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WO2023174383A1 - Dihydroisoquinoline compound and medical use thereof - Google Patents

Dihydroisoquinoline compound and medical use thereof Download PDF

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Publication number
WO2023174383A1
WO2023174383A1 PCT/CN2023/081999 CN2023081999W WO2023174383A1 WO 2023174383 A1 WO2023174383 A1 WO 2023174383A1 CN 2023081999 W CN2023081999 W CN 2023081999W WO 2023174383 A1 WO2023174383 A1 WO 2023174383A1
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Prior art keywords
substituted
unsubstituted
alkyl
group
membered
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PCT/CN2023/081999
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French (fr)
Chinese (zh)
Inventor
段文虎
耿美玉
詹正生
谢作权
姚珊燕
王玺渊
周晓倩
张燕
周鸿飞
丁健
Original Assignee
中国科学院上海药物研究所
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Priority to CN202380019535.0A priority Critical patent/CN118742543A/en
Publication of WO2023174383A1 publication Critical patent/WO2023174383A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/40—Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/572—Five-membered rings

Definitions

  • the present invention belongs to the field of medicinal chemistry and drug therapy, specifically relates to dihydroisoquinoline compounds and their medicinal uses, and also relates to pharmaceutical compositions of the compounds and their use as secretion regulators of type I interferon, especially as cGAS Use of targeted inhibitors of /STING signaling pathway in preparing drugs for preventing and/or treating inflammatory diseases and autoimmune diseases.
  • TMEM173 transmembrane protein 173
  • MPYS MPYS
  • MITA transmembrane protein 173
  • ERIS ERIS
  • cGAMP cyclic GMP-AMP synthase
  • STNG stimulator of interferon genes
  • IRF3 phosphorylating interferon regulatory factor 3
  • the cGAS/STING signaling pathway can be precisely regulated through physiological processes and pharmaceutical methods, including protein post-translational modifications (phosphorylation, ubiquitination, etc.), small molecule antagonists (such as H-151, C-176) and agonists (such as DMXAA, MSA-2).
  • protein post-translational modifications phosphorylation, ubiquitination, etc.
  • small molecule antagonists such as H-151, C-176) and agonists (such as DMXAA, MSA-2).
  • agonists Such as DMXAA, MSA-2
  • DMXAA lupus erythematosus
  • the purpose of the present invention is to provide a highly active and druggable small molecule inhibitor targeting the cGAS/STING signaling pathway, which can be used as a therapeutic drug for autoimmune diseases.
  • the first aspect of the present invention provides a compound represented by formula (I), or its prodrug, its enantiomers, diastereomers, racemates and mixtures thereof, or its pharmaceutical acceptable salt,
  • Q is selected from O or S;
  • Ring A is selected from the group consisting of substituted or unsubstituted groups: C6-C12 aryl and 5-12 membered heteroaryl; wherein said substitution means substitution by 1-5 R 1 ; wherein each R 1 is independently Selected from: hydrogen, halogen, carboxyl, hydroxyl, cyano, amino, -COOC1-C6 alkyl, nitro, -CO (3-8-membered substituted or unsubstituted heterocyclyl), -CO (C3-C8 substituted or Unsubstituted cycloalkyl), substituted or unsubstituted C6-C12 aryl C1-C6 alkyl, substituted or unsubstituted 5-12 membered heteroaryl C1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl , substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl,
  • E is NR 10 or CR 10 R 10' ;
  • R 10 is selected from: COOC1-C6 alkyl, -CO (3-8-membered substituted or unsubstituted heterocyclyl), -CO (C3-C8 substituted or unsubstituted cycloalkyl), substituted or unsubstituted C6-C12 Aryl C1-C6 alkyl, substituted or unsubstituted 5-12 membered heteroaryl C1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylacyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted C1-C6 alkylamide, substituted or Unsubstituted C1-
  • R 10' , R g , R g' , Rh, Rh ' , R i , R i' , R j and R j' are each independently selected from: hydrogen, halogen, carboxyl, hydroxyl, cyano, amino, -COOC1-C6 alkyl, nitro, -CO (3-8-membered substituted or unsubstituted heterocyclyl), -CO (C3-C8 substituted or unsubstituted cycloalkyl), substituted or unsubstituted C6-C12 aromatic Base C1-C6 alkyl, substituted or unsubstituted 5-12 membered heteroaryl C1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2 -C6 alkynyl, substituted or unsubstituted C1-C6 al
  • Ra is selected from: halogen, carboxyl, hydroxyl, cyano, nitro, amino, -COOC1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2 -C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylacyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted C1-C6 alkylamide, substituted or unsubstituted Substituted C1-C4 alkylamino, substituted or unsubstituted C6-C12 arylamino, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted
  • n 1 or 2.
  • Ra is selected from: halogen, carboxyl, hydroxyl, cyano, nitro, amino, -COOC1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkene group, substituted or unsubstituted C2-C6 alkynyl group, substituted or unsubstituted C1-C6 alkoxy group, substituted or unsubstituted C1-C6 alkyl acyl group, substituted or unsubstituted carbamoyl group, substituted or unsubstituted C1-C6 alkyl group amide group, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C6-C12 arylamino, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted C3-C8 cycloal
  • each R 1 is independently selected from: hydrogen, halogen, carboxyl, hydroxyl, cyano, amino, nitro, Substituted or unsubstituted benzyl.
  • ring A is selected from the following substituted or unsubstituted groups: five-membered heteroaryl, six-membered aryl, six-membered heteroaryl, [6+6]aryl or fused ring, [ 6+6]heteroaryl or fused ring, [6+5]heteroaryl or fused ring, [5+6]heteroaryl or fused ring, [5+5]heteroaryl or fused ring, where, The substitution refers to substitution by 1-5 R 1 ; wherein, each R 1 is independently selected from: hydrogen, halogen, carboxyl, hydroxyl, cyano, amino, -COOC1-C6 alkyl, nitro, -CO(3 -8-membered substituted or unsubstituted heterocyclyl), -CO (C3-C8 substituted or unsubstituted cycloalkyl), substituted or unsubstituted C6-C12 ary
  • substitution mentioned in R 1 refers to being substituted by one or more groups selected from the following group: halogen, carboxyl, -OP(O)(OH) 2 , hydroxyl, cyano group, amino group, Nitro, benzyl, C1-C6 alkyl OH, C1-C6 alkylamino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C10 aryl or 5-10 membered heteroaryl.
  • substitution described in R 1 refers to substitution by one or more groups selected from the following group: halogen, carboxyl, hydroxyl, cyano, amino, nitro, trifluoromethoxy, benzyl Base, HOCH 2 -, HOCH 2 CH 2 -, CF 2 CH-, CF 3 CH 2 CH 2 -, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl or 3-8 membered hetero ring base.
  • R g and R h together with the C atom to which they are connected form a substituted or unsubstituted 5-12-membered heteroaryl group or a substituted or unsubstituted C6-C12 aryl group, R g' and R h ' for non-existence.
  • R i and R j together with the C atoms to which they are connected form a substituted or unsubstituted 5-12-membered heteroaryl group or a substituted or unsubstituted C6-C12 aryl group, R i' and R j ' for non-existence.
  • R i and R 10 together with the C atom to which they are connected form a substituted or unsubstituted 5-12-membered heteroaryl group or a substituted or unsubstituted C6-C12 aryl group, R i' and R 10 ' for non-existence.
  • R h and R 10 together with the C atom to which they are connected form a substituted or unsubstituted 5-12-membered heteroaryl group or a substituted or unsubstituted C6-C12 aryl group, R h' and R 10 ' for non-existence.
  • Ra is selected from: halogen, carboxyl, hydroxyl, cyano, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted COOC1-C6 alkyl, substituted or unsubstituted CO-4-6 membered heterocyclyl, substituted or unsubstituted C6-C10 aryl base, substituted or unsubstituted 5-10-membered heteroaryl (preferably 5-6-membered or 9-10-membered, such as furyl, thienyl, pyridyl, pyrrolyl, pyrazolyl, imidazolyl, benzofuranyl , benzothienyl, pyridopyrazolyl), take Sub
  • Ring A is a substituted or unsubstituted [6+5] heteroaryl or fused ring, wherein said substitution means substitution by 1-5 R 1 ; preferably substituted or unsubstituted indolyl, more preferably substituted or unsubstituted Among them, R 1 is defined as above.
  • Ring A is selected from the following structures:
  • X is selected from: O, S, N or NH;
  • R 1 is a substituent at any position on the ring, the number is 1-5 (for example, 1, 2, 3 or 4), each R 1 is independently selected from: hydrogen, halogen, carboxyl, hydroxyl, cyano, amino , nitro, Substituted or unsubstituted benzyl, substituted or unsubstituted C6-C12 arylmethyl, substituted or unsubstituted 5-12 membered heteroarylmethyl, substituted or unsubstituted heteroarylmethyl, substituted or unsubstituted Substituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkyl acyl, substituted Or unsubstituted aminoacyl, substituted or unsubstituted C1
  • Ring A is selected from the following structures:
  • X is selected from NH;
  • R 1 is a substituent at any position on the ring, and the number is 1, 2 or 3.
  • R 1 is as defined above.
  • R 1 is selected from: hydrogen, halogen, cyano, C1-C6 alkyl, Halogenated C1-C6 alkyl, C1-C6 alkoxy, C6-C12 aryl, C6-C12 aryl NH, -OP(O)(OH) 2 substituted C1-C6 alkyl, amino C1-C6 alkyl C1-C6 alkyl substituted by COO; more preferably, R 1 is selected from: trifluoromethyl, phenyl, phenylamino, cyano, methoxy, Cl, F, Br, In another preferred example, Ring B is selected from the following structures:
  • M is N or CH
  • R 4 is selected from: halogen, carboxyl, hydroxyl, cyano, nitro, amino, -COOC1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylacyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted C1-C6 alkylamide, substituted or Unsubstituted C1-C4 alkylamino, substituted or unsubstituted C6-C12 arylamino, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstitute
  • R 10 is selected from: COOC1-C6 alkyl, -CO (3-8-membered substituted or unsubstituted heterocyclyl), -CO (C3-C8 substituted or unsubstituted cycloalkyl), substituted or unsubstituted C6-C12 Aryl C1-C6 alkyl, substituted or unsubstituted 5-12 membered heteroaryl C1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkyl acyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted C1-C6 alkylamide, substituted or unsubstituted Substitute
  • R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 9 are each independently selected from: H, halogen, carboxyl, hydroxyl, cyano, nitro, amino, -COOC1-C6 alkyl, substituted Or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkyl acyl , substituted or unsubstituted carbamoyl, substituted or unsubstituted C1-C6 alkylamido, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C6-C12 arylamino, substituted or unsubstituted 3-8 Membered heterocyclyl
  • R 2 and R 3 and the carbon atom to which they are connected form a substituted or unsubstituted phenyl group or a substituted or unsubstituted 5-8-membered heteroaryl group; wherein the substitution means being substituted by one or more selected from the following Group substitution of: halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyl OH, C1-C6 alkoxy or 3- 8-membered heterocyclyl;
  • R 3 and R 4 and the carbon atoms to which they are connected form a substituted or unsubstituted phenyl group or a substituted or unsubstituted 5-8-membered heteroaryl group; wherein the substitution means being substituted by one or more selected from the following Group substitution of: halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyl OH, C1-C6 alkoxy or 3- 8-membered heterocyclyl;
  • R 4 and R 5 and the carbon atoms to which they are connected form a substituted or unsubstituted phenyl group or a substituted or unsubstituted 5-8-membered heteroaryl group; wherein the substitution means being substituted by one or more selected from the following Group substitution of: halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyl OH, C1-C6 alkoxy or 3- 8-membered heterocyclyl;
  • R 6 and R 7 and the carbon atoms to which they are connected form a substituted or unsubstituted phenyl group or a substituted or unsubstituted 5-8 membered heteroaryl group; wherein the substitution means being substituted by one or more selected from the following Group substitution of: halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyl OH, C1-C6 alkoxy or 3- 8-membered heterocyclyl;
  • R 7 and R 8 and the carbon atom to which they are connected form a substituted or unsubstituted phenyl group or a substituted or unsubstituted 5-8 membered heteroaryl group; wherein the substitution means being substituted by one or more selected from the following Group substitution of: halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyl OH, C1-C6 alkoxy or 3- 8-membered heterocyclyl;
  • R 8 and R 9 and the carbon atom to which they are connected form a substituted or unsubstituted phenyl group or a substituted or unsubstituted 5-8 membered heteroaryl group; wherein the substitution means being substituted by one or more selected from the following Group substitution of: halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyl OH, C1-C6 alkoxy or 3- 8-membered heterocyclyl;
  • R a , R a' , R b , R b' , R c , R c' , R d , R d ' , R e , R e ' , R f , R f ' , R g , R g ' , R h , R h' , R i , R i' , R j and R j' are each independently selected from: hydrogen, halogen, carboxyl, hydroxyl, cyano, amino, -COOC1-C6 alkyl, nitro, -CO (3-8-membered substituted or unsubstituted heterocyclyl), -CO (C3-C8 substituted or unsubstituted cycloalkyl), substituted or unsubstituted C6-C12 aryl C1-C6 alkyl, substituted or unsubstituted 5-12 membered heteroaryl C1-C6 alkyl, substituted
  • Ring C is selected from: substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-8 membered heteroaryl, substituted or unsubstituted 6-12 membered aryl ;
  • the substitution refers to being substituted by one or more groups selected from the following group: halogen, carboxyl, hydroxyl, cyano, amino, nitro, benzyl, C1-C6 alkyl OH, C1-C6 alkyl amino group, C1-C6 alkyl group, halogenated C1-C6 alkyl group, C1-C6 alkoxy group, halogenated C1-C6 alkoxy group or 3-8 membered heterocyclyl group;
  • n 0, 1, 2, 3, 4 or 5;
  • n 1 or 2;
  • Ra is defined as above.
  • R a , R a' , R b , R b' , R c , R c ' , R d , R d' , Re , Re ' , R f , R f ' , R g , R g' , Rh , Rh ' , R i , R i' , R j , R j' are each independently selected from: hydrogen, halogen, carboxyl, hydroxyl, cyano, amino, nitro, Substituted or unsubstituted benzyl, substituted or unsubstituted C6-C12 arylmethyl, substituted or unsubstituted 5-12 membered heteroarylmethyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstit
  • R a and R a' are both oxygen atoms, they form a carbonyl group with the connected carbon atom; when R b and R b' are both oxygen atoms, they form a carbonyl group with the connected carbon atom.
  • R c and R c' are both oxygen atoms, they form a carbonyl group with the connected carbon atom; when R d and R d' are both oxygen atoms, they form a carbonyl group with the connected carbon atom; when R e and R When e' is an oxygen atom, it forms a carbonyl group with the connected carbon atom; when R f and R f' are both oxygen atoms, it forms a carbonyl group with the connected carbon atom; when R g and R g' are both oxygen atoms When R h and R h' are oxygen atoms, they form a carbonyl group with the connected carbon atom; when R h and R h' are both oxygen atoms, they form a carbonyl group with the connected carbon atom; when R i and R i' are both oxygen atoms, they form a carbonyl group with the connected carbon atom. Carbon atoms constitute a carbonyl group; when R j and R j' are
  • Ring B is selected from the following structures:
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R a , R a' , R b , R b' , R c , R c' , R g , R g' , Rh , Rh ' , R i , R i' , R j , R j' and n are defined as above.
  • R 4 is selected from: halogen, carboxyl, hydroxyl, cyano, amino, nitro, Substituted or unsubstituted benzyl, substituted or unsubstituted arylmethyl, substituted or unsubstituted heteroarylmethyl, substituted or unsubstituted heteroarylmethyl, substituted or unsubstituted C1-C6 alkyl, Substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkyl acyl, substituted or unsubstituted aminoacyl, substituted Or unsubstituted C1-C6 alkylamido, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted 6-12 membered
  • R 4 is selected from: halogen, hydroxyl, carboxyl, nitro, Cyano, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 5-8 membered heteroaryl, phenyl, naphthyl, C3-C8 cycloalkyl, 3 -8-membered heterocyclyl; wherein, the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 5-8-membered heteroaryl, phenyl, naphthyl, C3-C8 cycloalkyl and 3-8 membered heterocyclyl are optionally substituted by 1-3 of the following groups: halogen, hydroxyl, carboxyl, ester group, cyano group, SO 2 C1-C6 alkyl, CO 2 C1 -C6 alkyl, C1-C
  • R 10 is selected from: C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 5-8 membered heteroaryl, phenyl, naphthyl , C3-C8 cycloalkyl, 3-8 membered heterocyclyl; wherein, the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 5-8 membered heterocyclic group Aryl, phenyl, naphthyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl are optionally substituted by 1-3 of the following groups: halogen, hydroxyl, carboxyl, ester group, cyano group, C1- C6 alkyl, halogenated C1-C6 alkyl.
  • the compound has the structure represented by formulas II-1 to II-3
  • G is a 6-membered aryl group or heteroaryl group
  • G’ is C6-C12 aryl or 5-12 membered heteroaryl
  • G is C6-aryl or 5-6 membered heteroaryl
  • R m is each independently selected from: hydrogen, halogen, carboxyl, hydroxyl, cyano, amino, -COOC1-C6 alkyl, nitro, -CO (3-8 membered substituted or unsubstituted heterocyclyl), -CO( C3-C8 substituted or unsubstituted cycloalkyl), substituted or unsubstituted C6-C12 aryl C1-C6 alkyl, substituted or unsubstituted 5-12 membered heteroaryl C1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkyl acyl, substituted or Unsubstituted aminoacyl, substituted or un
  • R m' are each independently selected from: hydrogen, halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkoxy, haloC1- C6 alkoxy, C3-C8 cycloalkyl or 3-8 membered heterocyclyl;
  • R m" and R m"' are each independently selected from: H, halogen, carboxyl, hydroxyl, cyano, nitro, amino, -COOC1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted Substituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkyl acyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted Substituted C1-C6 alkylamido, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C6-C12 arylamino, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsub
  • n 1 or 2;
  • f, f’, f” and f”’ are each independently 0, 1, 2 or 3;
  • R 4 is defined as above.
  • ring A is Preferably More preferably
  • Rm and f are defined as above;
  • R m1 , R m2 and R m3 are the same as R m .
  • R m1 , R m2 and R m3 are each independently selected from: H, halogen, carboxyl, hydroxyl, cyano group, amino group, -COOC1-C6 Alkyl, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C6-C10 aryl, C6- C10 aryl NH, 5-6 membered heteroaryl, C6-C10 aryl substituted 5-6 membered heteroaryl, -OP(O)(OH) 2 substituted C1-C6 alkyl, amino C1-C6 alkyl C1-C6 alkyl group substituted by COO; preferably, R m1 , R m2 , and
  • B ring is selected from:
  • Ring B is Preferably More preferably selected from: Among them, R 4 , R m' , R m" , f' and f" are defined as above.
  • R 4 is selected from: H, halogen, carboxyl, hydroxyl, cyano, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or Unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted COOC1-C6 alkyl, substituted or unsubstituted CO-4-6 membered heterocyclyl, substituted or unsubstituted C6 -C10 aryl, substituted or unsubstituted 5-10-membered heteroaryl (preferably 5-6-membered or 9-10-membered, such as furyl, thienyl, pyridyl, pyrrolyl, pyrazolyl, imidazolyl, benzene Furyl, benzothienyl, pyridopyrazolyl
  • a prodrug of the compound of formula I has the structure shown in formula III-1 or III-2
  • L is C1-C6 alkylene
  • Rn is selected from: -P(O)(OH) 2 or amino C1-C6 alkyl CO; preferably
  • G, G', R 4 , R m' , R m" , R m"' , f', f" and f"' are defined as above.
  • Q, ring A, ring B, G, G′, G′′, E, R a , R a′ , R b , R b ′ , R c , R c′ , R d , R d' , R e , R e' , R f , R f' , R g , R g' , R h , R h' , R i, R i ', R j , R j ' , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R m , R m' , R m " and R m"' are the bases corresponding to each specific compound in the examples. group.
  • the compound is selected from the following compounds:
  • the compound is not
  • the present invention provides a pharmaceutical composition, which comprises a therapeutically effective amount selected from the first The compound described in the aspect, or one or more of its prodrugs, its enantiomers, diastereomers, racemates and mixtures thereof, or its pharmaceutically acceptable salts; and Optionally a pharmaceutically acceptable carrier.
  • the third aspect of the present invention provides a compound described in the first aspect, or its prodrug, its enantiomers, diastereomers, racemates and mixtures thereof, or its pharmaceutically acceptable
  • the salt or the use of the pharmaceutical composition as described in the second aspect characterized in that it is used to prepare a cGAS/STING pathway targeted inhibitor; or
  • the inflammatory disease and autoimmune disease are selected from: Singleton-Merten syndrome (SMS), Aicardi-Goutines syndrome (AGS), systemic lupus erythematosus (SLE), familial chilblains Lupus erythematosus (FCL), retinal vasculopathy and leukodystrophy (RVCL), STING-associated vasculopathy of infancy (SAVI), scleroderma, psoriasis, Sjogren's syndrome, rheumatoid joints inflammation, inflammatory bowel disease, multiple sclerosis, Crohn's disease, ulcerative colitis, autoimmune colitis, small intestinal malabsorption syndrome, irritable bowel syndrome, uveitis, mucositis, diabetes, cardiovascular disease diseases and neurodegenerative diseases.
  • SMS Singleton-Merten syndrome
  • APS Aicardi-Goutaires syndrome
  • SLE systemic lupus erythematosus
  • FCL familial chi
  • the fourth aspect of the present invention provides a method for inhibiting the activity of STING protein. Contacting the compound described in the first aspect with cells capable of expressing STING protein can inhibit the secretion of interferon by inhibiting the activity of STING protein.
  • the cells are of human and/or mouse origin.
  • the cells are THP1-Blue-ISG cells and/or Raw-lucia cells.
  • the halogen is F, Cl, Br or I.
  • C1-C6 means having 1, 2, 3, 4, 5 or 6 carbon atoms
  • C1-C8 means having 1, 2, 3, 4, 5, 6, 7 Or 8 carbon atoms, and so on.
  • 5-12 membered means having 5-12 ring atoms, and so on.
  • alkyl refers to a saturated linear or branched chain hydrocarbon moiety.
  • C1-C6 alkyl refers to a non-limiting linear or branched alkyl group having 1 to 6 carbon atoms. Include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl, etc.; preferably ethyl, propyl, isopropyl, butyl base, isobutyl, sec-butyl and tert-butyl.
  • alkoxy means an -O-(alkyl) group.
  • C1-C6 alkoxy refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, including, but not limited to, methoxy, ethoxy, propoxy, and isopropoxy and butoxy etc.
  • alkenyl refers to a straight-chain or branched hydrocarbon moiety containing at least one double bond.
  • C2-C6 alkenyl refers to a straight-chain or branched hydrocarbon moiety having 2 to 6 carbon atoms and containing one double bond.
  • Chain or branched alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl, and the like.
  • alkynyl refers to a straight chain or branched chain alkynyl group containing a triple bond.
  • C2-C6 alkynyl refers to a straight chain or branched chain alkynyl group having 2 to 6 carbon atoms and containing a triple bond.
  • Chain or branched alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, isobutynyl, pentynyl, hexynyl, and the like.
  • cycloalkyl refers to a saturated cyclic hydrocarbon moiety.
  • C3-C10 cycloalkyl refers to a cyclic alkyl group having 3 to 10 carbon atoms in the ring, without limitation. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclodecyl, etc.
  • C3-C8 cycloalkyl “C3-C7 cycloalkyl”
  • C3-C6 cycloalkyl have similar meanings.
  • heterocyclyl refers to a saturated or partially saturated cyclic group having a heteroatom selected from N, S and O, which may be a monocyclic or bicyclic form, such as a bridged ring or a spirocyclic form.
  • the heterocyclyl group is preferably a 3-8-membered heterocyclyl group, more preferably a 4-6-membered heterocyclyl group, and more preferably a 5-6-membered heterocyclyl group.
  • heterocyclyl groups include, but are not limited to: oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, tetrahydrofuranyl, morpholinyl and pyrrolidinyl, wait.
  • aryl means a hydrocarbyl moiety containing one or more aromatic rings.
  • C6-C12 aryl refers to an aromatic ring group with 6 to 12 carbon atoms that does not contain heteroatoms on the ring, preferably a C6-C10 aryl group, such as phenyl, naphthyl, etc.
  • C6-C12 aryl has a similar meaning. 6-12 membered aryl and C6-C12 aryl are used interchangeably. Examples of aryl groups include, but are not limited to, phenyl (Ph), naphthyl, pyrenyl, anthracenyl, and phenanthrenyl.
  • heteroaryl refers to a cyclic aromatic group having 1 to 3 heteroatoms selected from the group consisting of N, S and O, which may be a single ring or a condensed ring.
  • the heteroaryl group is preferably a 5-12-membered heteroaryl group, more preferably a 5-10-membered heteroaryl group, more preferably a 5-8-membered group, more preferably a 5-6-membered or 9-10-membered group.
  • heteroaryl groups include, but are not limited to: pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl, and (1,2,4)-Triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, carbazole, indolyl, indazolyl, benzothienyl, Benzofuranyl, benzimidazolyl, benzotriazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, isomerized quinolinyl, phthalazinyl, quinoxalinyl , quinazolinyl, cinnolinyl or naphthyridinyl and tetrazolyl, etc.
  • the heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, where the ring attached to the parent structure is the heteroaryl ring.
  • the term "[6+5+6]heteroaryl” refers to a fused 6, 5, 6 tricyclic system, such as dibenzo[b,d]thiophene, and the term "[6+5]heteroaryl” is Refers to a heteroaryl group in which a 6-membered aryl group or a heteroaryl group is fused with a 5-membered heteroaryl group, such as benzothienyl, indole, isoindole, benzofuranyl, benzimidazolyl, and benzotriazolyl , benzothiazolyl, benzothiadiazolyl, benzene Oxazolyl, "[6+6]heteroaryl” refers to a 6-membered aryl group or a heteroaryl group
  • Heteroaryl groups may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio , alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, amide, sulfonamide, Formyl group, formamide group, carboxyl group and carboxylate group, etc.
  • substituents “heteroaryl ring”, “heteroaromatic ring” and “heteroaryl group” have the same meaning.
  • [6+6] aryl or fused ring, [6+6] heteroaryl or fused ring, [6+5] heteroaryl or fused ring, [5+6] heteroaryl or fused ring , [5+5] Heteroaryl or fused ring in the fused ring refers to a ring in which a 5-6-membered aryl or heteroaryl is fused with a 5-6-membered cycloalkyl or heterocycloalkyl, including phenyl and 5 -6-membered heteroaryl, 5-6-membered heterocyclylaphenyl, C5-C6 cycloalkylphenyl, phenyl-5-6-membered heterocyclyl (such as ), phenyl C5-C6 cycloalkyl, 5-6 membered heterocyclyl and 5-6 membered heteroaryl, C5-C6 cycloalkyl 5-6 membered heteroaryl, 5-6
  • amino means having the structure -N(R)(R'), R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, Aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' may be the same or different in the dialkylamine moiety. Examples of amino groups are NH 2 , NHCH 3 , N(CH 3 ) 2 .
  • alkyl, alkoxy, cycloalkyl, heterocyclyl and aryl groups described herein are substituted and unsubstituted groups.
  • Possible substituents on alkyl, alkoxy, cycloalkyl, heterocyclyl and aryl include, but are not limited to: hydroxyl, amino, nitro, cyano, halogen, C1-C6 alkyl, C2-C10 alkene Base, C2-C10 alkynyl, C3-C20 cycloalkyl, C3-C20 cycloalkenyl, C3-C20 heterocycloalkyl, C3-C20 heterocycloalkenyl, C1-C6 alkoxy, aryl, heteroaryl group, heteroaryloxy group, C1-C10 alkylamino group, C1-C10 dialkylamino group, arylamino group, diarylamino group, C1-C10 alkylsulfamoyl, aryl
  • the substitution is mono-substitution or poly-substitution
  • the poly-substitution is disubstitution, tri-substitution, tetra-substitution or penta-substitution.
  • the disubstituted means having two substituents, and so on.
  • prodrug also known as prodrug, prodrug, prodrug, etc.
  • prodrug refers to a drug that is inactive or less active in vitro and is converted to active drugs in vivo through enzymatic or non-enzymatic transformation. And the compounds that exert medicinal effects.
  • salt refers to a salt (including zwitterions, etc.) that has an effect similar to that of the parent compound and is biologically or otherwise (e.g., neither toxic nor harmful to the subject). Salt). Accordingly, the embodiments of the invention provide pharmaceutically acceptable salts of the compounds of the invention.
  • salt as used herein means any of the following acid salts formed from inorganic and/or organic acids, as well as base salts formed from inorganic and/or organic bases.
  • Salts of the compounds of the present invention may be formed by methods known to those of ordinary skill in the art, for example, by combining a compound of the present invention with an amount of acid or base (e.g., equivalent amounts of acid or base) in a medium (e.g., such The medium can allow the salt to precipitate in it; or water can be used as the medium and then freeze-dried).
  • an amount of acid or base e.g., equivalent amounts of acid or base
  • a medium e.g., such
  • the medium can allow the salt to precipitate in it; or water can be used as the medium and then freeze-dried).
  • compound of the invention or “active ingredient of the invention” is used interchangeably and refers to a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound (e.g. deuterated compounds) or prodrugs.
  • the term also includes racemates, optical isomers.
  • the compound of formula I has the following structure
  • Rings A, Q and B are defined as above;
  • Ring A is selected from the following structures:
  • ring A is More preferably More preferably
  • Rm, f, R m1 , R m2 and R m3 are as mentioned above;
  • Ring B is selected from the following structures:
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R a , R a' , R b , R b' , R c , R c' , R g , R g' , R h , R h' , R i , R i' , R j , R j' and n are defined as above;
  • ring B is More preferably More preferably selected from: Among them, R 4 , R m' , R m" , f' and f" are defined as above;
  • R 4 is selected from: halogen, carboxyl, hydroxyl, cyano, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C2-C6 Alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted COOC1-C6 alkyl, substituted or unsubstituted CO-4-6 membered heterocyclyl, substituted or unsubstituted C6-C10 aryl, substituted Or unsubstituted 5-10 yuan heteroaryl (preferably 5-6 yuan or 9-10 yuan, such as furyl, thienyl, pyridyl, pyrrolyl, pyrazolyl, imidazolyl, benzofuranyl, benzo Thienyl, pyridopyrazolyl), substituted or un
  • salts refers to an acidic or basic salt formed from an inorganic or organic acid and a base.
  • a basic moiety which includes but is not limited to pyridine or imidazole
  • an acidic moiety including but is not limited to carboxylic acid
  • the zwitterion that may be formed is included in Within the scope of the term "salt”.
  • Pharmaceutically acceptable (i.e., nontoxic, physiologically acceptable) salts are preferred, although other salts are also useful, for example, in isolation or purification steps during preparation.
  • the compounds of the present invention may form salts, for example, compound I can be obtained by reacting with a certain amount of, for example, an equivalent amount of acid or base, salting out in a medium, or by freeze-drying in an aqueous solution.
  • the compounds of the present invention contain basic moieties, including but not limited to amines or pyridine or imidazole rings, which may form salts with organic or inorganic acids.
  • Typical acids that can form salts include acetates (eg, with acetic acid or trihaloacetic acids, such as trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, and benzoates.
  • benzenesulfonate hydrogen sulfate, borate, butyrate, citrate, camphor salt, camphor sulfonate, cyclopentane propionate, diglycolate, dodecyl sulfate, Ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, enanthate, caproate, hydrochloride, hydrobromide, hydroiodide, glycolate (e.g., 2-hydroxyethanesulfonate), lactate, maleate, methanesulfonate, naphthalenesulfonate (e.g., 2-naphthalenesulfonate), nicotinate, nitrate, oxalic acid Salt, pectate, persulfate, phenylpropionate (such as 3-phenylpropionate), phosphate, picrate, pivalate, propionate, sal
  • Certain compounds of the invention may contain acidic moieties, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases.
  • Typical salts formed with bases include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and salts formed with organic bases (such as organic amines), such as benzathine and dicyclohexylamine.
  • Hypamine salt with N,N-bis(dehydroabidyl)ethylenediamine
  • N-methyl-D-glucamine N-methyl-D-glucamide
  • tert-butyl Amines and salts formed with amino acids such as arginine, lysine, etc.
  • Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecule alkyl halides (such as chlorides, bromides and iodides of methyl, ethyl, propyl and butyl), dialkyl sulfates (such as dimethyl sulfate, diethyl sulfate, dibutyl ester and dipentyl ester), long chain halides (such as decyl, dodecyl, tetradecyl and tetradecyl chlorides, bromides and iodide), aralkyl halides (such as benzyl and phenyl bromide), etc.
  • small halides such as chlorides, bromides and iodides of methyl, ethyl, propyl and butyl
  • dialkyl sulfates such as dimethyl sulfate, diethyl sulfate, dibutyl este
  • Prodrugs and solvates of the compounds of the present invention are also within the scope of the invention.
  • the term "prodrug” here refers to a compound that undergoes chemical transformation through metabolism or chemical processes to produce the compound, salt, or solvate of the present invention when treating related diseases.
  • Compounds of the present invention include solvates, such as hydrates.
  • the compounds, salts or solvates of the present invention may exist in tautomeric forms (eg amides and imine ethers). All such tautomers are part of the present invention.
  • All stereoisomers of the compounds are contemplated by the present invention.
  • the compounds of the invention may be independent stereoisomers that do not exist simultaneously with other isomers (e.g., have a specific activity as a pure or substantially pure optical isomer), or they may be mixtures, e.g. Racemates, or mixtures with all other stereoisomers or portions thereof.
  • the chiral center of the present invention has two configurations: S or R, which are defined as recommended by the International Union of Theoretical and Applied Chemistry (IUPAC) in 1974.
  • Racemic forms can be resolved by physical methods, such as fractional crystallization, or by fractional crystallization by derivatization to diastereoisomers, or by chiral column chromatography.
  • Individual optical isomers can be obtained from the racemate by suitable methods, including but not limited to traditional methods, such as salt formation with an optically active acid followed by recrystallization.
  • the weight content of the compounds in the present invention obtained by sequential preparation, separation and purification is equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure" compounds), as described in the text List. Such "very pure” compounds of the invention are here also included as part of the invention.
  • Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention encompasses all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, elimination Spin mixtures and other mixtures.
  • asymmetric carbon atoms can represent substituents, such as alkyl groups. All isomers, as well as mixtures thereof, are included in the present invention.
  • the mixture of isomers may contain the isomers in various ratios.
  • a mixture of only two isomers can have the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98: All ratios of isomers 2, 99:1, or 100:0 are within the scope of the invention. Similar ratios, as well as ratios for more complex mixtures of isomers that are readily understood by those of ordinary skill in the art, are also within the scope of the present invention.
  • the present invention also includes isotopically labeled compounds that are equivalent to the original compounds disclosed herein. In practice, however, it often occurs that one or more atoms are replaced by atoms with a different atomic weight or mass number.
  • isotopes of compounds that may be included in the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes such as 2 H, 3H , 13C , 11C , 14C , 15N , 18O , 17O , 31P , 32P , 35S , 18F and 36Cl .
  • the compounds of the present invention or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, which contain isotopes or other isotope atoms of the above compounds are within the scope of the present invention.
  • Certain isotopically labeled compounds of the present invention such as radioactive isotopes of 3 H and 14 C, are also included and are useful in tissue distribution experiments of drugs and substrates. Tritium, or 3H , and carbon-14, or 14C , are relatively easy to prepare and detect. It is the first choice among isotopes.
  • heavier isotope substitutions such as deuterium, i.e.
  • Isotopically labeled compounds can be prepared by general methods by replacing readily available isotopically labeled reagents with non-isotopic reagents, using the protocols disclosed in the Examples.
  • a synthesis of a specific enantiomer of the compound of the present invention it can be prepared by asymmetric synthesis, or derivatized with a chiral auxiliary, and the resulting diastereomeric mixture is separated and then the chiral auxiliary is removed. Pure enantiomer.
  • a suitable optically active acid or base can be used to form a diastereomeric salt with it, and then through separation, crystallization or chromatography, etc. After separation by conventional means, the pure enantiomers are obtained.
  • the compounds of the present invention may be provided with any number of substituents or functional groups to broaden their encompassing scope.
  • substituents or functional groups in general, whether the term “substituted” appears before or after the term “optional”, the general formula of the substituent included in the formulation of the present invention means that the substituent of the specified structure is used in place of the hydrogen radical. When multiple positions in a specific structure are substituted by multiple specific substituents, the substituents may be the same or different at each position.
  • substitution as used herein includes all permissible substitutions of organic compounds. Broadly speaking, permissible substituents include acyclic, cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds.
  • heteroatoms such as nitrogen may have hydrogen substituents or any of the permissible organic compounds described above to supplement their valence. Furthermore, this invention is not intended to be limited in any way to the permitted substituted organic compounds.
  • the present invention considers that combinations of substituents and variable groups are excellent in the treatment of diseases in the form of stable compounds.
  • stable refers to a compound that is stable, detectable over a long enough period of time to maintain the structural integrity of the compound, and preferably effective over a long enough period of time, and is used herein for the above purposes.
  • each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (such as 0°C to 150°C, preferably 10°C to 100°C).
  • the reaction time is usually 0.1 hour-60 hours, preferably 0.5-48 hours Hour.
  • the compound of formula (I) of the present invention can be prepared by the following steps
  • the compound represented by formula (I) can be prepared by the following two methods as shown in the figure above:
  • Aromatic amines are treated with triphosgene to obtain isocyanates, which are then combined with Reaction occurs to obtain the compound represented by formula (I);
  • Aromatic acid is treated with DPPA (diphenylphosphoryl azide) to obtain acyl azide, which is then converted into isocyanate by heating, and then combined with The reaction occurs to obtain the compound represented by formula (I).
  • DPPA diphenylphosphoryl azide
  • compositions and methods of administration are provided.
  • the compound of the present invention has excellent agonistic activity of STING kinase
  • the compound of the present invention or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate, and the compound containing the compound of the present invention are the main active
  • Pharmaceutical compositions of ingredients may be used to prevent and/or treat (stabilize, alleviate or cure) STING kinase-related inflammatory diseases and autoimmune diseases.
  • the inflammatory disease and autoimmune disease are selected from: Singleton-Merten syndrome (SMS), Aicardi-Goutigres syndrome (AGS), systemic lupus erythematosus (SLE), familial chilblain lupus erythematosus (FCL), retinal Vascular disease and leukodystrophy (RVCL), STING-associated vasculopathy of infancy (SAVI), scleroderma, psoriasis, Sjogren's syndrome, rheumatoid arthritis, inflammatory bowel disease, Multiple sclerosis, Crohn's disease, ulcerative colitis, autoimmune colitis, small intestinal malabsorption syndrome, irritable bowel syndrome, uveitis, mucositis, diabetes, cardiovascular disease and neurodegenerative diseases, etc. .
  • the pharmaceutical composition of the present invention contains a compound of the present invention and a pharmaceutically acceptable excipient or carrier within a safe and effective amount.
  • the “safe and effective dose” refers to the amount of compound that is sufficient to significantly improve the condition without causing may cause serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention/dose, more preferably, it contains 10-200 mg of the compound of the present invention/dose.
  • the "dose" is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid filler or gel substances that are suitable for human use and must be of sufficient purity and low enough toxicity. "Compatibility” here means that the components of the composition can be blended with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • solid lubricants such as
  • the administration mode of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative administration modes include (but are not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous).
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) Humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) retarder, such as paraffin; (f) Absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl mono
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules may be prepared using coatings and shell materials such as enteric casings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxy substances. If necessary, the active compounds can also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils,
  • compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions may contain, besides the active compound, suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene Ensorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances, etc.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene Ensorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances, etc.
  • compositions for parenteral injection may contain physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • the compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds (eg, STING agonists).
  • other pharmaceutically acceptable compounds eg, STING agonists.
  • the pharmaceutical composition When administered in combination, the pharmaceutical composition also includes one or more (2, 3, 4, or more) other pharmaceutically acceptable compounds (eg, STING agonists).
  • One or more (2, 3, 4, or more) of the other pharmaceutically acceptable compounds may be used simultaneously, separately, or sequentially with the compound of the present invention to prevent and/or treat STING Diseases related to kinase activity or expression.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, and the dosage when administered is a pharmaceutically effective dosage.
  • a mammal such as a human
  • the daily dose is usually 1 to 2000 mg, preferably 20 to 500 mg.
  • the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the skill of a skilled physician.
  • Safe and effective dose refers to the amount of active ingredients that is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1 to 2000 mg of active ingredients/dose, and more preferably, contains 10 to 200 mg of active ingredients/dose.
  • the "dose” is a tablet.
  • the compound of the present invention has inhibitory activity against STING protein in human cells and/or mouse cells, and can be used as a targeted inhibitor of the cGAS/STING signaling pathway;
  • the compound of the present invention has good medicinal efficacy and pharmacokinetic properties.
  • N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-1(2H)-carboxamide (I-2) is the same as compound I-1.
  • N-(7-fluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-4) is the same as compound I-1.
  • N-(6-fluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-5) is the same as that of compound I-1.
  • N-(benzo[b]thiophen-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-8) is the same as that of the compound I-1.
  • N-(1H-indol-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-10) is the same as compound I-1.
  • N-(1H-indol-3-yl)-4-phenylpiperazine-1-carboxamide (I-12) is the same as that of compound I-1.
  • Step 2 8-(piperidine-1-carbonyl)-1,2,3,4-tetrahydroisoquinoline (15-2)
  • Step 2 6-(naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline (20-2)
  • Step 3 N-(1H-indol-3-yl)-6-(naphthyl-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-20)
  • N-(1H-indol-3-yl)-6-(naphthyl-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-20) is the same as that of the compound I-1.
  • Step 1 6-vinyl-3,4-dihydroisoquinoline-2(1H)-Boc(25-1)
  • Step 1 6-ethynyl-1,2,3,4-tetrahydroisoquinoline (26-1)
  • Step 1 7-phenyl-1,2,3,4-tetrahydroisoquinoline (35-1)
  • Step 1 8-phenyl-1,2,3,4-tetrahydroisoquinoline (36-1)
  • Step 1 6-(4,4-difluoropiperidin-1-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(42-1)
  • Step 3 6-(4,4-difluoropiperidin-1-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-42)
  • N-(5-cyano-1H-indol-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-48) is the same as that of the compound I-41.
  • Step 2 6-phenyl-N-(1H-pyrrolo[3,2-c]pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-55 )
  • Step 1 4-phenyl-1,4-diaza-1-Boc (56-1)
  • N-(1H-indol-3-yl)-4-(pyridin-4-yl)piperazine-1-carboxamide (I-58) is the same as compound I-1.
  • N-(1H-indol-3-yl)-4-(2-methoxyphenyl)piperazine-1-carboxamide (I-61) is the same as compound I-1.
  • N-(1H-indol-3-yl)-4-methylpiperazine-1-carboxamide (I-66) is the same as compound I-1.
  • Step 1 1-phenyl-1,2,3,4-tetrahydroquinoxaline (76-1)
  • Step 2 4-(benzo[d][1,3]dioxolane-5-yl)-N-(1H-indol-3-yl)piperazine-1-carboxamide (I-79)
  • Step 5 N-(5-(1-phenyl-1H-pyrazol-4-yl)-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-methyl Amide(I-82)
  • Step 3 N-(5-chloro-6-fluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-83)
  • Step 2 6-phenyl-N-(1H-pyrrolo[2,3-c]pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-86 )
  • Step 2 6-phenyl-N-(1H-pyrrolo[3,2-b]pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-88 )
  • Step 1 6-phenyl-1,2,3,4-tetrahydro-2,7-naphthyridine (89-1)
  • Step 2 N-(1H-indol-3-yl)-6-phenyl-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxamide (I-89)
  • Step 1 6-phenyl-1,4-dihydroisoquinolin-3(2H)-one (91-1)
  • Step 2 N-(1H-indol-3-yl)-3-oxo-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-91)
  • Step 1 6-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (94-1)
  • N-(5-chloro-1H-indol-3-yl)-6-(4-methoxyphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-97 ) is prepared by the same method as compound I-41.
  • N-(5-fluoro-1H-indol-3-yl)-6-(4-methoxyphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-98 ) is prepared by the same method as compound I-41.
  • Step 1 6-(3-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (99-1)
  • N-(5-chloro-1H-indol-3-yl)-6-(3-methoxyphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-102 ) is prepared by the same method as compound I-41.
  • N-(5-fluoro-1H-indol-3-yl)-6-(3-methoxyphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-103 ) is prepared by the same method as compound I-41.
  • Step 1 6-(2-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (104-1)
  • Step 2 N-(1H-indol-3-yl)-6-(2-methoxyphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-104)
  • Step 3 N-(5-chloro-1H-indol-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-105)
  • Step 2 N-(5-bromo-1H-indol-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-106)
  • Step 3 N-(5-nitro-1H-indol-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-107)
  • N-(5-methyl-1H-indol-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-109) is the same as that of the compound I-41.
  • Step 1 4,4,5,5-tetramethyl-2-(3-(methylsulfonyl)phenyl)-1,3,2-dioxaborane (110-1)
  • Step 2 6-(3-(methylsulfonyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-Boc(110-2)
  • Step 3 6-(3-(methylsulfonyl)phenyl)-1,2,4-tetrahydroisoquinoline (110-3)
  • Step 4 N-(1H-indol-3-yl)-6-(3-methylsulfonylphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-110)
  • Step 1 4,4,5,5-tetramethyl-2-(4-(methylsulfonyl)phenyl)-1,3,2-dioxaborane (111-1)
  • Step 2 6-(4-(methylsulfonyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-Boc(111-2)
  • Step 3 6-(4-(methylsulfonyl)phenyl)-1,2,4-tetrahydroisoquinoline (111-3)
  • Step 4 N-(1H-indol-3-yl)-6-(4-methylsulfonylphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-111)
  • N-(1H-indol-3-yl)-6-(1-methyl-1H-pyrrol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I- The preparation method of 112) is the same as that of compound I-41.
  • Step 1 6-(pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(113-1)
  • Step 3 6-(pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester (I-113)
  • Step 1 6-(pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(114-1)
  • N-(1H-indol-3-yl)-6-(pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-114) is the same as that of the compound I-1.
  • Step 1 6-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-3,4-dihydroisoquinoline-2(1H)- Boc(115-1)
  • Step 2 6-(pyridin-2-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(115-2)
  • Step 4 N-(1H-indol-3-yl)-6-(pyridin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-115)
  • N-(1H-indol-3-yl)-6-(pyridin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-115) is the same as that of the compound I-1.
  • Step 1 6-(1-(triisopropylsilyl)-1H-pyrrol-3-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(116-1)
  • Step 1 6-(1-methylpyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(117-1)
  • Step 2 6-(1-methylpyrazol-4-yl)-1,2,3,4-tetrahydroisoquinoline (117-2)
  • Step 3 N-indol-3-yl-6-(1-methylpyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-117)
  • Step 1 6-(thiophen-3-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(118-1)
  • Step 1 6(thiophen-2-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(119-1)
  • Step 1 6-anilino-3,4-dihydroisoquinoline-2(1H)-Boc(120-1)
  • N-phenyl-1,2,3,4-tetrahydroisoquinolin-6-amine 120-2
  • Step 1 6-(benzo[d][1,3]dioxolane-5-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(121-1)
  • Step 2 6-(benzo[d][1,3]dioxolane-5-yl)-1,2,3,4-tetrahydroisoquinoline (121-2)
  • Step 3 6-(benzo[d][1,3]dioxolane-5-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2 (1H)-Formamide (I-121)
  • Step 1 6-(2,2-difluorobenzo[d][1,3]dioxolane-5-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(126 -1)
  • Step 2 6-(2,2-difluorobenzo[d][1,3]dioxolane-5-yl)-1,2,3,4-tetrahydroisoquinoline (126-2)
  • Step 3 N-(5,6-difluoro-1H-indol-3-yl)-6-(2,2-difluorobenzo[d][1,3]dioxolane-5-yl )-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-126)
  • N-(5-chloro-6-fluoro-1H-indol-3-yl)-6-(piperidin-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (The preparation method of I-129) is the same as that of compound I-1.
  • Step 1 6-(3,4-dihydroquinoline-1(2H)-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(132-1)
  • Step 2 1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1,3,4-tetrahydroquinoline (132-2)
  • Step 3 6-(3,4-dihydroquinolin-1(2H)-yl)-N-(5-fluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline- 2(1H)-Carboxamide (I-132)
  • Step 1 3,3',4,4'-tetrahydro-1H-[2,6'-diisoquinoline]-2'(1'H)-Boc(133-1)
  • Step 2 1',2',3,3',4,4'-hexahydro-1H-2,6'-bisisoquinoline (133-2)
  • Step 3 N-(5-fluoro-1H-indol-3-yl)-3,3',4,4'-tetrahydro-1H-[2,6'-diisoquinoline]-2'( 1'H)-Carboxamide (I-133)
  • Step 1 6-(6-azaspiro[2.5]octane-6-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(134-1)
  • Step 2 6-(6-azaspiro[2.5]octane-6-yl)-1,2,4-tetrahydroisoquinoline (134-2)
  • Step 1 6-(pyrrol-1-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(135-1)
  • Step 1 6-(benzo[b]thiophen-3-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(136-1)
  • Step 2 6-(benzo[b]thiophen-3-yl)-1,2,3,4-tetrahydroisoquinoline (136-2)
  • Step 3 6-(benzo[b]thiophen-3-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-136)
  • Step 1 6-(benzofuran-5-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(137-1)
  • Step 3 6-(benzofuran-5-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-137)
  • Step 1 6-(Imidazo[1,2-a]pyridin-6-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(142-1)
  • Step 2 6-(imidazo[1,2-a]pyridin-6-yl)-1,2,3,4-tetrahydroisoquinoline (142-2)
  • Step 3 6-(imidazo[1,2-a]pyridin-6-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)- Formamide(I-142)
  • Step 1 6-(benzothiophen-5-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(143-1)
  • Step 3 6-(benzo[b]thiophen-5-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-143)
  • Step 1 6-(1H-indol-5-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(148-1)
  • Step 3 N-(1H-indol-3-yl)-6-(1H-indol-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-148 )
  • Step 1 6-(benzofuran-6-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(149-1)
  • Step 1 2-(benzo[b]thiophen-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (154-1)
  • Step 2 6-(benzothiophen-6-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(154-2)
  • Step 3 6-(benzo[b]thiophen-6-yl)-1,2,4-tetrahydroisoquinoline (154-3)
  • Step 4 6-(benzo[b]thiophen-6-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I -154)
  • Step 1 6-(benzofuran-4-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(159-1)
  • Step 3 6-(benzofuran-4-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-159)
  • Step 1 6-(benzofuran-7-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(160-1)
  • Step 2 6-(benzofuran-7-yl)-1,2,3,4-tetrahydroisoquinoline (160-2)
  • Step 1 6-(1-Boc-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(161-1)
  • Step 2 6-(dibenzo[b,d]thiophen-4-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(162-2)
  • Step 4 6-(dibenzo[b,d]thiophen-4-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-methyl Amide(I-162)
  • Step 1 6-morpholinyl-3,4-dihydroisoquinoline-2(1H)-Boc(163-1)
  • Step 3 N-(5-fluoro-1H-indol-3-yl)-6-morpholine-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-163)
  • Step 1 6-bromo-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (164-1)
  • Step 2 N-(1H-indol-3-yl)-6-(1H-indol-6-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-164 )
  • Step 1 6-bromo-5-fluoro-3,4-dihydroisoquinoline-2(1H)-Boc(165-1)
  • Step 3 5-fluoro-6-phenyl-1,2,3,4-tetrahydroisoquinoline (165-3)
  • Step 4 5-fluoro-N-(1H-indol-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-165)
  • Step 5 1-(6-bromo-5-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethane-1-one (166- 5)
  • Step 6 2,2,2-trifluoro-1-(5-methyl-6-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)ethane-1-one (166 -6)
  • Step 8 N-(1H-indol-3-yl)-5-methyl-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-166)
  • Step 1 (1-(2-(2,2,2-trifluoroacetyl)-1,2,4-tetrahydroisoquinolin-6-yl)piperidin-3-yl)amino-Boc(167 -1)
  • Step 2 (1-(1,2,3,4-tetrahydroisoquinolin-6-yl)piperidin-3-yl)amino-Boc(167-2)
  • Step 3 (1-(2-((5-fluoro-1H-indol-3-yl)carbamoyl)-1,2,4-tetrahydroisoquinolin-6-yl)piperidine-3- base) Amino-Boc(167-3)

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Abstract

Provided are a dihydroisoquinoline compound and a medical use thereof. Specifically, the compound has a structure as shown in formula (I), can be used as a regulator for secretion of type-I interferon, especially as a target inhibitor for cGAS/STING signaling pathway, and can be used in preparation of medicines for preventing and/or treating inflammatory diseases and autoimmune diseases.

Description

二氢异喹啉类化合物及其医药用途Dihydroisoquinoline compounds and their medicinal uses 技术领域Technical field
本发明属于药物化学和药物治疗学领域，具体涉及二氢异喹啉类化合物及其医药用途，也涉及所述化合物的药物组合物以及其作为I型干扰素的分泌调节剂，尤其是作为cGAS/STING信号通路靶向抑制剂，在制备预防和/或治疗炎症性疾病和自身免疫性疾病的药物中的用途。The present invention belongs to the field of medicinal chemistry and drug therapy, specifically relates to dihydroisoquinoline compounds and their medicinal uses, and also relates to pharmaceutical compositions of the compounds and their use as secretion regulators of type I interferon, especially as cGAS Use of targeted inhibitors of /STING signaling pathway in preparing drugs for preventing and/or treating inflammatory diseases and autoimmune diseases.
背景技术Background technique
STING，也称为跨膜蛋白173(TMEM173)、MPYS、MITA或ERIS，是人类TMEM173基因编码的蛋白质。cGAS/STING信号通路在先天免疫过程中发挥重要作用。当DNA感受器cGAS(cyclic GMP-AMP synthase)监测到病原体DNA后诱导产生cGAMP(cyclic GMP-AMP)；接着cGAMP激活干扰素基因刺激因子(stimulator of interferon genes，STNG)来招募STING下游TANK结合激酶1(TANK-binding kinase 1，TBK1)，通过磷酸化干扰素调节因子3(interferon regulatory factor3，IRF3)来诱导Ⅰ型干扰素和细胞因子的分泌，并通过一系列的级联反应来激活获得性免疫系统，活化T细胞从而发挥抗肿瘤免疫作用。先天免疫系统的异常激活能够诱发多种疾病，cGAS/STING信号通路的分子机制研究为靶向药物研发提供了新思路。STING, also known as transmembrane protein 173 (TMEM173), MPYS, MITA or ERIS, is the protein encoded by the human TMEM173 gene. The cGAS/STING signaling pathway plays an important role in the innate immune process. When the DNA sensor cGAS (cyclic GMP-AMP synthase) detects pathogen DNA, it induces the production of cGAMP (cyclic GMP-AMP); then cGAMP activates the stimulator of interferon genes (STNG) to recruit STING downstream TANK-binding kinase 1 (TANK-binding kinase 1, TBK1), induces the secretion of type I interferons and cytokines by phosphorylating interferon regulatory factor 3 (IRF3), and activates adaptive immunity through a series of cascade reactions system, activate T cells to exert anti-tumor immunity. Abnormal activation of the innate immune system can induce a variety of diseases. Research on the molecular mechanism of the cGAS/STING signaling pathway provides new ideas for the development of targeted drugs.
cGAS/STING信号通路可以通过机体生理过程和药物方法精密调控，包括蛋白质翻译后修饰(磷酸化、泛素化等)、小分子拮抗剂(如H-151、C-176)与激动剂等(如DMXAA、MSA-2)。cGAS/STING信号通路处于异常激活或过度激活时，会引发炎症性疾病及自身免疫性疾病，如AGS综合征、系统性红斑狼疮(SLE)。因此，不同于cGAS/STING激活剂对肿瘤细胞的免疫杀伤作用，靶向抑制cGAS/STING信号通路可用于该类炎症性疾病及自身免疫性疾病的治疗。The cGAS/STING signaling pathway can be precisely regulated through physiological processes and pharmaceutical methods, including protein post-translational modifications (phosphorylation, ubiquitination, etc.), small molecule antagonists (such as H-151, C-176) and agonists ( Such as DMXAA, MSA-2). When the cGAS/STING signaling pathway is abnormally activated or overactivated, it can cause inflammatory diseases and autoimmune diseases, such as AGS syndrome and systemic lupus erythematosus (SLE). Therefore, unlike the immune killing effect of cGAS/STING activators on tumor cells, targeted inhibition of the cGAS/STING signaling pathway can be used for the treatment of such inflammatory diseases and autoimmune diseases.
靶向抑制cGAS/STING信号通路的小分子化合物研究虽处于起步阶段，但其一直是医学生理学领域研究的热点。2018年Haag等在《Nature》上报道了一类硝基呋喃和吲哚脲类化合物(Nature 2018,559,269-273.)，这些化合物通过与STING蛋白上的Cys91共价结合来阻断STING活化所诱导的棕榈酰化，进而干扰其在高尔基体组装成多聚体复合物来抑制下游信号通路传导。此外，该类抑制剂还可以抑制小鼠细胞中STING蛋白介导的炎性细胞因子的分泌来减轻小鼠自身炎症疾病的病理特征。2019年，Lama等学者在《Nature Communication》上发表了吲哚并哌啶系列化合物(Nat.Commun.2019,10,2261.)，该类化合物在人类骨髓来源的巨噬细胞(BMMD)中能有效抑制cGAS活性。2021年，中国药科大学王琛团队报导了磺酰胺类化合物SN-011，该化合物与STING蛋白的环二核苷酸结合域结合而发挥STING抑制活性，其在Trex1-/-小鼠中能强烈抑制炎症和自身免疫性疾病(Proc.Natl.Acad.Sci.U S A.2021,118, e2105465118.)。因此，靶向抑制cGAS/STING信号通路的小分子抑制剂有望成为自身免疫性疾病的重要治疗药物。Although research on small molecule compounds that target the cGAS/STING signaling pathway is in its infancy, it has always been a hot topic in the field of medical physiology. In 2018, Haag et al. reported a class of nitrofurans and indolureas in Nature (Nature 2018, 559, 269-273.). These compounds block STING activation by covalently binding to Cys91 on the STING protein. Induced palmitoylation, thereby interfering with its assembly into multimeric complexes in the Golgi apparatus to inhibit downstream signaling pathways. In addition, this type of inhibitor can also inhibit the secretion of inflammatory cytokines mediated by STING protein in mouse cells to reduce the pathological characteristics of autoinflammatory diseases in mice. In 2019, Lama and other scholars published a series of indolopiperidine compounds in "Nature Communication" (Nat. Commun. 2019, 10, 2261.). This type of compounds can inhibit human bone marrow-derived macrophages (BMMD). Effectively inhibits cGAS activity. In 2021, Wang Chen's team at China Pharmaceutical University reported the sulfonamide compound SN-011, which binds to the cyclic dinucleotide binding domain of the STING protein to exert STING inhibitory activity. It can inhibit the growth of STING in Trex1 -/- mice. Strongly inhibit inflammation and autoimmune diseases (Proc.Natl.Acad.Sci.U S A.2021,118, e2105465118.). Therefore, small molecule inhibitors that target the cGAS/STING signaling pathway are expected to become important therapeutic drugs for autoimmune diseases.
近年来，诺华、拜尔、礼来等知名制药公司纷纷加入靶向cGAS/STING信号通路的小分子抑制剂的研发中。该类化合物大部分研究尚处于细胞活性验证阶段，目前还没有处于临床研究阶段的小分子抑制剂。因此，亟需研发高活性和成药性的靶向cGAS/STING信号通路的小分子抑制剂，从而开发出自身免疫性疾病的治疗药物。In recent years, well-known pharmaceutical companies such as Novartis, Bayer, and Eli Lilly have joined the research and development of small molecule inhibitors targeting the cGAS/STING signaling pathway. Most of the research on this type of compounds is still in the cell activity verification stage, and there are currently no small molecule inhibitors in the clinical research stage. Therefore, there is an urgent need to develop highly active and druggable small molecule inhibitors targeting the cGAS/STING signaling pathway to develop therapeutic drugs for autoimmune diseases.
发明内容Contents of the invention
本发明目的是提供一种高活性和成药性的靶向cGAS/STING信号通路的小分子抑制剂，其可作为用于自身免疫性疾病的治疗药物。The purpose of the present invention is to provide a highly active and druggable small molecule inhibitor targeting the cGAS/STING signaling pathway, which can be used as a therapeutic drug for autoimmune diseases.
本发明的第一方面，提供一种式(I)所示的化合物，或其前药、其对映异构体、非对映异构体、外消旋体及其混合物，或其药学上可接受的盐，
The first aspect of the present invention provides a compound represented by formula (I), or its prodrug, its enantiomers, diastereomers, racemates and mixtures thereof, or its pharmaceutical acceptable salt,
其中，Q选自O或S；Among them, Q is selected from O or S;
环A选自取代或非取代下组基团：C6-C12芳基和5-12元杂芳基；其中，所述取代是指被1-5个R1取代；其中，各R1独立地选自：氢、卤素、羧基、羟基、氰基、氨基、-COOC1-C6烷基、硝基、-CO(3-8元取代或未取代杂环基)、-CO(C3-C8取代或未取代环烷基)、取代或未取代的C6-C12芳基C1-C6烷基、取代或未取代的5-12元杂芳基C1-C6烷基、取代或未取代C1-C6烷基、取代或未取代C2-C6烯基、取代或未取代C2-C6炔基、取代或未取代C1-C6烷氧基、取代或未取代C1-C6烷基酰基、取代或未取代氨基酰基、取代或未取代C1-C6烷基酰胺基、取代或未取代C1-C4烷基氨基、取代或未取代C6-C12芳基氨基、取代或未取代3-8元杂环基、取代或未取代C3-C8环烷基、取代或未取代5-12元杂芳基、取代或未取代C6-C12芳基；R1中所述取代是指被一个或多个选自下组的基团取代：卤素、羧基、-OP(O)(OH)2、羟基、氰基、氨基、硝基、苄基、C1-C6烷基OH、C1-C6烷基氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C8环烷基或3-8元杂环基；Ring A is selected from the group consisting of substituted or unsubstituted groups: C6-C12 aryl and 5-12 membered heteroaryl; wherein said substitution means substitution by 1-5 R 1 ; wherein each R 1 is independently Selected from: hydrogen, halogen, carboxyl, hydroxyl, cyano, amino, -COOC1-C6 alkyl, nitro, -CO (3-8-membered substituted or unsubstituted heterocyclyl), -CO (C3-C8 substituted or Unsubstituted cycloalkyl), substituted or unsubstituted C6-C12 aryl C1-C6 alkyl, substituted or unsubstituted 5-12 membered heteroaryl C1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl , substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkyl acyl, substituted or unsubstituted aminoacyl, Substituted or unsubstituted C1-C6 alkylamido, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C6-C12 arylamino, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl; substituted in R 1 means substituted by one or more groups selected from the following group : Halogen, carboxyl, -OP(O)(OH) 2 , hydroxyl, cyano, amino, nitro, benzyl, C1-C6 alkyl OH, C1-C6 alkylamino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl or 3-8 membered heterocyclyl;
环B为 Ring B is
其中，E为NR10或CR10R10’； Among them, E is NR 10 or CR 10 R 10' ;
R10选自：COOC1-C6烷基、-CO(3-8元取代或未取代杂环基)、-CO(C3-C8取代或未取代环烷基)、取代或未取代的C6-C12芳基C1-C6烷基、取代或未取代的5-12元杂芳基C1-C6烷基、取代或未取代C1-C6烷基、取代或未取代C2-C6烯基、取代或未取代C2-C6炔基、取代或未取代C1-C6烷氧基、取代或未取代C1-C6烷基酰基、取代或未取代氨基甲酰基、取代或未取代C1-C6烷基酰胺基、取代或未取代C1-C4烷基氨基、取代或未取代C6-C12芳基氨基、取代或未取代3-8元杂环基、取代或未取代C3-C8环烷基、取代或未取代3-8元杂环基C1-C6烷基、取代或未取代C3-C8环烷基C1-C6烷基、取代或未取代5-12元杂芳基、取代或未取代C6-C12芳基；其中，所述取代是指被一个或多个选自下组的基团取代：卤素、羧基、羟基、氰基、氨基、硝基、苄基、C1-C6烷基OH、C1-C6烷基氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基或3-8元杂环基；R 10 is selected from: COOC1-C6 alkyl, -CO (3-8-membered substituted or unsubstituted heterocyclyl), -CO (C3-C8 substituted or unsubstituted cycloalkyl), substituted or unsubstituted C6-C12 Aryl C1-C6 alkyl, substituted or unsubstituted 5-12 membered heteroaryl C1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylacyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted C1-C6 alkylamide, substituted or Unsubstituted C1-C4 alkylamino, substituted or unsubstituted C6-C12 arylamino, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 Membered heterocyclyl C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl C1-C6 alkyl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl; wherein, The substitution means substitution by one or more groups selected from the following group: halogen, carboxyl, hydroxyl, cyano, amino, nitro, benzyl, C1-C6 alkyl OH, C1-C6 alkylamino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy or 3-8 membered heterocyclyl;
R10’、Rg、Rg’、Rh、Rh’、Ri、Ri’、Rj和Rj’各自独立地选自：氢、卤素、羧基、羟基、氰基、氨基、-COOC1-C6烷基、硝基、-CO(3-8元取代或未取代杂环基)、-CO(C3-C8取代或未取代环烷基)、取代或未取代的C6-C12芳基C1-C6烷基、取代或未取代的5-12元杂芳基C1-C6烷基、取代或未取代C1-C6烷基、取代或未取代C2-C6烯基、取代或未取代C2-C6炔基、取代或未取代C1-C6烷氧基、取代或未取代C1-C6烷基酰基、取代或未取代氨基酰基、取代或未取代C1-C6烷基酰胺基、取代或未取代C1-C4烷基氨基、取代或未取代C6-C12芳基氨基、取代或未取代3-8元杂环基、取代或未取代C3-C8环烷基、取代或未取代3-8元杂环基C1-C6烷基、取代或未取代C3-C8环烷基C1-C6烷基、取代或未取代5-12元杂芳基、取代或未取代C6-C12芳基；其中，所述取代是指被一个或多个Ra取代；R 10' , R g , R g' , Rh, Rh ' , R i , R i' , R j and R j' are each independently selected from: hydrogen, halogen, carboxyl, hydroxyl, cyano, amino, -COOC1-C6 alkyl, nitro, -CO (3-8-membered substituted or unsubstituted heterocyclyl), -CO (C3-C8 substituted or unsubstituted cycloalkyl), substituted or unsubstituted C6-C12 aromatic Base C1-C6 alkyl, substituted or unsubstituted 5-12 membered heteroaryl C1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2 -C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkyl acyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted C1-C6 alkylamide, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C6-C12 arylamino, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl Cyclic group C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl C1-C6 alkyl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl; wherein, the Substitute means to be replaced by one or more Ra;
或者，R10和R10’与它们连接的C原子共同形成氧代基(＝O)、取代或未取代3-8元杂环基、取代或未取代C3-C8环烷基、取代或未取代的5-12元杂芳基、取代或未取代C6-C12芳基；其中，所述取代是指被一个或多个Ra取代；Alternatively, R 10 and R 10' together with the C atom to which they are connected form an oxo group (=O), a substituted or unsubstituted 3-8 membered heterocyclyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted Substituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl; wherein, the substitution means substitution by one or more Ra;
或者，Rg和Rg’与它们连接的C原子共同形成氧代基(＝O)、取代或未取代3-8元杂环基、取代或未取代C3-C8环烷基、取代或未取代的5-12元杂芳基、取代或未取代C6-C12芳基；其中，所述取代是指被一个或多个Ra取代；Alternatively, R g and R g' together with the C atom to which they are connected form an oxo group (=O), a substituted or unsubstituted 3-8 membered heterocyclyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted Substituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl; wherein, the substitution means substitution by one or more Ra;
或者，Rh和Rh’与它们连接的C原子共同形氧代基(＝O)、成取代或未取代3-8元杂环基、取代或未取代C3-C8环烷基、取代或未取代的5-12元杂芳基、取代或未取代C6-C12芳基；其中，所述取代是指被一个或多个Ra取代；Alternatively, R h and R h' together with the C atom to which they are connected form an oxo group (=O), a substituted or unsubstituted 3-8 membered heterocyclyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or Unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl; wherein, the substitution means substitution by one or more Ra;
或者，Ri和Ri’与它们连接的C原子共同形成氧代基(＝O)、取代或未取代3-8元杂环基、取代或未取代C3-C8环烷基、取代或未取代的5-12元杂芳基、取代或未取代C6-C12芳基；其中，所述取代是指被一个或多个Ra取代；Alternatively, R i and R i' together with the C atom to which they are connected form an oxo group (=O), a substituted or unsubstituted 3-8 membered heterocyclyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted Substituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl; wherein, the substitution means substitution by one or more Ra;
或者，Rj和Rj’它们连接的C原子共同形成氧代基(＝O)、取代或未取代3-8元杂环基、取代或未取代C3-C8环烷基、取代或未取代的5-12元杂芳基、取代或未取代C6-C12芳基；其中，所述取代是指被一个或多个Ra取代； Alternatively, the C atoms to which R j and R j' are connected together form an oxo group (=O), a substituted or unsubstituted 3-8 membered heterocyclyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl; wherein, the substitution means substitution by one or more Ra;
或者，Rg和Rh与它们连接的C原子共同形成氧代基(＝O)、取代或未取代3-8元杂环基、取代或未取代C3-C8环烷基、取代或未取代的5-12元杂芳基、取代或未取代C6-C12芳基；其中，所述取代是指被一个或多个Ra取代；Alternatively, R g and R h together with the C atom to which they are connected form an oxo group (=O), a substituted or unsubstituted 3-8 membered heterocyclyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl; wherein, the substitution means substitution by one or more Ra;
或者，Ri和Rj与它们连接的C原子共同形成氧代基(＝O)、取代或未取代3-8元杂环基、取代或未取代C3-C8环烷基、取代或未取代的5-12元杂芳基、取代或未取代C6-C12芳基；其中，所述取代是指被一个或多个Ra取代；Alternatively, R i and R j together with the C atom to which they are connected form an oxo group (=O), a substituted or unsubstituted 3-8 membered heterocyclyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl; wherein, the substitution means substitution by one or more Ra;
或者，Ri和R10与它们连接的C原子共同形成氧代基(＝O)、取代或未取代3-8元杂环基、取代或未取代C3-C8环烷基、取代或未取代的5-12元杂芳基、取代或未取代C6-C12芳基；其中，所述取代是指被一个或多个Ra取代；Alternatively, R i and R 10 together with the C atom to which they are connected form an oxo group (=O), a substituted or unsubstituted 3-8 membered heterocyclyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl; wherein, the substitution means substitution by one or more Ra;
或者，Rh和R10与它们连接的C原子共同形成氧代基(＝O)、取代或未取代3-8元杂环基、取代或未取代C3-C8环烷基、取代或未取代的5-12元杂芳基、取代或未取代C6-C12芳基；其中，所述取代是指被一个或多个Ra取代；Alternatively, R h and R 10 together with the C atom to which they are connected form an oxo group (=O), a substituted or unsubstituted 3-8 membered heterocyclyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl; wherein, the substitution means substitution by one or more Ra;
Ra选自：卤素、羧基、羟基、氰基、硝基、氨基、-COOC1-C6烷基、取代或未取代C1-C6烷基、取代或未取代C2-C6烯基、取代或未取代C2-C6炔基、取代或未取代C1-C6烷氧基、取代或未取代C1-C6烷基酰基、取代或未取代氨基甲酰基、取代或未取代C1-C6烷基酰胺基、取代或未取代C1-C4烷基氨基、取代或未取代C6-C12芳基氨基、取代或未取代3-8元杂环基、取代或未取代C3-C8环烷基、取代或未取代的5-12元杂芳基、取代或未取代C6-C12芳基、取代或未取代的C6-C12芳基C1-C6烷基、取代或未取代的5-12元杂芳基C1-C6烷基、-CO(3-8元取代或未取代杂环基)、-CO(C3-C8取代或未取代环烷基)；其中，所述取代是指被一个或多个选自下组的基团取代：卤素、羧基、羟基、氰基、氨基、硝基、SO2C1-C6烷基、CO2C1-C6烷基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷基OH、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C8环烷基或3-8元杂环基；Ra is selected from: halogen, carboxyl, hydroxyl, cyano, nitro, amino, -COOC1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2 -C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylacyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted C1-C6 alkylamide, substituted or unsubstituted Substituted C1-C4 alkylamino, substituted or unsubstituted C6-C12 arylamino, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-12 1-membered heteroaryl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C6-C12 aryl C1-C6 alkyl, substituted or unsubstituted 5-12 membered heteroaryl C1-C6 alkyl, - CO (3-8-membered substituted or unsubstituted heterocyclyl), -CO (C3-C8 substituted or unsubstituted cycloalkyl); wherein, the substitution refers to being substituted by one or more groups selected from the following group : Halogen, carboxyl, hydroxyl, cyano, amino, nitro, SO 2 C1-C6 alkyl, CO 2 C1-C6 alkyl, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyl OH, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl or 3-8 membered heterocyclyl;
n为1或2。n is 1 or 2.
在另一优选例中，Ra选自：卤素、羧基、羟基、氰基、硝基、氨基、-COOC1-C6烷基、取代或未取代C1-C6烷基、取代或未取代C2-C6烯基、取代或未取代C2-C6炔基、取代或未取代C1-C6烷氧基、取代或未取代C1-C6烷基酰基、取代或未取代氨基甲酰基、取代或未取代C1-C6烷基酰胺基、取代或未取代C1-C4烷基氨基、取代或未取代C6-C12芳基氨基、取代或未取代3-8元杂环基、取代或未取代C3-C8环烷基、取代或未取代的5-12元杂芳基、取代或未取代C6-C12芳基、取代或未取代的C6-C12芳基C1-C6烷基、取代或未取代的5-12元杂芳基C1-C6烷基、-CO(3-8元取代或未取代杂环基)、-CO(C3-C8取代或未取代环烷基)；其中，所述取代是指被一个或多个选自下组的基团取代：卤素、羧基、羟基、氰基、氨基、硝基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷基OH、C1-C6烷氧基、C3-C8环烷基或3-8元杂环基。In another preferred example, Ra is selected from: halogen, carboxyl, hydroxyl, cyano, nitro, amino, -COOC1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkene group, substituted or unsubstituted C2-C6 alkynyl group, substituted or unsubstituted C1-C6 alkoxy group, substituted or unsubstituted C1-C6 alkyl acyl group, substituted or unsubstituted carbamoyl group, substituted or unsubstituted C1-C6 alkyl group amide group, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C6-C12 arylamino, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted Or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C6-C12 aryl C1-C6 alkyl, substituted or unsubstituted 5-12 membered heteroaryl C1-C6 alkyl, -CO (3-8-membered substituted or unsubstituted heterocyclyl), -CO (C3-C8 substituted or unsubstituted cycloalkyl); wherein, the substitution refers to being substituted by one or more selected Substituted with groups from the following group: halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyl OH, C1-C6 alkoxy, C3-C8 cycloalkyl or 3-8 membered heterocyclyl.
在另一优选例中，各R1独立地选自：氢、卤素、羧基、羟基、氰基、氨基、 硝基、取代或未取代的苄基。In another preferred embodiment, each R 1 is independently selected from: hydrogen, halogen, carboxyl, hydroxyl, cyano, amino, nitro, Substituted or unsubstituted benzyl.
在另一优选例中，环A选自取代或未取代的下组基团：五元杂芳基、六元芳基、六元杂芳基、[6+6]芳基或稠环、[6+6]杂芳基或稠环、[6+5]杂芳基或稠环、[5+6]杂芳基或稠环、[5+5]杂芳基或稠环，其中，所述取代是指被1-5个R1取代；其中，各R1独立地选自：氢、卤素、羧基、羟基、氰基、氨基、-COOC1-C6烷基、硝基、-CO(3-8元取代或未取代杂环基)、-CO(C3-C8取代或未取代环烷基)、取代或未取代的C6-C12芳基C1-C6烷基、取代或未取代的5-12元杂芳基C1-C6烷基、取代或未取代C1-C6烷基、取代或未取代C2-C6烯基、取代或未取代C2-C6炔基、取代或未取代C1-C6烷氧基、取代或未取代C1-C6烷基酰基、取代或未取代氨基酰基、取代或未取代C1-C6烷基酰胺基、取代或未取代C1-C4烷基氨基、取代或未取代C6-C12芳基氨基、取代或未取代3-8元杂环基、取代或未取代C3-C8环烷基、取代或未取代5-12元杂芳基、取代或未取代C6-C12芳基；R1中所述取代是指被一个或多个选自下组的基团取代：卤素、羧基、-OP(O)(OH)2、羟基、氰基、氨基、硝基、苄基、C1-C6烷基OH、C1-C6烷基氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C8环烷基或3-8元杂环基。In another preferred embodiment, ring A is selected from the following substituted or unsubstituted groups: five-membered heteroaryl, six-membered aryl, six-membered heteroaryl, [6+6]aryl or fused ring, [ 6+6]heteroaryl or fused ring, [6+5]heteroaryl or fused ring, [5+6]heteroaryl or fused ring, [5+5]heteroaryl or fused ring, where, The substitution refers to substitution by 1-5 R 1 ; wherein, each R 1 is independently selected from: hydrogen, halogen, carboxyl, hydroxyl, cyano, amino, -COOC1-C6 alkyl, nitro, -CO(3 -8-membered substituted or unsubstituted heterocyclyl), -CO (C3-C8 substituted or unsubstituted cycloalkyl), substituted or unsubstituted C6-C12 aryl C1-C6 alkyl, substituted or unsubstituted 5- 12-membered heteroaryl C1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy base, substituted or unsubstituted C1-C6 alkylamino group, substituted or unsubstituted aminoacyl group, substituted or unsubstituted C1-C6 alkylamido group, substituted or unsubstituted C1-C4 alkylamino group, substituted or unsubstituted C6-C12 Arylamino, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl; R The substitution mentioned in 1 refers to substitution by one or more groups selected from the following group: halogen, carboxyl, -OP(O)(OH) 2 , hydroxyl, cyano, amino, nitro, benzyl, C1- C6 alkyl OH, C1-C6 alkylamino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl or 3 -8-membered heterocyclyl.
在另一优选例中，R1中所述取代是指被一个或多个选自下组的基团取代：卤素、羧基、-OP(O)(OH)2、羟基、氰基、氨基、硝基、苄基、C1-C6烷基OH、C1-C6烷基氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C8环烷基、3-8元杂环基、C6-C10芳基或5-10元杂芳基。In another preferred embodiment, the substitution mentioned in R 1 refers to being substituted by one or more groups selected from the following group: halogen, carboxyl, -OP(O)(OH) 2 , hydroxyl, cyano group, amino group, Nitro, benzyl, C1-C6 alkyl OH, C1-C6 alkylamino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C10 aryl or 5-10 membered heteroaryl.
在另一优选例中，R1中所述取代是指被一个或多个选自下组的基团取代：卤素、羧基、羟基、氰基、氨基、硝基、三氟甲氧基、苄基、HOCH2-、HOCH2CH2-、CF2CH-、CF3CH2CH2-、C1-C6烷基、C1-C6烷氧基、C3-C8环烷基或3-8元杂环基。In another preferred embodiment, the substitution described in R 1 refers to substitution by one or more groups selected from the following group: halogen, carboxyl, hydroxyl, cyano, amino, nitro, trifluoromethoxy, benzyl Base, HOCH 2 -, HOCH 2 CH 2 -, CF 2 CH-, CF 3 CH 2 CH 2 -, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl or 3-8 membered hetero ring base.
在另一优选例中，Rg和Rh与它们连接的C原子共同形成取代或未取代的5-12元杂芳基、取代或未取代C6-C12芳基时，Rg’和Rh’为不存在。In another preferred embodiment, when R g and R h together with the C atom to which they are connected form a substituted or unsubstituted 5-12-membered heteroaryl group or a substituted or unsubstituted C6-C12 aryl group, R g' and R h ' for non-existence.
在另一优选例中，Ri和Rj与它们连接的C原子共同形成取代或未取代的5-12元杂芳基、取代或未取代C6-C12芳基时，Ri’和Rj’为不存在。In another preferred embodiment, when R i and R j together with the C atoms to which they are connected form a substituted or unsubstituted 5-12-membered heteroaryl group or a substituted or unsubstituted C6-C12 aryl group, R i' and R j ' for non-existence.
在另一优选例中，Ri和R10与它们连接的C原子共同形成取代或未取代的5-12元杂芳基、取代或未取代C6-C12芳基时，Ri’和R10’为不存在。In another preferred embodiment, when R i and R 10 together with the C atom to which they are connected form a substituted or unsubstituted 5-12-membered heteroaryl group or a substituted or unsubstituted C6-C12 aryl group, R i' and R 10 ' for non-existence.
在另一优选例中，Rh和R10与它们连接的C原子共同形成取代或未取代的5-12元杂芳基、取代或未取代C6-C12芳基时，Rh’和R10’为不存在。In another preferred embodiment, when R h and R 10 together with the C atom to which they are connected form a substituted or unsubstituted 5-12-membered heteroaryl group or a substituted or unsubstituted C6-C12 aryl group, R h' and R 10 ' for non-existence.
在另一优选例中，Ra选自：卤素、羧基、羟基、氰基、氨基、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代COOC1-C6烷基、取代或未取代CO-4-6元杂环基、取代或未取代的C6-C10芳基、取代或未取代的5-10元杂芳基(优选5-6元或9-10元，例如呋喃基、噻吩基、吡啶基、吡咯基、吡唑基、咪唑基、苯并呋喃基、苯并噻吩基、吡啶并吡唑基)、取 代或未取代的C3-C6环烷基、取代或未取代的4-10元杂环基(优选4-6元单环杂环基、7-11元螺杂环基，例如哌啶基、吗啉基、哌嗪基、四氢吡咯基、)、取代或未取代的取代或未取代的C6-C10芳基NH、取代或未取代的5-6元杂环基并苯基(如)、取代或未取代的C5-C6环烷基并苯基、取代或未取代的苯基并5-6元杂环基(如)、取代或未取代的苯基并C5-C6环烷基、取代或未取代的5-6元杂环基并5-6元杂芳基、取代或未取代的C5-C6环烷基并5-6元杂芳基、取代或未取代的5-6元杂芳基并5-6元杂环基、取代或未取代的5-6元杂芳基并C5-C6环烷基，其中，所述取代是指被选自下组的一个或多个基团取代：卤素、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基；优选地Ra选自：卤素、羧基、羟基、氰基、氨基、硝基、甲氧基、三氟甲氧基、乙烯基、乙炔基、乙基、苯基、萘基、COOCH3、 In another preferred embodiment, Ra is selected from: halogen, carboxyl, hydroxyl, cyano, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted COOC1-C6 alkyl, substituted or unsubstituted CO-4-6 membered heterocyclyl, substituted or unsubstituted C6-C10 aryl base, substituted or unsubstituted 5-10-membered heteroaryl (preferably 5-6-membered or 9-10-membered, such as furyl, thienyl, pyridyl, pyrrolyl, pyrazolyl, imidazolyl, benzofuranyl , benzothienyl, pyridopyrazolyl), take Substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclyl (preferably 4-6 membered monocyclic heterocyclyl, 7-11 membered spiroheterocyclyl, such as piperidinyl, Morpholinyl, piperazinyl, tetrahydropyrrolyl, ), substituted or unsubstituted Substituted or unsubstituted C6-C10 aryl NH, substituted or unsubstituted 5-6 membered heterocyclylacene (such as ), substituted or unsubstituted C5-C6 cycloalkylphenyl, substituted or unsubstituted phenyl 5-6 membered heterocyclyl (such as ), substituted or unsubstituted phenyl C5-C6 cycloalkyl, substituted or unsubstituted 5-6 membered heterocyclyl and 5-6 membered heteroaryl, substituted or unsubstituted C5-C6 cycloalkyl 5-6 membered heteroaryl, substituted or unsubstituted 5-6 membered heteroaryl and 5-6 membered heterocyclyl, substituted or unsubstituted 5-6 membered heteroaryl with C5-C6 cycloalkyl, wherein , the substitution refers to substitution with one or more groups selected from the following group: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy group; preferably Ra is selected from: halogen, carboxyl, hydroxyl, cyano, amino, nitro, methoxy, trifluoromethoxy, vinyl, ethynyl, ethyl, phenyl, naphthyl, COOCH 3 ,
在另一优选例中，环A为取代或未取代的[6+5]杂芳基或稠环，其中，所述取代是指被1-5个R1取代；优选地为取代或未取代的吲哚基，更优选地为取代或未取代的其中，R1的定义如上所述。In another preferred embodiment, Ring A is a substituted or unsubstituted [6+5] heteroaryl or fused ring, wherein said substitution means substitution by 1-5 R 1 ; preferably substituted or unsubstituted indolyl, more preferably substituted or unsubstituted Among them, R 1 is defined as above.
在另一优选例中，环A选自以下结构：
In another preferred example, Ring A is selected from the following structures:
其中X选自：O、S、N或NH；Where X is selected from: O, S, N or NH;
R1是环上任意位置的取代基，个数为1-5(例如，1、2、3或4)个，各R1独立地选自：氢、卤素、羧基、羟基、氰基、氨基、硝基、 取代或未取代的苄基、取代或未取代的C6-C12芳基甲基、取代或未取代的5-12元杂芳基甲基、取代或未取代的杂芳基甲基、取代或未取代C1-C6烷基、取代或未取代C2-C6烯基、取代或未取代C2-C6炔基、取代或未取代C1-C6烷氧基、取代或未取代C1-C6烷基酰基、取代或未取代氨基酰基、取代或未取代C1-C6烷基酰胺基、取代或未取代C1-C4烷基氨基、取代或未取代C6-C12芳基氨基、取代或未取代3-8元杂环基、取代或未取代3-8元环烷基、取代或未取代5-12元元杂芳基、取代或未取代C6-C12芳基；R1中所述取代是指被一个或多个选自下组的基团取代：卤素、羧基、-OP(O)(OH)2、羟基、氰基、氨基、硝基、苄基、C1-C6烷基OH、C1-C6烷基氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C8环烷基或3-8元杂环基。R 1 is a substituent at any position on the ring, the number is 1-5 (for example, 1, 2, 3 or 4), each R 1 is independently selected from: hydrogen, halogen, carboxyl, hydroxyl, cyano, amino , nitro, Substituted or unsubstituted benzyl, substituted or unsubstituted C6-C12 arylmethyl, substituted or unsubstituted 5-12 membered heteroarylmethyl, substituted or unsubstituted heteroarylmethyl, substituted or unsubstituted Substituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkyl acyl, substituted Or unsubstituted aminoacyl, substituted or unsubstituted C1-C6 alkylamido, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C6-C12 arylamino, substituted or unsubstituted 3-8 membered heterocycle base, substituted or unsubstituted 3-8-membered cycloalkyl, substituted or unsubstituted 5-12-membered heteroaryl, substituted or unsubstituted C6-C12 aryl; the substitution in R 1 means to be substituted by one or more Substitution with groups selected from the group consisting of: halogen, carboxyl, -OP(O)(OH) 2 , hydroxyl, cyano, amino, nitro, benzyl, C1-C6 alkylOH, C1-C6 alkylamino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl or 3-8 membered heterocyclyl.
在另一优选例中，环A选自以下结构：
In another preferred example, Ring A is selected from the following structures:
其中，X选自NH；Among them, X is selected from NH;
R1是环上任意位置的取代基，个数为1、2或3个，R1的定义如上所述，优选地，R1选自：氢、卤素、氰基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、C6-C12芳基、C6-C12芳基NH、-OP(O)(OH)2取代的C1-C6烷基、氨基C1-C6烷基COO取代的C1-C6烷基；更优选地，R1选自：三氟甲基、苯基、苯氨基、氰基、甲氧基、Cl、F、Br、 在另一优选例中，环B选自以下结构：
R 1 is a substituent at any position on the ring, and the number is 1, 2 or 3. R 1 is as defined above. Preferably, R 1 is selected from: hydrogen, halogen, cyano, C1-C6 alkyl, Halogenated C1-C6 alkyl, C1-C6 alkoxy, C6-C12 aryl, C6-C12 aryl NH, -OP(O)(OH) 2 substituted C1-C6 alkyl, amino C1-C6 alkyl C1-C6 alkyl substituted by COO; more preferably, R 1 is selected from: trifluoromethyl, phenyl, phenylamino, cyano, methoxy, Cl, F, Br, In another preferred example, Ring B is selected from the following structures:
其中，in,
M为N或CH；M is N or CH;
R4选自：卤素、羧基、羟基、氰基、硝基、氨基、-COOC1-C6烷基、取代或未取代C1-C6烷基、取代或未取代C2-C6烯基、取代或未取代C2-C6炔基、取代或未取代C1-C6烷氧基、取代或未取代C1-C6烷基酰基、取代或未取代氨基甲酰基、取代或未取代C1-C6烷基酰胺基、取代或未取代C1-C4烷基氨基、取代或未取代C6-C12芳基氨基、取代或未取代3-8元杂环基、取代或未取代C3-C8环烷基、取代或未取代的5-12元杂芳基、取代或未取代C6-C12芳基、取代或未取代的C6-C12芳基C1-C6烷基、取代或未取代的5-12元杂芳基C1-C6烷基、-CO(3-8元取代或未取代杂环基)、-CO(C3-C8取代或未取代环烷基)；其中，所述取代是指被一个或多个选自下组的基团取代：卤素、羧基、羟基、氰基、氨基、硝基、SO2C1-C6烷基、CO2C1-C6烷基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷基OH、C1-C6烷氧基、卤代C1-C6烷氧基或3-8元杂环基；R 4 is selected from: halogen, carboxyl, hydroxyl, cyano, nitro, amino, -COOC1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylacyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted C1-C6 alkylamide, substituted or Unsubstituted C1-C4 alkylamino, substituted or unsubstituted C6-C12 arylamino, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5- 12-membered heteroaryl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C6-C12 aryl C1-C6 alkyl, substituted or unsubstituted 5-12-membered heteroaryl C1-C6 alkyl, -CO (3-8-membered substituted or unsubstituted heterocyclyl), -CO (C3-C8 substituted or unsubstituted cycloalkyl); wherein the substitution refers to one or more groups selected from the following group Substitution: halogen, carboxyl, hydroxyl, cyano, amino, nitro, SO 2 C1-C6 alkyl, CO 2 C1-C6 alkyl, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyl Base OH, C1-C6 alkoxy group, halogenated C1-C6 alkoxy group or 3-8 membered heterocyclic group;
R10选自：COOC1-C6烷基、-CO(3-8元取代或未取代杂环基)、-CO(C3-C8取代或未取代环烷基)、取代或未取代的C6-C12芳基C1-C6烷基、取代或未取代的5-12元杂芳基C1-C6烷基、取代或未取代C1-C6烷基、取代或未取代C2-C6烯基、取代或未取代C2-C6炔基、取代或未取代C1-C6烷氧基、取代或未取代C1-C6烷基酰基、取代或未取代氨基酰基、取代或未取代C1-C6烷基酰胺基、取代或未取代C1-C4烷基氨基、取代或未取代C6-C12芳基氨基、取代或未取代3-8元杂环基、取代或未取代C3-C8环烷基、取代或未取代3-8元杂环基C1-C6烷基、取代或未取代C3-C8环烷基C1-C6烷基、取代或未取代5-12元杂芳基、取代或未取代C6-C12芳基；其中，所述取代是指被一个或多个选自下组的基团取代：卤素、羧基、羟基、氰基、氨基、硝基、苄基、C1-C6烷基OH、C1-C6烷基氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基或3-8元杂环基；R 10 is selected from: COOC1-C6 alkyl, -CO (3-8-membered substituted or unsubstituted heterocyclyl), -CO (C3-C8 substituted or unsubstituted cycloalkyl), substituted or unsubstituted C6-C12 Aryl C1-C6 alkyl, substituted or unsubstituted 5-12 membered heteroaryl C1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkyl acyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted C1-C6 alkylamide, substituted or unsubstituted Substituted C1-C4 alkylamino, substituted or unsubstituted C6-C12 arylamino, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 membered Heterocyclyl C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl C1-C6 alkyl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl; wherein, The substitution refers to substitution by one or more groups selected from the following group: halogen, carboxyl, hydroxyl, cyano, amino, nitro, benzyl, C1-C6 alkyl OH, C1-C6 alkylamino, C1 -C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy or 3-8 membered heterocyclyl;
R2、R3、R5、R6、R7、R8和R9各自独立地选自：H、卤素、羧基、羟基、氰基、硝基、氨基、-COOC1-C6烷基、取代或未取代C1-C6烷基、取代或未取代C2-C6烯基、取代或未取代C2-C6炔基、取代或未取代C1-C6烷氧基、取代或未取代C1-C6烷基酰基、取代或未取代氨基甲酰基、取代或未取代C1-C6烷基酰胺基、取代或未取代C1-C4烷基氨基、取代或未取代C6-C12芳基氨基、取代或未取代3-8元杂环基、取代或未取代C3-C8环烷基、取代或未取代的5-12元杂芳基、取代或未取代C6-C12芳基、取代或未取代的 C6-C12芳基C1-C6烷基、取代或未取代的5-12元杂芳基C1-C6烷基、-CO(3-8元取代或未取代杂环基)、-CO(C3-C8取代或未取代环烷基)；其中，所述取代是指被一个或多个选自下组的基团取代：卤素、羧基、羟基、氰基、氨基、硝基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷基OH、C1-C6烷氧基或3-8元杂环基；R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 9 are each independently selected from: H, halogen, carboxyl, hydroxyl, cyano, nitro, amino, -COOC1-C6 alkyl, substituted Or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkyl acyl , substituted or unsubstituted carbamoyl, substituted or unsubstituted C1-C6 alkylamido, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C6-C12 arylamino, substituted or unsubstituted 3-8 Membered heterocyclyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C6-C12 aryl C1-C6 alkyl, substituted or unsubstituted 5-12 membered heteroaryl C1-C6 alkyl, -CO (3-8 membered substituted or unsubstituted heterocyclyl), -CO(C3- C8 substituted or unsubstituted cycloalkyl); wherein the substitution means substitution by one or more groups selected from the following group: halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C6 alkyl , halogenated C1-C6 alkyl, C1-C6 alkyl OH, C1-C6 alkoxy or 3-8 membered heterocyclyl;
或者R2和R3与它们所连接的碳原子形成取代或未取代的苯基或取代或未取代的5-8元杂芳基；其中，所述取代是指被一个或多个选自下组的基团取代：卤素、羧基、羟基、氰基、氨基、硝基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷基OH、C1-C6烷氧基或3-8元杂环基；Or R 2 and R 3 and the carbon atom to which they are connected form a substituted or unsubstituted phenyl group or a substituted or unsubstituted 5-8-membered heteroaryl group; wherein the substitution means being substituted by one or more selected from the following Group substitution of: halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyl OH, C1-C6 alkoxy or 3- 8-membered heterocyclyl;
或者R3和R4与它们所连接的碳原子形成取代或未取代的苯基或取代或未取代的5-8元杂芳基；其中，所述取代是指被一个或多个选自下组的基团取代：卤素、羧基、羟基、氰基、氨基、硝基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷基OH、C1-C6烷氧基或3-8元杂环基；Or R 3 and R 4 and the carbon atoms to which they are connected form a substituted or unsubstituted phenyl group or a substituted or unsubstituted 5-8-membered heteroaryl group; wherein the substitution means being substituted by one or more selected from the following Group substitution of: halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyl OH, C1-C6 alkoxy or 3- 8-membered heterocyclyl;
或者R4和R5与它们所连接的碳原子形成取代或未取代的苯基或取代或未取代的5-8元杂芳基；其中，所述取代是指被一个或多个选自下组的基团取代：卤素、羧基、羟基、氰基、氨基、硝基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷基OH、C1-C6烷氧基或3-8元杂环基；Or R 4 and R 5 and the carbon atoms to which they are connected form a substituted or unsubstituted phenyl group or a substituted or unsubstituted 5-8-membered heteroaryl group; wherein the substitution means being substituted by one or more selected from the following Group substitution of: halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyl OH, C1-C6 alkoxy or 3- 8-membered heterocyclyl;
或者R6和R7与它们所连接的碳原子形成取代或未取代的苯基或取代或未取代的5-8元杂芳基；其中，所述取代是指被一个或多个选自下组的基团取代：卤素、羧基、羟基、氰基、氨基、硝基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷基OH、C1-C6烷氧基或3-8元杂环基；Or R 6 and R 7 and the carbon atoms to which they are connected form a substituted or unsubstituted phenyl group or a substituted or unsubstituted 5-8 membered heteroaryl group; wherein the substitution means being substituted by one or more selected from the following Group substitution of: halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyl OH, C1-C6 alkoxy or 3- 8-membered heterocyclyl;
或者R7和R8与它们所连接的碳原子形成取代或未取代的苯基或取代或未取代的5-8元杂芳基；其中，所述取代是指被一个或多个选自下组的基团取代：卤素、羧基、羟基、氰基、氨基、硝基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷基OH、C1-C6烷氧基或3-8元杂环基；Or R 7 and R 8 and the carbon atom to which they are connected form a substituted or unsubstituted phenyl group or a substituted or unsubstituted 5-8 membered heteroaryl group; wherein the substitution means being substituted by one or more selected from the following Group substitution of: halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyl OH, C1-C6 alkoxy or 3- 8-membered heterocyclyl;
或者R8和R9与它们所连接的碳原子形成取代或未取代的苯基或取代或未取代的5-8元杂芳基；其中，所述取代是指被一个或多个选自下组的基团取代：卤素、羧基、羟基、氰基、氨基、硝基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷基OH、C1-C6烷氧基或3-8元杂环基；Or R 8 and R 9 and the carbon atom to which they are connected form a substituted or unsubstituted phenyl group or a substituted or unsubstituted 5-8 membered heteroaryl group; wherein the substitution means being substituted by one or more selected from the following Group substitution of: halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyl OH, C1-C6 alkoxy or 3- 8-membered heterocyclyl;
Ra、Ra’、Rb、Rb’、Rc、Rc’、Rd、Rd’、Re、Re’、Rf、Rf’、Rg、Rg’、Rh、Rh’、Ri、Ri’、Rj和Rj’各自独立地选自：氢、卤素、羧基、羟基、氰基、氨基、-COOC1-C6烷基、硝基、-CO(3-8元取代或未取代杂环基)、-CO(C3-C8取代或未取代环烷基)、取代或未取代的C6-C12芳基C1-C6烷基、取代或未取代的5-12元杂芳基C1-C6烷基、取代或未取代C1-C6烷基、取代或未取代C2-C6烯基、取代或未取代C2-C6炔基、取代或未取代C1-C6烷氧基、取代或未取代C1-C6烷基酰基、取代或未取代氨基酰基、取代或未取代C1-C6烷基酰胺基、取代或未取代C1-C4烷基氨基、取代或未取代C6-C12芳基氨基、取代或未取代 3-8元杂环基、取代或未取代C3-C8环烷基、取代或未取代3-8元杂环基C1-C6烷基、取代或未取代C3-C8环烷基C1-C6烷基、取代或未取代5-12元杂芳基、取代或未取代C6-C12芳基；其中，所述取代是指被一个或多个Ra取代；R a , R a' , R b , R b' , R c , R c' , R d , R d ' , R e , R e ' , R f , R f ' , R g , R g ' , R h , R h' , R i , R i' , R j and R j' are each independently selected from: hydrogen, halogen, carboxyl, hydroxyl, cyano, amino, -COOC1-C6 alkyl, nitro, -CO (3-8-membered substituted or unsubstituted heterocyclyl), -CO (C3-C8 substituted or unsubstituted cycloalkyl), substituted or unsubstituted C6-C12 aryl C1-C6 alkyl, substituted or unsubstituted 5-12 membered heteroaryl C1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 Alkoxy, substituted or unsubstituted C1-C6 alkylamino, substituted or unsubstituted aminoacyl, substituted or unsubstituted C1-C6 alkylamido, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C6 -C12 arylamino, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl C1-C6 alkyl base, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl; wherein, the substitution means substitution by one or more Ra;
环C选自：取代或未取代3-8元杂环基、取代或未取代C3-C8环烷基、取代或未取代5-8元杂芳基、取代或未取代6-12元芳基；其中，所述取代是指被一个或多个选自下组的基团取代：卤素、羧基、羟基、氰基、氨基、硝基、苄基、C1-C6烷基OH、C1-C6烷基氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基或3-8元杂环基；Ring C is selected from: substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-8 membered heteroaryl, substituted or unsubstituted 6-12 membered aryl ; Wherein, the substitution refers to being substituted by one or more groups selected from the following group: halogen, carboxyl, hydroxyl, cyano, amino, nitro, benzyl, C1-C6 alkyl OH, C1-C6 alkyl amino group, C1-C6 alkyl group, halogenated C1-C6 alkyl group, C1-C6 alkoxy group, halogenated C1-C6 alkoxy group or 3-8 membered heterocyclyl group;
m为0、1、2、3、4或5；m is 0, 1, 2, 3, 4 or 5;
n为1或2；n is 1 or 2;
Ra的定义如上所述。Ra is defined as above.
在另一优选例中，Ra、Ra’、Rb、Rb’、Rc、Rc’、Rd、Rd’、Re、Re’、Rf、Rf’、Rg、Rg’、Rh、Rh’、Ri、Ri’、Rj、Rj’各自独立地选自：氢、卤素、羧基、羟基、氰基、氨基、硝基、取代或未取代的苄基、取代或未取代的C6-C12芳基甲基、取代或未取代的5-12元杂芳基甲基、取代或未取代C1-C6烷基、取代或未取代C2-C6烯基、取代或未取代C2-C6炔基、取代或未取代C1-C6烷氧基、取代或未取代C1-C6烷基酰基、取代或未取代氨基酰基、取代或未取代C1-C6烷基酰胺基、取代或未取代C1-C4烷基氨基、取代或未取代C6-C12芳基氨基、取代或未取代3-8元杂环基、取代或未取代3-8元环烷基、取代或未取代5-8元杂芳基、取代或未取代6-12元芳基；所述取代为单取代或多取代，各取代基独立为卤素、羧基、羟基、氰基、氨基、硝基、三氟甲氧基、苄基、HOCH2-、HOCH2CH2-、CF2CH-、CF3CH2CH2-、C1-C6烷基、C1-C6烷氧基或3-8元杂环基。In another preferred example, R a , R a' , R b , R b' , R c , R c ' , R d , R d' , Re , Re ' , R f , R f ' , R g , R g' , Rh , Rh ' , R i , R i' , R j , R j' are each independently selected from: hydrogen, halogen, carboxyl, hydroxyl, cyano, amino, nitro, Substituted or unsubstituted benzyl, substituted or unsubstituted C6-C12 arylmethyl, substituted or unsubstituted 5-12 membered heteroarylmethyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkyl acyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted C1 -C6 alkylamido, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C6-C12 arylamino, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted 3-8 membered ring Alkyl, substituted or unsubstituted 5-8-membered heteroaryl, substituted or unsubstituted 6-12-membered aryl; the substitution is mono-substituted or poly-substituted, and each substituent is independently halogen, carboxyl, hydroxyl, cyano, Amino, nitro, trifluoromethoxy, benzyl, HOCH 2 -, HOCH 2 CH 2 -, CF 2 CH-, CF 3 CH 2 CH 2 -, C1-C6 alkyl, C1-C6 alkoxy or 3-8 membered heterocyclyl.
在另一优选例中，当Ra和Ra’均为氧原子时，与所连接的碳原子构成羰基；当Rb和Rb’均为氧原子时，与所连接的碳原子构成羰基；当Rc和Rc’均为氧原子时，与所连接的碳原子构成羰基；当Rd和Rd’均为氧原子时，与所连接的碳原子构成羰基；当Re和Re’均为氧原子时，与所连接的碳原子构成羰基；当Rf和Rf’均为氧原子时，与所连接的碳原子构成羰基；当Rg和Rg’均为氧原子时，与所连接的碳原子构成羰基；当Rh和Rh’均为氧原子时，与所连接的碳原子构成羰基；当Ri和Ri’均为氧原子时，与所连接的碳原子构成羰基；当Rj和Rj’均为氧原子时，与所连接的碳原子构成羰基。In another preferred example, when R a and R a' are both oxygen atoms, they form a carbonyl group with the connected carbon atom; when R b and R b' are both oxygen atoms, they form a carbonyl group with the connected carbon atom. ; When R c and R c' are both oxygen atoms, they form a carbonyl group with the connected carbon atom; when R d and R d' are both oxygen atoms, they form a carbonyl group with the connected carbon atom; when R e and R When e' is an oxygen atom, it forms a carbonyl group with the connected carbon atom; when R f and R f' are both oxygen atoms, it forms a carbonyl group with the connected carbon atom; when R g and R g' are both oxygen atoms When R h and R h' are oxygen atoms, they form a carbonyl group with the connected carbon atom; when R h and R h' are both oxygen atoms, they form a carbonyl group with the connected carbon atom; when R i and R i' are both oxygen atoms, they form a carbonyl group with the connected carbon atom. Carbon atoms constitute a carbonyl group; when R j and R j' are both oxygen atoms, they form a carbonyl group with the connected carbon atom.
在另一优选例中，环B选自以下结构：
In another preferred example, Ring B is selected from the following structures:
M、R2、R3、R4、R5、R6、R7、R8、R9、R10、Ra、Ra’、Rb、Rb’、Rc、Rc’、Rg、Rg’、Rh、Rh’、Ri、Ri’、Rj、Rj’和n的定义如上所述。M, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R a , R a' , R b , R b' , R c , R c' , R g , R g' , Rh , Rh ' , R i , R i' , R j , R j' and n are defined as above.
在另一优选例中，R4选自：卤素、羧基、羟基、氰基、氨基、硝基、取代或未取代的苄基、取代或未取代的芳基甲基、取代或未取代的杂芳基甲基、取代或未取代的杂芳基甲基、取代或未取代C1-C6烷基、取代或未取代C2-C6烯基、取代或未取代C2-C6炔基、取代或未取代C1-C6烷氧基、取代或未取代C1-C6烷基酰基、取代或未取代氨基酰基、取代或未取代C1-C6烷基酰胺基、取代或未取代C1-C4烷基氨基、取代或未取代6-12元芳基氨基、取代或未取代3-8元杂环基、取代或未取代3-8元环烷基、取代或未取代5-8元杂芳基、取代或未取代6-12元芳基；其中，所述取代是指被一个或多个选自下组的基团取代：卤素、羧基、羟基、氰基、氨基、硝基、SO2C1-C6烷基、CO2C1-C6烷基、三氟甲氧基、苄基、HOCH2-、HOCH2CH2-、CF2CH-、CF3CH2CH2-、C1-C6烷基、C1-C6烷氧基或3-8元杂环基。In another preferred example, R 4 is selected from: halogen, carboxyl, hydroxyl, cyano, amino, nitro, Substituted or unsubstituted benzyl, substituted or unsubstituted arylmethyl, substituted or unsubstituted heteroarylmethyl, substituted or unsubstituted heteroarylmethyl, substituted or unsubstituted C1-C6 alkyl, Substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkyl acyl, substituted or unsubstituted aminoacyl, substituted Or unsubstituted C1-C6 alkylamido, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted 6-12 membered arylamino, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted 3-8-membered cycloalkyl, substituted or unsubstituted 5-8-membered heteroaryl, substituted or unsubstituted 6-12-membered aryl; wherein, the substitution refers to one or more groups selected from the following group Substitution: halogen, carboxyl, hydroxyl, cyano, amino, nitro, SO 2 C1-C6 alkyl, CO 2 C1-C6 alkyl, trifluoromethoxy, benzyl, HOCH 2 -, HOCH 2 CH 2 - , CF 2 CH-, CF 3 CH 2 CH 2 -, C1-C6 alkyl, C1-C6 alkoxy or 3-8 membered heterocyclyl.
在另一优选例中，R4选自：卤素、羟基、羧基、硝基、 氰基、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、5-8元杂芳基、苯基、萘基、C3-C8环烷基、3-8元杂环基；其中，所述C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、5-8元杂芳基、苯基、萘基、C3-C8环烷基、3-8元杂环基任选地被1-3个如下基团取代：卤素、羟基、羧基、酯基、氰基、SO2C1-C6烷基、CO2C1-C6烷基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基。In another preferred example, R 4 is selected from: halogen, hydroxyl, carboxyl, nitro, Cyano, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 5-8 membered heteroaryl, phenyl, naphthyl, C3-C8 cycloalkyl, 3 -8-membered heterocyclyl; wherein, the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 5-8-membered heteroaryl, phenyl, naphthyl, C3-C8 cycloalkyl and 3-8 membered heterocyclyl are optionally substituted by 1-3 of the following groups: halogen, hydroxyl, carboxyl, ester group, cyano group, SO 2 C1-C6 alkyl, CO 2 C1 -C6 alkyl, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy.
在另一优选例中，R10选自：C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、5-8元杂芳基、苯基、萘基、C3-C8环烷基、3-8元杂环基；其中，所述C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、5-8元杂芳基、苯基、萘基、C3-C8环烷基、3-8元杂环基任选地被1-3个如下基团取代：卤素、羟基、羧基、酯基、氰基、C1-C6烷基、卤代C1-C6烷基。In another preferred example, R 10 is selected from: C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 5-8 membered heteroaryl, phenyl, naphthyl , C3-C8 cycloalkyl, 3-8 membered heterocyclyl; wherein, the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 5-8 membered heterocyclic group Aryl, phenyl, naphthyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl are optionally substituted by 1-3 of the following groups: halogen, hydroxyl, carboxyl, ester group, cyano group, C1- C6 alkyl, halogenated C1-C6 alkyl.
在另一优选例中，所述化合物具有式II-1～II-3所示的结构
In another preferred example, the compound has the structure represented by formulas II-1 to II-3
式中，G为6元芳基或杂芳基；In the formula, G is a 6-membered aryl group or heteroaryl group;
G’为C6-C12芳基或5-12元杂芳基；G’ is C6-C12 aryl or 5-12 membered heteroaryl;
G”为C6-芳基或5-6元杂芳基；G” is C6-aryl or 5-6 membered heteroaryl;
Rm各自独立地选自：氢、卤素、羧基、羟基、氰基、氨基、-COOC1-C6烷基、硝基、-CO(3-8元取代或未取代杂环基)、-CO(C3-C8取代或未取代环烷基)、取代或未取代的C6-C12芳基C1-C6烷基、取代或未取代的5-12元杂芳基C1-C6烷基、取代或未取代C1-C6烷基、取代或未取代C2-C6烯基、取代或未取代C2-C6炔基、取代或未取代C1-C6烷氧基、取代或未取代C1-C6烷基酰基、取代或未取代氨基酰基、取代或未取代C1-C6烷基酰胺基、取代或未取代C1-C4烷基氨基、取代或未取代C6-C12芳基氨基、取代或未取代3-8元杂环基、取代或未取代C3-C8环烷基、取代或未取代5-12元杂芳基、取代或未取代C6-C12芳基；其中所述取代是指被一个或多个选自下组的基团取代：卤素、羧基、-OP(O)(OH)2、羟基、氰基、氨基、硝基、苄基、C1-C6烷基OH、C1-C6烷基氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C8环烷基或3-8元杂环基；优选地，Rm各自独立地选自：氢、卤素、氰基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、C6-C12芳基、5-12元杂芳基、C6-C12芳基NH、-OP(O)(OH)2取代的C1-C6烷基、氨基C1-C6烷基COO取代的C1-C6烷基；更优选地，Rm各自独立地选自：三氟甲基、苯基、苯氨基、氰基、甲氧基、Cl、F、Br、 R m is each independently selected from: hydrogen, halogen, carboxyl, hydroxyl, cyano, amino, -COOC1-C6 alkyl, nitro, -CO (3-8 membered substituted or unsubstituted heterocyclyl), -CO( C3-C8 substituted or unsubstituted cycloalkyl), substituted or unsubstituted C6-C12 aryl C1-C6 alkyl, substituted or unsubstituted 5-12 membered heteroaryl C1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkyl acyl, substituted or Unsubstituted aminoacyl, substituted or unsubstituted C1-C6 alkylamido, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C6-C12 arylamino, substituted or unsubstituted 3-8 membered heterocyclyl , substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl; wherein said substitution means being selected from the group consisting of one or more Group substitution: halogen, carboxyl, -OP(O)(OH) 2 , hydroxyl, cyano, amino, nitro, benzyl, C1-C6 alkyl OH, C1-C6 alkylamino, C1-C6 alkyl , halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl or 3-8 membered heterocyclyl; preferably, R m is each independently selected from : Hydrogen, halogen, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C6-C12 aryl, 5-12 membered heteroaryl, C6-C12 aryl NH, -OP(O)(OH) 2 substituted C1-C6 alkyl, amino C1-C6 alkyl COO substituted C1-C6 alkyl; more preferably, R m is each independently selected from: trifluoromethyl, benzene group, phenylamino, cyano, methoxy, Cl, F, Br,
Rm’各自独立地选自：氢、卤素、羧基、羟基、氰基、氨基、硝基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C8环烷基或3-8元杂环基；R m' are each independently selected from: hydrogen, halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkoxy, haloC1- C6 alkoxy, C3-C8 cycloalkyl or 3-8 membered heterocyclyl;
Rm”和Rm”’各自独立地选自：H、卤素、羧基、羟基、氰基、硝基、氨基、-COOC1-C6烷基、取代或未取代C1-C6烷基、取代或未取代C2-C6烯基、取代或未取代C2-C6炔基、取代或未取代C1-C6烷氧基、取代或未取代C1-C6烷基酰基、取代或未取代氨基甲酰基、取代或未取代C1-C6烷基酰胺基、取代或未取代C1-C4烷基氨基、取代或未取代C6-C12芳基氨基、取代或未取代3-8元杂环基、取代或未取代C3-C8环烷基、取代或未取代的5-12元杂芳基、取代或未取代C6-C12芳基、取代或未取代的C6-C12芳基C1-C6烷基、取代或未取代的5-12元杂芳基C1-C6烷基、-CO(3-8元取代或未取代杂环基)、-CO(C3-C8取代或未取代环烷基)；其中，所述取代是指被一个或多个选自下组的基团取代：卤素、羧基、羟基、氰基、氨基、硝基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷基OH、C1-C6烷氧基、C3-C8环烷基或3-8元杂环基； R m" and R m"' are each independently selected from: H, halogen, carboxyl, hydroxyl, cyano, nitro, amino, -COOC1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted Substituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkyl acyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted Substituted C1-C6 alkylamido, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C6-C12 arylamino, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted C3-C8 Cycloalkyl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C6-C12 aryl C1-C6 alkyl, substituted or unsubstituted 5- 12-membered heteroaryl C1-C6 alkyl, -CO (3-8-membered substituted or unsubstituted heterocyclyl), -CO (C3-C8 substituted or unsubstituted cycloalkyl); wherein, the substitution means by One or more groups selected from the following group are substituted: halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyl OH, C1- C6 alkoxy, C3-C8 cycloalkyl or 3-8 membered heterocyclyl;
n为1或2；n is 1 or 2;
f、f’、f”和f”’各自独立地为0、1、2或3；f, f’, f” and f”’ are each independently 0, 1, 2 or 3;
R4的定义如上所述。R 4 is defined as above.
在另一优选例中，环A为优选地为更优选地为 In another preferred example, ring A is Preferably More preferably
其中，Rm、f的定义如上所述；Among them, Rm and f are defined as above;
其中，Rm1、Rm2、Rm3的定义同Rm，优选地，Rm1、Rm2、Rm3各自独立地选自：H、卤素、羧基、羟基、氰基、氨基、-COOC1-C6烷基、硝基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、4-6元杂环基、C6-C10芳基、C6-C10芳基NH、5-6元杂芳基、C6-C10芳基取代的5-6元杂芳基、-OP(O)(OH)2取代的C1-C6烷基、氨基C1-C6烷基COO取代的C1-C6烷基；优选地，Rm1、Rm2、Rm3各自独立地选自：H、三氟甲基、 苯基、苯氨基、氰基、硝基、甲氧基、Cl、F、Br、 Wherein, the definitions of R m1 , R m2 and R m3 are the same as R m . Preferably, R m1 , R m2 and R m3 are each independently selected from: H, halogen, carboxyl, hydroxyl, cyano group, amino group, -COOC1-C6 Alkyl, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C6-C10 aryl, C6- C10 aryl NH, 5-6 membered heteroaryl, C6-C10 aryl substituted 5-6 membered heteroaryl, -OP(O)(OH) 2 substituted C1-C6 alkyl, amino C1-C6 alkyl C1-C6 alkyl group substituted by COO; preferably, R m1 , R m2 , and R m3 are each independently selected from: H, trifluoromethyl, Phenyl, phenylamino, cyano, nitro, methoxy, Cl, F, Br,
在另一优选例中，B环选自： In another preferred example, B ring is selected from:
在另一优选例中，环B为优选地为更优选地选自： 其中，R4、Rm’、Rm”、f’和f”的定义如上所述。In another preferred example, Ring B is Preferably More preferably selected from: Among them, R 4 , R m' , R m" , f' and f" are defined as above.
在另一优选例中，R4选自：H、卤素、羧基、羟基、氰基、氨基、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代COOC1-C6烷基、取代或未取代CO-4-6元杂环基、取代或未取代的C6-C10芳基、取代或未取代的5-10元杂芳基(优选5-6元或9-10元，例如呋喃基、噻吩基、吡啶基、吡咯基、吡唑基、咪唑基、苯并呋喃基、苯并噻吩基、吡啶并吡唑基)、取代或未取代的C3-C6环烷基、取代或未取代的4-10元杂环基(优选4-6元单环杂环基、7-11元螺杂环基，例如哌啶基、吗啉基、哌嗪基、四氢吡咯基、 )、取代或未取代的取代或未取代的C6-C10芳基NH、取代或未取代的5-6元杂环基并苯基(如)、取代或未取代的C5-C6环烷基并苯基、取代或未取代的苯基并5-6元杂环基(如)、取代或未取代的苯基并C5-C6环烷基、取代或未取代的5-6元杂环基并5-6元杂芳基、取代或未取代的C5-C6环烷基并5-6元杂芳基、取代或未取代的5-6元杂芳基并5-6元杂环基、取代或未取代的5-6元杂芳基并C5-C6环烷基，其中，所述取代是指被选自下组的一个或多个基团取代：卤素、羧基、羟基、氰基、氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基；优选地，R4选自：H、卤素、羧基、羟基、氰基、氨基、硝基、乙烯基、乙炔基、乙基、苯基、萘基、 In another preferred embodiment, R 4 is selected from: H, halogen, carboxyl, hydroxyl, cyano, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or Unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted COOC1-C6 alkyl, substituted or unsubstituted CO-4-6 membered heterocyclyl, substituted or unsubstituted C6 -C10 aryl, substituted or unsubstituted 5-10-membered heteroaryl (preferably 5-6-membered or 9-10-membered, such as furyl, thienyl, pyridyl, pyrrolyl, pyrazolyl, imidazolyl, benzene Furyl, benzothienyl, pyridopyrazolyl), substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclyl (preferably 4-6 membered monocyclic heterocycle base, 7-11 membered spiroheterocyclyl, such as piperidinyl, morpholinyl, piperazinyl, tetrahydropyrrolyl, ), substituted or unsubstituted Substituted or unsubstituted C6-C10 aryl NH, substituted or unsubstituted 5-6 membered heterocyclylacene (such as ), substituted or unsubstituted C5-C6 cycloalkylphenyl, substituted or unsubstituted phenyl 5-6 membered heterocyclyl (such as ), substituted or unsubstituted phenyl C5-C6 cycloalkyl, substituted or unsubstituted 5-6 membered heterocyclyl and 5-6 membered heteroaryl, substituted or unsubstituted C5-C6 cycloalkyl 5-6 membered heteroaryl, substituted or unsubstituted 5-6 membered heteroaryl and 5-6 membered heterocyclyl, substituted or unsubstituted 5-6 membered heteroaryl with C5-C6 cycloalkyl, wherein , the substitution refers to substitution with one or more groups selected from the following group: halogen, carboxyl, hydroxyl, cyano, amino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy group, halogenated C1-C6 alkoxy group; preferably, R 4 is selected from: H, halogen, carboxyl, hydroxyl, cyano, amino, nitro, vinyl, ethynyl, ethyl, phenyl, naphthyl,
在另一优选例中，一种式I化合物的前药，其具有式III-1或III-2所示的结构
In another preferred embodiment, a prodrug of the compound of formula I has the structure shown in formula III-1 or III-2
式中，L为C1-C6亚烷基；In the formula, L is C1-C6 alkylene;
Rn选自：-P(O)(OH)2或氨基C1-C6烷基CO；优选地为 Rn is selected from: -P(O)(OH) 2 or amino C1-C6 alkyl CO; preferably
G、G’、R4、Rm’、Rm”、Rm”’、f’、f”和f”’的定义如上所述。G, G', R 4 , R m' , R m" , R m"' , f', f" and f"' are defined as above.
在另一优选例中，Q、环A、环B、G、G’、G”、E、Ra、Ra’、Rb、Rb’、Rc、Rc’、Rd、Rd’、Re、Re’、Rf、Rf’、Rg、Rg’、Rh、Rh’、Ri、Ri’、Rj、Rj’、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、Rm、Rm’、Rm”和Rm”’为实施例中各具体化合物所对应基团。In another preferred example, Q, ring A, ring B, G, G′, G″, E, R a , R a′ , R b , R b ′ , R c , R c′ , R d , R d' , R e , R e' , R f , R f' , R g , R g' , R h , R h' , R i, R i ', R j , R j ' , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R m , R m' , R m " and R m"' are the bases corresponding to each specific compound in the examples. group.
在另一优选例中，所述化合物选自以下化合物：

In another preferred embodiment, the compound is selected from the following compounds:

在另一优选例中，所述化合物不为 In another preferred embodiment, the compound is not
本发明第二方面，提供一种药物组合物，所述药物组合物包含治疗有效量的选自第一 方面所述的化合物，或其前药、其对映异构体、非对映异构体、外消旋体及其混合物，或其药学上可接受的盐中的一种或多种；以及任选地药学上可接受的载体。In a second aspect, the present invention provides a pharmaceutical composition, which comprises a therapeutically effective amount selected from the first The compound described in the aspect, or one or more of its prodrugs, its enantiomers, diastereomers, racemates and mixtures thereof, or its pharmaceutically acceptable salts; and Optionally a pharmaceutically acceptable carrier.
本发明第三方面，提供一种第一方面所述的化合物，或其前药、其对映异构体、非对映异构体、外消旋体及其混合物，或其药学上可接受的盐或如第二方面所述的药物组合物的用途，其特征在于，用于制备cGAS/STING通路靶向抑制剂；或The third aspect of the present invention provides a compound described in the first aspect, or its prodrug, its enantiomers, diastereomers, racemates and mixtures thereof, or its pharmaceutically acceptable The salt or the use of the pharmaceutical composition as described in the second aspect, characterized in that it is used to prepare a cGAS/STING pathway targeted inhibitor; or
用于制备预防和/或治疗炎症性疾病和自身免疫性疾病的药物。For the preparation of drugs for the prevention and/or treatment of inflammatory diseases and autoimmune diseases.
在另一优选例中，所述炎症性疾病和自身免疫性疾病选自：Singleton-Merten综合征(SMS)、Aicardi–Goutières综合征(AGS)、系统性红斑狼疮(SLE)、家族性冻疮性红斑狼疮(FCL)、视网膜血管病与脑白质营养不良(RVCL)、STING相关的婴儿期发病血管病变(SAVI)、硬皮病、银肩病、斯耶格伦氏综合征、类风湿性关节炎、炎症性肠病、多发性硬化、克罗恩病、溃疡性结肠炎、自身免疫性结肠炎、小肠吸收不良综合征、肠易激综合征、葡萄膜炎、粘膜炎、糖尿病、心血管疾病和神经退行性疾病。In another preferred embodiment, the inflammatory disease and autoimmune disease are selected from: Singleton-Merten syndrome (SMS), Aicardi-Goutières syndrome (AGS), systemic lupus erythematosus (SLE), familial chilblains Lupus erythematosus (FCL), retinal vasculopathy and leukodystrophy (RVCL), STING-associated vasculopathy of infancy (SAVI), scleroderma, psoriasis, Sjogren's syndrome, rheumatoid joints inflammation, inflammatory bowel disease, multiple sclerosis, Crohn's disease, ulcerative colitis, autoimmune colitis, small intestinal malabsorption syndrome, irritable bowel syndrome, uveitis, mucositis, diabetes, cardiovascular disease diseases and neurodegenerative diseases.
本发明第四方面，提供了一种抑制STING蛋白活性的方法，将第一方面所述的化合物与能够表达STING蛋白的细胞接触，可以通过抑制STING蛋白的活性来抑制干扰素的分泌。The fourth aspect of the present invention provides a method for inhibiting the activity of STING protein. Contacting the compound described in the first aspect with cells capable of expressing STING protein can inhibit the secretion of interferon by inhibiting the activity of STING protein.
在另一优选例中，所述细胞为人源和/或鼠源的。In another preferred embodiment, the cells are of human and/or mouse origin.
在另一优选例中，所述细胞为THP1-Blue-ISG细胞和/或Raw-lucia细胞。In another preferred embodiment, the cells are THP1-Blue-ISG cells and/or Raw-lucia cells.
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described one by one here.
具体实施方式Detailed ways
本申请的发明人经过广泛而深入地研究，研发出一种二氢异喹啉类化合物，能够用作cGAS/STING信号通路靶向抑制剂，用于炎症性疾病和自身免疫性疾病的治疗。在此基础上，完成了本发明。After extensive and in-depth research, the inventor of the present application has developed a dihydroisoquinoline compound that can be used as a targeted inhibitor of the cGAS/STING signaling pathway for the treatment of inflammatory diseases and autoimmune diseases. On this basis, the present invention was completed.
术语the term
在本发明中，所述卤素为F、Cl、Br或I。In the present invention, the halogen is F, Cl, Br or I.
在本发明中，除非特别指出，所用术语具有本领域技术人员公知的一般含义。In the present invention, unless otherwise specified, the terms used have their ordinary meanings known to those skilled in the art.
在本发明中，术语“C1-C6”是指具有1、2、3、4、5或6个碳原子，“C1-C8”是指具有1、2、3、4、5、6、7或8个碳原子，依此类推。In the present invention, the term "C1-C6" means having 1, 2, 3, 4, 5 or 6 carbon atoms, and "C1-C8" means having 1, 2, 3, 4, 5, 6, 7 Or 8 carbon atoms, and so on.
“5-12元”是指具有5-12个环原子，依此类推。"5-12 membered" means having 5-12 ring atoms, and so on.
在本发明中，术语“烷基”表示饱和的线性或支链烃部分，例如术语“C1-C6烷基”是指具有1至6个碳原子的直链或支链烷基，非限制性地包括甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基和已基等；优选乙基、丙基、异丙基、丁 基、异丁基、仲丁基和叔丁基。In the present invention, the term "alkyl" refers to a saturated linear or branched chain hydrocarbon moiety. For example, the term "C1-C6 alkyl" refers to a non-limiting linear or branched alkyl group having 1 to 6 carbon atoms. Include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl, etc.; preferably ethyl, propyl, isopropyl, butyl base, isobutyl, sec-butyl and tert-butyl.
在本发明中，术语“烷氧基”表示-O-(烷基)基团。例如术语“C1-C6烷氧基”是指具有1至6个碳原子的直链或支链烷氧基，非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。In the present invention, the term "alkoxy" means an -O-(alkyl) group. For example, the term "C1-C6 alkoxy" refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, including, but not limited to, methoxy, ethoxy, propoxy, and isopropoxy and butoxy etc.
在本发明中，术语“烯基”表示包含至少一个双键的直链或支链烃基部分，例如术语“C2-C6烯基”是指具有2至6个碳原子的含有一个双键的直链或支链烯基，非限制性地包括乙烯基、丙烯基、丁烯基、异丁烯基、戊烯基和己烯基等。In the present invention, the term "alkenyl" refers to a straight-chain or branched hydrocarbon moiety containing at least one double bond. For example, the term "C2-C6 alkenyl" refers to a straight-chain or branched hydrocarbon moiety having 2 to 6 carbon atoms and containing one double bond. Chain or branched alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl, and the like.
在本发明中，术语“炔基”是指含有一个三键的直链或支链炔基，例如术语“C2-C6炔基”是指具有2至6个碳原子的含有一个三键的直链或支链炔基，非限制性地包括乙块基、丙块基、丁炔基、异丁炔基、戊炔基和己炔基等。In the present invention, the term "alkynyl" refers to a straight chain or branched chain alkynyl group containing a triple bond. For example, the term "C2-C6 alkynyl" refers to a straight chain or branched chain alkynyl group having 2 to 6 carbon atoms and containing a triple bond. Chain or branched alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, isobutynyl, pentynyl, hexynyl, and the like.
在本发明中，术语“环烷基”表示饱和的环状烃基部分，例如术语“C3-C10环烷基”是指在环上具有3至10个碳原子的环状烷基，非限制性地包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基和环癸基等。术语“C3-C8环烷基”、“C3-C7环烷基”、和“C3-C6环烷基”具有类似的含义。In the present invention, the term "cycloalkyl" refers to a saturated cyclic hydrocarbon moiety. For example, the term "C3-C10 cycloalkyl" refers to a cyclic alkyl group having 3 to 10 carbon atoms in the ring, without limitation. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclodecyl, etc. The terms "C3-C8 cycloalkyl", "C3-C7 cycloalkyl", and "C3-C6 cycloalkyl" have similar meanings.
术语“杂环基”是指具有选自N、S和O的杂原子的饱和或部分饱和的环状基团，其可以是单环，也可以是双环形式，例如桥环或螺环形式。杂环基优选3-8元杂环基，更优选地为4-6元杂环基，更优选地为5-6元杂环基。杂环基的实例包括但不限于：氧杂环丁烷、氮杂环丁烷、四氢-2H-吡喃基、哌啶基、哌嗪基、四氢呋喃基、吗啉基和吡咯烷基、等。The term "heterocyclyl" refers to a saturated or partially saturated cyclic group having a heteroatom selected from N, S and O, which may be a monocyclic or bicyclic form, such as a bridged ring or a spirocyclic form. The heterocyclyl group is preferably a 3-8-membered heterocyclyl group, more preferably a 4-6-membered heterocyclyl group, and more preferably a 5-6-membered heterocyclyl group. Examples of heterocyclyl groups include, but are not limited to: oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, tetrahydrofuranyl, morpholinyl and pyrrolidinyl, wait.
在本发明中，术语“芳基”表示包含一个或多个芳环的烃基部分。例如术语“C6-C12芳基”是指在环上不含杂原子的具有6至12个碳原子的芳香族环基，优选C6-C10芳基，如苯基、萘基等。术语“C6-C12芳基”具有类似的含义。6-12元芳基与C6-C12芳基可互换使用。芳基的例子包括但不限于苯基(Ph)、萘基、芘基、蒽基和菲基。In the present invention, the term "aryl" means a hydrocarbyl moiety containing one or more aromatic rings. For example, the term "C6-C12 aryl" refers to an aromatic ring group with 6 to 12 carbon atoms that does not contain heteroatoms on the ring, preferably a C6-C10 aryl group, such as phenyl, naphthyl, etc. The term "C6-C12 aryl" has a similar meaning. 6-12 membered aryl and C6-C12 aryl are used interchangeably. Examples of aryl groups include, but are not limited to, phenyl (Ph), naphthyl, pyrenyl, anthracenyl, and phenanthrenyl.
术语“杂芳基”指具有1-3个原子为选自下组N、S和O的杂原子的环状芳香基，其可以是单环，也可以是稠环形式。本发明中，杂芳基优选地为5-12元杂芳基，更优选5-10元，更优选5-8元，更优选5-6元或9-10元。杂芳基的实例包括但不限于：吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、吡咯基、吡唑基、咪唑基、(1,2,3)-三唑基以及(1,2,4)-三唑基、四唑基、呋喃基、噻吩基、异恶唑基、噻唑基、恶唑基、咔唑、吲哚基、吲唑基、苯并噻吩基、苯并呋喃基、苯并咪唑基、苯并三唑基、苯并噻唑基、苯并噻二唑基、苯并噁唑基、异构化的喹啉基、酞嗪基、喹喔啉基、喹唑啉基、噌啉基或萘啶基及四氮唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环。术语“[6+5+6]杂芳基”是指稠合的6、5、6三环体系，如二苯并[b,d]噻吩，术语“[6+5]杂芳基”是指6元芳基或杂芳基与5元杂芳基稠和的杂芳基，如苯并噻吩基、吲哚、异吲哚、苯并呋喃基、苯并咪唑基、苯并三唑基、苯并噻唑基、苯并噻二唑基、苯 并噁唑基，“[6+6]杂芳基”是指6元芳基或杂芳基与6元杂芳基稠和的杂芳基，如喹啉、异喹啉、喹喔啉等。“[5+5]杂芳基”具有类似含义。杂芳基可以是任选取代的或未取代的。当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、烷硫基、烷基氨基、卤素、氨基、硝基、羟基、巯基、氰基、环烷基、杂环基、芳基、杂芳基、环烷硫基、氧代基、酰胺基、磺酰胺基、甲酰基、甲酰胺基、羧基和羧酸酯基等。本发明中，取代基中，“杂芳环”、“芳杂环”、“杂芳基”具有相同含义。The term "heteroaryl" refers to a cyclic aromatic group having 1 to 3 heteroatoms selected from the group consisting of N, S and O, which may be a single ring or a condensed ring. In the present invention, the heteroaryl group is preferably a 5-12-membered heteroaryl group, more preferably a 5-10-membered heteroaryl group, more preferably a 5-8-membered group, more preferably a 5-6-membered or 9-10-membered group. Examples of heteroaryl groups include, but are not limited to: pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl, and (1,2,4)-Triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, carbazole, indolyl, indazolyl, benzothienyl, Benzofuranyl, benzimidazolyl, benzotriazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, isomerized quinolinyl, phthalazinyl, quinoxalinyl , quinazolinyl, cinnolinyl or naphthyridinyl and tetrazolyl, etc. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, where the ring attached to the parent structure is the heteroaryl ring. The term "[6+5+6]heteroaryl" refers to a fused 6, 5, 6 tricyclic system, such as dibenzo[b,d]thiophene, and the term "[6+5]heteroaryl" is Refers to a heteroaryl group in which a 6-membered aryl group or a heteroaryl group is fused with a 5-membered heteroaryl group, such as benzothienyl, indole, isoindole, benzofuranyl, benzimidazolyl, and benzotriazolyl , benzothiazolyl, benzothiadiazolyl, benzene Oxazolyl, "[6+6]heteroaryl" refers to a 6-membered aryl group or a heteroaryl group in which a heteroaryl group is fused with a 6-membered heteroaryl group, such as quinoline, isoquinoline, quinoxaline, etc. . "[5+5]heteroaryl" has a similar meaning. Heteroaryl groups may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio , alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, amide, sulfonamide, Formyl group, formamide group, carboxyl group and carboxylate group, etc. In the present invention, among the substituents, "heteroaryl ring", "heteroaromatic ring" and "heteroaryl group" have the same meaning.
本发明中，[6+6]芳基或稠环、[6+6]杂芳基或稠环、[6+5]杂芳基或稠环、[5+6]杂芳基或稠环、[5+5]杂芳基或稠环中稠环是指5-6元芳基或杂芳基与5-6元环烷基或杂环烷基稠和的环，包括苯基并5-6元杂芳基、5-6元杂环基并苯基、C5-C6环烷基并苯基、苯基并5-6元杂环基(如)、苯基并C5-C6环烷基、5-6元杂环基并5-6元杂芳基、C5-C6环烷基并5-6元杂芳基、5-6元杂芳基并5-6元杂环基、5-6元杂芳基并C5-C6环烷基，例如 等。In the present invention, [6+6] aryl or fused ring, [6+6] heteroaryl or fused ring, [6+5] heteroaryl or fused ring, [5+6] heteroaryl or fused ring , [5+5] Heteroaryl or fused ring in the fused ring refers to a ring in which a 5-6-membered aryl or heteroaryl is fused with a 5-6-membered cycloalkyl or heterocycloalkyl, including phenyl and 5 -6-membered heteroaryl, 5-6-membered heterocyclylaphenyl, C5-C6 cycloalkylphenyl, phenyl-5-6-membered heterocyclyl (such as ), phenyl C5-C6 cycloalkyl, 5-6 membered heterocyclyl and 5-6 membered heteroaryl, C5-C6 cycloalkyl 5-6 membered heteroaryl, 5-6 membered heteroaryl and 5-6 membered heterocyclyl, 5-6 membered heteroaryl and C5-C6 cycloalkyl, for example wait.
在本发明中，“氨基”是指具有-N(R)(R')结构，R和R'可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、芳基或取代的芳基、杂环或取代的杂环，如上文所定义。R和R'在二烷基胺片段中可以相同或不同。氨基的实例有NH2、NHCH3、N(CH3)2。In the present invention, "amino" means having the structure -N(R)(R'), R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, Aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' may be the same or different in the dialkylamine moiety. Examples of amino groups are NH 2 , NHCH 3 , N(CH 3 ) 2 .
在本发明中，“氨基甲酰基”是指具有NH2-C＝O-结构的基团，其中，基团中的H可以被取代。In the present invention, "carbamoyl" refers to a group with a NH 2 -C=O- structure, in which H in the group may be substituted.
除非另外说明，本文所述的烷基、烷氧基、环烷基、杂环基和芳基为取代的和未取代的基团。烷基、烷氧基、环烷基、杂环基和芳基上可能的取代基包括，但不限于：羟基、氨基、硝基、氰基、卤素、C1-C6烷基、C2-C10烯基、C2-C10炔基、C3-C20环烷基、C3-C20环烯基、C3-C20杂环烷基、C3-C20杂环烯基、C1-C6烷氧基、芳基、杂芳基、杂芳氧基、C1-C10烷基氨基、C1-C10二烷基氨基、芳基氨基、二芳基氨基、 C1-C10烷基氨磺酰基、芳基氨磺酰基、C1-C10烷基亚氨基、C1-C10烷基磺基亚氨基、芳基磺基亚氨基、巯基、C1-C10烷硫基、C1-C10烷基磺酰基、芳基磺酰基、酰基氨基、氨酰基、氨基硫代酰基、胍基、脲基、氰基、酰基、硫代酰基、酰氧基、羧基和羧酸酯基。另一方面，环烷基、杂环烷基、杂环烯基、芳基和杂芳基也可互相稠合。Unless otherwise stated, alkyl, alkoxy, cycloalkyl, heterocyclyl and aryl groups described herein are substituted and unsubstituted groups. Possible substituents on alkyl, alkoxy, cycloalkyl, heterocyclyl and aryl include, but are not limited to: hydroxyl, amino, nitro, cyano, halogen, C1-C6 alkyl, C2-C10 alkene Base, C2-C10 alkynyl, C3-C20 cycloalkyl, C3-C20 cycloalkenyl, C3-C20 heterocycloalkyl, C3-C20 heterocycloalkenyl, C1-C6 alkoxy, aryl, heteroaryl group, heteroaryloxy group, C1-C10 alkylamino group, C1-C10 dialkylamino group, arylamino group, diarylamino group, C1-C10 alkylsulfamoyl, arylsulfamoyl, C1-C10 alkylimino, C1-C10 alkylsulfimino, arylsulfimino, mercapto, C1-C10 alkylthio, C1 -C10 Alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl, guanidino, ureido, cyano, acyl, thioacyl, acyloxy, carboxyl and carboxylate groups. On the other hand, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl groups may also be fused to each other.
本发明中，所述取代为单取代或多取代，所述多取代为二取代、三取代、四取代、或五取代。所述二取代就是指具有两个取代基，依此类推。In the present invention, the substitution is mono-substitution or poly-substitution, and the poly-substitution is disubstitution, tri-substitution, tetra-substitution or penta-substitution. The disubstituted means having two substituents, and so on.
在本发明中，术语“多个”独立指2、3、4、5个。In the present invention, the term "plurality" independently refers to 2, 3, 4, and 5.
术语前药，也称前体药物、药物前体、前驱药物等，是指药物经过化学结构修饰后得到的在体外无活性或活性较小、在体内经酶或非酶的转化释放出活性药物而发挥药效的化合物。The term prodrug, also known as prodrug, prodrug, prodrug, etc., refers to a drug that is inactive or less active in vitro and is converted to active drugs in vivo through enzymatic or non-enzymatic transformation. And the compounds that exert medicinal effects.
术语“药物上可接受的盐”是指具有类似于母体化合物的功效且在生物学上或其他方面(例如，对受试者既无毒也无害)可接受的盐(包括两性离子等内盐)。因此，本发明的实施例提供了本发明化合物的药学上可接受盐。此处所用术语“盐”表示以下任何由无机和/或有机酸形成的酸式盐，以及由无机和/或有机碱形成的碱式盐。本发明化合物的盐可以由本领域普通技术人员已知的方法形成，例如，通过将本发明化合物与一定量的酸或碱(例如等当量的酸或碱)，在一种介质(例如，这种介质可以使得盐在其中沉淀；或者以水为介质，然后冻干)中反应获得。The term "pharmaceutically acceptable salt" refers to a salt (including zwitterions, etc.) that has an effect similar to that of the parent compound and is biologically or otherwise (e.g., neither toxic nor harmful to the subject). Salt). Accordingly, the embodiments of the invention provide pharmaceutically acceptable salts of the compounds of the invention. The term "salt" as used herein means any of the following acid salts formed from inorganic and/or organic acids, as well as base salts formed from inorganic and/or organic bases. Salts of the compounds of the present invention may be formed by methods known to those of ordinary skill in the art, for example, by combining a compound of the present invention with an amount of acid or base (e.g., equivalent amounts of acid or base) in a medium (e.g., such The medium can allow the salt to precipitate in it; or water can be used as the medium and then freeze-dried).
活性成分active ingredient
如本文所用，术语“本发明的化合物”或“本发明的活性成分”可互换使用，指式(I)化合物、或其药学上可接受的盐、水合物、溶剂化物、同位素化合物(如氘代化合物)或前药。该术语还包括外消旋体、光学异构体。As used herein, the term "compound of the invention" or "active ingredient of the invention" is used interchangeably and refers to a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound (e.g. deuterated compounds) or prodrugs. The term also includes racemates, optical isomers.
本发明中，式I化合物具有如下结构
In the present invention, the compound of formula I has the following structure
环A、Q和环B的定义如上所述；Rings A, Q and B are defined as above;
优选地，环A选自以下结构： Preferably, Ring A is selected from the following structures:
优选地，环A为更优选地为更优选地为 Preferably, ring A is More preferably More preferably
Rm、f、Rm1、Rm2、Rm3的定义如上所述；The definitions of Rm, f, R m1 , R m2 and R m3 are as mentioned above;
优选地，环B选自以下结构：
Preferably, Ring B is selected from the following structures:
M、R2、R3、R4、R5、R6、R7、R8、R9、R10、Ra、Ra’、Rb、Rb’、Rc、Rc’、Rg、Rg’、Rh、Rh’、Ri、Ri’、Rj、Rj’和n的定义如上所述；M, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R a , R a' , R b , R b' , R c , R c' , R g , R g' , R h , R h' , R i , R i' , R j , R j' and n are defined as above;
更优选地，环B为更优选地为更优选地选自： 其中，R4、Rm’、Rm”、f’和f”的定义如上所述；More preferably, ring B is More preferably More preferably selected from: Among them, R 4 , R m' , R m" , f' and f" are defined as above;
优选地，R4选自：卤素、羧基、羟基、氰基、氨基、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代COOC1-C6烷基、取代或未取代CO-4-6元杂环基、取代或未取代的C6-C10芳基、取代或未取代的5-10元杂芳基(优选5-6元或9-10元，例如呋喃基、噻吩基、吡啶基、吡咯基、吡唑基、咪唑基、苯并呋喃基、苯并噻吩基、吡啶并吡唑基)、取代或未取代的C3-C6环烷基、取代或未取代的4-10元杂环基(优选4-6元单环杂环基、7-11元螺杂环基，例如哌啶基、吗啉基、哌嗪基、四氢吡咯基、)、取代或未取代的取代或未取代的C6-C10芳基NH、取代或未取代的5-6元杂环基并苯基(如 )、取代或未取代的C5-C6环烷基并苯基、取代或未取代的苯基并5-6元杂环基(如)、取代或未取代的苯基并C5-C6环烷基、取代或未取代的5-6元杂环基并5-6元杂芳基、取代或未取代的C5-C6环烷基并5-6元杂芳基、取代或未取代的5-6元杂芳基并5-6元杂环基、取代或未取代的5-6元杂芳基并C5-C6环烷基，其中，所述取代是指被选自下组的一个或多个基团取代：卤素、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基；优选地，R4选自：卤素、羧基、羟基、氰基、氨基、硝基、乙烯基、乙炔基、乙基、苯基、萘基、 Preferably, R 4 is selected from: halogen, carboxyl, hydroxyl, cyano, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C2-C6 Alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted COOC1-C6 alkyl, substituted or unsubstituted CO-4-6 membered heterocyclyl, substituted or unsubstituted C6-C10 aryl, substituted Or unsubstituted 5-10 yuan heteroaryl (preferably 5-6 yuan or 9-10 yuan, such as furyl, thienyl, pyridyl, pyrrolyl, pyrazolyl, imidazolyl, benzofuranyl, benzo Thienyl, pyridopyrazolyl), substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclyl (preferably 4-6 membered monocyclic heterocyclyl, 7-11 membered Spiroheterocyclyl, such as piperidinyl, morpholinyl, piperazinyl, tetrahydropyrrolyl, ), substituted or unsubstituted Substituted or unsubstituted C6-C10 aryl NH, substituted or unsubstituted 5-6 membered heterocyclylacene (such as ), substituted or unsubstituted C5-C6 cycloalkylphenyl, substituted or unsubstituted phenyl 5-6 membered heterocyclyl (such as ), substituted or unsubstituted phenyl C5-C6 cycloalkyl, substituted or unsubstituted 5-6 membered heterocyclyl and 5-6 membered heteroaryl, substituted or unsubstituted C5-C6 cycloalkyl 5-6 membered heteroaryl, substituted or unsubstituted 5-6 membered heteroaryl and 5-6 membered heterocyclyl, substituted or unsubstituted 5-6 membered heteroaryl with C5-C6 cycloalkyl, wherein , the substitution refers to substitution with one or more groups selected from the following group: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy group; preferably, R 4 is selected from: halogen, carboxyl, hydroxyl, cyano, amino, nitro, vinyl, ethynyl, ethyl, phenyl, naphthyl,
化合物被理解为包括其盐类。在此使用的术语“盐”，指用无机或有机酸和碱形成酸式或碱式的盐。此外，当本发明中的化合物含一个碱性片段时，它包括但不限于吡啶或咪唑，含一个酸性片段时，包括但不限于羧酸，可能形成的两性离子(“内盐”)包含在术语“盐”的范围内。药学上可接受的(即无毒，生理可接受的)盐是首选，虽然其他盐类也有用，例如可以用在制备过程中的分离或纯化步骤。本发明的化合物可能形成盐，例如，化合物I与一定量如等当量的酸或碱反应，在介质中盐析出来，或在水溶液中冷冻干燥得来。Compounds are understood to include salts thereof. The term "salt" as used herein refers to an acidic or basic salt formed from an inorganic or organic acid and a base. In addition, when the compound of the present invention contains a basic moiety, which includes but is not limited to pyridine or imidazole, and when it contains an acidic moiety, including but is not limited to carboxylic acid, the zwitterion ("inner salt") that may be formed is included in Within the scope of the term "salt". Pharmaceutically acceptable (i.e., nontoxic, physiologically acceptable) salts are preferred, although other salts are also useful, for example, in isolation or purification steps during preparation. The compounds of the present invention may form salts, for example, compound I can be obtained by reacting with a certain amount of, for example, an equivalent amount of acid or base, salting out in a medium, or by freeze-drying in an aqueous solution.
本发明中的化合物含有的碱性片段，包括但不限于胺或吡啶或咪唑环，可能会和有机或无机酸形成盐。可以成盐的典型的酸包括醋酸盐(如用醋酸或三卤代醋酸，如三氟乙酸)、己二酸盐、藻朊酸盐、抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、硼酸盐、丁酸盐、柠檬酸盐、樟脑盐、樟脑磺酸盐、环戊烷丙酸盐、二甘醇酸盐、十二烷基硫酸盐、乙烷磺酸盐、延胡索酸盐、葡庚糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、羟基乙磺酸盐(如，2-羟基乙磺酸盐)、乳酸盐、马来酸盐、甲磺酸盐、萘磺酸盐(如，2-萘磺酸盐)、烟酸盐、硝酸盐、草酸盐、果胶酸盐、过硫酸盐、苯丙酸盐(如3-苯丙酸盐)、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐，水杨酸盐、琥珀酸盐、硫酸盐(如与硫酸形成的)、磺酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐如对甲苯磺酸盐、十二烷酸盐等等。The compounds of the present invention contain basic moieties, including but not limited to amines or pyridine or imidazole rings, which may form salts with organic or inorganic acids. Typical acids that can form salts include acetates (eg, with acetic acid or trihaloacetic acids, such as trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, and benzoates. , benzenesulfonate, hydrogen sulfate, borate, butyrate, citrate, camphor salt, camphor sulfonate, cyclopentane propionate, diglycolate, dodecyl sulfate, Ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, enanthate, caproate, hydrochloride, hydrobromide, hydroiodide, glycolate (e.g., 2-hydroxyethanesulfonate), lactate, maleate, methanesulfonate, naphthalenesulfonate (e.g., 2-naphthalenesulfonate), nicotinate, nitrate, oxalic acid Salt, pectate, persulfate, phenylpropionate (such as 3-phenylpropionate), phosphate, picrate, pivalate, propionate, salicylate, succinate, Sulfates (such as formed with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates such as p-toluenesulfonate, dodecanoate, etc.
本发明的某些化合物可能含有的酸性片段，包括但不限于羧酸，可能会和各种有机或无机碱形成盐。典型的碱形成的盐包括铵盐、碱金属盐如钠、锂、钾盐，碱土金属盐如钙、镁盐和有机碱形成的盐(如有机胺)，如苄星、二环已基胺、海巴胺(与N,N-二(去氢枞基)乙二胺形成的盐)、N-甲基-D-葡糖胺、N-甲基-D-葡糖酰胺、叔丁基胺，以及和氨基酸如精氨酸、赖氨酸等等形成的盐。碱性含氮基团可以与卤化物季铵盐，如小分子烷基卤化物(如甲基、乙基、丙基和丁基的氯化物、溴化物及碘化物)，二烷基硫酸盐(如，硫酸二甲酯、二乙酯，二丁酯和二戊酯)，长链卤化物(如癸基、十二烷基、十四烷基和十四烷基的氯化物、溴化物及碘化物)，芳烷基卤化物(如苄基和苯基溴化物)等等。Certain compounds of the invention may contain acidic moieties, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases. Typical salts formed with bases include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and salts formed with organic bases (such as organic amines), such as benzathine and dicyclohexylamine. , Hypamine (salt with N,N-bis(dehydroabidyl)ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, tert-butyl Amines, and salts formed with amino acids such as arginine, lysine, etc. Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecule alkyl halides (such as chlorides, bromides and iodides of methyl, ethyl, propyl and butyl), dialkyl sulfates (such as dimethyl sulfate, diethyl sulfate, dibutyl ester and dipentyl ester), long chain halides (such as decyl, dodecyl, tetradecyl and tetradecyl chlorides, bromides and iodide), aralkyl halides (such as benzyl and phenyl bromide), etc.
本发明中化合物的前药及溶剂合物也在涵盖的范围之内。此处术语“前药”是指一种化合物，在治疗相关疾病时，经过代谢或化学过程的化学转化而产生本发明中的化合物、盐、或溶剂合物。本发明的化合物包括溶剂合物，如水合物。 Prodrugs and solvates of the compounds of the present invention are also within the scope of the invention. The term "prodrug" here refers to a compound that undergoes chemical transformation through metabolism or chemical processes to produce the compound, salt, or solvate of the present invention when treating related diseases. Compounds of the present invention include solvates, such as hydrates.
本发明中的化合物、盐或溶剂合物，可能存在的互变异构形式(例如酰胺和亚胺醚)。所有这些互变异构体都是本发明的一部分。The compounds, salts or solvates of the present invention may exist in tautomeric forms (eg amides and imine ethers). All such tautomers are part of the present invention.
所有化合物的立体异构体(例如，那些由于对各种取代可能存在的不对称碳原子)，包括其对映体形式和非对映形式，都属于本发明的设想范围。本发明中的化合物独立的立体异构体可能不与其他异构体同时存在(例如，作为一个纯的或者实质上是纯的光学异构体具有特殊的活性)，或者也可能是混合物，如消旋体，或与所有其他立体异构体或其中的一部分形成的混合物。本发明的手性中心有S或R两种构型，由理论与应用化学国际联合会(IUPAC)1974年建议定义。外消旋形式可通过物理方法解决，例如分步结晶，或通过衍生为非对映异构体分离结晶，或通过手性柱色谱法分离。单个的光学异构体可通过合适的方法由外消旋体得到，包括但不限于传统的方法，例如与光学活性酸成盐后再结晶。All stereoisomers of the compounds (eg, those that may exist due to asymmetric carbon atoms for various substitutions), including their enantiomeric and diastereomeric forms, are contemplated by the present invention. The compounds of the invention may be independent stereoisomers that do not exist simultaneously with other isomers (e.g., have a specific activity as a pure or substantially pure optical isomer), or they may be mixtures, e.g. Racemates, or mixtures with all other stereoisomers or portions thereof. The chiral center of the present invention has two configurations: S or R, which are defined as recommended by the International Union of Theoretical and Applied Chemistry (IUPAC) in 1974. Racemic forms can be resolved by physical methods, such as fractional crystallization, or by fractional crystallization by derivatization to diastereoisomers, or by chiral column chromatography. Individual optical isomers can be obtained from the racemate by suitable methods, including but not limited to traditional methods, such as salt formation with an optically active acid followed by recrystallization.
本发明中的化合物，依次通过制备、分离纯化获得的该化合物其重量含量等于或大于90％，例如，等于或大于95％，等于或大于99％(“非常纯”的化合物)，在正文描述列出。此处这种“非常纯”本发明的化合物也作为本发明的一部分。The weight content of the compounds in the present invention obtained by sequential preparation, separation and purification is equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure" compounds), as described in the text List. Such "very pure" compounds of the invention are here also included as part of the invention.
本发明的化合物所有的构型异构体都在涵盖的范围之内，无论是混合物、纯的或非常纯的形式。在本发明化合物的定义包含顺式(Z)和返式(E)两种烯烃异构体，以及碳环和杂环的顺式和反式异构体。All configurational isomers of the compounds of the invention are included within the scope, whether in mixtures, pure or very pure form. The definition of compounds in the present invention includes both cis (Z) and ant (E) olefin isomers, as well as cis and trans isomers of carbocyclic and heterocyclic rings.
在整个说明书中，基团和取代基可以被选择以提供稳定的片段和化合物。Throughout the specification, groups and substituents may be selected to provide stable fragments and compounds.
特定官能团和化学术语定义都详细介绍如下。对本发明来说，化学元素与Periodic Table of the Elements，CAS version，Handbook of Chemistry and Physics，75th Ed.中定义的一致。特定官能团的定义也在其中描述。此外，有机化学的基本原则以及特定官能团和反应性在“Organic Chemistry”，Thomas Sorrell，University Science Books，Sausalito:1999，也有说明，其全部内容纳入参考文献之列。Definitions of specific functional groups and chemical terms are detailed below. For the purposes of this invention, chemical elements are as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Definitions of specific functional groups are also described therein. In addition, the basic principles of organic chemistry and specific functional groups and reactivities are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, the entire contents of which are incorporated by reference.
本发明的某些化合物可能存在于特定的几何或立体异构体形式。本发明涵盖所有的化合物，包括其顺式和反式异构体、R和S对映异构体、非对映体、(D)型异构体、(L)型异构体、外消旋混合物和其它混合物。另外不对称碳原子可表示取代基，如烷基。所有异构体以及它们的混合物，都包涵在本发明中。Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention encompasses all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, elimination Spin mixtures and other mixtures. In addition, asymmetric carbon atoms can represent substituents, such as alkyl groups. All isomers, as well as mixtures thereof, are included in the present invention.
按照本发明，同分异构体的混合物含有异构体的比率可以是多样的。例如，在只有两个异构体的混合物可以有以下组合：50:50，60:40，70:30，80:20，90:10，95:5，96:4，97:3，98:2，99:1，或100:0，异构体的所有比率都在本发明范围之内。本专业内一般技术人员容易理解的类似的比率，及为更复杂的异构体的混合物的比率也在本发明范围之内。According to the present invention, the mixture of isomers may contain the isomers in various ratios. For example, a mixture of only two isomers can have the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98: All ratios of isomers 2, 99:1, or 100:0 are within the scope of the invention. Similar ratios, as well as ratios for more complex mixtures of isomers that are readily understood by those of ordinary skill in the art, are also within the scope of the present invention.
本发明还包括同位素标记的化合物，等同于原始化合物在此公开。不过实际上对一个或更多的原子被与其原子量或质量序数不同的原子取代通常会出现。可以列为本发明的化合物同位素的例子包括氢、碳、氮、氧、磷、硫、氟和氯同位素，分别如2H、 3H、13C、11C、14C、15N、18O、17O、31P、32P、35S、18F和36Cl。本发明中的化合物，或对映体，非对映体，异构体，或药学上可接受的盐或溶剂化物，其中含有上述化合物的同位素或其他同位素原子都在本发明的范围之内。本发明中某些同位素标记化合物，例如3H和14C的放射性同位素也在其中，在药物和底物的组织分布实验中是有用的。氚，即3H和碳-14，即14C，它们的制备和检测比较容易。是同位素中的首选。此外，较重同位素取代如氘，即2H，由于其很好的代谢稳定性在某些疗法中有优势，例如在体内增加半衰期或减少用量，因此，在某些情况下可以优先考虑。同位素标记的化合物可以用一般的方法，通过用易得的同位素标记试剂替换为非同位素的试剂，用批露在示例中的方案可以制备。The present invention also includes isotopically labeled compounds that are equivalent to the original compounds disclosed herein. In practice, however, it often occurs that one or more atoms are replaced by atoms with a different atomic weight or mass number. Examples of isotopes of compounds that may be included in the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes such as 2 H, 3H , 13C , 11C , 14C , 15N , 18O , 17O , 31P , 32P , 35S , 18F and 36Cl . The compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, which contain isotopes or other isotope atoms of the above compounds are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as radioactive isotopes of 3 H and 14 C, are also included and are useful in tissue distribution experiments of drugs and substrates. Tritium, or 3H , and carbon-14, or 14C , are relatively easy to prepare and detect. It is the first choice among isotopes. In addition, heavier isotope substitutions such as deuterium, i.e. 2H , may have advantages in certain therapies due to their good metabolic stability, such as increased half-life in the body or reduced dosage, and therefore may be prioritized in certain circumstances. Isotopically labeled compounds can be prepared by general methods by replacing readily available isotopically labeled reagents with non-isotopic reagents, using the protocols disclosed in the Examples.
如果要设计一个本发明的化合物特定的对映体的合成，它可以不对称合成制备，或用手性辅剂衍生化，将所产生的非对映混合物分离，再除去手性辅剂而得到纯的对映体。另外，如果分子中含有一个碱性官能团，如氨基酸，或酸性官能团，如羧基，可以用合适的光学活性的酸或碱的与之形成非对映异构体盐，再通过分离结晶或色谱等常规手段分离，然后就得到了纯的对映体。If one wants to design a synthesis of a specific enantiomer of the compound of the present invention, it can be prepared by asymmetric synthesis, or derivatized with a chiral auxiliary, and the resulting diastereomeric mixture is separated and then the chiral auxiliary is removed. Pure enantiomer. In addition, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, a suitable optically active acid or base can be used to form a diastereomeric salt with it, and then through separation, crystallization or chromatography, etc. After separation by conventional means, the pure enantiomers are obtained.
如本文所述，本发明中的化合物可与任何数量取代基或官能团取而扩大其包涵范围。通常，术语“取代”不论在术语“可选”前面或后面出现，在本发明配方中包括取代基的通式，是指用指定结构取代基，代替氢自由基。当特定结构中的多个在位置被多个特定的取代基取代时，取代基每一个位置可以是相同或不同。本文中所使用的术语“取代”包括所有允许有机化合物取代。从广义上讲，允许的取代基包括非环状的、环状的、支链的非支链的、碳环的和杂环的，芳环的和非芳环的有机化合物。在本发明中，如杂原子氮可以有氢取代基或任何允许的上文所述的有机化合物来补充其价态。此外，本发明是无意以任何方式限制允许取代有机化合物。本发明认为取代基和可变基团的组合在以稳定化合物形式在疾病的治疗上是很好的。此处术语“稳定”是指具有稳定的化合物，在足够长的时间内检测足以维持化合物结构的完整性，最好是在足够长的时间内都在效，本文在此用于上述目的。As described herein, the compounds of the present invention may be provided with any number of substituents or functional groups to broaden their encompassing scope. In general, whether the term "substituted" appears before or after the term "optional", the general formula of the substituent included in the formulation of the present invention means that the substituent of the specified structure is used in place of the hydrogen radical. When multiple positions in a specific structure are substituted by multiple specific substituents, the substituents may be the same or different at each position. The term "substitution" as used herein includes all permissible substitutions of organic compounds. Broadly speaking, permissible substituents include acyclic, cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. In the present invention, heteroatoms such as nitrogen may have hydrogen substituents or any of the permissible organic compounds described above to supplement their valence. Furthermore, this invention is not intended to be limited in any way to the permitted substituted organic compounds. The present invention considers that combinations of substituents and variable groups are excellent in the treatment of diseases in the form of stable compounds. The term "stable" as used herein refers to a compound that is stable, detectable over a long enough period of time to maintain the structural integrity of the compound, and preferably effective over a long enough period of time, and is used herein for the above purposes.
本申请所涉及的化合物及其药学可接受的盐的代谢产物，以及可以在体内转变为本申请所涉及的化合物及其药学可接受的盐的结构的前药，也包含在本申请的权利要求中。The metabolites of the compounds involved in this application and their pharmaceutically acceptable salts, as well as the prodrugs that can be converted into the structures of the compounds involved in this application and their pharmaceutically acceptable salts in vivo, are also included in the claims of this application. middle.
化合物的制备方法Preparation methods of compounds
以下方案和实例中描述了制备式I的化合物的方法。原料和中间体从商业来源购买，由已知步骤制备，或以其他方式说明。在某些情况下，可以改变执行反应方案的步骤的顺序，以促进反应或避免不需要的副反应产物。Methods for preparing compounds of formula I are described in the following schemes and examples. Starting materials and intermediates were purchased from commercial sources, prepared by known procedures, or otherwise described. In some cases, the order of steps in performing a reaction scheme can be changed to facilitate the reaction or avoid undesired side reaction products.
通常，在制备流程中，各反应通常在惰性溶剂中，在室温至回流温度(如0℃～150℃，优选10℃～100℃)下进行。反应时间通常为0.1小时-60小时，较佳地为0.5-48 小时。Generally, in the preparation process, each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (such as 0°C to 150°C, preferably 10°C to 100°C). The reaction time is usually 0.1 hour-60 hours, preferably 0.5-48 hours Hour.
优选地，本发明式(I)化合物可用如下步骤制得
Preferably, the compound of formula (I) of the present invention can be prepared by the following steps
式(I)所示的化合物可以经上图所示的以下两种方法制得：The compound represented by formula (I) can be prepared by the following two methods as shown in the figure above:
1)芳胺经三光气处理得到异氰酸酯，然后与发生反应，得到式(I)所示的化合物；1) Aromatic amines are treated with triphosgene to obtain isocyanates, which are then combined with Reaction occurs to obtain the compound represented by formula (I);
2)芳酸经DPPA(叠氮磷酸二苯酯)处理得到酰基叠氮，再经加热转化为异氰酸酯，然后与发生反应得到式(I)所示的化合物。2) Aromatic acid is treated with DPPA (diphenylphosphoryl azide) to obtain acyl azide, which is then converted into isocyanate by heating, and then combined with The reaction occurs to obtain the compound represented by formula (I).
药物组合物和施用方法Pharmaceutical compositions and methods of administration
由于本发明化合物具有优异的STING激酶的激动活性，因此本发明化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物，以及含有本发明化合物为主要活性成分的药物组合物可用于预防和/或治疗(稳定、减轻或治愈)STING激酶相关的炎症性疾病和自身免疫性疾病。所述炎症性疾病和自身免疫性疾病选自:Singleton-Merten综合征(SMS)、Aicardi-Goutigres综合征(AGS)、系统性红斑狼疮(SLE)、家族性冻疮性红斑狼疮(FCL)、视网膜血管病与脑白质营养不良(RVCL)、STING相关的婴儿期发病血管病变(SAVI)、硬皮病、银肩病、斯耶格伦氏综合征、类风湿性关节炎、炎症性肠病、多发性硬化、克罗恩病、溃疡性结肠炎、自身免疫性结肠炎、小肠吸收不良综合征、肠易激综合征、葡萄膜炎、粘膜炎、糖尿病、心血管疾病和神经退行性疾病等。Since the compound of the present invention has excellent agonistic activity of STING kinase, the compound of the present invention or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate, and the compound containing the compound of the present invention are the main active Pharmaceutical compositions of ingredients may be used to prevent and/or treat (stabilize, alleviate or cure) STING kinase-related inflammatory diseases and autoimmune diseases. The inflammatory disease and autoimmune disease are selected from: Singleton-Merten syndrome (SMS), Aicardi-Goutigres syndrome (AGS), systemic lupus erythematosus (SLE), familial chilblain lupus erythematosus (FCL), retinal Vascular disease and leukodystrophy (RVCL), STING-associated vasculopathy of infancy (SAVI), scleroderma, psoriasis, Sjogren's syndrome, rheumatoid arthritis, inflammatory bowel disease, Multiple sclerosis, Crohn's disease, ulcerative colitis, autoimmune colitis, small intestinal malabsorption syndrome, irritable bowel syndrome, uveitis, mucositis, diabetes, cardiovascular disease and neurodegenerative diseases, etc. .
本发明的药物组合物包含安全有效量范围内的本发明化合物及药学上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至 于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有10-200mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。The pharmaceutical composition of the present invention contains a compound of the present invention and a pharmaceutically acceptable excipient or carrier within a safe and effective amount. The “safe and effective dose” refers to the amount of compound that is sufficient to significantly improve the condition without causing may cause serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention/dose, more preferably, it contains 10-200 mg of the compound of the present invention/dose. Preferably, the "dose" is a capsule or tablet.
“药学上可接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。"Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid filler or gel substances that are suitable for human use and must be of sufficient purity and low enough toxicity. "Compatibility" here means that the components of the composition can be blended with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、肠胃外(静脉内、肌肉内或皮下)。The administration mode of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative administration modes include (but are not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous).
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) Humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) retarder, such as paraffin; (f) Absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, hard Calcium fatty acid, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。Solid dosage forms such as tablets, dragees, capsules, pills and granules may be prepared using coatings and shell materials such as enteric casings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxy substances. If necessary, the active compounds can also be in microencapsulated form with one or more of the above-mentioned excipients.
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。Besides these inert diluents, the compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙 烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。Suspensions may contain, besides the active compound, suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene Ensorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances, etc.
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。Compositions for parenteral injection may contain physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
本发明化合物可以单独给药，或者与其他药学上可接受的化合物(例如STING激动剂)联合给药。The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds (eg, STING agonists).
联合给药时，所述药物组合物还包括与一种或多种(2种，3种，4种，或更多种)其他药学上可接受的化合物(例如STING激动剂)。该其他药学上可接受的化合物中的一种或多种(2种，3种，4种，或更多种)可与本发明的化合物同时、分开或顺序地用于预防和/或治疗STING激酶的活性或表达量相关的疾病。When administered in combination, the pharmaceutical composition also includes one or more (2, 3, 4, or more) other pharmaceutically acceptable compounds (eg, STING agonists). One or more (2, 3, 4, or more) of the other pharmaceutically acceptable compounds may be used simultaneously, separately, or sequentially with the compound of the present invention to prevent and/or treat STING Diseases related to kinase activity or expression.
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选20～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, and the dosage when administered is a pharmaceutically effective dosage. For a person weighing 60 kg, the daily dose is The dosage is usually 1 to 2000 mg, preferably 20 to 500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the skill of a skilled physician.
“安全有效量”指的是：活性成分的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有l～2000mg活性成分/剂，更佳地，含有10～200mg活性成分/剂。较佳地，所述的“一剂”为一个药片。"Safe and effective dose" refers to the amount of active ingredients that is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1 to 2000 mg of active ingredients/dose, and more preferably, contains 10 to 200 mg of active ingredients/dose. Preferably, the "dose" is a tablet.
本发明的主要优点在于：The main advantages of the present invention are:
1.本发明的化合物在人源细胞和/或鼠源细胞中对STING蛋白具有抑制活性，可以作为cGAS/STING信号通路靶向抑制剂；1. The compound of the present invention has inhibitory activity against STING protein in human cells and/or mouse cells, and can be used as a targeted inhibitor of the cGAS/STING signaling pathway;
2.本发明的化合物具有较好的药效及药代动力学特性。2. The compound of the present invention has good medicinal efficacy and pharmacokinetic properties.
以下的实施例中的详细实验步骤将进一步具体阐述本发明。这些示例化合物在下面的实施例中以中性形式绘制。在某些情况下，根据用于最终纯化的方法和/或内在分子性质，化合物被分离为盐。这些示例仅用于说明本发明，并不打算以任何方式限制本专利的范围。除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。The detailed experimental procedures in the following examples will further illustrate the present invention. These example compounds are plotted in neutral form in the examples below. In some cases, compounds are isolated as salts based on the methods used for final purification and/or intrinsic molecular properties. These examples are merely illustrative of the invention and are not intended to limit the scope of this patent in any way. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as familiar to one skilled in the art. In addition, any methods and materials similar or equivalent to those described can be used in the method of the present invention. The preferred implementation methods and materials described in this article are for demonstration purposes only.
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the invention and are not intended to limit the scope of the invention. Experimental methods without specifying specific conditions in the following examples usually follow conventional conditions or conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.
实施例Example
实施例1 N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-1)
Example 1 N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-1)
步骤①：1H-吲哚-3-酰基叠氮(1-1)
Step ①: 1H-indole-3-acyl azide (1-1)
将1克1H-吲哚-3-羧酸、1.12毫升的三乙胺和30毫升二氯甲烷混合物室温搅拌15分钟，分批加入1.35毫升叠氮磷酸二苯酯后室温搅拌过夜。反应液浓缩至干，残余物以乙酸乙酯：石油醚＝30:70柱层析，得白色固体1H-吲哚-3-酰基叠氮(1-1)949毫克，收率82％。1H NMR(400MHz,CDCl3)δ8.69(br s,1H),8.26–8.28(m,1H),7.96(d,J＝3.2Hz,1H),7.42–7.45(m,1H),7.29–7.35(m,2H).A mixture of 1 g of 1H-indole-3-carboxylic acid, 1.12 ml of triethylamine and 30 ml of methylene chloride was stirred at room temperature for 15 minutes. 1.35 ml of diphenylphosphoryl azide was added in batches and stirred at room temperature overnight. The reaction solution was concentrated to dryness, and the residue was subjected to column chromatography with ethyl acetate: petroleum ether = 30:70 to obtain 949 mg of 1H-indole-3-acyl azide (1-1) as a white solid, with a yield of 82%. 1 H NMR (400MHz, CDCl 3 ) δ8.69 (br s, 1H), 8.26–8.28 (m, 1H), 7.96 (d, J = 3.2Hz, 1H), 7.42–7.45 (m, 1H), 7.29 –7.35(m,2H).
步骤②：3-异氰酸基-1H-吲哚(1-2)
Step ②: 3-isocyanato-1H-indole (1-2)
将400毫克化合物1-1和40毫升甲苯的混合物于氩气氛下130℃加热搅拌过夜。反应液浓缩至干，得浅棕色固体3-异氰酸基-1H-吲哚(1-2)339毫克，收率100％。1H NMR(400MHz,CDCl3)δ8.02(s,1H),7.49(d,J＝8.7Hz,2H),7.33(d,J＝8.1Hz,1H),7.21(t,J＝7.5Hz,1H),7.13(t,J＝7.3Hz,1H),6.60(s,1H),3.82(s,3H).A mixture of 400 mg of compound 1-1 and 40 ml of toluene was heated and stirred at 130°C overnight under an argon atmosphere. The reaction solution was concentrated to dryness to obtain 339 mg of 3-isocyanato-1H-indole (1-2) as a light brown solid, with a yield of 100%. 1 H NMR (400MHz, CDCl 3 ) δ8.02 (s, 1H), 7.49 (d, J = 8.7Hz, 2H), 7.33 (d, J = 8.1Hz, 1H), 7.21 (t, J = 7.5Hz ,1H),7.13(t,J＝7.3Hz,1H),6.60(s,1H),3.82(s,3H).
步骤③：N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-1)
Step ③: N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-1)
将80毫克化合物1-2、80毫克1,2,3,4-四氢异喹啉和0.5毫升N,N-二甲基甲酰胺的混合物室温搅拌过夜。反应液加水，以乙酸乙酯萃取，有机相浓缩至干，以乙酸乙酯：石油醚＝1:1制备薄层，得类白色固体N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-1)52毫克，收率35％。1H NMR(400MHz,DMSO-d6)δ10.71(s,1H),8.25(s,1H),7.61(d,J＝8.0Hz,1H),7.36(d,J＝2.4Hz,1H),7.32(d,J＝8.0Hz,1H),7.17–7.20(m,4H),7.04–7.08(m,1H),6.93–6.97(m,1H),4.67(s,2H),3.75(t,J＝5.6Hz,2H),2.88(t,J＝5.6Hz,2H).A mixture of 80 mg of compound 1-2, 80 mg of 1,2,3,4-tetrahydroisoquinoline and 0.5 ml of N,N-dimethylformamide was stirred at room temperature overnight. Add water to the reaction solution, extract with ethyl acetate, concentrate the organic phase to dryness, prepare a thin layer with ethyl acetate: petroleum ether = 1:1, and obtain off-white solid N-(1H-indole-3-yl)-3, 52 mg of 4-dihydroisoquinoline-2(1H)-carboxamide (I-1), yield 35%. 1 H NMR (400MHz, DMSO-d 6 ) δ10.71 (s, 1H), 8.25 (s, 1H), 7.61 (d, J = 8.0Hz, 1H), 7.36 (d, J = 2.4Hz, 1H) ,7.32(d,J＝8.0Hz,1H),7.17–7.20(m,4H),7.04–7.08(m,1H),6.93–6.97(m,1H),4.67(s,2H),3.75(t ,J＝5.6Hz,2H),2.88(t,J＝5.6Hz,2H).
实施例2 N-(1H-吲哚-3-基)-3,4-二氢异喹啉-1(2H)-甲酰胺(I-2)
Example 2 N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-1(2H)-carboxamide (I-2)
N-(1H-吲哚-3-基)-3,4-二氢异喹啉-1(2H)-甲酰胺(I-2)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.77(s,1H),8.58(s,1H),7.60(d,J＝7.6Hz,1H),7.50(d,J＝8.0Hz,1H),7.44(d,J＝2.4Hz,1H),7.33(d,J＝8.0Hz,1H),7.06–7.13(m,3H),6.92–6.99(m,2H),7.91(t,J＝6.0Hz,2H),7.27(t,J＝6.4Hz,2H),1.88–1.94(m,2H).The preparation method of N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-1(2H)-carboxamide (I-2) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.77(s,1H),8.58(s,1H),7.60(d,J＝7.6Hz,1H),7.50(d,J＝8.0Hz,1H) ,7.44(d,J＝2.4Hz,1H),7.33(d,J＝8.0Hz,1H),7.06–7.13(m,3H),6.92–6.99(m,2H),7.91(t,J＝6.0 Hz,2H),7.27(t,J＝6.4Hz,2H),1.88–1.94(m,2H).
实施例3 6-溴-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-3)
Example 3 6-bromo-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-3)
6-溴-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-3)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.71(s,1H),8.27(s,1H),7.61(d,J＝8.0Hz,1H),7.30–7.43(m,4H),7.17(d,J＝7.6Hz,1H),7.08(t,J＝7.6Hz,1H),6.97(t,J＝7.2Hz,1H),4.63(s,2H),3.73(t,J＝6.0Hz,2H),2.89(t,J＝6.0Hz,2H).The preparation method of 6-bromo-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-3) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.71 (s, 1H), 8.27 (s, 1H), 7.61 (d, J = 8.0Hz, 1H), 7.30–7.43 (m, 4H), 7.17 ( d,J＝7.6Hz,1H),7.08(t,J＝7.6Hz,1H),6.97(t,J＝7.2Hz,1H),4.63(s,2H),3.73(t,J＝6.0Hz, 2H),2.89(t,J＝6.0Hz,2H).
实施例4 N-(7-氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-4)
Example 4 N-(7-fluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-4)
步骤①：7-氟-1H-吲哚-3-酰基叠氮(4-1)
Step ①: 7-fluoro-1H-indole-3-acyl azide (4-1)
7-氟-1H-吲哚-3-酰基叠氮(4-1)的制备方法同化合物1-1。1H NMR(400MHz,DMSO-d6)δ12.85(s,1H),8.25(d,J＝2.0Hz,1H),7.88(d,J＝8.0Hz,1H),7.19–7.27(m,1H),7.15(t,J＝8.0Hz,1H).The preparation method of 7-fluoro-1H-indole-3-acyl azide (4-1) is the same as that of compound 1-1. 1 H NMR (400MHz, DMSO-d 6 ) δ12.85 (s, 1H), 8.25 (d, J = 2.0Hz, 1H), 7.88 (d, J = 8.0Hz, 1H), 7.19–7.27 (m, 1H),7.15(t,J=8.0Hz,1H).
步骤②：7-氟-3-异氰酸基-1H-吲哚(4-2)
Step ②: 7-fluoro-3-isocyanato-1H-indole (4-2)
7-氟-3-异氰酸基-1H-吲哚(4-2)的制备方法同化合物1-2。LRMS(ESI)m/z[M+H]+:177.1. The preparation method of 7-fluoro-3-isocyanato-1H-indole (4-2) is the same as that of compound 1-2. LRMS(ESI)m/z[M+H] + :177.1.
步骤③：N-(7-氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-4)
Step ③: N-(7-fluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-4)
N-(7-氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-4)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ11.21(s,1H),8.33(s,1H),7.43–7.46(m,2H),7.19–7.20(m,4H),6.87–6.95(m,2H),4.67(s,2H),3.75(t,J＝6.0Hz,2H),2.88(t,J＝6.0Hz,2H).The preparation method of N-(7-fluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-4) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ11.21(s,1H),8.33(s,1H),7.43–7.46(m,2H),7.19–7.20(m,4H),6.87–6.95(m ,2H),4.67(s,2H),3.75(t,J＝6.0Hz,2H),2.88(t,J＝6.0Hz,2H).
实施例5 N-(6-氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-5)
Example 5 N-(6-fluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-5)
步骤①：6-氟-1H-吲哚-3-酰基叠氮(5-1)
Step ①: 6-fluoro-1H-indole-3-acyl azide (5-1)
6-氟-1H-吲哚-3-酰基叠氮(5-1)的制备方法同化合物1-1。LRMS(ESI)m/z[M+H]+:205.3.The preparation method of 6-fluoro-1H-indole-3-acyl azide (5-1) is the same as that of compound 1-1. LRMS(ESI)m/z[M+H] + :205.3.
步骤②：6-氟-3-异氰酸基-1H-吲哚(5-2)
Step ②: 6-fluoro-3-isocyanato-1H-indole (5-2)
6-氟-3-异氰酸基-1H-吲哚(5-2)的制备方法同化合物1-2。LRMS(ESI)m/z[M+H]+:177.2.The preparation method of 6-fluoro-3-isocyanato-1H-indole (5-2) is the same as that of compound 1-2. LRMS(ESI)m/z[M+H] + :177.2.
步骤③：N-(6-氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-5)
Step ③: N-(6-fluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-5)
N-(6-氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-5)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.78(s,1H),8.30(s,1H),7.60–7.63(m,1H),7.37(d,J＝1.6Hz,1H),7.19–7.20(m,4H),7.10(dd,J＝2.4,10.4Hz,1H),6.85(td,J＝2.0,9.6Hz,1H),4.67(s,2H),3.75(t,J＝6.0Hz,2H),2.87(t,J＝6.0Hz,2H).The preparation method of N-(6-fluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-5) is the same as that of compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.78 (s, 1H), 8.30 (s, 1H), 7.60–7.63 (m, 1H), 7.37 (d, J = 1.6Hz, 1H), 7.19– 7.20(m,4H),7.10(dd,J＝2.4,10.4Hz,1H),6.85(td,J＝2.0,9.6Hz,1H),4.67(s,2H),3.75(t,J＝6.0Hz ,2H),2.87(t,J=6.0Hz,2H).
实施例6 N-(5-氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-6)
Example 6 N-(5-fluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-6)
步骤①：5-氟-1H-吲哚-3-酰基叠氮(6-1)
Step ①: 5-fluoro-1H-indole-3-acyl azide (6-1)
5-氟-1H-吲哚-3-酰基叠氮(6-1)的制备方法同化合物1-1。LRMS(ESI)m/z[M+H]+:205.1.The preparation method of 5-fluoro-1H-indole-3-acyl azide (6-1) is the same as that of compound 1-1. LRMS(ESI)m/z[M+H] + :205.1.
步骤②：5-氟-3-异氰酸基-1H-吲哚(6-2)
Step ②: 5-fluoro-3-isocyanato-1H-indole (6-2)
5-氟-3-异氰酸基-1H-吲哚(6-2)的制备方法同化合物1-2。LRMS(ESI)m/z[M+H]+:177.3.The preparation method of 5-fluoro-3-isocyanato-1H-indole (6-2) is the same as that of compound 1-2. LRMS(ESI)m/z[M+H] + :177.3.
步骤③：N-(5-氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-6)
Step ③: N-(5-fluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-6)
N-(5-氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-6)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.83(s,1H),8.24(s,1H),7.45(d,J＝2.8Hz,1H),7.39(dd,J＝2.4,10.4Hz,1H),7.29–7.32(m,1H),7.14–7.21(m,4H),6.93(td,J＝1.8,9.2Hz,1H),4.67(s,2H),3.75(t,J＝6.0Hz,2H),2.88(t,J＝6.0Hz,2H).The preparation method of N-(5-fluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-6) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.83 (s, 1H), 8.24 (s, 1H), 7.45 (d, J = 2.8Hz, 1H), 7.39 (dd, J = 2.4, 10.4Hz, 1H),7.29–7.32(m,1H),7.14–7.21(m,4H),6.93(td,J＝1.8,9.2Hz,1H),4.67(s,2H),3.75(t,J＝6.0Hz ,2H),2.88(t,J＝6.0Hz,2H).
实施例7 N-(1H-吲哚-6-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-7)
Example 7 N-(1H-indol-6-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-7)
步骤①：1H-吲哚-6-酰基叠氮(7-1)
Step ①: 1H-indole-6-acyl azide (7-1)
1H-吲哚-6-酰基叠氮(7-1)的制备方法同化合物1-1。1H NMR(400MHz,DMSO-d6)δ11.67(s,1H),8.11(s,1H),7.30–7.70(m,3H),6.58(s,1H).The preparation method of 1H-indole-6-acyl azide (7-1) is the same as that of compound 1-1. 1 H NMR (400MHz, DMSO-d 6 ) δ11.67(s,1H),8.11(s,1H),7.30–7.70(m,3H),6.58(s,1H).
步骤②：6-异氰酸基-1H-吲哚(7-2)
Step ②: 6-isocyanato-1H-indole (7-2)
6-异氰酸基-1H-吲哚(7-2)的制备方法同化合物1-2。LRMS(ESI)m/z[M+H]+:159.1.The preparation method of 6-isocyanato-1H-indole (7-2) is the same as that of compound 1-2. LRMS(ESI)m/z[M+H] + :159.1.
步骤③：N-(1H-吲哚-6-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-7)
Step ③: N-(1H-indol-6-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-7)
N-(1H-吲哚-6-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-7)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.91(s,1H),8.45(s,1H),7.67(s,2H),7.38(d,J＝8.4Hz,1H),7.19–7.21(m,5H),7.05(dd,J＝2.0,8.4Hz,1H),6.32(t,J＝2.8Hz,1H),4.65(s,2H),3.73(t,J＝6.0Hz,2H),2.87(t,J＝6.0Hz,2H).The preparation method of N-(1H-indol-6-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-7) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.91 (s, 1H), 8.45 (s, 1H), 7.67 (s, 2H), 7.38 (d, J = 8.4Hz, 1H), 7.19–7.21 ( m,5H),7.05(dd,J＝2.0,8.4Hz,1H),6.32(t,J＝2.8Hz,1H),4.65(s,2H),3.73(t,J＝6.0Hz,2H), 2.87(t,J＝6.0Hz,2H).
实施例8 N-(苯并[b]噻吩-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-8)
Example 8 N-(benzo[b]thiophen-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-8)
步骤①：苯并[b]噻吩-3-酰基叠氮(8-1)
Step ①: Benzo[b]thiophene-3-acylazide (8-1)
苯并[b]噻吩-3-酰基叠氮(8-1)的制备方法同化合物1-1。1H NMR(400MHz,CDCl3)δ8.66(d,J＝8.1Hz,1H),8.46(s,1H),7.88(d,J＝8.1Hz,1H),7.58–7.40(m,2H).The preparation method of benzo[b]thiophene-3-acyl azide (8-1) is the same as that of compound 1-1. 1 H NMR (400MHz, CDCl 3 ) δ8.66(d,J＝8.1Hz,1H),8.46(s,1H),7.88(d,J＝8.1Hz,1H),7.58–7.40(m,2H) .
步骤②：3-异氰酸基苯并[b]噻吩(8-2)
Step ②: 3-isocyanatobenzo[b]thiophene (8-2)
3-异氰酸基苯并[b]噻吩(8-2)的制备方法同化合物1-2。1H NMR(400MHz,DMSO-d6)δ10.41(s,1H),8.40(d,J＝7.9Hz,1H),7.96(d,J＝7.7Hz,1H),7.77(s,1H),7.44(dt,J＝7.1,14.8Hz,2H).The preparation method of 3-isocyanatobenzo[b]thiophene (8-2) is the same as that of compound 1-2. 1 H NMR (400MHz, DMSO-d 6 ) δ10.41 (s, 1H), 8.40 (d, J = 7.9Hz, 1H), 7.96 (d, J = 7.7Hz, 1H), 7.77 (s, 1H) ,7.44(dt,J=7.1,14.8Hz,2H).
步骤③：N-(苯并[b]噻吩-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-8)
Step ③: N-(benzo[b]thiophen-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-8)
N-(苯并[b]噻吩-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-8)的制备方法同化合物 I-1。1H NMR(400MHz,CDCl3)δ7.87–7.81(m,1H),7.73(s,1H),7.58(d,J＝7.3Hz,1H),7.40(dt,J＝8.6,6.2Hz,2H),7.22(dd,J＝10.3,5.2Hz,4H),4.75(s,2H),3.81(t,J＝5.9Hz,2H),2.99(t,J＝5.8Hz,2H).The preparation method of N-(benzo[b]thiophen-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-8) is the same as that of the compound I-1. 1 H NMR (400MHz, CDCl 3 ) δ7.87–7.81 (m, 1H), 7.73 (s, 1H), 7.58 (d, J = 7.3Hz, 1H), 7.40 (dt, J = 8.6, 6.2Hz, 2H), 7.22 (dd, J＝10.3, 5.2Hz, 4H), 4.75 (s, 2H), 3.81 (t, J＝5.9Hz, 2H), 2.99 (t, J＝5.8Hz, 2H).
实施例9 N-(1H-吲哚-3-基)-6-三氟甲基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-9)
Example 9 N-(1H-indol-3-yl)-6-trifluoromethyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-9)
N-(1H-吲哚-3-基)-6-三氟甲基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-9)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.72(s,1H),8.32(s,1H),7.60(d,J＝8.2Hz,2H),7.55(d,J＝8.2Hz,1H),7.42(d,J＝8.0Hz,1H),7.36(d,J＝2.2Hz,1H),7.31(d,J＝8.1Hz,1H),7.06(t,J＝7.5Hz,1H),6.95(t,J＝7.4Hz,1H),4.75(s,2H),3.77(t,J＝5.8Hz,2H),2.96(t,J＝5.6Hz,2H).The preparation method of N-(1H-indol-3-yl)-6-trifluoromethyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-9) is the same as compound I-1 . 1 H NMR (400MHz, DMSO-d 6 ) δ10.72 (s, 1H), 8.32 (s, 1H), 7.60 (d, J = 8.2Hz, 2H), 7.55 (d, J = 8.2Hz, 1H) ,7.42(d,J＝8.0Hz,1H),7.36(d,J＝2.2Hz,1H),7.31(d,J＝8.1Hz,1H),7.06(t,J＝7.5Hz,1H),6.95 (t,J＝7.4Hz,1H),4.75(s,2H),3.77(t,J＝5.8Hz,2H),2.96(t,J＝5.6Hz,2H).
实施例10 N-(1H-吲哚-3-基)-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-10)
Example 10 N-(1H-indol-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-10)
步骤①：2-Boc-6-苯基-1,2,3,4-四氢异喹啉(10-1)
Step ①: 2-Boc-6-phenyl-1,2,3,4-tetrahydroisoquinoline (10-1)
将500毫克2-Boc-6-溴-1,2,3,4-四氢异喹啉、391毫克苯硼酸、1.04克碳酸铯、185毫克四(三苯基膦)钯和11毫升乙二醇二甲醚的混合物于氩气保护下85℃搅拌3小时。反应液浓缩至干，残余物以乙酸乙酯：石油醚＝2:98柱层析，得白色固体2-Boc-6-苯基-1,2,3,4-四氢异喹啉(10-1)413毫克，收率83％。1H NMR(400MHz,DMSO-d6)δ7.74(d,J＝7.5Hz,2H),7.56(q,J＝8.5Hz,4H),7.45(t,J＝7.3Hz,1H),7.35(d,J＝7.7Hz,1H),4.64(s,2H),3.68(t,J＝5.7Hz,2H),3.46(s,3H),2.95(t,J＝5.6Hz,2H),2.61(s,1H).500 mg of 2-Boc-6-bromo-1,2,3,4-tetrahydroisoquinoline, 391 mg of phenylboronic acid, 1.04 g of cesium carbonate, 185 mg of tetrakis(triphenylphosphine)palladium and 11 ml of ethylene di The mixture of glycol dimethyl ether was stirred at 85°C for 3 hours under argon protection. The reaction solution was concentrated to dryness, and the residue was subjected to column chromatography with ethyl acetate: petroleum ether = 2:98 to obtain a white solid 2-Boc-6-phenyl-1,2,3,4-tetrahydroisoquinoline (10 -1) 413 mg, yield 83%. 1 H NMR (400MHz, DMSO-d 6 ) δ7.74 (d, J = 7.5Hz, 2H), 7.56 (q, J = 8.5Hz, 4H), 7.45 (t, J = 7.3Hz, 1H), 7.35 (d,J＝7.7Hz,1H),4.64(s,2H),3.68(t,J＝5.7Hz,2H),3.46(s,3H),2.95(t,J＝5.6Hz,2H),2.61 (s,1H).
步骤②：6-苯基-1,2,3,4-四氢异喹啉(10-2)
Step ②: 6-phenyl-1,2,3,4-tetrahydroisoquinoline (10-2)
340毫克化合物10-1、2毫升三氟乙酸和8毫升水的混合物室温搅拌3小时。反应液加饱和碳酸氢钠稀释，以二氯甲烷萃取，有机水洗，浓缩至干，得6-苯基-1,2,3,4-四氢异喹啉(10-2)白色固体213毫克，收率93％。1H NMR(400MHz,DMSO-d6)δ7.62 (d,J＝7.7Hz,2H),7.49–7.30(m,5H),7.09(d,J＝7.8Hz,1H),3.86(s,2H),2.96(t,J＝5.8Hz,2H),2.76(d,J＝5.6Hz,2H).A mixture of 340 mg of compound 10-1, 2 ml of trifluoroacetic acid and 8 ml of water was stirred at room temperature for 3 hours. The reaction solution was diluted with saturated sodium bicarbonate, extracted with dichloromethane, washed with organic water, and concentrated to dryness to obtain 213 mg of 6-phenyl-1,2,3,4-tetrahydroisoquinoline (10-2) as a white solid. , yield 93%. 1 H NMR (400MHz, DMSO-d 6 ) δ7.62 (d,J＝7.7Hz,2H),7.49–7.30(m,5H),7.09(d,J＝7.8Hz,1H),3.86(s,2H),2.96(t,J＝5.8Hz,2H) ,2.76(d,J=5.6Hz,2H).
步骤③：N-(1H-吲哚-3-基)-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-10)
Step ③: N-(1H-indol-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-10)
N-(1H-吲哚-3-基)-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-10)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.71(s,1H),8.28(s,1H),7.66(d,J＝7.6Hz,2H),7.62(d,J＝7.8Hz,1H),7.47(dd,J＝16.4,8.6Hz,4H),7.41–7.21(m,4H),7.06(t,J＝7.4Hz,1H),6.96(t,J＝7.4Hz,1H),4.71(s,2H),3.77(t,J＝5.5Hz,2H),2.95(s,2H).The preparation method of N-(1H-indol-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-10) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.71 (s, 1H), 8.28 (s, 1H), 7.66 (d, J = 7.6Hz, 2H), 7.62 (d, J = 7.8Hz, 1H) ,7.47(dd,J＝16.4,8.6Hz,4H),7.41–7.21(m,4H),7.06(t,J＝7.4Hz,1H),6.96(t,J＝7.4Hz,1H),4.71( s,2H),3.77(t,J＝5.5Hz,2H),2.95(s,2H).
实施例11 N-(5,6-二氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-11)
Example 11 N-(5,6-difluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-11)
步骤①：5,6-二氟-1H-吲哚-3-酰基叠氮(11-1)
Step ①: 5,6-difluoro-1H-indole-3-acyl azide (11-1)
5,6-二氟-1H-吲哚-3-酰基叠氮(11-1)的制备方法同化合物1-1。1H NMR(400MHz,DMSO-d6)δ12.38(s,1H),8.32–8.17(m,1H),7.87(dd,J＝8.1,2.7Hz,1H),7.64–7.48(m,1H),7.44(d,J＝7.2Hz,1H),7.25(s,1H).The preparation method of 5,6-difluoro-1H-indole-3-acyl azide (11-1) is the same as that of compound 1-1. 1 H NMR (400MHz, DMSO-d 6 ) δ12.38 (s, 1H), 8.32–8.17 (m, 1H), 7.87 (dd, J = 8.1, 2.7Hz, 1H), 7.64–7.48 (m, 1H) ),7.44(d,J=7.2Hz,1H),7.25(s,1H).
步骤②：5,6-二氟-3-异氰酸基-1H-吲哚(11-2)
Step ②: 5,6-difluoro-3-isocyanato-1H-indole (11-2)
5,6-二氟-3-异氰酸基-1H-吲哚(11-2)的制备方法同化合物1-2。LRMS(ESI)m/z[M+H]+:195.1.The preparation method of 5,6-difluoro-3-isocyanato-1H-indole (11-2) is the same as that of compound 1-2. LRMS(ESI)m/z[M+H] + :195.1.
步骤③：N-(5,6-二氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-11)
Step ③: N-(5,6-difluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-11)
N-(5,6-二氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-11)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.89(s,1H),8.28(s,1H),7.60(dd,J＝ 11.6,8.2Hz,1H),7.45(d,J＝2.3Hz,1H),7.32(dd,J＝11.3,7.0Hz,1H),7.20(s,4H),4.67(s,2H),3.73(t,J＝5.9Hz,2H),2.87(t,J＝5.8Hz,2H).The preparation method of N-(5,6-difluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-11) is the same as compound I-1 . 1 H NMR (400MHz, DMSO-d 6 ) δ10.89 (s, 1H), 8.28 (s, 1H), 7.60 (dd, J＝ 11.6,8.2Hz,1H),7.45(d,J＝2.3Hz,1H),7.32(dd,J＝11.3,7.0Hz,1H),7.20(s,4H),4.67(s,2H),3.73( t,J＝5.9Hz,2H),2.87(t,J＝5.8Hz,2H).
实施例12 N-(1H-吲哚-3-基)-4-苯基哌嗪-1-甲酰胺(I-12)
Example 12 N-(1H-indol-3-yl)-4-phenylpiperazine-1-carboxamide (I-12)
N-(1H-吲哚-3-基)-4-苯基哌嗪-1-甲酰胺(I-12)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.70(s,1H),8.31(s,1H),7.61(d,J＝7.9Hz,1H),7.37(d,J＝2.0Hz,1H),7.30(d,J＝8.1Hz,1H),7.24(t,J＝7.8Hz,2H),7.09–6.92(m,4H),6.81(t,J＝7.2Hz,1H),3.69–3.55(m,4H),3.22–3.11(m,4H).The preparation method of N-(1H-indol-3-yl)-4-phenylpiperazine-1-carboxamide (I-12) is the same as that of compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.70 (s, 1H), 8.31 (s, 1H), 7.61 (d, J = 7.9Hz, 1H), 7.37 (d, J = 2.0Hz, 1H) ,7.30(d,J＝8.1Hz,1H),7.24(t,J＝7.8Hz,2H),7.09–6.92(m,4H),6.81(t,J＝7.2Hz,1H),3.69–3.55( m,4H),3.22–3.11(m,4H).
实施例13 N-(苯并呋喃-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-13)
Example 13 N-(benzofuran-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-13)
步骤①：苯并呋喃-3-酰基叠氮(13-1)
Step ①: Benzofuran-3-acyl azide (13-1)
苯并呋喃-3-酰基叠氮(13-1)的制备方法同化合物1-1。1H NMR(400MHz,DMSO-d6)δ8.90(s,1H),8.09–7.99(m,1H),7.82–7.71(m,1H),7.51–7.41(m,2H).The preparation method of benzofuran-3-acyl azide (13-1) is the same as that of compound 1-1. 1 H NMR (400MHz, DMSO-d 6 ) δ8.90(s,1H),8.09–7.99(m,1H),7.82–7.71(m,1H),7.51–7.41(m,2H).
步骤②：3-异氰酸基苯并呋喃(13-2)
Step ②: 3-isocyanatobenzofuran (13-2)
3-异氰酸基苯并呋喃(13-2)的制备方法同化合物1-2。LRMS(ESI)m/z[M+H]+:160.1.The preparation method of 3-isocyanatobenzofuran (13-2) is the same as that of compound 1-2. LRMS(ESI)m/z[M+H] + :160.1.
步骤③：N-(苯并呋喃-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-13)
Step ③: N-(benzofuran-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-13)
N-(苯并呋喃-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-13)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ8.67(s,1H),8.12(s,1H),7.93(d,J＝7.5Hz,1H),7.51(d,J＝8.1Hz,1H),7.29(dt,J＝24.9,7.3Hz,2H),7.20(s,4H),4.70(s,2H),3.76(t,J＝5.9Hz,2H),2.88(t,J＝5.8Hz,2H).The preparation method of N-(benzofuran-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-13) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ8.67 (s, 1H), 8.12 (s, 1H), 7.93 (d, J = 7.5Hz, 1H), 7.51 (d, J = 8.1Hz, 1H) ,7.29(dt,J＝24.9,7.3Hz,2H),7.20(s,4H),4.70(s,2H),3.76(t,J＝5.9Hz,2H),2.88(t,J＝5.8Hz, 2H).
实施例14 N-(苯并呋喃-3-基)-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-14)
Example 14 N-(benzofuran-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-14)
N-(苯并呋喃-3-基)-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-14)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),8.14(s,1H),7.95(d,J＝7.6Hz,1H),7.66(d,J＝7.6Hz,2H),7.40–7.57(m,5H),7.31–7.37(m,4H),4.75(s,2H),3.80(t,J＝5.8Hz,2H),2.96(t,J＝5.6Hz,2H).The preparation method of N-(benzofuran-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-14) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ8.70 (s, 1H), 8.14 (s, 1H), 7.95 (d, J = 7.6Hz, 1H), 7.66 (d, J = 7.6Hz, 2H) ,7.40–7.57(m,5H),7.31–7.37(m,4H),4.75(s,2H),3.80(t,J＝5.8Hz,2H),2.96(t,J＝5.6Hz,2H).
实施例15 N-(1H-吲哚-3-基)-8-(哌啶-1-羰基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-15)
Example 15 N-(1H-indol-3-yl)-8-(piperidine-1-carbonyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-15)
步骤①：2-Boc-8-(哌啶-1-羰基)-1,2,3,4-四氢异喹啉(15-1)
Step ①: 2-Boc-8-(piperidine-1-carbonyl)-1,2,3,4-tetrahydroisoquinoline (15-1)
将29毫克2-Boc-1,2,3,4-四氢异喹啉-8-甲酸、9毫克哌啶、22毫克三乙胺、32毫克N-甲基吗啉、60毫克苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐和0.2毫升N,N-二甲基甲酰胺的混合物室温搅拌过夜。反应液加水稀释，乙酸乙酯萃取，有机相浓缩至干；残余物以甲醇：二氯甲烷＝1：99柱层析，得2-Boc-8-(哌啶-1-羰基)-1,2,3,4-四氢异喹啉(15-1)无色油状物46毫克，收率95％。1H NMR(400MHz,CDCl3)δ8.00(s,1H),7.17(t,J＝7.4Hz,1H),7.12(d,J＝7.4Hz,1H),7.03(d,J＝7.2Hz,1H),4.52(d,J＝29.0Hz,2H),3.90(s,2H),3.34–3.55(m,2H),3.18(d,J＝17.0Hz,2H),3.03–2.66(m,4H),1.64(d,J＝17.5Hz,4H),1.55–1.38(m,12H).Combine 29 mg of 2-Boc-1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid, 9 mg of piperidine, 22 mg of triethylamine, 32 mg of N-methylmorpholine, and 60 mg of benzotriazine A mixture of azol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate and 0.2 ml of N,N-dimethylformamide was stirred at room temperature overnight. The reaction solution was diluted with water, extracted with ethyl acetate, and the organic phase was concentrated to dryness; the residue was subjected to column chromatography with methanol:dichloromethane=1:99 to obtain 2-Boc-8-(piperidine-1-carbonyl)-1, 46 mg of 2,3,4-tetrahydroisoquinoline (15-1) colorless oil, yield 95%. 1 H NMR (400MHz, CDCl 3 ) δ8.00 (s, 1H), 7.17 (t, J = 7.4Hz, 1H), 7.12 (d, J = 7.4Hz, 1H), 7.03 (d, J = 7.2Hz ,1H),4.52(d,J＝29.0Hz,2H),3.90(s,2H),3.34–3.55(m,2H),3.18(d,J＝17.0Hz,2H),3.03–2.66(m, 4H),1.64(d,J=17.5Hz,4H),1.55–1.38(m,12H).
步骤②：8-(哌啶-1-羰基)-1,2,3,4-四氢异喹啉(15-2)
Step ②: 8-(piperidine-1-carbonyl)-1,2,3,4-tetrahydroisoquinoline (15-2)
将46毫克化合物15-1、200微升三氟乙酸和3毫升二氯甲烷的混合物室温搅拌3小时。反应液加饱和碳酸氢钠水溶液处理，以二氯甲烷萃取，有机相浓缩至干，得8-(哌啶-1-羰基)-1,2,3,4-四氢异喹啉(15-2)油状物33毫克，收率100％。1H NMR(400MHz, CDCl3)δ7.13(t,J＝7.4Hz,1H),7.07(d,J＝7.5Hz,1H),6.96(d,J＝7.2Hz,1H),4.13(d,J＝16.5Hz,1H),3.77(d,J＝16.5Hz,2H),3.65(s,1H),3.22–3.05(m,4H),2.80–2.93(m,4H),1.63(s,4H),1.24(d,J＝7.6Hz,1H).A mixture of 46 mg of compound 15-1, 200 μl of trifluoroacetic acid and 3 ml of methylene chloride was stirred at room temperature for 3 hours. The reaction solution was treated with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, and the organic phase was concentrated to dryness to obtain 8-(piperidine-1-carbonyl)-1,2,3,4-tetrahydroisoquinoline (15- 2) 33 mg of oil, yield 100%. 1 H NMR (400MHz, CDCl 3 )δ7.13(t,J＝7.4Hz,1H),7.07(d,J＝7.5Hz,1H),6.96(d,J＝7.2Hz,1H),4.13(d,J＝16.5Hz, 1H),3.77(d,J＝16.5Hz,2H),3.65(s,1H),3.22–3.05(m,4H),2.80–2.93(m,4H),1.63(s,4H),1.24(d ,J＝7.6Hz,1H).
步骤③：N-(1H-吲哚-3-基)-8-(哌啶-1-羰基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-15)
Step ③: N-(1H-indol-3-yl)-8-(piperidine-1-carbonyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-15)
N-(1H-吲哚-3-基)-8-(哌啶-1-羰基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-15)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.70(s,1H),8.35(s,1H),7.58(d,J＝8.0Hz,1H),7.35(d,J＝2.4Hz,1H),7.30(d,J＝7.9Hz,1H),7.24(d,J＝5.6Hz,2H),7.06(t,J＝7.3Hz,2H),6.94(t,J＝7.3Hz,1H),4.52(d,J＝8.2Hz,2H),4.11(q,J＝5.2Hz,1H),3.84(s,1H),3.64(s,3H),3.17(d,J＝5.2Hz,3H),3.12(s,2H),2.91(s,2H),1.58(s,5H),1.39(s,2H).The preparation method of N-(1H-indol-3-yl)-8-(piperidine-1-carbonyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-15) is the same as Compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.70 (s, 1H), 8.35 (s, 1H), 7.58 (d, J = 8.0Hz, 1H), 7.35 (d, J = 2.4Hz, 1H) ,7.30(d,J＝7.9Hz,1H),7.24(d,J＝5.6Hz,2H),7.06(t,J＝7.3Hz,2H),6.94(t,J＝7.3Hz,1H),4.52 (d,J＝8.2Hz,2H),4.11(q,J＝5.2Hz,1H),3.84(s,1H),3.64(s,3H),3.17(d,J＝5.2Hz,3H),3.12 (s,2H),2.91(s,2H),1.58(s,5H),1.39(s,2H).
实施例16Example 16
N-(5-三氟甲基-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-16)
N-(5-Trifluoromethyl-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-16)
步骤①：5-三氟甲基-1H-吲哚-3-酰基叠氮(16-1)
Step ①: 5-trifluoromethyl-1H-indole-3-acyl azide (16-1)
5-三氟甲基-1H-吲哚-3-酰基叠氮(16-1)的制备方法同化合物1-1。1H NMR(400MHz,DMSO-d6)δ12.64(s,1H),8.71(d,J＝13.1Hz,1H),8.37(s,1H),7.87(d,J＝8.7Hz,1H),7.65(d,J＝8.4Hz,1H).The preparation method of 5-trifluoromethyl-1H-indole-3-acyl azide (16-1) is the same as that of compound 1-1. 1 H NMR (400MHz, DMSO-d 6 ) δ12.64(s,1H),8.71(d,J＝13.1Hz,1H),8.37(s,1H),7.87(d,J＝8.7Hz,1H) ,7.65(d,J＝8.4Hz,1H).
步骤②：3-异氰酸基-5-三氟甲基-1H-吲哚(16-2)
Step ②: 3-isocyanato-5-trifluoromethyl-1H-indole (16-2)
3-异氰酸基-5-三氟甲基-1H-吲哚(16-2)的制备方法同化合物1-2。LRMS(ESI)m/z[M+H]+:227.1.The preparation method of 3-isocyanato-5-trifluoromethyl-1H-indole (16-2) is the same as that of compound 1-2. LRMS(ESI)m/z[M+H] + :227.1.
步骤③：N-(5-三氟甲基-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-16)
Step ③: N-(5-trifluoromethyl-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-16)
N-(5-三氟甲基-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-16)的制备方法同化合物I-1。LRMS(ESI)m/z[M+H]+:360.3.The preparation method of N-(5-trifluoromethyl-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-16) is the same as compound I-1 . LRMS(ESI)m/z[M+H] + :360.3.
实施例17 2-((1H-吲哚-3-基)氨基甲酰基)-1,2,3,4-四氢异喹啉-8-甲酸(I-17)
Example 17 2-((1H-indol-3-yl)carbamoyl)-1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid (I-17)
2-((1H-吲哚-3-基)氨基甲酰基)-1,2,3,4-四氢异喹啉-8-甲酸(I-17)的制备方法同化合物I-1。LRMS(ESI)m/z[M–H]–:334.2.The preparation method of 2-((1H-indol-3-yl)carbamoyl)-1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid (I-17) is the same as compound I-1. LRMS(ESI)m/z[M–H] – :334.2.
实施例18 2-((1H-吲哚-3-基)氨基甲酰基)-1,2,3,4-四氢异喹啉-8-甲酸甲酯(I-18)
Example 18 2-((1H-indol-3-yl)carbamoyl)-1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid methyl ester (I-18)
2-((1H-吲哚-3-基)氨基甲酰基)-1,2,3,4-四氢异喹啉-8-甲酸甲酯(I-18)的制备方法同化合物I-1。LRMS(ESI)m/z[M+H]+:350.3.The preparation method of 2-((1H-indol-3-yl)carbamoyl)-1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid methyl ester (I-18) is the same as compound I-1 . LRMS(ESI)m/z[M+H] + :350.3.
实施例19 6-(呋喃-3-基)-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-19)
Example 19 6-(furan-3-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-19)
步骤①：2-Boc-6-(呋喃-3-基)-3,4-二氢异喹啉(19-1)
Step ①: 2-Boc-6-(furan-3-yl)-3,4-dihydroisoquinoline (19-1)
2-Boc-6-(呋喃-3-基)-3,4-二氢异喹啉(19-1)的制备同化合物10-1。1H NMR(400MHz,DMSO-d6)δ8.15(s,1H),7.72(t,J＝1.7Hz,1H),7.42(d,J＝7.8Hz,2H),7.17(d,J＝7.9Hz,1H),6.94(d,J＝1.0Hz,1H),4.48(s,2H),3.56(t,J＝5.9Hz,2H),2.79(t,J＝5.8Hz,2H),1.43(s,10H).The preparation of 2-Boc-6-(furan-3-yl)-3,4-dihydroisoquinoline (19-1) is the same as compound 10-1. 1 H NMR (400MHz, DMSO-d 6 ) δ8.15 (s, 1H), 7.72 (t, J = 1.7Hz, 1H), 7.42 (d, J = 7.8Hz, 2H), 7.17 (d, J = 7.9Hz,1H),6.94(d,J＝1.0Hz,1H),4.48(s,2H),3.56(t,J＝5.9Hz,2H),2.79(t,J＝5.8Hz,2H),1.43 (s,10H).
步骤②：6-(呋喃-3-基)-1,2,3,4-四氢异喹啉(19-2)
Step ②: 6-(furan-3-yl)-1,2,3,4-tetrahydroisoquinoline (19-2)
6-(呋喃-3-基)-1,2,3,4-四氢异喹啉(19-2)的制备同化合物10-2。1H NMR(400MHz,DMSO-d6)δ8.13(s,1H),7.71(s,1H),7.42–7.30(m,2H),7.04(d,J＝7.8Hz,1H),6.92(s,1H),3.89(s,2H),3.01(t,J＝5.9Hz,2H),2.75(t,J＝5.8Hz,2H).The preparation of 6-(furan-3-yl)-1,2,3,4-tetrahydroisoquinoline (19-2) is the same as compound 10-2. 1 H NMR (400MHz, DMSO-d 6 ) δ8.13 (s, 1H), 7.71 (s, 1H), 7.42–7.30 (m, 2H), 7.04 (d, J = 7.8Hz, 1H), 6.92 ( s,1H),3.89(s,2H),3.01(t,J＝5.9Hz,2H),2.75(t,J＝5.8Hz,2H).
步骤③：6-(呋喃-3-基)-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-19)
Step ③: 6-(furan-3-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-19)
6-(呋喃-3-基)-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-19)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.72(s,1H),8.36(s,1H),8.29(s,1H),7.96(d,J＝7.5Hz,1H),7.74–7.52(m,4H),7.35(ddd,J＝13.5,12.4,5.8Hz,5H),7.06(t,J＝7.4Hz,1H),6.96(t,J＝7.4Hz,1H),4.73(s,2H),3.79(t,J＝5.9Hz,2H),2.97(t,J＝5.4Hz,2H).The preparation method of 6-(furan-3-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-19) is the same as that of the compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.72 (s, 1H), 8.36 (s, 1H), 8.29 (s, 1H), 7.96 (d, J = 7.5Hz, 1H), 7.74–7.52 ( m,4H),7.35(ddd,J＝13.5,12.4,5.8Hz,5H),7.06(t,J＝7.4Hz,1H),6.96(t,J＝7.4Hz,1H),4.73(s,2H ), 3.79 (t, J = 5.9Hz, 2H), 2.97 (t, J = 5.4Hz, 2H).
实施例20 N-(1H-吲哚-3-基)-6-(萘-1-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-20)
Example 20 N-(1H-indol-3-yl)-6-(naphthyl-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-20)
步骤①：2-Boc-6-(萘-1-基)-3,4-二氢异喹啉(20-1)
Step ①: 2-Boc-6-(naphthyl-1-yl)-3,4-dihydroisoquinoline (20-1)
2-Boc-6-(萘-1-基)-3,4-二氢异喹(20-1)的制备同化合物10-1。1H NMR(400MHz,DMSO-d6)δ7.99(d,J＝7.7Hz,1H),7.94(d,J＝8.2Hz,1H),7.82(d,J＝8.2Hz,1H),7.52(ddd,J＝22.7,14.6,7.0Hz,3H),7.40(d,J＝7.0Hz,1H),7.30(dd,J＝17.3,7.5Hz,3H),4.60(s,2H),3.61(t,J＝5.9Hz,2H),2.86(t,J＝5.7Hz,2H),1.45(s,10H).The preparation of 2-Boc-6-(naphth-1-yl)-3,4-dihydroisoquine (20-1) is the same as that of compound 10-1. 1 H NMR (400MHz, DMSO-d 6 ) δ7.99 (d, J = 7.7Hz, 1H), 7.94 (d, J = 8.2Hz, 1H), 7.82 (d, J = 8.2Hz, 1H), 7.52 (ddd,J＝22.7,14.6,7.0Hz,3H),7.40(d,J＝7.0Hz,1H),7.30(dd,J＝17.3,7.5Hz,3H),4.60(s,2H),3.61( t,J＝5.9Hz,2H),2.86(t,J＝5.7Hz,2H),1.45(s,10H).
步骤②：6-(萘-1-基)-1,2,3,4-四氢异喹啉(20-2)
Step ②: 6-(naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline (20-2)
6-(萘-1-基)-1,2,3,4-四氢异喹啉(20-2)的制备同化合物10-2。1H NMR(400MHz,DMSO-d6)δ7.99(d,J＝7.7Hz,1H),7.93(d,J＝8.2Hz,1H),7.83(d,J＝8.3Hz,1H), 7.53(ddd,J＝13.0,12.0,7.1Hz,3H),7.40(d,J＝6.3Hz,1H),7.18(q,J＝7.5Hz,3H),3.94(s,2H),3.01(t,J＝5.9Hz,2H),2.77(t,J＝5.7Hz,2H).The preparation of 6-(naphth-1-yl)-1,2,3,4-tetrahydroisoquinoline (20-2) is the same as compound 10-2. 1 H NMR (400MHz, DMSO-d 6 ) δ7.99 (d, J = 7.7Hz, 1H), 7.93 (d, J = 8.2Hz, 1H), 7.83 (d, J = 8.3Hz, 1H), 7.53(ddd,J＝13.0,12.0,7.1Hz,3H),7.40(d,J＝6.3Hz,1H),7.18(q,J＝7.5Hz,3H),3.94(s,2H),3.01(t ,J＝5.9Hz,2H),2.77(t,J＝5.7Hz,2H).
步骤③：N-(1H-吲哚-3-基)-6-(萘-1-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-20)
Step ③: N-(1H-indol-3-yl)-6-(naphthyl-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-20)
N-(1H-吲哚-3-基)-6-(萘-1-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-20)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.72(s,1H),8.30(s,1H),8.00(d,J＝7.3Hz,1H),7.95(d,J＝8.5Hz,1H),7.85(d,J＝8.5Hz,1H),7.63(d,J＝7.8Hz,1H),7.60–7.46(m,3H),7.43(d,J＝6.1Hz,1H),7.38(d,J＝2.1Hz,1H),7.33(dd,J＝11.0,6.7Hz,4H),7.07(t,J＝7.1Hz,1H),6.96(t,J＝7.6Hz,1H),4.78(s,2H),3.81(s,2H),2.96(s,2H).The preparation method of N-(1H-indol-3-yl)-6-(naphthyl-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-20) is the same as that of the compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.72 (s, 1H), 8.30 (s, 1H), 8.00 (d, J = 7.3Hz, 1H), 7.95 (d, J = 8.5Hz, 1H) ,7.85(d,J＝8.5Hz,1H),7.63(d,J＝7.8Hz,1H),7.60–7.46(m,3H),7.43(d,J＝6.1Hz,1H),7.38(d, J＝2.1Hz,1H),7.33(dd,J＝11.0,6.7Hz,4H),7.07(t,J＝7.1Hz,1H),6.96(t,J＝7.6Hz,1H),4.78(s, 2H),3.81(s,2H),2.96(s,2H).
实施例21 6-(苯并呋喃-3-基)-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-21)
Example 21 6-(benzofuran-3-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-21)
步骤①：2-Boc-6-(苯并呋喃-3-基)-3,4-二氢异喹(21-1)
Step ①: 2-Boc-6-(benzofuran-3-yl)-3,4-dihydroisoquine (21-1)
2-Boc-6-(苯并呋喃-3-基)-3,4-二氢异喹(21-1)的制备同化合物10-1。1H NMR(400MHz,DMSO-d6)δ8.34(s,1H),7.93(d,J＝7.3Hz,1H),7.66(d,J＝7.8Hz,1H),7.55(d,J＝8.0Hz,2H),7.35(ddd,J＝23.8,16.8,7.4Hz,3H),4.55(s,2H),3.59(t,J＝5.7Hz,2H),2.87(t,J＝5.7Hz,2H),1.44(s,9H).The preparation of 2-Boc-6-(benzofuran-3-yl)-3,4-dihydroisoquine (21-1) is the same as compound 10-1. 1 H NMR (400MHz, DMSO-d 6 ) δ8.34 (s, 1H), 7.93 (d, J = 7.3Hz, 1H), 7.66 (d, J = 7.8Hz, 1H), 7.55 (d, J = 8.0Hz,2H),7.35(ddd,J＝23.8,16.8,7.4Hz,3H),4.55(s,2H),3.59(t,J＝5.7Hz,2H),2.87(t,J＝5.7Hz, 2H),1.44(s,9H).
步骤②：6-(苯并呋喃-3-基)-1,2,3,4-四氢异喹啉(21-2)
Step ②: 6-(benzofuran-3-yl)-1,2,3,4-tetrahydroisoquinoline (21-2)
6-(苯并呋喃-3-基)-1,2,3,4-四氢异喹啉(21-2)的制备同化合物10-2。1H NMR(400MHz,DMSO-d6)δ8.31(s,1H),7.91(d,J＝7.3Hz,1H),7.66(d,J＝7.7Hz,1H),7.50–7.42(m,2H),7.42–7.31(m,2H),7.15(d,J＝7.9Hz,1H),3.91(s,2H),3.00(t,J＝5.9Hz, 2H),2.79(t,J＝5.7Hz,2H).The preparation of 6-(benzofuran-3-yl)-1,2,3,4-tetrahydroisoquinoline (21-2) is the same as compound 10-2. 1 H NMR (400MHz, DMSO-d 6 ) δ8.31 (s, 1H), 7.91 (d, J = 7.3Hz, 1H), 7.66 (d, J = 7.7Hz, 1H), 7.50–7.42 (m, 2H),7.42–7.31(m,2H),7.15(d,J＝7.9Hz,1H),3.91(s,2H),3.00(t,J＝5.9Hz, 2H),2.79(t,J＝5.7Hz,2H).
步骤③：6-(苯并呋喃-3-基)-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-21)
Step ③: 6-(benzofuran-3-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-21)
6-(苯并呋喃-3-基)-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-21)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.72(s,1H),8.36(s,1H),8.29(s,1H),7.96(d,J＝7.5Hz,1H),7.74–7.52(m,4H),7.35(ddd,J＝13.5,12.4,5.8Hz,5H),7.06(t,J＝7.4Hz,1H),6.96(t,J＝7.4Hz,1H),4.73(s,2H),3.79(t,J＝5.9Hz,2H),2.97(t,J＝5.4Hz,2H).Preparation method of 6-(benzofuran-3-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-21) Same as compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.72 (s, 1H), 8.36 (s, 1H), 8.29 (s, 1H), 7.96 (d, J = 7.5Hz, 1H), 7.74–7.52 ( m,4H),7.35(ddd,J＝13.5,12.4,5.8Hz,5H),7.06(t,J＝7.4Hz,1H),6.96(t,J＝7.4Hz,1H),4.73(s,2H ), 3.79 (t, J = 5.9Hz, 2H), 2.97 (t, J = 5.4Hz, 2H).
实施例22 N-(1H-吲哚-3-基)-6-(哌啶-1-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-22)
Example 22 N-(1H-indol-3-yl)-6-(piperidin-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-22)
步骤①：2-Boc-6-(哌啶-1-基)-1,2,3,4-四氢异喹啉(22-1)
Step ①: 2-Boc-6-(piperidin-1-yl)-1,2,3,4-tetrahydroisoquinoline (22-1)
将167毫克2-Boc-6-溴-1,2,3,4-四氢异喹啉、137毫克哌啶、257毫克叔丁醇钠、22毫克[1,3-双(2,6-二异丙基苯)咪唑-2-叉](3-氯吡啶)二氯化钯和14毫升无水二氧六环的混合物于氩气保护下100℃搅拌过夜。反应液浓缩至干，残余物以乙酸乙酯：石油醚＝5:95柱层析，得白色固体2-Boc-6-(哌啶-1-基)-1,2,3,4-四氢异喹啉(22-1)117毫克，收率69％。1H NMR(400MHz,DMSO-d6)δ6.98(d,J＝8.6Hz,1H),6.80(d,J＝8.2Hz,1H),6.70(s,1H),4.48(s,2H),3.62(s,3H),3.14–3.05(m,4H),2.77(s,2H),1.69(d,J＝5.3Hz,3H),1.64(s,2H),1.57(d,J＝5.4Hz,2H),1.48(s,9H).167 mg of 2-Boc-6-bromo-1,2,3,4-tetrahydroisoquinoline, 137 mg of piperidine, 257 mg of sodium tert-butoxide, 22 mg of [1,3-bis(2,6- A mixture of diisopropylbenzene)imidazole-2-ylidene](3-chloropyridine)palladium dichloride and 14 ml of anhydrous dioxane was stirred overnight at 100°C under argon protection. The reaction solution was concentrated to dryness, and the residue was subjected to column chromatography with ethyl acetate: petroleum ether = 5:95 to obtain a white solid 2-Boc-6-(piperidin-1-yl)-1,2,3,4-tetrahydrofuran. Hydroisoquinoline (22-1) 117 mg, yield 69%. 1 H NMR (400MHz, DMSO-d 6 ) δ6.98 (d, J = 8.6 Hz, 1H), 6.80 (d, J = 8.2 Hz, 1H), 6.70 (s, 1H), 4.48 (s, 2H) ,3.62(s,3H),3.14–3.05(m,4H),2.77(s,2H),1.69(d,J＝5.3Hz,3H),1.64(s,2H),1.57(d,J＝5.4 Hz,2H),1.48(s,9H).
步骤②：6-(哌啶-1-基)-1,2,3,4-四氢异喹啉(22-2)
Step ②: 6-(piperidin-1-yl)-1,2,3,4-tetrahydroisoquinoline (22-2)
6-(哌啶-1-基)-1,2,3,4-四氢异喹啉(22-2)的制备同化合物10-2。LCMS(ESI)m/z[M+H]+:217.2. The preparation of 6-(piperidin-1-yl)-1,2,3,4-tetrahydroisoquinoline (22-2) is the same as compound 10-2. LCMS(ESI)m/z[M+H] + :217.2.
步骤③：N-(1H-吲哚-3-基)-6-(哌啶-1-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-22)
Step ③: N-(1H-indol-3-yl)-6-(piperidin-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-22)
N-(1H-吲哚-3-基)-6-(哌啶-1-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-22)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.70(s,1H),8.19(s,1H),7.61(d,J＝7.7Hz,1H),7.36(d,J＝2.3Hz,1H),7.31(d,J＝8.1Hz,1H),7.06(t,J＝7.4Hz,1H),7.02–6.93(m,2H),6.80(d,J＝8.5Hz,1H),6.74(s,1H),4.56(s,2H),3.69(t,J＝5.7Hz,2H),3.15–3.02(m,4H),2.80(t,J＝5.5Hz,2H),1.62(s,4H),1.53(d,J＝4.9Hz,2H).The preparation method of N-(1H-indol-3-yl)-6-(piperidin-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-22) is the same as Compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.70 (s, 1H), 8.19 (s, 1H), 7.61 (d, J = 7.7Hz, 1H), 7.36 (d, J = 2.3Hz, 1H) ,7.31(d,J＝8.1Hz,1H),7.06(t,J＝7.4Hz,1H),7.02–6.93(m,2H),6.80(d,J＝8.5Hz,1H),6.74(s, 1H),4.56(s,2H),3.69(t,J＝5.7Hz,2H),3.15–3.02(m,4H),2.80(t,J＝5.5Hz,2H),1.62(s,4H), 1.53(d,J＝4.9Hz,2H).
实施例23 N-(5,6-二氟-1H-吲哚-3-基)-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-23)
Example 23 N-(5,6-difluoro-1H-indol-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-23)
N-(5,6-二氟-1H-吲哚-3-基)-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-23)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.88(s,1H),8.30(s,1H),7.58–7.67(m,3H),7.54–7.40(m,5H),7.38–7.25(m,3H),4.71(s,2H),3.76(s,2H),2.94(s,2H).Preparation method of N-(5,6-difluoro-1H-indol-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-23) Same as compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.88(s,1H),8.30(s,1H),7.58–7.67(m,3H),7.54–7.40(m,5H),7.38–7.25(m ,3H),4.71(s,2H),3.76(s,2H),2.94(s,2H).
实施例24 N-(5-氟-1H-吲哚-3-基)-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-24)
Example 24 N-(5-fluoro-1H-indol-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-24)
N-(5-氟-1H-吲哚-3-基)-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-24)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.81(s,1H),8.25(s,1H),7.69–7.63(m,2H),7.50(d,J＝4.8Hz,2H),7.46(dd,J＝9.2,6.0Hz,3H),7.37(dt,J＝11.5,4.9Hz,2H),7.33–7.24(m,2H),6.90(td,J＝9.1,2.4Hz,1H),4.71(s,2H),3.77(t,J＝5.8Hz,2H),2.95(t,J＝5.6Hz,2H).LCMS(ESI)m/z[M+H]+:386.2.The preparation method of N-(5-fluoro-1H-indol-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-24) is the same as compound I -1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.81 (s, 1H), 8.25 (s, 1H), 7.69–7.63 (m, 2H), 7.50 (d, J = 4.8Hz, 2H), 7.46 ( dd,J＝9.2,6.0Hz,3H),7.37(dt,J＝11.5,4.9Hz,2H),7.33–7.24(m,2H),6.90(td,J＝9.1,2.4Hz,1H),4.71 (s,2H),3.77(t,J＝5.8Hz,2H),2.95(t,J＝5.6Hz,2H).LCMS(ESI)m/z[M+H] + :386.2.
实施例25 N-(1H-吲哚-3-基)-6-乙烯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-25)
Example 25 N-(1H-indol-3-yl)-6-vinyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-25)
步骤①：6-乙烯基-3,4-二氢异喹啉-2(1H)-Boc(25-1)
Step ①: 6-vinyl-3,4-dihydroisoquinoline-2(1H)-Boc(25-1)
将500毫克6-溴-3,4-二氢异喹啉-2(1H)-Boc、300毫克乙烯基硼酸频哪醇酯、230毫克叔丁醇钾、200毫克四(三苯基膦)钯和10毫升四氢呋喃的混合物于氩气保护下70℃搅拌5小时。反应液浓缩至干，残余物以乙酸乙酯：石油醚＝10:1柱层析，得6-乙烯基-3,4-二氢异喹啉-2(1H)-Boc(25-1)350毫克，收率84％。LCMS(ESI)m/z[M+Na]+:282.1.Combine 500 mg of 6-bromo-3,4-dihydroisoquinoline-2(1H)-Boc, 300 mg of pinacol vinyl borate, 230 mg of potassium tert-butoxide, and 200 mg of tetrakis(triphenylphosphine) A mixture of palladium and 10 ml of tetrahydrofuran was stirred at 70°C for 5 hours under argon protection. The reaction solution was concentrated to dryness, and the residue was subjected to column chromatography with ethyl acetate: petroleum ether = 10:1 to obtain 6-vinyl-3,4-dihydroisoquinoline-2(1H)-Boc(25-1) 350 mg, yield 84%. LCMS(ESI)m/z[M+Na] + :282.1.
步骤②：6-乙烯基-1,2,3,4-四氢异喹啉(25-2)
Step ②: 6-vinyl-1,2,3,4-tetrahydroisoquinoline (25-2)
6-乙烯基-1,2,3,4-四氢异喹啉(25-2)的制备同化合物10-2。LCMS(ESI)m/z[M+H]+:160.1.The preparation of 6-vinyl-1,2,3,4-tetrahydroisoquinoline (25-2) is the same as that of compound 10-2. LCMS(ESI)m/z[M+H] + :160.1.
步骤③：N-(1H-吲哚-3-基)-6-乙烯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-25)
Step ③: N-(1H-indol-3-yl)-6-vinyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-25)
N-(1H-吲哚-3-基)-6-乙烯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-25)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.70(s,1H),8.25(s,1H),7.60(d,J＝7.9Hz,1H),7.36(d,J＝2.5Hz,1H),7.32(t,J＝4.3Hz,1H),7.29(s,1H),7.16(d,J＝7.8Hz,1H),7.06(t,J＝7.5Hz,1H),6.95(t,J＝7.5Hz,1H),6.70(dd,J＝17.6,10.9Hz,1H),5.81(d,J＝17.6Hz,1H),5.23(d,J＝11.0Hz,1H),4.66(s,2H),3.73(t,J＝5.9Hz,2H),2.87(t,J＝5.9Hz,2H).LCMS(ESI)m/z[M+H]+:318.2.The preparation method of N-(1H-indol-3-yl)-6-vinyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-25) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.70 (s, 1H), 8.25 (s, 1H), 7.60 (d, J = 7.9Hz, 1H), 7.36 (d, J = 2.5Hz, 1H) ,7.32(t,J＝4.3Hz,1H),7.29(s,1H),7.16(d,J＝7.8Hz,1H),7.06(t,J＝7.5Hz,1H),6.95(t,J＝ 7.5Hz,1H),6.70(dd,J＝17.6,10.9Hz,1H),5.81(d,J＝17.6Hz,1H),5.23(d,J＝11.0Hz,1H),4.66(s,2H) ,3.73(t,J＝5.9Hz,2H),2.87(t,J＝5.9Hz,2H).LCMS(ESI)m/z[M+H] + :318.2.
实施例26 6-乙炔基-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-26)
Example 26 6-ethynyl-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-26)
步骤①：6-乙炔基-1,2,3,4-四氢异喹啉(26-1)
Step ①: 6-ethynyl-1,2,3,4-tetrahydroisoquinoline (26-1)
将100毫克6-溴-1,2,3,4-四氢异喹啉、180毫克三丁基乙烯锡、55毫克四(三苯基膦)钯和1.5毫升甲苯的混合物于氩气保护下80℃搅拌5小时。反应液浓缩至干，残余物以二氯甲烷：甲醇＝50:1制备薄层，得6-乙炔基-1,2,3,4-四氢异喹啉(26-1)65毫克，收率88％。LCMS(ESI)m/z[M+H]+:158.2.A mixture of 100 mg of 6-bromo-1,2,3,4-tetrahydroisoquinoline, 180 mg of tributylvinyltin, 55 mg of tetrakis(triphenylphosphine)palladium and 1.5 ml of toluene was placed under argon protection. Stir at 80°C for 5 hours. The reaction solution was concentrated to dryness, and the residue was prepared as a thin layer with dichloromethane: methanol = 50:1 to obtain 65 mg of 6-ethynyl-1,2,3,4-tetrahydroisoquinoline (26-1), which was collected. The rate is 88%. LCMS(ESI)m/z[M+H] + :158.2.
步骤②：6-乙炔基-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-26)
Step ②: 6-ethynyl-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-26)
6-乙炔基-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-26)的制备方法同化合物I-1。1H NMR(400MHz,CD3OD)δ7.55(d,J＝7.9Hz,1H),7.36–7.30(m,3H),7.26(s,1H),7.18(d,J＝7.9Hz,1H),7.12(t,J＝7.6Hz,1H),7.03(t,J＝7.5Hz,1H),4.73(s,2H),3.79(t,J＝5.9Hz,2H),3.47(s,1H),2.93(t,J＝5.9Hz,2H).LCMS(ESI)m/z[M+H]+:316.2.The preparation method of 6-ethynyl-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-26) is the same as compound I-1. 1 H NMR (400MHz, CD 3 OD) δ7.55 (d, J＝7.9Hz, 1H), 7.36–7.30 (m, 3H), 7.26 (s, 1H), 7.18 (d, J＝7.9Hz, 1H ),7.12(t,J＝7.6Hz,1H),7.03(t,J＝7.5Hz,1H),4.73(s,2H),3.79(t,J＝5.9Hz,2H),3.47(s,1H ),2.93(t,J＝5.9Hz,2H).LCMS(ESI)m/z[M+H] + :316.2.
实施例27 6-乙基-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-27)
Example 27 6-ethyl-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-27)
步骤①：6-乙基-1,2,3,4-四氢异喹啉(27-1)
Step ①: 6-ethyl-1,2,3,4-tetrahydroisoquinoline (27-1)
将100毫克6-乙烯基-1,2,3,4-四氢异喹啉(25-2)、10毫克钯碳和1毫升甲醇混合物于室温下氢化反应8小时。反应液过滤，滤液浓缩至干，得6-乙基-1,2,3,4-四氢异喹啉(27-1)80毫克，收率82％。LCMS(ESI)m/z[M+H]+:161.2。A mixture of 100 mg of 6-vinyl-1,2,3,4-tetrahydroisoquinoline (25-2), 10 mg of palladium on carbon and 1 ml of methanol was hydrogenated at room temperature for 8 hours. The reaction solution was filtered, and the filtrate was concentrated to dryness to obtain 80 mg of 6-ethyl-1,2,3,4-tetrahydroisoquinoline (27-1), with a yield of 82%. LCMS(ESI)m/z[M+H] + :161.2.
步骤②：6-乙基-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-27)
Step ②: 6-ethyl-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-27)
6-乙基-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-27)的制备方法同化合物I-1。1H NMR(400MHz,CD3OD)δ7.52(d,J＝7.9Hz,1H),7.32(d,J＝8.1Hz,1H),7.24(s,1H),7.13–7.07(m,2H),7.04(td,J＝8.3,4.3Hz,3H),4.69(s,2H),3.78(t,J＝5.9Hz,2H),2.92(t,J＝5.9Hz,2H),2.62(q,J＝7.6Hz,2H),1.23(t,J＝7.6Hz,3H).LCMS(ESI)m/z[M+H]+:320.2.The preparation method of 6-ethyl-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-27) is the same as compound I-1. 1 H NMR (400MHz, CD 3 OD) δ7.52(d,J＝7.9Hz,1H),7.32(d,J＝8.1Hz,1H),7.24(s,1H),7.13–7.07(m,2H ),7.04(td,J＝8.3,4.3Hz,3H),4.69(s,2H),3.78(t,J＝5.9Hz,2H),2.92(t,J＝5.9Hz,2H),2.62(q ,J＝7.6Hz,2H),1.23(t,J＝7.6Hz,3H).LCMS(ESI)m/z[M+H] + :320.2.
实施例28 5-溴-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-28)
Example 28 5-bromo-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-28)
5-溴-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-28)的制备同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.72(s,1H),8.36(s,1H),7.60(d,J＝7.9Hz,1H), 7.51(d,J＝7.7Hz,1H),7.36(d,J＝2.4Hz,1H),7.30(d,J＝8.1Hz,1H),7.23(d,J＝7.6Hz,1H),7.17(t,J＝7.7Hz,1H),7.06(t,J＝7.5Hz,1H),6.95(t,J＝7.5Hz,1H),4.69(s,2H),3.79(t,J＝6.0Hz,2H),2.82(t,J＝6.0Hz,2H).The preparation of 5-bromo-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-28) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.72 (s, 1H), 8.36 (s, 1H), 7.60 (d, J = 7.9Hz, 1H), 7.51(d,J＝7.7Hz,1H),7.36(d,J＝2.4Hz,1H),7.30(d,J＝8.1Hz,1H),7.23(d,J＝7.6Hz,1H),7.17( t,J＝7.7Hz,1H),7.06(t,J＝7.5Hz,1H),6.95(t,J＝7.5Hz,1H),4.69(s,2H),3.79(t,J＝6.0Hz, 2H),2.82(t,J＝6.0Hz,2H).
实施例29 7-溴-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-29)
Example 29 7-bromo-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-29)
7-溴-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-29)的制备同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.71(s,1H),8.27(s,1H),7.59(d,J＝8.0Hz,1H),7.41(s,1H),7.39–7.33(m,2H),7.31(dd,J＝8.1,1.0Hz,1H),7.16(d,J＝8.2Hz,1H),7.10–7.02(m,1H),6.95(ddd,J＝8.0,7.0,1.0Hz,1H),4.66(s,2H),3.73(t,J＝5.9Hz,2H),2.83(t,J＝5.8Hz,2H).The preparation of 7-bromo-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-29) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.71 (s, 1H), 8.27 (s, 1H), 7.59 (d, J = 8.0Hz, 1H), 7.41 (s, 1H), 7.39–7.33 ( m,2H),7.31(dd,J＝8.1,1.0Hz,1H),7.16(d,J＝8.2Hz,1H),7.10–7.02(m,1H),6.95(ddd,J＝8.0,7.0, 1.0Hz,1H),4.66(s,2H),3.73(t,J＝5.9Hz,2H),2.83(t,J＝5.8Hz,2H).
实施例30 8-溴-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-30)
Example 30 8-bromo-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-30)
8-溴-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-30)的制备同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.72(d,J＝2.3Hz,1H),8.45(s,1H),7.59(d,J＝7.9Hz,1H),7.49(dd,J＝7.9,1.3Hz,1H),7.36(d,J＝2.5Hz,1H),7.33–7.28(m,1H),7.24(d,J＝7.5Hz,1H),7.15(t,J＝7.7Hz,1H),7.06(ddd,J＝8.2,6.9,1.2Hz,1H),6.96(ddd,J＝7.9,6.9,1.1Hz,1H),4.59(s,2H),3.75(t,J＝5.8Hz,2H),3.07–2.81(m,2H).The preparation of 8-bromo-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-30) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.72 (d, J＝2.3Hz, 1H), 8.45 (s, 1H), 7.59 (d, J＝7.9Hz, 1H), 7.49 (dd, J＝ 7.9,1.3Hz,1H),7.36(d,J＝2.5Hz,1H),7.33–7.28(m,1H),7.24(d,J＝7.5Hz,1H),7.15(t,J＝7.7Hz, 1H),7.06(ddd,J＝8.2,6.9,1.2Hz,1H),6.96(ddd,J＝7.9,6.9,1.1Hz,1H),4.59(s,2H),3.75(t,J＝5.8Hz ,2H),3.07–2.81(m,2H).
实施例31 6-氟-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-31)
Example 31 6-fluoro-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-31)
6-氟-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-31)的制备同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.71(s,1H),8.26(s,1H),7.60(d,J＝7.9Hz,1H),7.36(d,J＝2.5Hz,1H),7.30(d,J＝8.1Hz,1H),7.22(dd,J＝8.2,5.9Hz,1H),7.09–7.00(m,3H),6.95(t,J＝7.3Hz,1H),4.64(s,2H),3.72(t,J＝5.9Hz,2H),2.87(t,J＝5.6Hz,2H).The preparation of 6-fluoro-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-31) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.71 (s, 1H), 8.26 (s, 1H), 7.60 (d, J = 7.9Hz, 1H), 7.36 (d, J = 2.5Hz, 1H) ,7.30(d,J＝8.1Hz,1H),7.22(dd,J＝8.2,5.9Hz,1H),7.09–7.00(m,3H),6.95(t,J＝7.3Hz,1H),4.64( s,2H),3.72(t,J＝5.9Hz,2H),2.87(t,J＝5.6Hz,2H).
实施例32 6-氯-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-32)
Example 32 6-Chloro-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-32)
6-氯-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-32)的制备同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.72(s,1H),8.28(s,1H),7.59(d,J＝8.0Hz,1H),7.35(d,J＝2.4Hz,1H),7.33–7.28(m,2H),7.27–7.19(m,2H),7.06(t,J＝7.5Hz,1H),6.95(t,J＝7.5Hz,1H),4.64(s,2H),3.72(t,J＝5.8Hz,2H),2.87(t,J＝6.0Hz,2H).The preparation of 6-chloro-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-32) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.72 (s, 1H), 8.28 (s, 1H), 7.59 (d, J = 8.0Hz, 1H), 7.35 (d, J = 2.4Hz, 1H) ,7.33–7.28(m,2H),7.27–7.19(m,2H),7.06(t,J＝7.5Hz,1H),6.95(t,J＝7.5Hz,1H),4.64(s,2H), 3.72(t,J＝5.8Hz,2H),2.87(t,J＝6.0Hz,2H).
实施例33 N-(1H-吲哚-3-基)-6,9-二氢呋喃并[3,2-h]异喹啉-8(7H)-甲酰胺(I-33)
Example 33 N-(1H-indol-3-yl)-6,9-dihydrofuro[3,2-h]isoquinoline-8(7H)-carboxamide (I-33)
实施例34 N-(1H-吲哚-3-基)-5-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-34)
Example 34 N-(1H-indol-3-yl)-5-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-34)
步骤①：5-苯基-1,2,3,4-四氢异喹啉(34-1)
Step ①: 5-phenyl-1,2,3,4-tetrahydroisoquinoline (34-1)
将100毫克5-溴-1,2,3,4-四氢异喹啉、87毫克苯硼酸、384毫克碳酸铯、35毫克PdCl2(dppf)、1毫升四氢呋喃和0.5毫升水的混合物于70℃氩气氛下加热搅拌5小时。反应液加水稀释，乙酸乙酯萃取，有机层至干，残余物以二氯甲烷：甲醇＝95：5柱层析，得棕褐色油状液体5-苯基-1,2,3,4-四氢异喹啉(34-1)75毫克，收率76％。LCMS(ESI)m/z[M+H]+:210.2.A mixture of 100 mg of 5-bromo-1,2,3,4-tetrahydroisoquinoline, 87 mg of phenylboronic acid, 384 mg of cesium carbonate, 35 mg of PdCl 2 (dppf), 1 ml of tetrahydrofuran and 0.5 ml of water was placed at 70 °C under an argon atmosphere with heating and stirring for 5 hours. The reaction solution was diluted with water, extracted with ethyl acetate, and the organic layer was dried. The residue was subjected to column chromatography with methylene chloride: methanol = 95:5 to obtain 5-phenyl-1,2,3,4-tetrakis as a brown oily liquid. Hydroisoquinoline (34-1) 75 mg, yield 76%. LCMS(ESI)m/z[M+H] + :210.2.
步骤②：N-(1H-吲哚-3-基)-5-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-34)
Step ②: N-(1H-indol-3-yl)-5-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-34)
N-(1H-吲哚-3-基)-5-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-34)的制备同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.71(s,1H),8.21(s,1H),7.61(d,J＝8.0Hz,1H),7.49–7.34(m,6H),7.30(t,J＝8.1Hz,2H),7.23(d,J＝7.6Hz,1H),7.13(d,J＝7.4Hz,1H),7.06(t,J＝7.5Hz,1H),6.96(t,J＝7.5Hz,1H),4.74(s,2H),3.64(t,J＝5.8Hz,2H),2.75(t,J＝5.8Hz,2H).The preparation of N-(1H-indol-3-yl)-5-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-34) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.71 (s, 1H), 8.21 (s, 1H), 7.61 (d, J = 8.0Hz, 1H), 7.49–7.34 (m, 6H), 7.30 ( t,J＝8.1Hz,2H),7.23(d,J＝7.6Hz,1H),7.13(d,J＝7.4Hz,1H),7.06(t,J＝7.5Hz,1H),6.96(t, J＝7.5Hz,1H),4.74(s,2H),3.64(t,J＝5.8Hz,2H),2.75(t,J＝5.8Hz,2H).
实施例35 N-(1H-吲哚-3-基)-7-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-35)
Example 35 N-(1H-indol-3-yl)-7-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-35)
步骤①：7-苯基-1,2,3,4-四氢异喹啉(35-1)
Step ①: 7-phenyl-1,2,3,4-tetrahydroisoquinoline (35-1)
7-苯基-1,2,3,4-四氢异喹啉(35-1)的制备同化合物34-1。LCMS(ESI)m/z[M+H]+:210.2.The preparation of 7-phenyl-1,2,3,4-tetrahydroisoquinoline (35-1) is the same as compound 34-1. LCMS(ESI)m/z[M+H] + :210.2.
步骤②：N-(1H-吲哚-3-基)-7-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-35)
Step ②: N-(1H-indol-3-yl)-7-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-35)
N-(1H-吲哚-3-基)-7-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-35)的制备同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.73(s,1H),8.30(s,1H),7.67(s,2H),7.65(s,1H),7.61(s,1H),7.49–7.43(m,5H),7.38(s,1H),7.31(d,J＝9.0Hz,1H),7.06(s,1H),6.96(s,1H),4.75(s,2H),3.78(s,2H),2.91(s,2H).The preparation of N-(1H-indol-3-yl)-7-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-35) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.73(s,1H),8.30(s,1H),7.67(s,2H),7.65(s,1H),7.61(s,1H),7.49– 7.43(m,5H),7.38(s,1H),7.31(d,J＝9.0Hz,1H),7.06(s,1H),6.96(s,1H),4.75(s,2H),3.78(s ,2H),2.91(s,2H).
实施例36 N-(1H-吲哚-3-基)-8-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-36)
Example 36 N-(1H-indol-3-yl)-8-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-36)
步骤①：8-苯基-1,2,3,4-四氢异喹啉(36-1)
Step ①: 8-phenyl-1,2,3,4-tetrahydroisoquinoline (36-1)
8-苯基-1,2,3,4-四氢异喹啉(36-1)的制备同化合物34-1。LCMS(ESI)m/z[M+H]+:210.2.The preparation of 8-phenyl-1,2,3,4-tetrahydroisoquinoline (36-1) is the same as compound 34-1. LCMS(ESI)m/z[M+H] + :210.2.
步骤②：N-(1H-吲哚-3-基)-8-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-36)
Step ②: N-(1H-indol-3-yl)-8-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-36)
N-(1H-吲哚-3-基)-8-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-36)的制备同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.68(s,1H),8.19(s,1H),7.53–7.44(m,3H), 7.43–7.39(m,1H),7.38–7.33(m,2H),7.31–7.22(m,4H),7.09(dd,J＝7.1,1.8Hz,1H),7.04(ddd,J＝8.2,6.9,1.2Hz,1H),6.93(ddd,J＝7.9,6.9,1.0Hz,1H),4.51(s,2H),3.76(t,J＝6.1Hz,2H),2.99(t,J＝6.1Hz,2H).The preparation of N-(1H-indol-3-yl)-8-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-36) is the same as compound I-1. 1 H NMR(400MHz, DMSO-d 6 )δ10.68(s,1H),8.19(s,1H),7.53–7.44(m,3H), 7.43–7.39(m,1H),7.38–7.33(m,2H),7.31–7.22(m,4H),7.09(dd,J＝7.1,1.8Hz,1H),7.04(ddd,J＝8.2,6.9 ,1.2Hz,1H),6.93(ddd,J＝7.9,6.9,1.0Hz,1H),4.51(s,2H),3.76(t,J＝6.1Hz,2H),2.99(t,J＝6.1Hz ,2H).
实施例37 4-苄基-N-(1H-吲哚-3-基)哌嗪-1-甲酰胺(I-37)
Example 37 4-benzyl-N-(1H-indol-3-yl)piperazine-1-carboxamide (I-37)
4-苄基-N-(1H-吲哚-3-基)哌嗪-1-甲酰胺(I-37)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.67(s,1H),8.16(s,1H),7.56(d,J＝7.9Hz,1H),7.40–7.19(m,7H),6.88–7.08(m,2H),3.45(t,J＝4.9Hz,4H),2.37(t,J＝4.9Hz,4H).The preparation method of 4-benzyl-N-(1H-indol-3-yl)piperazine-1-carboxamide (I-37) is the same as that of compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.67 (s, 1H), 8.16 (s, 1H), 7.56 (d, J = 7.9Hz, 1H), 7.40–7.19 (m, 7H), 6.88– 7.08(m,2H),3.45(t,J＝4.9Hz,4H),2.37(t,J＝4.9Hz,4H).
实施例38 N-(4-氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-38)
Example 38 N-(4-fluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-38)
步骤①：4-氟-1H-吲哚-3-酰基叠氮(38-1)
Step ①: 4-fluoro-1H-indole-3-acyl azide (38-1)
4-氟-1H-吲哚-3-酰基叠氮(38-1)的制备方法同化合物1-1。LRMS(ESI)m/z[M+H]+:205.1.The preparation method of 4-fluoro-1H-indole-3-acyl azide (38-1) is the same as that of compound 1-1. LRMS(ESI)m/z[M+H] + :205.1.
步骤②：4-氟-3-异氰酸基-1H-吲哚(38-2)
Step ②: 4-fluoro-3-isocyanato-1H-indole (38-2)
4-氟-3-异氰酸基-1H-吲哚(38-2)的制备方法同化合物1-2。LRMS(ESI)m/z[M+H]+:177.0.The preparation method of 4-fluoro-3-isocyanato-1H-indole (38-2) is the same as that of compound 1-2. LRMS(ESI)m/z[M+H] + :177.0.
步骤③：N-(4-氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-38)
Step ③: N-(4-fluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-38)
N-(4-氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-38)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),8.07(s,1H),7.27(d,J＝2.5Hz,1H),7.22–7.13(m,5H),7.01(td,J＝8.0,5.1Hz,1H),6.67(dd,J＝11.3,7.7Hz,1H),4.63(s,2H),3.69(t,J＝5.8Hz,2H),2.85(t,J＝5.9Hz,2H).The preparation method of N-(4-fluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-38) is the same as that of compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ11.09 (s, 1H), 8.07 (s, 1H), 7.27 (d, J = 2.5Hz, 1H), 7.22–7.13 (m, 5H), 7.01 ( td,J＝8.0,5.1Hz,1H),6.67(dd,J＝11.3,7.7Hz,1H),4.63(s,2H),3.69(t,J＝5.8Hz,2H),2.85(t,J =5.9Hz,2H).
实施例39 N-(5-氯-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-39)
Example 39 N-(5-chloro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-39)
N-(5-氯-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-39)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.92(s,1H),8.29(s,1H),7.70(s,1H),7.46(d,J＝2.3Hz,1H),7.32(d,J＝8.5Hz,1H),7.19(s,4H),7.07–7.02(m,1H),4.67(s,2H),3.73(t,J＝5.8Hz,2H),2.86(t,J＝5.8Hz,2H).The preparation method of N-(5-chloro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-39) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.92 (s, 1H), 8.29 (s, 1H), 7.70 (s, 1H), 7.46 (d, J = 2.3Hz, 1H), 7.32 (d, J＝8.5Hz,1H),7.19(s,4H),7.07–7.02(m,1H),4.67(s,2H),3.73(t,J＝5.8Hz,2H),2.86(t,J＝5.8 Hz,2H).
实施例40 N-(5-苯胺基-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-40)
Example 40 N-(5-anilino-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-40)
实施例41 N-(5-苯基-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-41)
Example 41 N-(5-phenyl-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-41)
步骤①：5-苯基-1H-吲哚-3-甲酸甲酯(41-1)
Step ①: 5-phenyl-1H-indole-3-carboxylic acid methyl ester (41-1)
将400毫克5-溴-1H-吲哚-3-甲酸甲酯、212毫克苯硼酸、42毫克三苯基磷、18毫克醋酸钯、368毫克碳酸钠、5毫升甲苯、1.2毫升甲醇、1.2毫升蒸馏水的混合物于氩气保护下90℃搅拌过夜。反应液浓缩至干，残余物以乙酸乙酯：石油醚＝40：60柱层析，得淡黄色固体5-苯基-1H-吲哚-3-甲酸甲酯(41-1)286毫克，收率72.4％。1H NMR(400MHz,DMSO-d6)δ12.03(s,1H),8.24(d,J＝1.7Hz,1H),8.14(d,J＝3.0Hz,1H),7.69–7.65(m,2H),7.59–7.55(m,1H),7.54–7.46(m,3H),7.35(t,J＝7.2Hz,1H),3.84(s,3H).400 mg of 5-bromo-1H-indole-3-carboxylic acid methyl ester, 212 mg of phenylboronic acid, 42 mg of triphenylphosphonium, 18 mg of palladium acetate, 368 mg of sodium carbonate, 5 ml of toluene, 1.2 ml of methanol, 1.2 ml The mixture of distilled water was stirred at 90°C overnight under argon protection. The reaction solution was concentrated to dryness, and the residue was subjected to column chromatography with ethyl acetate: petroleum ether = 40:60 to obtain 286 mg of 5-phenyl-1H-indole-3-carboxylic acid methyl ester (41-1) as a light yellow solid. The yield is 72.4%. 1 H NMR (400MHz, DMSO-d 6 ) δ12.03 (s, 1H), 8.24 (d, J = 1.7Hz, 1H), 8.14 (d, J = 3.0Hz, 1H), 7.69–7.65 (m, 2H),7.59–7.55(m,1H),7.54–7.46(m,3H),7.35(t,J=7.2Hz,1H),3.84(s,3H).
步骤②：5-苯基-1H-吲哚-3-甲酸(41-2)
Step ②: 5-phenyl-1H-indole-3-carboxylic acid (41-2)
将120毫克5-苯基-1H-吲哚-3-甲酸甲酯(41-1)、40毫克氢氧化钠、2.5毫升乙醇、2.5毫升蒸馏水的混合物于90℃反应2小时。反应液浓缩，残余物加入1N盐酸调pH至4左右，过滤，滤饼干燥，得白色固体5-苯基-1H-吲哚-3-甲酸(41-2)101毫克，收率89.2％。1H NMR(400MHz,DMSO-d6)δ12.02(s,1H),11.90(s,1H),8.25(d,J＝1.8Hz,1H), 8.05(d,J＝2.8Hz,1H),7.66(dd,J＝8.2,1.4Hz,2H),7.56(d,J＝8.5Hz,1H),7.51–7.44(m,4H),7.34(t,J＝7.3Hz,1H).A mixture of 120 mg of 5-phenyl-1H-indole-3-carboxylic acid methyl ester (41-1), 40 mg of sodium hydroxide, 2.5 ml of ethanol, and 2.5 ml of distilled water was reacted at 90°C for 2 hours. The reaction solution was concentrated, 1N hydrochloric acid was added to the residue to adjust the pH to about 4, filtered, and the filter cake was dried to obtain 101 mg of white solid 5-phenyl-1H-indole-3-carboxylic acid (41-2), with a yield of 89.2%. 1 H NMR (400MHz, DMSO-d 6 ) δ12.02 (s, 1H), 11.90 (s, 1H), 8.25 (d, J = 1.8Hz, 1H), 8.05(d,J＝2.8Hz,1H),7.66(dd,J＝8.2,1.4Hz,2H),7.56(d,J＝8.5Hz,1H),7.51–7.44(m,4H),7.34(t ,J＝7.3Hz,1H).
步骤③：5-苯基-1H-吲哚-3-酰基叠氮(41-3)
Step ③: 5-phenyl-1H-indole-3-acyl azide (41-3)
将80毫克5-苯基-1H-吲哚-3-羧酸(41-2)、73微升DPPA、61微升三乙胺和3毫升二氯甲烷的混合物于氩气保护下室温搅拌过夜。反应液浓缩至干，残余物以乙酸乙酯：石油醚＝1：1制备薄层，得淡黄色固体5-苯基-1H-吲哚-3-酰基叠氮(41-3)75毫克，收率83.7％。1H NMR(400MHz,DMSO-d6)δ12.31(s,1H),8.30(s,1H),8.25(s,1H),7.68(d,J＝7.6Hz,2H),7.62(d,J＝8.4Hz,1H),7.57(d,J＝8.2Hz,1H),7.49(t,J＝7.5Hz,2H),7.37(t,J＝7.7Hz,1H).A mixture of 80 mg of 5-phenyl-1H-indole-3-carboxylic acid (41-2), 73 μl of DPPA, 61 μl of triethylamine and 3 ml of dichloromethane was stirred overnight at room temperature under argon protection. . The reaction solution was concentrated to dryness, and a thin layer of the residue was prepared with ethyl acetate: petroleum ether = 1:1 to obtain 75 mg of light yellow solid 5-phenyl-1H-indole-3-acyl azide (41-3). The yield is 83.7%. 1 H NMR (400MHz, DMSO-d 6 ) δ12.31 (s, 1H), 8.30 (s, 1H), 8.25 (s, 1H), 7.68 (d, J = 7.6Hz, 2H), 7.62 (d, J＝8.4Hz,1H),7.57(d,J＝8.2Hz,1H),7.49(t,J＝7.5Hz,2H),7.37(t,J＝7.7Hz,1H).
步骤④：N-(5-苯基-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-41)
Step ④: N-(5-phenyl-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-41)
将60毫克5-苯基-1H-吲哚-3-酰基叠氮(41-3)、29微升四氢异喹啉、63微升三乙胺和1.2毫升甲苯溶液的混合物于90℃搅拌2小时，反应液浓缩至干，残余物以乙酸乙酯：石油醚＝1：1柱层析，得到淡黄色固体N-(5-苯基-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-41)44毫克，收率53.5％。1H NMR(400MHz,DMSO-d6)δ10.77(s,1H),8.30(s,1H),7.93(s,1H),7.66(d,J＝7.7Hz,2H),7.48–7.42(m,3H),7.38(s,2H),7.29(t,J＝7.4Hz,1H),7.19(s,4H),4.69(s,2H),3.76(t,J＝5.9Hz,2H),2.88(t,J＝5.8Hz,2H).LCMS(ESI)m/z[M+H]+:368.1.A mixture of 60 mg of 5-phenyl-1H-indole-3-acyl azide (41-3), 29 μl of tetrahydroisoquinoline, 63 μl of triethylamine and 1.2 ml of toluene solution was stirred at 90°C. After 2 hours, the reaction solution was concentrated to dryness, and the residue was subjected to column chromatography with ethyl acetate: petroleum ether = 1:1 to obtain light yellow solid N-(5-phenyl-1H-indol-3-yl)-3, 44 mg of 4-dihydroisoquinoline-2(1H)-carboxamide (I-41), yield 53.5%. 1 H NMR (400MHz, DMSO-d 6 ) δ10.77 (s, 1H), 8.30 (s, 1H), 7.93 (s, 1H), 7.66 (d, J = 7.7Hz, 2H), 7.48–7.42 ( m,3H),7.38(s,2H),7.29(t,J＝7.4Hz,1H),7.19(s,4H),4.69(s,2H),3.76(t,J＝5.9Hz,2H), 2.88(t,J＝5.8Hz,2H).LCMS(ESI)m/z[M+H] + :368.1.
实施例42 6-(4,4-二氟哌啶-1-基)-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-42)
Example 42 6-(4,4-difluoropiperidin-1-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-42)
步骤①：6-(4,4-二氟哌啶-1-基)-3,4-二氢异喹啉-2(1H)-Boc(42-1)
Step ①: 6-(4,4-difluoropiperidin-1-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(42-1)
6-(4,4-二氟哌啶-1-基)-3,4-二氢异喹啉-2(1H)-Boc(42-1)的制备同化合物22-1。。 1H NMR(400MHz,CDCl3)δ7.01(d,J＝8.1Hz,1H),6.80(d,J＝8.6Hz,1H),6.71(s,1H),4.50(s,2H),3.63(s,2H),3.43–3.15(m,4H),2.79(s,2H),2.16–2.03(m,4H),1.49(s,9H).The preparation of 6-(4,4-difluoropiperidin-1-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(42-1) is the same as compound 22-1. . 1 H NMR (400MHz, CDCl 3 ) δ7.01 (d, J = 8.1Hz, 1H), 6.80 (d, J = 8.6Hz, 1H), 6.71 (s, 1H), 4.50 (s, 2H), 3.63 (s,2H),3.43–3.15(m,4H),2.79(s,2H),2.16–2.03(m,4H),1.49(s,9H).
步骤②：6-(4,4-二氟哌啶-1-基)-1,2,3,4-四氢异喹啉(42-2)
Step ②: 6-(4,4-difluoropiperidin-1-yl)-1,2,3,4-tetrahydroisoquinoline (42-2)
6-(4,4-二氟哌啶-1-基)-1,2,3,4-四氢异喹啉(42-2)的制备同化合物10-2。LCMS(ESI)m/z[M+H]+:253.3.The preparation of 6-(4,4-difluoropiperidin-1-yl)-1,2,3,4-tetrahydroisoquinoline (42-2) is the same as compound 10-2. LCMS(ESI)m/z[M+H] + :253.3.
步骤③：6-(4,4-二氟哌啶-1-基)-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-42)
Step ③: 6-(4,4-difluoropiperidin-1-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-42)
6-(4,4-二氟哌啶-1-基)-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-42)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.68(s,1H),8.18(s,1H),7.60(d,J＝7.9Hz,1H),7.35(d,J＝2.4Hz,1H),7.30(d,J＝8.2Hz,1H),7.08–7.02(m,2H),6.95(t,J＝7.0Hz,1H),6.87(d,J＝8.5Hz,1H),6.82(s,1H),4.57(s,2H),3.69(t,J＝5.9Hz,2H),3.29(d,J＝5.8Hz,4H),2.81(s,2H),2.06(d,J＝14.7Hz,4H).LCMS(ESI)m/z[M+H]+:411.2.6-(4,4-difluoropiperidin-1-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I- The preparation method of 42) is the same as that of compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.68 (s, 1H), 8.18 (s, 1H), 7.60 (d, J = 7.9Hz, 1H), 7.35 (d, J = 2.4Hz, 1H) ,7.30(d,J＝8.2Hz,1H),7.08–7.02(m,2H),6.95(t,J＝7.0Hz,1H),6.87(d,J＝8.5Hz,1H),6.82(s, 1H),4.57(s,2H),3.69(t,J＝5.9Hz,2H),3.29(d,J＝5.8Hz,4H),2.81(s,2H),2.06(d,J＝14.7Hz, 4H).LCMS(ESI)m/z[M+H] + :411.2.
实施例43 6-(3,3-二氟环丁基)-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-43)
Example 43 6-(3,3-difluorocyclobutyl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I- 43)
实施例44 6-(6,6-二氟-2-氮杂螺[3.3]庚烷-2-基)-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-44)
Example 44 6-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquine Phenoline-2(1H)-carboxamide (I-44)
实施例45 N-(1H-吲哚-3-基)-6-(6-氮杂螺[2.5]辛烷-6-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-45)
Example 45 N-(1H-indol-3-yl)-6-(6-azaspiro[2.5]octane-6-yl)-3,4-dihydroisoquinoline-2(1H)- Formamide(I-45)
实施例46 N-(1H-吲哚-3-基)-6-(4-(3,3,3-三氟丙基)哌嗪-1-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-46)
Example 46 N-(1H-indol-3-yl)-6-(4-(3,3,3-trifluoropropyl)piperazin-1-yl)-3,4-dihydroisoquinoline -2(1H)-Carboxamide (I-46)
实施例47 6-(2,2-二甲基吗啉基)-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-47)
Example 47 6-(2,2-dimethylmorpholinyl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I -47)
实施例48 N-(5-氰基-1H-吲哚-3-基)-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-48)
Example 48 N-(5-cyano-1H-indol-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-48)
步骤①：5-氰基-1H-吲哚-3-酰基叠氮(48-1)
Step ①: 5-cyano-1H-indole-3-acyl azide (48-1)
5-氰基-1H-吲哚-3-酰基叠氮(48-1)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ12.70(s,1H),8.43(q,J＝0.9Hz,2H),7.71(dd,J＝8.4,0.8Hz,1H),7.65(dd,J＝8.5,1.6Hz,1H).The preparation method of 5-cyano-1H-indole-3-acyl azide (48-1) is the same as that of compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ12.70 (s, 1H), 8.43 (q, J = 0.9Hz, 2H), 7.71 (dd, J = 8.4, 0.8Hz, 1H), 7.65 (dd, J＝8.5,1.6Hz,1H).
步骤②：N-(5-氰基-1H-吲哚-3-基)-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-48)
Step ②: N-(5-cyano-1H-indol-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-48)
N-(5-氰基-1H-吲哚-3-基)-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-48)的制备方法同化合物I-41。1H NMR(400MHz,DMSO-d6)δ11.31(s,1H),8.45(s,1H),8.27(s,1H),7.69–7.59(m,3H),7.53–7.43(m,5H),7.42–7.27(m,3H),4.73(s,2H),3.79(t,J＝5.8Hz,2H),2.96(t,J＝5.9Hz,2H).LCMS(ESI)m/z[M-H]—:391.1. The preparation method of N-(5-cyano-1H-indol-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-48) is the same as that of the compound I-41. 1 H NMR (400MHz, DMSO-d 6 ) δ11.31(s,1H),8.45(s,1H),8.27(s,1H),7.69–7.59(m,3H),7.53–7.43(m,5H) ),7.42–7.27(m,3H),4.73(s,2H),3.79(t,J＝5.8Hz,2H),2.96(t,J＝5.9Hz,2H).LCMS(ESI)m/z[ MH] — :391.1.
实施例49 N-(5-氯-6-氟-1H-吲哚-3-基)-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-49)
Example 49 N-(5-chloro-6-fluoro-1H-indol-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-49 )
实施例50 N-(5-溴-1H-吡咯并[3,2-b]吡啶-3-基)-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-50)
Example 50 N-(5-bromo-1H-pyrrolo[3,2-b]pyridin-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-50)
实施例51 N-(5-甲氧基-1H-吡咯并[3,2-b]吡啶-3-基)-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-51)
Example 51 N-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)- Formamide(I-51)
实施例52 N-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-52)
Example 52 N-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-52)
实施例53 N-(5-氯-1H-吡咯并[2,3-b]吡啶-3-基)-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-53)
Example 53 N-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-53)
实施例54 N-(5-溴-1H-吡咯并[2,3-b]吡啶-3-基)-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-54)
Example 54 N-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-54)
实施例55 6-苯基-N-(1H-吡咯并[3,2-c]吡啶-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-55)
Example 55 6-phenyl-N-(1H-pyrrolo[3,2-c]pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-55 )
步骤①：1H-吲哚-[3,2-c]吡啶-3-酰基叠氮(55-1)
Step ①: 1H-indole-[3,2-c]pyridine-3-acyl azide (55-1)
1H-吲哚-[3,2-c]吡啶-3-酰基叠氮(55-1)的制备方法同化合物1-1。LCMS(ESI)m/z[M+H]+:188.1.The preparation method of 1H-indole-[3,2-c]pyridine-3-acyl azide (55-1) is the same as that of compound 1-1. LCMS(ESI)m/z[M+H] + :188.1.
步骤②：6-苯基-N-(1H-吡咯并[3,2-c]吡啶-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-55)
Step ②: 6-phenyl-N-(1H-pyrrolo[3,2-c]pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-55 )
6-苯基-N-(1H-吡咯并[3,2-c]吡啶-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-55)的制备方法同化合物I-41。1H NMR(400MHz,CD3OD)δ9.10(s,1H),8.24(d,J＝6.4Hz,1H),7.71(d,J＝6.5Hz,1H),7.67(s,1H),7.62(d,J＝7.6Hz,2H),7.49(d,J＝6.9Hz,2H),7.43(t,J＝7.6Hz,2H),7.32(dd,J＝17.3,7.9Hz,2H),4.81(s,2H),3.86(t,J＝5.8Hz,2H),3.05(t,J＝6.0Hz,2H).LCMS(ESI)m/z[M+H]+:369.1.Preparation of 6-phenyl-N-(1H-pyrrolo[3,2-c]pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-55) The method is the same as that of compound I-41. 1 H NMR (400MHz, CD 3 OD) δ9.10 (s, 1H), 8.24 (d, J = 6.4Hz, 1H), 7.71 (d, J = 6.5Hz, 1H), 7.67 (s, 1H), 7.62(d,J＝7.6Hz,2H),7.49(d,J＝6.9Hz,2H),7.43(t,J＝7.6Hz,2H),7.32(dd,J＝17.3,7.9Hz,2H), 4.81(s,2H),3.86(t,J＝5.8Hz,2H),3.05(t,J＝6.0Hz,2H).LCMS(ESI)m/z[M+H] + :369.1.
实施例56 N-(1H-吲哚-3-基)-4-苯基-1,4-二氮杂环庚烷-1-甲酰胺(I-56)
Example 56 N-(1H-indol-3-yl)-4-phenyl-1,4-diazepine-1-carboxamide (I-56)
步骤①：4-苯基-1,4-二氮杂-1-Boc(56-1)
Step ①: 4-phenyl-1,4-diaza-1-Boc (56-1)
将22毫克Pd2(dba)3、67毫克叔丁醇钠、39毫克2-二环己膦基-2'-(N,N-二甲胺)-联苯、500微升叔丁醇、1毫升1,4-二氧六环、100毫克碘苯和117毫克1,4-二氮杂-1-Boc的混合物80℃氩气氛下搅拌2.5小时。反应液加乙醚稀释，过滤，滤液浓缩，残余物以石油醚：乙酸乙酯＝5：1制备薄层，得棕色油状物(56-1)95毫克，收率70％。1H NMR(400MHz,DMSO-d6)δ7.12(dd,J＝8.6,7.0Hz,2H),6.70(dd,J＝8.3,4.9Hz,2H),6.55(t,J＝7.2Hz,1H),3.57(t,J＝5.8Hz,1H),3.52–3.47(m,3H),3.47(s,1H),3.25–3.08(m,4H),1.89–1.70(m,2H),1.25(s,9H).LCMS(ESI)m/z[M+H]+:277.2.Mix 22 mg of Pd 2 (dba) 3 , 67 mg of sodium tert-butoxide, 39 mg of 2-dicyclohexylphosphonyl-2'-(N,N-dimethylamine)-biphenyl, 500 μl of tert-butanol, A mixture of 1 ml of 1,4-dioxane, 100 mg of iodobenzene and 117 mg of 1,4-diaza-1-Boc was stirred at 80°C under an argon atmosphere for 2.5 hours. The reaction solution was diluted with diethyl ether, filtered, and the filtrate was concentrated. The residue was prepared as a thin layer using petroleum ether: ethyl acetate = 5:1 to obtain 95 mg of brown oil (56-1), with a yield of 70%. 1 H NMR (400MHz, DMSO-d 6 ) δ7.12 (dd, J＝8.6, 7.0Hz, 2H), 6.70 (dd, J＝8.3, 4.9Hz, 2H), 6.55 (t, J＝7.2Hz, 1H),3.57(t,J＝5.8Hz,1H),3.52–3.47(m,3H),3.47(s,1H),3.25–3.08(m,4H),1.89–1.70(m,2H),1.25 (s,9H).LCMS(ESI)m/z[M+H] + :277.2.
步骤②：1-苯基-1,4-二氮杂戊烷盐酸盐(56-2)
Step ②: 1-phenyl-1,4-diazapentane hydrochloride (56-2)
将94毫克化合物56-1、400微升盐酸-二氧六环和100微升甲醇的混合物常温下搅拌3小时。反应液浓缩至干，得类黄色固体1-苯基-1,4-二氮杂戊烷盐酸盐(56-2)88毫克，直接用于下一步反应。A mixture of 94 mg of compound 56-1, 400 μl of hydrochloric acid-dioxane and 100 μl of methanol was stirred at room temperature for 3 hours. The reaction solution was concentrated to dryness to obtain 88 mg of 1-phenyl-1,4-diazapentane hydrochloride (56-2) as a yellowish solid, which was directly used in the next reaction.
步骤③：N-(1H-吲哚-3-基)-4-苯基-1,4-二氮杂环庚烷-1-甲酰胺(I-56)
Step ③: N-(1H-indol-3-yl)-4-phenyl-1,4-diazepine-1-carboxamide (I-56)
N-(1H-吲哚-3-基)-4-苯基-1,4-二氮杂环庚烷-1-甲酰胺(I-56)的制备方法同化合物I-41。1H NMR(400MHz,DMSO-d6)δ10.67(s,1H),7.91(s,1H),7.42(d,J＝7.9Hz,1H),7.28(d,J＝8.1Hz,1H),7.25(d,J＝2.5Hz,1H),7.16(dd,J＝8.7,7.1Hz,2H),7.04(ddd,J＝8.2,6.9,1.2Hz,1H),6.93–6.88(m,1H),6.76(d,J＝8.2Hz,2H),6.59(t,J＝7.2Hz,1H),3.66(dd,J＝6.5,3.8Hz,2H),3.63–3.59(m,2H),3.56(t,J＝6.1Hz,2H),3.40(t,J＝5.9Hz,2H),2.00–1.91(m,2H).LCMS(ESI)m/z[M+H]+:335.1.The preparation method of N-(1H-indol-3-yl)-4-phenyl-1,4-diazepine-1-carboxamide (I-56) is the same as compound I-41. 1 H NMR (400MHz, DMSO-d 6 ) δ10.67 (s, 1H), 7.91 (s, 1H), 7.42 (d, J = 7.9Hz, 1H), 7.28 (d, J = 8.1Hz, 1H) ,7.25(d,J＝2.5Hz,1H),7.16(dd,J＝8.7,7.1Hz,2H),7.04(ddd,J＝8.2,6.9,1.2Hz,1H),6.93–6.88(m,1H ),6.76(d,J＝8.2Hz,2H),6.59(t,J＝7.2Hz,1H),3.66(dd,J＝6.5,3.8Hz,2H),3.63–3.59(m,2H),3.56 (t,J＝6.1Hz,2H),3.40(t,J＝5.9Hz,2H),2.00–1.91(m,2H).LCMS(ESI)m/z[M+H] + :335.1.
实施例57 4-苄基-N-(1H-吲哚-3-基)-1,4-二氮杂环庚烷-1-甲酰胺(I-57)
Example 57 4-benzyl-N-(1H-indol-3-yl)-1,4-diazepan-1-carboxamide (I-57)
实施例58 N-(1H-吲哚-3-基)-4-(吡啶-4-基)哌嗪-1-甲酰胺(I-58)
Example 58 N-(1H-indol-3-yl)-4-(pyridin-4-yl)piperazine-1-carboxamide (I-58)
N-(1H-吲哚-3-基)-4-(吡啶-4-基)哌嗪-1-甲酰胺(I-58)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.70(s,1H),8.32(s,1H),8.19(d,J＝6.3Hz,2H),7.61(d,J＝7.8Hz,1H),7.38(d,J＝2.4Hz,1H),7.31(d,J＝8.2Hz,1H),7.06(t,J＝7.3Hz,1H),6.96(t,J＝7.5Hz,1H),6.88(d,J＝6.3Hz,2H),3.71–3.53(m,4H),3.45–3.36(m,4H).LCMS(ESI)m/z[M+H]+:322.1.实施例59N-(1H-吲哚-3-基)-4-(3-甲氧基苯基)哌嗪-1-甲酰胺(I-59)
The preparation method of N-(1H-indol-3-yl)-4-(pyridin-4-yl)piperazine-1-carboxamide (I-58) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.70 (s, 1H), 8.32 (s, 1H), 8.19 (d, J = 6.3Hz, 2H), 7.61 (d, J = 7.8Hz, 1H) ,7.38(d,J＝2.4Hz,1H),7.31(d,J＝8.2Hz,1H),7.06(t,J＝7.3Hz,1H),6.96(t,J＝7.5Hz,1H),6.88 (d, J=6.3Hz, 2H), 3.71–3.53 (m, 4H), 3.45–3.36 (m, 4H). LCMS (ESI) m/z [M+H] + : 322.1. Example 59N-( 1H-indol-3-yl)-4-(3-methoxyphenyl)piperazine-1-carboxamide (I-59)
N-(1H-吲哚-3-基)-4-(3-甲氧基苯基)哌嗪-1-甲酰胺(I-59)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.71(s,1H),8.31(s,1H),7.61(d,J＝7.9Hz,1H),7.37(d,J＝2.4Hz,1H),7.31(d,J＝8.0Hz,1H),7.14(t,J＝8.1Hz,1H),7.06(t,J＝7.2Hz,1H),6.95(t,J＝7.4Hz,1H),6.59(d,J＝8.4Hz,1H),6.52(s,1H),6.41(d,J＝8.2Hz,1H),3.73(s,3H),3.67–3.54(m,4H),3.23–3.11(m,4H).The preparation method of N-(1H-indol-3-yl)-4-(3-methoxyphenyl)piperazine-1-carboxamide (I-59) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.71 (s, 1H), 8.31 (s, 1H), 7.61 (d, J = 7.9Hz, 1H), 7.37 (d, J = 2.4Hz, 1H) ,7.31(d,J＝8.0Hz,1H),7.14(t,J＝8.1Hz,1H),7.06(t,J＝7.2Hz,1H),6.95(t,J＝7.4Hz,1H),6.59 (d,J＝8.4Hz,1H),6.52(s,1H),6.41(d,J＝8.2Hz,1H),3.73(s,3H),3.67–3.54(m,4H),3.23–3.11( m,4H).
实施例60 4-(2-羟乙基)-N-(1H-吲哚-3-基)哌嗪-1-甲酰胺(I-60)
Example 60 4-(2-hydroxyethyl)-N-(1H-indol-3-yl)piperazine-1-carboxamide (I-60)
4-(2-羟乙基)-N-(1H-吲哚-3-基)哌嗪-1-甲酰胺(I-60)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ7.95(s,1H),7.54(d,J＝2.4Hz,1H),7.47(d,J＝8.0Hz,1H),7.35(d,J＝8.1Hz,1H),7.21(t,J＝7.5Hz,1H),7.12(t,J＝7.5Hz,1H),6.34(s,1H),3.74–3.63(m,2H),3.61–3.53(m,4H),2.60(dd,J＝10.6,5.9Hz,6H).LCMS(ESI)m/z[M+H]+:289.3.The preparation method of 4-(2-hydroxyethyl)-N-(1H-indol-3-yl)piperazine-1-carboxamide (I-60) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ7.95 (s, 1H), 7.54 (d, J = 2.4Hz, 1H), 7.47 (d, J = 8.0Hz, 1H), 7.35 (d, J = 8.1Hz,1H),7.21(t,J＝7.5Hz,1H),7.12(t,J＝7.5Hz,1H),6.34(s,1H),3.74–3.63(m,2H),3.61–3.53( m,4H),2.60(dd,J＝10.6,5.9Hz,6H).LCMS(ESI)m/z[M+H] + :289.3.
实施例61 N-(1H-吲哚-3-基)-4-(2-甲氧基苯基)哌嗪-1-甲酰胺(I-61)
Example 61 N-(1H-indol-3-yl)-4-(2-methoxyphenyl)piperazine-1-carboxamide (I-61)
N-(1H-吲哚-3-基)-4-(2-甲氧基苯基)哌嗪-1-甲酰胺(I-61)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.69(s,1H),8.25(s,1H),7.61(d,J＝7.7Hz,1H),7.37(d,J＝2.4Hz,1H),7.30(d,J＝8.1Hz,1H),7.05(t,J＝7.3Hz,1H),7.01–6.80(m,5H),3.80(s,3H),3.67–3.53(m,4H),3.05–2.89(m,4H).The preparation method of N-(1H-indol-3-yl)-4-(2-methoxyphenyl)piperazine-1-carboxamide (I-61) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.69 (s, 1H), 8.25 (s, 1H), 7.61 (d, J = 7.7Hz, 1H), 7.37 (d, J = 2.4Hz, 1H) ,7.30(d,J＝8.1Hz,1H),7.05(t,J＝7.3Hz,1H),7.01–6.80(m,5H),3.80(s,3H),3.67–3.53(m,4H), 3.05–2.89(m,4H).
实施例62 N-(1H-吲哚-3-基)-4-(4-甲氧基苯基)哌嗪-1-甲酰胺(I-62)
Example 62 N-(1H-indol-3-yl)-4-(4-methoxyphenyl)piperazine-1-carboxamide (I-62)
N-(1H-吲哚-3-基)-4-(4-甲氧基苯基)哌嗪-1-甲酰胺(I-62)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.71(s,1H),8.30(s,1H),7.61(d,J＝7.8Hz,1H),7.38(d,J＝2.4Hz,1H),7.31(d,J＝8.1Hz,1H),7.06(t,J＝7.4Hz,1H),6.95(t,J＝7.2Hz,3H),6.85(d,J＝9.0Hz,2H),3.70(s,3H),3.67–3.55(m,4H),3.10–2.97(m,4H).The preparation method of N-(1H-indol-3-yl)-4-(4-methoxyphenyl)piperazine-1-carboxamide (I-62) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.71 (s, 1H), 8.30 (s, 1H), 7.61 (d, J = 7.8Hz, 1H), 7.38 (d, J = 2.4Hz, 1H) ,7.31(d,J＝8.1Hz,1H),7.06(t,J＝7.4Hz,1H),6.95(t,J＝7.2Hz,3H),6.85(d,J＝9.0Hz,2H),3.70 (s,3H),3.67–3.55(m,4H),3.10–2.97(m,4H).
实施例63 N-(1H-吲哚-3-基)-4-(嘧啶-2-基)哌嗪-1-甲酰胺(I-63)
Example 63 N-(1H-indol-3-yl)-4-(pyrimidin-2-yl)piperazine-1-carboxamide (I-63)
N-(1H-吲哚-3-基)-4-(嘧啶-2-基)哌嗪-1-甲酰胺(I-63)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.69(s,1H),8.40(d,J＝4.7Hz,2H),8.28(s,1H),7.61(d,J＝7.7Hz,1H),7.37(d,J＝2.4Hz,1H),7.30(d,J＝7.9Hz,1H),7.06(t,J＝7.5Hz,1H),6.95(t,J＝7.4Hz,1H),6.66(t,J＝4.7Hz,1H),3.85–3.73(m,4H),3.62–3.50(m,4H).LCMS(ESI)m/z[M+H]+:323.1.The preparation method of N-(1H-indol-3-yl)-4-(pyrimidin-2-yl)piperazine-1-carboxamide (I-63) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.69 (s, 1H), 8.40 (d, J = 4.7Hz, 2H), 8.28 (s, 1H), 7.61 (d, J = 7.7Hz, 1H) ,7.37(d,J＝2.4Hz,1H),7.30(d,J＝7.9Hz,1H),7.06(t,J＝7.5Hz,1H),6.95(t,J＝7.4Hz,1H),6.66 (t,J＝4.7Hz,1H),3.85–3.73(m,4H),3.62–3.50(m,4H).LCMS(ESI)m/z[M+H] + :323.1.
实施例64 N-(1H-吲哚-3-基)-4-(4-甲基哌嗪-1-基)哌嗪-1-甲酰胺(I-64)
Example 64 N-(1H-indol-3-yl)-4-(4-methylpiperazin-1-yl)piperazine-1-carboxamide (I-64)
N-(1H-吲哚-3-基)-4-(4-甲基哌嗪-1-基)哌嗪-1-甲酰胺(I-64)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.65(s,1H),8.14(s,1H),7.58(d,J＝7.9Hz,1H),7.33(s,1H),7.29(d,J＝8.2Hz,1H),7.04(t,J＝7.4Hz,1H),6.94(t,J＝7.5Hz,1H),4.17(d,J＝13.2Hz,2H),3.32(s,4H),2.76(t,J＝12.1Hz,2H),2.31(s,5H),2.14(s,3H),1.76(d,J＝11.5Hz,2H),1.33(d,J＝10.3Hz,2H).LCMS(ESI)m/z[M+H]+:342.1.The preparation method of N-(1H-indol-3-yl)-4-(4-methylpiperazin-1-yl)piperazine-1-carboxamide (I-64) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.65 (s, 1H), 8.14 (s, 1H), 7.58 (d, J = 7.9Hz, 1H), 7.33 (s, 1H), 7.29 (d, J＝8.2Hz,1H),7.04(t,J＝7.4Hz,1H),6.94(t,J＝7.5Hz,1H),4.17(d,J＝13.2Hz,2H),3.32(s,4H) ,2.76(t,J＝12.1Hz,2H),2.31(s,5H),2.14(s,3H),1.76(d,J＝11.5Hz,2H),1.33(d,J＝10.3Hz,2H) .LCMS(ESI)m/z[M+H] + :342.1.
实施例65 4-环丙基-N-(1H-吲哚-3-基)哌嗪-1-甲酰胺(I-65)
Example 65 4-cyclopropyl-N-(1H-indol-3-yl)piperazine-1-carboxamide (I-65)
4-环丙基-N-(1H-吲哚-3-基)哌嗪-1-甲酰胺(I-65)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.68(s,1H),8.18(s,1H),7.59(d,J＝7.9Hz,1H),7.35(d,J＝2.4Hz,1H),7.30(d,J＝8.2Hz,1H),7.05(t,J＝7.5Hz,1H),6.94(t,J＝7.5Hz,1H),3.45–3.39(m,4H),2.58–2.52(m,4H),1.65(d,J＝3.5Hz,1H),0.47–0.41(m,2H),0.35(d,J＝3.2Hz,2H).The preparation method of 4-cyclopropyl-N-(1H-indol-3-yl)piperazine-1-carboxamide (I-65) is the same as that of compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.68 (s, 1H), 8.18 (s, 1H), 7.59 (d, J = 7.9Hz, 1H), 7.35 (d, J = 2.4Hz, 1H) ,7.30(d,J＝8.2Hz,1H),7.05(t,J＝7.5Hz,1H),6.94(t,J＝7.5Hz,1H),3.45–3.39(m,4H),2.58–2.52( m,4H),1.65(d,J＝3.5Hz,1H),0.47–0.41(m,2H),0.35(d,J＝3.2Hz,2H).
实施例66 N-(1H-吲哚-3-基)-4-甲基哌嗪-1-甲酰胺(I-66)
Example 66 N-(1H-indol-3-yl)-4-methylpiperazine-1-carboxamide (I-66)
N-(1H-吲哚-3-基)-4-甲基哌嗪-1-甲酰胺(I-66)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.71–10.65(m,1H),8.17(s,1H),7.58(d,J＝8.0Hz,1H),7.34(d,J＝2.4Hz,1H),7.29(d,J＝8.1Hz,1H),7.05(t,J＝7.5Hz,1H),6.94(t,J＝7.5Hz,1H),3.45(t,J＝5.0Hz,4H),2.32(t,J＝5.0Hz,4H),2.20(s,3H). The preparation method of N-(1H-indol-3-yl)-4-methylpiperazine-1-carboxamide (I-66) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.71–10.65 (m, 1H), 8.17 (s, 1H), 7.58 (d, J = 8.0Hz, 1H), 7.34 (d, J = 2.4Hz, 1H),7.29(d,J＝8.1Hz,1H),7.05(t,J＝7.5Hz,1H),6.94(t,J＝7.5Hz,1H),3.45(t,J＝5.0Hz,4H) ,2.32(t,J=5.0Hz,4H),2.20(s,3H).
实施例67 N-(1H-吲哚-7-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-67)
Example 67 N-(1H-indol-7-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-67)
步骤①：7-异氰酸基-1H-吲哚(67-1)
Step ①: 7-isocyanato-1H-indole (67-1)
100毫克1H-吲哚-7-胺、225毫克三光气溶于30毫升二氯甲烷中，然后滴加30毫升饱和碳酸氢钠溶液，滴毕在氩气氛下室温搅拌12小时，反应液加水稀释，乙酸乙酯萃取，有机层浓缩至干得灰色固体7-异氰酸基-1H-吲哚(67-1)100毫克，收率83％。LRMS(ESI)m/z[M+H]+:158.9.Dissolve 100 mg of 1H-indole-7-amine and 225 mg of triphosgene in 30 ml of methylene chloride, then add dropwise 30 ml of saturated sodium bicarbonate solution, stir at room temperature for 12 hours under an argon atmosphere, and dilute the reaction solution with water. , extracted with ethyl acetate, and the organic layer was concentrated to dryness to obtain 100 mg of gray solid 7-isocyanato-1H-indole (67-1), with a yield of 83%. LRMS(ESI)m/z[M+H] + :158.9.
步骤②：N-(1H-吲哚-7-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-67)
Step ②: N-(1H-indol-7-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-67)
N-(1H-吲哚-7-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-67)的制备同化合物I-1。LRMS(ESI)m/z[M+H]+:292.2.The preparation of N-(1H-indol-7-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-67) is the same as compound I-1. LRMS(ESI)m/z[M+H] + :292.2.
实施例68 N-(1H-吲哚-5-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-68)
Example 68 N-(1H-indol-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-68)
步骤①：5-异氰酸基-1H-吲哚(68-1)
Step ①: 5-isocyanato-1H-indole (68-1)
向100毫克1H-吲哚-5-胺、224.5毫克三光气和3毫升四氢呋喃的混合物中滴加210微升三乙胺，滴毕0℃搅拌2小时，反应液浓缩至干，残余物以石油醚：乙酸乙酯＝90:10柱层析得淡黄色固体5-异氰酸基-1H-吲哚(68-1)23.5毫克，收率20％。LRMS(ESI)m/z[M+H]+:158.9.To a mixture of 100 mg of 1H-indole-5-amine, 224.5 mg of triphosgene and 3 ml of tetrahydrofuran, 210 μl of triethylamine was added dropwise. After the drops were completed, the mixture was stirred at 0°C for 2 hours. The reaction solution was concentrated to dryness, and the residue was treated with petroleum. Ether:ethyl acetate=90:10 column chromatography yielded 23.5 mg of 5-isocyanato-1H-indole (68-1) as a light yellow solid, with a yield of 20%. LRMS(ESI)m/z[M+H] + :158.9.
步骤②：N-(1H-吲哚-5-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-68)
Step ②: N-(1H-indol-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-68)
N-(1H-吲哚-5-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-68)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.91(s,1H),8.35(s,1H),7.58(d,J＝2.0Hz,1H),7.28–7.22(m,2H),7.18(s,4H),7.12(dd,J＝8.6,2.1Hz,1H),6.32(t,J＝2.6Hz,1H),4.64(s,2H),3.70(t,J＝5.9Hz,2H),2.85(t,J＝5.9Hz,2H).The preparation method of N-(1H-indol-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-68) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.91 (s, 1H), 8.35 (s, 1H), 7.58 (d, J = 2.0Hz, 1H), 7.28–7.22 (m, 2H), 7.18 ( s,4H),7.12(dd,J＝8.6,2.1Hz,1H),6.32(t,J＝2.6Hz,1H),4.64(s,2H),3.70(t,J＝5.9Hz,2H), 2.85(t,J＝5.9Hz,2H).
实施例69 N-(1H-吲哚-4-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-69)
Example 69 N-(1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-69)
步骤①：4-异氰酸基-1H-吲哚(69-1)
Step ①: 4-isocyanato-1H-indole (69-1)
100毫克1H-吲哚-5-胺、225毫克三光气溶于10毫升甲苯于130℃搅拌5小时，反应液浓缩至干，加少量乙醚萃取，过滤，滤液浓缩至干得黄色油状物4-异氰酸基-1H-吲哚(8-1)47毫克，收率39％。LRMS(ESI)m/z[M+H]+:159.1.Dissolve 100 mg of 1H-indole-5-amine and 225 mg of triphosgene in 10 ml of toluene and stir at 130°C for 5 hours. The reaction solution is concentrated to dryness. Add a small amount of ether to extract, filter, and the filtrate is concentrated to dryness to obtain yellow oil 4- Isocyanato-1H-indole (8-1) 47 mg, yield 39%. LRMS(ESI)m/z[M+H] + :159.1.
步骤②：N-(1H-吲哚-4-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-69)
Step ②: N-(1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-69)
N-(1H-吲哚-4-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-69)的制备同化合物I-1。LRMS(ESI)m/z[M+H]+:292.1.The preparation of N-(1H-indol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-69) is the same as compound I-1. LRMS(ESI)m/z[M+H] + :292.1.
实施例70 N-(1H-吲哚-3-基)-4-苯基哌啶-1-甲酰胺(I-70)
Example 70 N-(1H-indol-3-yl)-4-phenylpiperidine-1-carboxamide (I-70)
N-(1H-吲哚-3-基)-4-苯基哌啶-1-甲酰胺(I-70)的制备方法同化合物I-41。1H NMR(400MHz,DMSO-d6)δ10.67(s,1H),8.18(s,1H),7.61(d,J＝7.9Hz,1H),7.37(d,J＝2.5Hz,1H),7.34–7.25(m,5H),7.20(t,J＝7.0Hz,1H),7.05(t,J＝7.5Hz,1H),6.95(t,J＝7.4Hz,1H),4.32(d,J＝13.1Hz,2H),2.88(t,J＝12.7Hz,2H),2.74(t,J＝12.4Hz,1H),1.80(d,J＝12.8Hz,2H),1.59(qd,J＝12.5,3.8Hz,2H).LCMS(ESI)m/z[M+H]+:320.2.The preparation method of N-(1H-indol-3-yl)-4-phenylpiperidine-1-carboxamide (I-70) is the same as compound I-41. 1 H NMR (400MHz, DMSO-d 6 ) δ10.67 (s, 1H), 8.18 (s, 1H), 7.61 (d, J = 7.9Hz, 1H), 7.37 (d, J = 2.5Hz, 1H) ,7.34–7.25(m,5H),7.20(t,J＝7.0Hz,1H),7.05(t,J＝7.5Hz,1H),6.95(t,J＝7.4Hz,1H),4.32(d, J＝13.1Hz,2H),2.88(t,J＝12.7Hz,2H),2.74(t,J＝12.4Hz,1H),1.80(d,J＝12.8Hz,2H),1.59(qd,J＝ 12.5,3.8Hz,2H).LCMS(ESI)m/z[M+H] + :320.2.
实施例71 N-(4-氟-1H-吲哚-3-基)-4-苯基哌嗪-1-甲酰胺(I-71)
Example 71 N-(4-fluoro-1H-indol-3-yl)-4-phenylpiperazine-1-carboxamide (I-71)
N-(4-氟-1H-吲哚-3-基)-4-苯基哌嗪-1-甲酰胺(I-71)的制备方法同化合物I-41。1H NMR(400MHz,DMSO-d6)δ11.81(s,1H),7.65(d,J＝2.4Hz,1H),7.29(d,J＝8.1Hz,1H),7.25–7.19(m,2H),7.14(td,J＝8.0,5.1Hz,1H),6.98–6.77(m,5H),3.67(s,4H),3.14(s,4H).LCMS(ESI)m/z[M+H]+:339.1.The preparation method of N-(4-fluoro-1H-indol-3-yl)-4-phenylpiperazine-1-carboxamide (I-71) is the same as that of compound I-41. 1 H NMR (400MHz, DMSO-d 6 ) δ11.81 (s, 1H), 7.65 (d, J = 2.4Hz, 1H), 7.29 (d, J = 8.1Hz, 1H), 7.25–7.19 (m, 2H),7.14(td,J＝8.0,5.1Hz,1H),6.98–6.77(m,5H),3.67(s,4H),3.14(s,4H).LCMS(ESI)m/z[M+ H] + :339.1.
实施例72 N-(5-氟-1H-吲哚-3-基)-4-苯基哌嗪-1-甲酰胺(I-72)
Example 72 N-(5-fluoro-1H-indol-3-yl)-4-phenylpiperazine-1-carboxamide (I-72)
N-(5-氟-1H-吲哚-3-基)-4-苯基哌嗪-1-甲酰胺(I-72)的制备方法同化合物1-41。1H NMR(400MHz,DMSO-d6)δ10.78(s,1H),8.35(s,1H),7.61(dd,J＝8.8,5.5Hz,1H),7.37(d,J＝2.3Hz,1H),7.24(t,J＝7.8Hz,2H),7.07(dd,J＝10.2,2.4Hz,1H),7.00(d,J＝8.2Hz,2H),6.82(ddd,J＝12.2,6.8,2.5Hz,2H),3.62(t,J＝5.1Hz,4H),3.17(t,J＝5.1Hz,4H).LCMS(ESI)m/z[M+H]+:339.1.The preparation method of N-(5-fluoro-1H-indol-3-yl)-4-phenylpiperazine-1-carboxamide (I-72) is the same as compound 1-41. 1 H NMR (400MHz, DMSO-d 6 ) δ10.78 (s, 1H), 8.35 (s, 1H), 7.61 (dd, J = 8.8, 5.5Hz, 1H), 7.37 (d, J = 2.3Hz, 1H),7.24(t,J＝7.8Hz,2H),7.07(dd,J＝10.2,2.4Hz,1H),7.00(d,J＝8.2Hz,2H),6.82(ddd,J＝12.2,6.8 ,2.5Hz,2H),3.62(t,J＝5.1Hz,4H),3.17(t,J＝5.1Hz,4H).LCMS(ESI)m/z[M+H] + :339.1.
实施例73 N-(6-氟-1H-吲哚-3-基)-4-苯基哌嗪-1-甲酰胺(I-73)
Example 73 N-(6-fluoro-1H-indol-3-yl)-4-phenylpiperazine-1-carboxamide (I-73)
N-(6-氟-1H-吲哚-3-基)-4-苯基哌嗪-1-甲酰胺(I-73)的制备方法同化合物I-41。1H NMR(400MHz,DMSO-d6)δ10.82(s,1H),8.29(s,1H),7.46(d,J＝2.5Hz,1H),7.37(dd,J＝10.2,2.6Hz,1H),7.30(dd,J＝8.8,4.5Hz,1H),7.27–7.20(m,2H),7.00(dd,J＝8.8,1.0Hz,2H),6.90(td,J＝9.1,2.6Hz,1H),6.81(tt,J＝7.1,1.0Hz,1H),3.62(t,J＝5.1Hz,4H),3.17(t,J＝5.1Hz,4H).LCMS(ESI)m/z[M+H]+:339.1.The preparation method of N-(6-fluoro-1H-indol-3-yl)-4-phenylpiperazine-1-carboxamide (I-73) is the same as compound I-41. 1 H NMR (400MHz, DMSO-d 6 ) δ10.82 (s, 1H), 8.29 (s, 1H), 7.46 (d, J = 2.5Hz, 1H), 7.37 (dd, J = 10.2, 2.6Hz, 1H),7.30(dd,J＝8.8,4.5Hz,1H),7.27–7.20(m,2H),7.00(dd,J＝8.8,1.0Hz,2H),6.90(td,J＝9.1,2.6Hz ,1H),6.81(tt,J＝7.1,1.0Hz,1H),3.62(t,J＝5.1Hz,4H),3.17(t,J＝5.1Hz,4H).LCMS(ESI)m/z[ M+H] + :339.1.
实施例74 N-(7-氟-1H-吲哚-3-基)-4-苯基哌嗪-1-甲酰胺(I-74)
Example 74 N-(7-fluoro-1H-indol-3-yl)-4-phenylpiperazine-1-carboxamide (I-74)
N-(7-氟-1H-吲哚-3-基)-4-苯基哌嗪-1-甲酰胺(I-74)的制备方法同化合物I-41。1H NMR(400MHz,DMSO-d6)δ11.21(s,1H),8.39(s,1H),7.45(dd,J＝6.4,2.2Hz,2H),7.27–7.21(m,2H),7.03–6.97(m,2H),6.95–6.86(m,2H),6.81(t,J＝7.2Hz,1H), 3.62(t,J＝5.2Hz,4H),3.17(t,J＝5.1Hz,4H).LCMS(ESI)m/z[M+H]+:339.1.The preparation method of N-(7-fluoro-1H-indol-3-yl)-4-phenylpiperazine-1-carboxamide (I-74) is the same as compound I-41. 1 H NMR (400MHz, DMSO-d 6 ) δ11.21 (s, 1H), 8.39 (s, 1H), 7.45 (dd, J = 6.4, 2.2Hz, 2H), 7.27–7.21 (m, 2H), 7.03–6.97(m,2H),6.95–6.86(m,2H),6.81(t,J＝7.2Hz,1H), 3.62(t,J＝5.2Hz,4H),3.17(t,J＝5.1Hz,4H).LCMS(ESI)m/z[M+H] + :339.1.
实施例75 N-(7-溴-1H-吲哚-3-基)-4-苯基哌嗪-1-甲酰胺(I-75)
Example 75 N-(7-bromo-1H-indol-3-yl)-4-phenylpiperazine-1-carboxamide (I-75)
步骤①：7-溴-1H-吲哚-3-酰基叠氮(75-1)
Step ①: 7-bromo-1H-indole-3-acyl azide (75-1)
7-溴-1H-吲哚-3-酰基叠氮(75-1)的制备方法同化合物1-1。1H NMR(400MHz,DMSO-d6)δ12.54(s,1H),8.18(s,1H),8.07(d,J＝7.9Hz,1H),7.50(d,J＝7.6Hz,1H),7.20(t,J＝7.8Hz,1H).The preparation method of 7-bromo-1H-indole-3-acyl azide (75-1) is the same as that of compound 1-1. 1 H NMR (400MHz, DMSO-d 6 ) δ12.54(s,1H),8.18(s,1H),8.07(d,J＝7.9Hz,1H),7.50(d,J＝7.6Hz,1H) ,7.20(t,J＝7.8Hz,1H).
步骤②：N-(7-溴-1H-吲哚-3-基)-4-苯基哌嗪-1-甲酰胺(I-75)
Step ②: N-(7-bromo-1H-indol-3-yl)-4-phenylpiperazine-1-carboxamide (I-75)
N-(7-溴-1H-吲哚-3-基)-4-苯基哌嗪-1-甲酰胺(I-75)的制备方法同化合物I-41。1H NMR(400MHz,DMSO-d6)δ10.94(s,1H),8.41(s,1H),7.66(d,J＝7.9Hz,1H),7.46(d,J＝2.5Hz,1H),7.29(d,J＝7.5Hz,1H),7.24(dd,J＝8.6,7.1Hz,2H),7.00(d,J＝7.8Hz,2H),6.92(t,J＝7.8Hz,1H),6.81(t,J＝7.2Hz,1H),3.63(t,J＝5.1Hz,4H),3.17(t,J＝5.1Hz,4H).LCMS(ESI)m/z[M+H]+:399.0.The preparation method of N-(7-bromo-1H-indol-3-yl)-4-phenylpiperazine-1-carboxamide (I-75) is the same as compound I-41. 1 H NMR (400MHz, DMSO-d 6 ) δ10.94 (s, 1H), 8.41 (s, 1H), 7.66 (d, J = 7.9Hz, 1H), 7.46 (d, J = 2.5Hz, 1H) ,7.29(d,J＝7.5Hz,1H),7.24(dd,J＝8.6,7.1Hz,2H),7.00(d,J＝7.8Hz,2H),6.92(t,J＝7.8Hz,1H) ,6.81(t,J＝7.2Hz,1H),3.63(t,J＝5.1Hz,4H),3.17(t,J＝5.1Hz,4H).LCMS(ESI)m/z[M+H] + :399.0.
实施例76 N-(1H-吲哚-3-基)-4-苯基-3,4-二氢喹喔林-1(2H)-甲酰胺(I-76)
Example 76 N-(1H-indol-3-yl)-4-phenyl-3,4-dihydroquinoxaline-1(2H)-carboxamide (I-76)
步骤①：1-苯基-1,2,3,4-四氢喹喔啉(76-1)
Step ①: 1-phenyl-1,2,3,4-tetrahydroquinoxaline (76-1)
将100毫克1,2,3,4-四氢喹喔啉、167毫克碘苯、35毫克2-双环已基膦-2',6'-二异丙氧基联苯、64毫克甲烷磺酸(2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)、215毫克叔丁醇钠和2毫升1,4-二氧六环的混合物于氩气氛下130℃搅拌过夜。反应液过滤，滤液浓缩至干，残余物以石油醚：乙酸乙酯＝5：1制备薄层，得白色固体1-苯基-1,2,3,4-四氢喹喔啉(76-1)78毫克，收率50％。1H NMR(400 MHz,DMSO-d6)δ7.31–7.25(m,2H),7.15–7.09(m,2H),6.98–6.91(m,1H),6.68(dd,J＝7.9,1.4Hz,1H),6.62(td,J＝7.5,7.1,1.4Hz,1H),6.55(dd,J＝7.9,1.6Hz,1H),6.37(ddd,J＝8.3,7.1,1.7Hz,1H),5.84(s,1H),3.58–3.53(m,2H),3.29–3.24(m,2H).LCMS(ESI)m/z[M+H]+:211.1.Combine 100 mg of 1,2,3,4-tetrahydroquinoxaline, 167 mg of iodobenzene, 35 mg of 2-bicyclohexylphosphine-2',6'-diisopropoxybiphenyl, and 64 mg of methane sulfonic acid. (2-Dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl ) Palladium (II), 215 mg of sodium tert-butoxide and 2 ml of 1,4-dioxane were stirred overnight at 130°C under an argon atmosphere. The reaction solution was filtered, and the filtrate was concentrated to dryness. The residue was prepared as a thin layer with petroleum ether: ethyl acetate = 5:1 to obtain a white solid 1-phenyl-1,2,3,4-tetrahydroquinoxaline (76- 1) 78 mg, yield 50%. 1 H NMR(400 MHz, DMSO-d 6 )δ7.31–7.25(m,2H),7.15–7.09(m,2H),6.98–6.91(m,1H),6.68(dd,J＝7.9,1.4Hz,1H), 6.62(td,J＝7.5,7.1,1.4Hz,1H),6.55(dd,J＝7.9,1.6Hz,1H),6.37(ddd,J＝8.3,7.1,1.7Hz,1H),5.84(s, 1H),3.58–3.53(m,2H),3.29–3.24(m,2H).LCMS(ESI)m/z[M+H] + :211.1.
步骤②：N-(1H-吲哚-3-基)-4-苯基-3,4-二氢喹喔林-1(2H)-甲酰胺(I-76)
Step ②: N-(1H-indol-3-yl)-4-phenyl-3,4-dihydroquinoxaline-1(2H)-carboxamide (I-76)
N-(1H-吲哚-3-基)-4-苯基-3,4-二氢喹喔林-1(2H)-甲酰胺(I-76)的制备方法同化合物I-41。1H NMR(400MHz,DMSO-d6)δ10.78(s,1H),8.58(s,1H),7.55(d,J＝7.9Hz,1H),7.48(dd,J＝8.0,1.6Hz,1H),7.45–7.38(m,3H),7.34–7.28(m,3H),7.15(t,J＝7.2Hz,1H),7.07(t,J＝7.7Hz,1H),6.97(ddd,J＝8.0,7.0,1.1Hz,1H),6.86(td,J＝7.6,1.6Hz,1H),6.79–6.72(m,2H),3.94(t,J＝5.2Hz,2H),3.74(t,J＝5.3Hz,2H).LCMS(ESI)m/z[M+H]+:369.2.The preparation method of N-(1H-indol-3-yl)-4-phenyl-3,4-dihydroquinoxaline-1(2H)-carboxamide (I-76) is the same as compound I-41. 1 H NMR (400MHz, DMSO-d 6 ) δ10.78 (s, 1H), 8.58 (s, 1H), 7.55 (d, J = 7.9Hz, 1H), 7.48 (dd, J = 8.0, 1.6Hz, 1H),7.45–7.38(m,3H),7.34–7.28(m,3H),7.15(t,J＝7.2Hz,1H),7.07(t,J＝7.7Hz,1H),6.97(ddd,J ＝8.0,7.0,1.1Hz,1H),6.86(td,J＝7.6,1.6Hz,1H),6.79–6.72(m,2H),3.94(t,J＝5.2Hz,2H),3.74(t, J＝5.3Hz,2H).LCMS(ESI)m/z[M+H] + :369.2.
实施例77 4-苯基-N-(5-苯基-1H-吲哚-3-基)哌嗪-1-甲酰胺(I-77)
Example 77 4-phenyl-N-(5-phenyl-1H-indol-3-yl)piperazine-1-carboxamide (I-77)
4-苯基-N-(5-苯基-1H-吲哚-3-基)哌嗪-1-甲酰胺(I-77)的制备同化合物I-41。1H NMR(400MHz,DMSO-d6)δ10.77(s,1H),8.38(s,1H),7.97(s,1H),7.68(d,J＝7.8Hz,2H),7.49–7.42(m,3H),7.40(s,2H),7.30(t,J＝7.5Hz,1H),7.25(dd,J＝8.5,7.1Hz,2H),7.01(d,J＝8.2Hz,2H),6.82(t,J＝7.2Hz,1H),3.66(t,J＝5.1Hz,4H),3.23–3.18(m,4H).LCMS(ESI)m/z[M+H]+:397.2.The preparation of 4-phenyl-N-(5-phenyl-1H-indol-3-yl)piperazine-1-carboxamide (I-77) is the same as compound I-41. 1 H NMR (400MHz, DMSO-d 6 ) δ10.77 (s, 1H), 8.38 (s, 1H), 7.97 (s, 1H), 7.68 (d, J = 7.8Hz, 2H), 7.49–7.42 ( m,3H),7.40(s,2H),7.30(t,J＝7.5Hz,1H),7.25(dd,J＝8.5,7.1Hz,2H),7.01(d,J＝8.2Hz,2H), 6.82(t,J＝7.2Hz,1H),3.66(t,J＝5.1Hz,4H),3.23–3.18(m,4H).LCMS(ESI)m/z[M+H] + :397.2.
实施例78 4-(苯并呋喃-3-基)-N-(1H-吲哚-3-基)哌嗪-1-甲酰胺(I-78)
Example 78 4-(benzofuran-3-yl)-N-(1H-indol-3-yl)piperazine-1-carboxamide (I-78)
步骤①：4-(苯并呋喃-3-基)哌嗪甲酸乙酯(78-1)
Step ①: ethyl 4-(benzofuran-3-yl)piperazinecarboxylate (78-1)
将300毫克3-苯并呋喃酮、470毫克N-哌嗪甲酸乙酯、1.12毫升四氯化钛和5毫升二氯甲烷混合物于-10℃搅拌5小时。反应液浓缩至干，得4-(苯并呋喃-3-基)哌嗪甲酸乙酯(78-1)300毫克，LCMS(ESI)m/z[M+H]+:275.1. A mixture of 300 mg of 3-benzofuranone, 470 mg of N-piperazinecarboxylic acid ethyl ester, 1.12 ml of titanium tetrachloride and 5 ml of methylene chloride was stirred at -10°C for 5 hours. The reaction solution was concentrated to dryness to obtain 300 mg of ethyl 4-(benzofuran-3-yl)piperazinecarboxylate (78-1), LCMS (ESI) m/z [M+H] + : 275.1.
步骤②：1-(苯并呋喃-3-基)哌嗪(78-2)
Step ②: 1-(benzofuran-3-yl)piperazine (78-2)
将100毫克4-(苯并呋喃-3-基)哌嗪甲酸乙酯(78-1)、1毫升乙醇和0.5毫升3N氢氧化钠混合物于85℃回流过夜。反应液浓缩至干，残余物以二氯甲烷:甲醇＝20:1制备薄层，得1-(苯并呋喃-3-基)哌嗪(78-2)60毫克，收率82％。LCMS(ESI)m/z[M+H]+:203.1.A mixture of 100 mg of ethyl 4-(benzofuran-3-yl)piperazinecarboxylate (78-1), 1 ml of ethanol and 0.5 ml of 3N sodium hydroxide was refluxed at 85°C overnight. The reaction solution was concentrated to dryness, and a thin layer of the residue was prepared with dichloromethane:methanol=20:1 to obtain 60 mg of 1-(benzofuran-3-yl)piperazine (78-2), with a yield of 82%. LCMS(ESI)m/z[M+H] + :203.1.
步骤③：4-(苯并呋喃-3-基)-N-(1H-吲哚-3-基)哌嗪-1-甲酰胺(I-78)
Step ③: 4-(benzofuran-3-yl)-N-(1H-indol-3-yl)piperazine-1-carboxamide (I-78)
4-(苯并呋喃-3-基)-N-(1H-吲哚-3-基)哌嗪-1-甲酰胺(I-78)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.73(s,1H),8.34(s,1H),7.75(s,1H),7.60(s,2H),7.51(s,1H),7.31(t,J＝25.4Hz,4H),7.01(d,J＝41.9Hz,2H),3.69(s,4H),3.06(d,J＝6.7Hz,4H).LCMS(ESI)m/z[M+H]+:361.2.The preparation method of 4-(benzofuran-3-yl)-N-(1H-indol-3-yl)piperazine-1-carboxamide (I-78) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.73(s,1H),8.34(s,1H),7.75(s,1H),7.60(s,2H),7.51(s,1H),7.31( t,J＝25.4Hz,4H),7.01(d,J＝41.9Hz,2H),3.69(s,4H),3.06(d,J＝6.7Hz,4H).LCMS(ESI)m/z[M +H] + :361.2.
实施例79 4-(苯并[d][1,3]二氧戊环-5-基)-N-(1H-吲哚-3-基)哌嗪-1-甲酰胺(I-79)
Example 79 4-(benzo[d][1,3]dioxolane-5-yl)-N-(1H-indol-3-yl)piperazine-1-carboxamide (I-79)
步骤①：1-(苯并[d][1,3]二氧戊环-5-基)哌嗪(79-1)
Step ①: 1-(benzo[d][1,3]dioxolane-5-yl)piperazine (79-1)
将100毫克1-溴-3,4-(亚甲二氧)苯、129毫克哌嗪、143毫克叔丁醇钠、8毫克醋酸钯、14毫克P(t-Bu)3HBF4和2毫升甲苯的混合物于氩气氛下110℃搅拌过夜。反应液加水稀释，乙酸乙酯萃取，有机相浓缩至干，残余物以二氯甲烷：甲醇＝10：1制备薄层，得白色固体1-(苯并[d][1,3]二氧戊环-5-基)哌嗪(79-1)85毫克，收率83％。1H NMR(400MHz,DMSO-d6)δ7.54(s,1H),6.77(d,J＝8.4Hz,1H),6.69(d,J＝2.4Hz,1H),6.35(dd,J＝8.5,2.4Hz,1H),5.92(s,2H),3.10(dd,J＝6.3,3.3Hz,4H),3.03(q,J＝4.1Hz,4H).LCMS(ESI)m/z[M+H]+:207.1.Combine 100 mg of 1-bromo-3,4-(methylenedioxy)benzene, 129 mg of piperazine, 143 mg of sodium tert-butoxide, 8 mg of palladium acetate, 14 mg of P(t-Bu) 3 HBF 4 and 2 ml of The toluene mixture was stirred at 110°C overnight under an argon atmosphere. The reaction solution was diluted with water, extracted with ethyl acetate, and the organic phase was concentrated to dryness. A thin layer of the residue was prepared with dichloromethane: methanol = 10:1 to obtain a white solid 1-(benzo[d][1,3]dioxy Pentylcyclo-5-yl)piperazine (79-1) 85 mg, yield 83%. 1 H NMR (400MHz, DMSO-d 6 ) δ7.54 (s, 1H), 6.77 (d, J = 8.4Hz, 1H), 6.69 (d, J = 2.4Hz, 1H), 6.35 (dd, J = 8.5,2.4Hz,1H),5.92(s,2H),3.10(dd,J＝6.3,3.3Hz,4H),3.03(q,J＝4.1Hz,4H).LCMS(ESI)m/z[M +H] + :207.1.
步骤②：4-(苯并[d][1,3]二氧戊环-5-基)-N-(1H-吲哚-3-基)哌嗪-1-甲酰胺(I-79)
Step ②: 4-(benzo[d][1,3]dioxolane-5-yl)-N-(1H-indol-3-yl)piperazine-1-carboxamide (I-79)
4-(苯并[d][1,3]二氧戊环-5-基)-N-(1H-吲哚-3-基)哌嗪-1-甲酰胺(I-79)的制备方 法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.70(s,1H),8.29(s,1H),7.60(d,J＝7.9Hz,1H),7.37(d,J＝2.5Hz,1H),7.30(d,J＝8.1Hz,1H),7.06(t,J＝7.5Hz,1H),6.95(t,J＝7.4Hz,1H),6.79(d,J＝8.4Hz,1H),6.75(d,J＝2.4Hz,1H),6.40(dd,J＝8.4,2.4Hz,1H),5.93(s,2H),3.59(t,J＝5.0Hz,4H),3.03(t,J＝4.9Hz,4H).LCMS(ESI)m/z[M+H]+:365.2.Preparation method of 4-(benzo[d][1,3]dioxolane-5-yl)-N-(1H-indol-3-yl)piperazine-1-carboxamide (I-79) The method is the same as compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.70 (s, 1H), 8.29 (s, 1H), 7.60 (d, J = 7.9Hz, 1H), 7.37 (d, J = 2.5Hz, 1H) ,7.30(d,J＝8.1Hz,1H),7.06(t,J＝7.5Hz,1H),6.95(t,J＝7.4Hz,1H),6.79(d,J＝8.4Hz,1H),6.75 (d,J＝2.4Hz,1H),6.40(dd,J＝8.4,2.4Hz,1H),5.93(s,2H),3.59(t,J＝5.0Hz,4H),3.03(t,J＝ 4.9Hz,4H).LCMS(ESI)m/z[M+H] + :365.2.
实施例80 N-(1H-吲哚-3-基)-4-(吡啶-2-基)哌嗪-1-甲酰胺(I-80)
Example 80 N-(1H-indol-3-yl)-4-(pyridin-2-yl)piperazine-1-carboxamide (I-80)
N-(1H-吲哚-3-基)-4-(吡啶-2-基)哌嗪-1-甲酰胺(I-80)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.68(s,1H),8.27(s,1H),8.11(d,J＝3.8Hz,1H),7.58(d,J＝8.0Hz,1H),7.53(t,J＝7.1Hz,1H),7.34(d,J＝2.0Hz,1H),7.28(d,J＝8.2Hz,1H),7.03(t,J＝7.5Hz,1H),6.92(t,J＝7.4Hz,1H),6.86(d,J＝8.5Hz,1H),6.68–6.59(m,1H),3.54(d,J＝8.2Hz,8H).LCMS(ESI)m/z[M+H]+:322.1.The preparation method of N-(1H-indol-3-yl)-4-(pyridin-2-yl)piperazine-1-carboxamide (I-80) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.68 (s, 1H), 8.27 (s, 1H), 8.11 (d, J = 3.8Hz, 1H), 7.58 (d, J = 8.0Hz, 1H) ,7.53(t,J＝7.1Hz,1H),7.34(d,J＝2.0Hz,1H),7.28(d,J＝8.2Hz,1H),7.03(t,J＝7.5Hz,1H),6.92 (t,J＝7.4Hz,1H),6.86(d,J＝8.5Hz,1H),6.68–6.59(m,1H),3.54(d,J＝8.2Hz,8H).LCMS(ESI)m/ z[M+H] + :322.1.
实施例81 N-(1H-吲哚-3-基)-3-氧-4-苯基哌嗪-1-甲酰胺(I-81)
Example 81 N-(1H-indol-3-yl)-3-oxo-4-phenylpiperazine-1-carboxamide (I-81)
步骤①：4-苄基-1-苯基哌嗪-2-酮(81-1)
Step ①: 4-benzyl-1-phenylpiperazin-2-one (81-1)
将100毫克4-苄基哌嗪-2-酮、128毫克碘苯、145毫克碳酸钾、10毫克碘化铜、6微升二乙胺和2毫升1,4-二氧六环的混合物于氩气氛下130℃微波反应1小时。反应液过滤，滤液浓缩至干并制砂，二氯甲烷：甲醇＝100：1柱层析，得白色固体4-苄基-1-苯基哌嗪-2-酮(81-1)99毫克，收率71％。1H NMR(400MHz,CD3OD)δ7.45–7.26(m,10H),3.71–3.65(m,4H),3.27(s,2H),2.85(t,J＝5.5Hz,2H).LCMS(ESI)m/z[M+H]+:267.1.A mixture of 100 mg of 4-benzylpiperazin-2-one, 128 mg of iodobenzene, 145 mg of potassium carbonate, 10 mg of copper iodide, 6 μl of diethylamine and 2 ml of 1,4-dioxane was added to Microwave reaction at 130°C for 1 hour under argon atmosphere. The reaction solution was filtered, and the filtrate was concentrated to dryness and sand was made. Dichloromethane: methanol = 100:1 column chromatography was used to obtain 99 mg of white solid 4-benzyl-1-phenylpiperazin-2-one (81-1). , the yield is 71%. 1 H NMR (400MHz, CD 3 OD) δ7.45–7.26 (m, 10H), 3.71–3.65 (m, 4H), 3.27 (s, 2H), 2.85 (t, J = 5.5Hz, 2H). LCMS (ESI)m/z[M+H] + :267.1.
步骤②：1-苯基哌嗪-2-酮(81-2)
Step ②: 1-phenylpiperazin-2-one (81-2)
将99毫克4-苄基-1-苯基哌嗪-2-酮(81-1)、50毫克钯碳和3毫升甲醇的混合物于室温常压氢化反应6小时。反应液经硅藻土过滤，滤液浓缩至干，得透明油状物1-苯基哌嗪-2-酮(81-2)60毫克，收率91％。LCMS(ESI)m/z[M+H]+:177.1.A mixture of 99 mg of 4-benzyl-1-phenylpiperazin-2-one (81-1), 50 mg of palladium on carbon and 3 ml of methanol was hydrogenated at room temperature and normal pressure for 6 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to dryness to obtain 60 mg of 1-phenylpiperazin-2-one (81-2) as a transparent oil, with a yield of 91%. LCMS(ESI)m/z[M+H] + :177.1.
步骤③：N-(1H-吲哚-3-基)-3-氧-4-苯基哌嗪-1-甲酰胺(I-81)
Step ③: N-(1H-indol-3-yl)-3-oxo-4-phenylpiperazine-1-carboxamide (I-81)
N-(1H-吲哚-3-基)-3-氧-4-苯基哌嗪-1-甲酰胺(I-81)的制备方法同化合物I-41。1H NMR(400MHz,DMSO-d6)δ10.75(d,J＝2.4Hz,1H),8.37(s,1H),7.64(d,J＝8.0Hz,1H),7.45–7.37(m,5H),7.33–7.26(m,2H),7.07(t,J＝7.5Hz,1H),6.97(t,J＝7.4Hz,1H),4.30(s,2H),3.87(t,J＝5.1Hz,2H),3.80(d,J＝5.4Hz,2H).LCMS(ESI)m/z[M+H]+:335.1.The preparation method of N-(1H-indol-3-yl)-3-oxo-4-phenylpiperazine-1-carboxamide (I-81) is the same as compound I-41. 1 H NMR (400MHz, DMSO-d 6 ) δ10.75(d,J＝2.4Hz,1H),8.37(s,1H),7.64(d,J＝8.0Hz,1H),7.45–7.37(m, 5H),7.33–7.26(m,2H),7.07(t,J＝7.5Hz,1H),6.97(t,J＝7.4Hz,1H),4.30(s,2H),3.87(t,J＝5.1 Hz, 2H), 3.80 (d, J = 5.4Hz, 2H). LCMS (ESI) m/z [M+H] + : 335.1.
实施例82 N-(5-(1-苯基-1H-吡唑-4-基)-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-82)
Example 82 N-(5-(1-phenyl-1H-pyrazol-4-yl)-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-methyl Amide(I-82)
步骤①：1-苯基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)吡唑(82-1)
Step ①: 1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)pyrazole (82-1)
将500毫克4-溴-1-苯基吡唑、2.87克4，4，5，5-四甲基-1,3,2-二氧杂硼烷、184毫克2-二环己基膦基-2’,6’-二甲氧基联苯基，29毫克Pd(CH3CN)2Cl2，780微升三乙胺和甲苯的混合物于氩气氛下90℃搅拌16小时，反应液浓缩至干，残余物，残余物以乙酸乙酯：石油醚＝8:92柱层析，得黄色油状物1-苯基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)吡唑(82-1)181毫克，收率：29.9％。1H NMR(400MHz,DMSO-d6)δ8.72(s,1H),7.90(d,J＝8.7,1.2Hz,2H),7.86(s,1H),7.48(t,J＝8.5,7.4Hz,2H),7.31(t,J＝7.4Hz,1H),1.28(s,12H).500 mg of 4-bromo-1-phenylpyrazole, 2.87 g of 4,4,5,5-tetramethyl-1,3,2-dioxaborane, and 184 mg of 2-dicyclohexylphosphino- A mixture of 2',6'-dimethoxybiphenyl, 29 mg Pd(CH 3 CN) 2 Cl 2 , 780 μl triethylamine and toluene was stirred at 90°C for 16 hours under an argon atmosphere, and the reaction solution was concentrated to Dry the residue. The residue was subjected to column chromatography with ethyl acetate: petroleum ether = 8:92 to obtain a yellow oily substance 1-phenyl-4-(4,4,5,5-tetramethyl-1,3, 181 mg of 2-dioxaboran-2-yl)pyrazole (82-1), yield: 29.9%. 1 H NMR (400MHz, DMSO-d 6 ) δ8.72 (s, 1H), 7.90 (d, J = 8.7, 1.2 Hz, 2H), 7.86 (s, 1H), 7.48 (t, J = 8.5, 7.4 Hz, 2H), 7.31 (t, J = 7.4Hz, 1H), 1.28 (s, 12H).
步骤②：5-(1-苯基吡唑-4-基)-1H-吲哚-3-甲酸甲酯(82-2)
Step ②: 5-(1-phenylpyrazol-4-yl)-1H-indole-3-carboxylic acid methyl ester (82-2)
化合物5-(1-苯基吡唑-4-基)-1H-吲哚-3-甲酸甲酯(82-2)的制备同化合物41-1。1H NMR(400MHz,DMSO-d6)δ11.95(s,1H),8.95(s,1H),8.28(d,J＝1.7Hz,1H),8.17(d,J＝0.7Hz,1H),8.09(d,J＝3.0Hz,1H),7.94(dd,J＝8.7,1.2Hz,2H),7.60–7.56(m,1H),7.56–7.48(m,3H),7.38–7.26(m,1H),3.84(s,3H).LCMS(ESI):m/z[M+H]+:318.1.The preparation of compound 5-(1-phenylpyrazol-4-yl)-1H-indole-3-carboxylic acid methyl ester (82-2) is the same as compound 41-1. 1 H NMR (400MHz, DMSO-d 6 ) δ11.95 (s, 1H), 8.95 (s, 1H), 8.28 (d, J = 1.7Hz, 1H), 8.17 (d, J = 0.7Hz, 1H) ,8.09(d,J＝3.0Hz,1H),7.94(dd,J＝8.7,1.2Hz,2H),7.60–7.56(m,1H),7.56–7.48(m,3H),7.38–7.26(m ,1H),3.84(s,3H).LCMS(ESI):m/z[M+H] + :318.1.
步骤③：5-(1-苯基吡唑-4-基)-1H-吲哚-3-甲酸(82-3)
Step ③: 5-(1-phenylpyrazol-4-yl)-1H-indole-3-carboxylic acid (82-3)
5-(1-苯基吡唑-4-基)-1H-吲哚-3-甲酸(82-3)的制备同化合物41-2。LCMS(ESI):m/z[M+H]+:304.1.The preparation of 5-(1-phenylpyrazol-4-yl)-1H-indole-3-carboxylic acid (82-3) is the same as compound 41-2. LCMS(ESI):m/z[M+H] + :304.1.
步骤④：5-(1-苯基吡唑-4-基)-1H-吲哚-3-酰基叠氮(82-4)
Step ④: 5-(1-phenylpyrazol-4-yl)-1H-indole-3-acylazide (82-4)
5-(1-苯基吡唑-4-基)-1H-吲哚-3-酰基叠氮(82-4)的制备同化合物41-3。1H NMR(400MHz,CD3OD)δ12.28(s,1H),9.00(s,1H),8.34(s,1H),8.20(d,J＝4.8Hz,2H),7.95(d,J＝8.1Hz,2H),7.64(d,J＝8.5Hz,1H),7.57–7.50(m,3H),7.32(t,J＝7.4Hz,1H).The preparation of 5-(1-phenylpyrazol-4-yl)-1H-indole-3-acylazide (82-4) is the same as compound 41-3. 1 H NMR (400MHz, CD 3 OD) δ12.28(s,1H),9.00(s,1H),8.34(s,1H),8.20(d,J＝4.8Hz,2H),7.95(d,J ＝8.1Hz,2H),7.64(d,J＝8.5Hz,1H),7.57–7.50(m,3H),7.32(t,J＝7.4Hz,1H).
步骤⑤：N-(5-(1-苯基-1H-吡唑-4-基)-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-82)
Step ⑤: N-(5-(1-phenyl-1H-pyrazol-4-yl)-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-methyl Amide(I-82)
N-(5-(1-苯基-1H-吡唑-4-基)-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-82)的制备同化合物I-41。1H NMR(400MHz,CD3OD)δ8.55(d,J＝0.8Hz,1H),8.09(d,J＝0.8Hz,1H),7.85(t,J＝1.1Hz,1H),7.81(dd,J＝8.6,1.2Hz,2H),7.55–7.43(m,3H),7.41–7.30(m,3H),7.23(s,4H),4.78(s,2H),3.84(t,2H),2.99(t,J＝5.9Hz,2H).LCMS(ESI)m/z[M+H]+:434.2.N-(5-(1-phenyl-1H-pyrazol-4-yl)-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I -82) was prepared in the same way as compound I-41. 1 H NMR (400MHz, CD 3 OD) δ8.55(d,J＝0.8Hz,1H),8.09(d,J＝0.8Hz,1H),7.85(t,J＝1.1Hz,1H),7.81( dd,J＝8.6,1.2Hz,2H),7.55–7.43(m,3H),7.41–7.30(m,3H),7.23(s,4H),4.78(s,2H),3.84(t,2H) ,2.99(t,J＝5.9Hz,2H).LCMS(ESI)m/z[M+H] + :434.2.
实施例83 N-(5-氯-6-氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-83)
Example 83 N-(5-chloro-6-fluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-83)
步骤①：5-氯-6-氟-1H-吲哚-3-酰基叠氮(83-1)
Step ①: 5-chloro-6-fluoro-1H-indole-3-acyl azide (83-1)
5-氯-6-氟-1H-吲哚-3-酰基叠氮(69-1)的制备方法同化合物1-1。1H NMR(400MHz,DMSO-d6)δ12.46(s,8H),8.30(s,7H),8.12(d,J＝7.4Hz,7H),7.58(d,J＝9.6Hz,7H),3.36(s,8H),2.52(s,18H),0.02(s,1H).The preparation method of 5-chloro-6-fluoro-1H-indole-3-acyl azide (69-1) is the same as that of compound 1-1. 1 H NMR (400MHz, DMSO-d 6 ) δ12.46 (s, 8H), 8.30 (s, 7H), 8.12 (d, J = 7.4Hz, 7H), 7.58 (d, J = 9.6Hz, 7H) ,3.36(s,8H),2.52(s,18H),0.02(s,1H).
步骤②：5-氯-6-氟-3-异氰酸酯-1H-吲哚(83-2)
Step ②: 5-chloro-6-fluoro-3-isocyanate-1H-indole (83-2)
5-氯-6-氟-3-异氰酸酯-1H-吲哚(83-2)的制备方法同化合物1-2。1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),7.69(s,1H),7.53(d,J＝2.5Hz,1H),7.41(s,1H). The preparation method of 5-chloro-6-fluoro-3-isocyanate-1H-indole (83-2) is the same as that of compound 1-2. 1 H NMR (400MHz, DMSO-d 6 ) δ 11.43 (s, 1H), 7.69 (s, 1H), 7.53 (d, J = 2.5Hz, 1H), 7.41 (s, 1H).
步骤③：N-(5-氯-6-氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-83)
Step ③: N-(5-chloro-6-fluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-83)
N-(5-氯-6-氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-83)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.96(s,1H),8.33(s,1H),7.85(d,J＝7.5Hz,1H),7.46(d,J＝2.2Hz,1H),7.31(d,J＝10.1Hz,1H),7.19(s,4H),4.67(s,2H),3.73(t,J＝5.9Hz,2H),2.86(t,J＝5.6Hz,2H).LCMS(ESI)m/z[M+H]+:344.1.The preparation method of N-(5-chloro-6-fluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-83) is the same as that of compound I- 1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.96 (s, 1H), 8.33 (s, 1H), 7.85 (d, J = 7.5Hz, 1H), 7.46 (d, J = 2.2Hz, 1H) ,7.31(d,J＝10.1Hz,1H),7.19(s,4H),4.67(s,2H),3.73(t,J＝5.9Hz,2H),2.86(t,J＝5.6Hz,2H) .LCMS(ESI)m/z[M+H] + :344.1.
实施例84 6-溴-N-(5-氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-84)
Example 84 6-bromo-N-(5-fluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-84)
6-溴-N-(5-氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-84)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.82(s,1H),8.25(s,1H),7.44(s,2H),7.37(t,J＝11.0Hz,2H),7.30(dd,J＝8.8,4.6Hz,1H),7.16(d,J＝8.2Hz,1H),6.90(t,J＝7.8Hz,1H),4.62(s,2H),3.71(t,J＝5.8Hz,2H),2.87(t,J＝5.4Hz,2H).LCMS(ESI)m/z[M+H]+:388.1.The preparation method of 6-bromo-N-(5-fluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-84) is the same as that of compound I- 1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.82 (s, 1H), 8.25 (s, 1H), 7.44 (s, 2H), 7.37 (t, J = 11.0Hz, 2H), 7.30 (dd, J＝8.8,4.6Hz,1H),7.16(d,J＝8.2Hz,1H),6.90(t,J＝7.8Hz,1H),4.62(s,2H),3.71(t,J＝5.8Hz, 2H),2.87(t,J＝5.4Hz,2H).LCMS(ESI)m/z[M+H] + :388.1.
实施例85 6-乙氧基-N-(1H-吲哚-3-基)-6,9-二氢呋喃并[3,2-h]异喹啉-8(7H)-甲酰胺(I-85)
Example 85 6-ethoxy-N-(1H-indol-3-yl)-6,9-dihydrofura[3,2-h]isoquinoline-8(7H)-carboxamide (I -85)
步骤①：N-羟基苯并呋喃-7-甲酰胺(85-1)
Step ①: N-hydroxybenzofuran-7-carboxamide (85-1)
将50毫克苯并呋喃-7-甲酸、150毫克卡特缩合剂、24毫克盐酸羟胺、130微升三乙胺和1毫升吡啶混合物在氩气保护下室温搅拌6小时。反应液浓缩至干，残余物以二氯甲烷:甲醇＝20:1制备薄层，得N-羟基苯并呋喃-7-甲酰胺(85-1)淡黄色油状物30毫克，收率55％。LCMS(ESI)m/z[M+H]+:178.1.A mixture of 50 mg benzofuran-7-carboxylic acid, 150 mg Carter's condensing agent, 24 mg hydroxylamine hydrochloride, 130 μl triethylamine and 1 ml pyridine was stirred at room temperature under argon protection for 6 hours. The reaction solution was concentrated to dryness, and the residue was prepared as a thin layer using dichloromethane:methanol=20:1 to obtain 30 mg of N-hydroxybenzofuran-7-carboxamide (85-1) as a light yellow oil, with a yield of 55%. . LCMS(ESI)m/z[M+H] + :178.1.
步骤②：N-(新戊酰氧基)苯并呋喃-7-甲酰胺(85-2)
Step ②: N-(pivaloyloxy)benzofuran-7-carboxamide (85-2)
将20毫克N-羟基苯并呋喃-7-甲酰胺(85-1)、15毫克新戊酰氯、20微升三乙胺和1毫升四氢呋喃混合物在氩气保护下室温搅拌3小时。反应液浓缩至干，残余物以二氯甲烷:甲醇＝20:1制备薄层，得N-(新戊酰氧基)苯并呋喃-7-甲酰胺(85-2)15毫克，收率51％。1H NMR(400MHz,CD3OD)δ7.89(d,J＝2.3Hz,1H),7.83(d,J＝7.7Hz,2H),7.35(t,J＝7.6Hz,1H),6.96(d,J＝2.3Hz,1H),1.37(s,10H).LCMS(ESI)m/z[M+H]+:262.1.A mixture of 20 mg N-hydroxybenzofuran-7-carboxamide (85-1), 15 mg pivaloyl chloride, 20 μl triethylamine and 1 ml tetrahydrofuran was stirred at room temperature under argon protection for 3 hours. The reaction solution was concentrated to dryness, and a thin layer of the residue was prepared with dichloromethane:methanol=20:1 to obtain 15 mg of N-(pivaloyloxy)benzofuran-7-carboxamide (85-2), yield 51%. 1 H NMR (400MHz, CD 3 OD) δ7.89 (d, J = 2.3Hz, 1H), 7.83 (d, J = 7.7Hz, 2H), 7.35 (t, J = 7.6Hz, 1H), 6.96 ( d,J＝2.3Hz,1H),1.37(s,10H).LCMS(ESI)m/z[M+H] + :262.1.
步骤③：6-乙氧基-7,8-二氢呋喃并[3,2-h]异喹啉酮(85-3)
Step ③: 6-ethoxy-7,8-dihydrofuro[3,2-h]isoquinolinone (85-3)
将20毫克N-(新戊酰氧基)苯并呋喃-7-羧酰胺、14毫克乙烯基乙醚、5毫克乙酸铯、3毫克二氯(五甲基环戊二烯基)合铑(III)二聚体和1毫升甲醇混合物于氩气保护下室温搅拌过夜。反应液浓缩至干，残余物以石油醚:乙酸乙酯＝1:1制备薄层，得6-乙氧基-7,8-二氢呋喃并[3,2-h]异喹啉(85-3)10毫克，收率57％。1H NMR(400MHz,CD3OD)δ7.90(d,J＝2.2Hz,1H),7.85(d,J＝7.8Hz,1H),7.38(d,J＝7.9Hz,1H),6.94(d,J＝2.3Hz,1H),4.59(t,J＝3.4Hz,1H),3.75–3.62(m,4H),1.18(t,J＝7.0Hz,3H).LCMS(ESI)m/z[M+H]+:232.1.20 mg N-(pivaloyloxy)benzofuran-7-carboxamide, 14 mg vinyl ether, 5 mg cesium acetate, 3 mg dichloro(pentamethylcyclopentadienyl)rhodium(III) ) dimer and 1 ml of methanol mixture were stirred at room temperature overnight under argon protection. The reaction solution was concentrated to dryness, and a thin layer of the residue was prepared with petroleum ether: ethyl acetate = 1:1 to obtain 6-ethoxy-7,8-dihydrofura[3,2-h]isoquinoline (85 -3) 10 mg, yield 57%. 1 H NMR (400MHz, CD 3 OD) δ7.90(d,J＝2.2Hz,1H),7.85(d,J＝7.8Hz,1H),7.38(d,J＝7.9Hz,1H),6.94( d,J＝2.3Hz,1H),4.59(t,J＝3.4Hz,1H),3.75–3.62(m,4H),1.18(t,J＝7.0Hz,3H).LCMS(ESI)m/z [M+H] + :232.1.
步骤④：6-乙氧基-6,7,8,9-四氢呋喃并[3,2-h]异喹啉(85-4)
Step ④: 6-ethoxy-6,7,8,9-tetrahydrofura[3,2-h]isoquinoline (85-4)
将10毫克6-乙氧基-7,8-二氢呋喃并[3,2-h]异喹啉酮(85-3)、65微升四氢铝锂和0.5毫升四氢呋喃混合物于氩气保护下60℃搅拌6小时。反应液浓缩至干，残余物以二氯甲烷:甲醇＝20:1制备薄层，得6-乙氧基-6,7,8,9-四氢呋喃并[3,2-h]异喹啉(85-4)10毫克，收率57％。1H NMR(400MHz,CD3OD)δ7.80(d,J＝2.2Hz,1H),7.55(d,J＝8.0Hz,1H),7.27(d,J＝8.1Hz,1H),6.86(d,J＝2.2Hz,1H),4.55(t,J＝3.1Hz,1H),4.44(d,J＝16.7Hz,1H),4.26(d,J＝16.7Hz,1H),3.84–3.61(m,2H),3.51(dd,J＝13.3,3.3Hz,1H),3.22(dd,J＝13.3,2.9Hz,1H),1.25(t,J＝7.0Hz,3H).LCMS(ESI)m/z[M+H]+:218.1.A mixture of 10 mg of 6-ethoxy-7,8-dihydrofuro[3,2-h]isoquinolinone (85-3), 65 μl of lithium aluminum tetrahydrogen and 0.5 ml of tetrahydrofuran was protected under argon gas. Stir at 60°C for 6 hours. The reaction solution was concentrated to dryness, and a thin layer of the residue was prepared with dichloromethane:methanol=20:1 to obtain 6-ethoxy-6,7,8,9-tetrahydrofura[3,2-h]isoquinoline ( 85-4) 10 mg, yield 57%. 1 H NMR (400MHz, CD 3 OD) δ7.80(d,J＝2.2Hz,1H),7.55(d,J＝8.0Hz,1H),7.27(d,J＝8.1Hz,1H),6.86( d,J＝2.2Hz,1H),4.55(t,J＝3.1Hz,1H),4.44(d,J＝16.7Hz,1H),4.26(d,J＝16.7Hz,1H),3.84–3.61( m,2H),3.51(dd,J＝13.3,3.3Hz,1H),3.22(dd,J＝13.3,2.9Hz,1H),1.25(t,J＝7.0Hz,3H).LCMS(ESI)m /z[M+H] + :218.1.
步骤⑤：6-乙氧基-N-(1H-吲哚-3-基)-6,9-二氢呋喃并[3,2-h]异喹啉-8(7H)-甲酰胺(I-85)
Step ⑤: 6-ethoxy-N-(1H-indol-3-yl)-6,9-dihydrofura[3,2-h]isoquinoline-8(7H)-carboxamide (I -85)
6-乙氧基-N-(1H-吲哚-3-基)-6,9-二氢呋喃并[3,2-h]异喹啉-8(7H)-甲酰胺(I-85) 的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.72(s,1H),8.40(s,1H),8.06(d,J＝2.1Hz,1H),7.62(d,J＝8.0Hz,1H),7.56(d,J＝8.0Hz,1H),7.36(d,J＝2.3Hz,1H),7.31(dd,J＝8.1,3.0Hz,2H),7.06(t,J＝7.5Hz,1H),7.01–6.90(m,2H),5.12(d,J＝17.0Hz,1H),4.81(d,J＝17.0Hz,1H),4.59(s,1H),3.86–3.57(m,2H),1.23(s,2H),1.14(t,J＝7.0Hz,3H).LCMS(ESI)m/z[M+Na]+:398.2.6-Ethoxy-N-(1H-indol-3-yl)-6,9-dihydrofuro[3,2-h]isoquinoline-8(7H)-carboxamide (I-85) The preparation method is the same as compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.72 (s, 1H), 8.40 (s, 1H), 8.06 (d, J = 2.1Hz, 1H), 7.62 (d, J = 8.0Hz, 1H) ,7.56(d,J＝8.0Hz,1H),7.36(d,J＝2.3Hz,1H),7.31(dd,J＝8.1,3.0Hz,2H),7.06(t,J＝7.5Hz,1H) ,7.01–6.90(m,2H),5.12(d,J＝17.0Hz,1H),4.81(d,J＝17.0Hz,1H),4.59(s,1H),3.86–3.57(m,2H), 1.23(s,2H),1.14(t,J＝7.0Hz,3H).LCMS(ESI)m/z[M+Na] + :398.2.
实施例86 6-苯基-N-(1H-吡咯并[2,3-c]吡啶-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-86)
Example 86 6-phenyl-N-(1H-pyrrolo[2,3-c]pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-86 )
步骤①：1H-吲哚-[2,3-c]吡啶-3-酰基叠氮(86-1)
Step ①: 1H-indole-[2,3-c]pyridine-3-acyl azide (86-1)
1H-吲哚-[2,3-c]吡啶-3-酰基叠氮(86-1)的制备方法同化合物1-1。LCMS(ESI)m/z[M+H]+:188.1.The preparation method of 1H-indole-[2,3-c]pyridine-3-acyl azide (86-1) is the same as that of compound 1-1. LCMS(ESI)m/z[M+H] + :188.1.
步骤②：6-苯基-N-(1H-吡咯并[2,3-c]吡啶-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-86)
Step ②: 6-phenyl-N-(1H-pyrrolo[2,3-c]pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-86 )
6-苯基-N-(1H-吡咯并[2,3-c]吡啶-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-86)的制备方法同化合物I-41。1H NMR(400MHz,DMSO-d6)δ8.86(s,1H),8.77(s,1H),8.11(s,1H),7.93(s,2H),7.65(s,2H),7.48(d,J＝18.4Hz,4H),7.32(d,J＝29.3Hz,2H),4.75(s,2H),3.80(s,2H),2.95(s,2H).LCMS(ESI)m/z[M+H]+:369.1.Preparation of 6-phenyl-N-(1H-pyrrolo[2,3-c]pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-86) The method is the same as that of compound I-41. 1 H NMR (400MHz, DMSO-d 6 ) δ8.86(s,1H),8.77(s,1H),8.11(s,1H),7.93(s,2H),7.65(s,2H),7.48( d,J＝18.4Hz,4H),7.32(d,J＝29.3Hz,2H),4.75(s,2H),3.80(s,2H),2.95(s,2H).LCMS(ESI)m/z [M+H] + :369.1.
实施例87 6-苯基-N-(1H-吡咯[2,3-b]吡啶-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-87)
Example 87 6-phenyl-N-(1H-pyrrole[2,3-b]pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-87)
步骤①：1H-吲哚-[2,3-b]吡啶-3-酰基叠氮(87-1)
Step ①: 1H-indole-[2,3-b]pyridine-3-acyl azide (87-1)
1H-吲哚-[2,3-b]吡啶-3-酰基叠氮(87-1)的制备方法同化合物1-1。LCMS(ESI)m/z[M+H]+:188.1.The preparation method of 1H-indole-[2,3-b]pyridine-3-acyl azide (87-1) is the same as that of compound 1-1. LCMS(ESI)m/z[M+H] + :188.1.
步骤②：6-苯基-N-(1H-吡咯[2,3-b]吡啶-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-87)
Step ②: 6-phenyl-N-(1H-pyrrole[2,3-b]pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-87)
6-苯基-N-(1H-吡咯[2,3-b]吡啶-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-87)的制备方法同化合物I-41。1H NMR(400MHz,DMSO-d6)δ11.25(s,1H),8.43(s,1H),8.18(s,1H),8.04(s,1H),7.66(s,2H),7.48(d,J＝20.3Hz,5H),7.36(s,1H),7.28(s,1H),7.02(s,1H),4.71(s,2H),3.77(s,2H),2.95(s,2H).LCMS(ESI)m/z[M+H]+:369.1.Preparation method of 6-phenyl-N-(1H-pyrrole[2,3-b]pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-87) Same as compound I-41. 1 H NMR (400MHz, DMSO-d 6 ) δ11.25(s,1H),8.43(s,1H),8.18(s,1H),8.04(s,1H),7.66(s,2H),7.48( d,J＝20.3Hz,5H),7.36(s,1H),7.28(s,1H),7.02(s,1H),4.71(s,2H),3.77(s,2H),2.95(s,2H ).LCMS(ESI)m/z[M+H] + :369.1.
实施例88 6-苯基-N-(1H-吡咯并[3,2-b]吡啶-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-88)
Example 88 6-phenyl-N-(1H-pyrrolo[3,2-b]pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-88 )
步骤①：1H-吲哚-[3,2-b]吡啶-3-酰基叠氮(88-1)
Step ①: 1H-indole-[3,2-b]pyridine-3-acyl azide (88-1)
1H-吲哚-[3,2-b]吡啶-3-酰基叠氮(88-1)的制备方法同化合物1-1。LCMS(ESI)m/z[M+H]+:188.1.The preparation method of 1H-indole-[3,2-b]pyridine-3-acyl azide (88-1) is the same as that of compound 1-1. LCMS(ESI)m/z[M+H] + :188.1.
步骤②：6-苯基-N-(1H-吡咯并[3,2-b]吡啶-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-88)
Step ②: 6-phenyl-N-(1H-pyrrolo[3,2-b]pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-88 )
6-苯基-N-(1H-吡咯并[3,2-b]吡啶-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-88)的制备方法同化合物I-41。1H NMR(400MHz,DMSO-d6)δ11.85(s,1H),8.42(d,J＝4.6Hz,1H),7.99(s,1H),7.87(d,J＝8.2Hz,1H),7.65(d,J＝7.6Hz,2H),7.48(s,2H),7.45(t,J＝7.4Hz,2H),7.34(t,J＝7.3Hz,1H),7.20(dd,J＝8.3,4.6Hz,1H),4.83(s,2H),3.84(s,2H),3.02(s,2H).LCMS(ESI)m/z[M+H]+:369.1.Preparation of 6-phenyl-N-(1H-pyrrolo[3,2-b]pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-88) The method is the same as that of compound I-41. 1 H NMR (400MHz, DMSO-d 6 ) δ11.85 (s, 1H), 8.42 (d, J = 4.6Hz, 1H), 7.99 (s, 1H), 7.87 (d, J = 8.2Hz, 1H) ,7.65(d,J＝7.6Hz,2H),7.48(s,2H),7.45(t,J＝7.4Hz,2H),7.34(t,J＝7.3Hz,1H),7.20(dd,J＝ 8.3,4.6Hz,1H),4.83(s,2H),3.84(s,2H),3.02(s,2H).LCMS(ESI)m/z[M+H] + :369.1.
实施例89 N-(1H-吲哚-3-基)-6-苯基-3,4-二氢-2,7-萘啶-2(1H)-甲酰胺(I-89)
Example 89 N-(1H-indol-3-yl)-6-phenyl-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxamide (I-89)
步骤①：6-苯基-1,2,3,4-四氢-2,7-萘啶(89-1)
Step ①: 6-phenyl-1,2,3,4-tetrahydro-2,7-naphthyridine (89-1)
6-苯基-1,2,3,4-四氢-2,7-二氮萘(89-1)的制备方法同化合物10-1。LCMS(ESI)m/z[M+H]+:211.1.The preparation method of 6-phenyl-1,2,3,4-tetrahydro-2,7-naphthalene (89-1) is the same as that of compound 10-1. LCMS(ESI)m/z[M+H] + :211.1.
步骤②：N-(1H-吲哚-3-基)-6-苯基-3,4-二氢-2,7-萘啶-2(1H)-甲酰胺(I-89)
Step ②: N-(1H-indol-3-yl)-6-phenyl-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxamide (I-89)
N-(1H-吲哚-3-基)-6-苯基-3,4-二氢-2,7-萘啶-2(1H)-甲酰胺(I-89)的制备方法同化合物I-1。1H NMR(400MHz,CD3OD)δ7.95(d,J＝7.1Hz,3H),7.70(d,J＝1.4Hz,2H),7.54(d,J＝7.9Hz,1H),7.50–7.46(m,3H),7.35(d,J＝8.8Hz,2H),7.14–7.07(m,1H),7.01(t,J＝7.5Hz,1H),4.82(s,2H),3.97(t,J＝5.9Hz,2H),3.16(t,J＝5.9Hz,2H).LCMS(ESI)m/z[M+H]+:369.1.The preparation method of N-(1H-indol-3-yl)-6-phenyl-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxamide (I-89) is the same as compound I -1. 1 H NMR (400MHz, CD 3 OD) δ7.95(d,J＝7.1Hz,3H),7.70(d,J＝1.4Hz,2H),7.54(d,J＝7.9Hz,1H),7.50– 7.46(m,3H),7.35(d,J＝8.8Hz,2H),7.14–7.07(m,1H),7.01(t,J＝7.5Hz,1H),4.82(s,2H),3.97(t ,J＝5.9Hz,2H),3.16(t,J＝5.9Hz,2H).LCMS(ESI)m/z[M+H] + :369.1.
实施例90 N-(1H-吲哚-3-基)-1-氧-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-90)
Example 90 N-(1H-indol-3-yl)-1-oxo-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-90)
N-(1H-吲哚-3-基)-1-氧-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-90)的制备方法同化合物I-41。1H NMR(400MHz,CD3OD)δ8.24(d,J＝8.2Hz,1H),7.75–7.69(m,3H),7.64(d,J＝4.1Hz,2H),7.58(d,J＝7.9Hz,1H),7.50(t,J＝7.5Hz,2H),7.43(d,J＝7.2Hz,1H),7.38(d,J＝8.1Hz,1H),7.17(t,J＝7.6Hz,1H),7.10(t,J＝7.3Hz,1H),4.30(t,J＝6.4Hz,2H),3.18(t,J＝6.4Hz,2H).LCMS(ESI)m/z[M+H]+:382.2.The preparation method of N-(1H-indol-3-yl)-1-oxo-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-90) is the same as compound I -41. 1 H NMR (400MHz, CD 3 OD) δ8.24(d,J＝8.2Hz,1H),7.75–7.69(m,3H),7.64(d,J＝4.1Hz,2H),7.58(d,J ＝7.9Hz,1H),7.50(t,J＝7.5Hz,2H),7.43(d,J＝7.2Hz,1H),7.38(d,J＝8.1Hz,1H),7.17(t,J＝7.6 Hz,1H),7.10(t,J＝7.3Hz,1H),4.30(t,J＝6.4Hz,2H),3.18(t,J＝6.4Hz,2H).LCMS(ESI)m/z[M +H] + :382.2.
实施例91 N-(1H-吲哚-3-基)-3-氧-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-91)
Example 91 N-(1H-indol-3-yl)-3-oxo-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-91)
步骤①：6-苯基-1,4-二氢异喹啉-3(2H)-酮(91-1)
Step ①: 6-phenyl-1,4-dihydroisoquinolin-3(2H)-one (91-1)
6-苯基-1,4-二氢异喹啉-3(2H)-酮(91-1)的制备方法同化合物10-1，LCMS(ESI)m/z[M+H]+:224.10.The preparation method of 6-phenyl-1,4-dihydroisoquinolin-3(2H)-one (91-1) is the same as compound 10-1, LCMS (ESI) m/z [M+H] + : 224.10 .
步骤②：N-(1H-吲哚-3-基)-3-氧-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-91)
Step ②: N-(1H-indol-3-yl)-3-oxo-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-91)
N-(1H-吲哚-3-基)-3-氧-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-91)的制备方法同化合物I-41。1H NMR(400MHz,DMSO-d6)δ11.37(s,1H),10.95(s,1H),7.69(dt,J＝6.0,1.3Hz,3H),7.62(d,J＝2.5Hz,1H),7.59(d,J＝1.7Hz,1H),7.56(d,J＝7.9Hz,1H),7.48(t,J＝7.7Hz,2H),7.43(d,J＝7.9Hz,1H),7.39(dd,J＝8.0,0.9Hz,2H),7.18–7.11(m,1H),7.05(ddd,J＝8.0,7.0,1.0Hz,1H),5.11(s,2H),4.03(s,2H).LCMS(ESI)m/z[M+H]+:382.2.The preparation method of N-(1H-indol-3-yl)-3-oxo-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-91) is the same as Compound I -41. 1 H NMR (400MHz, DMSO-d 6 ) δ11.37 (s, 1H), 10.95 (s, 1H), 7.69 (dt, J = 6.0, 1.3Hz, 3H), 7.62 (d, J = 2.5Hz, 1H),7.59(d,J＝1.7Hz,1H),7.56(d,J＝7.9Hz,1H),7.48(t,J＝7.7Hz,2H),7.43(d,J＝7.9Hz,1H) ,7.39(dd,J＝8.0,0.9Hz,2H),7.18–7.11(m,1H),7.05(ddd,J＝8.0,7.0,1.0Hz,1H),5.11(s,2H),4.03(s ,2H).LCMS(ESI)m/z[M+H] + :382.2.
实施例92 N-(1H-吲哚-3-基)-6-苯基异喹啉-2(1H)-甲酰胺(I-92)
Example 92 N-(1H-indol-3-yl)-6-phenylisoquinoline-2(1H)-carboxamide (I-92)
步骤①：6-苯基-1,2-二氢异喹啉(92-1)
Step ①: 6-phenyl-1,2-dihydroisoquinoline (92-1)
将100毫克6-苯基-1,2,3,4-四氢异喹啉、128毫克N-溴代丁二酰亚胺(NBS)、1.5毫升二氯甲烷和0.5毫升3N氢氧化钠溶液的混合物于室温下搅拌6过夜。反应液浓缩至干，残余物以二氯甲烷:甲醇＝20:1制备薄层，得6-苯基-1,2-二氢异喹啉(92-1)40毫克，收率41％。LCMS(ESI)m/z[M+H]+:208.1.Mix 100 mg of 6-phenyl-1,2,3,4-tetrahydroisoquinoline, 128 mg of N-bromosuccinimide (NBS), 1.5 ml of dichloromethane and 0.5 ml of 3N sodium hydroxide solution The mixture was stirred at room temperature for 6 overnight. The reaction solution was concentrated to dryness, and a thin layer of the residue was prepared with dichloromethane:methanol=20:1 to obtain 40 mg of 6-phenyl-1,2-dihydroisoquinoline (92-1), with a yield of 41%. LCMS(ESI)m/z[M+H] + :208.1.
步骤②：N-(1H-吲哚-3-基)-6-苯基异喹啉-2(1H)-甲酰胺(I-92)
Step ②: N-(1H-indol-3-yl)-6-phenylisoquinoline-2(1H)-carboxamide (I-92)
N-(1H-吲哚-3-基)-6-苯基异喹啉-2(1H)-甲酰胺(I-92)的制备方法同化合物I-41。 1H NMR(400MHz,CD3OD)δ7.91(s,1H),7.72–7.66(m,2H),7.65(s,1H),7.54(d,J＝8.6Hz,1H),7.47(t,J＝7.6Hz,2H),7.42(d,J＝8.1Hz,1H),7.38(d,J＝7.4Hz,1H),7.33(d,J＝8.1Hz,1H),7.27(d,J＝8.2Hz,1H),7.25(s,1H),7.20(d,J＝7.8Hz,1H),7.11(d,J＝7.9Hz,2H),7.03–6.94(m,1H),4.58(s,2H).LCMS(ESI)m/z[M+H]+:366.2.The preparation method of N-(1H-indol-3-yl)-6-phenylisoquinoline-2(1H)-carboxamide (I-92) is the same as compound I-41. 1 H NMR (400MHz, CD 3 OD) δ7.91 (s, 1H), 7.72–7.66 (m, 2H), 7.65 (s, 1H), 7.54 (d, J = 8.6Hz, 1H), 7.47 (t ,J＝7.6Hz,2H),7.42(d,J＝8.1Hz,1H),7.38(d,J＝7.4Hz,1H),7.33(d,J＝8.1Hz,1H),7.27(d,J ＝8.2Hz,1H),7.25(s,1H),7.20(d,J＝7.8Hz,1H),7.11(d,J＝7.9Hz,2H),7.03–6.94(m,1H),4.58(s ,2H).LCMS(ESI)m/z[M+H] + :366.2.
实施例93 N-(咪唑并[1,2-a]吡啶-3-基)-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-93)
Example 93 N-(imidazo[1,2-a]pyridin-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-93)
步骤①：咪唑并[1,2-a]吡啶-3-酰基叠氮(93-1)
Step ①: Imidazo[1,2-a]pyridine-3-acyl azide (93-1)
咪唑并[1,2-a]吡啶-3-酰基叠氮(93-1)的制备方法同化合物1-1。1H NMR(400MHz,DMSO-d6)δ9.30(dd,J＝7.0,1.2Hz,1H),8.38(s,1H),7.89(dd,J＝9.0,1.3Hz,1H),7.69(ddd,J＝8.9,7.2,1.3Hz,1H),7.35(t,J＝6.9Hz,1H).LCMS(ESI)m/z[M+H]+:188.0.The preparation method of imidazo[1,2-a]pyridine-3-acyl azide (93-1) is the same as that of compound 1-1. 1 H NMR (400MHz, DMSO-d 6 ) δ9.30 (dd, J＝7.0, 1.2Hz, 1H), 8.38 (s, 1H), 7.89 (dd, J＝9.0, 1.3Hz, 1H), 7.69 ( ddd,J＝8.9,7.2,1.3Hz,1H),7.35(t,J＝6.9Hz,1H).LCMS(ESI)m/z[M+H] + :188.0.
步骤②：N-(咪唑并[1,2-a]吡啶-3-基)-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-93)
Step ②: N-(imidazo[1,2-a]pyridin-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-93)
N-(咪唑并[1,2-a]吡啶-3-基)-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-93)的制备方法同化合物I-41。1H NMR(400MHz,DMSO-d6)δ8.80(s,1H),8.04(d,J＝6.8Hz,1H),7.67(d,J＝7.7Hz,2H),7.50(dt,J＝22.7,7.2Hz,6H),7.39(s,1H),7.31–7.19(m,3H),6.90(t,J＝6.7Hz,1H),4.73(s,2H),3.78(t,J＝5.9Hz,2H),2.98(t,J＝5.8Hz,2H).LCMS(ESI)m/z[M+H]+:369.3.The preparation method of N-(imidazo[1,2-a]pyridin-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-93) is the same as Compound 1-41. 1 H NMR (400MHz, DMSO-d 6 ) δ8.80 (s, 1H), 8.04 (d, J = 6.8Hz, 1H), 7.67 (d, J = 7.7Hz, 2H), 7.50 (dt, J = 22.7,7.2Hz,6H),7.39(s,1H),7.31–7.19(m,3H),6.90(t,J＝6.7Hz,1H),4.73(s,2H),3.78(t,J＝5.9 Hz,2H),2.98(t,J＝5.8Hz,2H).LCMS(ESI)m/z[M+H] + :369.3.
实施例94 N-(1H-吲哚-3-基)-6-(4-甲氧基苯基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-94)
Example 94 N-(1H-indol-3-yl)-6-(4-methoxyphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-94)
步骤①：6-(4-甲氧基苯基)-1,2,3,4-四氢异喹啉(94-1)
Step ①: 6-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (94-1)
将150毫克6-溴-1,2,3,4-四氢异喹啉、161毫克4-甲氧基苯硼酸、570毫克碳酸铯、55毫克PdCl2(dppf)、1毫升四氢呋喃和0.5毫升水的混合物在氩气保护下于75℃搅拌6小时。反应液浓缩至干，残余物以二氯甲烷:甲醇＝30:1柱层析，得6-(4-甲氧基苯基)-1,2,3,4-四氢异喹啉(94-1)黄色油状物90毫克，收率53％。LCMS(ESI)m/z[M+H]+:240.2.Combine 150 mg of 6-bromo-1,2,3,4-tetrahydroisoquinoline, 161 mg of 4-methoxyphenylboronic acid, 570 mg of cesium carbonate, 55 mg of PdCl 2 (dppf), 1 ml of tetrahydrofuran and 0.5 ml of The water mixture was stirred at 75°C for 6 hours under argon. The reaction solution was concentrated to dryness, and the residue was subjected to column chromatography with dichloromethane:methanol=30:1 to obtain 6-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (94 -1) 90 mg of yellow oil, yield 53%. LCMS(ESI)m/z[M+H] + :240.2.
步骤②：N-(1H-吲哚-3-基)-6-(4-甲氧基苯基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-94)
Step ②: N-(1H-indol-3-yl)-6-(4-methoxyphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-94)
N-(1H-吲哚-3-基)-6-(4-甲氧基苯基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-94)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.72(s,1H),8.27(s,1H),7.62(d,J＝6.5Hz,2H),7.60(d,J＝6.3Hz,1H),7.45(d,J＝4.0Hz,2H),7.37(d,J＝2.4Hz,1H),7.31(d,J＝8.2Hz,1H),7.24(d,J＝8.4Hz,1H),7.09–7.03(m,1H),7.01(d,J＝8.4Hz,2H),6.96(t,J＝7.4Hz,1H),4.69(s,2H),3.79(s,3H),3.77(t,J＝5.9Hz,2H),2.93(t,J＝6.0Hz,2H).LCMS(ESI)m/z[M+H]+:398.2.Preparation method of N-(1H-indol-3-yl)-6-(4-methoxyphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-94) Same as compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.72 (s, 1H), 8.27 (s, 1H), 7.62 (d, J = 6.5Hz, 2H), 7.60 (d, J = 6.3Hz, 1H) ,7.45(d,J＝4.0Hz,2H),7.37(d,J＝2.4Hz,1H),7.31(d,J＝8.2Hz,1H),7.24(d,J＝8.4Hz,1H),7.09 –7.03(m,1H),7.01(d,J＝8.4Hz,2H),6.96(t,J＝7.4Hz,1H),4.69(s,2H),3.79(s,3H),3.77(t, J＝5.9Hz,2H),2.93(t,J＝6.0Hz,2H).LCMS(ESI)m/z[M+H] + :398.2.
实施例95 N-(5-氯-6-氟-1H-吲哚-3-基)-6-(4-甲氧基苯基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-95)
Example 95 N-(5-chloro-6-fluoro-1H-indol-3-yl)-6-(4-methoxyphenyl)-3,4-dihydroisoquinoline-2(1H) -Formamide (I-95)
N-(5-氯-6-氟-1H-吲哚-3-基)-6-(4-甲氧基苯基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-95)的制备方法同化合物I-41。1H NMR(400MHz,DMSO-d6)δ10.97(s,1H),8.35(s,1H),7.86(d,J＝7.5Hz,1H),7.65–7.56(m,2H),7.50–7.39(m,3H),7.31(d,J＝10.2Hz,1H),7.24(d,J＝8.5Hz,1H),7.06–6.97(m,2H),4.69(s,2H),3.79(s,3H),3.76(t,J＝5.9Hz,2H),2.93(t,J＝5.8Hz,2H).LCMS(ESI)m/z[M+H]+:450.1.N-(5-chloro-6-fluoro-1H-indol-3-yl)-6-(4-methoxyphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide The preparation method of (I-95) is the same as that of compound I-41. 1 H NMR (400MHz, DMSO-d 6 ) δ10.97 (s, 1H), 8.35 (s, 1H), 7.86 (d, J = 7.5Hz, 1H), 7.65–7.56 (m, 2H), 7.50– 7.39(m,3H),7.31(d,J＝10.2Hz,1H),7.24(d,J＝8.5Hz,1H),7.06–6.97(m,2H),4.69(s,2H),3.79(s ,3H),3.76(t,J＝5.9Hz,2H),2.93(t,J＝5.8Hz,2H).LCMS(ESI)m/z[M+H] + :450.1.
实施例96 N-(5,6-二氟-1H-吲哚-3-基)-6-(4-甲氧基苯基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-96)
Example 96 N-(5,6-difluoro-1H-indol-3-yl)-6-(4-methoxyphenyl)-3,4-dihydroisoquinoline-2(1H)- Formamide (I-96)
N-(5,6-二氟-1H-吲哚-3-基)-6-(4-甲氧基苯基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-96)的制备方法同化合物I-41。1H NMR(400MHz,DMSO-d6)δ10.87(s,1H),8.28(s,1H),7.62–7.57(m,3H),7.45(d,J＝2.6Hz,3H),7.31(dd,J＝11.3,6.9Hz,1H),7.24(d,J＝8.5Hz,1H),7.04–6.99(m,2H),4.69(s,2H),3.79(s,3H),3.75(t,J＝5.9Hz,2H),2.93(t,J＝5.9Hz,2H).LCMS(ESI)m/z[M+H]+:434.2.N-(5,6-difluoro-1H-indol-3-yl)-6-(4-methoxyphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide ( The preparation method of I-96) is the same as that of compound I-41. 1 H NMR (400MHz, DMSO-d 6 ) δ10.87 (s, 1H), 8.28 (s, 1H), 7.62–7.57 (m, 3H), 7.45 (d, J = 2.6Hz, 3H), 7.31 ( dd,J＝11.3,6.9Hz,1H),7.24(d,J＝8.5Hz,1H),7.04–6.99(m,2H),4.69(s,2H),3.79(s,3H),3.75(t ,J＝5.9Hz,2H),2.93(t,J＝5.9Hz,2H).LCMS(ESI)m/z[M+H] + :434.2.
实施例97 N-(5-氯-1H-吲哚-3-基)-6-(4-甲氧基苯基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-97)
Example 97 N-(5-chloro-1H-indol-3-yl)-6-(4-methoxyphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide ( I-97)
N-(5-氯-1H-吲哚-3-基)-6-(4-甲氧基苯基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-97)的制备方法同化合物I-41。1H NMR(400MHz,DMSO-d6)δ10.92(s,1H),8.31(s,1H),7.72(d,J＝2.1Hz,1H),7.60(d,J＝8.6Hz,2H),7.50–7.42(m,3H),7.33(d,J＝8.6Hz,1H),7.24(d,J＝8.5Hz,1H),7.10–6.97(m,3H),4.70(s,2H),3.79(s,3H),3.79–3.73(m,2H),2.93(t,J＝5.8Hz,2H).LCMS(ESI)m/z[M+H]+:432.2.N-(5-chloro-1H-indol-3-yl)-6-(4-methoxyphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-97 ) is prepared by the same method as compound I-41. 1 H NMR (400MHz, DMSO-d 6 ) δ10.92 (s, 1H), 8.31 (s, 1H), 7.72 (d, J = 2.1Hz, 1H), 7.60 (d, J = 8.6Hz, 2H) ,7.50–7.42(m,3H),7.33(d,J＝8.6Hz,1H),7.24(d,J＝8.5Hz,1H),7.10–6.97(m,3H),4.70(s,2H), 3.79(s,3H),3.79–3.73(m,2H),2.93(t,J＝5.8Hz,2H).LCMS(ESI)m/z[M+H] + :432.2.
实施例98 N-(5-氟-1H-吲哚-3-基)-6-(4-甲氧基苯基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-98)
Example 98 N-(5-fluoro-1H-indol-3-yl)-6-(4-methoxyphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide ( I-98)
N-(5-氟-1H-吲哚-3-基)-6-(4-甲氧基苯基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-98)的制备方法同化合物I-41。1H NMR(400MHz,DMSO-d6)δ10.91(s,1H),8.35(s,1H),7.72(d,J＝2.3Hz,1H),7.58(d,J＝8.4Hz,2H),7.50–7.42(m,3H),7.33(d,J＝8.6Hz,1H),7.24(d,J＝8.5Hz,1H),7.13–6.99(m,3H),4.70(s,2H),3.79(s,3H),3.71(t,J＝5.7Hz,2H),2.93(t,J＝5.8Hz,2H).LCMS(ESI)m/z[M+H]+:416.2.N-(5-fluoro-1H-indol-3-yl)-6-(4-methoxyphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-98 ) is prepared by the same method as compound I-41. 1 H NMR (400MHz, DMSO-d 6 ) δ10.91 (s, 1H), 8.35 (s, 1H), 7.72 (d, J = 2.3Hz, 1H), 7.58 (d, J = 8.4Hz, 2H) ,7.50–7.42(m,3H),7.33(d,J＝8.6Hz,1H),7.24(d,J＝8.5Hz,1H),7.13–6.99(m,3H),4.70(s,2H), 3.79(s,3H),3.71(t,J＝5.7Hz,2H),2.93(t,J＝5.8Hz,2H).LCMS(ESI)m/z[M+H] + :416.2.
实施例99 N-(1H-吲哚-3-基)-6-(3-甲氧基苯基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-99)
Example 99 N-(1H-indol-3-yl)-6-(3-methoxyphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-99)
步骤①：6-(3-甲氧基苯基)-1,2,3,4-四氢异喹啉(99-1)
Step ①: 6-(3-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (99-1)
6-(3-甲氧基苯基)-1,2,3,4-四氢异喹啉(99-1)的制备方法同化合物94-1。LCMS(ESI)m/z[M+H]+:240.2.The preparation method of 6-(3-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (99-1) is the same as compound 94-1. LCMS(ESI)m/z[M+H] + :240.2.
步骤②：N-(1H-吲哚-3-基)-6-(3-甲氧基苯基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-99)
Step ②: N-(1H-indol-3-yl)-6-(3-methoxyphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-99)
N-(1H-吲哚-3-基)-6-(3-甲氧基苯基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-99)的制备方法同化合物I-1。1H NMR(400MHz,CD3OD)δ7.54(d,J＝7.6Hz,1H),7.46(s,2H),7.33(d,J＝9.2Hz,2H),7.27(d,J＝7.9Hz,2H),7.19(d,J＝8.0Hz,1H),7.15(s,1H),7.10(t,J＝7.3Hz,1H),7.01(t,J＝7.5Hz,1H),6.90(d,J＝8.2Hz,1H),4.78(s,2H),3.84(d,J＝7.5Hz,5H),3.03(s,2H).LCMS(ESI)m/z[M+H]+:398.2.Preparation method of N-(1H-indol-3-yl)-6-(3-methoxyphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-99) Same as compound I-1. 1 H NMR (400MHz, CD 3 OD) δ7.54 (d, J = 7.6 Hz, 1H), 7.46 (s, 2H), 7.33 (d, J = 9.2 Hz, 2H), 7.27 (d, J = 7.9 Hz,2H),7.19(d,J＝8.0Hz,1H),7.15(s,1H),7.10(t,J＝7.3Hz,1H),7.01(t,J＝7.5Hz,1H),6.90( d,J＝8.2Hz,1H),4.78(s,2H),3.84(d,J＝7.5Hz,5H),3.03(s,2H).LCMS(ESI)m/z[M+H] + : 398.2.
实施例100 N-(5-氯-6-氟-1H-吲哚-3-基)-6-(3-甲氧基苯基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-100)
Example 100 N-(5-chloro-6-fluoro-1H-indol-3-yl)-6-(3-methoxyphenyl)-3,4-dihydroisoquinoline-2(1H) -Formamide (I-100)
N-(5-氯-6-氟-1H-吲哚-3-基)-6-(3-甲氧基苯基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-100)的制备方法同化合物I-41。1H NMR(400MHz,DMSO-d6)δ11.03–10.90(m,1H),8.34(s,1H),7.86(d,J＝7.5Hz,1H),7.53–7.48(m,2H),7.47(d,J＝2.4Hz,1H),7.37(t,J＝7.9Hz,1H),7.31(d,J＝10.2Hz,1H),7.27(d,J＝8.6Hz,1H),7.22(dt,J＝7.9,1.1Hz,1H),7.18(t,J＝2.1Hz,1H),6.93(ddd,J＝8.2,2.6,0.9Hz,1H),4.71(s,2H),3.82(s,3H),3.77(t,J＝5.9Hz,2H),2.94(t,J＝5.9Hz,2H).LCMS(ESI)m/z[M+H]+:450.2.N-(5-chloro-6-fluoro-1H-indol-3-yl)-6-(3-methoxyphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide The preparation method of (I-100) is the same as that of compound I-41. 1 H NMR (400MHz, DMSO-d 6 ) δ11.03–10.90 (m, 1H), 8.34 (s, 1H), 7.86 (d, J = 7.5Hz, 1H), 7.53–7.48 (m, 2H), 7.47(d,J＝2.4Hz,1H),7.37(t,J＝7.9Hz,1H),7.31(d,J＝10.2Hz,1H),7.27(d,J＝8.6Hz,1H),7.22( dt,J＝7.9,1.1Hz,1H),7.18(t,J＝2.1Hz,1H),6.93(ddd,J＝8.2,2.6,0.9Hz,1H),4.71(s,2H),3.82(s ,3H),3.77(t,J＝5.9Hz,2H),2.94(t,J＝5.9Hz,2H).LCMS(ESI)m/z[M+H] + :450.2.
实施例101 N-(5,6-二氟-1H-吲哚-3-基)-6-(3-甲氧基苯基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-101)
Example 101 N-(5,6-difluoro-1H-indol-3-yl)-6-(3-methoxyphenyl)-3,4-dihydroisoquinoline-2(1H)- Formamide(I-101)
N-(5,6-二氟-1H-吲哚-3-基)-6-(3-甲氧基苯基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-101)的制备方法同化合物I-41。1H NMR(400MHz,DMSO-d6)δ11.82(s,1H),7.92(s,1H),7.91(s,1H),7.70(dd,J＝11.5,8.1Hz,1H),7.53–7.44(m,3H),7.36(t,J＝7.9Hz,1H),7.28(d,J＝7.9Hz,1H),7.22(d,J＝7.9Hz,1H),7.17(t,J＝2.1Hz,1H),6.92(dd,J＝8.2,2.5Hz,1H),4.87(s,2H),3.91(t,J＝5.9Hz,2H),3.82(s,3H),2.98(t,J＝5.9Hz,2H).LCMS(ESI)m/z[M+H]+:434.2.N-(5,6-difluoro-1H-indol-3-yl)-6-(3-methoxyphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide ( The preparation method of I-101) is the same as that of compound I-41. 1 H NMR (400MHz, DMSO-d 6 ) δ11.82 (s, 1H), 7.92 (s, 1H), 7.91 (s, 1H), 7.70 (dd, J = 11.5, 8.1Hz, 1H), 7.53– 7.44(m,3H),7.36(t,J＝7.9Hz,1H),7.28(d,J＝7.9Hz,1H),7.22(d,J＝7.9Hz,1H),7.17(t,J＝2.1 Hz,1H),6.92(dd,J＝8.2,2.5Hz,1H),4.87(s,2H),3.91(t,J＝5.9Hz,2H),3.82(s,3H),2.98(t,J ＝5.9Hz,2H).LCMS(ESI)m/z[M+H] + :434.2.
实施例102 N-(5-氯-1H-吲哚-3-基)-6-(3-甲氧基苯基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-102)
Example 102 N-(5-chloro-1H-indol-3-yl)-6-(3-methoxyphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide ( I-102)
N-(5-氯-1H-吲哚-3-基)-6-(3-甲氧基苯基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-102)的制备方法同化合物I-41。1H NMR(400MHz,DMSO-d6)δ10.92(s,1H),8.31(s,1H),7.72(d,J＝1.9Hz,1H),7.53–7.44(m,3H),7.40–7.31(m,2H),7.27(d,J＝8.2Hz,1H),7.22(d,J＝7.8Hz,1H),7.16(d,J＝14.4Hz,2H),7.05(d,J＝8.7Hz,1H),6.93(d,J＝8.1Hz,1H),4.71(s,2H),3.82(s,3H),3.77(t,J＝5.9Hz,2H),2.94(t,J＝5.8Hz,2H).LCMS(ESI)m/z[M+H]+:432.2.N-(5-chloro-1H-indol-3-yl)-6-(3-methoxyphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-102 ) is prepared by the same method as compound I-41. 1 H NMR (400MHz, DMSO-d 6 ) δ10.92 (s, 1H), 8.31 (s, 1H), 7.72 (d, J = 1.9Hz, 1H), 7.53–7.44 (m, 3H), 7.40– 7.31(m,2H),7.27(d,J＝8.2Hz,1H),7.22(d,J＝7.8Hz,1H),7.16(d,J＝14.4Hz,2H),7.05(d,J＝8.7 Hz,1H),6.93(d,J＝8.1Hz,1H),4.71(s,2H),3.82(s,3H),3.77(t,J＝5.9Hz,2H),2.94(t,J＝5.8 Hz,2H).LCMS(ESI)m/z[M+H] + :432.2.
实施例103 N-(5-氟-1H-吲哚-3-基)-6-(3-甲氧基苯基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-103)
Example 103 N-(5-fluoro-1H-indol-3-yl)-6-(3-methoxyphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide ( I-103)
N-(5-氟-1H-吲哚-3-基)-6-(3-甲氧基苯基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-103)的制备方法同化合物I-41。1H NMR(400MHz,DMSO-d6)δ10.92(s,1H),8.31(s,1H),7.72(d,J＝1.9Hz,1H),7.58(d,J＝8.4Hz,2H),7.50–7.42(m,3H),7.33(d,J＝8.6Hz,1H),7.24(d,J＝8.5Hz,1H),7.13–6.99(m,3H),4.71(s,2H),3.80(s,3H),3.77(t,J＝5.9Hz,2H),2.94(t,J＝5.8Hz,2H).LCMS(ESI)m/z[M+H]+:416.2.N-(5-fluoro-1H-indol-3-yl)-6-(3-methoxyphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-103 ) is prepared by the same method as compound I-41. 1 H NMR (400MHz, DMSO-d 6 ) δ10.92 (s, 1H), 8.31 (s, 1H), 7.72 (d, J = 1.9 Hz, 1H), 7.58 (d, J = 8.4 Hz, 2H) ,7.50–7.42(m,3H),7.33(d,J＝8.6Hz,1H),7.24(d,J＝8.5Hz,1H),7.13–6.99(m,3H),4.71(s,2H), 3.80(s,3H),3.77(t,J＝5.9Hz,2H),2.94(t,J＝5.8Hz,2H).LCMS(ESI)m/z[M+H] + :416.2.
实施例104 N-(1H-吲哚-3-基)-6-(2-甲氧基苯基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-104)
Example 104 N-(1H-indol-3-yl)-6-(2-methoxyphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-104)
步骤①：6-(2-甲氧基苯基)-1,2,3,4-四氢异喹啉(104-1)
Step ①: 6-(2-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (104-1)
6-(2-甲氧基苯基)-1,2,3,4-四氢异喹啉(104-1)的制备方法同化合物94-1。LCMS(ESI)m/z[M+H]+:240.2.The preparation method of 6-(2-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (104-1) is the same as compound 94-1. LCMS(ESI)m/z[M+H] + :240.2.
步骤②：N-(1H-吲哚-3-基)-6-(2-甲氧基苯基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-104)
Step ②: N-(1H-indol-3-yl)-6-(2-methoxyphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-104)
N-(1H-吲哚-3-基)-6-(2-甲氧基苯基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-104)的制备方法同化合物I-1。1H NMR(400MHz,CD3OD)δ7.97(s,1H),7.55(s,1H),7.31–7.35(m,4H),7.28(d,J＝1.5Hz,1H),7.21(s,1H),6.90–7.14(m,4H),4.76(s,2H),3.81(t,J＝5.2Hz,2H),3.79(s,3H),2.98(t,J＝5.2Hz,2H).LCMS(ESI)m/z[M+H]+:398.2.Preparation method of N-(1H-indol-3-yl)-6-(2-methoxyphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-104) Same as compound I-1. 1 H NMR (400MHz, CD 3 OD) δ7.97 (s, 1H), 7.55 (s, 1H), 7.31–7.35 (m, 4H), 7.28 (d, J = 1.5Hz, 1H), 7.21 (s ,1H),6.90–7.14(m,4H),4.76(s,2H),3.81(t,J＝5.2Hz,2H),3.79(s,3H),2.98(t,J＝5.2Hz,2H) .LCMS(ESI)m/z[M+H] + :398.2.
实施例105 N-(5-氯-1H-吲哚-3-基)-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-105)
Example 105 N-(5-chloro-1H-indol-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-105)
步骤①：5-氯-1H-吲哚-3-酰基叠氮(105-1)
Step ①: 5-chloro-1H-indole-3-acyl azide (105-1)
5-氯-1H-吲哚-3-酰基叠氮(105-1)的制备方法同化合物1-1。1H NMR(400MHz,DMSO-d6)δ12.41(s,1H),8.27(s,1H),8.01(s,1H),7.54(d,J＝8.6Hz,1H),7.28(dd,J＝8.7,1.8Hz,1H).The preparation method of 5-chloro-1H-indole-3-acyl azide (105-1) is the same as that of compound 1-1. 1 H NMR (400MHz, DMSO-d 6 ) δ12.41 (s, 1H), 8.27 (s, 1H), 8.01 (s, 1H), 7.54 (d, J = 8.6Hz, 1H), 7.28 (dd, J＝8.7,1.8Hz,1H).
步骤②：5-氯-3-异氰酸酯-1H-吲哚(105-2)
Step ②: 5-chloro-3-isocyanate-1H-indole (105-2)
5-氯-3-异氰酸酯-1H-吲哚(105-2)的制备方法同化合物1-2。1H NMR(400MHz,DMSO-d6)δ11.40(s,1H),7.54(d,J＝2.7Hz,2H),7.43(d,J＝8.7Hz,1H),7.18(d,J＝8.7Hz,1H).The preparation method of 5-chloro-3-isocyanate-1H-indole (105-2) is the same as that of compound 1-2. 1 H NMR (400MHz, DMSO-d 6 ) δ11.40 (s, 1H), 7.54 (d, J = 2.7Hz, 2H), 7.43 (d, J = 8.7Hz, 1H), 7.18 (d, J = 8.7Hz,1H).
步骤③：N-(5-氯-1H-吲哚-3-基)-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-105)
Step ③: N-(5-chloro-1H-indol-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-105)
N-(5-氯-1H-吲哚-3-基)-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-105)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.91(s,1H),8.31(s,1H),7.65–7.72(m,3H),7.52–7.43(m,5H),7.38–7.27(m,3H),7.05(dd,J＝8.6,2.0Hz,1H),4.71(s,2H),3.77(t,J＝5.9Hz,2H),2.96(d,J＝5.7Hz,2H).LCMS(ESI)m/z[M+H]+:402.1.The preparation method of N-(5-chloro-1H-indol-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-105) is the same as compound I -1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.91(s,1H),8.31(s,1H),7.65–7.72(m,3H),7.52–7.43(m,5H),7.38–7.27(m ,3H),7.05(dd,J＝8.6,2.0Hz,1H),4.71(s,2H),3.77(t,J＝5.9Hz,2H),2.96(d,J＝5.7Hz,2H).LCMS (ESI)m/z[M+H] + :402.1.
实施例106 N-(5-溴-1H-吲哚-3-基)-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-106)
Example 106 N-(5-bromo-1H-indol-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-106)
步骤①：5-溴-1H-吲哚-3-酰基叠氮(106-1)
Step ①: 5-bromo-1H-indole-3-acyl azide (106-1)
5-溴-1H-吲哚-3-酰基叠氮(106-1)的制备方法同化合物1-1。LCMS(ESI)m/z[M+H]+:264.8.The preparation method of 5-bromo-1H-indole-3-acyl azide (106-1) is the same as that of compound 1-1. LCMS(ESI)m/z[M+H] + :264.8.
步骤②：N-(5-溴-1H-吲哚-3-基)-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-106)
Step ②: N-(5-bromo-1H-indol-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-106)
N-(5-溴-1H-吲哚-3-基)-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-106)的制备方法同化合物I-41。1H NMR(400MHz,DMSO-d6)δ10.94(s,1H),8.34(s,1H),7.89(d,J＝2.0Hz,1H),7.67(d,J＝7.6Hz,2H),7.54–7.45(m,5H),7.37(t,J＝7.4Hz,1H),7.30(d,J＝8.4Hz,2H),7.18(dd,J＝8.6,1.9Hz,1H),4.73(s,2H),3.79(t,J＝5.9Hz,2H), 2.96(t,J＝5.9Hz,2H).LCMS(ESI)m/z[M+H]+:445.9.The preparation method of N-(5-bromo-1H-indol-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-106) is the same as compound I -41. 1 H NMR (400MHz, DMSO-d 6 ) δ10.94 (s, 1H), 8.34 (s, 1H), 7.89 (d, J = 2.0Hz, 1H), 7.67 (d, J = 7.6Hz, 2H) ,7.54–7.45(m,5H),7.37(t,J＝7.4Hz,1H),7.30(d,J＝8.4Hz,2H),7.18(dd,J＝8.6,1.9Hz,1H),4.73( s,2H),3.79(t,J＝5.9Hz,2H), 2.96(t,J＝5.9Hz,2H).LCMS(ESI)m/z[M+H] + :445.9.
实施例107 N-(5-硝基-1H-吲哚-3-基)-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-107)
Example 107 N-(5-nitro-1H-indol-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-107)
步骤①：5-硝基-1H-吲哚-3-酰基叠氮(107-1)
Step ①: 5-nitro-1H-indole-3-acyl azide (107-1)
5-硝基-1H-吲哚-3-酰基叠氮(107-1)的制备同化合物41-3。1H NMR(400MHz,DMSO-d6)δ12.83(s,1H),8.91(d,J＝2.3Hz,1H),8.49(s,1H),8.17(d,J＝2.4Hz,1H),7.73(d,J＝9.0Hz,1H).The preparation of 5-nitro-1H-indole-3-acyl azide (107-1) is the same as compound 41-3. 1 H NMR (400MHz, DMSO-d 6 ) δ12.83 (s, 1H), 8.91 (d, J = 2.3Hz, 1H), 8.49 (s, 1H), 8.17 (d, J = 2.4Hz, 1H) ,7.73(d,J=9.0Hz,1H).
步骤②：3-异氰酸酯-5-硝基吲哚(107-2)
Step ②: 3-isocyanate-5-nitroindole (107-2)
3-异氰酸酯-5-硝基吲哚(107-2)的制备同化合物41-4。LCMS(ESI)m/z[M+H]+:204.0[M-H]-:202.0.The preparation of 3-isocyanate-5-nitroindole (107-2) is the same as compound 41-4. LCMS(ESI)m/z[M+H] + :204.0[MH] - :202.0.
步骤③：N-(5-硝基-1H-吲哚-3-基)-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-107)
Step ③: N-(5-nitro-1H-indol-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-107)
化合物N-(5-硝基-1H-吲哚-3-基)-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-107)的制备同化合物I-1。1H NMR(400MHz,Acetone-d6)δ10.62(s,1H),8.78(d,J＝2.3Hz,1H),8.18(s,1H),8.01(dd,J＝9.0,2.3Hz,1H),7.87(d,J＝2.1Hz,1H),7.66(d,J＝7.6Hz,2H),7.55–7.48(m,3H),7.45(t,J＝7.6Hz,2H),7.38–7.33(m,1H),7.31(d,J＝8.0Hz,1H),4.85(s,2H),3.91(t,J＝5.9Hz,2H),3.03(t,J＝5.9Hz,2H).LCMS(ESI)m/z[M+H]+:413.2.Preparation of compound N-(5-nitro-1H-indol-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-107) is the same compound I-1. 1 H NMR (400MHz, Acetone-d 6 ) δ10.62 (s, 1H), 8.78 (d, J = 2.3Hz, 1H), 8.18 (s, 1H), 8.01 (dd, J = 9.0, 2.3Hz, 1H),7.87(d,J＝2.1Hz,1H),7.66(d,J＝7.6Hz,2H),7.55–7.48(m,3H),7.45(t,J＝7.6Hz,2H),7.38– 7.33(m,1H),7.31(d,J＝8.0Hz,1H),4.85(s,2H),3.91(t,J＝5.9Hz,2H),3.03(t,J＝5.9Hz,2H). LCMS(ESI)m/z[M+H] + :413.2.
实施例108 N-(5-氯-6-氟-1H-吲哚-3-基)-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-108)
Example 108 N-(5-chloro-6-fluoro-1H-indol-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-108 )
N-(5-氯-6-氟-1H-吲哚-3-基)-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-108)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.95(s,1H),8.35(s,1H),7.86(d,J＝7.5Hz,1H),7.66(d,J＝7.5Hz,2H),7.47(dd,J＝16.2,9.9Hz,5H),7.38–7.26(m,3H),4.71(s,2H),3.77(s,2H),2.95(s,2H).LCMS(ESI)m/z[M+H]+:420.1.Preparation of N-(5-chloro-6-fluoro-1H-indol-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-108) The method is the same as that of compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.95 (s, 1H), 8.35 (s, 1H), 7.86 (d, J = 7.5Hz, 1H), 7.66 (d, J = 7.5Hz, 2H) ,7.47(dd,J＝16.2,9.9Hz,5H),7.38–7.26(m,3H),4.71(s,2H),3.77(s,2H),2.95(s,2H).LCMS(ESI)m /z[M+H] + :420.1.
实施例109 N-(5-甲基-1H-吲哚-3-基)-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-109)
Example 109 N-(5-methyl-1H-indol-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-109)
步骤①：5-甲基-1H-吲哚-3-酰基叠氮(109-1)
Step ①: 5-methyl-1H-indole-3-acyl azide (109-1)
5-甲基-1H-吲哚-3-酰基叠氮(109-1)的制备方法同化合物1-1。LCMS(ESI)m/z[M+H]+:201.1.The preparation method of 5-methyl-1H-indole-3-acyl azide (109-1) is the same as that of compound 1-1. LCMS(ESI)m/z[M+H] + :201.1.
步骤②：N-(5-甲基-1H-吲哚-3-基)-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-109)
Step ②: N-(5-methyl-1H-indol-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-109)
N-(5-甲基-1H-吲哚-3-基)-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-109)的制备方法同化合物I-41。1H NMR(400MHz,DMSO-d6)δ10.56(s,1H),8.19(s,1H),7.66(d,J＝7.2Hz,2H),7.52–7.26(m,9H),7.19(d,J＝8.3Hz,1H),6.89(d,J＝7.7Hz,1H),4.71(s,2H),3.77(t,J＝5.9Hz,2H),2.95(t,J＝5.9Hz,2H),2.37(s,3H).LCMS(ESI)m/z[M+H]+:382.3.The preparation method of N-(5-methyl-1H-indol-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-109) is the same as that of the compound I-41. 1 H NMR (400MHz, DMSO-d 6 ) δ10.56 (s, 1H), 8.19 (s, 1H), 7.66 (d, J = 7.2Hz, 2H), 7.52–7.26 (m, 9H), 7.19 ( d,J＝8.3Hz,1H),6.89(d,J＝7.7Hz,1H),4.71(s,2H),3.77(t,J＝5.9Hz,2H),2.95(t,J＝5.9Hz, 2H),2.37(s,3H).LCMS(ESI)m/z[M+H] + :382.3.
实施例110 N-(1H-吲哚-3-基)-6-(3-甲砜基苯基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-110)
Example 110 N-(1H-indol-3-yl)-6-(3-methylsulfonylphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-110)
步骤①：4,4,5,5-四甲基-2-(3-(甲基磺酰基)苯基)-1,3,2-二氧杂硼烷(110-1)
Step ①: 4,4,5,5-tetramethyl-2-(3-(methylsulfonyl)phenyl)-1,3,2-dioxaborane (110-1)
将200毫克3-溴苯基甲基砜、432毫克联硼酸频那醇酯、167毫克醋酸钾、61毫克1,1'-双二苯基膦二茂铁二氯化钯和2毫升1,4-二氧六环的混合物于氩气氛下100℃搅拌2小时。反应液过滤，滤液浓缩至干，残余物以石油醚：乙酸乙酯＝1：1制备薄层，得白色固体4,4,5,5-四甲基-2-(3-(甲基磺酰基)苯基)-1,3,2-二氧杂硼烷(110-1)197毫克，收率82％。1H NMR(400MHz,CDCl3)δ8.33(s,1H),8.01(dt,J＝7.3,1.2Hz,1H),7.98(ddd,J＝7.9,2.1,1.3Hz,1H),7.52(t,J＝7.6Hz,1H),3.01(s,3H),1.31(s,12H).200 mg of 3-bromophenyl methyl sulfone, 432 mg of pinacol diborate, 167 mg of potassium acetate, 61 mg of 1,1'-bisdiphenylphosphine ferrocene palladium dichloride and 2 ml of 1, The mixture of 4-dioxane was stirred at 100°C for 2 hours under an argon atmosphere. The reaction solution was filtered, and the filtrate was concentrated to dryness. The residue was prepared as a thin layer with petroleum ether: ethyl acetate = 1:1 to obtain a white solid 4,4,5,5-tetramethyl-2-(3-(methylsulfonate). Acyl)phenyl)-1,3,2-dioxaborane (110-1) 197 mg, yield 82%. 1 H NMR (400MHz, CDCl 3 ) δ8.33 (s, 1H), 8.01 (dt, J＝7.3, 1.2Hz, 1H), 7.98 (ddd, J＝7.9, 2.1, 1.3Hz, 1H), 7.52 ( t,J＝7.6Hz,1H),3.01(s,3H),1.31(s,12H).
步骤②：6-(3-(甲基磺酰基)苯基)-3,4-二氢异喹啉-2(1H)-Boc(110-2)
Step ②: 6-(3-(methylsulfonyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-Boc(110-2)
6-(3-(甲基磺酰基)苯基)-3,4-二氢异喹啉-2(1H)-Boc(110-2)的制备方法同化合物10-1。1H NMR(400MHz,CD3OD)δ8.10(s,1H),7.91–7.84(m,2H),7.64(t,J＝7.8Hz,1H),7.44(d,J＝9.1Hz,2H),7.19(d,J＝7.9Hz,1H),4.55(s,2H),3.61(t,J＝6.0Hz,2H),3.13(s,3H),2.85(t,J＝5.9Hz,2H),1.46(s,9H).The preparation method of 6-(3-(methylsulfonyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-Boc(110-2) is the same as compound 10-1. 1 H NMR (400MHz, CD 3 OD) δ8.10 (s, 1H), 7.91–7.84 (m, 2H), 7.64 (t, J = 7.8Hz, 1H), 7.44 (d, J = 9.1Hz, 2H ),7.19(d,J＝7.9Hz,1H),4.55(s,2H),3.61(t,J＝6.0Hz,2H),3.13(s,3H),2.85(t,J＝5.9Hz,2H ),1.46(s,9H).
步骤③：6-(3-(甲基磺酰基)苯基)-1,2,4-四氢异喹啉(110-3)
Step ③: 6-(3-(methylsulfonyl)phenyl)-1,2,4-tetrahydroisoquinoline (110-3)
6-(3-(甲基磺酰基)苯基)-1,2,4-四氢异喹啉(110-3)的制备方法同化合物10-2。LCMS(ESI)m/z[M+H]+:288.1.The preparation method of 6-(3-(methylsulfonyl)phenyl)-1,2,4-tetrahydroisoquinoline (110-3) is the same as compound 10-2. LCMS(ESI)m/z[M+H] + :288.1.
步骤④：N-(1H-吲哚-3-基)-6-(3-甲砜基苯基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-110)
Step ④: N-(1H-indol-3-yl)-6-(3-methylsulfonylphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-110)
N-(1H-吲哚-3-基)-6-(3-甲砜基苯基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-110)的制备方法同化合物I-41。1H NMR(400MHz,DMSO-d6)δ10.71(s,1H),8.29(s,1H),8.16(d,J＝1.9Hz,1H),8.04(d,J＝7.9Hz,1H),7.90(d,J＝8.0Hz,1H),7.74(t,J＝7.8Hz,1H),7.61(d,J＝7.7Hz,3H),7.37(d,J＝2.5Hz,1H),7.32(dd,J＝11.6,7.9Hz,2H), 7.06(t,J＝7.1Hz,1H),6.95(t,J＝7.4Hz,1H),4.73(s,2H),3.78(t,J＝5.9Hz,2H),3.30(s,3H),2.97(t,J＝5.8Hz,2H).LCMS(ESI)m/z[M+H]+:446.3.Preparation method of N-(1H-indol-3-yl)-6-(3-methylsulfonylphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-110) Same as compound I-41. 1 H NMR (400MHz, DMSO-d 6 ) δ10.71 (s, 1H), 8.29 (s, 1H), 8.16 (d, J = 1.9 Hz, 1H), 8.04 (d, J = 7.9 Hz, 1H) ,7.90(d,J＝8.0Hz,1H),7.74(t,J＝7.8Hz,1H),7.61(d,J＝7.7Hz,3H),7.37(d,J＝2.5Hz,1H),7.32 (dd,J＝11.6,7.9Hz,2H), 7.06(t,J＝7.1Hz,1H),6.95(t,J＝7.4Hz,1H),4.73(s,2H),3.78(t,J＝5.9Hz,2H),3.30(s,3H), 2.97(t,J＝5.8Hz,2H).LCMS(ESI)m/z[M+H] + :446.3.
实施例111 N-(1H-吲哚-3-基)-6-(4-甲砜基苯基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-111)
Example 111 N-(1H-indol-3-yl)-6-(4-methylsulfonylphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-111)
步骤①：4,4,5,5-四甲基-2-(4-(甲基磺酰基)苯基)-1,3,2-二氧杂硼烷(111-1)
Step ①: 4,4,5,5-tetramethyl-2-(4-(methylsulfonyl)phenyl)-1,3,2-dioxaborane (111-1)
4,4,5,5-四甲基-2-(4-(甲基磺酰基)苯基)-1,3,2-二氧杂硼烷(111-1)的制备方法同化合物110-1。1H NMR(400MHz,CDCl3)δ7.92(d,J＝7.7Hz,2H),7.86(d,J＝7.8Hz,2H),2.97(s,3H),1.29(s,12H).The preparation method of 4,4,5,5-tetramethyl-2-(4-(methylsulfonyl)phenyl)-1,3,2-dioxaborane (111-1) is the same as compound 110- 1. 1 H NMR (400MHz, CDCl 3 ) δ7.92 (d, J = 7.7 Hz, 2H), 7.86 (d, J = 7.8 Hz, 2H), 2.97 (s, 3H), 1.29 (s, 12H).
步骤②：6-(4-(甲基磺酰基)苯基)-3,4-二氢异喹啉-2(1H)-Boc(111-2)
Step ②: 6-(4-(methylsulfonyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-Boc(111-2)
6-(4-(甲基磺酰基)苯基)-3,4-二氢异喹啉-2(1H)-Boc(111-2)的制备方法同化合物10-1。1H NMR(400MHz,DMSO-d6)δ8.00–7.91(m,4H),7.57(s,2H),7.32(d,J＝8.1Hz,1H),4.55(s,2H),3.64–3.56(m,2H),3.25(s,3H),2.87(t,J＝4.9Hz,2H),1.44(s,9H).The preparation method of 6-(4-(methylsulfonyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-Boc(111-2) is the same as compound 10-1. 1 H NMR (400MHz, DMSO-d 6 ) δ8.00–7.91 (m, 4H), 7.57 (s, 2H), 7.32 (d, J = 8.1Hz, 1H), 4.55 (s, 2H), 3.64– 3.56(m,2H),3.25(s,3H),2.87(t,J＝4.9Hz,2H),1.44(s,9H).
步骤③：6-(4-(甲基磺酰基)苯基)-1,2,4-四氢异喹啉(111-3)
Step ③: 6-(4-(methylsulfonyl)phenyl)-1,2,4-tetrahydroisoquinoline (111-3)
6-(4-(甲基磺酰基)苯基)-1,2,4-四氢异喹啉(111-3)的制备方法同化合物10-2。LCMS(ESI)m/z[M+H]+:288.1.The preparation method of 6-(4-(methylsulfonyl)phenyl)-1,2,4-tetrahydroisoquinoline (111-3) is the same as compound 10-2. LCMS(ESI)m/z[M+H] + :288.1.
步骤④：N-(1H-吲哚-3-基)-6-(4-甲砜基苯基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-111)
Step ④: N-(1H-indol-3-yl)-6-(4-methylsulfonylphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-111)
N-(1H-吲哚-3-基)-6-(4-甲砜基苯基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-111)的制备方法同化合物I-41。1H NMR(400MHz,DMSO-d6)δ10.72(s,1H),8.30(s,1H),8.02–7.93(m,4H),7.64–7.58(m,3H),7.37(d,J＝2.4Hz,1H),7.32(dd,J＝10.9,8.0Hz,2H),7.06(t,J＝7.5Hz,1H),6.96(t,J＝7.5Hz,1H),4.74(s,2H),3.78(t,J＝5.9Hz,2H),3.26(s,3H),2.97(t,J＝5.8Hz,2H).LCMS(ESI)m/z[M+H]+:446.1.Preparation method of N-(1H-indol-3-yl)-6-(4-methylsulfonylphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-111) Same as compound I-41. 1 H NMR (400MHz, DMSO-d 6 ) δ10.72(s,1H),8.30(s,1H),8.02–7.93(m,4H),7.64–7.58(m,3H),7.37(d,J ＝2.4Hz,1H),7.32(dd,J＝10.9,8.0Hz,2H),7.06(t,J＝7.5Hz,1H),6.96(t,J＝7.5Hz,1H),4.74(s,2H ),3.78(t,J＝5.9Hz,2H),3.26(s,3H),2.97(t,J＝5.8Hz,2H).LCMS(ESI)m/z[M+H] + :446.1.
实施例112 N-(1H-吲哚-3-基)-6-(1-甲基-1H-吡咯-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-112)
Example 112 N-(1H-indol-3-yl)-6-(1-methyl-1H-pyrrol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-112)
步骤①：6-(1-甲基-1H-吡咯-3-基)-3,4-二氢异喹啉-2(1H)-Boc(112-1)
Step ①: 6-(1-methyl-1H-pyrrol-3-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(112-1)
6-(1-甲基-1H-吡咯-3-基)-3,4-二氢异喹啉-2(1H)-Boc(112-1)的制备方法同化合物10-1。1H NMR(400MHz,CD3OD)δ7.33–7.25(m,2H),7.04–6.96(m,2H),6.63(t,J＝2.5Hz,1H),6.36–6.33(m,1H),4.50(s,2H),3.63(d,J＝6.9Hz,2H),2.81(t,J＝6.0Hz,2H),1.50(s,9H).The preparation method of 6-(1-methyl-1H-pyrrol-3-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(112-1) is the same as compound 10-1. 1 H NMR (400MHz, CD 3 OD) δ7.33–7.25(m,2H),7.04–6.96(m,2H),6.63(t,J＝2.5Hz,1H),6.36–6.33(m,1H) ,4.50(s,2H),3.63(d,J＝6.9Hz,2H),2.81(t,J＝6.0Hz,2H),1.50(s,9H).
步骤②：6-(1-甲基-1H-吡咯-3-基)-1,2,3,4-四氢异喹啉(112-2)
Step ②: 6-(1-methyl-1H-pyrrol-3-yl)-1,2,3,4-tetrahydroisoquinoline (112-2)
6-(1-甲基-1H-吡咯-3-基)-1,2,3,4-四氢异喹啉(112-2)的制备方法同化合物10-2。LCMS(ESI)m/z[M+H]+:213.0.The preparation method of 6-(1-methyl-1H-pyrrol-3-yl)-1,2,3,4-tetrahydroisoquinoline (112-2) is the same as compound 10-2. LCMS(ESI)m/z[M+H] + :213.0.
步骤③：N-(1H-吲哚-3-基)-6-(1-甲基-1H-吡咯-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-112)
Step ③: N-(1H-indol-3-yl)-6-(1-methyl-1H-pyrrol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-112)
N-(1H-吲哚-3-基)-6-(1-甲基-1H-吡咯-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-112)的制备方法同化合物I-41。1H NMR(400MHz,DMSO-d6)δ10.70(s,1H),8.22(s,1H),7.62(d,J＝8.0Hz,1H),7.36(d,J＝2.4Hz,1H),7.34–7.29(m,3H),7.15(s,1H),7.07(dd,J＝16.9,8.2Hz,2H),6.96(t,J＝7.5Hz,1H),6.73(s,1H),6.38(s,1H),4.64(s,2H),3.74(t,J＝5.7Hz,2H),3.63(s,3H),2.87(d,J＝5.8Hz,2H).LCMS(ESI)m/z[M+H]+:369.1.N-(1H-indol-3-yl)-6-(1-methyl-1H-pyrrol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I- The preparation method of 112) is the same as that of compound I-41. 1 H NMR (400MHz, DMSO-d 6 ) δ10.70 (s, 1H), 8.22 (s, 1H), 7.62 (d, J = 8.0Hz, 1H), 7.36 (d, J = 2.4Hz, 1H) ,7.34–7.29(m,3H),7.15(s,1H),7.07(dd,J＝16.9,8.2Hz,2H),6.96(t,J＝7.5Hz,1H),6.73(s,1H), 6.38(s,1H),4.64(s,2H),3.74(t,J＝5.7Hz,2H),3.63(s,3H),2.87(d,J＝5.8Hz,2H).LCMS(ESI)m /z[M+H] + :369.1.
实施例113 N-(1H-吲哚-3-基)-6-(吡啶-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-113)
Example 113 N-(1H-indol-3-yl)-6-(pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-113)
步骤①：6-(吡啶-3-基)-3,4-二氢异喹啉-2(1H)-Boc(113-1)
Step ①: 6-(pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(113-1)
化合物6-(吡啶-3-基)-3,4-二氢异喹啉-2(1H)-Boc(113-1)的制备同化合物10-1。1H NMR(400MHz,CD3OD)δ8.81(s,1H),8.52(d,J＝5.0Hz,1H),8.11(dt,J＝8.2,1.9Hz,1H),7.56–7.46(m,3H),7.30(d,J＝7.8Hz,1H),4.64(s,2H),3.70(t,J＝6.1Hz,2H),2.95(t,J＝5.9Hz,2H),1.53(s,9H).The preparation of compound 6-(pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(113-1) is the same as compound 10-1. 1 H NMR (400MHz, CD 3 OD) δ8.81(s,1H),8.52(d,J＝5.0Hz,1H),8.11(dt,J＝8.2,1.9Hz,1H),7.56–7.46(m ,3H),7.30(d,J＝7.8Hz,1H),4.64(s,2H),3.70(t,J＝6.1Hz,2H),2.95(t,J＝5.9Hz,2H),1.53(s ,9H).
步骤②：6-(吡啶-3-基)-1,2,3,4-四氢异喹啉(113-2)
Step ②: 6-(pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline (113-2)
6-(吡啶-3-基)-1,2,3,4-四氢异喹啉(113-2)的制备同化合物10-2。1H NMR(400MHz,CD3OD)δ8.77(dd,J＝2.4,0.9Hz,1H),8.49(dd,J＝4.8,1.6Hz,1H),8.07(ddd,J＝8.0,2.4,1.6Hz,1H),7.50(ddd,J＝8.0,4.9,0.9Hz,1H),7.45–7.40(m,2H),7.19(d,J＝7.7Hz,1H),4.02(s,2H),3.13(t,J＝6.0Hz,2H),2.94(t,J＝6.0Hz,2H).The preparation of 6-(pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline (113-2) is the same as compound 10-2. 1 H NMR (400MHz, CD 3 OD) δ8.77 (dd, J＝2.4, 0.9Hz, 1H), 8.49 (dd, J＝4.8, 1.6Hz, 1H), 8.07 (ddd, J＝8.0, 2.4, 1.6Hz,1H),7.50(ddd,J＝8.0,4.9,0.9Hz,1H),7.45–7.40(m,2H),7.19(d,J＝7.7Hz,1H),4.02(s,2H), 3.13(t,J＝6.0Hz,2H),2.94(t,J＝6.0Hz,2H).
步骤③：6-(吡啶-3-基)-3,4-二氢异喹啉-2(1H)-羧酸叔丁酯(I-113)
Step ③: 6-(pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester (I-113)
6-(吡啶-3-基)-3,4-二氢异喹啉-2(1H)-羧酸叔丁酯(I-113)的制备同化合物I-41。1H NMR(400MHz,DMSO-d6)δ10.71(s,1H),8.90(d,J＝2.4Hz,1H),8.57(dd,J＝4.9,1.6 Hz,1H),8.28(s,1H),8.08(dt,J＝8.0,2.0Hz,1H),7.66–7.56(m,3H),7.49(dd,J＝8.0,4.8Hz,1H),7.38(d,J＝2.4Hz,1H),7.34–7.29(m,2H),7.07(t,J＝7.6Hz,1H),6.96(t,J＝7.4Hz,1H),4.74(s,2H),3.79(t,J＝5.8Hz,2H),2.97(t,J＝5.8Hz,2H).LCMS(ESI)m/z[M+H]+:369.2.The preparation of tert-butyl 6-(pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (I-113) is the same as compound I-41. 1 H NMR (400MHz, DMSO-d 6 ) δ10.71 (s, 1H), 8.90 (d, J = 2.4Hz, 1H), 8.57 (dd, J = 4.9, 1.6 Hz,1H),8.28(s,1H),8.08(dt,J＝8.0,2.0Hz,1H),7.66–7.56(m,3H),7.49(dd,J＝8.0,4.8Hz,1H),7.38 (d,J＝2.4Hz,1H),7.34–7.29(m,2H),7.07(t,J＝7.6Hz,1H),6.96(t,J＝7.4Hz,1H),4.74(s,2H) ,3.79(t,J＝5.8Hz,2H),2.97(t,J＝5.8Hz,2H).LCMS(ESI)m/z[M+H] + :369.2.
实施例114 N-(1H-吲哚-3-基)-6-(吡啶-4-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-114)
Example 114 N-(1H-indol-3-yl)-6-(pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-114)
步骤①：6-(吡啶-4-基)-3,4-二氢异喹啉-2(1H)-Boc(114-1)
Step ①: 6-(pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(114-1)
6-(吡啶-4-基)-3,4-二氢异喹啉-2(1H)-羧酸叔丁酯(114-1)的制备方法同化合物10-1。1H NMR(400MHz,CD3OD)δ8.59–8.55(m,2H),7.74–7.70(m,2H),7.60(d,J＝7.6Hz,2H),7.29(d,J＝7.9Hz,1H),4.62(s,2H),3.68(t,J＝5.8Hz,2H),2.94(t,J＝5.9Hz,2H),1.51(s,9H).LCMS(ESI)m/z[M+H]+:311.1.The preparation method of 6-(pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester (114-1) is the same as compound 10-1. 1 H NMR (400MHz, CD 3 OD) δ8.59–8.55(m,2H),7.74–7.70(m,2H),7.60(d,J＝7.6Hz,2H),7.29(d,J＝7.9Hz ,1H),4.62(s,2H),3.68(t,J＝5.8Hz,2H),2.94(t,J＝5.9Hz,2H),1.51(s,9H).LCMS(ESI)m/z[ M+H] + :311.1.
步骤②：6-(吡啶-4-基)-1,2,4-四氢异喹啉(114-2)
Step ②: 6-(pyridin-4-yl)-1,2,4-tetrahydroisoquinoline (114-2)
6-(吡啶-4-基)-1,2,4-四氢异喹啉(114-2)的制备方法同化合物10-2。LCMS(ESI)m/z[M+H]+:211.1.The preparation method of 6-(pyridin-4-yl)-1,2,4-tetrahydroisoquinoline (114-2) is the same as compound 10-2. LCMS(ESI)m/z[M+H] + :211.1.
步骤③：N-(1H-吲哚-3-基)-6-(吡啶-4-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-114)
Step ③: N-(1H-indol-3-yl)-6-(pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-114)
N-(1H-吲哚-3-基)-6-(吡啶-4-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-114)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.72(s,1H),8.65–8.60(m,2H),8.29(s,1H),7.74–7.70(m,2H),7.68–7.59(m,3H),7.38–7.29(m,3H),7.09–7.03(m,1H),6.99–6.92(m,1H),4.73(s,2H),3.78(t,J＝5.9Hz,2H),2.97(t,J＝5.7Hz,2H).LCMS (ESI)m/z[M+H]+:369.2.The preparation method of N-(1H-indol-3-yl)-6-(pyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-114) is the same as that of the compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.72(s,1H),8.65–8.60(m,2H),8.29(s,1H),7.74–7.70(m,2H),7.68–7.59(m ,3H),7.38–7.29(m,3H),7.09–7.03(m,1H),6.99–6.92(m,1H),4.73(s,2H),3.78(t,J＝5.9Hz,2H), 2.97(t,J＝5.7Hz,2H).LCMS (ESI)m/z[M+H] + :369.2.
实施例115 N-(1H-吲哚-3-基)-6-(吡啶-2-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-115)
Example 115 N-(1H-indol-3-yl)-6-(pyridin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-115)
步骤①：6-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-3,4-二氢异喹啉-2(1H)-Boc(115-1)
Step ①: 6-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-3,4-dihydroisoquinoline-2(1H)- Boc(115-1)
6-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-3,4-二氢异喹啉-2(1H)-Boc(115-1)的制备方法同化合物110-1。1H NMR(400MHz,CD3OD)δ7.54(d,J＝6.9Hz,2H),7.12(d,J＝7.6Hz,1H),4.57(s,2H),3.70–3.57(m,2H),2.83(t,J＝5.9Hz,2H),1.49(s,9H),1.34(s,12H).6-(4,4,5,5-Tetramethyl-1,3,2-dioxaboran-2-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(115 The preparation method of -1) is the same as compound 110-1. 1 H NMR (400MHz, CD 3 OD) δ7.54(d,J＝6.9Hz,2H),7.12(d,J＝7.6Hz,1H),4.57(s,2H),3.70–3.57(m,2H ), 2.83 (t, J = 5.9Hz, 2H), 1.49 (s, 9H), 1.34 (s, 12H).
步骤②：6-(吡啶-2-基)-3,4-二氢异喹啉-2(1H)-Boc(115-2)
Step ②: 6-(pyridin-2-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(115-2)
6-(吡啶-2-基)-3,4-二氢异喹啉-2(1H)-Boc(115-2)的制备方法同化合物10-1。1H NMR(400MHz,CD3OD)δ8.54(d,J＝4.1Hz,1H),7.87–7.77(m,2H),7.71(d,J＝8.0Hz,2H),7.35–7.28(m,1H),7.21(d,J＝8.0Hz,1H),4.57(s,2H),3.64(t,J＝6.0Hz,2H),2.88(t,J＝5.9Hz,2H),1.47(s,9H).LCMS(ESI)m/z[M+H]+:311.1.The preparation method of 6-(pyridin-2-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(115-2) is the same as compound 10-1. 1 H NMR (400MHz, CD 3 OD) δ8.54(d,J＝4.1Hz,1H),7.87–7.77(m,2H),7.71(d,J＝8.0Hz,2H),7.35–7.28(m ,1H),7.21(d,J＝8.0Hz,1H),4.57(s,2H),3.64(t,J＝6.0Hz,2H),2.88(t,J＝5.9Hz,2H),1.47(s ,9H).LCMS(ESI)m/z[M+H] + :311.1.
步骤③：6-(吡啶-2-基)-1,2,4-四氢异喹啉(115-3)
Step ③: 6-(pyridin-2-yl)-1,2,4-tetrahydroisoquinoline (115-3)
6-(吡啶-2-基)-1,2,4-四氢异喹啉(115-3)的制备方法同化合物10-2。LCMS(ESI)m/z[M+H]+:211.1.The preparation method of 6-(pyridin-2-yl)-1,2,4-tetrahydroisoquinoline (115-3) is the same as that of compound 10-2. LCMS(ESI)m/z[M+H] + :211.1.
步骤④：N-(1H-吲哚-3-基)-6-(吡啶-2-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-115)
Step ④: N-(1H-indol-3-yl)-6-(pyridin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-115)
N-(1H-吲哚-3-基)-6-(吡啶-2-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-115)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.71(s,1H),8.65(dd,J＝5.0,1.8Hz,1H),8.29(s,1H),7.98–7.90(m,3H),7.87(td,J＝7.7,1.9Hz,1H),7.62(d,J＝7.9Hz,1H),7.40–7.27(m,4H),7.06(t,J＝7.5Hz,1H),6.96(t,J＝7.4Hz,1H),4.73(s,2H),3.78(t,J＝5.8Hz,2H),2.97(t,J＝5.9Hz,2H).LCMS(ESI)m/z[M+H]+:369.2.The preparation method of N-(1H-indol-3-yl)-6-(pyridin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-115) is the same as that of the compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.71 (s, 1H), 8.65 (dd, J = 5.0, 1.8Hz, 1H), 8.29 (s, 1H), 7.98–7.90 (m, 3H), 7.87(td,J＝7.7,1.9Hz,1H),7.62(d,J＝7.9Hz,1H),7.40–7.27(m,4H),7.06(t,J＝7.5Hz,1H),6.96(t ,J＝7.4Hz,1H),4.73(s,2H),3.78(t,J＝5.8Hz,2H),2.97(t,J＝5.9Hz,2H).LCMS(ESI)m/z[M+ H] + :369.2.
实施例116 N-(1H-吲哚-3-基)-6-(1H-吡咯-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-116)
Example 116 N-(1H-indol-3-yl)-6-(1H-pyrrol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-116)
步骤①：6-(1-(三异丙基硅烷基)-1H-吡咯-3-基)-3,4-二氢异喹啉-2(1H)-Boc(116-1)
Step ①: 6-(1-(triisopropylsilyl)-1H-pyrrol-3-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(116-1)
6-(1-(三异丙基硅烷基)-1H-吡咯-3-基)-3,4-二氢异喹啉-2(1H)-Boc(116-1)的制备方法同化合物10-1。1H NMR(400MHz,CD3OD)δ7.36–7.29(m,2H),7.08–7.01(m,2H),6.75(t,J＝2.4Hz,1H),6.42(t,J＝2.1Hz,1H),4.51(s,2H),3.63(s,2H),2.83(t,J＝6.0Hz,2H),1.50(s,13H),1.06(s,18H).The preparation method of 6-(1-(triisopropylsilyl)-1H-pyrrol-3-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(116-1) is the same as compound 10 -1. 1 H NMR (400MHz, CD 3 OD) δ7.36–7.29(m,2H),7.08–7.01(m,2H),6.75(t,J＝2.4Hz,1H),6.42(t,J＝2.1Hz ,1H),4.51(s,2H),3.63(s,2H),2.83(t,J=6.0Hz,2H),1.50(s,13H),1.06(s,18H).
步骤②：6-(1H-吡咯-3-基)-1,2,4-四氢异喹啉(116-2)
Step ②: 6-(1H-pyrrol-3-yl)-1,2,4-tetrahydroisoquinoline (116-2)
6-(1H-吡咯-3-基)-1,2,4-四氢异喹啉(116-2)的制备方法同化合物10-2。LCMS(ESI)m/z[M+H]+:199.1.The preparation method of 6-(1H-pyrrol-3-yl)-1,2,4-tetrahydroisoquinoline (116-2) is the same as compound 10-2. LCMS(ESI)m/z[M+H] + :199.1.
步骤③：N-(1H-吲哚-3-基)-6-(1H-吡咯-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-116)
Step ③: N-(1H-indol-3-yl)-6-(1H-pyrrol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-116)
N-(1H-吲哚-3-基)-6-(1H-吡咯-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-116)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.90(s,1H),10.70(s,1H),8.22(s,1H),7.61(d,J＝7.9Hz,1H),7.36(d,J＝3.5Hz,3H),7.32–7.29(m,1H),7.19(s,1H),7.11–7.03(m,2H),6.95(t,J＝7.4Hz,1H),6.78(d,J＝2.3Hz,1H),6.42(s,1H),4.63(s,2H),3.73(t,J＝5.8Hz,2H),2.86(t,J＝5.9Hz,2H).LCMS(ESI)m/z[M+H]+:357.0.Preparation method of N-(1H-indol-3-yl)-6-(1H-pyrrol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-116) Same as compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.90 (s, 1H), 10.70 (s, 1H), 8.22 (s, 1H), 7.61 (d, J = 7.9Hz, 1H), 7.36 (d, J＝3.5Hz,3H),7.32–7.29(m,1H),7.19(s,1H),7.11–7.03(m,2H),6.95(t,J＝7.4Hz,1H),6.78(d,J ＝2.3Hz,1H),6.42(s,1H),4.63(s,2H),3.73(t,J＝5.8Hz,2H),2.86(t,J＝5.9Hz,2H).LCMS(ESI)m /z[M+H] + :357.0.
实施例117 N-(1H-吲哚-3-基)-6-(1-甲基-1H-吡唑-4-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-117)
Example 117 N-(1H-indol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-methyl Amide(I-117)
步骤①：6-(1-甲基吡唑-4-基)-3,4-二氢异喹啉-2(1H)-Boc(117-1)
Step ①: 6-(1-methylpyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(117-1)
6-(1-甲基吡唑-4-基)-3,4-二氢异喹啉-2(1H)-Boc(117-1)的制备同化合物10-1。1H NMR(400MHz,DMSO-d6)δ8.10(s,1H),7.83(s,1H),7.38(d,J＝7.6Hz,2H),7.15(d,J＝7.8Hz,1H),4.05(s,2H),3.86(s,3H),3.57(t,J＝5.9Hz,2H),2.79(t,J＝5.9Hz,2H),1.45(s,9H).LCMS(ESI)m/z[M+H]+:314.2.The preparation of 6-(1-methylpyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(117-1) is the same as compound 10-1. 1 H NMR (400MHz, DMSO-d 6 ) δ8.10 (s, 1H), 7.83 (s, 1H), 7.38 (d, J = 7.6Hz, 2H), 7.15 (d, J = 7.8Hz, 1H) ,4.05(s,2H),3.86(s,3H),3.57(t,J＝5.9Hz,2H),2.79(t,J＝5.9Hz,2H),1.45(s,9H).LCMS(ESI) m/z[M+H] + :314.2.
步骤②：6-(1-甲基吡唑-4-基)-1,2,3,4-四氢异喹啉(117-2)
Step ②: 6-(1-methylpyrazol-4-yl)-1,2,3,4-tetrahydroisoquinoline (117-2)
6-(1-甲基吡唑-4-基)-1,2,3,4-四氢异喹啉(117-2)的制备同化合物10-2。1H NMR(400MHz,CD3OD)δ7.89(s,1H),7.76(s,1H),7.30(d,J＝9.4Hz,2H),7.03(d,J＝7.8Hz,1H),3.97(s,2H),3.90(s,3H),3.12(t,J＝6.1Hz,2H),2.87(t,J＝6.1Hz,2H).LCMS(ESI)m/z[M+H]+:214.2.The preparation of 6-(1-methylpyrazol-4-yl)-1,2,3,4-tetrahydroisoquinoline (117-2) is the same as compound 10-2. 1 H NMR (400MHz, CD 3 OD) δ7.89 (s, 1H), 7.76 (s, 1H), 7.30 (d, J = 9.4Hz, 2H), 7.03 (d, J = 7.8Hz, 1H), 3.97(s,2H),3.90(s,3H),3.12(t,J＝6.1Hz,2H),2.87(t,J＝6.1Hz,2H).LCMS(ESI)m/z[M+H] + :214.2.
步骤③：N-吲哚-3-基-6-(1-甲基吡唑-4-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-117)
Step ③: N-indol-3-yl-6-(1-methylpyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-117)
N-吲哚-3-基-6-(1-甲基吡唑-4-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-117)的制备同化合物I-41。1H NMR(400MHz,DMSO-d6)δ10.70(s,1H),8.23(s,1H),8.10(s,1H),7.83(s,1H),7.61(d,J＝7.9Hz,1H),7.42–7.35(m,3H),7.31(d,J＝8.2Hz,1H),7.16(d,J＝8.3Hz,1H),7.10–7.00(m,1H),6.95(t,J＝8.0,6.9Hz,1H),4.65(s,2H),3.86(s,3H),3.75(t,J＝5.9Hz,2H),2.88(t,J＝5.8Hz,2H).LCMS(ESI)m/z[M+H]+:372.2.Preparation of N-indol-3-yl-6-(1-methylpyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-117) Identical compound I-41. 1 H NMR (400MHz, DMSO-d 6 ) δ10.70 (s, 1H), 8.23 (s, 1H), 8.10 (s, 1H), 7.83 (s, 1H), 7.61 (d, J = 7.9Hz, 1H),7.42–7.35(m,3H),7.31(d,J＝8.2Hz,1H),7.16(d,J＝8.3Hz,1H),7.10–7.00(m,1H),6.95(t,J ＝8.0,6.9Hz,1H),4.65(s,2H),3.86(s,3H),3.75(t,J＝5.9Hz,2H),2.88(t,J＝5.8Hz,2H).LCMS(ESI )m/z[M+H] + :372.2.
实施例118 N-(1H-吲哚-3-基)-6-(噻吩-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-118)
Example 118 N-(1H-indol-3-yl)-6-(thiophen-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-118)
步骤①：6-(噻吩-3-基)-3,4-二氢异喹啉-2(1H)-Boc(118-1)
Step ①: 6-(thiophen-3-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(118-1)
6-(噻吩-3-基)-3,4-二氢异喹啉-2(1H)-Boc(118-1)的制备同化合物10-1。1H NMR(400MHz,CD3OD)δ7.52(s,1H),7.45–7.34(m,4H),7.08(d,J＝8.0Hz,1H),4.51(s,2H),3.60(t,J＝5.9Hz,2H),2.81(t,J＝6.0Hz,2H),1.49(s,9H).LCMS(ESI)m/z[M+Na]+:338.0.The preparation of 6-(thiophen-3-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(118-1) is the same as compound 10-1. 1 H NMR (400MHz, CD 3 OD) δ7.52 (s, 1H), 7.45–7.34 (m, 4H), 7.08 (d, J = 8.0Hz, 1H), 4.51 (s, 2H), 3.60 (t ,J＝5.9Hz,2H),2.81(t,J＝6.0Hz,2H),1.49(s,9H).LCMS(ESI)m/z[M+Na] + :338.0.
步骤②：6-噻吩-3-基-1,2,3,4-四氢异喹啉(118-2)
Step ②: 6-thiophen-3-yl-1,2,3,4-tetrahydroisoquinoline (118-2)
6-噻吩-3-基-1,2,3,4-四氢异喹啉(118-2)的制备同化合物10-2。1H NMR(400MHz,DMSO-d6)δ7.78(dd,J＝2.9,1.4Hz,1H),7.60(dd,J＝5.0,2.9Hz,1H),7.51(dd,J＝5.0,1.4Hz,1H),7.47–7.39(m,2H),7.03(d,J＝7.9Hz,1H),3.84(s,2H),2.95(t,J＝5.8Hz,2H),2.73(t,J＝5.8Hz,2H).LCMS(ESI)m/z[M+Na]+:216.1.The preparation of 6-thiophen-3-yl-1,2,3,4-tetrahydroisoquinoline (118-2) is the same as compound 10-2. 1 H NMR (400MHz, DMSO-d 6 ) δ7.78 (dd, J＝2.9, 1.4Hz, 1H), 7.60 (dd, J＝5.0, 2.9Hz, 1H), 7.51 (dd, J＝5.0, 1.4 Hz,1H),7.47–7.39(m,2H),7.03(d,J＝7.9Hz,1H),3.84(s,2H),2.95(t,J＝5.8Hz,2H),2.73(t,J ＝5.8Hz,2H).LCMS(ESI)m/z[M+Na] + :216.1.
步骤③：N-(1H-吲哚-3-基)-6-(噻吩-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-118)
Step ③: N-(1H-indol-3-yl)-6-(thiophen-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-118)
N-(1H-吲哚-3-基)-6-(噻吩-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-118)的制备同化合物I-41。1H NMR(400MHz,DMSO-d6)δ10.70(s,1H),8.25(s,1H),7.84(d,1H),7.70–7.59(m,2H),7.56(d,J＝5.4Hz,3H),7.37(d,J＝2.4Hz,1H),7.31(d,J＝8.1Hz,1H),7.23(d,1H),7.06(t,J＝7.5Hz,1H),6.96(t,J＝7.4Hz,1H),4.69(s,2H),3.76(t,J＝5.9Hz,2H), 2.93(t,J＝6.1Hz,2H).LCMS(ESI)m/z[M+Na]+:374.3.The preparation of N-(1H-indol-3-yl)-6-(thiophen-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-118) is the same as compound I -41. 1 H NMR (400MHz, DMSO-d 6 ) δ10.70 (s, 1H), 8.25 (s, 1H), 7.84 (d, 1H), 7.70–7.59 (m, 2H), 7.56 (d, J = 5.4 Hz,3H),7.37(d,J＝2.4Hz,1H),7.31(d,J＝8.1Hz,1H),7.23(d,1H),7.06(t,J＝7.5Hz,1H),6.96( t,J＝7.4Hz,1H),4.69(s,2H),3.76(t,J＝5.9Hz,2H), 2.93(t,J＝6.1Hz,2H).LCMS(ESI)m/z[M+Na] + :374.3.
实施例119 N-(1H-吲哚-3-基)-6-(噻吩-2-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-119)
Example 119 N-(1H-indol-3-yl)-6-(thiophen-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-119)
步骤①：6(噻吩-2-基)-3,4-二氢异喹啉-2(1H)-Boc(119-1)
Step ①: 6(thiophen-2-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(119-1)
化合物6(噻吩-2-基)-3,4-二氢异喹啉-2(1H)-Boc(119-1)的制备同化合物10-1。1H NMR(400MHz,CD3OD)δ7.49–7.44(m,2H),7.39–7.34(m,2H),7.16(d,J＝7.9Hz,1H),7.09(t,J＝4.9,3.6,0.9Hz,1H),4.58(s,2H),3.68(t,2H),2.88(t,J＝6.0Hz,2H),1.52(s,9H).LCMS(ESI)m/z[M+Na]+:338.1.The preparation of compound 6(thiophen-2-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(119-1) is the same as that of compound 10-1. 1 H NMR (400MHz, CD 3 OD) δ7.49–7.44(m,2H),7.39–7.34(m,2H),7.16(d,J＝7.9Hz,1H),7.09(t,J＝4.9, 3.6,0.9Hz,1H),4.58(s,2H),3.68(t,2H),2.88(t,J＝6.0Hz,2H),1.52(s,9H).LCMS(ESI)m/z[M +Na] + :338.1.
步骤②：6-噻吩-2-基-1,2,3,4-四氢异喹啉(119-2)
Step ②: 6-thiophen-2-yl-1,2,3,4-tetrahydroisoquinoline (119-2)
6-噻吩-2-基-1,2,3,4-四氢异喹啉(119-2)的制备同化合物10-2。1H NMR(400MHz,DMSO-d6)δ7.78(t,J＝2.9,1.4Hz,1H),7.60(q,J＝5.0,2.9Hz,1H),7.51(d,J＝5.0,1.4Hz,1H),7.47–7.39(m,2H),7.03(d,J＝7.9Hz,1H),3.84(s,2H),2.95(t,J＝5.8Hz,2H),2.73(t,J＝5.8Hz,2H).LCMS(ESI)m/z[M+Na]+:216.1.The preparation of 6-thiophen-2-yl-1,2,3,4-tetrahydroisoquinoline (119-2) is the same as compound 10-2. 1 H NMR (400MHz, DMSO-d 6 ) δ7.78 (t, J＝2.9, 1.4Hz, 1H), 7.60 (q, J＝5.0, 2.9Hz, 1H), 7.51 (d, J＝5.0, 1.4 Hz,1H),7.47–7.39(m,2H),7.03(d,J＝7.9Hz,1H),3.84(s,2H),2.95(t,J＝5.8Hz,2H),2.73(t,J ＝5.8Hz,2H).LCMS(ESI)m/z[M+Na] + :216.1.
步骤③：N-(1H-吲哚-3-基)-6-(噻吩-2-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-119)
Step ③: N-(1H-indol-3-yl)-6-(thiophen-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-119)
化合物N-(1H-吲哚-3-基)-6-(噻吩-2-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-119)的制备同化合物I-41。1H NMR(400MHz,DMSO-d6)δ10.70(s,1H),8.25(s,1H),7.61(d,J＝7.9Hz,1H),7.53–7.47(m,4H),7.36(d,J＝2.5Hz,1H),7.30(d,J＝8.2Hz,1H),7.23(d,J＝7.9Hz,1H),7.13(t,J＝5.1,3.6Hz,1H),7.06(t,J＝7.5Hz,1H),6.95(t,J＝7.5Hz,1H),4.68(s,2H),3.76(t,J＝5.8Hz,2H),2.92(t,J＝5.7Hz,2H).LCMS(ESI)m/z[M+Na]+:374.1.Preparation of compound N-(1H-indol-3-yl)-6-(thiophen-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-119) is the same compound I-41. 1 H NMR (400MHz, DMSO-d 6 ) δ10.70 (s, 1H), 8.25 (s, 1H), 7.61 (d, J = 7.9Hz, 1H), 7.53–7.47 (m, 4H), 7.36 ( d,J＝2.5Hz,1H),7.30(d,J＝8.2Hz,1H),7.23(d,J＝7.9Hz,1H),7.13(t,J＝5.1,3.6Hz,1H),7.06( t,J＝7.5Hz,1H),6.95(t,J＝7.5Hz,1H),4.68(s,2H),3.76(t,J＝5.8Hz,2H),2.92(t,J＝5.7Hz, 2H).LCMS(ESI)m/z[M+Na] + :374.1.
实施例120 N-(1H-吲哚-3-基)-6-苯胺基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-120)
Example 120 N-(1H-indol-3-yl)-6-anilino-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-120)
步骤①：6-苯胺基-3,4-二氢异喹啉-2(1H)-Boc(120-1)
Step ①: 6-anilino-3,4-dihydroisoquinoline-2(1H)-Boc(120-1)
6-苯胺基-3,4-二氢异喹啉-2(1H)-Boc(120-1)的制备方法同化合物34-1。1H NMR(400MHz,DMSO-d6)δ8.06(s,1H),7.23–7.18(m,2H),7.05–7.00(m,3H),6.92–6.84(m,2H),6.79(t,J＝7.3Hz,1H),4.40(s,2H),3.51(t,J＝5.9Hz,2H),2.70(t,J＝5.8Hz,2H),1.43(s,9H).步骤②：N-苯基-1,2,3,4-四氢异喹啉-6-胺(120-2)
The preparation method of 6-anilino-3,4-dihydroisoquinoline-2(1H)-Boc(120-1) is the same as compound 34-1. 1 H NMR (400MHz, DMSO-d 6 ) δ8.06(s,1H),7.23–7.18(m,2H),7.05–7.00(m,3H),6.92–6.84(m,2H),6.79(t ,J＝7.3Hz,1H),4.40(s,2H),3.51(t,J＝5.9Hz,2H),2.70(t,J＝5.8Hz,2H),1.43(s,9H). Step ②: N-phenyl-1,2,3,4-tetrahydroisoquinolin-6-amine (120-2)
N-苯基-1,2,3,4-四氢异喹啉-6-胺(120-2)的制备方法同化合物10-2。LCMS(ESI)m/z[M+H]+:225.1.The preparation method of N-phenyl-1,2,3,4-tetrahydroisoquinolin-6-amine (120-2) is the same as compound 10-2. LCMS(ESI)m/z[M+H] + :225.1.
步骤③：N-(1H-吲哚-3-基)-6-苯胺基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-120)
Step ③: N-(1H-indol-3-yl)-6-anilino-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-120)
N-(1H-吲哚-3-基)-6-苯胺基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-120)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.69(s,1H),8.20(s,1H),8.07(s,1H),7.60(d,J＝7.6Hz,1H),7.36(d,J＝2.3Hz,1H),7.30(d,J＝8.1Hz,1H),7.21(t,J＝7.8Hz,2H),7.05(d,J＝8.0Hz,4H),6.94(dd,J＝16.3,8.1Hz,3H),6.79(t,J＝7.3Hz,1H),4.59(s,2H),3.70(d,J＝5.7Hz,2H),2.80(s,2H).LCMS(ESI)m/z[M+H]+:383.2.The preparation method of N-(1H-indol-3-yl)-6-anilino-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-120) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.69 (s, 1H), 8.20 (s, 1H), 8.07 (s, 1H), 7.60 (d, J = 7.6Hz, 1H), 7.36 (d, J＝2.3Hz,1H),7.30(d,J＝8.1Hz,1H),7.21(t,J＝7.8Hz,2H),7.05(d,J＝8.0Hz,4H),6.94(dd,J＝ 16.3,8.1Hz,3H),6.79(t,J＝7.3Hz,1H),4.59(s,2H),3.70(d,J＝5.7Hz,2H),2.80(s,2H).LCMS(ESI) m/z[M+H] + :383.2.
实施例121 6-(苯并[d][1,3]二氧戊环-5-基)-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-121)
Example 121 6-(benzo[d][1,3]dioxolane-5-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2 (1H)-Formamide (I-121)
步骤①：6-(苯并[d][1,3]二氧戊环-5-基)-3,4-二氢异喹啉-2(1H)-Boc(121-1)
Step ①: 6-(benzo[d][1,3]dioxolane-5-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(121-1)
6-(苯并[d][1,3]二氧戊环-5-基)-3,4-二氢异喹啉-2(1H)-Boc(121-1)的制备方法同化合物10-1。1H NMR(400MHz,CDCl3)δ7.33(d,J＝8.1Hz,1H),7.28(s,1H),7.15(d,J＝8.0Hz,1H),7.09–6.99(m,2H),6.87(d,J＝8.0Hz,1H),6.00(s,2H),4.60(s,2H),3.67(s,2H),2.88(s,2H),1.50(s,9H).The preparation method of 6-(benzo[d][1,3]dioxolane-5-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(121-1) is the same as compound 10 -1. 1 H NMR (400MHz, CDCl 3 ) δ7.33(d,J＝8.1Hz,1H),7.28(s,1H),7.15(d,J＝8.0Hz,1H),7.09–6.99(m,2H) ,6.87(d,J=8.0Hz,1H),6.00(s,2H),4.60(s,2H),3.67(s,2H),2.88(s,2H),1.50(s,9H).
步骤②：6-(苯并[d][1,3]二氧戊环-5-基)-1,2,3,4-四氢异喹啉(121-2)
Step ②: 6-(benzo[d][1,3]dioxolane-5-yl)-1,2,3,4-tetrahydroisoquinoline (121-2)
6-(苯并[d][1,3]二氧戊环-5-基)-1,2,3,4-四氢异喹啉(121-2)的制备方法同化合物10-2。LCMS(ESI)m/z[M+H]+:254.2.The preparation method of 6-(benzo[d][1,3]dioxolane-5-yl)-1,2,3,4-tetrahydroisoquinoline (121-2) is the same as that of compound 10-2. LCMS(ESI)m/z[M+H] + :254.2.
步骤③：6-(苯并[d][1,3]二氧戊环-5-基)-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-121)
Step ③: 6-(benzo[d][1,3]dioxolane-5-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2 (1H)-Formamide (I-121)
6-(苯并[d][1,3]二氧戊环-5-基)-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-121)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.71(s,1H),8.26(s,1H),7.61(d,J＝8.0Hz,1H),7.43(d,J＝6.3Hz,2H),7.36(d,J＝2.3Hz,1H),7.31(d,J＝8.1Hz,1H),7.22(d,J＝8.8Hz,2H),7.14(dd,J＝8.1,1.5Hz,1H),7.06(t,J＝7.6Hz,1H),6.97(dd,J＝17.7,7.7Hz,2H),6.06(s,2H),4.69(s,2H),3.76(t,J＝5.8Hz,2H),2.92(t,J＝5.6Hz,2H).LCMS(ESI)m/z[M+H]+:412.0.6-(benzo[d][1,3]dioxolane-5-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H) - The preparation method of formamide (I-121) is the same as that of compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.71 (s, 1H), 8.26 (s, 1H), 7.61 (d, J = 8.0Hz, 1H), 7.43 (d, J = 6.3Hz, 2H) ,7.36(d,J＝2.3Hz,1H),7.31(d,J＝8.1Hz,1H),7.22(d,J＝8.8Hz,2H),7.14(dd,J＝8.1,1.5Hz,1H) ,7.06(t,J＝7.6Hz,1H),6.97(dd,J＝17.7,7.7Hz,2H),6.06(s,2H),4.69(s,2H),3.76(t,J＝5.8Hz, 2H), 2.92 (t, J = 5.6Hz, 2H). LCMS (ESI) m/z [M+H] + : 412.0.
实施例122 6-(苯并[d][1,3]二氧戊环-5-基)-N-(5-氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-122)
Example 122 6-(benzo[d][1,3]dioxolane-5-yl)-N-(5-fluoro-1H-indol-3-yl)-3,4-dihydroiso Quinoline-2(1H)-carboxamide (I-122)
6-(苯并[d][1,3]二氧戊环-5-基)-N-(5-氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-122)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.82(s,1H),8.25(s,1H),7.44(dd,J＝7.0,4.5Hz,3H),7.38(dd,J＝10.2,2.4Hz,1H),7.30(dd,J＝8.8,4.5Hz,1H),7.23(d,J＝8.3Hz,2H),7.14(d,J＝8.0Hz,1H),6.99(d,J＝8.1Hz,1H),6.90(td,J＝9.2,2.5Hz,1H),6.06(s,2H),4.68(s,2H),3.75(t,J＝5.8Hz,2H),2.92(t,J＝5.5Hz,2H).LCMS(ESI)m/z[M+H]+:430.1.6-(benzo[d][1,3]dioxolane-5-yl)-N-(5-fluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline- The preparation method of 2(1H)-carboxamide (I-122) is the same as that of compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.82 (s, 1H), 8.25 (s, 1H), 7.44 (dd, J = 7.0, 4.5 Hz, 3H), 7.38 (dd, J = 10.2, 2.4 Hz,1H),7.30(dd,J＝8.8,4.5Hz,1H),7.23(d,J＝8.3Hz,2H),7.14(d,J＝8.0Hz,1H),6.99(d,J＝8.1 Hz,1H),6.90(td,J＝9.2,2.5Hz,1H),6.06(s,2H),4.68(s,2H),3.75(t,J＝5.8Hz,2H),2.92(t,J ＝5.5Hz,2H).LCMS(ESI)m/z[M+H] + :430.1.
实施例123 6-(苯并[d][1,3]二氧戊环-5-基)-N-(5-氯-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-123)
Example 123 6-(benzo[d][1,3]dioxolane-5-yl)-N-(5-chloro-1H-indol-3-yl)-3,4-dihydroiso Quinoline-2(1H)-carboxamide (I-123)
6-(苯并[d][1,3]二氧戊环-5-基)-N-(5-氯-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-123)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.92(s,1H),8.31(s,1H),7.71(s,1H),7.45(t,J＝8.7Hz,3H),7.33(d,J＝8.6Hz,1H),7.23(d,J＝7.2Hz,2H),7.14(d,J＝8.0Hz,1H),7.05(d,J＝8.6Hz,1H),6.99(d,J＝8.1Hz,1H),6.06(s,2H),4.69(s,2H),3.76(t,J＝5.6Hz,2H),2.93(d,J＝5.2Hz,2H).LCMS(ESI)m/z[M+H]+:446.3.6-(Benzo[d][1,3]dioxolane-5-yl)-N-(5-chloro-1H-indol-3-yl)-3,4-dihydroisoquinoline- The preparation method of 2(1H)-carboxamide (I-123) is the same as that of compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.92 (s, 1H), 8.31 (s, 1H), 7.71 (s, 1H), 7.45 (t, J = 8.7Hz, 3H), 7.33 (d, J＝8.6Hz,1H),7.23(d,J＝7.2Hz,2H),7.14(d,J＝8.0Hz,1H),7.05(d,J＝8.6Hz,1H),6.99(d,J＝ 8.1Hz,1H),6.06(s,2H),4.69(s,2H),3.76(t,J＝5.6Hz,2H),2.93(d,J＝5.2Hz,2H).LCMS(ESI)m/ z[M+H] + :446.3.
实施例124 6-(苯并[d][1,3]二氧戊环-5-基)-N-(5-氯-6-氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-124)
Example 124 6-(benzo[d][1,3]dioxolane-5-yl)-N-(5-chloro-6-fluoro-1H-indol-3-yl)-3,4 -Dihydroisoquinoline-2(1H)-carboxamide (I-124)
6-(苯并[d][1,3]二氧戊环-5-基)-N-(5-氯-6-氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-124)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.96(s,1H),8.34(s,1H),7.86(d,J＝7.7Hz,1H),7.46(d,J＝2.4Hz,1H),7.43(d,J＝6.4Hz,2H),7.31(d,J＝10.2Hz,1H),7.23(d,J＝7.0Hz,2H),7.14(d,J＝8.1Hz,1H),6.98(d,J＝8.2Hz,1H),6.05(s,2H),4.68(s,2H),3.75(s,2H),2.91(s,2H).LCMS(ESI)m/z[M+H]+:464.1.6-(benzo[d][1,3]dioxolane-5-yl)-N-(5-chloro-6-fluoro-1H-indol-3-yl)-3,4-dihydro The preparation method of isoquinoline-2(1H)-carboxamide (I-124) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.96 (s, 1H), 8.34 (s, 1H), 7.86 (d, J = 7.7Hz, 1H), 7.46 (d, J = 2.4Hz, 1H) ,7.43(d,J＝6.4Hz,2H),7.31(d,J＝10.2Hz,1H),7.23(d,J＝7.0Hz,2H),7.14(d,J＝8.1Hz,1H),6.98 (d,J＝8.2Hz,1H),6.05(s,2H),4.68(s,2H),3.75(s,2H),2.91(s,2H).LCMS(ESI)m/z[M+H ] + :464.1.
实施例125 6-(苯并[d][1,3]二氧戊环-5-基)-N-(5,6-二氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-125)
Example 125 6-(benzo[d][1,3]dioxolane-5-yl)-N-(5,6-difluoro-1H-indol-3-yl)-3,4- Dihydroisoquinoline-2(1H)-carboxamide (I-125)
6-(苯并[d][1,3]二氧戊环-5-基)-N-(5,6-二氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-125)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.88(s,1H),8.29(s,1H),7.60(dd,J＝11.6,8.2Hz,1H),7.43(d,J＝6.6Hz,3H),7.31(dd,J＝11.3,6.9Hz,1H),7.23(d,J＝8.4Hz,2H),7.14(d,J＝8.1Hz,1H),6.99(d,J＝8.1Hz,1H),6.06(s,2H),4.68(s,2H),3.75(t,J＝5.7Hz,2H),2.92(t,J＝5.5Hz,2H).LCMS(ESI)m/z[M+H]+:448.2.6-(Benzo[d][1,3]dioxolane-5-yl)-N-(5,6-difluoro-1H-indol-3-yl)-3,4-dihydroiso The preparation method of quinoline-2(1H)-carboxamide (I-125) is the same as that of compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.88 (s, 1H), 8.29 (s, 1H), 7.60 (dd, J = 11.6, 8.2Hz, 1H), 7.43 (d, J = 6.6Hz, 3H),7.31(dd,J＝11.3,6.9Hz,1H),7.23(d,J＝8.4Hz,2H),7.14(d,J＝8.1Hz,1H),6.99(d,J＝8.1Hz, 1H),6.06(s,2H),4.68(s,2H),3.75(t,J＝5.7Hz,2H),2.92(t,J＝5.5Hz,2H).LCMS(ESI)m/z[M +H] + :448.2.
实施例126 N-(5,6-二氟-1H-吲哚-3-基)-6-(2,2-二氟苯并[d][1,3]二氧戊环-5-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-126)
Example 126 N-(5,6-difluoro-1H-indol-3-yl)-6-(2,2-difluorobenzo[d][1,3]dioxolane-5-yl )-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-126)
步骤①：6-(2,2-二氟苯并[d][1,3]二氧戊环-5-基)-3,4-二氢异喹啉-2(1H)-Boc(126-1)
Step ①: 6-(2,2-difluorobenzo[d][1,3]dioxolane-5-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(126 -1)
6-(2,2-二氟苯并[d][1,3]二氧戊环-5-基)-3,4-二氢异喹啉-2(1H)-Boc(126-1)的制备方法同化合物10-1。1H NMR(400MHz,CDCl3)δ7.50(d,J＝8.0Hz,1H),7.45(s,1H),7.24(s,1H),7.22(d,J＝7.9Hz,1H),7.14(t,J＝8.0Hz,1H),7.02(d,J＝7.6Hz,1H),4.63(s,2H),3.69(s,2H),2.92(s,2H),1.50(s,9H).6-(2,2-Difluorobenzo[d][1,3]dioxolane-5-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(126-1) The preparation method is the same as compound 10-1. 1 H NMR (400MHz, CDCl 3 ) δ7.50 (d, J = 8.0 Hz, 1H), 7.45 (s, 1H), 7.24 (s, 1H), 7.22 (d, J = 7.9 Hz, 1H), 7.14 (t,J＝8.0Hz,1H),7.02(d,J＝7.6Hz,1H),4.63(s,2H),3.69(s,2H),2.92(s,2H),1.50(s,9H) .
步骤②：6-(2,2-二氟苯并[d][1,3]二氧戊环-5-基)-1,2,3,4-四氢异喹啉(126-2)
Step ②: 6-(2,2-difluorobenzo[d][1,3]dioxolane-5-yl)-1,2,3,4-tetrahydroisoquinoline (126-2)
6-(2,2-二氟苯并[d][1,3]二氧戊环-5-基)-1,2,3,4-四氢异喹啉(126-2)的制备方法同化合物10-2。LCMS(ESI)m/z[M+H]+:290.3.Preparation method of 6-(2,2-difluorobenzo[d][1,3]dioxolane-5-yl)-1,2,3,4-tetrahydroisoquinoline (126-2) Same as compound 10-2. LCMS(ESI)m/z[M+H] + :290.3.
步骤③：N-(5,6-二氟-1H-吲哚-3-基)-6-(2,2-二氟苯并[d][1,3]二氧戊环-5-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-126)
Step ③: N-(5,6-difluoro-1H-indol-3-yl)-6-(2,2-difluorobenzo[d][1,3]dioxolane-5-yl )-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-126)
N-(5,6-二氟-1H-吲哚-3-基)-6-(2,2-二氟苯并[d][1,3]二氧戊环-5-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-126)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ 16.16–16.12(m,1H),10.91(s,1H),8.34(s,1H),7.62(dd,J＝11.5,8.2Hz,1H),7.55(d,J＝6.5Hz,2H),7.47(d,J＝8.2Hz,2H),7.33(ddd,J＝15.4,11.8,5.6Hz,4H),4.73(s,2H),3.77(t,J＝5.6Hz,2H),2.95(t,J＝5.3Hz,2H).LCMS(ESI)m/z[M+H]+:484.0.N-(5,6-difluoro-1H-indol-3-yl)-6-(2,2-difluorobenzo[d][1,3]dioxolane-5-yl)-3 , The preparation method of 4-dihydroisoquinoline-2(1H)-carboxamide (I-126) is the same as compound I-1. 1H NMR (400MHz, DMSO-d 6 )δ 16.16–16.12(m,1H),10.91(s,1H),8.34(s,1H),7.62(dd,J＝11.5,8.2Hz,1H),7.55(d,J＝6.5Hz,2H),7.47 (d,J＝8.2Hz,2H),7.33(ddd,J＝15.4,11.8,5.6Hz,4H),4.73(s,2H),3.77(t,J＝5.6Hz,2H),2.95(t, J＝5.3Hz,2H).LCMS(ESI)m/z[M+H] + :484.0.
实施例127 6-(2,2-二氟苯并[d][1,3]二氧戊环-5-基)-N-(5-氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-127)
Example 127 6-(2,2-difluorobenzo[d][1,3]dioxolane-5-yl)-N-(5-fluoro-1H-indol-3-yl)-3 ,4-dihydroisoquinoline-2(1H)-carboxamide (I-127)
6-(2,2-二氟苯并[d][1,3]二氧戊环-5-基)-N-(5-氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-127)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.85(s,1H),8.30(s,1H),7.56(d,J＝5.6Hz,2H),7.48(d,J＝8.4Hz,2H),7.43–7.20(m,5H),6.90(t,J＝8.1Hz,1H),4.74(s,2H),3.78(t,J＝5.3Hz,2H),2.96(s,2H).LCMS(ESI)m/z[M+H]+:466.2.6-(2,2-Difluorobenzo[d][1,3]dioxolane-5-yl)-N-(5-fluoro-1H-indol-3-yl)-3,4- The preparation method of dihydroisoquinoline-2(1H)-carboxamide (I-127) is the same as that of compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.85 (s, 1H), 8.30 (s, 1H), 7.56 (d, J = 5.6Hz, 2H), 7.48 (d, J = 8.4Hz, 2H) ,7.43–7.20(m,5H),6.90(t,J＝8.1Hz,1H),4.74(s,2H),3.78(t,J＝5.3Hz,2H),2.96(s,2H).LCMS( ESI)m/z[M+H] + :466.2.
实施例128 N-(5,6-二氟-1H-吲哚-3-基)-6-(哌啶-1-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-128)
Example 128 N-(5,6-difluoro-1H-indol-3-yl)-6-(piperidin-1-yl)-3,4-dihydroisoquinoline-2(1H)-methyl Amide(I-128)
N-(5,6-二氟-1H-吲哚-3-基)-6-(哌啶-1-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-128)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.86(s,1H),8.20(s,1H),7.66–7.52(m,1H),7.43(s,1H),7.30(dd,J＝11.5,7.0Hz,1H),7.00(d,J＝8.3Hz,1H),6.79(d,J＝8.1Hz,1H),6.73(s,1H),4.54(s,2H),3.67(s,2H),3.08(d,J＝5.5Hz,4H),2.79(s,2H),1.60(s,4H),1.53(s,2H).LCMS(ESI)m/z[M+H]+:411.2.N-(5,6-difluoro-1H-indol-3-yl)-6-(piperidin-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I The preparation method of -128) is the same as that of compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.86 (s, 1H), 8.20 (s, 1H), 7.66–7.52 (m, 1H), 7.43 (s, 1H), 7.30 (dd, J＝11.5 ,7.0Hz,1H),7.00(d,J＝8.3Hz,1H),6.79(d,J＝8.1Hz,1H),6.73(s,1H),4.54(s,2H),3.67(s,2H ),3.08(d,J＝5.5Hz,4H),2.79(s,2H),1.60(s,4H),1.53(s,2H).LCMS(ESI)m/z[M+H] + :411.2 .
实施例129 N-(5-氯-6-氟-1H-吲哚-3-基)-6-(哌啶-1-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-129)
Example 129 N-(5-chloro-6-fluoro-1H-indol-3-yl)-6-(piperidin-1-yl)-3,4-dihydroisoquinoline-2(1H)- Formamide(I-129)
N-(5-氯-6-氟-1H-吲哚-3-基)-6-(哌啶-1-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-129)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.94(s,1H),8.26(s,1H),7.84(d,J＝7.5Hz,1H),7.45(s,1H),7.30(d,J＝10.3Hz,1H),7.00(d,J＝8.8Hz,1H),6.79(d,J＝8.9Hz,1H),6.73(s,1H),4.55(s,2H),3.68(s,2H),3.08(d,J＝5.8Hz,4H),2.79(s,2H),1.61(s,4H),1.53(s,2H).LCMS(ESI)m/z[M+H]+:427.2.N-(5-chloro-6-fluoro-1H-indol-3-yl)-6-(piperidin-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide ( The preparation method of I-129) is the same as that of compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.94 (s, 1H), 8.26 (s, 1H), 7.84 (d, J = 7.5Hz, 1H), 7.45 (s, 1H), 7.30 (d, J＝10.3Hz,1H),7.00(d,J＝8.8Hz,1H),6.79(d,J＝8.9Hz,1H),6.73(s,1H),4.55(s,2H),3.68(s, 2H),3.08(d,J＝5.8Hz,4H),2.79(s,2H),1.61(s,4H),1.53(s,2H).LCMS(ESI)m/z[M+H] + : 427.2.
实施例130 N-(5-氟-1H-吲哚-3-基)-6-(哌啶-1-基)-3,4-二氢异喹啉-2(1H)-甲酰 胺(I-130)
Example 130 N-(5-fluoro-1H-indol-3-yl)-6-(piperidin-1-yl)-3,4-dihydroisoquinoline-2(1H)-formyl Amine(I-130)
N-(5-氟-1H-吲哚-3-基)-6-(哌啶-1-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-130)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.81(s,1H),8.17(s,1H),7.43(d,J＝2.3Hz,1H),7.36(dd,J＝10.2,2.3Hz,1H),7.29(dd,J＝8.8,4.5Hz,1H),7.00(d,J＝8.5Hz,1H),6.93–6.86(m,1H),6.79(d,J＝8.5Hz,1H),6.73(s,1H),4.55(s,2H),3.68(t,J＝5.8Hz,2H),3.14–3.02(m,4H),2.79(t,J＝5.6Hz,2H),1.61(s,4H),1.52(d,J＝4.5Hz,2H).LCMS(ESI)m/z[M+H]+:393.2.N-(5-fluoro-1H-indol-3-yl)-6-(piperidin-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-130) The preparation method is the same as compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.81 (s, 1H), 8.17 (s, 1H), 7.43 (d, J = 2.3Hz, 1H), 7.36 (dd, J = 10.2, 2.3Hz, 1H),7.29(dd,J＝8.8,4.5Hz,1H),7.00(d,J＝8.5Hz,1H),6.93–6.86(m,1H),6.79(d,J＝8.5Hz,1H), 6.73(s,1H),4.55(s,2H),3.68(t,J＝5.8Hz,2H),3.14–3.02(m,4H),2.79(t,J＝5.6Hz,2H),1.61(s ,4H),1.52(d,J＝4.5Hz,2H).LCMS(ESI)m/z[M+H] + :393.2.
实施例131 N-(5-氯-1H-吲哚-3-基)-6-(哌啶-1-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-131)
Example 131 N-(5-chloro-1H-indol-3-yl)-6-(piperidin-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I -131)
N-(5-氯-1H-吲哚-3-基)-6-(哌啶-1-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-131)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.92(s,1H),8.30(s,1H),7.70(d,J＝1.9Hz,1H),7.46(d,J＝2.4Hz,1H),7.34(s,1H),7.32(s,1H),7.19(s,1H),7.06(d,J＝2.0Hz,1H),7.04(d,J＝2.0Hz,1H),4.64(s,2H),3.73(s,6H),2.87(s,2H),1.76(s,4H),1.60(s,2H).LCMS(ESI)m/z[M+H]+:409.2.N-(5-chloro-1H-indol-3-yl)-6-(piperidin-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-131) The preparation method is the same as compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.92 (s, 1H), 8.30 (s, 1H), 7.70 (d, J = 1.9Hz, 1H), 7.46 (d, J = 2.4Hz, 1H) ,7.34(s,1H),7.32(s,1H),7.19(s,1H),7.06(d,J＝2.0Hz,1H),7.04(d,J＝2.0Hz,1H),4.64(s, 2H),3.73(s,6H),2.87(s,2H),1.76(s,4H),1.60(s,2H).LCMS(ESI)m/z[M+H] + :409.2.
实施例132 6-(3,4-二氢喹啉-1(2H)-基)-N-(5-氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-132)
Example 132 6-(3,4-dihydroquinolin-1(2H)-yl)-N-(5-fluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline- 2(1H)-Carboxamide (I-132)
步骤①：6-(3,4-二氢喹啉-1(2H)-基)-3,4-二氢异喹啉-2(1H)-Boc(132-1)
Step ①: 6-(3,4-dihydroquinoline-1(2H)-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(132-1)
将200毫克6-溴-3,4-二氢异喹啉-2(1H)-Boc、85毫克1,2,3,4-四氢喹啉、123毫克叔丁醇钠、59毫克三(二亚苄基丙酮)二钯、40毫克BINAP和10毫升甲苯的混合物于110℃氩气氛下搅拌过夜。反应液过滤，滤液浓缩至干，残余物石油醚：乙酸乙酯＝10：1柱层析，得黄色油状物6-(3,4-二氢喹啉-1(2H)-基)-3,4-二氢异喹啉-2(1H)-Boc(132-1) 117毫克，收率50％。1H NMR(400MHz,CD3OD)δ7.09(d,J＝8.3Hz,1H),7.05–6.96(m,3H),6.84(t,J＝7.6Hz,1H),6.65–6.57(m,2H),4.52(s,2H),3.62(t,J＝6.0Hz,2H),3.59–3.55(m,2H),2.80(q,J＝6.4Hz,4H),2.00(p,J＝6.2Hz,2H),1.50(s,9H).LCMS(ESI)m/z[M+H]+:365.2.200 mg of 6-bromo-3,4-dihydroisoquinoline-2(1H)-Boc, 85 mg of 1,2,3,4-tetrahydroquinoline, 123 mg of sodium tert-butoxide, 59 mg of tris( A mixture of dibenzylideneacetone) dipalladium, 40 mg BINAP and 10 ml toluene was stirred overnight at 110°C under an argon atmosphere. The reaction liquid was filtered, and the filtrate was concentrated to dryness. The residue was subjected to column chromatography with petroleum ether: ethyl acetate = 10:1 to obtain yellow oil 6-(3,4-dihydroquinolin-1(2H)-yl)-3. ,4-dihydroisoquinoline-2(1H)-Boc(132-1) 117 mg, yield 50%. 1 H NMR (400MHz, CD 3 OD) δ7.09 (d, J＝8.3Hz, 1H), 7.05–6.96 (m, 3H), 6.84 (t, J＝7.6Hz, 1H), 6.65–6.57 (m ,2H),4.52(s,2H),3.62(t,J＝6.0Hz,2H),3.59–3.55(m,2H),2.80(q,J＝6.4Hz,4H),2.00(p,J＝ 6.2Hz,2H),1.50(s,9H).LCMS(ESI)m/z[M+H] + :365.2.
步骤②：1-(1,2,3,4-四氢异喹啉-6-基)-1,3,4-四氢喹啉(132-2)
Step ②: 1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1,3,4-tetrahydroquinoline (132-2)
1-(1,2,3,4-四氢异喹啉-6-基)-1,3,4-四氢喹啉(132-2)的制备方法同化合物10-2。LCMS(ESI)m/z[M+H]+:265.2.The preparation method of 1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1,3,4-tetrahydroquinoline (132-2) is the same as compound 10-2. LCMS(ESI)m/z[M+H] + :265.2.
步骤③：6-(3,4-二氢喹啉-1(2H)-基)-N-(5-氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-132)
Step ③: 6-(3,4-dihydroquinolin-1(2H)-yl)-N-(5-fluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline- 2(1H)-Carboxamide (I-132)
6-(3,4-二氢喹啉-1(2H)-基)-N-(5-氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-132)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.82(s,1H),8.23(s,1H),7.45(d,J＝2.5Hz,1H),7.37(dd,J＝10.2,2.6Hz,1H),7.30(dd,J＝8.8,4.5Hz,1H),7.17(d,J＝8.6Hz,1H),7.08–7.03(m,2H),7.00(d,J＝7.5Hz,1H),6.94–6.84(m,2H),6.62(t,J＝7.3Hz,1H),6.57(d,J＝8.2Hz,1H),4.64(s,2H),3.72(t,J＝5.9Hz,2H),3.55(t,J＝5.7Hz,2H),2.84(t,J＝5.8Hz,2H),2.77(t,J＝6.4Hz,2H),1.94(p,J＝5.9Hz,2H).LCMS(ESI)m/z[M+H]+:441.1.6-(3,4-Dihydroquinolin-1(2H)-yl)-N-(5-fluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H The preparation method of )-formamide (I-132) is the same as that of compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.82 (s, 1H), 8.23 (s, 1H), 7.45 (d, J = 2.5Hz, 1H), 7.37 (dd, J = 10.2, 2.6Hz, 1H),7.30(dd,J＝8.8,4.5Hz,1H),7.17(d,J＝8.6Hz,1H),7.08–7.03(m,2H),7.00(d,J＝7.5Hz,1H), 6.94–6.84(m,2H),6.62(t,J＝7.3Hz,1H),6.57(d,J＝8.2Hz,1H),4.64(s,2H),3.72(t,J＝5.9Hz,2H ),3.55(t,J＝5.7Hz,2H),2.84(t,J＝5.8Hz,2H),2.77(t,J＝6.4Hz,2H),1.94(p,J＝5.9Hz,2H). LCMS(ESI)m/z[M+H] + :441.1.
实施例133 N-(5-氟-1H-吲哚-3-基)-3,3',4,4'-四氢-1H-[2,6'-二异喹啉]-2'(1'H)-甲酰胺(I-133)
Example 133 N-(5-fluoro-1H-indol-3-yl)-3,3',4,4'-tetrahydro-1H-[2,6'-diisoquinoline]-2'( 1'H)-Carboxamide (I-133)
步骤①：3,3',4,4'-四氢-1H-[2,6'-二异喹啉]-2'(1'H)-Boc(133-1)
Step ①: 3,3',4,4'-tetrahydro-1H-[2,6'-diisoquinoline]-2'(1'H)-Boc(133-1)
3,3',4,4'-四氢-1H-[2,6'-二异喹啉]-2'(1'H)-Boc(133-1)的制备方法同化合物132-1。1H NMR(400MHz,CD3OD)δ6.36–6.30(m,4H),6.20(d,J＝8.6Hz,1H),6.11–6.06(m,1H),6.01(d,J＝2.9Hz,1H),3.64(s,2H),3.51(s,2H),2.78(s,2H),2.69(t,J＝5.2Hz, 2H),2.13(d,J＝6.2Hz,2H),1.97(d,J＝6.5Hz,2H),0.68(s,9H).LCMS(ESI)m/z[M+H]+:365.3.The preparation method of 3,3',4,4'-tetrahydro-1H-[2,6'-diisoquinoline]-2'(1'H)-Boc(133-1) is the same as compound 132-1. 1 H NMR (400MHz, CD 3 OD) δ6.36–6.30(m,4H),6.20(d,J＝8.6Hz,1H),6.11–6.06(m,1H),6.01(d,J＝2.9Hz ,1H),3.64(s,2H),3.51(s,2H),2.78(s,2H),2.69(t,J＝5.2Hz, 2H), 2.13 (d, J＝6.2Hz, 2H), 1.97 (d, J＝6.5Hz, 2H), 0.68 (s, 9H). LCMS (ESI) m/z [M+H] + :365.3.
步骤②：1',2',3,3',4,4'-六氢-1H-2,6'-双异喹啉(133-2)
Step ②: 1',2',3,3',4,4'-hexahydro-1H-2,6'-bisisoquinoline (133-2)
1',2',3,3',4,4'-六氢-1H-2,6'-双异喹啉(133-2)的制备方法同化合物10-2。LCMS(ESI)m/z[M+H]+:265.2.The preparation method of 1',2',3,3',4,4'-hexahydro-1H-2,6'-bisisoquinoline (133-2) is the same as that of compound 10-2. LCMS(ESI)m/z[M+H] + :265.2.
步骤③：N-(5-氟-1H-吲哚-3-基)-3,3',4,4'-四氢-1H-[2,6'-二异喹啉]-2'(1'H)-甲酰胺(I-133)
Step ③: N-(5-fluoro-1H-indol-3-yl)-3,3',4,4'-tetrahydro-1H-[2,6'-diisoquinoline]-2'( 1'H)-Carboxamide (I-133)
N-(5-氟-1H-吲哚-3-基)-3,3',4,4'-四氢-1H-[2,6'-二异喹啉]-2'(1'H)-甲酰胺(I-133)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.81(s,1H),8.17(s,1H),7.44(d,J＝2.5Hz,1H),7.36(dd,J＝10.3,2.6Hz,1H),7.29(dd,J＝8.8,4.5Hz,1H),7.24–7.14(m,4H),7.04(d,J＝8.5Hz,1H),6.90(ddt,J＝9.2,6.3,2.9Hz,2H),6.83(d,J＝2.5Hz,1H),4.56(s,2H),4.35(s,2H),3.69(t,J＝5.7Hz,2H),3.51(t,J＝5.8Hz,2H),2.90(t,J＝6.0Hz,2H),2.82(t,J＝5.8Hz,2H).LCMS(ESI)m/z[M+H]+:441.1.N-(5-fluoro-1H-indol-3-yl)-3,3',4,4'-tetrahydro-1H-[2,6'-diisoquinoline]-2'(1'H The preparation method of )-formamide (I-133) is the same as that of compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.81 (s, 1H), 8.17 (s, 1H), 7.44 (d, J = 2.5Hz, 1H), 7.36 (dd, J = 10.3, 2.6Hz, 1H),7.29(dd,J＝8.8,4.5Hz,1H),7.24–7.14(m,4H),7.04(d,J＝8.5Hz,1H),6.90(ddt,J＝9.2,6.3,2.9Hz ,2H),6.83(d,J＝2.5Hz,1H),4.56(s,2H),4.35(s,2H),3.69(t,J＝5.7Hz,2H),3.51(t,J＝5.8Hz ,2H),2.90(t,J＝6.0Hz,2H),2.82(t,J＝5.8Hz,2H).LCMS(ESI)m/z[M+H] + :441.1.
实施例134 N-(5-氟-1H-吲哚-3-基)-6-(6-氮杂螺[2.5]辛烷-6-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-134)
Example 134 N-(5-fluoro-1H-indol-3-yl)-6-(6-azaspiro[2.5]octane-6-yl)-3,4-dihydroisoquinoline-2 (1H)-Carboxamide (I-134)
步骤①：6-(6-氮杂螺[2.5]辛烷-6-基)-3,4-二氢异喹啉-2(1H)-Boc(134-1)
Step ①: 6-(6-azaspiro[2.5]octane-6-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(134-1)
6-(6-氮杂螺[2.5]辛烷-6-基)-3,4-二氢异喹啉-2(1H)-Boc(134-1)的制备方法同化合物132-1。1H NMR(400MHz,CD3OD)δ7.09–6.71(m,3H),4.46(s,2H),3.32(s,3H),3.17(s,4H),2.79(s,2H),1.49(s,9H),1.30(s,2H),0.35(s,4H).LCMS(ESI)m/z[M+H]+:343.3.The preparation method of 6-(6-azaspiro[2.5]octan-6-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(134-1) is the same as that of compound 132-1. 1 H NMR (400MHz, CD 3 OD) δ7.09–6.71(m,3H),4.46(s,2H),3.32(s,3H),3.17(s,4H),2.79(s,2H),1.49 (s,9H),1.30(s,2H),0.35(s,4H).LCMS(ESI)m/z[M+H] + :343.3.
步骤②：6-(6-氮杂螺[2.5]辛烷-6-基)-1,2,4-四氢异喹啉(134-2)
Step ②: 6-(6-azaspiro[2.5]octane-6-yl)-1,2,4-tetrahydroisoquinoline (134-2)
6-(6-氮杂螺[2.5]辛烷-6-基)-1,2,4-四氢异喹啉(134-2)的制备方法同化合物10-2。LCMS(ESI)m/z[M+H]+:243.2.The preparation method of 6-(6-azaspiro[2.5]octane-6-yl)-1,2,4-tetrahydroisoquinoline (134-2) is the same as that of compound 10-2. LCMS(ESI)m/z[M+H] + :243.2.
步骤③：N-(5-氟-1H-吲哚-3-基)-6-(6-氮杂螺[2.5]辛烷-6-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-134)
Step ③: N-(5-fluoro-1H-indol-3-yl)-6-(6-azaspiro[2.5]octane-6-yl)-3,4-dihydroisoquinoline-2 (1H)-Carboxamide (I-134)
N-(5-氟-1H-吲哚-3-基)-6-(6-氮杂螺[2.5]辛烷-6-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-134)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.81(s,1H),8.17(s,1H),7.44(d,J＝2.5Hz,1H),7.36(dd,J＝10.2,2.6Hz,1H),7.29(dd,J＝8.8,4.5Hz,1H),7.01(d,J＝8.4Hz,1H),6.89(td,J＝9.3,2.6Hz,1H),6.82(dd,J＝8.4,2.6Hz,1H),6.76(d,J＝2.6Hz,1H),4.55(s,2H),3.68(t,J＝5.9Hz,2H),3.16(t,J＝5.4Hz,4H),2.79(t,J＝5.7Hz,2H),1.44(t,J＝5.4Hz,4H),0.32(s,4H).LCMS(ESI)m/z[M+H]+:419.0.N-(5-fluoro-1H-indol-3-yl)-6-(6-azaspiro[2.5]octane-6-yl)-3,4-dihydroisoquinoline-2(1H) - The preparation method of formamide (I-134) is the same as that of compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.81 (s, 1H), 8.17 (s, 1H), 7.44 (d, J = 2.5Hz, 1H), 7.36 (dd, J = 10.2, 2.6Hz, 1H),7.29(dd,J＝8.8,4.5Hz,1H),7.01(d,J＝8.4Hz,1H),6.89(td,J＝9.3,2.6Hz,1H),6.82(dd,J＝8.4 ,2.6Hz,1H),6.76(d,J＝2.6Hz,1H),4.55(s,2H),3.68(t,J＝5.9Hz,2H),3.16(t,J＝5.4Hz,4H), 2.79(t,J＝5.7Hz,2H),1.44(t,J＝5.4Hz,4H),0.32(s,4H).LCMS(ESI)m/z[M+H] + :419.0.
实施例135 N-(1H-吲哚-3-基)-6-(吡咯-1-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-135)
Example 135 N-(1H-indol-3-yl)-6-(pyrrol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-135)
步骤①：6-(吡咯-1-基)-3,4-二氢异喹啉-2(1H)-Boc(135-1)
Step ①: 6-(pyrrol-1-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(135-1)
6-(吡咯-1-基)-3,4-二氢异喹啉-2(1H)-Boc(135-1)的制备方法同化合物22-1。1H NMR(400MHz,CDCl3)δ6.96(d,J＝8.4Hz,1H),6.45(dd,J＝8.4,2.5Hz,1H),6.33(d,J＝2.2Hz,1H),4.47(s,2H),3.62(s,2H),3.32–3.19(m,4H),2.79(d,J＝5.0Hz,2H),2.04–1.90(m,4H),1.48(d,J＝8.3Hz,9H).The preparation method of 6-(pyrrol-1-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(135-1) is the same as that of compound 22-1. 1 H NMR (400MHz, CDCl 3 ) δ6.96 (d, J = 8.4Hz, 1H), 6.45 (dd, J = 8.4, 2.5Hz, 1H), 6.33 (d, J = 2.2Hz, 1H), 4.47 (s,2H),3.62(s,2H),3.32–3.19(m,4H),2.79(d,J＝5.0Hz,2H),2.04–1.90(m,4H),1.48(d,J＝8.3 Hz,9H).
步骤②：6-(吡咯-1-基)-3,4-二氢异喹啉-2(1H)-Boc(135-2)
Step ②: 6-(pyrrole-1-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(135-2)
6-(吡咯-1-基)-3,4-二氢异喹啉-2(1H)-Boc(135-2)的制备同化合物10-2。LCMS(ESI)m/z[M+H]+:203.2.The preparation of 6-(pyrrol-1-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(135-2) is the same as compound 10-2. LCMS(ESI)m/z[M+H] + :203.2.
步骤③：N-(1H-吲哚-3-基)-6-(吡咯-1-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-135)
Step ③: N-(1H-indol-3-yl)-6-(pyrrol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-135)
N-(1H-吲哚-3-基)-6-(吡咯烷-1-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-135)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.66(s,1H),8.12(s,1H),7.59(d,J＝8.1Hz,1H),7.33(d,J＝2.2Hz,1H),7.28(d,J＝8.1Hz,1H),7.04(t,J＝7.5Hz,1H),6.97–6.89(m,2H),6.40(d,J＝8.2Hz,1H),6.34(s,1H),4.52(s,2H),3.66(t,J＝5.9Hz,2H),3.17(d,J＝6.3Hz,4H),2.77(t,J＝5.5Hz,2H),1.92(s,4H).LCMS(ESI)m/z[M+H]+:361.2.The preparation method of N-(1H-indol-3-yl)-6-(pyrrolidin-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-135) is the same as Compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.66 (s, 1H), 8.12 (s, 1H), 7.59 (d, J = 8.1Hz, 1H), 7.33 (d, J = 2.2Hz, 1H) ,7.28(d,J＝8.1Hz,1H),7.04(t,J＝7.5Hz,1H),6.97–6.89(m,2H),6.40(d,J＝8.2Hz,1H),6.34(s, 1H),4.52(s,2H),3.66(t,J＝5.9Hz,2H),3.17(d,J＝6.3Hz,4H),2.77(t,J＝5.5Hz,2H),1.92(s, 4H).LCMS(ESI)m/z[M+H] + :361.2.
实施例136 6-(苯并[b]噻吩-3-基)-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-136)
Example 136 6-(benzo[b]thiophen-3-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I -136)
步骤①：6-(苯并[b]噻吩-3-基)-3,4-二氢异喹啉-2(1H)-Boc(136-1)
Step ①: 6-(benzo[b]thiophen-3-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(136-1)
6-(苯并[b]噻吩-3-基)-3,4-二氢异喹啉-2(1H)-Boc(136-1)的制备方法同化合物10-1。1H NMR(400MHz,CDCl3)δ7.98–7.83(m,2H),7.47–7.30(m,5H),7.23(d,J＝7.3Hz,1H),4.65(s,2H),3.71(s,2H),2.92(s,2H),1.51(s,9H).The preparation method of 6-(benzo[b]thiophen-3-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(136-1) is the same as compound 10-1. 1 H NMR (400MHz, CDCl 3 ) δ7.98–7.83 (m, 2H), 7.47–7.30 (m, 5H), 7.23 (d, J = 7.3Hz, 1H), 4.65 (s, 2H), 3.71 ( s,2H),2.92(s,2H),1.51(s,9H).
步骤②：6-(苯并[b]噻吩-3-基)-1,2,3,4-四氢异喹啉(136-2)
Step ②: 6-(benzo[b]thiophen-3-yl)-1,2,3,4-tetrahydroisoquinoline (136-2)
6-(苯并[b]噻吩-3-基)-1,2,3,4-四氢异喹啉(136-2)的制备方法同化合物10-2。LCMS(ESI)m/z[M+H]+:266.2.The preparation method of 6-(benzo[b]thiophen-3-yl)-1,2,3,4-tetrahydroisoquinoline (136-2) is the same as that of compound 10-2. LCMS(ESI)m/z[M+H] + :266.2.
步骤③：6-(苯并[b]噻吩-3-基)-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺 (I-136)
Step ③: 6-(benzo[b]thiophen-3-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-136)
6-(苯并[b]噻吩-3-基)-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-136)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.71(s,1H),8.28(s,1H),7.91–8.09(m,3H),7.80(s,1H),7.63(d,J＝7.8Hz,1H),7.51–7.27(m,6H),7.07(t,J＝7.6Hz,1H),6.96(t,J＝7.4Hz,1H),4.76(s,2H),3.80(t,J＝5.8Hz,2H),2.97(s,2H).LCMS(ESI)m/z[M+H]+:424.1.6-(benzo[b]thiophen-3-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-136) The preparation method is the same as compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.71 (s, 1H), 8.28 (s, 1H), 7.91–8.09 (m, 3H), 7.80 (s, 1H), 7.63 (d, J＝7.8 Hz,1H),7.51–7.27(m,6H),7.07(t,J＝7.6Hz,1H),6.96(t,J＝7.4Hz,1H),4.76(s,2H),3.80(t,J ＝5.8Hz,2H),2.97(s,2H).LCMS(ESI)m/z[M+H] + :424.1.
实施例137 6-(苯并呋喃-5-基)-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-137)
Example 137 6-(benzofuran-5-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-137)
步骤①：6-(苯并呋喃-5-基)-3,4-二氢异喹啉-2(1H)-Boc(137-1)
Step ①: 6-(benzofuran-5-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(137-1)
6-(苯并呋喃-5-基)-3,4-二氢异喹啉-2(1H)-Boc(137-1)的制备方法同化合物10-1。1H NMR(400MHz,CDCl3)δ7.77(s,1H),7.66(d,J＝2.1Hz,1H),7.55(d,J＝8.6Hz,1H),7.50(dd,J＝8.6,1.8Hz,1H),7.44(d,J＝8.0Hz,1H),7.39(s,1H),7.19(d,J＝7.6Hz,1H),6.81(d,J＝1.5Hz,1H),4.63(s,2H),3.69(s,2H),2.91(s,2H),1.51(s,9H).The preparation method of 6-(benzofuran-5-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(137-1) is the same as compound 10-1. 1 H NMR (400MHz, CDCl 3 ) δ7.77 (s, 1H), 7.66 (d, J = 2.1Hz, 1H), 7.55 (d, J = 8.6Hz, 1H), 7.50 (dd, J = 8.6, 1.8Hz,1H),7.44(d,J＝8.0Hz,1H),7.39(s,1H),7.19(d,J＝7.6Hz,1H),6.81(d,J＝1.5Hz,1H),4.63 (s,2H),3.69(s,2H),2.91(s,2H),1.51(s,9H).
步骤②：6-(苯并呋喃-5-基)-1,2,3,4-四氢异喹啉(137-2)
Step ②: 6-(benzofuran-5-yl)-1,2,3,4-tetrahydroisoquinoline (137-2)
6-(苯并呋喃-5-基)-1,2,3,4-四氢异喹啉(137-2)的制备方法同化合物10-2。LCMS(ESI)m/z[M+H]+:250.2.The preparation method of 6-(benzofuran-5-yl)-1,2,3,4-tetrahydroisoquinoline (137-2) is the same as that of compound 10-2. LCMS(ESI)m/z[M+H] + :250.2.
步骤③：6-(苯并呋喃-5-基)-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-137)Step ③: 6-(benzofuran-5-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-137)
6-(苯并呋喃-5-基)-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-137)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.70(s,1H),8.27(s,1H),8.03(d, J＝2.1Hz,1H),7.92(s,1H),7.68–7.57(m,3H),7.52(d,J＝5.8Hz,2H),7.37(d,J＝2.4Hz,1H),7.29(dd,J＝12.3,8.4Hz,2H),7.06(t,J＝7.5Hz,1H),7.01(s,1H),6.96(t,J＝7.6Hz,1H),4.72(s,2H),3.78(t,J＝5.9Hz,2H),2.96(t,J＝6.0Hz,2H).LCMS(ESI)m/z[M+H]+:408.1.Preparation method of 6-(benzofuran-5-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-137) Same as compound I-1. 1 H NMR(400MHz, DMSO-d 6 )δ10.70(s,1H),8.27(s,1H),8.03(d, J＝2.1Hz,1H),7.92(s,1H),7.68–7.57(m,3H),7.52(d,J＝5.8Hz,2H),7.37(d,J＝2.4Hz,1H),7.29( dd,J＝12.3,8.4Hz,2H),7.06(t,J＝7.5Hz,1H),7.01(s,1H),6.96(t,J＝7.6Hz,1H),4.72(s,2H), 3.78(t,J＝5.9Hz,2H),2.96(t,J＝6.0Hz,2H).LCMS(ESI)m/z[M+H] + :408.1.
实施例138 6-(苯并呋喃-5-基)-N-(5,6-二氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-138)
Example 138 6-(benzofuran-5-yl)-N-(5,6-difluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)- Formamide (I-138)
6-(苯并呋喃-5-基)-N-(5,6-二氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-138)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.89(s,1H),8.31(s,1H),8.04(d,J＝2.1Hz,1H),7.92(d,J＝1.4Hz,1H),7.66(t,J＝8.7Hz,2H),7.61(t,J＝5.9Hz,2H),7.52(s,1H),7.46(d,J＝2.4Hz,1H),7.30(dd,J＝13.0,6.3Hz,2H),7.01(d,J＝1.5Hz,1H),4.72(s,2H),3.77(t,J＝5.8Hz,2H),2.96(t,J＝5.6Hz,2H).LCMS(ESI)m/z[M+H]+:444.3.6-(Benzofuran-5-yl)-N-(5,6-difluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide ( The preparation method of I-138) is the same as that of compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.89 (s, 1H), 8.31 (s, 1H), 8.04 (d, J = 2.1Hz, 1H), 7.92 (d, J = 1.4Hz, 1H) ,7.66(t,J＝8.7Hz,2H),7.61(t,J＝5.9Hz,2H),7.52(s,1H),7.46(d,J＝2.4Hz,1H),7.30(dd,J＝ 13.0,6.3Hz,2H),7.01(d,J＝1.5Hz,1H),4.72(s,2H),3.77(t,J＝5.8Hz,2H),2.96(t,J＝5.6Hz,2H) .LCMS(ESI)m/z[M+H] + :444.3.
实施例139 6-(苯并呋喃-5-基)-N-(5-氯-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-139)
Example 139 6-(benzofuran-5-yl)-N-(5-chloro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide ( I-139)
6-(苯并呋喃-5-基)-N-(5-氯-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-139)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.92(s,1H),8.33(s,1H),8.03(d,J＝2.1Hz,1H),7.92(s,1H),7.72(d,J＝1.8Hz,1H),7.67(d,J＝8.6Hz,1H),7.60(dd,J＝8.6,1.6Hz,1H),7.52(d,J＝5.8Hz,2H),7.48(d,J＝2.3Hz,1H),7.31(dd,J＝16.8,8.5Hz,2H),7.06(dd,J＝8.6,2.0Hz,1H),7.01(d,J＝1.4Hz,1H),4.72(s,2H),3.78(t,J＝5.7Hz,2H),2.96(t,J＝5.6Hz,2H).LCMS(ESI)m/z[M+H]+:442.3.6-(Benzofuran-5-yl)-N-(5-chloro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-139 ), the preparation method is the same as compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.92 (s, 1H), 8.33 (s, 1H), 8.03 (d, J = 2.1Hz, 1H), 7.92 (s, 1H), 7.72 (d, J＝1.8Hz,1H),7.67(d,J＝8.6Hz,1H),7.60(dd,J＝8.6,1.6Hz,1H),7.52(d,J＝5.8Hz,2H),7.48(d, J＝2.3Hz,1H),7.31(dd,J＝16.8,8.5Hz,2H),7.06(dd,J＝8.6,2.0Hz,1H),7.01(d,J＝1.4Hz,1H),4.72( s,2H),3.78(t,J＝5.7Hz,2H),2.96(t,J＝5.6Hz,2H).LCMS(ESI)m/z[M+H] + :442.3.
实施例140 6-(苯并呋喃-5-基)-N-(5-氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-140)
Example 140 6-(benzofuran-5-yl)-N-(5-fluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide ( I-140)
6-(苯并呋喃-5-基)-N-(5-氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-140) 的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.82(s,1H),8.26(s,1H),8.03(d,J＝2.1Hz,1H),7.92(d,J＝1.5Hz,1H),7.67(d,J＝8.6Hz,1H),7.59(dd,J＝8.6,1.7Hz,1H),7.52(d,J＝5.7Hz,2H),7.46(d,J＝2.4Hz,1H),7.38(dd,J＝10.2,2.5Hz,1H),7.32–7.26(m,2H),7.01(d,J＝1.4Hz,1H),6.90(td,J＝9.1,2.5Hz,1H),4.71(s,2H),3.77(t,J＝5.8Hz,2H),2.95(t,J＝5.6Hz,2H).LCMS(ESI)m/z[M+H]+:426.3.6-(Benzofuran-5-yl)-N-(5-fluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-140 ) The preparation method is the same as compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.82 (s, 1H), 8.26 (s, 1H), 8.03 (d, J = 2.1Hz, 1H), 7.92 (d, J = 1.5Hz, 1H) ,7.67(d,J＝8.6Hz,1H),7.59(dd,J＝8.6,1.7Hz,1H),7.52(d,J＝5.7Hz,2H),7.46(d,J＝2.4Hz,1H) ,7.38(dd,J＝10.2,2.5Hz,1H),7.32–7.26(m,2H),7.01(d,J＝1.4Hz,1H),6.90(td,J＝9.1,2.5Hz,1H), 4.71(s,2H),3.77(t,J＝5.8Hz,2H),2.95(t,J＝5.6Hz,2H).LCMS(ESI)m/z[M+H] + :426.3.
实施例141 6-(苯并呋喃-5-基)-N-(5-氯-6-氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-141)
Example 141 6-(benzofuran-5-yl)-N-(5-chloro-6-fluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H) -Formamide (I-141)
6-(苯并呋喃-5-基)-N-(5-氯-6-氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-141)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.96(s,1H),8.36(s,1H),8.04(s,1H),7.92(s,1H),7.70–7.65(m,2H),7.61(s,2H),7.53(s,1H),7.48(d,J＝2.1Hz,1H),7.33–7.27(m,2H),7.01(s,1H),4.72(s,2H),3.78(t,J＝5.7Hz,2H),2.96(s,2H).LCMS(ESI)m/z[M+H]+:460.1.6-(Benzofuran-5-yl)-N-(5-chloro-6-fluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide The preparation method of (I-141) is the same as that of compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.96(s,1H),8.36(s,1H),8.04(s,1H),7.92(s,1H),7.70–7.65(m,2H), 7.61(s,2H),7.53(s,1H),7.48(d,J＝2.1Hz,1H),7.33–7.27(m,2H),7.01(s,1H),4.72(s,2H),3.78 (t,J＝5.7Hz,2H),2.96(s,2H).LCMS(ESI)m/z[M+H] + :460.1.
实施例142 6-(咪唑并[1,2-a]吡啶-6-基)-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-142)
Example 142 6-(imidazo[1,2-a]pyridin-6-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)- Formamide (I-142)
步骤①：6-(咪唑并[1,2-a]吡啶-6-基)-3,4-二氢异喹啉-2(1H)-Boc(142-1)
Step ①: 6-(Imidazo[1,2-a]pyridin-6-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(142-1)
6-(咪唑并[1,2-a]吡啶-6-基)-3,4-二氢异喹啉-2(1H)-Boc(142-1)的制备方法同化合物10-1。1H NMR(400MHz,CDCl3)δ8.30(s,1H),7.69(d,J＝4.8Hz,2H),7.54(dd,J＝7.5,1.5Hz,2H),7.44(dd,J＝4.8,1.7Hz,1H),7.42–7.32(m,2H),4.63(s,2H),3.70(d,J＝2.9Hz,2H),2.91(s,2H),1.49(d,J＝8.6Hz,9H).The preparation method of 6-(imidazo[1,2-a]pyridin-6-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(142-1) is the same as compound 10-1. 1 H NMR (400MHz, CDCl 3 ) δ8.30 (s, 1H), 7.69 (d, J = 4.8Hz, 2H), 7.54 (dd, J = 7.5, 1.5Hz, 2H), 7.44 (dd, J = 4.8,1.7Hz,1H),7.42–7.32(m,2H),4.63(s,2H),3.70(d,J＝2.9Hz,2H),2.91(s,2H),1.49(d,J＝8.6 Hz,9H).
步骤②：6-(咪唑并[1,2-a]吡啶-6-基)-1,2,3,4-四氢异喹啉(142-2)
Step ②: 6-(imidazo[1,2-a]pyridin-6-yl)-1,2,3,4-tetrahydroisoquinoline (142-2)
6-(咪唑并[1,2-a]吡啶-6-基)-1,2,3,4-四氢异喹啉(142-2)的制备方法同化合物10-2。LCMS(ESI)m/z[M+H]+:250.3.The preparation method of 6-(imidazo[1,2-a]pyridin-6-yl)-1,2,3,4-tetrahydroisoquinoline (142-2) is the same as compound 10-2. LCMS(ESI)m/z[M+H] + :250.3.
步骤③：6-(咪唑并[1,2-a]吡啶-6-基)-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-142)
Step ③: 6-(imidazo[1,2-a]pyridin-6-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)- Formamide(I-142)
6-(咪唑并[1,2-a]吡啶-6-基)-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-142)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.71(s,1H),8.93(s,1H),8.29(s,1H),7.96(s,1H),7.74–7.45(m,6H),7.37(d,J＝2.0Hz,1H),7.31(d,J＝8.0Hz,2H),7.06(t,J＝7.5Hz,1H),6.96(t,J＝7.3Hz,1H),4.72(s,2H),3.78(t,J＝5.8Hz,2H),2.96(s,2H).LCMS(ESI)m/z[M+H]+:408.2.6-(Imidazo[1,2-a]pyridin-6-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide ( The preparation method of I-142) is the same as that of compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.71(s,1H),8.93(s,1H),8.29(s,1H),7.96(s,1H),7.74–7.45(m,6H), 7.37(d,J＝2.0Hz,1H),7.31(d,J＝8.0Hz,2H),7.06(t,J＝7.5Hz,1H),6.96(t,J＝7.3Hz,1H),4.72( s,2H),3.78(t,J＝5.8Hz,2H),2.96(s,2H).LCMS(ESI)m/z[M+H] + :408.2.
实施例143 6-(苯并[b]噻吩-5-基)-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-143)
Example 143 6-(benzo[b]thiophen-5-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I -143)
步骤①：6-(苯并噻吩-5-基)-3,4-二氢异喹啉-2(1H)-Boc(143-1)
Step ①: 6-(benzothiophen-5-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(143-1)
6-(苯并噻吩-5-基)-3,4-二氢异喹啉-2(1H)-羧酸叔丁酯(143-1)的制备方法同化合物10-1。1H NMR(400MHz,CD3OD)δ8.03(s,1H),7.91(d,J＝8.4Hz,1H),7.61–7.54(m,2H),7.51–7.43(m,2H),7.40(d,J＝5.5Hz,1H),7.18(d,J＝8.0Hz,1H),4.58(s,2H),3.65(t,J＝5.9Hz,2H),2.88(t,J＝6.0Hz,2H),1.50(s,9H).The preparation method of 6-(benzothiophen-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester (143-1) is the same as compound 10-1. 1 H NMR (400MHz, CD 3 OD) δ8.03 (s, 1H), 7.91 (d, J = 8.4Hz, 1H), 7.61–7.54 (m, 2H), 7.51–7.43 (m, 2H), 7.40 (d,J＝5.5Hz,1H),7.18(d,J＝8.0Hz,1H),4.58(s,2H),3.65(t,J＝5.9Hz,2H),2.88(t,J＝6.0Hz ,2H),1.50(s,9H).
步骤②：6-(苯并噻吩-5-基)-1,2,4-四氢异喹啉(143-2)
Step ②: 6-(benzothiophen-5-yl)-1,2,4-tetrahydroisoquinoline (143-2)
6-(苯并噻吩-5-基)-1,2,4-四氢异喹啉(143-2)的制备方法同化合物10-2。LCMS(ESI)m/z[M+H]+:266.1.The preparation method of 6-(benzothiophen-5-yl)-1,2,4-tetrahydroisoquinoline (143-2) is the same as compound 10-2. LCMS(ESI)m/z[M+H] + :266.1.
步骤③：6-(苯并[b]噻吩-5-基)-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺 (I-143)
Step ③: 6-(benzo[b]thiophen-5-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-143)
6-(苯并[b]噻吩-5-基)-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-143)的制备方法同化合物I-41。1H NMR(400MHz,DMSO-d6)δ10.71(s,1H),8.28(s,1H),8.17(d,J＝1.8Hz,1H),8.07(d,J＝8.4Hz,1H),7.80(d,J＝5.4Hz,1H),7.67(dd,J＝8.4,1.8Hz,1H),7.64–7.56(m,3H),7.51(d,J＝5.4Hz,1H),7.37(d,J＝2.5Hz,1H),7.30(dd,J＝8.3,4.3Hz,2H),7.06(t,J＝7.5Hz,1H),6.95(t,J＝7.4Hz,1H),4.72(s,2H),3.78(t,J＝5.8Hz,2H),2.96(t,J＝5.9Hz,2H).LCMS(ESI)m/z[M+H]+:424.2.6-(benzo[b]thiophen-5-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-143) The preparation method is the same as compound I-41. 1 H NMR (400MHz, DMSO-d 6 ) δ10.71 (s, 1H), 8.28 (s, 1H), 8.17 (d, J = 1.8Hz, 1H), 8.07 (d, J = 8.4Hz, 1H) ,7.80(d,J＝5.4Hz,1H),7.67(dd,J＝8.4,1.8Hz,1H),7.64–7.56(m,3H),7.51(d,J＝5.4Hz,1H),7.37( d,J＝2.5Hz,1H),7.30(dd,J＝8.3,4.3Hz,2H),7.06(t,J＝7.5Hz,1H),6.95(t,J＝7.4Hz,1H),4.72( s,2H),3.78(t,J＝5.8Hz,2H),2.96(t,J＝5.9Hz,2H).LCMS(ESI)m/z[M+H] + :424.2.
实施例144 6-(苯并[b]噻吩-5-基)-N-(5-氯-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-144)
Example 144 6-(benzo[b]thiophen-5-yl)-N-(5-chloro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)- Formamide (I-144)
6-(苯并[b]噻吩-5-基)-N-(5-氯-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-144)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.93(s,1H),8.34(s,1H),8.18(d,J＝1.7Hz,1H),8.08(d,J＝8.4Hz,1H),7.81(d,J＝5.4Hz,1H),7.73(d,J＝2.1Hz,1H),7.68(dd,J＝8.5,1.8Hz,1H),7.58(d,J＝6.6Hz,2H),7.52(d,J＝5.4Hz,1H),7.48(d,J＝2.4Hz,1H),7.32(t,J＝8.6Hz,2H),7.06(dd,J＝8.6,2.1Hz,1H),4.73(s,2H),3.79(t,J＝5.8Hz,2H),2.97(t,J＝5.9Hz,2H).6-(benzo[b]thiophen-5-yl)-N-(5-chloro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide ( The preparation method of I-144) is the same as that of compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.93 (s, 1H), 8.34 (s, 1H), 8.18 (d, J = 1.7Hz, 1H), 8.08 (d, J = 8.4Hz, 1H) ,7.81(d,J＝5.4Hz,1H),7.73(d,J＝2.1Hz,1H),7.68(dd,J＝8.5,1.8Hz,1H),7.58(d,J＝6.6Hz,2H) ,7.52(d,J＝5.4Hz,1H),7.48(d,J＝2.4Hz,1H),7.32(t,J＝8.6Hz,2H),7.06(dd,J＝8.6,2.1Hz,1H) ,4.73(s,2H),3.79(t,J＝5.8Hz,2H),2.97(t,J＝5.9Hz,2H).
实施例145 6-(苯并[b]噻吩-5-基)-N-(5-氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-145)
Example 145 6-(benzo[b]thiophen-5-yl)-N-(5-fluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)- Formamide (I-145)
6-(苯并[b]噻吩-5-基)-N-(5-氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-145)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.83(s,1H),8.27(s,1H),8.18(s,1H),8.08(d,J＝8.4Hz,1H),7.81(d,J＝5.4Hz,1H),7.68(dd,J＝8.5,1.6Hz,1H),7.58(d,J＝7.0Hz,2H),7.52(d,J＝5.4Hz,1H),7.46(d,J＝2.4Hz,1H),7.39(dd,J＝10.4,2.6Hz,1H),7.31(dd,J＝9.0,3.7Hz,2H),6.90(td,J＝9.0,2.6Hz,1H),4.72(s,2H),3.78(t,J＝5.9Hz,2H),2.97(t,J＝5.7Hz,2H).LCMS(ESI)m/z [M+H]+:442.4.6-(benzo[b]thiophen-5-yl)-N-(5-fluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide ( The preparation method of I-145) is the same as that of compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.83 (s, 1H), 8.27 (s, 1H), 8.18 (s, 1H), 8.08 (d, J = 8.4Hz, 1H), 7.81 (d, J＝5.4Hz,1H),7.68(dd,J＝8.5,1.6Hz,1H),7.58(d,J＝7.0Hz,2H),7.52(d,J＝5.4Hz,1H),7.46(d, J＝2.4Hz,1H),7.39(dd,J＝10.4,2.6Hz,1H),7.31(dd,J＝9.0,3.7Hz,2H),6.90(td,J＝9.0,2.6Hz,1H), 4.72(s,2H),3.78(t,J＝5.9Hz,2H),2.97(t,J＝5.7Hz,2H).LCMS(ESI)m/z [M+H] + :442.4.
实施例146 6-(苯并[b]噻吩-5-基)-N-(5,6-二氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-146)
Example 146 6-(benzo[b]thiophen-5-yl)-N-(5,6-difluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2( 1H)-Formamide (I-146)
6-(苯并[b]噻吩-5-基)-N-(5,6-二氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-146)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.89(s,1H),8.31(s,1H),8.18(d,J＝1.8Hz,1H),8.08(d,J＝8.4Hz,1H),7.81(d,J＝5.4Hz,1H),7.67(dd,J＝8.4,1.8Hz,1H),7.65–7.61(m,1H),7.58(d,J＝6.9Hz,2H),7.52(d,J＝5.5Hz,1H),7.46(d,J＝2.5Hz,1H),7.32(dd,J＝10.8,7.5Hz,2H),4.72(s,2H),3.78(t,J＝5.9Hz,2H),2.97(t,J＝6.0Hz,2H).LCMS(ESI)m/z[M+H]+:460.1.6-(benzo[b]thiophen-5-yl)-N-(5,6-difluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)- The preparation method of formamide (I-146) is the same as that of compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.89 (s, 1H), 8.31 (s, 1H), 8.18 (d, J = 1.8Hz, 1H), 8.08 (d, J = 8.4Hz, 1H) ,7.81(d,J＝5.4Hz,1H),7.67(dd,J＝8.4,1.8Hz,1H),7.65–7.61(m,1H),7.58(d,J＝6.9Hz,2H),7.52( d,J＝5.5Hz,1H),7.46(d,J＝2.5Hz,1H),7.32(dd,J＝10.8,7.5Hz,2H),4.72(s,2H),3.78(t,J＝5.9 Hz,2H),2.97(t,J＝6.0Hz,2H).LCMS(ESI)m/z[M+H] + :460.1.
实施例147 6-(苯并[b]噻吩-5-基)-N-(5-氯-6-氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-147)
Example 147 6-(benzo[b]thiophen-5-yl)-N-(5-chloro-6-fluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2 (1H)-Carboxamide (I-147)
6-(苯并[b]噻吩-5-基)-N-(5-氯-6-氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-147)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.97(s,1H),8.37(s,1H),8.18(s,1H),8.08(d,J＝8.4Hz,1H),7.87(d,J＝7.5Hz,1H),7.81(d,J＝5.4Hz,1H),7.68(d,J＝8.6Hz,1H),7.58(d,J＝6.6Hz,2H),7.54–7.46(m,2H),7.35–7.27(m,2H),4.73(s,2H),3.78(t,J＝5.9Hz,2H),2.97(t,J＝5.8Hz,2H).6-(benzo[b]thiophen-5-yl)-N-(5-chloro-6-fluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H) - The preparation method of formamide (I-147) is the same as that of compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.97 (s, 1H), 8.37 (s, 1H), 8.18 (s, 1H), 8.08 (d, J = 8.4Hz, 1H), 7.87 (d, J＝7.5Hz,1H),7.81(d,J＝5.4Hz,1H),7.68(d,J＝8.6Hz,1H),7.58(d,J＝6.6Hz,2H),7.54–7.46(m, 2H),7.35–7.27(m,2H),4.73(s,2H),3.78(t,J＝5.9Hz,2H),2.97(t,J＝5.8Hz,2H).
实施例148 N-(1H-吲哚-3-基)-6-(1H-吲哚-5-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-148)
Example 148 N-(1H-indol-3-yl)-6-(1H-indol-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-148 )
步骤①：6-(1H-吲哚-5-基)-3,4-二氢异喹啉-2(1H)-Boc(148-1)
Step ①: 6-(1H-indol-5-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(148-1)
6-(1H-吲哚-5-基)-3,4-二氢异喹啉-2(1H)-Boc(148-1)的制备方法同化合物10-1。1H NMR(400MHz,CD3OD)δ7.72(d,J＝2.0Hz,1H),7.43–7.29(m,4H),7.23(t,J＝ 2.8Hz,1H),7.05(t,J＝9.5Hz,1H),6.47(d,J＝3.2Hz,1H),4.48(s,2H),3.54(t,J＝5.9Hz,2H),2.75(d,J＝6.2Hz,2H),1.47(s,9H).The preparation method of 6-(1H-indol-5-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(148-1) is the same as compound 10-1. 1 H NMR (400MHz, CD 3 OD) δ7.72 (d, J＝2.0Hz, 1H), 7.43–7.29 (m, 4H), 7.23 (t, J＝ 2.8Hz,1H),7.05(t,J＝9.5Hz,1H),6.47(d,J＝3.2Hz,1H),4.48(s,2H),3.54(t,J＝5.9Hz,2H),2.75 (d,J＝6.2Hz,2H),1.47(s,9H).
步骤②：6-(1H-吲哚-5-基)-1,2,4-四氢异喹啉(148-2)
Step ②: 6-(1H-indol-5-yl)-1,2,4-tetrahydroisoquinoline (148-2)
6-(1H-吲哚-5-基)-1,2,4-四氢异喹啉(148-2)的制备方法同化合物10-2。LCMS(ESI)m/z[M+H]+:249.1.The preparation method of 6-(1H-indol-5-yl)-1,2,4-tetrahydroisoquinoline (148-2) is the same as that of compound 10-2. LCMS(ESI)m/z[M+H] + :249.1.
步骤③：N-(1H-吲哚-3-基)-6-(1H-吲哚-5-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-148)
Step ③: N-(1H-indol-3-yl)-6-(1H-indol-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-148 )
N-(1H-吲哚-3-基)-6-(1H-吲哚-5-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-148)的制备方法同化合物I-41。1H NMR(400MHz,DMSO-d6)δ11.14(s,1H),10.71(s,1H),8.27(s,1H),7.81(s,1H),7.62(d,J＝7.9Hz,1H),7.51–7.44(m,3H),7.39(dd,J＝9.4,2.2Hz,3H),7.31(d,J＝8.1Hz,1H),7.24(d,J＝8.5Hz,1H),7.06(t,J＝7.5Hz,1H),6.96(t,J＝7.1Hz,1H),6.47(d,J＝2.6Hz,1H),4.70(s,2H),3.78(t,J＝5.8Hz,2H),2.95(t,J＝5.7Hz,2H).LCMS(ESI)m/z[M+H]+:406.9.Preparation of N-(1H-indol-3-yl)-6-(1H-indol-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-148) The method is the same as that of compound I-41. 1 H NMR (400MHz, DMSO-d 6 ) δ11.14 (s, 1H), 10.71 (s, 1H), 8.27 (s, 1H), 7.81 (s, 1H), 7.62 (d, J = 7.9Hz, 1H),7.51–7.44(m,3H),7.39(dd,J＝9.4,2.2Hz,3H),7.31(d,J＝8.1Hz,1H),7.24(d,J＝8.5Hz,1H), 7.06(t,J＝7.5Hz,1H),6.96(t,J＝7.1Hz,1H),6.47(d,J＝2.6Hz,1H),4.70(s,2H),3.78(t,J＝5.8 Hz, 2H), 2.95 (t, J = 5.7Hz, 2H). LCMS (ESI) m/z [M+H] + : 406.9.
实施例149 6-(苯并呋喃-6-基)-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-149)
Example 149 6-(benzofuran-6-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-149)
步骤①：6-(苯并呋喃-6-基)-3,4-二氢异喹啉-2(1H)-Boc(149-1)
Step ①: 6-(benzofuran-6-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(149-1)
6-(苯并呋喃-6-基)-3,4-二氢异喹啉-2(1H)-Boc(149-1)的制备方法同化合物10-1。1H NMR(400MHz,CDCl3)δ7.72(s,1H),7.64(d,J＝8.1Hz,2H),7.51–7.45(m,2H),7.42(s,1H),7.20(d,J＝7.9Hz,1H),6.82–6.77(m,1H),4.65(s,2H),3.71(s,2H),2.92(s,2H),1.55(s,9H). The preparation method of 6-(benzofuran-6-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(149-1) is the same as compound 10-1. 1 H NMR (400MHz, CDCl 3 ) δ7.72 (s, 1H), 7.64 (d, J = 8.1Hz, 2H), 7.51–7.45 (m, 2H), 7.42 (s, 1H), 7.20 (d, J＝7.9Hz,1H),6.82–6.77(m,1H),4.65(s,2H),3.71(s,2H),2.92(s,2H),1.55(s,9H).
步骤②：6-(苯并呋喃-6-基)-1,2,3,4-四氢异喹啉(149-2)
Step ②: 6-(benzofuran-6-yl)-1,2,3,4-tetrahydroisoquinoline (149-2)
6-(苯并呋喃-6-基)-1,2,3,4-四氢异喹啉(149-2)的制备方法同化合物10-2。LCMS(ESI)m/z[M+H]+:250.2.The preparation method of 6-(benzofuran-6-yl)-1,2,3,4-tetrahydroisoquinoline (149-2) is the same as compound 10-2. LCMS(ESI)m/z[M+H] + :250.2.
步骤③：6-(苯并呋喃-6-基)-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-149)
Step ③: 6-(benzofuran-6-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-149)
6-(苯并呋喃-6-基)-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-149)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.70(s,1H),8.27(s,1H),8.03(s,1H),7.89(s,1H),7.73(d,J＝8.2Hz,1H),7.62(d,J＝8.1Hz,1H),7.59(d,J＝4.4Hz,3H),7.38(s,1H),7.30(t,J＝9.2Hz,2H),7.06(t,J＝7.5Hz,1H),6.97(dd,J＝13.9,5.8Hz,2H),4.72(s,2H),3.78(t,J＝5.7Hz,2H),2.97(d,J＝5.1Hz,2H).LCMS(ESI)m/z[M+H]+:408.2.Preparation method of 6-(benzofuran-6-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-149) Same as compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.70 (s, 1H), 8.27 (s, 1H), 8.03 (s, 1H), 7.89 (s, 1H), 7.73 (d, J = 8.2Hz, 1H),7.62(d,J＝8.1Hz,1H),7.59(d,J＝4.4Hz,3H),7.38(s,1H),7.30(t,J＝9.2Hz,2H),7.06(t, J＝7.5Hz,1H),6.97(dd,J＝13.9,5.8Hz,2H),4.72(s,2H),3.78(t,J＝5.7Hz,2H),2.97(d,J＝5.1Hz, 2H).LCMS(ESI)m/z[M+H] + :408.2.
实施例150 6-(苯并呋喃-6-基)-N-(5,6-二氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-150)
Example 150 6-(benzofuran-6-yl)-N-(5,6-difluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)- Formamide(I-150)
6-(苯并呋喃-6-基)-N-(5,6-二氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-150)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.89(s,1H),8.31(s,1H),8.04(d,J＝2.1Hz,1H),7.90(s,1H),7.73(d,J＝8.2Hz,1H),7.67–7.52(m,4H),7.46(d,J＝2.3Hz,1H),7.37–7.25(m,2H),7.00(d,J＝1.5Hz,1H),4.72(s,2H),3.78(t,J＝5.8Hz,2H),2.97(t,J＝5.7Hz,2H).LCMS(ESI)m/z[M+H]+:444.0.6-(Benzofuran-6-yl)-N-(5,6-difluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide ( The preparation method of I-150) is the same as that of compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.89 (s, 1H), 8.31 (s, 1H), 8.04 (d, J = 2.1Hz, 1H), 7.90 (s, 1H), 7.73 (d, J＝8.2Hz,1H),7.67–7.52(m,4H),7.46(d,J＝2.3Hz,1H),7.37–7.25(m,2H),7.00(d,J＝1.5Hz,1H), 4.72(s,2H),3.78(t,J＝5.8Hz,2H),2.97(t,J＝5.7Hz,2H).LCMS(ESI)m/z[M+H] + :444.0.
实施例151 6-(苯并呋喃-6-基)-N-(5-氯-6-氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-151)
Example 151 6-(benzofuran-6-yl)-N-(5-chloro-6-fluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H) -Formamide (I-151)
6-(苯并呋喃-6-基)-N-(5-氯-6-氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-151)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.97(s,1H),8.36(s,1H),8.03(d,J＝2.0Hz,1H),7.95–7.80(m,2H),7.72(d,J＝8.1Hz,1H),7.58(d,J＝6.4Hz,3H),7.48(d,J＝2.2Hz,1H),7.31(t,J＝9.8Hz,2H),6.99(d,J＝1.5Hz,1H),4.72(s,2H),3.78(t,J＝5.7Hz,2H),2.96(t,J＝5.5Hz,2H).LCMS(ESI)m/z[M-H]-:458.0.6-(Benzofuran-6-yl)-N-(5-chloro-6-fluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide The preparation method of (I-151) is the same as that of compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.97 (s, 1H), 8.36 (s, 1H), 8.03 (d, J = 2.0Hz, 1H), 7.95–7.80 (m, 2H), 7.72 ( d,J＝8.1Hz,1H),7.58(d,J＝6.4Hz,3H),7.48(d,J＝2.2Hz,1H),7.31(t,J＝9.8Hz,2H),6.99(d, J＝1.5Hz,1H),4.72(s,2H),3.78(t,J＝5.7Hz,2H),2.96(t,J＝5.5Hz,2H).LCMS(ESI)m/z[MH] - :458.0.
实施例152 6-(苯并呋喃-6-基)-N-(5-氯-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-152)
Example 152 6-(benzofuran-6-yl)-N-(5-chloro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide ( I-152)
6-(苯并呋喃-6-基)-N-(5-氯-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-152)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.93(s,1H),8.33(s,1H),8.03(d,J＝2.1Hz,1H),7.89(s,1H),7.73(dd,J＝4.9,3.1Hz,2H),7.58(d,J＝6.0Hz,3H),7.48(d,J＝2.3Hz,1H),7.31(dd,J＝14.9,8.6Hz,2H),7.05(dd,J＝8.6,2.0Hz,1H),6.99(d,J＝1.5Hz,1H),4.72(s,2H),3.78(t,J＝5.8Hz,2H),2.96(t,J＝5.5Hz,2H).LCMS(ESI)m/z[M+Na]+:464.2.6-(Benzofuran-6-yl)-N-(5-chloro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-152 ), the preparation method is the same as compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.93 (s, 1H), 8.33 (s, 1H), 8.03 (d, J = 2.1Hz, 1H), 7.89 (s, 1H), 7.73 (dd, J＝4.9,3.1Hz,2H),7.58(d,J＝6.0Hz,3H),7.48(d,J＝2.3Hz,1H),7.31(dd,J＝14.9,8.6Hz,2H),7.05( dd,J＝8.6,2.0Hz,1H),6.99(d,J＝1.5Hz,1H),4.72(s,2H),3.78(t,J＝5.8Hz,2H),2.96(t,J＝5.5 Hz,2H).LCMS(ESI)m/z[M+Na] + :464.2.
实施例153 6-(苯并呋喃-6-基)-N-(5-氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-153)
Example 153 6-(benzofuran-6-yl)-N-(5-fluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide ( I-153)
6-(苯并呋喃-6-基)-N-(5-氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-153)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.84(s,1H),8.27(s,1H),8.03(d,J＝2.1Hz,1H),7.90(s,1H),7.73(d,J＝8.1Hz,1H),7.65–7.51(m,3H),7.46(d,J＝2.4Hz,1H),7.39(dd,J＝10.1,2.4Hz,1H),7.35–7.20(m,2H),7.00(d,J＝1.6Hz,1H),6.91(td,J＝9.2,2.5Hz,1H),4.72(s,2H),3.78(t,J＝5.8Hz,2H),2.96(t,J＝5.6Hz,2H).LCMS(ESI)m/z[M+H]+:426.3.6-(Benzofuran-6-yl)-N-(5-fluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-153 ), the preparation method is the same as compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.84 (s, 1H), 8.27 (s, 1H), 8.03 (d, J = 2.1Hz, 1H), 7.90 (s, 1H), 7.73 (d, J＝8.1Hz,1H),7.65–7.51(m,3H),7.46(d,J＝2.4Hz,1H),7.39(dd,J＝10.1,2.4Hz,1H),7.35–7.20(m,2H ),7.00(d,J＝1.6Hz,1H),6.91(td,J＝9.2,2.5Hz,1H),4.72(s,2H),3.78(t,J＝5.8Hz,2H),2.96(t ,J＝5.6Hz,2H).LCMS(ESI)m/z[M+H] + :426.3.
实施例154 6-(苯并[b]噻吩-6-基)-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-154)
Example 154 6-(benzo[b]thiophen-6-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I -154)
步骤①：2-(苯并[b]噻吩-6-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(154-1)
Step ①: 2-(benzo[b]thiophen-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (154-1)
2-(苯并[b]噻吩-6-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(154-1)的制备方法同化合物115-1。1H NMR(400MHz,CD3OD)δ8.27(s,1H),7.80(d,J＝8.0Hz,1H),7.68(dd,J＝8.0,1.0Hz,1H),7.62(d,J＝5.4Hz,1H),7.35(d,J＝5.5Hz,1H),1.34(s,12H).The preparation method of 2-(benzo[b]thiophen-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (154-1) is the same as that of compound 115- 1. 1 H NMR (400MHz, CD 3 OD) δ8.27(s,1H),7.80(d,J＝8.0Hz,1H),7.68(dd,J＝8.0,1.0Hz,1H),7.62(d,J =5.4Hz,1H),7.35(d,J=5.5Hz,1H),1.34(s,12H).
步骤②：6-(苯并噻吩-6-基)-3,4-二氢异喹啉-2(1H)-Boc(154-2)
Step ②: 6-(benzothiophen-6-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(154-2)
6-(苯并噻吩-6-基)-3,4-二氢异喹啉-2(1H)-Boc(154-2)的制备方法同化合物10-1。1H NMR(400MHz,CD3OD)δ8.03(d,J＝1.8Hz,1H),7.82(d,J＝8.3Hz,1H),7.57–7.51(m,2H),7.43(dd,J＝7.8,1.9Hz,1H),7.39(d,J＝1.9Hz,1H),7.34(d,J＝5.4Hz,1H),7.13(d,J＝8.0Hz,1H),4.53(s,2H),3.60(t,J＝5.8Hz,2H),2.82(t,J＝5.9Hz,2H),1.49(s,9H).The preparation method of 6-(benzothiophen-6-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(154-2) is the same as compound 10-1. 1 H NMR (400MHz, CD 3 OD) δ8.03(d,J＝1.8Hz,1H),7.82(d,J＝8.3Hz,1H),7.57–7.51(m,2H),7.43(dd,J ＝7.8,1.9Hz,1H),7.39(d,J＝1.9Hz,1H),7.34(d,J＝5.4Hz,1H),7.13(d,J＝8.0Hz,1H),4.53(s,2H ),3.60(t,J＝5.8Hz,2H),2.82(t,J＝5.9Hz,2H),1.49(s,9H).
步骤③：6-(苯并[b]噻吩-6-基)-1,2,4-四氢异喹啉(154-3)
Step ③: 6-(benzo[b]thiophen-6-yl)-1,2,4-tetrahydroisoquinoline (154-3)
6-(苯并[b]噻吩-6-基)-1,2,4-四氢异喹啉(154-3)的制备方法同化合物10-2。LCMS(ESI)m/z[M+H]+:266.0.The preparation method of 6-(benzo[b]thiophen-6-yl)-1,2,4-tetrahydroisoquinoline (154-3) is the same as that of compound 10-2. LCMS(ESI)m/z[M+H] + :266.0.
步骤④：6-(苯并[b]噻吩-6-基)-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-154)
Step ④: 6-(benzo[b]thiophen-6-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I -154)
6-(苯并[b]噻吩-6-基)-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-154)的制备方法同化合物I-41。1H NMR(400MHz,DMSO-d6)δ10.71(s,1H),8.32(s,1H),8.28(s,1H),7.95(d,J＝8.3Hz,1H),7.78(d,J＝5.4Hz,1H),7.70(dd,J＝8.4,1.7Hz,1H),7.64–7.58(m,3H),7.48(d,J＝5.4Hz,1H),7.37(d,J＝2.5Hz,1H),7.33–7.27(m,2H),7.06(t,J＝7.5Hz,1H),6.96(t,J＝7.5Hz,1H),4.73(s,2H),3.79(t,J＝5.9Hz,2H),2.96(t,J＝5.8Hz,2H).LCMS(ESI)m/z[M+H]+:424.2.6-(benzo[b]thiophen-6-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-154) The preparation method is the same as compound I-41. 1 H NMR (400MHz, DMSO-d 6 ) δ10.71 (s, 1H), 8.32 (s, 1H), 8.28 (s, 1H), 7.95 (d, J = 8.3Hz, 1H), 7.78 (d, J＝5.4Hz,1H),7.70(dd,J＝8.4,1.7Hz,1H),7.64–7.58(m,3H),7.48(d,J＝5.4Hz,1H),7.37(d,J＝2.5 Hz,1H),7.33–7.27(m,2H),7.06(t,J＝7.5Hz,1H),6.96(t,J＝7.5Hz,1H),4.73(s,2H),3.79(t,J ＝5.9Hz,2H),2.96(t,J＝5.8Hz,2H).LCMS(ESI)m/z[M+H] + :424.2.
实施例155 6-(苯并[b]噻吩-6-基)-N-(5-氯-1H-吲哚-3-基)-3,4-二氢异喹啉 -2(1H)-甲酰胺(I-155)
Example 155 6-(benzo[b]thiophen-6-yl)-N-(5-chloro-1H-indol-3-yl)-3,4-dihydroisoquinoline -2(1H)-Carboxamide (I-155)
6-(苯并[b]噻吩-6-基)-N-(5-氯-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-155)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.93(s,1H),8.33(s,1H),8.18(d,J＝1.8Hz,1H),8.08(d,J＝8.4Hz,1H),7.81(d,J＝5.5Hz,1H),7.74–7.66(m,2H),7.58(d,J＝7.0Hz,2H),7.52(d,J＝5.4Hz,1H),7.48(d,J＝2.5Hz,1H),7.32(t,J＝8.4Hz,2H),7.06(dd,J＝8.7,2.1Hz,1H),4.73(s,2H),3.79(t,J＝5.8Hz,2H),2.97(t,J＝5.9Hz,2H).6-(benzo[b]thiophen-6-yl)-N-(5-chloro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide ( The preparation method of I-155) is the same as that of compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.93 (s, 1H), 8.33 (s, 1H), 8.18 (d, J = 1.8Hz, 1H), 8.08 (d, J = 8.4Hz, 1H) ,7.81(d,J＝5.5Hz,1H),7.74–7.66(m,2H),7.58(d,J＝7.0Hz,2H),7.52(d,J＝5.4Hz,1H),7.48(d, J＝2.5Hz,1H),7.32(t,J＝8.4Hz,2H),7.06(dd,J＝8.7,2.1Hz,1H),4.73(s,2H),3.79(t,J＝5.8Hz, 2H),2.97(t,J=5.9Hz,2H).
实施例156 6-(苯并[b]噻吩-6-基)-N-(5-氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-156)
Example 156 6-(benzo[b]thiophen-6-yl)-N-(5-fluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)- Formamide(I-156)
6-(苯并[b]噻吩-6-基)-N-(5-氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-156)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.83(s,1H),8.27(s,1H),8.18(d,J＝1.8Hz,1H),8.08(d,J＝8.4Hz,1H),7.81(d,J＝5.4Hz,1H),7.68(dd,J＝8.5,1.8Hz,1H),7.58(d,J＝7.0Hz,2H),7.52(d,J＝5.4Hz,1H),7.46(d,J＝2.5Hz,1H),7.39(dd,J＝10.2,2.6Hz,1H),7.31(dd,J＝8.8,3.9Hz,2H),6.91(td,J＝9.2,2.6Hz,1H),4.72(s,2H),3.78(t,J＝5.8Hz,2H),2.97(t,J＝5.9Hz,2H).6-(benzo[b]thiophen-6-yl)-N-(5-fluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide ( The preparation method of I-156) is the same as that of compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.83 (s, 1H), 8.27 (s, 1H), 8.18 (d, J = 1.8Hz, 1H), 8.08 (d, J = 8.4Hz, 1H) ,7.81(d,J＝5.4Hz,1H),7.68(dd,J＝8.5,1.8Hz,1H),7.58(d,J＝7.0Hz,2H),7.52(d,J＝5.4Hz,1H) ,7.46(d,J＝2.5Hz,1H),7.39(dd,J＝10.2,2.6Hz,1H),7.31(dd,J＝8.8,3.9Hz,2H),6.91(td,J＝9.2,2.6 Hz,1H),4.72(s,2H),3.78(t,J＝5.8Hz,2H),2.97(t,J＝5.9Hz,2H).
实施例157 6-(苯并[b]噻吩-6-基)-N-(5,6-二氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-157)
Example 157 6-(benzo[b]thiophen-6-yl)-N-(5,6-difluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2( 1H)-Formamide (I-157)
6-(苯并[b]噻吩-6-基)-N-(5,6-二氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-157)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.90(s,1H),8.32(s,1H),8.17(d,J＝1.8Hz,1H),8.08(d,J＝8.4Hz,1H),7.81(d,J＝5.4Hz,1H),7.67(dd,J＝8.4,1.8Hz,1H),7.65–7.61(m,1H),7.58(d,J＝6.6Hz,2H),7.52(d,J＝5.5Hz,1H),7.46(d,J＝2.5Hz,1H),7.32(dd,J＝11.1,7.3Hz,2H),4.72(s,2H),3.78(t,J＝5.9Hz,2H),2.97(t,J＝5.8Hz,2H).6-(benzo[b]thiophen-6-yl)-N-(5,6-difluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)- The preparation method of formamide (I-157) is the same as that of compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.90 (s, 1H), 8.32 (s, 1H), 8.17 (d, J = 1.8Hz, 1H), 8.08 (d, J = 8.4Hz, 1H) ,7.81(d,J＝5.4Hz,1H),7.67(dd,J＝8.4,1.8Hz,1H),7.65–7.61(m,1H),7.58(d,J＝6.6Hz,2H),7.52( d,J＝5.5Hz,1H),7.46(d,J＝2.5Hz,1H),7.32(dd,J＝11.1,7.3Hz,2H),4.72(s,2H),3.78(t,J＝5.9 Hz,2H),2.97(t,J＝5.8Hz,2H).
实施例158 6-(苯并[b]噻吩-6-基)-N-(5-氯-6-氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-158)
Example 158 6-(benzo[b]thiophen-6-yl)-N-(5-chloro-6-fluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2 (1H)-Carboxamide (I-158)
6-(苯并[b]噻吩-6-基)-N-(5-氯-6-氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-158)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.97(s,1H),8.37(s,1H),8.18(d,J＝1.8Hz,1H),8.08(d,J＝8.4Hz,1H),7.87(d,J＝7.5Hz,1H),7.81(d,J＝5.4Hz,1H),7.67(dd,J＝8.3,1.8Hz,1H),7.58(d,J＝7.0Hz,2H),7.52(d,J＝5.4Hz,1H),7.48(d,J＝2.5Hz,1H),7.31(dd,J＝9.4,4.3Hz,2H),4.73(s,2H),3.78(t,J＝5.8Hz,2H),2.97(t,J＝5.8Hz,2H).6-(benzo[b]thiophen-6-yl)-N-(5-chloro-6-fluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H) - The preparation method of formamide (I-158) is the same as that of compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.97(s,1H),8.37(s,1H),8.18(d,J＝1.8Hz,1H),8.08(d,J＝8.4Hz,1H) ,7.87(d,J＝7.5Hz,1H),7.81(d,J＝5.4Hz,1H),7.67(dd,J＝8.3,1.8Hz,1H),7.58(d,J＝7.0Hz,2H) ,7.52(d,J＝5.4Hz,1H),7.48(d,J＝2.5Hz,1H),7.31(dd,J＝9.4,4.3Hz,2H),4.73(s,2H),3.78(t, J＝5.8Hz,2H),2.97(t,J＝5.8Hz,2H).
实施例159 6-(苯并呋喃-4-基)-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-159)
Example 159 6-(benzofuran-4-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-159)
步骤①：6-(苯并呋喃-4-基)-3,4-二氢异喹啉-2(1H)-Boc(159-1)
Step ①: 6-(benzofuran-4-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(159-1)
6-(苯并呋喃-4-基)-3,4-二氢异喹啉-2(1H)-Boc(159-1)的制备方法同化合物10-1。1H NMR(400MHz,CDCl3)δ7.67(d,J＝2.2Hz,1H),7.48(dd,J＝15.1,8.1Hz,2H),7.40(s,1H),7.36(t,J＝7.9Hz,1H),7.30(d,J＝7.4Hz,1H),7.23(d,J＝8.0Hz,1H),6.93(d,J＝2.1Hz,1H),4.65(s,2H),3.71(s,2H),2.92(s,2H),1.58(s,10H).The preparation method of 6-(benzofuran-4-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(159-1) is the same as compound 10-1. 1 H NMR (400MHz, CDCl 3 ) δ7.67 (d, J＝2.2Hz, 1H), 7.48 (dd, J＝15.1, 8.1Hz, 2H), 7.40 (s, 1H), 7.36 (t, J＝ 7.9Hz,1H),7.30(d,J＝7.4Hz,1H),7.23(d,J＝8.0Hz,1H),6.93(d,J＝2.1Hz,1H),4.65(s,2H),3.71 (s,2H),2.92(s,2H),1.58(s,10H).
步骤②：6-(苯并呋喃-4-基)-1,2,3,4-四氢异喹啉(159-2)
Step ②: 6-(benzofuran-4-yl)-1,2,3,4-tetrahydroisoquinoline (159-2)
6-(苯并呋喃-4-基)-1,2,3,4-四氢异喹啉(159-2)的制备方法同化合物10-2。LCMS(ESI)m/z[M+H]+:250.2.The preparation method of 6-(benzofuran-4-yl)-1,2,3,4-tetrahydroisoquinoline (159-2) is the same as that of compound 10-2. LCMS(ESI)m/z[M+H] + :250.2.
步骤③：6-(苯并呋喃-4-基)-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-159)
Step ③: 6-(benzofuran-4-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-159)
6-(苯并呋喃-4-基)-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-159)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.70(s,1H),8.28(s,1H),8.07(s,1H),7.61(t,J＝8.3Hz,2H),7.48(d,J＝6.7Hz,2H),7.45–7.24(m,5H),7.12–7.01(m,2H),6.96(t,J＝7.4Hz,1H),4.75(s,2H),3.80(s,2H),2.98(s,2H).LCMS(ESI)m/z[M+H]+:408.3.Preparation method of 6-(benzofuran-4-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-159) Same as compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.70 (s, 1H), 8.28 (s, 1H), 8.07 (s, 1H), 7.61 (t, J = 8.3Hz, 2H), 7.48 (d, J＝6.7Hz,2H),7.45–7.24(m,5H),7.12–7.01(m,2H),6.96(t,J＝7.4Hz,1H),4.75(s,2H),3.80(s,2H ),2.98(s,2H).LCMS(ESI)m/z[M+H] + :408.3.
实施例160 6-(苯并呋喃-7-基)-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-160)
Example 160 6-(benzofuran-7-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-160)
步骤①：6-(苯并呋喃-7-基)-3,4-二氢异喹啉-2(1H)-Boc(160-1)
Step ①: 6-(benzofuran-7-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(160-1)
6-(苯并呋喃-7-基)-3,4-二氢异喹啉-2(1H)-Boc(160-1)的制备方法同化合物10-1。1H NMR(400MHz,CDCl3)δ7.73–7.65(m,2H),7.64(s,1H),7.59(d,J＝6.6Hz,1H),7.44(d,J＝6.5Hz,1H),7.32(t,J＝7.6Hz,1H),7.24(s,1H),6.84(d,J＝2.2Hz,1H),4.65(s,2H),3.71(s,2H),2.95(s,2H),1.52(s,9H).The preparation method of 6-(benzofuran-7-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(160-1) is the same as compound 10-1. 1 H NMR (400MHz, CDCl 3 ) δ7.73–7.65(m,2H),7.64(s,1H),7.59(d,J＝6.6Hz,1H),7.44(d,J＝6.5Hz,1H) ,7.32(t,J＝7.6Hz,1H),7.24(s,1H),6.84(d,J＝2.2Hz,1H),4.65(s,2H),3.71(s,2H),2.95(s, 2H),1.52(s,9H).
步骤②：6-(苯并呋喃-7-基)-1,2,3,4-四氢异喹啉(160-2)
Step ②: 6-(benzofuran-7-yl)-1,2,3,4-tetrahydroisoquinoline (160-2)
6-(苯并呋喃-7-基)-1,2,3,4-四氢异喹啉(160-2)的制备方法同化合物10-2。LCMS(ESI)m/z[M+H]+:250.2.The preparation method of 6-(benzofuran-7-yl)-1,2,3,4-tetrahydroisoquinoline (160-2) is the same as compound 10-2. LCMS(ESI)m/z[M+H] + :250.2.
步骤③：6-(苯并呋喃-7-基)-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-160)
Step ③: 6-(benzofuran-7-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-160)
6-(苯并呋喃-7-基)-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-160)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.72(s,1H),8.29(s,1H),8.09(d,J＝2.2Hz,1H),7.71(d,J＝5.3Hz,2H),7.65(dd,J＝11.6,7.7Hz,2H),7.53(d,J＝7.6Hz,1H),7.41–7.28(m,4H),7.07(dd,J＝11.1,4.7Hz,2H),6.98(d,J＝7.9Hz,1H),4.76(s,2H),3.81(t,J＝5.9Hz,2H),2.98(t,J＝5.8Hz,2H).LCMS(ESI)m/z[M+H]+:408.1. Preparation method of 6-(benzofuran-7-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-160) Same as compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.72 (s, 1H), 8.29 (s, 1H), 8.09 (d, J = 2.2Hz, 1H), 7.71 (d, J = 5.3Hz, 2H) ,7.65(dd,J＝11.6,7.7Hz,2H),7.53(d,J＝7.6Hz,1H),7.41–7.28(m,4H),7.07(dd,J＝11.1,4.7Hz,2H), 6.98(d,J＝7.9Hz,1H),4.76(s,2H),3.81(t,J＝5.9Hz,2H),2.98(t,J＝5.8Hz,2H).LCMS(ESI)m/z [M+H] + :408.1.
实施例161 N,6-二(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-161)
Example 161 N,6-bis(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-161)
步骤①：6-(1-Boc-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-Boc(161-1)
Step ①: 6-(1-Boc-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(161-1)
6-(1-Boc-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-Boc(161-1)的制备方法同化合物10-1。1H NMR(400MHz,CDCl3)δ8.21(d,J＝8.1Hz,1H),7.79(d,J＝7.8Hz,1H),7.69(s,1H),7.47(d,J＝8.0Hz,1H),7.42(s,1H),7.37(t,J＝7.2Hz,1H),7.29(t,J＝7.4Hz,1H),7.21(d,J＝7.7Hz,1H),4.64(s,2H),3.70(s,2H),2.92(s,2H),1.69(s,9H),1.51(s,9H).The preparation method of 6-(1-Boc-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(161-1) is the same as compound 10-1. 1 H NMR (400MHz, CDCl 3 ) δ8.21(d,J＝8.1Hz,1H),7.79(d,J＝7.8Hz,1H),7.69(s,1H),7.47(d,J＝8.0Hz ,1H),7.42(s,1H),7.37(t,J＝7.2Hz,1H),7.29(t,J＝7.4Hz,1H),7.21(d,J＝7.7Hz,1H),4.64(s ,2H),3.70(s,2H),2.92(s,2H),1.69(s,9H),1.51(s,9H).
步骤②：6-(1H-吲哚-3-基)-1,2,3,4-四氢异喹啉(161-2)
Step ②: 6-(1H-indol-3-yl)-1,2,3,4-tetrahydroisoquinoline (161-2)
6-(1H-吲哚-3-基)-1,2,3,4-四氢异喹啉(161-2)的制备方法同化合物10-2。1H NMR(400MHz,DMSO-d6)δ11.39(s,1H),8.85(s,1H),7.87(d,J＝7.9Hz,1H),7.70(d,J＝2.6Hz,1H),7.57(d,J＝8.0Hz,1H),7.54(s,1H),7.45(d,J＝7.9Hz,1H),7.25(d,J＝8.0Hz,1H),7.16(t,J＝7.0Hz,1H),7.10(t,J＝7.1Hz,1H),4.26(s,2H),3.40(t,J＝6.3Hz,2H),3.06(t,J＝6.1Hz,2H).The preparation method of 6-(1H-indol-3-yl)-1,2,3,4-tetrahydroisoquinoline (161-2) is the same as that of compound 10-2. 1 H NMR (400MHz, DMSO-d 6 ) δ11.39(s,1H),8.85(s,1H),7.87(d,J＝7.9Hz,1H),7.70(d,J＝2.6Hz,1H) ,7.57(d,J＝8.0Hz,1H),7.54(s,1H),7.45(d,J＝7.9Hz,1H),7.25(d,J＝8.0Hz,1H),7.16(t,J＝ 7.0Hz,1H),7.10(t,J＝7.1Hz,1H),4.26(s,2H),3.40(t,J＝6.3Hz,2H),3.06(t,J＝6.1Hz,2H).
步骤③：N,6-二(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-161)
Step ③: N,6-bis(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-161)
N,6-二(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-161)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ11.32(s,1H),10.70(s,1H),8.25(s,1H),7.88(d,J＝7.9Hz,1H),7.66(d,J＝2.4Hz,1H),7.63(d,J＝7.9Hz,1H),7.52(d,J＝7.5Hz,2H),7.44(d,J＝7.9Hz,1H),7.38(d,J＝2.3Hz,1H),7.31(d,J＝8.2Hz,1H),7.24(d,J＝7.6Hz,1H),7.15(t,J＝7.4Hz,1H),7.04–7.11(m,2H),6.96(t,J＝7.4Hz,1H),4.70(s,2H),3.78(t,J＝5.7Hz,2H),2.95(t,J＝5.4Hz,2H).LCMS(ESI)m/z[M+H]+:407.3.The preparation method of N,6-bis(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-161) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ11.32 (s, 1H), 10.70 (s, 1H), 8.25 (s, 1H), 7.88 (d, J = 7.9Hz, 1H), 7.66 (d, J＝2.4Hz,1H),7.63(d,J＝7.9Hz,1H),7.52(d,J＝7.5Hz,2H),7.44(d,J＝7.9Hz,1H),7.38(d,J＝ 2.3Hz,1H),7.31(d,J＝8.2Hz,1H),7.24(d,J＝7.6Hz,1H),7.15(t,J＝7.4Hz,1H),7.04–7.11(m,2H) ,6.96(t,J＝7.4Hz,1H),4.70(s,2H),3.78(t,J＝5.7Hz,2H),2.95(t,J＝5.4Hz,2H).LCMS(ESI)m/ z[M+H] + :407.3.
实施例162 6-(二苯并[b,d]噻吩-4-基)-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)- 甲酰胺(I-162)
Example 162 6-(dibenzo[b,d]thiophen-4-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)- Formamide(I-162)
步骤①：2-(二苯并[b,d]噻吩-4-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(162-1)
Step ①: 2-(Dibenzo[b,d]thiophen-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (162-1)
2-(二苯并[b,d]噻吩-4-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(162-1)的制备方法同化合物115-1。1H NMR(400MHz,CD3OD)δ8.22(dt,J＝7.9,1.8Hz,1H),8.10(dt,J＝6.3,2.2Hz,1H),7.84(td,J＝7.2,3.8Hz,2H),7.45–7.36(m,3H),1.36(s,12H).The preparation method of 2-(dibenzo[b,d]thiophen-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (162-1) is the same as Compound 115-1. 1 H NMR (400MHz, CD 3 OD) δ8.22 (dt, J＝7.9, 1.8Hz, 1H), 8.10 (dt, J＝6.3, 2.2Hz, 1H), 7.84 (td, J＝7.2, 3.8Hz ,2H),7.45–7.36(m,3H),1.36(s,12H).
步骤②：6-(二苯并[b,d]噻吩-4-基)-3,4-二氢异喹啉-2(1H)-Boc(162-2)
Step ②: 6-(dibenzo[b,d]thiophen-4-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(162-2)
6-(二苯并[b,d]噻吩-4-基)-3,4-二氢异喹啉-2(1H)-Boc(162-2)的制备方法同化合物10-1。1H NMR(400MHz,CD3OD)δ8.21–8.12(m,2H),7.81–7.75(m,1H),7.50–7.37(m,6H),7.18(d,J＝7.9Hz,1H),4.57(d,J＝8.2Hz,2H),3.61(t,J＝5.9Hz,2H),2.82(t,J＝5.9Hz,2H),1.47(s,9H).The preparation method of 6-(dibenzo[b,d]thiophen-4-yl)-3,4-dihydroisoquinoline-2(1H)-Boc(162-2) is the same as compound 10-1. 1 H NMR (400MHz, CD 3 OD) δ8.21–8.12(m,2H),7.81–7.75(m,1H),7.50–7.37(m,6H),7.18(d,J＝7.9Hz,1H) ,4.57(d,J＝8.2Hz,2H),3.61(t,J＝5.9Hz,2H),2.82(t,J＝5.9Hz,2H),1.47(s,9H).
步骤③：6-(二苯并[b,d]噻吩-4-基)-1,2,4-四氢异喹啉(162-3)
Step ③: 6-(dibenzo[b,d]thiophen-4-yl)-1,2,4-tetrahydroisoquinoline (162-3)
6-(二苯并[b,d]噻吩-4-基)-1,2,4-四氢异喹啉(162-3)的制备方法同化合物10-2。LCMS(ESI)m/z[M+H]+:316.0.The preparation method of 6-(dibenzo[b,d]thiophen-4-yl)-1,2,4-tetrahydroisoquinoline (162-3) is the same as compound 10-2. LCMS(ESI)m/z[M+H] + :316.0.
步骤④：6-(二苯并[b,d]噻吩-4-基)-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-162)
Step ④: 6-(dibenzo[b,d]thiophen-4-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-methyl Amide(I-162)
6-(二苯并[b,d]噻吩-4-基)-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-162)的制备方法同化合物I-41。1H NMR(400MHz,DMSO-d6)δ9.90(s,1H),7.57(ddd,J＝ 9.2,6.9,2.2Hz,2H),7.49(s,1H),7.19(dt,J＝7.2,3.5Hz,1H),6.83–6.77(m,3H),6.75(d,J＝3.7Hz,2H),6.71(dd,J＝6.0,3.2Hz,2H),6.55(d,J＝6.4Hz,2H),6.48(d,J＝8.1Hz,1H),6.24(t,J＝7.5Hz,1H),6.14(t,J＝7.4Hz,1H),3.95(s,2H),2.99(t,J＝5.8Hz,2H),2.15(t,J＝5.8Hz,2H).LCMS(ESI)m/z[M+H]+:496.0.6-(Dibenzo[b,d]thiophen-4-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I The preparation method of -162) is the same as that of compound I-41. 1 H NMR (400MHz, DMSO-d 6 ) δ9.90 (s, 1H), 7.57 (ddd, J＝ 9.2,6.9,2.2Hz,2H),7.49(s,1H),7.19(dt,J＝7.2,3.5Hz,1H),6.83–6.77(m,3H),6.75(d,J＝3.7Hz,2H ),6.71(dd,J＝6.0,3.2Hz,2H),6.55(d,J＝6.4Hz,2H),6.48(d,J＝8.1Hz,1H),6.24(t,J＝7.5Hz,1H ),6.14(t,J＝7.4Hz,1H),3.95(s,2H),2.99(t,J＝5.8Hz,2H),2.15(t,J＝5.8Hz,2H).LCMS(ESI)m /z[M+H] + :496.0.
实施例163 N-(5-氟-1H-吲哚-3-基)-6-吗啡啉-3,4-二氢异喹啉-2(1H)-甲酰胺(I-162)
Example 163 N-(5-fluoro-1H-indol-3-yl)-6-morpholine-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-162)
步骤①：6-吗啉基-3,4-二氢异喹啉-2(1H)-Boc(163-1)
Step ①: 6-morpholinyl-3,4-dihydroisoquinoline-2(1H)-Boc(163-1)
6-吗啉基-3,4-二氢异喹啉-2(1H)-Boc(162-1)的制备方法同化合物132-1。1H NMR(400MHz,CD3OD)δ7.00(d,J＝8.5Hz,1H),6.82(dd,J＝8.5,2.5Hz,1H),6.74(d,J＝2.5Hz,1H),4.45(s,2H),3.83–3.78(m,4H),3.59(t,J＝5.4Hz,2H),3.09(dq,J＝4.6,2.7,2.0Hz,4H),2.78(t,J＝5.9Hz,2H),1.49(s,9H).LCMS(ESI)m/z[M+H]+:319.1.The preparation method of 6-morpholinyl-3,4-dihydroisoquinoline-2(1H)-Boc(162-1) is the same as that of compound 132-1. 1 H NMR (400MHz, CD 3 OD) δ7.00 (d, J＝8.5Hz, 1H), 6.82 (dd, J＝8.5, 2.5Hz, 1H), 6.74 (d, J＝2.5Hz, 1H), 4.45(s,2H),3.83–3.78(m,4H),3.59(t,J＝5.4Hz,2H),3.09(dq,J＝4.6,2.7,2.0Hz,4H),2.78(t,J＝ 5.9Hz,2H),1.49(s,9H).LCMS(ESI)m/z[M+H] + :319.1.
步骤②：4-(1,2,3,4-四氢异喹啉-6-基)吗啉(163-2)
Step ②: 4-(1,2,3,4-tetrahydroisoquinolin-6-yl)morpholine (163-2)
4-(1,2,3,4-四氢异喹啉-6-基)吗啉(163-2)的制备方法同化合物10-2。LCMS(ESI)m/z[M+H]+:219.1.The preparation method of 4-(1,2,3,4-tetrahydroisoquinolin-6-yl)morpholine (163-2) is the same as compound 10-2. LCMS(ESI)m/z[M+H] + :219.1.
步骤③：N-(5-氟-1H-吲哚-3-基)-6-吗啡啉-3,4-二氢异喹啉-2(1H)-甲酰胺(I-163)
Step ③: N-(5-fluoro-1H-indol-3-yl)-6-morpholine-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-163)
N-(5-氟-1H-吲哚-3-基)-6-吗啡啉-3,4-二氢异喹啉-2(1H)-甲酰胺(I-163)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.81(s,1H),8.18(s,1H),7.44(d,J＝2.5Hz,1H),7.36(dd,J＝10.2,2.6Hz,1H),7.30(dd,J＝8.8,4.5Hz,1H),7.04(d,J＝8.5Hz,1H),6.90(td,J＝9.1,2.6Hz,1H),6.82(dd,J＝8.4,2.6Hz,1H),6.75(d,J＝2.5Hz,1H),4.56(s,2H),3.73(t,J＝4.8Hz,4H),3.68(t,J＝5.8Hz,2H),3.11–3.03(m,4H),2.80(t,J＝5.8Hz,2H).LCMS(ESI)m/z[M+H]+:395.3.The preparation method of N-(5-fluoro-1H-indol-3-yl)-6-morpholine-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-163) is the same as compound I -1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.81 (s, 1H), 8.18 (s, 1H), 7.44 (d, J = 2.5Hz, 1H), 7.36 (dd, J = 10.2, 2.6Hz, 1H),7.30(dd,J＝8.8,4.5Hz,1H),7.04(d,J＝8.5Hz,1H),6.90(td,J＝9.1,2.6Hz,1H),6.82(dd,J＝8.4 ,2.6Hz,1H),6.75(d,J＝2.5Hz,1H),4.56(s,2H),3.73(t,J＝4.8Hz,4H),3.68(t,J＝5.8Hz,2H), 3.11–3.03(m,4H),2.80(t,J＝5.8Hz,2H).LCMS(ESI)m/z[M+H] + :395.3.
实施例164 N-(1H-吲哚-3-基)-6-(1H-吲哚-6-基)-3,4-二氢异喹啉-2(1H)-甲酰胺 (I-164)
Example 164 N-(1H-indol-3-yl)-6-(1H-indol-6-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-164)
步骤①：6-溴-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(164-1)
Step ①: 6-bromo-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (164-1)
6-溴-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(164-1)的制备方法同化合物I-41。1H NMR(400MHz,DMSO-d6)δ10.70(s,1H),8.26(s,1H),7.58(d,J＝7.9Hz,1H),7.41(d,J＝2.1Hz,1H),7.37(dd,J＝8.1,2.2Hz,1H),7.34(d,J＝2.5Hz,1H),7.29(d,J＝8.1Hz,1H),7.14(d,J＝8.2Hz,1H),7.04(t,J＝7.5Hz,1H),6.93(t,J＝7.4Hz,1H),4.61(s,2H),3.70(t,J＝5.9Hz,2H),2.85(t,J＝5.9Hz,2H).LCMS(ESI)m/z[M+H]+:370.0.The preparation method of 6-bromo-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (164-1) is the same as compound I-41. 1 H NMR (400MHz, DMSO-d 6 ) δ10.70 (s, 1H), 8.26 (s, 1H), 7.58 (d, J = 7.9Hz, 1H), 7.41 (d, J = 2.1Hz, 1H) ,7.37(dd,J＝8.1,2.2Hz,1H),7.34(d,J＝2.5Hz,1H),7.29(d,J＝8.1Hz,1H),7.14(d,J＝8.2Hz,1H) ,7.04(t,J＝7.5Hz,1H),6.93(t,J＝7.4Hz,1H),4.61(s,2H),3.70(t,J＝5.9Hz,2H),2.85(t,J＝ 5.9Hz,2H).LCMS(ESI)m/z[M+H] + :370.0.
步骤②：N-(1H-吲哚-3-基)-6-(1H-吲哚-6-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-164)
Step ②: N-(1H-indol-3-yl)-6-(1H-indol-6-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-164 )
N-(1H-吲哚-3-基)-6-(1H-吲哚-6-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-164)的制备方法同化合物10-1。1H NMR(400MHz,DMSO-d6)δ11.16(s,1H),10.72(s,1H),8.28(s,1H),7.65–7.57(m,3H),7.50(d,J＝6.2Hz,2H),7.37(d,J＝2.6Hz,2H),7.31(d,J＝6.8Hz,2H),7.26(d,J＝8.3Hz,1H),7.06(t,J＝7.3Hz,1H),6.96(t,J＝7.4Hz,1H),6.44(s,1H),4.71(s,2H),3.78(t,J＝5.7Hz,2H),2.96(t,J＝5.3Hz,2H).LCMS(ESI)m/z[M+H]+:407.3.Preparation of N-(1H-indol-3-yl)-6-(1H-indol-6-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-164) The method is the same as that of compound 10-1. 1 H NMR (400MHz, DMSO-d 6 ) δ11.16 (s, 1H), 10.72 (s, 1H), 8.28 (s, 1H), 7.65–7.57 (m, 3H), 7.50 (d, J = 6.2 Hz,2H),7.37(d,J＝2.6Hz,2H),7.31(d,J＝6.8Hz,2H),7.26(d,J＝8.3Hz,1H),7.06(t,J＝7.3Hz, 1H),6.96(t,J＝7.4Hz,1H),6.44(s,1H),4.71(s,2H),3.78(t,J＝5.7Hz,2H),2.96(t,J＝5.3Hz, 2H).LCMS(ESI)m/z[M+H] + :407.3.
实施例165 5-氟-N-(1H-吲哚-3-基)-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-165)
Example 165 5-fluoro-N-(1H-indol-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-165)
步骤①：6-溴-5-氟-3,4-二氢异喹啉-2(1H)-Boc(165-1)
Step ①: 6-bromo-5-fluoro-3,4-dihydroisoquinoline-2(1H)-Boc(165-1)
将100毫克6-溴-5-氟-1,2,3,4-四氢异喹啉、114毫克二碳酸二叔丁酯、120微升三乙胺和3毫升四氢呋喃的混合物于室温条件搅拌5小时。反应液浓缩至干，残余物以石油醚：乙酸乙酯＝10：1制备薄层，得透明油状物6-溴-5-氟-3,4-二氢异喹啉-2(1H)-Boc(165-1)140毫克，收率97％。1H NMR(400MHz,CD3OD)δ7.39(t,J＝7.6Hz,1H),6.89(d,J＝8.3Hz,1H),4.53(s,2H),3.65(t,J＝6.0Hz,2H),2.81(t,J＝6.0Hz,2H),1.49(s,9H).A mixture of 100 mg of 6-bromo-5-fluoro-1,2,3,4-tetrahydroisoquinoline, 114 mg of di-tert-butyl dicarbonate, 120 μl of triethylamine and 3 ml of tetrahydrofuran was stirred at room temperature. 5 hours. The reaction solution was concentrated to dryness, and the residue was prepared as a thin layer using petroleum ether: ethyl acetate = 10:1 to obtain a transparent oily substance 6-bromo-5-fluoro-3,4-dihydroisoquinoline-2(1H)- Boc(165-1) 140 mg, yield 97%. 1 H NMR (400MHz, CD 3 OD) δ7.39 (t, J = 7.6 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 4.53 (s, 2H), 3.65 (t, J = 6.0 Hz, 2H), 2.81 (t, J = 6.0Hz, 2H), 1.49 (s, 9H).
步骤②：5-氟-6-苯基-3,4-二氢异喹啉-2(1H)-Boc(165-2)
Step ②: 5-fluoro-6-phenyl-3,4-dihydroisoquinoline-2(1H)-Boc(165-2)
5-氟-6-苯基-3,4-二氢异喹啉-2(1H)-Boc(165-2)的制备方法同化合物10-1。1H NMR(400MHz,CD3OD)δ7.45(d,J＝7.5Hz,2H),7.37(t,J＝7.6Hz,2H),7.29(t,J＝7.3Hz,1H),7.23(t,J＝7.9Hz,1H),6.97(d,J＝8.0Hz,1H),4.55(s,2H),3.63(t,J＝6.0Hz,2H),2.79(t,J＝6.0Hz,2H),1.46(s,9H).The preparation method of 5-fluoro-6-phenyl-3,4-dihydroisoquinoline-2(1H)-Boc(165-2) is the same as compound 10-1. 1 H NMR (400MHz, CD 3 OD) δ7.45 (d, J = 7.5Hz, 2H), 7.37 (t, J = 7.6Hz, 2H), 7.29 (t, J = 7.3Hz, 1H), 7.23 ( t,J＝7.9Hz,1H),6.97(d,J＝8.0Hz,1H),4.55(s,2H),3.63(t,J＝6.0Hz,2H),2.79(t,J＝6.0Hz, 2H),1.46(s,9H).
步骤③：5-氟-6-苯基-1,2,3,4-四氢异喹啉(165-3)
Step ③: 5-fluoro-6-phenyl-1,2,3,4-tetrahydroisoquinoline (165-3)
5-氟-6-苯基-1,2,3,4-四氢异喹啉(165-3)的制备方法同化合物10-2。LCMS(ESI)m/z[M+H]+:228.1.The preparation method of 5-fluoro-6-phenyl-1,2,3,4-tetrahydroisoquinoline (165-3) is the same as that of compound 10-2. LCMS(ESI)m/z[M+H] + :228.1.
步骤④：5-氟-N-(1H-吲哚-3-基)-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-165)
Step ④: 5-fluoro-N-(1H-indol-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-165)
5-氟-N-(1H-吲哚-3-基)-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-165)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.72(s,1H),8.37(s,1H),7.61(d,J＝7.9Hz,1H),7.54(d,J＝7.9Hz,2H),7.48(t,J＝7.6Hz,2H),7.43–7.39(m,1H),7.38–7.34(m,2H),7.31(d,J＝8.1Hz,1H),7.14(d,J＝8.0Hz,1H),7.06(t,J＝7.5Hz,1H),6.96(t,J＝7.4Hz,1H),4.74(s,2H),3.82(t,J＝5.9Hz,2H),2.87(t,J＝5.8Hz,2H).LCMS(ESI)m/z[M+H]+:384.2.The preparation method of 5-fluoro-N-(1H-indol-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-165) is the same as compound I -1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.72 (s, 1H), 8.37 (s, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.54 ( d, J = 7.9 Hz, 2H) ,7.48(t,J＝7.6Hz,2H),7.43–7.39(m,1H),7.38–7.34(m,2H),7.31(d,J＝8.1Hz,1H),7.14(d,J＝8.0 Hz,1H),7.06(t,J＝7.5Hz,1H),6.96(t,J＝7.4Hz,1H),4.74(s,2H),3.82(t,J＝5.9Hz,2H),2.87( t,J＝5.8Hz,2H).LCMS(ESI)m/z[M+H] + :384.2.
实施例166 5-甲基-N-(1H-吲哚-3-基)-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-167)
Example 166 5-methyl-N-(1H-indol-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-167)
步骤①：1-溴-3-(氯甲基)-2-甲苯(166-1)
Step ①: 1-bromo-3-(chloromethyl)-2-toluene (166-1)
冰浴下向4克3-溴-2-甲基苯甲醇和15毫升N-甲基吡咯烷酮的混合物中滴加5毫升三氯氧磷，待恢复至室温后，室温搅拌2小时。反应液加入50毫升冰水中淬灭，滴加饱和碳酸氢钠溶液至pH为7，以乙酸乙酯萃取，有机层浓缩至干，残余物以石油醚：乙酸乙酯＝100：1柱层析，得黄色油状物1-溴-3-(氯甲基)-2-甲苯(166-1)4.24克，收率97％。1H NMR(400MHz,CD3OD)δ7.54(dd,J＝8.1,1.3Hz,1H),7.31(dd,J＝7.7,1.3Hz,1H),7.06(t,J＝7.8Hz,1H),4.70(s,2H),2.48(s,3H).Add 5 ml of phosphorus oxychloride dropwise to a mixture of 4 g of 3-bromo-2-methylbenzyl alcohol and 15 ml of N-methylpyrrolidone under an ice bath. After returning to room temperature, stir at room temperature for 2 hours. The reaction solution was quenched by adding 50 ml of ice water, saturated sodium bicarbonate solution was added dropwise until the pH was 7, extracted with ethyl acetate, the organic layer was concentrated to dryness, and the residue was subjected to column chromatography with petroleum ether: ethyl acetate = 100:1 , 4.24 g of 1-bromo-3-(chloromethyl)-2-toluene (166-1) was obtained as a yellow oil, with a yield of 97%. 1 H NMR (400MHz, CD 3 OD) δ7.54 (dd, J＝8.1, 1.3Hz, 1H), 7.31 (dd, J＝7.7, 1.3Hz, 1H), 7.06 (t, J＝7.8Hz, 1H ),4.70(s,2H),2.48(s,3H).
步骤②：3-溴-2-甲基苯乙腈(166-2)
Step ②: 3-bromo-2-methylphenylacetonitrile (166-2)
将4.2克化合物166-1、4.8毫升三甲基氰硅烷、3.2克碳酸钾和20毫升乙腈的混合物于80℃下搅拌过夜。反应液过滤，滤液浓缩至干，残余物以石油醚：乙酸乙酯＝20：1柱层析，得白色固体2-(3-溴-2-甲基苯基)乙腈(166-2)3.9克，收率97％。1H NMR(400MHz,CD3OD)δ7.57(dd,J＝8.1,1.3Hz,1H),7.36(d,J＝7.6Hz,1H),7.12(t,J＝7.9Hz,1H),3.94(s,2H),2.45(s,3H).A mixture of 4.2 g of compound 166-1, 4.8 ml of trimethylsilyl cyanide, 3.2 g of potassium carbonate and 20 ml of acetonitrile was stirred at 80°C overnight. The reaction solution was filtered, and the filtrate was concentrated to dryness. The residue was subjected to column chromatography with petroleum ether: ethyl acetate = 20:1 to obtain a white solid 2-(3-bromo-2-methylphenyl)acetonitrile (166-2) 3.9 grams, yield 97%. 1 H NMR (400MHz, CD 3 OD) δ7.57 (dd, J＝8.1, 1.3Hz, 1H), 7.36 (d, J＝7.6Hz, 1H), 7.12 (t, J＝7.9Hz, 1H), 3.94(s,2H),2.45(s,3H).
步骤③：2-(3-溴-2-甲基苯基)乙烷-1-胺(166-3)
Step ③: 2-(3-bromo-2-methylphenyl)ethane-1-amine (166-3)
冰浴下向1.2克化合物166-2和12毫升四氢呋喃的混合物中滴加57毫升硼烷四氢呋喃溶液并于氩气氛下60℃搅拌2.5小时。分别加入5毫升水和15毫升4N盐酸二氧六环溶液淬灭反应，反应液浓缩至干。残余物中加入20毫升乙醚搅拌，过滤，滤饼加10毫升甲醇复溶，滴加10％氢氧化钠水溶液至pH为10，以乙酸乙酯萃取，有机相浓缩至干，得黄色油状物2-(3-溴-2-甲基苯基)乙烷-1-胺(166-3)776毫克，收率64％。1H NMR(400MHz,CDCl3)δ7.42(dd,J＝8.0,1.3Hz,1H),7.08(dd,J＝7.6,1.3Hz,1H),6.97(t,J＝7.7Hz,1H),2.91(ddd,J＝7.4,6.6,1.2Hz,2H),2.84–2.78(m,2H),2.40(s,3H),1.31(s,2H).LCMS(ESI)m/z[M+H]+:214.1.To a mixture of 1.2 g of compound 166-2 and 12 ml of tetrahydrofuran, 57 ml of borane tetrahydrofuran solution was added dropwise under an ice bath, and the mixture was stirred at 60° C. for 2.5 hours under an argon atmosphere. 5 ml of water and 15 ml of 4N dioxane hydrochloric acid solution were added to quench the reaction, and the reaction solution was concentrated to dryness. Add 20 ml of diethyl ether to the residue, stir, and filter. Add 10 ml of methanol to the filter cake to redissolve it. Add 10% aqueous sodium hydroxide solution dropwise until the pH is 10. Extract with ethyl acetate. The organic phase is concentrated to dryness to obtain yellow oil 2. -(3-Bromo-2-methylphenyl)ethane-1-amine (166-3) 776 mg, yield 64%. 1 H NMR (400MHz, CDCl 3 ) δ7.42 (dd, J＝8.0, 1.3Hz, 1H), 7.08 (dd, J＝7.6, 1.3Hz, 1H), 6.97 (t, J＝7.7Hz, 1H) ,2.91(ddd,J＝7.4,6.6,1.2Hz,2H),2.84–2.78(m,2H),2.40(s,3H),1.31(s,2H).LCMS(ESI)m/z[M+ H] + :214.1.
步骤④：N-(3-溴-2-甲基苯乙基)-2,2,2-三氟乙酰胺(166-4)
Step ④: N-(3-bromo-2-methylphenylethyl)-2,2,2-trifluoroacetamide (166-4)
冰浴下向500毫克化合物166-3、650微升三乙胺和2毫升二氯甲烷的混合物中滴加650微升三氟乙酸酐，待恢复室温后于氩气氛室温搅拌16小时。反应液加水中稀释，以乙酸乙酯萃取，有机相浓缩至干，残余物以石油醚：乙酸乙酯＝20：1柱层析，得白色固体N-(3-溴-2-甲基苯乙基)-2,2,2-三氟乙酰胺(166-4)569毫克，收率79％。1H NMR(400MHz,DMSO-d6)δ9.55(t,J＝5.4Hz,1H),7.47(dd,J＝8.0,1.3Hz,1H),7.14(dd,J＝7.6,1.4Hz,1H),7.06(t,J＝7.7Hz,1H),3.39–3.34(m,2H),2.88(t,J＝7.5Hz,2H),2.37(s,3H).LCMS(ESI)m/z[M+H]+:309.9.650 μl of trifluoroacetic anhydride was added dropwise to a mixture of 500 mg of compound 166-3, 650 μl of triethylamine and 2 ml of methylene chloride under an ice bath. After returning to room temperature, the mixture was stirred at room temperature in an argon atmosphere for 16 hours. The reaction solution was diluted with water, extracted with ethyl acetate, and the organic phase was concentrated to dryness. The residue was subjected to column chromatography with petroleum ether: ethyl acetate = 20:1 to obtain white solid N-(3-bromo-2-methylbenzene). Ethyl)-2,2,2-trifluoroacetamide (166-4) 569 mg, yield 79%. 1 H NMR (400MHz, DMSO-d 6 ) δ9.55 (t, J = 5.4Hz, 1H), 7.47 (dd, J = 8.0, 1.3Hz, 1H), 7.14 (dd, J = 7.6, 1.4Hz, 1H),7.06(t,J＝7.7Hz,1H),3.39–3.34(m,2H),2.88(t,J＝7.5Hz,2H),2.37(s,3H).LCMS(ESI)m/z [M+H] + :309.9.
步骤⑤：1-(6-溴-5-甲基-3,4-二氢异喹啉-2(1H)-基)-2,2,2-三氟乙烷-1-酮(166-5)
Step ⑤: 1-(6-bromo-5-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethane-1-one (166- 5)
将500毫克化合物166-4、50毫克多聚甲醛、5毫升冰醋酸和2.5毫升硫酸的混合物于氩气氛79℃搅拌4小时。加入20毫升水中淬灭反应，以乙酸乙酯萃取，有机相浓缩至干，残余物以石油醚：乙酸乙酯＝20：1柱层析，得白色固体1-(6-溴-5-甲基-3,4-二氢异喹啉-2(1H)-基)-2,2,2-三氟乙烷-1-酮(166-5)350毫克，收率67％。1H NMR(400MHz,CD3OD)δ7.44(d,J＝8.3Hz,1H),6.96(d,J＝7.8Hz,1H),4.74(s,2H),3.91(t,J＝6.4Hz,2H),2.94(t,J＝6.8Hz,2H),2.37(s,3H).LCMS(ESI)m/z[M+H]+:322.0.A mixture of 500 mg of compound 166-4, 50 mg of paraformaldehyde, 5 ml of glacial acetic acid and 2.5 ml of sulfuric acid was stirred at 79°C under an argon atmosphere for 4 hours. Add 20 ml of water to quench the reaction, extract with ethyl acetate, concentrate the organic phase to dryness, and use petroleum ether: ethyl acetate = 20:1 column chromatography to obtain a white solid 1-(6-bromo-5-methyl). 350 mg of base-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethane-1-one (166-5), yield 67%. 1 H NMR (400MHz, CD 3 OD) δ7.44 (d, J = 8.3Hz, 1H), 6.96 (d, J = 7.8Hz, 1H), 4.74 (s, 2H), 3.91 (t, J = 6.4 Hz, 2H), 2.94 (t, J = 6.8Hz, 2H), 2.37 (s, 3H). LCMS (ESI) m/z [M+H] + : 322.0.
步骤⑥：2,2,2-三氟-1-(5-甲基-6-苯基-3,4-二氢异喹啉-2(1H)-基)乙烷-1-酮(166-6)
Step ⑥: 2,2,2-trifluoro-1-(5-methyl-6-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)ethane-1-one (166 -6)
2,2,2-三氟-1-(5-甲基-6-苯基-3,4-二氢异喹啉-2(1H)-基)乙烷-1-酮(166-6)的制备方法同化合物10-1。1H NMR(400MHz,MeOD-d4)δ7.40–7.35(m,2H),7.33–7.27(m,1H),7.23–7.19(m,2H),7.03(t,J＝1.7Hz,2H),4.78(s,2H),3.91(t,J＝6.1Hz,2H),2.89(t,J＝5.9Hz,2H),2.10(s,3H).LCMS(ESI)m/z[M+H]+:320.1.2,2,2-Trifluoro-1-(5-methyl-6-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)ethane-1-one (166-6) The preparation method is the same as compound 10-1. 1 H NMR (400MHz, MeOD-d 4 ) δ7.40–7.35(m,2H),7.33–7.27(m,1H),7.23–7.19(m,2H),7.03(t,J＝1.7Hz,2H ),4.78(s,2H),3.91(t,J＝6.1Hz,2H),2.89(t,J＝5.9Hz,2H),2.10(s,3H).LCMS(ESI)m/z[M+ H] + :320.1.
步骤⑦：5-甲基-6-苯基-1,2,3,4-四氢异喹啉(166-7)
Step ⑦: 5-methyl-6-phenyl-1,2,3,4-tetrahydroisoquinoline (166-7)
将120毫克化合物166-6、40毫克氢氧化锂一水合物、3毫升甲醇、0.5毫升水和0.5毫升四氢呋喃的混合物于氩气氛60℃搅拌2小时。反应液浓缩至干，残余物以5毫升乙酸乙酯复溶，过滤，滤液浓缩至干，得透明油状物5-甲基-6-苯基-1,2,3,4-四氢异喹啉 (166-7)84毫克，收率100％。LCMS(ESI)m/z[M+H]+:224.1.A mixture of 120 mg of compound 166-6, 40 mg of lithium hydroxide monohydrate, 3 ml of methanol, 0.5 ml of water and 0.5 ml of tetrahydrofuran was stirred at 60°C under an argon atmosphere for 2 hours. The reaction solution was concentrated to dryness, the residue was redissolved with 5 ml of ethyl acetate, filtered, and the filtrate was concentrated to dryness to obtain a transparent oily substance 5-methyl-6-phenyl-1,2,3,4-tetrahydroisoquine. phyline (166-7) 84 mg, yield 100%. LCMS(ESI)m/z[M+H] + :224.1.
步骤⑧：N-(1H-吲哚-3-基)-5-甲基-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-166)
Step ⑧: N-(1H-indol-3-yl)-5-methyl-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-166)
N-(1H-吲哚-3-基)-5-甲基-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(I-166)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.70(s,1H),8.31(s,1H),7.62(d,J＝7.9Hz,1H),7.46–7.42(m,2H),7.38–7.35(m,2H),7.32–7.27(m,3H),7.09–7.03(m,3H),6.96(ddd,J＝8.0,6.9,1.0Hz,1H),4.71(s,2H),3.82(t,J＝6.0Hz,2H),2.81(t,J＝5.9Hz,2H),2.11(s,3H).LCMS(ESI)m/z[M+H]+:382.4.The preparation method of N-(1H-indol-3-yl)-5-methyl-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-166) is the same as that of the compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.70 (s, 1H), 8.31 (s, 1H), 7.62 (d, J = 7.9Hz, 1H), 7.46–7.42 (m, 2H), 7.38– 7.35(m,2H),7.32–7.27(m,3H),7.09–7.03(m,3H),6.96(ddd,J＝8.0,6.9,1.0Hz,1H),4.71(s,2H),3.82( t,J＝6.0Hz,2H),2.81(t,J＝5.9Hz,2H),2.11(s,3H).LCMS(ESI)m/z[M+H] + :382.4.
实施例167 6-(3-氨基哌啶-1-基)-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-167)
Example 167 6-(3-aminopiperidin-1-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I- 167)
步骤①：(1-(2-(2,2,2-三氟乙酰基)-1,2,4-四氢异喹啉-6-基)哌啶-3-基)氨基-Boc(167-1)
Step ①: (1-(2-(2,2,2-trifluoroacetyl)-1,2,4-tetrahydroisoquinolin-6-yl)piperidin-3-yl)amino-Boc(167 -1)
(1-(2-(2,2,2-三氟乙酰基)-1,2,4-四氢异喹啉-6-基)哌啶-3-基)氨基-Boc(167-1)的制备方法同化合物168-2。1H NMR(400MHz,DMSO-d6)δ7.07(dd,J＝8.5,5.3Hz,1H),6.87(d,J＝7.7Hz,1H),6.83–6.76(m,1H),6.73(s,1H),4.63(d,J＝7.6Hz,2H),3.76(q,J＝6.6Hz,2H),3.62–3.47(m,2H),3.43(s,1H),2.85(t,J＝7.7Hz,2H),2.60(t,J＝11.8Hz,1H),2.48–2.41(m,1H),1.79(d,J＝12.2Hz,1H),1.71(d,J＝13.4Hz,1H),1.52(d,J＝12.5Hz,1H),1.17(t,J＝7.1Hz,1H).LCMS(ESI)m/z[M+H]+:428.2.(1-(2-(2,2,2-trifluoroacetyl)-1,2,4-tetrahydroisoquinolin-6-yl)piperidin-3-yl)amino-Boc(167-1) The preparation method is the same as compound 168-2. 1 H NMR (400MHz, DMSO-d 6 ) δ7.07 (dd, J＝8.5, 5.3Hz, 1H), 6.87 (d, J＝7.7Hz, 1H), 6.83–6.76 (m, 1H), 6.73 ( s,1H),4.63(d,J＝7.6Hz,2H),3.76(q,J＝6.6Hz,2H),3.62–3.47(m,2H),3.43(s,1H),2.85(t,J ＝7.7Hz,2H),2.60(t,J＝11.8Hz,1H),2.48–2.41(m,1H),1.79(d,J＝12.2Hz,1H),1.71(d,J＝13.4Hz,1H ),1.52(d,J＝12.5Hz,1H),1.17(t,J＝7.1Hz,1H).LCMS(ESI)m/z[M+H] + :428.2.
步骤②：(1-(1,2,3,4-四氢异喹啉-6-基)哌啶-3-基)氨基-Boc(167-2)
Step ②: (1-(1,2,3,4-tetrahydroisoquinolin-6-yl)piperidin-3-yl)amino-Boc(167-2)
(1-(1,2,3,4-四氢异喹啉-6-基)哌啶-3-基)氨基-Boc(167-2)的制备方法同化合物168-3。LCMS(ESI)m/z[M+H]+:332.2.The preparation method of (1-(1,2,3,4-tetrahydroisoquinolin-6-yl)piperidin-3-yl)amino-Boc (167-2) is the same as compound 168-3. LCMS(ESI)m/z[M+H] + :332.2.
步骤③：(1-(2-((5-氟-1H-吲哚-3-基)氨甲酰基)-1,2,4-四氢异喹啉-6-基)哌啶-3-基) 氨基-Boc(167-3)
Step ③: (1-(2-((5-fluoro-1H-indol-3-yl)carbamoyl)-1,2,4-tetrahydroisoquinolin-6-yl)piperidine-3- base) Amino-Boc(167-3)
(1-(2-((5-氟-1H-吲哚-3-基)氨甲酰基)-1,2,4-四氢异喹啉-6-基)哌啶-3-基)氨基-Boc(167-3)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.80(s,1H),8.16(s,1H),7.44(s,1H),7.36(d,J＝10.2Hz,1H),7.29(dd,J＝8.8,4.5Hz,1H),7.01(d,J＝8.4Hz,1H),6.88(q,J＝8.0Hz,2H),6.78(d,J＝8.6Hz,1H),6.73(s,1H),4.55(s,2H),4.16–4.04(m,1H),3.68(t,J＝5.6Hz,2H),3.60–3.42(m,3H),2.79(t,J＝5.9Hz,2H),2.61(d,J＝12.0Hz,1H),2.45(d,J＝10.8Hz,1H),1.80(d,J＝11.5Hz,1H),1.72(d,J＝13.5Hz,1H),1.54(d,J＝12.6Hz,1H),1.40(s,9H).LCMS(ESI)m/z[M+H]+:508.3.(1-(2-((5-fluoro-1H-indol-3-yl)carbamoyl)-1,2,4-tetrahydroisoquinolin-6-yl)piperidin-3-yl)amino -The preparation method of Boc(167-3) is the same as that of compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.80 (s, 1H), 8.16 (s, 1H), 7.44 (s, 1H), 7.36 (d, J = 10.2Hz, 1H), 7.29 (dd, J＝8.8,4.5Hz,1H),7.01(d,J＝8.4Hz,1H),6.88(q,J＝8.0Hz,2H),6.78(d,J＝8.6Hz,1H),6.73(s, 1H),4.55(s,2H),4.16–4.04(m,1H),3.68(t,J＝5.6Hz,2H),3.60–3.42(m,3H),2.79(t,J＝5.9Hz,2H ),2.61(d,J＝12.0Hz,1H),2.45(d,J＝10.8Hz,1H),1.80(d,J＝11.5Hz,1H),1.72(d,J＝13.5Hz,1H), 1.54(d,J＝12.6Hz,1H),1.40(s,9H).LCMS(ESI)m/z[M+H] + :508.3.
步骤④：6-(3-氨基哌啶-1-基)-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-167)
Step ④: 6-(3-aminopiperidin-1-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I- 167)
6-(3-氨基哌啶-1-基)-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-167)的制备方法同化合物10-2。LCMS(ESI)m/z[M+H]+:408.3.6-(3-Aminopiperidin-1-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-167) The preparation method is the same as compound 10-2. LCMS(ESI)m/z[M+H] + :408.3.
实施例168 6-(3-氨基吡咯-1-基)-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-168)
Example 168 6-(3-aminopyrrol-1-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-168 )
步骤①：1-(6-溴-3,4-二氢异喹啉-2(1H)-基)-2,2,2-三氟乙烷-1-酮(168-1)
Step ①: 1-(6-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethane-1-one (168-1)
冰浴下向1克6-溴-1,2,3,4-四氢异喹啉和10毫升二氯甲烷的混合物中滴加5毫升三氟乙酸酐，待恢复至室温后于氩气氛室温搅拌2小时。反应液加入20毫升冰水稀释，以乙酸乙酯萃取，有机相浓缩至干，残余物以石油醚：乙酸乙酯＝20：1柱层析，得黄色油状物1-(6-溴-3,4-二氢异喹啉-2(1H)-基)-2,2,2-三氟乙烷-1-酮(168-1)1.45克，收率100％。1H NMR(400MHz,CD3OD-d4)δ7.40–7.33(m,2H),7.11(d,J＝8.1Hz,1H),4.73(d,J＝7.1Hz,2H),3.85(t,J＝5.7Hz,2H),2.95(t,J＝6.4Hz,2H).LCMS(ESI)m/z[M+H]+:308.0. Add 5 ml of trifluoroacetic anhydride dropwise to a mixture of 1 gram of 6-bromo-1,2,3,4-tetrahydroisoquinoline and 10 ml of dichloromethane under an ice bath. After returning to room temperature, place it at room temperature in an argon atmosphere. Stir for 2 hours. The reaction solution was diluted with 20 ml of ice water, extracted with ethyl acetate, the organic phase was concentrated to dryness, and the residue was subjected to column chromatography with petroleum ether: ethyl acetate = 20:1 to obtain a yellow oily substance 1-(6-bromo-3 , 1.45 g of 4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethane-1-one (168-1), yield 100%. 1 H NMR (400MHz, CD 3 OD-d 4 ) δ7.40–7.33(m,2H),7.11(d,J＝8.1Hz,1H),4.73(d,J＝7.1Hz,2H),3.85( t,J＝5.7Hz,2H),2.95(t,J＝6.4Hz,2H).LCMS(ESI)m/z[M+H] + :308.0.
步骤②：(1-(2-(2,2,2-三氟乙酰基)-1,2,4-四氢异喹啉-6-基)吡咯烷-3-基)氨基-Boc(168-2)
Step ②: (1-(2-(2,2,2-trifluoroacetyl)-1,2,4-tetrahydroisoquinolin-6-yl)pyrrolidin-3-yl)amino-Boc(168 -2)
将200毫克化合物168-1、363毫克(吡咯烷-3-基)氨基-Boc、60毫克三(二亚苄基丙酮)二钯、40毫克1,1'-联萘-2,2'-双二苯膦、423毫克碳酸铯和6毫升1,4-二氧六环的混合物于氩气氛100℃搅拌过夜。反应液过滤，滤液浓缩至干，残余物以石油醚：乙酸乙酯＝10：1柱层析，得黄色固体(1-(2-(2,2,2-三氟乙酰基)-1,2,4-四氢异喹啉-6-基)吡咯烷-3-基)氨基-Boc(168-2)144毫克，收率54％。1H NMR(400MHz,DMSO-d6)δ7.18(d,J＝6.8Hz,1H),7.02(dd,J＝8.4,4.8Hz,1H),6.39(td,J＝8.7,2.2Hz,1H),6.33(dd,J＝6.2,2.3Hz,1H),4.60(d,J＝6.8Hz,2H),4.10(dd,J＝10.9,5.8Hz,1H),3.74(dt,J＝12.3,6.0Hz,2H),3.42(dd,J＝9.5,6.6Hz,1H),3.22–3.15(m,1H),2.99(dd,J＝9.6,5.2Hz,1H),2.84(q,J＝6.5Hz,2H),2.12(dq,J＝13.0,6.5Hz,1H),1.86(dq,J＝13.0,6.8Hz,1H),1.39(s,9H).LCMS(ESI)m/z[M+H]+:414.2.200 mg of compound 168-1, 363 mg of (pyrrolidin-3-yl)amino-Boc, 60 mg of tris(dibenzylideneacetone)dipalladium, 40 mg of 1,1'-binaphthyl-2,2'- A mixture of bisdiphenylphosphine, 423 mg of cesium carbonate and 6 ml of 1,4-dioxane was stirred overnight at 100°C under an argon atmosphere. The reaction solution was filtered, and the filtrate was concentrated to dryness. The residue was subjected to column chromatography with petroleum ether: ethyl acetate = 10:1 to obtain a yellow solid (1-(2-(2,2,2-trifluoroacetyl)-1, 2,4-Tetrahydroisoquinolin-6-yl)pyrrolidin-3-yl)amino-Boc (168-2) 144 mg, yield 54%. 1 H NMR (400MHz, DMSO-d 6 ) δ7.18 (d, J＝6.8Hz, 1H), 7.02 (dd, J＝8.4, 4.8Hz, 1H), 6.39 (td, J＝8.7, 2.2Hz, 1H),6.33(dd,J＝6.2,2.3Hz,1H),4.60(d,J＝6.8Hz,2H),4.10(dd,J＝10.9,5.8Hz,1H),3.74(dt,J＝12.3 ,6.0Hz,2H),3.42(dd,J＝9.5,6.6Hz,1H),3.22–3.15(m,1H),2.99(dd,J＝9.6,5.2Hz,1H),2.84(q,J＝ 6.5Hz,2H),2.12(dq,J＝13.0,6.5Hz,1H),1.86(dq,J＝13.0,6.8Hz,1H),1.39(s,9H).LCMS(ESI)m/z[M +H] + :414.2.
步骤③：(1-(1,2,3,4-四氢异喹啉-6-基)吡咯烷-3-基)氨基-Boc(168-3)
Step ③: (1-(1,2,3,4-tetrahydroisoquinolin-6-yl)pyrrolidin-3-yl)amino-Boc(168-3)
(1-(1,2,3,4-四氢异喹啉-6-基)吡咯烷-3-基)氨基-Boc(168-3)的制备方法同化合物166-7。LCMS(ESI)m/z[M+H]+:318.3.The preparation method of (1-(1,2,3,4-tetrahydroisoquinolin-6-yl)pyrrolidin-3-yl)amino-Boc (168-3) is the same as compound 166-7. LCMS(ESI)m/z[M+H] + :318.3.
步骤④：(1-(2-((5-氟-1H-吲哚-3-基)氨甲酰基)-1,2,4-四氢异喹啉-6-基)吡咯烷-3-基)氨基-Boc(168-4)
Step ④: (1-(2-((5-fluoro-1H-indol-3-yl)carbamoyl)-1,2,4-tetrahydroisoquinolin-6-yl)pyrrolidine-3- Base)Amino-Boc(168-4)
(1-(2-((5-氟-1H-吲哚-3-基)氨甲酰基)-1,2,4-四氢异喹啉-6-基)吡咯烷-3-基)氨基-Boc(168-4)的制备方法同化合物I-1。1H NMR(400MHz,DMSO-d6)δ10.79(s,1H),8.13(s,1H),7.43(d,J＝2.5Hz,1H),7.36(dd,J＝10.4,2.6Hz,1H),7.29(dd,J＝8.8,4.5Hz,1H),7.17(d,J＝6.9Hz,1H),6.97(d,J＝8.3Hz,1H),6.89(td,J＝9.1,2.6Hz,1H),6.39(dd,J＝8.7,2.5Hz,1H),6.33(d,J＝2.4Hz,1H),4.53(s,2H),4.15–4.05(m,1H),3.66(t,J＝5.9Hz,2H),3.48–3.39(m,1H),3.20(q,J＝7.7Hz,1H),3.01(dd,J＝9.7,5.3Hz,1H),2.79(t,J＝5.9Hz,2H),2.14(td,J＝12.5,6.0Hz,1H),1.87(dq,J＝12.6,6.7,6.1Hz,1H),1.39(s,9H),1.27–1.13(m,1H). (1-(2-((5-fluoro-1H-indol-3-yl)carbamoyl)-1,2,4-tetrahydroisoquinolin-6-yl)pyrrolidin-3-yl)amino -The preparation method of Boc(168-4) is the same as that of compound I-1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.79 (s, 1H), 8.13 (s, 1H), 7.43 (d, J = 2.5Hz, 1H), 7.36 (dd, J = 10.4, 2.6Hz, 1H),7.29(dd,J＝8.8,4.5Hz,1H),7.17(d,J＝6.9Hz,1H),6.97(d,J＝8.3Hz,1H),6.89(td,J＝9.1,2.6 Hz,1H),6.39(dd,J＝8.7,2.5Hz,1H),6.33(d,J＝2.4Hz,1H),4.53(s,2H),4.15–4.05(m,1H),3.66(t ,J＝5.9Hz,2H),3.48–3.39(m,1H),3.20(q,J＝7.7Hz,1H),3.01(dd,J＝9.7,5.3Hz,1H),2.79(t,J＝ 5.9Hz,2H),2.14(td,J＝12.5,6.0Hz,1H),1.87(dq,J＝12.6,6.7,6.1Hz,1H),1.39(s,9H),1.27–1.13(m,1H ).
步骤⑤：6-(3-氨基吡咯烷-1-基)-N-(5-氟-1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-168)
Step ⑤: 6-(3-aminopyrrolidin-1-yl)-N-(5-fluoro-1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-methyl Amide(I-168)
6-(3-氨基吡咯-1-基)-N-(1H-吲哚-3-基)-3,4-二氢异喹啉-2(1H)-甲酰胺(I-168)的制备方法同化合物10-2。1H NMR(400MHz,DMSO-d6)δ10.81(s,1H),8.16(s,1H),7.43(d,J＝2.5Hz,1H),7.36(dd,J＝10.2,2.6Hz,1H),7.30(dd,J＝8.8,4.6Hz,1H),7.09(s,2H),7.01(d,J＝8.4Hz,1H),6.89(td,J＝9.1,2.6Hz,1H),6.45(dd,J＝8.4,2.4Hz,1H),6.38(d,J＝2.5Hz,1H),4.55(s,2H),3.83(p,J＝5.7Hz,1H),3.68(t,J＝5.9Hz,2H),3.47–3.43(m,1H),3.24(dd,J＝8.9,3.2Hz,1H),3.17(dd,J＝10.2,4.0Hz,1H),2.81(t,J＝5.9Hz,2H),2.25(dd,J＝13.4,7.0Hz,1H),2.00–1.91(m,2H).LCMS(ESI)m/z[M+H]+:394.2.Preparation of 6-(3-aminopyrrol-1-yl)-N-(1H-indol-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (I-168) The method is the same as that of compound 10-2. 1 H NMR (400MHz, DMSO-d 6 ) δ10.81 (s, 1H), 8.16 (s, 1H), 7.43 (d, J = 2.5Hz, 1H), 7.36 (dd, J = 10.2, 2.6Hz, 1H),7.30(dd,J＝8.8,4.6Hz,1H),7.09(s,2H),7.01(d,J＝8.4Hz,1H),6.89(td,J＝9.1,2.6Hz,1H), 6.45(dd,J＝8.4,2.4Hz,1H),6.38(d,J＝2.5Hz,1H),4.55(s,2H),3.83(p,J＝5.7Hz,1H),3.68(t,J ＝5.9Hz,2H),3.47–3.43(m,1H),3.24(dd,J＝8.9,3.2Hz,1H),3.17(dd,J＝10.2,4.0Hz,1H),2.81(t,J＝ 5.9Hz,2H),2.25(dd,J＝13.4,7.0Hz,1H),2.00–1.91(m,2H).LCMS(ESI)m/z[M+H] + :394.2.
实施例169前药的制备Example 169 Preparation of Prodrugs
3-(3-(4-苯基哌嗪-1-甲酰胺)-1H-吲哚-1-基)二甲基甘氨酸丙酯(169-1)
3-(3-(4-phenylpiperazine-1-carboxamide)-1H-indol-1-yl)dimethylglycinate propyl ester (169-1)
3-(5-氟-3-(6-苯基-1,2,3,4-四氢异喹啉-2-甲酰胺)-1H-吲哚-1-基)二甲基甘氨酸丙酯(169-2)
3-(5-fluoro-3-(6-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxamide)-1H-indol-1-yl)dimethylglycinate propyl ester (169-2)
步骤①：1-(5-氟-3-吲哚基)-2,2,2-三氟乙酮(169-2-1)
Step ①: 1-(5-fluoro-3-indolyl)-2,2,2-trifluoroethanone (169-2-1)
冰浴下向1克5-氟-1H-吲哚和20毫升N,N-二甲基甲酰胺的混合物中加入2毫升三氟乙酸酐，于0℃搅拌5小时。反应液加入50毫升水中稀释，以乙酸乙酯萃取，有机相浓缩至干，得粉色固体1-(5-氟-3-吲哚基)-2,2,2-三氟乙酮(169-2-1)1.7克，收率99％。1H NMR(400MHz,DMSO-d6)δ12.84(s,1H),8.55(dt,J＝4.4,2.1Hz,1H),7.84(dd,J＝9.5,2.7Hz,1H),7.61(dd,J＝8.9,4.5Hz,1H),7.21(td,J＝9.1,2.6Hz,1H).LCMS(ESI)m/z[M+H]+:232.1.Add 2 ml of trifluoroacetic anhydride to a mixture of 1 g of 5-fluoro-1H-indole and 20 ml of N,N-dimethylformamide under an ice bath, and stir at 0°C for 5 hours. The reaction solution was diluted with 50 ml of water, extracted with ethyl acetate, and the organic phase was concentrated to dryness to obtain pink solid 1-(5-fluoro-3-indolyl)-2,2,2-trifluoroethanone (169- 2-1) 1.7 g, yield 99%. 1 H NMR (400MHz, DMSO-d 6 ) δ12.84 (s, 1H), 8.55 (dt, J = 4.4, 2.1Hz, 1H), 7.84 (dd, J = 9.5, 2.7Hz, 1H), 7.61 ( dd,J＝8.9,4.5Hz,1H),7.21(td,J＝9.1,2.6Hz,1H).LCMS(ESI)m/z[M+H] + :232.1.
步骤②：2,2,2-三氟-1-(5-氟-1-(3-甲氧基丙基)-1H-吲哚-3-基)乙烷-1-酮(169-2-2)
Step ②: 2,2,2-trifluoro-1-(5-fluoro-1-(3-methoxypropyl)-1H-indol-3-yl)ethane-1-one (169-2 -2)
将100毫克化合物169-2-1、3-溴丙基甲基醚、150毫克碳酸钾和2毫升N,N-二甲基甲酰胺的混合物于氩气氛60℃搅拌过夜。反应液加入10毫升水中稀释，以乙酸乙酯萃取，有机相浓缩至干，残余物以石油醚：乙酸乙酯＝1：1制备薄层，得黄色固体2,2,2-三氟-1-(5-氟-1-(3-甲氧基丙基)-1H-吲哚-3-基)乙烷-1-酮(169-2-2)122毫克，收率93％。1H NMR(400MHz,DMSO-d6)δ8.59(t,J＝2.0Hz,1H),7.87(dt,J＝9.4,2.4Hz,1H),7.77(ddd,J＝8.9,4.5,2.6Hz,1H),7.28(td,J＝9.2,2.7Hz,1H),4.43(t,J＝7.0Hz,2H),3.27(t,J＝5.9Hz,2H),3.20(s,3H),2.04(p,J＝6.4Hz,2H).LCMS(ESI)m/z[M+H]+:304.1.A mixture of 100 mg of compound 169-2-1, 3-bromopropyl methyl ether, 150 mg of potassium carbonate and 2 ml of N,N-dimethylformamide was stirred overnight at 60°C under an argon atmosphere. The reaction solution was diluted with 10 ml of water, extracted with ethyl acetate, and the organic phase was concentrated to dryness. The residue was prepared as a thin layer using petroleum ether: ethyl acetate = 1:1 to obtain a yellow solid 2,2,2-trifluoro-1. -(5-fluoro-1-(3-methoxypropyl)-1H-indol-3-yl)ethan-1-one (169-2-2) 122 mg, yield 93%. 1 H NMR (400MHz, DMSO-d 6 ) δ8.59 (t, J = 2.0 Hz, 1H), 7.87 (dt, J = 9.4, 2.4 Hz, 1H), 7.77 (ddd, J = 8.9, 4.5, 2.6 Hz,1H),7.28(td,J＝9.2,2.7Hz,1H),4.43(t,J＝7.0Hz,2H),3.27(t,J＝5.9Hz,2H),3.20(s,3H), 2.04(p,J＝6.4Hz,2H).LCMS(ESI)m/z[M+H] + :304.1.
步骤③：5-氟-1-(3-甲氧基丙基)-1H-吲哚-3-羧酸(169-2-3)
Step ③: 5-fluoro-1-(3-methoxypropyl)-1H-indole-3-carboxylic acid (169-2-3)
将120毫克化合物169-2-2和3毫升20％氢氧化钠水溶液的混合物于100℃搅拌过夜。向反应液中滴加6N盐酸溶液至pH为2-3，过滤，得白色固体5-氟-1-(3-甲氧基丙基)-1H-吲哚-3-羧酸(169-2-3)99毫克，收率100％。1H NMR(400MHz,DMSO-d6)δ12.09(s,1H),8.09(d,J＝6.6Hz,1H),7.66(d,J＝9.5Hz,1H),7.58(s,1H),7.10(s,1H),4.29(s,2H),3.33(s,4H),1.99(s,3H).A mixture of 120 mg of compound 169-2-2 and 3 ml of 20% aqueous sodium hydroxide solution was stirred at 100°C overnight. Add 6N hydrochloric acid solution dropwise to the reaction solution until the pH is 2-3, and filter to obtain a white solid 5-fluoro-1-(3-methoxypropyl)-1H-indole-3-carboxylic acid (169-2 -3) 99 mg, yield 100%. 1 H NMR (400MHz, DMSO-d 6 ) δ12.09 (s, 1H), 8.09 (d, J = 6.6Hz, 1H), 7.66 (d, J = 9.5Hz, 1H), 7.58 (s, 1H) ,7.10(s,1H),4.29(s,2H),3.33(s,4H),1.99(s,3H).
步骤④：5-氟-1-(3-甲氧基丙基)-1H-吲哚-3-酰基叠氮(169-2-4)
Step ④: 5-fluoro-1-(3-methoxypropyl)-1H-indole-3-acylazide (169-2-4)
5-氟-1-(3-甲氧基丙基)-1H-吲哚-3-酰基叠氮(169-2-4)的制备方法同化合物1-1。1H NMR(400MHz,CDCl3)δ7.90(dd,J＝9.5,2.6Hz,1H),7.85(s,1H),7.25–7.16(m,1H),7.05(td,J＝9.0,2.6Hz,1H),4.27(t,J＝6.8Hz,2H),3.33(s,3H),3.27(t,J＝5.6Hz,2H),2.12–2.05(m,2H).The preparation method of 5-fluoro-1-(3-methoxypropyl)-1H-indole-3-acyl azide (169-2-4) is the same as that of compound 1-1. 1 H NMR (400MHz, CDCl 3 ) δ7.90 (dd, J＝9.5, 2.6Hz, 1H), 7.85 (s, 1H), 7.25–7.16 (m, 1H), 7.05 (td, J＝9.0, 2.6 Hz,1H),4.27(t,J＝6.8Hz,2H),3.33(s,3H),3.27(t,J＝5.6Hz,2H),2.12–2.05(m,2H).
步骤⑤：5-氟-3-异氰酸酯-1-(3-甲氧基丙基)-1H-吲哚(169-2-5)
Step ⑤: 5-fluoro-3-isocyanate-1-(3-methoxypropyl)-1H-indole (169-2-5)
5-氟-3-异氰酸酯-1-(3-甲氧基丙基)-1H-吲哚(169-2-5)的制备方法同化合物1-2。 LCMS(ESI)m/z[M+H]+:249.1.The preparation method of 5-fluoro-3-isocyanate-1-(3-methoxypropyl)-1H-indole (169-2-5) is the same as that of compound 1-2. LCMS(ESI)m/z[M+H] + :249.1.
步骤⑥：N-(5-氟-1-(3-甲氧基丙基)-1H-吲哚-3-基)-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(169-2-6)
Step ⑥: N-(5-fluoro-1-(3-methoxypropyl)-1H-indol-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H )-Formamide (169-2-6)
N-(5-氟-1-(3-甲氧基丙基)-1H-吲哚-3-基)-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(169-2-6)的制备方法同化合物I-1。LCMS(ESI)m/z[M+H]+:458.1.N-(5-fluoro-1-(3-methoxypropyl)-1H-indol-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)-methyl The preparation method of amide (169-2-6) is the same as compound I-1. LCMS(ESI)m/z[M+H] + :458.1.
步骤⑦：N-(5-氟-1-(3-羟丙基)-1H-吲哚-3-基)-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(169-2-7)
Step ⑦: N-(5-fluoro-1-(3-hydroxypropyl)-1H-indol-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)- Formamide(169-2-7)
冰浴下向20毫克化合物169-2-6和1毫升二氯甲烷的混合物中滴加500微升1M三溴化硼二氯甲烷溶液恢复至室温后继续搅拌2小时。加入10毫升饱和碳酸氢钠水溶液淬灭反应，以乙酸乙酯萃取，有机相浓缩至干，残余物以二氯甲烷：甲醇＝10：1制备薄层，得黄色油状物N-(5-氟-1-(3-羟丙基)-1H-吲哚-3-基)-6-苯基-3,4-二氢异喹啉-2(1H)-甲酰胺(169-2-7)15毫克，收率77％。LCMS(ESI)m/z[M+H]+:444.3.To a mixture of 20 mg of compound 169-2-6 and 1 ml of dichloromethane, 500 μl of 1M boron tribromide dichloromethane solution was added dropwise in an ice bath, and the mixture was returned to room temperature and stirred for 2 hours. Add 10 ml of saturated sodium bicarbonate aqueous solution to quench the reaction, extract with ethyl acetate, concentrate the organic phase to dryness, and prepare a thin layer of the residue with dichloromethane:methanol=10:1 to obtain a yellow oily substance N-(5-fluoro -1-(3-hydroxypropyl)-1H-indol-3-yl)-6-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (169-2-7) 15 mg, yield 77%. LCMS(ESI)m/z[M+H] + :444.3.
步骤⑧：3-(5-氟-3-(6-苯基-1,2,3,4-四氢异喹啉-2-甲酰胺)-1H-吲哚-1-基)二甲基甘氨酸丙酯(169-2)
Step ⑧: 3-(5-fluoro-3-(6-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxamide)-1H-indol-1-yl)dimethyl Glycinate propyl ester (169-2)
向15毫克化合物169-2-7、6毫克N,N-二甲基甘氨酸、1毫克4-(二甲氨基)吡啶和1毫升二氯甲烷的混合物中滴加8微升N,N’-二异丙基碳二亚胺并于氩气氛60℃搅拌过夜。反应液浓缩至干，残余物以二氯甲烷：甲醇＝10：1制备薄层，得白色固体3-(5-氟-3-(6-苯基-1,2,3,4-四氢异喹啉-2-甲酰胺)-1H-吲哚-1-基)二甲基甘氨酸丙酯(169-2)1.4毫克，收率8％。1H NMR(400MHz,CDCl3)δ7.62–7.57(m,2H),7.50(s,1H),7.47– 7.42(m,4H),7.38–7.34(m,1H),7.28(s,1H),7.19(ddd,J＝14.8,9.1,3.3Hz,2H),6.95(td,J＝9.0,2.4Hz,1H),6.33(s,1H),4.76(s,2H),4.18(t,J＝6.7Hz,2H),4.10(t,J＝6.1Hz,2H),3.82(t,J＝5.9Hz,2H),3.17(s,2H),3.03(t,J＝5.8Hz,2H),2.37(s,6H),2.17(dt,J＝12.9,6.6Hz,2H).LCMS(ESI)m/z[M+H]+:529.2.To a mixture of 15 mg of compound 169-2-7, 6 mg of N,N-dimethylglycine, 1 mg of 4-(dimethylamino)pyridine and 1 ml of dichloromethane was added dropwise 8 μl of N,N'- diisopropylcarbodiimide and stirred overnight at 60°C under an argon atmosphere. The reaction solution was concentrated to dryness, and a thin layer of the residue was prepared with dichloromethane: methanol = 10:1 to obtain a white solid 3-(5-fluoro-3-(6-phenyl-1,2,3,4-tetrahydrogen) Isoquinoline-2-carboxamide)-1H-indol-1-yl)dimethylglycine propyl ester (169-2) 1.4 mg, yield 8%. 1 H NMR (400MHz, CDCl 3 ) δ7.62–7.57(m,2H),7.50(s,1H),7.47– 7.42(m,4H),7.38–7.34(m,1H),7.28(s,1H),7.19(ddd,J＝14.8,9.1,3.3Hz,2H),6.95(td,J＝9.0,2.4Hz, 1H),6.33(s,1H),4.76(s,2H),4.18(t,J＝6.7Hz,2H),4.10(t,J＝6.1Hz,2H),3.82(t,J＝5.9Hz, 2H),3.17(s,2H),3.03(t,J＝5.8Hz,2H),2.37(s,6H),2.17(dt,J＝12.9,6.6Hz,2H).LCMS(ESI)m/z [M+H] + :529.2.
(3-(4-苯基哌嗪-1-甲酰胺)-1H-吲哚-1-基)二氢磷酸甲酯(169-3)
(3-(4-Phenylpiperazine-1-carboxamide)-1H-indol-1-yl)dihydrogenphosphate methyl ester (169-3)
实施例170化合物对人源THP1-Blue-ISG细胞中干扰素刺激基因(ISG)表达的影响Effect of Example 170 Compounds on Interferon-Stimulated Gene (ISG) Expression in Human THP1-Blue-ISG Cells
1、实验方法：1. Experimental method:
96孔细胞培养板中的每孔加入10μL用PBS/生理盐水稀释的化合物，STING激动剂为MSA-2，加入计数后的细胞悬液中，终浓度为10μM，不加化合物对照组加10μL含2％DMSO的PBS/生理盐水，各设3个重复孔。THP1-Blue-ISG细胞计数，调整细胞浓度至4×105/mL，每孔加入190μL已加入STING激动剂的细胞进行孵育。因此，每个测试孔的终体积为200μL，DMSO的含量为0.1％，化合物的测试终浓度为1μM，孵育24小时；另空白组加190μL未加入STING激动剂的细胞及10μL含2％DMSO的生理盐水。各设3个重复孔。Add 10 μL of a compound diluted with PBS/physiological saline to each well of a 96-well cell culture plate. The STING agonist is MSA-2. Add it to the counted cell suspension to a final concentration of 10 μM. In the control group without compound, add 10 μL containing 2% DMSO in PBS/physiological saline, with three replicate wells each. Count THP1-Blue-ISG cells, adjust the cell concentration to 4×10 5 /mL, and add 190 μL of cells with STING agonist to each well for incubation. Therefore, the final volume of each test well is 200 μL, the DMSO content is 0.1%, the final test concentration of the compound is 1 μM, and incubated for 24 hours; in addition, the blank group is added with 190 μL of cells without STING agonist and 10 μL of cells containing 2% DMSO. saline. Each set has 3 duplicate holes.
24小时后，每孔取20μL的培养液至新的96孔板中，加入显色液Quanti-Blue 180μL.放置37℃的培养箱，2小时后测定OD650值。After 24 hours, take 20 μL of culture medium from each well into a new 96-well plate, add 180 μL of chromogenic solution Quanti-Blue. Place it in a 37°C incubator, and measure the OD650 value after 2 hours.
结果分析：Result analysis:
抑制率(％)＝(Con(OD650)-Treated(OD650))/Con(OD650)×100％Inhibition rate (%) = (Con (OD650) -Treated (OD650) )/Con (OD650) ×100%
2、实验结果2. Experimental results
测试结果如下表2所示。The test results are shown in Table 2 below.
表2：本发明化合物对人源THP1-Blue-ISG细胞中MSA-2诱导的ISG基因表达的抑制率

Table 2: Inhibition rate of the compounds of the present invention on MSA-2-induced ISG gene expression in human THP1-Blue-ISG cells

aH151为阳性化合物： a H151 is a positive compound:
实验结果表明本发明的二氢异喹啉类化合物在人源THP1-Blue-ISG细胞中具有抑制MSA-2诱导的ISG基因表达的功能，部分化合物在1μM浓度下对STING蛋白的抑 制活性与阳性化合物H151相当；专利化合物A的结构为：来源于专利WO2020010155A1实施例53。Experimental results show that the dihydroisoquinoline compounds of the present invention have the function of inhibiting MSA-2-induced ISG gene expression in human THP1-Blue-ISG cells. Some compounds inhibit STING protein at a concentration of 1 μM. The inhibitory activity is equivalent to that of positive compound H151; the structure of patented compound A is: Derived from Example 53 of patent WO2020010155A1.
实施例171化合物对鼠源RAW-Lucia细胞中ISG基因表达的影响Effect of Example 171 Compounds on ISG Gene Expression in Mouse RAW-Lucia Cells
1、实验方法：1. Experimental method:
96孔细胞培养板中的每孔加入10μL用PBS/生理盐水稀释的化合物，STING激动剂为DMXAA，加入计数后的细胞悬液中，终浓度为50μM，不加化合物对照组加10μL含2％DMSO的PBS/生理盐水，各设3个重复孔。RAW-Lucia细胞计数，调整细胞浓度至4×105/mL，每孔加入180μL的细胞进行孵育。因此，每个测试孔的终体积为200μL，DMSO的含量为0.1％，化合物的测试终浓度为1μM。STING激动剂为DMXAA的终浓度为50μM，孵育24小时；另空白组加200μL培液。各设3个重复孔。Add 10 μL of a compound diluted with PBS/physiological saline to each well of a 96-well cell culture plate. The STING agonist is DMXAA. Add it to the counted cell suspension to a final concentration of 50 μM. The control group without compound is added with 10 μL containing 2%. DMSO and PBS/physiological saline, each with 3 replicate wells. RAW-Lucia cells were counted, the cell concentration was adjusted to 4×10 5 /mL, and 180 μL of cells were added to each well for incubation. Therefore, the final volume of each test well is 200 μL, the content of DMSO is 0.1%, and the final concentration of the compound tested is 1 μM. The STING agonist is DMXAA with a final concentration of 50 μM and incubation for 24 hours; add 200 μL culture medium to the blank group. Each set has 3 duplicate holes.
24小时后，每孔取20μL的培养液至新的底部透光96孔板中，加入荧光素酶检测试剂QUANTI-LucTM50μL，立即测定荧光值(避光)。After 24 hours, take 20 μL of the culture medium from each well into a new 96-well plate with a transparent bottom, add 50 μL of luciferase detection reagent QUANTI-Luc TM , and measure the fluorescence value immediately (protect from light).
结果分析：Result analysis:
抑制率(％)＝(Con(Lum)-Treated(Lum))/Con(Lum)×100％Inhibition rate (%) = (Con (Lum) - Treated (Lum) )/Con (Lum) ×100%
2、实验结果2. Experimental results
实验结果如下表3所示。The experimental results are shown in Table 3 below.
表3：本发明化合物对鼠源RAW-Lucia细胞中DMXAA诱导的ISG基因表达的抑制率

Table 3: Inhibition rate of the compounds of the present invention on DMXAA-induced ISG gene expression in mouse RAW-Lucia cells

实验结果表明本发明的二氢异喹啉类化合物在鼠源RAW-Lucia细胞中具有抑制DMXAA诱导的ISG基因表达的功能，部分化合物在1μM浓度下对STING蛋白的抑制活性与阳性化合物H151相当；专利化合物A的结构为：来源于专利WO2020010155A1实施例53。Experimental results show that the dihydroisoquinoline compounds of the present invention have the function of inhibiting DMXAA-induced ISG gene expression in mouse RAW-Lucia cells. The inhibitory activity of some compounds on STING protein at a concentration of 1 μM is equivalent to that of the positive compound H151; The structure of patented compound A is: Derived from Example 53 of patent WO2020010155A1.
实施例172化合物对人源THP1-Blue-ISG细胞中干扰素刺激基因(ISG)表达的活性抑制剂IC50 IC 50 of the active inhibitor of the compound of Example 172 on the expression of interferon-stimulated genes (ISG) in human THP1-Blue-ISG cells
1、实验方法：1. Experimental method:
96孔细胞培养板中的每孔加入10μL用PBS/生理盐水稀释的化合物，STING激动 剂为MSA-2，加入计数后的细胞悬液中，终浓度为10μM，不加化合物对照组加10μL含2％DMSO的PBS/生理盐水，各设3个重复孔。THP1-Blue-ISG细胞计数，调整细胞浓度至4×105/mL，每孔加入190μL已加入STING激动剂的细胞进行孵育。因此，每个测试孔的终体积为200μL，DMSO的含量为0.1％，化合物的测试终浓度为10/3.3/1.1/0.4/0.13/0.04/0.013/0.004μM，孵育24小时；另空白组加190μL未加入STING激动剂的细胞及10μL含2％DMSO的生理盐水。各设3个重复孔。Add 10 μL of compound diluted in PBS/physiological saline to each well of a 96-well cell culture plate, and STING activates The agent was MSA-2, which was added to the counted cell suspension at a final concentration of 10 μM. In the control group without compound, 10 μL of PBS/physiological saline containing 2% DMSO was added. Three replicate wells were set up in each well. Count THP1-Blue-ISG cells, adjust the cell concentration to 4×10 5 /mL, and add 190 μL of cells with STING agonist to each well for incubation. Therefore, the final volume of each test well is 200 μL, the content of DMSO is 0.1%, the final test concentration of the compound is 10/3.3/1.1/0.4/0.13/0.04/0.013/0.004 μM, and incubated for 24 hours; in addition, the blank group is added 190 μL of cells without STING agonist and 10 μL of normal saline containing 2% DMSO. Each set has 3 duplicate holes.
24小时后，每孔取20μL的培养液至新的96孔板中，加入显色液Quanti-Blue 180μL.放置37℃的培养箱，2小时后测定OD650值。After 24 hours, take 20 μL of culture medium from each well into a new 96-well plate, add 180 μL of chromogenic solution Quanti-Blue. Place it in a 37°C incubator, and measure the OD650 value after 2 hours.
结果分析：Result analysis:
抑制率(％)＝(Con(OD650)-Treated(OD650))/Con(OD650)×100％Inhibition rate (%)=(Con(OD650)-Treated(OD650))/Con(OD650)×100%
抑制剂IC50计算由软件Graphpad Prism 8的计算方法log(inhibitor)vs.response--Variable slope(four parameters)实现，设置constrain区间为1-100。The inhibitor IC50 calculation is implemented by the calculation method log(inhibitor) vs. response--Variable slope(four parameters) of the software Graphpad Prism 8, and the constrain interval is set to 1-100.
2、实验结果2. Experimental results
测试结果如下表4所示。The test results are shown in Table 4 below.
表4：本发明化合物对人源THP1-Blue-ISG细胞中MSA-2诱导的ISG基因表达的抑制IC50
Table 4: Inhibition IC 50 of compounds of the present invention on MSA-2-induced ISG gene expression in human THP1-Blue-ISG cells
实施例173化合物对鼠源RAW-Lucia细胞中ISG基因表达的抑制活性IC50 Inhibitory activity IC 50 of the compound of Example 173 on ISG gene expression in mouse RAW-Lucia cells
1、实验方法： 1. Experimental method:
96孔细胞培养板中的每孔加入10μL用PBS/生理盐水稀释的化合物，STING激动剂为DMXAA，加入计数后的细胞悬液中，终浓度为50μM，不加化合物对照组加10μL含2％DMSO的PBS/生理盐水，各设3个重复孔。RAW-Lucia细胞计数，调整细胞浓度至4×105/mL，每孔加入180μL的细胞进行孵育。因此，每个测试孔的终体积为200μL，DMSO的含量为0.1％，化合物的测试终浓度为10/3.3/1.1/0.4/0.13/0.04/0.013/0.004μM。STING激动剂为DMXAA的终浓度为50μM，孵育24小时；另空白组加200μL培液。各设3个重复孔。Add 10 μL of a compound diluted with PBS/physiological saline to each well of a 96-well cell culture plate. The STING agonist is DMXAA. Add it to the counted cell suspension to a final concentration of 50 μM. The control group without compound is added with 10 μL containing 2%. DMSO and PBS/physiological saline, each with 3 replicate wells. RAW-Lucia cells were counted, the cell concentration was adjusted to 4×10 5 /mL, and 180 μL of cells were added to each well for incubation. Therefore, the final volume of each test well is 200 μL, the content of DMSO is 0.1%, and the final test concentration of the compound is 10/3.3/1.1/0.4/0.13/0.04/0.013/0.004 μM. The STING agonist is DMXAA with a final concentration of 50 μM and incubation for 24 hours; add 200 μL culture medium to the blank group. Each set has 3 duplicate holes.
24小时后，每孔取20μL的培养液至新的底部透光96孔板中，加入荧光素酶检测试剂QUANTI-LucTM50μL，立即测定荧光值(避光)。After 24 hours, take 20 μL of the culture medium from each well into a new 96-well plate with a transparent bottom, add 50 μL of luciferase detection reagent QUANTI-Luc TM , and measure the fluorescence value immediately (protect from light).
结果分析：Result analysis:
抑制率(％)＝(Con(Lum)-Treated(Lum))/Con(Lum)×100％Inhibition rate (%)=(Con(Lum)-Treated(Lum))/Con(Lum)×100%
抑制剂IC50计算由软件Graphpad Prism 8的计算方法log(inhibitor)vs.response--Variable slope(four parameters)实现，设置constrain区间为1-100。The inhibitor IC50 calculation is implemented by the calculation method log(inhibitor) vs. response--Variable slope(four parameters) of the software Graphpad Prism 8, and the constrain interval is set to 1-100.
2、实验结果2. Experimental results
实验结果如下表5所示。The experimental results are shown in Table 5 below.
表5：本发明化合物对鼠源RAW-Lucia细胞中DMXAA诱导的ISG基因表达的抑制IC50
Table 5: Inhibition IC 50 of compounds of the present invention on DMXAA-induced ISG gene expression in mouse RAW-Lucia cells
实施例174药物组合物的制备Example 174 Preparation of Pharmaceutical Compositions
药片
pill
将上述物质混合均匀，通过常规工艺制备1000片药片。可以使用适当的水性或非水性包衣以提高适口程度、改善外观和稳定性或延缓吸收。Mix the above materials evenly and prepare 1,000 tablets through conventional processes. Appropriate aqueous or non-aqueous coatings may be used to enhance palatability, improve appearance and stability, or delay absorption.
胶囊
化合物I-10       150克
淀粉             140克
微晶纤维素       80克 Capsule <br/> Compound I-10 150g starch 140g microcrystalline cellulose 80g
按常规方法，将上述物质混合均匀，装入普通明胶胶囊，制备1000颗胶囊。According to conventional methods, mix the above substances evenly and put them into ordinary gelatin capsules to prepare 1,000 capsules.
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。 All documents mentioned in this application are incorporated by reference in this application to the same extent as if each individual document was individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

Claims (14)

  1. [根据细则26改正 27.03.2023]
    式(I)所示的化合物，或其前药、其对映异构体、非对映异构体、外消旋体及其混合物，或其药学上可接受的盐，     [Amended in accordance with Rule 26 27.03.2023]
    The compound represented by formula (I), or its prodrug, its enantiomers, diastereomers, racemates and mixtures thereof, or its pharmaceutically acceptable salts,
    其中，Q选自O或S；Among them, Q is selected from O or S;
    环A选自取代或非取代下组基团：C6-C12芳基和5-12元杂芳基；其中，所述取代是指被1-5个R1取代；其中，各R1独立地选自：氢、卤素、羧基、羟基、氰基、氨基、-COOC1-C6烷基、硝基、-CO(3-8元取代或未取代杂环基)、-CO(C3-C8取代或未取代环烷基)、取代或未取代的C6-C12芳基C1-C6烷基、取代或未取代的5-12元杂芳基C1-C6烷基、取代或未取代C1-C6烷基、取代或未取代C2-C6烯基、取代或未取代C2-C6炔基、取代或未取代C1-C6烷氧基、取代或未取代C1-C6烷基酰基、取代或未取代氨基酰基、取代或未取代C1-C6烷基酰胺基、取代或未取代C1-C4烷基氨基、取代或未取代C6-C12芳基氨基、取代或未取代3-8元杂环基、取代或未取代C3-C8环烷基、取代或未取代5-12元杂芳基、取代或未取代C6-C12芳基；R1中所述取代是指被一个或多个选自下组的基团取代：卤素、羧基、-OP(O)(OH)2、羟基、氰基、氨基、硝基、苄基、C1-C6烷基OH、C1-C6烷基氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C8环烷基或3-8元杂环基；Ring A is selected from the group consisting of substituted or unsubstituted groups: C6-C12 aryl and 5-12 membered heteroaryl; wherein said substitution means substitution by 1-5 R 1 ; wherein each R 1 is independently Selected from: hydrogen, halogen, carboxyl, hydroxyl, cyano, amino, -COOC1-C6 alkyl, nitro, -CO (3-8-membered substituted or unsubstituted heterocyclyl), -CO (C3-C8 substituted or Unsubstituted cycloalkyl), substituted or unsubstituted C6-C12 aryl C1-C6 alkyl, substituted or unsubstituted 5-12 membered heteroaryl C1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl , substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkyl acyl, substituted or unsubstituted aminoacyl, Substituted or unsubstituted C1-C6 alkylamido, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C6-C12 arylamino, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl; substituted in R 1 means substituted by one or more groups selected from the following group : Halogen, carboxyl, -OP(O)(OH) 2 , hydroxyl, cyano, amino, nitro, benzyl, C1-C6 alkyl OH, C1-C6 alkylamino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl or 3-8 membered heterocyclyl;
    环B为 Ring B is
    其中，E为NR10或CR10R10’；Among them, E is NR 10 or CR 10 R 10' ;
    R10选自：COOC1-C6烷基、-CO(3-8元取代或未取代杂环基)、-CO(C3-C8取代或未取代环烷基)、取代或未取代的C6-C12芳基C1-C6烷基、取代或未取代的5-12元杂芳基C1-C6烷基、取代或未取代C1-C6烷基、取代或未取代C2-C6烯基、取代或未取代C2-C6炔基、取代或未取代C1-C6烷氧基、取代或未取代C1-C6烷基酰基、取代或未取代氨基甲酰基、取代或未取代C1-C6烷基酰胺基、取代或未取代C1-C4烷基氨基、取代或未取代C6-C12芳基氨基、取代或未取代3-8元杂环基、取代或未取代C3-C8环烷基、取代或未取代3-8元杂环基C1-C6烷基、取代或未取代C3-C8环烷基C1-C6烷基、取代或未取代5-12元杂芳基、取代或未取代C6-C12芳基；其中，所述取代是指被一个或多个选自下组的基团取代：卤素、羧基、羟基、氰基、氨基、硝基、苄基、C1-C6烷基OH、C1-C6烷基氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基或3-8元杂环基；R 10 is selected from: COOC1-C6 alkyl, -CO (3-8-membered substituted or unsubstituted heterocyclyl), -CO (C3-C8 substituted or unsubstituted cycloalkyl), substituted or unsubstituted C6-C12 Aryl C1-C6 alkyl, substituted or unsubstituted 5-12 membered heteroaryl C1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylacyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted C1-C6 alkylamide, substituted or Unsubstituted C1-C4 alkylamino, substituted or unsubstituted C6-C12 arylamino, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 Membered heterocyclyl C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl C1-C6 alkyl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl; wherein, The substitution means substitution by one or more groups selected from the following group: halogen, carboxyl, hydroxyl, cyano, amino, nitro, benzyl, C1-C6 alkyl OH, C1-C6 alkylamino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy or 3-8 membered heterocyclyl;
    R10’、Rg、Rg’、Rh、Rh’、Ri、Ri’、Rj和Rj’各自独立地选自：氢、卤素、羧基、羟基、氰基、氨基、-COOC1-C6烷基、硝基、-CO(3-8元取代或未取代杂环基)、-CO(C3-C8取代或未取代环烷基)、取代或未取代的C6-C12芳基C1-C6烷基、取代或未取代的5-12元杂芳基C1-C6烷基、取代或未取代C1-C6烷基、取代或未取代C2-C6烯基、取代或未取代C2-C6炔基、取代或未取代C1-C6烷氧基、取代或未取代C1-C6烷基酰基、取代或未取代氨基酰基、取代或未取代C1-C6烷基酰胺基、取代或未取代C1-C4烷基氨基、取代或未取代C6-C12芳基氨基、取代或未取代3-8元杂环基、取代或未取代C3-C8环烷基、取代或未取代3-8元杂环基C1-C6烷基、取代或未取代C3-C8环烷基C1-C6烷基、取代或未取代5-12元杂芳基、取代或未取代C6-C12芳基；其中，所述取代是指被一个或多个Ra取代；R 10' , R g , R g' , Rh, Rh ' , R i , R i' , R j and R j' are each independently selected from: hydrogen, halogen, carboxyl, hydroxyl, cyano, amino, -COOC1-C6 alkyl, nitro, -CO (3-8-membered substituted or unsubstituted heterocyclyl), -CO (C3-C8 substituted or unsubstituted cycloalkyl), substituted or unsubstituted C6-C12 aromatic Base C1-C6 alkyl, substituted or unsubstituted 5-12 membered heteroaryl C1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2 -C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkyl acyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted C1-C6 alkylamide, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C6-C12 arylamino, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl Cyclic group C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl C1-C6 alkyl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl; wherein, the Substitute means to be replaced by one or more Ra;
    或者，R10和R10’与它们连接的C原子共同形成氧代基(＝O)、取代或未取代3-8元杂环基、取代或未取代C3-C8环烷基、取代或未取代的5-12元杂芳基、取代或未取代C6-C12芳基；其中，所述取代是指被一个或多个Ra取代；Alternatively, R 10 and R 10' together with the C atom to which they are connected form an oxo group (=O), a substituted or unsubstituted 3-8 membered heterocyclyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted Substituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl; wherein, the substitution means substitution by one or more Ra;
    或者，Rg和Rg’与它们连接的C原子共同形成氧代基(＝O)、取代或未取代3-8元杂环基、取代或未取代C3-C8环烷基、取代或未取代的5-12元杂芳基、取代或未取代C6-C12芳基；其中，所述取代是指被一个或多个Ra取代；Alternatively, R g and R g' together with the C atom to which they are connected form an oxo group (=O), a substituted or unsubstituted 3-8 membered heterocyclyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted Substituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl; wherein, the substitution means substitution by one or more Ra;
    或者，Rh和Rh’与它们连接的C原子共同形氧代基(＝O)、成取代或未取代3-8元杂环基、取代或未取代C3-C8环烷基、取代或未取代的5-12元杂芳基、取代或未取代C6-C12芳基；其中，所述取代是指被一个或多个Ra取代；Alternatively, R h and R h' together with the C atom to which they are connected form an oxo group (=O), a substituted or unsubstituted 3-8 membered heterocyclyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or Unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl; wherein, the substitution means substitution by one or more Ra;
    或者，Ri和Ri’与它们连接的C原子共同形成氧代基(＝O)、取代或未取代3-8元杂环基、取代或未取代C3-C8环烷基、取代或未取代的5-12元杂芳基、取代或未取代C6-C12芳基；其中，所述取代是指被一个或多个Ra取代；Alternatively, R i and R i' together with the C atom to which they are connected form an oxo group (=O), a substituted or unsubstituted 3-8 membered heterocyclyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted Substituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl; wherein, the substitution means substitution by one or more Ra;
    或者，Rj和Rj’它们连接的C原子共同形成氧代基(＝O)、取代或未取代3-8元杂环基、取代或未取代C3-C8环烷基、取代或未取代的5-12元杂芳基、取代或未取代C6-C12芳基；其中，所述取代是指被一个或多个Ra取代；Alternatively, the C atoms to which R j and R j' are connected together form an oxo group (=O), a substituted or unsubstituted 3-8 membered heterocyclyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl; wherein, the substitution means substitution by one or more Ra;
    或者，Rg和Rh与它们连接的C原子共同形成氧代基(＝O)、取代或未取代3-8元杂环基、取代或未取代C3-C8环烷基、取代或未取代的5-12元杂芳基、取代或未取代C6-C12芳基；其中，所述取代是指被一个或多个Ra取代；Alternatively, R g and R h together with the C atom to which they are connected form an oxo group (=O), a substituted or unsubstituted 3-8 membered heterocyclyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl; wherein, the substitution means substitution by one or more Ra;
    或者，Ri和Rj与它们连接的C原子共同形成氧代基(＝O)、取代或未取代3-8元杂环基、取代或未取代C3-C8环烷基、取代或未取代的5-12元杂芳基、取代或未取代C6-C12芳基；其中，所述取代是指被一个或多个Ra取代；Alternatively, R i and R j together with the C atom to which they are connected form an oxo group (=O), a substituted or unsubstituted 3-8 membered heterocyclyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl; wherein, the substitution means substitution by one or more Ra;
    或者，Ri和R10与它们连接的C原子共同形成氧代基(＝O)、取代或未取代3-8元杂环基、取代或未取代C3-C8环烷基、取代或未取代的5-12元杂芳基、取代或未取代C6-C12芳基；其中，所述取代是指被一个或多个Ra取代；Alternatively, R i and R 10 together with the C atom to which they are connected form an oxo group (=O), a substituted or unsubstituted 3-8 membered heterocyclyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl; wherein, the substitution means substitution by one or more Ra;
    或者，Rh和R10与它们连接的C原子共同形成氧代基(＝O)、取代或未取代3-8元杂环基、取代或未取代C3-C8环烷基、取代或未取代的5-12元杂芳基、取代或未取代C6-C12芳基；其中，所述取代是指被一个或多个Ra取代；Alternatively, R h and R 10 together with the C atom to which they are connected form an oxo group (=O), a substituted or unsubstituted 3-8 membered heterocyclyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl; wherein, the substitution means substitution by one or more Ra;
    Ra选自：卤素、羧基、羟基、氰基、硝基、氨基、-COOC1-C6烷基、取代或未取代C1-C6烷基、取代或未取代C2-C6烯基、取代或未取代C2-C6炔基、取代或未取代C1-C6烷氧基、取代或未取代C1-C6烷基酰基、取代或未取代氨基甲酰基、取代或未取代C1-C6烷基酰胺基、取代或未取代C1-C4烷基氨基、取代或未取代C6-C12芳基氨基、取代或未取代3-8元杂环基、取代或未取代C3-C8环烷基、取代或未取代的5-12元杂芳基、取代或未取代C6-C12芳基、取代或未取代的C6-C12芳基C1-C6烷基、取代或未取代的5-12元杂芳基C1-C6烷基、-CO(3-8元取代或未取代杂环基)、-CO(C3-C8取代或未取代环烷基)；其中，所述取代是指被一个或多个选自下组的基团取代：卤素、羧基、羟基、氰基、氨基、硝基、SO2C1-C6烷基、CO2C1-C6烷基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷基OH、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C8环烷基或3-8元杂环基；Ra is selected from: halogen, carboxyl, hydroxyl, cyano, nitro, amino, -COOC1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2 -C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylacyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted C1-C6 alkylamide, substituted or unsubstituted Substituted C1-C4 alkylamino, substituted or unsubstituted C6-C12 arylamino, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-12 1-membered heteroaryl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C6-C12 aryl C1-C6 alkyl, substituted or unsubstituted 5-12 membered heteroaryl C1-C6 alkyl, - CO (3-8-membered substituted or unsubstituted heterocyclyl), -CO (C3-C8 substituted or unsubstituted cycloalkyl); wherein, the substitution refers to being substituted by one or more groups selected from the following group : Halogen, carboxyl, hydroxyl, cyano, amino, nitro, SO 2 C1-C6 alkyl, CO 2 C1-C6 alkyl, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyl OH, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl or 3-8 membered heterocyclyl;
    n为1或2。n is 1 or 2.
  2. [根据细则26改正 27.03.2023]
    如权利要求1所述的化合物，或其前药、其对映异构体、非对映异构体、外消旋体及其混合物，或其药学上可接受的盐，其特征在于，环A选自取代或未取代的下组基团：五元杂芳基、六元芳基、六元杂芳基、[6+6]芳基或稠环、[6+6]杂芳基或稠环、[6+5]杂芳基或稠环、[5+6]杂芳基或稠环、[5+5]杂芳基或稠环，其中，所述取代是指被1-5个R1取代；其中，各R1独立地选自：氢、卤素、羧基、羟基、氰基、氨基、-COOC1-C6烷基、硝基、-CO(3-8元取代或未取代杂环基)、-CO(C3-C8取代或未取代环烷基)、取代或未取代的C6-C12芳基C1-C6烷基、取代或未取代的5-12元杂芳基C1-C6烷基、取代或未取代C1-C6烷基、取代或未取代C2-C6烯基、取代或未取代C2-C6炔基、取代或未取代C1-C6烷氧基、取代或未取代C1-C6烷基酰基、取代或未取代氨基酰基、取代或未取代C1-C6烷基酰胺基、取代或未取代C1-C4烷基氨基、取代或未取代C6-C12芳基氨基、取代或未取代3-8元杂环基、取代或未取代C3-C8环烷基、取代或未取代5-12元杂芳基、取代或未取代C6-C12芳基；R1中所述取代是指被一个或多个选自下组的基团取代：卤素、羧基、-OP(O)(OH)2、羟基、氰基、氨基、硝基、苄基、C1-C6烷基OH、C1-C6烷基氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C8环烷基或3-8元杂环基。    [Amended in accordance with Rule 26 27.03.2023]
    The compound according to claim 1, or its prodrug, its enantiomer, diastereomer, racemate and mixture thereof, or its pharmaceutically acceptable salt, characterized in that: A is selected from the following substituted or unsubstituted groups: five-membered heteroaryl, six-membered aryl, six-membered heteroaryl, [6+6]aryl or fused ring, [6+6]heteroaryl or Condensed ring, [6+5]heteroaryl or fused ring, [5+6]heteroaryl or fused ring, [5+5]heteroaryl or fused ring, wherein the substitution means by 1-5 Each R 1 is substituted; wherein, each R 1 is independently selected from: hydrogen, halogen, carboxyl, hydroxyl, cyano, amino, -COOC1-C6 alkyl, nitro, -CO (3-8 yuan substituted or unsubstituted hetero Cyclic group), -CO (C3-C8 substituted or unsubstituted cycloalkyl), substituted or unsubstituted C6-C12 aryl C1-C6 alkyl, substituted or unsubstituted 5-12 membered heteroaryl C1-C6 Alkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1- C6 alkyl acyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted C1-C6 alkylamido, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C6-C12 arylamino, substituted or unsubstituted 3-8-membered heterocyclyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-12-membered heteroaryl, substituted or unsubstituted C6-C12 aryl; the substitution mentioned in R 1 means that it is substituted by One or more groups selected from the following group are substituted: halogen, carboxyl, -OP(O)(OH) 2 , hydroxyl, cyano, amino, nitro, benzyl, C1-C6 alkylOH, C1-C6 Alkylamino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl or 3-8 membered heterocyclyl.
  3. 如权利要求1所述的所述的化合物，或其前药、其对映异构体、非对映异构体、外消旋体及其混合物，或其药学上可接受的盐，其特征在于，环A选自以下结构： The compound as claimed in claim 1, or its prodrug, its enantiomers, diastereomers, racemates and mixtures thereof, or its pharmaceutically acceptable salts, characterized by That is, ring A is selected from the following structures:
    其中X选自：O、S、N或NH；Where X is selected from: O, S, N or NH;
    R1是环上任意位置的取代基，个数为1-5个，各R1独立地选自：氢、卤素、羧基、羟基、氰基、氨基、硝基、取代或未取代的苄基、取代或未取代的C6-C12芳基甲基、取代或未取代的5-12元杂芳基甲基、取代或未取代的杂芳基甲基、取代或未取代C1-C6烷基、取代或未取代C2-C6烯基、取代或未取代C2-C6炔基、取代或未取代C1-C6烷氧基、取代或未取代C1-C6烷基酰基、取代或未取代氨基酰基、取代或未取代C1-C6烷基酰胺基、取代或未取代C1-C4烷基氨基、取代或未取代C6-C12芳基氨基、取代或未取代3-8元杂环基、取代或未取代3-8元环烷基、取代或未取代5-12元元杂芳基、取代或未取代C6-C12芳基；R1中所述取代是指被一个或多个选自下组的基团取代：卤素、羧基、-OP(O)(OH)2、羟基、氰基、氨基、硝基、苄基、C1-C6烷基OH、C1-C6烷基氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C8环烷基或3-8元杂环基。R 1 is a substituent at any position on the ring, and the number is 1-5. Each R 1 is independently selected from: hydrogen, halogen, carboxyl, hydroxyl, cyano, amino, nitro, Substituted or unsubstituted benzyl, substituted or unsubstituted C6-C12 arylmethyl, substituted or unsubstituted 5-12 membered heteroarylmethyl, substituted or unsubstituted heteroarylmethyl, substituted or unsubstituted Substituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkyl acyl, substituted Or unsubstituted aminoacyl, substituted or unsubstituted C1-C6 alkylamido, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C6-C12 arylamino, substituted or unsubstituted 3-8 membered heterocycle base, substituted or unsubstituted 3-8-membered cycloalkyl, substituted or unsubstituted 5-12-membered heteroaryl, substituted or unsubstituted C6-C12 aryl; the substitution in R 1 means to be substituted by one or more Substitution with groups selected from the group consisting of: halogen, carboxyl, -OP(O)(OH) 2 , hydroxyl, cyano, amino, nitro, benzyl, C1-C6 alkylOH, C1-C6 alkylamino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl or 3-8 membered heterocyclyl.
  4. 如权利要求1所述的化合物，或其前药、其对映异构体、非对映异构体、外消旋体及其混合物，或其药学上可接受的盐，其特征在于，环B选自以下结构： The compound according to claim 1, or its prodrug, its enantiomer, diastereomer, racemate and mixture thereof, or its pharmaceutically acceptable salt, characterized in that: B is selected from the following structures:
    其中，in,
    M为N或CH；M is N or CH;
    R4选自：卤素、羧基、羟基、氰基、硝基、氨基、-COOC1-C6烷基、取代或未取代C1-C6烷基、取代或未取代C2-C6烯基、取代或未取代C2-C6炔基、取代或未取代C1-C6烷氧基、取代或未取代C1-C6烷基酰基、取代或未取代氨基甲酰基、取代或未取代C1-C6烷基酰胺基、取代或未取代C1-C4烷基氨基、取代或未取代C6-C12芳基氨基、取代或未取代3-8元杂环基、取代或未取代C3-C8环烷基、取代或未取代的5-12元杂芳基、取代或未取代C6-C12芳基、取代或未取代的C6-C12芳基C1-C6烷基、取代或未取代的5-12元杂芳基C1-C6烷基、-CO(3-8元取代或未取代杂环基)、-CO(C3-C8取代或未取代环烷基)；其中，所述取代是指被一个或多个选自下组的基团取代：卤素、羧基、羟基、氰基、氨基、硝基、SO2C1-C6烷基、CO2C1-C6烷基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷基OH、C1-C6烷氧基、卤代C1-C6烷氧基或3-8元杂环基；R 4 is selected from: halogen, carboxyl, hydroxyl, cyano, nitro, amino, -COOC1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylacyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted C1-C6 alkylamide, substituted or Unsubstituted C1-C4 alkylamino, substituted or unsubstituted C6-C12 arylamino, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5- 12-membered heteroaryl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C6-C12 aryl C1-C6 alkyl, substituted or unsubstituted 5-12-membered heteroaryl C1-C6 alkyl, -CO (3-8-membered substituted or unsubstituted heterocyclyl), -CO (C3-C8 substituted or unsubstituted cycloalkyl); wherein the substitution refers to one or more groups selected from the following group Substitution: halogen, carboxyl, hydroxyl, cyano, amino, nitro, SO 2 C1-C6 alkyl, CO 2 C1-C6 alkyl, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyl Base OH, C1-C6 alkoxy group, halogenated C1-C6 alkoxy group or 3-8 membered heterocyclic group;
    R10选自：COOC1-C6烷基、-CO(3-8元取代或未取代杂环基)、-CO(C3-C8取代或未取代环烷基)、取代或未取代的C6-C12芳基C1-C6烷基、取代或未取代的5-12元杂芳基C1-C6烷基、取代或未取代C1-C6烷基、取代或未取代C2-C6烯基、取代或未取代C2-C6炔基、取代或未取代C1-C6烷氧基、取代或未取代C1-C6烷基酰基、取代或未取代氨基酰基、取代或未取代C1-C6烷基酰胺基、取代或未取代C1-C4烷基氨基、取代或未取代C6-C12芳基氨基、取代或未取代3-8元杂环基、取代或未取代C3-C8环烷基、取代或未取代3-8元杂环基C1-C6烷基、取代或未取代C3-C8环烷基C1-C6烷基、取代或未取代5-12元杂芳基、取代或未取代C6-C12芳基；其中，所述取代是指被一个或多个选自下组的基团取代：卤素、羧基、羟基、氰基、氨基、硝基、苄基、C1-C6烷基OH、C1-C6烷基氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基或3-8元杂环基；R 10 is selected from: COOC1-C6 alkyl, -CO (3-8-membered substituted or unsubstituted heterocyclyl), -CO (C3-C8 substituted or unsubstituted cycloalkyl), substituted or unsubstituted C6-C12 Aryl C1-C6 alkyl, substituted or unsubstituted 5-12 membered heteroaryl C1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkyl acyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted C1-C6 alkylamide, substituted or unsubstituted Substituted C1-C4 alkylamino, substituted or unsubstituted C6-C12 arylamino, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 membered Heterocyclyl C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl C1-C6 alkyl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl; wherein, The substitution refers to substitution by one or more groups selected from the following group: halogen, carboxyl, hydroxyl, cyano, amino, nitro, benzyl, C1-C6 alkyl OH, C1-C6 alkylamino, C1 -C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy or 3-8 membered heterocyclyl;
    R2、R3、R5、R6、R7、R8和R9各自独立地选自：H、卤素、羧基、羟基、氰基、硝基、氨基、-COOC1-C6烷基、取代或未取代C1-C6烷基、取代或未取代C2-C6烯基、取代或未取代C2-C6炔基、取代或未取代C1-C6烷氧基、取代或未取代C1-C6烷基酰基、取代或未取代氨基甲酰基、取代或未取代C1-C6烷基酰胺基、取代或未取代C1-C4烷基氨基、取代或未取代C6-C12芳基氨基、取代或未取代3-8元杂环基、取代或未取代C3-C8环烷基、取代或未取代的5-12元杂芳基、取代或未取代C6-C12芳基、取代或未取代的C6-C12芳基C1-C6烷基、取代或未取代的5-12元杂芳基C1-C6烷基、-CO(3-8元取代或未取代杂环基)、-CO(C3-C8取代或未取代环烷基)；其中，所述取代是指被一个或多个选自下组的基团取代：卤素、羧基、羟基、氰基、氨基、硝基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷基OH、C1-C6烷氧基或3-8元杂环基；R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 9 are each independently selected from: H, halogen, carboxyl, hydroxyl, cyano, nitro, amino, -COOC1-C6 alkyl, substituted Or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkyl acyl , substituted or unsubstituted carbamoyl, substituted or unsubstituted C1-C6 alkylamido, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C6-C12 arylamino, substituted or unsubstituted 3-8 Membered heterocyclyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C6-C12 aryl C1 -C6 alkyl, substituted or unsubstituted 5-12 membered heteroaryl C1-C6 alkyl, -CO (3-8 membered substituted or unsubstituted heterocyclyl), -CO (C3-C8 substituted or unsubstituted ring Alkyl); wherein, the substitution means substitution by one or more groups selected from the following group: halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C6 alkyl, halogenated C1-C6 Alkyl, C1-C6 alkyl OH, C1-C6 alkoxy or 3-8 membered heterocyclyl;
    或者R2和R3与它们所连接的碳原子形成取代或未取代的苯基或取代或未取代的5-8元杂芳基；其中，所述取代是指被一个或多个选自下组的基团取代：卤素、羧基、羟基、氰基、氨基、硝基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷基OH、C1-C6烷氧基或3-8元杂环基；Or R 2 and R 3 and the carbon atom to which they are connected form a substituted or unsubstituted phenyl group or a substituted or unsubstituted 5-8-membered heteroaryl group; wherein the substitution means being substituted by one or more selected from the following Group substitution of: halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyl OH, C1-C6 alkoxy or 3- 8-membered heterocyclyl;
    或者R3和R4与它们所连接的碳原子形成取代或未取代的苯基或取代或未取代的5-8元杂芳基；其中，所述取代是指被一个或多个选自下组的基团取代：卤素、羧基、羟基、氰基、氨基、硝基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷基OH、C1-C6烷氧基或3-8元杂环基；Or R 3 and R 4 and the carbon atoms to which they are connected form a substituted or unsubstituted phenyl group or a substituted or unsubstituted 5-8-membered heteroaryl group; wherein the substitution means being substituted by one or more selected from the following Group substitution of: halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyl OH, C1-C6 alkoxy or 3- 8-membered heterocyclyl;
    或者R4和R5与它们所连接的碳原子形成取代或未取代的苯基或取代或未取代的5-8元杂芳基；其中，所述取代是指被一个或多个选自下组的基团取代：卤素、羧基、羟基、氰基、氨基、硝基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷基OH、C1-C6烷氧基或3-8元杂环基；Or R 4 and R 5 and the carbon atoms to which they are connected form a substituted or unsubstituted phenyl group or a substituted or unsubstituted 5-8-membered heteroaryl group; wherein the substitution means being substituted by one or more selected from the following Group substitution of: halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyl OH, C1-C6 alkoxy or 3- 8-membered heterocyclyl;
    或者R6和R7与它们所连接的碳原子形成取代或未取代的苯基或取代或未取代的5-8元杂芳基；其中，所述取代是指被一个或多个选自下组的基团取代：卤素、羧基、羟基、氰基、氨基、硝基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷基OH、C1-C6烷氧基或3-8元杂环基；Or R 6 and R 7 and the carbon atoms to which they are connected form a substituted or unsubstituted phenyl group or a substituted or unsubstituted 5-8 membered heteroaryl group; wherein the substitution means being substituted by one or more selected from the following Group substitution of: halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyl OH, C1-C6 alkoxy or 3- 8-membered heterocyclyl;
    或者R7和R8与它们所连接的碳原子形成取代或未取代的苯基或取代或未取代的5-8元杂芳基；其中，所述取代是指被一个或多个选自下组的基团取代：卤素、羧基、羟基、氰基、氨基、硝基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷基OH、C1-C6烷氧基或3-8元杂环基；Or R 7 and R 8 and the carbon atom to which they are connected form a substituted or unsubstituted phenyl group or a substituted or unsubstituted 5-8 membered heteroaryl group; wherein the substitution means being substituted by one or more selected from the following Group substitution of: halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyl OH, C1-C6 alkoxy or 3- 8-membered heterocyclyl;
    或者R8和R9与它们所连接的碳原子形成取代或未取代的苯基或取代或未取代的5-8元杂芳基；其中，所述取代是指被一个或多个选自下组的基团取代：卤素、羧基、羟基、氰基、氨基、硝基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷基OH、C1-C6烷氧基或3-8元杂环基；Or R 8 and R 9 and the carbon atom to which they are connected form a substituted or unsubstituted phenyl group or a substituted or unsubstituted 5-8 membered heteroaryl group; wherein the substitution means being substituted by one or more selected from the following Group substitution of: halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyl OH, C1-C6 alkoxy or 3- 8-membered heterocyclyl;
    Ra、Ra’、Rb、Rb’、Rc、Rc’、Rd、Rd’、Re、Re’、Rf、Rf’、Rg、Rg’、Rh、Rh’、Ri、Ri’、Rj和Rj’各自独立地选自：氢、卤素、羧基、羟基、氰基、氨基、-COOC1-C6烷基、硝基、-CO(3-8元取代或未取代杂环基)、-CO(C3-C8取代或未取代环烷基)、取代或未取代的C6-C12芳基C1-C6烷基、取代或未取代的5-12元杂芳基C1-C6烷基、取代或未取代C1-C6烷基、取代或未取代C2-C6烯基、取代或未取代C2-C6炔基、取代或未取代C1-C6烷氧基、取代或未取代C1-C6烷基酰基、取代或未取代氨基酰基、取代或未取代C1-C6烷基酰胺基、取代或未取代C1-C4烷基氨基、取代或未取代C6-C12芳基氨基、取代或未取代3-8元杂环基、取代或未取代C3-C8环烷基、取代或未取代3-8元杂环基C1-C6烷基、取代或未取代C3-C8环烷基C1-C6烷基、取代或未取代5-12元杂芳基、取代或未取代C6-C12芳基；其中，所述取代是指被一个或多个Ra取代；R a , R a' , R b , R b' , R c , R c' , R d , R d ' , R e , R e ' , R f , R f ' , R g , R g ' , R h , R h' , R i , R i' , R j and R j' are each independently selected from: hydrogen, halogen, carboxyl, hydroxyl, cyano, amino, -COOC1-C6 alkyl, nitro, -CO (3-8-membered substituted or unsubstituted heterocyclyl), -CO (C3-C8 substituted or unsubstituted cycloalkyl), substituted or unsubstituted C6-C12 aryl C1-C6 alkyl, substituted or unsubstituted 5-12 membered heteroaryl C1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 Alkoxy, substituted or unsubstituted C1-C6 alkylamino, substituted or unsubstituted aminoacyl, substituted or unsubstituted C1-C6 alkylamido, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C6 -C12 arylamino, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl C1-C6 alkyl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl; wherein the substitution means substitution by one or more Ra;
    环C选自：取代或未取代3-8元杂环基、取代或未取代C3-C8环烷基、取代或未取代5-8元杂芳基、取代或未取代6-12元芳基；其中，所述取代是指被一个或多个选自下组的基团取代：卤素、羧基、羟基、氰基、氨基、硝基、苄基、C1-C6烷基OH、C1-C6烷基氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基或3-8元杂环基；Ring C is selected from: substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-8 membered heteroaryl, substituted or unsubstituted 6-12 membered aryl ; Wherein, the substitution refers to being substituted by one or more groups selected from the following group: halogen, carboxyl, hydroxyl, cyano, amino, nitro, benzyl, C1-C6 alkyl OH, C1-C6 alkyl amino group, C1-C6 alkyl group, halogenated C1-C6 alkyl group, C1-C6 alkoxy group, halogenated C1-C6 alkoxy group or 3-8 membered heterocyclyl group;
    m为0、1、2、3、4或5；m is 0, 1, 2, 3, 4 or 5;
    n为1或2；n is 1 or 2;
    Ra的定义如权利要求1所述。Ra is defined as in claim 1.
  5. 如权利要求4所述的化合物，或其前药、其对映异构体、非对映异构体、外消旋体及其混合物，或其药学上可接受的盐，其特征在于，R4选自：卤素、羧基、羟基、氰基、氨基、硝基、取代或未取代的苄基、取代或未取代的芳基甲基、取代或未取代的杂芳基甲基、取代或未取代的杂芳基甲基、取代或未取代C1-C6烷基、取代或未取代C2-C6烯基、取代或未取代C2-C6炔基、取代或未取代C1-C6烷氧基、取代或未取代C1-C6烷基酰基、取代或未取代氨基酰基、取代或未取代C1-C6烷基酰胺基、取代或未取代C1-C4烷基氨基、取代或未取代6-12元芳基氨基、取代或未取代3-8元杂环基、取代或未取代3-8元环烷基、取代或未取代5-8元杂芳基、取代或未取代6-12元芳基；其中，所述取代是指被一个或多个选自下组的基团取代：卤素、羧基、羟基、氰基、氨基、硝基、SO2C1-C6烷基、CO2C1-C6烷基、三氟甲氧基、苄基、HOCH2-、HOCH2CH2-、CF2CH-、CF3CH2CH2-、C1-C6烷基、C1-C6烷氧基或3-8元杂环基。The compound according to claim 4, or its prodrug, its enantiomer, diastereomer, racemate and mixture thereof, or its pharmaceutically acceptable salt, characterized in that, R 4 is selected from: halogen, carboxyl, hydroxyl, cyano, amino, nitro, Substituted or unsubstituted benzyl, substituted or unsubstituted arylmethyl, substituted or unsubstituted heteroarylmethyl, substituted or unsubstituted heteroarylmethyl, substituted or unsubstituted C1-C6 alkyl, Substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkyl acyl, substituted or unsubstituted aminoacyl, substituted Or unsubstituted C1-C6 alkylamido, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted 6-12 membered arylamino, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted 3-8-membered cycloalkyl, substituted or unsubstituted 5-8-membered heteroaryl, substituted or unsubstituted 6-12-membered aryl; wherein, the substitution refers to one or more groups selected from the following group Substitution: halogen, carboxyl, hydroxyl, cyano, amino, nitro, SO 2 C1-C6 alkyl, CO 2 C1-C6 alkyl, trifluoromethoxy, benzyl, HOCH 2 -, HOCH 2 CH 2 - , CF 2 CH-, CF 3 CH 2 CH 2 -, C1-C6 alkyl, C1-C6 alkoxy or 3-8 membered heterocyclyl.
  6. 如权利要求1-5中任一项所述的化合物，或其前药、其对映异构体、非对映异构体、外消旋体及其混合物，或其药学上可接受的盐，其特征在于，所述化合物具有式II-1～II-3所示的结构 The compound according to any one of claims 1 to 5, or its prodrug, its enantiomers, diastereomers, racemates and mixtures thereof, or its pharmaceutically acceptable salts , characterized in that the compound has a structure represented by formulas II-1 to II-3
    式中，G为6元芳基或杂芳基；In the formula, G is a 6-membered aryl group or heteroaryl group;
    G’为C6-C12芳基或5-12元杂芳基；G’ is C6-C12 aryl or 5-12 membered heteroaryl;
    G”为C6-芳基或5-6元杂芳基；G” is C6-aryl or 5-6 membered heteroaryl;
    Rm各自独立地选自：氢、卤素、羧基、羟基、氰基、氨基、-COOC1-C6烷基、硝基、-CO(3-8元取代或未取代杂环基)、-CO(C3-C8取代或未取代环烷基)、取代或未取代的C6-C12芳基C1-C6烷基、取代或未取代的5-12元杂芳基C1-C6烷基、取代或未取代C1-C6烷基、取代或未取代C2-C6烯基、取代或未取代C2-C6炔基、取代或未取代C1-C6烷氧基、取代或未取代C1-C6烷基酰基、取代或未取代氨基酰基、取代或未取代C1-C6烷基酰胺基、取代或未取代C1-C4烷基氨基、取代或未取代C6-C12芳基氨基、取代或未取代3-8元杂环基、取代或未取代C3-C8环烷基、取代或未取代5-12元杂芳基、取代或未取代C6-C12芳基；其中所述取代是指被一个或多个选自下组的基团取代：卤素、羧基、-OP(O)(OH)2、羟基、氰基、氨基、硝基、苄基、C1-C6烷基OH、C1-C6烷基氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C8环烷基或3-8元杂环基；优选地，Rm各自独立地选自：氢、卤素、氰基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、C6-C12芳基、5-12元杂芳基、C6-C12芳基NH、-OP(O)(OH)2取代的C1-C6烷基、氨基C1-C6烷基COO取代的C1-C6烷基；更优选地，Rm各自独立地选自：三氟甲基、苯基、苯氨基、氰基、甲氧基、Cl、F、Br、 R m is each independently selected from: hydrogen, halogen, carboxyl, hydroxyl, cyano, amino, -COOC1-C6 alkyl, nitro, -CO (3-8 membered substituted or unsubstituted heterocyclyl), -CO( C3-C8 substituted or unsubstituted cycloalkyl), substituted or unsubstituted C6-C12 aryl C1-C6 alkyl, substituted or unsubstituted 5-12 membered heteroaryl C1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkyl acyl, substituted or Unsubstituted aminoacyl, substituted or unsubstituted C1-C6 alkylamido, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C6-C12 arylamino, substituted or unsubstituted 3-8 membered heterocyclyl , substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl; wherein said substitution means being selected from the group consisting of one or more Group substitution: halogen, carboxyl, -OP(O)(OH) 2 , hydroxyl, cyano, amino, nitro, benzyl, C1-C6 alkyl OH, C1-C6 alkylamino, C1-C6 alkyl , halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl or 3-8 membered heterocyclyl; preferably, R m is each independently selected from : Hydrogen, halogen, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C6-C12 aryl, 5-12 membered heteroaryl, C6-C12 aryl NH, -OP(O)(OH) 2 substituted C1-C6 alkyl, amino C1-C6 alkyl COO substituted C1-C6 alkyl; more preferably, R m is each independently selected from: trifluoromethyl, benzene group, phenylamino, cyano, methoxy, Cl, F, Br,
    Rm’各自独立地选自：氢、卤素、羧基、羟基、氰基、氨基、硝基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C3-C8环烷基或3-8元杂环基；R m' are each independently selected from: hydrogen, halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkoxy, haloC1- C6 alkoxy, C3-C8 cycloalkyl or 3-8 membered heterocyclyl;
    Rm”和Rm”’各自独立地选自：H、卤素、羧基、羟基、氰基、硝基、氨基、-COOC1-C6烷基、取代或未取代C1-C6烷基、取代或未取代C2-C6烯基、取代或未取代C2-C6炔基、取代或未取代C1-C6烷氧基、取代或未取代C1-C6烷基酰基、取代或未取代氨基甲酰基、取代或未取代C1-C6烷基酰胺基、取代或未取代C1-C4烷基氨基、取代或未取代C6-C12芳基氨基、取代或未取代3-8元杂环基、取代或未取代C3-C8环烷基、取代或未取代的5-12元杂芳基、取代或未取代C6-C12芳基、取代或未取代的C6-C12芳基C1-C6烷基、取代或未取代的5-12元杂芳基C1-C6烷基、-CO(3-8元取代或未取代杂环基)、-CO(C3-C8取代或未取代环烷基)；其中，所述取代是指被一个或多个选自下组的基团取代：卤素、羧基、羟基、氰基、氨基、硝基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷基OH、C1-C6烷氧基、C3-C8环烷基或3-8元杂环基； Rm " and Rm "' are each independently selected from: H, halogen, carboxyl, hydroxyl, cyano, nitro, amino, -COOC1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted Substituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkyl acyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted Substituted C1-C6 alkylamido, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C6-C12 arylamino, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted C3-C8 Cycloalkyl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C6-C12 aryl C1-C6 alkyl, substituted or unsubstituted 5- 12-membered heteroaryl C1-C6 alkyl, -CO (3-8-membered substituted or unsubstituted heterocyclyl), -CO (C3-C8 substituted or unsubstituted cycloalkyl); wherein, the substitution means by One or more groups selected from the following group are substituted: halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyl OH, C1- C6 alkoxy, C3-C8 cycloalkyl or 3-8 membered heterocyclyl;
    n为1或2；n is 1 or 2;
    f、f’、f”和f”’各自独立地为0、1、2或3；f, f’, f” and f”’ are each independently 0, 1, 2 or 3;
    R4的定义如权利要求4所述。R 4 is as defined in claim 4.
  7. 如权利要求4-6中任一项所述的化合物，或其前药、其对映异构体、非对映异构体、外消旋体及其混合物，或其药学上可接受的盐，其特征在于，R4选自：H、卤素、羧基、羟基、氰基、氨基、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代COOC1-C6烷基、取代或未取代CO-4-6元杂环基、取代或未取代的C6-C10芳基、取代或未取代的5-10元杂芳基(优选5-6元或9-10元，例如呋喃基、噻吩基、吡啶基、吡咯基、吡唑基、咪唑基、苯并呋喃基、苯并噻吩基、吡啶并吡唑基)、取代或未取代的C3-C6环烷基、取代或未取代的4-10元杂环基(优选4-6元单环杂环基、7-11元螺杂环基，例如哌啶基、吗啉基、哌嗪基、四氢吡咯基、)、取代或未取代的取代或未取代的C6-C10芳基NH、取代或未取代的5-6元杂环基并苯基(如)、取代或未取代的C5-C6环烷基并苯基、取代或未取代的苯基并5-6元杂环基(如)、取代或未取代的苯基并C5-C6环烷基、取代或未取代的5-6元杂环基并5-6元杂芳基、取代或未取代的C5-C6环烷基并5-6元杂芳基、取代或未取代的5-6元杂芳基并5-6元杂环基、取代或未取代的5-6元杂芳基并C5-C6环烷基，其中，所述取代是指被选自下组的一个或多个基团取代：卤素、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基；优选地，R4选自：H、卤素、羧基、羟基、氰基、氨基、硝基、乙烯基、乙炔基、乙基、苯基、萘基、 The compound according to any one of claims 4 to 6, or its prodrug, its enantiomers, diastereomers, racemates and mixtures thereof, or its pharmaceutically acceptable salts , characterized in that R 4 is selected from: H, halogen, carboxyl, hydroxyl, cyano, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted COOC1-C6 alkyl, substituted or unsubstituted CO-4-6 membered heterocyclyl, substituted or unsubstituted C6-C10 Aryl, substituted or unsubstituted 5-10-membered heteroaryl (preferably 5-6-membered or 9-10-membered, such as furyl, thienyl, pyridyl, pyrrolyl, pyrazolyl, imidazolyl, benzofuran base, benzothienyl, pyridopyrazolyl), substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 4-10 membered heterocyclyl (preferably 4-6 membered monocyclic heterocyclyl, 7-11 membered spiroheterocyclyl, such as piperidyl, morpholinyl, piperazinyl, tetrahydropyrrolyl, ), substituted or unsubstituted Substituted or unsubstituted C6-C10 aryl NH, substituted or unsubstituted 5-6 membered heterocyclylacene (such as ), substituted or unsubstituted C5-C6 cycloalkylphenyl, substituted or unsubstituted phenyl 5-6 membered heterocyclyl (such as ), substituted or unsubstituted phenyl C5-C6 cycloalkyl, substituted or unsubstituted 5-6 membered heterocyclyl and 5-6 membered heteroaryl, substituted or unsubstituted C5-C6 cycloalkyl 5-6 membered heteroaryl, substituted or unsubstituted 5-6 membered heteroaryl and 5-6 membered heterocyclyl, substituted or unsubstituted 5-6 membered heteroaryl with C5-C6 cycloalkyl, wherein , the substitution refers to substitution with one or more groups selected from the following group: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy group; preferably, R 4 is selected from: H, halogen, carboxyl, hydroxyl, cyano, amino, nitro, vinyl, ethynyl, ethyl, phenyl, naphthyl,
  8. 如权利要求1所述的化合物，或其前药、其对映异构体、非对映异构体、外消旋体及其混合物，或其药学上可接受的盐，其特征在于，环A为优选地为更优选地为 The compound according to claim 1, or its prodrug, its enantiomer, diastereomer, racemate and mixture thereof, or its pharmaceutically acceptable salt, characterized in that: A is Preferably More preferably
    其中，Rm、f的定义如权利要求6所述；Wherein, the definitions of Rm and f are as stated in claim 6;
    其中，Rm1、Rm2、Rm3的定义同Rm，优选地，Rm1、Rm2、Rm3各自独立地选自：H、卤素、羧基、羟基、氰基、氨基、-COOC1-C6烷基、硝基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、4-6元杂环基、C6-C10芳基、C6-C10芳基NH、5-6元杂芳基、C6-C10芳基取代的5-6元杂芳基、-OP(O)(OH)2取代的C1-C6烷基、氨基C1-C6烷基COO取代的C1-C6烷基；优选地，Rm1、Rm2、Rm3各自独立地选自：H、三氟甲基、苯基、苯氨基、氰基、硝基、甲氧基、Cl、F、Br、 Wherein, the definitions of R m1 , R m2 and R m3 are the same as R m . Preferably, R m1 , R m2 and R m3 are each independently selected from: H, halogen, carboxyl, hydroxyl, cyano group, amino group, -COOC1-C6 Alkyl, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, C6-C10 aryl, C6- C10 aryl NH, 5-6 membered heteroaryl, C6-C10 aryl substituted 5-6 membered heteroaryl, -OP(O)(OH) 2 substituted C1-C6 alkyl, amino C1-C6 alkyl C1-C6 alkyl group substituted by COO; preferably, R m1 , R m2 , and R m3 are each independently selected from: H, trifluoromethyl, phenyl, phenylamino, cyano, nitro, methoxy, Cl, F, Br,
  9. 如权利要求1所述的化合物，或其前药、其对映异构体、非对映异构体、外消旋体及其混合物，或其药学上可接受的盐，其特征在于，B环选自： The compound according to claim 1, or its prodrug, its enantiomer, diastereomer, racemate and mixture thereof, or its pharmaceutically acceptable salt, characterized in that, B Rings selected from:
  10. 一种如权利要求1所述的式I化合物的前药，其具有式III-1或III-2所示的结构 A prodrug of the compound of formula I as claimed in claim 1, which has the structure shown in formula III-1 or III-2
    式中，L为C1-C6亚烷基；In the formula, L is C1-C6 alkylene;
    Rn选自：-P(O)(OH)2或氨基C1-C6烷基CO；优选地为 Rn is selected from: -P(O)(OH) 2 or amino C1-C6 alkyl CO; preferably
    G、G’、R4、Rm’、Rm”、Rm”’、f’、f”和f”’的定义如权利要求6所述。G, G', R 4 , R m' , R m" , R m"' , f', f" and f"' are as defined in claim 6.
  11. 如权利要求1所述的化合物，或其前药、其对映异构体、非对映异构体、外消旋体及其混合物，或其药学上可接受的盐，其特征在于，所述化合物选自以下化合物： The compound according to claim 1, or its prodrug, its enantiomer, diastereomer, racemate and mixture thereof, or its pharmaceutically acceptable salt, characterized in that, Said compound is selected from the following compounds:
  12. 一种药物组合物，所述药物组合物包含治疗有效量的选自如权利要求1-11中任一项所述的化合物，或其前药、其对映异构体、非对映异构体、外消旋体及其混合物，或其药学上可接受的盐中的一种或多种；以及任选地药学上可接受的载体。A pharmaceutical composition comprising a therapeutically effective amount of a compound selected from the group consisting of any one of claims 1-11, or a prodrug thereof, an enantiomer or a diastereomer thereof. , racemates and mixtures thereof, or one or more of its pharmaceutically acceptable salts; and optionally a pharmaceutically acceptable carrier.
  13. 如权利要求1-11所述化合物，或其前药、其对映异构体、非对映异构体、外消旋体及其混合物，或其药学上可接受的盐或如权利要求12所述的药物组合物的用途，其特征在于，用于制备cGAS/STING通路靶向抑制剂；或The compound as claimed in claims 1-11, or its prodrug, its enantiomer, diastereomer, racemate and mixtures thereof, or its pharmaceutically acceptable salt or as claimed in claim 12 The use of the pharmaceutical composition is characterized in that it is used to prepare cGAS/STING pathway targeted inhibitors; or
    用于制备预防和/或治疗炎症性疾病和自身免疫性疾病的药物。For the preparation of drugs for the prevention and/or treatment of inflammatory diseases and autoimmune diseases.
  14. 如权利要求13所述的用途，其特征在于，所述炎症性疾病和自身免疫性疾病选自：Singleton-Merten综合征(SMS)、Aicardi–Goutières综合征(AGS)、系统性红斑狼疮(SLE)、家族性冻疮性红斑狼疮(FCL)、视网膜血管病与脑白质营养不良(RVCL)、STING相关的婴儿期发病血管病变(SAVI)、硬皮病、银肩病、斯耶格伦氏综合征、类风湿性关节炎、炎症性肠病、多发性硬化、克罗恩病、溃疡性结肠炎、自身免疫性结肠炎、小肠吸收不良综合征、肠易激综合征、葡萄膜炎、粘膜炎、糖尿病、心血管疾病和神经退行性疾病。The use according to claim 13, wherein the inflammatory disease and the autoimmune disease are selected from the group consisting of: Singleton-Merten syndrome (SMS), Aicardi-Goutières syndrome (AGS), systemic lupus erythematosus (SLE) ), familial chilblain lupus erythematosus (FCL), retinal vasculopathy and leukodystrophy (RVCL), STING-associated vasculopathy of infancy (SAVI), scleroderma, psoriasis, Sjogren's syndrome syndrome, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, Crohn's disease, ulcerative colitis, autoimmune colitis, small intestinal malabsorption syndrome, irritable bowel syndrome, uveitis, mucosal inflammation, diabetes, cardiovascular disease and neurodegenerative diseases.
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