd : methyl, ethyl, propyl, 1,2,3,4-tetra Hydroisoquinolinyl, azetidinyl, azetidinyl ethyl, azetidinyl propyl, tetrahydropyrrole methyl, tetrahydropyrrolyl ethyl, tetrahydropyrrolyl propyl, morpholinyl, Piperazinyl, piperidinyl, piperidinyl ethyl, piperidinyl propyl, morpholinopropyl, pyrimidinyl, pyrimidine methyl, pyrimidine ethyl, In some embodiments, R 3 is selected from H or the following groups optionally substituted with 1, 2, 3, or 4 Rd : tetrahydropyrrolemethyl, tetrahydropyrrole
  • R d is independently selected from halogen, oxo, -OH, -NH 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, di-C 1 -4 alkylamino, 4-7 membered heterocycloalkyl, or 4-7 membered heterocycloalkyl C 1-3 alkyl, wherein the C 1-4 alkylamino, di-C 1-4 alkyl The amino group is optionally substituted with 1 or 2 substituents selected from cyano or 5-6 membered heteroaryl.
  • R d is independently selected from fluorine, oxo, -OH, -NH 2 , methyl, ethyl, isopropyl, tert-butyl, methoxy, dimethylamino, diethyl Amino, morpholinyl, tetrahydropyranyl, tetrahydropyrrolylmethyl, piperidine methyl,
  • R d is independently selected from halogen, or C 1-4 alkyl.
  • R d is independently selected from fluorine, or methyl.
  • the R 3 is selected from H, In some embodiments, the R 3 is selected from In some embodiments, the R 3 is selected from
  • Y is selected from single bonds.
  • B is selected from optionally substituted 1,2,3,4,5, or 6 R e following groups: phenyl, indenyl, indanyl, naphthyl Tetralin, 1,2,3,4-tetralin, pyrrolyl, furyl, thienyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl , Isoquinolinyl, tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, quinoxalinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzene And thienyl, benzimidazolyl, benzopyrazolyl, indolyl, isoindolyl, indolinyl, or benzo[d][1,3]
  • B is selected from optionally substituted 1,2,3,4,5, or 6 R e following groups: phenyl, indanyl, naphthyl, thienyl Group, thiazolyl, pyridyl, benzopyrazolyl, or benzo[d][1,3]dioxole.
  • B is selected from optionally substituted 2, 3, 4, or R e is substituted phenyl, naphthyl, benzo pyrazolyl, or pyridyl.
  • B is selected from optionally substituted 2, 3, 4, or R e is substituted phenyl.
  • B is selected from optionally substituted with 1,2, 3 or 4 substituents R e naphthyl.
  • B is selected from optionally substituted 2, 3, or 4 R e substituted pyridyl.
  • R e is independently selected from halogen, -CN, -OH, -NH 2 , C 1-4 alkyl, halo C 1-4 alkyl, halo C 1-4 alkoxy, Halogenated C 1-4 alkylthio, C 1-4 alkoxy, C 1-4 alkylamino, di-C 1-4 alkylamino, or optionally substituted with 1, 2 or 3 R e1
  • R e is independently selected from fluorine, chlorine, bromine, iodine, -CN, -OH, -NH 2 , methyl, ethyl, n-propyl, isopropyl, difluoromethyl, tri Fluoromethyl, Difluoromethoxy, trifluoromethoxy, difluoromethylthio, trifluoromethylthio, methoxy, ethoxy, methylamino, dimethylamino, or optionally by 1, 2 or The following groups substituted by 3 R e1 : cyclopropanyl, cyclobutanyl, cyclopentyl, cyclohexyl, tetrahydropyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, and Linyl, tetrahydropyrrolidine methyl, piperidinyl methyl, piperazine methyl, tetrahydropyranyl methyl, or
  • R e is independently selected from fluorine, chlorine, bromine, iodine, -CN, -OH, -NH 2 , methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, Trifluoromethoxy, trifluoromethylthio, methoxy, methylamino, dimethylamino, or the following groups optionally substituted with 1, 2 or 3 R e1 : cyclopropyl, morpholine Group, piperazine methyl, or morpholino methyl.
  • R e1 is independently selected from fluorine, chlorine, bromine, iodine, -CN, -OH, -NH 2 , methyl, ethyl, trifluoromethyl, methoxy, methylamino, or Dimethylamino. In some embodiments, R e1 is independently selected from fluorine, -CN, -OH, -NH 2 , methyl, or ethyl.
  • B is selected from
  • B is selected from
  • B is selected from In some embodiments, B is selected from
  • B is selected from In some embodiments, B is selected from
  • B is selected from
  • B is selected from
  • B is selected from
  • B is selected from
  • R 3 when R 3 is not a tetrahydropyrrole C 1-3 alkyl optionally substituted with 1, 2, 3, or 4 R d , B is selected from In some embodiments, when R 3 is not tetrahydropyrrolemethyl optionally substituted with 1, 2, 3, or 4 Rd , B is selected from
  • R 4 and R 5 are independently selected from H, halogen, -OH, -NH 2 , -CN, C 1-4 alkyl, C 1-4 alkoxy, or halogenated C 1- 4 alkyl. In some embodiments, R 4 and R 5 are independently selected from H, halogen, -OH, -NH 2 , -CN, methyl, ethyl, methoxy, difluoromethyl, or trifluoromethyl. In some embodiments, R 4 and R 5 are independently selected from H, halogen, or methyl. In some embodiments, R 4 and R 5 are both methyl or R 4 and R 5 are both fluorine. In some embodiments, both R 4 and R 5 are H.
  • R 4 and R 5 together form a carbonyl group. In some embodiments, R 4 and R 5 together form a 3-6 membered cycloalkyl group. In some embodiments, R 4 and R 5 together form a cyclopropanyl group, a cyclobutanyl group, or a cyclopentyl group. In some embodiments, R 4 and R 5 together form a cyclopropyl group.
  • R 6 and R 7 are independently selected from H, halogen, -OH, -NH 2 , -CN, C 1-4 alkyl, C 1-4 alkoxy, or halogenated C 1- 4 alkyl. In some embodiments, R 6 and R 7 are independently selected from H, halogen, -OH, -NH 2 , -CN, methyl, ethyl, methoxy, difluoromethyl, or trifluoromethyl. In some embodiments, R 6 and R 7 are independently selected from H, halogen, or methyl. In some embodiments, both R 6 and R 7 are H.
  • R 6 and R 7 together form a carbonyl group. In some embodiments, R 6 and R 7 together form a 3-6 membered cycloalkyl group. In some embodiments, R 6 and R 7 together form a cyclopropanyl group, a cyclobutanyl group, or a cyclopentyl group. In some embodiments, R 6 and R 7 together form a cyclopropyl group.
  • the C 1-6 alkyl group is selected from C 1-4 alkyl groups. In some embodiments, the C 1-4 alkyl group is selected from C 1-3 alkyl group or C 1-2 alkyl group.
  • the heterocycloalkyl group contains 1 or 2 heteroatoms selected from N or O.
  • the heterocycloalkyl group contains 1 N atom.
  • the heterocycloalkyl group contains 2 N atoms.
  • the heterocycloalkyl group contains 1 O atom.
  • the heterocycloalkyl group contains 1 N atom and 1 O atom.
  • the heterocyclic group contains 1 or 2 heteroatoms selected from N or O.
  • the heterocyclic group contains 1 N atom.
  • the heterocyclic group contains 2 O atoms.
  • the heteroaryl group contains 1, 2, or 3 heteroatoms selected from S, N, or O.
  • the heteroaryl group contains 1 or 2 heteroatoms selected from S and N.
  • the heteroaryl group contains 1 or 2 N atoms.
  • the heterocycloalkyl group includes a monocyclic ring, a spiro ring, or a bridged ring. In some embodiments, the heterocycloalkyl group includes a monocyclic ring or a spiro ring. In some embodiments, the heterocycloalkyl group includes monocyclic or bridged rings.
  • This application relates to a compound of formula (IIa) or formula (IIb) or formula (IIc) or a pharmaceutically acceptable salt thereof,
  • This application relates to a compound of formula (Ia) or formula (Ib) or formula (Ic) or formula (Id) or formula (Ie) or formula (If) or a pharmaceutically acceptable salt thereof,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X, m, A and B are as defined above.
  • R 3 R a, R b, X, B, p, q are as defined above.
  • the present application relates to a pharmaceutical composition, which comprises the compound of formula (I) of the present application or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the present application further includes pharmaceutically acceptable excipients.
  • this application relates to a method for treating KRas G12C-related diseases in mammals, including administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a mammal in need of such treatment, preferably a human Pharmaceutical composition.
  • this application relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicine for treating KRas G12C-related diseases.
  • this application relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the treatment of KRas G12C related diseases.
  • this application relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treating KRas G12C-related diseases.
  • the KRas G12C related disease is preferably cancer.
  • the cancer includes lung cancer and pancreatic cancer.
  • the cancer is lung cancer, preferably non-small cell lung cancer.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, as long as the valence of the specific atom is normal and the substituted compound is stable.
  • the term “optional” or “optionally” means that the event or situation described later can occur or not occur, and the description includes occurrence of said event or situation and non-occurrence of said event or situation.
  • the ethyl group is "optionally" substituted by halogen, meaning that the ethyl group can be unsubstituted (CH 2 CH 3 ), monosubstituted (such as CH 2 CH 2 F), or polysubstituted (such as CHFCH 2 F, CH 2 CHF 2 etc.) or completely substituted (CF 2 CF 3 ).
  • CH 2 CH 3 unsubstituted
  • monosubstituted such as CH 2 CH 2 F
  • polysubstituted such as CHFCH 2 F, CH 2 CHF 2 etc.
  • CF 2 CF 3 completely substituted
  • C mn in this context means that the part has an integer number of carbon atoms in a given range.
  • C 1-6 means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.
  • any variable such as R
  • its definition in each case is independent. So, for example, if a group is replaced by 2 Rs, then each R has independent options.
  • linking group When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a covalent bond.
  • the linking direction is arbitrary.
  • the linking group L is -M-W-, which means that the structure can be A-M-W-Z or A-W-M-Z.
  • the substituent can be bonded to any atom on the ring.
  • the structural unit It means that it can be substituted at any position on the cyclohexyl or cyclohexadiene.
  • halo or halogen refers to fluorine, chlorine, bromine and iodine.
  • hydroxy refers to the -OH group.
  • cyano refers to the -CN group.
  • mercapto refers to the -SH group.
  • amino refers to the -NH 2 group.
  • nitro refers to the -NO 2 group.
  • alkyl refers to a hydrocarbon group of the general formula C n H 2n+1.
  • the alkyl group may be linear or branched.
  • C 1-6 alkyl refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, Tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.).
  • alkyl moiety (ie, alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio have the same definition as described above.
  • alkoxy refers to -O-alkyl
  • alkylamino refers to -NH-alkyl
  • dialkylamino refers to -N(alkyl) 2 .
  • alkyl sulfonyl refers to -SO 2 - group.
  • alkylthio refers to -S-alkyl.
  • alkenyl refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond.
  • alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.
  • alkynyl refers to a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group with at least one triple bond composed of carbon atoms and hydrogen atoms.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), 1-propynyl (-C ⁇ C-CH 3 ), 2-propynyl (-CH 2 -C ⁇ CH), 1,3-Butadiynyl (-C ⁇ CC ⁇ CH) and so on.
  • cycloalkyl refers to a carbocyclic ring that is fully saturated and may exist as a monocyclic, bridged, or spiro ring. Unless otherwise indicated, the carbocyclic ring is usually a 3 to 10 membered ring.
  • Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, diamond Alkyl and so on.
  • cycloalkenyl refers to a non-aromatic carbocyclic ring that is not fully saturated and may exist as a single ring, a bridged ring, or a spiro ring. Unless otherwise indicated, the carbocyclic ring is usually a 5- to 8-membered ring.
  • Non-limiting examples of cycloalkenyl include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, and the like.
  • heterocyclyl refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic) and may exist as a single ring, bridged ring, or spiro ring.
  • the heterocyclic ring is generally a 3 to 7 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, and/or nitrogen.
  • heterocyclic groups include, but are not limited to, oxiranyl, tetrahydrofuryl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl , Pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, etc.
  • heterocycloalkyl refers to a cyclic group that is fully saturated and may exist as a monocyclic, bridged, or spiro ring. Unless otherwise indicated, the heterocyclic ring is generally a 3 to 12 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, and/or nitrogen. Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxirane, sulfidene, and azaethylenyl.
  • Non-limiting examples of 4-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetin
  • Examples of cyclic group, thiabutanyl, 5-membered heterocycloalkyl include but are not limited to tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidine
  • 6-membered heterocycloalkyl groups include but are not limited to piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1, Examples of 4-thiaxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, 1,4-dithianyl, and 7-membered heterocycloalkyl include But it is not limited
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated ⁇ -electron system.
  • the aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms.
  • Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, 1,2,3,4-tetralin and the like.
  • heteroaryl refers to a monocyclic or condensed polycyclic ring system, which contains at least one ring atom selected from N, O, and S, the remaining ring atoms are C, and have at least one aromatic ring.
  • Preferred heteroaryl groups have a single 4 to 8 membered ring, especially 5 to 8 membered ring, or multiple fused rings containing 6 to 14, especially 6 to 10 ring atoms.
  • heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl , Tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc.
  • treatment means administering the compound or formulation described in this application to prevent, ameliorate or eliminate a disease or one or more symptoms related to the disease, and includes:
  • terapéuticaally effective amount means (i) treatment or prevention of a specific disease, condition or disorder, (ii) reduction, amelioration or elimination of one or more symptoms of a specific disease, condition or disorder, or (iii) prevention or delay
  • the amount of the compound of the present application that constitutes a “therapeutically effective amount” varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but it can be routinely determined by those skilled in the art. It is determined by its own knowledge and the content of this disclosure.
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues, but not Many toxicity, irritation, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.
  • salts for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, etc. can be mentioned. .
  • pharmaceutical composition refers to a mixture of one or more of the compounds of the application or their salts and pharmaceutically acceptable excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration of the compound of the present application to the organism.
  • pharmaceutically acceptable excipients refers to those excipients that have no obvious stimulating effect on the organism and will not damage the biological activity and performance of the active compound.
  • Suitable auxiliary materials are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
  • tautomer or "tautomeric form” refers to structural isomers of different energies that can interconvert via a low energy barrier.
  • proton tautomers also called proton transfer tautomers
  • proton migration such as keto-enol and imine-enamine isomerization.
  • a specific example of a proton tautomer is the imidazole moiety, in which protons can migrate between two ring nitrogens.
  • Valence tautomers include interconversion through the recombination of some bonding electrons.
  • the present application also includes compounds of the present application that are the same as those described herein, but have one or more atoms replaced by an isotope-labeled atom having an atomic weight or mass number different from the atomic weight or mass number commonly found in nature.
  • isotopes that can be bound to the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.
  • isotope-labeled compounds of the application can be used in compound and/or substrate tissue distribution analysis. Tritiated (i.e. 3 H) and carbon-14 (i.e. 14 C) isotopes are especially preferred due to their ease of preparation and detectability. Positron emission isotopes such as 15 O, 13 N, 11 C, and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy.
  • PET positron emission tomography
  • the isotopically-labeled compounds of the present application can be prepared by the following procedures similar to those disclosed in the schemes and/or examples below, by replacing non-isotopically-labeled reagents with isotope-labeled reagents.
  • substitution with heavier isotopes can provide certain therapeutic advantages resulting from higher metabolic stability (for example, increased in vivo half-life or reduced dosage requirements), and therefore in certain situations
  • deuterium substitution can be partial or complete
  • partial deuterium substitution refers to the substitution of at least one hydrogen with at least one deuterium.
  • the compounds of the present application may be asymmetric, for example, have one or more stereoisomers. Unless otherwise specified, all stereoisomers include, for example, enantiomers and diastereomers.
  • the compounds of the present application containing asymmetric carbon atoms can be isolated in an optically pure form or in a racemic form. The optically active pure form can be resolved from the racemic mixture or synthesized by using chiral raw materials or chiral reagents.
  • Non-limiting examples of stereoisomers include, but are not limited to:
  • the compound of the present application may have one or more atropisomers, unless otherwise specified, the atropisomers refer to photoactive isomers produced due to hindered free rotation between single bonds.
  • the compounds of the present application containing a chiral axis can be isolated in racemic form. When the energy barrier for free rotation of the single bond of the chiral axis compound in this application is sufficiently high, its atropisomers can be separated in an optically pure form.
  • Non-limiting examples of atropisomers include, but are not limited to:
  • the pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, and powders. , Granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • Typical routes for administering the compound of the present application or a pharmaceutically acceptable salt or pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, and intravenous administration.
  • the pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing method, dissolution method, granulation method, sugar-coated pill method, grinding method, emulsification method, freeze-drying method, etc.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These auxiliary materials enable the compound of the present application to be formulated into tablets, pills, lozenges, sugar-coated agents, capsules, gels, slurries, suspensions, etc., for oral administration to patients.
  • the solid oral composition can be prepared by conventional mixing, filling or tabletting methods. For example, it can be obtained by the following method: mixing the active compound with solid excipients, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain tablets Or the core of the dragee.
  • suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
  • the pharmaceutical composition may also be suitable for parenteral administration, such as a sterile solution, suspension or lyophilized product in a suitable unit dosage form.
  • the daily dose is 0.01 to 200 mg/kg body weight.
  • the compound of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the following The specific embodiments of, the embodiments formed by combining them with other chemical synthesis methods, and equivalent alternatives known to those skilled in the art, preferred embodiments include, but are not limited to, the examples of the present application.
  • the compound of formula (Ia) of the present application can be prepared by those skilled in the art of organic synthesis through Route 1, wherein the R 2 , R 3 , X, A and B moieties are as defined above.
  • the substitution reaction of the raw material 1a-1 produces the intermediate 1a-2
  • the molecular lactone of the intermediate 1a-2 is condensed to obtain the intermediate 1a-3
  • the condensation reaction takes place to obtain the intermediate 1a-4 and the intermediate 1a.
  • -4 is reacted to obtain intermediate 1a-5.
  • Intermediate 1a-5 is substituted with the corresponding ring A compound to obtain intermediate 1a-6, and then the N atom of ring A is protected to obtain intermediate 1a-7.
  • Intermediate 1a-7 is substituted to obtain intermediate 1a- 8.
  • Remove the N atom protecting group on the seven-membered ring to obtain Intermediate 1a-9.
  • Intermediate 1a-9 is coupled with the corresponding ring B compound to obtain intermediate 1a-10, deprotected to obtain intermediate 1a-11, and finally reacted with the corresponding acid halide compound of R 2 to obtain the compound of formula (Ia).
  • the compound of formula (Ib) of the present application can be prepared by those skilled in the art of organic synthesis through Route 2, wherein the R 2 , R 3 , X, A, and B moieties are as defined above.
  • the raw material 1b-1 undergoes condensation reaction to obtain intermediate 1b-2, which is then reacted to obtain intermediate 1b-3, and intermediate 1b-3 undergoes substitution reaction with the corresponding ring A compound to obtain intermediate 1b-4.
  • the N atom of ring A is protected to obtain intermediate 1b-5.
  • Intermediate 1b-5 is substituted to obtain intermediate 1b-6, and then the N atom protecting group on the seven-membered ring is removed to obtain intermediate 1b-7.
  • Intermediate 1b-7 is coupled with the corresponding ring B compound to obtain intermediate 1b-8, deprotected to obtain intermediate 1b-9, and finally reacted with the corresponding acid halide compound of R 2 to obtain the compound of formula (Ib).
  • Each product obtained from the reaction in the above route can be obtained by traditional separation techniques, which include but are not limited to filtration, distillation, crystallization, chromatographic separation and the like.
  • the starting materials can be synthesized by oneself or purchased from commercial institutions (for example, but not limited to Adrich or Sigma). These raw materials can be characterized by conventional means, such as physical constants and spectral data.
  • the compounds described in this application can be synthesized into a single isomer or a mixture of isomers.
  • aq stands for aqueous; SEMCl stands for (2-(chloromethoxy)ethyl)trimethylsilane; eq stands for equivalent; 1,3-DPPP stands for 1,3-bis(diphenylphosphino)propane; DCM stands for Dichloromethane; DMSO stands for dimethyl sulfoxide; Tol stands for toluene; PE stands for petroleum ether; DMF stands for N,N-dimethylformamide; NMP stands for N-methylpyrrolidone; EtOAc stands for ethyl acetate; i-PrOH Stands for isopropanol; EtOH stands for ethanol; MeOH stands for methanol; MeONa stands for sodium methoxide; THF stands for tetrahydrofuran; BPO stands for benzoyl peroxide; Boc stands for tert-butoxycarbonyl; Bn stands for benzyl; T 3 P stands for propyl phosphoric anhydride ; H
  • the compound is artificially or
  • the software is named, and the commercially available compounds use the supplier catalog name.
  • the raw material 1-11 (15.0 mg) was dissolved in dichloromethane (2 ml), and after cooling to -40 degrees Celsius, triethylamine (13.8 mg) and acryloyl chloride (2.47 mg) were sequentially added. The resulting solution was reacted at -40 degrees Celsius for 10 minutes. After the reaction was completed, it was quenched by adding water (5 mL) and concentrated to dryness.
  • the obtained crude product was purified with a preparative chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 ml/min; gradient: 38-59%; time 8 minutes; detector wavelength 254/220 nm) to obtain product 1 (10.8 mg).
  • a preparative chromatography column column, 5um, 19*150mm
  • mobile phase A water (10 mmol/L, ammonium bicarbonate)
  • mobile phase B acetonitrile
  • flow rate 25 ml/min
  • gradient 38-59%
  • time 8 minutes detector wavelength 254/220 nm
  • the obtained crude product was purified with a preparative chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; 25 ml/min; gradient: 37-63%; time 8 minutes; detector wavelength 254/220 nm) to obtain product 5 (2.00 mg).
  • Example 10 Example 11 and Example 12
  • Compound 10 was prepared and resolved by chiral high pressure (column type: CHIRAL ART Cellulose-SB2*25cm, 5um; mobile phase A: n-hexane (0.1%, diethylamine), mobile phase: isopropanol; flow rate: 20 ml/min ; Gradient: 30%, time 20 minutes; detector wavelength 254/220 nm). ) Are products 11 and 12 .
  • step 1
  • step 1
  • step 1
  • step 1
  • step 1
  • step 1
  • step 1
  • step 1
  • the racemate compound 34 is split into monomers 35 and 36 by chiral high pressure preparation.
  • step 1
  • step 1
  • step 1
  • the starting material 1-7 (3.60 g) was dissolved in 1,2-dichloroethane (100 ml).
  • N,N-diisopropylethylamine (2.81 g) and 1-chloroethyl chloroformate (2.59 g) sequentially. React at room temperature for 1 hour.
  • methanol 100 ml was added to dissolve, and the reaction solution was refluxed and reacted at 70 degrees Celsius for 1 hour. It was quenched by slowly adding water (100 mL). Extract with ethyl acetate (100 mL x 3). The organic phases were combined and washed with saturated brine (100 mL).
  • the raw material 42-1 (2.42g) was dissolved in toluene (50ml), and 8-methyl-1-bromonaphthalene (2.62g), sodium tert-butoxide (1.99g), methanesulfonic acid ( 2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (0.497 g). After the obtained mixed solution was replaced with nitrogen three times, the reaction was carried out at 90 degrees Celsius for 3 hours. After the reaction was completed, it was quenched by adding water (100 mL).
  • the raw material 42-3 (53.9 mg) was dissolved in a 1,4-dioxane solution (4 mol/L, 10 mL) of hydrogen chloride. React at room temperature for 1 hour. After the reaction was completed, it was concentrated under reduced pressure to obtain crude product 42-4 (44.9 mg). No purification is required, and it is directly used in the next reaction.
  • the crude product was purified by a preparative reversed-phase chromatography column (column type: SunFire Prep C18 OBD Column, 5um 10nm, 19*150mm; mobile phase A: water (0.05%, trifluoroacetic acid), mobile phase B: acetonitrile; flow rate: 25 ml /Min; gradient: 35-70%; time 8 minutes; detector wavelength 254/220 nm) to obtain product 42 (24.8 mg).
  • step 1
  • step 1
  • step 1
  • step 1
  • step 1
  • step 1
  • step 1
  • step 1
  • the raw material 50-3 (1.10 g) was dissolved in acetonitrile (5 ml), and potassium carbonate (3.06 g) and bromopropanol (1.68 g) were added sequentially.
  • the resulting reaction solution was reacted at 90 degrees Celsius for 12 hours.
  • water 150 mL was added for quenching.
  • Extract with ethyl acetate 150 mL x 3).
  • the organic phases were combined and washed with saturated brine (150 mL). After the organic phase was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain the product 50-4 (799.2 mg).
  • compound 50-2 For the synthesis of compound 50-2 , refer to compound 42-4 . Among them, raw material 50-1 (50.5 mg), 1,4-dioxane solution of hydrogen chloride (4 mol/liter, 10 ml). Product 50-2 (41.4 mg) was obtained. No purification is required, and it is directly used in the next reaction.
  • the raw material 51-3 (1.19 g) was dissolved in anhydrous methanol (30 ml), and palladium on carbon (10%) (0.119 g) was sequentially added under the protection of nitrogen.
  • the resulting reaction solution was replaced with hydrogen three times and reacted at room temperature for 16 hours. After the reaction is completed, the palladium carbon is filtered off. The filtrate was concentrated to dryness to obtain product 51-4 (0.913 g).
  • the raw material 51-6 (30.0 mg) was dissolved in dichloromethane (5 ml), and after cooling to -40 degrees Celsius, triethylamine (31.4 mg) and acryloyl chloride (8.44 mg) were sequentially added. The resulting solution was reacted at -40 degrees Celsius for 10 minutes. After the reaction was completed, it was quenched by adding water (5 mL) and concentrated to dryness.
  • the obtained crude product was purified with a preparative chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 ml/min; gradient: 38-59%; time 8 minutes; detector wavelength 254/220 nm) to obtain product 51 (11.2 mg).
  • a preparative chromatography column column, 5um, 19*150mm
  • mobile phase A water (10 mmol/L, ammonium bicarbonate)
  • mobile phase B acetonitrile
  • flow rate 25 ml/min
  • gradient 38-59%
  • time 8 minutes detector wavelength 254/220 nm
  • step 1
  • Raw material 51-4 (Compound raw material 1 (50.0 mg), 8-chloro-1-bromonaphthalene (40.3 mg), sodium tert-butoxide (108 mg), methanesulfonic acid (2-dicyclohexylphosphino-2', 6'-Diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (28.1 mg), toluene (2 mL).
  • the product 52-1 (50.0 mg) was obtained.
  • step 1
  • the raw material 53-3 (120 mg) was dissolved in toluene (3 ml), and 1-bromo-8-methylnaphthalene (115 mg), sodium tert-butoxide (250 mg) and methanesulfonic acid were added in sequence.
  • (2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II ) (65.3 mg).
  • the resulting solution was stirred at 90 degrees Celsius for 3 hours.
  • the raw material 53-5 (75.9 mg) was dissolved in dichloromethane (10 mL), and after cooling to -40 degrees Celsius, triethylamine (71.7 mg) and acryloyl chloride (15.3 mg) were sequentially added. The resulting solution was reacted at -40 degrees Celsius for 10 minutes. After the reaction was completed, it was quenched by adding water (10 mL), extracted with ethyl acetate (15 mL ⁇ 3), and the organic phases were combined and concentrated to dryness.
  • the crude product obtained was purified with a preparative chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 Ml/min; gradient: 35-80%; time 12 minutes; detector wavelength 254/220 nanometers) to obtain product 53 (57.1 mg).
  • a preparative chromatography column column, 5um, 19*150mm
  • mobile phase A water (10 mmol/L, ammonium bicarbonate)
  • mobile phase B acetonitrile
  • flow rate 25 Ml/min
  • gradient 35-80%
  • time 12 minutes detector wavelength 254/220 nanometers
  • step 1
  • compound 54-1 For the synthesis of compound 54-1 , refer to compound 53-4 .
  • the raw material 53-3 120 mg
  • 8-chloro-1-bromonaphthalene 125 mg
  • sodium tert-butoxide 250.5 mg
  • methanesulfonic acid (2-dicyclohexylphosphino-2',6'- Diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (65.5 mg), toluene (3 mL).
  • the product 54-1 (107 mg) was obtained.
  • step 1
  • step 1
  • the raw material 58-6 (4.20 g) was dissolved in anhydrous methanol (100 ml), and palladium on carbon (10%) (0.42 g) and ammonia methanol solution (7 mol/L) (10 ml) were added in sequence under the protection of nitrogen. .
  • the resulting reaction solution was replaced with hydrogen three times, and reacted at 40 degrees Celsius for 3 hours.
  • the palladium carbon is filtered off. The filtrate was concentrated to dryness to obtain product 58-7 (2.50 g).
  • the raw material 58-9 (15.0 mg) was dissolved in dichloromethane (2 ml), and after cooling to -40 degrees Celsius, triethylamine (13.8 mg) and acryloyl chloride (2.5 mg) were sequentially added. The resulting solution was reacted at -40 degrees Celsius for 1 hour. After the reaction was completed, it was quenched by adding water (5 mL) and concentrated to dryness.
  • the obtained crude product was purified with a preparative chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 ML/min; gradient; 42-61%; time 8 minutes; detector wavelength 254/220 nanometers) to obtain product 58 (7.8 mg).
  • a preparative chromatography column column, 5um, 19*150mm
  • mobile phase A water (10 mmol/L, ammonium bicarbonate)
  • mobile phase B acetonitrile
  • flow rate 25 ML/min
  • gradient 42-61%
  • time 8 minutes detector wavelength 254/220 nanometers
  • the raw material 62-6 (15.0 mg) was dissolved in dichloromethane (2 ml), and after cooling to -40 degrees Celsius, triethylamine (13.4 mg) and acryloyl chloride (2.4 mg) were sequentially added. The resulting solution was reacted at -40 degrees Celsius for 1 hour. After the reaction was completed, it was quenched by adding water (5 mL) and concentrated to dryness.
  • the obtained crude product was purified with a preparative chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 25 Ml/min; gradient: 42-61%; time 8 minutes; detector wavelength 254/220 nanometers) to obtain product 62 (7.8 mg).
  • the raw material 62-6 (15.5 mg) was dissolved in dichloromethane (2 ml), and after cooling to -40 degrees Celsius, triethylamine (13.8 mg) and vinylsulfonyl chloride (3.5 mg) were sequentially added. The resulting solution was reacted at -40 degrees Celsius for 10 minutes. After the reaction was completed, it was quenched by adding water (5 mL), and extracted with ethyl acetate (10 mL ⁇ 3). The organic phases were combined and washed with saturated brine (150 mL). After the organic phase was dried over anhydrous sodium sulfate, it was concentrated to dryness under reduced pressure.
  • the obtained crude product was purified with a preparative chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 Ml/min; gradient: 40-75%; time 8 minutes; detector wavelength 254/220 nanometers) to obtain product 63 (10.8 mg).
  • a preparative chromatography column column, 5um, 19*150mm
  • mobile phase A water (10 mmol/L, ammonium bicarbonate)
  • mobile phase B acetonitrile
  • flow rate 25 Ml/min
  • gradient 40-75%
  • time 8 minutes detector wavelength 254/220 nanometers
  • the obtained crude product was purified with a preparative chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm: mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 Ml/min; gradient: 35-72%; time 8 minutes; detector wavelength 254/220 nanometers) to obtain product 64 (10.5 mg).
  • a preparative chromatography column column, 5um, 19*150mm: mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 Ml/min; gradient: 35-72%; time 8 minutes; detector wavelength 254/220 nanometers
  • the raw material 62-6 (15.5 mg) was dissolved in dichloromethane (2 ml), and after cooling to -40 degrees Celsius, N,N-diisopropylethylamine (7.1 mg), propyl phosphoric anhydride (50 % Ethyl acetate solution) (35.1 mg), 2-butynoic acid (4.6 mg). The resulting solution was reacted at 0 degrees Celsius for 1 hour. After the reaction was completed, it was quenched by adding water (5 mL), and extracted with ethyl acetate (10 mL ⁇ 3). The organic phases were combined and washed with saturated brine (150 mL). After the organic phase was dried over anhydrous sodium sulfate, it was concentrated to dryness under reduced pressure.
  • the obtained crude product was purified with a preparative chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 Ml/min; gradient: 32-70%; time 8 minutes; detector wavelength 254/220 nanometers) to obtain product 65 (8.1 mg).
  • a preparative chromatography column column, 5um, 19*150mm
  • mobile phase A water (10 mmol/L, ammonium bicarbonate)
  • mobile phase B acetonitrile
  • flow rate 25 Ml/min
  • gradient 32-70%
  • time 8 minutes detector wavelength 254/220 nanometers
  • the raw material 66-3 (2.25 g) was dissolved in anhydrous methanol (80 ml), and palladium carbon (10%) (0.22 g) and ammonia methanol solution (7 mol/L) (8 ml) were added in sequence under the protection of nitrogen. .
  • the resulting reaction solution was replaced with hydrogen three times, and reacted at 40 degrees Celsius for 3 hours. After the reaction is completed, the palladium carbon is filtered off. The filtrate was concentrated to dryness to obtain product 66-4 (1.60 g).
  • the obtained crude product was purified with a preparative chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 Ml/min; gradient: 42-61%; time 8 minutes; detector wavelength 254/220 nanometers) to obtain product 66 (7.8 mg).
  • a preparative chromatography column column, 5um, 19*150mm
  • mobile phase A water (10 mmol/L, ammonium bicarbonate)
  • mobile phase B acetonitrile
  • flow rate 25 Ml/min
  • gradient 42-61%
  • time 8 minutes detector wavelength 254/220 nanometers
  • step 1
  • step 1
  • step 1
  • the raw material 70-5 (15.0 mg) was dissolved in dichloromethane (2 ml), and after cooling to -40 degrees Celsius, triethylamine (14.5 mg) and acryloyl chloride (2.6 mg) were sequentially added. The resulting solution was reacted at -40 degrees Celsius for 1 hour. After the reaction was completed, it was quenched by adding water (5 mL) and concentrated to dryness.
  • the obtained crude product was purified with a preparative chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 Ml/min; gradient: 30-65%; time 8 minutes; detector wavelength 254/220 nanometers) to obtain product 70 (7.8 mg).
  • a preparative chromatography column column, 5um, 19*150mm
  • mobile phase A water (10 mmol/L, ammonium bicarbonate)
  • mobile phase B acetonitrile
  • flow rate 25 Ml/min
  • gradient 30-65%
  • time 8 minutes detector wavelength 254/220 nanometers

Abstract

Provided are azepino pyrimidine derivatives and medical use thereof, and the specific structure is shown in formula (I). Also provided are a preparation method for the compound, a pharmaceutical composition thereof, and use thereof as a KRas G12C inhibitor in the treatment of cancer.

Description

氮杂环庚烷并嘧啶类衍生物及其医药用途Azepanopyrimidine derivatives and their medical uses
交叉参考相关引用Cross reference related references
本申请要求2019年9月6日递交的申请号为201910843832.2、发明名称为“氮杂环庚烷并嘧啶类衍生物及其医药用途”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。This application claims the priority of the Chinese patent application filed on September 6, 2019 with the application number 201910843832.2 and the invention title "Azepanopyrimidine Derivatives and Their Medical Uses", the entire content of which is incorporated by reference In this application.
技术领域Technical field
本申请涉及氮杂环庚烷并嘧啶类衍生物、其制备方法、含有该化合物的药物组合物、以及其作为KRas G12C抑制剂在治疗癌症中的用途。This application relates to azepanopyrimidine derivatives, their preparation methods, pharmaceutical compositions containing the compounds, and their use as KRas G12C inhibitors in the treatment of cancer.
背景技术Background technique
Ras基因是重要的原癌基因，因发现于大鼠肉瘤病毒而得名，其编码的Ras蛋白定位于细胞膜内侧，能与GTP/GDP结合并可在GTP酶激活蛋白(GAP)的协助下水解GTP。通过在活性(GTP结合型)和非活性(GDP结合型)构象之间相互转化，Ras蛋白控制着生长因子和细胞因子等信号传递过程中的“开”与“关”，在细胞增殖、分化、衰老和凋亡等生命过程起重要作用(Bos J L等人，Cell,2007,129(5):865-877)。人类Ras基因家族有三个成员：哈维大鼠肉瘤病毒致癌同源物(HRas)、神经母细胞瘤大鼠肉瘤病毒致癌基因同源物(NRas)和克尔斯滕大鼠肉瘤病毒致癌基因同源物(KRas)，其中KRas主要在肠、肺和胸腺中表达(Rajalingam K等人，Biochim Biophys Acta,2007,1773(8):1177-1195)。Ras gene is an important proto-oncogene, named after it is found in rat sarcoma virus. The Ras protein encoded by it is located on the inner side of the cell membrane and can bind to GTP/GDP and can be hydrolyzed with the assistance of GTPase activating protein (GAP) GTP. By transforming between the active (GTP-binding) and inactive (GDP-binding) conformations, Ras protein controls the "on" and "off" in the signal transmission process of growth factors and cytokines, and promotes cell proliferation and differentiation. Life processes such as aging, aging and apoptosis play an important role (Bos J L et al., Cell, 2007,129(5):865-877). The human Ras gene family has three members: Harvey rat sarcoma virus carcinogenic homolog (HRas), neuroblastoma rat sarcoma virus oncogene homolog (NRas) and Kirsten rat sarcoma virus oncogene Source material (KRas), of which KRas is mainly expressed in the intestine, lung and thymus (Rajalingam K et al., Biochim Biophys Acta, 2007, 1773(8): 1177-1195).
研究表明，超过30％的人类肿瘤中存在Ras基因突变，其中KRas突变约占86％(Riely G J等人，Proc Am Thorac Soc,2009,6(2):201-205)。对于KRas突变，12位甘氨酸(G12)的突变约占80％，而G12C突变(12位甘氨酸突变为半胱氨酸)大约占G12全部突变的14％(Prior I A等人，Cancer Res,2012,72(10):2457-2467；Hobbs G A等人，Cancer Cell,2016,29(3):251-253)。G12处突变会降低GAP的催化活性，最终促使Ras持续激活，使之无法有效调控细胞信号转导，进而促进肿瘤的发生与发展。Studies have shown that more than 30% of human tumors have Ras gene mutations, of which KRas mutations account for about 86% (Riely GJ et al., Proc Am Thorac Soc, 2009, 6(2): 201-205). For KRas mutations, mutations at position 12 glycine (G12) accounted for about 80%, while mutations in G12C (mutation of glycine at position 12 to cysteine) accounted for about 14% of all mutations in G12 (Prior I A et al., Cancer Res, 2012, 72(10): 2457-2467; Hobbs G A et al. Cancer Cell, 2016, 29(3): 251-253). Mutations in G12 will reduce the catalytic activity of GAP, and ultimately promote the continuous activation of Ras, making it unable to effectively regulate cell signal transduction, thereby promoting the occurrence and development of tumors.
近几年，人们利用KRas G12C突变体的变构位点进行药物研发取得了一定进展。目前，在研的KRas G12C抑制剂有ARS-1620、MRTX-1257、AMG-510和MRTX-849，其中，AMG-510和MRTX-849已进入临床试验阶段。In recent years, people have made some progress in drug research and development using the allosteric sites of KRas G12C mutants. Currently, KRas G12C inhibitors under development include ARS-1620, MRTX-1257, AMG-510 and MRTX-849, of which AMG-510 and MRTX-849 have entered clinical trials.
Figure PCTCN2020119633-appb-000001
Figure PCTCN2020119633-appb-000001
发明详述Detailed description of the invention
本申请涉及式(I)化合物或其药学上可接受的盐，This application relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2020119633-appb-000002
Figure PCTCN2020119633-appb-000002
其中，among them,
q为0时，p为2，
Figure PCTCN2020119633-appb-000003
选自单键； When q is 0, p is 2,
Figure PCTCN2020119633-appb-000003
Selected from single bond;
或者，当q为1时，p为1，
Figure PCTCN2020119633-appb-000004
选自单键或双键； Or, when q is 1, p is 1,
Figure PCTCN2020119633-appb-000004
Selected from single bond or double bond;
或者，当q为2时，p为0，
Figure PCTCN2020119633-appb-000005
选自单键； Or, when q is 2, p is 0,
Figure PCTCN2020119633-appb-000005
Selected from single bond;
当
Figure PCTCN2020119633-appb-000006
选自双键时，R 4和/或R 6不存在； when
Figure PCTCN2020119633-appb-000006
When selected from a double bond, R 4 and/or R 6 are not present;
A部分选自
Figure PCTCN2020119633-appb-000007
或
Figure PCTCN2020119633-appb-000008
其中，R选自H或C 1-6烷基； Part A is selected from
Figure PCTCN2020119633-appb-000007
or
Figure PCTCN2020119633-appb-000008
Wherein, R is selected from H or C 1-6 alkyl;
或者，A-R 2部分共同选自
Figure PCTCN2020119633-appb-000009
Or, the AR 2 part is jointly selected from
Figure PCTCN2020119633-appb-000009
Figure PCTCN2020119633-appb-000010
为至少含有两个N原子的4-10元杂环烷基；
Figure PCTCN2020119633-appb-000011
为至少含有一个N原子的4-7元杂环烷基；
Figure PCTCN2020119633-appb-000010
Is a 4-10 membered heterocycloalkyl containing at least two N atoms;
Figure PCTCN2020119633-appb-000011
Is a 4-7 membered heterocycloalkyl containing at least one N atom;
每个R 1取代在环上，其独立地选自卤素、氧代、-OH、-NH 2、-CN、或任选地被1、2或3个R 0取代的如下基团：C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、或二C 1-6烷基氨基； Each R 1 is substituted on the ring, which is independently selected from halogen, oxo, -OH, -NH 2 , -CN, or the following groups optionally substituted with 1, 2 or 3 R 0 : C 1 -6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, or di-C 1-6 alkylamino;
每个R 0独立地选自卤素、-OH、-NH 2、-CN、C 1-4烷氧基、C 1-4烷基氨基、或二C 1-4烷基氨基； Each R 0 is independently selected from halogen, -OH, -NH 2 , -CN, C 1-4 alkoxy, C 1-4 alkylamino, or di-C 1-4 alkylamino;
m是0、1、2、3、4、5或6；m is 0, 1, 2, 3, 4, 5 or 6;
每个R 2独立地选自C 1-6烷基羰基、卤代C 1-6烷基羰基、C 1-6烷氧基羰基、C 1-6烷基磺酰基、-C(O)C≡CR b、-SO 2C≡CR b、-C(O)C(R a)＝C(R b) 2、或-SO 2C(R a)＝C(R b) 2； Each R 2 is independently selected from C 1-6 alkylcarbonyl, halogenated C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylsulfonyl, -C(O)C ≡CR b , -SO 2 C≡CR b , -C(O)C(R a )=C(R b ) 2 , or -SO 2 C(R a )=C(R b ) 2 ;
每个R a独立地选自H、卤素、或C 1-4烷基； Each R a is independently selected from H, halo, or C 1-4 alkyl;
每个R b独立地选自H或任选地被1、2或3个R c取代的如下基团：C 1-6烷基、C 1-4烷氧基C 1-3烷基、C 1-4烷基氨基C 1-3烷基、二C 1-4烷基氨基C 1-3烷基、3-7元环烷基C 1-3烷基、或4-7元杂环烷基C 1-3烷基； Each R b is independently selected from H or the following groups optionally substituted with 1, 2 or 3 R c : C 1-6 alkyl, C 1-4 alkoxy C 1-3 alkyl, C 1-4 alkylamino C 1-3 alkyl, di-C 1-4 alkylamino C 1-3 alkyl, 3-7 membered cycloalkyl C 1-3 alkyl, or 4-7 membered heterocycloalkane Group C 1-3 alkyl;
每个R c独立地选自卤素、-OH、-NH 2、-CN、C 1-6烷基、C 1-6烷氧基、或卤代C 1-6烷基； Each R c is independently selected from halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 alkoxy, or halo C 1-6 alkyl;
X选自单键、-S-、-O-、-NH-、或-N(C 1-3烷基)-； X is selected from a single bond, -S-, -O-, -NH-, or -N(C 1-3 alkyl)-;
R 3选自H或任选地被1、2、3或4个R d取代的如下基团：C 1-6烷基、3-7元环烷基、4-7元杂环烷基、5-6元杂芳基、苯基、苯并4-6元杂环基、4-7元杂环烷基C 1-3烷基、或5-6元杂芳基C 1-3烷基； R 3 is selected from H or the following groups optionally substituted with 1, 2, 3 or 4 R d : C 1-6 alkyl, 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, benzo 4-6 membered heterocyclic group, 4-7 membered heterocycloalkyl C 1-3 alkyl, or 5-6 membered heteroaryl C 1-3 alkyl ；
每个R d独立地选自卤素、-OH、氧代、-NH 2、-CN、C 1-4烷基、C 1-4烷氧基、C 1-4烷基氨基、二C 1-4烷基氨基、3-7元环烷基、4-7元杂环烷基、或4-7元杂环烷基C 1-3烷基，其中，所述C 1-4烷基氨基、二C 1-4烷基氨基任选地被选自1个或2个氰基或5-6元杂芳基的 取代基取代； Each R d is independently selected from halogen, -OH, oxo, -NH 2 , -CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, di-C 1- 4 -alkylamino, 3-7-membered cycloalkyl, 4-7-membered heterocycloalkyl, or 4-7-membered heterocycloalkyl C 1-3 alkyl, wherein the C 1-4 alkylamino, The di-C 1-4 alkylamino group is optionally substituted with a substituent selected from 1 or 2 cyano groups or 5-6 membered heteroaryl groups;
Y选自单键、-CH 2-、或羰基； Y is selected from a single bond, -CH 2 -, or a carbonyl group;
B选自任选地被1、2、3、4、5或6个R e取代的苯基、萘基、5-6元杂芳基、苯并5-6元环烯基、苯并5-6元杂环基、或苯并5-6元杂芳基； B is selected from phenyl, naphthyl, 5-6 membered heteroaryl, benzo5-6 membered cycloalkenyl, benzo5 optionally substituted with 1, 2, 3, 4, 5 or 6 R e -6 membered heterocyclic group, or benzo 5-6 membered heteroaryl group;
每个R e独立地选自卤素、-CN、-OH、-NH 2、C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6烷基氨基、二C 1-6烷基氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、卤代C 1-6烷硫基、卤代C 1-6烷基氨基、二(卤代C 1-6烷基)氨基，或任选地被1、2或3个R e1取代的如下基团：3-7元环烷基、3-7元环烷基C 1-3烷基、4-7元杂环烷基、或4-7元杂环烷基C 1-3烷基； Each R e is independently selected from halogen, -CN, -OH, -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino , Two C 1-6 alkylamino, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, halogenated C 1-6 alkylthio, halogenated C 1-6 alkylamino, two (Halo C 1-6 alkyl) amino group, or optionally substituted with 1, 2 or 3 R e1 as follows: 3-7 membered cycloalkyl, 3-7 membered cycloalkyl C 1-3 Alkyl, 4-7 membered heterocycloalkyl, or 4-7 membered heterocycloalkyl C 1-3 alkyl;
每个R e1独立地选自卤素、-CN、-OH、-NH 2、C 1-4烷基、卤代C 1-4烷基、C 1-4烷氧基、C 1-4烷基氨基、或二C 1-4烷基氨基； Each R e1 is independently selected from halogen, -CN, -OH, -NH 2 , C 1-4 alkyl, halo C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkyl Amino, or di-C 1-4 alkylamino;
R 4、R 5独立地选自H、卤素、-OH、-NH 2、-CN、C 1-6烷基、C 1-6烷氧基、或卤代C 1-6烷基，或者，R 4和R 5一起形成羰基、3～6元环烷基或4～6元杂环烷基； R 4 and R 5 are independently selected from H, halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 alkoxy, or halogenated C 1-6 alkyl, or, R 4 and R 5 together form a carbonyl group, a 3-6 membered cycloalkyl group or a 4-6 membered heterocycloalkyl group;
R 6、R 7独立地选自H、卤素、-OH、-NH 2、-CN、C 1-6烷基、C 1-6烷氧基、或卤代C 1-6烷基，或者，R 6和R 7一起形成羰基、3～6元环烷基或4～6元杂环烷基。 R 6 and R 7 are independently selected from H, halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 alkoxy, or halogenated C 1-6 alkyl, or, R 6 and R 7 together form a carbonyl group, a 3-6 membered cycloalkyl group or a 4-6 membered heterocycloalkyl group.
在一些实施方案中，
Figure PCTCN2020119633-appb-000012
为含有两个N的4-10元或4-9元杂环烷基；在一些实施方案中，
Figure PCTCN2020119633-appb-000013
为含有一个N的4-7元或4-6杂环烷基；在一些实施方案中，所述杂环烷基是单环杂环或螺杂环。 In some embodiments,
Figure PCTCN2020119633-appb-000012
Is a 4-10 membered or 4-9 membered heterocycloalkyl containing two Ns; in some embodiments,
Figure PCTCN2020119633-appb-000013
It is a 4-7 membered or 4-6 heterocycloalkyl group containing one N; in some embodiments, the heterocycloalkyl group is a monocyclic heterocyclic ring or a spiro heterocyclic ring.
在一些实施方案中，A部分选自
Figure PCTCN2020119633-appb-000014
Figure PCTCN2020119633-appb-000015
Figure PCTCN2020119633-appb-000016
其中，R选自H、或C 1-6烷基。 In some embodiments, Part A is selected from
Figure PCTCN2020119633-appb-000014
Figure PCTCN2020119633-appb-000015
Figure PCTCN2020119633-appb-000016
Wherein, R is selected from H or C 1-6 alkyl.
在一些实施方案中，A-R 2部分共同选自
Figure PCTCN2020119633-appb-000017
In some embodiments, the AR 2 moiety is collectively selected from
Figure PCTCN2020119633-appb-000017
在一些实施方案中，A部分选自
Figure PCTCN2020119633-appb-000018
其中，R选自H、或C 1-6烷基。在一些实施方案中，A部分选自
Figure PCTCN2020119633-appb-000019
In some embodiments, Part A is selected from
Figure PCTCN2020119633-appb-000018
Wherein, R is selected from H or C 1-6 alkyl. In some embodiments, Part A is selected from
Figure PCTCN2020119633-appb-000019
在一些实施方案中，A-R 2部分共同选自
Figure PCTCN2020119633-appb-000020
Figure PCTCN2020119633-appb-000021
其中，R选自H、或C 1-6烷基。 In some embodiments, the AR 2 moiety is collectively selected from
Figure PCTCN2020119633-appb-000020
Figure PCTCN2020119633-appb-000021
Wherein, R is selected from H or C 1-6 alkyl.
在一些实施方案中，R选自H。在一些实施方案中，R选自C 1-4烷基。在一些实施方案中，R选自甲基或乙基。 In some embodiments, R is selected from H. In some embodiments, R is selected from C 1-4 alkyl. In some embodiments, R is selected from methyl or ethyl.
在一些实施方案中，R 1独立地选自卤素、氧代、-OH、-NH 2、-CN、或任选地被1、2或3个R 0取代的如下基团：C 1-4烷基、C 1-4烷氧基、C 1-4烷基氨基、或二C 1-4烷基氨基。在一些实施方案中，R 1独立地选自任选地被1、2或3个R 0取代的C 1-4烷基。 In some embodiments, R 1 is independently selected from halogen, oxo, -OH, -NH 2 , -CN, or the following groups optionally substituted with 1, 2, or 3 R 0 : C 1-4 Alkyl, C 1-4 alkoxy, C 1-4 alkylamino, or di-C 1-4 alkylamino. In some embodiments, R 1 is independently selected from C 1-4 alkyl optionally substituted with 1, 2, or 3 R 0.
在一些实施方案中，R 0独立地选自卤素、-OH、-NH 2、-CN、C 1-3烷氧基、C 1-3烷基氨基、或二C 1-3烷基氨基。在一些实施方案中，R 0独立地选自-CN、或C 1-3烷氧基。 In some embodiments, R 0 is independently selected from halogen, -OH, -NH 2 , -CN, C 1-3 alkoxy, C 1-3 alkylamino, or di-C 1-3 alkylamino. In some embodiments, R 0 is independently selected from -CN, or C 1-3 alkoxy.
在一些实施方案中，R 1独立地选自C 1-4烷基、氰基C 1-3烷基、或C 1-3烷氧基C 1-3烷基。在一些实施方案中，R 1独立地选自甲基、氰基甲基、或甲氧基甲基。在一些实施方案中，R 1独立地选自氰基甲基。 In some embodiments, R 1 is independently selected from C 1-4 alkyl, cyano C 1-3 alkyl, or C 1-3 alkoxy C 1-3 alkyl. In some embodiments, R 1 is independently selected from methyl, cyanomethyl, or methoxymethyl. In some embodiments, R 1 is independently selected from cyanomethyl.
在一些实施方案中，m是0、1、2、3或4。在一些实施方案中，m是0、1或2。In some embodiments, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0, 1, or 2.
在一些实施方案中，A-R 2部分共同选自
Figure PCTCN2020119633-appb-000022
Figure PCTCN2020119633-appb-000023
Figure PCTCN2020119633-appb-000024
在一些实施方案中，A-R 2部分共同选自
Figure PCTCN2020119633-appb-000025
Figure PCTCN2020119633-appb-000026
Figure PCTCN2020119633-appb-000027
在一些实施方案中，A-R 2部分共同选自
Figure PCTCN2020119633-appb-000028
Figure PCTCN2020119633-appb-000029
在一些实施方案中，A-R 2部分共同选自
Figure PCTCN2020119633-appb-000030
在一些实施方案中，A-R 2部分共同选自
Figure PCTCN2020119633-appb-000031
在一些实施方案中，A-R 2部分共同选自
Figure PCTCN2020119633-appb-000032
In some embodiments, the AR 2 moiety is collectively selected from
Figure PCTCN2020119633-appb-000022
Figure PCTCN2020119633-appb-000023
Figure PCTCN2020119633-appb-000024
In some embodiments, the AR 2 moiety is collectively selected from
Figure PCTCN2020119633-appb-000025
Figure PCTCN2020119633-appb-000026
Figure PCTCN2020119633-appb-000027
In some embodiments, the AR 2 moiety is collectively selected from
Figure PCTCN2020119633-appb-000028
Figure PCTCN2020119633-appb-000029
In some embodiments, the AR 2 moiety is collectively selected from
Figure PCTCN2020119633-appb-000030
In some embodiments, the AR 2 moiety is collectively selected from
Figure PCTCN2020119633-appb-000031
In some embodiments, the AR 2 moiety is collectively selected from
Figure PCTCN2020119633-appb-000032
在一些实施方案中，R 2独立地选自C 1-4烷基羰基、C 1-4烷氧基羰基、或C 1-4烷基磺酰基。 In some embodiments, R 2 is independently selected from C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl, or C 1-4 alkylsulfonyl.
在一些实施方案中，R 2独立地选自卤代C 1-4烷基羰基。在一些实施方案中，R 2独立地选自氟代C 1-4烷基羰基或氯代C 1-4烷基羰基。 In some embodiments, R 2 is independently selected from halo C 1-4 alkylcarbonyl. In some embodiments, R 2 is independently selected from fluoro C 1-4 alkylcarbonyl or chloro C 1-4 alkylcarbonyl.
在一些实施方案中，R 2独立地选自-C(O)C≡CR b、-SO 2C≡CR b、-C(O)C(R a)＝C(R b) 2、或-SO 2C(R a)＝C(R b) 2。在一些实施方案中，R 2独立地选自-C(O)C≡CR b、-C(O)C(R a)＝CH(R b)、或-SO 2CH＝CH(R b)。在一些实施方案中，R 2独立地选自-C(O)C(R a)＝CH(R b)。 In some embodiments, R 2 is independently selected from -C(O)C≡CR b , -SO 2 C≡CR b , -C(O)C(R a )=C(R b ) 2 , or- SO 2 C(R a )=C(R b ) 2 . In some embodiments, R 2 is independently selected from -C(O)C≡CR b , -C(O)C(R a )=CH(R b ), or -SO 2 CH=CH(R b ) . In some embodiments, R 2 is independently selected from -C(O)C(R a )=CH(R b ).
在一些实施方案中，R a独立地选自H、氟、氯、甲基或乙基。在一些实施方案中，R a独立地选自H。 In some embodiments, R a is independently selected from H, fluoro, chloro, methyl or ethyl. In some embodiments, R a is independently selected from H.
在一些实施方案中，R b独立地选自H或任选地被1、2或3个R c取代的如下基团：C 1-4烷基、二C 1-3烷基氨基C 1-2烷基、或4-6元杂环烷基C 1-2烷基。在一些实施方案中，R b独立地选自H或任选地被1、2或3个R c取代的如下基团：甲基、二甲基氨基甲基、吗啉基甲基、哌啶基甲基、四氢吡咯基甲基、或氮杂环丁基甲基。在一些实施方案中，R b独立地选自H。 In some embodiments, R b is independently selected from H or the following groups optionally substituted with 1, 2, or 3 R c : C 1-4 alkyl, di-C 1-3 alkylamino C 1- 2- alkyl, or 4-6 membered heterocycloalkyl C 1-2 alkyl. In some embodiments, R b is independently selected from H or the following groups optionally substituted with 1, 2, or 3 R c : methyl, dimethylaminomethyl, morpholinomethyl, piperidine Alkylmethyl, tetrahydropyrrolylmethyl, or azetidinylmethyl. In some embodiments, R b is independently selected from H.
在一些实施方案中，R c独立地选自氟、氯、-OH、-NH 2、-CN、C 1-3烷基、C 1-3烷氧基、或氟代C 1-3烷基。在一些实施方案中，R c独立地选自氟、氯、甲基、乙基或三氟甲基。 In some embodiments, R c is independently selected from fluorine, chlorine, -OH, -NH 2 , -CN, C 1-3 alkyl, C 1-3 alkoxy, or fluoro C 1-3 alkyl . In some embodiments, R c is independently selected from fluorine, chlorine, methyl, ethyl, or trifluoromethyl.
在一些实施方案中，所述R 2选自如下基团：
Figure PCTCN2020119633-appb-000033
Figure PCTCN2020119633-appb-000034
在一些实施方案 中，所述R 2选自如下基团：
Figure PCTCN2020119633-appb-000035
Figure PCTCN2020119633-appb-000036
在一些实施方案中，所述R 2选自如下基团：
Figure PCTCN2020119633-appb-000037
在一些实施方案中，所述R 2选自如下基团：
Figure PCTCN2020119633-appb-000038
In some embodiments, the R 2 is selected from the following groups:
Figure PCTCN2020119633-appb-000033
Figure PCTCN2020119633-appb-000034
In some embodiments, the R 2 is selected from the following groups:
Figure PCTCN2020119633-appb-000035
Figure PCTCN2020119633-appb-000036
In some embodiments, the R 2 is selected from the following groups:
Figure PCTCN2020119633-appb-000037
In some embodiments, the R 2 is selected from the following groups:
Figure PCTCN2020119633-appb-000038
在一些实施方案中，X选自单键、-O-、或-NH-。在一些实施方案中，X选自-O-、或-NH-。在一些实施方案中，X选自-O-。In some embodiments, X is selected from a single bond, -O-, or -NH-. In some embodiments, X is selected from -O-, or -NH-. In some embodiments, X is selected from -O-.
在一些实施方案中，R 3选自H或任选地被1、2、3或4个R d取代的如下基团：C 1-4烷基、4-7元杂环烷基、5-6元杂芳基、苯基、苯并5-6元杂环基、4-7元杂环烷基C 1-3烷基、或5-6元杂芳基C 1-3烷基。在一些实施方案中，R 3选自任选地被1、2、3或4个R d取代的如下基团：4-7元杂环烷基、5-6元杂芳基、4-7元杂环烷基C 1-3烷基、或5-6元杂芳基C 1-3烷基。在一些实施方案中，R 3选自任选地被1、2、3或4个R d取代的如下基团：4-7元杂环烷基C 1-3烷基。在一些实施方案中，R 3选自H或任选地被1、2、3或4个R d取代的如下基团：甲基、乙基、丙基、1,2,3,4-四氢异喹啉基、氮杂环丁基、氮杂环丁基乙基、氮杂环丁基丙基、四氢吡咯甲基、四氢吡咯乙基、四氢吡咯丙基、吗啉基、哌嗪基、哌啶基、哌啶乙基、哌啶丙基、吗啉丙基、嘧啶基、嘧啶甲基、嘧啶乙基、
Figure PCTCN2020119633-appb-000039
在一些实施方案中，R 3选自H或任选地被1、2、3或4个R d取代的如下基团：四氢吡咯甲基、四氢吡咯乙基、四氢吡咯丙基、吗啉基、哌嗪基、哌啶基、哌啶乙基、哌啶丙基、吗啉丙基、嘧啶基、嘧啶甲基、嘧啶乙基、
Figure PCTCN2020119633-appb-000040
在一些实施方案中，R 3选自H或任选地被1、2、3或4个R d取代的如下基团：四氢吡咯甲基、四氢吡咯乙基、四氢吡咯丙基、吗啉丙基、
Figure PCTCN2020119633-appb-000041
在一些实施方案中，R 3选自任选地被1、2、3或4个R d取代的四氢吡咯甲基。 In some embodiments, R 3 is selected from H or the following groups optionally substituted with 1, 2, 3, or 4 Rd : C 1-4 alkyl, 4-7 membered heterocycloalkyl, 5- 6-membered heteroaryl, phenyl, benzo 5-6 membered heterocyclyl, 4-7 membered heterocycloalkyl C 1-3 alkyl, or 5-6 membered heteroaryl C 1-3 alkyl. In some embodiments, R 3 is selected from the following groups optionally substituted with 1, 2, 3, or 4 R d : 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, 4-7 A membered heterocycloalkyl C 1-3 alkyl group, or a 5-6 membered heteroaryl C 1-3 alkyl group. In some embodiments, R 3 is selected from the following groups optionally substituted with 1, 2, 3, or 4 Rd : 4-7 membered heterocycloalkyl C 1-3 alkyl. In some embodiments, R 3 is selected from H or the following groups optionally substituted with 1, 2, 3, or 4 Rd : methyl, ethyl, propyl, 1,2,3,4-tetra Hydroisoquinolinyl, azetidinyl, azetidinyl ethyl, azetidinyl propyl, tetrahydropyrrole methyl, tetrahydropyrrolyl ethyl, tetrahydropyrrolyl propyl, morpholinyl, Piperazinyl, piperidinyl, piperidinyl ethyl, piperidinyl propyl, morpholinopropyl, pyrimidinyl, pyrimidine methyl, pyrimidine ethyl,
Figure PCTCN2020119633-appb-000039
In some embodiments, R 3 is selected from H or the following groups optionally substituted with 1, 2, 3, or 4 Rd : tetrahydropyrrolemethyl, tetrahydropyrroleethyl, tetrahydropyrrolepropyl, Morpholinyl, piperazinyl, piperidinyl, piperidinyl, piperidinyl, morpholinyl, pyrimidinyl, pyrimidine methyl, pyrimidine ethyl,
Figure PCTCN2020119633-appb-000040
In some embodiments, R 3 is selected from H or the following groups optionally substituted with 1, 2, 3, or 4 Rd : tetrahydropyrrolemethyl, tetrahydropyrroleethyl, tetrahydropyrrolepropyl, Morpholinopropyl,
Figure PCTCN2020119633-appb-000041
In some embodiments, R 3 is selected from tetrahydropyrrolemethyl optionally substituted with 1, 2, 3, or 4 Rd.
在一些实施方案中，R d独立地选自卤素、氧代、-OH、-NH 2、C 1-4烷基、C 1-4烷氧基、C 1-4烷基氨基、二C 1-4烷基氨基、4-7元杂环烷基、或4-7元杂环烷基C 1-3烷基，其中，所述C 1-4烷基氨基、二C 1-4烷基氨基任选地被1个或2个选自氰基或5-6元杂芳基的取代基取代。在一些实施方案中，R d独立地选自氟、氧代、-OH、-NH 2、甲基、乙基、异丙基、叔丁基、甲氧基、二甲基氨基、二乙基氨基、吗啉基、四氢吡喃基、四氢吡咯基甲基、哌啶甲基、
Figure PCTCN2020119633-appb-000042
在一些实施方案中，R d独立地选自卤素、或C 1-4烷基。在一些实施方案中，R d独立地选自氟、或甲基。 In some embodiments, R d is independently selected from halogen, oxo, -OH, -NH 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, di-C 1 -4 alkylamino, 4-7 membered heterocycloalkyl, or 4-7 membered heterocycloalkyl C 1-3 alkyl, wherein the C 1-4 alkylamino, di-C 1-4 alkyl The amino group is optionally substituted with 1 or 2 substituents selected from cyano or 5-6 membered heteroaryl. In some embodiments, R d is independently selected from fluorine, oxo, -OH, -NH 2 , methyl, ethyl, isopropyl, tert-butyl, methoxy, dimethylamino, diethyl Amino, morpholinyl, tetrahydropyranyl, tetrahydropyrrolylmethyl, piperidine methyl,
Figure PCTCN2020119633-appb-000042
In some embodiments, R d is independently selected from halogen, or C 1-4 alkyl. In some embodiments, R d is independently selected from fluorine, or methyl.
在一些实施方案中，所述R 3选自H、
Figure PCTCN2020119633-appb-000043
Figure PCTCN2020119633-appb-000044
Figure PCTCN2020119633-appb-000045
在一些实施方案中，所述R 3选自
Figure PCTCN2020119633-appb-000046
Figure PCTCN2020119633-appb-000047
Figure PCTCN2020119633-appb-000048
在一些实施方案中，所述R 3选自
Figure PCTCN2020119633-appb-000049
Figure PCTCN2020119633-appb-000050
In some embodiments, the R 3 is selected from H,
Figure PCTCN2020119633-appb-000043
Figure PCTCN2020119633-appb-000044
Figure PCTCN2020119633-appb-000045
In some embodiments, the R 3 is selected from
Figure PCTCN2020119633-appb-000046
Figure PCTCN2020119633-appb-000047
Figure PCTCN2020119633-appb-000048
In some embodiments, the R 3 is selected from
Figure PCTCN2020119633-appb-000049
Figure PCTCN2020119633-appb-000050
在一些实施方案中，Y选自单键。In some embodiments, Y is selected from single bonds.
在一些实施方案中，B选自任选地被1、2、3、4、5、或6个R e取代的如下基团：苯基、茚基、2,3-二氢茚基、萘基、1,2,3,4-四氢化萘、吡咯基、呋喃基、噻吩基、咪唑基、噻唑基、噁唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、喹啉基、异喹啉基、四氢喹啉基、1,2,3,4-四氢异喹啉基、喹喔啉基、四唑基、***基、三嗪基、苯并呋喃基、苯并噻吩基、苯并咪唑基、苯并吡唑基、吲哚基、异吲哚基、吲哚啉基、或苯并[d][1,3]二氧杂环戊烯。在一些实施方案中，B选自任选地被1、2、3、4、5、或6个R e取代的如下基团：苯基、2,3-二氢茚基、萘基、噻吩基、噻唑基、吡啶基、苯并吡唑基、或苯并 [d][1,3]二氧杂环戊烯。在一些实施方案中，B选自任选地被1、2、3、或4个R e取代的苯基、萘基、苯并吡唑基、或吡啶基。在一些实施方案中，B选自任选地被1、2、3、或4个R e取代的苯基。在一些实施方案中，B选自任选地被1、2、3、或4个R e取代的萘基。在一些实施方案中，B选自任选地被1、2、3、或4个R e取代的吡啶基。 In some embodiments, B is selected from optionally substituted 1,2,3,4,5, or 6 R e following groups: phenyl, indenyl, indanyl, naphthyl Tetralin, 1,2,3,4-tetralin, pyrrolyl, furyl, thienyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl , Isoquinolinyl, tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, quinoxalinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzene And thienyl, benzimidazolyl, benzopyrazolyl, indolyl, isoindolyl, indolinyl, or benzo[d][1,3]dioxole. In some embodiments, B is selected from optionally substituted 1,2,3,4,5, or 6 R e following groups: phenyl, indanyl, naphthyl, thienyl Group, thiazolyl, pyridyl, benzopyrazolyl, or benzo[d][1,3]dioxole. In some embodiments, B is selected from optionally substituted 2, 3, 4, or R e is substituted phenyl, naphthyl, benzo pyrazolyl, or pyridyl. In some embodiments, B is selected from optionally substituted 2, 3, 4, or R e is substituted phenyl. In some embodiments, B is selected from optionally substituted with 1,2, 3 or 4 substituents R e naphthyl. In some embodiments, B is selected from optionally substituted 2, 3, or 4 R e substituted pyridyl.
在一些实施方案中，R e独立地选自卤素、-CN、-OH、-NH 2、C 1-4烷基、卤代C 1-4烷基、卤代C 1-4烷氧基、卤代C 1-4烷硫基、C 1-4烷氧基、C 1-4烷基氨基、二C 1-4烷基氨基，或任选地被1、2或3个R e1取代的如下基团：3-6元环烷基、4-7元杂环烷基、或4-7元杂环烷基C 1-3烷基。在一些实施方案中，R e独立地选自氟、氯、溴、碘、-CN、-OH、-NH 2、甲基、乙基、正丙基、异丙基、二氟甲基、三氟甲基、
Figure PCTCN2020119633-appb-000051
二氟甲氧基、三氟甲氧基、二氟甲硫基、三氟甲硫基、甲氧基、乙氧基、甲基氨基、二甲基氨基，或任选地被1、2或3个R e1取代的如下基团：环丙烷基、环丁烷基、环戊烷基、环己烷基、四氢吡咯烷基、哌啶基、哌嗪基、四氢吡喃基、吗啉基、四氢吡咯烷甲基、哌啶甲基、哌嗪甲基、四氢吡喃甲基、或吗啉甲基。在一些实施方案中，R e独立地选自氟、氯、溴、碘、-CN、-OH、-NH 2、甲基、乙基、异丙基、二氟甲基、三氟甲基、
Figure PCTCN2020119633-appb-000052
三氟甲氧基、三氟甲硫基、甲氧基、甲基氨基、二甲基氨基，或任选地被1、2或3个R e1取代的如下基团：环丙烷基、吗啉基、哌嗪甲基、或吗啉甲基。 In some embodiments, R e is independently selected from halogen, -CN, -OH, -NH 2 , C 1-4 alkyl, halo C 1-4 alkyl, halo C 1-4 alkoxy, Halogenated C 1-4 alkylthio, C 1-4 alkoxy, C 1-4 alkylamino, di-C 1-4 alkylamino, or optionally substituted with 1, 2 or 3 R e1 The following groups: 3-6 membered cycloalkyl, 4-7 membered heterocycloalkyl, or 4-7 membered heterocycloalkyl C 1-3 alkyl. In some embodiments, R e is independently selected from fluorine, chlorine, bromine, iodine, -CN, -OH, -NH 2 , methyl, ethyl, n-propyl, isopropyl, difluoromethyl, tri Fluoromethyl,
Figure PCTCN2020119633-appb-000051
Difluoromethoxy, trifluoromethoxy, difluoromethylthio, trifluoromethylthio, methoxy, ethoxy, methylamino, dimethylamino, or optionally by 1, 2 or The following groups substituted by 3 R e1 : cyclopropanyl, cyclobutanyl, cyclopentyl, cyclohexyl, tetrahydropyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, and Linyl, tetrahydropyrrolidine methyl, piperidinyl methyl, piperazine methyl, tetrahydropyranyl methyl, or morpholinyl methyl. In some embodiments, R e is independently selected from fluorine, chlorine, bromine, iodine, -CN, -OH, -NH 2 , methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl,
Figure PCTCN2020119633-appb-000052
Trifluoromethoxy, trifluoromethylthio, methoxy, methylamino, dimethylamino, or the following groups optionally substituted with 1, 2 or 3 R e1 : cyclopropyl, morpholine Group, piperazine methyl, or morpholino methyl.
在一些实施方案中，R e1独立地选自氟、氯、溴、碘、-CN、-OH、-NH 2、甲基、乙基、三氟甲基、甲氧基、甲基氨基、或二甲基氨基。在一些实施方案中，R e1独立地选自氟、-CN、-OH、-NH 2、甲基、或乙基。 In some embodiments, R e1 is independently selected from fluorine, chlorine, bromine, iodine, -CN, -OH, -NH 2 , methyl, ethyl, trifluoromethyl, methoxy, methylamino, or Dimethylamino. In some embodiments, R e1 is independently selected from fluorine, -CN, -OH, -NH 2 , methyl, or ethyl.
在一些实施方案中，B选自
Figure PCTCN2020119633-appb-000053
Figure PCTCN2020119633-appb-000054
Figure PCTCN2020119633-appb-000055
In some embodiments, B is selected from
Figure PCTCN2020119633-appb-000053
Figure PCTCN2020119633-appb-000054
Figure PCTCN2020119633-appb-000055
在一些实施方案中，B选自
Figure PCTCN2020119633-appb-000056
Figure PCTCN2020119633-appb-000057
In some embodiments, B is selected from
Figure PCTCN2020119633-appb-000056
Figure PCTCN2020119633-appb-000057
在一些实施方案中，B选自
Figure PCTCN2020119633-appb-000058
Figure PCTCN2020119633-appb-000059
Figure PCTCN2020119633-appb-000060
在一些实施方案中，B选自
Figure PCTCN2020119633-appb-000061
Figure PCTCN2020119633-appb-000062
In some embodiments, B is selected from
Figure PCTCN2020119633-appb-000058
Figure PCTCN2020119633-appb-000059
Figure PCTCN2020119633-appb-000060
In some embodiments, B is selected from
Figure PCTCN2020119633-appb-000061
Figure PCTCN2020119633-appb-000062
在一些实施方案中，B选自
Figure PCTCN2020119633-appb-000063
Figure PCTCN2020119633-appb-000064
Figure PCTCN2020119633-appb-000065
在一些实施方案中，B选自
Figure PCTCN2020119633-appb-000066
In some embodiments, B is selected from
Figure PCTCN2020119633-appb-000063
Figure PCTCN2020119633-appb-000064
Figure PCTCN2020119633-appb-000065
In some embodiments, B is selected from
Figure PCTCN2020119633-appb-000066
在一些实施方案中，B选自
Figure PCTCN2020119633-appb-000067
Figure PCTCN2020119633-appb-000068
In some embodiments, B is selected from
Figure PCTCN2020119633-appb-000067
Figure PCTCN2020119633-appb-000068
在一些实施方案中，B选自
Figure PCTCN2020119633-appb-000069
Figure PCTCN2020119633-appb-000070
Figure PCTCN2020119633-appb-000071
In some embodiments, B is selected from
Figure PCTCN2020119633-appb-000069
Figure PCTCN2020119633-appb-000070
Figure PCTCN2020119633-appb-000071
在一些实施方案中，B选自
Figure PCTCN2020119633-appb-000072
Figure PCTCN2020119633-appb-000073
In some embodiments, B is selected from
Figure PCTCN2020119633-appb-000072
Figure PCTCN2020119633-appb-000073
在一些实施方案中，B选自
Figure PCTCN2020119633-appb-000074
In some embodiments, B is selected from
Figure PCTCN2020119633-appb-000074
在一些实施方案中，当R 3不是任选被1、2、3或4个R d取代的四氢吡咯C 1-3烷基，B选自
Figure PCTCN2020119633-appb-000075
在一些实施方案中，当R 3不是任选被1、2、3或4个R d取代的四氢吡咯甲基，B选自
Figure PCTCN2020119633-appb-000076
In some embodiments, when R 3 is not a tetrahydropyrrole C 1-3 alkyl optionally substituted with 1, 2, 3, or 4 R d , B is selected from
Figure PCTCN2020119633-appb-000075
In some embodiments, when R 3 is not tetrahydropyrrolemethyl optionally substituted with 1, 2, 3, or 4 Rd , B is selected from
Figure PCTCN2020119633-appb-000076
在一些实施方案中，R 4、R 5独立地选自H、卤素、-OH、-NH 2、-CN、C 1-4烷基、C 1-4烷氧基、或卤代C 1-4烷基。在一些实施方案中，R 4、R 5独立地选自H、卤素、-OH、-NH 2、-CN、甲基、乙基、甲氧基、二氟甲基、或三氟甲基。在一些实施方案中，R 4、R 5独立地选自H、卤素、或甲基。在一些实施方案中，R 4、R 5均为甲基或者R 4、R 5均为氟。在一些实施方案中，R 4、R 5均为H。 In some embodiments, R 4 and R 5 are independently selected from H, halogen, -OH, -NH 2 , -CN, C 1-4 alkyl, C 1-4 alkoxy, or halogenated C 1- 4 alkyl. In some embodiments, R 4 and R 5 are independently selected from H, halogen, -OH, -NH 2 , -CN, methyl, ethyl, methoxy, difluoromethyl, or trifluoromethyl. In some embodiments, R 4 and R 5 are independently selected from H, halogen, or methyl. In some embodiments, R 4 and R 5 are both methyl or R 4 and R 5 are both fluorine. In some embodiments, both R 4 and R 5 are H.
在一些实施方案中，R 4和R 5一起形成羰基。在一些实施方案中，R 4和R 5一起形成3～6元环烷基。在一些实施方案中，R 4和R 5一起形成环丙烷基、环丁烷基、或环戊烷基。在一些实施方案中，R 4和R 5一起形成环丙烷基。 In some embodiments, R 4 and R 5 together form a carbonyl group. In some embodiments, R 4 and R 5 together form a 3-6 membered cycloalkyl group. In some embodiments, R 4 and R 5 together form a cyclopropanyl group, a cyclobutanyl group, or a cyclopentyl group. In some embodiments, R 4 and R 5 together form a cyclopropyl group.
在一些实施方案中，R 6、R 7独立地选自H、卤素、-OH、-NH 2、-CN、C 1-4烷基、C 1-4烷氧基、或卤代C 1-4烷基。在一些实施方案中，R 6、R 7独立地选自H、卤素、-OH、-NH 2、-CN、甲基、乙基、甲氧基、二氟甲基、或三氟甲基。在一些实施方案中，R 6、R 7独立地选自H、卤素、或甲基。在一些实施方案中，R 6、R 7均为H。 In some embodiments, R 6 and R 7 are independently selected from H, halogen, -OH, -NH 2 , -CN, C 1-4 alkyl, C 1-4 alkoxy, or halogenated C 1- 4 alkyl. In some embodiments, R 6 and R 7 are independently selected from H, halogen, -OH, -NH 2 , -CN, methyl, ethyl, methoxy, difluoromethyl, or trifluoromethyl. In some embodiments, R 6 and R 7 are independently selected from H, halogen, or methyl. In some embodiments, both R 6 and R 7 are H.
在一些实施方案中，R 6和R 7一起形成羰基。在一些实施方案中，R 6和R 7一起形成3～6元环烷基。在一些实施方案中，R 6和R 7一起形成环丙烷基、环丁烷基、或环戊烷基。在一些实施方案中，R 6和R 7一起形成环丙烷基。 In some embodiments, R 6 and R 7 together form a carbonyl group. In some embodiments, R 6 and R 7 together form a 3-6 membered cycloalkyl group. In some embodiments, R 6 and R 7 together form a cyclopropanyl group, a cyclobutanyl group, or a cyclopentyl group. In some embodiments, R 6 and R 7 together form a cyclopropyl group.
在一些实施方案中，所述C 1-6烷基选自C 1-4烷基。在一些实施方案中，所述C 1-4烷基选自C 1-3烷基或C 1-2烷基。 In some embodiments, the C 1-6 alkyl group is selected from C 1-4 alkyl groups. In some embodiments, the C 1-4 alkyl group is selected from C 1-3 alkyl group or C 1-2 alkyl group.
在一些实施方案中，所述杂环烷基含有1个或2个选自N或O的杂原子。In some embodiments, the heterocycloalkyl group contains 1 or 2 heteroatoms selected from N or O.
在一些实施方案中，所述杂环烷基含有1个N原子。In some embodiments, the heterocycloalkyl group contains 1 N atom.
在一些实施方案中，所述杂环烷基含有2个N原子。In some embodiments, the heterocycloalkyl group contains 2 N atoms.
在一些实施方案中，所述杂环烷基含有1个O原子。In some embodiments, the heterocycloalkyl group contains 1 O atom.
在一些实施方案中，所述杂环烷基含有1个N原子和1个O原子。In some embodiments, the heterocycloalkyl group contains 1 N atom and 1 O atom.
在一些实施方案中，所述杂环基含有1个或2个选自N或O的杂原子。In some embodiments, the heterocyclic group contains 1 or 2 heteroatoms selected from N or O.
在一些实施方案中，所述杂环基含有1个N原子。In some embodiments, the heterocyclic group contains 1 N atom.
在一些实施方案中，所述杂环基含有2个O原子。In some embodiments, the heterocyclic group contains 2 O atoms.
在一些实施方案中，所述杂芳基含有1、2或3个选自S、N或O的杂原子。In some embodiments, the heteroaryl group contains 1, 2, or 3 heteroatoms selected from S, N, or O.
在一些实施方案中，所述杂芳基含有1或2个选自S、N的杂原子。In some embodiments, the heteroaryl group contains 1 or 2 heteroatoms selected from S and N.
在一些实施方案中，所述杂芳基含有1或2个N原子。In some embodiments, the heteroaryl group contains 1 or 2 N atoms.
在一些实施方案中，所述杂环烷基包括单环、螺环或桥环。在一些实施方案中，所述杂环烷基包括单环或螺环。在一些实施方案中，所述杂环烷基包括单环或桥环。In some embodiments, the heterocycloalkyl group includes a monocyclic ring, a spiro ring, or a bridged ring. In some embodiments, the heterocycloalkyl group includes a monocyclic ring or a spiro ring. In some embodiments, the heterocycloalkyl group includes monocyclic or bridged rings.
在一些实施方案中，当q为1，p为1，
Figure PCTCN2020119633-appb-000077
选自单键或双键时，式(I)化合物中的两个
Figure PCTCN2020119633-appb-000078
不同时选自双键。 In some embodiments, when q is 1, p is 1,
Figure PCTCN2020119633-appb-000077
When selected from a single bond or a double bond, two of the compounds of formula (I)
Figure PCTCN2020119633-appb-000078
They are not selected from double bonds at the same time.
本申请涉及式(IIa)或式(IIb)或式(IIc)化合物或其药学上可接受的盐，This application relates to a compound of formula (IIa) or formula (IIb) or formula (IIc) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2020119633-appb-000079
Figure PCTCN2020119633-appb-000079
其中，R 2、R 3、R 4、R 5、R 6、R 7、X、Y、A、B、p、q和
Figure PCTCN2020119633-appb-000080
部分如上定义。 Among them, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X, Y, A, B, p, q and
Figure PCTCN2020119633-appb-000080
The part is as defined above.
本申请涉及式(Ia)或式(Ib)或式(Ic)或式(Id)或式(Ie)或式(If)化合物或其药学上可接受的盐，This application relates to a compound of formula (Ia) or formula (Ib) or formula (Ic) or formula (Id) or formula (Ie) or formula (If) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2020119633-appb-000081
Figure PCTCN2020119633-appb-000081
其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、X、m、A和B部分如上定义。 Wherein, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X, m, A and B are as defined above.
本申请涉及以下式(III)或式(IIIa)或式(IIIb)或式(IIIc)或式(IIId)或式(IIIe)化合物或其药学上可接受的盐：This application relates to the following compound of formula (III) or formula (IIIa) or formula (IIIb) or formula (IIIc) or formula (IIId) or formula (IIIe) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2020119633-appb-000082
Figure PCTCN2020119633-appb-000082
Figure PCTCN2020119633-appb-000083
Figure PCTCN2020119633-appb-000083
其中，R 3、R a、R b、X、B、p、q如上定义。 Wherein, R 3, R a, R b, X, B, p, q are as defined above.
本申请还涉及以下化合物或其药学上可接受的盐：This application also relates to the following compounds or pharmaceutically acceptable salts thereof:
Figure PCTCN2020119633-appb-000084
Figure PCTCN2020119633-appb-000084
Figure PCTCN2020119633-appb-000085
Figure PCTCN2020119633-appb-000085
Figure PCTCN2020119633-appb-000086
Figure PCTCN2020119633-appb-000086
本申请还涉及以下化合物或其药学上可接受的盐：This application also relates to the following compounds or pharmaceutically acceptable salts thereof:
Figure PCTCN2020119633-appb-000087
Figure PCTCN2020119633-appb-000087
Figure PCTCN2020119633-appb-000088
Figure PCTCN2020119633-appb-000088
另一方面，本申请涉及药物组合物，其包含本申请的式(I)化合物或其药学上可接受的盐。在一些实施方案中，本申请的药物组合物还包括药学上可接受的辅料。In another aspect, the present application relates to a pharmaceutical composition, which comprises the compound of formula (I) of the present application or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition of the present application further includes pharmaceutically acceptable excipients.
另一方面，本申请涉及治疗哺乳动物KRas G12C相关疾病的方法，包括对需要该治疗的哺乳动物，优选人类，给予治疗有效量的式(I)化合物或其药学上可接受的盐、或其药物组合物。On the other hand, this application relates to a method for treating KRas G12C-related diseases in mammals, including administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a mammal in need of such treatment, preferably a human Pharmaceutical composition.
另一方面，本申请涉及式(I)化合物或其药学上可接受的盐、或其药物组合物在制备治疗KRas G12C相关疾病的药物中的用途。On the other hand, this application relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicine for treating KRas G12C-related diseases.
另一方面，本申请涉及式(I)化合物或其药学上可接受的盐、或其药物组合物在治疗KRas G12C相关疾病中的用途。On the other hand, this application relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the treatment of KRas G12C related diseases.
另一方面，本申请涉及治疗KRas G12C相关疾病的式(I)化合物或其药学上可接受的盐、或其药物组合物。On the other hand, this application relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treating KRas G12C-related diseases.
在本申请的一些实施方案中，所述KRas G12C相关疾病优选为癌症。In some embodiments of the present application, the KRas G12C related disease is preferably cancer.
在本申请的一些实施方案中，所述癌症包括肺癌、胰腺癌。In some embodiments of the application, the cancer includes lung cancer and pancreatic cancer.
在本申请的一些实施方案中，所述癌症是肺癌，优选为非小细胞肺癌。In some embodiments of the application, the cancer is lung cancer, preferably non-small cell lung cancer.
定义definition
除非另有说明，本申请中所用的下列术语具有下列含义。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照本领域普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。Unless otherwise stated, the following terms used in this application have the following meanings. A specific term should not be considered uncertain or unclear without a special definition, but should be understood according to the ordinary meaning in the field. When a trade name appears in this article, it is meant to refer to its corresponding commodity or its active ingredient.
术语“被取代”是指特定原子上的任意一个或多个氢原子被取代基取代，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧代(即＝O)时，意味 着两个氢原子被取代，氧代不会发生在芳香基上。The term "substituted" means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, as long as the valence of the specific atom is normal and the substituted compound is stable. When the substituent is oxo (i.e. =O), it means that two hydrogen atoms are replaced, and the oxo will not occur on the aromatic group.
术语“任选”或“任选地”是指随后描述的事件或情况可以发生或不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，乙基“任选”被卤素取代，指乙基可以是未被取代的(CH 2CH 3)、单取代的(如CH 2CH 2F)、多取代的(如CHFCH 2F、CH 2CHF 2等)或完全被取代的(CF 2CF 3)。本领域技术人员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。 The term "optional" or "optionally" means that the event or situation described later can occur or not occur, and the description includes occurrence of said event or situation and non-occurrence of said event or situation. For example, the ethyl group is "optionally" substituted by halogen, meaning that the ethyl group can be unsubstituted (CH 2 CH 3 ), monosubstituted (such as CH 2 CH 2 F), or polysubstituted (such as CHFCH 2 F, CH 2 CHF 2 etc.) or completely substituted (CF 2 CF 3 ). Those skilled in the art can understand that for any group containing one or more substituents, any substitution or substitution pattern that is impossible to exist in space and/or cannot be synthesized will not be introduced.
本文中的C m-n，是该部分具有给定范围中的整数个碳原子。例如“C 1-6”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子。 C mn in this context means that the part has an integer number of carbon atoms in a given range. For example, "C 1-6 "means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被2个R所取代，则每个R都有独立的选项。When any variable (such as R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. So, for example, if a group is replaced by 2 Rs, then each R has independent options.
当一个连接基团的数量为0时，比如-(CH 2) 0-，表示该连接基团为共价键。 When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a covalent bond.
当其中一个变量选自共价键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表共价键时表示该结构实际上是A-Z。When one of the variables is selected from a covalent bond, it means that the two groups connected are directly connected. For example, when L in A-L-Z represents a covalent bond, it means that the structure is actually A-Z.
当所列举的连接基团没有指明其连接方向，其连接方向是任意的，比如A-L-Z中，连接基团L为-M-W-，此时表示该结构可以为A-M-W-Z或者A-W-M-Z。When the linking group listed does not specify the linking direction, the linking direction is arbitrary. For example, in A-L-Z, the linking group L is -M-W-, which means that the structure can be A-M-W-Z or A-W-M-Z.
当一个取代基的键交叉连接到一个环上的两个原子时，这种取代基可以与这个环上的任意原子相键合。例如，结构单元
Figure PCTCN2020119633-appb-000089
表示其可在环己基或者环己二烯上的任意一个位置发生取代。 When the bond of a substituent is cross-linked to two atoms on a ring, the substituent can be bonded to any atom on the ring. For example, the structural unit
Figure PCTCN2020119633-appb-000089
It means that it can be substituted at any position on the cyclohexyl or cyclohexadiene.
术语“卤”或“卤素”是指氟、氯、溴和碘。The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.
术语“羟基”指-OH基团。The term "hydroxy" refers to the -OH group.
术语“氰基”指-CN基团。The term "cyano" refers to the -CN group.
术语“巯基”指-SH基团。The term "mercapto" refers to the -SH group.
术语“氨基”指-NH 2基团。 The term "amino" refers to the -NH 2 group.
术语“硝基”指-NO 2基团。 The term "nitro" refers to the -NO 2 group.
术语“烷基”是指通式为C nH 2n+1的烃基。该烷基可以是直链或支链的。例如，术语“C 1-6烷基”指含有1至6个碳原子的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、新戊基、己基、2-甲基戊基等)。类似地，烷氧基、烷基氨基、二烷基氨基、烷基磺酰基和烷硫基的烷基部分(即烷基)具有上述相同定义。 The term "alkyl" refers to a hydrocarbon group of the general formula C n H 2n+1. The alkyl group may be linear or branched. For example, the term "C 1-6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, Tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl moiety (ie, alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio have the same definition as described above.
术语“烷氧基”指-O-烷基。The term "alkoxy" refers to -O-alkyl.
术语“烷基氨基”指-NH-烷基。The term "alkylamino" refers to -NH-alkyl.
术语“二烷基氨基”指-N(烷基) 2。 The term "dialkylamino" refers to -N(alkyl) 2 .
术语“烷基磺酰基”指-SO 2-烷基。 The term "alkyl sulfonyl" refers to -SO 2 - group.
术语“烷硫基”指-S-烷基。The term "alkylthio" refers to -S-alkyl.
术语“烯基”是指由碳原子和氢原子组成的直链或支链的具有至少一个双键的不饱和脂肪族烃基。烯基的非限制性实例包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、异丁烯基、1,3-丁二烯基等。The term "alkenyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond. Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.
术语“炔基”是指由碳原子和氢原子组成的直链或支链的具有至少一个三键的不饱和脂肪族烃基。炔基的非限制性实例包括但不限于乙炔基(-C≡CH)、1-丙炔基(-C≡C-CH 3)、2-丙炔基(-CH 2-C≡CH)、1,3-丁二炔基(-C≡C-C≡CH)等。 The term "alkynyl" refers to a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group with at least one triple bond composed of carbon atoms and hydrogen atoms. Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), 1-propynyl (-C≡C-CH 3 ), 2-propynyl (-CH 2 -C≡CH), 1,3-Butadiynyl (-C≡CC≡CH) and so on.
术语“环烷基”指完全饱和的并且可以以呈单环、桥环或螺环存在的碳环。除非另 有指示，该碳环通常为3至10元环。环烷基非限制性实例包括但不限于环丙基、环丁基、环戊基、环己基、降冰片基(双环[2.2.1]庚基)、双环[2.2.2]辛基、金刚烷基等。The term "cycloalkyl" refers to a carbocyclic ring that is fully saturated and may exist as a monocyclic, bridged, or spiro ring. Unless otherwise indicated, the carbocyclic ring is usually a 3 to 10 membered ring. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, diamond Alkyl and so on.
术语“环烯基”是指不完全饱和的并且可以以呈单环、桥环或螺环存在的非芳族碳环。除非另有指示，该碳环通常为5至8元环。环烯基的非限制性实例包括但不限于环戊烯基、环戊二烯基、环己烯基、环己二烯基、环庚烯基、环庚二烯基等。The term "cycloalkenyl" refers to a non-aromatic carbocyclic ring that is not fully saturated and may exist as a single ring, a bridged ring, or a spiro ring. Unless otherwise indicated, the carbocyclic ring is usually a 5- to 8-membered ring. Non-limiting examples of cycloalkenyl include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, and the like.
术语“杂环基”是指完全饱和的或部分不饱和的(但不是完全不饱和的杂芳族)并且可以以单环、桥环或螺环存在的非芳族环。除非另有指示，该杂环通常为含有1至3个独立地选自硫、氧和/或氮的杂原子(优选1或2个杂原子)的3至7元环。杂环基的非限制性实例包括但不限于环氧乙烷基、四氢呋喃基、二氢呋喃基、吡咯烷基、N-甲基吡咯烷基、二氢吡咯基、哌啶基、哌嗪基、吡唑烷基、4H-吡喃基、吗啉基、硫代吗啉基、四氢噻吩基等。The term "heterocyclyl" refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic) and may exist as a single ring, bridged ring, or spiro ring. Unless otherwise indicated, the heterocyclic ring is generally a 3 to 7 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, and/or nitrogen. Non-limiting examples of heterocyclic groups include, but are not limited to, oxiranyl, tetrahydrofuryl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl , Pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, etc.
术语“杂环烷基”是指完全饱和的并且可以以单环、桥环或螺环存在的环状基团。除非另有指示，该杂环通常为含有1至3个独立地选自硫、氧和/或氮的杂原子(优选1或2个杂原子)的3至12元环。3元杂环烷基的实例包括但不限于环氧乙烷基、环硫乙烷基、环氮乙烷基，4元杂环烷基的非限制性实例包括但不限于吖丁啶基、噁丁环基、噻丁环基，5元杂环烷基的实例包括但不限于四氢呋喃基、四氢噻吩基、吡咯烷基、异噁唑烷基、噁唑烷基、异噻唑烷基、噻唑烷基、咪唑烷基、四氢吡唑基，6元杂环烷基的实例包括但不限于哌啶基、四氢吡喃基、四氢噻喃基、吗啉基、哌嗪基、1,4-噻噁烷基、1,4-二氧六环基、硫代吗啉基、1,3-二噻烷基、1,4-二噻烷基，7元杂环烷基的实例包括但不限于氮杂环庚烷基、氧杂环庚烷基、硫杂环庚烷基。The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and may exist as a monocyclic, bridged, or spiro ring. Unless otherwise indicated, the heterocyclic ring is generally a 3 to 12 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, and/or nitrogen. Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxirane, sulfidene, and azaethylenyl. Non-limiting examples of 4-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetin Examples of cyclic group, thiabutanyl, 5-membered heterocycloalkyl include but are not limited to tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidine Examples of 6-membered heterocycloalkyl groups include but are not limited to piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1, Examples of 4-thiaxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, 1,4-dithianyl, and 7-membered heterocycloalkyl include But it is not limited to azepanyl, oxepanyl, and thieppanyl.
术语“芳基”是指具有共轭的π电子体系的全碳单环或稠合多环的芳香环基团。例如，芳基可以具有6-20个碳原子，6-14个碳原子或6-12个碳原子。芳基的非限制性实例包括但不限于苯基、萘基、蒽基和1,2,3,4-四氢化萘等。The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π-electron system. For example, the aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, 1,2,3,4-tetralin and the like.
术语“杂芳基”是指单环或稠合多环体系，其中含有至少一个选自N、O、S的环原子，其余环原子为C，并且具有至少一个芳香环。优选的杂芳基具有单个4至8元环，尤其是5至8元环，或包含6至14个，尤其是6至10个环原子的多个稠合环。杂芳基的非限制性实例包括但不限于吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、喹啉基、异喹啉基、四唑基、***基、三嗪基、苯并呋喃基、苯并噻吩基、吲哚基、异吲哚基等。The term "heteroaryl" refers to a monocyclic or condensed polycyclic ring system, which contains at least one ring atom selected from N, O, and S, the remaining ring atoms are C, and have at least one aromatic ring. Preferred heteroaryl groups have a single 4 to 8 membered ring, especially 5 to 8 membered ring, or multiple fused rings containing 6 to 14, especially 6 to 10 ring atoms. Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl , Tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc.
术语“治疗”意为将本申请所述化合物或制剂进行给药以预防、改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：The term "treatment" means administering the compound or formulation described in this application to prevent, ameliorate or eliminate a disease or one or more symptoms related to the disease, and includes:
(i)预防疾病或疾病状态在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病状态，但尚未被诊断为已患有该疾病状态时；(i) Preventing the occurrence of a disease or disease state in mammals, especially when such mammals are susceptible to the disease state, but have not been diagnosed as having the disease state;
(ii)抑制疾病或疾病状态，即遏制其发展；(ii) Suppress the disease or disease state, that is, curb its development;
(iii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。(iii) Alleviate the disease or disease state, even if the disease or disease state subsides.
术语“治疗有效量”意指(i)治疗或预防特定疾病、病况或障碍，(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状，或(iii)预防或延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本申请化合物的用量。构成“治疗有效量”的本申请化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。The term "therapeutically effective amount" means (i) treatment or prevention of a specific disease, condition or disorder, (ii) reduction, amelioration or elimination of one or more symptoms of a specific disease, condition or disorder, or (iii) prevention or delay The amount of the compound of the present application for the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of the compound of the present application that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but it can be routinely determined by those skilled in the art. It is determined by its own knowledge and the content of this disclosure.
术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues, but not Many toxicity, irritation, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.
作为药学上可接受的盐，例如，可以提及金属盐、铵盐、与有机碱形成的盐、与无机酸形成的盐、与有机酸形成的盐、与碱性或者酸性氨基酸形成的盐等。As pharmaceutically acceptable salts, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, etc. can be mentioned. .
术语“药物组合物”是指一种或多种本申请的化合物或其盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对有机体给予本申请的化合物。The term "pharmaceutical composition" refers to a mixture of one or more of the compounds of the application or their salts and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound of the present application to the organism.
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。The term "pharmaceutically acceptable excipients" refers to those excipients that have no obvious stimulating effect on the organism and will not damage the biological activity and performance of the active compound. Suitable auxiliary materials are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
词语“包括(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising应理解为开放的、非排他性的意义，即“包括但不限于”。The word "comprise" or "comprise" and its English variants such as comprises or comprising should be understood as an open, non-exclusive meaning, that is, "including but not limited to".
本申请的化合物和中间体还可以以不同的互变异构体形式存在，并且所有这样的形式包含于本申请的范围内。术语“互变异构体”或“互变异构体形式”是指可经由低能垒互变的不同能量的结构异构体。例如，质子互变异构体(也称为质子转移互变异构体)包括经由质子迁移的互变，如酮-烯醇及亚胺-烯胺异构化。质子互变异构体的具体实例是咪唑部分，其中质子可在两个环氮间迁移。价互变异构体包括通过一些成键电子的重组的互变。The compounds and intermediates of the present application may also exist in different tautomeric forms, and all such forms are included in the scope of the present application. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also called proton transfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerization. A specific example of a proton tautomer is the imidazole moiety, in which protons can migrate between two ring nitrogens. Valence tautomers include interconversion through the recombination of some bonding electrons.
本申请还包括与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本申请化合物。可结合到本申请化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为 2H、 3H、 11C、 13C、 14C、 13N、 15N、 15O、 17O、 18O、 31P、 32P、 35S、 18F、 123I、 125I和 36Cl等。 The present application also includes compounds of the present application that are the same as those described herein, but have one or more atoms replaced by an isotope-labeled atom having an atomic weight or mass number different from the atomic weight or mass number commonly found in nature. Examples of isotopes that can be bound to the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.
某些同位素标记的本申请化合物(例如用 3H及 14C标记的那些)可用于化合物和/或底物组织分布分析中。氚化(即 3H)和碳-14(即 14C)同位素对于由于它们易于制备和可检测性是尤其优选的。正电子发射同位素，诸如 15O、 13N、 11C和 18F可用于正电子发射断层扫描(PET)研究以测定底物占有率。通常可以通过与公开于下文的方案和/或实施例中的那些类似的下列程序，通过同位素标记试剂取代未经同位素标记的试剂来制备同位素标记的本申请化合物。 Certain isotope-labeled compounds of the application (such as those labeled with 3 H and 14 C) can be used in compound and/or substrate tissue distribution analysis. Tritiated (i.e. 3 H) and carbon-14 (i.e. 14 C) isotopes are especially preferred due to their ease of preparation and detectability. Positron emission isotopes such as 15 O, 13 N, 11 C, and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Generally, the isotopically-labeled compounds of the present application can be prepared by the following procedures similar to those disclosed in the schemes and/or examples below, by replacing non-isotopically-labeled reagents with isotope-labeled reagents.
此外，用较重同位素(诸如氘(即 2H))取代可以提供某些由更高的代谢稳定性产生的治疗优点(例如增加的体内半衰期或降低的剂量需求)，并且因此在某些情形下可能是优选的，其中氘取代可以是部分或完全的，部分氘取代是指至少一个氢被至少一个氘取代。 In addition, substitution with heavier isotopes (such as deuterium (ie 2 H)) can provide certain therapeutic advantages resulting from higher metabolic stability (for example, increased in vivo half-life or reduced dosage requirements), and therefore in certain situations The following may be preferred, where the deuterium substitution can be partial or complete, and partial deuterium substitution refers to the substitution of at least one hydrogen with at least one deuterium.
本申请化合物可以是不对称的，例如，具有一个或多个立体异构体。除非另有说明，所有立体异构体都包括，如对映异构体和非对映异构体。本申请的含有不对称碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。立体异构体的非限制性实例包括但不限于：The compounds of the present application may be asymmetric, for example, have one or more stereoisomers. Unless otherwise specified, all stereoisomers include, for example, enantiomers and diastereomers. The compounds of the present application containing asymmetric carbon atoms can be isolated in an optically pure form or in a racemic form. The optically active pure form can be resolved from the racemic mixture or synthesized by using chiral raw materials or chiral reagents. Non-limiting examples of stereoisomers include, but are not limited to:
Figure PCTCN2020119633-appb-000090
Figure PCTCN2020119633-appb-000090
本申请化合物可以具有一个或多个阻转异构体，除非另有说明，所述阻转异构体是指由于单键之间的自由旋转受阻而产生的光活性异构体。本申请的含有手性轴的化合物可以以外消旋形式被分离出来。当本申请含有手性轴化合物的单键自由旋转的能垒足够 高时，其阻转异构体可以以光活性纯的形式被分离出来。阻转异构体的非限制性实例包括但不限于：The compound of the present application may have one or more atropisomers, unless otherwise specified, the atropisomers refer to photoactive isomers produced due to hindered free rotation between single bonds. The compounds of the present application containing a chiral axis can be isolated in racemic form. When the energy barrier for free rotation of the single bond of the chiral axis compound in this application is sufficiently high, its atropisomers can be separated in an optically pure form. Non-limiting examples of atropisomers include, but are not limited to:
Figure PCTCN2020119633-appb-000091
Figure PCTCN2020119633-appb-000091
本申请的药物组合物可通过将本申请的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。The pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, and powders. , Granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
给予本申请化合物或其药学上可接受的盐或其药物组合物的典型途径包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、***内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。Typical routes for administering the compound of the present application or a pharmaceutically acceptable salt or pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, and intravenous administration.
本申请的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。The pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing method, dissolution method, granulation method, sugar-coated pill method, grinding method, emulsification method, freeze-drying method, etc.
在一些实施方案中，药物组合物是口服形式。对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的辅料混合，来配制该药物组合物。这些辅料能使本申请的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These auxiliary materials enable the compound of the present application to be formulated into tablets, pills, lozenges, sugar-coated agents, capsules, gels, slurries, suspensions, etc., for oral administration to patients.
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体辅料混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。The solid oral composition can be prepared by conventional mixing, filling or tabletting methods. For example, it can be obtained by the following method: mixing the active compound with solid excipients, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain tablets Or the core of the dragee. Suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。The pharmaceutical composition may also be suitable for parenteral administration, such as a sterile solution, suspension or lyophilized product in a suitable unit dosage form.
本文所述的通式Ⅰ化合物的所有施用方法中，每天给药的剂量为0.01到200mg/kg体重，本申请的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本申请的实施例。In all the methods of administration of the compound of general formula I described herein, the daily dose is 0.01 to 200 mg/kg body weight. The compound of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the following The specific embodiments of, the embodiments formed by combining them with other chemical synthesis methods, and equivalent alternatives known to those skilled in the art, preferred embodiments include, but are not limited to, the examples of the present application.
本申请具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本申请的化学变化及其所需的试剂和物料。为了获得本申请的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。The chemical reaction in the specific embodiment of the application is completed in a suitable solvent, and the solvent must be suitable for the chemical change of the application and the required reagents and materials. In order to obtain the compound of the present application, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction schemes on the basis of the existing embodiments.
在一些实施方案中，本申请式(Ia)化合物可由有机合成领域技术人员通过路线1来制备，其中R 2、R 3、X、A和B部分如上定义。 In some embodiments, the compound of formula (Ia) of the present application can be prepared by those skilled in the art of organic synthesis through Route 1, wherein the R 2 , R 3 , X, A and B moieties are as defined above.
Figure PCTCN2020119633-appb-000092
Figure PCTCN2020119633-appb-000092
路线1Route 1
在合适的条件下，原料1a-1发生取代反应得到中间体1a-2，中间体1a-2分子内酯缩合得到中间体1a-3，接着发生缩合反应得到中间体1a-4，中间体1a-4经反应得到中间体1a-5。中间体1a-5与相应的环A化合物发生取代反应得到中间体1a-6，随后对环A的N原子进行保护得到中间体1a-7，中间体1a-7经取代反应得到中间体1a-8，再脱去七元环上N原子保护基得到中间体1a-9。中间体1a-9与相应的环B化合物发生偶联反应得到中间体1a-10，脱保护得到中间体1a-11，最后与R 2相应的酰卤化合物反应得到式(Ia)化合物。 Under suitable conditions, the substitution reaction of the raw material 1a-1 produces the intermediate 1a-2, the molecular lactone of the intermediate 1a-2 is condensed to obtain the intermediate 1a-3, and then the condensation reaction takes place to obtain the intermediate 1a-4 and the intermediate 1a. -4 is reacted to obtain intermediate 1a-5. Intermediate 1a-5 is substituted with the corresponding ring A compound to obtain intermediate 1a-6, and then the N atom of ring A is protected to obtain intermediate 1a-7. Intermediate 1a-7 is substituted to obtain intermediate 1a- 8. Remove the N atom protecting group on the seven-membered ring to obtain Intermediate 1a-9. Intermediate 1a-9 is coupled with the corresponding ring B compound to obtain intermediate 1a-10, deprotected to obtain intermediate 1a-11, and finally reacted with the corresponding acid halide compound of R 2 to obtain the compound of formula (Ia).
在一些实施方案中，本申请式(Ib)化合物可由有机合成领域技术人员通过路线2来制备，其中R 2、R 3、X、A和B部分如上定义。 In some embodiments, the compound of formula (Ib) of the present application can be prepared by those skilled in the art of organic synthesis through Route 2, wherein the R 2 , R 3 , X, A, and B moieties are as defined above.
Figure PCTCN2020119633-appb-000093
Figure PCTCN2020119633-appb-000093
路线2Route 2
在合适的条件下，原料1b-1发生缩合反应得到中间体1b-2，接着反应得到中间体1b-3，中间体1b-3与相应的环A化合物发生取代反应得到中间体1b-4，随后对环A的N原子进行保护得到中间体1b-5，中间体1b-5经取代反应得到中间体1b-6，再脱去七元环上N原子保护基得到中间体1b-7。中间体1b-7与相应的环B化合物发生偶联反应得到中间体1b-8，脱保护得到中间体1b-9，最后与R 2相应的酰卤化合物反应得到式(Ib)化合物。 Under suitable conditions, the raw material 1b-1 undergoes condensation reaction to obtain intermediate 1b-2, which is then reacted to obtain intermediate 1b-3, and intermediate 1b-3 undergoes substitution reaction with the corresponding ring A compound to obtain intermediate 1b-4. Subsequently, the N atom of ring A is protected to obtain intermediate 1b-5. Intermediate 1b-5 is substituted to obtain intermediate 1b-6, and then the N atom protecting group on the seven-membered ring is removed to obtain intermediate 1b-7. Intermediate 1b-7 is coupled with the corresponding ring B compound to obtain intermediate 1b-8, deprotected to obtain intermediate 1b-9, and finally reacted with the corresponding acid halide compound of R 2 to obtain the compound of formula (Ib).
上述路线中反应所得的每一个产物可以通过传统分离技术来得到，这种传统技术包 括但不限于过滤、蒸馏、结晶、色谱分离等。起始原料可以通过自己合成或从商业机构(例如，但不限于Adrich或Sigma)购买获得。这些原料可以使用常规手段进行表征，比如物理常数和光谱数据。本申请所描述的化合物可以使用合成方法得到单一的异构体或者是异构体的混合物。Each product obtained from the reaction in the above route can be obtained by traditional separation techniques, which include but are not limited to filtration, distillation, crystallization, chromatographic separation and the like. The starting materials can be synthesized by oneself or purchased from commercial institutions (for example, but not limited to Adrich or Sigma). These raw materials can be characterized by conventional means, such as physical constants and spectral data. The compounds described in this application can be synthesized into a single isomer or a mixture of isomers.
本申请采用下述缩略词：This application uses the following acronyms:
aq代表含水的；SEMCl代表(2-(氯甲氧基)乙基)三甲基硅烷；eq代表当量；1,3-DPPP代表1,3-双(二苯基膦基)丙烷；DCM代表二氯甲烷；DMSO代表二甲基亚砜；Tol代表甲苯；PE代表石油醚；DMF代表N，N-二甲基甲酰胺；NMP代表N-甲基吡咯烷酮；EtOAc代表乙酸乙酯；i-PrOH代表异丙醇；EtOH代表乙醇；MeOH是甲醇；MeONa是甲醇钠；THF代表四氢呋喃；BPO代表过氧苯甲酰；Boc代表叔丁氧羰基；Bn代表苄基；T 3P是丙基磷酸酐；HOAc为乙酸；NaCNBH 3是氰基硼氢化钠；LAH为氢化铝锂；9-BBN是9-硼二环壬烷；MsCl是甲磺酰氯；rt为室温；O/N为过夜；Boc 2O是二叔丁基二碳酸酯；TFA为三氟乙酸；TFAA为三氟乙酸酐；TEA是三乙胺；DIEA是N,N-二异丙基乙胺；DIBAL-H为二异丁基氢化铝；NBS为溴代丁二酰胺；DPPF是1,1'-双(二苯基膦基)二茂铁；Ph 3P是三苯基膦；Pd(OAc) 2是乙酸钯；Pd(PPh 3P) 2CL 2是双(三苯基膦)氯化钯；Pd 2(dba) 3是三(亚苄基丙酮)二钯；XANTPHOS是4,5-双(二苯基膦基)-9,9-二甲基氧杂蒽；n-BuLi是正丁基锂；t-BuOK是叔丁醇钾；t-BuONa是叔丁醇钠；NaOt-Bu是叔丁醇钠；NaO tBu是叔丁醇钠；RuPhos-Pd-G3是甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)；HATU是2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐；ACE-Cl是1-氯乙基氯甲酸酯；DCE是1,2-二氯乙烷；ACN是乙腈；THP是2-四氢吡喃基。 aq stands for aqueous; SEMCl stands for (2-(chloromethoxy)ethyl)trimethylsilane; eq stands for equivalent; 1,3-DPPP stands for 1,3-bis(diphenylphosphino)propane; DCM stands for Dichloromethane; DMSO stands for dimethyl sulfoxide; Tol stands for toluene; PE stands for petroleum ether; DMF stands for N,N-dimethylformamide; NMP stands for N-methylpyrrolidone; EtOAc stands for ethyl acetate; i-PrOH Stands for isopropanol; EtOH stands for ethanol; MeOH stands for methanol; MeONa stands for sodium methoxide; THF stands for tetrahydrofuran; BPO stands for benzoyl peroxide; Boc stands for tert-butoxycarbonyl; Bn stands for benzyl; T 3 P stands for propyl phosphoric anhydride ; HOAc is acetic acid; NaCNBH 3 is sodium cyanoborohydride; LAH is lithium aluminum hydride; 9-BBN is 9-borobicyclononane; MsCl is methanesulfonyl chloride; rt is room temperature; O/N is overnight; Boc 2 O is di-tert-butyl dicarbonate; TFA is trifluoroacetic acid; TFAA is trifluoroacetic anhydride; TEA is triethylamine; DIEA is N,N-diisopropylethylamine; DIBAL-H is diisobutyl Aluminum hydride; NBS is bromosuccinamide; DPPF is 1,1'-bis(diphenylphosphino)ferrocene; Ph 3 P is triphenylphosphine; Pd(OAc) 2 is palladium acetate; Pd( PPh 3 P) 2 CL 2 is bis(triphenylphosphine) palladium chloride; Pd 2 (dba) 3 is tris(benzylideneacetone) dipalladium; XANTPHOS is 4,5-bis(diphenylphosphine) -9,9-Dimethylxanthene; n-BuLi is n-butyl lithium; t-BuOK is potassium tert-butoxide; t-BuONa is sodium tert-butoxide; NaOt-Bu is sodium tert-butoxide; NaO t Bu Is sodium tert-butoxide; RuPhos-Pd-G3 is methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2-amino- 1,1'-Biphenyl-2-yl)palladium(II); HATU is 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate ; ACE-Cl is 1-chloroethyl chloroformate; DCE is 1,2-dichloroethane; ACN is acetonitrile; THP is 2-tetrahydropyranyl.
化合物经人工或者
Figure PCTCN2020119633-appb-000094
软件命名，市售化合物采用供应商目录名称。 The compound is artificially or
Figure PCTCN2020119633-appb-000094
The software is named, and the commercially available compounds use the supplier catalog name.
为清楚起见，进一步用实施例来阐述本发明，但是实施例并非限制本申请的范围。本文已详细描述了本申请，并公开了其具体实施例，对本领域的技术人员而言，在不脱离本申请的精神和范围的情况下针对本申请的实施例进行各种变化和改进将是显而易见的。For clarity, examples are further used to illustrate the present invention, but the examples do not limit the scope of the application. This article has described the application in detail and disclosed its specific embodiments. For those skilled in the art, various changes and improvements will be made to the embodiments of the application without departing from the spirit and scope of the application. Obvious.
本申请所使用的所有试剂是市售的，无需进一步纯化即可使用。All reagents used in this application are commercially available and can be used without further purification.
实施例Example
实施例1Example 1
Figure PCTCN2020119633-appb-000095
Figure PCTCN2020119633-appb-000095
步骤1step 1
将原料 1-1(10.0克)溶于N,N-二甲基甲酰胺(100毫升)中，依次加入5-溴丁酸乙酯(11.9克)，三乙胺(8.00g)。所得溶液于100摄氏度下搅拌16小时。反应完毕后冷却至室温，加入水(200毫升)稀释，并用乙酸乙酯(200毫升x3)萃取。有机相合并后浓缩至干。所得粗品用硅胶柱层析纯化(乙酸乙酯/石油醚＝10％-20％)得产品 1-2(11.4克)。 Raw material 1-1 (10.0 g) was dissolved in N,N-dimethylformamide (100 ml), and ethyl 5-bromobutyrate (11.9 g) and triethylamine (8.00 g) were added in sequence. The resulting solution was stirred at 100 degrees Celsius for 16 hours. After the reaction was completed, it was cooled to room temperature, diluted with water (200 mL), and extracted with ethyl acetate (200 mL×3). The organic phases were combined and concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 10%-20%) to obtain product 1-2 (11.4 g).
LC-MS:m/z 322(M+H) + LC-MS: m/z 322(M+H) +
步骤2Step 2
将原料 1-2(11.4克)溶于甲苯(50毫升)中，于0摄氏度下加入叔丁醇(3.70克)、叔丁醇钾(5.97克)。所得混合物升温至100摄氏度搅拌2小时。反应完毕后，将反应液冷却至室温。加入水(200毫升)稀释，并用乙酸乙酯(200毫升x3)萃取。有机相合所得粗并后浓缩至干。品用硅胶柱层析纯化(乙酸乙酯/石油醚＝10％-20％)得产品 1-3(6.14克)。 The raw material 1-2 (11.4 g) was dissolved in toluene (50 ml), and tert-butanol (3.70 g) and potassium tert-butoxide (5.97 g) were added at 0 degrees Celsius. The resulting mixture was heated to 100 degrees Celsius and stirred for 2 hours. After the completion of the reaction, the reaction solution was cooled to room temperature. It was diluted with water (200 mL) and extracted with ethyl acetate (200 mL×3). The crude obtained from the organic phase was combined and concentrated to dryness. The product was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 10%-20%) to obtain product 1-3 (6.14 g).
LC-MS:m/z 276(M+H) + LC-MS: m/z 276(M+H) +
步骤3Step 3
将原料 1-3(14.3克)溶于无水甲醇(200毫升)中，于0摄氏度下加入甲醇钠的甲醇溶液(30％)(36.0克)、硫脲(15.2克)。所得混合物升温至80摄氏度搅拌1小时。反应完毕后，将反应液冷却至室温。加入稀盐酸(1摩尔/升)调节PH＝7。过滤收集析出的固体，并用水(50毫升)洗涤。固体干燥后，得产品 1-4(13.0克)。 The raw materials 1-3 (14.3 g) were dissolved in anhydrous methanol (200 ml), and sodium methoxide methanol solution (30%) (36.0 g) and thiourea (15.2 g) were added at 0 degrees Celsius. The resulting mixture was heated to 80 degrees Celsius and stirred for 1 hour. After the completion of the reaction, the reaction solution was cooled to room temperature. Add dilute hydrochloric acid (1 mol/L) to adjust PH=7. The precipitated solid was collected by filtration and washed with water (50 mL). After the solid was dried, product 1-4 (13.0 g) was obtained.
LC-MS:m/z 288(M+H) + LC-MS: m/z 288(M+H) +
步骤4Step 4
将原料 1-4(13.0克)悬浮于三氯氧磷(130毫升)中，加入N,N-二甲基甲酰胺(13.0毫升)。所得悬浊液于100摄氏度下搅拌5小时。反应完毕后，将反应液浓缩至干。残余物加入水(100毫升)并用无水碳酸钠调节PH至为8。混合液用乙酸乙酯(200毫升x3)萃取。有机相合并后浓缩至干。所得粗品用硅胶柱层析纯化(乙酸乙酯/石油醚 ＝10％-50％)得产品 1-5(7.50克)。 Raw material 1-4 (13.0 g) was suspended in phosphorus oxychloride (130 ml), and N,N-dimethylformamide (13.0 ml) was added. The resulting suspension was stirred at 100 degrees Celsius for 5 hours. After the completion of the reaction, the reaction solution was concentrated to dryness. Add water (100 ml) to the residue and adjust the pH to 8 with anhydrous sodium carbonate. The mixture was extracted with ethyl acetate (200 mL×3). The organic phases were combined and concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 10%-50%) to obtain product 1-5 (7.50 g).
LC-MS:m/z 308(M+H) + LC-MS: m/z 308(M+H) +
步骤5Step 5
将原料 1-5(7.50克)溶于异丙醇(100毫升)中，依次加入2-氰甲基哌嗪二盐酸盐(5.29克)、二异丙基乙胺(12.6克)。所得混合液于80摄氏度下反应12小时。反应完毕后，加入水(200毫升)稀释。并用乙酸乙酯(200毫升x3)萃取。有机相合并后，用饱和食盐水(200毫升)洗涤，并用无水硫酸钠干燥后浓缩至干，得产品 1-6(7.00克)。 Raw material 1-5 (7.50 g) was dissolved in isopropanol (100 ml), and 2-cyanomethylpiperazine dihydrochloride (5.29 g) and diisopropylethylamine (12.6 g) were sequentially added. The resulting mixture was reacted at 80 degrees Celsius for 12 hours. After the reaction is complete, add water (200 mL) to dilute. It was extracted with ethyl acetate (200 mL×3). After the organic phases were combined, they were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate and concentrated to dryness to obtain product 1-6 (7.00 g).
LC-MS:m/z 397(M+H) + LC-MS: m/z 397(M+H) +
步骤6Step 6
将原料 1-6(7.00克)溶于无水四氢呋喃(100毫升)中，依次加入二碳酸二叔丁酯(4.61克)、二异丙基乙胺(2.72克，21.1毫摩尔)。所得溶液于室温下反应3小时。反应完毕后，加入水(150毫升)稀释，并用乙酸乙酯(150毫升x3)萃取。有机相合并后浓缩至干。所得粗品用硅胶柱层析纯化(乙酸乙酯/石油醚＝30％-60％)得产品 1-7(6.30克)。 Raw material 1-6 (7.00 g) was dissolved in anhydrous tetrahydrofuran (100 ml), and di-tert-butyl dicarbonate (4.61 g) and diisopropylethylamine (2.72 g, 21.1 mmol) were sequentially added. The resulting solution was reacted at room temperature for 3 hours. After the reaction was completed, it was diluted with water (150 mL), and extracted with ethyl acetate (150 mL×3). The organic phases were combined and concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=30%-60%) to obtain product 1-7 (6.30 g).
LC-MS:m/z 497(M+H) + LC-MS: m/z 497(M+H) +
步骤7Step 7
将(S)-脯氨醇(2.18克)溶于无水四氢呋喃(80毫升)中，于0摄氏度下加入氢化钠(60％)(0.760克)。0摄氏度下反应30分钟后，加入原料 1-7(6.30克)。所得溶液于70摄氏度下反应3小时。反应完毕后，冷却至室温。加入饱和氯化铵水溶液(150毫升)淬灭，并用乙酸乙酯(150毫升x3)萃取。有机相合并后浓缩至干。所得粗品用硅胶柱层析纯化(甲醇/二氯甲烷＝5％-20％)得产品 1-8(4.20克)。 (S)-Prolinol (2.18 g) was dissolved in anhydrous tetrahydrofuran (80 ml), and sodium hydride (60%) (0.760 g) was added at 0 degrees Celsius. After reacting for 30 minutes at 0 degrees Celsius, raw materials 1-7 (6.30 g) were added. The resulting solution was reacted at 70 degrees Celsius for 3 hours. After the reaction is complete, cool to room temperature. It was quenched by adding saturated aqueous ammonium chloride solution (150 mL), and extracted with ethyl acetate (150 mL×3). The organic phases were combined and concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (methanol/dichloromethane=5%-20%) to obtain product 1-8 (4.20 g).
LC-MS:m/z 576(M+H) + LC-MS: m/z 576(M+H) +
步骤8Step 8
将原料 1-8(4.20克)溶于无水甲醇(100毫升)中，氮气保护下依次加入钯碳(10％)(0.42克)、氨的甲醇溶液(7摩尔/升)(10毫升)。所得反应液用氢气置换3次，并于40摄氏度反应16小时。反应完毕后，将钯碳滤除。滤液浓缩至干，得产品 1-9(2.55克)。 Dissolve raw materials 1-8 (4.20 g) in dry methanol (100 ml), and add palladium on carbon (10%) (0.42 g) and ammonia methanol solution (7 mol/L) (10 ml) under nitrogen protection. . The resulting reaction solution was replaced with hydrogen three times, and reacted at 40 degrees Celsius for 16 hours. After the reaction is completed, the palladium carbon is filtered off. The filtrate was concentrated to dryness to obtain product 1-9 (2.55 g).
LC-MS:m/z 486(M+H) + LC-MS: m/z 486(M+H) +
步骤9Step 9
将原料 1-9(50.0毫克)溶于甲苯(2毫升)中，依次加入1-溴萘(25.5毫克)，叔丁醇钠(49.4毫克)、甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(25.8毫克)。所得溶液于90摄氏度下搅拌3小时。反应完毕后冷却至室温，加入水(15毫升)稀释，并用乙酸乙酯(15毫升x3)萃取。有机相合并后浓缩至干。所得粗品用硅胶柱层析纯化(二氯甲烷/甲醇＝10％-20％)得产品 1-10(25.0毫克)。 Dissolve raw materials 1-9 (50.0 mg) in toluene (2 ml), add 1-bromonaphthalene (25.5 mg), sodium tert-butoxide (49.4 mg), methanesulfonic acid (2-dicyclohexylphosphino- 2',6'-Diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg). The resulting solution was stirred at 90 degrees Celsius for 3 hours. After the reaction was completed, it was cooled to room temperature, diluted with water (15 mL), and extracted with ethyl acetate (15 mL×3). The organic phases were combined and concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (dichloromethane/methanol=10%-20%) to obtain product 1-10 (25.0 mg).
LC-MS:m/z 612(M+H) + LC-MS: m/z 612(M+H) +
步骤10Step 10
向原料 1-10(25.0毫克)中加入氯化氢的1,4-二氧六环溶液(2毫升)。所得溶液于室温下搅拌10分钟。反应完毕后浓缩至干，得产品 1-11(15.0毫克)。无需纯化，直接用于下步反应。 To raw material 1-10 (25.0 mg), a 1,4-dioxane solution (2 ml) of hydrogen chloride was added. The resulting solution was stirred at room temperature for 10 minutes. After the reaction was completed, it was concentrated to dryness to obtain product 1-11 (15.0 mg). No purification is required, and it is directly used in the next reaction.
LC-MS:m/z 512(M+H) + LC-MS: m/z 512(M+H) +
步骤11Step 11
将原料 1-11(15.0毫克)溶于二氯甲烷(2毫升)中，冷却至-40摄氏度后，依次 加入三乙胺(13.8毫克)、丙烯酰氯(2.47毫克)。所得溶液于-40摄氏度下反应10分钟。反应完毕后，加入水(5毫升)淬灭并浓缩至干。所得粗品用制备型色谱柱纯化(柱型:XBridge Shield RP18 OBD Column,,5um,19*150mm；流动相A:水(10毫摩尔/升，碳酸氢铵),流动相B:乙腈；流速:25毫升/分钟；梯度:38-59％；时间8分钟；检测器波长254/220纳米)，得产品 1(10.8毫克)。 The raw material 1-11 (15.0 mg) was dissolved in dichloromethane (2 ml), and after cooling to -40 degrees Celsius, triethylamine (13.8 mg) and acryloyl chloride (2.47 mg) were sequentially added. The resulting solution was reacted at -40 degrees Celsius for 10 minutes. After the reaction was completed, it was quenched by adding water (5 mL) and concentrated to dryness. The obtained crude product was purified with a preparative chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 ml/min; gradient: 38-59%; time 8 minutes; detector wavelength 254/220 nm) to obtain product 1 (10.8 mg).
LC-MS:m/z 566(M+H) + LC-MS: m/z 566(M+H) +
1H-NMR(CD 3OD)δ:7.95(d,J＝8.4Hz,1H),7.82(d,J＝9.0Hz,1H),7.56(d,J＝8.1Hz,1H),7.46-7.31(m,3H),7.22(d,J＝7.8Hz,1H),7.00-6.75(m,1H),6.31(dd,J 1＝1.5Hz,J 2＝16.5Hz,1H),5.85(dd,J 1＝1.5Hz,J 2＝10.5Hz,1H),5.12-4.60(m,1H),4.43-4.30(m,4H),4.21-4.08(m,1H),4.06-3.91(m,2H),3.82-3.63(m,1H),3.58-3.43(m,3H),3.16-2.93(m,6H),2.83-2.67(m,1H),2.50(s,3H),2.40-2.31(m,1H),2.25-2.03(m,3H),1.87-1.65(m,3H). 1 H-NMR (CD 3 OD) δ: 7.95 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 9.0 Hz, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.46-7.31 (m, 3H), 7.22 (d, J = 7.8 Hz, 1H), 7.00-6.75 (m, 1H), 6.31 (dd, J 1 = 1.5 Hz, J 2 =16.5 Hz, 1H), 5.85 (dd, J 1 ＝1.5Hz, J 2 ＝10.5Hz,1H), 5.12-4.60(m,1H),4.43-4.30(m,4H),4.21-4.08(m,1H),4.06-3.91(m,2H) ,3.82-3.63(m,1H),3.58-3.43(m,3H),3.16-2.93(m,6H),2.83-2.67(m,1H),2.50(s,3H),2.40-2.31(m, 1H), 2.25-2.03 (m, 3H), 1.87-1.65 (m, 3H).
实施例2Example 2
Figure PCTCN2020119633-appb-000096
Figure PCTCN2020119633-appb-000096
步骤1step 1
化合物 2-1的合成参考化合物 1-10。原料 1-9(50.0毫克)，8-氯-1-溴萘(49.5毫克)，叔丁醇钠(98.9毫克)，甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(25.8毫克)，甲苯(2毫升)。得产品 2-1(25.0毫克)。 For the synthesis of compound 2-1 , refer to compound 1-10 . Raw material 1-9 (50.0 mg), 8-chloro-1-bromonaphthalene (49.5 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-di Isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 ml). Product 2-1 (25.0 mg) was obtained.
LC-MS:m/z 646(M+H) + LC-MS: m/z 646(M+H) +
步骤2Step 2
化合物 2-2的合成参考化合物 1-11。原料 2-1(25.0毫克)，氯化氢的1,4-二氧六环溶液(4摩尔/升，2毫升)。得产品 2-2(20.0毫克)。 For the synthesis of compound 2-2 , refer to compound 1-11 . Raw material 2-1 (25.0 mg), 1,4-dioxane solution of hydrogen chloride (4 mol/L, 2 mL). Product 2-2 (20.0 mg) was obtained.
LC-MS:m/z 546(M+H) +. LC-MS: m/z 546(M+H) + .
步骤3Step 3
化合物 2的合成参考化合物 1。原料 2-2(20.0毫克)，三乙胺(17.4毫克)，丙烯酰氯(4.6毫克)，二氯甲烷(5毫升)。得产品 2(4.1毫克)。 The synthesis of compound 2 refers to compound 1 . Raw material 2-2 (20.0 mg), triethylamine (17.4 mg), acryloyl chloride (4.6 mg), dichloromethane (5 mL). Obtained product 2 (4.1 mg).
LC-MS:m/z 600(M+H) + LC-MS: m/z 600(M+H) +
1H-NMR(DMSO)δ:7.90-7.83(m,1H),7.73-7.63(m,1H),7.55-7.22(m,4H),6.97-6.77(m,1H),6.19(d,J＝15.6Hz,1H),5.77(d,J＝10.5Hz,1H),5.04-4.76(m,1H),4.53-4.10(m,4H),4.08-3.96(m,1H),3.74-3.41(m,5H),3.15-2.85(m,3H),2.83-2.66(m,6H),2.30(s,3H),2.21-2.10(m,1H),2.02-1.76(m,2H),1.69-1.51(m,3H). 1 H-NMR (DMSO) δ: 7.90-7.83 (m, 1H), 7.73-7.63 (m, 1H), 7.55-7.22 (m, 4H), 6.97-6.77 (m, 1H), 6.19 (d, J = 15.6Hz, 1H), 5.77 (d, J = 10.5Hz, 1H), 5.04-4.76 (m, 1H), 4.53-4.10 (m, 4H), 4.08-3.96 (m, 1H), 3.74-3.41 ( m,5H),3.15-2.85(m,3H),2.83-2.66(m,6H),2.30(s,3H),2.21-2.10(m,1H),2.02-1.76(m,2H),1.69- 1.51(m,3H).
实施例3Example 3
Figure PCTCN2020119633-appb-000097
Figure PCTCN2020119633-appb-000097
步骤1step 1
化合物 3-1的合成参考化合物 1-10。原料 1-9(50.0毫克)，8-氟-1-溴萘(46.2毫克)，叔丁醇钠(98.9毫克)，甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(25.8毫克)，甲苯(2毫升)。得产品 3-1(25.0毫克)。 For the synthesis of compound 3-1 , refer to compound 1-10 . Raw material 1-9 (50.0 mg), 8-fluoro-1-bromonaphthalene (46.2 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-di Isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 ml). Product 3-1 (25.0 mg) was obtained.
LC-MS:m/z 630(M+H) + LC-MS: m/z 630(M+H) +
步骤2Step 2
化合物 3-2的合成参考化合物 1-11。原料 3-1(25.0毫克)，氯化氢的1,4-二氧六环溶液(4摩尔/升，2毫升)。得产品 3-2(20.0毫克)。 For the synthesis of compound 3-2 , refer to compound 1-11 . Raw material 3-1 (25.0 mg), 1,4-dioxane solution of hydrogen chloride (4 mol/L, 2 mL). Product 3-2 (20.0 mg) was obtained.
LC-MS:m/z 530(M+H) +. LC-MS: m/z 530(M+H) + .
步骤3Step 3
化合物 3的合成参考化合物 1。原料 3-2(20.0毫克)，三乙胺(17.4毫克)，丙烯酰氯(4.6毫克)，二氯甲烷(5毫升)。得产品 3(4.1毫克)。 For the synthesis of compound 3 , refer to compound 1 . Raw material 3-2 (20.0 mg), triethylamine (17.4 mg), acryloyl chloride (4.6 mg), dichloromethane (5 mL). Product 3 (4.1 mg) was obtained.
LC-MS:m/z 584(M+H) + LC-MS: m/z 584(M+H) +
1H-NMR(DMSO)δ:7.90-7.83(m,1H),7.73-7.63(m,1H),7.55-7.22(m,4H),6.97-6.77(m,1H),6.19(d,J＝15.6Hz,1H),5.77(d,J＝10.5Hz,1H),5.04-4.76(m,1H),4.53-4.10(m,4H),4.08-3.96(m,1H),3.74-3.41(m,5H),3.15-2.85(m,3H),2.83-2.66(m,6H),2.30(s,3H),2.21-2.10(m,1H),2.02-1.76(m,2H),1.69-1.51(m,3H). 1 H-NMR (DMSO) δ: 7.90-7.83 (m, 1H), 7.73-7.63 (m, 1H), 7.55-7.22 (m, 4H), 6.97-6.77 (m, 1H), 6.19 (d, J = 15.6Hz, 1H), 5.77 (d, J = 10.5Hz, 1H), 5.04-4.76 (m, 1H), 4.53-4.10 (m, 4H), 4.08-3.96 (m, 1H), 3.74-3.41 ( m,5H),3.15-2.85(m,3H),2.83-2.66(m,6H),2.30(s,3H),2.21-2.10(m,1H),2.02-1.76(m,2H),1.69- 1.51(m,3H).
实施例5Example 5
Figure PCTCN2020119633-appb-000098
Figure PCTCN2020119633-appb-000098
步骤1step 1
化合物 5-1的合成参考化合物 1。原料 4-2(20.0毫克)，4-溴巴豆酰氯(8.34毫克)，二氯甲烷(5毫升)。得产品 5-1(18.3毫克)。 For the synthesis of compound 5-1 , refer to compound 1 . Raw material 4-2 (20.0 mg), 4-bromocrotonyl chloride (8.34 mg), dichloromethane (5 mL). Product 5-1 (18.3 mg) was obtained.
LC-MS:m/z 672(M+H) + LC-MS: m/z 672(M+H) +
步骤2Step 2
将原料 5-1(18.3毫克)溶于N,N-二甲基甲酰胺(3毫升)中，依次加入N,N-二异丙基乙胺(7.02毫克)、***啉(2.86毫克)。所得溶液于室温下反应16小时。反应完毕后，加入水(5毫升)淬灭并浓缩至干。所得粗品用制备型色谱柱纯化(柱型:XBridge Shield RP18 OBD Column,,5um,19*150mm；流动相A:水(10毫摩尔/升，碳酸氢铵),流动相B:乙腈；流速:25毫升/分钟；梯度:37-63％；时间8分钟；检测器波长254/220纳米)，得产品 5(2.00毫克)。 Raw material 5-1 (18.3 mg) was dissolved in N,N-dimethylformamide (3 mL), and N,N-diisopropylethylamine (7.02 mg) and morpholine (2.86 mg) were added in sequence. The resulting solution was reacted at room temperature for 16 hours. After the reaction was completed, it was quenched by adding water (5 mL) and concentrated to dryness. The obtained crude product was purified with a preparative chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; 25 ml/min; gradient: 37-63%; time 8 minutes; detector wavelength 254/220 nm) to obtain product 5 (2.00 mg).
LC-MS:m/z 679(M+H) + LC-MS: m/z 679(M+H) +
1H-NMR(CD 3OD)δ:7.72-7.61(m,2H),7.44-7.11(m,4H),6.92-6.67(m,2H),5.17-5.05(m,1H),4.70-4.56(m,1H),4.49-4.28(m,3H),4.25-4.07(m,2H),3.97-3.59(m,7H),3.54-3.39(m,2H),3.27-3.22(m,2H),3.14-2.87(m,6H),2.86-2.70(m,4H),2.60-2.44(m,5H),2.44-2.33(m,1H),2.19-1.94(m,4H),1.88-1.58(m,4H). 1 H-NMR (CD 3 OD) δ: 7.72-7.61 (m, 2H), 7.44-7.11 (m, 4H), 6.92-6.67 (m, 2H), 5.17-5.05 (m, 1H), 4.70-4.56 (m, 1H), 4.49-4.28 (m, 3H), 4.25-4.07 (m, 2H), 3.97-3.59 (m, 7H), 3.54-3.39 (m, 2H), 3.27-3.22 (m, 2H) ,3.14-2.87(m,6H),2.86-2.70(m,4H),2.60-2.44(m,5H),2.44-2.33(m,1H),2.19-1.94(m,4H),1.88-1.58( m,4H).
实施例6Example 6
Figure PCTCN2020119633-appb-000099
Figure PCTCN2020119633-appb-000099
化合物 6的合成参考化合物 5。原料 5-1(15毫克)，N,N-二异丙基乙胺(7.19毫克)，3-氟丫丁啶盐酸盐(2.00毫克)N,N-二甲基甲酰胺(3毫升)。得产品 6(0.30毫克)。 For the synthesis of compound 6 , refer to compound 5 . Raw material 5-1 (15mg), N,N-diisopropylethylamine (7.19mg), 3-fluoroabutidine hydrochloride (2.00mg) N,N-dimethylformamide (3ml) . Product 6 (0.30 mg) was obtained.
LC-MS:m/z 667(M+H) + LC-MS: m/z 667(M+H) +
1H-NMR(CD 3OD)δ:7.81-7.53(m,2H),7.49-7.11(m,4H),6.89-6.54(m,2H),5.35-5.20(m,1H),5.18-4.99(m,2H),4.67-4.60(m,2H),4.59-4.50(m,1H),4.49-4.29(m,2H),4.26-4.06(m,2H),4.02-3.62(m,5H),3.59-3.35(m,6H),3.30-2.88(m,7H),3.87-2.45(m,5H),2.44-2.16(m,2H),2.13-2.74(m,4H). 1 H-NMR (CD 3 OD) δ: 7.81-7.53 (m, 2H), 7.49-7.11 (m, 4H), 6.89-6.54 (m, 2H), 5.35-5.20 (m, 1H), 5.18-4.99 (m, 2H), 4.67-4.60 (m, 2H), 4.59-4.50 (m, 1H), 4.49-4.29 (m, 2H), 4.26-4.06 (m, 2H), 4.02-3.62 (m, 5H) , 3.59-3.35 (m, 6H), 3.30-2.88 (m, 7H), 3.87-2.45 (m, 5H), 2.44-2.16 (m, 2H), 2.13-2.74 (m, 4H).
实施例10、实施例11和实施例12Example 10, Example 11 and Example 12
Figure PCTCN2020119633-appb-000100
Figure PCTCN2020119633-appb-000100
步骤1step 1
化合物 10-1的合成参考化合物 1-10。原料 1-9(50.0毫克)，2-溴-6-甲基-三氟甲苯(49.0毫克)，叔丁醇钠(98.9毫克)，甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(25.8毫克)，甲苯(2毫升)。得产品 10-1(25.0毫克)。 For the synthesis of compound 10-1 , refer to compound 1-10 . Raw material 1-9 (50.0 mg), 2-bromo-6-methyl-benzotrifluoride (49.0 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2', 6'-Diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). Product 10-1 (25.0 mg) was obtained.
LC-MS:m/z 644(M+H) + LC-MS: m/z 644(M+H) +
步骤2Step 2
化合物 10-2的合成参考化合物 1-11。原料 10-1(25.0毫克)，氯化氢的1,4-二氧六环溶液(4摩尔/升，5毫升)。得产品 10-2(21.0毫克)。 For the synthesis of compound 10-2 , refer to compound 1-11 . Raw material 10-1 (25.0 mg), 1,4-dioxane solution of hydrogen chloride (4 mol/L, 5 mL). Product 10-2 (21.0 mg) was obtained.
LC-MS:m/z 544(M+H) +. LC-MS: m/z 544(M+H) + .
步骤3Step 3
化合物 10的合成参考化合物 1。原料 10-2(21.0毫克)，三乙胺(18.3毫克)，丙烯酰氯(4.93毫克)，二氯甲烷(5毫升)。得产品 10(13.5毫克)。 For the synthesis of compound 10 , refer to compound 1 . Raw material 10-2 (21.0 mg), triethylamine (18.3 mg), acryloyl chloride (4.93 mg), dichloromethane (5 mL). Product 10 (13.5 mg) was obtained.
LC-MS:m/z 598(M+H) + LC-MS: m/z 598(M+H) +
1H-NMR(CD 3OD)δ:7.42(t,J＝7.8Hz,1H),7.30(d,J＝8.1Hz,1H),7.11(d,J＝7.5Hz,1H),6.94-6.74(m,1H),6.30(d,J＝16.5Hz,1H),5.84(d,J＝10.5Hz,1H),5.22-5.04(m,1H),4.71-4.47(m,1H),4.42-4.28(m,2H),4.27-4.06(m,3H),3.97-3.78(m,2H),3.57-3.37(m,1H),3.30-3.20(m,2H),3.16-2.93(m,4H),2.93-2.70(m，3H),2.51(s,3H),2.47(q,J＝3.6Hz,3H),2.42-2.31(m,1H),2.17-1.93(m,3H),1.90-1.63(m,3H). 1 H-NMR(CD 3 OD)δ:7.42(t,J=7.8Hz,1H), 7.30(d,J=8.1Hz,1H), 7.11(d,J=7.5Hz,1H), 6.94-6.74 (m, 1H), 6.30 (d, J = 16.5 Hz, 1H), 5.84 (d, J = 10.5 Hz, 1H), 5.22-5.04 (m, 1H), 4.71-4.47 (m, 1H), 4.42 4.28 (m, 2H), 4.27-4.06 (m, 3H), 3.97-3.78 (m, 2H), 3.57-3.37 (m, 1H), 3.30-3.20 (m, 2H), 3.16-2.93 (m, 4H) ), 2.93-2.70(m,3H),2.51(s,3H),2.47(q,J=3.6Hz,3H),2.42-2.31(m,1H),2.17-1.93(m,3H),1.90- 1.63(m,3H).
步骤4Step 4
化合物 10经手性高压制备拆分(柱型：CHIRAL ART Cellulose-SB2*25cm,5um；流动相A:正己烷(0.1％,二乙胺)，流动相:异丙醇；流速:20毫升/分钟；梯度:30％，时间20分钟；检测器波长254/220纳米)。)为产品 11和 12。 Compound 10 was prepared and resolved by chiral high pressure (column type: CHIRAL ART Cellulose-SB2*25cm, 5um; mobile phase A: n-hexane (0.1%, diethylamine), mobile phase: isopropanol; flow rate: 20 ml/min ; Gradient: 30%, time 20 minutes; detector wavelength 254/220 nm). ) Are products 11 and 12 .
产品 11：保留时间为2.09分钟， Product 11 : retention time is 2.09 minutes,
1H-NMR(CD 3OD)δ:7.42(t,J＝7.8Hz,1H),7.31(d,J＝8.1Hz,1H),7.11(d,J＝7.5Hz,1H),6.96-6.76(m,1H),6.30(d,J＝16.6Hz,1H),5.85(d,J＝10.6Hz,1H),5.23-5.03(m,1H),4.68-4.58(m,1H),4.40-4.28(m,2H),4.27-4.07(m,3H),3.97-3.80(m,2H),3.72-3.58(m,1H),3.29-3.22(m,2H),3.13-2.75(m,7H),2.51(s,3H),2.47(q,J＝3.6Hz,3H),2.43-2.35(m,1H),2.14-1.96(m,3H),1.88-1.68(m,3H). 1 H-NMR (CD 3 OD) δ: 7.42 (t, J = 7.8 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 7.11 (d, J = 7.5 Hz, 1H), 6.96-6.76 (m, 1H), 6.30 (d, J = 16.6 Hz, 1H), 5.85 (d, J = 10.6 Hz, 1H), 5.23-5.03 (m, 1H), 4.68-4.58 (m, 1H), 4.40- 4.28(m,2H),4.27-4.07(m,3H),3.97-3.80(m,2H),3.72-3.58(m,1H),3.29-3.22(m,2H),3.13-2.75(m,7H) ), 2.51 (s, 3H), 2.47 (q, J = 3.6 Hz, 3H), 2.43-2.35 (m, 1H), 2.14-1.96 (m, 3H), 1.88-1.68 (m, 3H).
化合物 12：保留时间为3.20分钟， Compound 12 : Retention time is 3.20 minutes,
1H-NMR(CD 3OD)δ:7.42-7.39(m,1H),7.31(d,J＝8.1Hz,1H),7.12(d,J＝7.5Hz,1H),6.96-6.76(m,1H),6.30(d,J＝16.6Hz,1H),5.87(d,J＝10.6Hz,1H),5.26-5.05(m,1H),4.70-4.59(m,1H),4.40-4.32(m,2H),4.29-4.07(m,3H),3.97-3.81(m,2H),3.70-3.58(m,1H),3.33-3.22(m,3H),3.13-3.07(m,1H),3.06-2.98(m,2H),2.92-2.80(m,3H),2.51(s,3H),2.47-2.40(m,4H),2.15-1.90(m,3H),1.88-1.68(m,3H). 1 H-NMR(CD 3 OD)δ:7.42-7.39(m,1H), 7.31(d,J=8.1Hz,1H), 7.12(d,J=7.5Hz,1H), 6.96-6.76(m, 1H), 6.30 (d, J = 16.6 Hz, 1H), 5.87 (d, J = 10.6 Hz, 1H), 5.26-5.05 (m, 1H), 4.70-4.59 (m, 1H), 4.40-4.32 (m ,2H),4.29-4.07(m,3H),3.97-3.81(m,2H),3.70-3.58(m,1H),3.33-3.22(m,3H),3.13-3.07(m,1H),3.06 -2.98 (m, 2H), 2.92-2.80 (m, 3H), 2.51 (s, 3H), 2.47-2.40 (m, 4H), 2.15-1.90 (m, 3H), 1.88-1.68 (m, 3H) .
实施例13Example 13
Figure PCTCN2020119633-appb-000101
Figure PCTCN2020119633-appb-000101
步骤1step 1
化合物 13-1的合成参考化合物 1-10。原料 1-9(50.0毫克)，2-溴-6-氯三氟甲苯(53.1毫克)，叔丁醇钠(98.9毫克)，甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(25.8毫克)，甲苯(2毫升)。得产品 13-1(28.0毫克)。 For the synthesis of compound 13-1 , refer to compound 1-10 . Raw material 1-9 (50.0 mg), 2-bromo-6-chlorobenzotrifluoride (53.1 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2', 6'-Diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 ml). The product 13-1 (28.0 mg) was obtained.
LC-MS:m/z 664(M+H) + LC-MS: m/z 664(M+H) +
步骤2Step 2
化合物 13-2的合成参考化合物 1-11。原料 13-1(28.0毫克)，氯化氢的1,4-二氧六环溶液(4摩尔/升，5毫升)。得产品 13-2(24.3毫克)。 For the synthesis of compound 13-2 , refer to compound 1-11 . Raw material 13-1 (28.0 mg), 1,4-dioxane solution of hydrogen chloride (4 mol/L, 5 mL). The product 13-2 (24.3 mg) was obtained.
LC-MS:m/z 564(M+H) +. LC-MS: m/z 564(M+H) + .
步骤3Step 3
化合物 13的合成参考化合物 1。原料 13-2(23.3毫克)，三乙胺(19.6毫克)，丙烯酰氯(5.28毫克)，二氯甲烷(5毫升)。得产品 13(8.70毫克)。 The synthesis of compound 13 refers to compound 1 . Starting material 13-2 (23.3 mg), triethylamine (19.6 mg), acryloyl chloride (5.28 mg), dichloromethane (5 mL). Product 13 (8.70 mg) was obtained.
LC-MS:m/z 618(M+H) + LC-MS: m/z 618(M+H) +
1H-NMR(CD 3OD)δ:7.43(t,J＝8.2Hz,1H),7.30-7.22(m,2H),6.94-6.75(m,1H),6.30(d,J＝16.5Hz,1H),5.84(d,J＝10.5Hz,1H),5.19-5.01(m,1H),4.69-4.46(m,1H),4.41-4.20(m,4H),3.99-3.75(m,3H),3.69-3.59(m,1H),3.47-3.36(m,1H),3.29-3.22(m,1H),3.19-2.89(m,4H),2.88-2.73(m,3H),2.53(s,3H),2.45-2.33(m,1H),2.19-1.94(m,3H),1.91-1.67(m,3H). 1 H-NMR (CD 3 OD) δ: 7.43 (t, J = 8.2 Hz, 1H), 7.30-7.22 (m, 2H), 6.94-6.75 (m, 1H), 6.30 (d, J = 16.5 Hz, 1H), 5.84 (d, J = 10.5 Hz, 1H), 5.19-5.01 (m, 1H), 4.69-4.46 (m, 1H), 4.41-4.20 (m, 4H), 3.99-3.75 (m, 3H) , 3.69-3.59 (m, 1H), 3.47-3.36 (m, 1H), 3.29-3.22 (m, 1H), 3.19-2.89 (m, 4H), 2.88-2.73 (m, 3H), 2.53 (s, 3H), 2.45-2.33 (m, 1H), 2.19-1.94 (m, 3H), 1.91-1.67 (m, 3H).
实施例15Example 15
Figure PCTCN2020119633-appb-000102
Figure PCTCN2020119633-appb-000102
步骤1step 1
化合物 15-1的合成参考化合物 1-10。原料 1-9(50.0毫克)，1-溴-7-甲基萘(34.0毫克)，叔丁醇钠(98.9毫克)，甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(25.8毫克)，甲苯(2毫升)。得产品 15-1(25.0毫克)。 For the synthesis of compound 15-1 , refer to compound 1-10 . Raw material 1-9 (50.0 mg), 1-bromo-7-methylnaphthalene (34.0 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'- Diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). Product 15-1 (25.0 mg) was obtained.
LC-MS:m/z 626(M+H) + LC-MS: m/z 626(M+H) +
步骤2Step 2
化合物 15-2的合成参考化合物 1-11。原料 15-1(25.0毫克)，氯化氢的1,4-二氧六环溶液(4摩尔/升，5毫升)。得产品 15-2(21.5毫克)。 For the synthesis of compound 15-2 , refer to compound 1-11 . Raw material 15-1 (25.0 mg), 1,4-dioxane solution of hydrogen chloride (4 mol/L, 5 mL). Product 15-2 (21.5 mg) was obtained.
LC-MS:m/z 526(M+H) +. LC-MS: m/z 526(M+H) + .
步骤3Step 3
化合物 15的合成参考化合物 1。原料 15-2(21.5毫克)，三乙胺(19.4毫克)，丙烯酰氯(5.20毫克)，二氯甲烷(5毫升)。得产品 15(4.8毫克)。 The synthesis of compound 15 refers to compound 1 . Starting material 15-2 (21.5 mg), triethylamine (19.4 mg), acryloyl chloride (5.20 mg), dichloromethane (5 mL). Product 15 (4.8 mg) was obtained.
LC-MS:m/z 580(M+H) + LC-MS: m/z 580(M+H) +
1H-NMR(CD 3OD)δ:7.78-7.65(m,2H),7.50(d,J＝8.1Hz,1H),7.37-7.24(m,2H),7.17(d,J＝7.4Hz,1H),6.93-6.79(m,1H),6.31(d,J＝16.6Hz,1H),5.85(d,J＝10.7Hz,1H),5.22-5.08(m,1H),4.69-4.53(m,1H),4.49-4.31(m,2H),4.23-4.09(m,1H),4.05-3.88(m,2H),3.80-3.66(m,1H),3.61-3.41(m,3H),3.41-3.38(m,1H),3.22-2.91(m,6H),2.84-2.74(m,1H),2.52(s,3H),2.42-2.37(m,1H),2.35(s,3H),2.25-2.01(m,3H),1.91-1.67(m,3H). 1 H-NMR (CD 3 OD) δ: 7.78-7.65 (m, 2H), 7.50 (d, J = 8.1 Hz, 1H), 7.37-7.24 (m, 2H), 7.17 (d, J = 7.4 Hz, 1H), 6.93-6.79 (m, 1H), 6.31 (d, J = 16.6Hz, 1H), 5.85 (d, J = 10.7Hz, 1H), 5.22-5.08 (m, 1H), 4.69-4.53 (m ,1H),4.49-4.31(m,2H),4.23-4.09(m,1H),4.05-3.88(m,2H),3.80-3.66(m,1H),3.61-3.41(m,3H),3.41 -3.38(m,1H),3.22-2.91(m,6H),2.84-2.74(m,1H),2.52(s,3H),2.42-2.37(m,1H),2.35(s,3H),2.25 -2.01(m,3H),1.91-1.67(m,3H).
实施例16Example 16
Figure PCTCN2020119633-appb-000103
Figure PCTCN2020119633-appb-000103
步骤1step 1
化合物 16-1的合成参考化合物 1-10。原料 1-9(50.0毫克)，1-溴-7-氯萘(49.4毫克)，叔丁醇钠(98.9毫克)，甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(25.8毫克)，甲苯(2毫升)。得产品 16-1(29.0毫克)。 For the synthesis of compound 16-1 , refer to compound 1-10 . Raw material 1-9 (50.0 mg), 1-bromo-7-chloronaphthalene (49.4 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-di Isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 ml). The product 16-1 (29.0 mg) was obtained.
LC-MS:m/z 646(M+H) + LC-MS: m/z 646(M+H) +
步骤2Step 2
化合物 16-2的合成参考化合物 1-11。原料 16-1(29.0毫克)，氯化氢的1,4-二氧六环溶液(4摩尔/升，5毫升)。得产品 16-2(24.5毫克)。 For the synthesis of compound 16-2 , refer to compound 1-11 . Raw material 16-1 (29.0 mg), 1,4-dioxane solution of hydrogen chloride (4 mol/L, 5 mL). Product 16-2 (24.5 mg) was obtained.
LC-MS:m/z 546(M+H) +. LC-MS: m/z 546(M+H) + .
步骤3Step 3
化合物 16的合成参考化合物 1。原料 16-2(24.5毫克)，三乙胺(21.3毫克)，丙烯酰氯(5.73毫克)，二氯甲烷(5毫升)。得产品 16(5.0毫克)。 The synthesis of compound 16 refers to compound 1 . Raw material 16-2 (24.5 mg), triethylamine (21.3 mg), acryloyl chloride (5.73 mg), dichloromethane (5 mL). Obtained product 16 (5.0 mg).
LC-MS:m/z 600(M+H) + LC-MS: m/z 600(M+H) +
1H-NMR(CD 3OD)δ:7.93-7.78(m,2H),7.58(d,J＝8.1Hz,1H),7.51-7.36(m,2H),7.29(d,J＝7.8Hz,1H),6.91-6.78(m,1H),6.31(d,J＝16.5Hz,1H),5.85(d,J＝10.7Hz,1H),5.21-5.07(m,1H)，4.70-4.54(m,1H),4.49-4.35(m,2H),4.28(d,J＝4.2Hz,2H),4.08-3.90(m,2H),3.81-3.65(m,1H),3.61-3.52(m,1H),3.51-3.37(m,2H),3.31-2.81(m,7H),2.55(s,3H),2.47-2.37(m,1H),2.28-2.02(m,3H),1.92-1.72(m,3H). 1 H-NMR (CD 3 OD) δ: 7.93-7.78 (m, 2H), 7.58 (d, J = 8.1 Hz, 1H), 7.51-7.36 (m, 2H), 7.29 (d, J = 7.8 Hz, 1H), 6.91-6.78 (m, 1H), 6.31 (d, J = 16.5 Hz, 1H), 5.85 (d, J = 10.7 Hz, 1H), 5.21-5.07 (m, 1H), 4.70-4.54 (m ,1H),4.49-4.35(m,2H),4.28(d,J=4.2Hz,2H),4.08-3.90(m,2H),3.81-3.65(m,1H),3.61-3.52(m,1H) ), 3.51-3.37 (m, 2H), 3.31-2.81 (m, 7H), 2.55 (s, 3H), 2.47-2.37 (m, 1H), 2.28-2.02 (m, 3H), 1.92-1.72 (m ,3H).
实施例17Example 17
Figure PCTCN2020119633-appb-000104
Figure PCTCN2020119633-appb-000104
步骤1step 1
化合物 17-1的合成参考化合物 1-10。原料 1-9(50.0毫克)，2-溴-6-甲氧基三氟甲苯(52.3毫克)，叔丁醇钠(98.9毫克)，甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(25.8毫克)，甲苯(2毫升)。得产品 17-1(32.0毫克)。 For the synthesis of compound 17-1 , refer to compound 1-10 . Raw material 1-9 (50.0 mg), 2-bromo-6-methoxybenzotrifluoride (52.3 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2', 6'-Diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). The product 17-1 (32.0 mg) was obtained.
LC-MS:m/z 660(M+H) + LC-MS: m/z 660(M+H) +
步骤2Step 2
化合物 17-2的合成参考化合物 1-11。原料 17-1(32.0毫克)，氯化氢的1,4-二氧六环溶液(4摩尔/升，5毫升)。得产品 17-2(27.8毫克)。 For the synthesis of compound 17-2 , refer to compound 1-11 . Raw material 17-1 (32.0 mg), 1,4-dioxane solution of hydrogen chloride (4 mol/L, 5 mL). The product 17-2 (27.8 mg) was obtained.
LC-MS:m/z 560(M+H) +. LC-MS: m/z 560(M+H) + .
步骤3Step 3
化合物 17的合成参考化合物 1。原料 17-2(27.8毫克)，三乙胺(23.6毫克)，丙烯酰氯(6.34毫克)，二氯甲烷(5毫升)。得产品 17(9.20毫克)。 For the synthesis of compound 17 , refer to compound 1 . Starting material 17-2 (27.8 mg), triethylamine (23.6 mg), acryloyl chloride (6.34 mg), dichloromethane (5 mL). Product 17 (9.20 mg) was obtained.
LC-MS:m/z 614(M+H) + LC-MS: m/z 614(M+H) +
1H-NMR(CD 3OD)δ:7.41(t,J＝8.1Hz,1H),6.96-6.71(m,3H),6.30(d,J＝16.8Hz,1H),5.84(d,J＝10.8Hz,1H),5.21-5.05(m,1H),4.76-4.46(m,1H),4.43-4.33(m,2H),4.33-4.17(m,2H),4.16-4.00(m,1H),3.98-3.88(m,1H),3.86(s,3H),3.83-3.74(m,1H),3.71-3.54(m,1H),3.49-3.35(m,2H),3.24-2.77(m,7H),2.56(s,3H),2.49-2.36(m,1H),2.18-1.93(m,3H),1.91-1.68(m,3H). 1 H-NMR (CD 3 OD) δ: 7.41 (t, J = 8.1 Hz, 1H), 6.96-6.71 (m, 3H), 6.30 (d, J = 16.8 Hz, 1H), 5.84 (d, J = 10.8Hz, 1H), 5.21-5.05 (m, 1H), 4.76-4.46 (m, 1H), 4.43-4.33 (m, 2H), 4.33-4.17 (m, 2H), 4.16-4.00 (m, 1H) ,3.98-3.88(m,1H),3.86(s,3H),3.83-3.74(m,1H),3.71-3.54(m,1H),3.49-3.35(m,2H),3.24-2.77(m, 7H), 2.56 (s, 3H), 2.49-2.36 (m, 1H), 2.18-1.93 (m, 3H), 1.91-1.68 (m, 3H).
实施例18Example 18
Figure PCTCN2020119633-appb-000105
Figure PCTCN2020119633-appb-000105
步骤1step 1
化合物 18-1的合成参考化合物 1-10。原料 1-9(50.0毫克)，3-溴-4-三氟甲基吡啶(46.4毫克)，叔丁醇钠(98.9毫克)，甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(25.8毫克)，甲苯(2毫升)。得产品 18-1(26.0毫克)。 For the synthesis of compound 18-1 , refer to compound 1-10 . Raw material 1-9 (50.0 mg), 3-bromo-4-trifluoromethylpyridine (46.4 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2', 6 '-Diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). The product 18-1 (26.0 mg) was obtained.
LC-MS:m/z 631(M+H) + LC-MS: m/z 631(M+H) +
步骤2Step 2
化合物 18-2的合成参考化合物 1-11。原料 18-1(26.0毫克)，氯化氢的1,4-二氧六环溶液(4摩尔/升，5毫升)。得产品 18-2(22.5毫克)。 For the synthesis of compound 18-2 , refer to compound 1-11 . Raw material 18-1 (26.0 mg), 1,4-dioxane solution of hydrogen chloride (4 mol/L, 5 mL). Product 18-2 (22.5 mg) was obtained.
LC-MS:m/z 531(M+H) +. LC-MS: m/z 531(M+H) + .
步骤3Step 3
化合物 18的合成参考化合物 1。原料 18-2(22.5毫克)，三乙胺(20.1毫克)，丙烯酰氯(5.40毫克)，二氯甲烷(5毫升)。得产品 18(8.30毫克)。 For the synthesis of compound 18 , refer to compound 1 . Raw material 18-2 (22.5 mg), triethylamine (20.1 mg), acryloyl chloride (5.40 mg), dichloromethane (5 mL). Product 18 (8.30 mg) was obtained.
LC-MS:m/z 585(M+H) + LC-MS: m/z 585(M+H) +
1H-NMR(CD 3OD)δ:8.69(s,1H),8.48(d,J＝5.1Hz,1H),7.64(d,J＝5.1Hz,1H),6.94-6.76(m,1H),6.30(d,J＝16.5Hz,1H),5.85(d,J＝10.6Hz,1H),5.21-5.03(m,1H),4.81-4.51(m,1H),4.44-4.25(m,4H),4.21-4.04(m,1H),3.96-3.78(m,2H),3.75-3.59(m,1H),3.56-3.41(m,2H),3.16-2.69(m,7H),2.52(s,3H),2.44-2.32(m,1H),2.19-1.99(m,3H),1.89-1.65(m,3H). 1 H-NMR(CD 3 OD)δ: 8.69(s,1H), 8.48(d,J=5.1Hz,1H), 7.64(d,J=5.1Hz,1H), 6.94-6.76(m,1H) ,6.30(d,J=16.5Hz,1H),5.85(d,J=10.6Hz,1H),5.21-5.03(m,1H),4.81-4.51(m,1H),4.44-4.25(m,4H ),4.21-4.04(m,1H),3.96-3.78(m,2H),3.75-3.59(m,1H),3.56-3.41(m,2H),3.16-2.69(m,7H),2.52(s ,3H),2.44-2.32(m,1H),2.19-1.99(m,3H),1.89-1.65(m,3H).
实施例19Example 19
Figure PCTCN2020119633-appb-000106
Figure PCTCN2020119633-appb-000106
步骤1step 1
化合物 19-1的合成参考化合物 1-10。原料 1-9(50.0毫克)，2-溴-6-氟三氟甲苯(49.9毫克)，叔丁醇钠(98.9毫克)，甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(25.8毫克)，甲苯(2毫升)。得产品 19-1(27.0毫克)。 For the synthesis of compound 19-1 , refer to compound 1-10 . Raw material 1-9 (50.0 mg), 2-bromo-6-fluorobenzotrifluoride (49.9 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2', 6'-Diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 ml). The product 19-1 (27.0 mg) was obtained.
LC-MS:m/z 648(M+H) + LC-MS: m/z 648(M+H) +
步骤2Step 2
化合物 19-2的合成参考化合物 1-11。原料 19-1(27.0毫克)，氯化氢的1,4-二氧六环溶液(4摩尔/升，5毫升)。得产品 19-2(25.6毫克)。 For the synthesis of compound 19-2 , refer to compound 1-11 . Raw material 19-1 (27.0 mg), 1,4-dioxane solution of hydrogen chloride (4 mol/L, 5 mL). Product 19-2 (25.6 mg) was obtained.
LC-MS:m/z 548(M+H) +. LC-MS: m/z 548(M+H) + .
步骤3Step 3
化合物 19的合成参考化合物 1。原料 19-2(25.6毫克)，三乙胺(22.2毫克)，丙烯酰氯(5.96毫克)，二氯甲烷(5毫升)。得产品 19(5.9毫克)。 For the synthesis of compound 19 , refer to compound 1 . Starting material 19-2 (25.6 mg), triethylamine (22.2 mg), acryloyl chloride (5.96 mg), dichloromethane (5 mL). Obtained product 19 (5.9 mg).
LC-MS:m/z 602(M+H) + LC-MS: m/z 602(M+H) +
1H-NMR(CD 3OD)δ:7.65-7.57(m,1H),7.45-7.35(m,2H),6.93-4.78(m,1H),6.30(d,J＝16.5Hz,1H),5.85(d,J＝10.6Hz,1H),5.22-5.07(m,1H),4.82-4.48(m,1H),4.40-4.27(m,2H),4.24-4.01(m,2H),4.00-3.79(m,2H),3.75-3.44(m,2H),3.28-3.17(m,2H),3.13-2.70(m,7H),2.50(s,3H),2.42-2.32(m,1H),2.15-1.93(m,3H),1.88-1.67(m,3H). 1 H-NMR(CD 3 OD)δ:7.65-7.57(m,1H),7.45-7.35(m,2H),6.93-4.78(m,1H),6.30(d,J=16.5Hz,1H), 5.85(d,J=10.6Hz,1H),5.22-5.07(m,1H),4.82-4.48(m,1H),4.40-4.27(m,2H),4.24-4.01(m,2H),4.00- 3.79(m, 2H), 3.75-3.44(m, 2H), 3.28-3.17(m, 2H), 3.13-2.70(m, 7H), 2.50(s, 3H), 2.42-2.32(m, 1H), 2.15-1.93 (m, 3H), 1.88-1.67 (m, 3H).
实施例20Example 20
Figure PCTCN2020119633-appb-000107
Figure PCTCN2020119633-appb-000107
步骤1step 1
化合物 20-1的合成参考化合物 1-10。原料 1-9(50.0毫克)，2-氟-溴苯(35.8 毫克)，叔丁醇钠(98.9毫克)，甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(25.8毫克)，甲苯(2毫升)。得产品 20-1(31.0毫克)。 For the synthesis of compound 20-1 , refer to compound 1-10 . Raw material 1-9 (50.0 mg), 2-fluoro-bromobenzene (35.8 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropyl Oxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). Obtained product 20-1 (31.0 mg).
LC-MS:m/z 580(M+H) + LC-MS: m/z 580(M+H) +
步骤2Step 2
化合物 20-2的合成参考化合物 1-11。原料 20-1(31.0毫克)，氯化氢的1,4-二氧六环溶液(4摩尔/升，5毫升)。得产品 20-2(26.6毫克)。 For the synthesis of compound 20-2 , refer to compound 1-11 . Raw material 20-1 (31.0 mg), 1,4-dioxane solution of hydrogen chloride (4 mol/L, 5 mL). Product 20-2 (26.6 mg) was obtained.
LC-MS:m/z 480(M+H) +. LC-MS: m/z 480(M+H) + .
步骤3Step 3
化合物 20的合成参考化合物 1。原料 20-2(26.6毫克)，三乙胺(26.1毫克)，丙烯酰氯(7.02毫克)，二氯甲烷(5毫升)。得产品 20(6.8毫克)。 For the synthesis of compound 20 , refer to compound 1 . Raw material 20-2 (26.6 mg), triethylamine (26.1 mg), acryloyl chloride (7.02 mg), dichloromethane (5 mL). Obtained product 20 (6.8 mg).
LC-MS:m/z 534(M+H) + LC-MS: m/z 534(M+H) +
1H-NMR(CD 3OD)δ:7.06-6.95(m,3H),6.93-6.73(m,5H),6.28(d,J＝16.5Hz,1H),5.83(d,J＝10.5Hz,1H),5.18-5.02(m,1H),4.78-4.50(m,1H),4.47-4.26(m,4H),3.96-3.95(m,2H),3.56(t,J＝6.3Hz,2H),3.29-2.71(m,6H),2.52(s,3H),2.38(q,J＝9.0Hz,1H),2.17-1.99(m,3H),1.90-1.68(m,3H). 1 H-NMR (CD 3 OD) δ: 7.06-6.95 (m, 3H), 6.93-6.73 (m, 5H), 6.28 (d, J = 16.5 Hz, 1H), 5.83 (d, J = 10.5 Hz, 1H),5.18-5.02(m,1H),4.78-4.50(m,1H),4.47-4.26(m,4H),3.96-3.95(m,2H),3.56(t,J=6.3Hz,2H) , 3.29-2.71 (m, 6H), 2.52 (s, 3H), 2.38 (q, J = 9.0Hz, 1H), 2.17-1.99 (m, 3H), 1.90-1.68 (m, 3H).
实施例21Example 21
Figure PCTCN2020119633-appb-000108
Figure PCTCN2020119633-appb-000108
步骤1step 1
化合物 21-1的合成参考化合物 1-10。原料 1-9(50.0毫克)，1-溴-4-氟-2,3-邻二甲苯(41.6毫克)，叔丁醇钠(98.9毫克)，甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(25.8毫克)，甲苯(2毫升)。得产品 21-1(32.0毫克)。 For the synthesis of compound 21-1 , refer to compound 1-10 . Raw material 1-9 (50.0 mg), 1-bromo-4-fluoro-2,3-o-xylene (41.6 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino- 2',6'-Diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 Ml). The product 21-1 (32.0 mg) was obtained.
LC-MS:m/z 608(M+H) + LC-MS: m/z 608(M+H) +
步骤2Step 2
化合物 21-2的合成参考化合物 1-11。原料 21-1(32.0毫克)，氯化氢的1,4-二氧六环溶液(4摩尔/升，5毫升)。得产品 21-2(27.8毫克)。 For the synthesis of compound 21-2 , refer to compound 1-11 . Raw material 21-1 (32.0 mg), 1,4-dioxane solution of hydrogen chloride (4 mol/L, 5 mL). The product 21-2 (27.8 mg) was obtained.
LC-MS:m/z 508(M+H) +. LC-MS: m/z 508(M+H) + .
步骤3Step 3
化合物 21的合成参考化合物 1。原料 21-2(27.8毫克)，三乙胺(25.9毫克)，丙烯酰氯(6.95毫克)，二氯甲烷(5毫升)。得产品 21(8.8毫克)。 For the synthesis of compound 21 , refer to compound 1 . Starting material 21-2 (27.8 mg), triethylamine (25.9 mg), acryloyl chloride (6.95 mg), dichloromethane (5 mL). Obtained product 21 (8.8 mg).
LC-MS:m/z 562(M+H) + LC-MS: m/z 562(M+H) +
1H-NMR(CD 3OD)δ:7.08-6.98(m,1H),6.94-6.78(m,2H),6.30(d,J＝16.5Hz,1H), 5.85(d,J＝10.5Hz,1H),5.20-5.07(m,1H),4.82-4.47(m,1H),4.44-4.31(m,2H),4.19-3.81(m,5H),3.74-3.54(m,1H),3.29-2.82(m,9H),2.55(s,3H),2.49-2.37(m,1H),2.17(d,J＝2.1Hz,3H),2.15(s,3H),2.13-1.94(m,3H),1.92-1.69(m,3H). 1 H-NMR(CD 3 OD)δ: 7.08-6.98(m,1H), 6.94-6.78(m,2H), 6.30(d,J=16.5Hz,1H), 5.85(d,J=10.5Hz, 1H), 5.20-5.07 (m, 1H), 4.82-4.47 (m, 1H), 4.44-4.31 (m, 2H), 4.19-3.81 (m, 5H), 3.74-3.54 (m, 1H), 3.29- 2.82(m,9H),2.55(s,3H),2.49-2.37(m,1H), 2.17(d,J=2.1Hz,3H), 2.15(s,3H),2.13-1.94(m,3H) ,1.92-1.69(m,3H).
实施例23Example 23
Figure PCTCN2020119633-appb-000109
Figure PCTCN2020119633-appb-000109
步骤1step 1
化合物 23-1的合成参考化合物 1-10。原料 1-9(50.0毫克)，1-溴-2-氯-3-氟苯(42.8毫克)，叔丁醇钠(98.9毫克)，甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(25.8毫克)，甲苯(2毫升)。得产品 23-1(31.0毫克)。 For the synthesis of compound 23-1 , refer to compound 1-10 . Raw material 1-9 (50.0 mg), 1-bromo-2-chloro-3-fluorobenzene (42.8 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2', 6'-Diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). The product 23-1 (31.0 mg) was obtained.
LC-MS:m/z 614(M+H) + LC-MS: m/z 614(M+H) +
步骤2Step 2
化合物 23-2的合成参考化合物 1-11。原料 23-1(31.0毫克)，氯化氢的1,4-二氧六环溶液(4摩尔/升，5毫升)。得产品 23-2(27.2毫克)。 For the synthesis of compound 23-2 , refer to compound 1-11 . Raw material 23-1 (31.0 mg), 1,4-dioxane solution of hydrogen chloride (4 mol/L, 5 mL). The product 23-2 (27.2 mg) was obtained.
LC-MS:m/z 514(M+H) +. LC-MS: m/z 514(M+H) + .
步骤3Step 3
化合物 23的合成参考化合物 1。原料 23-2(27.2毫克)，三乙胺(25.0毫克)，丙烯酰氯(6.72毫克)，二氯甲烷(5毫升)。得产品 23(6.8毫克)。 The synthesis of compound 23 refers to compound 1 . Raw material 23-2 (27.2 mg), triethylamine (25.0 mg), acryloyl chloride (6.72 mg), dichloromethane (5 mL). Obtained product 23 (6.8 mg).
LC-MS:m/z 568(M+H) + LC-MS: m/z 568(M+H) +
1H-NMR(CD 3OD)δ:7.27-7.18(m,1H),7.02-6.95(m,1H),6.93-6.74(m,2H),6.29(d,J＝16.5Hz,1H),5.84(d,J＝10.5Hz,1H),5.19-5.04(m,1H),4.69-4.51(m,1H),4.43-4.29(m,3H),4.14-3.82(m,3H),3.74-3.58(m,1H),3.51-3.38(m,2H),3.30-3.25(m,1H),3.16-2.73(m,7H),2.53(s,3H),2.44-2.34(m,1H),2.22-2.01(m,3H),1.89-1.68(m,3H). 1 H-NMR(CD 3 OD)δ: 7.27-7.18(m,1H),7.02-6.95(m,1H),6.93-6.74(m,2H), 6.29(d,J=16.5Hz,1H), 5.84(d,J=10.5Hz,1H), 5.19-5.04(m,1H), 4.69-4.51(m,1H),4.43-4.29(m,3H),4.14-3.82(m,3H), 3.74 3.58 (m, 1H), 3.51-3.38 (m, 2H), 3.30-3.25 (m, 1H), 3.16-2.73 (m, 7H), 2.53 (s, 3H), 2.44-2.34 (m, 1H), 2.22-2.01 (m, 3H), 1.89-1.68 (m, 3H).
实施例24Example 24
Figure PCTCN2020119633-appb-000110
Figure PCTCN2020119633-appb-000110
步骤1step 1
化合物 24-1的合成参考化合物 1-10。原料 1-9(50.0毫克)，2-溴-6-氟-苯甲醚(42.0毫克)，叔丁醇钠(98.9毫克)，甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(25.8毫克)，甲苯(2毫升)。得产品 24-1(26.0毫克)。 For the synthesis of compound 24-1 , refer to compound 1-10 . Raw material 1-9 (50.0 mg), 2-bromo-6-fluoro-anisole (42.0 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2', 6 '-Diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). The product 24-1 (26.0 mg) was obtained.
LC-MS:m/z 610(M+H) + LC-MS: m/z 610(M+H) +
步骤2Step 2
化合物 24-2的合成参考化合物 1-11。原料 24-1(26.0毫克)，氯化氢的1,4-二氧六环溶液(4摩尔/升，5毫升)。得产品 24-2(22.8毫克)。 For the synthesis of compound 24-2 , refer to compound 1-11 . Raw material 24-1 (26.0 mg), 1,4-dioxane solution of hydrogen chloride (4 mol/L, 5 mL). The product 24-2 (22.8 mg) was obtained.
LC-MS:m/z 510(M+H) +. LC-MS: m/z 510(M+H) + .
步骤3Step 3
化合物 24的合成参考化合物 1。原料 24-2(22.8毫克)，三乙胺(21.1毫克)，丙烯酰氯(5.67毫克)，二氯甲烷(5毫升)。得产品 24(7.2毫克)。 For the synthesis of compound 24 , refer to compound 1 . Raw material 24-2 (22.8 mg), triethylamine (21.1 mg), acryloyl chloride (5.67 mg), dichloromethane (5 mL). Obtained product 24 (7.2 mg).
LC-MS:m/z 564(M+H) + LC-MS: m/z 564(M+H) +
1H-NMR(CD 3OD)δ:6.96-6.62(m,4H),6.29(d,J＝16.5Hz,1H),5.83(d,J＝10.5Hz,1H),5.20-5.02(m,1H),4.79-4.52(m,1H),4.42-4.35(m,3H),4.13-3.79(m,3H),3.72-3.58(m,1H),3.54(s,3H),3.52-3.42(m,2H),3.30-2.74(m,8H),2.54(s,3H),2.43-2.34(m,1H),2.19-1.98(m,3H),1.91-1.68(m,3H). 1 H-NMR (CD 3 OD) δ: 6.96-6.62 (m, 4H), 6.29 (d, J = 16.5 Hz, 1H), 5.83 (d, J = 10.5 Hz, 1H), 5.20-5.02 (m, 1H), 4.79-4.52 (m, 1H), 4.42-4.35 (m, 3H), 4.13-3.79 (m, 3H), 3.72-3.58 (m, 1H), 3.54 (s, 3H), 3.52-3.42 ( m, 2H), 3.30-2.74 (m, 8H), 2.54 (s, 3H), 2.43-2.34 (m, 1H), 2.19-1.98 (m, 3H), 1.91-1.68 (m, 3H).
实施例25Example 25
Figure PCTCN2020119633-appb-000111
Figure PCTCN2020119633-appb-000111
步骤1step 1
化合物 25-1的合成参考化合物 1-10。原料 1-9(50.0毫克)，2-溴三氟甲氧基苯(49.4毫克)，叔丁醇钠(98.9毫克)，甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(25.8毫克)，甲苯(2毫升)。得产品 25-1(32.0毫克)。 For the synthesis of compound 25-1 , refer to compound 1-10 . Raw material 1-9 (50.0 mg), 2-bromotrifluoromethoxybenzene (49.4 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'- Diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). The product 25-1 (32.0 mg) was obtained.
LC-MS:m/z 646(M+H) + LC-MS: m/z 646(M+H) +
步骤2Step 2
化合物 25-2的合成参考化合物 1-11。原料 25-1(32.0毫克)，氯化氢的1,4-二氧六环溶液(4摩尔/升，5毫升)。得产品 25-2(27.9毫克)。 For the synthesis of compound 25-2 , refer to compound 1-11 . Raw material 25-1 (32.0 mg), 1,4-dioxane solution of hydrogen chloride (4 mol/L, 5 mL). The product 25-2 (27.9 mg) was obtained.
LC-MS:m/z 546(M+H) +. LC-MS: m/z 546(M+H) + .
步骤3Step 3
化合物 25的合成参考化合物 1。原料 25-2(27.9毫克)，三乙胺(24.3毫克)，丙烯酰氯(6.52毫克)，二氯甲烷(5毫升)。得产品 25(7.7毫克)。 For the synthesis of compound 25 , refer to compound 1 . Raw material 25-2 (27.9 mg), triethylamine (24.3 mg), acryloyl chloride (6.52 mg), dichloromethane (5 mL). Product 25 (7.7 mg) was obtained.
LC-MS:m/z 600(M+H) + LC-MS: m/z 600(M+H) +
1H-NMR(CD 3OD)δ:7.29-7.16(m,2H),7.15-7.07(m,1H),7.00-6.73(m,2H),6.29(d,J＝16.5Hz,1H),5.83(d,J＝10.5Hz,1H),5.20-5.01(m,1H),4.80-4.50(m,1H),4.44-4.30(m,3H),4.15-3.75(m,3H),3.71-3.54(m,1H),3.51-3.37(m,2H),3.26-2.74(m,8H),2.53(s,3H),2.43-2.33(m,1H),2.20-2.02(m,3H),1.89-1.68(m,3H). 1 H-NMR (CD 3 OD) δ: 7.29-7.16 (m, 2H), 7.15-7.07 (m, 1H), 7.00-6.73 (m, 2H), 6.29 (d, J = 16.5 Hz, 1H), 5.83 (d, J = 10.5Hz, 1H), 5.20-5.01 (m, 1H), 4.80-4.50 (m, 1H), 4.44-4.30 (m, 3H), 4.15 to 3.75 (m, 3H), 3.71 3.54(m,1H),3.51-3.37(m,2H),3.26-2.74(m,8H),2.53(s,3H),2.43-2.33(m,1H),2.20-2.02(m,3H), 1.89-1.68(m,3H).
实施例26Example 26
Figure PCTCN2020119633-appb-000112
Figure PCTCN2020119633-appb-000112
步骤1step 1
化合物 26-1的合成参考化合物 1-10。原料 1-9(50.0毫克)，4-溴-3-三氟甲基-吡啶(46.3毫克)，叔丁醇钠(98.9毫克)，甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(25.8毫克)，甲苯(2毫升)。得产品 26-1(29.0毫克)。 For the synthesis of compound 26-1 , refer to compound 1-10 . Raw material 1-9 (50.0 mg), 4-bromo-3-trifluoromethyl-pyridine (46.3 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2', 6'-Diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). The product 26-1 (29.0 mg) was obtained.
LC-MS:m/z 631(M+H) + LC-MS: m/z 631(M+H) +
步骤2Step 2
化合物 26-2的合成参考化合物 1-11。原料 26-1(29.0毫克)，氯化氢的1,4-二氧六环溶液(4摩尔/升，5毫升)。得产品 26-2(25.5毫克)。 For the synthesis of compound 26-2 , refer to compound 1-11 . Raw material 26-1 (29.0 mg), 1,4-dioxane solution of hydrogen chloride (4 mol/L, 5 mL). The product 26-2 (25.5 mg) was obtained.
LC-MS:m/z 531(M+H) + LC-MS: m/z 531(M+H) +
步骤3Step 3
化合物 26的合成参考化合物 1。原料 26-2(25.5毫克)，三乙胺(22.7毫克)，丙烯酰氯(6.12毫克)，二氯甲烷(5毫升)。得产品 26(8.9毫克)。 For the synthesis of compound 26 , refer to compound 1 . Raw material 26-2 (25.5 mg), triethylamine (22.7 mg), acryloyl chloride (6.12 mg), dichloromethane (5 mL). Product 26 (8.9 mg) was obtained.
LC-MS:m/z 585(M+H) + LC-MS: m/z 585(M+H) +
1H-NMR(CD 3OD)δ:8.39(d,J＝4.2Hz,1H),7.93(d,J＝8.4,1H),7.67-7.58(m,1H),7.96-7.76(m,1H),6.30(d,J＝16.5Hz,1H),5.85(d,J＝10.5Hz,1H),5.22-5.03(m,1H),4.81-4.51(m,1H),4.42-4.20(m,4H),4.14-3.81(m,3H),3.76-3.62(m,1H),3.47-3.39(m,1H),3.30-3.23(m,1H),3.14-2.73(m,7H),2.51(s,3H),2.40-2.32(m,1H),2.15-1.95(m,3H),1.87-1.64(m,3H). 1 H-NMR (CD 3 OD) δ: 8.39 (d, J = 4.2 Hz, 1H), 7.93 (d, J = 8.4, 1H), 7.67-7.58 (m, 1H), 7.96-7.76 (m, 1H) ), 6.30 (d, J = 16.5 Hz, 1H), 5.85 (d, J = 10.5 Hz, 1H), 5.22-5.03 (m, 1H), 4.81-4.51 (m, 1H), 4.42-4.20 (m, 4H), 4.14-3.81(m,3H), 3.76-3.62(m,1H), 3.47-3.39(m,1H), 3.30-3.23(m,1H), 3.14-2.73(m,7H), 2.51( s, 3H), 2.40-2.32 (m, 1H), 2.15-1.95 (m, 3H), 1.87-1.64 (m, 3H).
实施例27Example 27
Figure PCTCN2020119633-appb-000113
Figure PCTCN2020119633-appb-000113
步骤1：step 1:
化合物 27-1的合成参考化合物 1-10。原料 1-9(50.0毫克)，2-溴-4氟三氟甲苯(49.8毫克)，叔丁醇钠(98.9毫克)，甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(25.8毫克)，甲苯(2毫升)。得产品 27-1(27.5毫克)。 For the synthesis of compound 27-1 , refer to compound 1-10 . Raw material 1-9 (50.0 mg), 2-bromo-4 fluorobenzotrifluoride (49.8 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'- Diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). The product 27-1 (27.5 mg) was obtained.
LC-MS:m/z 648(M+H) + LC-MS: m/z 648(M+H) +
步骤2：Step 2:
化合物 27-2的合成参考化合物 1-11。原料 27-1(27.5毫克)，氯化氢的1,4-二氧六环溶液(4摩尔/升，5毫升)。得产品 27-2(24.3毫克)。 For the synthesis of compound 27-2 , refer to compound 1-11 . Raw material 27-1 (27.5 mg), 1,4-dioxane solution of hydrogen chloride (4 mol/L, 5 mL). The product 27-2 (24.3 mg) was obtained.
LC-MS:m/z 548(M+H) + LC-MS: m/z 548(M+H) +
步骤3Step 3
化合物 27的合成参考化合物 1。原料 27-2(24.3毫克)，三乙胺(0.0289毫升)，丙烯酰氯(4.50毫克)，二氯甲烷(5毫升)。得产品 27(7.5毫克)。 For the synthesis of compound 27 , refer to compound 1 . Starting material 27-2 (24.3 mg), triethylamine (0.0289 ml), acryloyl chloride (4.50 mg), dichloromethane (5 ml). Obtained product 27 (7.5 mg).
LC-MS:m/z 602(M+H) + LC-MS: m/z 602(M+H) +
1H-NMR(CD 3OD)δ:7.74-7.61(m,1H),7.35-7.20(m,1H),7.10-6.98(m,1H),6.97-6.70(m,1H),6.29(d,J＝16.5Hz,1H),5.84(d,J＝10.5Hz,1H),5.19-4.98(m,1H),4.77-4.41(m,3H),4.37-4.10(m,3H),3.98(d,J＝15.0Hz,1H),3.85(d,J＝12.0Hz,1H),3.74-3.43(m,3H),3.19-2.89(m,7H),2.87(s,3H),2.37-2.25(m,1H),2.25-1.67(m,6H). 1 H-NMR(CD 3 OD)δ:7.74-7.61(m,1H), 7.35-7.20(m,1H), 7.10-6.98(m,1H), 6.97-6.70(m,1H), 6.29(d ,J=16.5Hz,1H),5.84(d,J=10.5Hz,1H),5.19-4.98(m,1H),4.77-4.41(m,3H),4.37-4.10(m,3H),3.98( d,J=15.0Hz,1H),3.85(d,J=12.0Hz,1H),3.74-3.43(m,3H),3.19-2.89(m,7H),2.87(s,3H),2.37-2.25 (m,1H),2.25-1.67(m,6H).
实施例28Example 28
Figure PCTCN2020119633-appb-000114
Figure PCTCN2020119633-appb-000114
步骤1：step 1:
化合物 28-1的合成参考化合物 1-10。原料 1-9(50.0毫克)，3-溴-2-甲基三氟甲苯(49.0毫克)，叔丁醇钠(98.9毫克)，甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(25.8毫克)，甲苯(2毫升)。得产品 28-1(31.4毫克)。 For the synthesis of compound 28-1 , refer to compound 1-10 . Raw material 1-9 (50.0 mg), 3-bromo-2-methylbenzotrifluoride (49.0 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2', 6 '-Diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). The product 28-1 (31.4 mg) was obtained.
LC-MS:m/z 644(M+H) + LC-MS: m/z 644(M+H) +
步骤2：Step 2:
化合物 28-2的合成参考化合物 1-11。原料 28-1(31.4毫克)，氯化氢的1,4-二氧六环溶液(4摩尔/升，5毫升)。得产品 28-2(27.3毫克)。 For the synthesis of compound 28-2 , refer to compound 1-11 . Raw material 28-1 (31.4 mg), 1,4-dioxane solution of hydrogen chloride (4 mol/L, 5 mL). The product 28-2 (27.3 mg) was obtained.
LC-MS:m/z 544(M+H) + LC-MS: m/z 544(M+H) +
步骤3Step 3
化合物 28的合成参考化合物 1。原料 28-2(27.3毫克)，三乙胺(0.0310毫升)，丙烯酰氯(4.83毫克)，二氯甲烷(5毫升)。得产品 28(8.2毫克)。 For the synthesis of compound 28 , refer to compound 1 . Starting material 28-2 (27.3 mg), triethylamine (0.0310 ml), acryloyl chloride (4.83 mg), dichloromethane (5 ml). Product 28 (8.2 mg) was obtained.
LC-MS:m/z 598(M+H) + LC-MS: m/z 598(M+H) +
1H-NMR(CD 3OD)δ:7.47-7.25(m,3H),6.91-6.76(m,1H),6.29(d,J＝16.5Hz,1H),5.34(d,J＝10.5Hz,1H),5.19-5.02(m,1H),4.66-4.51(m,1H),4.43-4.23(m,2H),4.21-4.03(m,3H),4.01-3.84(m,2H),3.76-3.60(m,1H),3.46-3.35(m,1H),3.29-3.22(m,1H),3.16-2.88(m,6H),2.83-2.70(m,1H),2.52(s,3H),2.44-2.32(m,1H),2.27(s,3H),2.18-1.98(m,3H),1.89-1.66(m,3H). 1 H-NMR (CD 3 OD) δ: 7.47-7.25 (m, 3H), 6.91-6.76 (m, 1H), 6.29 (d, J = 16.5 Hz, 1H), 5.34 (d, J = 10.5 Hz, 1H), 5.19-5.02 (m, 1H), 4.66-4.51 (m, 1H), 4.43-4.23 (m, 2H), 4.21-4.03 (m, 3H), 4.01-3.84 (m, 2H), 3.76 3.60(m,1H),3.46-3.35(m,1H),3.29-3.22(m,1H),3.16-2.88(m,6H), 2.83-2.70(m,1H),2.52(s,3H), 2.44-2.32 (m, 1H), 2.27 (s, 3H), 2.18-1.98 (m, 3H), 1.89-1.66 (m, 3H).
实施例29Example 29
Figure PCTCN2020119633-appb-000115
Figure PCTCN2020119633-appb-000115
步骤1：step 1:
化合物 29-1的合成参考化合物 1-10。原料 1-9(50.0毫克)，2-溴-6-氯甲苯(46.7毫克)，叔丁醇钠(98.9毫克)，甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(25.8毫克)，甲苯(2毫升)。得产品 29-1(29.3毫克)。 For the synthesis of compound 29-1 , refer to compound 1-10 . Raw material 1-9 (50.0 mg), 2-bromo-6-chlorotoluene (46.7 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-di Isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 ml). The product 29-1 (29.3 mg) was obtained.
LC-MS:m/z 610(M+H) + LC-MS: m/z 610(M+H) +
步骤2：Step 2:
化合物 29-2的合成参考化合物 1-11。原料 29-1(29.3毫克)，氯化氢的1,4-二氧六环溶液(4摩尔/升，5毫升)。得产品 29-2(25.8毫克)。 For the synthesis of compound 29-2 , refer to compound 1-11 . Raw material 29-1 (29.3 mg), 1,4-dioxane solution of hydrogen chloride (4 mol/L, 5 mL). Obtained product 29-2 (25.8 mg).
LC-MS:m/z 510(M+H) +. LC-MS: m/z 510(M+H) + .
步骤3Step 3
化合物 29的合成参考化合物 1。原料 29-2(25.8毫克)，三乙胺(0.0329毫升)，丙烯酰氯(5.16毫克)，二氯甲烷(5毫升)。得产品 29(7.9毫克)。 The synthesis of compound 29 refers to compound 1 . Starting material 29-2 (25.8 mg), triethylamine (0.0329 ml), acryloyl chloride (5.16 mg), dichloromethane (5 ml). Obtained product 29 (7.9 mg).
LC-MS:m/z 564(M+H) + LC-MS: m/z 564(M+H) +
1H-NMR(CD 3OD)δ:7.20-7.01(m,3H),6.98-6.75(m,1H),6.30(d,J＝16.5Hz,1H),5.84(d,J＝10.5Hz,1H),5.20-5.03(m,1H),4.72-4.48(m,1H),4.43-4.27(m,2H),4.26-4.03(m,3H),4.03-3.81(m,2H),3.78-3.61(m,1H),3.61-3.44(m,1H),3.44-3.35(m,1H),3.30-3.23(m,1H),3.19-2.85(m,5H),2.85-2.72(m,1H),2.52(s,3H),2.46-2.31(m,1H),2.21(s,3H),2.17-1.94(m,3H),1.93-1.65(m,3H). 1 H-NMR (CD 3 OD) δ: 7.20-7.01 (m, 3H), 6.98-6.75 (m, 1H), 6.30 (d, J = 16.5 Hz, 1H), 5.84 (d, J = 10.5 Hz, 1H), 5.20-5.03 (m, 1H), 4.72-4.48 (m, 1H), 4.43-4.27 (m, 2H), 4.26-4.03 (m, 3H), 4.03-3.81 (m, 2H), 3.78- 3.61 (m, 1H), 3.61-3.44 (m, 1H), 3.44-3.35 (m, 1H), 3.30-3.23 (m, 1H), 3.19-2.85 (m, 5H), 2.85-2.72 (m, 1H) ),2.52(s,3H),2.46-2.31(m,1H),2.21(s,3H),2.17-1.94(m,3H),1.93-1.65(m,3H).
实施例30Example 30
Figure PCTCN2020119633-appb-000116
Figure PCTCN2020119633-appb-000116
步骤1：step 1:
化合物 30-1的合成参考化合物 1-10。原料 1-9(50.0毫克)，2,3-二氟溴苯(39.6毫克)，叔丁醇钠(98.9毫克)，甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(25.8毫克)，甲苯(2毫升)。得产品 30-1(29.1毫克)。 For the synthesis of compound 30-1 , refer to compound 1-10 . Raw material 1-9 (50.0 mg), 2,3-difluorobromobenzene (39.6 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-di Isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 ml). The product 30-1 (29.1 mg) was obtained.
LC-MS:m/z 598(M+H) +. LC-MS: m/z 598(M+H) + .
步骤2：Step 2:
化合物 30-2的合成参考化合物 1-11。原料 30-1(29.1毫克)，氯化氢的1,4-二氧六环溶液(4摩尔/升，5毫升)。得产品 30-2(25.1毫克)。 For the synthesis of compound 30-2 , refer to compound 1-11 . Raw material 30-1 (29.1 mg), 1,4-dioxane solution of hydrogen chloride (4 mol/L, 5 mL). The product 30-2 (25.1 mg) was obtained.
LC-MS:m/z 498(M+H) +. LC-MS: m/z 498(M+H) + .
步骤3Step 3
化合物 30的合成参考化合物 1。原料 30-2(25.1毫克)，三乙胺(0.0327毫升)，丙烯酰氯(5.11毫克)，二氯甲烷(5毫升)。得产品 30(5.7毫克)。 For the synthesis of compound 30 , refer to compound 1 . Raw material 30-2 (25.1 mg), triethylamine (0.0327 ml), acryloyl chloride (5.11 mg), dichloromethane (5 ml). Obtained product 30 (5.7 mg).
LC-MS:m/z 552(M+H) + LC-MS: m/z 552(M+H) +
1H-NMR(CD 3OD)δ:6.98-6.63(m,4H),6.23(d,J＝16.5Hz,1H),5.83(d,J＝10.5Hz,1H),5.17-5.03(m,1H),4.67-4.57(m,1H),4.51-4.29(m,4H),4.16-4.00(m,1H),3.98-3.85(m,1H),3.79(d,J＝9.6Hz,1H),3.65-3.58(m,2H),3.27-2.74(m,8H),2.54(s,3H),2.46-2.36(m,1H),2.20-1.99(m,3H),1.92-1.68(m,3H). 1 H-NMR (CD 3 OD) δ: 6.98-6.63 (m, 4H), 6.23 (d, J = 16.5 Hz, 1H), 5.83 (d, J = 10.5 Hz, 1H), 5.17-5.03 (m, 1H), 4.67-4.57(m,1H),4.51-4.29(m,4H),4.16-4.00(m,1H),3.98-3.85(m,1H), 3.79(d,J=9.6Hz,1H) ,3.65-3.58(m,2H),3.27-2.74(m,8H),2.54(s,3H),2.46-2.36(m,1H),2.20-1.99(m,3H),1.92-1.68(m, 3H).
实施例31Example 31
Figure PCTCN2020119633-appb-000117
Figure PCTCN2020119633-appb-000117
步骤1：step 1:
化合物 31-1的合成参考化合物 1-10。原料 1-9(50.0毫克)，2,3-二甲基溴苯(37.9毫克)，叔丁醇钠(98.9毫克)，甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(25.8毫克)，甲苯(2毫升)。得产品 31-1(30.1毫克)。 For the synthesis of compound 31-1 , refer to compound 1-10 . Raw material 1-9 (50.0 mg), 2,3-dimethyl bromobenzene (37.9 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'- Diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). The product 31-1 (30.1 mg) was obtained.
LC-MS:m/z 590(M+H) +. LC-MS: m/z 590(M+H) + .
步骤2：Step 2:
化合物 31-2的合成参考化合物 1-11。原料 31-1(30.1毫克)，氯化氢的1,4-二氧六环溶液(4摩尔/升，5毫升)。得产品 31-2(26.1毫克)。 For the synthesis of compound 31-2 , refer to compound 1-11 . Raw material 31-1 (30.1 mg), 1,4-dioxane solution of hydrogen chloride (4 mol/L, 5 mL). The product 31-2 (26.1 mg) was obtained.
LC-MS:m/z 490(M+H) +. LC-MS: m/z 490(M+H) + .
步骤3Step 3
化合物 31的合成参考化合物 1。原料 31-2(26.1毫克)，三乙胺(0.0345毫升)，丙烯酰氯(5.39毫克)，二氯甲烷(5毫升)。得产品 31(7.3毫克)。 The synthesis of compound 31 refers to compound 1 . Starting material 31-2 (26.1 mg), triethylamine (0.0345 ml), acryloyl chloride (5.39 mg), dichloromethane (5 ml). Product 31 (7.3 mg) was obtained.
LC-MS:m/z 544(M+H) + LC-MS: m/z 544(M+H) +
1H-NMR(CD 3OD)δ:7.07-6.95(m,2H),6.94-6.76(m,2H),6.29(d,J＝16.5Hz,1H),5.84(d,J＝10.5Hz,1H),5.20-5.04(m,1H),4.70-4.50(m,1H),4.44-4.28(m,2H),4.21-3.80(m,5H),3.76-3.55(m,1H),3.30-3.18(m,3H),3.15-3.07(m,1H),3.06-2.96(m,2H),2.95-2.85(m,2H),2.85-2.74(m,1H),2.53(s,3H),2.44-2.33(m,1H),2.24(s,3H),2.16-2.11(m,1H),2.09(s,3H),2.07-1.92(m,2H),1.90-1.66(m,3H). 1 H-NMR (CD 3 OD) δ: 7.07-6.95 (m, 2H), 6.94-6.76 (m, 2H), 6.29 (d, J = 16.5 Hz, 1H), 5.84 (d, J = 10.5 Hz, 1H), 5.20-5.04 (m, 1H), 4.70-4.50 (m, 1H), 4.44-4.28 (m, 2H), 4.21-3.80 (m, 5H), 3.76-3.55 (m, 1H), 3.30- 3.18(m,3H),3.15-3.07(m,1H),3.06-2.96(m,2H),2.95-2.85(m,2H),2.85-2.74(m,1H),2.53(s,3H), 2.44-2.33 (m, 1H), 2.24 (s, 3H), 2.16-2.11 (m, 1H), 2.09 (s, 3H), 2.07-1.92 (m, 2H), 1.90-1.66 (m, 3H).
实施例32Example 32
Figure PCTCN2020119633-appb-000118
Figure PCTCN2020119633-appb-000118
步骤1：step 1:
化合物 32-1的合成参考化合物 1-10。原料 1-9(50.0毫克)，3溴-2-甲基苯甲醚(41.2毫克)，叔丁醇钠(98.9毫克)，甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(25.8毫克)，甲苯(2毫升)。得产品 32-1(31.4毫克)。 For the synthesis of compound 32-1 , refer to compound 1-10 . Raw material 1-9 (50.0 mg), 3-bromo-2-methyl anisole (41.2 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2', 6'-Diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 ml). The product 32-1 (31.4 mg) was obtained.
LC-MS:m/z 606(M+H) +. LC-MS: m/z 606(M+H) + .
步骤2：Step 2:
化合物 32-2的合成参考化合物 1-11。原料 32-1(31.4毫克)，氯化氢的1,4-二氧六环溶液(4摩尔/升，5毫升)。得产品 32-2(27.1毫克)。 For the synthesis of compound 32-2 , refer to compound 1-11 . Raw material 32-1 (31.4 mg), 1,4-dioxane solution of hydrogen chloride (4 mol/L, 5 mL). The product 32-2 (27.1 mg) was obtained.
LC-MS:m/z 506(M+H) +. LC-MS: m/z 506(M+H) + .
步骤3Step 3
化合物 32的合成参考化合物 1。原料 32-2(27.1毫克)，三乙胺(0.0348毫升)，丙烯酰氯(5.42毫克)，二氯甲烷(5毫升)。得产品 32(7.9毫克)。 For the synthesis of compound 32 , refer to compound 1 . Raw material 32-2 (27.1 mg), triethylamine (0.0348 ml), acryloyl chloride (5.42 mg), dichloromethane (5 ml). Obtained product 32 (7.9 mg).
LC-MS:m/z 560(M+H) + LC-MS: m/z 560(M+H) +
1H-NMR(CD 3OD)δ:7.10(t,J＝8.4Hz,1H),7.01-6.79(m,1H),6.76(d,J＝8.1Hz,1H),6.66(d,J＝8.1Hz,1H),6.29(d,J＝16.5Hz,1H),5.84(d,J＝10.5Hz,1H),5.20-5.06(m,1H),4.64(m,1H),4.41-4.29(m,2H),4.11(q,J＝17.1Hz,3H),3.99-3.85(m,2H),3.80(s,3H),3.74-3.57(m,1H),3.29-3.18(m,2H),3.13-2.71(m,7H),2.51(s,3H),2.43-2.31(m,1H),2.23-2.02(m,3H),2.00(s,3H),1.91-1.64(m,3H). 1 H-NMR (CD 3 OD) δ: 7.10 (t, J = 8.4 Hz, 1H), 7.01-6.79 (m, 1H), 6.76 (d, J = 8.1 Hz, 1H), 6.66 (d, J = 8.1Hz, 1H), 6.29 (d, J = 16.5 Hz, 1H), 5.84 (d, J = 10.5 Hz, 1H), 5.20-5.06 (m, 1H), 4.64 (m, 1H), 4.41-4.29 ( m, 2H), 4.11 (q, J = 17.1 Hz, 3H), 3.99-3.85 (m, 2H), 3.80 (s, 3H), 3.74-3.57 (m, 1H), 3.29-3.18 (m, 2H) ,3.13-2.71(m,7H),2.51(s,3H),2.43-2.31(m,1H),2.23-2.02(m,3H),2.00(s,3H),1.91-1.64(m,3H) .
实施例33Example 33
Figure PCTCN2020119633-appb-000119
Figure PCTCN2020119633-appb-000119
步骤1：step 1:
化合物 33-1的合成参考化合物 1-10。原料 1-9(50.0毫克)，间三氟甲基溴苯(46.1毫克)，叔丁醇钠(98.9毫克)，甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(25.8毫克)，甲苯(2毫升)。得产品 33-1(32.4毫克)。 For the synthesis of compound 33-1 , refer to compound 1-10 . Raw material 1-9 (50.0 mg), m-trifluoromethyl bromobenzene (46.1 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diiso Propoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). The product 33-1 (32.4 mg) was obtained.
LC-MS:m/z 630(M+H) +. LC-MS: m/z 630(M+H) + .
步骤2：Step 2:
化合物 33-2的合成参考化合物 1-11。原料 33-1(32.4毫克)，氯化氢的1,4-二氧六环溶液(4摩尔/升，5毫升)。得产品 33-2(28.4毫克)。 For the synthesis of compound 33-2 , refer to compound 1-11 . Raw material 33-1 (32.4 mg), 1,4-dioxane solution of hydrogen chloride (4 mol/L, 5 mL). Product 33-2 (28.4 mg) was obtained.
LC-MS:m/z 530(M+H) +. LC-MS: m/z 530(M+H) + .
步骤3Step 3
化合物 33的合成参考化合物 1。原料 33-2(28.4毫克)，三乙胺(0.0349毫升)，丙烯酰氯(5.45毫克)，二氯甲烷(5毫升)。得产品 33(8.8毫克)。 Refer to compound 1 for the synthesis of compound 33 . Raw material 33-2 (28.4 mg), triethylamine (0.0349 ml), acryloyl chloride (5.45 mg), dichloromethane (5 ml). Product 33 (8.8 mg) was obtained.
LC-MS:m/z 584(M+H) + LC-MS: m/z 584(M+H) +
1H-NMR(CD 3OD)δ:7.28(t,J＝7.5Hz,1H),7.19-6.97(m,2H),6.95-6.68(m,2H),6.25(d,J＝16.5Hz,1H),5.81(d,J＝10.5Hz,1H),4.71-4.57(m,3H),4.46-4.28(m,2H),4.18-3.49(m,6H),3.25-3.03(m,3H),3.03-2.75(m,5H),2.54(s,3H),2.46-2.31(m,1H),2.28-1.64(m,6H). 1 H-NMR(CD 3 OD)δ: 7.28(t,J=7.5Hz,1H),7.19-6.97(m,2H),6.95-6.68(m,2H),6.25(d,J=16.5Hz, 1H), 5.81(d,J=10.5Hz,1H),4.71-4.57(m,3H),4.46-4.28(m,2H),4.18-3.49(m,6H),3.25-3.03(m,3H) ,3.03-2.75(m,5H),2.54(s,3H),2.46-2.31(m,1H),2.28-1.64(m,6H).
化合物34Compound 34
Figure PCTCN2020119633-appb-000120
Figure PCTCN2020119633-appb-000120
步骤1：step 1:
化合物 34-1的合成参考化合物 1-10。原料 1-9(50.0毫克)，2,3-二氯溴苯(46.4毫克)，叔丁醇钠(98.9毫克)，甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(25.8毫克)，甲苯(2毫升)。得产品 34-1(34.5毫克)。 For the synthesis of compound 34-1 , refer to compound 1-10 . Raw material 1-9 (50.0 mg), 2,3-dichlorobromobenzene (46.4 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-di Isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 ml). The product 34-1 (34.5 mg) was obtained.
LC-MS:m/z 630(M+H) +. LC-MS: m/z 630(M+H) + .
步骤2：Step 2:
化合物 34-2的合成参考化合物 1-11。原料 34-1(34.5毫克)，氯化氢的1,4-二氧六环溶液(4摩尔/升，5毫升)。得产品 34-2(30.1毫克)。 For the synthesis of compound 34-2 , refer to compound 1-11 . Raw material 34-1 (34.5 mg), 1,4-dioxane solution of hydrogen chloride (4 mol/L, 5 mL). The product 34-2 (30.1 mg) was obtained.
LC-MS:m/z 530(M+H) +. LC-MS: m/z 530(M+H) + .
步骤3Step 3
化合物 34的合成参考化合物 1。原料 34-2(30.1毫克)，三乙胺(0.0370毫升)，丙烯酰氯(5.77毫克)，二氯甲烷(5毫升)。得产品 34(7.3毫克)。 The synthesis of compound 34 refers to compound 1 . Raw material 34-2 (30.1 mg), triethylamine (0.0370 ml), acryloyl chloride (5.77 mg), dichloromethane (5 ml). The product 34 (7.3 mg) was obtained.
LC-MS:m/z 584(M+H) + LC-MS: m/z 584(M+H) +
1H-NMR(CD 3OD)δ:7.26-7.10(m,3H),6.95-6.74(m,1H),6.29(d,J＝16.8Hz,1H),5.84(d,J＝10.8Hz,1H),5.19-5.07(m,1H),4.76-4.63(m,1H),4.45-4.18(m,4H),4.15-3.74(m,3H),3.73-3.54(m,1H),3.50-3.36(m,2H),3.30-3.23(m,1H),3.1 4-2.72(m,6H),2.52(s,3H),2.44-2.32(m,1H),2.22-1.98(m,3H),1.90-1.65(m,3H). 1 H-NMR (CD 3 OD) δ: 7.26-7.10 (m, 3H), 6.95-6.74 (m, 1H), 6.29 (d, J = 16.8 Hz, 1H), 5.84 (d, J = 10.8 Hz, 1H),5.19-5.07(m,1H),4.76-4.63(m,1H),4.45-4.18(m,4H),4.15-3.74(m,3H),3.73-3.54(m,1H),3.50- 3.36 (m, 2H), 3.30-3.23 (m, 1H), 3.1 4-2.72 (m, 6H), 2.52 (s, 3H), 2.44-2.32 (m, 1H), 2.22-1.98 (m, 3H) ,1.90-1.65(m,3H).
实施例35和实施例36Example 35 and Example 36
Figure PCTCN2020119633-appb-000121
Figure PCTCN2020119633-appb-000121
消旋体化合物 34经手性高压制备拆分为单体 35和 36。柱型：CHIRAL PAK IC 2*25cm,5um；流动相A:甲基叔丁基醚(0.1％二乙胺)，流动相:乙醇；流速:20毫升/分钟；梯度:40％，时间20分钟；检测器波长254/220纳米)。 The racemate compound 34 is split into monomers 35 and 36 by chiral high pressure preparation. Column type: CHIRAL PAK IC 2*25cm, 5um; mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase: ethanol; flow rate: 20 ml/min; gradient: 40%, time 20 minutes ; Detector wavelength 254/220 nm).
化合物 35：保留时间为1.26分钟， Compound 35 : retention time is 1.26 minutes,
1H-NMR(CD 3OD)δ:7.28-7.08(m,3H),6.93-6.72(m,1H),6.29(d,J＝16.2Hz,1H),5.84(d,J＝10.7Hz,1H),5.19-5.00(m,1H),4.78-4.49(m,1H),4.43-4.32(m,2H),4.30-4.19(m,2H),4.10-3.82(m,2H),3.75-3.37(m,3H),3.29-3.22(m,1H),3.19-2.80(m,7H),2.57(s,3H),2.50-2.38(m,1H),2.25-2.00(m,3H),1.97-1.66(m,3H). 1 H-NMR (CD 3 OD) δ: 7.28-7.08 (m, 3H), 6.93-6.72 (m, 1H), 6.29 (d, J = 16.2 Hz, 1H), 5.84 (d, J = 10.7 Hz, 1H), 5.19-5.00 (m, 1H), 4.78-4.49 (m, 1H), 4.43-4.32 (m, 2H), 4.30-4.19 (m, 2H), 4.10-3.82 (m, 2H), 3.75 3.37(m,3H), 3.29-3.22(m,1H), 3.19-2.80(m,7H), 2.57(s,3H), 2.50-2.38(m,1H),2.25-2.00(m,3H), 1.97-1.66 (m, 3H).
化合物 36：保留时间为1.68分钟， Compound 36 : retention time is 1.68 minutes,
1H-NMR(CD 3OD)δ:7.28-7.08(m,3H),6.93-6.72(m,1H),6.29(d,J＝16.5Hz,1H),5.84(d,J＝10.7Hz,1H),5.19-5.00(m,1H),4.78-4.49(m,1H),4.43-4.32(m,2H),4.30-4.19(m,2H),4.10-3.82(m,2H),3.75-3.37(m,3H),3.29-3.22(d,J＝3.9Hz,1H),3.19-2.80(m,7H),2.57(s,3H),2.50-2.38(m,1H),2.25-2.00(m,3H),1.97-1.66(m,3H). 1 H-NMR (CD 3 OD) δ: 7.28-7.08 (m, 3H), 6.93-6.72 (m, 1H), 6.29 (d, J = 16.5 Hz, 1H), 5.84 (d, J = 10.7 Hz, 1H), 5.19-5.00 (m, 1H), 4.78-4.49 (m, 1H), 4.43-4.32 (m, 2H), 4.30-4.19 (m, 2H), 4.10-3.82 (m, 2H), 3.75 3.37(m,3H), 3.29-3.22(d,J=3.9Hz,1H), 3.19-2.80(m,7H), 2.57(s,3H), 2.50-2.38(m,1H),2.25-2.00( m,3H),1.97-1.66(m,3H).
实施例37Example 37
Figure PCTCN2020119633-appb-000122
Figure PCTCN2020119633-appb-000122
步骤1：step 1:
化合物 37-1的合成参考化合物 1-10。原料 1-9(50.0毫克)，3-溴-6-氟三氟甲苯(49.8毫克)，叔丁醇钠(98.9毫克)，R甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(25.8毫克)，甲苯(2毫升)。得产 品 37-1(33.7毫克)。 For the synthesis of compound 37-1 , refer to compound 1-10 . Raw material 1-9 (50.0 mg), 3-bromo-6-fluorobenzotrifluoride (49.8 mg), sodium tert-butoxide (98.9 mg), R methanesulfonic acid (2-dicyclohexylphosphino-2', 6 '-Diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). The product 37-1 (33.7 mg) was obtained.
LC-MS:m/z 648(M+H) + LC-MS: m/z 648(M+H) +
步骤2：Step 2:
化合物 37-2的合成参考化合物 1-11。原料 37-1(33.7毫克)，氯化氢的1,4-二氧六环溶液(4摩尔/升，5毫升)。得产品 37-2(29.7毫克)。 For the synthesis of compound 37-2 , refer to compound 1-11 . Raw material 37-1 (33.7 mg), 1,4-dioxane solution of hydrogen chloride (4 mol/L, 5 mL). The product 37-2 (29.7 mg) was obtained.
LC-MS:m/z 548(M+H) + LC-MS: m/z 548(M+H) +
步骤3Step 3
化合物 37的合成参考化合物 1。原料 37-2(29.7毫克)，三乙胺(0.0354毫升)，烯酰氯(5.53毫克)，二氯甲烷(5毫升)。得产品 37(9.3毫克)。 The synthesis of compound 37 refers to compound 1 . Starting material 37-2 (29.7 mg), triethylamine (0.0354 ml), enoyl chloride (5.53 mg), dichloromethane (5 ml). Obtained product 37 (9.3 mg).
LC-MS:m/z 602(M+H) + LC-MS: m/z 602(M+H) +
1H-NMR(CD 3OD)δ:7.13-6.99(m,3H),6.94-6.66(m,1H),6.26(d,J＝16.2Hz,1H),5.81(d,J＝10.8Hz,1H),5.15-4.99(m,1H),4.69-4.53(m,3H),4.44-4.30(m,2H),4.11-3.54(m,5H),3.24-2.73(m,8H),2.53(s,3H),2.46-2.34(m,1H),2.20-1.66(m,6H). 1 H-NMR (CD 3 OD) δ: 7.13-6.99 (m, 3H), 6.94-6.66 (m, 1H), 6.26 (d, J = 16.2 Hz, 1H), 5.81 (d, J = 10.8 Hz, 1H), 5.15-4.99 (m, 1H), 4.69-4.53 (m, 3H), 4.44-4.30 (m, 2H), 4.11-3.54 (m, 5H), 3.24-2.73 (m, 8H), 2.53 ( s, 3H), 2.46-2.34 (m, 1H), 2.20-1.66 (m, 6H).
实施例38Example 38
Figure PCTCN2020119633-appb-000123
Figure PCTCN2020119633-appb-000123
步骤1：step 1:
化合物 38-1的合成参考化合物 1-10。原料 1-9(50.0毫克)，3-溴-2-氯甲苯(42.0毫克)，叔丁醇钠(98.9毫克)，甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(25.8毫克)，甲苯(2毫升)。得产品 38-1(32.9毫克)。 For the synthesis of compound 38-1 , refer to compound 1-10 . Raw material 1-9 (50.0 mg), 3-bromo-2-chlorotoluene (42.0 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-di Isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 ml). The product 38-1 (32.9 mg) was obtained.
LC-MS:m/z 610(M+H) +. LC-MS: m/z 610(M+H) + .
步骤2：Step 2:
化合物 38-2的合成参考化合物 1-11。原料 38-1(32.9毫克)，氯化氢的1,4-二氧六环溶液(4摩尔/升，5毫升)。得产品 38-2(29.0毫克)。 For the synthesis of compound 38-2 , refer to compound 1-11 . Raw material 38-1 (32.9 mg), 1,4-dioxane solution of hydrogen chloride (4 mol/L, 5 mL). The product 38-2 (29.0 mg) was obtained.
LC-MS:m/z 510(M+H) +. LC-MS: m/z 510(M+H) + .
步骤3Step 3
化合物 38的合成参考化合物 1。原料 38-2(29.0毫克)，三乙胺(0.0369毫升)，丙烯酰氯(5.75毫克)，二氯甲烷(5毫升)。得产品 38(9.0毫克)。 Refer to compound 1 for the synthesis of compound 38 . Raw material 38-2 (29.0 mg), triethylamine (0.0369 ml), acryloyl chloride (5.75 mg), dichloromethane (5 ml). Product 38 (9.0 mg) was obtained.
LC-MS:m/z 564(M+H) + LC-MS: m/z 564(M+H) +
1H-NMR(CD 3OD)δ:7.18-7.01(m,2H),6.96(d,J＝7.5Hz,1H),6.92-6.72(m,1H),6.29(d,J＝16.8Hz,1H),5.84(d,J＝10.8Hz,1H),5.21-5.08(m,1H),4.73-4.50(m,2H),4.44-4.27(m,2H),4.26-4.18(m,2H),4.01-3.81(m,2H),3.74-3.53(m, 1H),3.52-3.35(m,2H),3.28-3.20(m,1H),3.14-2.74(m,6H),2.53(s,3H),2.46-2.37(m,1H),2.34(s,3H),2.25-1.94(m,3H),1.94-1.64(m,3H). 1 H-NMR (CD 3 OD) δ: 7.18-7.01 (m, 2H), 6.96 (d, J = 7.5 Hz, 1H), 6.92-6.72 (m, 1H), 6.29 (d, J = 16.8 Hz, 1H), 5.84(d,J=10.8Hz,1H),5.21-5.08(m,1H),4.73-4.50(m,2H),4.44-4.27(m,2H),4.26-4.18(m,2H) ,4.01-3.81(m,2H),3.74-3.53(m,1H),3.52-3.35(m,2H),3.28-3.20(m,1H),3.14-2.74(m,6H),2.53(s, 3H), 2.46-2.37 (m, 1H), 2.34 (s, 3H), 2.25-1.94 (m, 3H), 1.94-1.64 (m, 3H).
实施例39Example 39
Figure PCTCN2020119633-appb-000124
Figure PCTCN2020119633-appb-000124
步骤1step 1
化合物 39-1的合成参考化合物 1-10。原料 1-9(50.0毫克)，1-溴-2-氟-3-甲氧基-苯(40.0毫克)，叔丁醇钠(98.9毫克)，甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(25.8毫克)，甲苯(2毫升)。得产品 39-1(29.0毫克，)。 For the synthesis of compound 39-1 , refer to compound 1-10 . Raw material 1-9 (50.0 mg), 1-bromo-2-fluoro-3-methoxy-benzene (40.0 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino- 2',6'-Diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 Ml). The product 39-1 (29.0 mg,) was obtained.
LC-MS:m/z 610(M+H) + LC-MS: m/z 610(M+H) +
步骤2Step 2
化合物 39-2的合成参考化合物 1-11。原料 39-1(29.0毫克)，氯化氢的1,4-二氧六环溶液(4摩尔/升，5毫升)。得产品 39-2(25.3毫克)。 For the synthesis of compound 39-2 , refer to compound 1-11 . Raw material 39-1 (29.0 mg), 1,4-dioxane solution of hydrogen chloride (4 mol/L, 5 mL). The product 39-2 (25.3 mg) was obtained.
LC-MS:m/z 510(M+H) +. LC-MS: m/z 510(M+H) + .
步骤3Step 3
化合物 39的合成参考化合物 1。原料 39-2(25.3毫克)，三乙胺(23.4毫克)，丙烯酰氯(6.30毫克)，二氯甲烷(5毫升)。得产品 39(7.8毫克)。 For the synthesis of compound 39 , refer to compound 1 . Raw material 39-2 (25.3 mg), triethylamine (23.4 mg), acryloyl chloride (6.30 mg), dichloromethane (5 mL). Product 39 (7.8 mg) was obtained.
LC-MS:m/z 564(M+H) + LC-MS: m/z 564(M+H) +
1H-NMR(CD 3OD)δ:6.96-6.71(m,2H),6.65-6.52(m,2H),6.28(d,J＝16.8Hz,1H),5.83(d,J＝10.5Hz,1H),5.18-5.00(m,1H),4.67-4.58(m,1H),4.46-4.31(m,4H),4.07-3.87(m,1H),3.82(s,3H),3.80-3.72(m,1H),3.61-3.49(m,2H),3.28-3.09(m,3H),3.06-2.76(m,6H),2.54(s,3H),2.46-2.32(m,1H),2.17-1.99(m,3H),1.93-1.69(m,3H). 1 H-NMR(CD 3 OD)δ: 6.96-6.71(m,2H),6.65-6.52(m,2H), 6.28(d,J=16.8Hz,1H), 5.83(d,J=10.5Hz, 1H), 5.18-5.00 (m, 1H), 4.67-4.58 (m, 1H), 4.46-4.31 (m, 4H), 4.07-3.87 (m, 1H), 3.82 (s, 3H), 3.80-3.72 ( m,1H),3.61-3.49(m,2H),3.28-3.09(m,3H),3.06-2.76(m,6H),2.54(s,3H),2.46-2.32(m,1H),2.17- 1.99 (m, 3H), 1.93-1.69 (m, 3H).
实施例40Example 40
Figure PCTCN2020119633-appb-000125
Figure PCTCN2020119633-appb-000125
步骤1step 1
化合物 40-1的合成参考化合物 1-10。原料 1-9(50.0毫克)，1-溴-3-氟-2-二氟甲苯(46.1毫克)，叔丁醇钠(98.9毫克)，甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(25.8毫克)，甲苯(2毫升)。得产品 40-1(32.0毫克)。 For the synthesis of compound 40-1 , refer to compound 1-10 . Raw material 1-9 (50.0 mg), 1-bromo-3-fluoro-2-difluorotoluene (46.1 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-Diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8mg), toluene (2ml) . Obtained product 40-1 (32.0 mg).
LC-MS:m/z 630(M+H) + LC-MS: m/z 630(M+H) +
步骤2Step 2
化合物 40-2的合成参考化合物 1-11。原料 40-1(32.0毫克)，氯化氢的1,4-二氧六环溶液(4摩尔/升，5毫升)。得产品 40-2(28.1毫克)。 For the synthesis of compound 40-2 , refer to compound 1-11 . Raw material 40-1 (32.0 mg), 1,4-dioxane solution of hydrogen chloride (4 mol/L, 5 mL). Obtained product 40-2 (28.1 mg).
LC-MS:m/z 530(M+H) +. LC-MS: m/z 530(M+H) + .
步骤3Step 3
化合物 40的合成参考化合物 1。原料 40-2(28.1毫克)，三乙胺(25.1毫克)，丙烯酰氯(6.75毫克)，二氯甲烷(5毫升)。得产品 40(8.8毫克)。 For the synthesis of compound 40 , refer to compound 1 . Raw material 40-2 (28.1 mg), triethylamine (25.1 mg), acryloyl chloride (6.75 mg), dichloromethane (5 mL). Obtained product 40 (8.8 mg).
LC-MS:m/z 584(M+H) + LC-MS: m/z 584(M+H) +
1H-NMR(CD 3OD)δ:7.46(q,J＝7.2Hz,1H),7.10(d,J＝9.0Hz,1H),6.98-6.66(m,3H),6.30(d,J＝16.9Hz,1H),5.85(d,J＝10.5Hz,1H),5.19-5.01(m,1H),4.75-4.48(m,1H),4.42(d,J＝5.7Hz,2H),4.37-4.19(m,2H),4.16-3.82(m,3H),3.74-3.38(m,3H),3.27-2.84(m,7H),2.63(s,3H),2.58-2.48(m,1H),2.21-1.67(m,6H). 1 H-NMR (CD 3 OD) δ: 7.46 (q, J = 7.2 Hz, 1H), 7.10 (d, J = 9.0 Hz, 1H), 6.98-6.66 (m, 3H), 6.30 (d, J = 16.9Hz, 1H), 5.85 (d, J = 10.5 Hz, 1H), 5.19-5.01 (m, 1H), 4.75-4.48 (m, 1H), 4.42 (d, J = 5.7 Hz, 2H), 4.37- 4.19(m, 2H), 4.16-3.82(m, 3H), 3.74-3.38(m, 3H), 3.27-2.84(m, 7H), 2.63(s, 3H), 2.58-2.48(m, 1H), 2.21-1.67(m,6H).
实施例41Example 41
Figure PCTCN2020119633-appb-000126
Figure PCTCN2020119633-appb-000126
步骤1step 1
化合物 41-1的合成参考化合物 1-10。原料 1-9(50.0毫克)，1-溴-3-二氟甲基-2-甲苯(45.3毫克)，叔丁醇钠(98.9毫克)，甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(25.8毫克)，甲苯(2毫升)。得产品 41-1(35.0毫克)。 For the synthesis of compound 41-1 , refer to compound 1-10 . Raw material 1-9 (50.0 mg), 1-bromo-3-difluoromethyl-2-toluene (45.3 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6'-Diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8mg), toluene (2ml ). The product 41-1 (35.0 mg) was obtained.
LC-MS:m/z 626(M+H) + LC-MS: m/z 626(M+H) +
步骤2Step 2
化合物 41-2的合成参考化合物 1-11。原料 41-1(35.0毫克)，氯化氢的1,4-二氧六环溶液(4摩尔/升，5毫升)。得产品 41-2(30.9毫克)。 For the synthesis of compound 41-2 , refer to compound 1-11 . Raw material 41-1 (35.0 mg), 1,4-dioxane solution of hydrogen chloride (4 mol/L, 5 mL). The product 41-2 (30.9 mg) was obtained.
LC-MS:m/z 526(M+H) +. LC-MS: m/z 526(M+H) + .
步骤3Step 3
化合物 41的合成参考化合物 1。原料 41-2(30.9毫克)，三乙胺(27.8毫克)，丙烯酰氯(7.47毫克)，二氯甲烷(5毫升)。得产品 41(9.8毫克)。 The synthesis of compound 41 refers to compound 1 . Raw material 41-2 (30.9 mg), triethylamine (27.8 mg), acryloyl chloride (7.47 mg), dichloromethane (5 mL). Obtained product 41 (9.8 mg).
LC-MS:m/z 580(M+H) + LC-MS: m/z 580(M+H) +
1H-NMR(CD 3OD)δ:7.34-7.20(m,3H),7.07-6.66(m,2H),6.30(d,J＝16.5Hz,1H),5.85(d,J＝10.5Hz,1H),5.24-5.04(m,1H),4.69-4.57(m,1H),4.42-4.30(m,2H),4.21-4.03(m,3H),4.01-3.81(m,2H),3.73-3.45(m,1H),3.42-3.35(m,1H),3.31-3.24(m,1H),3.18-2.74(m,7H),2.53(s,3H),2.45-2.34(m,1H),2.23(t,J＝1.4Hz,3H),2.18-1.98(m,3H),1.93-1.67(m,3H). 1 H-NMR (CD 3 OD) δ: 7.34-7.20 (m, 3H), 7.07-6.66 (m, 2H), 6.30 (d, J = 16.5 Hz, 1H), 5.85 (d, J = 10.5 Hz, 1H), 5.24-5.04 (m, 1H), 4.69-4.57 (m, 1H), 4.42-4.30 (m, 2H), 4.21-4.03 (m, 3H), 4.01-3.81 (m, 2H), 3.73 3.45(m,1H),3.42-3.35(m,1H),3.31-3.24(m,1H),3.18-2.74(m,7H),2.53(s,3H),2.45-2.34(m,1H), 2.23 (t, J = 1.4Hz, 3H), 2.18-1.98 (m, 3H), 1.93-1.67 (m, 3H).
实施例42Example 42
Figure PCTCN2020119633-appb-000127
Figure PCTCN2020119633-appb-000127
步骤1：step 1:
室温条件下，将原料 1-7(3.60克)溶于1,2-二氯乙烷(100毫升)中。依次加入N,N-二异丙基乙胺(2.81克)，1-氯乙基氯甲酸酯(2.59克)。室温下反应1小时。减压浓缩后加入甲醇(100毫升)溶解，反应液70摄氏度下回流反应1小时。缓慢加入水(100毫升)淬灭。用乙酸乙酯(100毫升x3)萃取。有机相合并后用饱和食盐水(100毫升)洗涤。有机相用无水硫酸钠干燥后，减压浓缩得粗品。粗品用硅胶柱层析纯化(甲醇/二氯甲烷＝5％-15％)，得产品 42-1(2.42克)。 At room temperature, the starting material 1-7 (3.60 g) was dissolved in 1,2-dichloroethane (100 ml). Add N,N-diisopropylethylamine (2.81 g) and 1-chloroethyl chloroformate (2.59 g) sequentially. React at room temperature for 1 hour. After concentration under reduced pressure, methanol (100 ml) was added to dissolve, and the reaction solution was refluxed and reacted at 70 degrees Celsius for 1 hour. It was quenched by slowly adding water (100 mL). Extract with ethyl acetate (100 mL x 3). The organic phases were combined and washed with saturated brine (100 mL). After the organic phase was dried with anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (methanol/dichloromethane=5%-15%) to obtain the product 42-1 (2.42 g).
LC-MS:m/z 407(M+H) +. LC-MS: m/z 407(M+H) + .
步骤2：Step 2:
室温条件下，将原料 42-1(2.42克)溶于甲苯(50毫升)中，依次加入8-甲基-1溴萘(2.62克)，叔丁醇钠(1.99克)，甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(0.497克)。所得混合液用氮气置换3次后，90摄氏度下反应3小时。反应完毕后，加入水(100毫升)淬灭。用乙酸乙酯(100毫 升x3)萃取。有机相合并后用饱和食盐水(100毫升)洗涤。有机相用无水硫酸钠干燥后，减压浓缩得粗品。粗品用硅胶柱层析纯化(石油醚/乙酸乙酯＝15％-30％)，得产品 42-2(1.75克)。 At room temperature, the raw material 42-1 (2.42g) was dissolved in toluene (50ml), and 8-methyl-1-bromonaphthalene (2.62g), sodium tert-butoxide (1.99g), methanesulfonic acid ( 2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (0.497 g). After the obtained mixed solution was replaced with nitrogen three times, the reaction was carried out at 90 degrees Celsius for 3 hours. After the reaction was completed, it was quenched by adding water (100 mL). Extract with ethyl acetate (100 mL x 3). The organic phases were combined and washed with saturated brine (100 mL). After drying the organic phase with anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 15%-30%) to obtain product 42-2 (1.75 g).
LC-MS:m/z 547(M+H) +. LC-MS: m/z 547(M+H) + .
步骤3：Step 3:
室温条件下，将N-甲基-4,4-二氟-L-脯氨醇(69.5毫克)溶于四氢呋喃(5.0毫升)中，0摄氏度下加入氢化钠(60％)(18.3毫克)。室温反应30分钟后，加入原料 42-2(50.0毫克)。反应液70摄氏度下反应2小时。反应完毕后，加入水(20毫升)淬灭。用乙酸乙酯(20毫升x3)萃取。有机相合并后用饱和食盐水(20毫升)洗涤。有机相用无水硫酸钠干燥后，减压浓缩得粗品。粗品用硅胶柱层析纯化(甲醇/二氯甲烷＝5％-20％)，得产品 42-3(53.9毫克)。 At room temperature, N-methyl-4,4-difluoro-L-prolinol (69.5 mg) was dissolved in tetrahydrofuran (5.0 mL), and sodium hydride (60%) (18.3 mg) was added at 0 degrees Celsius. After reacting at room temperature for 30 minutes, raw material 42-2 (50.0 mg) was added. The reaction solution was reacted at 70 degrees Celsius for 2 hours. After the reaction was completed, it was quenched by adding water (20 mL). Extract with ethyl acetate (20 mL x 3). The organic phases were combined and washed with saturated brine (20 mL). After drying the organic phase with anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (methanol/dichloromethane=5%-20%) to obtain product 42-3 (53.9 mg).
LC-MS:m/z 662(M+H) +. LC-MS: m/z 662(M+H) + .
步骤4：Step 4:
室温条件下，将原料 42-3(53.9毫克)溶于氯化氢的1,4-二氧六环溶液(4摩尔/升,10毫升)中。室温反应1小时。反应完毕后减压浓缩得粗品 42-4(44.9毫克)。无需纯化，直接用于下步反应。 At room temperature, the raw material 42-3 (53.9 mg) was dissolved in a 1,4-dioxane solution (4 mol/L, 10 mL) of hydrogen chloride. React at room temperature for 1 hour. After the reaction was completed, it was concentrated under reduced pressure to obtain crude product 42-4 (44.9 mg). No purification is required, and it is directly used in the next reaction.
LC-MS:m/z 562(M+H) +. LC-MS: m/z 562(M+H) + .
步骤5：Step 5:
室温条件下，将原料 42-4(44.9毫克)悬浮于二氯甲烷(10毫升)中，在-40摄氏度下，依次加入三乙胺(37.9毫克)，丙烯酰氯(8.1毫克)。反应液于-40摄氏度下反应1小时。反应完毕后，加入水(20毫升)淬灭。用二氯甲烷(20毫升x3)萃取。有机相合并后用饱和食盐水(20毫升)洗涤。有机相用无水硫酸钠干燥后，减压浓缩得粗品。粗品用制备型反相色谱柱纯化(柱型:SunFire Prep C18 OBD Column,5um 10nm,19*150mm；流动相A:水(0.05％,三氟乙酸),流动相B:乙腈；流速:25毫升/分钟；梯度:35-70％；时间8分钟；检测器波长254/220纳米)，得产品 42(24.8毫克)。 At room temperature, raw material 42-4 (44.9 mg) was suspended in dichloromethane (10 mL), and at -40 degrees Celsius, triethylamine (37.9 mg) and acryloyl chloride (8.1 mg) were added in sequence. The reaction solution was reacted at -40 degrees Celsius for 1 hour. After the reaction was completed, water (20 mL) was added for quenching. Extract with dichloromethane (20 mL x 3). The organic phases were combined and washed with saturated brine (20 mL). After the organic phase was dried with anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain a crude product. The crude product was purified by a preparative reversed-phase chromatography column (column type: SunFire Prep C18 OBD Column, 5um 10nm, 19*150mm; mobile phase A: water (0.05%, trifluoroacetic acid), mobile phase B: acetonitrile; flow rate: 25 ml /Min; gradient: 35-70%; time 8 minutes; detector wavelength 254/220 nm) to obtain product 42 (24.8 mg).
LC-MS:m/z 616(M+H) +. LC-MS: m/z 616(M+H) + .
1H-NMR(CD 3OD)δ:7.69-7.66(m,2H),7.42-7.19(m,4H),7.00-6.80(m,1H),6.32(d,J＝16.8Hz,1H),5.86(d,J＝10.5Hz,1H),5.15(s,1H),4.62-4.41(m,4H),4.17(t,J＝12.6Hz,2H),3.95-3.56(m,3H),3.47-3.39(m,3H),3.04-2.93(m,6H),2.83(s,3H),2.77-2.66(m,1H),2.59-2.50(m,1H),2.45(s,3H),2.22-2.04(m,3H). 1 H-NMR(CD 3 OD)δ: 7.69-7.66(m,2H),7.42-7.19(m,4H),7.00-6.80(m,1H),6.32(d,J=16.8Hz,1H), 5.86(d,J=10.5Hz,1H),5.15(s,1H),4.62-4.41(m,4H),4.17(t,J=12.6Hz,2H),3.95-3.56(m,3H),3.47 -3.39 (m, 3H), 3.04-2.93 (m, 6H), 2.83 (s, 3H), 2.77-2.66 (m, 1H), 2.59-2.50 (m, 1H), 2.45 (s, 3H), 2.22 -2.04(m,3H).
实施例43Example 43
Figure PCTCN2020119633-appb-000128
Figure PCTCN2020119633-appb-000128
Figure PCTCN2020119633-appb-000129
步骤1：
Figure PCTCN2020119633-appb-000129
step 1:
将原料 43-3(2克)溶于干燥的四氢呋喃(100毫升)溶液中，通入氮气鼓泡2分钟，在0摄氏度下，缓慢滴加四氢铝锂的四氢呋喃溶液(1摩尔每升，34.3毫升)。反应液在0摄氏度下反应1小时后继续在70摄氏度下反应2小时。反应完成后冷至室温，加入十水硫酸钠(10克)淬灭，用乙酸乙酯萃取(150毫升x3)。有机相用饱和食盐水洗涤，然后浓缩得化合物 43-4(844毫克)。 Dissolve the raw material 43-3 (2 g) in a dry tetrahydrofuran (100 ml) solution, bubbling with nitrogen for 2 minutes, and slowly add a tetrahydrofuran solution of lithium aluminum tetrahydrofuran (1 mole per liter) at 0 degrees Celsius. 34.3 ml). The reaction solution was reacted at 0 degrees Celsius for 1 hour and then continued to react at 70 degrees Celsius for 2 hours. After the reaction was completed, it was cooled to room temperature, quenched with sodium sulfate decahydrate (10 g), and extracted with ethyl acetate (150 ml×3). The organic phase was washed with saturated brine, and then concentrated to obtain compound 43-4 (844 mg).
LC-MS m/z 134(M+H) +. LC-MS m/z 134(M+H) + .
步骤2：Step 2:
化合物 43-1的合成参考化合物 42-3。其中原料 42-2(50.0毫克)，(2S,4R) 43-4(60.8毫克)，氢化钠(60％)(18.3毫克)，四氢呋喃(5毫升)。得到产品 43-1(47.4毫克)。 For the synthesis of compound 43-1 , refer to compound 42-3 . Among them, raw material 42-2 (50.0 mg), (2S, 4R) 43-4 (60.8 mg), sodium hydride (60%) (18.3 mg), tetrahydrofuran (5 ml). Product 43-1 (47.4 mg) was obtained.
LC-MS:m/z 644(M+H) +. LC-MS: m/z 644(M+H) + .
步骤3：Step 3:
化合物 43-2的合成参考化合物 42-4。其中原料 43-1(47.4毫克)，氯化氢的1,4-二氧六环溶液(4摩尔/升，10毫升)。得到产品 43-2(40.7毫克)。无需纯化，直接用于下步反应。 For the synthesis of compound 43-2 , refer to compound 42-4 . Among them, raw material 43-1 (47.4 mg), 1,4-dioxane solution of hydrogen chloride (4 mol/L, 10 ml). Product 43-2 (40.7 mg) was obtained. No purification is required, and it is directly used in the next reaction.
LC-MS:m/z 544(M+H) +. LC-MS: m/z 544(M+H) + .
步骤4：Step 4:
化合物 43的合成参考化合物 42。其中原料 43-2(40.7毫克)，三乙胺(35.6毫克)，丙烯酰氯(7.6毫克)，二氯甲烷(10毫升)。反应后产物用制备型反相色谱柱纯化(柱型:XBridge Shield RP18 OBD Column,5um,19*150mm；流动相A:水(10毫摩尔/升，碳酸氢铵),流动相B:乙腈；流速:25毫升/分钟；梯度:43-70％；时间8分钟；检测器波长254/220纳米)，得产品 43(24.9毫克)。 For the synthesis of compound 43 , refer to compound 42 . Among them, raw material 43-2 (40.7 mg), triethylamine (35.6 mg), acryloyl chloride (7.6 mg), methylene chloride (10 ml). After the reaction, the product was purified with a preparative reverse phase chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; Flow rate: 25 ml/min; gradient: 43-70%; time 8 minutes; detector wavelength 254/220 nm) to obtain product 43 (24.9 mg).
LC-MS:m/z 598(M+H) +. LC-MS: m/z 598(M+H) + .
1H-NMR(CD 3OD)δ:7.74-7.67(m,2H),7.45-7.31(m,3H),7.21(d,J＝4.8Hz,1H),7.00-6.80(m,1H),6.20(d,J＝16.8Hz,1H),5.86(d,J＝10.5Hz,1H),5.08-5.01(m,1H),4.39(t,J＝17.1Hz,2H),4.28-4.23(m,1H),4.17-3.96(m,3H),3.72-3.59(m,3H),3.46-3.39(m,2H),3.31-3.21(m,2H),3.17-3.14(m,1H),3.10-3.05(m,1H),3.01-2.92(m,2H),2.85-2.82(m,2H),2.77(d,J＝6.0Hz,4H),2.34(s,3H),2.12-1.79(m,4H). 1 H-NMR(CD 3 OD)δ:7.74-7.67(m,2H),7.45-7.31(m,3H), 7.21(d,J=4.8Hz,1H), 7.00-6.80(m,1H), 6.20 (d, J = 16.8 Hz, 1H), 5.86 (d, J = 10.5 Hz, 1H), 5.08-5.01 (m, 1H), 4.39 (t, J = 17.1 Hz, 2H), 4.28-4.23 (m ,1H),4.17-3.96(m,3H),3.72-3.59(m,3H),3.46-3.39(m,2H),3.31-3.21(m,2H),3.17-3.14(m,1H),3.10 -3.05(m,1H),3.01-2.92(m,2H),2.85-2.82(m,2H),2.77(d,J=6.0Hz,4H),2.34(s,3H),2.12-1.79(m ,4H).
实施例44Example 44
Figure PCTCN2020119633-appb-000130
Figure PCTCN2020119633-appb-000130
Figure PCTCN2020119633-appb-000131
步骤1：
Figure PCTCN2020119633-appb-000131
step 1:
将原料 44-3(2克)溶于干燥的四氢呋喃(100毫升)溶液中，通入氮气鼓泡2分钟，在0摄氏度下，缓慢滴加四氢铝锂的四氢呋喃溶液(1摩尔每升,34.3毫升)。反应液在0摄氏度下反应1小时后继续在70摄氏度下反应2小时。反应完成后冷至室温，加入十水硫酸钠(10克)淬灭，用乙酸乙酯萃取(150毫升x3)。有机相用饱和食盐水洗涤，然后浓缩得化合物 44-4(844毫克)。 Dissolve the raw material 44-3 (2 g) in a dry tetrahydrofuran (100 ml) solution, bubbling with nitrogen for 2 minutes, and slowly add a tetrahydrofuran solution of lithium aluminum tetrahydrofuran (1 mole per liter) at 0 degrees Celsius. 34.3 ml). The reaction solution was reacted at 0 degrees Celsius for 1 hour and then continued to react at 70 degrees Celsius for 2 hours. After the reaction was completed, it was cooled to room temperature, quenched with sodium sulfate decahydrate (10 g), and extracted with ethyl acetate (150 ml×3). The organic phase was washed with saturated brine, and then concentrated to obtain compound 44-4 (844 mg).
LC-MS m/z 134(M+H) +. LC-MS m/z 134(M+H) + .
步骤2：Step 2:
化合物 44-1的合成参考化合物 42-3。其中原料 42-2(50.00毫克)， 44-4(61.2毫克)，氢化钠(60％)(18.3毫克)，四氢呋喃(5毫升)。得到产品 44-1(52.3毫克)。 For the synthesis of compound 44-1 , refer to compound 42-3 . Among them, raw materials 42-2 (50.00 mg), 44-4 (61.2 mg), sodium hydride (60%) (18.3 mg), and tetrahydrofuran (5 mL). Product 44-1 (52.3 mg) was obtained.
LC-MS:m/z 644(M+H) +. LC-MS: m/z 644(M+H) + .
步骤3：Step 3:
化合物 44-2的合成参考化合物 42-4。其中原料 44-1(52.3毫克)，氯化氢的1,4-二氧六环溶液(4摩尔/升，10毫升)。得到产品 44-2(45.4毫克)。无需纯化，直接用于下步反应。 For the synthesis of compound 44-2 , refer to compound 42-4 . Among them, raw material 44-1 (52.3 mg), 1,4-dioxane solution of hydrogen chloride (4 mol/L, 10 ml). Product 44-2 (45.4 mg) was obtained. No purification is required, and it is directly used in the next reaction.
LC-MS:m/z 544(M+H) +. LC-MS: m/z 544(M+H) + .
步骤4：Step 4:
化合物 44的合成参考化合物 42。其中原料 44-2(45.4毫克)，三乙胺(40.5毫克)，丙烯酰氯(9.0毫克)，二氯甲烷(10毫升)。反应后产物用制备型反相色谱柱纯化(柱型:XBridge Prep C18 OBD Column,5um,19*150mm；流动相A:水(10毫摩尔/升，碳酸氢铵),流动相B:乙腈；流速:25毫升/分钟；梯度:36-64％；时间10分钟；检测器波长254/220纳米)，得产品 44(26.8毫克)。 For the synthesis of compound 44 , refer to compound 42 . Among them, raw material 44-2 (45.4 mg), triethylamine (40.5 mg), acryloyl chloride (9.0 mg), dichloromethane (10 ml). After the reaction, the product was purified with a preparative reverse phase chromatography column (column type: XBridge Prep C18 OBD Column, 5um, 19*150mm; mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; Flow rate: 25 ml/min; gradient: 36-64%; time 10 minutes; detector wavelength 254/220 nm) to obtain product 44 (26.8 mg).
LC-MS:m/z 598(M+H) +. LC-MS: m/z 598(M+H) + .
1H-NMR(CD 3OD)δ:7.68-7.64(m,2H),7.43-7.19(m,4H),7.00-6.80(m,1H),6.31(d,J＝12.6Hz,1H),5.86(d,J＝8.1Hz,1H),5.21-5.05(m,1H),4.61(s,1H),4.47-4.31(m,3H),4.17(t,J＝12.3Hz,2H),3.94-3.57(m,4H),3.51-3.37(m,2H),3.30-3.23(m,2H),3.15-3.00(m,3H),2.95-2.89(m,1H),2.83(s,3H),2.80-2.77(m,1H),2.58-2.51(m,1H),2.47(s,3H),2.21-1.84(m,4H). 1 H-NMR (CD 3 OD) δ: 7.68-7.64 (m, 2H), 7.43-7.19 (m, 4H), 7.00-6.80 (m, 1H), 6.31 (d, J=12.6Hz, 1H), 5.86 (d, J = 8.1 Hz, 1H), 5.21-5.05 (m, 1H), 4.61 (s, 1H), 4.47-4.31 (m, 3H), 4.17 (t, J = 12.3 Hz, 2H), 3.94 -3.57(m,4H),3.51-3.37(m,2H),3.30-3.23(m,2H),3.15-3.00(m,3H),2.95-2.89(m,1H), 2.83(s,3H) , 2.80-2.77 (m, 1H), 2.58-2.51 (m, 1H), 2.47 (s, 3H), 2.21-1.84 (m, 4H).
实施例45Example 45
Figure PCTCN2020119633-appb-000132
Figure PCTCN2020119633-appb-000132
步骤1：step 1:
化合物 45-1的合成参考化合物 42-3。其中原料 42-2(50.0毫克)，N-羟乙基哌啶(58.9毫克)，氢化钠(60％)(18.3毫克)，四氢呋喃(5毫升)。得到产品 45-1(53.3毫克)。 For the synthesis of compound 45-1 , refer to compound 42-3 . Among them, raw material 42-2 (50.0 mg), N-hydroxyethylpiperidine (58.9 mg), sodium hydride (60%) (18.3 mg), tetrahydrofuran (5 ml). Product 45-1 (53.3 mg) was obtained.
LC-MS:m/z 640(M+H) +. LC-MS: m/z 640(M+H) + .
步骤2：Step 2:
化合物 45-2的合成参考化合物 42-4。其中原料 45-1(53.3毫克)，氯化氢的1,4-二氧六环溶液(4摩尔/升，10毫升)。得到产品 45-2(45.7毫克)。无需纯化，直接用于下步反应。 For the synthesis of compound 45-2 , refer to compound 42-4 . Among them, raw material 45-1 (53.3 mg), 1,4-dioxane solution of hydrogen chloride (4 mol/L, 10 ml). Product 45-2 (45.7 mg) was obtained. No purification is required, and it is directly used in the next reaction.
LC-MS:m/z 540(M+H) +. LC-MS: m/z 540(M+H) + .
步骤3：Step 3:
化合物 45的合成参考化合物 42。其中原料 45-2(45.7毫克)，三乙胺(40.3毫克)，丙烯酰氯(8.6毫克)，二氯甲烷(10毫升)。反应后产物用制备型反相色谱柱纯化(柱型:XBridge Shield RP18 OBD Column,5um,19*150mm；流动相A:水(10毫摩尔/升，碳酸氢铵),流动相B:乙腈；流速:25毫升/分钟；梯度:35-80％；时间8分钟；检测器波长254/220纳米)，得产品 45(24.3毫克)。 For the synthesis of compound 45 , refer to compound 42 . Among them, raw material 45-2 (45.7 mg), triethylamine (40.3 mg), acryloyl chloride (8.6 mg), dichloromethane (10 ml). After the reaction, the product was purified with a preparative reverse phase chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; Flow rate: 25 ml/min; gradient: 35-80%; time 8 minutes; detector wavelength 254/220 nm) to obtain product 45 (24.3 mg).
LC-MS:m/z 594(M+H) +. LC-MS: m/z 594(M+H) + .
1H-NMR(CD 3OD)δ:7.69-7.63(m,2H),7.43-7.19(m,4H),7.00-6.80(m,1H),6.31(d,J＝17.1Hz,1H),5.86(d,J＝10.8Hz,1H),5.15(s,1H),4.50-4.39(m,3H),4.16(t,J＝12.6Hz,2H),3.92-3.67(m,3H),3.46-3.36(m,3H),3.30-3.24(m,1H),3.11-2.86(m,5H),2.84(s,3H),2.76(t,J＝2.4Hz,2H),2.55(s,3H),2.03(s,2H),1.64-1.57(m,4H),1.50-1.43(m,2H). 1 H-NMR (CD 3 OD) δ: 7.69-7.63 (m, 2H), 7.43-7.19 (m, 4H), 7.00-6.80 (m, 1H), 6.31 (d, J=17.1Hz, 1H), 5.86(d,J=10.8Hz,1H),5.15(s,1H),4.50-4.39(m,3H),4.16(t,J=12.6Hz,2H),3.92-3.67(m,3H),3.46 -3.36(m,3H),3.30-3.24(m,1H),3.11-2.86(m,5H),2.84(s,3H),2.76(t,J=2.4Hz,2H),2.55(s,3H) ), 2.03 (s, 2H), 1.64-1.57 (m, 4H), 1.50-1.43 (m, 2H).
实施例46Example 46
Figure PCTCN2020119633-appb-000133
Figure PCTCN2020119633-appb-000133
Figure PCTCN2020119633-appb-000134
Figure PCTCN2020119633-appb-000134
步骤1：step 1:
室温条件下，将原料 46-3(1.10克)溶于乙腈(50毫升)中，依次加入碳酸钾(965毫克)，溴乙醇(915毫克)。所得反应液90摄氏度下反应12小时。反应完毕后，加入水(150毫升)淬灭。用乙酸乙酯(150毫升x3)萃取。有机相合并后用饱和食盐水(150毫升)洗涤。有机相用无水硫酸钠干燥后，减压浓缩得产品 46-4(525.0毫克)。 At room temperature, the raw material 46-3 (1.10 g) was dissolved in acetonitrile (50 ml), and potassium carbonate (965 mg) and bromoethanol (915 mg) were sequentially added. The resulting reaction solution was reacted at 90 degrees Celsius for 12 hours. After the reaction was completed, water (150 mL) was added for quenching. Extract with ethyl acetate (150 mL x 3). The organic phases were combined and washed with saturated brine (150 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain product 46-4 (525.0 mg).
LC-MS:m/z 166(M+H) +. LC-MS: m/z 166(M+H) + .
步骤2：Step 2:
化合物 46-1的合成参考化合物 42-3。其中原料 42-2(50.0毫克)， 46-4(75.6毫克)，氢化钠(60％)(18.3毫克)，四氢呋喃(5毫升)。得到产品 46-1(54.0毫克)。 For the synthesis of compound 46-1 , refer to compound 42-3 . Among them, raw materials 42-2 (50.0 mg), 46-4 (75.6 mg), sodium hydride (60%) (18.3 mg), and tetrahydrofuran (5 mL). Product 46-1 (54.0 mg) was obtained.
LC-MS:m/z 676(M+H) +. LC-MS: m/z 676(M+H) + .
步骤3：Step 3:
化合物 46-2的合成参考化合物 42-4。其中原料 46-1(54.0毫克)，氯化氢的1,4-二氧六环溶液(4摩尔/升，10毫升)。得到产品 46-2(45.9毫克)。无需纯化，直接用于下步反应。 For the synthesis of compound 46-2 , refer to compound 42-4 . Among them, raw material 46-1 (54.0 mg), 1,4-dioxane solution of hydrogen chloride (4 mol/L, 10 ml). Product 46-2 (45.9 mg) was obtained. No purification is required, and it is directly used in the next reaction.
LC-MS:m/z 576(M+H) +. LC-MS: m/z 576(M+H) + .
步骤4：Step 4:
化合物 46的合成参考化合物 42。其中原料 46-2(45.9毫克)，三乙胺(33.8毫克)，丙烯酰氯(8.1毫克)，二氯甲烷(10毫升)。反应后产物用制备型反相色谱柱纯化(柱型:XBridge Shield RP18 OBD Column,5um,19*150mm；流动相A：水(10毫摩尔/升，碳酸氢铵)，流动相B：乙腈；流速:25毫升/分钟；梯度:50-75％；时间8分钟；检测器波长254/220纳米)，得产品 46(26.9毫克)。 For the synthesis of compound 46 , refer to compound 42 . Among them, raw material 46-2 (45.9 mg), triethylamine (33.8 mg), acryloyl chloride (8.1 mg), dichloromethane (10 ml). After the reaction, the product was purified with a preparative reverse phase chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; Flow rate: 25 ml/min; gradient: 50-75%; time 8 minutes; detector wavelength 254/220 nm) to obtain product 46 (26.9 mg).
LC-MS:m/z 630(M+H) +. LC-MS: m/z 630(M+H) + .
1H-NMR(CD 3OD)δ:7.68-7.64(m,2H),7.43-7.18(m,4H),7.00-6.80(m,1H),6.31(d,J＝16.5Hz,1H),5.86(d,J＝10.5Hz,1H),5.2(s,1H),4.49-4.39(m,3H),4.15(t,J＝12.3Hz,2H),3.92-3.66(m,3H),3.45-3.36(m,2H),3.30-3.25(m,1H),3.15-3.00(m,4H),2.94-2.83(m,6H),2.69(s,4H),2.04-1.91(m,6H). 1 H-NMR (CD 3 OD) δ: 7.68-7.64 (m, 2H), 7.43-7.18 (m, 4H), 7.00-6.80 (m, 1H), 6.31 (d, J=16.5Hz, 1H), 5.86(d,J=10.5Hz,1H),5.2(s,1H),4.49-4.39(m,3H),4.15(t,J=12.3Hz,2H),3.92-3.66(m,3H),3.45 -3.36(m,2H),3.30-3.25(m,1H),3.15-3.00(m,4H),2.94-2.83(m,6H),2.69(s,4H),2.04-1.91(m,6H) .
实施例47Example 47
Figure PCTCN2020119633-appb-000135
Figure PCTCN2020119633-appb-000135
Figure PCTCN2020119633-appb-000136
Figure PCTCN2020119633-appb-000136
步骤1：step 1:
室温条件下，将原料 47-3(1.10克)溶于乙腈(50毫升)中，依次加入碳酸钾(965毫克)，溴乙醇(915毫克)。所得反应液90摄氏度下反应12小时。反应完毕后，加入水(150毫升)淬灭。用乙酸乙酯(150毫升x3)萃取。有机相合并后用饱和食盐水(150毫升)洗涤。有机相用无水硫酸钠干燥后，减压浓缩得产品 47-4(586毫克)。 At room temperature, the raw material 47-3 (1.10 g) was dissolved in acetonitrile (50 ml), and potassium carbonate (965 mg) and bromoethanol (915 mg) were sequentially added. The resulting reaction solution was reacted at 90 degrees Celsius for 12 hours. After the reaction was completed, water (150 mL) was added for quenching. Extract with ethyl acetate (150 mL x 3). The organic phases were combined and washed with saturated brine (150 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain product 47-4 (586 mg).
LC-MS:m/z 166(M+H) +. LC-MS: m/z 166(M+H) + .
步骤2：Step 2:
化合物 47-1的合成参考化合物 42-3。其中原料 42-2(50.0毫克)， 47-4(75.6毫克)，氢化钠(60％)(18.3毫克)，四氢呋喃(5毫升)。得到产品 47-1(53.5毫克)。 For the synthesis of compound 47-1 , refer to compound 42-3 . Among them, raw materials 42-2 (50.0 mg), 47-4 (75.6 mg), sodium hydride (60%) (18.3 mg), tetrahydrofuran (5 ml). The product 47-1 (53.5 mg) was obtained.
LC-MS:m/z 676(M+H) +. LC-MS: m/z 676(M+H) + .
步骤3：Step 3:
化合物 47-2的合成参考化合物 42-4。其中原料 47-1(53.5毫克)，氯化氢的1,4-二氧六环溶液(4摩尔/升，10毫升)。得到产品 47-2(45.8毫克)。无需纯化，直接用于下步反应。 For the synthesis of compound 47-2 , refer to compound 42-4 . Among them, raw material 47-1 (53.5 mg), 1,4-dioxane solution of hydrogen chloride (4 mol/L, 10 ml). Product 47-2 (45.8 mg) was obtained. No purification is required, and it is directly used in the next reaction.
LC-MS:m/z 576(M+H) +. LC-MS: m/z 576(M+H) + .
步骤4：Step 4:
化合物 47的合成参考化合物 42。其中原料 47-2(45.8毫克)，三乙胺(33.8毫克)，丙烯酰氯(8.1毫克)，二氯甲烷(10毫升)。反应后产物用制备型反相色谱柱纯化(柱型:XBridge Shield RP18 OBD Column,5um,19*150mm；流动相A：水(10毫摩尔/升，碳酸氢铵)，流动相B：乙腈；流速:25毫升/分钟；梯度:55-70％；时间8分钟；检测器波长254/220纳米)，得产品 47(26.1毫克)。 For the synthesis of compound 47 , refer to compound 42 . Among them, raw material 47-2 (45.8 mg), triethylamine (33.8 mg), acryloyl chloride (8.1 mg), dichloromethane (10 ml). After the reaction, the product was purified with a preparative reverse phase chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; Flow rate: 25 ml/min; gradient: 55-70%; time 8 minutes; detector wavelength 254/220 nm) to obtain product 47 (26.1 mg).
LC-MS:m/z 630(M+H) +. LC-MS: m/z 630(M+H) + .
1H-NMR(CD 3OD)δ:7.69-7.64(m,2H),7.42-7.19(m,4H),7.00-6.80(m,1H),6.32(d,J＝17.1Hz,1H),5.87(d,J＝11.4Hz,1H),5.15-5.05(m,1H),4.50-4.40(m,3H),4.17(t,J＝12.0Hz,2H),3.94-3.67(m,3H),3.47-3.38(m,2H),3.30-3.26(m,1H),3.11-3.00(m,4H),2.95-2.75(m,8H),2.58(s,2H),2.04-1.74(m,6H). 1 H-NMR (CD 3 OD) δ: 7.69-7.64 (m, 2H), 7.42-7.19 (m, 4H), 7.00-6.80 (m, 1H), 6.32 (d, J=17.1Hz, 1H), 5.87(d,J=11.4Hz,1H),5.15-5.05(m,1H),4.50-4.40(m,3H), 4.17(t,J=12.0Hz,2H),3.94-3.67(m,3H) ,3.47-3.38(m,2H),3.30-3.26(m,1H),3.11-3.00(m,4H),2.95-2.75(m,8H),2.58(s,2H),2.04-1.74(m, 6H).
实施例48Example 48
Figure PCTCN2020119633-appb-000137
Figure PCTCN2020119633-appb-000137
Figure PCTCN2020119633-appb-000138
Figure PCTCN2020119633-appb-000138
步骤1：step 1:
室温条件下，将原料 48-3(1.10克)溶于乙腈(50毫升)中，依次加入碳酸钾(3.47克)，溴丙醇(1.91克)。所得反应液90摄氏度下反应12小时。反应完毕后，加入水(150毫升)淬灭。用乙酸乙酯(150毫升x3)萃取。有机相合并后用饱和食盐水(150毫升)洗涤。有机相用无水硫酸钠干燥后，减压浓缩得产品 48-4(1.06克)。 At room temperature, the raw material 48-3 (1.10 g) was dissolved in acetonitrile (50 ml), and potassium carbonate (3.47 g) and bromopropanol (1.91 g) were added sequentially. The resulting reaction solution was reacted at 90 degrees Celsius for 12 hours. After the reaction was completed, water (150 mL) was added for quenching. Extract with ethyl acetate (150 mL x 3). The organic phases were combined and washed with saturated brine (150 mL). After the organic phase was dried with anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain product 48-4 (1.06 g).
LC-MS:m/z 146(M+H) +. LC-MS: m/z 146(M+H) + .
步骤2：Step 2:
化合物 48-1的合成参考化合物 42-3。其中原料 42-2(50.0毫克)， 48-4(66.7毫克)，氢化钠(60％)(18.3毫克)，四氢呋喃(5毫升)。得到产品 48-1(50.1毫克)。 For the synthesis of compound 48-1 , refer to compound 42-3 . Among them, raw materials 42-2 (50.0 mg), 48-4 (66.7 mg), sodium hydride (60%) (18.3 mg), and tetrahydrofuran (5 mL). Product 48-1 (50.1 mg) was obtained.
LC-MS:m/z 656(M+H) +. LC-MS: m/z 656(M+H) + .
步骤3：Step 3:
化合物 48-2的合成参考化合物 42-4。其中原料 48-1(50.1毫克)，氯化氢的1,4-二氧六环溶液(4摩尔/升，10毫升)。得到产品 48-2(40.5毫克)。无需纯化，直接用于下步反应。 For the synthesis of compound 48-2 , refer to compound 42-4 . Among them, raw material 48-1 (50.1 mg), 1,4-dioxane solution of hydrogen chloride (4 mol/L, 10 ml). Product 48-2 (40.5 mg) was obtained. No purification is required, and it is directly used in the next reaction.
LC-MS:m/z 556(M+H) +. LC-MS: m/z 556(M+H) + .
步骤4：Step 4:
化合物 48的合成参考化合物 42。其中原料 48-2(40.5毫克)，三乙胺(34.8毫克)，丙烯酰氯(7.4毫克)，二氯甲烷(10毫升)。反应后产物用制备型反相色谱柱纯化(柱型:XBridge Shield RP18 OBD Column,5um,19*150mm；流动相A:水(10毫摩尔/升，碳酸氢铵)，流动相B:乙腈；流速:25毫升/分钟；梯度:55-65％；时间8分钟；检测器波长254/220纳米)，得产品 48(22.0毫克)。 For the synthesis of compound 48 , refer to compound 42 . Among them, raw material 48-2 (40.5 mg), triethylamine (34.8 mg), acryloyl chloride (7.4 mg), dichloromethane (10 ml). After the reaction, the product was purified with a preparative reverse phase chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; Flow rate: 25 ml/min; gradient: 55-65%; time 8 minutes; detector wavelength 254/220 nm) to obtain product 48 (22.0 mg).
LC-MS:m/z 610(M+H) +. LC-MS: m/z 610(M+H) + .
1H-NMR(CD 3OD)δ:7.69-7.64(m,2H),7.42-7.20(m,4H),7.00-6.80(m,1H),6.32(d,J＝17.1Hz,1H),5.87(d,J＝9.9Hz,1H),4.64(s,1H),4.46-4.37(m,3H),4.16(t,J＝12.6Hz,2H),3.93-3.73(m,3H),3.67(s,5H),3.51-3.38(m,2H),3.29-3.25(m,1H),3.10-3.01(m,3H),2.96-2.92(m,1H),2.84(s,3H),2.55-2.48(m,6H),2.09-1.94(m,4H). 1 H-NMR (CD 3 OD) δ: 7.69-7.64 (m, 2H), 7.42-7.20 (m, 4H), 7.00-6.80 (m, 1H), 6.32 (d, J=17.1Hz, 1H), 5.87(d,J=9.9Hz,1H),4.64(s,1H),4.46-4.37(m,3H),4.16(t,J=12.6Hz,2H),3.93-3.73(m,3H),3.67 (s, 5H), 3.51-3.38 (m, 2H), 3.29-3.25 (m, 1H), 3.10-3.01 (m, 3H), 2.96-2.92 (m, 1H), 2.84 (s, 3H), 2.55 -2.48(m,6H),2.09-1.94(m,4H).
实施例49Example 49
Figure PCTCN2020119633-appb-000139
Figure PCTCN2020119633-appb-000139
Figure PCTCN2020119633-appb-000140
Figure PCTCN2020119633-appb-000140
步骤1：step 1:
室温条件下，将原料 49-3(1.10克)溶于乙腈(50毫升)中，依次加入碳酸钾(3.06克)，溴丙醇(1.68克)。所得反应液90摄氏度下反应12小时。反应完毕后，加入水(150毫升)淬灭。用乙酸乙酯(150毫升x3)萃取。有机相合并后用饱和食盐水(150毫升)洗涤。有机相用无水硫酸钠干燥后，减压浓缩得产品 49-4(841.0毫克)。 At room temperature, raw material 49-3 (1.10 g) was dissolved in acetonitrile (50 ml), and potassium carbonate (3.06 g) and bromopropanol (1.68 g) were added sequentially. The resulting reaction solution was reacted at 90 degrees Celsius for 12 hours. After the reaction was completed, water (150 mL) was added for quenching. Extract with ethyl acetate (150 mL x 3). The organic phases were combined and washed with saturated brine (150 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated to give product 49-4 (841.0 mg) under reduced pressure.
LC-MS:m/z 158(M+H) +. LC-MS: m/z 158(M+H) + .
步骤2：Step 2:
化合物 49-1的合成参考化合物 42-3。其中原料 42-2(50.0毫克)， 49-4(71.9毫克)，氢化钠(60％)(18.3毫克)，四氢呋喃(5毫升)。得到产品 49-1(49.9毫克)。 For the synthesis of compound 49-1 , refer to compound 42-3 . Among them, raw materials 42-2 (50.0 mg), 49-4 (71.9 mg), sodium hydride (60%) (18.3 mg), tetrahydrofuran (5 ml). Product 49-1 (49.9 mg) was obtained.
LC-MS:m/z 668(M+H) +. LC-MS: m/z 668(M+H) + .
步骤3：Step 3:
化合物 49-2的合成参考化合物 42-4。其中原料 49-1(49.9毫克)，氯化氢的1,4-二氧六环溶液(4摩尔/升，10毫升)。得到产品 49-2(39.4毫克)。无需纯化，直接用于下步反应。 For the synthesis of compound 49-2 , refer to compound 42-4 . Among them, raw material 49-1 (49.9 mg), 1,4-dioxane solution of hydrogen chloride (4 mol/L, 10 ml). The product 49-2 (39.4 mg) was obtained. No purification is required, and it is directly used in the next reaction.
LC-MS:m/z 568(M+H) +. LC-MS: m/z 568(M+H) + .
步骤4：Step 4:
化合物 49的合成参考化合物 42。其中原料 49-2(39.4毫克)，三乙胺(33.8毫克)，丙烯酰氯(7.2毫克)，二氯甲烷(10毫升)。反应后产物用制备型反相色谱柱纯化(柱型:XBridge Shield RP18 OBD Column,5um,19*150mm；流动相A:水(10毫摩尔/升，碳酸氢铵)，流动相B:乙腈；流速:25毫升/分钟；梯度:40-58％；时间8分钟；检测器波长254/220纳米)，得产品 49(21.0毫克)。 For the synthesis of compound 49 , refer to compound 42 . Among them, raw material 49-2 (39.4 mg), triethylamine (33.8 mg), acryloyl chloride (7.2 mg), methylene chloride (10 ml). After the reaction, the product was purified with a preparative reverse phase chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; Flow rate: 25 ml/min; gradient: 40-58%; time 8 minutes; detector wavelength 254/220 nm) to obtain product 49 (21.0 mg).
LC-MS:m/z 622(M+H) +. LC-MS: m/z 622(M+H) + .
1H-NMR(CD 3OD)δ:7.68-7.64(m,2H),7.43-7.19(m,4H),7.00-6.80(m,1H),6.31(d,J＝16.5Hz,1H),5.86(d,J＝10.5Hz,1H),5.15-5.05(m,1H),4.63(s,3H),4.45-4.37(m,4H),4.15(t,J＝12.6Hz,2H),4.00(d,J＝6.30Hz,1H),3.92-3.77(m,2H),3.59-3.58(m,2H),3.46-3.36(m,2H),3.30-3.25(m,1H),3.10-2.99(m,3H),2.94-2.78(m,5H),2.76-2.69(m,1H),2.58(d,J＝6.6Hz,1H),2.10-1.86(m,5H),1.731(d,J＝7.8Hz,1H). 1 H-NMR (CD 3 OD) δ: 7.68-7.64 (m, 2H), 7.43-7.19 (m, 4H), 7.00-6.80 (m, 1H), 6.31 (d, J=16.5Hz, 1H), 5.86(d,J=10.5Hz,1H),5.15-5.05(m,1H),4.63(s,3H),4.45-4.37(m,4H),4.15(t,J=12.6Hz,2H),4.00 (d,J=6.30Hz,1H),3.92-3.77(m,2H),3.59-3.58(m,2H),3.46-3.36(m,2H),3.30-3.25(m,1H),3.10-2.99 (m,3H),2.94-2.78(m,5H),2.76-2.69(m,1H),2.58(d,J=6.6Hz,1H),2.10-1.86(m,5H),1.731(d,J =7.8Hz, 1H).
实施例50Example 50
Figure PCTCN2020119633-appb-000141
Figure PCTCN2020119633-appb-000141
Figure PCTCN2020119633-appb-000142
Figure PCTCN2020119633-appb-000142
步骤1：step 1:
室温条件下，将原料 50-3(1.10克)溶于乙腈(5毫升)中，依次加入碳酸钾(3.06克)，溴丙醇(1.68克)。所得反应液90摄氏度下反应12小时。反应完毕后，加入水(150毫升)淬灭。用乙酸乙酯(150毫升x3)萃取。有机相合并后用饱和食盐水(150毫升)洗涤。有机相用无水硫酸钠干燥后，减压浓缩得产品 50-4(799.2毫克)。 At room temperature, the raw material 50-3 (1.10 g) was dissolved in acetonitrile (5 ml), and potassium carbonate (3.06 g) and bromopropanol (1.68 g) were added sequentially. The resulting reaction solution was reacted at 90 degrees Celsius for 12 hours. After the reaction was completed, water (150 mL) was added for quenching. Extract with ethyl acetate (150 mL x 3). The organic phases were combined and washed with saturated brine (150 mL). After the organic phase was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain the product 50-4 (799.2 mg).
LC-MS:m/z 158(M+H) +. LC-MS: m/z 158(M+H) + .
步骤2：Step 2:
化合物 50-1的合成参考化合物 42-3。其中原料 42-2(50.0毫克)， 50-4(71.9毫克)，氢化钠(60％)(18.3毫克)，四氢呋喃(5毫升)。得到产品 50-1(50.5毫克)。 For the synthesis of compound 50-1 , refer to compound 42-3 . Among them, raw materials 42-2 (50.0 mg), 50-4 (71.9 mg), sodium hydride (60%) (18.3 mg), tetrahydrofuran (5 mL). Product 50-1 (50.5 mg) was obtained.
LC-MS:m/z 668(M+H) +. LC-MS: m/z 668(M+H) + .
步骤3：Step 3:
化合物 50-2的合成参考化合物 42-4。其中原料 50-1(50.5毫克)，氯化氢的1,4-二氧六环溶液(4摩尔/升，10毫升)。得到产品 50-2(41.4毫克)。无需纯化，直接用于下步反应。 For the synthesis of compound 50-2 , refer to compound 42-4 . Among them, raw material 50-1 (50.5 mg), 1,4-dioxane solution of hydrogen chloride (4 mol/liter, 10 ml). Product 50-2 (41.4 mg) was obtained. No purification is required, and it is directly used in the next reaction.
LC-MS:m/z 568(M+H) +. LC-MS: m/z 568(M+H) + .
步骤4：Step 4:
化合物 50的合成参考化合物 42。其中原料 50-2(41.4毫克)，三乙胺(34.7毫克)，丙烯酰氯(7.4毫克)，二氯甲烷(10毫升)。反应后产物用制备型反相色谱柱纯化(柱型:XBridge Shield RP18 OBD Column,5um,19*150mm；流动相A:水(10毫摩尔/升，碳酸氢铵)，流动相B:乙腈；流速:25毫升/分钟；梯度:38-52％；时间8分钟；检测器波长254/220纳米)，得产品 50(22.8毫克)。 For the synthesis of compound 50 , refer to compound 42 . Among them, raw material 50-2 (41.4 mg), triethylamine (34.7 mg), acryloyl chloride (7.4 mg), dichloromethane (10 ml). After the reaction, the product was purified with a preparative reverse phase chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; Flow rate: 25 ml/min; gradient: 38-52%; time 8 minutes; detector wavelength 254/220 nm) to obtain product 50 (22.8 mg).
LC-MS:m/z 622(M+H) +. LC-MS: m/z 622(M+H) + .
1H-NMR(CD 3OD)δ:7.68-7.64(m,2H),7.43-7.19(m,4H),7.00-6.80(m,1H),6.31(d,J＝12.3Hz,1H),5.86(d,J＝8.1Hz,1H),5.15-5.05(m,1H),4.82-4.60(m,1H),4.44-4.37(m,4H),4.15(t,J＝12.6Hz,2H),4.00(d,J＝6.60Hz,1H),3.92-3.67(m,3H),3.59-3.57(m,2H),3.45-3.35(m,2H),3.30-3.25(m,1H),3.15-2.97(m,4H),2.93-2.88(m,1H),2.85-2.79(m,4H),2.76-2.69(m,1H),2.57(d,J＝8.1Hz,1H),2.10-1.86(m,5H),1.72(d,J＝7.5Hz,1H). 1 H-NMR (CD 3 OD) δ: 7.68-7.64 (m, 2H), 7.43-7.19 (m, 4H), 7.00-6.80 (m, 1H), 6.31 (d, J=12.3Hz, 1H), 5.86(d,J=8.1Hz,1H),5.15-5.05(m,1H),4.82-4.60(m,1H),4.44-4.37(m,4H),4.15(t,J=12.6Hz,2H) ,4.00(d,J=6.60Hz,1H),3.92-3.67(m,3H),3.59-3.57(m,2H),3.45-3.35(m,2H),3.30-3.25(m,1H),3.15 -2.97(m,4H),2.93-2.88(m,1H),2.85-2.79(m,4H),2.76-2.69(m,1H), 2.57(d,J=8.1Hz,1H),2.10-1.86 (m,5H),1.72(d,J=7.5Hz,1H).
实施例51Example 51
Figure PCTCN2020119633-appb-000143
Figure PCTCN2020119633-appb-000143
步骤1step 1
将原料 1-5(1.50克)溶于异丙醇(30毫升)中，依次加入N-Boc-哌嗪(1.10克)、二异丙基乙胺(1.26克)。所得混合液于80摄氏度下反应12小时。反应完毕后，加入水(100毫升)稀释。并用乙酸乙酯(100毫升x3)萃取。有机相合并后，用饱和食盐水(200毫升)洗涤，并用无水硫酸钠干燥后浓缩至干，得产品 51-2(1.34克)。 Raw materials 1-5 (1.50 g) were dissolved in isopropanol (30 ml), and N-Boc-piperazine (1.10 g) and diisopropylethylamine (1.26 g) were added in sequence. The resulting mixture was reacted at 80 degrees Celsius for 12 hours. After the reaction is complete, add water (100 ml) to dilute. It was extracted with ethyl acetate (100 mL×3). After the organic phases were combined, they were washed with saturated brine (200 ml), dried over anhydrous sodium sulfate and concentrated to dryness to obtain product 51-2 (1.34 g).
LC-MS:m/z 458(M+H) + LC-MS: m/z 458(M+H) +
步骤2Step 2
将(S)-脯氨醇(0.51克)溶于无水四氢呋喃(15毫升)中，于0摄氏度下加入氢化钠(60％)(0.188克)。0摄氏度下反应30分钟后，加入原料 51-2(1.34克)。所得溶液于70摄氏度下反应3小时。反应完毕后，冷却至室温。加入饱和氯化铵水溶液(50毫升)淬灭，并用乙酸乙酯(80毫升x3)萃取。有机相合并后浓缩至干。所得粗品用硅胶柱层析纯化(甲醇/二氯甲烷＝5％-20％)得产品 51-3(1.19克)。 (S)-Prolinol (0.51 g) was dissolved in anhydrous tetrahydrofuran (15 ml), and sodium hydride (60%) (0.188 g) was added at 0 degrees Celsius. After reacting for 30 minutes at 0 degrees Celsius, raw material 51-2 (1.34 g) was added. The resulting solution was reacted at 70 degrees Celsius for 3 hours. After the reaction is complete, cool to room temperature. It was quenched by adding saturated aqueous ammonium chloride solution (50 mL), and extracted with ethyl acetate (80 mL×3). The organic phases were combined and concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (methanol/dichloromethane=5%-20%) to obtain product 51-3 (1.19 g).
LC-MS:m/z 537(M+H) + LC-MS: m/z 537(M+H) +
步骤3Step 3
将原料 51-3(1.19克)溶于无水甲醇(30毫升)中，氮气保护下依次加入钯碳(10％)(0.119克)。所得反应液用氢气置换3次，并于室温反应16小时。反应完毕后，将钯碳滤除。滤液浓缩至干，得产品 51-4(0.913克)。 The raw material 51-3 (1.19 g) was dissolved in anhydrous methanol (30 ml), and palladium on carbon (10%) (0.119 g) was sequentially added under the protection of nitrogen. The resulting reaction solution was replaced with hydrogen three times and reacted at room temperature for 16 hours. After the reaction is completed, the palladium carbon is filtered off. The filtrate was concentrated to dryness to obtain product 51-4 (0.913 g).
LC-MS:m/z 447(M+H) + LC-MS: m/z 447(M+H) +
步骤4Step 4
将原料 51-4(50.0毫克)溶于甲苯(2毫升)中，依次加入8-甲基-1-溴萘(37.0毫克)，叔丁醇钠(108毫克)、甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(28.1毫克)。所得溶液于90摄氏度下搅拌3小时。反应完毕后冷却至室温，加入水(15毫升)稀释，并用乙酸乙酯(15毫升x3)萃取。有机相合并后浓缩至干。所得粗品用硅胶柱层析纯化(二氯甲烷/甲醇＝10％-20％)得产品 51-5(40.0毫克)。 The raw material 51-4 (50.0 mg) was dissolved in toluene (2 ml), and 8-methyl-1-bromonaphthalene (37.0 mg), sodium tert-butoxide (108 mg), methanesulfonic acid (2-two Cyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2-yl)palladium(II) (28.1 mg ). The resulting solution was stirred at 90 degrees Celsius for 3 hours. After the reaction was completed, it was cooled to room temperature, diluted with water (15 mL), and extracted with ethyl acetate (15 mL×3). The organic phases were combined and concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (dichloromethane/methanol=10%-20%) to obtain product 51-5 (40.0 mg).
LC-MS:m/z 587(M+H) + LC-MS: m/z 587(M+H) +
步骤5Step 5
向原料 51-5(40.0毫克)中加入氯化氢的1,4-二氧六环溶液(5毫升)。所得溶 液于室温下搅拌10分钟。反应完毕后浓缩至干，得产品 51-6(30毫克)。无需纯化，直接用于下步反应。 A 1,4-dioxane solution (5 mL) of hydrogen chloride was added to the raw material 51-5 (40.0 mg). The resulting solution was stirred at room temperature for 10 minutes. After the reaction was completed, it was concentrated to dryness to obtain product 51-6 (30 mg). No purification is required, and it is directly used in the next reaction.
LC-MS:m/z 487(M+H) + LC-MS: m/z 487(M+H) +
步骤6Step 6
将原料 51-6(30.0毫克)溶于二氯甲烷(5毫升)中，冷却至-40摄氏度后，依次加入三乙胺(31.4毫克)、丙烯酰氯(8.44毫克)。所得溶液于-40摄氏度下反应10分钟。反应完毕后，加入水(5毫升)淬灭并浓缩至干。所得粗品用制备型色谱柱纯化(柱型:XBridge Shield RP18 OBD Column,,5um,19*150mm；流动相A:水(10毫摩尔/升，碳酸氢铵),流动相B:乙腈；流速:25毫升/分钟；梯度:38-59％；时间8分钟；检测器波长254/220纳米)，得产品 51(11.2毫克)。 The raw material 51-6 (30.0 mg) was dissolved in dichloromethane (5 ml), and after cooling to -40 degrees Celsius, triethylamine (31.4 mg) and acryloyl chloride (8.44 mg) were sequentially added. The resulting solution was reacted at -40 degrees Celsius for 10 minutes. After the reaction was completed, it was quenched by adding water (5 mL) and concentrated to dryness. The obtained crude product was purified with a preparative chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 ml/min; gradient: 38-59%; time 8 minutes; detector wavelength 254/220 nm) to obtain product 51 (11.2 mg).
LC-MS:m/z 541(M+H) + LC-MS: m/z 541(M+H) +
1H-NMR(CD 3OD)δ:7.69-7.62(m,2H),7.42-7.36(m,2H),7.29(t,J＝7.2Hz,1H),7.19(d,J＝6.9Hz,1H),6.89-6.78(m,1H),6.31-6.22(m,1H),5.84-5.78(m,1H),4.44-4.25(m,3H),4.14(d,J＝15.3Hz,1H),3.92-3.77(m,4H),3.54-3.31(m,6H),3.11-2.99(m,2H),2.94-2.85(m,1H),2.83(s,3H),2.78-2.68(m,1H),2.47(d,J＝2.7Hz,3H),2.41-2.28(m,1H),2.11-1.95(m,3H),1.87-1.65(m,3H). 1 H-NMR (CD 3 OD) δ: 7.69-7.62 (m, 2H), 7.42-7.36 (m, 2H), 7.29 (t, J = 7.2 Hz, 1H), 7.19 (d, J = 6.9 Hz, 1H), 6.89-6.78(m,1H),6.31-6.22(m,1H),5.84-5.78(m,1H),4.44-4.25(m,3H), 4.14(d,J=15.3Hz,1H) ,3.92-3.77(m,4H),3.54-3.31(m,6H),3.11-2.99(m,2H),2.94-2.85(m,1H),2.83(s,3H),2.78-2.68(m, 1H), 2.47 (d, J = 2.7 Hz, 3H), 2.41-2.28 (m, 1H), 2.11-1.95 (m, 3H), 1.87-1.65 (m, 3H).
实施例52Example 52
Figure PCTCN2020119633-appb-000144
Figure PCTCN2020119633-appb-000144
步骤1：step 1:
化合物 52-1的合成参考化合物 51-5。原料 51-4(将原料1(50.0毫克)，8-氯-1-溴萘(40.3毫克)，叔丁醇钠(108毫克)，甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(28.1毫克)，甲苯(2毫升)。得产品 52-1(50.0毫克)。 For the synthesis of compound 52-1 , refer to compound 51-5 . Raw material 51-4 (Compound raw material 1 (50.0 mg), 8-chloro-1-bromonaphthalene (40.3 mg), sodium tert-butoxide (108 mg), methanesulfonic acid (2-dicyclohexylphosphino-2', 6'-Diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (28.1 mg), toluene (2 mL). The product 52-1 (50.0 mg) was obtained.
LC-MS:m/z 607(M+H) +. LC-MS: m/z 607(M+H) + .
步骤2：Step 2:
化合物 52-2的合成参考化合物 51-6。原料 52-1(50.0毫克)，氯化氢的1,4-二氧六环溶液(4摩尔/升，5毫升)。得产品 52-2(43.0毫克)。 For the synthesis of compound 52-2 , refer to compound 51-6 . Raw material 52-1 (50.0 mg), 1,4-dioxane solution of hydrogen chloride (4 mol/L, 5 mL). The product 52-2 (43.0 mg) was obtained.
LC-MS:m/z 507(M+H) +. LC-MS: m/z 507(M+H) + .
步骤3Step 3
化合物 52的合成参考化合物 51。原料 52-2(43.0毫克)，三乙胺(40.1毫克)，丙烯酰氯(10.8毫克)，二氯甲烷(5毫升)。得产品 52(7.8毫克)。 For the synthesis of compound 52 , refer to compound 51 . Starting material 52-2 (43.0 mg), triethylamine (40.1 mg), acryloyl chloride (10.8 mg), dichloromethane (5 mL). Product 52 (7.8 mg) was obtained.
LC-MS:m/z 561(M+H) + LC-MS: m/z 561(M+H) +
1H-NMR(CD 3OD)δ:7.79(d,J＝8.4Hz,1H),7.64(d,J＝8.1Hz,1H),7.48(d, J＝7.8Hz,1H),7.45-7.31(m,3H),6.90-6.77(m,1H),6.25(d,J＝16.5Hz,1H),5.80(d,J＝10.5Hz,1H),4.41-4.23(m,4H),3.92-3.72(m,4H),3.60-3.36(m,6H),3.12-2.98(m,2H),2.90-2.99(m,2H),4.48(d,J＝1.2Hz,3H),2.40-2.30(m,1H),2.18-1.65(m,6H). 1 H-NMR (CD 3 OD) δ: 7.79 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.45-7.31 (m, 3H), 6.90-6.77 (m, 1H), 6.25 (d, J = 16.5 Hz, 1H), 5.80 (d, J = 10.5 Hz, 1H), 4.41-4.23 (m, 4H), 3.92 3.72(m,4H), 3.60-3.36(m,6H),3.12-2.98(m,2H), 2.90-2.99(m,2H), 4.48(d,J=1.2Hz,3H), 2.40-2.30( m,1H), 2.18-1.65(m,6H).
实施例53Example 53
Figure PCTCN2020119633-appb-000145
Figure PCTCN2020119633-appb-000145
步骤1：step 1:
室温条件下，将原料 1-5(2.00克)溶于异丙醇(50毫升)中，依次加入二异丙基乙胺(2.52克)、(S)-4-N-叔丁氧羰基-2-甲基哌嗪(1.43克)。所得混合液于80摄氏度下反应12小时。反应完毕后，加入水(100毫升)稀释。并用乙酸乙酯(100毫升x3)萃取。有机相合并后，用饱和食盐水(200毫升)洗涤，并用无水硫酸钠干燥后浓缩至干，得产品 53-1(1.04克)。 At room temperature, dissolve raw materials 1-5 (2.00 g) in isopropanol (50 ml), and add diisopropylethylamine (2.52 g), (S)-4-N-tert-butoxycarbonyl- 2-methylpiperazine (1.43 g). The resulting mixture was reacted at 80 degrees Celsius for 12 hours. After the reaction is complete, add water (100 ml) to dilute. It was extracted with ethyl acetate (100 mL×3). After the organic phases were combined, they were washed with saturated brine (200 ml), dried over anhydrous sodium sulfate and concentrated to dryness to obtain the product 53-1 (1.04 g).
LC-MS:m/z 472(M+H) +. LC-MS: m/z 472(M+H) + .
步骤2：Step 2:
将(S)-脯氨醇(0.41克)溶于无水四氢呋喃(20毫升)中，于0摄氏度下加入氢化钠(60％)(0.14克)。0摄氏度下反应30分钟后，加入原料 53-1(1.04克)。所得溶液于70摄氏度下反应3小时。反应完毕后，冷却至室温。加入饱和氯化铵水溶液(50毫升)淬灭，并用乙酸乙酯(80毫升x3)萃取。有机相合并后浓缩至干。所得粗品用硅胶柱层析纯化(甲醇/二氯甲烷＝5％-20％)得产品 53-2(716毫克)。 (S)-Prolinol (0.41 g) was dissolved in anhydrous tetrahydrofuran (20 ml), and sodium hydride (60%) (0.14 g) was added at 0 degrees Celsius. After reacting for 30 minutes at 0 degrees Celsius, raw material 53-1 (1.04 g) was added. The resulting solution was reacted at 70 degrees Celsius for 3 hours. After the reaction is complete, cool to room temperature. It was quenched by adding saturated aqueous ammonium chloride solution (50 mL), and extracted with ethyl acetate (80 mL×3). The organic phases were combined and concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (methanol/dichloromethane=5%-20%) to obtain product 53-2 (716 mg).
LC-MS:m/z 551(M+H) +. LC-MS: m/z 551(M+H) + .
步骤3：Step 3:
室温条件下，将原料 53-2(716毫克)溶于无水甲醇(30毫升)中，氮气保护下加入钯碳(10％)(71.6毫克)。所得反应液用氢气置换3次，并于室温反应2小时。反应完毕后，将钯碳滤除。滤液浓缩至干，得产品 53-3(540毫克)。 At room temperature, the raw material 53-2 (716 mg) was dissolved in anhydrous methanol (30 ml), and palladium on carbon (10%) (71.6 mg) was added under the protection of nitrogen. The resulting reaction liquid was replaced with hydrogen three times, and reacted at room temperature for 2 hours. After the reaction is completed, the palladium carbon is filtered off. The filtrate was concentrated to dryness to obtain product 53-3 (540 mg).
LC-MS:m/z 461(M+H) +. LC-MS: m/z 461(M+H) + .
步骤4：Step 4:
室温条件下，将原料 53-3(120毫克)溶于甲苯(3毫升)中，依次加入1-溴-8-甲基萘(115毫克)，叔丁醇钠(250毫克)、甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(65.3毫克)。所得溶液于90摄氏 度下搅拌3小时。反应完毕后冷却至室温，加入水(15毫升)稀释，并用乙酸乙酯(15毫升x3)萃取，有机相合并后浓缩至干。所得粗品用硅胶柱层析纯化(二氯甲烷/甲醇＝10％-20％)得产品 53-4(92.8毫克)。 At room temperature, the raw material 53-3 (120 mg) was dissolved in toluene (3 ml), and 1-bromo-8-methylnaphthalene (115 mg), sodium tert-butoxide (250 mg) and methanesulfonic acid were added in sequence. (2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II ) (65.3 mg). The resulting solution was stirred at 90 degrees Celsius for 3 hours. After the reaction was completed, it was cooled to room temperature, diluted with water (15 mL), and extracted with ethyl acetate (15 mL×3). The organic phases were combined and concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (dichloromethane/methanol=10%-20%) to obtain product 53-4 (92.8 mg).
LC-MS:m/z 601(M+H) +. LC-MS: m/z 601(M+H) + .
步骤5：Step 5:
室温条件下，向原料 53-4(92.8毫克)中加入氯化氢的1,4-二氧六环溶液(10毫升)。所得溶液于室温下搅拌10分钟。反应完毕后浓缩至干，得产品 53-5(75.9毫克)。无需纯化，直接用于下步反应。 At room temperature, a 1,4-dioxane solution (10 ml) of hydrogen chloride was added to the raw material 53-4 (92.8 mg). The resulting solution was stirred at room temperature for 10 minutes. After the reaction was completed, it was concentrated to dryness to obtain the product 53-5 (75.9 mg). No purification is required, and it is directly used in the next reaction.
LC-MS:m/z 501(M+H) +. LC-MS: m/z 501(M+H) + .
步骤6：Step 6:
将原料 53-5(75.9毫克)溶于二氯甲烷(10毫升)中，冷却至-40摄氏度后，依次加入三乙胺(71.7毫克)、丙烯酰氯(15.3毫克)。所得溶液于-40摄氏度下反应10分钟。反应完毕后，加入水(10毫升)淬灭，用乙酸乙酯(15毫升x3)萃取，有机相合并后浓缩至干。所得粗品用制备型色谱柱纯化(柱型:XBridge Shield RP18 OBD Column,5um,19*150mm；流动相A：水(10毫摩尔/升，碳酸氢铵)，流动相B：乙腈；流速：25毫升/分钟；梯度：35-80％；时间12分钟；检测器波长254/220纳米)，得产品 53(57.1毫克)。 The raw material 53-5 (75.9 mg) was dissolved in dichloromethane (10 mL), and after cooling to -40 degrees Celsius, triethylamine (71.7 mg) and acryloyl chloride (15.3 mg) were sequentially added. The resulting solution was reacted at -40 degrees Celsius for 10 minutes. After the reaction was completed, it was quenched by adding water (10 mL), extracted with ethyl acetate (15 mL×3), and the organic phases were combined and concentrated to dryness. The crude product obtained was purified with a preparative chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 Ml/min; gradient: 35-80%; time 12 minutes; detector wavelength 254/220 nanometers) to obtain product 53 (57.1 mg).
LC-MS:m/z 555(M+H) +. LC-MS: m/z 555(M+H) + .
1H-NMR(CD 3OD)δ:7.69-7.62(m,2H),7.43-7.18(m,4H),6.93-6.77(m,1H),6.29(d,J＝16.2Hz,1H),5.82(d,J＝11.1Hz,1H),4.52-4.27(m,4H),4.19-3.93(m,3H),3.73-3.35(m,5H),3.29-3.15(m,1H),3.10-2.99(m,2H),2.91-2.86(m,1H),2.83(d,J＝5.7Hz,3H),2.80-2.68(m,1H),2.47(d,J＝2.7Hz,3H),2.34(q,J＝9.0Hz,1H),2.13-1.96(m,3H),1.85-1.76(m,2H),1.73-1.62(m,1H),1.31-1.18(m,3H). 1 H-NMR(CD 3 OD)δ: 7.69-7.62(m,2H),7.43-7.18(m,4H),6.93-6.77(m,1H), 6.29(d,J=16.2Hz,1H), 5.82(d,J=11.1Hz,1H),4.52-4.27(m,4H),4.19-3.93(m,3H),3.73-3.35(m,5H),3.29-3.15(m,1H),3.10- 2.99(m,2H),2.91-2.86(m,1H), 2.83(d,J=5.7Hz,3H), 2.80-2.68(m,1H), 2.47(d,J=2.7Hz,3H), 2.34 (q,J=9.0Hz,1H),2.13-1.96(m,3H),1.85-1.76(m,2H),1.73-1.62(m,1H),1.31-1.18(m,3H).
实施例54Example 54
Figure PCTCN2020119633-appb-000146
Figure PCTCN2020119633-appb-000146
步骤1：step 1:
化合物 54-1的合成参考化合物 53-4。其中原料 53-3(120毫克)，8-氯-1-溴萘(125毫克)，叔丁醇钠(250.5毫克)，甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(65.5毫克)，甲苯(3毫升)。得到产品 54-1(107毫克)。 For the synthesis of compound 54-1 , refer to compound 53-4 . The raw material 53-3 (120 mg), 8-chloro-1-bromonaphthalene (125 mg), sodium tert-butoxide (250.5 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'- Diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (65.5 mg), toluene (3 mL). The product 54-1 (107 mg) was obtained.
LC-MS:m/z 621(M+H) +. LC-MS: m/z 621(M+H) + .
步骤2：Step 2:
化合物 54-2的合成参考化合物 53-5。其中原料 54-1(107毫克)，氯化氢的1,4- 二氧六环溶液(4摩尔/升，10毫升)。得产品 54-2(90.7毫克)。 For the synthesis of compound 54-2 , refer to compound 53-5 . Among them, raw material 54-1 (107 mg), 1,4-dioxane solution of hydrogen chloride (4 mol/L, 10 ml). The product 54-2 (90.7 mg) was obtained.
LC-MS:m/z 521(M+H) +. LC-MS: m/z 521(M+H) + .
步骤3：Step 3:
化合物 54的合成参考化合物 53。原料 54-2(90.7毫克)，三乙胺(82.6毫克)，丙烯酰氯(17.7毫克)，二氯甲烷(1毫升)。得到产品 54(61.7毫克)。 The synthesis of compound 54 refers to compound 53 . Starting material 54-2 (90.7 mg), triethylamine (82.6 mg), acryloyl chloride (17.7 mg), dichloromethane (1 ml). Product 54 (61.7 mg) was obtained.
LC-MS:m/z 575(M+H) +. LC-MS: m/z 575(M+H) + .
1H-NMR(CD 3OD)δ:7.79(d,J＝8.1Hz,1H),7.64(t,J＝7.5Hz,1H),7.50-7.29(m,4H),6.93-6.77(m,1H),6.29(d,J＝16.8Hz,1H),5.81(d,J＝10.8Hz,1H),4.58-4.38(m,1H),4.33-4.27(m,4H),4.13-3.92(m,2H),3.73-3.37(m,5H),3.29-3.16(m,1H),3.11-2.97(m,2H),2.87-2.70(m,2H),2.47(d,J＝1.5Hz,3H),2.35(q,J＝9.0Hz,1H),2.19-2.02(m,2H),1.97-1.90(m,1H),1.86-1.77(m,2H),1.74-1.63(m,1H),1.28-1.16(m,3H). 1 H-NMR (CD 3 OD) δ: 7.79 (d, J = 8.1 Hz, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.50-7.29 (m, 4H), 6.93-6.77 (m, 1H), 6.29 (d, J = 16.8 Hz, 1H), 5.81 (d, J = 10.8 Hz, 1H), 4.58-4.38 (m, 1H), 4.33-4.27 (m, 4H), 4.13-3.92 (m ,2H),3.73-3.37(m,5H),3.29-3.16(m,1H),3.11-2.97(m,2H),2.87-2.70(m,2H),2.47(d,J=1.5Hz,3H ), 2.35(q,J=9.0Hz,1H),2.19-2.02(m,2H),1.97-1.90(m,1H),1.86-1.77(m,2H),1.74-1.63(m,1H), 1.28-1.16(m,3H).
实施例56Example 56
Figure PCTCN2020119633-appb-000147
Figure PCTCN2020119633-appb-000147
步骤1：step 1:
化合物 56-1的合成参考化合物 1-10。原料 1-9(50.0毫克)，4-溴-2氯苯甲醚(45.3毫克)，叔丁醇钠(98.9毫克)，甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(25.8毫克)，甲苯(2毫升)。得产品 56-1(29.0毫克)。 For the synthesis of compound 56-1 , refer to compound 1-10 . Raw material 1-9 (50.0 mg), 4-bromo-2-chloroanisole (45.3 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'- Diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). The product 56-1 (29.0 mg) was obtained.
LC-MS:m/z 626(M+H) +. LC-MS: m/z 626(M+H) + .
步骤2：Step 2:
化合物 56-2的合成参考化合物 1-11。原料 56-1(30毫克)，氯化氢的1,4-二氧六环溶液(4摩尔/升，5毫升)。得产品 56-2(25.7毫克)。 For the synthesis of compound 56-2 , refer to compound 1-11 . Raw material 56-1 (30 mg), 1,4-dioxane solution of hydrogen chloride (4 mol/liter, 5 ml). The product 56-2 (25.7 mg) was obtained.
LC-MS:m/z 526(M+H) +. LC-MS: m/z 526(M+H) + .
步骤3Step 3
化合物 56的合成参考化合物 1。原料 56-2(25.7毫克)，三乙胺(0.0318毫升)，烯酰氯(5.16毫克)，二氯甲烷(5毫升)。得产品 56(7.0毫克)。 The synthesis of compound 56 refers to compound 1 . Starting material 56-2 (25.7 mg), triethylamine (0.0318 mL), enoyl chloride (5.16 mg), dichloromethane (5 mL). Obtained product 56 (7.0 mg).
LC-MS:m/z 580(M+H) + LC-MS: m/z 580(M+H) +
1H-NMR(CD 3OD)δ:6.92-6.66(m,4H),6.25(d,J＝16.8Hz,1H),5.81(d,J＝10.5Hz,1H),5.11-5.03(m,1H),4.67-4.59(m,1H),4.57-4.50(m,2H),4.50-4.30(m,2H),4.16-3.96(m,1H),3.95-3.78(m,2H),3.75(s,3H),3.72-3.50(m,2H),3.26-2.73(m,8H),2.53(s,3H),2.46-2.29(m,1H),2.25-1.65(m,6H). 1 H-NMR (CD 3 OD) δ: 6.92-6.66 (m, 4H), 6.25 (d, J=16.8 Hz, 1H), 5.81 (d, J=10.5 Hz, 1H), 5.11-5.03 (m, 1H), 4.67-4.59 (m, 1H), 4.57-4.50 (m, 2H), 4.50-4.30 (m, 2H), 4.16-3.96 (m, 1H), 3.95-3.78 (m, 2H), 3.75 ( s,3H),3.72-3.50(m,2H),3.26-2.73(m,8H),2.53(s,3H),2.46-2.29(m,1H),2.25-1.65(m,6H).
实施例57Example 57
Figure PCTCN2020119633-appb-000148
Figure PCTCN2020119633-appb-000148
步骤1：step 1:
化合物 57-1的合成参考化合物 1-10。原料 1-9(50.0毫克)，3-溴-5-氯-4-甲基吡啶(42.2毫克)，叔丁醇钠(98.9毫克)，甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(25.8毫克)，甲苯(2毫升)。得产品 57-1(34.4毫克)。 For the synthesis of compound 57-1 , refer to compound 1-10 . Raw material 1-9 (50.0 mg), 3-bromo-5-chloro-4-methylpyridine (42.2 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-Diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8mg), toluene (2ml) . The product 57-1 (34.4 mg) was obtained.
LC-MS:m/z 611(M+H) +. LC-MS: m/z 611(M+H) + .
步骤2：Step 2:
化合物 57-2的合成参考化合物 1-11。原料 57-1(34.4毫克)，氯化氢的1，4-二氧六环溶液(4摩尔/升，5毫升)。得产品 57-2(30.0毫克)。 For the synthesis of compound 57-2 , refer to compound 1-11 . Raw material 57-1 (34.4 mg), 1,4-dioxane solution of hydrogen chloride (4 mol/liter, 5 ml). The product 57-2 (30.0 mg) was obtained.
LC-MS:m/z 511(M+H) +. LC-MS: m/z 511(M+H) + .
步骤3Step 3
化合物 57的合成参考化合物 1。原料 57-2(30.0毫克)，三乙胺(0.0382毫升)，丙烯酰氯(5.96毫克)，二氯甲烷(5毫升)。得产品 57(8.8毫克)。 For the synthesis of compound 57 , refer to compound 1 . Starting material 57-2 (30.0 mg), triethylamine (0.0382 ml), acryloyl chloride (5.96 mg), dichloromethane (5 ml). Obtained product 57 (8.8 mg).
LC-MS:m/z 565(M+H) + LC-MS: m/z 565(M+H) +
1H-NMR(CD 3OD)δ:8.20(d,J＝3.9Hz,2H),6.98-6.72(m,1H),6.29(d,J＝16.8Hz,1H),5.84(d,J＝10.8Hz,1H),5.21-5.02(m,1H),4.68-4.54(m,1H),4.39-4.14(m,4H),4.03-3.82(m,2H),3.79-3.36(m,4H),3.17-2.71(m,7H),2.51(s,3H),2.45-2.31(m,1H),2.26(s,3H),2.21-1.99(m,3H),1.92-1.66(m,3H). 1 H-NMR (CD 3 OD) δ: 8.20 (d, J = 3.9 Hz, 2H), 6.98-6.72 (m, 1H), 6.29 (d, J = 16.8 Hz, 1H), 5.84 (d, J = 10.8Hz, 1H), 5.21-5.02 (m, 1H), 4.68-4.54 (m, 1H), 4.39-4.14 (m, 4H), 4.03-3.82 (m, 2H), 3.79-3.36 (m, 4H) ,3.17-2.71(m,7H),2.51(s,3H),2.45-2.31(m,1H),2.26(s,3H),2.21-1.99(m,3H),1.92-1.66(m,3H) .
实施例58Example 58
Figure PCTCN2020119633-appb-000149
Figure PCTCN2020119633-appb-000149
步骤1step 1
将原料 58-1(10.0克)溶于无水甲醇(150毫升)中，于0摄氏度下加入甲醇钠的甲醇溶液(30％)(26.2克)、硫脲(11.0克)。所得混合物升温至80摄氏度搅拌1小时。反应完毕后，将反应液冷却至室温。加入稀盐酸(1摩尔/升)调节PH＝7。过滤收集析出的固体，并用水(50毫升)洗涤。固体干燥后，得产品 58-2(8.10克)。无需纯化，直接用于下步反应。 The raw material 58-1 (10.0 g) was dissolved in anhydrous methanol (150 ml), and a methanol solution of sodium methoxide (30%) (26.2 g) and thiourea (11.0 g) were added at 0 degrees Celsius. The resulting mixture was heated to 80 degrees Celsius and stirred for 1 hour. After the completion of the reaction, the reaction solution was cooled to room temperature. Add dilute hydrochloric acid (1 mol/L) to adjust PH=7. The precipitated solid was collected by filtration and washed with water (50 mL). After the solid was dried, product 58-2 (8.10 g) was obtained. No purification is required, and it is directly used in the next reaction.
LC-MS:m/z 288(M+H) + LC-MS: m/z 288(M+H) +
步骤2Step 2
将原料 58-2(8.10克)悬浮于三氯氧磷(100毫升)中，加入N,N-二甲基甲酰胺(10毫升)。所得悬浊液于100摄氏度下搅拌12小时。反应完毕后，将反应液浓缩至干。残余物加入水(100毫升)并用无水碳酸钠溶液调节PH至8。混合液用乙酸乙酯(200毫升x3)萃取。有机相合并后浓缩至干。所得粗品用硅胶柱层析纯化(乙酸乙酯/石油醚＝10％-50％)得产品 58-3(6.50克)。 Raw material 58-2 (8.10 g) was suspended in phosphorus oxychloride (100 mL), and N,N-dimethylformamide (10 mL) was added. The resulting suspension was stirred at 100 degrees Celsius for 12 hours. After the completion of the reaction, the reaction solution was concentrated to dryness. The residue was added with water (100 ml) and the pH was adjusted to 8 with anhydrous sodium carbonate solution. The mixture was extracted with ethyl acetate (200 mL×3). The organic phases were combined and concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 10%-50%) to obtain product 58-3 (6.50 g).
LC-MS:m/z 308(M+H) + LC-MS: m/z 308(M+H) +
步骤3Step 3
将原料 58-3(6.50克)溶于异丙醇(100毫升)中，依次加入2-氰甲基哌嗪二盐酸盐(4.59克)、二异丙基乙胺(10.9克)。所得混合液于80摄氏度下反应24小时。反应完毕后，加入水(200毫升)淬灭。并用乙酸乙酯(200毫升x3)萃取。有机相合并后，用饱和食盐水(200毫升)洗涤，并用无水硫酸钠干燥后浓缩至干，得产品 58-4(6.10克)。无需纯化，直接用于下步反应。 Raw material 58-3 (6.50 g) was dissolved in isopropanol (100 ml), and 2-cyanomethylpiperazine dihydrochloride (4.59 g) and diisopropylethylamine (10.9 g) were added sequentially. The resulting mixture was reacted at 80 degrees Celsius for 24 hours. After the reaction was completed, it was quenched by adding water (200 mL). It was extracted with ethyl acetate (200 mL×3). After the organic phases were combined, they were washed with saturated brine (200 ml), dried with anhydrous sodium sulfate and concentrated to dryness to obtain product 58-4 (6.10 g). No purification is required, and it is directly used in the next reaction.
LC-MS:m/z 397(M+H) + LC-MS: m/z 397(M+H) +
步骤4Step 4
将原料 58-4(6.10克)溶于无水四氢呋喃(100毫升)中，依次加入二碳酸二叔丁酯(4.03克)、二异丙基乙胺(2.38克)。所得溶液回流反应1小时。反应完毕后，冷却至室温。加入水(150毫升)稀释，并用乙酸乙酯(150毫升x3)萃取。有机相合并后浓缩至干。所得粗品用硅胶柱层析纯化(乙酸乙酯/石油醚＝30％-60％)得产品 58-5(5.50克)。 Raw material 58-4 (6.10 g) was dissolved in anhydrous tetrahydrofuran (100 ml), and di-tert-butyl dicarbonate (4.03 g) and diisopropylethylamine (2.38 g) were added in sequence. The resulting solution was refluxed and reacted for 1 hour. After the reaction is complete, cool to room temperature. It was diluted with water (150 mL) and extracted with ethyl acetate (150 mL×3). The organic phases were combined and concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=30%-60%) to obtain product 58-5 (5.50 g).
LC-MS:m/z 497(M+H) + LC-MS: m/z 497(M+H) +
步骤5Step 5
将(S)-脯氨醇(1.91克)溶于无水四氢呋喃(100毫升)中，于0摄氏度下加入氢化钠(60％)(0.665克)。0摄氏度下反应30分钟后，加入原料 58-5(5.50克)。所得溶液回流反应3小时。反应完毕后，冷却至室温。加入饱和氯化铵水溶液(150毫升)淬灭，并用乙酸乙酯(150毫升x3)萃取。有机相合并后浓缩至干。所得粗品用硅胶柱层析纯化(甲醇/二氯甲烷＝5％-20％)得产品 58-6(4.20克)。 (S)-Prolinol (1.91 g) was dissolved in anhydrous tetrahydrofuran (100 ml), and sodium hydride (60%) (0.665 g) was added at 0 degrees Celsius. After reacting for 30 minutes at 0 degrees Celsius, raw material 58-5 (5.50 g) was added. The resulting solution was refluxed and reacted for 3 hours. After the reaction is complete, cool to room temperature. It was quenched by adding saturated aqueous ammonium chloride solution (150 mL), and extracted with ethyl acetate (150 mL×3). The organic phases were combined and concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (methanol/dichloromethane=5%-20%) to obtain product 58-6 (4.20 g).
LC-MS:m/z 576(M+H) + LC-MS: m/z 576(M+H) +
步骤6Step 6
将原料 58-6(4.20克)溶于无水甲醇(100毫升)中，氮气保护下依次加入钯碳(10％)(0.42克)、氨的甲醇溶液(7摩尔/升)(10毫升)。所得反应液用氢气置换3次，并于40摄氏度反应3小时。反应完毕后，将钯碳滤除。滤液浓缩至干，得产品 58-7(2.50克)。 The raw material 58-6 (4.20 g) was dissolved in anhydrous methanol (100 ml), and palladium on carbon (10%) (0.42 g) and ammonia methanol solution (7 mol/L) (10 ml) were added in sequence under the protection of nitrogen. . The resulting reaction solution was replaced with hydrogen three times, and reacted at 40 degrees Celsius for 3 hours. After the reaction is completed, the palladium carbon is filtered off. The filtrate was concentrated to dryness to obtain product 58-7 (2.50 g).
LC-MS:m/z 486(M+H) + LC-MS: m/z 486(M+H) +
步骤7Step 7
将原料 58-7(50.0毫克)溶于甲苯(2毫升)中，依次加入1-溴萘(25.5毫克)，叔丁醇钠(49.4毫克)、甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(8.6毫克)。所得溶液于90摄氏度下搅拌3小时。反应完毕后冷却至室温，加入水(15毫升)稀释，并用乙酸乙酯(15毫升x3)萃取。有机相合并后浓缩至干。所得粗品用硅胶柱层析纯化(二氯甲烷/甲醇＝10％-20％)得产品 58-8(25.0毫克)。 The raw material 58-7 (50.0 mg) was dissolved in toluene (2 ml), and 1-bromonaphthalene (25.5 mg), sodium tert-butoxide (49.4 mg), methanesulfonic acid (2-dicyclohexylphosphino- 2',6'-Diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (8.6 mg). The resulting solution was stirred at 90 degrees Celsius for 3 hours. After the reaction was completed, it was cooled to room temperature, diluted with water (15 mL), and extracted with ethyl acetate (15 mL×3). The organic phases were combined and concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (dichloromethane/methanol=10%-20%) to obtain product 58-8 (25.0 mg).
LC-MS:m/z 612(M+H) + LC-MS: m/z 612(M+H) +
步骤8Step 8
向原料 58-8(25.0毫克)中加入氯化氢的1,4-二氧六环溶液(2毫升)。所得溶液于室温下搅拌1小时。反应完毕后浓缩至干，得产品 58-9(15.0毫克)。无需纯化，直接用于下步反应。 To raw material 58-8 (25.0 mg) was added a 1,4-dioxane solution (2 ml) of hydrogen chloride. The resulting solution was stirred at room temperature for 1 hour. After the reaction was completed, it was concentrated to dryness to obtain product 58-9 (15.0 mg). No purification is required, and it is directly used in the next reaction.
LC-MS:m/z 512(M+H) + LC-MS: m/z 512(M+H) +
步骤9Step 9
将原料 58-9(15.0毫克)溶于二氯甲烷(2毫升)中，冷却至-40摄氏度后，依次加入三乙胺(13.8毫克)、丙烯酰氯(2.5毫克)。所得溶液于-40摄氏度下反应1小时。反应完毕后，加入水(5毫升)淬灭并浓缩至干。所得粗品用制备型色谱柱纯化(柱型：XBridge Shield RP18 OBD Column,5um,19*150mm；流动相A：水(10毫摩尔/升，碳酸氢铵)，流动相B：乙腈；流速：25毫升/分钟；梯度；42-61％；时间8分钟；检测器波长254/220纳米)，得产品 58(7.8毫克)。 The raw material 58-9 (15.0 mg) was dissolved in dichloromethane (2 ml), and after cooling to -40 degrees Celsius, triethylamine (13.8 mg) and acryloyl chloride (2.5 mg) were sequentially added. The resulting solution was reacted at -40 degrees Celsius for 1 hour. After the reaction was completed, it was quenched by adding water (5 mL) and concentrated to dryness. The obtained crude product was purified with a preparative chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 ML/min; gradient; 42-61%; time 8 minutes; detector wavelength 254/220 nanometers) to obtain product 58 (7.8 mg).
LC-MS:m/z 566(M+H) + LC-MS: m/z 566(M+H) +
1H-NMR(CD 3OD)δ:8.37(d,J＝8.1Hz,1H),7.85(d,J＝6.6Hz,1H),7.60-7.46(m,3H),7.40(t,J＝8.1Hz,1H),7.16(d,J＝6.9Hz,1H),6.93-6.75(m,1H),6.29(dd,J 1＝1.5Hz,J 2＝16.5Hz,1H),5.84(dd,J 1＝1.5Hz,J 2＝10.5Hz,1H),5.12-4.60(m,1H),4.45-4.35(m,2H),4.18-4.03(m,1H),3.93-3.77(m,2H),3.71-3.51(m,2H),3.30-3.23(m,6H),3.22-3.01(m,6H),2.89-2.77(m,1H),2.56(s,3H),2.46-2.38(m,1H),2.18-2.07(m,1H),1.91-1.71(m,3H). 1 H-NMR (CD 3 OD) δ: 8.37 (d, J = 8.1 Hz, 1H), 7.85 (d, J = 6.6 Hz, 1H), 7.60-7.46 (m, 3H), 7.40 (t, J = 8.1Hz,1H),7.16(d,J=6.9Hz,1H),6.93-6.75(m,1H),6.29(dd,J 1 =1.5Hz,J 2 =16.5Hz,1H),5.84(dd, J 1 ＝1.5Hz, J 2 =10.5Hz, 1H), 5.12-4.60(m, 1H), 4.45-4.35(m, 2H), 4.18-4.03(m, 1H), 3.93-3.77(m, 2H) ,3.71-3.51(m,2H),3.30-3.23(m,6H),3.22-3.01(m,6H),2.89-2.77(m,1H),2.56(s,3H),2.46-2.38(m, 1H), 2.18-2.07 (m, 1H), 1.91-1.71 (m, 3H).
实施例59Example 59
Figure PCTCN2020119633-appb-000150
Figure PCTCN2020119633-appb-000150
步骤1step 1
化合物 59-1的合成参考化合物 58-8。原料 58-7(50.0毫克)，8-甲基-1-溴萘(45.3毫克)，叔丁醇钠(98.9毫克)，甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(25.8毫克)，甲苯(2毫升)。得产品 59-1(27.0毫克)。 For the synthesis of compound 59-1 , refer to compound 58-8 . Raw material 58-7 (50.0 mg), 8-methyl-1-bromonaphthalene (45.3 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'- Diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). The product 59-1 (27.0 mg) was obtained.
LC-MS:m/z 626(M+H) + LC-MS: m/z 626(M+H) +
步骤2Step 2
化合物 59-2的合成参考化合物 58-9。原料 59-1(27.0毫克)，1,4-二氧六环(4摩尔/升，2毫升)。得产品 59-2(22.0毫克)。 For the synthesis of compound 59-2 , refer to compound 58-9 . Raw material 59-1 (27.0 mg), 1,4-dioxane (4 mol/liter, 2 ml). The product 59-2 (22.0 mg) was obtained.
LC-MS:m/z 526(M+H) + LC-MS: m/z 526(M+H) +
步骤3Step 3
化合物 59的合成参考化合物 58。原料 59-2(22.0毫克)，三乙胺(19.8毫克)，丙烯酰氯(5.3毫克)，二氯甲烷(5毫升)。得产品 59(7.2毫克)。 For the synthesis of compound 59 , refer to compound 58 . Raw material 59-2 (22.0 mg), triethylamine (19.8 mg), acryloyl chloride (5.3 mg), dichloromethane (5 mL). Obtained product 59 (7.2 mg).
LC-MS:m/z 580(M+H) + LC-MS: m/z 580(M+H) +
1H-NMR(CD 3OD)δ:7.70-7.63(m,2H),7.40-7.28(m,4H),6.94-6.70(m,1H),6.29(d,J＝16.5Hz,1H),5.83(d,J＝10.5Hz,1H),5.12-4.66(m,1H),4.46-4.36(m,2H),4.16-3.99(m,1H),3.91-3.74(m,2H),3.55-3.36(m,5H),3.16(d,J＝7.2Hz,3H),3.13-2.82(m,10H),2.54(s,3H),2.47(q,J＝3.6Hz,1H),2.21-2.09(m,1H),1.95-1.72(m,3H). 1 H-NMR (CD 3 OD) δ: 7.70-7.63 (m, 2H), 7.40-7.28 (m, 4H), 6.94-6.70 (m, 1H), 6.29 (d, J=16.5Hz, 1H), 5.83(d,J=10.5Hz,1H),5.12-4.66(m,1H),4.46-4.36(m,2H),4.16-3.99(m,1H),3.91-3.74(m,2H),3.55- 3.36(m,5H), 3.16(d,J=7.2Hz,3H),3.13-2.82(m,10H),2.54(s,3H),2.47(q,J=3.6Hz,1H),2.21-2.09 (m,1H),1.95-1.72(m,3H).
实施例60Example 60
Figure PCTCN2020119633-appb-000151
Figure PCTCN2020119633-appb-000151
步骤1step 1
化合物 60-1的合成参考化合物 58-8。原料 58-7(50.0毫克)，8-氟-1-溴萘(46.2毫克)，叔丁醇钠(98.9毫克)，甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'- 联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(25.8毫克)，甲苯(2毫升)。得产品 60-1(24.0毫克)。 For the synthesis of compound 60-1 , refer to compound 58-8 . Raw material 58-7 (50.0 mg), 8-fluoro-1-bromonaphthalene (46.2 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-di Isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). The product 60-1 (24.0 mg) was obtained.
LC-MS:m/z 630(M+H) + LC-MS: m/z 630(M+H) +
步骤2Step 2
化合物 60-2的合成参考化合物 58-9。原料 60-1(24.0毫克)，1,4-二氧六环(4摩尔/升，2毫升)。得产品 60-2(20.0毫克)。 For the synthesis of compound 60-2 , refer to compound 58-9 . Raw material 60-1 (24.0 mg), 1,4-dioxane (4 mol/L, 2 ml). Obtained product 60-2 (20.0 mg).
LC-MS:m/z 530(M+H) + LC-MS: m/z 530(M+H) +
步骤3Step 3
化合物 60的合成参考化合物 58。原料 60-2(20.0毫克)，三乙胺(17.8毫克)，丙烯酰氯(4.8毫克)，二氯甲烷(5毫升)。得产品 60(8.0毫克)。 For the synthesis of compound 60 , refer to compound 58 . Raw material 60-2 (20.0 mg), triethylamine (17.8 mg), acryloyl chloride (4.8 mg), dichloromethane (5 mL). Obtained product 60 (8.0 mg).
LC-MS:m/z 584(M+H) + LC-MS: m/z 584(M+H) +
1H-NMR(CD 3OD)δ:7.67(d,J＝6.9Hz,1H),7.57(d,J＝8.1Hz,1H),7.46-7.38(m,2H),7.21-7.12(m,2H),6.97-6.74(m,1H),6.28(d,J＝16.5Hz,1H),5.84(d,J＝10.5Hz,1H),5.13-4.65(m,1H),4.40-4.17(m,2H),4.21-4.04(m,1H),3.96-3.83(m,1H),3.81-3.55(m,4H),3.48-3.35(m,1H),3.29-3.18(m,2H),3.16-2.90(m,9H),2.63(s,3H),2.53(q,J＝3.6Hz,1H),2.25-2.10(m,1H),1.96-1.75(m,3H). 1 H-NMR(CD 3 OD)δ: 7.67(d,J=6.9Hz,1H), 7.57(d,J=8.1Hz,1H),7.46-7.38(m,2H),7.21-7.12(m, 2H), 6.97-6.74 (m, 1H), 6.28 (d, J=16.5Hz, 1H), 5.84 (d, J=10.5Hz, 1H), 5.13-4.65 (m, 1H), 4.40-4.17 (m ,2H),4.21-4.04(m,1H),3.96-3.83(m,1H),3.81-3.55(m,4H),3.48-3.35(m,1H),3.29-3.18(m,2H),3.16 -2.90(m,9H), 2.63(s,3H), 2.53(q,J=3.6Hz,1H), 2.25-2.10(m,1H),1.96-1.75(m,3H).
实施例61Example 61
Figure PCTCN2020119633-appb-000152
Figure PCTCN2020119633-appb-000152
步骤1step 1
化合物 61-1的合成参考化合物 58-8。原料 58-7(50.0毫克)，8-氯-1-溴萘(49.5毫克)，叔丁醇钠(98.9毫克)，甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(25.8毫克)，甲苯(2毫升)。得产品 61-1(25.0毫克)。 For the synthesis of compound 61-1 , refer to compound 58-8 . Raw material 58-7 (50.0 mg), 8-chloro-1-bromonaphthalene (49.5 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-di Isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 ml). The product 61-1 (25.0 mg) was obtained.
LC-MS:m/z 646(M+H) + LC-MS: m/z 646(M+H) +
步骤2Step 2
化合物 61-2的合成参考化合物 58-9。原料 61-1(25.0毫克)，1,4-二氧六环(4摩尔/升，2毫升)。得产品 61-2(21.0毫克)。 For the synthesis of compound 61-2 , refer to compound 58-9 . Raw material 61-1 (25.0 mg), 1,4-dioxane (4 mol/L, 2 mL). The product 61-2 (21.0 mg) was obtained.
LC-MS:m/z 546(M+H) + LC-MS: m/z 546(M+H) +
步骤3Step 3
化合物 61的合成参考化合物 58。原料 61-2(21.0毫克)，三乙胺(18.2毫克)，丙烯酰氯(4.9毫克)，二氯甲烷(5毫升)。得产品 61(8.5毫克)。 For the synthesis of compound 61 , refer to compound 58 . Raw material 61-2 (21.0 mg), triethylamine (18.2 mg), acryloyl chloride (4.9 mg), dichloromethane (5 mL). Product 61 (8.5 mg) was obtained.
LC-MS:m/z 600(M+H) + LC-MS: m/z 600(M+H) +
1H-NMR(CD 3OD)δ:7.81(d,J＝7.2Hz,1H),7.66(d,J＝7.8Hz,1H),7.58(d,J＝6.9Hz,1H),7.47-7.31(m,3H),6.94-6.71(m,1H),6.28(d,J＝16.5Hz,1H), 5.84(d,J＝10.5Hz,1H),5.13-4.65(m,1H),4.40-4.13(m,2H),4.18-4.03(m,1H),3.91-3.75(m,2H),3.67-3.50(m,4H),3.31-3.20(m,2H),3.17-3.07(m,2H),3.03-2.79(m,7H),2.55(s,3H),2.41(q,J＝3.6Hz,1H),2.17-2.06(m,1H),1.90-1.68(m,3H). 1 H-NMR (CD 3 OD) δ: 7.81 (d, J = 7.2 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.58 (d, J = 6.9 Hz, 1H), 7.47-7.31 (m,3H),6.94-6.71(m,1H),6.28(d,J=16.5Hz,1H), 5.84(d,J=10.5Hz,1H),5.13-4.65(m,1H), 4.40- 4.13 (m, 2H), 4.18-4.03 (m, 1H), 3.91-3.75 (m, 2H), 3.67-3.50 (m, 4H), 3.31-3.20 (m, 2H), 3.17-3.07 (m, 2H) ),3.03-2.79(m,7H),2.55(s,3H),2.41(q,J=3.6Hz,1H), 2.17-2.06(m,1H),1.90-1.68(m,3H).
实施例62Example 62
Figure PCTCN2020119633-appb-000153
Figure PCTCN2020119633-appb-000153
步骤1step 1
将原料 58-3(3.00克)溶于异丙醇(80毫升)中，依次加入(S)-2-氰甲基哌嗪二盐酸盐(2.31克)、二异丙基乙胺(5.04克)。所得混合液于80摄氏度下反应24小时。反应完毕后，加入水(200毫升)稀释。并用乙酸乙酯(200毫升x3)萃取。有机相合并后，用饱和食盐水(200毫升)洗涤，并用无水硫酸钠干燥后浓缩至干，得产品 62-1(2.80克)。 Raw material 58-3 (3.00 g) was dissolved in isopropanol (80 ml), and (S)-2-cyanomethylpiperazine dihydrochloride (2.31 g), diisopropylethylamine (5.04 G). The resulting mixture was reacted at 80 degrees Celsius for 24 hours. After the reaction is complete, add water (200 mL) to dilute. It was extracted with ethyl acetate (200 mL×3). After the organic phases were combined, they were washed with saturated brine (200 ml), dried over anhydrous sodium sulfate and concentrated to dryness to obtain product 62-1 (2.80 g).
LC-MS:m/z 397(M+H) + LC-MS: m/z 397(M+H) +
步骤2Step 2
将原料 62-1(2.80克)溶于无水四氢呋喃(50毫升)中，依次加入二碳酸二叔丁酯(1.85克)、二异丙基乙胺(1.37克)。所得溶液回流反应1小时。反应完毕后，冷却至室温。加入水(150毫升)稀释，并用乙酸乙酯(150毫升x3)萃取。有机相合并后浓缩至干。所得粗品用硅胶柱层析纯化(乙酸乙酯/石油醚＝30％-60％)得产品 62-2(2.70克)。 Raw material 62-1 (2.80 g) was dissolved in anhydrous tetrahydrofuran (50 ml), and di-tert-butyl dicarbonate (1.85 g) and diisopropylethylamine (1.37 g) were sequentially added. The resulting solution was refluxed and reacted for 1 hour. After the reaction is complete, cool to room temperature. It was diluted with water (150 mL) and extracted with ethyl acetate (150 mL×3). The organic phases were combined and concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=30%-60%) to obtain product 62-2 (2.70 g).
LC-MS:m/z 497(M+H) + LC-MS: m/z 497(M+H) +
步骤3Step 3
将(S)-脯氨醇(0.938克)溶于无水四氢呋喃(100毫升)中，于0摄氏度下加入氢化钠(60％)(0.326克)。0摄氏度下反应30分钟后，加入原料 62-2(2.70克)。所得溶液于70摄氏度下反应3小时。反应完毕后，冷却至室温。加入饱和氯化铵水溶液(150毫升)淬灭，并用乙酸乙酯(150毫升x3)萃取。有机相合并后浓缩至干。所得粗品用硅胶柱层析纯化(甲醇/二氯甲烷＝5％-20％)得产品 62-3(2.20克)。 (S)-Prolinol (0.938 g) was dissolved in anhydrous tetrahydrofuran (100 ml), and sodium hydride (60%) (0.326 g) was added at 0 degrees Celsius. After reacting for 30 minutes at 0 degrees Celsius, raw material 62-2 (2.70 g) was added. The resulting solution was reacted at 70 degrees Celsius for 3 hours. After the reaction is complete, cool to room temperature. It was quenched by adding saturated aqueous ammonium chloride solution (150 mL), and extracted with ethyl acetate (150 mL×3). The organic phases were combined and concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (methanol/dichloromethane=5%-20%) to obtain product 62-3 (2.20 g).
LC-MS:m/z 576(M+H) + LC-MS: m/z 576(M+H) +
步骤4Step 4
将原料 62-3(2.20克)溶于无水甲醇(80毫升)中，氮气保护下依次加入钯碳(10％)(0.22克)、氨的甲醇溶液(7摩尔/升)(8毫升)。所得反应液用氢气置换3次，并 于40摄氏度反应3小时。反应完毕后，将钯碳滤除。滤液浓缩至干，得产品 62-4(1.50克)。 Dissolve raw material 62-3 (2.20 g) in anhydrous methanol (80 ml), and add palladium carbon (10%) (0.22 g) and ammonia methanol solution (7 mol/L) (8 ml) under nitrogen protection. . The resulting reaction solution was replaced with hydrogen three times, and reacted at 40 degrees Celsius for 3 hours. After the reaction is completed, the palladium carbon is filtered off. The filtrate was concentrated to dryness to obtain product 62-4 (1.50 g).
LC-MS:m/z 486(M+H) + LC-MS: m/z 486(M+H) +
步骤5Step 5
将原料 62-4(50.0毫克)溶于甲苯(2毫升)中，依次加入8-甲基-1-溴萘(27.2毫克)，叔丁醇钠(49.4毫克)、甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(8.6毫克)。所得溶液于90摄氏度下反应3小时。反应完毕后冷却至室温，加入水(15毫升)稀释，并用乙酸乙酯(15毫升x3)萃取。有机相合并后浓缩至干。所得粗品用硅胶柱层析纯化(二氯甲烷/甲醇＝10％-20％)得产品 62-5(24.0毫克)。 The raw material 62-4 (50.0 mg) was dissolved in toluene (2 ml), and 8-methyl-1-bromonaphthalene (27.2 mg), sodium tert-butoxide (49.4 mg), methanesulfonic acid (2-two Cyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (8.6 mg ). The resulting solution was reacted at 90 degrees Celsius for 3 hours. After the reaction was completed, it was cooled to room temperature, diluted with water (15 mL), and extracted with ethyl acetate (15 mL×3). The organic phases were combined and concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (dichloromethane/methanol=10%-20%) to obtain product 62-5 (24.0 mg).
LC-MS:m/z 626(M+H) + LC-MS: m/z 626(M+H) +
步骤6Step 6
向原料 62-5(24.0毫克)中加入氯化氢的1,4-二氧六环溶液(2毫升)。所得溶液于室温下搅拌1小时。反应完毕后浓缩至干，得产品 62-6(15.0毫克)。无需纯化，直接用于下步反应。 To raw material 62-5 (24.0 mg) was added a 1,4-dioxane solution (2 ml) of hydrogen chloride. The resulting solution was stirred at room temperature for 1 hour. After the reaction was completed, it was concentrated to dryness to obtain product 62-6 (15.0 mg). No purification is required, and it is directly used in the next reaction.
LC-MS:m/z 526(M+H) + LC-MS: m/z 526(M+H) +
步骤7Step 7
将原料 62-6(15.0毫克)溶于二氯甲烷(2毫升)中，冷却至-40摄氏度后，依次加入三乙胺(13.4毫克)、丙烯酰氯(2.4毫克)。所得溶液于-40摄氏度下反应1小时。反应完毕后，加入水(5毫升)淬灭并浓缩至干。所得粗品用制备型色谱柱纯化(柱型：XBridge Shield RP18 OBD Column,5um,19*150mm；流动相A：水(10毫摩尔/升，碳酸氢铵)，流动相B：乙腈，流速：25毫升/分钟；梯度：42-61％；时间8分钟；检测器波长254/220纳米)，得产品 62(7.8毫克)。 The raw material 62-6 (15.0 mg) was dissolved in dichloromethane (2 ml), and after cooling to -40 degrees Celsius, triethylamine (13.4 mg) and acryloyl chloride (2.4 mg) were sequentially added. The resulting solution was reacted at -40 degrees Celsius for 1 hour. After the reaction was completed, it was quenched by adding water (5 mL) and concentrated to dryness. The obtained crude product was purified with a preparative chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 25 Ml/min; gradient: 42-61%; time 8 minutes; detector wavelength 254/220 nanometers) to obtain product 62 (7.8 mg).
LC-MS:m/z 580(M+H) + LC-MS: m/z 580(M+H) +
1H-NMR(CD 3OD)δ:7.74-7.62(m,2H),7.45-7.28(m,4H),6.95-6.77(m,1H),6.29(dd,J 1＝1.5Hz,J 2＝16.5Hz,1H),5.84(dd,J 1＝1.5Hz,J 2＝10.5Hz,1H),5.12-4.60(m,1H),4.45-4.35(m,2H),4.18-4.03(m,1H),3.93-3.77(m,2H),3.71-3.51(m,2H),3.50-3.36(m,3H),3.35-3.28(m,2H)，3.19(d,J＝7.2Hz,3H),3.16-3.09(m,4H),3.07-2.82(m,5H),2.72(s,3H),2.30-2.15(m,1H),2.00-1.80(m,3H). 1 H-NMR(CD 3 OD)δ:7.74-7.62(m,2H),7.45-7.28(m,4H),6.95-6.77(m,1H), 6.29(dd,J 1 ＝1.5Hz,J 2 ＝16.5Hz,1H), 5.84(dd,J 1 ＝1.5Hz,J 2 ＝10.5Hz,1H),5.12-4.60(m,1H),4.45-4.35(m,2H),4.18-4.03(m, 1H),3.93-3.77(m,2H),3.71-3.51(m,2H),3.50-3.36(m,3H),3.35-3.28(m,2H), 3.19(d,J=7.2Hz,3H) ,3.16-3.09(m,4H),3.07-2.82(m,5H), 2.72(s,3H), 2.30-2.15(m,1H),2.00-1.80(m,3H).
实施例63Example 63
Figure PCTCN2020119633-appb-000154
Figure PCTCN2020119633-appb-000154
将原料 62-6(15.5毫克)溶于二氯甲烷(2毫升)中，冷却至-40摄氏度后，依次加入三乙胺(13.8毫克)、乙烯基磺酰氯(3.5毫克)。所得溶液于-40摄氏度下反应10分钟。反应完毕后，加入水(5毫升)淬灭，用乙酸乙酯(10毫升x3)萃取。有机相合并后用饱和食盐水(150毫升)洗涤。有机相用无水硫酸钠干燥后，减压浓缩至干。所得粗品用制备型色谱柱纯化(柱型：XBridge Shield RP18 OBD Column,5um,19*150mm；流动相A：水(10毫摩尔/升，碳酸氢铵)，流动相B：乙腈；流速：25毫升/分钟；梯度：40-75％；时间8分钟；检测器波长254/220纳米)，得产品 63(10.8毫克)。 The raw material 62-6 (15.5 mg) was dissolved in dichloromethane (2 ml), and after cooling to -40 degrees Celsius, triethylamine (13.8 mg) and vinylsulfonyl chloride (3.5 mg) were sequentially added. The resulting solution was reacted at -40 degrees Celsius for 10 minutes. After the reaction was completed, it was quenched by adding water (5 mL), and extracted with ethyl acetate (10 mL×3). The organic phases were combined and washed with saturated brine (150 mL). After the organic phase was dried over anhydrous sodium sulfate, it was concentrated to dryness under reduced pressure. The obtained crude product was purified with a preparative chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 Ml/min; gradient: 40-75%; time 8 minutes; detector wavelength 254/220 nanometers) to obtain product 63 (10.8 mg).
LC-MS:m/z 616(M+H) + LC-MS: m/z 616(M+H) +
1H-NMR(CD 3OD)δ:7.66(dd,J 1＝7.2Hz,J 2＝5.4Hz,2H),7.39-7.27(m,4H),6.78 (dd,J 1＝9.9Hz,J 2＝6.6Hz,1H),6.27(d,J＝16.2Hz,1H),6.06(d,J＝9.6Hz,1H),4.54(q,J 1＝11.7Hz,J 2＝13.2Hz,2H),4.43-4.39(m,1H),3.88(d,J＝13.8Hz,1H),3.73-3.67(m,2H),3.56-3.37(m,7H),3.15(d,J＝9.6Hz,4H),3.10-2.88(m,8H),2.83(s,3H),2.36-2.21(m,1H),2.10-1.85(m,3H). 1 H-NMR (CD 3 OD) δ: 7.66 (dd, J 1 ＝7.2Hz, J 2 ＝5.4Hz, 2H), 7.39-7.27 (m, 4H), 6.78 (dd, J 1 ＝9.9Hz, J 2 ＝6.6Hz,1H), 6.27(d,J＝16.2Hz,1H), 6.06(d,J＝9.6Hz,1H), 4.54(q,J 1 ＝11.7Hz,J 2 ＝13.2Hz,2H) ,4.43-4.39(m,1H),3.88(d,J=13.8Hz,1H),3.73-3.67(m,2H),3.56-3.37(m,7H),3.15(d,J=9.6Hz,4H ), 3.10-2.88 (m, 8H), 2.83 (s, 3H), 2.36-2.21 (m, 1H), 2.10-1.85 (m, 3H).
实施例64Example 64
Figure PCTCN2020119633-appb-000155
Figure PCTCN2020119633-appb-000155
将原料 62-6(15.5毫克)溶于二氯甲烷(2毫升)中，冷却至-40摄氏度后，依次加入三乙胺(13.8毫克)、3-(N,N-二甲氨基)甲基丙烯酰氯(4.0毫克)。所得溶液于-40摄氏度下反应10分钟。反应完毕后，加入水(10毫升)淬灭，用乙酸乙酯(10毫升x3)萃取。有机相合并后用饱和食盐水(10毫升)洗涤。有机相用无水硫酸钠干燥后，减压浓缩至干。所得粗品用制备型色谱柱纯化(柱型：XBridge Shield RP18 OBD Column,5um,19*150mm：流动相A：水(10毫摩尔/升，碳酸氢铵)，流动相B：乙腈；流速：25毫升/分钟；梯度：35-72％；时间8分钟；检测器波长254/220纳米)，得产品 64(10.5毫克)。 Dissolve raw material 62-6 (15.5 mg) in dichloromethane (2 ml), after cooling to -40 degrees Celsius, add triethylamine (13.8 mg) and 3-(N,N-dimethylamino)methyl in sequence Acryloyl chloride (4.0 mg). The resulting solution was reacted at -40 degrees Celsius for 10 minutes. After the reaction was completed, it was quenched by adding water (10 mL), and extracted with ethyl acetate (10 mL×3). The organic phases were combined and washed with saturated brine (10 mL). After the organic phase was dried over anhydrous sodium sulfate, it was concentrated to dryness under reduced pressure. The obtained crude product was purified with a preparative chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm: mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 Ml/min; gradient: 35-72%; time 8 minutes; detector wavelength 254/220 nanometers) to obtain product 64 (10.5 mg).
LC-MS:m/z 637(M+H) + LC-MS: m/z 637(M+H) +
1H-NMR(CD 3OD)δ:7.72-7-64(m,2H),7.40-7.27(m,4H),6.91-6.63(m,2H),5.09(s,1H),4.46(d,J＝5.4Hz,2H),3.60-3.40(m,4H),3.29-3.22(m,4H),3.16(d,J＝6.3Hz,3H),3.12-2.87(m,8H),2.67(s,3H),2.62-2.54(m,1H),2.33(s,6H),2.26-2.10(m,2H),1.98-1.90(m,3H),1.88-1.75(m,2H),1.61(s,1H). 1 H-NMR (CD 3 OD) δ: 7.72-7-64 (m, 2H), 7.40-7.27 (m, 4H), 6.91-6.63 (m, 2H), 5.09 (s, 1H), 4.46 (d ,J=5.4Hz,2H), 3.60-3.40(m,4H), 3.29-3.22(m,4H), 3.16(d,J=6.3Hz,3H), 3.12-2.87(m,8H), 2.67( s,3H),2.62-2.54(m,1H),2.33(s,6H),2.26-2.10(m,2H),1.98-1.90(m,3H),1.88-1.75(m,2H),1.61( s,1H).
实施例65Example 65
Figure PCTCN2020119633-appb-000156
Figure PCTCN2020119633-appb-000156
将原料 62-6(15.5毫克)溶于二氯甲烷(2毫升)中，冷却至-40摄氏度后，依次加入N,N-二异丙基乙胺(7.1毫克)、丙基磷酸酐(50％乙酸乙酯溶液)(35.1毫克)、2-丁炔酸(4.6毫克)。所得溶液于0摄氏度下反应1小时。反应完毕后，加入水(5毫升)淬灭，用乙酸乙酯(10毫升x3)萃取。有机相合并后用饱和食盐水(150毫升)洗涤。有机相用无水硫酸钠干燥后，减压浓缩至干。所得粗品用制备型色谱柱纯化(柱型：XBridge Shield RP18 OBD Column,5um,19*150mm；流动相A：水(10毫摩尔/升，碳酸氢铵)，流动相B：乙腈；流速：25毫升/分钟；梯度：32-70％；时间8分钟；检测器波长254/220纳米)，得产品 65(8.1毫克)。 The raw material 62-6 (15.5 mg) was dissolved in dichloromethane (2 ml), and after cooling to -40 degrees Celsius, N,N-diisopropylethylamine (7.1 mg), propyl phosphoric anhydride (50 % Ethyl acetate solution) (35.1 mg), 2-butynoic acid (4.6 mg). The resulting solution was reacted at 0 degrees Celsius for 1 hour. After the reaction was completed, it was quenched by adding water (5 mL), and extracted with ethyl acetate (10 mL×3). The organic phases were combined and washed with saturated brine (150 mL). After the organic phase was dried over anhydrous sodium sulfate, it was concentrated to dryness under reduced pressure. The obtained crude product was purified with a preparative chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 Ml/min; gradient: 32-70%; time 8 minutes; detector wavelength 254/220 nanometers) to obtain product 65 (8.1 mg).
LC-MS:m/z 592(M+H) + LC-MS: m/z 592(M+H) +
1H-NMR(CD 3OD)δ:7.66(dd,J 1＝7.5Hz,J 2＝5.4Hz,2H),7.39-7.27(m,4H),5.02(s,1H),4.48-4.45(m,2H),3.53-3.40(m,4H),3.29-2.26(m,1H),3.23-3.20(m,1H),3.17-3.08(m,7H),3.05-2.86(m,6H),2.70(d,J＝3.3Hz,3H),2.65-2.60(m,1H),2.25-2.16(m,2H),2.09(d,J＝11.1Hz,3H),2.00-1.80(m,4H). 1 H-NMR(CD 3 OD)δ: 7.66(dd, J 1 =7.5Hz, J 2 =5.4Hz, 2H), 7.39-7.27(m,4H), 5.02(s,1H), 4.48-4.45( m, 2H), 3.53-3.40 (m, 4H), 3.29-2.26 (m, 1H), 3.23-3.20 (m, 1H), 3.17-3.08 (m, 7H), 3.05-2.86 (m, 6H), 2.70(d,J=3.3Hz,3H),2.65-2.60(m,1H),2.25-2.16(m,2H),2.09(d,J=11.1Hz,3H),2.00-1.80(m,4H) .
实施例66Example 66
Figure PCTCN2020119633-appb-000157
Figure PCTCN2020119633-appb-000157
步骤1step 1
将原料 58-3(3.00克)溶于异丙醇(80毫升)中，依次加入(R)-2-氰甲基哌嗪二盐酸盐(2.31克)、二异丙基乙胺(5.04克)。所得混合液于80摄氏度下反应24小时。反应完毕后，加入水(200毫升)稀释。并用乙酸乙酯(200毫升x3)萃取。有机相合并后，用饱和食盐水(200毫升)洗涤，并用无水硫酸钠干燥后浓缩至干，得产品 66-1(2.70克)。 Raw material 58-3 (3.00 g) was dissolved in isopropanol (80 ml), and (R)-2-cyanomethylpiperazine dihydrochloride (2.31 g), diisopropylethylamine (5.04 G). The resulting mixture was reacted at 80 degrees Celsius for 24 hours. After the reaction is complete, add water (200 mL) to dilute. It was extracted with ethyl acetate (200 mL×3). After the organic phases were combined, they were washed with saturated brine (200 ml), dried over anhydrous sodium sulfate and concentrated to dryness to obtain product 66-1 (2.70 g).
LC-MS:m/z 397(M+H) + LC-MS: m/z 397(M+H) +
步骤2Step 2
将原料 66-1(2.70克)溶于无水四氢呋喃(50毫升)中，依次加入二碳酸二叔丁酯(1.78克)、二异丙基乙胺(1.32克)。所得溶液回流反应1小时。反应完毕后，冷却至室温。加入水(150毫升)稀释，并用乙酸乙酯(150毫升x3)萃取。有机相合并后浓缩至干。所得粗品用硅胶柱层析纯化(乙酸乙酯/石油醚＝30％-60％)得产品 66-2(2.70克)。 Raw material 66-1 (2.70 g) was dissolved in anhydrous tetrahydrofuran (50 ml), and di-tert-butyl dicarbonate (1.78 g) and diisopropylethylamine (1.32 g) were sequentially added. The resulting solution was refluxed and reacted for 1 hour. After the reaction is complete, cool to room temperature. It was diluted with water (150 mL) and extracted with ethyl acetate (150 mL×3). The organic phases were combined and concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=30%-60%) to obtain product 66-2 (2.70 g).
LC-MS:m/z 497(M+H) + LC-MS: m/z 497(M+H) +
步骤3Step 3
将(S)-脯氨醇(0.938克)溶于无水四氢呋喃(100毫升)中，于0摄氏度下加入氢化钠(60％)(0.326克)。0摄氏度下反应30分钟后，加入原料 66-2(2.70克)。所得溶液于70摄氏度下反应3小时。反应完毕后，冷却至室温。加入饱和氯化铵水溶液(150毫升)淬灭，并用乙酸乙酯(150毫升x3)萃取。有机相合并后浓缩至干。所得粗品用硅胶柱层析纯化(甲醇/二氯甲烷＝5％-20％)得产品 66-3(2.25克)。 (S)-Prolinol (0.938 g) was dissolved in anhydrous tetrahydrofuran (100 ml), and sodium hydride (60%) (0.326 g) was added at 0 degrees Celsius. After reacting for 30 minutes at 0 degrees Celsius, raw material 66-2 (2.70 g) was added. The resulting solution was reacted at 70 degrees Celsius for 3 hours. After the reaction is complete, cool to room temperature. It was quenched by adding saturated aqueous ammonium chloride solution (150 mL), and extracted with ethyl acetate (150 mL×3). The organic phases were combined and concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (methanol/dichloromethane=5%-20%) to obtain product 66-3 (2.25 g).
LC-MS:m/z 576(M+H) + LC-MS: m/z 576(M+H) +
步骤4Step 4
将原料 66-3(2.25克)溶于无水甲醇(80毫升)中，氮气保护下依次加入钯碳(10％)(0.22克)、氨的甲醇溶液(7摩尔/升)(8毫升)。所得反应液用氢气置换3次，并于40摄氏度反应3小时。反应完毕后，将钯碳滤除。滤液浓缩至干，得产品 66-4(1.60克)。 The raw material 66-3 (2.25 g) was dissolved in anhydrous methanol (80 ml), and palladium carbon (10%) (0.22 g) and ammonia methanol solution (7 mol/L) (8 ml) were added in sequence under the protection of nitrogen. . The resulting reaction solution was replaced with hydrogen three times, and reacted at 40 degrees Celsius for 3 hours. After the reaction is completed, the palladium carbon is filtered off. The filtrate was concentrated to dryness to obtain product 66-4 (1.60 g).
LC-MS:m/z 486(M+H) + LC-MS: m/z 486(M+H) +
步骤5Step 5
将原料 66-4(50.0毫克)溶于甲苯(2毫升)中，依次加入8-甲基-1-溴萘(27.2 毫克)，叔丁醇钠(49.4毫克)、甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(8.6毫克)。所得溶液于90摄氏度下搅拌3小时。反应完毕后冷却至室温，加入水(15毫升)稀释，并用乙酸乙酯(15毫升x3)萃取。有机相合并后浓缩至干。所得粗品用硅胶柱层析纯化(二氯甲烷/甲醇＝10％-20％)得产品 66-5(24.0毫克)。 The raw material 66-4 (50.0 mg) was dissolved in toluene (2 ml), and 8-methyl-1-bromonaphthalene (27.2 mg), sodium tert-butoxide (49.4 mg), methanesulfonic acid (2-two Cyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (8.6 mg ). The resulting solution was stirred at 90 degrees Celsius for 3 hours. After the reaction was completed, it was cooled to room temperature, diluted with water (15 mL), and extracted with ethyl acetate (15 mL×3). The organic phases were combined and concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (dichloromethane/methanol=10%-20%) to obtain product 66-5 (24.0 mg).
LC-MS:m/z 626(M+H) + LC-MS: m/z 626(M+H) +
步骤6Step 6
向原料 66-5(24.0毫克)中加入氯化氢的1,4-二氧六环溶液(2毫升)。所得溶液于室温下搅拌1小时。反应完毕后浓缩至干，得产品 66-6(15.0毫克)。无需纯化，直接用于下步反应。 To raw material 66-5 (24.0 mg) was added 1,4-dioxane solution (2 ml) of hydrogen chloride. The resulting solution was stirred at room temperature for 1 hour. After the reaction was completed, it was concentrated to dryness to obtain product 66-6 (15.0 mg). No purification is required, and it is directly used in the next reaction.
LC-MS:m/z 526(M+H) + LC-MS: m/z 526(M+H) +
步骤7Step 7
将原料 66-6(15.0毫克)溶于二氯甲烷(2毫升)中，冷却至-40摄氏度后，依次加入三乙胺(13.4毫克)、丙烯酰氯(2.4毫克)。所得溶液于-40摄氏度下反应1小时。反应完毕后，加入水(5毫升)淬灭并浓缩至干。所得粗品用制备型色谱柱纯化(柱型：XBridge Shield RP18 OBD Column,5um,19*150mm；流动相A：水(10毫摩尔/升，碳酸氢铵)，流动相B：乙腈；流速：25毫升/分钟；梯度：42-61％；时间8分钟；检测器波长254/220纳米)，得产品 66(7.8毫克)。 Raw material 66-6 (15.0 mg) was dissolved in dichloromethane (2 ml), and after cooling to -40 degrees Celsius, triethylamine (13.4 mg) and acryloyl chloride (2.4 mg) were added in sequence. The resulting solution was reacted at -40 degrees Celsius for 1 hour. After the reaction was completed, it was quenched by adding water (5 mL) and concentrated to dryness. The obtained crude product was purified with a preparative chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 Ml/min; gradient: 42-61%; time 8 minutes; detector wavelength 254/220 nanometers) to obtain product 66 (7.8 mg).
LC-MS:m/z 580(M+H) + LC-MS: m/z 580(M+H) +
1H-NMR(CD 3OD)δ:7.70-7.63(m,2H),7.39-7.27(m,4H),6.92-6.75(m,1H),6.28(d,J＝16.5Hz,1H),5.83(d,J＝10.5Hz,1H),5.12-4.60(m,1H),4.50-4.22(m,2H),4.18-4.01(m,1H),3.93-3.77(m,2H),3.71-3.62(m,1H),3.55-3.39(m,4H),3.30-3.23(m,2H)，3.19-3.06(m,7H),3.04-2.83(m,5H),2.72(s,3H),2.27-2.17(m,1H),2.01-1.79(m,3H). 1 H-NMR (CD 3 OD) δ: 7.70-7.63 (m, 2H), 7.39-7.27 (m, 4H), 6.92-6.75 (m, 1H), 6.28 (d, J=16.5Hz, 1H), 5.83(d,J=10.5Hz,1H),5.12-4.60(m,1H),4.50-4.22(m,2H),4.18-4.01(m,1H),3.93-3.77(m,2H),3.71- 3.62(m,1H),3.55-3.39(m,4H), 3.30-3.23(m,2H), 3.19-3.06(m,7H),3.04-2.83(m,5H), 2.72(s,3H), 2.27-2.17(m,1H), 2.01-1.79(m,3H).
实施例67Example 67
Figure PCTCN2020119633-appb-000158
Figure PCTCN2020119633-appb-000158
步骤1：step 1:
化合物 67-1的合成参考化合物 66-5。原料 66-4(50.0毫克)，1-溴萘(42.4毫克)，叔丁醇钠(98.9毫克)，甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(25.8毫克)，甲苯(2毫升)。得产品 67-1(30.0毫克)。 For the synthesis of compound 67-1, refer to compound 66-5 . Raw material 66-4 (50.0 mg), 1-bromonaphthalene (42.4 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy) -1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). The product 67-1 (30.0 mg) was obtained.
LC-MS:m/z 612(M+H) + LC-MS: m/z 612(M+H) +
步骤2：Step 2:
化合物 67-2的合成参考化合物 66-6。原料 67-1(30.0毫克)，1,4-二氧六环(4摩尔/升，5毫升)。得产品 67-2(26.0毫克)。 For the synthesis of compound 67-2, refer to compound 66-6 . Raw material 67-1 (30.0 mg), 1,4-dioxane (4 mol/liter, 5 ml). The product 67-2 (26.0 mg) was obtained.
LC-MS:m/z 512(M+H) + LC-MS: m/z 512(M+H) +
步骤3：Step 3:
化合物 67的合成参考化合物 66。原料 67-2(26.0毫克)，三乙胺(24.0毫克)，丙烯酰氯(6.45毫克)，二氯甲烷(5毫升)。得产品 67(3.7毫克)。 For the synthesis of compound 67 , refer to compound 66 . Raw material 67-2 (26.0 mg), triethylamine (24.0 mg), acryloyl chloride (6.45 mg), dichloromethane (5 mL). Product 67 (3.7 mg) was obtained.
LC-MS:m/z 566(M+H) + LC-MS: m/z 566(M+H) +
1H-NMR(CD 3OD)δ:8.36(d,J＝8.4Hz,1H),7.89-7.82(m,1H),7.63-7.36(m,4H),7.16(d,J＝7.5Hz,1H),6.94-6.73(m,1H),6.29(d,J＝16.7Hz,1H),5.84(d,J＝10.6Hz,1H),5.17-5.05(m,1H),4.81-4.52(m,1H),4.54-4.43(m,2H),4.17-4.01(m,1H),3.99-3.52(m,4H),3.31-2.88(m,11H),2.69(s,3H),2.67-2.52(m,1H),2.3-2.14(m,1H),2.06-1.71(m,4H). 1 H-NMR(CD 3 OD)δ: 8.36(d,J=8.4Hz,1H),7.89-7.82(m,1H),7.63-7.36(m,4H),7.16(d,J=7.5Hz, 1H), 6.94-6.73 (m, 1H), 6.29 (d, J = 16.7Hz, 1H), 5.84 (d, J = 10.6Hz, 1H), 5.17-5.05 (m, 1H), 4.81-4.52 (m ,1H),4.54-4.43(m,2H),4.17-4.01(m,1H),3.99-3.52(m,4H),3.31-2.88(m,11H),2.69(s,3H),2.67-2.52 (m,1H),2.3-2.14(m,1H),2.06-1.71(m,4H).
实施例68Example 68
Figure PCTCN2020119633-appb-000159
Figure PCTCN2020119633-appb-000159
步骤1：step 1:
化合物 68-1的合成参考化合物 66-5。原料 66-4(50.0毫克)，8-氯-1-溴萘(49.4毫克)，叔丁醇钠(98.9毫克)，甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(25.8毫克)，甲苯(2毫升)。得产品 68-1(48.0毫克)。 For the synthesis of compound 68-1 , refer to compound 66-5 . Raw material 66-4 (50.0 mg), 8-chloro-1-bromonaphthalene (49.4 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-di Isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 ml). The product 68-1 (48.0 mg) was obtained.
LC-MS:m/z 646(M+H) + LC-MS: m/z 646(M+H) +
步骤2：Step 2:
化合物 68-2的合成参考化合物 66-6。原料 68-1(48.0毫克)，1,4-二氧六环(4摩尔/升，5毫升)。得产品 68-2(42.0毫克)。 For the synthesis of compound 68-2 , refer to compound 66-6 . Raw material 68-1 (48.0 mg), 1,4-dioxane (4 mol/L, 5 mL). The product 68-2 (42.0 mg) was obtained.
LC-MS:m/z 546(M+H) + LC-MS: m/z 546(M+H) +
步骤3：Step 3:
化合物 68的合成参考化合物 66。原料 68-2(42.0毫克)，三乙胺(36.5毫克)，丙烯酰氯(9.81毫克)，二氯甲烷(5毫升)。得产品 68(6.0毫克)。 For the synthesis of compound 68 , refer to compound 66 . Raw material 68-2 (42.0 mg), triethylamine (36.5 mg), acryloyl chloride (9.81 mg), dichloromethane (5 mL). Product 68 (6.0 mg) was obtained.
LC-MS:m/z 600(M+H) + LC-MS: m/z 600(M+H) +
1H-NMR(CD 3OD)δ:7.82(d,J＝7.7Hz,1H),7.67(d,J＝8.0Hz,1H),7.58(d,J＝7.5Hz,1H),7.49-7.31(m,3H),6.95-6.72(m,1H),6.29(d,J＝16.5Hz,1H),5.83(d,J＝10.6Hz,1H),5.18-5.04(m,1H),4.81-4.55(m,1H),4.34(d,J＝5.7Hz,2H),4.17-3.71(m,4H),3.70-3.48(m,4H),3.33-3.16(m,2H),3.13-2.83(m,7H),2.63(s,3H),2.59-2.45(m,1H),2.25-2.06(m,1H),2.01-1.71(m,3H). 1 H-NMR (CD 3 OD) δ: 7.82 (d, J = 7.7 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.49-7.31 (m, 3H), 6.95-6.72 (m, 1H), 6.29 (d, J = 16.5 Hz, 1H), 5.83 (d, J = 10.6 Hz, 1H), 5.18-5.04 (m, 1H), 4.81 4.55(m,1H), 4.34(d,J=5.7Hz,2H), 4.17-3.71(m,4H), 3.70-3.48(m,4H),3.33-3.16(m,2H),3.13-2.83( m, 7H), 2.63 (s, 3H), 2.59-2.45 (m, 1H), 2.25-2.06 (m, 1H), 2.01-1.71 (m, 3H).
实施例69Example 69
Figure PCTCN2020119633-appb-000160
Figure PCTCN2020119633-appb-000160
步骤1：step 1:
化合物 69-1的合成参考化合物 66-5。原料 66-4(50.0毫克)，8-乙基-1-溴萘(48.2毫克)，叔丁醇钠(98.9毫克)，甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(25.8毫克)，甲苯(2毫升)。得产品 69-1(36.0毫克)。 For the synthesis of compound 69-1 , refer to compound 66-5 . Raw material 66-4 (50.0 mg), 8-ethyl-1-bromonaphthalene (48.2 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'- Diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 mL). The product 69-1 (36.0 mg) was obtained.
LC-MS:m/z 640(M+H) + LC-MS: m/z 640(M+H) +
步骤2：Step 2:
化合物 69-2的合成参考化合物 66-6。原料 69-1(36.0毫克)，1,4-二氧六环(4摩尔/升，5毫升)。得产品 69-2(31.4毫克)。 For the synthesis of compound 69-2 , refer to compound 66-6 . Raw material 69-1 (36.0 mg), 1,4-dioxane (4 mol/L, 5 mL). The product 69-2 (31.4 mg) was obtained.
LC-MS:m/z 540(M+H) + LC-MS: m/z 540(M+H) +
步骤3：Step 3:
化合物 69的合成参考化合物 66。原料 69-2(31.4毫克)，三乙胺(27.6毫克)，丙烯酰氯(7.4毫克)，二氯甲烷(5毫升)。得产品 69(7.4毫克)。 For the synthesis of compound 69 , refer to compound 66 . Raw material 69-2 (31.4 mg), triethylamine (27.6 mg), acryloyl chloride (7.4 mg), dichloromethane (5 mL). The product 69 (7.4 mg) was obtained.
LC-MS:m/z 594(M+H) + LC-MS: m/z 594(M+H) +
1H-NMR(CD 3OD)δ:7.72-7.64(m,2H),7.40-7.30(m,4H),6.89-6.72(m,1H),6.28(d,J＝4.8Hz,1H),5.83(d,J＝10.5Hz,1H),5.18-4.97(m,1H),4.79-4.38(m,3H),4.21-3.37(m,12H),3.21-2.90(m,7H),2.89-2.83(m,1H),2.81(s,3H),2.34-2.20(m,1H),2.10-1.81(m,3H),1.28(q,J＝7.5Hz,3H). 1 H-NMR(CD 3 OD)δ:7.72-7.64(m,2H), 7.40-7.30(m,4H), 6.89-6.72(m,1H), 6.28(d,J=4.8Hz,1H), 5.83 (d, J = 10.5Hz, 1H), 5.18-4.97 (m, 1H), 4.79-4.38 (m, 3H), 4.21-3.37 (m, 12H), 3.21-2.90 (m, 7H), 2.89- 2.83(m,1H), 2.81(s,3H), 2.34-2.20(m,1H), 2.10-1.81(m,3H), 1.28(q,J=7.5Hz,3H).
实施例70Example 70
Figure PCTCN2020119633-appb-000161
Figure PCTCN2020119633-appb-000161
步骤1step 1
将原料 58-3(2.00克)溶于异丙醇(80毫升)中，依次加入哌嗪甲酸叔丁酯(1.45克)、二异丙基乙胺(1.68克)。所得混合液于80摄氏度下反应24小时。反应完毕后，加入水(200毫升)稀释。并用乙酸乙酯(100毫升x3)萃取。有机相合并后，用饱和食盐水(100毫升)洗涤，并用无水硫酸钠干燥后浓缩至干，得产品 70-1(1.30克)。 Raw material 58-3 (2.00 g) was dissolved in isopropanol (80 ml), and tert-butyl piperazinecarboxylate (1.45 g) and diisopropylethylamine (1.68 g) were added sequentially. The resulting mixture was reacted at 80 degrees Celsius for 24 hours. After the reaction is complete, add water (200 mL) to dilute. It was extracted with ethyl acetate (100 mL×3). After the organic phases were combined, they were washed with saturated brine (100 ml), dried with anhydrous sodium sulfate and concentrated to dryness to obtain product 70-1 (1.30 g).
LC-MS:m/z 458(M+H) + LC-MS: m/z 458(M+H) +
步骤2Step 2
将(S)-脯氨醇(0.528克)溶于无水四氢呋喃(100毫升)中，于0摄氏度下加入氢化钠(60％)(0.183克)。0摄氏度下反应30分钟后，加入原料 70-1(1.30克)。所得溶液于70摄氏度下反应3小时。反应完毕后，冷却至室温。加入饱和氯化铵水溶液(100毫升)淬灭，并用乙酸乙酯(100毫升x3)萃取。有机相合并后浓缩至干。所得粗品用硅胶柱层析纯化(甲醇/二氯甲烷＝5％-20％)得产品 70-2(1.10克)。 (S)-Prolinol (0.528 g) was dissolved in anhydrous tetrahydrofuran (100 ml), and sodium hydride (60%) (0.183 g) was added at 0 degrees Celsius. After reacting for 30 minutes at 0 degrees Celsius, raw material 70-1 (1.30 g) was added. The resulting solution was reacted at 70 degrees Celsius for 3 hours. After the reaction is complete, cool to room temperature. It was quenched by adding saturated aqueous ammonium chloride solution (100 mL), and extracted with ethyl acetate (100 mL×3). The organic phases were combined and concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (methanol/dichloromethane=5%-20%) to obtain product 70-2 (1.10 g).
LC-MS:m/z 537(M+H) + LC-MS: m/z 537(M+H) +
步骤3Step 3
将原料 70-2(1.10克)溶于无水甲醇(40毫升)中，氮气保护下依次加入钯碳(10％)(0.11克)、氨的甲醇溶液(7摩尔/升)(4毫升)。所得反应液用氢气置换3次，并于40摄氏度反应3小时。反应完毕后，将钯碳滤除。滤液浓缩至干，得产品 70-3(0.80克)。 Dissolve raw material 70-2 (1.10g) in dry methanol (40ml), add palladium on carbon (10%) (0.11g) and ammonia methanol solution (7mol/L) (4ml) under nitrogen protection. . The resulting reaction solution was replaced with hydrogen three times, and reacted at 40 degrees Celsius for 3 hours. After the reaction is completed, the palladium carbon is filtered off. The filtrate was concentrated to dryness to obtain product 70-3 (0.80 g).
LC-MS:m/z 447(M+H) + LC-MS: m/z 447(M+H) +
步骤4Step 4
将原料 70-3(50.0毫克)溶于甲苯(2毫升)中，依次加入8-甲基-1-溴萘(49.2毫克)，叔丁醇钠(53.7毫克)、甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(9.4毫克)。所得溶液于90摄氏度下搅拌3小时。反应完毕后冷却至室温，加入水(15毫升)稀释，并用乙酸乙酯(15毫升x3)萃取。有机相合并后浓缩至干。所得粗品用硅胶柱层析纯化(二氯甲烷/甲醇＝10％-20％)得产品 70-4(21.0毫克)。 The raw material 70-3 (50.0 mg) was dissolved in toluene (2 ml), and 8-methyl-1-bromonaphthalene (49.2 mg), sodium tert-butoxide (53.7 mg), methanesulfonic acid (2-two Cyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (9.4 mg ). The resulting solution was stirred at 90 degrees Celsius for 3 hours. After the reaction was completed, it was cooled to room temperature, diluted with water (15 mL), and extracted with ethyl acetate (15 mL×3). The organic phases were combined and concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (dichloromethane/methanol=10%-20%) to obtain product 70-4 (21.0 mg).
LC-MS:m/z 587(M+H) + LC-MS: m/z 587(M+H) +
步骤5Step 5
向原料 70-4(21.0毫克)中加入氯化氢的1,4-二氧六环溶液(2毫升)。所得溶液于室温下搅拌1小时。反应完毕后浓缩至干，得产品 70-5(15.0毫克)。无需纯化，直接用于下步反应。 A 1,4-dioxane solution (2 mL) of hydrogen chloride was added to raw material 70-4 (21.0 mg). The resulting solution was stirred at room temperature for 1 hour. After the reaction was completed, it was concentrated to dryness to obtain product 70-5 (15.0 mg). No purification is required, and it is directly used in the next reaction.
LC-MS:m/z 487(M+H) + LC-MS: m/z 487(M+H) +
步骤6Step 6
将原料 70-5(15.0毫克)溶于二氯甲烷(2毫升)中，冷却至-40摄氏度后，依次加入三乙胺(14.5毫克)、丙烯酰氯(2.6毫克)。所得溶液于-40摄氏度下反应1小时。反应完毕后，加入水(5毫升)淬灭并浓缩至干。所得粗品用制备型色谱柱纯化(柱型：XBridge Shield RP18 OBD Column,5um,19*150mm；流动相A：水(10毫摩尔/升，碳酸氢铵)，流动相B：乙腈；流速：25毫升/分钟；梯度：30-65％；时间8分钟；检测器波长254/220纳米)，得产品 70(7.8毫克)。 The raw material 70-5 (15.0 mg) was dissolved in dichloromethane (2 ml), and after cooling to -40 degrees Celsius, triethylamine (14.5 mg) and acryloyl chloride (2.6 mg) were sequentially added. The resulting solution was reacted at -40 degrees Celsius for 1 hour. After the reaction was completed, it was quenched by adding water (5 mL) and concentrated to dryness. The obtained crude product was purified with a preparative chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 Ml/min; gradient: 30-65%; time 8 minutes; detector wavelength 254/220 nanometers) to obtain product 70 (7.8 mg).
LC-MS:m/z 541(M+H) + LC-MS: m/z 541(M+H) +
1H-NMR(CD 3OD)δ:7.70-7.63(m,2H),7.39-7.27(m,4H),6.85-6.76(m,1H),6.29(dd,J 1＝2.1Hz,J 2＝16.8Hz,1H),5.79(dd,J 1＝2.1Hz,J 2＝10.8Hz,1H),4.61-4.45(m,2H),3.84-3.77(m,4H),3.52-3.37(m,9H),3.16(s,3H),3.13-2.95(m,4H),2.90-2.85(m,2H),2.84(s,3H),2.33-2.22(m,1H),2.09-1.88(m,3H). 1 H-NMR (CD 3 OD) δ: 7.70-7.63 (m, 2H), 7.39-7.27 (m, 4H), 6.85-6.76 (m, 1H), 6.29 (dd, J 1 ＝2.1Hz, J 2 = 16.8Hz, 1H), 5.79 (dd, J 1 = 2.1Hz, J 2 = 10.8Hz, 1H), 4.61-4.45 (m, 2H), 3.84-3.77 (m, 4H), 3.52-3.37 (m, 9H), 3.16 (s, 3H), 3.13-2.95 (m, 4H), 2.90-2.85 (m, 2H), 2.84 (s, 3H), 2.33-2.22 (m, 1H), 2.09-1.88 (m, 3H).
实施例71Example 71
Figure PCTCN2020119633-appb-000162
Figure PCTCN2020119633-appb-000162
步骤1step 1
将原料 58-3(2.00克)溶于异丙醇(80毫升)中，依次加入(S)-3-甲基哌嗪甲酸叔丁酯(1.56克)、二异丙基乙胺(1.68克)。所得混合液于80摄氏度下反应24小时。反应完毕后，加入水(200毫升)稀释。并用乙酸乙酯(100毫升x3)萃取。有机相合并后，用饱和食盐水(100毫升)洗涤，并用无水硫酸钠干燥后浓缩至干，得产品 71-1(1.00克)。 Raw material 58-3 (2.00 g) was dissolved in isopropanol (80 ml), and (S) tert-butyl-3-methylpiperazinecarboxylate (1.56 g) and diisopropylethylamine (1.68 g) were added in sequence. ). The resulting mixture was reacted at 80 degrees Celsius for 24 hours. After the reaction is complete, add water (200 mL) to dilute. It was extracted with ethyl acetate (100 mL×3). After the organic phases were combined, they were washed with saturated brine (100 ml), dried over anhydrous sodium sulfate and concentrated to dryness to obtain product 71-1 (1.00 g).
LC-MS:m/z 472(M+H) + LC-MS: m/z 472(M+H) +
步骤2Step 2
将(S)-脯氨醇(0.365克)溶于无水四氢呋喃(100毫升)中，于0摄氏度下加入氢化钠(60％)(0.127克)。0摄氏度下反应30分钟后，加入原料 71-1(1.00克)。所得溶液于70摄氏度下反应3小时。反应完毕后，冷却至室温。加入饱和氯化铵水溶液(50毫升)淬灭，并用乙酸乙酯(50毫升x3)萃取。有机相合并后浓缩至干。所得粗 品用硅胶柱层析纯化(甲醇/二氯甲烷＝5％-20％)得产品 71-2(0.850克)。 (S)-Prolinol (0.365 g) was dissolved in anhydrous tetrahydrofuran (100 ml), and sodium hydride (60%) (0.127 g) was added at 0 degrees Celsius. After reacting for 30 minutes at 0 degrees Celsius, raw material 71-1 (1.00 g) was added. The resulting solution was reacted at 70 degrees Celsius for 3 hours. After the reaction is complete, cool to room temperature. It was quenched by adding saturated aqueous ammonium chloride solution (50 mL), and extracted with ethyl acetate (50 mL×3). The organic phases were combined and concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (methanol/dichloromethane=5%-20%) to obtain product 71-2 (0.850 g).
LC-MS:m/z 551(M+H) + LC-MS: m/z 551(M+H) +
步骤3Step 3
将原料 71-2(0.850克)溶于无水甲醇(25毫升)中，氮气保护下依次加入钯碳(10％)(0.085克)、氨的甲醇溶液(7摩尔/升)(2.5毫升)。所得反应液用氢气置换3次，并于40摄氏度反应3小时。反应完毕后，将钯碳滤除。滤液浓缩至干，得产品 71-3(0.550克)。 Dissolve the raw material 71-2 (0.850g) in dry methanol (25ml), add palladium on carbon (10%) (0.085g) and ammonia methanol solution (7mol/L) (2.5ml) under the protection of nitrogen. . The resulting reaction solution was replaced with hydrogen three times, and reacted at 40 degrees Celsius for 3 hours. After the reaction is completed, the palladium carbon is filtered off. The filtrate was concentrated to dryness to obtain the product 71-3 (0.550 g).
LC-MS:m/z 461(M+H) + LC-MS: m/z 461(M+H) +
步骤4Step 4
将原料 71-3(50.0毫克)溶于甲苯(2毫升)中，依次加入8-甲基-1-溴萘(47.7毫克)，叔丁醇钠(51.8毫克)、甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(9.0毫克)。所得溶液于90摄氏度下搅拌3小时。反应完毕后冷却至室温，加入水(15毫升)稀释，并用乙酸乙酯(15毫升x3)萃取。有机相合并后浓缩至干。所得粗品用硅胶柱层析纯化(二氯甲烷/甲醇＝10％-20％)得产品 71-4(23.0毫克)。 The raw material 71-3 (50.0 mg) was dissolved in toluene (2 ml), and 8-methyl-1-bromonaphthalene (47.7 mg), sodium tert-butoxide (51.8 mg), methanesulfonic acid (2-bis Cyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (9.0 mg ). The resulting solution was stirred at 90 degrees Celsius for 3 hours. After the reaction was completed, it was cooled to room temperature, diluted with water (15 mL), and extracted with ethyl acetate (15 mL×3). The organic phases were combined and concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (dichloromethane/methanol=10%-20%) to obtain product 71-4 (23.0 mg).
LC-MS:m/z 601(M+H) + LC-MS: m/z 601(M+H) +
步骤5Step 5
向原料 71-4(23.0毫克)中加入氯化氢的1,4-二氧六环溶液(2毫升)。所得溶液于室温下搅拌1小时。反应完毕后浓缩至干，得产品 71-5(15.0毫克)。无需纯化，直接用于下步反应。 To the raw material 71-4 (23.0 mg) was added a 1,4-dioxane solution (2 ml) of hydrogen chloride. The resulting solution was stirred at room temperature for 1 hour. After the reaction was completed, it was concentrated to dryness to obtain the product 71-5 (15.0 mg). No purification is required, and it is directly used in the next reaction.
LC-MS:m/z 501(M+H) + LC-MS: m/z 501(M+H) +
步骤6Step 6
将原料 71-5(15.0毫克)溶于二氯甲烷(2毫升)中，冷却至-40摄氏度后，依次加入三乙胺(14.5毫克)、丙烯酰氯(2.5毫克)。所得溶液于-40摄氏度下反应1小时。反应完毕后，加入水(5毫升)淬灭并浓缩至干。所得粗品用制备型色谱柱纯化(柱型：XBridge Shield RP18 OBD Column,5um,19*150mm；流动相A：水(10毫摩尔/升，碳酸氢铵)，流动相B：乙腈；流速：25毫升/分钟；梯度：42-62％；时间8分钟；检测器波长254/220纳米)，得产品 71(7.8毫克)。 The raw material 71-5 (15.0 mg) was dissolved in dichloromethane (2 ml), and after cooling to -40 degrees Celsius, triethylamine (14.5 mg) and acryloyl chloride (2.5 mg) were sequentially added. The resulting solution was reacted at -40 degrees Celsius for 1 hour. After the reaction was completed, it was quenched by adding water (5 mL) and concentrated to dryness. The obtained crude product was purified with a preparative chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 Ml/min; gradient: 42-62%; time 8 minutes; detector wavelength 254/220 nanometers) to obtain product 71 (7.8 mg).
LC-MS:m/z 555(M+H) + LC-MS: m/z 555(M+H) +
1H-NMR(CD 3OD)δ:7.70-7.63(m,2H),7.39-7.27(m,4H),6.88-6.73(m,1H),6.27(dd,J 1＝2.1Hz,J 2＝16.8Hz,1H),5.80(dd,J 1＝2.1Hz,J 2＝10.8Hz,1H),4.56-4.38(m,3H),4.23-4.02(m,3H),3.95-3.82(m,1H),3.69-3.37(m,6H),3.30-3.21(m,2H),3.16(d,J＝4.8Hz,3H),3.12-2.93(m,4H),2.89-2.80(m,1H),2.77(s,3H),2.28-2.18(m,1H),2.02-1.82(m,3H),1.24-1.19(m,3H) 1 H-NMR (CD 3 OD) δ: 7.70-7.63 (m, 2H), 7.39-7.27 (m, 4H), 6.88-6.73 (m, 1H), 6.27 (dd, J 1 ＝2.1Hz, J 2 = 16.8Hz, 1H), 5.80 (dd, J 1 = 2.1Hz, J 2 = 10.8Hz, 1H), 4.56-4.38 (m, 3H), 4.23-4.02 (m, 3H), 3.95-3.82 (m, 1H), 3.69-3.37(m,6H), 3.30-3.21(m,2H), 3.16(d,J=4.8Hz,3H), 3.12-2.93(m,4H), 2.89-2.80(m,1H) ,2.77(s,3H),2.28-2.18(m,1H),2.02-1.82(m,3H),1.24-1.19(m,3H)
实施例72Example 72
Figure PCTCN2020119633-appb-000163
Figure PCTCN2020119633-appb-000163
步骤1step 1
化合物 72-1的合成参考化合物 1-10。原料 1-9(50.0毫克)，3-(1,1-二氟乙基)-溴苯(45.3毫克)，叔丁醇钠(98.9毫克)，甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(25.8毫克)，甲苯(2毫升)。得产品 72-1(32.0毫克)。 For the synthesis of compound 72-1 , refer to compound 1-10 . Raw material 1-9 (50.0 mg), 3-(1,1-difluoroethyl)-bromobenzene (45.3 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino- 2',6'-Diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 Ml). The product 72-1 (32.0 mg) was obtained.
LC-MS:m/z 626(M+H) + LC-MS: m/z 626(M+H) +
步骤2Step 2
化合物 72-2的合成参考化合物 1-11。原料 72-1(32.0毫克)，氯化氢的1,4-二氧六环溶液(4摩尔/升，5毫升)。得产品 72-2(28.4毫克)。 For the synthesis of compound 72-2 , refer to compound 1-11 . Raw material 72-1 (32.0 mg), 1,4-dioxane solution of hydrogen chloride (4 mol/L, 5 mL). The product 72-2 (28.4 mg) was obtained.
LC-MS:m/z 526(M+H) +. LC-MS: m/z 526(M+H) + .
步骤3Step 3
化合物 72的合成参考化合物 1。原料 72-2(28.4毫克)，三乙胺(25.6毫克)，丙烯酰氯(6.88毫克)，二氯甲烷(5毫升)。得产品 72(8.9毫克)。 For the synthesis of compound 72 , refer to compound 1 . Starting material 72-2 (28.4 mg), triethylamine (25.6 mg), acryloyl chloride (6.88 mg), dichloromethane (5 mL). Obtained product 72 (8.9 mg).
LC-MS:m/z 580(M+H) + LC-MS: m/z 580(M+H) +
1H-NMR(CD 3OD)δ:7.19(t,J＝8.0Hz,1H),6.97(s,1H),6.90(d,J＝8.7Hz,1H),6.85-6.68(m,J＝7.5Hz,2H),6.26(d,J＝16.7Hz,1H),5.81(d,J＝10.5Hz,1H),4.63(d,J＝2.3Hz,2H),4.46-4.32(m,2H),4.12-3.46(m,6H),3.24-3.06(m,3H),3.02-2.73(m,6H),2.56(s,3H),2.47-2.37(m,1H),2.17-1.75(m,9H). 1 H-NMR (CD 3 OD) δ: 7.19 (t, J = 8.0 Hz, 1H), 6.97 (s, 1H), 6.90 (d, J = 8.7 Hz, 1H), 6.85-6.68 (m, J = 7.5Hz, 2H), 6.26 (d, J = 16.7 Hz, 1H), 5.81 (d, J = 10.5 Hz, 1H), 4.63 (d, J = 2.3 Hz, 2H), 4.46-4.32 (m, 2H) ,4.12-3.46(m,6H),3.24-3.06(m,3H),3.02-2.73(m,6H),2.56(s,3H),2.47-2.37(m,1H),2.17-1.75(m, 9H).
实施例73Example 73
Figure PCTCN2020119633-appb-000164
Figure PCTCN2020119633-appb-000164
Figure PCTCN2020119633-appb-000165
Figure PCTCN2020119633-appb-000165
步骤1：step 1:
室温条件下，将原料 73-3(1.00克)溶于THF(5毫升)中，依次加入三乙胺(0.734克)，溴甲基甲醚(0.722克)。所得反应液置于室温反应2小时。反应完毕后，加入水(50毫升)淬灭。用乙酸乙酯(50毫升x3)萃取。有机相合并后用饱和食盐水(50毫升)洗涤。有机相用无水硫酸钠干燥后，减压浓缩得产品 73-4(1.10克)。 At room temperature, raw material 73-3 (1.00 g) was dissolved in THF (5 ml), and triethylamine (0.734 g) and bromomethyl methyl ether (0.722 g) were added in sequence. The resulting reaction solution was left at room temperature to react for 2 hours. After the reaction was completed, water (50 mL) was added for quenching. Extract with ethyl acetate (50 mL x 3). The organic phases were combined and washed with saturated brine (50 mL). After the organic phase was dried with anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain the product 73-4 (1.10 g).
LC-MS:m/z 251(M+H) + LC-MS: m/z 251(M+H) +
步骤2：Step 2:
化合物 73-1的合成参考化合物 1-10。原料 1-9(50.0毫克)， 73-4(51.5毫克)，叔丁醇钠(98.9毫克)，甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(25.8毫克)，甲苯(2毫升)。得产品 73-1(35.0毫克)。 For the synthesis of compound 73-1 , refer to compound 1-10 . Raw material 1-9 (50.0 mg), 73-4 (51.5 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy- 1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 ml). The product 73-1 (35.0 mg) was obtained.
LC-MS:m/z 656(M+H) + LC-MS: m/z 656(M+H) +
步骤3：Step 3:
化合物 73-2的合成参考化合物 1-11。原料 73-1(35.0毫克)，氯化氢的1,4-二氧六环溶液(4摩尔/升，5毫升)。得产品 73-2(28.9毫克)。 For the synthesis of compound 73-2, refer to compound 1-11 . Raw material 73-1 (35.0 mg), 1,4-dioxane solution of hydrogen chloride (4 mol/liter, 5 ml). The product 73-2 (28.9 mg) was obtained.
LC-MS:m/z 512(M+H) +. LC-MS: m/z 512(M+H) + .
步骤4：Step 4:
化合物 73的合成参考化合物 1。原料 73-2(28.9毫克)，三乙胺(26.7毫克)，丙烯酰氯(5.27毫克)，二氯甲烷(5毫升)。所得粗品用制备型色谱柱纯化(柱型:XBridge Shield RP18 OBD Column,,5um,19*150mm；流动相A:水(0.5％甲酸),流动相B:乙腈；流速:25毫升/分钟；梯度:27％-47％；时间8分钟；检测器波长254/220纳米)，得产品 73(5.3毫克)。 For the synthesis of compound 73 , refer to compound 1 . Raw material 73-2 (28.9 mg), triethylamine (26.7 mg), acryloyl chloride (5.27 mg), dichloromethane (5 mL). The obtained crude product was purified with a preparative chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase A: water (0.5% formic acid), mobile phase B: acetonitrile; flow rate: 25 ml/min; gradient : 27%-47%; time 8 minutes; detector wavelength 254/220 nm), product 73 (5.3 mg) is obtained.
LC-MS:m/z 566(M+H) + LC-MS: m/z 566(M+H) +
1H-NMR(CD 3OD)δ:8.58(s,1H),7.05(t,J＝8.1Hz,1H),6.91-6.74(m,1H),6.70(d,J＝8.3Hz,1H),6.63(d,J＝8.1Hz,1H),6.30(d,J＝16.8Hz,1H),5.85(d,J＝10.5Hz,1H),5.18-5.08(m,1H),4.70-4.48(m,2H),4.26(s,2H),4.17-3.84(m,3H),3.75-3.54(m,3H),3.53-3.35(m,3H),3.30-2.99(m,5H),2.97(s,3H),2.92-2.86(m,1H),2.40-2.28(m,1H),2.19-1.96(m,5H). 1 H-NMR (CD 3 OD) δ: 8.58 (s, 1H), 7.05 (t, J = 8.1 Hz, 1H), 6.91-6.74 (m, 1H), 6.70 (d, J = 8.3 Hz, 1H) , 6.63 (d, J = 8.1 Hz, 1H), 6.30 (d, J = 16.8 Hz, 1H), 5.85 (d, J = 10.5 Hz, 1H), 5.18-5.08 (m, 1H), 4.70-4.48 ( m, 2H), 4.26(s, 2H), 4.17-3.84(m, 3H), 3.75-3.54(m, 3H), 3.53-3.35(m, 3H), 3.30-2.99(m, 5H), 2.97( s, 3H), 2.92-2.86 (m, 1H), 2.40-2.28 (m, 1H), 2.19-1.96 (m, 5H).
实施例74Example 74
Figure PCTCN2020119633-appb-000166
Figure PCTCN2020119633-appb-000166
步骤1：step 1:
化合物 74-1的合成参考化合物 1-10。原料 1-9(50.0毫克)，3,4-二氯溴苯(46.1毫克)，叔丁醇钠(98.9毫克)，甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(25.8毫克)，甲苯(2毫升)。得产品 74-1(31.9毫克)。 For the synthesis of compound 74-1 , refer to compound 1-10 . Raw material 1-9 (50.0 mg), 3,4-dichlorobromobenzene (46.1 mg), sodium tert-butoxide (98.9 mg), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-di Isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (25.8 mg), toluene (2 ml). The product 74-1 (31.9 mg) was obtained.
LC-MS:m/z 630(M+H) + LC-MS: m/z 630(M+H) +
步骤2：Step 2:
化合物 74-2的合成参考化合物 1-10。原料 74-1(31.9毫克)，氯化氢的1,4-二氧六环溶液(4摩尔/升，5毫升)。得产品 74-2(28.5毫克)。 For the synthesis of compound 74-2 , refer to compound 1-10 . Raw material 74-1 (31.9 mg), 1,4-dioxane solution of hydrogen chloride (4 mol/L, 5 mL). The product 74-2 (28.5 mg) was obtained.
LC-MS:m/z 530(M+H) + LC-MS: m/z 530(M+H) +
步骤3Step 3
化合物 74的合成参考化合物 1。原料 74-2(28.5毫克)，三乙胺(25.4毫克)，丙烯酰氯(5.77毫克)，二氯甲烷(5毫升)。得产品 74(7.0毫克)。 The synthesis of compound 74 refers to compound 1 . Raw material 74-2 (28.5 mg), triethylamine (25.4 mg), acryloyl chloride (5.77 mg), dichloromethane (5 mL). The product 74 (7.0 mg) was obtained.
LC-MS:m/z 584(M+H) + LC-MS: m/z 584(M+H) +
1H-NMR(CD 3OD)δ:7.19(d,J＝9.0Hz,1H),6.96(d,J＝3.0Hz,1H),6.91-6.67(m,2H),6.26(d,J＝16.8Hz,1H),5.81(d,J＝10.5Hz,1H),5.15-4.97(m,1H),4.64-4.51(m,2H),4.41(d,J＝5.7Hz,2H),4.13-3.96(m,1H),3.95-3.71(m,3H),3.69-3.44(m,2H),3.27-3.07(m,3H),3.02-2.80(m,5H),2.58(s,3H),2.53-2.41(m,1H),2.24-2.06(m,1H),2.04-1.67(m,5H). 1 H-NMR (CD 3 OD) δ: 7.19 (d, J = 9.0 Hz, 1H), 6.96 (d, J = 3.0 Hz, 1H), 6.91-6.67 (m, 2H), 6.26 (d, J = 16.8Hz, 1H), 5.81 (d, J = 10.5 Hz, 1H), 5.15 to 4.97 (m, 1H), 4.64-4.51 (m, 2H), 4.41 (d, J = 5.7 Hz, 2H), 4.13 3.96(m,1H), 3.95-3.71(m,3H), 3.69-3.44(m,2H), 3.27-3.07(m,3H), 3.02-2.80(m,5H), 2.58(s,3H), 2.53-2.41 (m, 1H), 2.24-2.06 (m, 1H), 2.04-1.67 (m, 5H).
实施例75Example 75
Figure PCTCN2020119633-appb-000167
Figure PCTCN2020119633-appb-000167
步骤1：step 1:
化合物 75-1的合成参考化合物 42-2。其中原料 42-1(1.00克)，2,3-二氯-1-溴苯(1.10克)，叔丁醇钠(1.18克)，甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(0.206克)，甲苯(20毫升)。得产品 75-1(400毫克)。 For the synthesis of compound 75-1 , refer to compound 42-2 . The raw material 42-1 (1.00 g), 2,3-dichloro-1-bromobenzene (1.10 g), sodium tert-butoxide (1.18 g), methanesulfonic acid (2-dicyclohexylphosphino-2', 6'-Diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (0.206g), toluene (20ml). Obtained product 75-1 (400 mg).
LC-MS:m/z 551(M+H) + LC-MS: m/z 551(M+H) +
步骤2：Step 2:
室温条件下，将原料 75-1(50.0毫克)和3-氨基-N,N-二甲基丙酰胺(21.1毫克)溶于二甲基亚砜(2.0毫升)中，加入N,N-二异丙基乙胺(35.2毫克)。将反应液置于120摄氏度下反应过夜。反应完毕后，加入水(20毫升)淬灭。用乙酸乙酯(20毫升x3)萃取。有机相合并后用饱和食盐水(20毫升)洗涤。有机相用无水硫酸钠干燥后，减压浓缩得粗品。粗品用硅胶柱层析纯化(甲醇/二氯甲烷＝5％-20％)，得产品 75-2(25.0毫克)。 At room temperature, the raw material 75-1 (50.0 mg) and 3-amino-N,N-dimethylpropionamide (21.1 mg) were dissolved in dimethyl sulfoxide (2.0 ml), and N,N-bis Isopropylethylamine (35.2 mg). The reaction solution was placed at 120 degrees Celsius to react overnight. After the reaction was completed, it was quenched by adding water (20 mL). Extract with ethyl acetate (20 mL x 3). The organic phases were combined and washed with saturated brine (20 mL). After drying the organic phase with anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (methanol/dichloromethane=5%-20%) to obtain product 75-2 (25.0 mg).
LC-MS:m/z 631(M+H) + LC-MS: m/z 631(M+H) +
步骤3：Step 3:
化合物 75-3的合成参考化合物 42-4。其中原料 75-2(25.0毫克)，氯化氢的1,4-二氧六环溶液(4摩尔/升，5毫升)。得到产品 75-3(22.3毫克)。无需纯化，直接用于下步反应。 For the synthesis of compound 75-3 , refer to compound 42-4 . Among them, raw material 75-2 (25.0 mg), 1,4-dioxane solution of hydrogen chloride (4 mol/L, 5 ml). The product 75-3 (22.3 mg) was obtained. No purification is required, and it is directly used in the next reaction.
LC-MS:m/z 531(M+H) + LC-MS: m/z 531(M+H) +
步骤4：Step 4:
化合物 75的合成参考化合物 42。其中原料 75-3(22.3毫克)，三乙胺(19.9毫克)，丙烯酰氯(5.35毫克)，二氯甲烷(5毫升)。得到产品 75(4.0毫克)。 For the synthesis of compound 75 , refer to compound 42 . Among them, raw material 75-3 (22.3 mg), triethylamine (19.9 mg), acryloyl chloride (5.35 mg), dichloromethane (5 ml). Product 75 (4.0 mg) was obtained.
LC-MS:m/z 585(M+H) + LC-MS: m/z 585(M+H) +
1H-NMR(CD 3OD)δ:7.25-7.10(m,3H),6.94-6.78(m,1H),6.29(d,J＝16.8Hz,1H),5.84(d,J＝10.5Hz,1H),5.25-5.11(m,1H),4.22-4.04(m,3H),3.88-3.74(m,2H),3.70-3.58(m,3H),3.50-3.35(m,3H),3.21-3.14(m,1H),3.05(s,3H),3.04-2.95(m,2H),2.93(s,3H),2.81(t,J＝5.2Hz,2H),2.70(t,J＝6.6Hz,2H),2.17-1.95(m,2H). 1 H-NMR (CD 3 OD) δ: 7.25-7.10 (m, 3H), 6.94-6.78 (m, 1H), 6.29 (d, J = 16.8 Hz, 1H), 5.84 (d, J = 10.5 Hz, 1H), 5.25-5.11 (m, 1H), 4.22-4.04 (m, 3H), 3.88-3.74 (m, 2H), 3.70-3.58 (m, 3H), 3.50-3.35 (m, 3H), 3.21 3.14(m,1H),3.05(s,3H),3.04-2.95(m,2H),2.93(s,3H),2.81(t,J=5.2Hz,2H),2.70(t,J=6.6Hz ,2H),2.17-1.95(m,2H).
实施例76Example 76
Figure PCTCN2020119633-appb-000168
Figure PCTCN2020119633-appb-000168
步骤1：step 1:
化合物 76-1的合成参考化合物 42-2。其中原料 42-1(1.00克)，1-溴-3-甲基-2-三氟甲苯(1.17克)，叔丁醇钠(1.18克)，甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(0.206克)，甲苯(20毫升)。得 产品 76-1(350毫克)。 For the synthesis of compound 76-1 , refer to compound 42-2 . Among them, the raw material 42-1 (1.00 g), 1-bromo-3-methyl-2-benzotrifluoride (1.17 g), sodium tert-butoxide (1.18 g), methanesulfonic acid (2-dicyclohexylphosphino- 2',6'-Diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (0.206g), toluene (20 Ml). The product 76-1 (350 mg) was obtained.
LC-MS:m/z 565(M+H) + LC-MS: m/z 565(M+H) +
步骤2：Step 2:
化合物 76-2的合成参考化合物 42-3。其中原料 76-1(50.0毫克)和5-羟基嘧啶(12.8毫克)，氢化钠(60％)(5.32毫克)，四氢呋喃(5.0毫升)。得产品 76-2(27.0毫克)。 For the synthesis of compound 76-2, refer to compound 42-3 . Among them, raw material 76-1 (50.0 mg) and 5-hydroxypyrimidine (12.8 mg), sodium hydride (60%) (5.32 mg), tetrahydrofuran (5.0 ml). The product 76-2 (27.0 mg) was obtained.
LC-MS:m/z 625(M+H) + LC-MS: m/z 625(M+H) +
步骤3：Step 3:
化合物 76-3的合成参考化合物 42-4。其中原料 76-2(27.0毫克)，氯化氢的1,4-二氧六环溶液(4摩尔/升，5毫升)。得到产品 76-3(23.5毫克)。无需纯化，直接用于下步反应。 For the synthesis of compound 76-3 , refer to compound 42-4 . Among them, raw material 76-2 (27.0 mg), 1,4-dioxane solution of hydrogen chloride (4 mol/L, 5 ml). Product 76-3 (23.5 mg) was obtained. No purification is required, and it is directly used in the next reaction.
LC-MS:m/z 525(M+H) + LC-MS: m/z 525(M+H) +
步骤4：Step 4:
化合物 76的合成参考化合物 42。其中原料 76-3(23.5毫克)，三乙胺(21.1毫克)，丙烯酰氯(5.66毫克)，二氯甲烷(5毫升)。得到产品 76(8.2毫克)。 For the synthesis of compound 76 , refer to compound 42 . Among them, raw material 76-3 (23.5 mg), triethylamine (21.1 mg), acryloyl chloride (5.66 mg), dichloromethane (5 ml). Product 76 (8.2 mg) was obtained.
LC-MS:m/z 579(M+H) + LC-MS: m/z 579(M+H) +
1H-NMR(CDCl 3)δ:9.06(s,1H),8.72(s,2H),7.36(d,J＝8.0Hz,1H),7.19(d,J＝8.1Hz,1H),7.06(d,J＝7.8Hz,1H),6.65-6.52(m,1H),6.40(d,J＝16.5Hz,1H),5.84(d,J＝10.2Hz,1H),5.24-4.97(m,1H),4.28-4.04(m,2H),3.91-3.52(m,3H),3.38-3.11(m,3H),3.07-3.65(m,5H),2.49(s,3H),2.19-1.89(m,3H). 1 H-NMR (CDCl 3 ) δ: 9.06 (s, 1H), 8.72 (s, 2H), 7.36 (d, J = 8.0 Hz, 1H), 7.19 (d, J = 8.1 Hz, 1H), 7.06 ( d,J=7.8Hz,1H),6.65-6.52(m,1H),6.40(d,J=16.5Hz,1H), 5.84(d,J=10.2Hz,1H),5.24-4.97(m,1H ), 4.28-4.04 (m, 2H), 3.91-3.52 (m, 3H), 3.38-3.11 (m, 3H), 3.07-3.65 (m, 5H), 2.49 (s, 3H), 2.19-1.89 (m ,3H).
实施例77Example 77
Figure PCTCN2020119633-appb-000169
Figure PCTCN2020119633-appb-000169
步骤1：step 1:
化合物 77-1的合成参考化合物 42-3。其中原料 76-1(50.0毫克)和嘧啶-2-甲醇(14.6毫克)，氢化钠(60％)(5.32毫克)，四氢呋喃(5.0毫升)。得产品 77-1(27.8毫克)。 For the synthesis of compound 77-1 , refer to compound 42-3 . Among them, raw material 76-1 (50.0 mg) and pyrimidine-2-methanol (14.6 mg), sodium hydride (60%) (5.32 mg), tetrahydrofuran (5.0 ml). The product 77-1 (27.8 mg) was obtained.
LC-MS:m/z 639(M+H) + LC-MS: m/z 639(M+H) +
步骤2：Step 2:
化合物 77-2的合成参考化合物 42-4。其中原料 77-1(27.8毫克)，氯化氢的1,4-二氧六环溶液(4摩尔/升，5毫升)。得到产品 77-2(24.5毫克)。无需纯化，直接用于下步反应。 For the synthesis of compound 77-2 , refer to compound 42-4 . Among them, the raw material 77-1 (27.8 mg), the 1,4-dioxane solution of hydrogen chloride (4 mol/L, 5 ml). Product 77-2 (24.5 mg) was obtained. No purification is required, and it is directly used in the next reaction.
LC-MS:m/z 539(M+H) + LC-MS: m/z 539(M+H) +
步骤3：Step 3:
化合物 77的合成参考化合物 42。其中原料 77-2(24.5毫克)，三乙胺(21.6毫克)，丙烯酰氯(5.80毫克)，二氯甲烷(5毫升)。得到产品 77(4.0毫克)。 For the synthesis of compound 77 , refer to compound 42 . Among them, the raw material 77-2 (24.5 mg), triethylamine (21.6 mg), acryloyl chloride (5.80 mg), dichloromethane (5 ml). Product 77 (4.0 mg) was obtained.
LC-MS:m/z 593(M+H) + LC-MS: m/z 593(M+H) +
1H-NMR(CDCl 3)δ:8.74(d,J＝4.9Hz,2H),7.33(t,J＝7.9Hz,1H),7.22(t,J＝4.9Hz,1H),7.14(d,J＝8.1Hz,1H),7.02(d,J＝7.6Hz,1H),6.67-6.50(m,1H),6.38(d,J＝16.7Hz,1H),5.82(d,J＝10.0Hz,1H),5.56(s,2H),5.23-4.91(m,1H),4.73-4.43(m,1H),4.19(q,J＝17.4Hz,2H),3.91-3.51(m,3H),3.32-3.11(m,3H),3.00-2.65(m,5H),2.48(s,3H),2.09-1.91(m,2H). 1 H-NMR (CDCl 3 ) δ: 8.74 (d, J = 4.9 Hz, 2H), 7.33 (t, J = 7.9 Hz, 1H), 7.22 (t, J = 4.9 Hz, 1H), 7.14 (d, J = 8.1 Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H), 6.67-6.50 (m, 1H), 6.38 (d, J = 16.7 Hz, 1H), 5.82 (d, J = 10.0 Hz, 1H),5.56(s,2H),5.23-4.91(m,1H),4.73-4.43(m,1H),4.19(q,J=17.4Hz,2H),3.91-3.51(m,3H),3.32 -3.11 (m, 3H), 3.00-2.65 (m, 5H), 2.48 (s, 3H), 2.09-1.91 (m, 2H).
实施例78Example 78
Figure PCTCN2020119633-appb-000170
Figure PCTCN2020119633-appb-000170
步骤1step 1
将原料 78-1(22.0克)溶于N,N-二甲基甲酰胺(250毫升)中，依次加入5-溴戊酸乙酯(26.3克)，N,N-二异丙基乙胺(17.9克)。所得溶液于80摄氏度下搅拌24小时。反应完毕后冷却至室温，加入水(200毫升)稀释，并用乙酸乙酯(200毫升x3)萃取。有机相合并后浓缩至干。所得粗品用硅胶柱层析纯化(乙酸乙酯/石油醚＝10％-20％)得产品 78-2(13.1克)。 Dissolve raw material 78-1 (22.0g) in N,N-dimethylformamide (250ml), add ethyl 5-bromovalerate (26.3g) and N,N-diisopropylethylamine in sequence (17.9 grams). The resulting solution was stirred at 80 degrees Celsius for 24 hours. After the reaction was completed, it was cooled to room temperature, diluted with water (200 mL), and extracted with ethyl acetate (200 mL×3). The organic phases were combined and concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 10%-20%) to obtain product 78-2 (13.1 g).
LC-MS:m/z 304(M+H) + LC-MS: m/z 304(M+H) +
步骤2Step 2
将原料 78-2(13.1克)溶于N,N-二甲基甲酰胺(150毫升)中，依次加入N,N-二异丙基乙胺(6.65克)，草酰氯单乙酯(6.42克)。所得溶液于室温下搅拌16小时。反应完毕后加入水(150毫升)稀释，并用乙酸乙酯(200毫升x3)萃取。有机相合并后浓缩至干。所得粗品用硅胶柱层析纯化(乙酸乙酯/石油醚＝10％-20％)得产品 78-3(8.00克)。 Raw material 78-2 (13.1g) was dissolved in N,N-dimethylformamide (150ml), and N,N-diisopropylethylamine (6.65g), oxalyl chloride monoethyl (6.42 G). The resulting solution was stirred at room temperature for 16 hours. After the reaction was completed, water (150 mL) was added to dilute, and the mixture was extracted with ethyl acetate (200 mL×3). The organic phases were combined and concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 10%-20%) to obtain product 78-3 (8.00 g).
LC-MS:m/z 404(M+H) + LC-MS: m/z 404(M+H) +
步骤3Step 3
将原料 78-3(8.00克)溶于N,N-二甲基甲酰胺(100毫升)中，加入氢化钠(1.20克)。所得溶液于110摄氏度下搅拌16小时。反应完毕后冷却至室温，加入水(100毫升)稀释，并用乙酸乙酯(200毫升x3)萃取。有机相合并后浓缩至干。所得粗品用硅胶柱层析纯化(乙酸乙酯/石油醚＝20％-30％)得产品 78-4(4.00克)。 Raw material 78-3 (8.00 g) was dissolved in N,N-dimethylformamide (100 ml), and sodium hydride (1.20 g) was added. The resulting solution was stirred at 110 degrees Celsius for 16 hours. After the reaction was completed, it was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (200 mL×3). The organic phases were combined and concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 20%-30%) to obtain product 78-4 (4.00 g).
LC-MS:m/z 358(M+H) + LC-MS: m/z 358(M+H) +
步骤4Step 4
将原料 78-4(4.00克)溶于乙醇(100毫升)中，依次加入乙醇钠的乙醇溶液(1.20克)。所得溶液于80摄氏度下搅拌16小时。反应完毕后冷却至室温，用稀盐酸调节PH值至弱酸性，加入水(100毫升)稀释，并用乙酸乙酯(200毫升x3)萃取。有机相合并后浓缩至干。所得粗品用硅胶柱层析纯化(乙酸乙酯/石油醚＝20％-30％)得产品 78-5(400毫克)。 The raw material 78-4 (4.00 g) was dissolved in ethanol (100 ml), and the ethanol solution of sodium ethoxide (1.20 g) was sequentially added. The resulting solution was stirred at 80 degrees Celsius for 16 hours. After the reaction was completed, it was cooled to room temperature, the pH was adjusted to weak acidity with dilute hydrochloric acid, diluted with water (100 mL), and extracted with ethyl acetate (200 mL×3). The organic phases were combined and concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 20%-30%) to obtain product 78-5 (400 mg).
LC-MS:m/z 370(M+H) + LC-MS: m/z 370(M+H) +
步骤5Step 5
将原料 78-5(400毫克)悬浮于三氯氧磷(100毫升)中，加入N,N-二甲基甲酰胺(1毫升)。所得溶液于80摄氏度下搅拌16小时。反应完毕后，将反应液浓缩至干。残余物加入水(100毫升)并用无水碳酸钠调节PH至为8。加入水(100毫升)稀释，并用乙酸乙酯(100毫升x3)萃取。有机相合并后浓缩至干。所得粗品用硅胶柱层析纯化(乙酸乙酯/石油醚＝20％-30％)得产品 78-6(326毫克)。 Raw material 78-5 (400 mg) was suspended in phosphorus oxychloride (100 mL), and N,N-dimethylformamide (1 mL) was added. The resulting solution was stirred at 80 degrees Celsius for 16 hours. After the completion of the reaction, the reaction solution was concentrated to dryness. Add water (100 ml) to the residue and adjust the pH to 8 with anhydrous sodium carbonate. It was diluted with water (100 mL) and extracted with ethyl acetate (100 mL×3). The organic phases were combined and concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 20%-30%) to obtain product 78-6 (326 mg).
LC-MS:m/z 390(M+H) + LC-MS: m/z 390(M+H) +
步骤6Step 6
将原料 78-6(326毫克)溶于异丙醇(100毫升)中，依次加入2-氰甲基哌嗪二盐酸盐(182毫克)、N,N-二异丙基乙胺(377毫克)。所得溶液于室温下搅拌1小时。反应完毕后加入水(100毫升)稀释，并用乙酸乙酯(100毫升x3)萃取。有机相合并后浓缩至干得产品 78-7(294毫克)。 The raw material 78-6 (326 mg) was dissolved in isopropanol (100 ml), and 2-cyanomethylpiperazine dihydrochloride (182 mg), N,N-diisopropylethylamine (377 Mg). The resulting solution was stirred at room temperature for 1 hour. After the reaction was completed, water (100 mL) was added to dilute, and the mixture was extracted with ethyl acetate (100 mL×3). The organic phases were combined and concentrated to dryness to obtain product 78-7 (294 mg).
LC-MS:m/z 479(M+H) + LC-MS: m/z 479(M+H) +
步骤7Step 7
将原料 78-7(294毫克)溶于无水四氢呋喃(50毫升)中，依次加入二碳酸二叔丁酯(160毫克)、N,N-二异丙基乙胺(119毫克)。所得溶液于50摄氏度下反应2小时。反应完毕后，加入水(50毫升)稀释，并用乙酸乙酯(50毫升x3)萃取。有机相合并后浓缩至干。所得粗品用硅胶柱层析纯化(乙酸乙酯/石油醚＝30％-60％)得产品 78-8(254毫克)。 Raw material 78-7 (294 mg) was dissolved in anhydrous tetrahydrofuran (50 ml), and di-tert-butyl dicarbonate (160 mg) and N,N-diisopropylethylamine (119 mg) were added in sequence. The resulting solution was reacted at 50 degrees Celsius for 2 hours. After the reaction was completed, it was diluted with water (50 mL), and extracted with ethyl acetate (50 mL×3). The organic phases were combined and concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether=30%-60%) to obtain product 78-8 (254 mg).
LC-MS:m/z 579(M+H) + LC-MS: m/z 579(M+H) +
步骤8Step 8
将(S)-脯氨醇(75.7毫克)溶于无水四氢呋喃(50毫升)中，于0摄氏度下加入氢化钠(60％)(26.3毫克)。0摄氏度下反应30分钟后，加入原料 78-8(254毫克)。所得溶液于70摄氏度下反应3小时。反应完毕后，冷却至室温。加入饱和氯化铵水溶液(50毫升)淬灭，并用乙酸乙酯(50毫升x3)萃取。有机相合并后浓缩至干。所得粗品用硅胶柱层析纯化(甲醇/二氯甲烷＝5％-20％)得产品 78-9(98.0毫克)。 (S)-Prolinol (75.7 mg) was dissolved in anhydrous tetrahydrofuran (50 ml), and sodium hydride (60%) (26.3 mg) was added at 0 degrees Celsius. After reacting for 30 minutes at 0 degrees Celsius, raw material 78-8 (254 mg) was added. The resulting solution was reacted at 70 degrees Celsius for 3 hours. After the reaction is complete, cool to room temperature. It was quenched by adding saturated aqueous ammonium chloride solution (50 mL), and extracted with ethyl acetate (50 mL×3). The organic phases were combined and concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (methanol/dichloromethane=5%-20%) to obtain product 78-9 (98.0 mg).
LC-MS:m/z 658(M+H) + LC-MS: m/z 658(M+H) +
步骤9Step 9
向原料 78-9(98.0毫克)中加入氯化氢的1,4-二氧六环溶液(5毫升)。所得溶液于室温下搅拌10分钟。反应完毕后浓缩至干，得产品 78-10(53.0毫克)。无需纯化，直接用于下步反应。 To raw material 78-9 (98.0 mg) was added 1,4-dioxane solution (5 mL) of hydrogen chloride. The resulting solution was stirred at room temperature for 10 minutes. After the reaction was completed, it was concentrated to dryness to obtain product 78-10 (53.0 mg). No purification is required, and it is directly used in the next reaction.
LC-MS:m/z 558(M+H) + LC-MS: m/z 558(M+H) +
步骤10Step 10
将原料 78-10(53.0毫克)溶于二氯甲烷(5毫升)中，冷却至-40摄氏度后，依次加入三乙胺(28.8毫克)、丙烯酰氯(12.8毫克)。所得溶液于-40摄氏度下反应10分钟。反应完毕后，加入水(5毫升)淬灭并浓缩至干。所得粗品用制备型色谱柱纯化(柱型:XBridge Shield RP18 OBD Column,5um,19*150mm；流动相A:水(0.5％甲酸)；流动相B:乙腈；流速:25毫升/分钟；梯度:40-70％；时间8分钟；检测器波长254/220纳米)，得产品 78(10.0毫克)。 Raw material 78-10 (53.0 mg) was dissolved in dichloromethane (5 ml), and after cooling to -40 degrees Celsius, triethylamine (28.8 mg) and acryloyl chloride (12.8 mg) were added in sequence. The resulting solution was reacted at -40 degrees Celsius for 10 minutes. After the reaction was completed, it was quenched by adding water (5 mL) and concentrated to dryness. The obtained crude product was purified with a preparative chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase A: water (0.5% formic acid); mobile phase B: acetonitrile; flow rate: 25 ml/min; gradient: 40-70%; time 8 minutes; detector wavelength 254/220 nanometers) to obtain product 78 (10.0 mg).
LC-MS:m/z 612(M+H) + LC-MS: m/z 612(M+H) +
1H-NMR(CD 3OD)δ:8.52(s,1H),7.77(d,J＝6.8Hz,1H),7.65-7.45(m,2H),6.84(s,1H),6.32(d,J＝16.0Hz,1H),5.86(d,J＝12.0Hz,1H),5.31-5.06(m,1H),4.43-4.02(m,3H),4.00-3.75(m,2H),3.75-3.50(m,4H),3.22-2.87(m,9H),2.42(s,3H),2.40-2.20(m,3H),2.18-1.89(m,5H). 1 H-NMR (CD 3 OD) δ: 8.52 (s, 1H), 7.77 (d, J = 6.8 Hz, 1H), 7.65-7.45 (m, 2H), 6.84 (s, 1H), 6.32 (d, J = 16.0Hz, 1H), 5.86 (d, J = 12.0Hz, 1H), 5.31-5.06 (m, 1H), 4.43-4.02 (m, 3H), 4.00-3.75 (m, 2H), 3.75-3.50 (m, 4H), 3.22-2.87 (m, 9H), 2.42 (s, 3H), 2.40-2.20 (m, 3H), 2.18-1.89 (m, 5H).
实施例79Example 79
Figure PCTCN2020119633-appb-000171
Figure PCTCN2020119633-appb-000171
步骤1：step 1:
室温条件下，将原料 1-9(126.4毫克)溶于甲苯(3毫升)中，依次加入2-溴-3-氟苯甲醚(106.4毫克)，叔丁醇钠(250毫克)、甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(65.3毫克)。所得溶液于90摄氏度下搅拌3小时。反应完毕后冷却至室温，加入水(15毫升)稀释，并用乙酸乙酯(15毫升x3)萃取，有机相合并后浓缩至干。所得粗品用硅胶柱层析纯化(二氯甲烷/甲醇＝10％-20％)得产品 79-1(96.7毫克)。 At room temperature, dissolve raw materials 1-9 (126.4 mg) in toluene (3 ml), and add 2-bromo-3-fluoroanisole (106.4 mg), sodium tert-butoxide (250 mg), methanesulfonate Acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2-amino-1,1'-biphenyl-2-yl)palladium ( II) (65.3 mg). The resulting solution was stirred at 90 degrees Celsius for 3 hours. After the reaction was completed, it was cooled to room temperature, diluted with water (15 mL), and extracted with ethyl acetate (15 mL×3). The organic phases were combined and concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (dichloromethane/methanol=10%-20%) to obtain product 79-1 (96.7 mg).
LC-MS:m/z 610(M+H) +. LC-MS: m/z 610(M+H) + .
步骤2：Step 2:
室温条件下，向原料 79-1(96.7毫克)中加入氯化氢的1,4-二氧六环溶液(10毫升)。所得溶液于室温下搅拌10分钟。反应完毕后浓缩至干，得产品 79-2(79.6毫克)。无需纯化，直接用于下步反应。 At room temperature, a 1,4-dioxane solution (10 ml) of hydrogen chloride was added to raw material 79-1 (96.7 mg). The resulting solution was stirred at room temperature for 10 minutes. After the reaction was completed, it was concentrated to dryness to obtain product 79-2 (79.6 mg). No purification is required, and it is directly used in the next reaction.
LC-MS:m/z 510(M+H) +. LC-MS: m/z 510(M+H) + .
步骤3：Step 3:
将原料 79-2(79.6毫克)溶于二氯甲烷(10毫升)中，冷却至-40摄氏度后，依次加入三乙胺(71.7毫克)、丙烯酰氯(15.3毫克)。所得溶液于-40摄氏度下反应10分钟。反应完毕后，加入水(10毫升)淬灭，用乙酸乙酯(15毫升x3)萃取，有机相合并后浓缩至干。所得粗品用制备型色谱柱纯化(柱型:XBridge Shield RP18 OBD Column,5um,19*150mm；流动相A：水(10毫摩尔/升，碳酸氢铵)，流动相B：乙腈；流速：25毫升/分钟；梯度：35-80％；时间12分钟；检测器波长254/220纳米)，得产品 79 (59.6毫克)。 The raw material 79-2 (79.6 mg) was dissolved in dichloromethane (10 ml), and after cooling to -40 degrees Celsius, triethylamine (71.7 mg) and acryloyl chloride (15.3 mg) were added in sequence. The resulting solution was reacted at -40 degrees Celsius for 10 minutes. After the reaction was completed, it was quenched by adding water (10 mL), extracted with ethyl acetate (15 mL×3), and the organic phases were combined and concentrated to dryness. The crude product obtained was purified with a preparative chromatography column (column type: XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase A: water (10 mmol/L, ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 Ml/min; gradient: 35-80%; time 12 minutes; detector wavelength 254/220 nanometers) to obtain product 79 (59.6 mg).
LC-MS:m/z 564(M+H) + LC-MS: m/z 564(M+H) +
1H-NMR(CD 3OD)δ:7.05-7.04(m,1H),7.03-6.77(m,2H),6.67-6.66(m,1H),6.30(d,J＝12.3Hz,1H),5.85(dd,J＝7.8Hz,1H),5.12-5.03(m,1H),4.56-4.40(m,2H),4.43-4.40(m,2H),4.39-4.20(m,2H),3.98-3.80(m,2H),3.77(s,3H),3.75-3.62(m,1H),3.52-3.47(m,1H),3.35-3.25(m,3H),3.11-2.97(m,3H),2.95-2.91(m,2H),2.70-2.60(m,4H),2.20-2.10(m,1H),2.05-1.89(m,4H),1.85-1.75(m,1H). 1 H-NMR (CD 3 OD)δ: 7.05-7.04 (m, 1H), 7.03-6.77 (m, 2H), 6.67-6.66 (m, 1H), 6.30 (d, J=12.3Hz, 1H), 5.85(dd,J=7.8Hz,1H),5.12-5.03(m,1H),4.56-4.40(m,2H),4.43-4.40(m,2H),4.39-4.20(m,2H),3.98- 3.80(m,2H),3.77(s,3H),3.75-3.62(m,1H),3.52-3.47(m,1H),3.35-3.25(m,3H),3.11-2.97(m,3H), 2.95-2.91 (m, 2H), 2.70-2.60 (m, 4H), 2.20-2.10 (m, 1H), 2.05-1.89 (m, 4H), 1.85-1.75 (m, 1H).
试验例1 蛋白共价加成反应产物检测Test Example 1 Detection of protein covalent addition reaction product
取3uM待测化合物与2uM GDP-His-KRAS-G12C蛋白复合物于反应缓冲液中(12.5mM HEPES,pH7.5,75mM NaCl,1mM MgCl 2)在室温条件下分别孵育5和30分钟，之后用终浓度为5％的甲酸终止反应。样品经15,000转离心10分钟后取上清进入Waters Acquity I Class仪器分析，分别检测His-KRAS-G12C，及与化合物发生共价结合的His-KRAS-G12C复合物的相对含量。 Take 3uM test compound and 2uM GDP-His-KRAS-G12C protein complex in reaction buffer (12.5mM HEPES, pH7.5, 75mM NaCl, 1mM MgCl 2 ) and incubate at room temperature for 5 and 30 minutes, respectively. The reaction was terminated with formic acid at a final concentration of 5%. The sample was centrifuged at 15,000 rpm for 10 minutes, and the supernatant was taken into the Waters Acquity I Class instrument for analysis. The relative content of His-KRAS-G12C and the His-KRAS-G12C complex covalently bound to the compound were detected respectively.
按如下公式分别计算孵育5和30分钟后化合物与KRAS-G12C蛋白的结合量(POC值，percent of control)：Calculate the binding amount (POC value, percent of control) between the compound and KRAS-G12C protein after incubation for 5 and 30 minutes according to the following formula:
POC，％＝蛋白与化合物加成反应后复合体的峰值/(蛋白与化合物加成反应后复合体的峰值+蛋白的峰值)×100POC,% = the peak value of the complex after the addition reaction of the protein and the compound/(the peak value of the complex after the addition reaction of the protein and the compound + the peak value of the protein)×100
实施例化合物的测试结果如表1所示。The test results of the example compounds are shown in Table 1.
表1：化合物与KRAS-G12C蛋白的结合量Table 1: The binding capacity of the compound and KRAS-G12C protein
Figure PCTCN2020119633-appb-000172
Figure PCTCN2020119633-appb-000172
Figure PCTCN2020119633-appb-000173
Figure PCTCN2020119633-appb-000173
注：+代表30％≤POC值＜50％；Note: + means 30%≤POC value＜50%;
++代表50％≤POC值＜80％；++ means 50%≤POC value＜80%;
+++代表POC值≥80％。+++ represents POC value ≥ 80%.
试验例2 KRAS-G12C抑制活性Test Example 2 KRAS-G12C inhibitory activity
1.ERK蛋白磷酸化检测1. ERK protein phosphorylation detection
将表达KRAS-G12C蛋白的H358细胞(ATCC,CRL-5807)或MIA PaCa-2(ATCC，CRL-1420)按6000个细胞每孔接种于多聚赖氨酸包被的384孔细胞培养板中(Corning，BD356663)，培养基成分为RPMI1640(Gibco，A10491-01)，10％FBS(Gibco，10099141C)和1％Pen/Strep(Gibco，15140-122)，于5％二氧化碳细胞培养箱中培养16小时；用Echo550将梯度稀释的化合物加入到细胞培养基中，DMSO终浓度为0.5％，继续培养3小时；之后加入40uL/孔的8％多聚甲醛(Solarbio，P1112)，室温孵育20分钟；PBS洗一次后加入40uL/孔冷的100％甲醇，室温下渗透10分钟；PBS洗一次后加入20uL/孔的封闭液(LI-COR，927-40000)，室温封闭1小时；之后用封闭液按1:1000稀释兔抗phospho-p44/42MAPK(T202/Y204)抗体(CST，4370S)，按1:2000稀释鼠抗GAPDH(D4C6R)抗体(CST，97166S)，按20uL/孔加入细胞中，于4度封闭过夜；PBST洗3次，每次孵育2分钟，之后用封闭液按1:1000稀释羊抗兔800CW抗体(LI-COR，926-32211)和羊抗鼠680RD抗体(LI-COR，926-68070)，按20uL/孔加入细胞中，室温下孵育45分钟；PBST洗3次，每次孵育2分钟，最后将细胞培养板倒扣离心，1000rpm，1分钟，之后用Odyssey CLx读取荧光信号值。Inoculate H358 cells (ATCC, CRL-5807) or MIA PaCa-2 (ATCC, CRL-1420) expressing KRAS-G12C protein in a 384-well cell culture plate coated with polylysine at 6000 cells per well (Corning, BD356663), the medium components are RPMI1640 (Gibco, A10491-01), 10% FBS (Gibco, 10099141C) and 1% Pen/Strep (Gibco, 15140-122), cultured in a 5% carbon dioxide cell incubator 16 hours; use Echo550 to add the compounds diluted in gradients to the cell culture medium, the final concentration of DMSO is 0.5%, continue to incubate for 3 hours; then add 40uL/well of 8% paraformaldehyde (Solarbio, P1112), and incubate at room temperature for 20 minutes ; PBS wash once and add 40uL/well cold 100% methanol, permeate at room temperature for 10 minutes; PBS wash once, add 20uL/well blocking solution (LI-COR, 927-40000), block at room temperature for 1 hour; then block with Dilute the rabbit anti-phospho-p44/42MAPK (T202/Y204) antibody (CST, 4370S) at 1:1000, dilute the mouse anti-GAPDH (D4C6R) antibody (CST, 97166S) at 1:2000, and add 20uL/well to the cells Block overnight at 4°C; wash 3 times with PBST, incubate for 2 minutes each time, then dilute goat anti-rabbit 800CW antibody (LI-COR, 926-32211) and goat anti-mouse 680RD antibody (LI- COR, 926-68070), add 20uL/well to the cells, incubate at room temperature for 45 minutes; wash 3 times with PBST, incubate for 2 minutes each time, finally centrifuge the cell culture plate upside down, 1000rpm, 1 minute, and then use Odyssey CLx Read the fluorescence signal value.
数据由XLFit 5.0按4参数公式Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))拟合计算IC 50值。 According to data from the XLFit 5.0 four parameter equation Y = Bottom + (Top-Bottom ) / (1 + 10 ^ ((LogIC50-X) * HillSlope)) 50 fit values calculated IC.
实施例化合物的测试结果如表2所示。The test results of the example compounds are shown in Table 2.
表2：化合物ERK蛋白磷酸化检测结果Table 2: Test results of compound ERK protein phosphorylation
Figure PCTCN2020119633-appb-000174
Figure PCTCN2020119633-appb-000174
Figure PCTCN2020119633-appb-000175
Figure PCTCN2020119633-appb-000175
注：A代表IC 50≤50nM； Note: A represents IC 50 ≤50nM;
B代表50nM＜IC 50≤150nM； B represents 50nM＜IC 50 ≤150nM;
C代表150nM＜IC 50≤500nM； C represents 150nM＜IC 50 ≤500nM;
D代表500nM＜IC 50≤999nM； D represents 500nM＜IC 50 ≤999nM;
——代表IC 50值未检测。 ——The IC 50 value has not been tested.
2.细胞增殖抑制检测2. Detection of cell proliferation inhibition
用Echo550将梯度稀释的化合物加入到低吸附圆底384孔细胞培养板中(Corning，CLS3830-50EA)，每孔加入40uL含400个H358或MIA PaCa-2细胞的悬液，于37S℃,5％二氧化碳细胞培养箱中继续培养3天；提前一天将3D CellTiter-Glo试剂(Promega，G9683)放入4度冰箱融化，使用前放入室温平衡30分钟，按每孔20uL加入细胞培养板中，100rpm，30分钟后室温下静置2小时，用Envision 2104读取luminescence信号值。Use Echo550 to add the gradiently diluted compounds to a low-adsorption round-bottomed 384-well cell culture plate (Corning, CLS3830-50EA), add 40uL to each well of a suspension containing 400 H358 or MIA PaCa-2 cells at 37S℃, 5 Continue to culture for 3 days in a %CO2 cell incubator; put 3D CellTiter-Glo reagent (Promega, G9683) in a 4 degree refrigerator one day in advance to melt, put it at room temperature for 30 minutes before use, and add 20uL per well to the cell culture plate. 100rpm, after 30 minutes, let it stand at room temperature for 2 hours, and use Envision 2104 to read the luminescence signal value.
数据由XLFit 5.0按4参数公式Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))拟合计算IC 50值。 According to data from the XLFit 5.0 four parameter equation Y = Bottom + (Top-Bottom ) / (1 + 10 ^ ((LogIC50-X) * HillSlope)) 50 fit values calculated IC.
实施例化合物的测试结果如表3所示。The test results of the example compounds are shown in Table 3.
表3：化合物细胞增殖抑制检测结果Table 3: Test results of compound cell proliferation inhibition
Figure PCTCN2020119633-appb-000176
Figure PCTCN2020119633-appb-000176
注：A代表IC 50≤50nM； Note: A represents IC 50 ≤50nM;
B代表50nM＜IC 50≤150nM； B represents 50nM＜IC 50 ≤150nM;
C代表150nM＜IC 50≤500nM； C represents 150nM＜IC 50 ≤500nM;
D代表500nM＜IC 50≤999nM。 D represents 500nM<IC 50 ≤999nM.
试验例3 药代动力学实验Test Example 3 Pharmacokinetic experiment
1.肝微粒体代谢稳定性实验1. Metabolic stability test of liver microsomes
1)按照下表配制反应体系1) Prepare the reaction system according to the following table
Figure PCTCN2020119633-appb-000177
Figure PCTCN2020119633-appb-000177
2)将该反应体系放在37℃水浴中预孵育10分钟。向反应体系中加入40μL 10mM NADPH溶液，NADPH的最终浓度分别为1mM。用40μL超纯水代替NADPH溶液作为阴性对照。阴性对照的作用是排除化合物自身化学稳定性的影响。2) Pre-incubate the reaction system in a 37°C water bath for 10 minutes. Add 40μL of 10mM NADPH solution to the reaction system, the final concentration of NADPH is 1mM respectively. Use 40μL ultrapure water instead of NADPH solution as a negative control. The role of the negative control is to exclude the influence of the chemical stability of the compound itself.
3)向反应体系中加入4μL的200μM的待测化合物启动反应，药物最终浓度为2μM。3) Add 4 μL of 200 μM test compound to the reaction system to start the reaction, and the final concentration of the drug is 2 μM.
4)在0，15，30，45和60分钟分别取出50μL反应样品，用4倍的含有内标(200nM阿普***、200nM拉贝洛尔、2μM酮洛芬、200nM咖啡因)的冷乙腈淬灭。样品在3,220g转速下离心45分钟。离心完成后取90μL上清液和90μL超纯水混匀用于LC-MS/MS分析检测。4) Take out 50μL reaction samples at 0, 15, 30, 45 and 60 minutes, and use 4 times the cold containing internal standard (200nM alprazolam, 200nM labetalol, 2μM ketoprofen, 200nM caffeine). Acetonitrile quenched. The sample was centrifuged at 3,220g for 45 minutes. After centrifugation, take 90μL of supernatant and 90μL of ultrapure water and mix it for LC-MS/MS analysis and detection.
实施例66化合物的测试结果如表4所示。The test results of the compound of Example 66 are shown in Table 4.
表4：化合物肝微粒体稳定性实验结果Table 4: Results of stability test of compound liver microsomes
Figure PCTCN2020119633-appb-000178
Figure PCTCN2020119633-appb-000178
2.血浆稳定性实验2. Plasma stability test
代表性实施例化合物的测试结果如表5所示。The test results of representative example compounds are shown in Table 5.
表5：化合物小鼠血浆稳定性实验结果Table 5: Experimental results of compound mouse plasma stability
Figure PCTCN2020119633-appb-000179
Figure PCTCN2020119633-appb-000179

Claims (11)

  1. 式(I)化合物或其药学上可接受的盐，The compound of formula (I) or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2020119633-appb-100001
    Figure PCTCN2020119633-appb-100001
    其中，among them,
    q为0时，p为2，
    Figure PCTCN2020119633-appb-100002
    选自单键；     When q is 0, p is 2,
    Figure PCTCN2020119633-appb-100002
    Selected from single bond;
    或者，当q为1时，p为1，
    Figure PCTCN2020119633-appb-100003
    选自单键或双键；     Or, when q is 1, p is 1,
    Figure PCTCN2020119633-appb-100003
    Selected from single bond or double bond;
    或者，当q为2时，p为0，且
    Figure PCTCN2020119633-appb-100004
    选自单键；     Or, when q is 2, p is 0, and
    Figure PCTCN2020119633-appb-100004
    Selected from single bond;
    当
    Figure PCTCN2020119633-appb-100005
    选自双键时，R 4和/或R 6不存在；     when
    Figure PCTCN2020119633-appb-100005
    When selected from a double bond, R 4 and/or R 6 are not present;
    A部分选自
    Figure PCTCN2020119633-appb-100006
    其中，R选自H或C 1-6烷基；     Part A is selected from
    Figure PCTCN2020119633-appb-100006
    Wherein, R is selected from H or C 1-6 alkyl;
    或者，A-R 2部分共同选自
    Figure PCTCN2020119633-appb-100007
    Or, the AR 2 part is jointly selected from
    Figure PCTCN2020119633-appb-100007
    Figure PCTCN2020119633-appb-100008
    为至少含有两个N原子的4-10元杂环烷基；
    Figure PCTCN2020119633-appb-100009
    为至少含有一个N原子的4-7元杂环烷基；
    Figure PCTCN2020119633-appb-100008
    Is a 4-10 membered heterocycloalkyl containing at least two N atoms;
    Figure PCTCN2020119633-appb-100009
    Is a 4-7 membered heterocycloalkyl containing at least one N atom;
    每个R 1取代在环上，其独立地选自卤素、氧代、-OH、-NH 2、-CN、或任选地被1、2或3个R 0取代的如下基团：C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、或二C 1-6烷基氨基； Each R 1 is substituted on the ring, which is independently selected from halogen, oxo, -OH, -NH 2 , -CN, or the following groups optionally substituted with 1, 2 or 3 R 0 : C 1 -6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, or di-C 1-6 alkylamino;
    每个R 0独立地选自卤素、-OH、-NH 2、-CN、C 1-4烷氧基、C 1-4烷基氨基、或二C 1-4烷基氨基； Each R 0 is independently selected from halogen, -OH, -NH 2 , -CN, C 1-4 alkoxy, C 1-4 alkylamino, or di-C 1-4 alkylamino;
    m是0、1、2、3、4、5或6；m is 0, 1, 2, 3, 4, 5 or 6;
    每个R 2独立地选自C 1-6烷基羰基、卤代C 1-6烷基羰基、C 1-6烷氧基羰基、C 1-6烷基磺酰基、-C(O)C≡CR b、-SO 2C≡CR b、-C(O)C(R a)＝C(R b) 2、或-SO 2C(R a)＝C(R b) 2； Each R 2 is independently selected from C 1-6 alkylcarbonyl, halogenated C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylsulfonyl, -C(O)C ≡CR b , -SO 2 C≡CR b , -C(O)C(R a )=C(R b ) 2 , or -SO 2 C(R a )=C(R b ) 2 ;
    每个R a独立地选自H、卤素、或C 1-4烷基； Each R a is independently selected from H, halo, or C 1-4 alkyl;
    每个R b独立地选自H或任选地被1、2或3个R c取代的如下基团：C 1-6烷基、C 1-4烷氧基C 1-3烷基、C 1-4烷基氨基C 1-3烷基、二C 1-4烷基氨基C 1-3烷基、3-7元环烷基C 1-3烷基、4-7元杂环烷基C 1-3烷基； Each R b is independently selected from H or the following groups optionally substituted with 1, 2 or 3 R c : C 1-6 alkyl, C 1-4 alkoxy C 1-3 alkyl, C 1-4 alkylamino C 1-3 alkyl, di-C 1-4 alkylamino C 1-3 alkyl, 3-7 membered cycloalkyl C 1-3 alkyl, 4-7 membered heterocycloalkyl C 1-3 alkyl;
    每个R c独立地选自卤素、-OH、-NH 2、-CN、C 1-6烷基、C 1-6烷氧基、或卤代C 1-6烷基； Each R c is independently selected from halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 alkoxy, or halo C 1-6 alkyl;
    X选自单键、-S-、-O-、-NH-、或-N(C 1-3烷基)-； X is selected from a single bond, -S-, -O-, -NH-, or -N(C 1-3 alkyl)-;
    R 3选自H或任选地被1、2、3或4个R d取代的如下基团：C 1-6烷基、3-7元环烷基、4-7元杂环烷基、5-6元杂芳基、苯基、苯并4-6元杂环基、4-7元杂环烷基C 1-3烷基、或5-6元杂芳基C 1-3烷基； R 3 is selected from H or the following groups optionally substituted with 1, 2, 3 or 4 R d : C 1-6 alkyl, 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl, benzo 4-6 membered heterocyclic group, 4-7 membered heterocycloalkyl C 1-3 alkyl, or 5-6 membered heteroaryl C 1-3 alkyl ；
    每个R d独立地选自卤素、-OH、氧代、-NH 2、-CN、C 1-4烷基、C 1-4烷氧基、C 1-4烷基氨 基、二C 1-4烷基氨基、3-7元环烷基、4-7元杂环烷基、4-7元杂环烷基C 1-3烷基，其中，所述C 1-4烷基氨基、二C 1-4烷基氨基任选地被选自1个或2个氰基或5-6元杂芳基的取代基取代； Each R d is independently selected from halogen, -OH, oxo, -NH 2 , -CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, di-C 1- 4 alkylamino, 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, 4-7 membered heterocycloalkyl C 1-3 alkyl, wherein the C 1-4 alkyl amino, two The C 1-4 alkylamino group is optionally substituted with a substituent selected from 1 or 2 cyano groups or 5-6 membered heteroaryl groups;
    Y选自单键、-CH 2-、或羰基； Y is selected from a single bond, -CH 2 -, or a carbonyl group;
    B选自任选地被1、2、3、4、5或6个R e取代的苯基、萘基、5-6元杂芳基、苯并5-6元环烯基、苯并5-6元杂环基、或苯并5-6元杂芳基； B is selected from phenyl, naphthyl, 5-6 membered heteroaryl, benzo5-6 membered cycloalkenyl, benzo5 optionally substituted with 1, 2, 3, 4, 5 or 6 R e -6 membered heterocyclic group, or benzo 5-6 membered heteroaryl group;
    每个R e独立地选自卤素、-CN、-OH、-NH 2、C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6烷基氨基、二C 1-6烷基氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、卤代C 1-6烷硫基、卤代C 1-6烷基氨基、二(卤代C 1-6烷基)氨基，或任选地被1、2或3个R e1取代的如下基团：3-7元环烷基、3-7元环烷基C 1-3烷基、4-7元杂环烷基、4-7元杂环烷基C 1-3烷基； Each R e is independently selected from halogen, -CN, -OH, -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino , Two C 1-6 alkylamino, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, halogenated C 1-6 alkylthio, halogenated C 1-6 alkylamino, two (Halo C 1-6 alkyl) amino group, or the following group optionally substituted with 1, 2 or 3 R e1 : 3-7 membered cycloalkyl, 3-7 membered cycloalkyl C 1-3 Alkyl, 4-7 membered heterocycloalkyl, 4-7 membered heterocycloalkyl C 1-3 alkyl;
    每个R e1独立地选自卤素、-CN、-OH、-NH 2、C 1-4烷基、卤代C 1-4烷基、C 1-4烷氧基、C 1-4烷基氨基、二C 1-4烷基氨基； Each R e1 is independently selected from halogen, -CN, -OH, -NH 2 , C 1-4 alkyl, halo C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkyl Amino, di-C 1-4 alkylamino;
    R 4、R 5独立地选自H、卤素、-OH、-NH 2、-CN、C 1-6烷基、C 1-6烷氧基、或卤代C 1-6烷基，或者，R 4和R 5一起形成羰基、3～6元环烷基或4～6元杂环烷基； R 4 and R 5 are independently selected from H, halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 alkoxy, or halogenated C 1-6 alkyl, or, R 4 and R 5 together form a carbonyl group, a 3-6 membered cycloalkyl group or a 4-6 membered heterocycloalkyl group;
    R 6、R 7独立地选自H、卤素、-OH、-NH 2、-CN、C 1-6烷基、C 1-6烷氧基、或卤代C 1-6烷基，或者，R 6和R 7一起形成羰基、3～6元环烷基或4～6元杂环烷基， R 6 and R 7 are independently selected from H, halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 alkoxy, or halogenated C 1-6 alkyl, or, R 6 and R 7 together form a carbonyl group, a 3-6 membered cycloalkyl group or a 4-6 membered heterocycloalkyl group,
    条件是所述式(I)化合物不是Provided that the compound of formula (I) is not
    Figure PCTCN2020119633-appb-100010
    Figure PCTCN2020119633-appb-100010
    Figure PCTCN2020119633-appb-100011
    Figure PCTCN2020119633-appb-100011
  2. 如权利要求1所述的式(I)化合物或其药学上可接受的盐，其特征在于，A-R 2部分 共同选自
    Figure PCTCN2020119633-appb-100012
    其中，R选自H、或C 1-6烷基。     The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the AR 2 part is jointly selected from
    Figure PCTCN2020119633-appb-100012
    Wherein, R is selected from H or C 1-6 alkyl.
  3. 如权利要求1-2任一项所述的式(I)化合物或其药学上可接受的盐，其特征在于，所述R 1独立地选自卤素、氧代、-OH、-NH 2、-CN、或任选地被1、2或3个R 0取代的如下基团：C 1-4烷基、C 1-4烷氧基、C 1-4烷基氨基、或二C 1-4烷基氨基，其中，R 0独立地选自卤素、-OH、-NH 2、-CN、C 1-3烷氧基、C 1-3烷基氨基、或二C 1-3烷基氨基。 The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, wherein said R 1 is independently selected from halogen, oxo, -OH, -NH 2 , -CN, or the following groups optionally substituted with 1, 2 or 3 R 0 : C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, or di-C 1- 4 Alkylamino, wherein R 0 is independently selected from halogen, -OH, -NH 2 , -CN, C 1-3 alkoxy, C 1-3 alkylamino, or di-C 1-3 alkylamino .
  4. 如权利要求1-3任一项所述的式(I)化合物或其药学上可接受的盐，其特征在于，所述R 2选自如下基团：
    Figure PCTCN2020119633-appb-100013
    Figure PCTCN2020119633-appb-100014
    The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein the R 2 is selected from the following groups:
    Figure PCTCN2020119633-appb-100013
    Figure PCTCN2020119633-appb-100014
  5. 如权利要求1-4任一项所述的式(I)化合物或其药学上可接受的盐，其特征在于，所述R 3选自任选地被1、2、3或4个R d取代的如下基团：4-7元杂环烷基、5-6元杂芳基、4-7元杂环烷基C 1-3烷基、或5-6元杂芳基C 1-3烷基；优选的，R 3选自H或任选地被1、2、3或4个R d取代的如下基团：四氢吡咯甲基、四氢吡咯乙基、四氢吡咯丙基、吗啉丙基、
    Figure PCTCN2020119633-appb-100015
    The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein the R 3 is selected from the group consisting of 1, 2, 3, or 4 R d. The following groups are substituted: 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl C 1-3 alkyl, or 5-6 membered heteroaryl C 1-3 Alkyl; preferably, R 3 is selected from H or the following groups optionally substituted with 1, 2, 3 or 4 Rd : tetrahydropyrrole methyl, tetrahydropyrrolyl ethyl, tetrahydropyrrolyl propyl, Morpholine propyl,
    Figure PCTCN2020119633-appb-100015
  6. 如权利要求1-5任一项所述的式(I)化合物或其药学上可接受的盐，其特征在于，所述R 3选自H、
    Figure PCTCN2020119633-appb-100016
    Figure PCTCN2020119633-appb-100017
    Figure PCTCN2020119633-appb-100018
    The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein said R 3 is selected from H,
    Figure PCTCN2020119633-appb-100016
    Figure PCTCN2020119633-appb-100017
    Figure PCTCN2020119633-appb-100018
  7. 如权利要求1-6任一项所述的式(I)化合物或其药学上可接受的盐，其特征在于，B选自
    Figure PCTCN2020119633-appb-100019
    Figure PCTCN2020119633-appb-100020
    Figure PCTCN2020119633-appb-100021
    The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-6, wherein B is selected from
    Figure PCTCN2020119633-appb-100019
    Figure PCTCN2020119633-appb-100020
    Figure PCTCN2020119633-appb-100021
  8. 如权利要求1-7任一项所述的式(I)化合物或其药学上可接受的盐，其选自如下通式所示的化合物或其药学上可接受的盐，The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-7, which is selected from the compound represented by the following general formula or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2020119633-appb-100022
    Figure PCTCN2020119633-appb-100022
    其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、X、m、A和B部分如上权利要求1-10所定义。 Wherein, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X, m, A and B are as defined in claims 1-10 above.
  9. 如权利要求1-8任一项所述的式(I)化合物或其药学上可接受的盐，其选自以下化合物或其药学上可接受的盐，The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-8, which is selected from the following compounds or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2020119633-appb-100023
    Figure PCTCN2020119633-appb-100023
    Figure PCTCN2020119633-appb-100024
    Figure PCTCN2020119633-appb-100024
    Figure PCTCN2020119633-appb-100025
    Figure PCTCN2020119633-appb-100025
    Figure PCTCN2020119633-appb-100026
    Figure PCTCN2020119633-appb-100026
  10. 药物组合物，其包含如权利要求1-9任一项所述的化合物或其药学上可接受的盐。A pharmaceutical composition comprising the compound according to any one of claims 1-9 or a pharmaceutically acceptable salt thereof.
  11. 一种治疗哺乳动物KRas G12C相关疾病的方法，包括对需要该治疗的哺乳动物，优选人类，给予治疗有效量的权利要求1-9任一项所述的化合物或其药学上可接受的盐、或权利要求10所述的药物组合物。A method for treating KRas G12C-related diseases in mammals, comprising administering a therapeutically effective amount of the compound according to any one of claims 1-9 or a pharmaceutically acceptable salt thereof to a mammal in need of the treatment, preferably a human, Or the pharmaceutical composition of claim 10.
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