WO2023174383A1 - Composé de dihydroisoquinoléine et son utilisation médicale - Google Patents

Composé de dihydroisoquinoléine et son utilisation médicale Download PDF

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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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substituted
unsubstituted
alkyl
group
membered
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PCT/CN2023/081999
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English (en)
Chinese (zh)
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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
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中国科学院上海药物研究所
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Publication of WO2023174383A1 publication Critical patent/WO2023174383A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—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
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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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    • A61K31/495—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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    • C07D403/02—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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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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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

L'invention concerne un composé de dihydroisoquinoléine et son utilisation médicale. Spécifiquement, le composé a une structure telle que représentée dans la formule (I), peut être utilisé en tant que régulateur pour la sécrétion d'interféron de type I, en particulier en tant qu'inhibiteur cible pour la voie de signalisation cGAS/STING, et peut être utilisé dans la préparation de médicaments pour la prévention et/ou le traitement de maladies inflammatoires et de maladies auto-immunes.
PCT/CN2023/081999 2022-03-17 2023-03-16 Composé de dihydroisoquinoléine et son utilisation médicale WO2023174383A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020257621A1 (fr) * 2019-06-21 2020-12-24 Ifm Due, Inc. Méthodes de traitement du cancer
CN112823151A (zh) * 2018-07-03 2021-05-18 艾福姆德尤股份有限公司 用于治疗与sting活性有关的疾病的化合物和组合物
CN112823036A (zh) * 2018-07-03 2021-05-18 艾福姆德尤股份有限公司 用于治疗与sting活性有关的疾病的化合物和组合物
WO2021161230A1 (fr) * 2020-02-12 2021-08-19 Curadev Pharma Pvt. Ltd. Antagonistes de sting à petites molécules
WO2022150585A1 (fr) * 2021-01-08 2022-07-14 Ifm Due, Inc. Composés hétérobicycliques ayant une urée ou un analogue et leurs compositions pour le traitement d'états associés à une activité de sting

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112823151A (zh) * 2018-07-03 2021-05-18 艾福姆德尤股份有限公司 用于治疗与sting活性有关的疾病的化合物和组合物
CN112823036A (zh) * 2018-07-03 2021-05-18 艾福姆德尤股份有限公司 用于治疗与sting活性有关的疾病的化合物和组合物
WO2020257621A1 (fr) * 2019-06-21 2020-12-24 Ifm Due, Inc. Méthodes de traitement du cancer
WO2021161230A1 (fr) * 2020-02-12 2021-08-19 Curadev Pharma Pvt. Ltd. Antagonistes de sting à petites molécules
WO2022150585A1 (fr) * 2021-01-08 2022-07-14 Ifm Due, Inc. Composés hétérobicycliques ayant une urée ou un analogue et leurs compositions pour le traitement d'états associés à une activité de sting

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE REGISTRY 19 December 2022 (2022-12-19), ANONYMOUS: "1H-1,4-Diazepine-1-carboxamide, hexahydro-N-1H-indol-3-yl-4-(phenylmethyl)- (CA INDEX NAME)", XP093091855, retrieved from STNext Database accession no. 2871213-42-0 *
DATABASE REGISTRY 9 August 2006 (2006-08-09), ANONYMOUS: "2(1H)-Isoquinolinecarboxamide, 3,4-dihydro-N-1H-indol-3-yl- (CA INDEX NAME)", XP093091853, retrieved from STNext Database accession no. 899965-01-6 *

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