WO2018233727A1 - Indole compound and application thereof, and pharmaceutical composition and application thereof - Google Patents

Indole compound and application thereof, and pharmaceutical composition and application thereof Download PDF

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WO2018233727A1
WO2018233727A1 PCT/CN2018/101765 CN2018101765W WO2018233727A1 WO 2018233727 A1 WO2018233727 A1 WO 2018233727A1 CN 2018101765 W CN2018101765 W CN 2018101765W WO 2018233727 A1 WO2018233727 A1 WO 2018233727A1
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group
alkyl
acetyl
synthesis
phenyl
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PCT/CN2018/101765
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French (fr)
Chinese (zh)
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许�永
向秋萍
张岩
薛晓纤
王超
宋明
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中国科学院广州生物医药与健康研究院
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Publication of WO2018233727A1 publication Critical patent/WO2018233727A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—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 carbon chain containing only aliphatic carbon atoms
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • 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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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • 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
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
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    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • 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
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/435—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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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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
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/26—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
    • C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
    • C07D243/24—Oxygen atoms
    • C07D243/30—Preparation including building-up the benzodiazepine skeleton from compounds already containing hetero rings
    • C07D243/36—Preparation including building-up the benzodiazepine skeleton from compounds already containing hetero rings containing an indole or hydrogenated indole ring system
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    • 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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    • C07D405/02—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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    • C07D409/06—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 carbon chain containing only aliphatic carbon atoms
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    • C07D409/02—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
    • 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

Definitions

  • the present application relates to the field of chemical medicine, and in particular to an anthraquinone compound and application thereof.
  • Bromodomains are a class of evolutionarily conserved modules that mediate protein-protein interactions.
  • the bromodomain is a reader of histone acetylation, which specifically recognizes histone acetylated lysine residues, thereby affecting the transcription and translation of target genes.
  • the dysfunction of this protein complex is associated with the occurrence of various diseases, which makes Bromodomain proteins have become a novel class of targets.
  • Inhibitors of bromodomain proteins have important biological significance. For example, a large number of compounds have been reported to have therapeutic effects in diseases such as cancer, inflammatory diseases, autoimmune diseases, sepsis, and viral infections.
  • Bromine domain proteins are named for their first discovery in Drosophila genes, since bromodomain proteins have been found in many nuclear proteins, such as histone acetyltransferases (HATs), ATP-dependent chromatin remodeling complexes, Base transferase and transcriptional coactivator and the like.
  • HATs histone acetyltransferases
  • ATP-dependent chromatin remodeling complexes Base transferase and transcriptional coactivator and the like.
  • the 61 bromodomains encoded by the human proteome are present in 46 different nuclear and cytoplasmic proteins.
  • the bromodomain protein family can be divided into eight subfamilies according to its function. Among them, histone acetyltransferase is one of them, which includes: CBP, EP300, P/CAF and GCN5. CBP and EP300 are homologous proteins.
  • CBP/EP300 is a multifunctional transcriptional coactivator of cAMP response element binding protein CREB, which is involved in various physiological processes: cell cycle regulation, cell differentiation and apoptosis.
  • CBP/EP300 protein acts as a bridge between transcription factor and target DNA through its own HAT; it can inhibit cell replication and keep cells in G1 phase; CBP/EP300 protein itself has the function of tumor suppressor, and also participates in multiple inhibition Cancer information transmission pathway.
  • CBP/EP300 is also associated with various diseases such as prostate cancer and inflammatory treatment (pulmonary inflammation and asthma).
  • Targeting CBP/EP300 proteins can help provide new therapeutic strategies for diseases such as cancer, neurodegenerative diseases and inflammation.
  • the present application provides an indole compound and an application thereof, which are effective for inhibiting a CBP/EP300 bromodomain receptor, and are useful as drugs for cancer, inflammatory diseases, autoimmune diseases, sepsis, and viral infections.
  • One of the objects of the present application is to provide an anthraquinone compound having the structure of the following chemical formula I and formula II:
  • R 1 is C 1 -C 4 alkyl
  • R 2 is H, C 1 -C 7 alkyl, -RX 1 or -X 2
  • R 3 is H, C 1 -C 5 alkyl, C 3 to C 5 cycloalkyl, -OX 3 , -NHX 3 or -N(X 3 ) 2 ;
  • R is a C 1 -C 4 alkylene group
  • X 1 is -OX 3 , -COOX 4 , -CONHX 4 , a cycloalkyl group, a heterocyclic group, -COX 5 or -S(O) m X 5
  • X 2 is C 3 -C 7 cycloalkyl, phenyl, naphthyl, heterocyclic, -COX 5 or -S(O) m X 5 ;
  • n is 0 or 2
  • X 3 , X 4 and X 5 are independently H, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, phenyl, naphthyl or heterocyclic;
  • R 4 is a C 1 -C 4 alkyl group
  • R 5 is a C 1 -C 7 alkyl group, -R'-Y 1 , Y 1 '-(C 1 -C 4 alkyl group)-Y 1 Or Y 2
  • R 6 is H, C 1 -C 5 alkyl, C 3 -C 5 cycloalkyl, -OY 3 , -NHY 3 or -N(Y 3 ) 2 ;
  • R' is a C 1 -C 4 alkylene group
  • Y 1 is -NHCOO t Bu, C 3 -C 7 cycloalkyl, phenyl, naphthyl, -OY 4 , -COY 4 , -COOY 4 , - NHCOY 4 or -S(O) m Y 4
  • Y 1 ' is -NHCOO t Bu, C 3 -C 7 cycloalkyl, phenyl, naphthyl, -OY 4 , -COY 4 , -COOY 4 , -NHCOY 4 or -S(O) m Y 4
  • Y 2 is a C 3 -C 7 cycloalkyl group, a phenyl group, a naphthyl group or a heterocyclic group;
  • n is 0 or 2
  • Y 4 is H, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, phenyl, naphthyl or heterocyclic.
  • R 1 may be C 1 , C 2 , C 3 or C 4 alkyl
  • R 2 may be C 1 , C 2 , C 3 , C 4 , C 5 , C 6 or C 7 alkyl
  • R 3 may be C 1 , C 2 , C 3 , C 4 or C 5 alkyl
  • R 3 may be C 3 , C 4 or C 5 cycloalkyl
  • R may be C 1 , C 2 , C 3 or C 4 alkylene
  • X 2 may be C 3 , C 4 , C 5 , C 6 or C 7 cycloalkyl
  • X 3 , X 4 and X 5 may independently be C 1 , C 2 , C 3 or C
  • the alkyl group, X 3 , X 4 and X 5 may independently be a C 3 , C 4 , C 5 , C 6 or C 7 cycloalkyl group.
  • R 4 may be C 1 , C 2 , C 3 or C 4 alkyl
  • R 5 may be C 1 , C 2 , C 3 , C 4 , C 5 , C 6 or C 7 alkyl
  • Y 1 '-(C 1 -C 4 alkyl)-Y 1 intermediate alkyl may be C 1 alkyl, C 2 alkyl, C 3 alkyl or C 4 alkyl
  • R 6 It may be C 1 , C 2 , C 3 , C 4 or C 5 alkyl
  • R 6 may be C 3 , C 4 or C 5 cycloalkyl
  • R' may be C 1 , C 2 , C 3 or C 4
  • Y 1 may be a C 3 , C 4 , C 5 , C 6 or C 7 cycloalkyl group
  • Y 1 ' may be a C 3 , C 4 , C 5 , C 6 or C 7 cycloalkyl group
  • Y 2 may be
  • R 1 in the formula I includes a methyl group, an ethyl group, a n-propyl group, an isopropyl group or a t-butyl group.
  • R 2 in the formula I includes -RX 1 or -X 2 , wherein R is a C 1 -C 2 alkylene group, and X 1 is -COOX 4 , -CONHX 4 , a cycloalkyl or a heterocyclic group, X 2 is -COX 5 or -S(O) 2 X 5 , wherein X 5 is a C 1 -C 3 alkyl group, a C 3 -C 7 cycloalkyl group, a phenyl group, a naphthyl group or a heterocyclic group.
  • R 3 in the formula I includes H, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, phenolic hydroxyl, Methoxy, ethoxy, propoxy, butoxy, nitrogen methyl, nitrogen ethyl, nitrogen propyl or nitrogen butyl.
  • R 4 in formula II includes methyl, ethyl, n-propyl, isopropyl or t-butyl.
  • R 5 in the formula II includes -R'-Y 1 or Y 2 , wherein R' is a C 1 -C 4 alkylene group, and Y 1 is a C 3 -C 7 cycloalkyl group, a phenyl group, a naphthalene group.
  • Y 2 is a C 3 -C 7 cycloalkyl group, a phenyl group, a naphthyl group or a heterocyclic group, wherein Y 4 is H, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, phenyl, naphthyl or heterocyclic.
  • R 6 in the formula II includes H, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, phenolic hydroxyl, Methoxy, ethoxy, propoxy, butoxy, nitrogen methyl, nitrogen ethyl, nitrogen propyl or nitrogen butyl.
  • the C 3 -C 7 cycloalkyl group, the phenyl group and the naphthyl group in the formula I contain 0 to 3 substituents, and the number of the substituents may be 0, 1, 2 or 3.
  • the substituent is halogen, C 1 -C 4 alkyl, trifluoromethyl, cyano, nitro, amino, amide, -COOX 6 , -COX 6 , -OX 6 , -NHCOX 6 , - C 6 H 5 X 7 , morpholinyl, piperidinyl, furyl, tetrahydrofuranyl or pyridyl, wherein X 6 is H, C 1 -C 4 alkyl, phenyl, X 7 is C 1 -C 4 alkane Base, halogen, trifluoromethyl, cyano, nitro, amino, amide, acetyl, methoxy or ethoxy.
  • substituent may be C 1 , C 2 , C 3 or C 4 alkyl
  • X 6 may be C 1 , C 2 , C 3 or C 4 alkyl
  • X 7 may be C 1 , C 2 , C 3 Or C 4 alkyl.
  • the heterocyclic group in the formula I is azetidinyl, oxetanyl, azacyclopentyl, oxetanyl, azacyclohexyl, oxetanyl. , azacyclohexyl, imidazol-2-one, imidazolyl, furyl, thienyl, oxazolyl, isoxazolyl, pyrimidinyl, pyrrolyl, piperazinyl, tetrahydropyrrolyl, piperidinyl, Morpholinyl, 1,3-dioxolanyl or benzo[d]thiazolyl.
  • the heterocyclic group in the formula I contains 0 to 3 substituents, and the number of substituents may be 0, 1, 2 or 3.
  • the substituent is halogen, C 1 -C 4 alkyl, trifluoromethyl, cyano, nitro, amino, amide, -COOX 6 , -COX 6 , -OX 6 , -NHCOX 6 , - C 6 H 5 X 7 , morpholinyl, piperidinyl, furyl, tetrahydrofuranyl or pyridyl wherein X 6 is H, C 1 -C 4 alkyl, phenyl, X 7 is C 1 -C 4 alkyl Halogen, trifluoromethyl, cyano, nitro, amino, amide, acetyl, methoxy or ethoxy.
  • substituent may be C 1 , C 2 , C 3 or C 4 alkyl
  • X 6 may be C 1 , C 2 , C 3 or C 4 alkyl
  • X 7 may be C 1 , C 2 , C 3 Or C 4 alkyl.
  • the C 3 -C 7 cycloalkyl group, the phenyl group and the naphthyl group in the formula II contain 0 to 3 substituents, and the number of the substituents may be 0, 1, 2 or 3.
  • the substituent is halogen, C 1 -C 4 alkyl, trifluoromethyl, cyano, nitro, amino, 1,3-dioxolanyl, -COOY 5 , -COY 5 , - OY 5 , -NHCOY 5 , -C 6 H 5 Y 6 , -(CH 2 ) n NHY 7 , -NHCOO t Bu, -CH 2 OCOO t Bu, 1-methylpiperazine, morpholinyl, isoxazole , 3,5-dimethylisoxazolyl, quinolyl, isoquinolinyl, piperidinyl, thienyl, furyl, tetrahydrofuranyl, pyridyl, pyrimidinyl, 2-morpholinylpyridyl, Mercapto, 1,4-benzodioxyl, benzofuranyl, benzothienyl, 1-methyl-1H-carbazolyl
  • substituent may be C 1 , C 2 , C 3 or C 4 alkyl
  • Y 6 may be C 1 , C 2 , C 3 or C 4 alkyl
  • Y 7 may be C 1 , C 2 , C 3 , C 4 or C 5 alkyl
  • Y 7 may be phenyl, C 1 alkylene-phenyl or C 2 alkylene-phenyl
  • Y 7 may be naphthyl, C 1 alkylene-naphthyl or C 2 alkylene-naphthyl
  • Y 7 may be heterocyclic, C 1 alkylene-heterocyclyl or C 2 alkylene-heterocyclyl, phenyl, naphthyl or heterocyclic in Y 7
  • the group is substituted by 0, 1, 2 or 3 substituents, and the substituent in Y 7 may be C 1 , C 2 , C 3 or C 4 alkyl.
  • the heterocyclic group in the formula II is azetidinyl, oxetanyl, azacyclopentyl, oxetanyl, azacyclohexyl, oxetanyl.
  • the heterocyclic group in the formula II contains 0 to 3 substituents, and the number of the substituents may be 0, 1, 2 or 3.
  • the substituent is halogen, C 1 -C 4 alkyl, trifluoromethyl, cyano, carboxyl, nitro, amino, 1,3-dioxolanyl, -COOY 5 , -COY 5 , -OY 5 , -NHCOY 5 , -NHCOO t Bu or -C 6 H 5 Y 6 , wherein Y 5 is hydrogen, C 1 -C 4 alkyl or phenyl, Y 6 is C 1 -C 4 alkyl, Halogen, acetyl, methoxy or ethoxy.
  • substituent may be C 1 , C 2 , C 3 or C 4 alkyl
  • Y 5 may be C 1 , C 2 , C 3 or C 4 alkyl
  • Y 6 may be C 1 , C 2 , C 3 Or C 4 alkyl.
  • the compound can be prepared by the following reaction:
  • the second object of the present application is to provide an application of the above quinone compound for the preparation of a CBP/EP300 bromodomain receptor inhibitor.
  • the CBP/EP300 bromodomain receptor inhibitor is used for preparing cancer, cell proliferative disorder, inflammatory disease and autoimmune disease, sepsis, viral infection, neurodegenerative disease. drug.
  • the third object of the present application is to provide a pharmaceutical composition comprising the above-described terpenoid compound.
  • the pharmaceutical composition is for treating, preventing or ameliorating cancer, cell proliferative disorder, inflammation, autoimmune disease, sepsis, viral infection or neurodegenerative disease.
  • the medicament prepared by the CBP/EP300 bromodomain receptor inhibitor, and the cancer treatable by the pharmaceutical composition include adrenal tumor, acoustic neuroma, acromegaly, acromegaly, acute eosinophilic leukemia, acute red leukemia Acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adipose tissue tumor, adrenocortical carcinoma, adult T cell leukemia/ Lymphoma, AIDS-associated lymphoma, alveolar rhabdomyosarcoma, alveolar soft sarcoma, ameloblastic fibroma, anaplastic large cell lymphoma, undifferentiated thyroid carcinoma, angiomyolipoma, angiosarcoma, astrocytoma, atypical Abnormal rod-shaped tumor, B-cell
  • a medicament prepared by a CBP/EP300 bromodomain receptor inhibitor, and a cell proliferative disorder treatable by the pharmaceutical composition include a benign soft tissue tumor, a brain and spinal cord tumor, an orbital and orbital tumor, a granuloma, a lipoma, a meninges Tumor, multiple endocrine neoplasms, nasal polyps, pituitary tumors, prolactinoma, seborrheic keratin, gastric polyps, thyroid nodules, hepatic hemangioma, vocal cord nodules, polyps, cysts, stagnation, cutaneous fibroids, skin Lal cyst or pyogenic granuloma.
  • the medicament prepared by the CBP/EP300 bromodomain receptor inhibitor, and the inflammatory diseases treatable by the pharmaceutical composition include inflammatory pelvic disease, urethritis, sunburn, sinusitis, pneumonia, encephalitis, meningitis, myocarditis, Nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, pancreatitis, psoriasis, allergies, Crohn's disease, intestinal syndrome, ulcerative colitis, tissue transplant rejection, organ transplant rejection, Asthma, allergic rhinitis, chronic obstructive pulmonary disease, autoimmune disease, autoimmune alopecia, anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic And thrombocytopenia, pulmonary hemorrhagic nephritis syndrome, atherosclerosis, Addison
  • a medicament prepared by a CBP/EP300 bromodomain receptor inhibitor, and a viral infection treatable by the pharmaceutical composition including human papillomavirus, herpes virus, Barr virus, human immunodeficiency virus, hepatitis B virus or hepatitis C Virus infection, etc.
  • a medicament prepared by a CBP/EP300 bromodomain receptor inhibitor, and a neurodegenerative disease treatable by the pharmaceutical composition including Alzheimer's disease, amyotrophic lateral sclerosis, ataxia telangiectasia , bovine spongiform encephalopathy, Creutzfeldt-Jakob disease, Huntington's disease, cerebellar atrophy, multiple sclerosis, Parkinson's disease, primary lateral sclerosis or spinal muscular atrophy.
  • the medicament prepared by the CBP/EP300 bromodomain receptor inhibitor, and the pharmaceutical composition can be applied to various administration routes, and typical but non-limiting examples of the administration route are: oral, buccal, inhalation, sublingual , rectal, vaginal, intracranial or intrathecal, through lumbar puncture, transurethral, transcutaneous or extraintestinal (including intravenous, intramuscular, subcutaneous, intradermal, intra-abdominal, intrathecal, surgical implantation, etc.) .
  • compositions described herein may be in liquid, semi-liquid or solid form, formulated in a manner suitable for the route of administration employed.
  • the compositions described herein can be administered by oral, parenteral, intraperitoneal, intravenous, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, liposome, and the like.
  • the pharmaceutical composition for oral administration can be a solid, a gel or a liquid.
  • solid preparations include, but are not limited to, tablets, capsules, granules, and bulk powders. These preparations may optionally contain a binder, a diluent, a disintegrant, a lubricant, a glidant, a sweetener, a flavoring agent and the like.
  • binders include, but are not limited to, microcrystalline cellulose, dextrose solution, gum arabic, gelatin solution, sucrose, and starch paste;
  • examples of lubricants include, but are not limited to, talc, starch, magnesium stearate, calcium stearate And stearic acid;
  • examples of diluents include, but are not limited to, lactose, sucrose, starch, mannitol, dicalcium phosphate;
  • examples of glidants include, but are not limited to, silica;
  • examples of disintegrants include, but are not limited to, Sodium carboxymethylcellulose, sodium starch glycolate, alginic acid, corn starch, potato starch, methyl cellulose, agar and carboxymethyl cellulose.
  • compositions described herein are administered parenterally, generally by injection, including subcutaneous, intramuscular or intravenous injection.
  • the injection can be formulated into any conventional form, such as a liquid solution or suspension, a solid form or emulsion suitable for dissolution or suspension in a liquid prior to injection.
  • pharmaceutically acceptable carriers that can be used in the injectables of the present application include, but are not limited to, aqueous carriers, nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, suspending and dispersing agents, emulsifying agents, chelating agents. And other pharmaceutically acceptable substances.
  • aqueous carrier examples include sodium chloride injection, lin format injection, isotonic glucose injection, sterile water injection, glucose and lactated Ringer's injection;
  • examples of the non-aqueous carrier include fixed oil of plant origin, Cottonseed oil, corn oil, sesame oil and peanut oil;
  • examples of the antimicrobial agent include m-cresol, benzyl alcohol, chlorobutanol, benzalkonium chloride, etc.;
  • isotonic agents include sodium chloride and glucose; buffers include phosphate And citrate.
  • compositions of the invention may also be prepared as sterile lyophilized powders in which the compound is dissolved in a sodium phosphate buffer solution containing glucose or other suitable excipients, followed by standard conditions known to those skilled in the art. The solution is sterile filtered and then lyophilized to give the desired formulation.
  • any variable e.g., R1, R2, etc.
  • the definition of each occurrence thereof is independent of the definition of each occurrence.
  • combinations of substituents and variables are allowed as long as such combinations stabilize the compound.
  • a line drawn from a substituent into the ring system means that the bond referred to can be attached to any ring atom that can be substituted. If the ring system is polycyclic, it means that such a bond is only attached to any suitable carbon atom of the adjacent ring. It will be appreciated that one of ordinary skill in the art can select substituents and substitution patterns for the compounds of the present application to provide compounds which are chemically stable and which are readily synthesized by the art and from readily available starting materials.
  • substituent itself is substituted by more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms as long as the structure is stabilized.
  • the phrase "optionally substituted with one or more substituents” is considered to be equivalent to the phrase “optionally substituted with at least one substituent” and in this case the preferred embodiment will have 0-3 substituents.
  • alkyl and alkylene as used herein are meant to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • the definition of "C1 to C4" in the "C1-C4" alkyl group includes a group having 1, 2, 3, 4, carbon atoms arranged in a straight chain or a branched chain.
  • “C1-C4" alkyl” “specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl.
  • cycloalkyl refers to the number of specific carbon atoms. Monocyclic saturated aliphatic hydrocarbon group.
  • cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, naphthyl, methyl-cyclopropyl, 2,2- Dimethyl-cyclobutyl, 2-ethyl-cyclopentyl and the like.
  • alkyl, benzene, naphthalene, cycloalkyl and heterocyclyl substituents may be unsubstituted or substituted.
  • a C1-C4 alkyl group may be selected from one, two or three selected from the group consisting of halogen, alkoxy, methyl, ethyl, propyl, isopropyl, t-butyl, trifluoromethyl, cyano, carboxy.
  • a nitro group an amino group, a methylsulfonyl group, a phenyldiazenyl group or a heterocyclic group, for example, a morpholinyl group, a piperidinyl group, a quinolyl group, a furyl group, a tetrahydrofuranyl group, a pyridyl group or the like.
  • the present application includes free forms of the compounds of Formula I and Formula II, as well as pharmaceutically acceptable salts and stereoisomers thereof.
  • Some specific exemplary compounds herein are protonated salts of amine compounds.
  • the term "free form" refers to an amine compound in a non-salt form.
  • Included pharmaceutically acceptable salts include not only the exemplary salts of the particular compounds described herein, but also all of the typical pharmaceutically acceptable salts of the free forms of the compounds of Formula I and Formula II.
  • the free form of the particular salt of the compound can be isolated using techniques known in the art.
  • the free form can be regenerated by treating the salt with a suitable dilute aqueous base such as a dilute aqueous solution of NaOH, a dilute aqueous solution of potassium carbonate, dilute aqueous ammonia, and a dilute aqueous solution of sodium bicarbonate.
  • a suitable dilute aqueous base such as a dilute aqueous solution of NaOH, a dilute aqueous solution of potassium carbonate, dilute aqueous ammonia, and a dilute aqueous solution of sodium bicarbonate.
  • the free form differs somewhat from its respective salt form in solubility in certain physical properties, such as in polar solvents, but for purposes of the invention such acid and base salts are otherwise pharmaceutically equivalent to their respective free forms.
  • the pharmaceutically acceptable salts of the present application can be synthesized from the compounds of the present application containing a basic moiety or an acidic moiety by conventional chemical methods.
  • salts of basic compounds are prepared by ion exchange chromatography or by reaction of a free base with a stoichiometric or excess amount of an inorganic or organic acid in the desired salt form in a suitable solvent or combination of solvents.
  • a salt of an acidic compound is formed by reaction with a suitable inorganic or organic base.
  • pharmaceutically acceptable salts of the compounds of the present application include the conventional non-toxic salts of the compounds of the present invention formed by the reaction of a basic compound of the present application with an inorganic or organic acid.
  • conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, and also include organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, and hard.
  • Fatty acid lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetyl A salt prepared from oxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid or the like.
  • a suitable “pharmaceutically acceptable salt” refers to a salt prepared by pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases.
  • Salts derived from inorganic bases include aluminum salts, ammonium salts. Salt, calcium salt, copper salt, iron salt, ferrous salt, lithium salt, magnesium salt, manganese salt, manganese salt, potassium salt, sodium salt, zinc salt and the like. Ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts are particularly preferred.
  • a salt derived from a pharmaceutically acceptable organic non-toxic base comprising a salt of a primary, secondary and tertiary amine, the substituted amine comprising a naturally occurring substituted amine, a cyclic amine and a basic ion exchange resin such as a fine Amino acid, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, B Diamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine , piperidine, guanidine, polyamine resin, procaine, guanidine, theobromine, triethylamine, trimethylamine, tripropylamine, t
  • the acidic moiety such as a carboxyl group
  • a cationic moiety such as tetravalent
  • the compounds of the present application are potential internal salts or zwitterions.
  • the present application has at least the following beneficial effects:
  • the present application provides an anthraquinone compound which can effectively inhibit the CBP/EP300 bromodomain receptor and can be used as a therapeutic cancer, a cell proliferative disorder, an inflammatory disease, an autoimmune disease, a sepsis, a viral infection. Or a therapeutic drug for neurodegenerative diseases.
  • the compound 1-(2-(3-acetyl-1H-indol-1-yl)acetyl)piperidine-4-carboxylic acid methyl ester (284 mg, 0.83 mmol) was dissolved in 8 mL of MeOH. 1 M NaOH (4 mL, 4.15 mmol) was added. The reaction system was stirred at room temperature for 2 h and monitored by TLC. After the reaction was completed, most of the solvent was evaporated in vacuo, and the remaining solution was adjusted to a weak acidity with a 1M hydrochloric acid solution, and a large amount of a white solid was precipitated, and filtered under reduced pressure.
  • Methyl 1-(2-(3-acetyl-6-methoxy-1H-indol-1-yl)acetyl)piperidine-4-carboxylate (100 mg, 0.27 mmol) was dissolved in 15 mL of dichloro Methane, BBr3 (167 mg, 0.68 mmol) was dissolved in 10 mL of DCM, and dropped into the reaction system under ice bath, then transferred to room temperature for reaction and monitored by TLC. The reaction was completed, and the mixture was stirred with EtOAc EtOAc EtOAc EtOAc (EtOAc) ).
  • 1-acetyl-1H-indole-3-carboxylic acid is the same as described above.
  • 1-(3-Aminophenyl)ethan-1-one 110 mg, 0.82 mmol
  • 2-chloro-1-methylpyridine iodide 502 mg, 1.96 mmol
  • n-Bu3N 729 mg, 3.93 mmol
  • the in vitro activity test materials include: a protein of interest CBP; an experimental buffer (10 ⁇ ) MOPS (500 mm), CHAPS (0.5 mm), NaF (500 mm), BSA (1 mg/mL), pH 7.4; Body microbead 50 ⁇ g/mL, acceptor microbead 50 ⁇ g/mL; CBP ligand, short peptide H4KAc4-botin(SGRG ⁇ Lys-Ac ⁇ GG ⁇ Lys-Ac ⁇ GLG ⁇ Lys-Ac ⁇ GGA ⁇ Lys-Ac ⁇ RHR ⁇ Lys(biotin) ⁇ ) 50nM; 150 ⁇ L reaction system: CBP: 15 ⁇ L, experimental buffer: 15 ⁇ L, deionized water: 15 ⁇ L, small molecule compound: 15 ⁇ L, donor microbead: 15 ⁇ L, acceptor microbead: 15 ⁇ L; Positive inhibitor: SGC-CBP30.
  • the in vitro activity test method is to add protein and short peptide to the reaction solution, incubate at 20 ° C for 1.5 h, add donor and acceptor beads, and incubate for 1 h in the dark. Transfer to a 384-well plate, transfer 40 ⁇ L of liquid per well, and pass the PE Envison 2104 multi-function detection microplate reader, excitation wavelength: 680 nM, emission wavelength 520-620 nM detection reading.
  • Comparative Example 1 was verified by AlphaScreen detection technology. The verification results are shown in Table 1:
  • Example 1 Compound number Inhibition rate Compound number Inhibition rate Compound number Inhibition rate Comparative example 1 98% Example 1 47% Example 2 35% Example 3 36% Example 4 20% Example 5 98% Example 6 -3% Example 7 74% Example 8 40% Example 9 88% Example 10 94% Example 11 57% Example 12 twenty four% Example 13 27% Example 14 11% Example 15 44% Example 16 42% Example 17 54% Example 18 37% Example 19 12% Example 20 31% Example 21 63% Example 22 88% Example 23 88% Example 24 67% Example 25 91% Example 26 50% Example 27 3.89 Example 28 91% Example 29 72% Example 30 96% Example 31 71% Example 32 61% Example 33 73% Example 34 96% Example 35 58% Example 36 79% Example 37 19% Example 38 94% Example 39 94% Example 40 68% Example 41 30% Example 42 70% Example 43 58% Example 44 86% Example 45 91% Example 46 88% Example 47 29% Example 48 97% Example 49 71% Example 50 15% Example 51 96% Example 52 55% Example 53 98% Example 54 81% Example 55 91% Example 56 62% Example 57 93%
  • Example 108 92% Example 109 98% Example 110 96%
  • Example 111 98%
  • Example 112 89%
  • Example 114 98%
  • Example 115 twenty three%
  • Example 116 1%
  • Example 117 12%
  • Example 118 -8% Example 119 3%
  • Example 120 98%
  • Example 121 97%
  • Example 122 95%
  • Example 123 97%
  • Example 124 95%
  • Example 126 92% Example 127 4%
  • Example 128 1% 129 -8%
  • Example 130 80%
  • Example 132 98%
  • Example 133 80%
  • Example 135 10%
  • Example 136 98%
  • Example 137 1%
  • Example 138 87%
  • Example 140 88%
  • Example 141 95%
  • Example 142 20%
  • Prostate cancer cells (LNCaP and 22Rv1) were cultured with RPMI1640 and 10% FBS was added. The cells were grown in a 5% CO2 incubator at 37 °C. To test the viability of the cells, cells were seeded at a total volume of 20 ⁇ L of medium at 1000 cells/well (optimum growth density) in 384 opaque plates with a transparent bottom. After 12 hours, a total volume of 10 [mu]L of medium (three dilutions) of compound was added to each well to a final concentration of 5 nM to 100 [mu]M. For LNCaP cells, the medium was RPMI 1640 containing 10% FBS.
  • the medium was RPMI 1640 containing 10% cds-FBS.
  • the assay was performed 96 hours after inoculation, and 25 ⁇ L LCell-Titer GLO reagent (Promega) was added and the luminescence was measured on a GLOMAX microplate luminometer (Promega) according to the manufacturer's instructions.
  • the estimated in vitro maximum half inhibitory concentration (IC50) values were calculated using GraphPad Prism 6 software.
  • the cell viability of Examples 115, 132 and 142 was within 5 ⁇ M.

Abstract

Provided are an indole compound and an application thereof. The compound is capable of effectively inhibiting CBP/EP300 bromodomain receptors, and may be used as a drug for cancers, inflammatory diseases, autoimmune diseases, septicaemia and viral infections.

Description

一种吲哚类化合物及其应用，一种药物组合物及其应用Terpenoid compound and application thereof, pharmaceutical composition and application thereof 技术领域Technical field
本申请涉及化学医药技术领域，具体涉及一种吲哚类化合物及其应用。The present application relates to the field of chemical medicine, and in particular to an anthraquinone compound and application thereof.
背景技术Background technique
溴结构域(Bromodomain)是一类进化保守，可以介导蛋白-蛋白相互作用的模块。溴结构域是组蛋白乙酰化的读者，可特异性识别组蛋白乙酰化赖氨酸残基，从而影响靶基因的转录和翻译，该蛋白复合的功能异常与多种疾病的发生相关，这使得溴结构域蛋白成为一类新颖的靶点。溴结构域蛋白的抑制剂具有重要的生物学意义，例如已有大量化合物被报道其在癌症、炎症疾病及自身免疫疾病、败血症、病毒感染等疾病具有疗效。Bromodomains are a class of evolutionarily conserved modules that mediate protein-protein interactions. The bromodomain is a reader of histone acetylation, which specifically recognizes histone acetylated lysine residues, thereby affecting the transcription and translation of target genes. The dysfunction of this protein complex is associated with the occurrence of various diseases, which makes Bromodomain proteins have become a novel class of targets. Inhibitors of bromodomain proteins have important biological significance. For example, a large number of compounds have been reported to have therapeutic effects in diseases such as cancer, inflammatory diseases, autoimmune diseases, sepsis, and viral infections.
溴结构域蛋白因首先在果蝇基因中发现而得名，自此溴结构域蛋白在很多核蛋白中发现，如组蛋白乙酰转移酶(HATs)，ATP依赖的染色质重塑复合物，甲基转移酶和转录共激活因子等。人类蛋白质组编码的61种溴结构域，目前存在于46个不同的核蛋白和胞质蛋白中。溴结构域蛋白家族根据其功能可划分为8个亚家族。其中组蛋白乙酰化转移酶是其中一类，它包括：CBP、EP300、P/CAF和GCN5等。CBP与EP300为同源蛋白。Bromine domain proteins are named for their first discovery in Drosophila genes, since bromodomain proteins have been found in many nuclear proteins, such as histone acetyltransferases (HATs), ATP-dependent chromatin remodeling complexes, Base transferase and transcriptional coactivator and the like. The 61 bromodomains encoded by the human proteome are present in 46 different nuclear and cytoplasmic proteins. The bromodomain protein family can be divided into eight subfamilies according to its function. Among them, histone acetyltransferase is one of them, which includes: CBP, EP300, P/CAF and GCN5. CBP and EP300 are homologous proteins.
CBP/EP300是cAMP反应元件结合蛋白CREB的多功能转录辅激活因子，它参与多种生理过程：细胞周期调控、细胞分化和细胞凋亡等。CBP/EP300蛋白通过自身的HAT发挥转录因子与靶DNA之间的桥梁作用；可以抑制细胞复制，使细胞停留在G1期；CBP/EP300蛋白本身具有抑癌因子的功能，同时还参与多条抑癌信息传导通路。CBP/EP300除与复发性急性淋巴细胞白血病、RTS和神经退行性疾病有关以外，同时还与***癌、炎症治疗(肺炎症和哮喘)相关等各种疾病相关。靶向CBP/EP300蛋白有助于为癌症、神经退行性疾病和炎症等疾病提供新的治疗策略。CBP/EP300 is a multifunctional transcriptional coactivator of cAMP response element binding protein CREB, which is involved in various physiological processes: cell cycle regulation, cell differentiation and apoptosis. CBP/EP300 protein acts as a bridge between transcription factor and target DNA through its own HAT; it can inhibit cell replication and keep cells in G1 phase; CBP/EP300 protein itself has the function of tumor suppressor, and also participates in multiple inhibition Cancer information transmission pathway. In addition to recurrent acute lymphoblastic leukemia, RTS, and neurodegenerative diseases, CBP/EP300 is also associated with various diseases such as prostate cancer and inflammatory treatment (pulmonary inflammation and asthma). Targeting CBP/EP300 proteins can help provide new therapeutic strategies for diseases such as cancer, neurodegenerative diseases and inflammation.
周明明和其团队在研究中发现CBP溴结构域与p53蛋白中肿瘤抑制基因KAc382相互作用。为了抑制CBP-p53的相互作用，周明明和同事利用核磁共振技术发现了CBP/EP300溴结构域小分子抑制剂MS2126和MS7972。随后，通过表观遗传学筛选和靶向生物化学等手段的应用，已有一些的小分子化合物被发现，但目前无进入临床研究的化合物。Zhou Mingming and his team found in the study that the CBP bromodomain interacts with the tumor suppressor gene KAc382 in the p53 protein. In order to inhibit the interaction of CBP-p53, Zhou Mingming and colleagues used nuclear magnetic resonance technology to discover CBP/EP300 bromodomain small molecule inhibitors MS2126 and MS7972. Subsequently, through the application of epigenetic screening and targeted biochemistry, some small molecule compounds have been discovered, but there are no compounds that have entered clinical research.
发明内容Summary of the invention
以下是对本文详细描述的主题的概述。本概述并非是为了限制权利要求的保护范围。The following is an overview of the topics detailed in this document. This Summary is not intended to limit the scope of the claims.
本申请提供一种吲哚化合物及其应用，所述化合物可有效抑制CBP/EP300溴结构域受体，可作为癌症、炎症疾病及自身免疫疾病、败血症、病毒感染的药物。The present application provides an indole compound and an application thereof, which are effective for inhibiting a CBP/EP300 bromodomain receptor, and are useful as drugs for cancer, inflammatory diseases, autoimmune diseases, sepsis, and viral infections.
为达到上述目的，本申请采用以下技术方案：To achieve the above objectives, the present application adopts the following technical solutions:
本申请目的之一在于提供一种吲哚类化合物，所述化合物具有下述化学式I和化学式II的结构：One of the objects of the present application is to provide an anthraquinone compound having the structure of the following chemical formula I and formula II:
Figure PCTCN2018101765-appb-000001
Figure PCTCN2018101765-appb-000001
式I中，R 1为C 1～C 4烷基，R 2为H、C 1～C 7烷基、-R-X 1或-X 2，R 3为H、C 1～C 5烷基、C 3～C 5环烷基、-OX 3、-NHX 3或-N(X 3) 2； In formula I, R 1 is C 1 -C 4 alkyl, R 2 is H, C 1 -C 7 alkyl, -RX 1 or -X 2 , R 3 is H, C 1 -C 5 alkyl, C 3 to C 5 cycloalkyl, -OX 3 , -NHX 3 or -N(X 3 ) 2 ;
其中，R为C 1～C 4亚烷基，X 1为-OX 3、-COOX 4、-CONHX 4、环烷基、杂环基、-COX 5或-S(O) mX 5，X 2为C 3～C 7环烷基、苯基、萘基、杂环基、-COX 5或-S(O) mX 5； Wherein R is a C 1 -C 4 alkylene group, X 1 is -OX 3 , -COOX 4 , -CONHX 4 , a cycloalkyl group, a heterocyclic group, -COX 5 or -S(O) m X 5 , X 2 is C 3 -C 7 cycloalkyl, phenyl, naphthyl, heterocyclic, -COX 5 or -S(O) m X 5 ;
其中，m为0或2，X 3、X 4和X 5独立地为H、C 1～C 4烷基、C 3～C 7环烷基、苯基、萘基 或杂环基； Wherein m is 0 or 2, and X 3 , X 4 and X 5 are independently H, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, phenyl, naphthyl or heterocyclic;
式II中，R 4为C 1～C 4烷基，R 5为C 1～C 7烷基、-R′-Y 1、Y 1′-(C 1-C 4次烷基)-Y 1或Y 2，R 6为H、C 1～C 5烷基、C 3～C 5环烷基、-OY 3、-NHY 3或-N(Y 3) 2； In the formula II, R 4 is a C 1 -C 4 alkyl group, R 5 is a C 1 -C 7 alkyl group, -R'-Y 1 , Y 1 '-(C 1 -C 4 alkyl group)-Y 1 Or Y 2 , R 6 is H, C 1 -C 5 alkyl, C 3 -C 5 cycloalkyl, -OY 3 , -NHY 3 or -N(Y 3 ) 2 ;
其中，R′为C 1～C 4亚烷基，Y 1为-NHCOO tBu、C 3～C 7环烷基、苯基、萘基、-OY 4、-COY 4、-COOY 4、-NHCOY 4或-S(O) mY 4，Y 1′为-NHCOO tBu、C 3～C 7环烷基、苯基、萘基、-OY 4、-COY 4、-COOY 4、-NHCOY 4或-S(O) mY 4，Y 2为C 3～C 7环烷基、苯基、萘基或杂环基； Wherein R' is a C 1 -C 4 alkylene group, Y 1 is -NHCOO t Bu, C 3 -C 7 cycloalkyl, phenyl, naphthyl, -OY 4 , -COY 4 , -COOY 4 , - NHCOY 4 or -S(O) m Y 4 , Y 1 ' is -NHCOO t Bu, C 3 -C 7 cycloalkyl, phenyl, naphthyl, -OY 4 , -COY 4 , -COOY 4 , -NHCOY 4 or -S(O) m Y 4 , Y 2 is a C 3 -C 7 cycloalkyl group, a phenyl group, a naphthyl group or a heterocyclic group;
其中，m为0或2，Y 4为H、C 1～C 4烷基、C 3～C 7环烷基、苯基、萘基或杂环基。 Wherein m is 0 or 2, and Y 4 is H, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, phenyl, naphthyl or heterocyclic.
其中，式I中，R 1可以是C 1、C 2、C 3或C 4烷基，R 2可以是C 1、C 2、C 3、C 4、C 5、C 6或C 7烷基，R 3可以是C 1、C 2、C 3、C 4或C 5烷基，R 3可以是C 3、C 4或C 5环烷基，R可以是C 1、C 2、C 3或C 4亚烷基，X 2可以是C 3、C 4、C 5、C 6或C 7环烷基，X 3、X 4和X 5独立地可以是C 1、C 2、C 3或C 4烷基，X 3、X 4和X 5独立地可以是C 3、C 4、C 5、C 6或C 7环烷基。 Wherein, in Formula I, R 1 may be C 1 , C 2 , C 3 or C 4 alkyl, and R 2 may be C 1 , C 2 , C 3 , C 4 , C 5 , C 6 or C 7 alkyl R 3 may be C 1 , C 2 , C 3 , C 4 or C 5 alkyl, R 3 may be C 3 , C 4 or C 5 cycloalkyl, and R may be C 1 , C 2 , C 3 or C 4 alkylene, X 2 may be C 3 , C 4 , C 5 , C 6 or C 7 cycloalkyl, and X 3 , X 4 and X 5 may independently be C 1 , C 2 , C 3 or C The alkyl group, X 3 , X 4 and X 5 may independently be a C 3 , C 4 , C 5 , C 6 or C 7 cycloalkyl group.
其中，式II中，R 4可以是C 1、C 2、C 3或C 4烷基，R 5可以是C 1、C 2、C 3、C 4、C 5、C 6或C 7烷基，Y 1′-(C 1-C 4次烷基)-Y 1中次烷基可以是C 1次烷基、C 2次烷基、C 3次烷基或C 4次烷基，R 6可以是C 1、C 2、C 3、C 4或C 5烷基，R 6可以是C 3、C 4或C 5环烷基，R′可以是C 1、C 2、C 3或C 4亚烷基，Y 1可以是C 3、C 4、C 5、C 6或C 7环烷基，Y 1′可以是C 3、C 4、C 5、C 6或C 7环烷基，Y 2可以是C 3、C 4、C 5、C 6或C 7环烷基，Y 4可以是C 1、C 2、C 3或C 4烷基，Y 4可以是C 3、C 4、C 5、C 6或C 7环烷基。 Wherein, in Formula II, R 4 may be C 1 , C 2 , C 3 or C 4 alkyl, and R 5 may be C 1 , C 2 , C 3 , C 4 , C 5 , C 6 or C 7 alkyl , Y 1 '-(C 1 -C 4 alkyl)-Y 1 intermediate alkyl may be C 1 alkyl, C 2 alkyl, C 3 alkyl or C 4 alkyl, R 6 It may be C 1 , C 2 , C 3 , C 4 or C 5 alkyl, R 6 may be C 3 , C 4 or C 5 cycloalkyl, and R' may be C 1 , C 2 , C 3 or C 4 An alkylene group, Y 1 may be a C 3 , C 4 , C 5 , C 6 or C 7 cycloalkyl group, and Y 1 ' may be a C 3 , C 4 , C 5 , C 6 or C 7 cycloalkyl group, Y 2 may be C 3 , C 4 , C 5 , C 6 or C 7 cycloalkyl, Y 4 may be C 1 , C 2 , C 3 or C 4 alkyl, and Y 4 may be C 3 , C 4 , C 5 , C 6 or C 7 cycloalkyl.
作为本申请优选的技术方案，所述式I中R 1包括甲基、乙基、正丙基、异丙基或叔丁基。 As a preferred embodiment of the present application, R 1 in the formula I includes a methyl group, an ethyl group, a n-propyl group, an isopropyl group or a t-butyl group.
优选地，所述式I中R 2包括-R-X 1或-X 2，其中R为C 1～C 2亚烷基，X 1为-COOX 4、-CONHX 4、环烷基或杂环基，X 2为-COX 5或-S(O) 2X 5，其中X 5为C 1～C 3烷基、C 3～C 7环烷基、苯基、萘基或杂环基。 Preferably, R 2 in the formula I includes -RX 1 or -X 2 , wherein R is a C 1 -C 2 alkylene group, and X 1 is -COOX 4 , -CONHX 4 , a cycloalkyl or a heterocyclic group, X 2 is -COX 5 or -S(O) 2 X 5 , wherein X 5 is a C 1 -C 3 alkyl group, a C 3 -C 7 cycloalkyl group, a phenyl group, a naphthyl group or a heterocyclic group.
优选地，所述式I中R 3包括H、甲基、乙基、正丙基、异丙基、正丁基、正戊基、环丙基、环丁基、环戊基、酚羟基、甲氧基、乙氧基、丙氧基、丁氧基、氮甲基、氮乙基、氮丙基或氮丁基。 Preferably, R 3 in the formula I includes H, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, phenolic hydroxyl, Methoxy, ethoxy, propoxy, butoxy, nitrogen methyl, nitrogen ethyl, nitrogen propyl or nitrogen butyl.
优选地，所述式II中R 4包括甲基、乙基、正丙基、异丙基或叔丁基。 Preferably, R 4 in formula II includes methyl, ethyl, n-propyl, isopropyl or t-butyl.
优选地，所述式II中R 5包括-R′-Y 1或Y 2，其中R′为C 1～C 4亚烷基，Y 1为C 3～C 7环烷基、苯基、萘基、-OY 4、-COY 4、-COOY 4、-NHCOY 4或-S(O) 2Y 4，Y 2为C 3～C 7环烷基、苯基、萘基或杂环基，其中Y 4为H、C 1～C 4烷基、C 3～C 7环烷基、苯基、萘基或杂环基。 Preferably, R 5 in the formula II includes -R'-Y 1 or Y 2 , wherein R' is a C 1 -C 4 alkylene group, and Y 1 is a C 3 -C 7 cycloalkyl group, a phenyl group, a naphthalene group. a group, -OY 4 , -COY 4 , -COOY 4 , -NHCOY 4 or -S(O) 2 Y 4 , Y 2 is a C 3 -C 7 cycloalkyl group, a phenyl group, a naphthyl group or a heterocyclic group, wherein Y 4 is H, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, phenyl, naphthyl or heterocyclic.
优选地，所述式II中R 6包括H、甲基、乙基、正丙基、异丙基、正丁基、正戊基、环丙基、环丁基、环戊基、酚羟基、甲氧基、乙氧基、丙氧基、丁氧基、氮甲基、氮乙基、氮丙基或氮丁基。 Preferably, R 6 in the formula II includes H, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, phenolic hydroxyl, Methoxy, ethoxy, propoxy, butoxy, nitrogen methyl, nitrogen ethyl, nitrogen propyl or nitrogen butyl.
作为本申请优选的技术方案，式I中所述C 3～C 7环烷基、苯基以及萘基含有0～3个取代基，取代基个数可以是0、1、2或3个。 As a preferred embodiment of the present invention, the C 3 -C 7 cycloalkyl group, the phenyl group and the naphthyl group in the formula I contain 0 to 3 substituents, and the number of the substituents may be 0, 1, 2 or 3.
优选地，所述取代基为卤素、C 1～C 4烷基、三氟甲基、氰基、硝基、氨基、酰胺、-COOX 6、-COX 6、-OX 6、-NHCOX 6、-C 6H 5X 7、吗啉基、哌啶基、呋喃基、四氢呋喃基或吡啶基，其中X 6为H、C 1～C 4烷基、苯基，X 7为C 1～C 4烷基、卤素、三氟甲基、氰基、硝基、氨基、酰胺、乙酰基、甲氧基或乙氧基。 Preferably, the substituent is halogen, C 1 -C 4 alkyl, trifluoromethyl, cyano, nitro, amino, amide, -COOX 6 , -COX 6 , -OX 6 , -NHCOX 6 , - C 6 H 5 X 7 , morpholinyl, piperidinyl, furyl, tetrahydrofuranyl or pyridyl, wherein X 6 is H, C 1 -C 4 alkyl, phenyl, X 7 is C 1 -C 4 alkane Base, halogen, trifluoromethyl, cyano, nitro, amino, amide, acetyl, methoxy or ethoxy.
其中，取代基可以是C 1、C 2、C 3或C 4烷基，X 6可以是C 1、C 2、C 3或C 4烷基，X 7可以是C 1、C 2、C 3或C 4烷基。 Wherein the substituent may be C 1 , C 2 , C 3 or C 4 alkyl, X 6 may be C 1 , C 2 , C 3 or C 4 alkyl, and X 7 may be C 1 , C 2 , C 3 Or C 4 alkyl.
作为本申请优选的技术方案，式I中所述杂环基为氮杂环丁基、氧杂环丁基、氮杂环戊基、氧杂环戊基、氮杂环己基、氧杂环己基、氮杂环己基、咪唑-2-酮基、咪唑基、呋喃基、噻吩基、噁唑基、异噁唑基、嘧啶基、吡咯基、哌嗪基、四氢吡咯基、哌啶基、吗啉基、1，3-二氧戊环基或苯并[d]噻唑基。As a preferred embodiment of the present application, the heterocyclic group in the formula I is azetidinyl, oxetanyl, azacyclopentyl, oxetanyl, azacyclohexyl, oxetanyl. , azacyclohexyl, imidazol-2-one, imidazolyl, furyl, thienyl, oxazolyl, isoxazolyl, pyrimidinyl, pyrrolyl, piperazinyl, tetrahydropyrrolyl, piperidinyl, Morpholinyl, 1,3-dioxolanyl or benzo[d]thiazolyl.
优选地，式I中所述杂环基含有0～3个取代基，取代基个数可以是0、1、2或3个。Preferably, the heterocyclic group in the formula I contains 0 to 3 substituents, and the number of substituents may be 0, 1, 2 or 3.
优选地，所述取代基为卤素、C 1～C 4烷基、三氟甲基、氰基、硝基、氨基、酰胺、-COOX 6、 -COX 6、-OX 6、-NHCOX 6、-C 6H 5X 7、吗啉基、哌啶基、呋喃基、四氢呋喃基或吡啶基其中X 6为H、C 1～C 4烷基、苯基，X 7为C 1～C 4烷基、卤素、三氟甲基、氰基、硝基、氨基、酰胺、乙酰基、甲氧基或乙氧基。 Preferably, the substituent is halogen, C 1 -C 4 alkyl, trifluoromethyl, cyano, nitro, amino, amide, -COOX 6 , -COX 6 , -OX 6 , -NHCOX 6 , - C 6 H 5 X 7 , morpholinyl, piperidinyl, furyl, tetrahydrofuranyl or pyridyl wherein X 6 is H, C 1 -C 4 alkyl, phenyl, X 7 is C 1 -C 4 alkyl Halogen, trifluoromethyl, cyano, nitro, amino, amide, acetyl, methoxy or ethoxy.
其中，取代基可以是C 1、C 2、C 3或C 4烷基，X 6可以是C 1、C 2、C 3或C 4烷基，X 7可以是C 1、C 2、C 3或C 4烷基。 Wherein the substituent may be C 1 , C 2 , C 3 or C 4 alkyl, X 6 may be C 1 , C 2 , C 3 or C 4 alkyl, and X 7 may be C 1 , C 2 , C 3 Or C 4 alkyl.
作为本申请优选的技术方案，式II中所述C 3～C 7环烷基、苯基以及萘基含有0～3个取代基，取代基个数可以是0、1、2或3个。 As a preferred embodiment of the present application, the C 3 -C 7 cycloalkyl group, the phenyl group and the naphthyl group in the formula II contain 0 to 3 substituents, and the number of the substituents may be 0, 1, 2 or 3.
优选地，所述取代基为卤素、C 1～C 4烷基、三氟甲基、氰基、硝基、氨基、1，3-二氧戊环基、-COOY 5、-COY 5、-OY 5、-NHCOY 5、-C 6H 5Y 6、-(CH 2) nNHY 7、-NHCOO tBu、-CH 2OCOO tBu、1-甲基哌嗪、吗啉基、异噁唑基、3，5-二甲基异恶唑基、喹啉基、异喹啉基、哌啶基、噻吩基、呋喃基、四氢呋喃基、吡啶基、嘧啶基、2-吗啉基吡啶基、吲哚基、1，4-苯并二氧杂环基、苯并呋喃基、苯并噻吩基、1-甲基-1H-吲唑基、吡咯基、1H-吡唑基、1-甲基-1H-吡唑基或四氢吡喃基，其中n为0～2，Y 5为自氢、C 1～C 4烷基或苯基，Y 6为氢、C 1～C 4烷基、卤素、甲酰基、乙酰基、甲氧基、乙氧基、三氟甲基、氰基或甲砜基，Y 7为C 1～C 5烷基、C 0～C 2亚烷基-苯基、C 0～C 2亚烷基-萘基或C 0～C 2亚烷基-杂环基，其中Y 7中所述苯基、萘基或杂环基被0～3个卤素、C 1～C 4烷基、三氟甲基、氰基、硝基或氨基取代。 Preferably, the substituent is halogen, C 1 -C 4 alkyl, trifluoromethyl, cyano, nitro, amino, 1,3-dioxolanyl, -COOY 5 , -COY 5 , - OY 5 , -NHCOY 5 , -C 6 H 5 Y 6 , -(CH 2 ) n NHY 7 , -NHCOO t Bu, -CH 2 OCOO t Bu, 1-methylpiperazine, morpholinyl, isoxazole , 3,5-dimethylisoxazolyl, quinolyl, isoquinolinyl, piperidinyl, thienyl, furyl, tetrahydrofuranyl, pyridyl, pyrimidinyl, 2-morpholinylpyridyl, Mercapto, 1,4-benzodioxyl, benzofuranyl, benzothienyl, 1-methyl-1H-carbazolyl, pyrrolyl, 1H-pyrazolyl, 1-methyl -1H-pyrazolyl or tetrahydropyranyl, wherein n is 0 to 2, Y 5 is hydrogen, C 1 -C 4 alkyl or phenyl, Y 6 is hydrogen, C 1 -C 4 alkyl, Halogen, formyl, acetyl, methoxy, ethoxy, trifluoromethyl, cyano or methylsulfonyl, Y 7 is C 1 -C 5 alkyl, C 0 -C 2 alkylene-phenyl a C 0 -C 2 alkylene-naphthyl group or a C 0 -C 2 alkylene-heterocyclic group, wherein the phenyl, naphthyl or heterocyclic group in Y 7 is 0 to 3 halogens, C 1 ~C 4 alkyl, trifluoromethyl Substituted by a cyano group, a nitro group or an amino group.
其中，取代基可以是C 1、C 2、C 3或C 4烷基，Y 6可以是C 1、C 2、C 3或C 4烷基，Y 7可以是C 1、C 2、C 3、C 4或C 5烷基，Y 7可以是苯基、C 1亚烷基-苯基或C 2亚烷基-苯基，Y 7可以是萘基、C 1亚烷基-萘基或C 2亚烷基-萘基，Y 7可以是杂环基、C 1亚烷基-杂环基或C 2亚烷基-杂环基，Y 7中所述苯基、萘基或杂环基被0、1、2或3个取代基取代，Y 7中的取代基可以是C 1、C 2、C 3或C 4烷基。 Wherein the substituent may be C 1 , C 2 , C 3 or C 4 alkyl, Y 6 may be C 1 , C 2 , C 3 or C 4 alkyl, and Y 7 may be C 1 , C 2 , C 3 , C 4 or C 5 alkyl, Y 7 may be phenyl, C 1 alkylene-phenyl or C 2 alkylene-phenyl, and Y 7 may be naphthyl, C 1 alkylene-naphthyl or C 2 alkylene-naphthyl, Y 7 may be heterocyclic, C 1 alkylene-heterocyclyl or C 2 alkylene-heterocyclyl, phenyl, naphthyl or heterocyclic in Y 7 The group is substituted by 0, 1, 2 or 3 substituents, and the substituent in Y 7 may be C 1 , C 2 , C 3 or C 4 alkyl.
作为本申请优选的技术方案，式II中所述杂环基为氮杂环丁基、氧杂环丁基、氮杂环戊基、氧杂环戊基、氮杂环己基、氧杂环己基、氮杂环己基、呋喃基、噻吩基、噁唑基、异噁唑基、嘧啶基、吡咯基、四氢吡咯基、吗啉基、1，3-二氧戊环基、苯并[d]噻唑基、吡啶基、1，4-苯并二氧杂环基、吲唑基、N-甲基苯并咪唑基、吲哚基、二氢吲哚基或2-咪唑烷酮基；As a preferred embodiment of the present application, the heterocyclic group in the formula II is azetidinyl, oxetanyl, azacyclopentyl, oxetanyl, azacyclohexyl, oxetanyl. , azacyclohexyl, furyl, thienyl, oxazolyl, isoxazolyl, pyrimidinyl, pyrrolyl, tetrahydropyrrolyl, morpholinyl, 1,3-dioxolanyl, benzo[d Thiazolyl, pyridyl, 1,4-benzodioxyl, oxazolyl, N-methylbenzimidazolyl, indolyl, indanyl or 2-imidazolidinone;
优选地，式II中所述杂环基含有0～3个取代基，取代基个数可以是0、1、2或3个。Preferably, the heterocyclic group in the formula II contains 0 to 3 substituents, and the number of the substituents may be 0, 1, 2 or 3.
优选地，所述取代基为卤素、C 1～C 4烷基、三氟甲基、氰基、羧基、硝基、氨基、1，3-二氧戊环基、-COOY 5、-COY 5、-OY 5、-NHCOY 5、-NHCOO tBu或-C 6H 5Y 6，其中Y 5为氢、C 1～C 4烷基或苯基，Y 6为C 1～C 4烷基、卤素、乙酰基、甲氧基或乙氧基。 Preferably, the substituent is halogen, C 1 -C 4 alkyl, trifluoromethyl, cyano, carboxyl, nitro, amino, 1,3-dioxolanyl, -COOY 5 , -COY 5 , -OY 5 , -NHCOY 5 , -NHCOO t Bu or -C 6 H 5 Y 6 , wherein Y 5 is hydrogen, C 1 -C 4 alkyl or phenyl, Y 6 is C 1 -C 4 alkyl, Halogen, acetyl, methoxy or ethoxy.
其中，取代基可以是C 1、C 2、C 3或C 4烷基，Y 5可以是C 1、C 2、C 3或C 4烷基，Y 6可以是C 1、C 2、C 3或C 4烷基。 Wherein the substituent may be C 1 , C 2 , C 3 or C 4 alkyl, Y 5 may be C 1 , C 2 , C 3 or C 4 alkyl, and Y 6 may be C 1 , C 2 , C 3 Or C 4 alkyl.
当结构类型为式I时，化合物可以通过下述反应制备得到：When the structure type is formula I, the compound can be prepared by the following reaction:
Figure PCTCN2018101765-appb-000002
Figure PCTCN2018101765-appb-000002
当式I中R 2为-R-COX 5时，化合物可以通过下述反应制备得到： When R 2 in formula I is -R-COX 5 , the compound can be prepared by the following reaction:
Figure PCTCN2018101765-appb-000003
Figure PCTCN2018101765-appb-000003
当式I中R 2为-S(O) mX 5(m＝2)时，化合物可以通过下述反应制备得到： When R 2 in formula I is -S(O) m X 5 (m=2), the compound can be prepared by the following reaction:
Figure PCTCN2018101765-appb-000004
Figure PCTCN2018101765-appb-000004
当结构类型为式II时，可以通过下述2步反应制备得到：When the structure type is Formula II, it can be prepared by the following two-step reaction:
Figure PCTCN2018101765-appb-000005
Figure PCTCN2018101765-appb-000005
上述制备方法是以说明为的目，而非用来局限于所列化合物或任何特定的取代基。方案中显示的取代基数目并不必需符合权利要求中所用的数目，且为清楚起见，显示单取代基连接到在上文中式I和式II的定义下允许有多取代基的化合物上。The above preparation methods are for illustrative purposes, and are not intended to be limited to the listed compounds or any particular substituents. The number of substituents shown in the schemes does not necessarily have to correspond to the number used in the claims, and for the sake of clarity, it is shown that the mono-substituents are attached to a compound which allows multiple substituents under the definitions of Formulas I and II above.
本申请目的之二在于提供一种上述吲哚类化合物的应用，述吲哚类化合物用于制备CBP/EP300溴结构域受体抑制剂。The second object of the present application is to provide an application of the above quinone compound for the preparation of a CBP/EP300 bromodomain receptor inhibitor.
作为本申请优选的技术方案，所述CBP/EP300溴结构域受体抑制剂用于制备治疗癌症、细胞增殖性紊乱疾病、炎症疾病及自身免疫疾病、败血症、病毒感染、神经性衰退性疾病的药物。As a preferred technical solution of the present application, the CBP/EP300 bromodomain receptor inhibitor is used for preparing cancer, cell proliferative disorder, inflammatory disease and autoimmune disease, sepsis, viral infection, neurodegenerative disease. drug.
本申请目的之三在于提供一种药物组合物，所述药物组合物含有上述所述吲哚类化合物。The third object of the present application is to provide a pharmaceutical composition comprising the above-described terpenoid compound.
作为本申请优选的技术方案，所述药物组合物用于治疗、预防或改善癌症、细胞增殖性紊乱、炎症、自身免疫性疾病、败血症、病毒感染或神经性衰退性疾病。As a preferred technical solution of the present application, the pharmaceutical composition is for treating, preventing or ameliorating cancer, cell proliferative disorder, inflammation, autoimmune disease, sepsis, viral infection or neurodegenerative disease.
CBP/EP300溴结构域受体抑制剂制备的药物，以及所述药物组合物可治疗的癌症包括肾上腺肿瘤、听神经瘤、肢端黑色素瘤、肢端汗腺瘤、急性嗜酸性白血病、急性红色的白血病、急性淋巴母细胞性白血病、急性巨核细胞白血病、急性单核细胞的白血病、急性早幼粒细胞性白血病、腺癌、腺样囊性癌、脂肪组织肿瘤、肾上腺皮质癌、成人T细胞白血病/淋巴瘤、艾滋病相关淋巴瘤、肺泡横纹肌肉瘤、肺泡软肉瘤、成釉细胞的纤维瘤、间变性大细胞淋巴瘤、未分化甲状腺癌、血管肌脂肪瘤、血管肉瘤、星形细胞瘤、非典型畸形杆状的肿瘤、B细胞慢性淋巴细胞白血病、B细胞前淋巴细胞白血病、B细胞淋巴瘤、基底细胞癌、胆道癌、膀胱癌、胚细胞瘤、骨肿瘤、棕色肿瘤、伯基特淋巴瘤、乳腺癌、脑癌、原位癌、软骨瘤、牙骨质瘤、髓系肉瘤、软骨瘤、脊索瘤、绒毛膜癌、脉络丛***状瘤、肾透明细胞肉瘤、颅咽管瘤、皮肤t细胞淋巴瘤、***、结肠癌、小圆细胞肿瘤、细胞弥漫型B细胞淋巴瘤、神经上皮的肿瘤、无性细胞瘤、胚胎性癌内分泌腺肿瘤、内胚层窦肿瘤、食道癌、纤维瘤、纤维肉瘤、滤泡淋巴瘤、滤泡星形胶质细胞瘤、甲状腺癌胃肠道癌症、生殖细胞肿瘤、妊娠期绒毛膜癌、巨细胞成纤维细胞瘤、骨巨细胞瘤、神经胶质细胞瘤、多形性胶质母细胞瘤、神经胶质瘤、颗粒细胞瘤、男性细胞瘤、胆囊癌症、胃癌、成血管细胞瘤、头部和颈部癌症、血管外皮细胞瘤恶性肿瘤、肝母细胞癌、细胞淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、浸润性小叶癌、肠道癌症、肾癌、喉癌、致命的中线癌、白血病、***细胞瘤、脂肪肉瘤、肺癌、***瘤、淋巴上皮瘤、淋巴瘤、急性***肉瘤，淋巴细胞性白血病、慢性淋巴细胞白血病、肝癌，小细胞肺癌、非小细胞肺癌、麦芽淋巴瘤、恶性纤维组织细胞瘤、恶性周 围神经鞘瘤、边缘区b细胞淋巴瘤、肥大细胞白血病、纵隔生殖细胞肿瘤、乳腺髓样癌、髓样甲状腺癌、成神经管细胞瘤、黑色素瘤、脑膜瘤、默克尔细胞癌症、间皮瘤、转移性细胞癌、混合缪氏肿瘤、粘液性肿瘤、多发性骨髓瘤、肌肉组织肿瘤、蕈样黏液样脂肪肉瘤、粘液瘤、粘液肉瘤、鼻咽癌、神经母细胞瘤、神经纤维瘤、神经瘤、眼部癌症、嗜酸性、视神经鞘脑膜瘤、肿瘤、口腔癌、骨肉瘤、卵巢癌、***状甲状腺癌、肿瘤副神经节瘤、成松果体细胞瘤、垂体细胞瘤、前体T-淋巴母细胞性淋巴瘤、原发性中枢神经***淋巴瘤，腹膜癌、***癌、胰腺癌、咽癌、肾细胞癌、肾髓样癌、成视网膜细胞瘤、横纹肌瘤、横纹肌肉瘤、直肠癌、肉瘤、***瘤、滋养细胞肿瘤、皮肤癌、小圆细胞肿瘤、小细胞癌、软组织肉瘤、生长抑素瘤、脊髓肿瘤、脾边缘带淋巴瘤、鳞状细胞癌、滑膜肉瘤、小肠癌症、鳞状细胞癌、胃癌、T细胞淋巴瘤、睾丸癌、甲状腺癌症、移行细胞癌、喉癌、脐尿管癌、泌尿生殖癌症、子宫癌症、疣状癌、视觉途径神经胶质瘤、外阴癌或***癌等。The medicament prepared by the CBP/EP300 bromodomain receptor inhibitor, and the cancer treatable by the pharmaceutical composition include adrenal tumor, acoustic neuroma, acromegaly, acromegaly, acute eosinophilic leukemia, acute red leukemia Acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adipose tissue tumor, adrenocortical carcinoma, adult T cell leukemia/ Lymphoma, AIDS-associated lymphoma, alveolar rhabdomyosarcoma, alveolar soft sarcoma, ameloblastic fibroma, anaplastic large cell lymphoma, undifferentiated thyroid carcinoma, angiomyolipoma, angiosarcoma, astrocytoma, atypical Abnormal rod-shaped tumor, B-cell chronic lymphocytic leukemia, B-cell pro-lymphocytic leukemia, B-cell lymphoma, basal cell carcinoma, biliary tract cancer, bladder cancer, blastoma, bone tumor, brown tumor, Burkitt's lymphoma , breast cancer, brain cancer, carcinoma in situ, chondroma, cementum, myeloid sarcoma, chondroma, chordoma Choriocarcinoma, choroid plexus papilloma, renal clear cell sarcoma, craniopharyngioma, cutaneous t-cell lymphoma, cervical cancer, colon cancer, small round cell tumor, diffuse B-cell lymphoma, neuroepithelial neoplasm, Asexual cell tumor, embryonic cancer endocrine gland tumor, endoderm sinus tumor, esophageal cancer, fibroid, fibrosarcoma, follicular lymphoma, follicular astrocytoma, thyroid cancer, gastrointestinal cancer, germ cell tumor, Chorionic choriocarcinoma, giant cell fibroblastoma, giant cell tumor, glioma, glioblastoma multiforme, glioma, granulosa cell tumor, male cell tumor, gallbladder cancer, gastric cancer , hemangioblastoma, head and neck cancer, hemangioperic cell tumor malignancy, hepatoblastoma, cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, invasive lobular carcinoma, intestinal cancer , kidney cancer, laryngeal cancer, fatal midline cancer, leukemia, testicular stromal cell tumor, liposarcoma, lung cancer, lymphangioma, lymphoid epithelioma, lymphoma, acute lymphangiosarcoma, lymphocytes Leukemia, chronic lymphocytic leukemia, liver cancer, small cell lung cancer, non-small cell lung cancer, malt lymphoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, marginal b-cell lymphoma, mast cell leukemia, mediastinal germ cell tumor, Medullary carcinoma of the breast, medullary thyroid carcinoma, medulloblastoma, melanoma, meningioma, Merkel cell carcinoma, mesothelioma, metastatic cell carcinoma, mixed sputum tumor, mucinous tumor, multiple myeloma , muscle tissue tumor, sputum mucinous liposarcoma, myxoma, mucinous sarcoma, nasopharyngeal carcinoma, neuroblastoma, neurofibromatosis, neuroma, ocular cancer, eosinophilia, optic nerve sheath meningioma, tumor, oral cancer , osteosarcoma, ovarian cancer, papillary thyroid carcinoma, paraneoplastic ganglionoma, adult pineal cell tumor, pituitary cell tumor, precursor T-lymphoblastic lymphoma, primary central nervous system lymphoma, peritoneal cancer , prostate cancer, pancreatic cancer, pharyngeal cancer, renal cell carcinoma, renal medullary carcinoma, retinoblastoma, rhabdomyomas, rhabdomyosarcoma, rectum , sarcoma, seminoma, trophoblastic tumor, skin cancer, small round cell tumor, small cell carcinoma, soft tissue sarcoma, somatostatin, spinal cord tumor, spleen marginal lymphoma, squamous cell carcinoma, synovial sarcoma, Small bowel cancer, squamous cell carcinoma, gastric cancer, T-cell lymphoma, testicular cancer, thyroid cancer, transitional cell carcinoma, laryngeal cancer, urachal cancer, genitourinary cancer, uterine cancer, verrucous cancer, visual pathway glioma , vulvar cancer or vaginal cancer.
CBP/EP300溴结构域受体抑制剂制备的药物，以及所述药物组合物可治疗的细胞增殖性紊乱疾病包括良性软组织肿瘤、脑和脊髓肿瘤、眼睑和轨道肿瘤、肉芽肿、脂肪瘤、脑膜瘤、多发性内分泌瘤、鼻息肉、垂体肿瘤、泌乳素瘤、脂溢性角质的、胃息肉、甲状腺结节、肝血管瘤、声带结节、息肉、囊肿、藏毛病、皮肤纤维瘤、皮拉尔囊肿或化脓性肉芽肿等。A medicament prepared by a CBP/EP300 bromodomain receptor inhibitor, and a cell proliferative disorder treatable by the pharmaceutical composition include a benign soft tissue tumor, a brain and spinal cord tumor, an orbital and orbital tumor, a granuloma, a lipoma, a meninges Tumor, multiple endocrine neoplasms, nasal polyps, pituitary tumors, prolactinoma, seborrheic keratin, gastric polyps, thyroid nodules, hepatic hemangioma, vocal cord nodules, polyps, cysts, stagnation, cutaneous fibroids, skin Lal cyst or pyogenic granuloma.
CBP/EP300溴结构域受体抑制剂制备的药物，以及所述药物组合物可治疗的炎症疾病包括炎症盆腔疾病、尿道炎、皮肤晒伤、鼻窦炎、肺炎、脑炎、脑膜炎、心肌炎、肾炎、骨髓炎、肌炎、肝炎、胃炎、肠炎、皮炎、牙龈炎、胰腺炎、牛皮癣、过敏、克罗恩氏病、肠道综合症、溃疡性结肠炎、组织移植排斥、器官移植排斥、哮喘、过敏性鼻炎、慢性阻塞性肺疾病、自身免疫性疾病、自身免疫性脱发、贫血、肾小球肾炎、皮肌炎、多发性硬化症、硬皮病、血管炎、自身免疫性溶血性和血小板减少、肺出血肾炎综合征、动脉粥样硬化、阿狄森氏病、帕金森氏症、阿尔茨海默氏症、糖尿病、感染性休克、***性红斑狼疮、类风湿性关节炎、银屑病关节炎、骨关节炎、慢性特发性血小板减少性紫癜、重症肌无力、桥本甲状腺炎、过敏性皮肤炎、退化性关节疾病、格林-巴利综合征、蕈样真菌病或急性炎症反应等。The medicament prepared by the CBP/EP300 bromodomain receptor inhibitor, and the inflammatory diseases treatable by the pharmaceutical composition include inflammatory pelvic disease, urethritis, sunburn, sinusitis, pneumonia, encephalitis, meningitis, myocarditis, Nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, pancreatitis, psoriasis, allergies, Crohn's disease, intestinal syndrome, ulcerative colitis, tissue transplant rejection, organ transplant rejection, Asthma, allergic rhinitis, chronic obstructive pulmonary disease, autoimmune disease, autoimmune alopecia, anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic And thrombocytopenia, pulmonary hemorrhagic nephritis syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock, systemic lupus erythematosus, rheumatoid arthritis, Psoriatic arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, myasthenia gravis, Hashimoto's thyroiditis, allergic dermatitis, degenerative joint disease Guillain - Barre syndrome, mycosis fungoides or acute inflammatory response.
CBP/EP300溴结构域受体抑制剂制备的药物，以及所述药物组合物可治疗的病毒感染包括人类***瘤病毒、疱疹病毒、巴尔病毒、人类免疫缺陷病毒、乙型肝炎病毒或丙型肝炎病毒感染等。A medicament prepared by a CBP/EP300 bromodomain receptor inhibitor, and a viral infection treatable by the pharmaceutical composition, including human papillomavirus, herpes virus, Barr virus, human immunodeficiency virus, hepatitis B virus or hepatitis C Virus infection, etc.
CBP/EP300溴结构域受体抑制剂制备的药物，以及所述药物组合物可治疗的神经性衰退性疾病包括阿兹海默病、肌肉萎缩性侧索硬化症、共济失调毛细血管扩张症、牛海绵状脑病、克雅二氏病、亨廷顿氏病、小脑萎缩症、多发性硬化症、帕金森氏病、原发性侧索硬化或脊髓性肌萎缩症等。A medicament prepared by a CBP/EP300 bromodomain receptor inhibitor, and a neurodegenerative disease treatable by the pharmaceutical composition, including Alzheimer's disease, amyotrophic lateral sclerosis, ataxia telangiectasia , bovine spongiform encephalopathy, Creutzfeldt-Jakob disease, Huntington's disease, cerebellar atrophy, multiple sclerosis, Parkinson's disease, primary lateral sclerosis or spinal muscular atrophy.
CBP/EP300溴结构域受体抑制剂制备的药物，以及所述药物组合物可适用于各种给药途径，所述给药途径典型但非限制性实例有：口服、颊、吸入、舌下、直肠、***、脑池内的或鞘内、通过腰椎穿刺、经尿道、经皮肤或肠外(包括静脉注射、肌肉注射、皮下、行皮内注射、腹腔内、鞘内、手术植入)等。The medicament prepared by the CBP/EP300 bromodomain receptor inhibitor, and the pharmaceutical composition, can be applied to various administration routes, and typical but non-limiting examples of the administration route are: oral, buccal, inhalation, sublingual , rectal, vaginal, intracranial or intrathecal, through lumbar puncture, transurethral, transcutaneous or extraintestinal (including intravenous, intramuscular, subcutaneous, intradermal, intra-abdominal, intrathecal, surgical implantation, etc.) .
本申请所述的药物组合物可以是液体、半液体或固体形式，按照适合于所用的给药途径的方式配制。本申请所述的组合物可以按照下列给药方式给药：口服、肠胃外、腹膜内、静脉内、透皮、舌下、肌内、直肠、口腔、鼻内、脂质体等方式。The pharmaceutical compositions described herein may be in liquid, semi-liquid or solid form, formulated in a manner suitable for the route of administration employed. The compositions described herein can be administered by oral, parenteral, intraperitoneal, intravenous, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, liposome, and the like.
口服的药物组合物可以是固体、凝胶或液体。固体制剂的实例包括但不限于片剂、胶囊剂、颗粒剂和散装粉剂。这些制剂可以选择地含有粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂和矫味剂等。粘合剂的实例包括但不限于微晶纤维素、葡萄糖溶液、***胶浆、明胶溶液、蔗糖和淀粉糊；润滑剂的实例包括但不限于滑石、淀粉、硬脂酸镁、硬脂酸钙、硬脂酸；稀释剂的实例包括但不限于乳糖、蔗糖、淀粉、甘露糖醇、磷酸二钙；助流剂的实例包括但不限于二氧化硅；崩解剂的实例包括但不限于交联羧甲基纤维素钠、淀粉羟乙酸钠、藻酸、玉米淀粉、马铃薯淀粉、甲基纤维素、琼脂和羧甲基纤维素。The pharmaceutical composition for oral administration can be a solid, a gel or a liquid. Examples of solid preparations include, but are not limited to, tablets, capsules, granules, and bulk powders. These preparations may optionally contain a binder, a diluent, a disintegrant, a lubricant, a glidant, a sweetener, a flavoring agent and the like. Examples of binders include, but are not limited to, microcrystalline cellulose, dextrose solution, gum arabic, gelatin solution, sucrose, and starch paste; examples of lubricants include, but are not limited to, talc, starch, magnesium stearate, calcium stearate And stearic acid; examples of diluents include, but are not limited to, lactose, sucrose, starch, mannitol, dicalcium phosphate; examples of glidants include, but are not limited to, silica; examples of disintegrants include, but are not limited to, Sodium carboxymethylcellulose, sodium starch glycolate, alginic acid, corn starch, potato starch, methyl cellulose, agar and carboxymethyl cellulose.
以肠胃外给予本申请所述药物组合物，一般以注射为主，包括皮下、肌内或静脉内注射。注射剂可以被制成任何常规形式，如液体溶液或悬液、适合于在注射之前溶解或悬浮在液体中的固体形式或者乳剂。可用于本申请注射剂的药学上可接收的载体的实例包括但不限于水性载体、非水性载体、抗微生物剂、等渗剂、缓冲剂、抗氧剂、悬浮与分散剂、乳化剂、螯合剂和其它药学上可接受的物质。水性载体的实例包括氯化钠注射液、林格式注射液、等渗葡萄糖注射液、无菌水注射液、葡萄糖与乳酸化林格氏注射液；非水性载体的实例包括植物来源的固定油、棉籽油、玉米油、芝麻油和花生油；抗微生物剂的实例包括间甲酚、苄醇、氯丁醇、苯扎氯铵等；等渗剂的实例包括氯化钠和葡萄糖；缓冲剂包括磷酸盐和柠檬酸盐。The pharmaceutical compositions described herein are administered parenterally, generally by injection, including subcutaneous, intramuscular or intravenous injection. The injection can be formulated into any conventional form, such as a liquid solution or suspension, a solid form or emulsion suitable for dissolution or suspension in a liquid prior to injection. Examples of pharmaceutically acceptable carriers that can be used in the injectables of the present application include, but are not limited to, aqueous carriers, nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, suspending and dispersing agents, emulsifying agents, chelating agents. And other pharmaceutically acceptable substances. Examples of the aqueous carrier include sodium chloride injection, lin format injection, isotonic glucose injection, sterile water injection, glucose and lactated Ringer's injection; examples of the non-aqueous carrier include fixed oil of plant origin, Cottonseed oil, corn oil, sesame oil and peanut oil; examples of the antimicrobial agent include m-cresol, benzyl alcohol, chlorobutanol, benzalkonium chloride, etc.; examples of isotonic agents include sodium chloride and glucose; buffers include phosphate And citrate.
发明所述药物组合物还可以制备成无菌的冻干粉针剂，将化合物溶于磷酸钠缓冲溶液，其中含有葡萄糖或其他适合的赋形剂，随后在本领域技术人员已知的标准条件下将溶液无菌过滤，继之以冷冻干燥，得到所需的制剂。The pharmaceutical compositions of the invention may also be prepared as sterile lyophilized powders in which the compound is dissolved in a sodium phosphate buffer solution containing glucose or other suitable excipients, followed by standard conditions known to those skilled in the art. The solution is sterile filtered and then lyophilized to give the desired formulation.
本申请所述化合物中，当任何变量(例如R1、R2等)在任何组分中出现超过一次，则其每次出现的定义独立于其它每次出现的定义。同样，允许取代基及变量的组合，只要这种组合使化合物稳定。自取代基划入环***的线表示所指的键可连接到任何能取代的环原子上。如果环***为多环，其意味着这种键仅连接到邻近环的任何适当的碳原子上。要理解本领域普通技术人员可选择本申请化合物的取代基及取代型式而提供化学上稳定的并可通过本领域技术和自可容易获得的原料容易的合成的化合物。如果取代基自身被超过一个基团取代，应理解这些基团可在相同碳原子上或不同碳原子上，只要使结构稳定。短语“任选被一个或多个取代基取代”被认为与短语“任选被至少一个取代基取代”相当且在此情况下优选的实施方案将具有0-3个取代基。In the compounds described herein, when any variable (e.g., R1, R2, etc.) occurs more than once in any of the components, the definition of each occurrence thereof is independent of the definition of each occurrence. Also, combinations of substituents and variables are allowed as long as such combinations stabilize the compound. A line drawn from a substituent into the ring system means that the bond referred to can be attached to any ring atom that can be substituted. If the ring system is polycyclic, it means that such a bond is only attached to any suitable carbon atom of the adjacent ring. It will be appreciated that one of ordinary skill in the art can select substituents and substitution patterns for the compounds of the present application to provide compounds which are chemically stable and which are readily synthesized by the art and from readily available starting materials. If the substituent itself is substituted by more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms as long as the structure is stabilized. The phrase "optionally substituted with one or more substituents" is considered to be equivalent to the phrase "optionally substituted with at least one substituent" and in this case the preferred embodiment will have 0-3 substituents.
本文所用术语“烷基”和“亚烷基”意指包括具有特定碳原子数目的支链的和直链的饱和脂肪烃基。例如，“C1～C4”烷基中“C1～C4”的定义包括以直链或支链排列的具有1、2、3、4、碳原子的基团。例如，“C1～C4”烷基“具体包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基。术语“环烷基”指具有特定碳原子数目的单环饱和脂肪烃基。例如“环烷基”包括环丙基、环丁基、环戊基、环己基、环庚基、苯基、萘基、甲基-环丙基、2，2-二甲基-环丁基、2-乙基-环戊基等。The terms "alkyl" and "alkylene" as used herein are meant to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, the definition of "C1 to C4" in the "C1-C4" alkyl group includes a group having 1, 2, 3, 4, carbon atoms arranged in a straight chain or a branched chain. For example, "C1-C4" alkyl "specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl. The term "cycloalkyl" refers to the number of specific carbon atoms. Monocyclic saturated aliphatic hydrocarbon group. For example, "cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, naphthyl, methyl-cyclopropyl, 2,2- Dimethyl-cyclobutyl, 2-ethyl-cyclopentyl and the like.
除非另有定义，烷基、苯环、萘环、环烷基和杂环基取代基可为未被取代的或取代的。例如，C1～C4烷基可被一个、两个或三个选自卤素、烷氧基、甲基、乙基、丙基、异丙基、叔丁基、三氟甲基、氰基、羧基、硝基、氨基、甲砜基、苯基二氮烯基或杂环基取代，例如吗啉基、哌啶基、喹啉基、呋喃基、四氢呋喃基、吡啶基等取代基取代。Unless otherwise defined, alkyl, benzene, naphthalene, cycloalkyl and heterocyclyl substituents may be unsubstituted or substituted. For example, a C1-C4 alkyl group may be selected from one, two or three selected from the group consisting of halogen, alkoxy, methyl, ethyl, propyl, isopropyl, t-butyl, trifluoromethyl, cyano, carboxy. Substituted with a nitro group, an amino group, a methylsulfonyl group, a phenyldiazenyl group or a heterocyclic group, for example, a morpholinyl group, a piperidinyl group, a quinolyl group, a furyl group, a tetrahydrofuranyl group, a pyridyl group or the like.
本申请包括式I和式II化合物的游离形式，也包括其药学上可接受的盐及立体异构体。本文中一些特定的示例性化合物为胺类化合物的质子化了的盐。术语“游离形式”指以非盐形式的胺类化合物。包括在内的药学上可接受盐不仅包括本文所述特定化合物的示例性盐，也包括所有式I和式II化合物游离形式的典型的药学上可接受的盐。可使用本领域已知技术分离所述化合物特定盐的游离形式。例如，可通过用适当的碱稀水溶液例如NaOH稀水溶液、碳酸钾稀水溶液、稀氨水及碳酸氢钠稀水溶液处理该盐使游离形式再生。游离形式在某些物理性质例如在极性溶剂中溶解度上与其各自盐形式多少有些区别，但是为发明的目的这种酸盐及碱盐在其它药学方面与其各自游离形式相当。The present application includes free forms of the compounds of Formula I and Formula II, as well as pharmaceutically acceptable salts and stereoisomers thereof. Some specific exemplary compounds herein are protonated salts of amine compounds. The term "free form" refers to an amine compound in a non-salt form. Included pharmaceutically acceptable salts include not only the exemplary salts of the particular compounds described herein, but also all of the typical pharmaceutically acceptable salts of the free forms of the compounds of Formula I and Formula II. The free form of the particular salt of the compound can be isolated using techniques known in the art. For example, the free form can be regenerated by treating the salt with a suitable dilute aqueous base such as a dilute aqueous solution of NaOH, a dilute aqueous solution of potassium carbonate, dilute aqueous ammonia, and a dilute aqueous solution of sodium bicarbonate. The free form differs somewhat from its respective salt form in solubility in certain physical properties, such as in polar solvents, but for purposes of the invention such acid and base salts are otherwise pharmaceutically equivalent to their respective free forms.
可通过常规化学方法自含有碱性部分或酸性部分的本申请化合物合成本申请的药学上可接受的盐。通常，通过离子交换色谱或通过游离碱和化学计算量或过量的所需盐形式的无机或有机酸在适当溶剂或多种溶剂的组合中反应制备碱性化合物的盐。类似的，通过和适当的无机或有机碱反应形成酸性化合物的盐。The pharmaceutically acceptable salts of the present application can be synthesized from the compounds of the present application containing a basic moiety or an acidic moiety by conventional chemical methods. Generally, salts of basic compounds are prepared by ion exchange chromatography or by reaction of a free base with a stoichiometric or excess amount of an inorganic or organic acid in the desired salt form in a suitable solvent or combination of solvents. Similarly, a salt of an acidic compound is formed by reaction with a suitable inorganic or organic base.
因此，本申请化合物的药学上可接受的盐包括通过碱性本申请化合物和无机或有机酸反应形成的本申请化合物的常规无毒盐。例如，常规的无毒盐包括得自无机酸例如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等的盐，也包括自有机酸例如乙酸、丙酸、琥珀酸、乙醇 酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、扑酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、2-乙酰氧基-苯甲酸、富马酸、甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟乙基磺酸、三氟乙酸等制备的盐。Thus, pharmaceutically acceptable salts of the compounds of the present application include the conventional non-toxic salts of the compounds of the present invention formed by the reaction of a basic compound of the present application with an inorganic or organic acid. For example, conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, and also include organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, and hard. Fatty acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetyl A salt prepared from oxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid or the like.
如果本申请化合物为酸性的，则适当的“药学上可接受的盐”指通过药学上可接受的无毒碱包括无机碱及有机碱制备的盐.得自无机碱的盐包括铝盐、铵盐、钙盐、铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、亚锰盐、钾盐、钠盐、锌盐等。特别优选铵盐、钙盐、镁盐、钾盐和钠盐。得自药学上可接受的有机无毒碱的盐，所述碱包括伯胺、仲胺和叔胺的盐，取代的胺包括天然存在的取代胺、环状胺及碱性离子交换树脂例如精氨酸、甜菜碱、咖啡因、胆碱、N，N′-二苄基乙二胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡萄糖胺、氨基葡萄糖、组氨酸、羟钴胺、异丙基胺、赖氨酸、甲基葡萄糖胺、吗啉、哌嗪，哌啶、呱咤、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨基丁三醇等。If the compound of the present application is acidic, a suitable "pharmaceutically acceptable salt" refers to a salt prepared by pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum salts, ammonium salts. Salt, calcium salt, copper salt, iron salt, ferrous salt, lithium salt, magnesium salt, manganese salt, manganese salt, potassium salt, sodium salt, zinc salt and the like. Ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts are particularly preferred. A salt derived from a pharmaceutically acceptable organic non-toxic base, the base comprising a salt of a primary, secondary and tertiary amine, the substituted amine comprising a naturally occurring substituted amine, a cyclic amine and a basic ion exchange resin such as a fine Amino acid, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, B Diamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine , piperidine, guanidine, polyamine resin, procaine, guanidine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
由于在生理条件下化合物中脱质子化的酸性部分例如羧基可为阴离子的，而这种带有的电荷然后可被内部带有阳离子的质子化了的或烷基化的碱性部分例如四价氮原子平衡抵消，所以应注意本申请化合物是潜在的内盐或两性离子。Since the acidic moiety, such as a carboxyl group, which is deprotonated in a compound under physiological conditions, can be anionic, such charged charge can then be protonated or alkylated in the interior with a cationic moiety such as tetravalent The balance of nitrogen atoms is counteracted, so it should be noted that the compounds of the present application are potential internal salts or zwitterions.
与相关技术方案相比，本申请至少具有以下有益效果：Compared with the related technical solutions, the present application has at least the following beneficial effects:
本申请提供了一种吲哚类化合物，所述吲哚类化合物可有效抑制CBP/EP300溴结构域受体，可作为治疗癌症、细胞增殖性紊乱、炎症疾病、自身免疫疾病、败血症、病毒感染或神经性衰退性疾病的治疗药物。The present application provides an anthraquinone compound which can effectively inhibit the CBP/EP300 bromodomain receptor and can be used as a therapeutic cancer, a cell proliferative disorder, an inflammatory disease, an autoimmune disease, a sepsis, a viral infection. Or a therapeutic drug for neurodegenerative diseases.
在阅读并理解了详细描述后，可以明白其他方面。After reading and understanding the detailed description, other aspects can be understood.
具体实施方式Detailed ways
下面通过具体实施方式来进一步说明本申请的技术方案。The technical solutions of the present application are further described below by way of specific embodiments.
为更好地说明本申请，便于理解本申请的技术方案，本申请的典型但非限制性的实施例如下：To better illustrate the present application, to facilitate understanding of the technical solutions of the present application, a typical but non-limiting implementation of the present application is as follows:
实施例1Example 1
1-(2-(3-乙酰基-1H-吲哚-1-基)乙酰基)哌啶-4-羧酸甲酯的合成：Synthesis of methyl 1-(2-(3-acetyl-1H-indol-1-yl)acetyl)piperidine-4-carboxylate:
(1)1-(2-氯乙酰基)哌啶-4-甲酸甲酯的合成Synthesis of (1) Methyl 1-(2-chloroacetyl)piperidine-4-carboxylate
将甲基哌啶-4-羧酸乙酯(2g，14mmol)溶于20mL DCM溶液中，然后加入2-氯乙酰氯(1.16mL，15.4mmol)和K2CO3(5.8g，42mmol)。反应体系在室温下搅拌5h。TLC监测，反应结束后加入30mL水，用DCM萃取(3×20mL)，有机相用饱和食盐水洗涤一次，无水硫酸钠干燥。真空旋干有机相，得到黄色油状物2.072g(产率67.4％)。1H NMR(400MHz，CDCl3)δ4.32(m，1H)，4.10(m，1H)，4.02-3.76(s，3H)，3.70(s，2H)，3.30-3.14(m，1H)，2.94(td，J＝13.4，2.9Hz，1H)，2.70-2.50(m，1H)，2.08-1.90(m，2H)，1.90-1.61(m，2H).Ethyl methylpiperidine-4-carboxylate (2 g, 14 mmol) was dissolved in 20 mL DCM solution then 2-chloroacetyl chloride (1.16mL, 15.4mmol) and K2CO3 (5.8g, 42mmol). The reaction system was stirred at room temperature for 5 h. After the reaction was completed, 30 mL of water was added, and the mixture was extracted with DCM (3×20 mL). The organic phase was dried <RTI ID=0.0> 1H NMR (400MHz, CDCl3) δ 4.32 (m, 1H), 4.10 (m, 1H), 4.02-3.76 (s, 3H), 3.70 (s, 2H), 3.30-3.14 (m, 1H), 2.94 ( Td, J = 13.4, 2.9 Hz, 1H), 2.70-2.50 (m, 1H), 2.08-1.90 (m, 2H), 1.90 - 1.61 (m, 2H).
(2)QP19 1-(2-(3-乙酰基-1H-吲哚-1-基)乙酰基)哌啶-4-羧酸甲酯的合成(2) Synthesis of QP19 methyl 1-(2-(3-acetyl-1H-indol-1-yl)acetyl)piperidine-4-carboxylate
将中间体1-(2-氯乙酰基)哌啶-4-甲酸甲酯(437.48mg，2mmol)溶于50mL丙酮中，再加入1-乙酰基吲哚(264mg，1.66mmol)，K2CO3(688mg，4.98mmol，KI(42mg，0.252mmol)。反应体系在56℃搅拌5h。反应结束后，冷却至室温，加入20mL水，用EA萃取(3×30mL)，有机相用饱和食盐水洗涤一次，无水硫酸钠干燥。真空旋干有机相，粗产物经硅胶柱分离(MeOH∶DCM＝1∶10)，白色固体397mg(产率70％)。1H NMR(400MHz，DMSO-d6)δ8.24(s，1H)，8.18(d，J＝6.9Hz，1H)，7.44(d，J＝7.2Hz，1H)，7.20(s，2H)，5.29(m，2H)，4.17(d，J＝12.5Hz，1H)，3.94(d，J＝12.9Hz，1H)，3.64(s，3H)，3.24(t，J＝12.1Hz，1H)，2.80(t，J＝11.7Hz，1H)，2.69(t，J＝10.7Hz，1H)，2.42(s，3H)，1.94(d，J＝11.6Hz，1H)，1.86(d，J＝12.6Hz，1H)，1.71(d，J＝10.5Hz，1H)，1.44(d，J＝9.9Hz，1H).The intermediate 1-(2-chloroacetyl)piperidine-4-carboxylic acid methyl ester (437.48 mg, 2 mmol) was dissolved in 50 mL of acetone, followed by 1-acetyl hydrazine (264 mg, 1.66 mmol), K2CO3 (688 mg) 4.98 mmol, KI (42 mg, 0.252 mmol). The reaction system was stirred at 56 ° C for 5 h. After the reaction was completed, it was cooled to room temperature, 20 mL of water was added, extracted with EA (3×30 mL), and the organic phase was washed once with saturated brine. Drying over anhydrous sodium sulfate. The organic phase was evaporated to drynessjjjjjjjjjjjjjjjjjjjjjjjjjjj (s, 1H), 8.18 (d, J = 6.9 Hz, 1H), 7.44 (d, J = 7.2 Hz, 1H), 7.20 (s, 2H), 5.29 (m, 2H), 4.17 (d, J = 12.5 Hz, 1H), 3.94 (d, J = 12.9 Hz, 1H), 3.64 (s, 3H), 3.24 (t, J = 12.1 Hz, 1H), 2.80 (t, J = 11.7 Hz, 1H), 2.69 (t, J = 10.7 Hz, 1H), 2.42 (s, 3H), 1.94 (d, J = 11.6 Hz, 1H), 1.86 (d, J = 12.6 Hz, 1H), 1.71 (d, J = 10.5 Hz) , 1H), 1.44 (d, J = 9.9 Hz, 1H).
实施例2Example 2
乙基2-(3-乙酰基-1H-吲哚-1-基)乙酸酯的合成，合成方法如实施例1。1H NMR(400MHz， CDCl3)δ8.39(dd，J＝6.4，2.6Hz，1H)，7.76(s，1H)，7.31(dt，J＝6.9，3.5Hz，2H)，7.26(s，1H)，4.88(s，2H)，4.25(q，J＝7.1Hz，2H)，1.60(s，3H)，1.28(d，J＝7.1Hz，3H).Synthesis of ethyl 2-(3-acetyl-1H-indol-1-yl)acetate, as described in Example 1. 1H NMR (400MHz, CDCl3) δ 8.39 (dd, J = 6.4, 2.6 Hz, 1H), 7.76 (s, 1H), 7.31 (dt, J = 6.9, 3.5 Hz, 2H), 7.26 (s, 1H), 4.88 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H) ), 1.60 (s, 3H), 1.28 (d, J = 7.1 Hz, 3H).
实施例3Example 3
2-(3-乙酰基-1H-吲哚-1-基)乙酸的合成，合成方法如实施例8。1H NMR(400MHz，DMSO)δ8.32(s，1H)，8.22-8.16(m，1H)，7.49(d，J＝7.4Hz，1H)，7.28-7.18(m，2H)，5.12(s，2H)，2.44(s，3H).Synthesis of 2-(3-acetyl-1H-indol-1-yl)acetic acid, as described in Example 8. 1H NMR (400 MHz, DMSO) δ 8.32 (s, 1H), 8.22-8.16 (m, 1H), 7.49 (d, J = 7.4 Hz, 1H), 7.28-7.18 (m, 2H), 5.12 (s, 2H), 2.44 (s, 3H).
实施例4Example 4
(3-乙酰基-1H-吲哚-1-基)-N-异丁基乙酰胺的合成，合成方法如实施例1。1H NMR(400MHz，CDCl3)δ8.47-8.34(m，1H)，7.74(s，1H)，7.42-7.29(m，3H)，5.46(s，1H)，4.85(s，2H)，3.03(t，J＝6.5Hz，2H)，2.51(s，3H)，0.74(d，J＝6.7Hz，6H).Synthesis of (3-acetyl-1H-indol-1-yl)-N-isobutylacetamide, the synthesis method is as in Example 1. 1H NMR (400MHz, CDCl3) δ 8.47-8.34 (m, 1H) , 7.74 (s, 1H), 7.42 - 7.29 (m, 3H), 5.46 (s, 1H), 4.85 (s, 2H), 3.03 (t, J = 6.5 Hz, 2H), 2.51 (s, 3H), 0.74 (d, J = 6.7 Hz, 6H).
实施例5Example 5
(3-乙酰基-1H-吲哚-1-基)乙酰胺的合成，合成方法如实施例1。1H NMR(400MHz，CDCl3)δ8.29(s，1H)，8.18(d，J＝7.9Hz，1H)，7.71(s，1H)，7.41(d，J＝7.6Hz，1H)，7.34(s，1H)，7.31-7.15(m，2H)，4.89(s，2H)，2.44(s，3H).Synthesis of (3-acetyl-1H-indol-1-yl)acetamide as described in Example 1. 1H NMR (400MHz, CDCl3) δ 8.29 (s, 1H), 8.18 (d, J = 7.9 Hz, 1H), 7.71 (s, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.34 (s, 1H), 7.31-7.15 (m, 2H), 4.89 (s, 2H), 2.44 (s) , 3H).
实施例6Example 6
乙基3-(3-乙酰基-1H-吲哚-1-基)丙酸酯的合成，合成方法如实施例1。1H NMR(400MHz，CDCl3)δ8.46-8.32(m，1H)，7.83(s，1H)，7.35(dd，J＝10.0，5.2Hz，1H)，7.33-7.27(m，2H)，4.50(t，J＝6.5Hz，2H)，4.13(q，J＝7.1Hz，2H)，2.87(t，J＝6.5Hz，2H)，2.52(s，3H)，1.21(t，J＝7.1Hz，3H).Synthesis of ethyl 3-(3-acetyl-1H-indol-1-yl)propionate as described in Example 1. 1H NMR (400MHz, CDCl3) δ 8.46-8.32 (m, 1H), 7.83 (s, 1H), 7.35 (dd, J = 10.0, 5.2 Hz, 1H), 7.33 - 7.27 (m, 2H), 4.50 (t, J = 6.5 Hz, 2H), 4.13 (q, J = 7.1 Hz) , 2H), 2.87 (t, J = 6.5 Hz, 2H), 2.52 (s, 3H), 1.21 (t, J = 7.1 Hz, 3H).
实施例7Example 7
(3-乙酰基-1H-吲哚-1-基)-1-(哌啶-1-基)乙酮的合成，合成方法如实施例1。1H NMR(400MHz，DMSO)δ8.24(s，1H)，8.19-8.15(m，1H)，7.42(dd，J＝6.7，1.7Hz，1H)，7.25-7.16(m，2H)，5.26(s，2H)，3.53(s，2H)，3.48-3.39(m，2H)，2.43(s，3H)，1.63(s，4H)，1.47(s，2H).Synthesis of (3-acetyl-1H-indol-1-yl)-1-(piperidin-1-yl)ethanone, as described in Example 1. 1H NMR (400 MHz, DMSO) δ 8.24 (s) , 1H), 8.19-8.15 (m, 1H), 7.42 (dd, J = 6.7, 1.7 Hz, 1H), 7.25-7.16 (m, 2H), 5.26 (s, 2H), 3.53 (s, 2H), 3.48-3.39 (m, 2H), 2.43 (s, 3H), 1.63 (s, 4H), 1.47 (s, 2H).
实施例8Example 8
1-(2-(3-乙酰基-1H-吲哚-1-基)乙酰基)哌啶-4-羧酸合成，1-(2-(3-乙酰基-1H-吲哚-1-基)乙酰基)哌啶-4-羧酸甲酯合成如实施例1。Synthesis of 1-(2-(3-acetyl-1H-indol-1-yl)acetyl)piperidine-4-carboxylic acid, 1-(2-(3-acetyl-1H-indole-1- Methyl)acetyl)piperidine-4-carboxylic acid methyl ester was synthesized as in Example 1.
将化合物1-(2-(3-乙酰基-1H-吲哚-1-基)乙酰基)哌啶-4-羧酸甲酯(284mg，0.83mmol)溶于8mL MeOH中，向反应体系中加入1M NaOH(4mL，4.15mmol)。反应体系在室温下搅拌2h，TLC跟踪监测。反应结束后，真空旋去大部分溶剂，剩余溶液用1M盐酸溶液调节pH至弱酸性，有大量白色固体析出，减压抽滤，用20mL水洗涤滤饼，真空干燥得白色固体156mg(产率57.2％)。合成方法如实施例1。1H NMR(400MHz，DMSO)δ12.32(s，1H)，8.23(s，1H)，8.20-8.09(m，1H)，7.44(d，J＝7.2Hz，1H)，7.27-7.14(m，2H)，5.28(d，J＝3.9Hz，2H)，4.16(d，J＝13.0Hz，1H)，3.94(d，J＝13.4Hz，1H)，3.27-3.19(m，1H)，2.81(t，J＝11.1Hz，1H)，2.61-2.55(m，1H)，2.43(s，3H)，1.98-1.89(m，1H)，1.85(d，J＝11.2Hz，1H)，1.69(d，J＝10.6Hz，1H)，1.43(d，J＝9.9Hz，1H)，1.24(s，1H).The compound 1-(2-(3-acetyl-1H-indol-1-yl)acetyl)piperidine-4-carboxylic acid methyl ester (284 mg, 0.83 mmol) was dissolved in 8 mL of MeOH. 1 M NaOH (4 mL, 4.15 mmol) was added. The reaction system was stirred at room temperature for 2 h and monitored by TLC. After the reaction was completed, most of the solvent was evaporated in vacuo, and the remaining solution was adjusted to a weak acidity with a 1M hydrochloric acid solution, and a large amount of a white solid was precipitated, and filtered under reduced pressure. The filter cake was washed with 20 mL of water and dried in vacuo to give a white solid 156 mg. 57.2%). The synthesis method is as in Example 1. 1H NMR (400MHz, DMSO) δ 12.32 (s, 1H), 8.23 (s, 1H), 8.20-8.09 (m, 1H), 7.44 (d, J = 7.2 Hz, 1H) , 7.27-7.14 (m, 2H), 5.28 (d, J = 3.9 Hz, 2H), 4.16 (d, J = 13.0 Hz, 1H), 3.94 (d, J = 13.4 Hz, 1H), 3.27-3.19 ( m,1H), 2.81 (t, J = 11.1 Hz, 1H), 2.61-2.55 (m, 1H), 2.43 (s, 3H), 1.98-1.89 (m, 1H), 1.85 (d, J = 11.2 Hz) , 1H), 1.69 (d, J = 10.6 Hz, 1H), 1.43 (d, J = 9.9 Hz, 1H), 1.24 (s, 1H).
实施例9Example 9
1-(2-(3-乙酰基-1H-吲哚-1-基)乙酰基)哌啶-3-羧酸甲酯的合成，合成方法如实施例1。1H NMR(400MHz，DMSO)δ8.21(d，J＝6.4Hz，1H)，8.18(d，J＝6.8Hz，1H)，7.42(t，J＝7.6Hz，1H)，7.21(m，2H)，5.33(d，J＝7.8Hz，1H)，5.27(s，1H)，3.86(t，J＝11.7Hz，1H)，3.76(s，1H)，3.64(s，3H)，3.57-3.48(m，1H)，3.16(dt，J＝19.7，10.4Hz，1H)，2.77(s，1H)，2.43(s，3H)，1.99(s，1H)，1.79(d，J＝9.9Hz，1H)，1.72-1.52(m，1H)，1.43(d，J＝9.2Hz，1H).Synthesis of methyl 1-(2-(3-acetyl-1H-indol-1-yl)acetyl)piperidine-3-carboxylate, as described in Example 1. 1H NMR (400 MHz, DMSO) δ 8 .21 (d, J = 6.4 Hz, 1H), 8.18 (d, J = 6.8 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.21 (m, 2H), 5.33 (d, J = 7.8 Hz, 1H), 5.27 (s, 1H), 3.86 (t, J = 11.7 Hz, 1H), 3.76 (s, 1H), 3.64 (s, 3H), 3.57-3.48 (m, 1H), 3.16 ( Dt, J = 19.7, 10.4 Hz, 1H), 2.77 (s, 1H), 2.43 (s, 3H), 1.99 (s, 1H), 1.79 (d, J = 9.9 Hz, 1H), 1.72-1.52 (m) , 1H), 1.43 (d, J = 9.2 Hz, 1H).
实施例10Example 10
1-(2-(3-乙酰基-1H-吲哚-1-基)乙酰基)哌啶-3-羧酸的合成，合成方法如实施例8。1H NMR(400MHz，DMSO)δ8.21(d，J＝12.3Hz，1H)，8.17(d，J＝8.4Hz，1H)，7.44(d，J＝5.7Hz，1H)，7.25-7.16(m，2H)，5.44-5.24(m，2H)，3.83(dd，J＝12，11.9Hz，1H)，3.66-3.55(m，1H)， 2.89-2.78(m，1H)，2.66(s，1H)，2.43(s，3H)，2.34(s，1H)，2.00(d，J＝8.3Hz，1H)，1.78(s，1H)，1.69-1.49(m，1H)，1.44(s，1H).Synthesis of 1-(2-(3-acetyl-1H-indol-1-yl)acetyl)piperidine-3-carboxylic acid, as described in Example 8. 1H NMR (400 MHz, DMSO) δ 8.21. (d, J = 12.3 Hz, 1H), 8.17 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 5.7 Hz, 1H), 7.25-7.16 (m, 2H), 5.44 - 5.24 (m, 2H), 3.83 (dd, J=12, 11.9 Hz, 1H), 3.66-3.55 (m, 1H), 2.89-2.78 (m, 1H), 2.66 (s, 1H), 2.43 (s, 3H), 2.34 (s, 1H), 2.00 (d, J = 8.3 Hz, 1H), 1.78 (s, 1H), 1.69-1.49 (m, 1H), 1.44 (s, 1H).
实施例11Example 11
1-(1-(噻吩-2-羰基)-1H-吲哚-3-基)乙酮的合成，将1-(1H-吲哚-3-基)乙-1-酮(100mg，0.628mmol)溶于30mL四氢呋喃中，再加入叔丁醇甲(281.87mg，2.512mmol)，在常温下搅拌15min，向反应体系中加入噻吩-2-羰基氯(184.1mg，1.256mmol)，常温搅拌。TLC监测，反应结束后加入水，用DCM萃取(3×20mL)，有机相用饱和食盐水洗涤一次，无水硫酸钠干燥。真空旋干有机相，粗产物用硅胶柱分离(PE∶EA＝10∶1，4∶1)得到产物152mg(产率90％)。1H NMR(400MHz，DMSO)δ8.71(s，1H)，8.28(dd，J＝6.3，2.4Hz，1H)，8.23(dd，J＝5.0，1.0Hz，1H)，8.19(dd，J＝6.7，2.1Hz，1H)，8.03(dd，J＝3.8，1.0Hz，1H)，7.45-7.41(m，2H)，7.39(dd，J＝4.9，3.9Hz，1H)，2.57(s，3H).Synthesis of 1-(1-(thiophene-2-carbonyl)-1H-indol-3-yl)ethanone, 1-(1H-indol-3-yl)ethan-1-one (100 mg, 0.628 mmol) It was dissolved in 30 mL of tetrahydrofuran, and then tert-butanol A (281.87 mg, 2.512 mmol) was added thereto, and stirred at normal temperature for 15 min, and thiophene-2-carbonyl chloride (184.1 mg, 1.256 mmol) was added to the reaction mixture, and stirred at room temperature. After the reaction was completed, water was added, and the mixture was evaporated to dryness (3×20 mL). The organic phase was dried <RTI ID=0.0></RTI> to <RTI ID=0.0> 1H NMR (400MHz, DMSO) δ 8.71 (s, 1H), 8.28 (dd, J = 6.3, 2.4 Hz, 1H), 8.23 (dd, J = 5.0, 1.0 Hz, 1H), 8.19 (dd, J = 6.7, 2.1 Hz, 1H), 8.03 (dd, J = 3.8, 1.0 Hz, 1H), 7.45-7.41 (m, 2H), 7.39 (dd, J = 4.9, 3.9 Hz, 1H), 2.57 (s, 3H) ).
实施例12Example 12
1-(1-(丙基磺酰基)-1H-吲哚-3-基)乙酮的合成，将1-(1H-吲哚-3-基)乙-1-酮(100mg，0.628mmol)溶于30mL四氢呋喃中，把反应体系置于0℃，向其中加入NaH(75.2mg，1.88mmol)，在常温下搅拌1h，向体系中加入丙烷-1-磺酰氯(98.325mg，0.7mmol)。TLC监测，反应结束后加入水，用EA萃取(3×20mL)，有机相用饱和食盐水洗涤一次，无水硫酸钠干燥。真空旋干有机相，粗产物用硅胶柱分离(PE∶EA＝4∶1)得到产物117mg(产率70.27％)。1H NMR(400MHz，CDCl3)δ8.46-8.34(m，1H)，8.06(s，1H)，7.87(dt，J＝4.8，3.0Hz，1H)，7.48-7.36(m，2H)，3.42-3.26(m，2H)，2.57(s，3H)，1.83-1.68(m，2H)，0.99(t，J＝7.4Hz，3H).Synthesis of 1-(1-(propylsulfonyl)-1H-indol-3-yl)ethanone, 1-(1H-indol-3-yl)ethan-1-one (100 mg, 0.628 mmol) The mixture was dissolved in 30 mL of THF. The reaction mixture was placed at 0 ° C. NaH (75.2 mg, 1.88 mmol) was added and stirred at room temperature for 1 hour, and propane-1-sulfonyl chloride (98.325 mg, 0.7 mmol) was added to the system. After the reaction was completed, water was added, and the mixture was extracted with EA (3×20 mL). The organic phase was dried in vacuo, and the crude product was purified eluting with silica gel column (PE: EA = 4:1) to afford product 117 mg (yield 70.27%). 1H NMR (400MHz, CDCl3) δ 8.46-8.34 (m, 1H), 8.06 (s, 1H), 7.87 (dt, J = 4.8, 3.0 Hz, 1H), 7.48-7.36 (m, 2H), 3.42 3.26 (m, 2H), 2.57 (s, 3H), 1.83-1.68 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H).
实施例13Example 13
1-(1-(苯基磺酰基)-1H-吲哚-3-基)乙酮的合成，合成方法如实施例12。1H NMR(400MHz，CDCl3)δ8.38-8.29(m，1H)，8.21(s，1H)，7.95(t，J＝7.8Hz，3H)，7.60(t，J＝7.5Hz，1H)，7.50(t，J＝7.8Hz，2H)，7.44-7.30(m，2H)，2.58(s，3H).Synthesis of 1-(1-(phenylsulfonyl)-1H-indol-3-yl)ethanone, as described in Example 12. 1H NMR (400MHz, CDCl3) δ 8.38-8.29 (m, 1H) , 8.21 (s, 1H), 7.95 (t, J = 7.8 Hz, 3H), 7.60 (t, J = 7.5 Hz, 1H), 7.50 (t, J = 7.8 Hz, 2H), 7.44-7.30 (m, 2H), 2.58 (s, 3H).
实施例14Example 14
1-(1-(噻吩-2-基磺酰基)-1H-吲哚-3-基)乙酮的合成，合成方法如实施例12。1H NMR(400MHz，DMSO)δ8.75(s，1H)，8.21(d，J＝7.7Hz，1H)，8.14(s，1H)，8.13(q，J＝1.4Hz，1H)，7.97(d，J＝8.3Hz，1H)，7.50-7.43(m，1H)，7.43-7.36(m，1H)，7.24(dd，J＝4.7，4.2Hz，1H)，2.59(s，3H).Synthesis of 1-(1-(thiophen-2-ylsulfonyl)-1H-indol-3-yl)ethanone, as described in Example 12. 1H NMR (400 MHz, DMSO) δ 8.75 (s, 1H) ), 8.21 (d, J = 7.7 Hz, 1H), 8.14 (s, 1H), 8.13 (q, J = 1.4 Hz, 1H), 7.97 (d, J = 8.3 Hz, 1H), 7.50 - 7.43 (m) , 1H), 7.43 - 7.36 (m, 1H), 7.24 (dd, J = 4.7, 4.2 Hz, 1H), 2.59 (s, 3H).
实施例15Example 15
1-(2-(3-乙酰基-6-甲氧基-1H-吲哚-1-基)乙酰基)哌啶-4-羧酸甲酯的合成，合成方法如实施例1。1H NMR(400MHz，DMSO)δ8.10(s，1H)，8.02(d，J＝8.7Hz，1H)，6.99(d，J＝2.0Hz，1H)，6.83(dd，J＝8.7，2.2Hz，1H)，5.23(d，J＝3.0Hz，2H)，4.18(d，J＝13.4Hz，1H)，3.94(d，J＝13.6Hz，1H)，3.78(s，3H)，3.64(s，3H)，2.81(t，J＝11.5Hz，1H)，2.69(dd，J＝12.9，9.1Hz，1H)，2.39(s，3H)，2.03-1.82(m，2H)，1.71(d，J＝9.4Hz，1H)，1.52-1.37(m，1H)，1.20(d，J＝23.7Hz，1H).Synthesis of methyl 1-(2-(3-acetyl-6-methoxy-1H-indol-1-yl)acetyl)piperidine-4-carboxylate, as described in Example 1. 1H NMR (400MHz, DMSO) δ 8.10 (s, 1H), 8.02 (d, J = 8.7 Hz, 1H), 6.99 (d, J = 2.0 Hz, 1H), 6.83 (dd, J = 8.7, 2.2 Hz, 1H) ), 5.23 (d, J = 3.0 Hz, 2H), 4.18 (d, J = 13.4 Hz, 1H), 3.94 (d, J = 13.6 Hz, 1H), 3.78 (s, 3H), 3.64 (s, 3H) ), 2.81 (t, J = 11.5 Hz, 1H), 2.69 (dd, J = 12.9, 9.1 Hz, 1H), 2.39 (s, 3H), 2.03-1.82 (m, 2H), 1.71 (d, J = 9.4 Hz, 1H), 1.52-1.37 (m, 1H), 1.20 (d, J = 23.7 Hz, 1H).
实施例16Example 16
1-(2-(3-乙酰基-6-甲氧基-1H-吲哚-1-基)乙酰基)哌啶-4-羧酸的合成，合成方法如实施例8。1H NMR(400MHz，DMSO)δ8.10(s，1H)，8.02(d，J＝8.7Hz，1H)，6.99(d，J＝1.9Hz，1H)，6.83(dd，J＝8.7，2.1Hz，1H)，5.29-5.14(m，2H)，4.17(d，J＝13.1Hz，1H)，3.93(d，J＝13.6Hz，1H)，3.78(s，3H)，2.81(t，J＝11.2Hz，1H)，2.56(m，1H)，2.39(s，3H)，1.89(m，2H)，1.69(m，1H)，1.50-1.34(m，1H).Synthesis of 1-(2-(3-acetyl-6-methoxy-1H-indol-1-yl)acetyl)piperidine-4-carboxylic acid, as described in Example 8. 1H NMR (400 MHz , DMSO) δ 8.10 (s, 1H), 8.02 (d, J = 8.7 Hz, 1H), 6.99 (d, J = 1.9 Hz, 1H), 6.83 (dd, J = 8.7, 2.1 Hz, 1H), 5.29-5.14(m,2H), 4.17(d,J=13.1Hz,1H),3.93(d,J=13.6Hz,1H),3.78(s,3H),2.81(t,J=11.2Hz,1H ), 2.56 (m, 1H), 2.39 (s, 3H), 1.89 (m, 2H), 1.69 (m, 1H), 1.50-1.34 (m, 1H).
实施例17Example 17
1-(2-(3-乙酰基-6-羟基-1H-吲哚-1-基)乙酰基)哌啶-4-羧酸甲酯的合成：Synthesis of methyl 1-(2-(3-acetyl-6-hydroxy-1H-indol-1-yl)acetyl)piperidine-4-carboxylate:
1-(2-(3-乙酰基-6-甲氧基-1H-吲哚-1-基)乙酰基)哌啶-4-羧酸甲酯合成方法如实施例1。A method for synthesizing methyl 1-(2-(3-acetyl-6-methoxy-1H-indol-1-yl)acetyl)piperidine-4-carboxylate is as in Example 1.
将1-(2-(3-乙酰基-6-甲氧基-1H-吲哚-1-基)乙酰基)哌啶-4-羧酸甲酯(100mg，0.27mmol)溶于15mL二氯甲烷，取BBr3(167mg，0.68mmol)溶于10mL DCM，冰浴条件下滴入到反应体系，后转至室温反应，TLC监测。反应结束，缓慢滴加甲醇和NH4Cl水溶液淬灭，加水，EA萃取(3×30mL)，饱和食盐水洗涤，无水硫酸钠干燥，旋干，重结晶，得白色固体76.86mg(产率57.2％)。1H NMR(400MHz，DMSO)δ9.34(s，1H)，8.04(s，1H)，7.90(d，J＝8.7Hz，1H)，6.72(d，J＝8.1Hz，2H)，5.23-5.06(m，2H)，4.15(d，J＝13.4Hz，1H)，3.93(d，J＝12.7Hz，1H)，3.63(s，1H)，3.21(s，2H)，2.80(t，J＝11.9Hz，1H)，2.36(s，3H)，2.02-1.76(m，2H)，1.64(d，J＝9.9Hz，1H)，1.42(s，1H)，1.22(s，2H).Methyl 1-(2-(3-acetyl-6-methoxy-1H-indol-1-yl)acetyl)piperidine-4-carboxylate (100 mg, 0.27 mmol) was dissolved in 15 mL of dichloro Methane, BBr3 (167 mg, 0.68 mmol) was dissolved in 10 mL of DCM, and dropped into the reaction system under ice bath, then transferred to room temperature for reaction and monitored by TLC. The reaction was completed, and the mixture was stirred with EtOAc EtOAc EtOAc EtOAc (EtOAc) ). 1H NMR (400MHz, DMSO) δ 9.34 (s, 1H), 8.04 (s, 1H), 7.90 (d, J = 8.7 Hz, 1H), 6.72 (d, J = 8.1 Hz, 2H), 5.23-5.06 (m, 2H), 4.15 (d, J = 13.4 Hz, 1H), 3.93 (d, J = 12.7 Hz, 1H), 3.63 (s, 1H), 3.21 (s, 2H), 2.80 (t, J = 11.9 Hz, 1H), 2.36 (s, 3H), 2.02-1.76 (m, 2H), 1.64 (d, J = 9.9 Hz, 1H), 1.42 (s, 1H), 1.22 (s, 2H).
实施例18Example 18
1-(2-(3-乙酰基-6-羟基-1H-吲哚-1-基)乙酰基)哌啶-4-羧酸的合成，合成方法如实施例8。1H NMR(400MHz，DMSO)δ9.22(s，1H)，8.02(s，1H)，7.98-7.85(m，1H)，6.70(s，2H)，5.25-5.04(m，2H)，4.16(d，J＝12.9Hz，1H)，3.93(d，J＝12.9Hz，1H)，2.80(t，J＝11.8Hz，1H)，2.37(s，3H)，1.89(dd，J＝29.8，11.7Hz，2H)，1.65(d，J＝10.9Hz，1H)，1.41(d，J＝10.8Hz，1H)，1.23(s，1H).Synthesis of 1-(2-(3-acetyl-6-hydroxy-1H-indol-1-yl)acetyl)piperidine-4-carboxylic acid, as described in Example 8. 1H NMR (400 MHz, DMSO ) δ 9.22 (s, 1H), 8.02 (s, 1H), 7.98-7.85 (m, 1H), 6.70 (s, 2H), 5.25-5.04 (m, 2H), 4.16 (d, J = 12.9 Hz) , 1H), 3.93 (d, J = 12.9 Hz, 1H), 2.80 (t, J = 11.8 Hz, 1H), 2.37 (s, 3H), 1.89 (dd, J = 29.8, 11.7 Hz, 2H), 1.65 (d, J = 10.9 Hz, 1H), 1.41 (d, J = 10.8 Hz, 1H), 1.23 (s, 1H).
实施例19Example 19
1-(6-甲氧基-1-(苯基磺酰基)-1H-吲哚-3-基)乙酮的合成，合成方法如实施例12。1H NMR(400MHz，CDCl3)δ8.19(d，J＝8.8Hz，1H)，8.09(s，1H)，7.98-7.85(m，2H)，7.62(t，J＝7.5Hz，1H)，7.51(t，J＝7.8Hz，2H)，7.44(d，J＝2.2Hz，1H)，6.96(dd，J＝8.8，2.3Hz，1H)，3.87(s，3H)，2.55(s，3H).Synthesis of 1-(6-methoxy-1-(phenylsulfonyl)-1H-indol-3-yl)ethanone, as described in Example 12. 1H NMR (400 MHz, CDCl3) δ 8.19 ( d, J = 8.8 Hz, 1H), 8.09 (s, 1H), 7.98-7.85 (m, 2H), 7.62 (t, J = 7.5 Hz, 1H), 7.51 (t, J = 7.8 Hz, 2H), 7.44 (d, J = 2.2 Hz, 1H), 6.96 (dd, J = 8.8, 2.3 Hz, 1H), 3.87 (s, 3H), 2.55 (s, 3H).
结构类型为II时：When the structure type is II:
实施例20Example 20
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)吡咯烷-1-羧酸叔丁酯的合成：Synthesis of 3-(1-acetyl-1H-indole-3-carboxamido)pyrrolidine-1-carboxylic acid tert-butyl ester:
(1)1-乙酰基-1H-吲哚-3-羧酸的合成(1) Synthesis of 1-acetyl-1H-indole-3-carboxylic acid
将3-吲哚甲酸(1.5g，9.3mmol)加入12mL DCE中，再加入Et3N(4mL，27.9mmol)，DMAP(0.114g，0.93mmol)，乙酸酐(2.8mL，27.9mmol)。反应体系在60℃下反应3h，TLC跟踪监测反应。反应结束，真空旋去大部分溶剂，用EA重新溶解，用饱和的NaHCO3洗，弃除有机相，水层用1M HCl溶液酸化，产生大量白色沉淀，真空抽滤，滤饼用水洗三遍，真空干燥得白色固体1.20g(产率63％)。1H NMR(400MHz，DMSO)δ8.42(s，1H)，8.35(dd，J＝6.9，1.8Hz，1H)，8.08(dd，J＝6.5，2.1Hz，1H)，7.44-7.28(m，2H)，2.73(s，3H).3-indolecarboxylic acid (1.5 g, 9.3 mmol) was added to 12 mL DCE, then Et3N (4 mL, 27.9 mmol), DMAP (0.114 g, 0.93 The reaction system was reacted at 60 ° C for 3 h, and the reaction was monitored by TLC. At the end of the reaction, most of the solvent was removed by vacuum, re-dissolved with EA, washed with saturated NaHCO3, and the organic phase was discarded. The aqueous layer was acidified with 1M HCl solution to yield a large white precipitate, which was vacuum filtered and washed three times with water. Drying in vacuo gave 1.20 g (yield: 63%) as a white solid. 1H NMR (400MHz, DMSO) δ 8.42 (s, 1H), 8.35 (dd, J = 6.9, 1.8 Hz, 1H), 8.08 (dd, J = 6.5, 2.1 Hz, 1H), 7.44 - 7.28 (m, 2H), 2.73 (s, 3H).
(2)3-(1-乙酰基-1H-吲哚-3-甲酰氨基)吡咯烷-1-羧酸叔丁酯的合成(2) Synthesis of 3-(1-acetyl-1H-indole-3-carboxamido)pyrrolidine-1-carboxylic acid tert-butyl ester
将30mL DCM加入到中间体1-乙酰基-1H-吲哚-3-羧酸中(100mg，0.49mmol)中，再加入HATU(218mg，0.74mmol)，DIPEA(191mg，1.48mmol)。室温搅拌30min以后，加入3-氨基吡咯烷-1-羧酸叔丁酯(111.9mg，0.74mmol)。反应体系在室温下搅拌过夜。反应结束后加入20mL水，用EA萃取(3×30mL)，再用饱和食盐水洗涤一遍，最后用无水硫酸钠干燥。真空旋干有机相，粗产物用硅胶柱分离(PE∶EA＝2∶1)。得到白色固体130mg(产率71.5％)。1H NMR(400MHz，DMSO)δ8.56(s，1H)，8.32(d，J＝7.4Hz，2H)，8.23-8.15(m，1H)，7.35(tt，J＝7.3，6.0Hz，2H)，4.46(s，1H)，3.60(s，1H)，3.44(dt，J＝14.1，5.8Hz，2H)，3.21(d，J＝7.8Hz，1H)，2.70(s，3H)，2.14(dt，J＝13.4，6.6Hz，1H)，1.91(s，1H)，1.41(s，9H).30 mL of DCM was added to the intermediate 1-acetyl-1H-indole-3-carboxylic acid (100 mg, 0.49 mmol), then HATU (218 mg, 0.74 mmol), DIPEA (191 mg, 1.48 mmol). After stirring at room temperature for 30 min, tert-butyl 3-aminopyrrolidin-1-carboxylate (111.9 mg, 0.74 mmol) was added. The reaction system was stirred at room temperature overnight. After completion of the reaction, 20 mL of water was added, and the mixture was extracted with EA (3×30 mL), and then washed with brine, and then dried over anhydrous sodium sulfate. The organic phase was dried in vacuo and the crude material was purified eluting with silica gel (PE: EA = 2:1). A white solid of 130 mg (yield 71.5%) was obtained. 1H NMR (400MHz, DMSO) δ 8.56 (s, 1H), 8.32 (d, J = 7.4 Hz, 2H), 8.23-8.15 (m, 1H), 7.35 (tt, J = 7.3, 6.0 Hz, 2H) , 4.46 (s, 1H), 3.60 (s, 1H), 3.44 (dt, J = 14.1, 5.8 Hz, 2H), 3.21 (d, J = 7.8 Hz, 1H), 2.70 (s, 3H), 2.14 ( Dt, J = 13.4, 6.6 Hz, 1H), 1.91 (s, 1H), 1.41 (s, 9H).
实施例21Example 21
N-(2-乙酰氨基乙基)-1-乙酰基-1H-吲哚-3-甲酰胺的合成，合成方法如实施例20。1H NMR(400MHz，CDCl3)δ8.51-8.43(m，1H)，8.12-8.05(m，1H)，8.02(s，1H)，7.46-7.37(m，2H)，7.17(s，1H)，6.34(s，1H)，3.64(dd，J＝10.7，5.0Hz，2H)，3.55(dd，J＝10.9，5.5Hz，2H)，2.70(s，3H)，2.03(s，3H).Synthesis of N-(2-acetamidoethyl)-1-acetyl-1H-indole-3-carboxamide, as described in Example 20. 1H NMR (400 MHz, CDCl3) δ 8.51 - 8.43 (m, 1H), 8.12-8.05 (m, 1H), 8.02 (s, 1H), 7.46-7.37 (m, 2H), 7.17 (s, 1H), 6.34 (s, 1H), 3.64 (dd, J = 10.7, 5.0 Hz, 2H), 3.55 (dd, J = 10.9, 5.5 Hz, 2H), 2.70 (s, 3H), 2.03 (s, 3H).
实施例22Example 22
4-(1-乙酰基-1H-吲哚-3-甲酰胺基)丁基)氨基甲酸叔丁酯的合成，合成方法如实施例 20。1H NMR(400MHz，DMSO)δ8.50(s，1H)，8.32(d，J＝7.8Hz，1H)，8.30-8.14(m，2H)，7.34(dq，J＝7.3，6.2Hz，2H)，6.80(s，1H)，3.29-3.15(m，2H)，2.95(dd，J＝12.6，6.4Hz，2H)，2.69(s，3H)，1.62-1.41(m，4H)，1.38(d，J＝11.5Hz，9H)，1.23(s，1H).Synthesis of 4-(1-acetyl-1H-indole-3-carboxamido)butyl)carbamic acid tert-butyl ester, as described in Example 20. 1H NMR (400 MHz, DMSO) δ 8.50 (s, 1H), 8.32 (d, J = 7.8 Hz, 1H), 8.30-8.14 (m, 2H), 7.34 (dq, J = 7.3, 6.2 Hz, 2H), 6.80 (s, 1H), 3.29-3.15 (m , 2H), 2.95 (dd, J = 12.6, 6.4 Hz, 2H), 2.69 (s, 3H), 1.62-1.41 (m, 4H), 1.38 (d, J = 11.5 Hz, 9H), 1.23 (s, 1H).
实施例23Example 23
1-乙酰基-N-(2-(2-氧代咪唑烷-1-基)乙基)-1H-吲哚-3-甲酰胺的合成，合成方法如实施例20。1H NMR(400MHz，DMSO)δ8.48(s，1H)，8.33(d，J＝8.2Hz，2H)，8.19(d，J＝7.4Hz，1H)，7.43-7.25(m，2H)，6.29(s，1H)，3.51-3.37(m，4H)，3.23(dd，J＝13.8，6.9Hz，4H)，2.69(s，3H).Synthesis of 1-acetyl-N-(2-(2-oxoimidazolidin-1-yl)ethyl)-1H-indole-3-carboxamide as described in Example 20. 1H NMR (400 MHz, DMSO) δ 8.48 (s, 1H), 8.33 (d, J = 8.2 Hz, 2H), 8.19 (d, J = 7.4 Hz, 1H), 7.43 - 7.25 (m, 2H), 6.29 (s, 1H) , 3.51-3.37 (m, 4H), 3.23 (dd, J = 13.8, 6.9 Hz, 4H), 2.69 (s, 3H).
实施例24Example 24
1-乙酰基-N-(2-(吡啶-2-基)乙基)-1H-吲哚-3-甲酰胺的合成，合成方法如实施例20。1HNMR(400MHz，DMSO)δ8.53(d，J＝3.9Hz，1H)，8.48(s，1H)，8.38(t，J＝5.5Hz，1H)，8.32(d，J＝7.4Hz，1H)，8.21-8.15(m，1H)，7.72(td，J＝7.6，1.8Hz，1H)，7.40-7.29(m，3H)，7.23(dd，J＝7.0，5.3Hz，1H)，3.72-3.61(m，2H)，3.03(t，J＝7.4Hz，2H)，2.68(s，3H).Synthesis of 1-acetyl-N-(2-(pyridin-2-yl)ethyl)-1H-indole-3-carboxamide as described in Example 20. 1H NMR (400 MHz, DMSO) δ 8.53 ( d, J = 3.9 Hz, 1H), 8.48 (s, 1H), 8.38 (t, J = 5.5 Hz, 1H), 8.32 (d, J = 7.4 Hz, 1H), 8.21 - 8.15 (m, 1H), 7.72 (td, J = 7.6, 1.8 Hz, 1H), 7.40-7.29 (m, 3H), 7.23 (dd, J = 7.0, 5.3 Hz, 1H), 3.72-3.61 (m, 2H), 3.03 (t, J = 7.4 Hz, 2H), 2.68 (s, 3H).
实施例25Example 25
1-乙酰基-N-(2-氯苯乙基)-1H-吲哚-3-甲酰胺的合成，合成方法如实施例20。1H NMR(400MHz，DMSO)δ8.48(s，1H)，8.41(t，J＝5.6Hz，1H)，8.32(d，J＝7.9Hz，1H)，8.18(d，J＝7.0Hz，1H)，7.44(dd，J＝7.4，1.7Hz，1H)，7.42-7.20(m，5H)，3.53(dd，J＝14.1，6.3Hz，2H)，3.00(t，J＝7.4Hz，2H)，2.68(s，3H).Synthesis of 1-acetyl-N-(2-chlorophenethyl)-1H-indole-3-carboxamide, as described in Example 20. 1H NMR (400 MHz, DMSO) δ 8.48 (s, 1H) , 8.41 (t, J = 5.6 Hz, 1H), 8.32 (d, J = 7.9 Hz, 1H), 8.18 (d, J = 7.0 Hz, 1H), 7.44 (dd, J = 7.4, 1.7 Hz, 1H) , 7.42-7.20 (m, 5H), 3.53 (dd, J = 14.1, 6.3 Hz, 2H), 3.00 (t, J = 7.4 Hz, 2H), 2.68 (s, 3H).
实施例26Example 26
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)氮杂环丁烷-1-羧酸叔丁酯的合成，合成方法如实施例20。1H NMR(400MHz，DMSO)δ8.80(d，J＝7.3Hz，1H)，8.56(s，1H)，8.33(d，J＝7.8Hz，1H)，8.18(d，J＝7.2Hz，1H)，7.35(m，2H)，4.81-4.59(m，1H)，4.18(t，J＝8.1Hz，2H)，3.95-3.74(m，2H)，2.71(s，3H)，1.40(s，9H).Synthesis of 3-(1-acetyl-1H-indole-3-carboxamido)azetidin-1-carboxylic acid tert-butyl ester, as described in Example 20. 1H NMR (400 MHz, DMSO) δ 8 .80 (d, J = 7.3 Hz, 1H), 8.56 (s, 1H), 8.33 (d, J = 7.8 Hz, 1H), 8.18 (d, J = 7.2 Hz, 1H), 7.35 (m, 2H) , 4.81-4.59 (m, 1H), 4.18 (t, J = 8.1 Hz, 2H), 3.95-3.74 (m, 2H), 2.71 (s, 3H), 1.40 (s, 9H).
实施例27Example 27
1-乙酰基-N-(3-氯苄基)-1H-吲哚-3-甲酰胺的合成，合成方法如实施例20。1H NMR(400MHz，CDCl3)δ8.45(d，J＝7.8Hz，1H)，8.00(s，1H)，7.90(d，J＝7.3Hz，1H)，7.40(dd，J＝19.7，7.6Hz，3H)，7.27(s，4H)，6.44(s，1H)，4.66(d，J＝5.6Hz，2H)，2.66(s，3H).Synthesis of 1-acetyl-N-(3-chlorobenzyl)-1H-indole-3-carboxamide, as described in Example 20. 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J = 7.8 Hz, 1H), 8.00 (s, 1H), 7.90 (d, J = 7.3 Hz, 1H), 7.40 (dd, J = 19.7, 7.6 Hz, 3H), 7.27 (s, 4H), 6.44 (s, 1H) ), 4.66 (d, J = 5.6 Hz, 2H), 2.66 (s, 3H).
实施例28Example 28
1-乙酰基-N-((6-氯吡啶-3-基)甲基)-1H-吲哚-3-甲酰胺的合成，合成方法如实施例20。1H NMR(400MHz，CDCl3)δ8.46(d，J＝8.1Hz，1H)，8.41(d，J＝2.2Hz，1H)，8.02(s，1H)，7.88(d，J＝7.4Hz，1H)，7.74(dd，J＝8.2，2.5Hz，1H)，7.48-7.30(m，3H)，6.47(s，1H)，4.69(d，J＝6.0Hz，2H)，2.69(s，3H).Synthesis of 1-acetyl-N-((6-chloropyridin-3-yl)methyl)-1H-indole-3-carboxamide, as described in Example 20. 1H NMR (400 MHz, CDCl3) δ 8. 46 (d, J = 8.1 Hz, 1H), 8.41 (d, J = 2.2 Hz, 1H), 8.02 (s, 1H), 7.88 (d, J = 7.4 Hz, 1H), 7.74 (dd, J = 8.2 , 2.5 Hz, 1H), 7.48-7.30 (m, 3H), 6.47 (s, 1H), 4.69 (d, J = 6.0 Hz, 2H), 2.69 (s, 3H).
实施例29Example 29
1-乙酰基-N-(3，5-双(三氟甲基)苄基)-1H-吲哚-3-甲酰胺的合成，合成方法如实施例20。1H NMR(400MHz，DMSO)δ9.00(t，J＝5.9Hz，1H)，8.58(s，1H)，8.34(d，J＝7.8Hz，1H)，8.19(d，J＝7.3Hz，1H)，8.06(s，2H)，8.01(s，1H)，7.36(ddd，J＝13.6，10.5，6.1Hz，2H)，4.69(d，J＝5.9Hz，2H)，2.70(s，3H).Synthesis of 1-acetyl-N-(3,5-bis(trifluoromethyl)benzyl)-1H-indole-3-carboxamide as described in Example 20. 1H NMR (400 MHz, DMSO) δ 9 .00 (t, J = 5.9 Hz, 1H), 8.58 (s, 1H), 8.34 (d, J = 7.8 Hz, 1H), 8.19 (d, J = 7.3 Hz, 1H), 8.06 (s, 2H) , 8.01 (s, 1H), 7.36 (ddd, J = 13.6, 10.5, 6.1 Hz, 2H), 4.69 (d, J = 5.9 Hz, 2H), 2.70 (s, 3H).
实施例30Example 30
1-乙酰基-N-(4-甲氧基苄基)-1H-吲哚-3-甲酰胺的合成，合成方法如实施例20。1H NMR(400MHz，DMSO)δ8.70(t，J＝5.8Hz，1H)，8.58(s，1H)，8.33(d，J＝7.6Hz，1H)，8.27-8.19(m，1H)，7.40-7.32(m，2H)，7.30(s，1H)，7.28(s，1H)，6.92(s，1H)，6.90(s，1H)，4.44(d，J＝5.8Hz，2H)，3.73(s，3H)，2.68(s，3H).Synthesis of 1-acetyl-N-(4-methoxybenzyl)-1H-indole-3-carboxamide as described in Example 20. 1H NMR (400 MHz, DMSO) δ 8.70 (t, J = 5.8 Hz, 1H), 8.58 (s, 1H), 8.33 (d, J = 7.6 Hz, 1H), 8.27-8.19 (m, 1H), 7.40-7.32 (m, 2H), 7.30 (s, 1H) , 7.28 (s, 1H), 6.92 (s, 1H), 6.90 (s, 1H), 4.44 (d, J = 5.8 Hz, 2H), 3.73 (s, 3H), 2.68 (s, 3H).
实施例31Example 31
1-乙酰基-N-(3，4，5-三氟苄基)-1H-吲哚-3-甲酰胺的合成，合成方法如实施例20。1H NMR(400MHz，DMSO)δ8.88(t，J＝5.9Hz，1H)，8.59(s，1H)，8.34(d，J＝7.7Hz，1H)，8.22-8.15(m， 1H)，7.42-7.35(m，1H)，7.35-7.24(m，3H)，4.49(d，J＝5.9Hz，2H)，2.70(s，3H).Synthesis of 1-acetyl-N-(3,4,5-trifluorobenzyl)-1H-indole-3-carboxamide as described in Example 20. 1H NMR (400 MHz, DMSO) δ 8.88 ( t, J = 5.9 Hz, 1H), 8.59 (s, 1H), 8.34 (d, J = 7.7 Hz, 1H), 8.22 - 8.15 (m, 1H), 7.42 - 7.35 (m, 1H), 7.35-7.24 (m, 3H), 4.49 (d, J = 5.9 Hz, 2H), 2.70 (s, 3H).
实施例32Example 32
1-乙酰基-N-(吡啶-4-基甲基)-1H-吲哚-3-甲酰胺的合成，合成方法如实施例20。1H NMR(400MHz，DMSO)δ8.91(s，1H)，8.62(s，1H)，8.53(d，J＝4.6Hz，3H)，8.35(d，J＝7.8Hz，1H)，8.21(d，J＝7.5Hz，1H)，8.17-8.03(m，1H)，7.51-7.21(m，5H)，7.13(dd，J＝14.3，7.5Hz，1H)，4.52(dd，J＝16.4，5.6Hz，3H)，2.71(s，3H).Synthesis of 1-acetyl-N-(pyridin-4-ylmethyl)-1H-indole-3-carboxamide as described in Example 20. 1H NMR (400 MHz, DMSO) δ 8.91 (s, 1H) ), 8.62 (s, 1H), 8.53 (d, J = 4.6 Hz, 3H), 8.35 (d, J = 7.8 Hz, 1H), 8.21 (d, J = 7.5 Hz, 1H), 8.17 - 8.03 (m) , 1H), 7.51-7.21 (m, 5H), 7.13 (dd, J = 14.3, 7.5 Hz, 1H), 4.52 (dd, J = 16.4, 5.6 Hz, 3H), 2.71 (s, 3H).
实施例33Example 33
1-乙酰基-N-(2-氯-4-氟苄基)-1H-吲哚-3-甲酰胺的合成，合成方法如实施例20。1H NMR(400MHz，DMSO)δ8.56(s，1H)，8.48(t，J＝4.5Hz，1H)，8.32(d，J＝7.5Hz，1H)，8.23(d，J＝7.1Hz，1H)，7.47-7.24(m，5H)，4.63(d，J＝3.6Hz，2H)，2.66(s，3H).Synthesis of 1-acetyl-N-(2-chloro-4-fluorobenzyl)-1H-indole-3-carboxamide, as described in Example 20. 1H NMR (400 MHz, DMSO) δ 8.56 (s) , 1H), 8.48 (t, J = 4.5 Hz, 1H), 8.32 (d, J = 7.5 Hz, 1H), 8.23 (d, J = 7.1 Hz, 1H), 7.47-7.24 (m, 5H), 4.63 (d, J = 3.6 Hz, 2H), 2.66 (s, 3H).
实施例34Example 34
1-乙酰基-N-((5-甲基-1H-吲唑-3-基)甲基)-1H-吲哚-3-甲酰胺的合成，合成方法如实施例20。1H NMR(400MHz，DMSO)δ12.75(s，1H)，8.76(t，J＝5.5Hz，1H)，8.57(s，1H)，8.37-8.23(m，2H)，7.60(s，1H)，7.44-7.30(m，3H)，7.17(d，J＝8.4Hz，1H)，4.82(d，J＝5.7Hz，2H)，2.64(s，3H)，2.36(s，3H).Synthesis of 1-acetyl-N-((5-methyl-1H-indazol-3-yl)methyl)-1H-indole-3-carboxamide, as described in Example 20. 1H NMR (400 MHz , DMSO) δ12.75 (s, 1H), 8.76 (t, J = 5.5 Hz, 1H), 8.57 (s, 1H), 8.37-8.23 (m, 2H), 7.60 (s, 1H), 7.44-7.30 (m, 3H), 7.17 (d, J = 8.4 Hz, 1H), 4.82 (d, J = 5.7 Hz, 2H), 2.64 (s, 3H), 2.36 (s, 3H).
实施例35Example 35
1-乙酰基-N-((4-甲基-6-(三氟甲基)嘧啶-2-基)甲基)-1H-吲哚-3-甲酰胺的合成，合成方法如实施例20。1H NMR(400MHz，CDCl3)δ8.57-8.44(m，1H)，8.23-8.08(m，2H)，7.54(s，1H)，7.49-7.37(m，3H)，5.01(d，J＝4.6Hz，2H)，2.70(s，6H).Synthesis of 1-acetyl-N-((4-methyl-6-(trifluoromethyl)pyrimidin-2-yl)methyl)-1H-indole-3-carboxamide, as in Example 20 1H NMR (400MHz, CDCl3) δ 8.57-8.44 (m, 1H), 8.23-8.08 (m, 2H), 7.54 (s, 1H), 7.49-7.37 (m, 3H), 5.01 (d, J = 4.6 Hz, 2H), 2.70 (s, 6H).
实施例36Example 36
1-乙酰基-N-(4-氟-3-(三氟甲基)苄基)-1H-吲哚-3-甲酰胺的合成，合成方法如实施例20。1H NMR(400MHz，DMSO)δ8.90(t，J＝5.6Hz，1H)，8.57(s，1H)，8.34(d，J＝7.9Hz，1H)，8.20(d，J＝7.2Hz，1H)，7.77(d，J＝6.9Hz，2H)，7.57-7.45(m，1H)，7.45-7.28(m，2H)，4.57(d，J＝5.8Hz，2H)，2.69(s，3H).Synthesis of 1-acetyl-N-(4-fluoro-3-(trifluoromethyl)benzyl)-1H-indole-3-carboxamide as described in Example 20. 1H NMR (400 MHz, DMSO) δ 8.90 (t, J = 5.6 Hz, 1H), 8.57 (s, 1H), 8.34 (d, J = 7.9 Hz, 1H), 8.20 (d, J = 7.2 Hz, 1H), 7.77 (d, J) = 6.9 Hz, 2H), 7.57-7.45 (m, 1H), 7.45-7.28 (m, 2H), 4.57 (d, J = 5.8 Hz, 2H), 2.69 (s, 3H).
实施例37Example 37
1-乙酰基-N-((1-甲基-5-(三氟甲基)-1H-苯并[d]咪唑-2-基)甲基)-1H-吲哚-3-甲酰胺的合成，合成方法如实施例20。1H NMR(400MHz，DMSO)δ8.98(t，J＝5.4Hz，1H)，8.66(s，1H)，8.34(d，J＝7.7Hz，1H)，8.24(d，J＝7.2Hz，1H)，7.96(s，1H)，7.79(d，J＝8.5Hz，1H)，7.58(d，J＝8.5Hz，1H)，7.43-7.28(m，2H)，4.86(d，J＝5.5Hz，2H)，3.92(s，3H)，2.68(s，3H).1-acetyl-N-((1-methyl-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)methyl)-1H-indole-3-carboxamide Synthesis, synthesis method as in Example 20. 1H NMR (400 MHz, DMSO) δ 8.98 (t, J = 5.4 Hz, 1H), 8.66 (s, 1H), 8.34 (d, J = 7.7 Hz, 1H), 8.24 (d, J = 7.2 Hz, 1H), 7.96 (s, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.43 - 7.28 (m, 2H) , 4.86 (d, J = 5.5 Hz, 2H), 3.92 (s, 3H), 2.68 (s, 3H).
实施例38Example 38
1-乙酰基-N-((5-氟-1H-吲哚-2-基)甲基)-1H-吲哚-3-甲酰胺的合成，合成方法如实施例20。1H NMR(400MHz，DMSO)δ11.11(s，1H)，8.78(t，J＝5.5Hz，1H)，8.62(s，1H)，8.34(d，J＝7.2Hz，1H)，8.29-8.19(m，1H)，7.35(ddt，J＝11.0，8.9，5.3Hz，3H)，7.22(dd，J＝10.0，2.5Hz，1H)，6.87(td，J＝9.4，2.6Hz，1H)，6.36(s，1H)，4.64(d，J＝5.5Hz，2H)，2.68(s，3H).Synthesis of 1-acetyl-N-((5-fluoro-1H-indol-2-yl)methyl)-1H-indole-3-carboxamide, as described in Example 20. 1H NMR (400 MHz, DMSO) δ11.11(s,1H), 8.78 (t, J=5.5 Hz, 1H), 8.62 (s, 1H), 8.34 (d, J = 7.2 Hz, 1H), 8.29-8.19 (m, 1H) , 7.35 (ddt, J = 11.0, 8.9, 5.3 Hz, 3H), 7.22 (dd, J = 10.0, 2.5 Hz, 1H), 6.87 (td, J = 9.4, 2.6 Hz, 1H), 6.36 (s, 1H) ), 4.64 (d, J = 5.5 Hz, 2H), 2.68 (s, 3H).
实施例39Example 39
1-乙酰基-N-((5-甲氧基-1H-吲哚-2-基)甲基)-1H-吲哚-3-甲酰胺的合成，合成方法如实施例20。1H NMR(400MHz，DMSO)δ10.82(s，1H)，8.73(t，J＝5.4Hz，1H)，8.62(s，1H)，8.42-8.30(m，1H)，8.30-8.21(m，1H)，7.36(dq，J＝7.3，5.8Hz，2H)，7.23(d，J＝8.7Hz，1H)，6.97(d，J＝2.3Hz，1H)，6.68(dd，J＝8.7，2.4Hz，1H)，6.28(s，1H)，4.62(d，J＝5.5Hz，2H)，3.72(s，3H)，2.68(d，J＝4.9Hz，4H).Synthesis of 1-acetyl-N-((5-methoxy-1H-indol-2-yl)methyl)-1H-indole-3-carboxamide as synthesized in Example 20. 1H NMR ( 400MHz, DMSO) δ 10.82 (s, 1H), 8.73 (t, J = 5.4 Hz, 1H), 8.62 (s, 1H), 8.42-8.30 (m, 1H), 8.30-8.21 (m, 1H), 7.36 (dq, J = 7.3, 5.8 Hz, 2H), 7.23 (d, J = 8.7 Hz, 1H), 6.97 (d, J = 2.3 Hz, 1H), 6.68 (dd, J = 8.7, 2.4 Hz, 1H) ), 6.28 (s, 1H), 4.62 (d, J = 5.5 Hz, 2H), 3.72 (s, 3H), 2.68 (d, J = 4.9 Hz, 4H).
实施例40Example 40
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-3-(3，5-二甲基苯基)丙酸甲酯的合成，合成方法如实施例20。1H NMR(400MHz，CDCl3)δ8.46(dd，J＝5.9，3.1Hz，1H)，8.00(t，J＝4.3Hz，2H)，7.45-7.36(m，2H)，7.26-7.18(m，2H)，6.99(d，J＝9.9Hz，2H)，5.81(dd，J＝13.9，6.2Hz，1H)，3.65(s，3H)，2.96(dd，J＝6.2，2.4Hz，2H)，2.64(s，3H)，2.45(s，3H)，2.28(s，3H).Synthesis of methyl 3-(1-acetyl-1H-indole-3-carboxamido)-3-(3,5-dimethylphenyl)propanoate as synthesized in Example 20. 1H NMR ( 400MHz, CDCl3) δ 8.46 (dd, J = 5.9, 3.1 Hz, 1H), 8.00 (t, J = 4.3 Hz, 2H), 7.45-7.36 (m, 2H), 7.26-7.18 (m, 2H), 6.99 (d, J = 9.9 Hz, 2H), 5.81 (dd, J = 13.9, 6.2 Hz, 1H), 3.65 (s, 3H), 2.96 (dd, J = 6.2, 2.4 Hz, 2H), 2.64 (s) , 3H), 2.45 (s, 3H), 2.28 (s, 3H).
实施例41Example 41
2-((1-乙酰基-1H-吲哚-3-甲酰氨基)甲基)苯甲酸甲酯的合成，合成方法如实施例20。1H NMR(400MHz，DMSO)δ8.71(s，1H)，8.38(d，J＝8.0Hz，1H)，7.92(d，J＝7.4Hz，1H)，7.85(d，J＝7.6Hz，1H)，7.79(t，J＝7.3Hz，1H)，7.74(d，J＝7.5Hz，1H)，7.59(t，J＝7.2Hz，1H)，7.39(dt，J＝20.9，6.9Hz，2H)，5.10(s，2H)，3.83(s，3H)，2.71(s，3H).Synthesis of methyl 2-((1-acetyl-1H-indole-3-carboxamido)methyl)benzoate as synthesized in Example 20. 1H NMR (400 MHz, DMSO) δ 8.71 (s, 1H), 8.38 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 7.4 Hz, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.79 (t, J = 7.3 Hz, 1H) , 7.74 (d, J = 7.5 Hz, 1H), 7.59 (t, J = 7.2 Hz, 1H), 7.39 (dt, J = 20.9, 6.9 Hz, 2H), 5.10 (s, 2H), 3.83 (s, 3H), 2.71 (s, 3H).
实施例42Example 42
2-(1-乙酰基-1H-吲哚-3-甲酰氨基)-3-(呋喃-2-基)丙酸甲酯的合成，合成方法如实施例20。1H NMR(400MHz，DMSO)δ8.70(d，J＝7.8Hz，1H)，8.62(s，1H)，8.33(d，J＝8.1Hz，1H)，8.15(d，J＝7.4Hz，1H)，7.55(d，J＝0.8Hz，1H)，7.35(dt，J＝14.3，6.9Hz，2H)，6.39-6.30(m，1H)，6.23(d，J＝2.9Hz，1H)，4.81(dd，J＝14.1，8.4Hz，1H)，3.67(s，3H)，3.20(m，2H)，2.71(s，3H).Synthesis of methyl 2-(1-acetyl-1H-indole-3-carboxamido)-3-(furan-2-yl)propanoate as synthesized in Example 20. 1H NMR (400 MHz, DMSO) δ 8.70 (d, J = 7.8 Hz, 1H), 8.62 (s, 1H), 8.33 (d, J = 8.1 Hz, 1H), 8.15 (d, J = 7.4 Hz, 1H), 7.55 (d, J) =0.8 Hz, 1H), 7.35 (dt, J = 14.3, 6.9 Hz, 2H), 6.39-6.30 (m, 1H), 6.23 (d, J = 2.9 Hz, 1H), 4.81 (dd, J = 14.1, 8.4 Hz, 1H), 3.67 (s, 3H), 3.20 (m, 2H), 2.71 (s, 3H).
实施例43Example 43
乙基3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-(5-甲基呋喃-2-基)丁酸乙酯的合成，合成方法如实施例20。1H NMR(400MHz，DMSO)δ8.62(d，J＝8.4Hz，1H)，8.58(s，1H)，8.33(d，J＝7.6Hz，1H)，8.22(d，J＝7.0Hz，1H)，7.42-7.28(m，2H)，6.21(d，J＝3.0Hz，1H)，6.01(d，J＝2.2Hz，1H)，5.58(q，J＝7.8Hz，1H)，4.12-4.00(m，2H)，2.98-2.84(m，2H)，2.69(s，3H)，2.24(s，3H)，1.23(s，2H)，1.13(t，J＝7.1Hz，3H).Synthesis of ethyl 3-(1-acetyl-1H-indole-3-carboxamido)-4-(5-methylfuran-2-yl)butanoate as a synthesis method as in Example 20. 1H NMR (400MHz, DMSO) δ 8.62 (d, J = 8.4 Hz, 1H), 8.58 (s, 1H), 8.33 (d, J = 7.6 Hz, 1H), 8.22 (d, J = 7.0 Hz, 1H) , 7.42-7.28 (m, 2H), 6.21 (d, J = 3.0 Hz, 1H), 6.01 (d, J = 2.2 Hz, 1H), 5.58 (q, J = 7.8 Hz, 1H), 4.12-4.00 ( m, 2H), 2.98-2.84 (m, 2H), 2.69 (s, 3H), 2.24 (s, 3H), 1.23 (s, 2H), 1.13 (t, J = 7.1 Hz, 3H).
实施例44Example 44
4-((1-乙酰基-1H-吲哚-3-甲酰胺基)甲基)噻吩-2-羧酸甲酯的合成，合成方法如实施例20。1H NMR(400MHz，DMSO)δ9.04(t，J＝5.9Hz，1H)，8.58(s，1H)，8.34(d，J＝7.6Hz，1H)，8.22(d，J＝7.2Hz，1H)，7.68(d，J＝3.8Hz，1H)，7.46-7.28(m，2H)，7.15(d，J＝3.8Hz，1H)，4.70(d，J＝5.8Hz，2H)，3.79(s，3H)，2.69(s，3H).Synthesis of methyl 4-((1-acetyl-1H-indole-3-carboxamido)methyl)thiophene-2-carboxylate, as described in Example 20. 1H NMR (400 MHz, DMSO) δ 9. 04 (t, J = 5.9 Hz, 1H), 8.58 (s, 1H), 8.34 (d, J = 7.6 Hz, 1H), 8.22 (d, J = 7.2 Hz, 1H), 7.68 (d, J = 3.8) Hz, 1H), 7.46-7.28 (m, 2H), 7.15 (d, J = 3.8 Hz, 1H), 4.70 (d, J = 5.8 Hz, 2H), 3.79 (s, 3H), 2.69 (s, 3H) ).
实施例45Example 45
4-((1-乙酰基-1H-吲哚-3-甲酰胺基)甲基)噻吩-2-羧酸的合成，合成方法如实施例8。1H NMR(400MHz，DMSO)δ9.03(t，J＝5.8Hz，1H)，8.59(s，1H)，8.40-8.30(m，1H)，8.22(dd，J＝6.9，1.7Hz，1H)，7.59(d，J＝3.7Hz，1H)，7.36(pd，J＝7.2，1.4Hz，2H)，7.12(d，J＝3.7Hz，1H)，4.68(d，J＝5.8Hz，2H)，2.69(s，3H).Synthesis of 4-((1-acetyl-1H-indol-3-carboxamido)methyl)thiophene-2-carboxylic acid, as in Example 8. 1H NMR (400 MHz, DMSO) δ 9.03 ( t, J = 5.8 Hz, 1H), 8.59 (s, 1H), 8.40-8.30 (m, 1H), 8.22 (dd, J = 6.9, 1.7 Hz, 1H), 7.59 (d, J = 3.7 Hz, 1H) ), 7.36 (pd, J = 7.2, 1.4 Hz, 2H), 7.12 (d, J = 3.7 Hz, 1H), 4.68 (d, J = 5.8 Hz, 2H), 2.69 (s, 3H).
实施例46Example 46
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-3-(3，5-二甲基苯基)丙酸的合成，合成方法如实施例8。1H NMR(400MHz，DMSO)δ12.25(s，1H)，8.61(s，1H)，8.59(s，1H)，8.32(d，J＝8.0Hz，1H)，8.17(d，J＝7.1Hz，1H)，7.36(d，J＝7.4Hz，1H)，7.32(d，J＝4.0Hz，1H)，7.29(d，J＝7.3Hz，1H)，7.00(d，J＝8.1Hz，1H)，6.97(s，1H)，5.70-5.56(m，1H)，2.86-2.73(m，2H)，2.71(s，3H)，2.40(s，3H)，2.23(s，3H).Synthesis of 3-(1-acetyl-1H-indole-3-carboxamido)-3-(3,5-dimethylphenyl)propanoic acid as described in Example 8. 1H NMR (400 MHz, DMSO) δ12.25 (s, 1H), 8.61 (s, 1H), 8.59 (s, 1H), 8.32 (d, J = 8.0 Hz, 1H), 8.17 (d, J = 7.1 Hz, 1H), 7.36 (d, J = 7.4 Hz, 1H), 7.32 (d, J = 4.0 Hz, 1H), 7.29 (d, J = 7.3 Hz, 1H), 7.00 (d, J = 8.1 Hz, 1H), 6.97 (s) , 1H), 5.70-5.56 (m, 1H), 2.86-2.73 (m, 2H), 2.71 (s, 3H), 2.40 (s, 3H), 2.23 (s, 3H).
实施例47Example 47
1-乙酰基-N-(3-乙酰基苯基)-1H-吲哚-3-甲酰胺的合成Synthesis of 1-acetyl-N-(3-acetylphenyl)-1H-indole-3-carboxamide
结构类型为II时：When the structure type is II:
1-乙酰基-1H-吲哚-3-羧酸的合成与上述方法相同。将1-(3-氨基苯基)乙-1-酮(110mg，0.82mmol)溶解在30mL甲苯中，再加入中间体1-乙酰基-1H-吲哚-3-羧酸(200mg，0.98mmol)，2-氯-1-甲基吡啶碘化物(502mg，1.96mmol)和n-Bu3N(729mg，3.93mmol)。反应体系在氮气保护下，90℃下搅拌过夜。反应结束后，冷却至室温，加入30mL水，用EA萃取(3×30mL)，有机相用饱和食盐水洗涤一遍，无水硫酸钠干燥。真空旋干有机相，粗产物用硅胶柱分离(PE∶EA＝4∶1)。得到白色固体105mg(产率33.4％)。1H NMR(400MHz，DMSO)δ10.27(s，1H)，8.81(s，1H)，8.36(d，J＝7.4Hz，1H)，8.29(s，1H)，8.26(d，J＝7.1Hz，1H)，8.10(d，J＝8.1Hz，1H)，7.73(d，J＝7.7Hz，1H)，7.54(t，J＝7.9Hz，1H)，7.48-7.30(m，2H)，2.76(s，3H)，2.50(s，3H).The synthesis of 1-acetyl-1H-indole-3-carboxylic acid is the same as described above. 1-(3-Aminophenyl)ethan-1-one (110 mg, 0.82 mmol) was dissolved in 30 mL of toluene, then intermediate 1-acetyl-1H-indole-3-carboxylic acid (200 mg, 0.98 mmol) , 2-chloro-1-methylpyridine iodide (502 mg, 1.96 mmol) and n-Bu3N (729 mg, 3.93 mmol). The reaction system was stirred at 90 ° C overnight under a nitrogen atmosphere. After completion of the reaction, the mixture was cooled to room temperature, and then added with 30 mL of water, EtOAc (3×30 mL). The organic phase was dried <RTI ID=0.0></RTI> to <RTI ID=0.0> 105 mg of a white solid were obtained (yield 33.4%). 1H NMR (400MHz, DMSO) δ 10.27 (s, 1H), 8.81 (s, 1H), 8.36 (d, J = 7.4 Hz, 1H), 8.29 (s, 1H), 8.26 (d, J = 7.1 Hz) , 1H), 8.10 (d, J = 8.1 Hz, 1H), 7.73 (d, J = 7.7 Hz, 1H), 7.54 (t, J = 7.9 Hz, 1H), 7.48-7.30 (m, 2H), 2.76 (s, 3H), 2.50 (s, 3H).
实施例48Example 48
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)苯甲酸甲酯的合成，合成方法如实施例47。1H NMR(400MHz，CDCl3)δ8.45(d，J＝7.6Hz，1H)，8.15(s，1H)，8.10(s，1H)，8.08-8.04(m，1H)，8.03(s，1H)，8.02(s，1H)，7.81(d，J＝7.8Hz，1H)，7.48-7.44(m，1H)，7.42(d，J＝1.7Hz，1H)，7.42-7.38(m，1H)，3.91(s，3H)，2.68(s，3H).Synthesis of methyl 3-(1-acetyl-1H-indole-3-carboxamido)benzoate, the synthesis method is as in Example 47. 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J = 7.6 Hz , 1H), 8.15 (s, 1H), 8.10 (s, 1H), 8.08-8.04 (m, 1H), 8.03 (s, 1H), 8.02 (s, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.48-7.44 (m, 1H), 7.42 (d, J = 1.7 Hz, 1H), 7.42 - 7.38 (m, 1H), 3.91 (s, 3H), 2.68 (s, 3H).
实施例49Example 49
1-乙酰基-N-(3，5-二硝基苯基)-1H-吲哚-3-甲酰胺的合成，合成方法如实施例47。1H NMR(400MHz，DMSO)δ10.88(s，1H)，9.17-9.02(m，2H)，8.87(s，1H)，8.51(d，J＝26.7Hz，1H)，8.37(d，J＝7.5Hz，1H)，8.28(d，J＝7.4Hz，1H)，7.58-7.33(m，2H)，2.79(s，3H).Synthesis of 1-acetyl-N-(3,5-dinitrophenyl)-1H-indole-3-carboxamide, as described in Example 47. 1H NMR (400 MHz, DMSO) δ 10.88 (s) , 1H), 9.17-9.02 (m, 2H), 8.87 (s, 1H), 8.51 (d, J = 26.7 Hz, 1H), 8.37 (d, J = 7.5 Hz, 1H), 8.28 (d, J = 7.4 Hz, 1H), 7.58-7.33 (m, 2H), 2.79 (s, 3H).
实施例50Example 50
1-乙酰基-N-(4-溴-2-硝基苯基)-1H-吲哚-3-甲酰胺的合成，合成方法如实施例47。1H NMR(400MHz，CDCl3)δ11.07(s，1H)，8.93(d，J＝9.1Hz，1H)，8.55-8.35(m，2H)，8.20(dd，J＝5.8，3.0Hz，1H)，8.12(s，1H)，7.81(dd，J＝9.1，2.2Hz，1H)，7.54-7.40(m，2H)，2.76(s，3H).Synthesis of 1-acetyl-N-(4-bromo-2-nitrophenyl)-1H-indole-3-carboxamide as described in Example 47. 1H NMR (400 MHz, CDCl3) δ 11.07 ( s, 1H), 8.93 (d, J = 9.1 Hz, 1H), 8.55-8.35 (m, 2H), 8.20 (dd, J = 5.8, 3.0 Hz, 1H), 8.12 (s, 1H), 7.81 (dd , J = 9.1, 2.2 Hz, 1H), 7.54 - 7.40 (m, 2H), 2.76 (s, 3H).
实施例51Example 51
1-乙酰基-N-(2，3-二氢苯并[b][1，4]二氧杂环己烯-6-基)-1H-吲哚-3-甲酰胺的合成，合成方法如实施例47。1H NMR(400MHz，DMSO)δ9.91(s，1H)，8.72(s，1H)，8.36(d，J＝7.8Hz，1H)，8.23(d，J＝7.2Hz，1H)，7.45-7.29(m，3H)，7.16(dd，J＝8.7，2.3Hz，1H)，6.85(d，J＝8.7Hz，1H)，4.24(dd，J＝9.8，5.1Hz，4H)，2.72(d，J＝21.3Hz，3H).Synthesis, synthesis method of 1-acetyl-N-(2,3-dihydrobenzo[b][1,4]dioxine-6-yl)-1H-indole-3-carboxamide Example 47. 1H NMR (400MHz, DMSO) δ 9.91 (s, 1H), 8.72 (s, 1H), 8.36 (d, J = 7.8 Hz, 1H), 8.23 (d, J = 7.2 Hz, 1H) ), 7.45-7.29 (m, 3H), 7.16 (dd, J = 8.7, 2.3 Hz, 1H), 6.85 (d, J = 8.7 Hz, 1H), 4.24 (dd, J = 9.8, 5.1 Hz, 4H) , 2.72 (d, J = 21.3 Hz, 3H).
实施例52Example 52
(1-乙酰基-1H-吲哚-3-甲酰氨基)间苯二甲酸二甲酯的合成，合成方法如实施例47。1H NMR(400MHz，CDCl3)δ8.52(s，2H)，8.45(d，J＝8.8Hz，2H)，8.15(s，1H)，8.11(s，1H)，8.05(d，J＝7.1Hz，1H)，7.44(m，2H)，3.95(s，6H)，2.72(s，3H).Synthesis of dimethyl (1-acetyl-1H-indole-3-carboxamido) isophthalate, as described in Example 47. 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 2H), 8.45 (d, J = 8.8 Hz, 2H), 8.15 (s, 1H), 8.11 (s, 1H), 8.05 (d, J = 7.1 Hz, 1H), 7.44 (m, 2H), 3.95 (s, 6H) ), 2.72 (s, 3H).
实施例53Example 53
N-(3-(1，3-二氧戊环-2-基)苯基)-1-乙酰基-1H-吲哚-3-甲酰胺的合成，合成方法如实施例47。1H NMR(400MHz，DMSO)δ10.12(s，1H)，8.81(s，1H)，8.37(d，J＝7.7Hz，1H)，8.26(d，J＝7.0Hz，1H)，7.94-7.77(m，2H)，7.47-7.29(m，3H)，7.17(d，J＝7.6Hz，1H)，5.75(s，1H)，4.07(dd，J＝8.9，4.8Hz，2H)，4.04-4.01(m，1H)，3.98(dd，J＝9.0，4.8Hz，2H)，2.76(s，3H)，2.50(s，2H)，2.05-1.90(m，1H)，1.17(t，J＝7.1Hz，1H).Synthesis of N-(3-(1,3-dioxolan-2-yl)phenyl)-1-acetyl-1H-indole-3-carboxamide, as described in Example 47. 1H NMR ( 400MHz, DMSO) δ10.12 (s, 1H), 8.81 (s, 1H), 8.37 (d, J = 7.7 Hz, 1H), 8.26 (d, J = 7.0 Hz, 1H), 7.94 - 7.77 (m, 2H), 7.47-7.29 (m, 3H), 7.17 (d, J = 7.6 Hz, 1H), 5.75 (s, 1H), 4.07 (dd, J = 8.9, 4.8 Hz, 2H), 4.04-4.01 (m , 1H), 3.98 (dd, J=9.0, 4.8 Hz, 2H), 2.76 (s, 3H), 2.50 (s, 2H), 2.05-1.90 (m, 1H), 1.17 (t, J = 7.1 Hz, 1H).
实施例54Example 54
1-乙酰基-N-(1-乙酰基二氢吲哚-5-基)-1H-吲哚-3-甲酰胺的合成Synthesis of 1-acetyl-N-(1-acetyldihydroindol-5-yl)-1H-indole-3-carboxamide
合成方法如实施例47。1H NMR(400MHz，DMSO)δ9.99(s，1H)，8.75(s，1H)，8.36(d，J＝8.0Hz，1H)，8.24(d，J＝7.3Hz，1H)，8.02(d，J＝8.7Hz，1H)，7.74(s，1H)，7.52-7.29(m，3H)，4.11(t，J＝8.5Hz，2H)，3.17(t，J＝8.4Hz，2H)，2.75(s，3H)，2.15(s，3H).The synthesis method is as in Example 47. 1H NMR (400MHz, DMSO) δ 9.99 (s, 1H), 8.75 (s, 1H), 8.36 (d, J = 8.0 Hz, 1H), 8.24 (d, J = 7.3 Hz) , 1H), 8.02 (d, J = 8.7 Hz, 1H), 7.74 (s, 1H), 7.52 - 7.29 (m, 3H), 4.11 (t, J = 8.5 Hz, 2H), 3.17 (t, J = 8.4 Hz, 2H), 2.75 (s, 3H), 2.15 (s, 3H).
实施例55Example 55
(1-乙酰基-1H-吲哚-3-甲酰氨基)苯甲酸的合成，合成方法如实施例8。1H NMR(400MHz，DMSO)δ12.99(s，1H)，10.24(s，1H)，8.84(s，1H)，8.38(d，J＝1.1Hz，1H)，8.36(d，J＝1.9Hz，1H)，8.27(dd，J＝6.5，1.3Hz，1H)，8.11(dd，J＝8.1，1.1Hz，1H)，7.68(d，J＝7.8Hz，1H)，7.51(t，J＝7.9Hz，1H)，7.40(pd，J＝7.2，1.4Hz，2H)，2.76(s，3H).Synthesis of (1-acetyl-1H-indole-3-carboxamido)benzoic acid, as described in Example 8. 1H NMR (400 MHz, DMSO) δ 12.99 (s, 1H), 10.24 (s, 1H) ), 8.84 (s, 1H), 8.38 (d, J = 1.1 Hz, 1H), 8.36 (d, J = 1.9 Hz, 1H), 8.27 (dd, J = 6.5, 1.3 Hz, 1H), 8.11 (dd) , J = 8.1, 1.1 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.51 (t, J = 7.9 Hz, 1H), 7.40 (pd, J = 7.2, 1.4 Hz, 2H), 2.76 (s, 3H).
实施例56Example 56
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-5-溴苯甲酸甲酯的合成，合成方法如实施例47。1H NMR(400MHz，DMSO)δ10.39(s，1H)，8.83(s，1H)，8.44(s，1H)，8.37(s，1H)，8.35(s，1H)，8.26(d，J＝7.1Hz，1H)，7.77(s，1H)，7.56-7.31(m，2H)，3.90(s，3H)，2.76(s，3H).Synthesis of methyl 3-(1-acetyl-1H-indole-3-carboxamido)-5-bromobenzoate as described in Example 47. 1H NMR (400 MHz, DMSO) δ 10.39 (s, 1H), 8.83 (s, 1H), 8.44 (s, 1H), 8.37 (s, 1H), 8.35 (s, 1H), 8.26 (d, J = 7.1 Hz, 1H), 7.77 (s, 1H), 7.56-7.31 (m, 2H), 3.90 (s, 3H), 2.76 (s, 3H).
实施例57Example 57
(1-乙酰基-1H-吲哚-3-甲酰氨基)-5-溴苯甲酸的合成，合成方法如实施例8。1H NMR(400MHz，DMSO)δ10.38(s，1H)，8.84(s，1H)，8.41(t，J＝1.9Hz，1H)，8.36(d，J＝7.3Hz，1H)，8.34- 8.31(m，1H)，8.28-8.23(m，1H)，7.78-7.74(m，1H)，7.45-7.35(m，2H)，2.76(s，3H).Synthesis of (1-acetyl-1H-indole-3-carboxamido)-5-bromobenzoic acid as described in Example 8. 1H NMR (400 MHz, DMSO) δ 10.38 (s, 1H), 8.84 (s, 1H), 8.41 (t, J = 1.9 Hz, 1H), 8.36 (d, J = 7.3 Hz, 1H), 8.34 - 8.31 (m, 1H), 8.28-8.23 (m, 1H), 7.78- 7.74 (m, 1H), 7.45-7.35 (m, 2H), 2.76 (s, 3H).
实施例58Example 58
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-5-(呋喃-2-基)苯甲酸甲酯的合成，合成方法如实施例47。1H NMR(400MHz，DMSO)δ10.35(s，1H)，8.87(s，1H)，8.47(s，1H)，8.37(d，J＝7.7Hz，1H)，8.34(s，1H)，8.30(d，J＝7.0Hz，1H)，7.98(s，1H)，7.84(s，1H)，7.54-7.28(m，2H)，7.07(d，J＝3.0Hz，1H)，6.66(s，1H)，3.92(s，3H)，2.77(s，3H).Synthesis of methyl 3-(1-acetyl-1H-indole-3-carboxamido)-5-(furan-2-yl)benzoate as synthesized in Example 47. 1H NMR (400 MHz, DMSO) δ 10.35 (s, 1H), 8.87 (s, 1H), 8.47 (s, 1H), 8.37 (d, J = 7.7 Hz, 1H), 8.34 (s, 1H), 8.30 (d, J = 7.0 Hz) , 1H), 7.98 (s, 1H), 7.84 (s, 1H), 7.54-7.28 (m, 2H), 7.07 (d, J = 3.0 Hz, 1H), 6.66 (s, 1H), 3.92 (s, 3H), 2.77 (s, 3H).
实施例59Example 59
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-5-(((四氢-2H-吡喃-2-基)氧基)甲基)苯甲酸甲酯的合成，合成方法如实施例47。1H NMR(400MHz，DMSO)δ10.29(s，1H)，8.84(s，1H)，8.38(s，2H)，8.27(d，J＝7.2Hz，1H)，8.09(s，1H)，7.67(s，1H)，7.46-7.28(m，2H)，4.77(s，1H)，4.73(d，J＝6.7Hz，1H)，4.55(d，J＝12.4Hz，1H)，3.89(s，3H)，3.86-3.77(m，1H)，3.55-3.47(m，1H)，2.76(s，3H)，1.84-1.64(m，2H)，1.62-1.42(m，4H).Synthesis of methyl 3-(1-acetyl-1H-indole-3-carboxamido)-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)benzoate, The synthesis method is as in Example 47. 1H NMR (400 MHz, DMSO) δ 10.29 (s, 1H), 8.84 (s, 1H), 8.38 (s, 2H), 8.27 (d, J = 7.2 Hz, 1H), 8.09 (s, 1H), 7.67 (s, 1H), 7.46-7.28 (m, 2H), 4.77 (s, 1H), 4.73 (d, J = 6.7 Hz, 1H), 4.55 (d, J = 12.4 Hz, 1H), 3.89 (s, 3H), 3.86-3.77 (m, 1H), 3.55-3.47 (m, 1H), 2.76 (s, 3H), 1.84-1.64 (m, 2H), 1.62-1.42 (m, 4H).
实施例60Example 60
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-5-(4-甲基哌嗪-1-基)苯甲酸甲酯的合成，合成方法如实施例47。1H NMR(400MHz，DMSO)δ10.34(s，1H)，8.97(s，1H)，8.37(d，J＝7.9Hz，1H)，8.27(d，J＝7.6Hz，1H)，7.93(s，2H)，7.46-7.33(m，2H)，7.31(s，1H)，3.87(s，4H)，3.50(s，3H)，3.18(s，4H)，2.85(s，3H)，2.77(s，3H).Synthesis of methyl 3-(1-acetyl-1H-indole-3-carboxamido)-5-(4-methylpiperazin-1-yl)benzoate as synthesized in Example 47. 1H NMR (400MHz, DMSO) δ10.34 (s, 1H), 8.97 (s, 1H), 8.37 (d, J = 7.9 Hz, 1H), 8.27 (d, J = 7.6 Hz, 1H), 7.93 (s, 2H) ), 7.46-7.33 (m, 2H), 7.31 (s, 1H), 3.87 (s, 4H), 3.50 (s, 3H), 3.18 (s, 4H), 2.85 (s, 3H), 2.77 (s, 3H).
实施例61Example 61
(1-乙酰基-1H-吲哚-3-甲酰氨基)-5-(((四氢-2H-吡喃-2-基)氧基)甲基)苯甲酸的合成，合成方法如实施例7。1H NMR(400MHz，DMSO)δ13.04(s，1H)，10.27(s，1H)，8.85(s，1H)，8.37(d，J＝7.8Hz，1H)，8.34(s，1H)，8.27(d，J＝7.1Hz，1H)，8.07(s，1H)，7.65(s，1H)，7.46-7.32(m，2H)，4.74(t，J＝7.9Hz，2H)，4.54(d，J＝12.4Hz，1H)，3.82(m，1H)，3.53-3.48(m，1H)，2.76(s，3H)，1.74(m，2H)，1.53(m，4H).Synthesis of (1-acetyl-1H-indole-3-formylamino)-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)benzoic acid, synthesis method as implemented Example 7. 1H NMR (400MHz, DMSO) δ 13.04 (s, 1H), 10.27 (s, 1H), 8.85 (s, 1H), 8.37 (d, J = 7.8 Hz, 1H), 8.34 (s, 1H) ), 8.27 (d, J = 7.1 Hz, 1H), 8.07 (s, 1H), 7.65 (s, 1H), 7.46-7.32 (m, 2H), 4.74 (t, J = 7.9 Hz, 2H), 4.54 (d, J = 12.4 Hz, 1H), 3.82 (m, 1H), 3.53-3.48 (m, 1H), 2.76 (s, 3H), 1.74 (m, 2H), 1.53 (m, 4H).
实施例62Example 62
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-5-(羟甲基)苯甲酸甲酯的合成，合成方法如实施例47。1H NMR(400MHz，DMSO)δ10.25(s，1H)，8.83(s，1H)，8.36(dd，J＝7.1，1.3Hz，1H)，8.31(s，1H)，8.29-8.24(m，1H)，8.08(s，1H)，7.66(s，1H)，7.39(pd，J＝7.2Hz，1.4Hz，2H)，5.45(t，J＝5.7Hz，1H)，4.59(d，J＝5.5Hz，2H)，3.88(s，3H)，2.75(s，3H).Synthesis of methyl 3-(1-acetyl-1H-indole-3-carboxamido)-5-(hydroxymethyl)benzoate, as described in Example 47. 1H NMR (400 MHz, DMSO) δ 10. 25(s,1H),8.83(s,1H),8.36(dd,J=7.1,1.3Hz,1H),8.31(s,1H),8.29-8.24(m,1H),8.08(s,1H) , 7.66 (s, 1H), 7.39 (pd, J = 7.2 Hz, 1.4 Hz, 2H), 5.45 (t, J = 5.7 Hz, 1H), 4.59 (d, J = 5.5 Hz, 2H), 3.88 (s) , 3H), 2.75 (s, 3H).
实施例63Example 63
(1-乙酰基-1H-吲哚-3-甲酰氨基)-5-(呋喃-2-基)苯甲酸的合成，合成方法如实施例8。1H NMR(400MHz，DMSO)δ10.34(s，1H)，8.88(s，1H)，8.45(s，1H)，8.37(d，J＝7.4Hz，1H)，8.31(s，1H)，8.28(d，J＝1.5Hz，1H)，7.98(s，1H)，7.83(s，1H)，7.47-7.34(m，2H)，7.05(d，J＝3.4Hz，1H)，6.65(m，1H)，2.77(s，3H).Synthesis of (1-acetyl-1H-indole-3-carboxamido)-5-(furan-2-yl)benzoic acid, as described in Example 8. 1H NMR (400 MHz, DMSO) δ 10.34 ( s, 1H), 8.88 (s, 1H), 8.45 (s, 1H), 8.37 (d, J = 7.4 Hz, 1H), 8.31 (s, 1H), 8.28 (d, J = 1.5 Hz, 1H), 7.98 (s, 1H), 7.83 (s, 1H), 7.47-7.34 (m, 2H), 7.05 (d, J = 3.4 Hz, 1H), 6.65 (m, 1H), 2.77 (s, 3H).
实施例64Example 64
(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-((3-氟苯基)氨基)苯甲酸甲酯的合成，合成方法如实施例47。1H NMR(400MHz，DMSO)δ9.74(s，1H)，8.73(s，1H)，8.37(d，J＝7.4Hz，1H)，8.28(s，1H)，8.23-8.17(m，1H)，8.11(d，J＝2.0Hz，1H)，7.77(dd，J＝8.6，2.0Hz，1H)，7.43(d，J＝3.6Hz，1H)，7.41(s，1H)，7.39(t，J＝1.7Hz，1H)，7.30(dd，J＝15.2，8.1Hz，1H)，6.97(dd，J＝8.1，1.4Hz，1H)，6.90(dt，J＝11.5，2.2Hz，1H)，6.73(td，J＝8.4，2.2Hz，1H)，3.84(s，3H)，2.71(s，3H).Synthesis of methyl (1-acetyl-1H-indole-3-carboxamido)-4-((3-fluorophenyl)amino)benzoate as synthesized in Example 47. 1H NMR (400 MHz, DMSO ) δ 9.74 (s, 1H), 8.73 (s, 1H), 8.37 (d, J = 7.4 Hz, 1H), 8.28 (s, 1H), 8.23-8.17 (m, 1H), 8.11 (d, J) =2.0 Hz, 1H), 7.77 (dd, J = 8.6, 2.0 Hz, 1H), 7.43 (d, J = 3.6 Hz, 1H), 7.41 (s, 1H), 7.39 (t, J = 1.7 Hz, 1H) ), 7.30 (dd, J = 15.2, 8.1 Hz, 1H), 6.97 (dd, J = 8.1, 1.4 Hz, 1H), 6.90 (dt, J = 11.5, 2.2 Hz, 1H), 6.73 (td, J = 8.4, 2.2 Hz, 1H), 3.84 (s, 3H), 2.71 (s, 3H).
实施例65Example 65
3-(1-乙酰基-1H-吲哚-3-甲酰胺基)-4-(苄基氨基)苯甲酸甲酯的合成，合成方法如实施例47。1H NMR(400MHz，DMSO)δ9.67(s，1H)，8.80(s，1H)，8.37(d，J＝7.5Hz，1H)，8.28-8.19(m，1H)，7.77(d，J＝2.0Hz，1H)，7.63(dd，J＝8.6，2.0Hz，1H)，7.45-7.40(m，2H)，7.40-7.36(m，2H)，7.33(t，J＝7.5Hz，2H)，7.23(t，J＝7.2Hz，1H)，6.68(t，J＝6.1Hz，1H)，6.59(d，J＝ 8.7Hz，1H)，4.47(d，J＝6.0Hz，2H)，3.76(s，3H)，2.75(s，3H).Synthesis of methyl 3-(1-acetyl-1H-indole-3-carboxamido)-4-(benzylamino)benzoate, as described in Example 47. 1H NMR (400 MHz, DMSO) δ 9. 67(s,1H), 8.80(s,1H), 8.37(d,J=7.5Hz,1H), 8.28-8.19(m,1H),7.77(d,J=2.0Hz,1H),7.63(dd , J=8.6, 2.0 Hz, 1H), 7.45-7.40 (m, 2H), 7.40-7.36 (m, 2H), 7.33 (t, J = 7.5 Hz, 2H), 7.23 (t, J = 7.2 Hz, 1H), 6.68 (t, J = 6.1 Hz, 1H), 6.59 (d, J = 8.7 Hz, 1H), 4.47 (d, J = 6.0 Hz, 2H), 3.76 (s, 3H), 2.75 (s, 3H).
实施例66Example 66
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-(环戊基氨基)苯甲酸甲酯的合成，合成方法如实施例47。1H NMR(400MHz，DMSO)δ9.59(s，1H)，8.78(s，1H)，8.37(d，J＝7.6Hz，1H)，8.25-8.09(m，1H)，7.80(d，J＝2.0Hz，1H)，7.73(dd，J＝8.6，2.0Hz，1H)，7.47-7.32(m，2H)，6.81(d，J＝8.8Hz，1H)，5.60(d，J＝6.4Hz，1H)，3.88(dd，J＝12.2，6.5Hz，1H)，3.78(s，3H)，2.74(s，3H)，2.10-1.95(m，2H)，1.67(d，J＝6.4Hz，2H)，1.57(dd，J＝9.8，5.4Hz，2H)，1.54-1.46(m，2H).Synthesis of methyl 3-(1-acetyl-1H-indole-3-carboxamido)-4-(cyclopentylamino)benzoate as synthesized in Example 47. 1H NMR (400 MHz, DMSO) δ 9 .59(s,1H), 8.78(s,1H), 8.37(d,J=7.6Hz,1H), 8.25-8.09(m,1H), 7.80(d,J=2.0Hz,1H),7.73( Dd, J = 8.6, 2.0 Hz, 1H), 7.47-7.32 (m, 2H), 6.81 (d, J = 8.8 Hz, 1H), 5.60 (d, J = 6.4 Hz, 1H), 3.88 (dd, J =12.2, 6.5 Hz, 1H), 3.78 (s, 3H), 2.74 (s, 3H), 2.10 - 1.95 (m, 2H), 1.67 (d, J = 6.4 Hz, 2H), 1.57 (dd, J = 9.8, 5.4 Hz, 2H), 1.54-1.46 (m, 2H).
实施例67Example 67
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-(环丙基氨基)苯甲酸甲酯的合成，合成方法如实施例47。1H NMR(400MHz，DMSO)δ9.46(s，1H)，8.77(s，1H)，8.37(d，J＝7.6Hz，1H)，8.23-8.11(m，1H)，7.83(d，J＝2.0Hz，1H)，7.77(dd，J＝8.6，2.0Hz，1H)，7.48-7.28(m，2H)，7.11(d，J＝8.6Hz，1H)，6.35(s，1H)，3.79(s，3H)，2.74(s，3H)，1.65-1.51(m，1H)，0.84-0.75(m，2H)，0.54-0.45(m，2H).Synthesis of methyl 3-(1-acetyl-1H-indole-3-carboxamido)-4-(cyclopropylamino)benzoate as synthesized in Example 47. 1H NMR (400 MHz, DMSO) δ 9 .46(s,1H), 8.77(s,1H), 8.37(d,J=7.6Hz,1H), 8.23-8.11(m,1H),7.83(d,J=2.0Hz,1H),7.77( Dd, J = 8.6, 2.0 Hz, 1H), 7.48-7.28 (m, 2H), 7.11 (d, J = 8.6 Hz, 1H), 6.35 (s, 1H), 3.79 (s, 3H), 2.74 (s) , 3H), 1.65-1.51 (m, 1H), 0.84-0.75 (m, 2H), 0.54-0.45 (m, 2H).
实施例68Example 68
(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-(环戊基氨基)苯甲酸的合成，合成方法如实施例7。1H NMR(400MHz，DMSO)δ12.17(s，1H)，9.62(s，1H)，8.79(s，1H)，8.37(d，J＝7.7Hz，1H)，8.18(d，J＝7.0Hz，1H)，7.77(d，J＝1.9Hz，1H)，7.71(dd，J＝8.6，1.9Hz，1H)，7.46-7.32(m，2H)，6.79(d，J＝8.7Hz，1H)，5.51(d，J＝6.3Hz，1H)，3.87(dd，J＝12.5，6.3Hz，1H)，2.74(s，3H)，2.10-1.95(m，2H)，1.67(d，J＝6.6Hz，2H)，1.62-1.54(m，2H)，1.50(dd，J＝12.1，6.7Hz，2H).Synthesis of (1-acetyl-1H-indole-3-carboxamido)-4-(cyclopentylamino)benzoic acid, as described in Example 7. 1H NMR (400 MHz, DMSO) δ 12.17 (s , 1H), 9.62 (s, 1H), 8.79 (s, 1H), 8.37 (d, J = 7.7 Hz, 1H), 8.18 (d, J = 7.0 Hz, 1H), 7.77 (d, J = 1.9 Hz) , 1H), 7.71 (dd, J = 8.6, 1.9 Hz, 1H), 7.46-7.32 (m, 2H), 6.79 (d, J = 8.7 Hz, 1H), 5.51 (d, J = 6.3 Hz, 1H) , 3.87 (dd, J = 12.5, 6.3 Hz, 1H), 2.74 (s, 3H), 2.10 - 1.95 (m, 2H), 1.67 (d, J = 6.6 Hz, 2H), 1.62-1.54 (m, 2H) ), 1.50 (dd, J = 12.1, 6.7 Hz, 2H).
实施例69Example 69
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-(异丙基氨基)苯甲酸甲酯的合成，合成方法如实施例47。1H NMR(400MHz，DMSO)δ9.55(s，1H)，8.78(s，1H)，8.37(d，J＝7.9Hz，1H)，8.18(d，J＝7.6Hz，1H)，7.78(s，1H)，7.73(d，J＝8.6Hz，1H)，7.51-7.27(m，2H)，6.79(d，J＝8.8Hz，1H)，5.46(d，J＝7.5Hz，1H)，3.77(s，3H)，2.74(s，3H)，1.20(d，J＝6.3Hz，6H).Synthesis of methyl 3-(1-acetyl-1H-indole-3-carboxamido)-4-(isopropylamino)benzoate as synthesized in Example 47. 1H NMR (400 MHz, DMSO) δ 9 .55(s,1H), 8.78(s,1H), 8.37(d,J=7.9Hz,1H), 8.18(d,J=7.6Hz,1H),7.78(s,1H),7.73(d, J=8.6 Hz, 1H), 7.51-7.27 (m, 2H), 6.79 (d, J = 8.8 Hz, 1H), 5.46 (d, J = 7.5 Hz, 1H), 3.77 (s, 3H), 2.74 ( s, 3H), 1.20 (d, J = 6.3 Hz, 6H).
实施例70Example 70
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-(丁基氨基)苯甲酸叔丁酯的合成，合成方法如实施例47。1H NMR(400MHz，DMSO)δ9.79(s，1H)，8.40(s，1H)，8.35(d，J＝8.2Hz，1H)，8.23(d，J＝8.3Hz，1H)，8.02(d，J＝7.8Hz，1H)，7.91(s，1H)，7.79(dd，J＝12.6，8.9Hz，2H)，7.47(d，J＝8.3Hz，1H)，7.40(t，J＝7.6Hz，1H)，7.31(t，J＝7.6Hz，2H)，7.19(t，J＝7.6Hz，1H)，2.63(s，3H)，2.32(s，3H)，1.54(s，9H)，0.86(dd，J＝14.6，7.7Hz，6H).Synthesis of tert-butyl 3-(1-acetyl-1H-indole-3-carboxamido)-4-(butylamino)benzoate, as described in Example 47. 1H NMR (400 MHz, DMSO) δ9 .79(s,1H), 8.40(s,1H), 8.35(d,J=8.2Hz,1H), 8.23(d,J=8.3Hz,1H),8.02(d,J=7.8Hz,1H) , 7.91 (s, 1H), 7.79 (dd, J = 12.6, 8.9 Hz, 2H), 7.47 (d, J = 8.3 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.31 (t, J = 7.6 Hz, 2H), 7.19 (t, J = 7.6 Hz, 1H), 2.63 (s, 3H), 2.32 (s, 3H), 1.54 (s, 9H), 0.86 (dd, J = 14.6, 7.7 Hz, 6H).
实施例71Example 71
(1-乙酰基-1H-吲哚-3-甲酰胺基)-4-(丁基氨基)苯甲酸的合成，3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-(丁基氨基)苯甲酸叔丁酯合成方法如实施例45。Synthesis of (1-acetyl-1H-indole-3-carboxamido)-4-(butylamino)benzoic acid, 3-(1-acetyl-1H-indole-3-carboxamido)- The synthesis method of tert-butyl 4-(butylamino)benzoate was as in Example 45.
将3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-(丁基氨基)苯甲酸叔丁酯(50mg，0.112mmol)溶于二氯甲烷(20mL)中，加入三氟乙酸(0.5mL)。室温反应5h，水洗，DCM萃取(3×20mL)，合并有机层，饱和氯化钠溶液洗一遍，无水硫酸钠干燥，旋干，用乙酸乙酯和石油醚重结晶，得到产物28.9mg(57.5％)。1H NMR(400MHz，DMSO)δ9.77(s，1H)，8.39(s，1H)，8.34(d，J＝8.3Hz，1H)，8.23(d，J＝8.3Hz，1H)，8.05-7.94(m，2H)，7.85(d，J＝8.2Hz，1H)，7.78(d，J＝7.8Hz，1H)，7.48(d，J＝8.2Hz，1H)，7.39(t，J＝7.7Hz，1H)，7.30(t，J＝8.6Hz，2H)，7.18(t，J＝7.5Hz，1H)，2.63(s，3H)，2.30(s，3H)，0.87(m，6H).tert-Butyl 3-(1-acetyl-1H-indole-3-carboxamido)-4-(butylamino)benzoate (50 mg, 0.112 mmol) was dissolved in dichloromethane (20 mL) Trifluoroacetic acid (0.5 mL). The reaction was carried out for 5 h at room temperature, EtOAc (EtOAc m. 57.5%). 1H NMR (400MHz, DMSO) δ 9.77 (s, 1H), 8.39 (s, 1H), 8.34 (d, J = 8.3 Hz, 1H), 8.23 (d, J = 8.3 Hz, 1H), 8.05-7.94 (m, 2H), 7.85 (d, J = 8.2 Hz, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.48 (d, J = 8.2 Hz, 1H), 7.39 (t, J = 7.7 Hz) , 1H), 7.30 (t, J = 8.6 Hz, 2H), 7.18 (t, J = 7.5 Hz, 1H), 2.63 (s, 3H), 2.30 (s, 3H), 0.87 (m, 6H).
实施例72Example 72
(1-乙酰基-1H-吲哚-3-甲酰胺基)-4-(丙基氨基)苯甲酸的合成，合成方法如实施例71。1H NMR(400MHz，DMSO)δ12.24(s，1H)，9.56(s，1H)，8.77(s，1H)，8.37(d，J＝7.9Hz，1H)，8.19(d，J＝7.4Hz，1H)，7.74(s，1H)，7.71(d，J＝8.6Hz，1H)，7.51-7.27(m，2H)，6.74(d，J＝8.6 Hz，1H)，5.80(s，1H)，3.14(t，J＝6.9Hz，3H)，2.74(s，3H)，1.59(dd，J＝14.4，7.2Hz，2H)，0.93(t，J＝7.3Hz，3H).Synthesis of (1-acetyl-1H-indole-3-carboxamido)-4-(propylamino)benzoic acid as described in Example 71. 1H NMR (400 MHz, DMSO) δ 12.24 (s, 1H), 9.56 (s, 1H), 8.77 (s, 1H), 8.37 (d, J = 7.9 Hz, 1H), 8.19 (d, J = 7.4 Hz, 1H), 7.74 (s, 1H), 7.71 ( d, J = 8.6 Hz, 1H), 7.51-7.27 (m, 2H), 6.74 (d, J = 8.6 Hz, 1H), 5.80 (s, 1H), 3.14 (t, J = 6.9 Hz, 3H), 2.74 (s, 3H), 1.59 (dd, J = 14.4, 7.2 Hz, 2H), 0.93 (t, J = 7.3 Hz, 3H).
实施例73Example 73
(1-乙酰基-1H-吲哚-3-甲酰胺基)-4-氟苯甲酸的合成，合成方法如实施例71。1H NMR(400MHz，DMSO)δ10.11(s，1H)，8.84(s，1H)，8.37(d，J＝7.2Hz，2H)，8.21(d，J＝7.3Hz，1H)，7.83(s，1H)，7.50-7.33(m，3H)，2.75(s，3H).Synthesis of (1-acetyl-1H-indole-3-carboxamido)-4-fluorobenzoic acid, as described in Example 71. 1H NMR (400 MHz, DMSO) δ 10.11 (s, 1H), 8.84 (s, 1H), 8.37 (d, J = 7.2 Hz, 2H), 8.21 (d, J = 7.3 Hz, 1H), 7.83 (s, 1H), 7.50 - 7.33 (m, 3H), 2.75 (s, 3H).
实施例74Example 74
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-(苄基氨基)苯甲酸叔丁酯的合成，合成方法如实施例47。1H NMR(400MHz，DMSO)δ9.69(s，1H)，8.80(s，1H)，8.37(d，J＝7.5Hz，1H)，8.27-8.19(m，1H)，7.67(d，J＝1.9Hz，1H)，7.57(dd，J＝8.6，1.9Hz，1H)，7.39(dd，J＝7.1，5.2Hz，4H)，7.32(t，J＝7.5Hz，3H)，7.23(d，J＝7.2Hz，1H)，6.56(d，J＝8.8Hz，2H)，4.46(d，J＝6.0Hz，2H)，2.75(s，3H)，1.50(s，9H).Synthesis of tert-butyl 3-(1-acetyl-1H-indole-3-carboxamido)-4-(benzylamino)benzoate as synthesized in Example 47. 1H NMR (400 MHz, DMSO) δ 9 .69(s,1H), 8.80(s,1H), 8.37(d,J=7.5Hz,1H), 8.27-8.19(m,1H), 7.67(d,J=1.9Hz,1H),7.57( Dd, J = 8.6, 1.9 Hz, 1H), 7.39 (dd, J = 7.1, 5.2 Hz, 4H), 7.32 (t, J = 7.5 Hz, 3H), 7.23 (d, J = 7.2 Hz, 1H), 6.56 (d, J = 8.8 Hz, 2H), 4.46 (d, J = 6.0 Hz, 2H), 2.75 (s, 3H), 1.50 (s, 9H).
实施例75Example 75
(1-乙酰基-1H-吲哚-3-甲酰胺基)-4-(苄基氨基)苯甲酸的合成，合成方法如实施例71。1H NMR(400MHz，DMSO)δ12.46(s，1H)，9.66(s，1H)，8.80(s，1H)，8.38(d，J＝7.4Hz，1H)，8.23(d，J＝7.5Hz，1H)，7.75(s，1H)，7.61(d，J＝8.1Hz，1H)，7.40(d，J＝7.3Hz，4H)，7.34(d，J＝7.5Hz，2H)，7.24(d，J＝7.0Hz，1H)，6.57(d，J＝8.4Hz，1H)，4.47(s，2H)，2.75(s，3H).Synthesis of (1-acetyl-1H-indole-3-carboxamido)-4-(benzylamino)benzoic acid, as described in Example 71. 1H NMR (400 MHz, DMSO) δ 12.46 (s, 1H), 9.66 (s, 1H), 8.80 (s, 1H), 8.38 (d, J = 7.4 Hz, 1H), 8.23 (d, J = 7.5 Hz, 1H), 7.75 (s, 1H), 7.61 ( d, J = 8.1 Hz, 1H), 7.40 (d, J = 7.3 Hz, 4H), 7.34 (d, J = 7.5 Hz, 2H), 7.24 (d, J = 7.0 Hz, 1H), 6.57 (d, J = 8.4 Hz, 1H), 4.47 (s, 2H), 2.75 (s, 3H).
实施例76Example 76
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-(环丙基氨基)苯甲酸叔丁酯的合成，合成方法如实施例47。1H NMR(400MHz，DMSO)δ9.48(s，1H)，8.76(s，1H)，8.37(d，J＝7.8Hz，1H)，8.19(d，J＝7.1Hz，1H)，7.77-7.66(m，2H)，7.44-7.30(m，2H)，7.08(d，J＝9.1Hz，1H)，6.24(s，1H)，2.73(s，3H)，1.52(s，9H)，1.17(t，J＝7.1Hz，1H)，0.85(dd，J＝7.2，5.0Hz，2H)，0.78(d，J＝4.7Hz，2H).Synthesis of tert-butyl 3-(1-acetyl-1H-indole-3-carboxamido)-4-(cyclopropylamino)benzoate, as described in Example 47. 1H NMR (400 MHz, DMSO) δ 9.48 (s, 1H), 8.76 (s, 1H), 8.37 (d, J = 7.8 Hz, 1H), 8.19 (d, J = 7.1 Hz, 1H), 7.77 - 7.66 (m, 2H), 7.44 -7.30 (m, 2H), 7.08 (d, J = 9.1 Hz, 1H), 6.24 (s, 1H), 2.73 (s, 3H), 1.52 (s, 9H), 1.17 (t, J = 7.1 Hz, 1H), 0.85 (dd, J = 7.2, 5.0 Hz, 2H), 0.78 (d, J = 4.7 Hz, 2H).
实施例77Example 77
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-((环己基甲基)氨基)苯甲酸叔丁酯的合成，合成方法如实施例47。1H NMR(400MHz，DMSO)δ9.59(s，1H)，8.76(s，1H)，8.37(d，J＝7.9Hz，1H)，8.18(d，J＝7.8Hz，1H)，7.68(s，1H)，7.65(d，J＝4.2Hz，1H)，7.44-7.33(m，2H)，6.72(d，J＝8.7Hz，1H)，5.80(t，J＝5.7Hz，1H)，3.02(t，J＝6.2Hz，2H)，2.74(s，3H)，1.78(d，J＝12.5Hz，2H)，1.66(s，2H)，1.59(s，1H)，1.51(s，9H)，1.14(d，J＝8.2Hz，2H)，0.97-0.91(m，2H)，0.87-0.80(m，2H).Synthesis of tert-butyl 3-(1-acetyl-1H-indole-3-carboxamido)-4-((cyclohexylmethyl)amino)benzoate as synthesized in Example 47. 1H NMR (400 MHz , DMSO) δ 9.59 (s, 1H), 8.76 (s, 1H), 8.37 (d, J = 7.9 Hz, 1H), 8.18 (d, J = 7.8 Hz, 1H), 7.68 (s, 1H), 7.65 (d, J = 4.2 Hz, 1H), 7.44 - 7.33 (m, 2H), 6.72 (d, J = 8.7 Hz, 1H), 5.80 (t, J = 5.7 Hz, 1H), 3.02 (t, J = 6.2 Hz, 2H), 2.74 (s, 3H), 1.78 (d, J = 12.5 Hz, 2H), 1.66 (s, 2H), 1.59 (s, 1H), 1.51 (s, 9H), 1.14 (d) , J = 8.2 Hz, 2H), 0.97-0.91 (m, 2H), 0.87-0.80 (m, 2H).
实施例78Example 78
(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-((环己基甲基)氨基)苯甲酸的合成，合成方法如实施例71。1H NMR(400MHz，DMSO)δ12.25(s，1H)，9.58(s，1H)，8.77(s，1H)，8.37(d，J＝7.9Hz，1H)，8.18(d，J＝7.4Hz，1H)，7.72(s，1H)，7.69(s，1H)，7.43-7.32(m，2H)，6.72(d，J＝8.5Hz，1H)，3.03(d，J＝6.6Hz，2H)，2.74(s，3H)，1.79(d，J＝12.5Hz，2H)，1.67(d，J＝10.8Hz，2H)，1.61(d，J＝4.0Hz，2H)，1.23(s，1H)，1.16(s，2H)，0.94(dd，J＝22.5，11.0Hz，2H).Synthesis of (1-acetyl-1H-indole-3-carboxamido)-4-((cyclohexylmethyl)amino)benzoic acid, as described in Example 71. 1H NMR (400 MHz, DMSO) δ 12. 25(s,1H), 9.58(s,1H),8.77(s,1H),8.37(d,J=7.9Hz,1H),8.18(d,J=7.4Hz,1H),7.72(s,1H) ), 7.69 (s, 1H), 7.43 - 7.32 (m, 2H), 6.72 (d, J = 8.5 Hz, 1H), 3.03 (d, J = 6.6 Hz, 2H), 2.74 (s, 3H), 1.79 (d, J = 12.5 Hz, 2H), 1.67 (d, J = 10.8 Hz, 2H), 1.61 (d, J = 4.0 Hz, 2H), 1.23 (s, 1H), 1.16 (s, 2H), 0.94 (dd, J=22.5, 11.0 Hz, 2H).
实施例79Example 79
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-((3-氟苯基)氨基)苯甲酸叔丁酯的合成，合成方法如实施例47。1H NMR(400MHz，DMSO)δ10.37(s，1H)，8.84(s，1H)，8.40(s，1H)，8.38(d，J＝7.6Hz，1H)，8.33(s，1H)，8.28(d，J＝7.3Hz，1H)，7.88(s，1H)，7.56(m，3H)，7.46-7.36(m，2H)，7.28(t，J＝8.3Hz，1H)，2.78(s，3H)，1.60(s，9H).Synthesis of tert-butyl 3-(1-acetyl-1H-indole-3-carboxamido)-4-((3-fluorophenyl)amino)benzoate as synthesized in Example 47. 1H NMR ( 400MHz, DMSO) δ 10.37 (s, 1H), 8.84 (s, 1H), 8.40 (s, 1H), 8.38 (d, J = 7.6 Hz, 1H), 8.33 (s, 1H), 8.28 (d, J=7.3 Hz, 1H), 7.88 (s, 1H), 7.56 (m, 3H), 7.46-7.36 (m, 2H), 7.28 (t, J = 8.3 Hz, 1H), 2.78 (s, 3H), 1.60(s,9H).
实施例80Example 80
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-(苯基氨基)苯甲酸甲酯的合成，合成方法如实施例47。1H NMR(400MHz，DMSO)δ9.73(s，1H)，8.75(s，1H)，8.37(d，J＝7.4Hz，1H)，8.26-8.17(m，1H)，8.08(s，1H)，8.06(d，J＝2.0Hz，1H)，7.73(dd，J＝8.6，2.0Hz，1H)，7.44-7.36(m， 2H)，7.36-7.33(m，1H)，7.32(d，J＝2.5Hz，1H)，7.30(d，J＝1.3Hz，1H)，7.18(s，1H)，7.16(s，1H)，6.99(t，J＝7.3Hz，1H)，3.82(s，3H)，2.72(s，3H).Synthesis of methyl 3-(1-acetyl-1H-indole-3-carboxamido)-4-(phenylamino)benzoate, as described in Example 47. 1H NMR (400 MHz, DMSO) δ 9. 73(s,1H), 8.75(s,1H), 8.37(d,J=7.4Hz,1H), 8.26-8.17(m,1H),8.08(s,1H),8.06(d,J=2.0Hz , 1H), 7.73 (dd, J = 8.6, 2.0 Hz, 1H), 7.44 - 7.36 (m, 2H), 7.36-7.33 (m, 1H), 7.32 (d, J = 2.5 Hz, 1H), 7.30 ( d, J = 1.3 Hz, 1H), 7.18 (s, 1H), 7.16 (s, 1H), 6.99 (t, J = 7.3 Hz, 1H), 3.82 (s, 3H), 2.72 (s, 3H).
实施例81Example 81
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-(丙基氨基)苯甲酸叔丁酯的合成，合成方法如实施例47。1H NMR(400MHz，DMSO)δ9.58(s，1H)，8.77(s，1H)，8.37(d，J＝8.0Hz，1H)，8.19(d，J＝7.4Hz，1H)，7.68(s，1H)，7.66(s，1H)，7.46-7.32(m，2H)，6.73(d，J＝9.2Hz，1H)，5.79(t，J＝5.4Hz，1H)，3.13(dd，J＝13.3，6.5Hz，2H)，2.74(s，3H)，1.58(d，J＝7.6Hz，2H)，1.51(s，9H)，0.93(t，J＝7.3Hz，3H).Synthesis of tert-butyl 3-(1-acetyl-1H-indole-3-carboxamido)-4-(propylamino)benzoate as synthesized in Example 47. 1H NMR (400 MHz, DMSO) δ 9 .58(s,1H), 8.77(s,1H), 8.37(d,J=8.0Hz,1H), 8.19(d,J=7.4Hz,1H), 7.68(s,1H),7.66(s, 1H), 7.46-7.32 (m, 2H), 6.73 (d, J = 9.2 Hz, 1H), 5.79 (t, J = 5.4 Hz, 1H), 3.13 (dd, J = 13.3, 6.5 Hz, 2H), 2.74 (s, 3H), 1.58 (d, J = 7.6 Hz, 2H), 1.51 (s, 9H), 0.93 (t, J = 7.3 Hz, 3H).
实施例82Example 82
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-(环庚基氨基)苯甲酸叔丁酯的合成，合成方法如实施例47。1H NMR(400MHz，DMSO)δ9.62(s，1H)，8.77(s，1H)，8.37(d，J＝7.7Hz，1H)，8.18(d，J＝6.9Hz，1H)，7.68(dd，J＝4.4，2.5Hz，2H)，7.48-7.33(m，2H)，6.69(d，J＝9.3Hz，1H)，5.34(d，J＝7.5Hz，1H)，3.55(m，1H)，2.74(s，3H)，1.91(m，2H)，1.64(m，3H)，1.56(m，3H)，1.51(s，9H).Synthesis of tert-butyl 3-(1-acetyl-1H-indole-3-carboxamido)-4-(cycloheptylamino)benzoate as described in Example 47. 1H NMR (400 MHz, DMSO) δ 9.62 (s, 1H), 8.77 (s, 1H), 8.37 (d, J = 7.7 Hz, 1H), 8.18 (d, J = 6.9 Hz, 1H), 7.68 (dd, J = 4.4, 2.5 Hz) , 2H), 7.48-7.33 (m, 2H), 6.69 (d, J = 9.3 Hz, 1H), 5.34 (d, J = 7.5 Hz, 1H), 3.55 (m, 1H), 2.74 (s, 3H) , 1.91 (m, 2H), 1.64 (m, 3H), 1.56 (m, 3H), 1.51 (s, 9H).
实施例83Example 83
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-((环丙基甲基)氨基)苯甲酸叔丁酯的合成，合成方法如实施例47。1H NMR(400MHz，DMSO)δ9.64(s，1H)，8.79(s，1H)，8.37(d，J＝7.6Hz，1H)，8.23-8.17(m，1H)，7.68(s，1H)，7.67(d，J＝2.0Hz，1H)，7.45-7.33(m，2H)，6.77(d，J＝9.3Hz，1H)，5.81(t，J＝5.5Hz，1H)，3.07(t，J＝6.1Hz，2H)，2.74(s，3H)，1.52(s，9H)，1.13-1.04(m，1H)，0.51-0.42(m，2H)，0.30-0.21(m，2H).Synthesis of tert-butyl 3-(1-acetyl-1H-indole-3-carboxamido)-4-((cyclopropylmethyl)amino)benzoate as synthesized in Example 47. 1H NMR ( 400MHz, DMSO) δ 9.64 (s, 1H), 8.79 (s, 1H), 8.37 (d, J = 7.6 Hz, 1H), 8.23-8.17 (m, 1H), 7.68 (s, 1H), 7.67 ( d, J = 2.0 Hz, 1H), 7.45-7.33 (m, 2H), 6.77 (d, J = 9.3 Hz, 1H), 5.81 (t, J = 5.5 Hz, 1H), 3.07 (t, J = 6.1) Hz, 2H), 2.74 (s, 3H), 1.52 (s, 9H), 1.13-1.04 (m, 1H), 0.51-0.42 (m, 2H), 0.30-0.21 (m, 2H).
实施例84Example 84
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-(异丁基氨基)苯甲酸叔丁酯的合成，合成方法如实施例47。1H NMR(400MHz，DMSO)δ9.63(s，1H)，8.78(s，1H)，8.37(d，J＝7.9Hz，1H)，8.19(d，J＝7.2Hz，1H)，7.68(s，1H)，7.65(d，J＝2.7Hz，1H)，7.46-7.31(m，2H)，6.73(d，J＝8.6Hz，1H)，5.79(t，J＝5.7Hz，1H)，2.99(t，J＝6.3Hz，2H)，2.74(s，3H)，1.88(dt，J＝13.3，6.7Hz，1H)，1.52(s，9H)，0.92(d，J＝6.6Hz，6H).Synthesis of tert-butyl 3-(1-acetyl-1H-indole-3-carboxamido)-4-(isobutylamino)benzoate, as described in Example 47. 1H NMR (400 MHz, DMSO) δ 9.63 (s, 1H), 8.78 (s, 1H), 8.37 (d, J = 7.9 Hz, 1H), 8.19 (d, J = 7.2 Hz, 1H), 7.68 (s, 1H), 7.65 (d) , J=2.7Hz, 1H), 7.46-7.31(m, 2H), 6.73(d, J=8.6Hz, 1H), 5.79(t, J=5.7Hz, 1H), 2.99(t, J=6.3Hz , 2H), 2.74 (s, 3H), 1.88 (dt, J = 13.3, 6.7 Hz, 1H), 1.52 (s, 9H), 0.92 (d, J = 6.6 Hz, 6H).
实施例85Example 85
(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-(环庚基氨基)苯甲酸的合成，合成方法如实施例71。1H NMR(400MHz，DMSO)δ12.18(s，1H)，9.62(s，1H)，8.78(s，1H)，8.37(d，J＝7.9Hz，1H)，8.18(d，J＝7.5Hz，1H)，7.75(s，1H)，7.71(d，J＝8.6Hz，1H)，7.46-7.31(m，2H)，6.69(d，J＝8.7Hz，1H)，5.37(d，J＝7.1Hz，1H)，3.58(m，1H)，2.74(s，3H)，1.97-1.85(m，2H)，1.71-1.46(m，10H).Synthesis of (1-acetyl-1H-indole-3-carboxamido)-4-(cycloheptylamino)benzoic acid, as described in Example 71. 1H NMR (400 MHz, DMSO) δ 12.18 (s , 1H), 9.62 (s, 1H), 8.78 (s, 1H), 8.37 (d, J = 7.9 Hz, 1H), 8.18 (d, J = 7.5 Hz, 1H), 7.75 (s, 1H), 7.71 (d, J = 8.6 Hz, 1H), 7.46 - 7.31 (m, 2H), 6.69 (d, J = 8.7 Hz, 1H), 5.37 (d, J = 7.1 Hz, 1H), 3.58 (m, 1H) , 2.74 (s, 3H), 1.97-1.85 (m, 2H), 1.71-1.46 (m, 10H).
实施例86Example 86
(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-((环丙基甲基)氨基)苯甲酸的合成，合成方法如实施例71。1H NMR(400MHz，DMSO)δ12.22(s，1H)，9.63(s，1H)，8.79(s，1H)，8.37(d，J＝7.9Hz，1H)，8.20(d，J＝7.4Hz，1H)，7.75(s，1H)，7.71(d，J＝8.5Hz，1H)，7.48-7.30(m，2H)，6.77(d，J＝8.6Hz，1H)，5.82(s，1H)，3.07(d，J＝4.9Hz，2H)，2.74(s，3H)，1.10(m，1H)，0.47(m，2H)，0.26(m，2H).Synthesis of (1-acetyl-1H-indole-3-carboxamido)-4-((cyclopropylmethyl)amino)benzoic acid, as described in Example 71. 1H NMR (400 MHz, DMSO) δ12 .22(s,1H), 9.63(s,1H), 8.79(s,1H), 8.37(d,J=7.9Hz,1H), 8.20(d,J=7.4Hz,1H),7.75(s, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.48-7.30 (m, 2H), 6.77 (d, J = 8.6 Hz, 1H), 5.82 (s, 1H), 3.07 (d, J = 4.9) Hz, 2H), 2.74 (s, 3H), 1.10 (m, 1H), 0.47 (m, 2H), 0.26 (m, 2H).
实施例87Example 87
(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-(异丁基氨基)苯甲酸的合成，合成方法如实施例71。1H NMR(400MHz，DMSO)δ12.34(s，1H)，8.78(s，1H)，8.37(d，J＝7.9Hz，1H)，8.19(d，J＝7.7Hz，1H)，7.72(d，J＝2.2Hz，1H)，7.70(d，J＝1.7Hz，1H)，7.45-7.32(m，2H)，6.74(d，J＝8.6Hz，1H)，3.00(d，J＝6.8Hz，2H)，2.74(s，3H)，1.89(dt，J＝13.3，6.6Hz，1H)，0.93(d，J＝6.6Hz，6H).Synthesis of (1-acetyl-1H-indole-3-carboxamido)-4-(isobutylamino)benzoic acid, as described in Example 71. 1H NMR (400 MHz, DMSO) δ 12.. , 1H), 8.78 (s, 1H), 8.37 (d, J = 7.9 Hz, 1H), 8.19 (d, J = 7.7 Hz, 1H), 7.72 (d, J = 2.2 Hz, 1H), 7.70 (d , J = 1.7 Hz, 1H), 7.45-7.32 (m, 2H), 6.74 (d, J = 8.6 Hz, 1H), 3.00 (d, J = 6.8 Hz, 2H), 2.74 (s, 3H), 1.89 (dt, J = 13.3, 6.6 Hz, 1H), 0.93 (d, J = 6.6 Hz, 6H).
实施例88Example 88
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯甲酸叔丁酯的合成，合成方法如实施例47。1H NMR(400MHz，DMSO)δ9.59(s，1H)，8.76(s，1H)，8.37(d，J＝7.7Hz，1H)，8.24-8.13(m，1H)，7.67(dd，J＝8.6，1.9Hz，1H)，7.64(d，J＝1.9Hz，1H)，7.43-7.31(m，2H)，6.76(d，J＝8.7Hz，1H)，5.87(t，J＝5.8Hz，1H)，3.84(dd，J＝11.1，2.9Hz，2H)，3.24(t，J＝10.9Hz，2H)，3.08(t，J＝6.3Hz，2H)，2.74(s，3H)，2.32(t，J＝6.9Hz，1H)，1.90-1.77(m，1H)，1.65(d，J＝12.3Hz，2H)，1.51(s，9H)，0.88-0.83(m，2H).Synthesis of tert-butyl 3-(1-acetyl-1H-indole-3-carboxamido)-4-((tetrahydro-2H-pyran-4-yl)methyl)amino)benzoate, The synthesis method is as in Example 47. 1H NMR (400MHz, DMSO) δ 9.59 (s, 1H), 8.76 (s, 1H), 8.37 (d, J = 7.7 Hz, 1H), 8.24 - 8.13 (m, 1H) , 7.67 (dd, J = 8.6, 1.9 Hz, 1H), 7.64 (d, J = 1.9 Hz, 1H), 7.43 - 7.31 (m, 2H), 6.76 (d, J = 8.7 Hz, 1H), 5.87 ( t, J = 5.8 Hz, 1H), 3.84 (dd, J = 11.1, 2.9 Hz, 2H), 3.24 (t, J = 10.9 Hz, 2H), 3.08 (t, J = 6.3 Hz, 2H), 2.74 ( s, 3H), 2.32 (t, J = 6.9 Hz, 1H), 1.90-1.77 (m, 1H), 1.65 (d, J = 12.3 Hz, 2H), 1.51 (s, 9H), 0.88-0.83 (m) , 2H).
实施例89Example 89
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯甲酸的合成，合成方法如实施例71。1H NMR(400MHz，DMSO)δ12.21(s，1H)，9.57(s，1H)，8.76(s，1H)，8.37(d，J＝7.9Hz，1H)，8.18(d，J＝7.3Hz，1H)，7.72(s，1H)，7.70(d，J＝1.9Hz，1H)，7.45-7.30(m，2H)，6.77(d，J＝8.4Hz，1H)，5.88(s，1H)，3.84(dd，J＝11.0，2.9Hz，2H)，3.27(d，J＝10.7Hz，2H)，3.09(d，J＝6.6Hz，2H)，2.74(s，3H)，1.92-1.78(m，1H)，1.67(d，J＝12.6Hz，2H)，1.24(m，2H).Synthesis of 3-(1-acetyl-1H-indole-3-carboxamido)-4-((tetrahydro-2H-pyran-4-yl)methyl)amino)benzoic acid, synthesis method Example 71. 1H NMR (400 MHz, DMSO) δ 12.21. (s, 1H), 9.57 (s, 1H), 8.76 (s, 1H), 8.37 (d, J = 7.9 Hz, 1H), 8.18 (d, J = 7.3 Hz, 1H), 7.72 (s, 1H), 7.70 (d, J = 1.9 Hz, 1H), 7.45-7.30 (m, 2H), 6.77 (d, J = 8.4 Hz, 1H), 5.88 ( s, 1H), 3.84 (dd, J = 11.0, 2.9 Hz, 2H), 3.27 (d, J = 10.7 Hz, 2H), 3.09 (d, J = 6.6 Hz, 2H), 2.74 (s, 3H), 1.92-1.78 (m, 1H), 1.67 (d, J = 12.6 Hz, 2H), 1.24 (m, 2H).
实施例90Example 90
(1-乙酰基-1H-吲哚-3-甲酰氨基)-4-((四氢-2H-吡喃-4-基)氨基)苯甲酸的合成，合成方法如实施例71。1H NMR(400MHz，DMSO)δ12.26(s，1H)，9.58(s，1H)，8.78(s，1H)，8.37(d，J＝7.8Hz，1H)，8.19(d，J＝7.4Hz，1H)，7.78(s，1H)，7.70(d，J＝8.3Hz，1H)，7.46-7.32(m，2H)，6.87(d，J＝8.7Hz，1H)，5.49(s，1H)，3.87(d，J＝11.2Hz，2H)，3.67(m，1H)，3.46(d，J＝11.2Hz，2H)，2.74(s，3H)，1.92(d，J＝12.2Hz，2H)，1.49(m，2H).Synthesis of (1-acetyl-1H-indole-3-carboxamido)-4-((tetrahydro-2H-pyran-4-yl)amino)benzoic acid as synthesized in Example 71. 1H NMR (400MHz, DMSO) δ12.26(s,1H), 9.58(s,1H), 8.78(s,1H), 8.37(d,J=7.8Hz,1H), 8.19(d,J=7.4Hz,1H ), 7.78 (s, 1H), 7.70 (d, J = 8.3 Hz, 1H), 7.46-7.32 (m, 2H), 6.87 (d, J = 8.7 Hz, 1H), 5.49 (s, 1H), 3.87 (d, J = 11.2 Hz, 2H), 3.67 (m, 1H), 3.46 (d, J = 11.2 Hz, 2H), 2.74 (s, 3H), 1.92 (d, J = 12.2 Hz, 2H), 1.49 (m, 2H).
实施例91Example 91
(1-乙酰基-1H-吲哚-3-甲酰氨基)-5-(((叔丁氧羰基)氧基)甲基)苯甲酸甲酯的合成，合成方法如实施例47。1H NMR(500MHz，DMSO)δ10.32(s，1H)，8.84(s，1H)，8.41-8.34(m，2H)，8.27(d，J＝7.8Hz，1H)，8.13(s，1H)，7.68(s，1H)，7.48-7.33(m，2H)，5.17(s，2H)，3.90(s，3H)，2.76(s，3H)，1.45(s，9H).Synthesis of methyl (1-acetyl-1H-indole-3-carboxamido)-5-(((tert-butoxycarbonyl)oxy)methyl)benzoate, synthesized as in Example 47. 1H NMR (500MHz, DMSO) δ 10.32 (s, 1H), 8.84 (s, 1H), 8.41 - 8.34 (m, 2H), 8.27 (d, J = 7.8 Hz, 1H), 8.13 (s, 1H), 7.68 (s, 1H), 7.48-7.33 (m, 2H), 5.17 (s, 2H), 3.90 (s, 3H), 2.76 (s, 3H), 1.45 (s, 9H).
实施例92Example 92
(1-乙酰基-1H-吲哚-3-甲酰氨基)-5-环丙基苯甲酸的合成，合成方法如实施例71。1H NMR(400MHz，DMSO)δ12.97(s，1H)，10.18(s，1H)，8.83(d，J＝4.0Hz，1H)，8.37(d，J＝7.7Hz，1H)，8.27(d，J＝5.4Hz，1H)，8.20(s，1H)，7.94(s，1H)，7.52(s，1H)，7.45-7.34(m，2H)，2.76(d，J＝4.0Hz，3H)，2.66(d，J＝7.4Hz，2H)，1.65(d，J＝7.4Hz，1H)，0.93(m，2H).Synthesis of (1-acetyl-1H-indole-3-carboxamido)-5-cyclopropylbenzoic acid as described in Example 71. 1H NMR (400 MHz, DMSO) δ 12.97 (s, 1H) , 10.18 (s, 1H), 8.83 (d, J = 4.0 Hz, 1H), 8.37 (d, J = 7.7 Hz, 1H), 8.27 (d, J = 5.4 Hz, 1H), 8.20 (s, 1H) , 7.94 (s, 1H), 7.52 (s, 1H), 7.45-7.34 (m, 2H), 2.76 (d, J = 4.0 Hz, 3H), 2.66 (d, J = 7.4 Hz, 2H), 1.65 ( d, J = 7.4 Hz, 1H), 0.93 (m, 2H).
实施例93Example 93
甲基3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-5-(((2-氟苯基)氨基)甲基)苯甲酸甲酯的合成，合成方法如实施例47。1H NMR(500MHz，DMSO)δ10.27(s，1H)，8.82(s，1H)，8.36(d，J＝7.9Hz，1H)，8.31(s，1H)，8.26(d，J＝7.8Hz，1H)，8.10(s，1H)，7.72(s，1H)，7.38(dq，J＝13.7，7.0Hz，2H)，7.03(dd，J＝11.8，8.0Hz，1H)，6.87(t，J＝7.6Hz，1H)，6.53(t，J＝6.9Hz，2H)，6.35(s，1H)，4.42(d，J＝5.8Hz，2H)，3.87(s，3H)，2.75(s，3H).Synthesis of methyl 3-(1-acetyl-1H-indole-3-formylamino)-5-(((2-fluorophenyl)amino)methyl)benzoic acid methyl ester, synthesis method as in the examples 47. 1H NMR (500MHz, DMSO) δ 10.27 (s, 1H), 8.82 (s, 1H), 8.36 (d, J = 7.9 Hz, 1H), 8.31 (s, 1H), 8.26 (d, J = 7.8 Hz, 1H), 8.10 (s, 1H), 7.72 (s, 1H), 7.38 (dq, J = 13.7, 7.0 Hz, 2H), 7.03 (dd, J = 11.8, 8.0 Hz, 1H), 6.87 ( t, J = 7.6 Hz, 1H), 6.53 (t, J = 6.9 Hz, 2H), 6.35 (s, 1H), 4.42 (d, J = 5.8 Hz, 2H), 3.87 (s, 3H), 2.75 ( s, 3H).
实施例94Example 94
甲基3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-5-(((环丙基甲基)氨基)甲基)苯甲酸甲酯的合成，合成方法如实施例47。1H NMR(400MHz，DMSO)δ10.31(s，1H)，8.82(s，1H)，8.36(dd，J＝10.9，4.0Hz，2H)，8.28(d，J＝7.0Hz，1H)，8.22(s，1H)，8.09(s，1H)，7.76(d，J＝7.6Hz，1H)，7.46-7.30(m，4H)，4.94(s，2H)，3.89(s，3H)，2.76(s，3H)，2.51-2.49(m，2H)，0.83(dd，J＝11.7，5.9Hz，1H)，0.43(s，2H)，0.13(s，2H).Synthesis of methyl 3-(1-acetyl-1H-indole-3-formylamino)-5-(((cyclopropylmethyl)amino)methyl)benzoic acid methyl ester, synthesis method as in the examples 47. 1H NMR (400MHz, DMSO) δ 10.31 (s, 1H), 8.82 (s, 1H), 8.36 (dd, J = 10.9, 4.0 Hz, 2H), 8.28 (d, J = 7.0 Hz, 1H) , 8.22 (s, 1H), 8.09 (s, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.46-7.30 (m, 4H), 4.94 (s, 2H), 3.89 (s, 3H), 2.76(s,3H), 2.51-2.49 (m, 2H), 0.83 (dd, J=11.7, 5.9 Hz, 1H), 0.43 (s, 2H), 0.13 (s, 2H).
实施例95Example 95
5-(1-乙酰基-1H-吲哚-3-甲酰氨基)-[1，1′-联苯]-3-羧酸的合成，合成方法如实施例71。1H NMR(400MHz，DMSO)δ13.07(s，1H)，10.33(s，1H)，8.86(s，1H)，8.42(s，1H)，8.39(s，1H)，8.37(s，1H)，8.29(d，J＝7.2Hz，1H)，7.92(s，1H)，7.72(s，1H)，7.70(s，1H)，7.54(t，J＝7.6Hz， 2H)，7.48-7.35(m，3H)，2.78(s，3H).Synthesis of 5-(1-acetyl-1H-indole-3-carboxamido)-[1,1'-biphenyl]-3-carboxylic acid, as described in Example 71. 1H NMR (400 MHz, DMSO ) δ13.07(s,1H), 10.33(s,1H),8.86(s,1H), 8.42(s,1H), 8.39(s,1H),8.37(s,1H),8.29(d,J = 7.2 Hz, 1H), 7.92 (s, 1H), 7.72 (s, 1H), 7.70 (s, 1H), 7.54 (t, J = 7.6 Hz, 2H), 7.48-7.35 (m, 3H), 2.78 (s, 3H).
实施例96Example 96
5-(1-乙酰基-1H-吲哚-3-甲酰氨基)-3′-氟-[1，1′-联苯]-3-羧酸的合成，合成方法如实施例71。1H NMR(400MHz，DMSO)δ13.15(s，1H)，10.34(s，1H)，8.85(s，1H)，8.41(d，J＝0.9Hz，2H)，8.38(d，J＝7.8Hz，1H)，8.29(d，J＝7.1Hz，1H)，7.93(s，1H)，7.61-7.50(m，3H)，7.46-7.35(m，2H)，7.28(t，J＝7.8Hz，1H)，2.77(s，3H).Synthesis of 5-(1-acetyl-1H-indole-3-carboxamido)-3'-fluoro-[1,1'-biphenyl]-3-carboxylic acid, the synthesis method is as in Example 71. 1H NMR (400 MHz, DMSO) δ 13.15 (s, 1H), 10.34 (s, 1H), 8.85 (s, 1H), 8.41 (d, J = 0.9 Hz, 2H), 8.38 (d, J = 7.8 Hz, 1H), 8.29 (d, J = 7.1 Hz, 1H), 7.93 (s, 1H), 7.61-7.50 (m, 3H), 7.46-7.35 (m, 2H), 7.28 (t, J = 7.8 Hz, 1H) ), 2.77 (s, 3H).
实施例97Example 97
甲基3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-5-(((3-氟苯基)氨基)甲基)苯甲酸甲酯的合成，合成方法如实施例47。1H NMR(400MHz，DMSO)δ10.27(s，1H)，8.83(s，1H)，8.37(d，J＝7.8Hz，1H)，8.30(s，1H)，8.26(d，J＝7.3Hz，1H)，8.12(s，1H)，7.71(s，1H)，7.38(m，2H)，7.06(m，1H)，6.74(s，1H)，6.42(d，J＝7.8Hz，1H)，6.30(m，2H)，4.37(d，J＝5.5Hz，2H)，3.87(s，3H)，2.75(s，3H).Synthesis of methyl 3-(1-acetyl-1H-indole-3-formylamino)-5-(((3-fluorophenyl)amino)methyl)benzoic acid methyl ester, synthesis method as in the examples 47.1H NMR (400MHz, DMSO) δ 10.27 (s, 1H), 8.83 (s, 1H), 8.37 (d, J = 7.8 Hz, 1H), 8.30 (s, 1H), 8.26 (d, J = 7.3 Hz, 1H), 8.12 (s, 1H), 7.71 (s, 1H), 7.38 (m, 2H), 7.06 (m, 1H), 6.74 (s, 1H), 6.42 (d, J = 7.8 Hz, 1H), 6.30 (m, 2H), 4.37 (d, J = 5.5 Hz, 2H), 3.87 (s, 3H), 2.75 (s, 3H).
实施例98Example 98
甲基3-(1-乙酰基-1H-吲哚-3-甲酰胺基)-5-((环戊基氨基)甲基)苯甲酸甲酯的合成，合成方法如实施例47。1H NMR(400MHz，DMSO)δ10.31(s，1H)，8.84(s，1H)，8.37(t，J＝8.1Hz，2H)，8.30(d，J＝6.7Hz，1H)，8.14(s，1H)，8.04(s，1H)，7.46-7.36(m，3H)，4.78(s，2H)，3.90(s，3H)，2.77(s，3H)，1.79(s，2H)，1.63(s，4H)，1.42(s，2H)，1.23(s，1H).Synthesis of methyl 3-(1-acetyl-1H-indole-3-carboxamido)-5-((cyclopentylamino)methyl)benzoate as a synthesis method as in Example 47. 1H NMR (400MHz, DMSO) δ 10.31 (s, 1H), 8.84 (s, 1H), 8.37 (t, J = 8.1 Hz, 2H), 8.30 (d, J = 6.7 Hz, 1H), 8.14 (s, 1H) ), 8.04 (s, 1H), 7.46-7.36 (m, 3H), 4.78 (s, 2H), 3.90 (s, 3H), 2.77 (s, 3H), 1.79 (s, 2H), 1.63 (s, 4H), 1.42 (s, 2H), 1.23 (s, 1H).
实施例99Example 99
(1-乙酰基-1H-吲哚-3-甲酰氨基)-5-异丁基苯甲酸的合成，合成方法如实施例71。1H NMR(400MHz，DMSO)δ12.87(s，1H)，10.17(s，1H)，8.83(s，1H)，8.37(d，J＝7.8Hz，1H)，8.27(d，J＝7.4Hz，1H)，8.22(s，1H)，7.91(s，1H)，7.49(s，1H)，7.45-7.34(m，2H)，2.76(s，3H)，2.54(d，J＝7.0Hz，2H)，1.87(m，1H)，0.91(d，J＝6.5Hz，6H).Synthesis of (1-acetyl-1H-indole-3-carboxamido)-5-isobutylbenzoic acid, as described in Example 71. 1H NMR (400 MHz, DMSO) δ 12.87 (s, 1H) , 10.17 (s, 1H), 8.83 (s, 1H), 8.37 (d, J = 7.8 Hz, 1H), 8.27 (d, J = 7.4 Hz, 1H), 8.22 (s, 1H), 7.91 (s, 1H), 7.49 (s, 1H), 7.45-7.34 (m, 2H), 2.76 (s, 3H), 2.54 (d, J = 7.0 Hz, 2H), 1.87 (m, 1H), 0.91 (d, J) =6.5Hz, 6H).
实施例100Example 100
(1-乙酰基-1H-吲哚-3-甲酰氨基)-5-环戊基苯甲酸的合成，合成方法如实施例71。1H NMR(400MHz，DMSO)δ10.17(s，1H)，8.83(s，1H)，8.37(d，J＝7.9Hz，1H)，8.27(d，J＝7.1Hz，1H)，8.22(s，1H)，7.98(s，1H)，7.57(s，1H)，7.46-7.33(m，2H)，3.10-3.04(m，1H)，2.76(s，3H)，2.07(m，2H)，1.81(m，2H)，1.70(m，2H)，1.64-1.51(m，2H).Synthesis of (1-acetyl-1H-indole-3-carboxamido)-5-cyclopentylbenzoic acid as described in Example 71. 1H NMR (400 MHz, DMSO) δ 10.17 (s, 1H) , 8.83 (s, 1H), 8.37 (d, J = 7.9 Hz, 1H), 8.27 (d, J = 7.1 Hz, 1H), 8.22 (s, 1H), 7.98 (s, 1H), 7.57 (s, 1H), 7.46-7.33 (m, 2H), 3.10-3.04 (m, 1H), 2.76 (s, 3H), 2.07 (m, 2H), 1.81 (m, 2H), 1.70 (m, 2H), 1.64 -1.51 (m, 2H).
实施例101Example 101
(1-乙酰基-1H-吲哚-3-甲酰氨基)-5-环己基苯甲酸的合成，合成方法如实施例71。1H NMR(400MHz，DMSO)δ12.97(s，1H)，10.16(s，1H)，8.82(s，1H)，8.37(d，J＝7.7Hz，1H)，8.27(d，J＝7.1Hz，1H)，8.20(s，1H)，7.97(s，1H)，7.55(s，1H)，7.45-7.35(m，2H)，2.76(s，3H)，2.60(s，1H)，1.84(m，4H)，1.73(m，1H)，1.51-1.34(m，5H).Synthesis of (1-acetyl-1H-indole-3-carboxamido)-5-cyclohexylbenzoic acid as described in Example 71. 1H NMR (400 MHz, DMSO) δ 12.97 (s, 1H), 10.16(s,1H),8.82(s,1H), 8.37(d,J=7.7Hz,1H), 8.27(d,J=7.1Hz,1H),8.20(s,1H),7.97(s,1H ), 7.55 (s, 1H), 7.45-7.35 (m, 2H), 2.76 (s, 3H), 2.60 (s, 1H), 1.84 (m, 4H), 1.73 (m, 1H), 1.51-1.34 ( m, 5H).
实施例102Example 102
(1-乙酰基-1H-吲哚-3-甲酰氨基)-5-(2-甲基吡啶-4-基)苯甲酸的合成，合成方法如实施例71。1H NMR(500MHz，DMSO)δ10.43(s，1H)，8.92(s，1H)，8.88(s，1H)，8.65(s，1H)，8.51(s，1H)，8.44(s，1H)，8.38(d，J＝7.9Hz，1H)，8.34(s，1H)，8.29(d，J＝7.7Hz，1H)，8.02(s，1H)，7.41(m，2H)，2.78(s，3H)，2.51(s，3H).Synthesis of (1-acetyl-1H-indole-3-carboxamido)-5-(2-methylpyridin-4-yl)benzoic acid as described in Example 71. 1H NMR (500 MHz, DMSO) δ 10.43 (s, 1H), 8.92 (s, 1H), 8.88 (s, 1H), 8.65 (s, 1H), 8.51 (s, 1H), 8.44 (s, 1H), 8.38 (d, J = 7.9 Hz, 1H), 8.34 (s, 1H), 8.29 (d, J = 7.7 Hz, 1H), 8.02 (s, 1H), 7.41 (m, 2H), 2.78 (s, 3H), 2.51 (s, 3H).
实施例103Example 103
(1-乙酰基-1H-吲哚-3-甲酰氨基)-5-(苯并呋喃-3-基)苯甲酸的合成，合成方法如实施例71。1HNMR(400MHz，DMSO)δ10.39(s，1H)，8.85(s，1H)，8.27(d，J＝7.5Hz，1H)，8.12(d，J＝7.7Hz，1H)，7.99(s，1H)，7.97(s，1H)，7.89(s，1H)，7.56-7.45(m，2H)，7.45-7.34(m，2H)，2.77(s，3H).Synthesis of (1-acetyl-1H-indole-3-carboxamido)-5-(benzofuran-3-yl)benzoic acid, as described in Example 71. 1H NMR (400 MHz, DMSO) δ 10.39 (s, 1H), 8.85 (s, 1H), 8.27 (d, J = 7.5 Hz, 1H), 8.12 (d, J = 7.7 Hz, 1H), 7.99 (s, 1H), 7.97 (s, 1H) , 7.89 (s, 1H), 7.56-7.45 (m, 2H), 7.45-7.34 (m, 2H), 2.77 (s, 3H).
实施例104Example 104
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-5-乙基苯甲酸的合成，合成方法如实施例71。1H NMR(500MHz，DMSO)δ12.95(s，1H)，10.17(s，1H)，8.83(s，1H)，8.37(d，J＝8.0Hz，1H)，8.27(d，J ＝7.2Hz，1H)，8.21(s，1H)，7.96(s，1H)，7.54(s，1H)，7.39(m，2H)，2.76(s，3H)，2.70(q，J＝7.5Hz，2H)，1.24(t，J＝7.6Hz，3H).Synthesis of 3-(1-acetyl-1H-indole-3-carboxamido)-5-ethylbenzoic acid as described in Example 71. 1H NMR (500 MHz, DMSO) δ 12.95 (s, 1H) ), 10.17 (s, 1H), 8.83 (s, 1H), 8.37 (d, J = 8.0 Hz, 1H), 8.27 (d, J = 7.2 Hz, 1H), 8.21 (s, 1H), 7.96 (s) , 1H), 7.54 (s, 1H), 7.39 (m, 2H), 2.76 (s, 3H), 2.70 (q, J = 7.5 Hz, 2H), 1.24 (t, J = 7.6 Hz, 3H).
实施例105Example 105
(1-乙酰基-1H-吲哚-3-甲酰氨基)-5-苯乙基苯甲酸的合成，合成方法如实施例71。1H NMR(500MHz，DMSO)δ12.97(s，1H)，10.18(d，J＝5.1Hz，1H)，8.82(d，J＝14.8Hz，1H)，8.37(d，J＝7.6Hz，1H)，8.30-8.24(m，1H)，8.22(s，1H)，7.98(d，J＝12.1Hz，1H)，7.57(s，1H)，7.39(dd，J＝15.2，7.9Hz，2H)，7.35-7.26(m，4H)，7.19(d，J＝6.4Hz，1H)，2.95(d，J＝6.6Hz，3H)，2.76(d，J＝6.3Hz，3H)，1.63(d，J＝7.1Hz，1H).Synthesis of (1-acetyl-1H-indole-3-carboxamido)-5-phenethylbenzoic acid as described in Example 71. 1H NMR (500 MHz, DMSO) δ 12.97 (s, 1H) , 10.18 (d, J = 5.1 Hz, 1H), 8.82 (d, J = 14.8 Hz, 1H), 8.37 (d, J = 7.6 Hz, 1H), 8.30-8.24 (m, 1H), 8.22 (s, 1H), 7.98 (d, J = 12.1 Hz, 1H), 7.57 (s, 1H), 7.39 (dd, J = 15.2, 7.9 Hz, 2H), 7.35-7.26 (m, 4H), 7.19 (d, J) = 6.4 Hz, 1H), 2.95 (d, J = 6.6 Hz, 3H), 2.76 (d, J = 6.3 Hz, 3H), 1.63 (d, J = 7.1 Hz, 1H).
实施例106Example 106
5-(1-乙酰基-1H-吲哚-3-甲酰氨基)-3′-(三氟甲基)-[1，1′-联苯]-3-羧酸的合成，合成方法如实施例71。1H NMR(500MHz，DMSO)δ10.37(s，1H)，8.85(s，1H)，8.48(s，1H)，8.41(s，1H)，8.37(d，J＝8.1Hz，1H)，8.29(d，J＝7.6Hz，1H)，8.03(d，J＝7.4Hz，1H)，7.99(s，1H)，7.96(s，1H)，7.79(m，2H)，7.47-7.33(m，2H)，2.77(s，3H).Synthesis of 5-(1-acetyl-1H-indole-3-carboxamido)-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-carboxylic acid, synthesis method Example 71. 1H NMR (500MHz, DMSO) δ 10.37 (s, 1H), 8.85 (s, 1H), 8.48 (s, 1H), 8.41 (s, 1H), 8.37 (d, J = 8.1 Hz, 1H), 8.29 (d, J = 7.6 Hz, 1H), 8.03 (d, J = 7.4 Hz, 1H), 7.99 (s, 1H), 7.96 (s, 1H), 7.79 (m, 2H), 7.47- 7.33 (m, 2H), 2.77 (s, 3H).
实施例107Example 107
5-(1-乙酰基-1H-吲哚-3-甲酰氨基)-3′-甲氧基-[1，1′-联苯]-3-羧酸的合成，合成方法如实施例71。1H NMR(500MHz，DMSO)δ10.33(s，1H)，8.85(s，1H)，8.41(s，1H)，8.38(d，J＝7.9Hz，2H)，8.29(d，J＝7.7Hz，1H)，7.91(s，1H)，7.50-7.36(m，3H)，7.26(d，J＝7.6Hz，1H)，7.20(s，1H)，7.02(d，J＝8.2，2.0Hz，1H)，3.85(s，3H)，2.77(s，3H).Synthesis of 5-(1-acetyl-1H-indole-3-carboxamido)-3'-methoxy-[1,1'-biphenyl]-3-carboxylic acid, as in Example 71 1H NMR (500MHz, DMSO) δ 10.33 (s, 1H), 8.85 (s, 1H), 8.41 (s, 1H), 8.38 (d, J = 7.9 Hz, 2H), 8.29 (d, J = 7.7 Hz, 1H), 7.91 (s, 1H), 7.50-7.36 (m, 3H), 7.26 (d, J = 7.6 Hz, 1H), 7.20 (s, 1H), 7.02 (d, J = 8.2, 2.0 Hz) , 1H), 3.85 (s, 3H), 2.77 (s, 3H).
实施例108Example 108
5-(1-乙酰基-1H-吲哚-3-甲酰氨基)-3′-氯-[1，1′-联苯]-3-羧酸的合成，合成方法如实施例71。1H NMR(500MHz，DMSO)δ13.13(s，1H)，10.35(s，1H)，8.86(s，1H)，8.41(s，1H)，8.39(s，1H)，8.37(s，1H)，8.29(d，J＝6.8Hz，1H)，7.92(s，1H)，7.71(s，1H)，7.70(s，1H)，7.54(t，J＝7.6Hz，2H)，7.48-7.35(m，3H)，2.77(s，3H).Synthesis of 5-(1-acetyl-1H-indole-3-formylamino)-3'-chloro-[1,1'-biphenyl]-3-carboxylic acid, as described in Example 71. 1H NMR (500MHz, DMSO) δ 13.13 (s, 1H), 10.35 (s, 1H), 8.86 (s, 1H), 8.41 (s, 1H), 8.39 (s, 1H), 8.37 (s, 1H), 8.29 (d, J = 6.8 Hz, 1H), 7.92 (s, 1H), 7.71 (s, 1H), 7.70 (s, 1H), 7.54 (t, J = 7.6 Hz, 2H), 7.48-7.35 (m) , 3H), 2.77 (s, 3H).
实施例109Example 109
3-(1-乙酰基-1H-吲哚-3-甲酰氨基)-5-(1-甲基-1H-吲唑-5-基)苯甲酸的合成，合成方法如实施例71。1H NMR(500MHz，DMSO)δ10.34(s，1H)，8.87(s，1H)，8.46(s，1H)，8.39(s，1H)，8.37(s，1H)，8.30(d，J＝7.6Hz，1H)，8.16(s，1H)，8.09(s，1H)，7.97(s，1H)，7.77(dd，J＝18.6，8.8Hz，2H)，7.47-7.36(m，2H)，4.10(s，3H)，2.78(s，3H).Synthesis of 3-(1-acetyl-1H-indole-3-carboxamido)-5-(1-methyl-1H-indazol-5-yl)benzoic acid, as described in Example 71. 1H NMR (500MHz, DMSO) δ 10.34 (s, 1H), 8.87 (s, 1H), 8.46 (s, 1H), 8.39 (s, 1H), 8.37 (s, 1H), 8.30 (d, J = 7.6 Hz, 1H), 8.16 (s, 1H), 8.09 (s, 1H), 7.97 (s, 1H), 7.77 (dd, J = 18.6, 8.8 Hz, 2H), 7.47-7.36 (m, 2H), 4.10 (s, 3H), 2.78 (s, 3H).
实施例110Example 110
3-(1-乙酰基-5-甲氧基-1H-吲哚-3-甲酰氨基)-5-(呋喃-2-基)苯甲酸的合成，合成方法如实施例71。1H NMR(400MHz，DMSO)δ13.19(s，1H)，8.84(s，1H)，8.44(s，1H)，8.32(s，1H)，8.25(d，J＝9.0Hz，1H)，7.98(s，1H)，7.83(d，J＝1.2Hz，1H)，7.80(d，J＝2.5Hz，1H)，7.06(d，J＝3.3Hz，1H)，7.01(m，1H)，6.65(m，1H)，3.84(s，3H)，2.74(s，3H).Synthesis of 3-(1-acetyl-5-methoxy-1H-indole-3-carboxamido)-5-(furan-2-yl)benzoic acid as described in Example 71. 1H NMR ( 400MHz, DMSO) δ13.19 (s, 1H), 8.84 (s, 1H), 8.44 (s, 1H), 8.32 (s, 1H), 8.25 (d, J = 9.0 Hz, 1H), 7.98 (s, 1H), 7.83 (d, J = 1.2 Hz, 1H), 7.80 (d, J = 2.5 Hz, 1H), 7.06 (d, J = 3.3 Hz, 1H), 7.01 (m, 1H), 6.65 (m, 1H), 3.84 (s, 3H), 2.74 (s, 3H).
实施例111Example 111
3-(1-乙酰基-5-羟基-1H-吲哚-3-甲酰氨基)-5-(呋喃-2-基)苯甲酸的合成，合成方法如实施例17。1H NMR(500MHz，DMSO)δ13.15(s，1H)，10.25(s，1H)，9.40(s，1H)，8.78(s，1H)，8.45(s，1H)，8.29(s，1H)，8.15(s，1H)，7.97(s，1H)，7.83(s，1H)，7.67(s，1H)，7.04(s，1H)，6.86(s，1H)，6.65(s，1H)，2.72(s，3H).Synthesis of 3-(1-acetyl-5-hydroxy-1H-indole-3-carboxamido)-5-(furan-2-yl)benzoic acid as described in Example 17. 1H NMR (500 MHz, DMSO) δ 13.15 (s, 1H), 10.25 (s, 1H), 9.40 (s, 1H), 8.78 (s, 1H), 8.45 (s, 1H), 8.29 (s, 1H), 8.15 (s, 1H), 7.97 (s, 1H), 7.83 (s, 1H), 7.67 (s, 1H), 7.04 (s, 1H), 6.86 (s, 1H), 6.65 (s, 1H), 2.72 (s, 3H) ).
实施例112Example 112
(1-乙酰基-5-乙氧基-1H-吲哚-3-甲酰氨基)-5-(呋喃-2-基)苯甲酸的合成，3-(1-乙酰基-5-羟基-1H-吲哚-3-甲酰氨基)-5-(呋喃-2-基)苯甲酸合成方法如实例17。Synthesis of (1-acetyl-5-ethoxy-1H-indole-3-carboxamido)-5-(furan-2-yl)benzoic acid, 3-(1-acetyl-5-hydroxy- The synthesis method of 1H-indole-3-formylamino)-5-(furan-2-yl)benzoic acid was as in Example 17.
3-(1-乙酰基-5-羟基-1H-吲哚-3-甲酰氨基)-5-(呋喃-2-基)苯甲酸(120mg，0.26mmol)溶于20mL丙酮中，随后加入K2CO3(107.6g，0.78mmol)，碘乙烷(0.037ml，0.39mmol)，70℃搅拌过夜。反应结束后，丙酮真空旋干，加水，乙酸乙酯萃取(3×50mL)，有机层用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，硅胶柱层析分离，得到白色固体(56mg，48.27％)。 1H NMR(500MHz，DMSO)δ11.89(s，1H)，10.06(s，1H)，8.50(s，1H)，8.42(d，J＝2.3Hz，1H)，8.31(s，1H)，7.92(s，2H)，7.83(s，1H)，7.49(d，J＝8.7Hz，1H)，7.02(d，J＝3.0Hz，1H)，6.96(d，J＝8.6Hz，1H)，6.65(s，1H)，4.29(t，J＝6.6Hz，2H)，2.29(s，3H)，1.77(dd，J＝14.1，7.0Hz，2H)，1.01(t，J＝7.4Hz，3H).3-(1-Acetyl-5-hydroxy-1H-indole-3-carboxamido)-5-(furan-2-yl)benzoic acid (120 mg, 0.26 mmol) was dissolved in 20 mL of acetone then K2CO3 (107.6 g, 0.78 mmol), iodoethane (0.037 ml, 0.39 mmol). After the completion of the reaction, the title compound was evaporated, evaporated, evaporated, evaporated, evaporated. , 48.27%). 1H NMR (500MHz, DMSO) δ 11.89 (s, 1H), 10.06 (s, 1H), 8.50 (s, 1H), 8.42 (d, J = 2.3 Hz, 1H), 8.31 (s, 1H), 7.92 (s, 2H), 7.83 (s, 1H), 7.49 (d, J = 8.7 Hz, 1H), 7.02 (d, J = 3.0 Hz, 1H), 6.96 (d, J = 8.6 Hz, 1H), 6.65 (s, 1H), 4.29 (t, J = 6.6 Hz, 2H), 2.29 (s, 3H), 1.77 (dd, J = 14.1, 7.0 Hz, 2H), 1.01 (t, J = 7.4 Hz, 3H) .
实施例113Example 113
3-(1-乙酰基-5-丙氧基-1H-吲哚-3-甲酰氨基)-5-(呋喃-2-基)苯甲酸的合成，合成方法如实例112。1H NMR(500MHz，DMSO)δ11.89(s，1H)，10.06(s，1H)，8.50(s，1H)，8.42(d，J＝2.3Hz，1H)，8.31(s，1H)，7.92(s，2H)，7.83(s，1H)，7.49(d，J＝8.7Hz，1H)，7.02(d，J＝3.0Hz，1H)，6.96(d，J＝8.6Hz，1H)，6.65(s，1H)，4.29(t，J＝6.6Hz，2H)，2.29(s，3H)，1.77(dd，J＝14.1，7.0Hz，2H)，1.01(t，J＝7.4Hz，3H).Synthesis of 3-(1-acetyl-5-propoxy-1H-indole-3-carboxamido)-5-(furan-2-yl)benzoic acid, as described in Example 112. 1H NMR (500MHz , DMSO) δ11.89 (s, 1H), 10.06 (s, 1H), 8.50 (s, 1H), 8.42 (d, J = 2.3 Hz, 1H), 8.31 (s, 1H), 7.92 (s, 2H) ), 7.83 (s, 1H), 7.49 (d, J = 8.7 Hz, 1H), 7.02 (d, J = 3.0 Hz, 1H), 6.96 (d, J = 8.6 Hz, 1H), 6.65 (s, 1H) ), 4.29 (t, J = 6.6 Hz, 2H), 2.29 (s, 3H), 1.77 (dd, J = 14.1, 7.0 Hz, 2H), 1.01 (t, J = 7.4 Hz, 3H).
实施例114Example 114
3-(1-乙酰基-5-甲氧基-1H-吲哚-3-甲酰胺基)-5-(1-甲基-1H-吡唑-4-基)苯甲酸的合成，合成方法如实例71。1H NMR(500MHz，DMSO)δ13.07(s，1H)，10.22(s，1H)，8.83(s，1H)，8.25(t，J＝6.5Hz，3H)，8.19(s，1H)，7.87(s，1H)，7.83(s，1H)，7.79(d，J＝2.3Hz，1H)，7.01(dd，J＝9.0，2.5Hz，1H)，3.90(s，3H)，3.84(s，3H)，2.74(s，3H).Synthesis, synthesis method of 3-(1-acetyl-5-methoxy-1H-indole-3-carboxamido)-5-(1-methyl-1H-pyrazol-4-yl)benzoic acid Example 71. 1H NMR (500MHz, DMSO) δ 13.07 (s, 1H), 10.22 (s, 1H), 8.83 (s, 1H), 8.25 (t, J = 6.5 Hz, 3H), 8.19 (s, 1H), 7.87 (s, 1H), 7.83 (s, 1H), 7.79 (d, J = 2.3 Hz, 1H), 7.01 (dd, J = 9.0, 2.5 Hz, 1H), 3.90 (s, 3H), 3.84(s,3H), 2.74(s,3H).
实施例115Example 115
3-(1-乙酰基-5-甲氧基-1H-吲哚-3-甲酰胺基)-5-(呋喃-2-基)苯甲酸甲酯的合成，合成方法如实例47。1H NMR(400MHz，DMSO)δ10.31(s，1H)，8.84(s，1H)，8.47(t，J＝1.7Hz，1H)，8.38-8.30(m，1H)，8.25(d，J＝9.1Hz，1H)，7.98(s，1H)，7.84(d，J＝1.3Hz，1H)，7.79(d，J＝2.6Hz，1H)，7.08(d，J＝3.3Hz，1H)，7.01(m，1H)，6.66(dd，J＝3.4，1.8Hz，1H)，3.92(s，3H)，3.84(s，3H)，2.74(s，3H).Synthesis of methyl 3-(1-acetyl-5-methoxy-1H-indole-3-carboxamido)-5-(furan-2-yl)benzoate as synthesized in Example 47. 1H NMR (400MHz, DMSO) δ10.31 (s, 1H), 8.84 (s, 1H), 8.47 (t, J = 1.7 Hz, 1H), 8.38-8.30 (m, 1H), 8.25 (d, J = 9.1 Hz) , 1H), 7.98 (s, 1H), 7.84 (d, J = 1.3 Hz, 1H), 7.79 (d, J = 2.6 Hz, 1H), 7.08 (d, J = 3.3 Hz, 1H), 7.01 (m) , 1H), 6.66 (dd, J = 3.4, 1.8 Hz, 1H), 3.92 (s, 3H), 3.84 (s, 3H), 2.74 (s, 3H).
实施例116Example 116
3-(1-乙酰基-5-甲氧基-1H-吲哚-3-甲酰氨基)-5-(1-甲基-1H-吡唑-4-基)苯甲酸叔丁酯的合成，合成方法如实例47。1H NMR(400MHz，DMSO)δ10.24(s，1H)，8.81(s，1H)，8.29-8.23(m，2H)，8.22(s，1H)，8.07(s，1H)，7.86(s，1H)，7.78(d，J＝2.0Hz，2H)，7.02(m，1H)，3.90(s，3H)，3.83(s，3H)，2.74(s，3H)，1.59(s，9H).Synthesis of tert-butyl 3-(1-acetyl-5-methoxy-1H-indole-3-carboxamido)-5-(1-methyl-1H-pyrazol-4-yl)benzoate , Synthesis method as Example 47. 1H NMR (400 MHz, DMSO) δ 10.24 (s, 1H), 8.81 (s, 1H), 8.29-8.23 (m, 2H), 8.22 (s, 1H), 8.07 (s, 1H), 7.86 (s, 1H), 7.78 (d, J = 2.0 Hz, 2H), 7.02 (m, 1H), 3.90 (s, 3H), 3.83 (s, 3H), 2.74 (s, 3H), 1.59(s,9H).
实施例117Example 117
3-(1-乙酰基-5-甲氧基-1H-吲哚-3-甲酰胺基)-5-(1-甲基-1H-吡唑-4-基)苯甲酸甲酯的合成，合成方法如实例47。1H NMR(400MHz，DMSO)δ10.31(s，1H)，8.89(s，1H)，8.26(dd，J＝12.2，7.9Hz，4H)，7.88(s，1H)，7.84(s，1H)，7.79(d，J＝2.3Hz，1H)，7.01(dd，J＝9.0，2.2Hz，1H)，3.90(s，3H)，3.83(s，3H)，2.74(s，3H).Synthesis of methyl 3-(1-acetyl-5-methoxy-1H-indole-3-carboxamido)-5-(1-methyl-1H-pyrazol-4-yl)benzoate, The synthesis method is as shown in Example 47. 1H NMR (400MHz, DMSO) δ 10.31 (s, 1H), 8.89 (s, 1H), 8.26 (dd, J = 12.2, 7.9 Hz, 4H), 7.88 (s, 1H), 7.84 (s, 1H), 7.79 (d, J = 2.3 Hz, 1H), 7.01 (dd, J = 9.0, 2.2 Hz, 1H), 3.90 (s, 3H), 3.83 (s, 3H), 2.74 (s) , 3H).
实施例118Example 118
3-(1-乙酰基-5-甲氧基-1H-吲哚-3-甲酰氨基)-5-(2，3-二氢苯并[b][1，4]二氧杂环己烯-6-基)苯甲酸叔丁酯的合成，合成方法如实例47。1H NMR(400MHz，DMSO)δ10.28(s，1H)，8.81(s，1H)，8.33(s，1H)，8.28-8.20(m，2H)，7.78(s，2H)，7.19-7.13(m，2H)，7.02(d，J＝4.0Hz，1H)，7.00(d，J＝3.9Hz，1H)，4.30(s，4H)，3.83(s，3H)，2.74(s，3H)，1.59(s，9H).3-(1-acetyl-5-methoxy-1H-indole-3-carboxamido)-5-(2,3-dihydrobenzo[b][1,4]dioxine Synthesis of tert-butylene-6-yl)benzoate, as described in Example 47. 1H NMR (400MHz, DMSO) δ 10.28 (s, 1H), 8.81 (s, 1H), 8.33 (s, 1H), 8.28-8.20 (m, 2H), 7.78 (s, 2H), 7.19-7.13 (m, 2H), 7.02 (d, J = 4.0 Hz, 1H), 7.00 (d, J = 3.9 Hz, 1H), 4.30 (s, 4H), 3.83 (s, 3H), 2.74 (s, 3H), 1.59 (s, 9H).
实施例119Example 119
3-(1-乙酰基-5-甲氧基-1H-吲哚-3-甲酰胺基)-5-(1-甲基-1H-吲唑-5-基)苯甲酸叔丁酯的合成，合成方法如实例47。1H NMR(400MHz，DMSO)δ10.33(s，1H)，8.83(s，1H)，8.45(s，1H)，8.27(s，1H)，8.24(s，1H)，8.16(s，1H)，8.07(s，1H)，7.91(s，1H)，7.79(d，J＝8.8Hz，2H)，7.74(d，J＝8.8Hz，1H)，7.02(dd，J＝9.0，2.5Hz，1H)，4.10(s，3H)，3.83(s，3H)，2.75(s，3H)，1.61(s，9H).Synthesis of tert-butyl 3-(1-acetyl-5-methoxy-1H-indole-3-carboxamido)-5-(1-methyl-1H-indazol-5-yl)benzoate , Synthesis method as Example 47. 1H NMR (400MHz, DMSO) δ 10.33 (s, 1H), 8.83 (s, 1H), 8.45 (s, 1H), 8.27 (s, 1H), 8.24 (s, 1H) , 8.16 (s, 1H), 8.07 (s, 1H), 7.91 (s, 1H), 7.79 (d, J = 8.8 Hz, 2H), 7.74 (d, J = 8.8 Hz, 1H), 7.02 (dd, J=9.0, 2.5 Hz, 1H), 4.10 (s, 3H), 3.83 (s, 3H), 2.75 (s, 3H), 1.61 (s, 9H).
实施例120Example 120
3-(1-乙酰基-5-甲氧基-1H-吲哚-3-甲酰氨基)-5-(2，3-二氢苯并[b][1，4]二氧杂环己烯-6-基)苯甲酸的合成，合成方法如实例71。1H NMR(400MHz，DMSO)δ13.05(s，1H)，8.82(s， 1H)，8.34(s，1H)，8.31(s，1H)，8.25(d，J＝9.0Hz，1H)，7.83(s，1H)，7.79(s，1H)，7.17(d，J＝6.1Hz，2H)，7.00(d，J＝7.7Hz，2H)，4.30(s，4H)，3.83(s，3H)，2.74(s，3H).3-(1-acetyl-5-methoxy-1H-indole-3-carboxamido)-5-(2,3-dihydrobenzo[b][1,4]dioxine Synthesis of ene-6-yl)benzoic acid, as described in Example 71. 1H NMR (400MHz, DMSO) δ 13.05 (s, 1H), 8.82 (s, 1H), 8.34 (s, 1H), 8.31 (s , 1H), 8.25 (d, J = 9.0 Hz, 1H), 7.83 (s, 1H), 7.79 (s, 1H), 7.17 (d, J = 6.1 Hz, 2H), 7.00 (d, J = 7.7 Hz) , 2H), 4.30 (s, 4H), 3.83 (s, 3H), 2.74 (s, 3H).
实施例121Example 121
(1-乙酰基-5-甲氧基-1H-吲哚-3-甲酰胺基)-5-(1-甲基-1H-吲唑-5-基)苯甲酸的合成，合成方法如实例71。1H NMR(400MHz，DMSO)δ13.19(s，1H)，10.30(s，1H)，8.85(s，1H)，8.44(s，1H)，8.39(s，1H)，8.25(d，J＝8.2Hz，1H)，8.16(s，1H)，8.09(s，1H)，7.97(s，1H)，7.79(m，3H)，7.02(s，1H)，4.10(s，3H)，3.83(s，3H)，2.75(s，3H).Synthesis of (1-acetyl-5-methoxy-1H-indole-3-carboxamido)-5-(1-methyl-1H-indazol-5-yl)benzoic acid, synthesis method as an example 71H NMR (400MHz, DMSO) δ 13.19 (s, 1H), 10.30 (s, 1H), 8.85 (s, 1H), 8.44 (s, 1H), 8.39 (s, 1H), 8.25 (d, J = 8.2 Hz, 1H), 8.16 (s, 1H), 8.09 (s, 1H), 7.97 (s, 1H), 7.79 (m, 3H), 7.02 (s, 1H), 4.10 (s, 3H), 3.83 (s, 3H), 2.75 (s, 3H).
实施例122Example 122
N-([1，1′-联苯]-3-基)-1-乙酰基-5-甲氧基-1H-吲哚-3-甲酰胺的合成，合成方法如实例47。1H NMR(500MHz，DMSO)δ10.15(s，1H)，8.79(s，1H)，8.25(d，J＝9.1Hz，1H)，8.08(s，1H)，7.80(s，1H)，7.77(d，J＝2.7Hz，1H)，7.68(s，1H)，7.67(s，1H)，7.49(m，3H)，7.41(s，1H)，7.40(s，1H)，7.01(m，1H)，3.82(s，3H)，2.74(s，3H).Synthesis of N-([1,1'-biphenyl]-3-yl)-1-acetyl-5-methoxy-1H-indole-3-carboxamide, as described in Example 47. 1H NMR ( 500MHz, DMSO) δ 10.15 (s, 1H), 8.79 (s, 1H), 8.25 (d, J = 9.1 Hz, 1H), 8.08 (s, 1H), 7.80 (s, 1H), 7.77 (d, J=2.7 Hz, 1H), 7.68 (s, 1H), 7.67 (s, 1H), 7.49 (m, 3H), 7.41 (s, 1H), 7.40 (s, 1H), 7.01 (m, 1H), 3.82 (s, 3H), 2.74 (s, 3H).
实施例123Example 123
1-乙酰基-5-甲氧基-N-(3-(1-甲基-1H-吲唑-5-基)苯基)-1H-吲哚-3-甲酰胺的合成，合成方法如实例47。1H NMR(500MHz，DMSO)δ10.14(s，1H)，8.80(s，1H)，8.25(d，J＝9.0Hz，1H)，8.13(s，1H)，8.11(s，1H)，8.03(s，1H)，7.80-7.76(m，2H)，7.75(s，1H)，7.74(d，J＝1.4Hz，1H)，7.51-7.41(m，2H)，7.01(m，1H)，4.09(s，3H)，3.83(s，3H)，2.74(s，3H).Synthesis of 1-acetyl-5-methoxy-N-(3-(1-methyl-1H-indazol-5-yl)phenyl)-1H-indole-3-carboxamide, Example 47. 1H NMR (500MHz, DMSO) δ 10.14 (s, 1H), 8.80 (s, 1H), 8.25 (d, J = 9.0 Hz, 1H), 8.13 (s, 1H), 8.11 (s, 1H) ), 8.03 (s, 1H), 7.80-7.76 (m, 2H), 7.75 (s, 1H), 7.74 (d, J = 1.4 Hz, 1H), 7.51-7.41 (m, 2H), 7.01 (m, 1H), 4.09 (s, 3H), 3.83 (s, 3H), 2.74 (s, 3H).
实施例124Example 124
N-([1，1′-联苯]-3-基)-1-乙酰基-5-羟基-1H-吲哚-3-甲酰胺的合成，合成方法如实例17。1H NMR(500MHz，DMSO)δ10.10(s，1H)，9.40(s，1H)，8.72(s，1H)，8.15(d，J＝8.7Hz，1H)，8.07(s，1H)，7.79(d，J＝7.7Hz，1H)，7.67(d，J＝7.8Hz，3H)，7.57-7.43(m，3H)，7.40(m，2H)，6.84(d，J＝8.4Hz，1H)，2.72(s，3H).Synthesis of N-([1,1'-biphenyl]-3-yl)-1-acetyl-5-hydroxy-1H-indole-3-carboxamide, as described in Example 17. 1H NMR (500 MHz, DMSO) δ 10.10 (s, 1H), 9.40 (s, 1H), 8.72 (s, 1H), 8.15 (d, J = 8.7 Hz, 1H), 8.07 (s, 1H), 7.79 (d, J = 7.7 Hz, 1H), 7.67 (d, J = 7.8 Hz, 3H), 7.57-7.43 (m, 3H), 7.40 (m, 2H), 6.84 (d, J = 8.4 Hz, 1H), 2.72 (s, 3H).
实施例125Example 125
1-乙酰基-5-羟基-N-(3-(1-甲基-1H-吲唑-5-基)苯基)-1H-吲哚-3-甲酰胺的合成，合成方法如实例17。1H NMR(500MHz，DMSO)δ10.09(s，1H)，9.40(s，1H)，8.73(s，1H)，8.14(m，3H)，8.03(s，1H)，7.76(m，3H)，7.67(s，1H)，7.46(m，2H)，6.84(d，J＝7.1Hz，1H)，4.09(s，3H)，2.72(s，3H).Synthesis of 1-acetyl-5-hydroxy-N-(3-(1-methyl-1H-indazol-5-yl)phenyl)-1H-indole-3-carboxamide, as shown in Example 17 1H NMR (500MHz, DMSO) δ 10.09 (s, 1H), 9.40 (s, 1H), 8.73 (s, 1H), 8.14 (m, 3H), 8.03 (s, 1H), 7.76 (m, 3H) ), 7.67 (s, 1H), 7.46 (m, 2H), 6.84 (d, J = 7.1 Hz, 1H), 4.09 (s, 3H), 2.72 (s, 3H).
实施例126Example 126
1-乙酰基-5-甲氧基-N-(3-(1-甲基-1H-吡唑-4-基)苯基)-1H-吲哚-3-甲酰胺的合成，合成方法如实例47。1H NMR(500MHz，DMSO)δ10.06(s，1H)，8.78(s，1H)，8.25(d，J＝9.0Hz，1H)，8.11(s，1H)，7.92(s，1H)，7.81(s，1H)，7.77(s，1H)，7.59(d，J＝7.8Hz，1H)，7.36(t，J＝7.8Hz，1H)，7.30(d，J＝7.6Hz，1H)，7.00(d，J＝9.0Hz，1H)，3.88(s，3H)，3.82(s，3H)，2.73(s，3H).Synthesis of 1-acetyl-5-methoxy-N-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)-1H-indole-3-carboxamide, synthesis method Example 47. 1H NMR (500MHz, DMSO) δ 10.06 (s, 1H), 8.78 (s, 1H), 8.25 (d, J = 9.0 Hz, 1H), 8.11 (s, 1H), 7.92 (s, 1H) ), 7.81 (s, 1H), 7.77 (s, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H) ), 7.00 (d, J = 9.0 Hz, 1H), 3.88 (s, 3H), 3.82 (s, 3H), 2.73 (s, 3H).
实施例127Example 127
1-乙酰基-5-羟基-N-(3-(1-甲基-1H-吡唑-4-基)苯基)-1H-吲哚-3-甲酰胺的合成，合成方法如实例17。1H NMR(500MHz，DMSO)δ10.09(s，1H)，9.40(s，1H)，8.80(s，1H)，8.15(d，J＝8.9Hz，1H)，8.10(s，1H)，7.94(s，1H)，7.80(s，1H)，7.65(s，1H)，7.61(d，J＝8.0Hz，1H)，7.35(t，J＝7.8Hz，1H)，7.29(d，J＝7.4Hz，1H)，6.89-6.79(m，1H)，3.89(s，3H)，2.72(s，3H).Synthesis of 1-acetyl-5-hydroxy-N-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)-1H-indole-3-carboxamide, as shown in Example 17 1H NMR (500MHz, DMSO) δ 10.09 (s, 1H), 9.40 (s, 1H), 8.80 (s, 1H), 8.15 (d, J = 8.9 Hz, 1H), 8.10 (s, 1H), 7.94(s,1H), 7.80(s,1H), 7.65(s,1H), 7.61(d,J=8.0Hz,1H),7.35(t,J=7.8Hz,1H),7.29(d,J =7.4 Hz, 1H), 6.89-6.79 (m, 1H), 3.89 (s, 3H), 2.72 (s, 3H).
实施例128Example 128
(呋喃-2-基)-5-(1H-吲哚-3-甲酰氨基)苯甲酸的合成，(1-乙酰基-1H-吲哚-3-甲酰氨基)-5-(呋喃-2-基)苯甲酸合成方法如实施例7。Synthesis of (furan-2-yl)-5-(1H-indole-3-formylamino)benzoic acid, (1-acetyl-1H-indole-3-formylamino)-5-(furan- The 2-phenyl)benzoic acid synthesis method is as in Example 7.
将(1-乙酰基-1H-吲哚-3-甲酰氨基)-5-(呋喃-2-基)苯甲酸(100mg，0.25mmol)溶于8mL MeOH中，向反应体系中加入1M NaOH(1.25mL，1.25mmol)。反应体系在室温下搅拌，TLC跟踪监测。反应结束后，真空旋去大部分溶剂，剩余溶液用1M盐酸溶液调节pH至弱酸性，有大量白色固体析出，减压抽滤，用20mL水洗涤滤饼，真空干燥得白色固体49.52mg(产率57.20％)。1H NMR(400MHz，DMSO)δ11.85(s，1H)，9.97(s，1H)，8.44(s，1H)，8.40 (d，J＝2.8Hz，1H)，8.27(s，1H)，8.24(d，J＝7.4Hz，1H)，7.92(s，1H)，7.81(s，1H)，7.48(d，J＝7.6Hz，1H)，7.25-7.10(m，2H)，6.96(d，J＝3.2Hz，1H)，6.63(m，1H).(1-Acetyl-1H-indole-3-carboxamido)-5-(furan-2-yl)benzoic acid (100 mg, 0.25 mmol) was dissolved in 8 mL of MeOH, and 1 M NaOH was added to the reaction system. 1.25 mL, 1.25 mmol). The reaction system was stirred at room temperature and monitored by TLC. After the reaction was completed, most of the solvent was removed by vacuum, and the remaining solution was adjusted to a weak acidity with a 1 M hydrochloric acid solution. A large amount of a white solid was precipitated, and filtered under reduced pressure. The filter cake was washed with 20 mL of water and dried in vacuo to give a white solid. The rate is 57.20%). 1H NMR (400MHz, DMSO) δ 11.85 (s, 1H), 9.97 (s, 1H), 8.44 (s, 1H), 8.40 (d, J = 2.8 Hz, 1H), 8.27 (s, 1H), 8.24 (d, J = 7.4 Hz, 1H), 7.92 (s, 1H), 7.81 (s, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.25-7.10 (m, 2H), 6.96 (d, J = 3.2 Hz, 1H), 6.63 (m, 1H).
实施例129Example 129
3-(呋喃-2-基)-5-(1-丙酰基-1H-吲哚-3-甲酰氨基)苯甲酸叔丁酯的合成，合成方法如实例47。1H NMR(400MHz，DMSO)δ10.32(s，1H)，8.90(s，1H)，8.47-8.43(m，1H)，8.40(d，J＝7.5Hz，1H)，8.33-8.26(m，1H)，8.22(d，J＝1.5Hz，1H)，7.92(s，1H)，7.84(d，J＝1.2Hz，1H)，7.40(tt，J＝7.2，3.8Hz，2H)，7.04(d，J＝3.3Hz，1H)，6.66(dd，J＝3.4，1.8Hz，1H)，3.18(q，J＝7.2Hz，2H)，1.60(s，9H)，1.24(d，J＝7.2Hz，3H).Synthesis of tert-butyl 3-(furan-2-yl)-5-(1-propionyl-1H-indole-3-carboxamido)benzoate, as described in Example 47. 1H NMR (400 MHz, DMSO) δ 10.32 (s, 1H), 8.90 (s, 1H), 8.47-8.43 (m, 1H), 8.40 (d, J = 7.5 Hz, 1H), 8.33 - 8.26 (m, 1H), 8.22 (d, J = 1.5 Hz, 1H), 7.92 (s, 1H), 7.84 (d, J = 1.2 Hz, 1H), 7.40 (tt, J = 7.2, 3.8 Hz, 2H), 7.04 (d, J = 3.3 Hz, 1H), 6.66 (dd, J = 3.4, 1.8 Hz, 1H), 3.18 (q, J = 7.2 Hz, 2H), 1.60 (s, 9H), 1.24 (d, J = 7.2 Hz, 3H).
实施例130Example 130
(呋喃-2-基)-5-(1-丙酰基-1H-吲哚-3-甲酰氨基)苯甲酸的合成，合成方法如实例71。1H NMR(400MHz，DMSO)δ10.30(s，1H)，8.92(s，1H)，8.45(s，1H)，8.41(d，J＝7.6Hz，1H)，8.31(s，1H)，8.29(s，1H)，7.98(s，1H)，7.83(d，J＝1.2Hz，1H)，7.46-7.35(m，2H)，7.05(d，J＝3.3Hz，1H)，6.65(dd，J＝3.3，1.8Hz，1H)，3.21-3.16(m，2H)，1.25(d，J＝7.3Hz，3H).Synthesis of (furan-2-yl)-5-(1-propionyl-1H-indole-3-carboxamido)benzoic acid, as described in Example 71. 1H NMR (400 MHz, DMSO) δ 10.30 (s) , 1H), 8.92 (s, 1H), 8.45 (s, 1H), 8.41 (d, J = 7.6 Hz, 1H), 8.31 (s, 1H), 8.29 (s, 1H), 7.98 (s, 1H) , 7.83 (d, J = 1.2 Hz, 1H), 7.46-7.35 (m, 2H), 7.05 (d, J = 3.3 Hz, 1H), 6.65 (dd, J = 3.3, 1.8 Hz, 1H), 3.21 3.16 (m, 2H), 1.25 (d, J = 7.3 Hz, 3H).
实施例131Example 131
3-(1-乙酰基-5-甲氧基-1H-吲哚-3-甲酰氨基)-4-氟-5-(1-甲基-1H-吡唑-4-基)苯甲酸的合成，合成方法如实施例71。1H NMR(500MHz，DMSO)δ13.16(s，1H)，10.10(s，1H)，8.85(s，1H)，8.29(s，1H)，8.26(d，J＝9.1Hz，1H)，8.19(d，J＝5.4Hz，1H)，8.07(d，J＝4.9Hz，1H)，7.96(s，1H)，7.74(s，1H)，7.01(d，J＝8.9Hz，1H)，3.92(s，3H)，3.81(s，3H)，2.73(s，3H).3-(1-acetyl-5-methoxy-1H-indole-3-carboxamido)-4-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzoic acid Synthesis, synthesis method as in Example 71. 1H NMR (500 MHz, DMSO) δ 13.16 (s, 1H), 10.10 (s, 1H), 8.85 (s, 1H), 8.29 (s, 1H), 8.26 (d, J = 9.1 Hz, 1H), 8.19 (d, J = 5.4 Hz, 1H), 8.07 (d, J = 4.9 Hz, 1H), 7.96 (s, 1H), 7.74 (s, 1H), 7.01 (d, J=8.9 Hz, 1H), 3.92 (s, 3H), 3.81 (s, 3H), 2.73 (s, 3H).
实施例132Example 132
3-(1-乙酰基-5-甲氧基-1H-吲哚-3-甲酰氨基)-4-氟-5-(1-甲基-1H-吡唑-4-基)苯甲酸叔丁酯的合成，合成方法如实施例71。1H NMR(400MHz，DMSO)δ10.13(s，1H)，8.83(s，1H)，8.31-8.24(m，2H)，8.06(d，J＝6.8Hz，1H)，8.03(d，J＝6.4Hz，1H)，7.96(s，1H)，7.72(d，J＝2.1Hz，1H)，7.01(dd，J＝9.0，2.1Hz，1H)，3.92(s，3H)，3.81(s，3H)，2.73(s，3H)，1.58(s，9H).3-(1-acetyl-5-methoxy-1H-indole-3-carboxamido)-4-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzoic acid Synthesis of butyl ester, the synthesis method is as in Example 71. 1H NMR (400MHz, DMSO) δ 10.13 (s, 1H), 8.83 (s, 1H), 8.31-8.24 (m, 2H), 8.06 (d, J = 6.8 Hz, 1H), 8.03 (d, J = 6.4 Hz, 1H), 7.96 (s, 1H), 7.72 (d, J = 2.1 Hz, 1H), 7.01 (dd, J = 9.0, 2.1 Hz, 1H) , 3.92 (s, 3H), 3.81 (s, 3H), 2.73 (s, 3H), 1.58 (s, 9H).
实施例133Example 133
3-(1-乙酰基-5-甲氧基-1H-吲哚-3-甲酰胺基)-4-氟-5-(1-甲基-1H-吲唑-6-基)苯甲酸叔丁酯的合成，合成方法如实施例47。1H NMR(500MHz，DMSO)δ10.17(s，1H)，8.84(s，1H)，8.26(d，J＝9.1Hz，2H)，8.16(s，1H)，7.99(s，1H)，7.88(d，J＝6.6Hz，1H)，7.79(d，J＝8.7Hz，1H)，7.73(s，1H)，7.61(d，J＝8.8Hz，1H)，7.02(d，J＝9.1Hz，1H)，4.10(s，3H)，3.82(s，3H)，2.73(s，3H)，1.99(d，J＝1.6Hz，2H)，1.58(s，9H).3-(1-acetyl-5-methoxy-1H-indole-3-carboxamido)-4-fluoro-5-(1-methyl-1H-indazol-6-yl)benzoic acid Synthesis of butyl ester, the synthesis method is as in Example 47. 1H NMR (500MHz, DMSO) δ 10.17 (s, 1H), 8.84 (s, 1H), 8.26 (d, J = 9.1 Hz, 2H), 8.16 (s , 1H), 7.99 (s, 1H), 7.88 (d, J = 6.6 Hz, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.73 (s, 1H), 7.61 (d, J = 8.8 Hz) , 1H), 7.02 (d, J = 9.1 Hz, 1H), 4.10 (s, 3H), 3.82 (s, 3H), 2.73 (s, 3H), 1.99 (d, J = 1.6 Hz, 2H), 1.58 (s, 9H).
实施例134Example 134
3-(1-乙酰基-5-甲氧基-1H-吲哚-3-甲酰氨基)-4-氟-5-(1-甲基-1H-吲唑-6-基)苯甲酸的合成，合成方法如实施例71。1H NMR(400MHz，DMSO)δ10.15(s，1H)，8.86(s，1H)，8.38(dd，J＝6.8，1.9Hz，1H)，8.26(d，J＝9.1Hz，1H)，8.15(s，1H)，8.01(s，1H)，7.93(dd，J＝6.8，2.0Hz，1H)，7.79(d，J＝8.8Hz，1H)，7.75(d，J＝2.6Hz，1H)，7.63(d，J＝8.6Hz，1H)，7.02(dd，J＝9.1，2.6Hz，1H)，4.10(s，3H)，3.82(s，3H)，2.73(s，3H).3-(1-acetyl-5-methoxy-1H-indole-3-carboxamido)-4-fluoro-5-(1-methyl-1H-indazol-6-yl)benzoic acid Synthesis, synthesis method as in Example 71. 1H NMR (400 MHz, DMSO) δ 10.15 (s, 1H), 8.86 (s, 1H), 8.38 (dd, J = 6.8, 1.9 Hz, 1H), 8.26 (d, J = 9.1 Hz, 1H), 8.15 (s, 1H), 8.01 (s, 1H), 7.93 (dd, J = 6.8, 2.0 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.75 ( d, J = 2.6 Hz, 1H), 7.63 (d, J = 8.6 Hz, 1H), 7.02 (dd, J = 9.1, 2.6 Hz, 1H), 4.10 (s, 3H), 3.82 (s, 3H), 2.73 (s, 3H).
实施例135Example 135
3-(1-乙酰基-5-甲氧基-1H-吲哚-3-甲酰氨基)-5-(苯并呋喃-6-基)-4-氟苯甲酸叔丁酯的合成，合成方法如实施例47。1H NMR(500MHz，DMSO)δ10.18(s，1H)，8.84(s，1H)，8.26(d，J＝9.3Hz，2H)，8.09(s，1H)，7.92-7.85(m，2H)，7.79-7.70(m，2H)，7.52(d，J＝8.2Hz，1H)，7.07(s，1H)，7.02(d，J＝9.0Hz，1H)，3.81(s，3H)，2.73(s，3H)，1.58(s，9H).Synthesis and Synthesis of Tert-Butyl 3-(1-Acetyl-5-methoxy-1H-indole-3-carboxamido)-5-(benzofuran-6-yl)-4-fluorobenzoate The procedure is as in Example 47. 1H NMR (500MHz, DMSO) δ 10.18 (s, 1H), 8.84 (s, 1H), 8.26 (d, J = 9.3 Hz, 2H), 8.09 (s, 1H), 7.92 7.85 (m, 2H), 7.79-7.70 (m, 2H), 7.52 (d, J = 8.2 Hz, 1H), 7.07 (s, 1H), 7.02 (d, J = 9.0 Hz, 1H), 3.81 (s) , 3H), 2.73 (s, 3H), 1.58 (s, 9H).
实施例136Example 136
3-(1-乙酰基-5-甲氧基-1H-吲哚-3-甲酰氨基)-5-(苯并呋喃-6-基)-4-氟苯甲酸的合成，合成方法如实施例71。1H NMR(400MHz，DMSO)δ13.03(s，1H)，10.15(s，1H)，8.86(s，1H)，8.39(d，J＝5.0Hz，1H)，8.26(d，J＝9.1Hz，1H)，8.09(d，J＝2.0Hz，1H)，7.92(s，1H)，7.90(s，1H)，7.76(d，J＝6.4Hz，1H)，7.74(s，1H)，7.06(d，J＝1.2Hz，1H)，7.01(dd，J＝9.1，2.5Hz，1H)，3.82(s，3H)，2.73(s，3H).Synthesis of 3-(1-acetyl-5-methoxy-1H-indole-3-carboxamido)-5-(benzofuran-6-yl)-4-fluorobenzoic acid, synthesis method as implemented Example 71. 1H NMR (400 MHz, DMSO) δ 13.03 (s, 1H), 10.15 (s, 1H), 8.86 (s, 1H), 8.39 (d, J = 5.0 Hz, 1H), 8.26 (d, J) = 9.1 Hz, 1H), 8.09 (d, J = 2.0 Hz, 1H), 7.92 (s, 1H), 7.90 (s, 1H), 7.76 (d, J = 6.4 Hz, 1H), 7.74 (s, 1H) ), 7.06 (d, J = 1.2 Hz, 1H), 7.01 (dd, J = 9.1, 2.5 Hz, 1H), 3.82 (s, 3H), 2.73 (s, 3H).
实施例137Example 137
3-(1-乙酰基-5-甲氧基-1H-吲哚-3-甲酰氨基)-5-(2，3-二氢苯并[b][1，4]二恶英-6-基)-4-氟苯甲酸叔丁酯的合成，合成方法如实施例47。1H NMR(400MHz，DMSO)δ10.13(s，1H)，8.83(s，1H)，8.24(dd，J＝11.7，7.7Hz，2H)，7.77(dd，J＝6.7，2.1Hz，1H)，7.72(d，J＝2.6Hz，1H)，7.08(s，2H)，7.01(d，J＝7.9Hz，2H)，4.31(s，4H)，3.81(s，3H)，2.72(s，3H)，1.57(s，9H).3-(1-acetyl-5-methoxy-1H-indole-3-carboxamido)-5-(2,3-dihydrobenzo[b][1,4]dioxin-6 Synthesis of tert-butyl 4-fluorobenzoate, as described in Example 47. 1H NMR (400 MHz, DMSO) δ 10.13 (s, 1H), 8.83 (s, 1H), 8.24 (dd, J =11.7, 7.7 Hz, 2H), 7.77 (dd, J = 6.7, 2.1 Hz, 1H), 7.72 (d, J = 2.6 Hz, 1H), 7.08 (s, 2H), 7.01 (d, J = 7.9 Hz) , 2H), 4.31 (s, 4H), 3.81 (s, 3H), 2.72 (s, 3H), 1.57 (s, 9H).
实施例138Example 138
3-(1-乙酰基-5-甲氧基-1H-吲哚-3-甲酰氨基)-5-(2，3-二氢苯并[b][1，4]二恶英-6-基)-4-氟苯甲酸的合成，合成方法如实施例71。1H NMR(400MHz，DMSO)δ13.07(s，1H)，10.12(s，1H)，8.85(s，1H)，8.34(d，J＝5.1Hz，1H)，8.25(d，J＝9.1Hz，1H)，7.82(d，J＝5.1Hz，1H)，7.73(d，J＝2.3Hz，1H)，7.08(d，J＝13.1Hz，2H)，7.05-6.93(m，2H)，4.31(s，4H)，3.81(s，3H)，2.73(s，3H).3-(1-acetyl-5-methoxy-1H-indole-3-carboxamido)-5-(2,3-dihydrobenzo[b][1,4]dioxin-6 Synthesis of 4-fluorobenzoic acid, as described in Example 71. 1H NMR (400 MHz, DMSO) δ 13.07 (s, 1H), 10.12 (s, 1H), 8.85 (s, 1H), 8.34 (d, J = 5.1 Hz, 1H), 8.25 (d, J = 9.1 Hz, 1H), 7.82 (d, J = 5.1 Hz, 1H), 7.73 (d, J = 2.3 Hz, 1H), 7.08 (d , J = 13.1 Hz, 2H), 7.05 - 6.93 (m, 2H), 4.31 (s, 4H), 3.81 (s, 3H), 2.73 (s, 3H).
实施例139Example 139
甲基3-(1-乙酰基-5-甲氧基-1H-吲哚-3-甲酰氨基)-5-(2，3-二氢苯并[b][1，4]二恶英-6-基)-4-氟苯甲酸酯的合成，合成方法如实施例47。1H NMR(400MHz，DMSO)δ10.14(s，1H)，8.85(s，1H)，8.38(dd，J＝6.7，2.1Hz，1H)，8.26(d，J＝9.1Hz，1H)，7.83(dd，J＝6.8，2.2Hz，1H)，7.73(d，J＝2.6Hz，1H)，7.13-7.05(m，2H)，7.01(dd，J＝8.7，2.9Hz，2H)，4.31(s，4H)，3.90(s，3H)，3.82(s，3H)，2.73(s，3H).Methyl 3-(1-acetyl-5-methoxy-1H-indole-3-carboxamido)-5-(2,3-dihydrobenzo[b][1,4]dioxin Synthesis of -6-yl)-4-fluorobenzoate, as described in Example 47. 1H NMR (400 MHz, DMSO) δ 10.14 (s, 1H), 8.85 (s, 1H), 8.38 (dd, J = 6.7, 2.1 Hz, 1H), 8.26 (d, J = 9.1 Hz, 1H), 7.83 (dd, J = 6.8, 2.2 Hz, 1H), 7.73 (d, J = 2.6 Hz, 1H), 7.13 7.05 (m, 2H), 7.01 (dd, J = 8.7, 2.9 Hz, 2H), 4.31 (s, 4H), 3.90 (s, 3H), 3.82 (s, 3H), 2.73 (s, 3H).
实施例140Example 140
甲基3-(1-乙酰基-5-甲氧基-1H-吲哚-3-甲酰氨基)-5-(苯并呋喃-6-基)-4-氟苯甲酸甲酯的合成，合成方法如实施例47。1H NMR(400MHz，DMSO)δ10.17(s，1H)，8.86(s，1H)，8.43(dd，J＝6.7，2.1Hz，1H)，8.26(d，J＝9.1Hz，1H)，8.09(d，J＝2.1Hz，1H)，7.93(dd，J＝8.4，3.7Hz，2H)，7.75(t，J＝6.3Hz，2H)，7.56(dd，J＝12.8，5.5Hz，1H)，7.07(d，J＝2.1Hz，1H)，7.02(dd，J＝9.1，2.6Hz，1H).Synthesis of methyl 3-(1-acetyl-5-methoxy-1H-indole-3-carboxamido)-5-(benzofuran-6-yl)-4-fluorobenzoic acid methyl ester, The synthesis method is as in Example 47. 1H NMR (400 MHz, DMSO) δ 10.17 (s, 1H), 8.86 (s, 1H), 8.43 (dd, J = 6.7, 2.1 Hz, 1H), 8.26 (d, J = 9.1 Hz, 1H), 8.09 (d, J = 2.1 Hz, 1H), 7.93 (dd, J = 8.4, 3.7 Hz, 2H), 7.75 (t, J = 6.3 Hz, 2H), 7.56 (dd, J = 12.8, 5.5 Hz, 1H), 7.07 (d, J = 2.1 Hz, 1H), 7.02 (dd, J = 9.1, 2.6 Hz, 1H).
实施例141Example 141
甲基3-(1-乙酰基-5-甲氧基-1H-吲哚-3-甲酰氨基)-4-氟-5-(1-甲基-1H-吲唑-6-基)苯甲酸甲酯的合成，合成方法如实施例47。1H NMR(400MHz，DMSO)δ10.16(s，1H)，8.86(s，1H)，8.42(dd，J＝6.7，2.0Hz，1H)，8.26(d，J＝9.1Hz，1H)，8.16(s，1H)，8.01(s，1H)，7.94(dd，J＝6.8，2.1Hz，1H)，7.79(d，J＝8.8Hz，1H)，7.74(d，J＝2.6Hz，1H)，7.63(d，J＝8.7Hz，1H)，7.02(dd，J＝9.0，2.6Hz，1H)，4.10(s，3H)，3.91(s，3H)，3.82(s，3H)，2.73(s，3H).Methyl 3-(1-acetyl-5-methoxy-1H-indole-3-carboxamido)-4-fluoro-5-(1-methyl-1H-indazol-6-yl)benzene Synthesis of methyl formate, the synthesis method is as in Example 47. 1H NMR (400 MHz, DMSO) δ 10.16 (s, 1H), 8.86 (s, 1H), 8.42 (dd, J = 6.7, 2.0 Hz, 1H), 8.26 (d, J = 9.1 Hz, 1H), 8.16 (s, 1H), 8.01 (s, 1H), 7.94 (dd, J = 6.8, 2.1 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H) ), 7.74 (d, J = 2.6 Hz, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.02 (dd, J = 9.0, 2.6 Hz, 1H), 4.10 (s, 3H), 3.91 (s) , 3H), 3.82 (s, 3H), 2.73 (s, 3H).
实施例142Example 142
3-(1-乙酰基-5-甲氧基-1H-吲哚-3-甲酰氨基)-5-(呋喃-2-基)苯甲酸叔丁酯的合成，合成方法如实施例47。1H NMR(400MHz，DMSO)δ10.31(s，1H)，8.82(s，1H)，8.45(s，1H)，8.25(d，J＝9.0Hz，1H)，8.19(s，1H)，7.92(s，1H)，7.84(d，J＝1.2Hz，1H)，7.78(d，J＝2.6Hz，1H)，7.01(m，2H)，6.66(dd，J＝3.3，1.8Hz，1H)，3.84(s，3H)，2.74(s，3H)，1.60(s，9H).Synthesis of tert-butyl 3-(1-acetyl-5-methoxy-1H-indole-3-carboxamido)-5-(furan-2-yl)benzoate as described in Example 47. 1H NMR (400MHz, DMSO) δ 10.31 (s, 1H), 8.82 (s, 1H), 8.45 (s, 1H), 8.25 (d, J = 9.0 Hz, 1H), 8.19 (s, 1H), 7.92 (s, 1H), 7.84 (d, J = 1.2 Hz, 1H), 7.78 (d, J = 2.6 Hz, 1H), 7.01 (m, 2H), 6.66 (dd, J = 3.3, 1.8 Hz, 1H) , 3.84 (s, 3H), 2.74 (s, 3H), 1.60 (s, 9H).
对比例1Comparative example 1
对SGC-CBP30体外活性实验，采用AlphaScreen检测技术验证本申请化合物的对CBP/EP300蛋白抑制能力。For the in vitro activity assay of SGC-CBP30, the ability of the compound of the present application to inhibit CBP/EP300 protein was verified by AlphaScreen detection technique.
实施例1-142以及对比例1的化合物结构如表1所示。The structures of the compounds of Examples 1-142 and Comparative Example 1 are shown in Table 1.
Figure PCTCN2018101765-appb-000006
Figure PCTCN2018101765-appb-000006
Figure PCTCN2018101765-appb-000007
Figure PCTCN2018101765-appb-000007
Figure PCTCN2018101765-appb-000008
Figure PCTCN2018101765-appb-000008
Figure PCTCN2018101765-appb-000009
Figure PCTCN2018101765-appb-000009
Figure PCTCN2018101765-appb-000010
Figure PCTCN2018101765-appb-000010
Figure PCTCN2018101765-appb-000011
Figure PCTCN2018101765-appb-000011
Figure PCTCN2018101765-appb-000012
Figure PCTCN2018101765-appb-000012
对实施例1-142制备得到的吲哚类化合物进行体外活性实验：本申请采用AlphaScreen检测技术验证本申请化合物的对CBP/EP300蛋白抑制能力。In vitro activity experiments were carried out on the terpenoids prepared in Examples 1-142: This application uses the AlphaScreen detection technique to verify the ability of the compounds of the present application to inhibit CBP/EP300 protein.
所述体外活性实验材料包括：目的蛋白CBP；实验缓冲液(10×)MOPS(500mm)，CHAPS(0.5mm)，NaF(500mm)，BSA(1mg/mL)，PH7.4；试剂盒中供体微珠50μg/mL，受体微珠50μg/mL；CBP配体，短肽H4KAc4-botin(SGRG{Lys-Ac}GG{Lys-Ac}GLG{Lys-Ac}GGA{Lys-Ac}RHR{Lys(biotin)})50nM；150μL 反应体系中：CBP：15μL，实验缓冲液：15μL，去离子水：15μL，小分子化合物：15μL，供体微珠：15μL，受体微珠：15μL；阳性抑制剂：SGC-CBP30。The in vitro activity test materials include: a protein of interest CBP; an experimental buffer (10×) MOPS (500 mm), CHAPS (0.5 mm), NaF (500 mm), BSA (1 mg/mL), pH 7.4; Body microbead 50μg/mL, acceptor microbead 50μg/mL; CBP ligand, short peptide H4KAc4-botin(SGRG{Lys-Ac}GG{Lys-Ac}GLG{Lys-Ac}GGA{Lys-Ac}RHR {Lys(biotin)}) 50nM; 150μL reaction system: CBP: 15μL, experimental buffer: 15μL, deionized water: 15μL, small molecule compound: 15μL, donor microbead: 15μL, acceptor microbead: 15μL; Positive inhibitor: SGC-CBP30.
所述体外活性实验方法为将蛋白、短肽加入反应溶液中，在20℃下孵育1.5h，加入供体和受体微珠，避光孵育1h。转移至384孔板，每孔转移40μL液体，通过PE Envison2104多功能检测酶标仪，激发波长：680nM，发射波长520-620nM检测读数。The in vitro activity test method is to add protein and short peptide to the reaction solution, incubate at 20 ° C for 1.5 h, add donor and acceptor beads, and incubate for 1 h in the dark. Transfer to a 384-well plate, transfer 40 μL of liquid per well, and pass the PE Envison 2104 multi-function detection microplate reader, excitation wavelength: 680 nM, emission wavelength 520-620 nM detection reading.
对比例1采用AlphaScreen检测技术验证结果，验证结果见表1：Comparative Example 1 was verified by AlphaScreen detection technology. The verification results are shown in Table 1:
表1Table 1
化合物编号Compound number 抑制率Inhibition rate 化合物编号Compound number 抑制率Inhibition rate 化合物编号Compound number 抑制率Inhibition rate
对比例1Comparative example 1 98％98% 实施例1Example 1 47％47% 实施例2Example 2 35％35%
实施例3Example 3 36％36% 实施例4Example 4 20％20% 实施例5Example 5 98％98%
实施例6Example 6 -3％-3% 实施例7Example 7 74％74% 实施例8Example 8 40％40%
实施例9Example 9 88％88% 实施例10Example 10 94％94% 实施例11Example 11 57％57%
实施例12Example 12 24％twenty four% 实施例13Example 13 27％27% 实施例14Example 14 11％11%
实施例15Example 15 44％44% 实施例16Example 16 42％42% 实施例17Example 17 54％54%
实施例18Example 18 37％37% 实施例19Example 19 12％12% 实施例20Example 20 31％31%
实施例21Example 21 63％63% 实施例22Example 22 88％88% 实施例23Example 23 88％88%
实施例24Example 24 67％67% 实施例25Example 25 91％91% 实施例26Example 26 50％50%
实施例27Example 27 3.893.89 实施例28Example 28 91％91% 实施例29Example 29 72％72%
实施例30Example 30 96％96% 实施例31Example 31 71％71% 实施例32Example 32 61％61%
实施例33Example 33 73％73% 实施例34Example 34 96％96% 实施例35Example 35 58％58%
实施例36Example 36 79％79% 实施例37Example 37 19％19% 实施例38Example 38 94％94%
实施例39Example 39 94％94% 实施例40Example 40 68％68% 实施例41Example 41 30％30%
实施例42Example 42 70％70% 实施例43Example 43 58％58% 实施例44Example 44 86％86%
实施例45Example 45 91％91% 实施例46Example 46 88％88% 实施例47Example 47 29％29%
实施例48Example 48 97％97% 实施例49Example 49 71％71% 实施例50Example 50 15％15%
实施例51Example 51 96％96% 实施例52Example 52 55％55% 实施例53Example 53 98％98%
实施例54Example 54 81％81% 实施例55Example 55 91％91% 实施例56Example 56 62％62%
实施例57Example 57 93％93% 实施例58Example 58 89％89% 实施例59Example 59 89％89%
实施例60Example 60 85％85% 实施例61Example 61 97％97% 实施例62Example 62 65％65%
实施例63Example 63 98％98% 实施例64Example 64 96％96% 实施例65Example 65 89％89%
实施例66Example 66 93％93% 实施例67Example 67 2％2% 实施例68Example 68 81％81%
实施例69Example 69 98％98% 实施例70Example 70 -3％-3% 实施例71Example 71 45％45%
实施例72Example 72 97％97% 实施例73Example 73 98％98% 实施例74Example 74 26％26%
实施例75Example 75 98％98% 实施例76Example 76 54％54% 实施例77Example 77 38％38%
实施例78Example 78 98％98% 实施例79Example 79 44％44% 实施例80Example 80 77％77%
实施例81Example 81 40％40% 实施例82Example 82 26％26% 实施例83Example 83 52％52%
实施例84Example 84 52％52% 实施例85Example 85 91％91% 实施例86Example 86 97％97%
实施例87Example 87 98％98% 实施例88Example 88 73％73% 实施例89Example 89 97％97%
实施例90Example 90 69％69% 实施例91Example 91 90％90% 实施例92Example 92 94％94%
实施例93Example 93 58％58% 实施例94Example 94 31％31% 实施例95Example 95 94％94%
实施例96Example 96 92％92% 实施例97Example 97 87％87% 实施例98Example 98 20％20%
实施例99Example 99 91％91% 实施例100Example 100 90％90% 实施例101Example 101 94％94%
实施例102Example 102 96％96% 实施例103Example 103 94％94% 实施例104Example 104 88％88%
实施例105Example 105 98％98% 实施例106Example 106 87％87% 实施例107Example 107 78％78%
实施例108Example 108 92％92% 实施例109Example 109 98％98% 实施例110Example 110 96％96%
实施例111Example 111 98％98% 实施例112Example 112 89％89% 实施例113Example 113 86％86%
实施例114Example 114 98％98% 实施例115Example 115 23％twenty three% 实施例116Example 116 1％1%
实施例117Example 117 12％12% 实施例118Example 118 -8％-8% 实施例119Example 119 3％3%
实施例120Example 120 98％98% 实施例121Example 121 97％97% 实施例122Example 122 95％95%
实施例123Example 123 97％97% 实施例124Example 124 95％95% 实施例125Example 125 98％98%
实施例126Example 126 92％92% 实施例127Example 127 4％4% 实施例128Example 128 1％1%
实施例129Example 129 -8％-8% 实施例130Example 130 80％80% 实施例131Example 131 98％98%
实施例132Example 132 98％98% 实施例133Example 133 80％80% 实施例134Example 134 95％95%
实施例135Example 135 10％10% 实施例136Example 136 98％98% 实施例137Example 137 1％1%
实施例138Example 138 87％87% 实施例139Example 139 96％96% 实施例140Example 140 88％88%
实施例141Example 141 95％95% 实施例142Example 142 20％20%    
注：以上活性数据针对溴结构域家族的CBP/EP300蛋白。Note: The above activity data is for the CBP/EP300 protein of the bromodomain family.
表中的部分化合物表现出与阳性对照SGC-CBP30相当的活性，虽然较SGC-CBP30略低，但也显示出较强的活性。其中实施例44，46，51，63，73，109，110，111，114，120，121和131已达到纳摩尔水平，特别是实施例110，111，114和131所介绍的化合物与阳性化合物相当，且对比阳性化合物具有结构稳定和容易制备的优点。且大部分实施例对CBP/EP300有很好的选择性。表1分子水平活性数据表明，这些化合物可以有效结合具有溴结构域的蛋白。Some of the compounds in the table showed comparable activity to the positive control SGC-CBP30, although slightly lower than SGC-CBP30, but also showed stronger activity. Among them, Examples 44, 46, 51, 63, 73, 109, 110, 111, 114, 120, 121 and 131 have reached nanomolar levels, particularly the compounds and positive compounds described in Examples 110, 111, 114 and 131. Quite, and the comparative positive compounds have the advantage of being structurally stable and easy to prepare. And most of the examples have good selectivity for CBP/EP300. The molecular level activity data of Table 1 indicates that these compounds can efficiently bind to proteins having a bromodomain.
吲哚类化合物细胞活性测定：用RPMI1640培养***癌细胞(LNCaP和22Rv1)，并加上10％FBS。让细胞在37℃在5％CO2培养箱中生长。为了测试细胞的存活能力，将细胞以总体积为20μL的培养基以1000个细胞/孔(最佳生长密度)接种在具有透明底部的384个不透壁板中。12小时后，向每个孔中加入总体积为10μL培养基(三次稀释)的化合物，最终浓度为5nM至100μM。对于LNCaP细胞，培养基是含有10％FBS的RPMI1640。对于22Rv1细胞，培养基是含有10％cds-FBS的RPMI1640。接种后96小时进行测定，加入25μLCell-Titer GLO试剂(Promega)，根据制造商的说明书，在GLOMAX微孔板光度计(Promega)上测量发光。使用GraphPad Prism 6软件计算估计的体外最大半抑制浓度(IC50)值。其中实施例115，132和142细胞活性为5μM以内的水平。Determination of steroid activity in cells: Prostate cancer cells (LNCaP and 22Rv1) were cultured with RPMI1640 and 10% FBS was added. The cells were grown in a 5% CO2 incubator at 37 °C. To test the viability of the cells, cells were seeded at a total volume of 20 μL of medium at 1000 cells/well (optimum growth density) in 384 opaque plates with a transparent bottom. After 12 hours, a total volume of 10 [mu]L of medium (three dilutions) of compound was added to each well to a final concentration of 5 nM to 100 [mu]M. For LNCaP cells, the medium was RPMI 1640 containing 10% FBS. For 22Rv1 cells, the medium was RPMI 1640 containing 10% cds-FBS. The assay was performed 96 hours after inoculation, and 25 μL LCell-Titer GLO reagent (Promega) was added and the luminescence was measured on a GLOMAX microplate luminometer (Promega) according to the manufacturer's instructions. The estimated in vitro maximum half inhibitory concentration (IC50) values were calculated using GraphPad Prism 6 software. The cell viability of Examples 115, 132 and 142 was within 5 μM.
对于集落形成，将1000个22Rv1细胞和2000个C4-2B细胞分别接种在6孔板的孔中，并用载体或指示浓度的化合物与3mL培养基一起培养14天。当细胞克隆生长可见时，除去培养基，并将板用2mL PBS洗涤一次。细胞集落用2.5％结晶紫(在MeOH中)染色2小时。用水清洗3次后，计数菌落数。实施例115在细胞克隆形成实验中，表现出5μM以内的水平。因此充分表明这类化合物具有成为癌症、炎症疾病及自身免疫疾病、败血症、病毒感染等疾病的潜力。For colony formation, 1000 22Rv1 cells and 2000 C4-2B cells were seeded in wells of a 6-well plate, respectively, and cultured for 14 days with vehicle or indicated concentration of compound with 3 mL of medium. When cell clone growth was visible, the medium was removed and the plates were washed once with 2 mL PBS. Cell colonies were stained with 2.5% crystal violet (in MeOH) for 2 hours. After washing three times with water, the number of colonies was counted. Example 115 showed a level within 5 μM in the cell clone formation experiment. Therefore, it has been sufficiently demonstrated that such compounds have the potential to become diseases such as cancer, inflammatory diseases, autoimmune diseases, sepsis, and viral infections.
申请人声明，本申请通过上述实施例来说明本申请的详细结构特征，但本申请并不局限于上述详细结构特征，即不意味着本申请必须依赖上述详细结构特征才能实施。所属技术领域的技术人员应该明了，对本申请的任何改进，对本申请所选用部件的等效替换以及辅助部件的增加、具体方式的选择等，均落在本申请的保护范围和公开范围之内。The Applicant claims that the detailed structural features of the present application are described by the above embodiments, but the present application is not limited to the above detailed structural features, that is, the application does not necessarily depend on the detailed structural features described above. It is to be understood by those skilled in the art that any modifications of the present application, equivalent substitutions of the components selected for the present application, and the addition of the components, the selection of the specific manners, and the like, are all within the scope of the present disclosure.
以上详细描述了本申请的优选实施方式，但是，本申请并不限于上述实施方式中的具体细节，在本申请的技术构思范围内，可以对本申请的技术方案进行多种简单变型，这些简单变型均属于本申请的保护范围。另外需要说明的是，在上述具体实施方式中所描述的各个具体技术特征，在不矛盾的情况下，可以通过任何合适的方式进行组合，为了避免不必要的重复，本申请对各种可能的组合方式不再另行说明。此外，本申请的各种不同的实施方式之间也可以进行任意组合，只要其不违背本申请的思想，其同样应当视为本申请所公开的内容。The preferred embodiments of the present application have been described in detail above. However, the present application is not limited to the specific details in the foregoing embodiments, and various simple modifications may be made to the technical solutions of the present application within the technical concept of the present application. All belong to the scope of protection of this application. It should be further noted that the specific technical features described in the above specific embodiments may be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present application has various possibilities. The combination method will not be described separately. In addition, any combination of various embodiments of the present application may be made as long as it does not contradict the idea of the present application, and it should also be regarded as the content disclosed in the present application.

Claims (12)

  1. 一种吲哚类化合物，所述化合物具有下述化学式I和化学式II的结构：An anthraquinone compound having the structure of the following chemical formula I and formula II:
    Figure PCTCN2018101765-appb-100001
    Figure PCTCN2018101765-appb-100001
    式I中，R 1为C 1～C 4烷基，R 2为H、C 1～C 7烷基、-R-X 1或-X 2，R 3为H、C 1～C 5烷基、C 3～C 5环烷基、-OX 3、-NHX 3或-N(X 3) 2； In formula I, R 1 is C 1 -C 4 alkyl, R 2 is H, C 1 -C 7 alkyl, -RX 1 or -X 2 , R 3 is H, C 1 -C 5 alkyl, C 3 to C 5 cycloalkyl, -OX 3 , -NHX 3 or -N(X 3 ) 2 ;
    其中，R为C 1～C 4亚烷基，X 1为-OX 3、-COOX 4、-CONHX 4、环烷基、杂环基、-COX 5或-S(O) mX 5，X 2为C 3～C 7环烷基、苯基、萘基、杂环基、-COX 5或-S(O) mX 5； Wherein R is a C 1 -C 4 alkylene group, X 1 is -OX 3 , -COOX 4 , -CONHX 4 , a cycloalkyl group, a heterocyclic group, -COX 5 or -S(O) m X 5 , X 2 is C 3 -C 7 cycloalkyl, phenyl, naphthyl, heterocyclic, -COX 5 or -S(O) m X 5 ;
    其中，m为0或2，X 3，X 4和X 5独立地为H、C 1～C 4烷基、C 3～C 7环烷基、苯基、萘基或杂环基； Wherein m is 0 or 2, and X 3 , X 4 and X 5 are independently H, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, phenyl, naphthyl or heterocyclic;
    式II中，R 4为C 1～C 4烷基，R 5为C 1～C 7烷基、-R′-Y 1、Y 1′-(C 1-C 4次烷基)-Y 1或Y 2，R 6为H、C 1～C 5烷基、C 3～C 5环烷基、-OY 3、-NHY 3或-N(Y 3) 2； In the formula II, R 4 is a C 1 -C 4 alkyl group, R 5 is a C 1 -C 7 alkyl group, -R'-Y 1 , Y 1 '-(C 1 -C 4 alkyl group)-Y 1 Or Y 2 , R 6 is H, C 1 -C 5 alkyl, C 3 -C 5 cycloalkyl, -OY 3 , -NHY 3 or -N(Y 3 ) 2 ;
    其中，R′为C 1～C 4亚烷基，Y 1为-NHCOO tBu、C 3～C 7环烷基、苯基、萘基、-OY 4、-COY 4、-COOY 4、-NHCOY 4或-S(O) mY 4，Y 1′为-NHCOO tBu、C 3～C 7环烷基、苯基、萘基、-OY 4、-COY 4、-COOY 4、-NHCOY 4或-S(O) mY 4，Y 2为C 3～C 7环烷基、苯基、萘基或杂环基； Wherein R' is a C 1 -C 4 alkylene group, Y 1 is -NHCOO t Bu, C 3 -C 7 cycloalkyl, phenyl, naphthyl, -OY 4 , -COY 4 , -COOY 4 , - NHCOY 4 or -S(O) m Y 4 , Y 1 ' is -NHCOO t Bu, C 3 -C 7 cycloalkyl, phenyl, naphthyl, -OY 4 , -COY 4 , -COOY 4 , -NHCOY 4 or -S(O) m Y 4 , Y 2 is a C 3 -C 7 cycloalkyl group, a phenyl group, a naphthyl group or a heterocyclic group;
    其中，m为0或2，Y 4为H、C 1～C 4烷基、C 3～C 7环烷基、苯基、萘基或杂环基。 Wherein m is 0 or 2, and Y 4 is H, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, phenyl, naphthyl or heterocyclic.
  2. 根据权利要求1所述的化合物，其中，所述式I中R 1包括甲基、乙基、正丙基、异丙基或叔丁基。 The compound according to claim 1, wherein R 1 in the formula I comprises a methyl group, an ethyl group, a n-propyl group, an isopropyl group or a t-butyl group.
  3. 根据权利要求2所述的化合物，其中，所述式I中R 2包括-R-X 1或-X 2，其中R为C 1～C 2亚烷基，X 1为-COOX 4、-CONHX 4、环烷基或杂环基，X 2为-COX 5或-S(O) 2X 5，其中X 5为C 1～C 3烷基、C 3～C 7环烷基、苯基、萘基或杂环基。 The compound according to claim 2, wherein R 2 in the formula I includes -RX 1 or -X 2 , wherein R is a C 1 -C 2 alkylene group, and X 1 is -COOX 4 , -CONHX 4 , a cycloalkyl or heterocyclic group, X 2 is -COX 5 or -S(O) 2 X 5 , wherein X 5 is C 1 -C 3 alkyl, C 3 -C 7 cycloalkyl, phenyl, naphthyl Or a heterocyclic group.
  4. 根据权利要求2所述的化合物，其中，所述式I中R 3包括H、甲基、乙基、正丙基、异丙基、正丁基、正戊基、环丙基、环丁基、环戊基、酚羟基、甲氧基、乙氧基、丙氧基、丁氧基、氮甲基、氮乙基、氮丙基或氮丁基； The compound according to claim 2, wherein R 3 in the formula I includes H, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, cyclopropyl, cyclobutyl , cyclopentyl, phenolic hydroxyl, methoxy, ethoxy, propoxy, butoxy, nitrogen methyl, nitrogen ethyl, nitrogen propyl or nitrogen butyl;
    优选地，所述式II中R 4包括甲基、乙基、正丙基、异丙基或叔丁基； Preferably, R 4 in the formula II includes methyl, ethyl, n-propyl, isopropyl or t-butyl;
    优选地，所述式II中R 5包括-R′-Y 1或Y 2，其中R′为C 1～C 4亚烷基，Y 1为C 3～C 7环烷基、苯基、萘基、-OY 4、-COY 4、-COOY 4、-NHCOY 4或-S(O) 2Y 4，Y 2为C 3～C 7环烷基、苯基、萘基或杂环基，其中Y 4为H、C 1～C 4烷基、C 3～C 7环烷基、苯基、萘基或杂环基； Preferably, R 5 in the formula II includes -R'-Y 1 or Y 2 , wherein R' is a C 1 -C 4 alkylene group, and Y 1 is a C 3 -C 7 cycloalkyl group, a phenyl group, a naphthalene group. a group, -OY 4 , -COY 4 , -COOY 4 , -NHCOY 4 or -S(O) 2 Y 4 , Y 2 is a C 3 -C 7 cycloalkyl group, a phenyl group, a naphthyl group or a heterocyclic group, wherein Y 4 is H, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, phenyl, naphthyl or heterocyclic;
    优选地，所述式II中R 6包括H、甲基、乙基、正丙基、异丙基、正丁基、正戊基、环丙基、环丁基、环戊基、酚羟基、甲氧基、乙氧基、丙氧基、丁氧基、氮甲基、氮乙基、氮丙基或氮丁基。 Preferably, R 6 in the formula II includes H, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, phenolic hydroxyl, Methoxy, ethoxy, propoxy, butoxy, nitrogen methyl, nitrogen ethyl, nitrogen propyl or nitrogen butyl.
  5. 根据权利要求1或2所述化合物，其中，式I中所述C 3～C 7环烷基、苯基以及萘基含有0～3个取代基； The compound according to claim 1 or 2, wherein the C 3 -C 7 cycloalkyl group, the phenyl group and the naphthyl group in the formula I contain 0 to 3 substituents;
    优选地，所述取代基为卤素、C 1～C 4烷基、三氟甲基、氰基、硝基、氨基、酰胺、-COOX 6、-COX 6、-OX 6、-NHCOX 6、-C 6H 5X 7、吗啉基、哌啶基、呋喃基、四氢呋喃基或吡啶基，其中X 6为H、C 1～C 4烷基、苯基，X 7为C 1～C 4烷基、卤素、三氟甲基、氰基、硝基、氨基、酰胺、乙酰基、甲氧基或乙氧基。 Preferably, the substituent is halogen, C 1 -C 4 alkyl, trifluoromethyl, cyano, nitro, amino, amide, -COOX 6 , -COX 6 , -OX 6 , -NHCOX 6 , - C 6 H 5 X 7 , morpholinyl, piperidinyl, furyl, tetrahydrofuranyl or pyridyl, wherein X 6 is H, C 1 -C 4 alkyl, phenyl, X 7 is C 1 -C 4 alkane Base, halogen, trifluoromethyl, cyano, nitro, amino, amide, acetyl, methoxy or ethoxy.
  6. 根据权利要求1-4所述化合物，其中，式I中所述杂环基为氮杂环丁基、氧杂环丁基、氮杂环戊基、氧杂环戊基、氮杂环己基、氧杂环己基、氮杂环己基、咪唑-2-酮基、咪唑基、呋喃基、噻吩基、噁唑基、异噁唑基、嘧啶基、吡咯基、哌嗪基、四氢吡咯基、哌啶基、吗啉基、1，3-二氧戊环基或苯并[d]噻唑基；A compound according to claims 1-4, wherein the heterocyclic group in the formula I is azetidinyl, oxetanyl, azacyclopentyl, oxetanyl, azacyclohexyl, Oxecyclohexyl, azacyclohexyl, imidazol-2-one, imidazolyl, furyl, thienyl, oxazolyl, isoxazolyl, pyrimidinyl, pyrrolyl, piperazinyl, tetrahydropyrrolyl, Piperidinyl, morpholinyl, 1,3-dioxolanyl or benzo[d]thiazolyl;
    优选地，式I中所述杂环基含有0～3个取代基；Preferably, the heterocyclic group in formula I contains 0 to 3 substituents;
    优选地，所述取代基为卤素、C 1～C 4烷基、三氟甲基、氰基、硝基、氨基、酰胺、-COOX 6、-COX 6、-OX 6、-NHCOX 6、-C 6H 5X 7、吗啉基、哌啶基、呋喃基、四氢呋喃基或吡啶基，其中X 6为H、C 1～C 4烷基、苯基，X 7为C 1～C 4烷基、卤素、三氟甲基、氰基、硝基、氨基、酰胺、乙酰基、甲氧基或乙氧基。 Preferably, the substituent is halogen, C 1 -C 4 alkyl, trifluoromethyl, cyano, nitro, amino, amide, -COOX 6 , -COX 6 , -OX 6 , -NHCOX 6 , - C 6 H 5 X 7 , morpholinyl, piperidinyl, furyl, tetrahydrofuranyl or pyridyl, wherein X 6 is H, C 1 -C 4 alkyl, phenyl, X 7 is C 1 -C 4 alkane Base, halogen, trifluoromethyl, cyano, nitro, amino, amide, acetyl, methoxy or ethoxy.
  7. 根据权利要求1或2所述的化合物，其中，式II中所述C 3～C 7环烷基、苯基以及萘基含有0～3个取代基； The compound according to claim 1 or 2, wherein the C 3 -C 7 cycloalkyl group, the phenyl group and the naphthyl group in the formula II contain 0 to 3 substituents;
    优选地，所述取代基为卤素、C 1～C 4烷基、三氟甲基、氰基、硝基、氨基、1，3-二氧戊环基、-COOY 5、-COY 5、-OY 5、-NHCOY 5、-C 6H 5Y 6、-(CH 2) nNHY 7、-NHCOO tBu、-CH 2OCOO tBu、1-甲基哌嗪、吗啉基、异噁唑基、3，5-二甲基异恶唑基、喹啉基、异喹啉基、哌啶基、噻吩基、呋喃基、四氢呋喃基、吡啶基、嘧啶基、2-吗啉基吡啶基、吲哚基、1，4-苯并二氧杂环基、苯并呋喃基、苯并噻吩基、1-甲基-1H-吲唑基、吡咯基、1H-吡唑基、1-甲基-1H-吡唑基或四氢吡喃基，其中n为0～2，Y 5为自氢、C 1～C 4烷基或苯基，Y 6为氢、C 1～C 4烷基、卤素、甲酰基、乙酰基、甲氧基、乙氧基、三氟甲基、氰基或甲砜基，Y 7为C 1～C 5烷基、C 0～C 2亚烷基-苯基、C 0～C 2亚烷基-萘基或C 0～C 2亚烷基-杂环基，其中Y 7中所述苯基、萘基或杂环基被0～3个卤素、C 1～C 4烷基、三氟甲基、氰基、硝基或氨基取代。 Preferably, the substituent is halogen, C 1 -C 4 alkyl, trifluoromethyl, cyano, nitro, amino, 1,3-dioxolanyl, -COOY 5 , -COY 5 , - OY 5 , -NHCOY 5 , -C 6 H 5 Y 6 , -(CH 2 ) n NHY 7 , -NHCOO t Bu, -CH 2 OCOO t Bu, 1-methylpiperazine, morpholinyl, isoxazole , 3,5-dimethylisoxazolyl, quinolyl, isoquinolinyl, piperidinyl, thienyl, furyl, tetrahydrofuranyl, pyridyl, pyrimidinyl, 2-morpholinylpyridyl, Mercapto, 1,4-benzodioxyl, benzofuranyl, benzothienyl, 1-methyl-1H-carbazolyl, pyrrolyl, 1H-pyrazolyl, 1-methyl -1H-pyrazolyl or tetrahydropyranyl, wherein n is 0 to 2, Y 5 is hydrogen, C 1 -C 4 alkyl or phenyl, Y 6 is hydrogen, C 1 -C 4 alkyl, Halogen, formyl, acetyl, methoxy, ethoxy, trifluoromethyl, cyano or methylsulfonyl, Y 7 is C 1 -C 5 alkyl, C 0 -C 2 alkylene-phenyl a C 0 -C 2 alkylene-naphthyl group or a C 0 -C 2 alkylene-heterocyclic group, wherein the phenyl, naphthyl or heterocyclic group in Y 7 is 0 to 3 halogens, C 1 ~C 4 alkyl, trifluoromethyl Substituted by a cyano group, a nitro group or an amino group.
  8. 根据权利要求1-7任一项所述的化合物，其中，式II中所述杂环基为氮杂环丁基、氧杂环丁基、氮杂环戊基、氧杂环戊基、氮杂环己基、氧杂环己基、氮杂环己基、呋喃基、噻吩基、噁唑基、异噁唑基、嘧啶基、吡咯基、四氢吡咯基、吗啉基、1，3-二氧戊环基、苯并[d]噻唑基、吡啶基、1，4-苯并二氧杂环基、吲唑基、N-甲基苯并咪唑基、吲哚基、二氢吲哚基或2-咪唑烷酮基；The compound according to any one of claims 1 to 7, wherein the heterocyclic group in the formula II is azetidinyl, oxetanyl, azacyclopentyl, oxolane, nitrogen Heterocyclohexyl, oxetanyl, azacyclohexyl, furyl, thienyl, oxazolyl, isoxazolyl, pyrimidinyl, pyrrolyl, tetrahydropyrrolyl, morpholinyl, 1,3-dioxo Pentocyclo, benzo[d]thiazolyl, pyridyl, 1,4-benzodioxyl, oxazolyl, N-methylbenzimidazolyl, indolyl, indanyl or 2-imidazolidinone;
    优选地，式II中所述杂环基含有0～3个取代基；Preferably, the heterocyclic group in the formula II contains 0 to 3 substituents;
    优选地，所述取代基为卤素、C 1～C 4烷基、三氟甲基、氰基、羧基、硝基、氨基、1，3-二氧戊环基、-COOY 5、-COY 5、-OY 5、-NHCOY 5、-NHCOO tBu或-C 6H 5Y 6，其中Y 5为氢、C 1～C 4烷基或苯基，Y 6为C 1～C 4烷基、卤素、乙酰基、甲氧基或乙氧基。 Preferably, the substituent is halogen, C 1 -C 4 alkyl, trifluoromethyl, cyano, carboxyl, nitro, amino, 1,3-dioxolanyl, -COOY 5 , -COY 5 , -OY 5 , -NHCOY 5 , -NHCOO t Bu or -C 6 H 5 Y 6 , wherein Y 5 is hydrogen, C 1 -C 4 alkyl or phenyl, Y 6 is C 1 -C 4 alkyl, Halogen, acetyl, methoxy or ethoxy.
  9. 一种权利要求1-8任一项所述吲哚类化合物的应用，所述吲哚类化合物用于制备CBP/EP300溴结构域受体抑制剂。Use of a terpenoid according to any one of claims 1-8 for the preparation of a CBP/EP300 bromodomain receptor inhibitor.
  10. 根据权利要求9所述的应用，其中，所述CBP/EP300溴结构域受体抑制剂用于制备治疗癌症、细胞增殖性紊乱疾病、炎症疾病及自身免疫疾病、败血症、病毒感染、神经性衰退性疾病的药物。The use according to claim 9, wherein the CBP/EP300 bromodomain receptor inhibitor is used for the preparation of a cancer, cell proliferative disorder, inflammatory disease and autoimmune disease, sepsis, viral infection, neurodegenerative Drugs for sexual diseases.
  11. 一种药物组合物，所述药物组合物含有权利要求1-8任一项所述吲哚类化合物。A pharmaceutical composition comprising the terpenoid compound of any one of claims 1-8.
  12. 根据权利要求11所述的药物组合物，其中，所述药物组合物用于治疗、预防或改善癌症、细胞增殖性紊乱、炎症、自身免疫性疾病、败血症、病毒感染或神经性衰退性疾病。The pharmaceutical composition according to claim 11, wherein the pharmaceutical composition is for treating, preventing or ameliorating cancer, cell proliferative disorder, inflammation, autoimmune disease, sepsis, viral infection or neurodegenerative disease.
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