WO2021143753A1 - 基于吲哚母核的atx抑制剂及其制备方法和应用 - Google Patents

基于吲哚母核的atx抑制剂及其制备方法和应用 Download PDF

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WO2021143753A1
WO2021143753A1 PCT/CN2021/071682 CN2021071682W WO2021143753A1 WO 2021143753 A1 WO2021143753 A1 WO 2021143753A1 CN 2021071682 W CN2021071682 W CN 2021071682W WO 2021143753 A1 WO2021143753 A1 WO 2021143753A1
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ethyl
heterocyclic ring
thiazol
methyl
indole
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PCT/CN2021/071682
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French (fr)
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翟鑫
类红瑞
马恩龙
贾芳
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沈阳药科大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the invention belongs to the technical field of medicine, and relates to an ATX inhibitor based on an indole core and its optical isomers, pharmaceutically acceptable salts, solvates or prodrugs, their preparation methods and their applications.
  • ATX Autotaxin
  • LPC lysophosphatidylcholine
  • LPA lysophosphatidate, lysophosphatidate
  • ATX-LPA functional axis plays an important role in fibrotic diseases. Inhibitors against this functional axis are mainly divided into ATX inhibitors, LPA receptor inhibitors and LPA monoclonal antibodies. Selective inhibition of ATX is to reduce the production of LPA from the source, which can effectively control the process of fibrosis. By inhibiting the ATX-mediated LPA production process, the biological effect produced is better than that of using LPA receptor antagonists alone.
  • ATX inhibitors have inhibitory effects on pulmonary fibrosis.
  • the compound GLPG-1690 developed by Galapagos for the treatment of pulmonary fibrosis is currently in the phase III clinical research phase.
  • the purpose of the present invention is to provide a compound with excellent ATX inhibitory activity and its preparation method and application.
  • the compound of the present invention has good anti-tumor activity and fibrosis inhibitory activity.
  • the present invention provides an indole derivative represented by general formula I or an optical isomer, pharmaceutically acceptable salt, solvate or prodrug thereof,
  • R is H, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl;
  • X is O, S or NH
  • R 1 and R 2 are the same or different, and are independently selected from hydrogen, hydroxyl, carbamoyl, aminosulfonyl, C1-C6 acyl, substituted sulfonyl, and the substituents are C1-C4 alkyl, C2- C4 alkenyl or C2-C4 alkynyl;
  • R 1 and R 2 are C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl optionally substituted by one or more of the following substituents, the substituents being: hydrogen, halogen, halo C1-C4 hydrocarbon group, halogenated C1-C4 alkoxy group, amino group, cyano group, hydroxyl group, mercapto group, carboxyl group, carbamoyl group, aminosulfonyl group, -NR n R o , -OR n , -C(O)R n , -C(O)OR n , -OC(O)R n , -C(O)N(R o )R n , -N(R o )C(O)R n , -S(O) y R n (where y is 0, 1 or 2), -SO 2 N(R o )R n , -N(R
  • R 1 and R 2 together with the nitrogen atom to which they are connected form a 4-7 membered heterocyclic ring or a 5-6 membered aromatic heterocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1-3 N, O and/or
  • the heteroatom of S, the heterocyclic ring and/or aromatic heterocyclic ring may be substituted by 1 to 3 identical or different R 9 ;
  • R 9 is hydrogen, carboxyl, hydroxyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C6 hydrocarbyl or substituted C1-C6 hydrocarbyl, and the substituents are: cyano, amino, C1-C4 alkane An amino group or a C1-C4 sulfonyl group, and the C1-C6 hydrocarbon group is an alkyl group, a C2-C6 alkenyl group or a C2-C6 alkynyl group;
  • R 3 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-6 membered saturated or unsaturated carbocyclic or C1-C6 alkoxy;
  • R 4 does not exist, or is C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, substituted or unsubstituted 5-6 membered aromatic heterocycle, and the substituent is C1-C4 alkyl, C2 -C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, hydroxyl, cyano, C1-C4 alkoxy, halogen substituted (CH 2 ) n , where n is 1, 2 or 3,
  • the aromatic heterocyclic ring contains 1-3 N, O and/or S;
  • R 5 , R 6 , R 7 , and R 8 are each independently selected from hydrogen, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 alkoxy , C1-C4 alkylthio, hydroxyl, carboxyl, cyano, C1-C4 amide, C1-C4 hydrocarbyl substituted carbamoyl, C1-C4 hydrocarbyl substituted sulfonamide, amino, C1-C4 alkyl sulfone, C1-C4 alkyl sulfoxide, and its number and combination are not limited;
  • R 4 and R 5 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered heterocyclic ring or aromatic heterocyclic ring, 4-7 membered unsaturated carbocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1- 3 heteroatoms of N, O and/or S;
  • R 5 and R 6 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1- 3 heteroatoms of N, O and/or S;
  • R 6 and R 7 together with the carbon atoms on the benzene ring they are connected to form a 3-7 membered unsaturated carbocyclic ring, 4-7 membered heterocyclic ring or aromatic heterocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1- 3 heteroatoms of N, O and/or S;
  • R 7 and R 8 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1- 3 heteroatoms of N, O and/or S.
  • the C1-C6 (or C1-C4) hydrocarbon group is C1-C6 (or C1-C4) alkyl, C2-C6 (or C2-C4) alkenyl or C2-C6 ( Or C2-C4) alkynyl.
  • the present invention is preferably the indole derivative represented by the general formula I or its optical isomer, pharmaceutically acceptable salt, solvate or prodrug,
  • R is H or C1-C4 alkyl
  • X is O, S or NH
  • R 1 and R 2 are the same or different, and are independently selected from hydrogen, hydroxy, carbamoyl, aminosulfonyl, C1-C6 acyl or substituted sulfonyl, and the substituents are C1-C4 alkyl, C2- C4 alkenyl or C2-C4 alkynyl;
  • R 1 and R 2 are C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl optionally substituted by one or more of the following substituents, the substituents being: hydrogen, halogen, halo C1-C4 hydrocarbon group, halogenated C1-C4 alkoxy group, amino group, cyano group, hydroxyl group, mercapto group, carboxyl group, carbamoyl group, aminosulfonyl group, -NR n R o , -OR n , -C(O)R n , -C(O)OR n , -OC(O)R n , -C(O)N(R o )R n , -N(R o )C(O)R n , -S(O) y R n (where y is 0, 1 or 2), -SO 2 N(R o )R n , -N(R
  • R 1 and R 2 together with the nitrogen atom to which they are connected form a 4-7 membered heterocyclic ring or a 5-6 membered aromatic heterocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1-3 N, O and/or The heteroatom of S, the heterocyclic ring or aromatic heterocyclic ring may be substituted by 1 to 3 identical or different R 9 ;
  • R 9 is hydrogen, carboxyl, hydroxyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C6 hydrocarbon group or substituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, said The substituent is a cyano group, an amino group, a C1-C4 alkylamino group or a C1-C4 sulfonyl group, etc., and the hydrocarbyl group is an alkyl group, an alkenyl group or an alkynyl group;
  • R 3 is hydrogen, C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl;
  • R 4 does not exist, or is C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, substituted or unsubstituted 5-6 membered aromatic heterocycle, and the substituent is C1-C4 alkyl, C2 -C4 alkenyl or C2-C4 alkynyl, C3-C6 cycloalkyl, cyano, C1-C4 alkoxy, halogen substituted (CH 2 ) n , where n is 1, 2 or 3, said
  • the aromatic heterocycle contains 1-3 N, O and/or S;
  • R 5 , R 6 , R 7 , and R 8 are each independently selected from hydrogen, halogen, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 alkylthio, hydroxyl, carboxyl, cyano, C1-C4 Amido, C1-C4 alkyl or C2-C4 alkenyl or C2-C4 alkynyl substituted carbamoyl, C1-C4 alkyl or C2-C4 alkenyl or C2-C4 alkynyl substituted sulfonamide, amino , C1-C4 alkyl sulfone, C1-C4 alkyl sulfoxide, and their number and combination are not limited;
  • R 4 and R 5 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered heterocyclic ring or aromatic heterocyclic ring, 4-7 membered unsaturated carbocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1- 3 heteroatoms of N, O and/or S;
  • R 5 and R 6 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1- 3 heteroatoms of N, O and/or S;
  • R 6 and R 7 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered heterocyclic ring or aromatic heterocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1-3 N, O and/or S Heteroatom
  • R 7 and R 8 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1- 3 heteroatoms of N, O and/or S.
  • the present invention is preferably the indole derivative represented by the general formula I or its optical isomer, pharmaceutically acceptable salt, solvate or prodrug,
  • X is O, S or NH
  • R is H, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl;
  • R 1 and R 2 are optionally C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl substituted by hydroxy or carboxy, or R 1 and R 2 together with the nitrogen atom to which they are attached form 4 -7-membered heterocyclic ring or 5-6-membered aromatic heterocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1-3 N, O and/or S heteroatoms, said heterocyclic ring or heteroaromatic ring may be 1- 3 same or different R 9 substitutions;
  • R 9 is hydrogen, carboxyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, substituted or unsubstituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, the substituent It is a sulfonyl group substituted with a cyano group, an amino group, a C1-C4 alkylamino group, a C1-C4 alkyl group, a C2-C4 alkenyl group or a C2-C4 alkynyl group;
  • R 3 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-6 membered saturated or unsaturated carbocyclic or C1-C6 alkoxy;
  • R 4 does not exist, or is a C1-C4 alkyl, alkenyl, substituted or unsubstituted 5-6 membered aromatic heterocycle, and the substituents are C1-C4 alkyl, C3-C6 cycloalkyl, cyano, (CH 2 ) n substituted by C1-C6 alkoxy and halogen, where n is 1, 2 or 3, and the aromatic heterocyclic ring contains 1-3 N, O and/or S;
  • R 5 , R 6 , R 7 , and R 8 may be independently selected from hydrogen, halogen, halogenated C1-C4 alkyl or C2-C4 alkenyl or C2-C4 alkynyl, C1-C4 haloalkyl, C1- C4 alkoxy, C1-C4 alkylthio, hydroxyl, carboxyl, cyano, C1-C4 amide, C1-C4 hydrocarbyl substituted carbamoyl, C1-C4 hydrocarbyl substituted sulfonamide, amino, C1-C4 Alkyl sulfone, C1-C4 alkyl sulfoxide, and their number and combination are not limited;
  • R 4 and R 5 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered heterocyclic ring or aromatic heterocyclic ring, 4-7 membered unsaturated carbocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1- 3 heteroatoms of N, O and/or S;
  • R 5 and R 6 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1- 3 heteroatoms of N, O and/or S;
  • R 6 and R 7 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered heterocyclic ring or aromatic heterocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1-3 N, O and/or S Heteroatom
  • R 7 and R 8 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1- 3 heteroatoms of N, O and/or S.
  • the present invention is preferably the indole derivative represented by the general formula I or its optical isomer, pharmaceutically acceptable salt, solvate or prodrug,
  • X is O, S or NH
  • R is H or C1-C4 alkyl
  • R 1 and R 2 together with the nitrogen atom to which they are connected form a 4-7 membered heterocyclic ring or a 5-6 membered aromatic heterocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1-3 N, O and/or S
  • the heteroatom, or the heterocyclic or heteroaromatic ring may be substituted by 1-3 R 9 which are the same or different;
  • R 9 is hydrogen, carboxyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, substituted or unsubstituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, the substituent It is a cyano group, an amino group, a C1-C4 alkylamino group or a C1-C4 hydrocarbon group substituted sulfonyl group, etc.;
  • R 3 is hydrogen or C1-C4 alkyl
  • R 4 does not exist
  • R 5 , R 6 , R 7 , and R 8 may be independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylthio, hydroxyl, carboxyl. , Cyano, C1-C4 amide, C1-C4 alkyl substituted carbamoyl, C1-C4 alkyl substituted sulfonamide, amino, C1-C4 alkyl sulfone, C1-C4 alkyl sulfoxide, and The number and combination are not limited;
  • R 4 and R 5 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered heterocyclic ring or aromatic heterocyclic ring, 4-7 membered unsaturated carbocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1- 3 heteroatoms of N, O and/or S;
  • R 5 and R 6 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1- 3 heteroatoms of N, O and/or S;
  • R 6 and R 7 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered heterocyclic ring or aromatic heterocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1-3 N, O and/or S Heteroatom
  • R 7 and R 8 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1- 3 heteroatoms of N, O and/or S;
  • the present invention is preferably the indole derivative represented by the general formula I or its optical isomer, pharmaceutically acceptable salt, solvate or prodrug,
  • X is O, S or NH
  • R is H or C1-C4 alkyl
  • R 1 and R 2 form together with the nitrogen atom to which they are attached And can be substituted by 1-3 same or different R 9 ;
  • R 9 is hydrogen, carboxyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkyl or substituted C1-C4 alkyl;
  • R 3 is hydrogen or C1-C4 alkyl
  • R 4 does not exist
  • R 5 , R 6 , R 7 , and R 8 may be independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, hydroxyl, carboxy, cyano, C1- C4 amide group, C1-C4 alkyl substituted carbamoyl group, C1-C4 alkyl substituted sulfonamide group, amino group, C1-C4 alkyl sulfone, C1-C4 alkyl sulfoxide, and their number and combination are not limited ;
  • R 4 and R 5 form together with the benzene ring to which they are connected
  • R 6 and R 7 form together with the benzene ring to which they are connected
  • the present invention is preferably the indole derivative represented by the general formula I or its optical isomer, pharmaceutically acceptable salt, solvate or prodrug,
  • X is O, S or NH
  • R is H or methyl
  • R 1 and R 2 form together with the nitrogen atom to which they are attached And can be substituted by 1-3 same or different R 9 ;
  • R 9 is hydrogen, methyl, ethyl, hydroxymethyl, hydroxyethyl, carboxyl or hydroxyl;
  • R 3 is hydrogen, methyl or ethyl
  • R 4 does not exist
  • R 5 , R 6 , R 7 , and R 8 can be independently selected from hydrogen, halogen, C1-C4 alkyl, and C1-C4 alkoxy, and the number and combination thereof are not limited.
  • the present invention is preferably the indole derivative represented by the general formula I or its optical isomer, pharmaceutically acceptable salt, solvate or prodrug,
  • R 1 and R 2 form together with the nitrogen atom to which they are attached
  • R 3 is methyl
  • R 4 does not exist
  • R 5 , R 6 , R 7 , and R 8 can be independently selected from hydrogen or halogen, and their number and combination are not limited;
  • R 6 and R 7 form together with the benzene ring to which they are connected
  • the present invention is preferably the indole derivative represented by the general formula I or its optical isomer, pharmaceutically acceptable salt, solvate or prodrug,
  • R is H or methyl
  • R 1 and R 2 form together with the nitrogen atom to which they are attached
  • R 3 is ethyl
  • R 4 does not exist
  • R 5 , R 6 , R 7 , and R 8 may be independently selected from hydrogen, halogen, or methoxy, and the number and combination thereof are not limited;
  • R 4 and R 5 form together with the benzene ring to which they are connected
  • R 6 and R 7 form together with the benzene ring to which they are connected
  • the present invention is preferably the indole derivative represented by the general formula I or its optical isomer, pharmaceutically acceptable salt, solvate or prodrug,
  • X is O, S or NH
  • R 1 and R 2 are optionally substituted by hydroxyl, carboxyl, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, or R 1 and R 2 together with the nitrogen atom to which they are attached form 4 -7-membered heterocyclic ring or 5-6-membered aromatic heterocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1-3 N, O and/or S heteroatoms, said heterocyclic ring and heteroaromatic ring may be 1- 3 same or different R 9 substitutions;
  • R 9 is hydrogen, carboxyl, hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkoxy, substituted or unsubstituted C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, the substituent A sulfonyl group substituted with a cyano group, an amino C1-C4 alkylamino group or a C1-C4 hydrocarbon group;
  • R 3 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, 3-6 membered saturated or unsaturated carbocyclic or C1-C6 alkoxy;
  • R 4 does not exist, or is C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl, substituted or unsubstituted 5-6 membered aromatic heterocycle, and the substituent is C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl, C3-C6 cycloalkyl, cyano, C1-C6 alkoxy, halogen substituted (CH 2 ) n , where n is 1, 2 or 3, the The aromatic heterocycle contains 1-3 N, O and/or S;
  • R 5 , R 6 , R 7 , and R 8 may be independently selected from hydrogen, halogen, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylthio, hydroxyl, carboxyl, cyano, C1- C4 amide, C1-C4 alkyl or C2-C4 alkenyl or C2-C4 alkynyl substituted carbamoyl, C1-C4 alkyl or C2-C4 alkenyl or C2-C4 alkynyl substituted sulfonamide, Amino, C1-C4 alkyl sulfone, C1-C4 alkyl sulfoxide, and their number and combination are not limited;
  • R 4 and R 5 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered heterocyclic ring or aromatic heterocyclic ring, 4-7 membered unsaturated carbocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1- 3 heteroatoms of N, O and/or S;
  • R 5 and R 6 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1- 3 heteroatoms of N, O and/or S;
  • R 6 and R 7 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered heterocyclic ring or aromatic heterocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1-3 N, O and/or S Heteroatom
  • R 7 and R 8 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1- 3 heteroatoms of N, O and/or S.
  • the indole derivative represented by the general formula I or its optical isomer, pharmaceutically acceptable salt, solvate or prodrug thereof is preferred,
  • X is O, S or NH
  • R 1 and R 2 together with the nitrogen atom to which they are connected form a 4-7 membered heterocyclic ring or a 5-6 membered aromatic heterocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1-3 N, O and/or S
  • the heteroatoms, the heterocyclic or aromatic heterocyclic ring may be substituted by 1-3 identical or different R 9 ;
  • R 9 is hydrogen, carboxyl, hydroxyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, substituted or unsubstituted C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl, the substituent It is a cyano group, an amino group, a C1-C4 alkylamino group, a C1-C4 alkyl substituted sulfonyl group;
  • R 3 is hydrogen or C1-C4 alkyl
  • R 4 does not exist, or is a C1-C4 alkyl group
  • R 5 , R 6 , R 7 , and R 8 may be independently selected from hydrogen, halogen, C1-C4 alkoxy, C1-C4 alkylthio, hydroxyl, carboxy, cyano, C1-C4 amide, C1- C4 alkyl substituted carbamoyl, C1-C4 alkyl substituted sulfonamide, amino, C1-C4 alkyl sulfone or C1-C4 alkyl sulfoxide, and their number and combination are not limited;
  • R 4 and R 5 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered heterocyclic ring or aromatic heterocyclic ring, 4-7 membered unsaturated carbocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1- 3 heteroatoms of N, O and/or S;
  • R 5 and R 6 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1- 3 heteroatoms of N, O and/or S;
  • R 6 and R 7 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered heterocyclic ring or aromatic heterocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1-3 N, O and/or S Heteroatom
  • R 7 and R 8 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1- 3 heteroatoms of N, O and/or S.
  • the present invention is preferably the indole derivative represented by the general formula I or its optical isomer, pharmaceutically acceptable salt, solvate or prodrug,
  • X is O, S or NH
  • R 1 and R 2 together with the nitrogen atom to which they are connected form a 4-7 membered heterocyclic ring, the heterocyclic ring containing 1-3 N, O and/or S heteroatoms, or the heterocyclic ring may be 1 -3 same or different R 9 substitutions;
  • R 9 is hydrogen, methyl, ethyl, hydroxymethyl, hydroxyethyl, carboxyl or hydroxyl;
  • R 3 is hydrogen, methyl or ethyl
  • R 4 does not exist, or is (CH 2 ) n , where n is 1, 2 or 3;
  • R 5 , R 6 , R 7 , and R 8 may be independently selected from hydrogen, halogen, C1-C4 hydrocarbon alkyl, C1-C4 alkoxy, and the number and combination thereof are not limited;
  • R 4 and R 5 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1- 3 heteroatoms of N, O and/or S;
  • R 5 and R 6 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered unsaturated carbocyclic ring;
  • R 6 and R 7 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered heterocyclic ring or aromatic heterocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1-3 N, O and/or S Heteroatom
  • R 7 and R 8 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1- 3 heteroatoms of N, O and/or S;
  • the present invention is preferably the indole derivative represented by the general formula I or its optical isomer, pharmaceutically acceptable salt, solvate or prodrug,
  • R 1 and R 2 form together with the nitrogen atom to which they are attached
  • R 3 is ethyl
  • R 4 is optionally (CH 2 ) n , where n is 1;
  • R 5 , R 6 , R 7 , and R 8 can be independently selected from hydrogen, halogen, or methyl, and the number and combination are not limited;
  • R 6 and R 7 form together with the benzene ring to which they are connected
  • the present invention is preferably the indole derivative represented by the general formula I or its optical isomer, pharmaceutically acceptable salt, solvate or prodrug,
  • X is O, S or NH
  • R 1 and R 2 are optionally substituted by hydroxyl, carboxyl, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, or R 1 and R 2 together with the nitrogen atom to which they are attached form 4 -7-membered heterocyclic ring or 5-6-membered aromatic heterocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1-3 N, O and/or S heteroatoms, or said heterocyclic ring or aromatic heterocyclic ring may be 1 -3 same or different R 9 substitutions;
  • R 9 is hydrogen, carboxyl, hydroxyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl or substituted C1-C6 alkyl, so
  • the substituent is a cyano group, an amino group, a C1-C4 alkylamino group or a C1-C4 alkyl substituted sulfonyl group;
  • R 3 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-6 membered saturated or unsaturated carbocyclic or C1-C6 alkoxy;
  • R 4 does not exist, or is a 5-6 membered aromatic heterocyclic ring (the aromatic heterocyclic ring contains 1-3 N, O and/or S), or is optionally substituted by C1-C4 alkyl, C3-C6 (CH 2 ) n substituted by cycloalkyl, cyano, alkoxy, or halogen, where n is 1, 2 or 3;
  • R 5 , R 6 , R 7 , and R 8 may be independently selected from hydrogen, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 alkoxy Group, C1-C4 alkylthio, hydroxyl, carboxyl, cyano, C1-C4 amide, C1-C4 alkyl substituted carbamoyl, C1-C4 alkyl substituted sulfonamide, amino, C1-C4 alkane Base sulfone, C1-C4 alkyl sulfoxide, and their number and combination are not limited;
  • R 4 and R 5 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered heterocyclic ring or aromatic heterocyclic ring, 4-7 membered unsaturated carbocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1- 3 heteroatoms of N, O and/or S;
  • R 5 and R 6 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1- 3 heteroatoms of N, O and/or S;
  • R 6 and R 7 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered heterocyclic ring or aromatic heterocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1-3 N, O and/or S Heteroatom
  • R 7 and R 8 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1- 3 heteroatoms of N, O and/or S.
  • the indole derivative represented by the general formula I or its optical isomer, pharmaceutically acceptable salt, solvate or prodrug thereof is preferred,
  • X is O, S or NH
  • R 1 and R 2 are optionally C1-C6 alkyl substituted by hydroxy or carboxy, or R 1 and R 2 together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic ring or a 5-6 membered aromatic heterocycle Ring, the heterocyclic ring or aromatic heterocyclic ring contains 1-3 N, O and/or S heteroatoms, and the heterocyclic ring and/or aromatic heterocyclic ring may be substituted by 1-3 identical or different R 9 ;
  • R 9 is hydrogen, carboxyl, hydroxyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C6 alkyl or substituted C1-C6 alkyl, and the substituent is cyano, amino, C1-C4 Alkylamino, C1-C4 alkyl substituted sulfonyl, etc.;
  • R 3 is hydrogen or C1-C4 alkyl
  • R 4 does not exist, or is a cyano substituted thiazole ring, optionally substituted with C1-C4 alkyl, C3-C6 cycloalkyl, cyano, C1-C6 alkoxy or halogen (CH 2 ) n , Where n is 1, 2 or 3;
  • R 5 , R 6 , R 7 , and R 8 may be independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylthio, hydroxyl, carboxyl. , Cyano, C1-C4 amide, C1-C4 alkyl substituted carbamoyl, C1-C4 alkyl substituted sulfonamide, amino, C1-C4 alkyl sulfone or C1-C4 alkyl sulfoxide, and The number and combination are not limited;
  • R 4 and R 5 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered heterocyclic ring or aromatic heterocyclic ring, 4-7 membered unsaturated carbocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1- 3 heteroatoms of N, O and/or S;
  • R 5 and R 6 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1- 3 heteroatoms of N, O and/or S;
  • R 6 and R 7 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered heterocyclic ring or aromatic heterocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1-3 N, O and/or S Heteroatom
  • R 7 and R 8 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1- 3 heteroatoms of N, O and/or S.
  • the present invention is preferably the indole derivative represented by the general formula I or its optical isomer, pharmaceutically acceptable salt, solvate or prodrug,
  • X is O, S or NH
  • R 1 and R 2 are optionally C1-C6 alkyl substituted by hydroxy or carboxy, or R 1 and R 2 together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic ring, said heterocyclic ring containing 1 -3 heteroatoms of N, O and/or S, or the heterocyclic ring may be substituted by 1 to 3 identical or different R 9 ;
  • R 9 is hydrogen, methyl, ethyl, hydroxymethyl, hydroxyethyl, carboxyl or hydroxyl;
  • R 3 is hydrogen, methyl or ethyl
  • R 4 is absent, or optionally (CH 2 ) n , where n is 1, 2 or 3;
  • R 5 , R 6 , R 7 , and R 8 can be independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, and the number and combination thereof are not limited;
  • R 4 and R 5 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1- 3 heteroatoms of N, O and/or S;
  • R 5 and R 6 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered unsaturated carbocyclic ring;
  • R 6 and R 7 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered heterocyclic ring or aromatic heterocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1-3 N, O and/or S Heteroatom
  • R 7 and R 8 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1- 3 heteroatoms of N, O and/or S.
  • the present invention is preferably the indole derivative represented by the general formula I or its optical isomer, pharmaceutically acceptable salt, solvate or prodrug,
  • R 1 and R 2 form together with the nitrogen atom to which they are attached
  • R 3 is ethyl
  • R 4 is optionally (CH 2 ) n , where n is 1;
  • R 5 , R 6 , R 7 , and R 8 may be independently selected from hydrogen, halogen, or methoxy, and the number and combination thereof are not limited.
  • the indole derivative represented by the general formula I or its optical isomer, pharmaceutically acceptable salt, solvate or prodrug thereof is preferred,
  • X is O, S or NH
  • R 1 and R 2 are optionally substituted by hydroxyl, carboxyl, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, or R 1 and R 2 together with the nitrogen atom to which they are attached form 4 -7-membered heterocyclic ring or 5-6-membered aromatic heterocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1-3 N, O and/or S heteroatoms, or said heterocyclic ring or aromatic heterocyclic ring may be 1 -3 same or different R 9 substitutions;
  • R 9 is hydrogen, carboxyl, hydroxyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl or substituted C1-C6 alkyl, so The substituents are cyano, amino, C1-C4 alkylamino or C1-C4 alkyl substituted sulfonyl, etc.;
  • R 3 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-6 membered saturated or unsaturated carbocyclic or C1-C6 alkoxy;
  • R 4 does not exist, or is a 5-6 membered aromatic heterocyclic ring (the aromatic heterocyclic ring contains 1-3 N, O and/or S), or is optionally substituted by C1-C4 alkyl, C2-C4 alkene Group, C2-C4 alkynyl, C3-C6 cycloalkyl, cyano, alkoxy, halogen substituted (CH 2 ) n , where n is 1, 2 or 3;
  • R 5 , R 6 , R 7 , and R 8 may be independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C2-C4 alkenyl, C2-C4 alkyne Group, C1-C4 alkylthio, hydroxyl, carboxyl, cyano, C1-C4 amide, C1-C4 alkyl substituted carbamoyl, C1-C4 alkyl substituted sulfonamide, amino, C1-C4 alkane Base sulfone or C1-C4 alkyl sulfoxide, and its number and combination are not limited;
  • R 4 and R 5 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered heterocyclic ring or aromatic heterocyclic ring, a 4-7 membered saturated or partially unsaturated carbocyclic ring, the heterocyclic ring or aromatic heterocyclic ring Contain 1-3 N, O and/or S heteroatoms;
  • R 5 and R 6 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, and the heterocyclic ring or aromatic heterocyclic ring contains 1-3 N, O and/or S heteroatoms;
  • R 6 and R 7 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered heterocyclic ring or aromatic heterocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1-3 N, O and/or S Heteroatom
  • R 7 and R 8 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1- 3 heteroatoms of N, O and/or S.
  • the present invention is preferably the indole derivative represented by the general formula I or its optical isomer, pharmaceutically acceptable salt, solvate or prodrug,
  • X is O, S or NH
  • R 1 and R 2 together with the nitrogen atom to which they are connected form a 4-7 membered heterocyclic ring or a 5-6 membered aromatic heterocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1-3 N, O and/or S
  • the heteroatoms of, or the heterocyclic or aromatic heterocyclic ring may be substituted by 1-3 R 9 which are the same or different;
  • R 9 is hydrogen, carboxyl, hydroxyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy or C1-C6 alkyl;
  • R 3 is hydrogen or C1-C4 alkyl
  • R 4 does not exist, or is a 5-6 membered aromatic heterocyclic ring (the aromatic heterocyclic ring contains 1-3 N, O and/or S), or is optionally substituted by C1-C4 alkyl, alkoxy or (CH 2 ) n substituted by halogen, where n is 1, 2 or 3;
  • R 5 , R 6 , R 7 , and R 8 may be independently selected from hydrogen, halogen, C1-C4 haloalkyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, hydroxyl, and carboxyl. , Cyano, C1-C4 amide, C1-C4 alkyl substituted carbamoyl, C1-C4 alkyl substituted sulfonamide, amino, C1-C4 alkyl sulfone or C1-C4 alkyl sulfoxide, and The number and combination are not limited;
  • R 4 and R 5 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered heterocyclic ring or aromatic heterocyclic ring, 4-7 membered unsaturated carbocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1- 3 heteroatoms of N, O and/or S;
  • R 5 and R 6 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1- 3 heteroatoms of N, O and/or S;
  • R 6 and R 7 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered heterocyclic ring or aromatic heterocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1-3 N, O and/or S Heteroatom
  • R 7 and R 8 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1- 3 heteroatoms of N, O and/or S.
  • the present invention is preferably the indole derivative represented by the general formula I or its optical isomer, pharmaceutically acceptable salt, solvate or prodrug,
  • X is O, S or NH
  • R 1 and R 2 together with the nitrogen atom to which they are connected form a 4-7 membered heterocyclic ring, the heterocyclic ring containing 1-3 N, O and/or S heteroatoms, or the heterocyclic ring may be 1 -3 same or different R 9 substitutions;
  • R 9 is hydrogen, methyl, ethyl, hydroxymethyl, hydroxyethyl, carboxyl or hydroxyl;
  • R 3 is hydrogen, methyl or ethyl
  • R 4 does not exist, or is a cyano-substituted thiazole ring, or optionally (CH 2 ) n , where n is 1, 2 or 3;
  • R 5 , R 6 , R 7 , and R 8 are each independently selected from hydrogen, halogen, C1-C4 alkyl or C1-C4 alkoxy, and the number and combination thereof are not limited;
  • R 4 and R 5 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1- 3 heteroatoms of N, O and/or S;
  • R 5 and R 6 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered unsaturated carbocyclic ring;
  • R 6 and R 7 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered heterocyclic ring or aromatic heterocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1-3 N, O and/or S Heteroatom
  • R 7 and R 8 together with the carbon atoms on the benzene ring to which they are connected form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic ring or aromatic heterocyclic ring containing 1- 3 heteroatoms of N, O and/or S.
  • the present invention is preferably the indole derivative represented by the general formula I or its optical isomer, pharmaceutically acceptable salt, solvate or prodrug,
  • R 1 and R 2 form together with the nitrogen atom to which they are attached
  • R 3 is ethyl
  • R 4 is a thiazole ring substituted with a cyano group
  • R 5 , R 6 , R 7 , and R 8 are each independently selected from hydrogen, halogen, or methoxy, and the number and combination thereof are not limited.
  • the present invention is preferably the indole derivative represented by the general formula I or its optical isomer, pharmaceutically acceptable salt, solvate or prodrug,
  • R 1 and R 2 form together with the nitrogen atom to which they are attached
  • R 3 is ethyl
  • R 4 does not exist
  • R 5 , R 6 , R 7 , and R 8 are each independently selected from hydrogen, halogen or methoxy, and the number and combination thereof are not limited;
  • R 4 and R 5 form together with the benzene ring to which they are connected
  • the compounds of the present invention or their optical isomers, pharmaceutically acceptable salts, solvates or prodrugs are preferably the following compounds, but these compounds do not imply any limitation on the present invention:
  • the indole derivative of the general formula I of the present invention can form a pharmaceutically acceptable salt with an acid.
  • Pharmaceutically acceptable addition salts include inorganic acid and organic acid addition salts, among which salts formed with the following acids are particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, and p-toluenesulfonic acid , Benzenesulfonic acid, naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, or benzoic acid.
  • Part of the indole derivatives of the general formula I of the present invention can form pharmaceutically acceptable salts with bases, among which the salts formed with the following bases are preferred: triethylamine sodium hydroxide, lithium hydroxide, calcium hydroxide or hydroxide Potassium.
  • bases among which the salts formed with the following bases are preferred: triethylamine sodium hydroxide, lithium hydroxide, calcium hydroxide or hydroxide Potassium.
  • the example compound containing the hydrazone structure can form a salt with triethylamine, and the ratio of the compound and its salt can be seen from the NMR spectrum (for example, the product corresponding to Examples 1-10 and its triethylamine salt ).
  • the present invention also includes prodrugs of the derivatives of the present invention.
  • the prodrugs of the derivatives of the present invention are indole derivatives of general formula I. They may have weak or even no activity by themselves, but after administration, under physiological conditions (for example, by metabolism, solvolysis or other means) ) Is converted into the corresponding biologically active form.
  • the acetyl-protected derivative is the prodrug of the indole derivative of its corresponding hydrolysate (for example, the corresponding product in Examples 39-51 and its acetyl-protected prodrug).
  • halogen refers to fluorine, chlorine, bromine or iodine
  • alkyl refers to straight or branched chain alkyl
  • alkylene refers to straight or branched alkylene
  • the present inventors have found that the compound of the present invention has strong ATX inhibitory activity in vitro, and therefore, it can be used for the preparation of drugs for the treatment and/or prevention of tumors or fibrotic diseases.
  • the tumors mainly include breast, lung, liver, kidney, colon, rectum, stomach, prostate, bladder, uterus, pancreas, bone marrow, testis, ovary, lymph, soft tissue, head and neck, thyroid cancer and leukemia, neuroblastoma, etc.;
  • Fibrotic diseases mainly include pulmonary fibrosis, liver fibrosis, myocardial fibrosis, kidney fibrosis and so on.
  • the present invention found that the compound of the present invention has a better proliferation inhibitory effect on breast cancer cells, but shows certain selectivity for A549 cells.
  • the active compound of the present invention or its pharmaceutically acceptable salt or solvate thereof can be used alone as the only anti-tumor or anti-fibrosis drug, or can be combined with currently marketed anti-tumor/anti-fibrosis drugs (such as pirfenidone, Nintedanib, paclitaxel, etc.) are used in combination. Combination therapy is achieved by administering the individual therapeutic components simultaneously, sequentially or separately.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the indole derivative represented by the general formula I of the present invention or its optical isomer, pharmaceutically acceptable salt, solvate or pro Drugs and pharmaceutically acceptable carriers.
  • the present invention also provides a method for treating tumors and/or fibrotic diseases, which comprises administering to a subject in need a therapeutically effective amount of the indole derivative represented by the general formula I of the present invention or its optical isoforms. Constructs, pharmaceutically acceptable salts, solvates or prodrugs.
  • the intermediates M 1 , M 2 , M 2 ' , and M 3 can be passed in the corresponding solvents according to the methods of Route 1, Route 2, Route 3, Route 4 and Route 5, respectively.
  • Rearrangement or condensation reaction system L, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 and R 8 in the compound are as defined in the claims.
  • Intermediate M 1 can be obtained from Intermediate IV through acylation according to Route 6, and then through N-alkylation.
  • L, R 1 , R 2 and R 3 in the compound are as defined in the claims.
  • Intermediate M 2 can be obtained by hydrolysis of Intermediate M 1 according to Route 7.
  • L, R 1 , R 2 and R 3 in the compound are as defined in the claims.
  • Intermediate M 3 can be obtained by esterification reaction of intermediate M 2 with methanol under the catalysis of concentrated sulfuric acid according to route 8 and then hydrazinolysis.
  • L, R 1 , R 2 and R 3 in the compound are as defined in the claims.
  • Intermediate VIII can be obtained from the intermediate via buckle according to route 9.
  • L, R 1 , R 2 and R 3 in the compound are as defined in the claims.
  • Intermediate X can be obtained from Intermediate VIII via Sandmeier reaction and hydrazinolysis reaction according to route 9.
  • L, R 1 , R 2 and R 3 , R 7 in the compound are as defined in the claims.
  • Figure 1 shows the improvement effect of the compound of Example 34 of the present invention on myocardial fibrosis in a myocardial infarction model
  • control group is normal myocardial tissue
  • the myocardial infarction model is the myocardial fibrosis tissue of the myocardial infarction model
  • the myocardial infarction model+34 is the myocardial fibrosis tissue in the myocardial infarction model treated with the compound (34) in Example 34.
  • Figure 2 and Figure 3 respectively show the results of the in vivo anti-pulmonary fibrosis activity of the inventive compound analyzed and determined by H&E staining and Masson staining methods on lung tissue sections;
  • control group (A) is normal lung tissue
  • model group (E) is the staining situation of the bleomycin-induced pulmonary fibrosis model group
  • 34 (B, C) is the example 34 compound 34 at 20
  • F, G is the lung tissue staining of Example 46 compound 46 at a concentration of 20 and 60 mg/kg
  • D is the lung tissue of the positive control GLPG-1690 at a concentration of 60 mg/kg
  • the histogram is the pulmonary fibrosis degree rating of each group of pictures.
  • the proton nuclear magnetic resonance spectrum of the compound was determined by Bruker ARX-400/600, and the mass spectrometer was determined by Agilent 1100 LC/MSD; the reagents used were all analytical or chemical pure, including NaH, 5-cyanoindole, 1,3-dichloro
  • the main reagents such as acetone and trifluoroacetic anhydride were purchased from Sinopharm Group, and the main reaction solvents such as dichloromethane, ethyl acetate and methanol were purchased from Tianjin Damao Chemical Reagent Factory.
  • Step D 1-(5-(4-(chloromethyl)thiazol-2-yl)-1-ethyl-1H-indol-3-yl)-2,2,2-trifluoroethyl-1- Ketone (V)
  • Step E 1-(1-Ethyl-5-(4-(morpholinylmethyl)thiazol-2-yl)-1H-indol-3-yl)-2,2,2-trifluoroethyl- 1-ketone (M 1 )
  • Step F (Z)-2-(2-(1-(1-ethyl-5-(4-(morpholinylmethyl)thiazol-2-yl)-1H-indol-3-yl)-2 ,2,2-Trifluoroethylidene)hydrazino)-4-(4-fluorophenyl)thiazole-5-carbonitrile (Example 1)
  • the compound of Example (Table 1) 2-10 was prepared by using M 1-1 as a raw material and hydrazine for condensation reaction.
  • the compound of Examples 12-13 was prepared by using the intermediate M 1 as the raw material and the intermediate XI to conduct a condensation reaction.
  • the compound of Examples 15-17 was prepared by condensation reaction with aldehyde or ketone using the intermediate M 1 as a raw material.
  • the compounds of Examples 19 and 20 were prepared by the condensation reaction of the intermediate M 1 as a raw material with an aldehyde or a ketone.
  • the compounds of Examples 22-33 are prepared by condensation reaction of the intermediate M 1 as a raw material with an aldehyde or a ketone.
  • the compounds of Examples 35-38 were prepared by Curtius rearrangement reaction with the intermediate M 2 as a raw material and alcohol.
  • Step B (S)-(1-((2-(3-((((3,5-Dichlorobenzyl)oxy)carbonyl)amino)-1-ethyl-1H-indol-5-yl )Thiazol-4-yl)methyl)pyrrolidin-2-yl)methyl acetate
  • step A At room temperature, 3.2 g (0.008 mol) of the product obtained from step A was dissolved in dry toluene, 2 mL triethylamine and 3 mL diphenyl azide phosphate were added, stirred for 30 minutes, and 3,5-dichlorobenzyl alcohol was added. Reflux for 2h. After the reaction was completed, it was cooled to room temperature, the toluene was evaporated, water and dichloromethane were added for liquid separation, and the organic layer was evaporated to dryness to obtain 3.6 g of oil, with a yield of 72%.
  • step B At room temperature, 3.6 g of the product obtained from step B was dissolved in 15 mL of dioxane, 20 mL of 2M sodium hydroxide solution was added, and the reaction was carried out at 50° C. for 2 hours. After the reaction was completed, 30 mL of water was added, extracted with dichloromethane (25 mL ⁇ 2), and the organic layer was evaporated to dryness to obtain a crude product. The crude product is purified by column chromatography to obtain the target compound.
  • the compounds of Examples 40-51 were prepared by esterification, rearrangement, and hydrolysis with the intermediate M 2 as a raw material.
  • Step B 1-((2-(3-(3-(3-chloro-4-methoxyphenyl)ureido)-1-ethyl-1H-indol-5-yl)thiazol-4-yl )Methyl)piperidin-4-yl acetate
  • step A At room temperature, 3.3g (0.008mol) of the product obtained from step A was dissolved in dry toluene, 2mL triethylamine and 3mL diphenyl azide phosphate were added, stirred for 30 minutes and then added 3-chloro-4-methoxy Benzylamine, reflux reaction for 2h. After the reaction was completed, it was cooled to room temperature, the toluene was distilled off, water and dichloromethane were added for liquid separation, and the organic layer was evaporated to dryness to obtain 3.57 g of an oily substance with a yield of 75%.
  • step B At room temperature, 3.57 g of the product obtained from step B was dissolved in 15 mL of dioxane, 20 mL of 2M sodium hydroxide solution was added, and the reaction was carried out at 50° C. for 2 hours. After the reaction was completed, 30 mL of water was added, extracted with dichloromethane (25 mL ⁇ 2), and the organic layer was evaporated to dryness to obtain a crude product. The crude product was purified by thin layer chromatography to obtain the target compound with a yield of 19%.
  • FS-3 (Echelon Biosciences, Inc. Salt Lake City, UT) was used as a substrate to test the inhibitory effect of the compound of the present invention and the positive control drug GLPG-1690 on ATX.
  • the indole derivative represented by the general formula I of the present invention was subjected to in vitro MCF-7 breast cancer cell activity test and EGFR high-expressing human lung adenocarcinoma cell A549 activity screening.
  • the cell line used was purchased from the Shanghai Cell Bank of the Chinese Academy of Sciences.
  • test sample Dissolve the test sample with 50 ⁇ L of dimethyl sulfoxide, then add an appropriate amount of culture medium to dissolve the sample into a 2mg/mL drug solution, and then dilute the sample to 20, 4, 0.8, 0.16, and 0.16 in a 24-well plate. 0.032 ⁇ g/mL. Add 3 wells for each concentration. The growth of the surrounding two rows and two columns is greatly affected by the environment, so they are only used as blank cell wells. Put the 96-well plate in the incubator for 72 hours.
  • the SPF mice used in the present invention were purchased from Liaoning Changsheng Biotechnology Co., Ltd., strain C57BL/6, weight 17-20 grams, male sex, all passed the Liaoning Provincial Laboratory Animal Quality Inspection Center certification to comply with the ARRIVE regulations, and the animal in vivo test process complies with Regulations of the Animal Ethics Committee of Shenyang Pharmaceutical University.
  • a rat myocardial infarction (MI) model was established.
  • the method is as follows: male Wistar rats, weighing 200-230 g, were randomly divided into 2 groups, each with 30 rats. Respectively, the control group (sham operation group) and myocardial infarction group.
  • the chest was opened between the 4-5th intercostal space, and the heart capsule was cut and ligated at the lower edge of the left atrial appendage 2mm
  • the anterior descending branch of the left coronary artery was immediately closed, and the ECG and arrhythmia were observed. With the significant elevation of the ST segment of the ECG as the model's success sign, the sham operation group was threaded without ligation.
  • the myocardial tissue section Dewax the myocardial tissue section to distilled water, stain with hematoxylin for 5-10min, differentiate with hydrochloric acid and alcohol, blue in running water, wash in distilled water, stain in Ponceau acid fuchsin solution for 5-8min, wash in distilled water, stain in 1% phosphomolybdic acid 1 ⁇ 3min, do not wash with water directly into aniline blue liquid or bright green liquid for 5min, wash with water quickly, dry in a 60°C incubator, transparent xylene, and seal.
  • the collagen fibers are blue (counter-stained with aniline blue) or green (counter-stained with bright green), the cytoplasm, muscle fibers and red blood cells are red, and the nucleus is blue-brown.
  • mice were given GLPG-1690 (60mg/kg) and compounds 34 and 46 (20/60mg/kg) by gavage, once a day, for a total of 31 days (day -3 to day 3). 28 days).
  • the experimental group including the model group and the administration group, with 5 animals in each group was intratracheally administered bleomycin to establish a pulmonary fibrosis model.
  • the model group replaced the test compound with normal saline, and the control group was an untreated group with normal lung tissue.
  • H&E staining and Masson staining were used to analyze lung tissue sections, and the results are shown in Figure 2 and Figure 3. The results show that the tested compounds of the present invention all show significant lung tissue protective effects, and their protective effects are comparable to the positive control GLPG-1690.

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Abstract

本发明涉及通式I所示的吲哚衍生物或其光学异构体、药学上可接受的盐、溶剂化物或前药，及其制备方法和应用，其中，通式I中R1、R 2、R3、R4、R5、R6、R7、R8、R、X、L如本发明权利要求和说明书中所定义。本发明的化合物可作为强效的ATX抑制剂，并用于纤维化及肿瘤等相关疾病的治疗。

Description

基于吲哚母核的ATX抑制剂及其制备方法和应用 技术领域
本发明属于医药技术领域，涉及基于吲哚母核的ATX抑制剂及其光学异构体、药学上可接受的盐、溶剂化物或前药，它们的制备方法以及其应用。
背景技术
自分泌运动因子(Autotaxin,ATX)可以将LPC(lysophosphatidylcholine,溶血磷脂胆碱)水解为胆碱和具有广泛炎症介导活性的LPA(lysophosphatidate,溶血磷脂酸)，LPA的受体LPAR是有6种亚型的G-蛋白偶联受体，其中LPAR 1-3与纤维化的关系更加密切。ATX-LPA功能轴在纤维化疾病中扮演着重要的作用，针对该功能轴的抑制剂主要分为ATX抑制剂、LPA受体抑制剂以及LPA单克隆抗体等。选择性抑制ATX，是从源头上减少LPA的产生，可以有效控制纤维化的进程。通过抑制ATX介导的LPA的产生过程，所产生的生物学效果要好于单独应用LPA受体拮抗剂。
目前针对ATX靶点的研究多集中于体外药理研究(以酶活性测试及分子机制研究为主)，而其抑制剂所针对的适应症以肿瘤为主。与此同时，ATX抑制剂具有肺纤维化抑制作用已经成为广泛的共识。尤其是Galapagos公司开发的化合物GLPG-1690用于肺纤维化治疗目前已经处于临床三期研究阶段。
Figure PCTCN2021071682-appb-000001
发明内容
本发明的目的是提供一种具有优良ATX抑制活性的化合物及其制备方法和应用。本发明的化合物具有较好的抗肿瘤活性和纤维化抑制活性。
本发明的目的是通过以下技术方案来实现的：
本发明提供通式Ⅰ所示的吲哚衍生物或其光学异构体、药学上可接受的盐、溶剂化物或前药，
Figure PCTCN2021071682-appb-000002
其中，
L为
Figure PCTCN2021071682-appb-000003
R为H、C1-C6烷基、C2-C6烯基或C2-C6炔基；
X为O、S或NH；
R 1和R 2相同或不同，分别独立地任选自氢、羟基、氨基甲酰基、氨基磺酰基、C1-C6酰基、取代的磺酰基，所述取代基为C1-C4烷基、C2-C4烯基或C2-C4炔基；
或R 1和R 2为任选的被一个或多个如下取代基取代的C1-C6烷基、C2-C6烯基或C2-C6炔基，所述取代基为：氢、卤素、卤代C1-C4烃基、卤代C1-C4烷氧基、氨基、氰基、羟基、巯基、羧基、氨基甲酰基、氨基磺酰基、-NR nR o、-OR n、-C(O)R n、-C(O)OR n、-OC(O)R n、-C(O)N(R o)R n、-N(R o)C(O)R n、-S(O) yR n(其中y是0、1或2)、-SO 2N(R o)R n、-N(R o)SO 2R n或-(CH 2) zNR oR n(其中z是1、2或3)，其中R n和R o各自独立地选自H或C1-C4烃基，卤素为氟、氯或溴；
或R 1和R 2与和它们所连接的氮原子一起形成4-7元杂环或5-6元芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子，所述杂环和/或芳杂环可被1-3个相同或不同的R 9取代；
R 9为氢、羧基、羟基、C1-C4羟烷基、C1-C4烷氧基、C1-C6烃基或取代的C1-C6烃基，所述取代基为：氰基、氨基、C1-C4烷胺基或C1-C4磺酰基，所述C1-C6烃基为烷基、C2-C6烯基或C2-C6炔基；
R 3为氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、3-6元饱和或不饱和碳环或C1-C6烷氧基；
R 4不存在，或为C1-C4烷基、C2-C4烯基、C2-C4炔基、取代或未取代的5-6元芳杂环，所述取代基为C1-C4烷基、C2-C4烯基、C2-C4炔基、C3-C6环烷基、羟基、氰基、C1-C4烷氧基、卤素所取代的(CH 2) n，其中，n是1、2或3，所述芳杂环含有1-3个N、O和/或S；
R 5、R 6、R 7、R 8分别独立地选自氢、卤素、C1-C4烷基、C2-C4烯基、 C2-C4炔基、C1-C4卤代烷基、C1-C4烷氧基、C1-C4烷硫基、羟基、羧基、氰基、C1-C4酰胺基、C1-C4烃基取代的氨甲酰基、C1-C4烃基取代的磺酰胺基、氨基、C1-C4烷基砜、C1-C4烷基亚砜，且其数目及组合不限；
或R 4与R 5与它们所连接的苯环上的碳原子一起形成4-7元杂环或芳杂环、4-7元不饱和碳环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子；
或R 5与R 6与它们所连接的苯环上的碳原子一起形成4-7元不饱和碳环、4-7元杂环或芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子；
或R 6与R 7与它们所连接的苯环上的碳原子一起形成3-7元不饱和碳环、4-7元杂环或芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子；
或R 7与R 8与它们所连接的苯环上的碳原子一起形成4-7元不饱和碳环、4-7元杂环或芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子。
在本发明优选的实施方案中，所述C1-C6(或C1-C4)烃基为C1-C6(或C1-C4)烷基、C2-C6(或C2-C4)烯基或C2-C6(或C2-C4)炔基。
本发明优选通式Ⅰ所示的吲哚衍生物或其光学异构体、药学上可接受的盐、溶剂化物或前药，
其中，
L为
Figure PCTCN2021071682-appb-000004
R为H或C1-C4烷基；
X为O、S或NH；
R 1和R 2相同或不同，分别独立地任选自氢、羟基、氨基甲酰基、氨基磺酰基、C1-C6酰基或取代的磺酰基，所述取代基为C1-C4烷基、C2-C4烯基或C2-C4炔基；
或R 1和R 2为任选的被一个或多个如下取代基取代的C1-C6烷基、C2-C6烯基或C2-C6炔基，所述取代基为：氢、卤素、卤代C1-C4烃基、卤代C1-C4烷氧基、氨基、氰基、羟基、巯基、羧基、氨基甲酰基、氨基磺酰基、-NR nR o、-OR n、-C(O)R n、-C(O)OR n、-OC(O)R n、-C(O)N(R o)R n、-N(R o)C(O)R n、-S(O) yR n(其中y是0、1或2)、-SO 2N(R o)R n、-N(R o)SO 2R n 或-(CH 2) zNR oR n(其中z是1、2或3)，其中R n和R o各自独立地选自H或C1-C4烷基，卤素为氟、氯或溴；
或R 1和R 2与和它们所连接的氮原子一起形成4-7元杂环或5-6元芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子，所述杂环或芳杂环可被1-3个相同或不同的R 9取代；
R 9为氢、羧基、羟基、C1-C4羟烷基、C1-C4烷氧基、C1-C6烃基或取代的C1-C6烷基、C2-C6烯基或C2-C6炔基，所述取代基为氰基、氨基、C1-C4烷胺基或C1-C4磺酰基等，所述烃基为烷基、烯基或炔基；
R 3为氢、C1-C4烷基、C2-C4烯基或C2-C4炔基；
R 4不存在，或为C1-C4烷基、C2-C4烯基、C2-C4炔基、取代或未取代的5-6元芳杂环，所述取代基为C1-C4烷基、C2-C4烯基或C2-C4炔基、C3-C6环烷基、氰基、C1-C4烷氧基、卤素所取代的(CH 2) n，其中，n是1、2或3，所述芳杂环含有1-3个N、O和/或S；
R 5、R 6、R 7、R 8分别独立地选自氢、卤素、C1-C4烷氧基、C1-C4卤代烷基、C1-C4烷硫基、羟基、羧基、氰基、C1-C4酰胺基、C1-C4烷基或C2-C4烯基或C2-C4炔基取代的氨甲酰基、C1-C4烷基或C2-C4烯基或C2-C4炔基取代的磺酰胺基、氨基、C1-C4烷基砜、C1-C4烷基亚砜，且其数目及组合不限；
或R 4与R 5与它们所连接的苯环上的碳原子一起形成4-7元杂环或芳杂环、4-7元不饱和碳环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子；
或R 5与R 6与它们所连接的苯环上的碳原子一起形成4-7元不饱和碳环、4-7元杂环或芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子；
或R 6与R 7与它们所连接的苯环上的碳原子一起形成4-7元杂环或芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子；
或R 7与R 8与它们所连接的苯环上的碳原子一起形成4-7元不饱和碳环、4-7元杂环或芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子。
本发明优选通式Ⅰ所示的吲哚衍生物或其光学异构体、药学上可接受的盐、溶剂化物或前药，
其中，
L为
Figure PCTCN2021071682-appb-000005
X为O、S或NH；
R为H、C1-C6烷基、C2-C6烯基或C2-C6炔基；
R 1和R 2为任选的被羟基、羧基取代的C1-C6烷基、C2-C6烯基或C2-C6炔基，或R 1和R 2与和它们所连接的氮原子一起形成4-7元杂环或5-6元芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子，所述杂环或杂芳环可被1-3个相同或不同的R 9取代；
R 9为氢、羧基、羟基、C1-C4羟烷基、C1-C4烷氧基、取代或未取代的C1-C6烷基、C2-C6烯基或C2-C6炔基，所述取代基为氰基、氨基、C1-C4烷胺基、C1-C4烷基或C2-C4烯基或C2-C4炔基取代的磺酰基；
R 3为氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、3-6元饱和或不饱和碳环或C1-C6烷氧基；
R 4不存在，或为C1-C4烷基、烯基、取代或未取代的5-6元芳杂环，所述的取代基为C1-C4烷基、C3-C6环烃基、氰基、C1-C6烷氧基、卤素所取代的(CH 2) n，其中，n是1、2或3，所述芳杂环含有1-3个N、O和/或S；
R 5、R 6、R 7、R 8可分别独立地选自氢、卤素、卤代的C1-C4烷基或C2-C4烯基或C2-C4炔基、C1-C4卤代烷基、C1-C4烷氧基、C1-C4烷硫基、羟基、羧基、氰基、C1-C4酰胺基、C1-C4烃基取代的氨甲酰基、C1-C4烃基取代的磺酰胺基、氨基、C1-C4烷基砜、C1-C4烷基亚砜，且其数目及组合不限；
或R 4与R 5与它们所连接的苯环上的碳原子一起形成4-7元杂环或芳杂环、4-7元不饱和碳环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子；
或R 5与R 6与它们所连接的苯环上的碳原子一起形成4-7元不饱和碳环、4-7元杂环或芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子；
或R 6与R 7与它们所连接的苯环上的碳原子一起形成4-7元杂环或芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子；
或R 7与R 8与它们所连接的苯环上的碳原子一起形成4-7元不饱和碳环、4-7元杂环或芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子。
本发明优选通式Ⅰ所示的吲哚衍生物或其光学异构体、药学上可接受的盐、溶剂化物或前药，
其中，
L为
Figure PCTCN2021071682-appb-000006
X为O、S或NH；
R为H或C1-C4烷基；
R 1和R 2与和它们所连接的氮原子一起形成4-7元杂环或5-6元芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子，或所述杂环或杂芳环可被1-3个相同或不同的R 9取代；
R 9为氢、羧基、羟基、C1-C4羟烷基、C1-C4烷氧基、取代或未取代的C1-C6烷基、C2-C6烯基或C2-C6炔基，所述取代基为氰基、氨基、C1-C4烷胺基或C1-C4烃基取代的磺酰基等；
R 3为氢或C1-C4烷基；
R 4不存在；
R 5、R 6、R 7、R 8可分别独立地选自氢、卤素、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基、C1-C4烷硫基、羟基、羧基、氰基、C1-C4酰胺基、C1-C4烷基取代的氨甲酰基、C1-C4烷基取代的磺酰胺基、氨基、C1-C4烷基砜、C1-C4烷基亚砜，且其数目及组合不限；
或R 4与R 5与它们所连接的苯环上的碳原子一起形成4-7元杂环或芳杂环、4-7元不饱和碳环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子；
或R 5与R 6与它们所连接的苯环上的碳原子一起形成4-7元不饱和碳环、4-7元杂环或芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子；
或R 6与R 7与它们所连接的苯环上的碳原子一起形成4-7元杂环或芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子；
或R 7与R 8与它们所连接的苯环上的碳原子一起形成4-7元不饱和碳环、4-7元杂环或芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子；
本发明优选通式Ⅰ所示的吲哚衍生物或其光学异构体、药学上可接受的盐、溶剂化物或前药，
其中，
L为
Figure PCTCN2021071682-appb-000007
X为O、S或NH；
R为H或C1-C4烷基；
R 1和R 2与和它们所连接的氮原子一起形成
Figure PCTCN2021071682-appb-000008
Figure PCTCN2021071682-appb-000009
且可被1-3个相同或不同的R 9取代；
R 9为氢、羧基、羟基、C1-C4羟烷基、C1-C4烷氧基、C1-C4烷基或取代的C1-C4烷基；
R 3为氢或C1-C4烷基；
R 4不存在；
R 5、R 6、R 7、R 8可分别独立地选自氢、卤素、C1-C4烷基、C1-C4烷氧基、C1-C4烷硫基、羟基、羧基、氰基、C1-C4酰胺基、C1-C4烷基取代的氨甲酰基、C1-C4烷基取代的磺酰胺基、氨基、C1-C4烷基砜、C1-C4烷基亚砜，且其数目及组合不限；
或R 4与R 5与它们所连接的苯环一起形成
Figure PCTCN2021071682-appb-000010
或R 4、R 5与L及它们所连接的苯环一起形成
Figure PCTCN2021071682-appb-000011
或R 6与R 7与它们所连接的苯环一起形成
Figure PCTCN2021071682-appb-000012
本发明优选通式Ⅰ所示的吲哚衍生物或其光学异构体、药学上可接受的盐、溶剂化物或前药，
其中，
L为
Figure PCTCN2021071682-appb-000013
X为O、S或NH；
R为H或甲基；
R 1和R 2与和它们所连接的氮原子一起形成
Figure PCTCN2021071682-appb-000014
Figure PCTCN2021071682-appb-000015
且可被1-3个相同或不同的R 9取代；
R 9为氢、甲基、乙基、羟甲基、羟乙基、羧基或羟基；
R 3为氢、甲基或乙基；
R 4不存在；
R 5、R 6、R 7、R 8可分别独立地选自氢、卤素、C1-C4烷基、C1-C4烷氧基，且其数目及组合不限。
本发明优选通式Ⅰ所示的吲哚衍生物或其光学异构体、药学上可接受的盐、溶剂化物或前药，
R 1和R 2与和它们所连接的氮原子一起形成
Figure PCTCN2021071682-appb-000016
R 3为甲基；
R 4不存在；
R 5、R 6、R 7、R 8可分别独立地选自氢或卤素，且其数目及组合不限；
或R 6与R 7与它们所连接的苯环一起形成
Figure PCTCN2021071682-appb-000017
本发明优选通式Ⅰ所示的吲哚衍生物或其光学异构体、药学上可接受的盐、溶剂化物或前药，
R为H或甲基；
R 1和R 2与和它们所连接的氮原子一起形成
Figure PCTCN2021071682-appb-000018
Figure PCTCN2021071682-appb-000019
R 3为乙基；
R 4不存在；
R 5、R 6、R 7、R 8可分别独立地选自氢、卤素或甲氧基，且其数目及组合不限；
或R 4和R 5与它们所连接的苯环一起形成
Figure PCTCN2021071682-appb-000020
或R 6与R 7与它们所连接的苯环一起形成
Figure PCTCN2021071682-appb-000021
本发明优选通式Ⅰ所示的吲哚衍生物或其光学异构体、药学上可接受的盐、溶剂化物或前药，
其中，
L为
Figure PCTCN2021071682-appb-000022
X为O、S或NH；
R 1和R 2为任选的被羟基、羧基取代的C1-C6烷基，C2-C6烯基或C2-C6炔基，或R 1和R 2与和它们所连接的氮原子一起形成4-7元杂环或5-6元芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子，所述杂环与杂芳环可被1-3个相同或不同的R 9取代；
R 9为氢、羧基、羟基、C1-C4羟烷基、C1-C4烷氧基、取代或未取代的C1-C6烷基、C2-C6烯基或C2-C6炔基，所述取代基为氰基、氨基C1-C4烷胺基或C1-C4烃基取代的磺酰基；
R 3为氢、C1-C6烷基、C2-C6烯基或C2-C6炔基、3-6元饱和或不饱和碳环或C1-C6烷氧基；
R 4不存在，或为C1-C4烷基、C2-C4烯基或C2-C4炔基、取代或未取代的5-6元芳杂环，所述的取代基为C1-C4烷基、C2-C4烯基或C2-C4炔基、C3-C6环烃基、氰基、C1-C6烷氧基、卤素所取代的(CH 2) n，其中，n是1、2或3，所述芳杂环含有1-3个N、O和/或S；
R 5、R 6、R 7、R 8可分别独立地选自氢、卤素、C1-C4卤代烷基、C1-C4烷氧基、C1-C4烷硫基、羟基、羧基、氰基、C1-C4酰胺基、C1-C4烷基或C2-C4烯基或C2-C4炔基取代的氨甲酰基、C1-C4烷基或C2-C4烯基或C2-C4炔基取代的磺酰胺基、氨基、C1-C4烷基砜、C1-C4烷基亚砜，且其数目及组合不限；
或R 4与R 5与它们所连接的苯环上的碳原子一起形成4-7元杂环或芳杂环、4-7元不饱和碳环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子；
或R 5与R 6与它们所连接的苯环上的碳原子一起形成4-7元不饱和碳环、4-7元杂环或芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子；
或R 6与R 7与它们所连接的苯环上的碳原子一起形成4-7元杂环或芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子；
或R 7与R 8与它们所连接的苯环上的碳原子一起形成4-7元不饱和碳环、4-7元杂环或芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子。
本发明优选通式Ⅰ所示的吲哚衍生物或其光学异构体、药学上可接受的 盐、溶剂化物或前药，
其中，
L为
Figure PCTCN2021071682-appb-000023
X为O、S或NH；
R 1和R 2与和它们所连接的氮原子一起形成4-7元杂环或5-6元芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子，所述杂环或芳杂环可被1-3个相同或不同的R 9取代；
R 9为氢、羧基、羟基、C1-C4羟烷基、C1-C4烷氧基、取代或未取代的C1-C4烷基或C2-C4烯基或C2-C4炔基，所述取代基为氰基、氨基、C1-C4烷胺基、C1-C4烷基取代的磺酰基；
R 3为氢或C1-C4烷基；
R 4不存在，或为C1-C4烷基；
R 5、R 6、R 7、R 8可分别独立地选自氢、卤素、C1-C4烷氧基、C1-C4烷硫基、羟基、羧基、氰基、C1-C4酰胺基、C1-C4烷基取代的氨甲酰基、C1-C4烷基取代的磺酰胺基、氨基、C1-C4烷基砜或C1-C4烷基亚砜，且其数目及组合不限；
或R 4与R 5与它们所连接的苯环上的碳原子一起形成4-7元杂环或芳杂环、4-7元不饱和碳环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子；
或R 5与R 6与它们所连接的苯环上的碳原子一起形成4-7元不饱和碳环、4-7元杂环或芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子；
或R 6与R 7与它们所连接的苯环上的碳原子一起形成4-7元杂环或芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子；
或R 7与R 8与它们所连接的苯环上的碳原子一起形成4-7元不饱和碳环、4-7元杂环或芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子。
本发明优选通式Ⅰ所示的吲哚衍生物或其光学异构体、药学上可接受的盐、溶剂化物或前药，
其中，
L为
Figure PCTCN2021071682-appb-000024
X为O、S或NH；
R 1和R 2与和它们所连接的氮原子一起形成4-7元杂环，所述杂环含有1-3个N、O和/或S的杂原子，或所述杂环可被1-3个相同或不同的R 9取代；
R 9为氢、甲基、乙基、羟甲基、羟乙基、羧基或羟基；
R 3为氢、甲基或乙基；
R 4不存在，或为(CH 2) n，其中，n是1、2或3；
R 5、R 6、R 7、R 8可分别独立地选自氢、卤素、C1-C4烃烷基、C1-C4烷氧基，且其数目及组合不限；
或R 4和R 5与它们所连接的苯环上的碳原子一起形成4-7元不饱和碳环、4-7元杂环或芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子；
或R 5与R 6与它们所连接的苯环上的碳原子一起形成4-7元不饱和碳环；
或R 6与R 7与它们所连接的苯环上的碳原子一起形成4-7元杂环或芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子；
或R 7与R 8与它们所连接的苯环上的碳原子一起形成4-7元不饱和碳环、4-7元杂环或芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子；
本发明优选通式Ⅰ所示的吲哚衍生物或其光学异构体、药学上可接受的盐、溶剂化物或前药，
R 1和R 2与和它们所连接的氮原子一起形成
Figure PCTCN2021071682-appb-000025
Figure PCTCN2021071682-appb-000026
R 3为乙基；
R 4是任选地(CH 2) n，其中，n是1；
R 5、R 6、R 7、R 8可分别独立地选自氢、卤素或甲基，且其数目及组合不限；
或R 6与R 7与它们所连接的苯环一起形成
Figure PCTCN2021071682-appb-000027
本发明优选通式Ⅰ所示的吲哚衍生物或其光学异构体、药学上可接受的盐、溶剂化物或前药，
其中，
L为
Figure PCTCN2021071682-appb-000028
X为O、S或NH；
R 1和R 2为任选的被羟基、羧基取代的C1-C6烷基，C2-C6烯基或C2-C6炔基，或R 1和R 2与和它们所连接的氮原子一起形成4-7元杂环或5-6元芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子，或所述杂环或芳杂环可被1-3个相同或不同的R 9取代；
R 9为氢、羧基、羟基、C1-C4羟烷基、C1-C4烷氧基、C1-C6烷基、C2-C6烯基或C2-C6炔基或取代的C1-C6烷基，所述取代基为氰基、氨基、C1-C4烷胺基或C1-C4烷基取代的磺酰基；
R 3为氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、3-6元饱和或不饱和碳环或C1-C6烷氧基；
R 4不存在，或为5-6元芳杂环(所述芳杂环含有1-3个N、O和/或S)，亦或是任选地被C1-C4烷基、C3-C6环烷基、氰基、烷氧基、卤素所取代的(CH 2) n，其中，n是1、2或3；
R 5、R 6、R 7、R 8可分别独立地选自氢、卤素、C1-C4烷基、C2-C4烯基、C2-C4炔基、C1-C4卤代烷基、C1-C4烷氧基、C1-C4烷硫基、羟基、羧基、氰基、C1-C4酰胺基、C1-C4烷基取代的氨甲酰基、C1-C4烷基取代的磺酰胺基、氨基、C1-C4烷基砜、C1-C4烷基亚砜，且其数目及组合不限；
或R 4与R 5与它们所连接的苯环上的碳原子一起形成4-7元杂环或芳杂环、4-7元不饱和碳环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子；
或R 5与R 6与它们所连接的苯环上的碳原子一起形成4-7元不饱和碳环、4-7元杂环或芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子；
或R 6与R 7与它们所连接的苯环上的碳原子一起形成4-7元杂环或芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子；
或R 7与R 8与它们所连接的苯环上的碳原子一起形成4-7元不饱和碳环、4-7元杂环或芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子。
本发明优选通式Ⅰ所示的吲哚衍生物或其光学异构体、药学上可接受的 盐、溶剂化物或前药，
其中，
L为
Figure PCTCN2021071682-appb-000029
X为O、S或NH；
R 1和R 2为任选的被羟基、羧基取代的C1-C6烷基，或R 1和R 2与和它们所连接的氮原子一起形成4-7元杂环或5-6元芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子，且所述杂环和/或芳杂环可被1-3个相同或不同的R 9取代；
R 9为氢、羧基、羟基、C1-C4羟烷基、C1-C4烷氧基、C1-C6烷基或取代的C1-C6烷基，所述取代基为氰基、氨基、C1-C4烷胺基、C1-C4烷基取代的磺酰基等；
R 3为氢或C1-C4烷基；
R 4不存在，或为氰基取代的噻唑环，任选地被C1-C4烷基、C3-C6环烷基、氰基、C1-C6烷氧基或卤素所取代的(CH 2) n，其中，n是1、2或3；
R 5、R 6、R 7、R 8可分别独立地选自氢、卤素、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基、C1-C4烷硫基、羟基、羧基、氰基、C1-C4酰胺基、C1-C4烷基取代的氨甲酰基、C1-C4烷基取代的磺酰胺基、氨基、C1-C4烷基砜或C1-C4烷基亚砜，且其数目及组合不限；
或R 4与R 5与它们所连接的苯环上的碳原子一起形成4-7元杂环或芳杂环、4-7元不饱和碳环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子；
或R 5与R 6与它们所连接的苯环上的碳原子一起形成4-7元不饱和碳环、4-7元杂环或芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子；
或R 6与R 7与它们所连接的苯环上的碳原子一起形成4-7元杂环或芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子；
或R 7与R 8与它们所连接的苯环上的碳原子一起形成4-7元不饱和碳环、4-7元杂环或芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子。
本发明优选通式Ⅰ所示的吲哚衍生物或其光学异构体、药学上可接受的盐、溶剂化物或前药，
其中，
L为
Figure PCTCN2021071682-appb-000030
X为O、S或NH；
R 1和R 2为任选的被羟基或羧基取代的C1-C6烷基，或R 1和R 2与和它们所连接的氮原子一起形成4-7元杂环，所述杂环含有1-3个N、O和/或S的杂原子，或所述杂环可被1-3个相同或不同的R 9取代；
R 9为氢、甲基、乙基、羟甲基、羟乙基、羧基或羟基；
R 3为氢、甲基或乙基；
R 4不存在，或是任选地(CH 2) n，其中，n是1、2或3；
R 5、R 6、R 7、R 8可分别独立地选自氢、卤素、C1-C4烷基、C1-C4烷氧基，且其数目及组合不限；
或R 4和R 5与它们所连接的苯环上的碳原子一起形成4-7元不饱和碳环、4-7元杂环或芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子；
或R 5与R 6与它们所连接的苯环上的碳原子一起形成4-7元不饱和碳环；
或R 6与R 7与它们所连接的苯环上的碳原子一起形成4-7元杂环或芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子；
或R 7与R 8与它们所连接的苯环上的碳原子一起形成4-7元不饱和碳环、4-7元杂环或芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子。
本发明优选通式Ⅰ所示的吲哚衍生物或其光学异构体、药学上可接受的盐、溶剂化物或前药，
其中，
R 1和R 2与和它们所连接的氮原子一起形成
Figure PCTCN2021071682-appb-000031
Figure PCTCN2021071682-appb-000032
R 3为乙基；
R 4是任选地(CH 2) n，其中，n是1；
R 5、R 6、R 7、R 8可分别独立地选自氢、卤素或甲氧基，且其数目及组合不限。
本发明优选通式Ⅰ所示的吲哚衍生物或其光学异构体、药学上可接受的 盐、溶剂化物或前药，
其中，
L为
Figure PCTCN2021071682-appb-000033
X为O、S或NH；
R 1和R 2为任选的被羟基、羧基取代的C1-C6烷基，C2-C6烯基或C2-C6炔基，或R 1和R 2与和它们所连接的氮原子一起形成4-7元杂环或5-6元芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子，或所述杂环或芳杂环可被1-3个相同或不同的R 9取代；
R 9为氢、羧基、羟基、C1-C4羟烷基、C1-C4烷氧基、C1-C6烷基、C2-C6烯基或C2-C6炔基或取代的C1-C6烷基，所述取代基为氰基、氨基、C1-C4烷胺基或C1-C4烷基取代的磺酰基等；
R 3为氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、3-6元饱和或不饱和碳环或C1-C6烷氧基；
R 4不存在，或为5-6元芳杂环(所述芳杂环含有1-3个N、O和/或S)，或是任选地被C1-C4烷基、C2-C4烯基、C2-C4炔基、C3-C6环烷基、氰基、烷氧基、卤素所取代的(CH 2) n，其中，n是1、2或3；
R 5、R 6、R 7、R 8可分别独立地选自氢、卤素、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基、C2-C4烯基、C2-C4炔基、C1-C4烷硫基、羟基、羧基、氰基、C1-C4酰胺基、C1-C4烷基取代的氨甲酰基、C1-C4烷基取代的磺酰胺基、氨基、C1-C4烷基砜或C1-C4烷基亚砜，且其数目及组合不限；
或R 4与R 5与它们所连接的苯环上的碳原子一起形成4-7元杂环或芳杂环、4-7元饱和或部分不饱和碳环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子；
R 5与R 6与它们所连接的苯环上的碳原子一起形成4-7元不饱和碳环、4-7元杂环或芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子；
或R 6与R 7与它们所连接的苯环上的碳原子一起形成4-7元杂环或芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子；
或R 7与R 8与它们所连接的苯环上的碳原子一起形成4-7元不饱和碳环、4-7元杂环或芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子。
本发明优选通式Ⅰ所示的吲哚衍生物或其光学异构体、药学上可接受的盐、溶剂化物或前药，
其中，
L为
Figure PCTCN2021071682-appb-000034
X为O、S或NH；
R 1和R 2与和它们所连接的氮原子一起形成4-7元杂环或5-6元芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子，或所述杂环或芳杂环可被1-3个相同或不同的R 9取代；
R 9为氢、羧基、羟基、C1-C4羟烷基、C1-C4烷氧基或C1-C6烷基；
R 3为氢或C1-C4烷基；
R 4不存在，或为5-6元芳杂环(所述芳杂环含有1-3个N、O和/或S)，或是任选地被C1-C4烷基、烷氧基或卤素所取代的(CH 2) n，其中，n是1、2或3；
R 5、R 6、R 7、R 8可分别独立地选自氢、卤素、C1-C4卤代烷基、C1-C4烷基、C1-C4烷氧基、C1-C4烷硫基、羟基、羧基、氰基、C1-C4酰胺基、C1-C4烷基取代的氨甲酰基、C1-C4烷基取代的磺酰胺基、氨基、C1-C4烷基砜或C1-C4烷基亚砜，且其数目及组合不限；
或R 4与R 5与它们所连接的苯环上的碳原子一起形成4-7元杂环或芳杂环、4-7元不饱和碳环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子；
或R 5与R 6与它们所连接的苯环上的碳原子一起形成4-7元不饱和碳环、4-7元杂环或芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子；
或R 6与R 7与它们所连接的苯环上的碳原子一起形成4-7元杂环或芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子；
或R 7与R 8与它们所连接的苯环上的碳原子一起形成4-7元不饱和碳环、4-7元杂环或芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子。
本发明优选通式Ⅰ所示的吲哚衍生物或其光学异构体、药学上可接受的盐、溶剂化物或前药，
其中，
L为
Figure PCTCN2021071682-appb-000035
X为O、S或NH；
R 1和R 2与和它们所连接的氮原子一起形成4-7元杂环，所述杂环含有1-3个N、O和/或S的杂原子，或所述杂环可被1-3个相同或不同的R 9取代；
R 9为氢、甲基、乙基、羟甲基、羟乙基、羧基或羟基；
R 3为氢、甲基或乙基；
R 4不存在，或为氰基取代的噻唑环，或是任选地(CH 2) n，其中，n是1、2或3；
R 5、R 6、R 7、R 8分别独立地选自氢、卤素、C1-C4烷基或C1-C4烷氧基，且其数目及组合不限；
或R 4和R 5与它们所连接的苯环上的碳原子一起形成4-7元不饱和碳环、4-7元杂环或芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子；
或R 5与R 6与它们所连接的苯环上的碳原子一起形成4-7元不饱和碳环；
或R 6与R 7与它们所连接的苯环上的碳原子一起形成4-7元杂环或芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子；
或R 7与R 8与它们所连接的苯环上的碳原子一起形成4-7元不饱和碳环、4-7元杂环或芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子。
本发明优选通式Ⅰ所示的吲哚衍生物或其光学异构体、药学上可接受的盐、溶剂化物或前药，
其中，
R 1和R 2与和它们所连接的氮原子一起形成
Figure PCTCN2021071682-appb-000036
Figure PCTCN2021071682-appb-000037
R 3为乙基；
R 4为氰基取代的噻唑环；
R 5、R 6、R 7、R 8分别独立地选自氢、卤素或甲氧基，且其数目及组合不限。
本发明优选通式Ⅰ所示的吲哚衍生物或其光学异构体、药学上可接受的盐、溶剂化物或前药，
其中，
R 1和R 2与和它们所连接的氮原子一起形成
Figure PCTCN2021071682-appb-000038
R 3为乙基；
R 4不存在；
R 5、R 6、R 7、R 8分别独立地选自氢、卤素或甲氧基，且其数目及组合不限；
或R 4和R 5与它们所连接的苯环一起形成
Figure PCTCN2021071682-appb-000039
本发明化合物或其光学异构体、药学上可接受的盐、溶剂化物或前药优选以下化合物，但这些化合物并不意味着对本发明的任何限制：
(Z)-2-(2-(1-(1-乙基-5-(4-(吗啉基甲基)噻唑-2-基)-1H-吲哚-3-基)-2,2,2-三氟乙叉基)肼基)-4-(4-氟苯基)噻唑-5-甲腈，
(Z)-((2-(3-(1-(2-(5-氰基-4-(4-氟苯基)噻唑-2-基)肼基)-2,2,2-三氟乙基)-1-乙基-1H-吲哚-5-基)-噻唑-4-基)-甲基)-L-脯氨酸，
(Z)-((2-(3-(1-(2-(5-氰基-4-(4-甲氧基苯基)噻唑-2-基)肼基)-2,2,2-三氟乙基)-1-乙基-1H-吲哚-5-基)-噻唑-4-基)-甲基)-L-脯氨酸，
(Z)-2-(2-(1-(1-乙基-5-(4-(吡咯-1-基甲基)噻唑-2-基)-1H-吲哚-3-基)-2,2,2-三氟乙叉基)肼基)-4-(4-氟苯基)噻唑-5-甲腈，
(Z)-2-(2-(1-(1-乙基-5-(4-(哌啶-1-基甲基)噻唑-2-基)-1H-吲哚-3-基)-2,2,2-三氟乙叉基)肼基)-4-(4-氟苯基)噻唑-5-甲腈，
(Z)-2-(2-(1-(1-乙基-5-(4-((4-甲基哌啶-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)-2,2,2-三氟乙叉基)肼基)-4-(4-甲氧基苯基)噻唑-5-甲腈，
(S,Z)-2-(2-(1-(1-乙基-5-(4-((2-(羟甲基)四氢吡咯-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)-2,2,2-三氟乙叉基)肼基)-4-(4-氟苯基)噻唑-5-甲腈，
(Z)-2-(2-(1-(1-乙基-5-(4-((3-羟基氮杂环丁烷-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)-2,2,2-三氟乙叉基)肼基)-4-(4-氟苯基)噻唑-5-甲腈，
(Z)-2-(2-(1-(1-乙基-5-(4-((4-(2-羟乙基)哌嗪-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)-2,2,2-三氟乙叉基)肼基)-4-(4-氟苯基)噻唑-5-甲腈，
(Z)-2-(2-(1-(1-乙基-5-(4-((4-羟基哌啶-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)-2,2,2-三氟乙叉基)肼基)-4-(4-氟苯基)噻唑-5-甲腈，
(Z)-4-((2-(3-(1-(2-(苯并[d]噻唑-2-基)肼基)-2,2,2-三氟乙叉基)-1-乙基-1H-吲哚-5-基)-噻唑-4-基)甲基)吗啉，
(Z)-2-(2-(1-(1-乙基-5-(4-(哌啶-1-基甲基)噻唑-2-基)-1H-吲哚-3-基)-2,2,2-三氟乙叉基)肼基)苯并[d]噻唑-5-腈，
(Z)-1-((2-(3-(1-(2-(苯并[d]噻唑-2-基)肼基)-2,2,2-三氟乙叉基)-1-乙基-1H-吲哚-5-基)噻唑-4-基)甲基)哌啶-4-醇，
(E)-1-乙基-N′-(4-氟苯甲叉基)-5-(4-(吗啉基甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼，
(E)-1-乙基-N′-(4-甲氧基苯甲叉基)-5-(4-(吗啉基甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼，
(E)-N′-(苯并[d][1,3]二氧戊环-5-基甲叉基)-1-乙基-5-(4-(吗啉基甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼，
(E)-1-乙基-5-(4-(吗啉基甲基)噻唑-2-基)5-N′-((4-氧-4H-色酮-3-基)甲叉基)-1H-吲哚-3-甲酰肼，
(E)-N′-(4-氟苯甲叉基)-1-甲基-5-(4-(吗啉基甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼，
(E)-N′-(苯并[d][1,3]二氧戊环-5-基甲叉基)-1-甲基-5-(4-(吗啉基甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼，
(E)-1-乙基-N′-(4-氟苯甲叉基)-5-(4-(哌啶-1-基甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼，
(E)-1-乙基-N′-(4-甲氧基苯甲叉基)-5-(4-(四氢吡咯-1-基甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼，
(E)-N′-(苯并[d][1,3]二氧戊环-5-基甲叉基)-1-乙基-5-(4-((4-甲基哌嗪-1-基)甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼，
(E)-N′-(4-氯苯甲叉基)-1-甲基-5-(4-((4-甲基哌嗪-1-基)甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼，
(E)-1-乙基-N′-(4-氟苯甲叉基)-5-(4-((4-甲基哌啶-1-基)甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼，
(E)-1-乙基-N′-(4-氟苯甲叉基)-5-(4-((4-羟基哌啶-1-基)甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼，
(E)-N′-(苯并[d][1,3]二氧戊环-5-基甲叉基)-1-乙基-5-(4-((4-羟基哌啶-1-基)甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼，
(E)-N′-(4-氯苯甲叉基)-1-乙基-5-(4-((4-羟基哌啶-1-基)甲基)噻唑-2- 基)-1H-吲哚-3-甲酰肼，
(E)-1-乙基-N′-(4-氟苯甲叉基)-5-(4-((2-(羟甲基)四氢吡咯-1-基)甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼，
(E)-1-乙基-N′-(1-(4-氟苯基)乙叉基)-5-(4-((2-(羟甲基)四氢吡咯-1-基)甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼，
(E)-N′-(苯并[d][1,3]二氧戊环-5-基甲叉基)-1-乙基-5-(4-((2-(羟甲基)四氢吡咯-1-基)甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼，
(E)-N′-(4-氯苯甲叉基)-1-乙基-5-(4-((4-(2-羟乙基)哌嗪-1-基)甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼，
(E)-1-乙基-N′-(4-氟苯甲叉基)-5-(4-((4-(2-(羟乙基)哌嗪-1-基)甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼，
(E)-N′-(苯并[d][1,3]二氧戊环-5-基甲叉基)-1-乙基-5-(4-((4-(2-羟乙基)哌嗪-1-基)甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼，
3,5-二氯苯甲基(1-乙基-5-(4-(吗啉基甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯，
3,5-二氯苯甲基(1-乙基-5-(4-(四氢吡咯-1-基甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯，
(R)-1-(4-甲基苯基)乙基(1-乙基-5-(4-(四氢吡咯-1-基甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯，
3,5-二氯苯甲基(1-乙基-5-(4-((4-甲基哌啶-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯，
3,5-二氯苯甲基(1-乙基-5-(4-((4-甲基哌嗪-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯，
3,5-二氯苯甲基(S)-(1-乙基-5-(4-((2-(羟甲基)四氢吡咯-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯，
(R)-1-(对-甲基苯基)乙基(1-乙基-5-(4-(((S)-2-(羟甲基)四氢吡咯-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯，
(R)-1-(2-氯苯基)乙基(1-乙基-5-(4-(((S)-2-(羟甲基)四氢吡咯-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯，
苯甲基(S)-(1-乙基-5-(4-((2-(羟甲基)四氢吡咯-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯，
苯并[d][1,3]二氧戊环-5-基甲基(S)-(1-乙基-5-(4-((2-(羟甲基)四氢吡咯-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯，
3,5-二氯苄基(1-乙基-5-(4-((4-羟基哌啶-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯，
苯并[d][1,3]二氧戊环-5-基甲基(1-乙基-5-(4-((4-羟基哌啶-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯，
3,4-二氟苄基(1-乙基-5-(4-((4-羟基哌啶-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯，
(R)-1-(2-氯苯基)乙基(1-乙基-5-(4-((4-羟基哌啶-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯，
3,5-二氯苄基(5-(4-((双(2-羟乙基)氨基)甲基)噻唑-2-基)-1-乙基-1H-吲哚-3-基)氨基甲酸酯，
3,5-二氯苄基(1-乙基-5-(4-((4-(2-羟乙基)哌嗪-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯，
3,4-二氟苄基(1-乙基-5-(4-((4-(2-羟乙基)哌嗪-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯，
苯甲基(1-乙基-5-(4-((4-(2-羟乙基)哌嗪-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯，
1-苯甲基-3-(1-乙基-5-(4-(吗啉甲基)噻唑-2-基)-1H-吲哚-3-基)脲，
1-(1-乙基-5-(4-((4-甲基哌啶-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)-3-(4-氟苯甲基)脲，
1-(4-氯苯甲基)-3-(1-乙基-5-(4-((4-甲基哌嗪-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)脲，
1-(3-氯-4-甲氧基苯甲基)-3-(1-乙基-5-(4-((4-羟基哌啶-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)脲，和
1-(5-(4-((双(2-羟乙基)氨基)甲基)噻唑-2-基)-1-乙基-1H-吲哚-3-基)-3-(3-氯-4-甲氧基苄基)脲。
而且，按照本发明所属领域的一些通常方法，本发明中通式Ⅰ的吲哚衍生物可以与酸生成药学上可接受的盐。可药用加成盐包括无机酸和有机酸加成盐，其中与下列酸形成的盐是特别优选的：盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘二磺酸、乙酸、丙酸、乳酸、三氟乙酸、马来酸、柠檬酸、富马酸、草酸、酒石酸、或苯甲酸等。部分本发明通式Ⅰ的吲哚衍生物可与碱生成药学上可接受的盐，其中与下列碱生成的盐是优选的：三乙胺氢氧化钠、氢氧化锂、氢氧化钙或氢氧化钾。其中，含腙结构的实施例化合物可与三乙胺成盐，并可从核磁谱图中看出 化合物与其盐二者的比例(例如实施例1-10所对应的产物及其三乙胺盐)。
此外，本发明还包括本发明衍生物的前药。本发明衍生物的前药是通式Ⅰ的吲哚衍生物，它们自身可能具有较弱的活性甚至没有活性，但是在给药后，在生理条件下(例如通过代谢、溶剂分解或另外的方式)被转化成相应的生物活性形式。其中，乙酰基保护的衍生物即为其对应水解产物吲哚衍生物的前药(例如实施例39-51所对应的产物及其乙酰基保护的前药)。
本发明中“卤素”是指氟、氯、溴或碘代；“烷基”是指直链或支链的烷基；“亚烷基”是指直链或支链的亚烷基。
本发明人已发现本发明化合物体外具有较强的ATX抑制活性，因此，它可以用作制备治疗和/或预防肿瘤或纤维化疾病的药物。所述肿瘤主要包括乳腺、肺、肝脏、肾脏、结肠、直肠、胃、前列腺、膀胱、子宫、胰腺、骨髓、睾丸、卵巢、淋巴、软组织、头颈、甲状腺癌和白血病、成神经细胞瘤等；纤维化疾病主要包括肺纤维化、肝纤维化、心肌纤维化、肾纤维化等。
本发明通过体外抑制MCF-7乳腺癌细胞的试验，发现本发明化合物对乳腺癌细胞具有较好的增殖抑制作用，而对A549细胞则表现出一定的选择性。
体内实验初步表明，本发明的化合物对于心梗后的心肌纤维化组织具有较好的预后作用，显示了该系列化合物可以用作潜在心肌纤维化及肺纤维化的治疗药物。
本发明的活性化合物或其可药用盐或其溶剂化物可作为唯一的抗肿瘤或抗纤维化药物单独使用，或者可以与现已上市的抗肿瘤/抗纤维化药物(如吡非尼酮、尼达尼布、紫杉醇等)联合使用。联合治疗通过将各个治疗组分同时、顺序或隔开给药来实现。
另一方面，本发明还提供了一种药物组合物，其包含本发明所述的通式Ⅰ所示的吲哚衍生物或其光学异构体、药学上可接受的盐、溶剂化物或前药和药学上可接受的载体。
又一方面，本发明还提供了一种治疗肿瘤和/或纤维化疾病的方法，包括给予需要的受试者治疗有效量的本发明的通式Ⅰ所示的吲哚衍生物或其光学异构体、药学上可接受的盐、溶剂化物或前药。
下文中提供的实施例和制备例进一步阐明和举例说明本发明化合物及其制备方法。应当理解，下述实施例和制备例的范围并不足以任何方式限制本发明的范围。
下面的合成路线概括并描述了本发明的式Ⅰ衍生物的制备，所有的原料都是通过这些路线中描述的方式、通过有机化学领域普通技术人员熟知的方法制备的或者可商购。本发明的全部最终衍生物都是通过这些路线中描述的方法或通过与其类似的方法制备的，这些方法是有机化学领域普通技术人员熟知的。这些路线中应用的全部可变因素如下文的定义或如权利要求中的定义。
路线1
Figure PCTCN2021071682-appb-000040
路线2
Figure PCTCN2021071682-appb-000041
路线3
Figure PCTCN2021071682-appb-000042
路线4
Figure PCTCN2021071682-appb-000043
路线5
Figure PCTCN2021071682-appb-000044
按照本发明的式Ⅰ衍生物，都可分别按照路线1、路线2、路线3、路线4和路线5的方法由中间体M 1、M 2、M 2’ 、M 3在相应溶剂中，通过重排或缩合反应制得。其中，化合物中的L、R 1、R 2、R 3、R 5、R 6、R 7和R 8如权利要求中所定义。
路线6
Figure PCTCN2021071682-appb-000045
路线7
Figure PCTCN2021071682-appb-000046
路线8
Figure PCTCN2021071682-appb-000047
路线9
Figure PCTCN2021071682-appb-000048
中间体M 1可按照路线6由中间体IV经酰化先得到中间体V，再经N-烃化得到。其中，化合物中的L、R 1、R 2和R 3如权利要求中所定义。
中间体M 2可按照路线7由中间体M 1水解得到。其中，化合物中的L、R 1、R 2和R 3如权利要求中所定义。
中间体M 3可按照路线8由中间体M 2在浓硫酸催化下与甲醇发生酯化反应，再经肼解得到。其中，化合物中的L、R 1、R 2和R 3如权利要求中所定义。
中间体VIII可按照路线9由中间体经扣环得到。其中，化合物中的L、R 1、R 2和R 3如权利要求中所定义。
中间体X可按照路线9由中间体VIII经桑德迈尔反应、肼解反应得到。其中，化合物中的L、R 1、R 2和R 3、R 7如权利要求中所定义。
当L为
Figure PCTCN2021071682-appb-000049
R 1和R 2与和它们所连接的氮原子一起形成
Figure PCTCN2021071682-appb-000050
R 3为乙基，化合物M 1-1、I 1-1和I 2-1的制备方法如路线11，其他取代基如权利要求中所定义。
当L为
Figure PCTCN2021071682-appb-000051
R 1和R 2与和它们所连接的氮原子一起形成
Figure PCTCN2021071682-appb-000052
R 3为乙基，化合物M 1-1、I 3-1和I 4-1的制备方法如路线12，其他取代基如权利要求中所定义。
当L为
Figure PCTCN2021071682-appb-000053
R 1和R 2与和它们所连接的氮原子一起形成
Figure PCTCN2021071682-appb-000054
R 3为乙基，化合物I 5-1的制备方法如路线13，其他取代基如权利要求中所定义。
当L为
Figure PCTCN2021071682-appb-000055
R为H时，R 1和R 2与和它们所连接的氮原子一起形成
Figure PCTCN2021071682-appb-000056
R 3为乙基，化合物M 3-1、I 6-1、I 7-1的制备方法如路线14，其他取代基如权利要求中所定义。
当L为
Figure PCTCN2021071682-appb-000057
R为-CH 3时，R 1和R 2与和它们所连接的氮原子一起形成
Figure PCTCN2021071682-appb-000058
R 3为乙基，化合物I 8-1的制备方法如路线15，其他取代基如权利要求中所定义。
当L为
Figure PCTCN2021071682-appb-000059
R与所连接侧链成环时，R 1和R 2与和它们所连接的氮原子一起形成
Figure PCTCN2021071682-appb-000060
R 3为乙基，化合物I 9-1、I 10-1的制备方法如路线16，其他取代基如权利要求中所定义。
路线10
Figure PCTCN2021071682-appb-000061
路线11
Figure PCTCN2021071682-appb-000062
路线12
Figure PCTCN2021071682-appb-000063
路线13
Figure PCTCN2021071682-appb-000064
路线14
Figure PCTCN2021071682-appb-000065
路线15
Figure PCTCN2021071682-appb-000066
路线16
Figure PCTCN2021071682-appb-000067
附图的简要说明
图1示出了本发明实施例34的化合物对于心梗模型心肌纤维化组织的改善作用；
其中，对照组为正常心肌组织，心梗模型为心梗模型心肌纤维化组织，心梗模型+34为用实施例34中化合物(34)处理的心梗模型中心肌纤维化组织。
图2、图3分别为采用H&E染色及Masson染色方法对肺组织切片进行分析测定的发明化合物体内抗肺纤维化活性结果；
其中，对照组(A)为正常肺组织，模型组(E)为博来霉素诱导的肺纤维化模型组染色情况，34(B、C)为实施例34化合物34在20、60mg/kg浓度下的肺组织染色情况，46(F、G)为实施例46化合物46在20、60mg/kg浓度下的肺组织染色情况，D为阳性对照GLPG-1690在60mg/kg浓度下的肺组织染色情况，柱形图为各组图片肺纤维化程度评级情况。
具体实施方式
以下实施例旨在阐述而不是限制本发明的范围。化合物的核磁共振氢谱采用Bruker ARX-400/600测定，质谱用Agilent 1100 LC/MSD测定；所用试剂均为分析纯或化学纯，其中NaH、5-氰基吲哚、1,3-二氯丙酮、三氟乙酸酐等主要试剂购自国药集团，二氯甲烷、乙酸乙酯、甲醇等主要反应溶剂购自天津市大茂化学试剂厂。
本发明实施例1～56中制备的化合物的取代基如下所示：
Figure PCTCN2021071682-appb-000068
当L为
Figure PCTCN2021071682-appb-000069
时，Y为
Figure PCTCN2021071682-appb-000070
表一
Figure PCTCN2021071682-appb-000071
Figure PCTCN2021071682-appb-000072
当L为
Figure PCTCN2021071682-appb-000073
时，Y为
Figure PCTCN2021071682-appb-000074
表二
Figure PCTCN2021071682-appb-000075
当L为
Figure PCTCN2021071682-appb-000076
时，Y为
Figure PCTCN2021071682-appb-000077
表三
Figure PCTCN2021071682-appb-000078
当L为
Figure PCTCN2021071682-appb-000079
时，Y为
Figure PCTCN2021071682-appb-000080
表四
Figure PCTCN2021071682-appb-000081
实施例1
步骤A 1-乙基-1H-吲哚-5-甲腈(II)
Figure PCTCN2021071682-appb-000082
室温下将200.2g(5.0mol)60％NaH加入1300mL N,N-二甲基甲酰胺中，搅拌，缓慢升温至40℃，加入5-氰基吲哚284.0g(2.0mol)，待H 2逸出后，冷却至25℃，加入碘乙烷468.0g(3.0mol)，室温反应2h。反应毕，加入水5000mL，搅拌30min后，抽滤得固体299.2g，收率88.0％。
步骤B 1-乙基-1H-吲哚-5-硫代甲酰胺(III)
Figure PCTCN2021071682-appb-000083
室温下将硫氢化钠(85.0g，3.5mol)、六水合氯化镁(406.0g，2.0mol)加入600mL N,N-二甲基甲酰胺中，搅拌下加入170.0g(0.7mol)中间体1-乙基-1H-吲哚-5-甲腈(II)，25℃反应3h。反应毕，冷却至室温，反应混合物倒入大量水中，搅拌15min，抽滤，滤饼加入到600mL 1M盐酸中搅拌20min，抽滤，用大量水洗涤滤饼，干燥后得黄色固体147.0g，收率72.1％。
步骤C 4-(氯甲基)-2-(1-乙基-1H-吲哚-5-基)噻唑(IV)
Figure PCTCN2021071682-appb-000084
室温下将102.0g(0.5mol)中间体1-乙基-1H-吲哚-5-硫代甲酰胺(III)和1,3-二氯丙酮63.0g(0.5mol)加入600mL甲苯中，回流反应2.5h。 反应毕，蒸除甲苯，加入800mL水，搅拌30min后抽滤，水洗，干燥后得到土黄色固体109.0g，收率78.9％。
步骤D 1-(5-(4-(氯甲基)噻唑-2-基)-1-乙基-1H-吲哚-3-基)-2,2,2-三氟乙基-1-酮(V)
Figure PCTCN2021071682-appb-000085
室温下将108.0g(0.4mol)中间体4-(氯甲基)-2-(1-乙基-1H-吲哚-5-基)噻唑(IV)溶于800mL N,N-二甲基甲酰胺中，搅拌，冰浴条件下滴加三氟乙酸酐83mL(0.6mol)，滴毕，室温反应1.5h。反应毕，倒入2500mL水中，搅拌30min后抽滤得固体113.5g，收率78.1％。
步骤E 1-(1-乙基-5-(4-(吗啉基甲基)噻唑-2-基)-1H-吲哚-3-基)-2,2,2-三氟乙基-1-酮(M 1)
Figure PCTCN2021071682-appb-000086
室温下将中间体37.0g(0.1mol)V、18mL(0.2mol)吗啉、28.0g(0.2mol)碳酸钾溶于200mL乙腈中，搅拌，室温下反应2h。反应毕，抽滤除去碳酸钾，将乙腈蒸干，加入300mL水，搅拌20min后抽滤得到棕色固体32.9g，收率80.1％。
步骤F (Z)-2-(2-(1-(1-乙基-5-(4-(吗啉基甲基)噻唑-2-基)-1H-吲哚-3-基)-2,2,2-三氟乙叉基)肼基)-4-(4-氟苯基)噻唑-5-甲腈(实施例1)
Figure PCTCN2021071682-appb-000087
室温下将42.3g(0.1mol)中间体M 1加入150mL甲苯中，搅拌，加入23.4g(0.1mol)中间体X和34.5g(0.2mol)对甲苯磺酸，回流反应3h。反应毕，蒸除甲苯，加入300mL二氯甲烷溶解，用饱和碳酸氢钠溶液洗涤，有机层蒸干，经柱层析纯化得固体13.4g，收率21.0％。m.p.:213.8-214.2℃；MS(ESI)m/z:640.24[M+H],638.20[M-H]； 1H NMR(400MHz,DMSO-d 6)δ12.18(s,1H),8.07(s,1H),7.98(s,1H),7.95(dd,J＝8.8,5.5Hz,2H),7.86–7.83(m,1H),7.75(d,J＝8.7Hz,1H),7.47(s,1H),7.34(t, J＝8.9Hz,2H),4.35(q,J＝7.1Hz,2H),3.75(s,1H),3.58(s,4H),2.58(s,3H),1.44(t,J＝7.2Hz,3H).
按照实施例1的方法，以M 1-1等为原料与肼进行缩合反应制备得到实施例(表一)2-10的化合物。
实施例2(Z)-((2-(3-(1-(2-(5-氰基-4-(4-氟苯基)噻唑-2-基)肼基)-2,2,2-三氟乙基)-1-乙基-1H-吲哚-5-基)-噻唑-4-基)-甲基)-L-脯氨酸
Figure PCTCN2021071682-appb-000088
m.p.:183.0-184.2℃；MS(ESI)m/z:668.46[M+H],690.41[M+Na],666.24[M-H]； 1H NMR(400MHz,DMSO-d 6)δ12.15(s,2H),8.07(s,1H),7.98(s,1H),7.95(dd,J＝8.7,5.6Hz,2H),7.87(d,J＝8.7Hz,1H),7.77(d,J＝8.7Hz,1H),7.59(s,1H),7.35(t,J＝8.8Hz,2H),4.36(q,J＝7.0Hz,2H),4.24(d,J＝13.9Hz,1H),4.10(d,J＝13.9Hz,1H),3.77–3.69(m,1H),3.28(d,J＝10.3Hz,1H),2.87(dd,J＝17.5,8.6Hz,1H),2.09(td,J＝17.1,8.4Hz,1H),1.94–1.81(m,1H),1.72(ddd,J＝28.8,14.2,8.1Hz,2H),1.45(t,J＝7.2Hz,3H).
实施例3 (Z)-((2-(3-(1-(2-(5-氰基-4-(4-甲氧基苯基)噻唑-2-基)肼基)-2,2,2-三氟乙基)-1-乙基-1H-吲哚-5-基)-噻唑-4-基)-甲基)-L-脯氨酸
Figure PCTCN2021071682-appb-000089
m.p.:129.7-131.1℃；MS(ESI)m/z:680.27[M+H],702.20[M+Na],678.27[M-H]； 1H NMR(400MHz,DMSO-d 6)δ12.07(s,2H),8.05(s,1H),7.95(s,1H),7.88(s,2H),7.86(s,1H),7.78(d,J＝8.7Hz,1H),7.57(s,1H),7.05(d,J＝8.8Hz,2H),4.36(q,J＝7.1Hz,2H),4.20(d,J＝14.0Hz,1H),4.06(d,J＝13.9Hz,1H),3.80(s,3H),3.69–3.61(m,1H),3.23(s,1H),2.82(dd,J＝17.2,8.4Hz,1H),2.05(td,J＝16.8,8.3Hz,1H),1.90–1.79(m,1H),1.70(ddd,J＝29.1,14.6,8.4Hz,2H),1.45(t,J＝7.2Hz,3H).
实施例4 (Z)-2-(2-(1-(1-乙基-5-(4-(吡咯-1-基甲基)噻唑-2-基)-1H-吲哚 -3-基)-2,2,2-三氟乙叉基)肼基)-4-(4-氟苯基)噻唑-5-甲腈
Figure PCTCN2021071682-appb-000090
m.p.:125.0-126.5℃；MS(ESI)m/z:624.31[M+H],622.27[M-H]； 1H NMR(400MHz,DMSO-d 6)δ10.88(s,1H),8.17(s,1H),8.08(s,1H),7.95(dd,J＝8.8,5.5Hz,2H),7.83(d,J＝8.6Hz,1H),7.78(s,1H),7.72(d,J＝8.7Hz,1H),7.30(t,J＝8.8Hz,2H),4.44(s,2H),4.34(q,J＝7.1Hz,2H),3.27(s,4H),1.87(s,4H),1.43(t,J＝7.2Hz,3H).
实施例5 (Z)-2-(2-(1-(1-乙基-5-(4-(哌啶-1-基甲基)噻唑-2-基)-1H-吲哚-3-基)-2,2,2-三氟乙叉基)肼基)-4-(4-氟苯基)噻唑-5-甲腈
Figure PCTCN2021071682-appb-000091
m.p.:120.0-121.3℃；ESI-MS[M+H](m/z):638.32； 1H NMR(600MHz,CDCl 3)δ8.04(s,1H),7.94(s,1H),7.89(d,J＝8.6Hz,1H),7.85(dd,J＝8.4,5.4Hz,2H),7.46(d,J＝8.7Hz,1H),7.41(s,1H),7.00(t,J＝8.5Hz,2H),4.23(q,J＝7.3Hz,2H),3.83(s,2H),2.64(s,4H),1.65(s,4H),1.52(t,J＝7.3Hz,3H),1.38(d,J＝21.7Hz,2H).
实施例6 (Z)-2-(2-(1-(1-乙基-5-(4-((4-甲基哌啶-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)-2,2,2-三氟乙叉基)肼基)-4-(4-甲氧基苯基)噻唑-5-甲腈
Figure PCTCN2021071682-appb-000092
m.p.:112.8-114.4℃；MS(ESI)m/z:664.18[M+H],662.23[M-H]； 1H NMR(400MHz,DMSO-d 6)δ10.51(s,1H),8.14(s,1H),8.07(s,1H),7.89(s,1H),7.87(s,1H),7.80(dd,J＝8.6,1.2Hz,1H),7.70(d,J＝8.7Hz,1H),7.62(s,1H),7.01(s,1H),6.99(s,1H),4.34(q,J＝7.1Hz,2H),4.12(s,2H),3.79 (s,3H),3.22(d,J＝11.2Hz,2H),2.65(s,2H),1.63(d,J＝12.9Hz,2H),1.43(t,J＝7.2Hz,3H),1.27(d,J＝11.7Hz,1H),1.23(s,2H),0.85(d,J＝6.4Hz,3H).
实施例7 (S,Z)-2-(2-(1-(1-乙基-5-(4-((2-(羟甲基)四氢吡咯-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)-2,2,2-三氟乙叉基)肼基)-4-(4-氟苯基)噻唑-5-甲腈
Figure PCTCN2021071682-appb-000093
m.p.:128.4-129.3℃；MS(ESI)m/z:654.20[M+H],676.24[M+Na],652.23[M-H]； 1H NMR(400MHz,DMSO-d 6)δ10.05(s,1H),8.19(s,1H),8.11(s,1H),7.95(s,2H),7.81(s,1H),7.71(s,1H),7.70–7.66(m,1H),7.29(s,2H),5.22(s,1H),4.49(s,1H),4.34(s,1H),4.33(s,2H),3.58(s,2H),3.08(s,2H),1.96(s,1H),1.74(s,2H),1.67(s,2H),1.42(s,3H).
实施例8 (Z)-2-(2-(1-(1-乙基-5-(4-((3-羟基氮杂环丁烷-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)-2,2,2-三氟乙叉基)肼基)-4-(4-氟苯基)噻唑-5-甲腈
Figure PCTCN2021071682-appb-000094
m.p.:174.7-175.2℃；MS(ESI)m/z:626.47[M+H],624.27[M-H]； 1H NMR(400MHz,DMSO-d 6)δ8.23(s,1H),8.19(s,1H),7.97(s,2H),7.79(d,J＝8.1Hz,1H),7.67(d,J＝8.6Hz,1H),7.53(s,1H),7.28(t,J＝8.5Hz,2H),5.74(s,1H),4.33(d,J＝6.7Hz,2H),4.12(s,2H),3.96(s,2H),3.86(s,1H),3.44(s,2H),1.42(t,J＝6.9Hz,3H).
实施例9 (Z)-2-(2-(1-(1-乙基-5-(4-((4-(2-羟乙基)哌嗪-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)-2,2,2-三氟乙叉基)肼基)-4-(4-氟苯基)噻唑-5-甲腈
Figure PCTCN2021071682-appb-000095
m.p.:102.4-103.6℃；MS(ESI)m/z:683.27[M+H],705.24[M+Na],681.31[M-H]； 1H NMR(400MHz,DMSO-d 6)δ8.18(s,1H),8.17(s,1H),7.97(dd,J＝8.2,5.7Hz,2H),7.79(d,J＝8.6Hz,1H),7.65(d,J＝8.6Hz,1H),7.40(s,1H),7.28(t,J＝8.7Hz,2H),4.86(s,1H),4.33(dd,J＝14.2,7.0Hz,2H),3.72(s,2H),3.59(s,2H),2.86(s,4H),2.72(m,6H),1.42(t,J＝7.2Hz,3H).
实施例10 (Z)-2-(2-(1-(1-乙基-5-(4-((4-羟基哌啶-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)-2,2,2-三氟乙叉基)肼基)-4-(4-氟苯基)噻唑-5-甲腈
Figure PCTCN2021071682-appb-000096
m.p.:142.7-145.3℃；MS(ESI)m/z:654.27[M+H],652.31[M-H]； 1H NMR(400MHz,DMSO-d 6)δ12.63(s,1H),10.65(s,1H),8.06(s,1H),7.98–7.94(m,2H),7.94(d,J＝4.6Hz,2H),7.91(s,1H),7.83(d,J＝8.6Hz,1H),7.37(t,J＝8.8Hz,2H),4.98(s,1H),4.40(s,2H),4.39–4.33(m,2H),3.35(s,2H),3.23(s,2H),3.01(s,1H),1.92(d,J＝11.4Hz,2H),1.70(d,J＝11.8Hz,2H),1.47(t,J＝7.2Hz,3H).
实施例11 (Z)-4-((2-(3-(1-(2-(苯并[d]噻唑-2-基)肼基)-2,2,2-三氟乙叉基)-1-乙基-1H-吲哚-5-基)噻唑-4-基)甲基)吗啉
Figure PCTCN2021071682-appb-000097
室温下将4.3g(0.01mol)中间体M 1加入30mL甲苯中，搅拌，加入1.7g(0.01mol)中间体XI和3.5g(0.02mol)对甲苯磺酸，回流反应3h。反应毕，蒸除甲苯，加入100mL二氯甲烷溶解，用饱和碳酸氢钠溶液洗涤，有机层蒸干，经柱层析纯化得固体0.95g，收率19.1％。
m.p.:120.0-122.1℃；MS(ESI)m/z:571.18[M+H],593.23[M+Na],569.20[M-H]； 1H NMR(400MHz,DMSO-d 6)δ12.15(s,1H),8.03(s,2H),7.86–7.81(m,1H),7.72(t,J＝9.1Hz,2H),7.36(s,1H),7.29(t,J＝7.6Hz,1H),7.21(d,J＝7.8Hz,1H),7.13(t,J＝7.6Hz,1H),4.34(q,J＝7.1Hz,2H),3.58(s,3H),3.55–3.49(m,4H),2.42(s,4H),1.44(t,J＝7.2Hz,3H).
按照实施例11的方法，以中间体M 1为原料与中间体XI进行缩合反应制备得到实施例12-13的化合物。
实施例12 (Z)-2-(2-(1-(1-乙基-5-(4-(哌啶-1-基甲基)噻唑-2-基)-1H-吲哚-3-基)-2,2,2-三氟乙叉基)肼基)苯并[d]噻唑-5-腈
Figure PCTCN2021071682-appb-000098
m.p.:123.6-124.7℃；MS(ESI)m/z:569.20[M+H],567.23[M-H]； 1H NMR(400MHz,DMSO-d 6)δ12.00(s,1H),8.03(s,1H),7.82(dd,J＝8.6,1.5Hz,1H),7.72(d,J＝4.1Hz,1H),7.70(d,J＝5.1Hz,1H),7.34(s,1H),7.28(t,J＝7.2Hz,1H),7.20(d,J＝7.8Hz,1H),7.12(t,J＝7.6Hz,1H),4.34(q,J＝7.1Hz,2H),3.59(s,1H),2.43(s,3H),1.43(t,J＝7.2Hz,3H),1.30(s,2H).
实施例13 (Z)-1-((2-(3-(1-(2-(苯并[d]噻唑-2-基)肼基)-2,2,2-三氟乙叉基)-1-乙基-1H-吲哚-5-基)噻唑-4-基)甲基)哌啶-4-醇
Figure PCTCN2021071682-appb-000099
m.p.:79.4-81.8℃；MS(ESI)m/z:585.23[M+H],583.20[M-H]； 1H NMR(400MHz,DMSO-d 6)δ12.13(s,1H),8.05(s,1H),8.02(s,1H),7.83(dd,J＝8.7,1.4Hz,1H),7.71(t,J＝6.8Hz,2H),7.33(s,1H),7.28(t,J＝7.6Hz,1H),7.21(d,J＝7.8Hz,1H),7.12(t,J＝7.6Hz,1H),4.54(s,1H),4.34(q,J＝7.1Hz,2H),3.58(s,2H),3.42(m,1H),2.76(d,J＝11.3Hz,2H),2.13(t,J＝10.0Hz,2H),1.68(d,J＝9.9Hz,2H),1.44(t,J＝7.2Hz,3H),1.41–1.33(m,2H).
实施例14
步骤A 1-乙基-5-(4-(吗啉基甲基)噻唑-2-基)-1H-吲哚-3-羧酸(M 2)
Figure PCTCN2021071682-appb-000100
室温下将中间体84.6g(0.2mol)M 2加入4M NaOH溶液中(300mL)，回流反应2h。反应毕，冷却至室温，用6M HCl调pH至3，抽滤，滤饼干燥得固体70.1g,收率79％。
步骤B 1-乙基-5-(4-(2-(哌啶-1-基)乙基)噻唑-2-基)-1H-吲哚-3-羧酸甲酯(VI)
Figure PCTCN2021071682-appb-000101
将中间体70.0g(0.19mol)M 2溶于200mL甲醇中，加入浓硫酸，回流反应2h。反应毕，蒸除溶剂，加入600mL水，用乙酸乙酯萃取(800mL)，饱和碳酸氢钠溶液洗涤，有机层蒸干得固体54.4g，收率75％。
步骤C 1-乙基-5-(4-(吗啉基甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼(M 3)
Figure PCTCN2021071682-appb-000102
室温下将3.85g(0.01mol)中间体VI、15mL水合肼加入40mL乙醇中，搅拌，回流反应2.5h。反应毕，蒸除溶剂，加入水和二氯甲烷分液，有机层蒸干得淡黄色固体2.5g，收率64.9％。
步骤D (E)-1-乙基-N′-(4-氟苯甲叉基)-5-(4-(吗啉基甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼(实施例14)
Figure PCTCN2021071682-appb-000103
室温下将1.9g(0.005mol)中间体M 3和0.6g(0.005mol)对氟苯甲醛加入15mL无水乙醇中，回流反应3h。反应毕，冷却至室温，抽滤得终产品1.4g，收率48％。
m.p.:213.2-214.8℃；MS(ESI)m/z:492.24[M+H],514.27[M+Na],490.24[M-H]； 1H NMR(400MHz,DMSO-d 6)δ8.60(s,1H),8.27(s, 1H),7.84(dd,J＝8.6,1.5Hz,1H),7.72(d,J＝8.7Hz,1H),7.44(s,1H),4.32(q,J＝7.2Hz,2H),3.84(s,3H),3.66(s,2H),2.51(s,7H),2.22(s,3H),1.41(t,J＝7.2Hz,3H).
按照实施例14的方法，以中间体M 1为原料与醛或酮进行缩合反应制备得到实施例15-17的化合物。
实施例15 (E)-1-乙基-N′-(4-甲氧基苯甲叉基)-5-(4-(吗啉基甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼
Figure PCTCN2021071682-appb-000104
m.p.:223.2-225.0℃；MS(ESI)m/z:504.23[M+H],526.20[M+Na],502.20[M-H]； 1H NMR(400MHz,DMSO-d 6)δ11.45(s,1H),8.85(s,1H),8.33(s,1H),7.84(d,J＝8.2Hz,1H),7.69(d,J＝7.7Hz,3H),7.45(s,1H),7.04(d,J＝7.9Hz,2H),4.35(s,2H),3.82(s,3H),3.66(s,2H),3.61(s,3H),2.51(s,3H),1.47(t,J＝6.6Hz,3H).
实施例16 (E)-N′-(苯并[d][1,3]二氧戊环-5-基甲叉基)-1-乙基-5-(4-(吗啉基甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼
Figure PCTCN2021071682-appb-000105
m.p.:209.0-211.3℃；MS(ESI)m/z:518.18[M+H],540.23[M+Na],516.23[M-H]； 1H NMR(400MHz,DMSO-d 6)δ11.47(s,1H),8.85(s,1H),8.31(s,1H),7.76(d,J＝53.4Hz,2H),7.39(d,J＝41.6Hz,3H),7.09(d,J＝58.7Hz,2H),6.11(s,2H),4.34(s,2H),3.64(d,J＝11.1Hz,4H),3.64(d,J＝11.1Hz,3H),1.47(s,3H).
实施例17 (E)-1-乙基-5-(4-(吗啉基甲基)噻唑-2-基)5-N′-((4-氧-4H-色酮-3-基)甲叉基)-1H-吲哚-3-甲酰肼
Figure PCTCN2021071682-appb-000106
m.p.:217.6-217.4℃；MS(ESI)m/z:542.24[M+H],564.24[M+Na]； 1H NMR(400MHz,DMSO-d 6)δ11.63(s,1H),8.86(s,2H),8.36(s,1H),8.17(s,1H),7.85(s,2H),7.73(m,2H),7.57(s,1H),7.45(s,1H),4.37(s,2H),3.65(s,2H),3.61(s,2H),2.50(s,4H),1.49(s,3H).
实施例18
步骤A 1-甲基-5-(4-(吗啉基甲基)噻唑-2-基)-1H-吲哚-3-羧酸(M 2′)
Figure PCTCN2021071682-appb-000107
室温下将中间体84.6g(0.2mol)M 1′加入4M NaOH溶液中，回流反应2h。反应毕，冷却至室温，用6M HCl调pH至5，抽滤，滤饼干燥得固体53.7g,收率79％。
步骤B 1-甲基-5-(4-(吗啉基甲基)噻唑-2-基)-1H-吲哚-3-羧酸甲酯(VI′)
Figure PCTCN2021071682-appb-000108
室温下将中间体53.6g(0.15mol)M 2′溶于200mL甲醇中，加入浓硫酸，回流反应2h。反应毕，蒸除溶剂，加入600mL水，用乙酸乙酯萃取(400*2mL)，饱和碳酸氢钠溶液洗涤，有机层蒸干得固体42.3g，收率76％。
步骤C 1-甲基-5-(4-(吗啉基甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼(M 3′)
Figure PCTCN2021071682-appb-000109
室温下将3.7g(0.01mol)中间体VI′、15mL水合肼加入40mL乙醇中，搅拌，回流反应2.5h。反应毕，蒸除溶剂，加入水和二氯甲烷分液，有机层蒸干得淡黄色固体2.4g，收率65％。
步骤D (E)-N′-(4-氟苯甲叉基)-1-甲基-5-(4-(吗啉基甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼(实施例18)
Figure PCTCN2021071682-appb-000110
室温下将1.85g(0.005mol)中间体M 3′和0.6g(0.005mol)对氟苯甲醛加入15mL无水乙醇中，回流反应3h。反应毕，冷却至室温，抽滤得终产品1.15g，收率48％。
m.p.:222.3-223.2℃；MS(ESI)m/z:478.32[M+H],500.32,[M+Na],476.31[M-H]； 1H NMR(600MHz,DMSO-d 6)δ11.57(s,1H),8.84(s,1H),8.36(s,2H),7.86(dd,J＝8.6,1.6Hz,1H),7.80(dd,J＝8.2,5.8Hz,2H),7.66(d,J＝8.6Hz,1H),7.46(s,1H),7.31(t,J＝8.6Hz,2H),3.94(s,4H),3.66(s,2H),3.61(m,6H).
按照实施例18的方法，以中间体M 1为原料与醛或酮进行缩合反应制备得到实施例19、20的化合物。
实施例19 (E)-N′-(苯并[d][1,3]二氧戊环-5-基甲叉基)-1-甲基-5-(4-(吗啉基甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼
Figure PCTCN2021071682-appb-000111
m.p.:173.9-174.4℃；MS(ESI)m/z:504.28[M+H],502.19[M-H]； 1H NMR(600MHz,DMSO-d 6)δ11.47(s,1H),8.82(s,1H),8.28(m,2H),7.85(dd,J＝8.6,1.6Hz,1H),7.65(d,J＝8.6Hz,1H),7.45(s,1H),7.33(d,J＝1.4Hz,1H),7.17(d,J＝7.8Hz,1H),7.00(d,J＝7.9Hz,1H),6.10(s,2H),3.93(s,3H),3.65(s,2H),3.62–3.59(m,4H),2.49–2.47(m,4H).
实施例20 (E)-N′-(4-氯苯甲叉基)-1-甲基-5-(4-((4-甲基哌嗪-1-基)甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼
Figure PCTCN2021071682-appb-000112
m.p.:247.0-248.5℃；MS(ESI)m/z:507.23[M+H],505.19[M-H]； 1H  NMR(600MHz,DMSO-d 6)δ11.60(s,1H),8.82(s,1H),8.28(s,2H),7.86(dd,J＝8.6,1.8Hz,1H),7.78(s,1H),7.76(s,1H),7.66(s,1H),7.65(s,1H),7.54(s,1H),7.53(s,1H),7.42(s,1H),3.94(s,3H),3.64(s,2H),2.49–2.43(m,4H),2.39(s,4H),2.16(s,3H).
实施例21 (E)-1-乙基-N′-(4-氟苯甲叉基)-5-(4-(哌啶-1-基甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼
Figure PCTCN2021071682-appb-000113
室温下将1.85g(0.005mol)中间体M 3和0.6g(0.005mol)对氟苯甲醛加入15mL无水乙醇中，回流反应3h。反应毕，冷却至室温，加入水和二氯甲烷分液，有机层蒸干经柱层析纯化得固体0.94g，收率33％。
m.p.:201.8-202.7℃；MS(ESI)m/z:490.45[M+H],488.37[M-H]； 1H NMR(400MHz,DMSO-d 6)δ11.60(s,1H),8.84(s,1H),8.42(s,1H),7.84(dd,J＝8.6,1.5Hz,1H),7.80(dd,J＝8.5,5.7Hz,2H),7.70(d,J＝8.6Hz,1H),7.43(s,1H),7.31(t,J＝8.8Hz,2H),4.35(d,J＝6.3Hz,2H),3.68(s,2H),3.38(s,4H),1.54(d,J＝5.1Hz,3H),1.47(t,J＝7.2Hz,3H),1.40(d,J＝4.3Hz,2H).
按照实施例21的方法，以中间体M 1为原料与醛或酮进行缩合反应制备得到实施例22-33的化合物。
实施例22 (E)-1-乙基-N′-(4-甲氧基苯甲叉基)-5-(4-(四氢吡咯-1-基甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼
Figure PCTCN2021071682-appb-000114
m.p.:193.8-194.1℃；MS(ESI)m/z:542.24[M+H],564.24[M+Na]； 1H NMR(400MHz,DMSO-d 6)δ11.81(s,1H),8.88(s,1H),8.49(s,1H),7.83(d,J＝8.4Hz,1H),7.75(d,J＝8.2Hz,2H),7.67(d,J＝8.6Hz,1H),7.51(d,J＝8.2Hz,2H),7.47(s,1H),4.32(d,J＝4.4Hz,3H),3.86(d,J＝21.1Hz,2H), 2.69(s,5H),1.74(s,5H),1.46(t,J＝7.1Hz,4H).
实施例23 (E)-N′-(苯并[d][1,3]二氧戊环-5-基甲叉基)-1-乙基-5-(4-((4-甲基哌嗪-1-基)甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼
Figure PCTCN2021071682-appb-000115
m.p.:204.9-205.2℃；MS(ESI)m/z:531.43[M+H],529.58[M-H]； 1H NMR(400MHz,DMSO-d 6)δ11.44(s,1H),8.84(s,1H),8.32(s,1H),7.83(s,1H),7.71(s,1H),7.36(d,J＝24.2Hz,2H),7.18(s,1H),7.02(s,1H),6.11(s,2H),4.35(s,2H),3.62(s,2H),2.51(s,3H),2.46(s,3H),1.52(s,5H),1.40(s,3H).
实施例24 (E)-1-乙基-N′-(4-氟苯甲叉基)-5-(4-((4-甲基哌啶-1-基)甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼
Figure PCTCN2021071682-appb-000116
m.p.:291.2-292.0℃；MS(ESI)m/z:MS(ESI)m/z:504.60[M+H],502.58[M-H]； 1H NMR(400MHz,DMSO-d 6)δ11.63(s,1H),8.86(s,1H),8.44(s,2H),7.85(dd,J＝8.7,1.4Hz,1H),7.80(dd,J＝8.6,5.7Hz,2H),7.71(d,J＝8.6Hz,1H),7.52(s,1H),7.32(t,J＝7.2Hz,2H),4.35(d,J＝6.6Hz,2H),3.83(s,2H),3.03(d,J＝11.0Hz,2H),2.27(s,2H),1.64(d,J＝12.0Hz,2H),1.47(t,J＝7.2Hz,3H),1.40(m,1H)1.24(d,J＝11.0Hz,2H),0.90(d,J＝6.4Hz,3H).
实施例25 (E)-1-乙基-N′-(4-氟苯甲叉基)-5-(4-((4-羟基哌啶-1-基)甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼
Figure PCTCN2021071682-appb-000117
m.p.:163.5-165.6℃；MS(ESI)m/z:506.43[M+H],528.36[M+Na],504.41[M-H]； 1H NMR(600MHz,DMSO-d 6)δ11.59(s,1H),8.86(s,1H),8.37(s,2H),7.84(dd,J＝8.6,1.6Hz,1H),7.80(dd,J＝8.5,5.7Hz,2H),7.70(d,J＝8.6Hz,1H),7.41(s,1H),7.32(t,J＝8.7Hz,2H),4.58(s,1H),4.35(s,2H),3.65(s,2H),3.47(s,1H),2.81(s,2H),2.18(s,2H),1.74(d,J＝9.7Hz,2H),1.47(t,J＝7.2Hz,3H),1.45–1.41(m,2H).
实施例26 (E)-N′-(苯并[d][1,3]二氧戊环-5-基甲叉基)-1-乙基-5-(4-((4-羟基哌啶-1-基)甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼
Figure PCTCN2021071682-appb-000118
m.p.:166.5-167.9℃；MS(ESI)m/z:532.45[M+H],554.38[M+Na],530.43[M-H]； 1H NMR(600MHz,DMSO-d 6)δ11.52(s,1H),8.83(s,1H),8.34(s,2H),7.84(d,J＝8.5Hz,1H),7.70(d,J＝8.6Hz,1H),7.46(s,1H),7.33(s,1H),7.16(d,J＝7.4Hz,1H),7.01(d,J＝7.9Hz,1H),6.10(s,2H),4.63(s,1H),4.34(s,2H),3.72(s,2H),3.51(s,1H),3.35(s,2H),2.87(s,2H),2.26(s,2H),1.75(s,2H),1.47(t,J＝7.2Hz,3H).
实施例27 (E)-N′-(4-氯苯甲叉基)-1-乙基-5-(4-((4-羟基哌啶-1-基)甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼
Figure PCTCN2021071682-appb-000119
m.p.:143.6-144.7℃；MS(ESI)m/z:522.24[M+H],544.26[M+Na]； 1H NMR(600MHz,DMSO-d 6)δ11.66(s,1H),8.84(s,1H),8.39(s,2H),7.84(d,J＝8.4Hz,1H),7.77(d,J＝6.9Hz,2H),7.70(d,J＝8.5Hz,1H),7.54(d,J＝ 6.9Hz,2H),7.42(s,1H),4.58(s,1H),4.35(s,2H),3.67(s,2H),3.48(s,1H),2.82(s,2H),2.20(s,2H),1.73(s,2H),1.47(t,J＝7.1Hz,3H),1.43(s,2H).
实施例28 (E)-1-乙基-N′-(4-氟苯甲叉基)-5-(4-((2-(羟甲基)四氢吡咯-1-基)甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼
Figure PCTCN2021071682-appb-000120
m.p.:147.8-148.6℃；MS(ESI)m/z:506.43[M+H],504.41[M-H]； 1H NMR(600MHz,DMSO-d 6)δ11.56(s,1H),8.83(s,1H),8.36(s,2H),7.84(dd,J＝8.6,1.7Hz,1H),7.80(dd,J＝8.6,5.6Hz,2H),7.70(d,J＝8.7Hz,1H),7.42(s,1H),7.32(t,J＝8.8Hz,2H),4.35(s,2H),4.13(d,J＝14.2Hz,1H),3.71(d,J＝14.2Hz,1H),3.47(dd,J＝10.6,4.7Hz,1H),3.32(dd,J＝10.6,6.4Hz,1H),3.03(dt,J＝9.2,4.6Hz,1H),2.71(s,1H),2.40(dd,J＝16.5,8.2Hz,1H),1.91(s,1H),1.84(dq,J＝12.2,8.2Hz,1H),1.69–1.62(m,2H),1.58(dt,J＝19.1,6.5Hz,1H),1.47(t,J＝7.3Hz,3H).
实施例29 (E)-1-乙基-N′-(1-(4-氟苯基)乙叉基)-5-(4-((2-(羟甲基)四氢吡咯-1-基)甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼
Figure PCTCN2021071682-appb-000121
m.p.:185.7-186.4℃；MS(ESI)m/z:520.42[M+H],542.41[M+Na],518.46[M-H]； 1H NMR(400MHz,DMSO-d 6)δ10.39(s,1H),8.83(s,1H),8.43(s,1H),7.93–7.87(m,2H),7.84(d,J＝8.7Hz,1H),7.70(d,J＝8.6Hz,1H),7.45(s,1H),7.28(t,J＝8.7Hz,2H),4.39–4.28(m,2H),4.17(d,J＝13.7Hz,1H),3.76(d,J＝12.3Hz,1H),3.49(d,J＝6.0Hz,1H),3.48(d,J＝4.3Hz,1H),3.06(s,1H),2.78(s,1H),2.39(s,3H),1.85(d,J＝9.7Hz,1H),1.67(s,2H),1.63–1.55(m,1H),1.46(t,J＝7.1Hz,3H).
实施例30 (E)-N′-(苯并[d][1,3]二氧戊环-5-基甲叉基)-1-乙基-5-(4-((2-(羟甲基)四氢吡咯-1-基)甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼
Figure PCTCN2021071682-appb-000122
m.p.:129.0-131.6℃；MS(ESI)m/z:532.45[M+H],530.43[M-H]； 1H NMR(400MHz,DMSO-d 6)δ11.49(s,1H),8.85(s,1H),8.35(s,1H),7.85(d,J＝8.5Hz,1H),7.69(d,J＝8.6Hz,1H),7.44(s,1H),7.34(s,1H),7.17(d,J＝7.8Hz,1H),7.00(d,J＝7.9Hz,1H),6.11(s,2H),4.33(s,2H),4.18(d,J＝14.2Hz,1H),3.76(d,J＝14.1Hz,1H),3.50(dd,J＝10.6,4.5Hz,1H),3.40–3.32(m,1H),3.10–3.01(m,1H),2.78(s,1H),2.47(d,J＝8.3Hz,1H),1.92(s,1H),1.85(dd,J＝19.0,8.2Hz,1H),1.65(dd,J＝20.8,6.7Hz,2H),1.64–1.54(m,1H),1.47(t,J＝7.1Hz,3H).
实施例31 (E)-N′-(4-氯苯甲叉基)-1-乙基-5-(4-((4-(2-羟乙基)哌嗪-1-基)甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼
Figure PCTCN2021071682-appb-000123
m.p.:157.9-158.8℃；MS(ESI)m/z:551.42[M+H],573.41[M+Na],549.46[M-H]； 1H NMR(400MHz,DMSO-d 6)δ11.64(s,1H),8.83(s,1H),8.42(s,2H),7.84(d,J＝8.2Hz,1H),7.76(d,J＝8.3Hz,2H),7.70(d,J＝8.7Hz,1H),7.54(d,J＝8.3Hz,2H),7.41(s,1H),4.36(s,2H),3.64(s,2H),3.48(s,2H),2.45(s,2H),2.38(t,J＝6.2Hz,3H),1.47(t,J＝7.1Hz,3H).
实施例32 (E)-1-乙基-N′-(4-氟苯甲叉基)-5-(4-((4-(2-(羟乙基)哌嗪-1-基)甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼
Figure PCTCN2021071682-appb-000124
m.p.:133.6-135.1℃；MS(ESI)m/z:535.41[M+H],557.40[M+Na],533.46[M-H]； 1H NMR(400MHz,DMSO-d 6)δ11.55(s,1H),8.84(s,1H), 8.38(s,1H),7.80(s,3H),7.70(d,J＝8.6Hz,1H),7.41(s,1H),7.31(s,2H),4.36(s,2H),3.65(s,2H),3.49(s,2H),2.50(s,4H),2.42(s,2H),1.47(s,3H).
实施例33 (E)-N′-(苯并[d][1,3]二氧戊环-5-基甲叉基)-1-乙基-5-(4-((4-(2-羟乙基)哌嗪-1-基)甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼
Figure PCTCN2021071682-appb-000125
m.p.:157.9-159.5℃；MS(ESI)m/z:561.44[M+H],583.43[M+Na],559.47[M-H]； 1H NMR(600MHz,DMSO-d 6)δ11.47(s,1H),8.82(s,1H),8.31(s,2H),7.83(dd,J＝8.6,1.7Hz,1H),7.70(d,J＝8.7Hz,1H),7.42(s,1H),7.32(s,1H),7.16(d,J＝7.7Hz,1H),7.01(d,J＝8.0Hz,1H),6.10(s,2H),4.45(s,1H),4.34(s,2H),3.66(s,2H),3.50(s,2H),3.34(s,2H),2.52(m,4H),2.49–2.37(m,4H),1.47(t,J＝7.2Hz,3H).
实施例34 3,5-二氯苯甲基(1-乙基-5-(4-(吗啉基甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯
Figure PCTCN2021071682-appb-000126
室温下将中间体3.5g(0.01mol)M 2溶于干燥甲苯中，加入3mL三乙胺和3mL叠氮磷酸二苯酯，搅拌30min后，加入2.7g(0.015mol)3,5-二氯苄醇，回流反应3h。反应毕，蒸除溶剂，加入水与二氯甲烷分液，有机层蒸干后得粗产物。粗产物经柱层析纯化后得目标化合物2.2g，收率42％。
m.p.:160.1-162.0℃；MS(ESI)m/z:545.47[M+H],568.39[M+Na],543.34[M-H]； 1H NMR(400MHz,DMSO-d 6)δ9.95(s,1H),8.47(s,1H),7.74(d,J＝8.6Hz,1H),7.60(s,2H),7.54(s,2H),7.52(d,J＝8.9Hz,1H),7.39(s,1H),5.20(s,2H),4.20(q,J＝7.0Hz,2H),3.63(s,2H),3.61(d,J＝4.0Hz,4H),2.49(d,J＝10.6Hz,4H),1.34(t,J＝7.1Hz,3H).
按照实施例34的方法，以中间体M 2为原料与醇进行Curtius重排反应制备得到实施例35-38的化合物。
实施例35 3,5-二氯苯甲基(1-乙基-5-(4-(四氢吡咯-1-基甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯
Figure PCTCN2021071682-appb-000127
m.p.:183.5-184.8℃；MS(ESI)m/z:529.38[M+H],551.38[M+Na]； 1H NMR(400MHz,DMSO-d 6)δ9.97(s,1H),8.51(s,1H),7.80(d,J＝8.8Hz,1H),7.74(s,1H),7.56(s,1H),7.23(s,1H),7.11(s,1H),6.95(t,J＝7.2Hz,2H),5.20(s,2H),4.40(s,2H),4.21(q,J＝7.1Hz,2H),3.25(s,4H),1.91(s,4H),1.34(t,J＝7.1Hz,3H).
实施例36 (R)-1-(4-甲基苯基)乙基(1-乙基-5-(4-(四氢吡咯-1-基甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯
Figure PCTCN2021071682-appb-000128
m.p.:127.6-129.4℃；MS(ESI)m/z:489.44[M+H],487.34[M-H]； 1H NMR(400MHz,DMSO-d 6)δ9.83(s,1H),8.49(s,1H),7.73(d,J＝8.3Hz,1H),7.55(s,1H),7.49(d,J＝8.6Hz,1H),7.38(s,1H),7.34(d,J＝7.1Hz,2H),7.19(d,J＝6.7Hz,2H),5.79(d,J＝6.4Hz,1H),4.17(dd,J＝7.0Hz,2H),3.79(s,2H),2.62(s,4H),2.29(s,3H),1.73(s,4H),1.55(d,J＝6.1Hz,3H),1.32(t,J＝6.9Hz,3H).
实施例37 3,5-二氯苯甲基(1-乙基-5-(4-((4-甲基哌啶-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯
Figure PCTCN2021071682-appb-000129
m.p.:125.2-127.1℃；MS(ESI)m/z:557.44[M+H],579.41[M+Na],555.48[M-H]； 1H NMR(400MHz,DMSO-d 6)δ9.95(s,1H),8.46(s,1H),7.73(dd,J＝8.7,1.5Hz,1H),7.60(s,2H),7.54(s,2H),7.52(d,J＝8.9Hz, 1H),7.36(s,1H),5.20(s,2H),4.20(q,J＝7.1Hz,2H),3.65(s,2H),2.93(d,J＝10.6Hz,2H),2.08(s,2H),1.59(d,J＝11.8Hz,2H),1.34(t,J＝7.1Hz,3H),1.23(s,1H),1.18(d,J＝9.7Hz,2H),0.89(d,J＝6.4Hz,3H).
实施例38 3,5-二氯苯甲基(1-乙基-5-(4-((4-甲基哌嗪-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯
Figure PCTCN2021071682-appb-000130
m.p.:137.5-139.6℃；MS(ESI)m/z:557.24[M+H],555.47[M-H]； 1H NMR(400MHz,DMSO-d 6)δ9.95(s,1H),8.47(s,1H),7.73(dd,J＝8.7,1.5Hz,1H),7.60(s,2H),7.54(s,2H),7.52(d,J＝8.8Hz,1H),7.36(s,1H),5.20(s,2H),4.20(q,J＝7.1Hz,2H),3.62(s,2H),2.50(s,4H),2.41(s,4H),2.20(s,3H),1.34(t,J＝7.2Hz,3H).
实施例39
步骤A (S)-5-(4-((2-(乙酰氧基甲基)吡咯烷-1-基)甲基)噻唑-2-基)-1-乙基-1H-吲哚-3-羧酸
Figure PCTCN2021071682-appb-000131
室温下，将中间体4g(0.01mol)M 2、2mL乙酸酐、3mL三乙胺和0.1g 4-二甲氨基吡啶依次加入25mL二氯甲烷中，室温反应1.5h。反应毕，加入水与二氯甲烷分液，蒸干有机层得黄色固体3.2g，收率75％。
步骤B(S)-(1-((2-(3-((((3,5-二氯苄基)氧基)羰基)氨基)-1-乙基-1H-吲哚-5-基)噻唑-4-基)甲基)吡咯烷-2-基)乙酸甲酯
Figure PCTCN2021071682-appb-000132
室温下，将从步骤A得到的产物3.2g(0.008mol)溶于干燥甲苯中，加入2mL三乙胺和3mL叠氮磷酸二苯酯，搅拌30分钟后加入3,5-二氯 苄醇，回流反应2h。反应毕，冷却至室温，蒸除甲苯，加入水与二氯甲烷分液，有机层蒸干得油状物3.6g，收率72％。
步骤C 3,5-二氯苯甲基(S)-(1-乙基-5-(4-((2-(羟甲基)四氢吡咯-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯(实施例39)
Figure PCTCN2021071682-appb-000133
室温下，将从步骤B得到的产物3.6g溶于15mL二氧六环中，加入2M的氢氧化钠溶液20mL，50℃反应2h。反应毕，加入水30mL，用二氯甲烷萃取(25mL×2)，有机层蒸干得粗产物。粗产物经柱层析纯化得到目标化合物。
m.p.:60.2-62.9℃；MS(ESI)m/z:559.39[M+H]； 1H NMR(600MHz,DMSO-d 6)δ10.40(s,1H),10.02(s,1H),8.52(s,1H),7.79(dd,J＝8.7,1.1Hz,1H),7.63(s,1H),7.60(s,1H),7.42(d,J＝6.8Hz,1H),7.30(s,1H),6.97(t,J＝7.2Hz,2H),5.67(s,1H),5.20(s,2H),4.85(s,1H),4.80(s,1H),4.63(s,1H),4.42(s,1H),4.21(q,J＝7.1Hz,2H),3.70(s,3H),3.42(s,1H),2.05(s,1H),1.86(d,J＝28.9Hz,2H),1.72(s,1H),1.34(t,J＝7.2Hz,3H).
按照实施例39的方法，以中间体M 2为原料进行酯化、重排、水解反应制备得到实施例40-51的化合物。
实施例40 (R)-1-(对-甲基苯基)乙基(1-乙基-5-(4-(((S)-2-(羟甲基)四氢吡咯-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯
Figure PCTCN2021071682-appb-000134
m.p.:63.0-65.4℃；ESI-MS(m/z):519.23[M+H]； 1H NMR(400MHz,DMSO-d 6)δ9.82(s,1H),8.47(s,1H),7.76–7.71(m,1H),7.55(s,1H),7.49(d,J＝8.7Hz,1H),7.38(d,J＝11.2Hz,1H),7.34(d,J＝7.8Hz,2H),7.20(dd,J＝7.6,3.9Hz,2H),5.82–5.76(m,1H),4.48(s,1H),4.17(dd,J＝15.3,8.2Hz,2H),3.70(d,J＝14.1Hz,1H),3.47(dd,J＝10.6,4.7Hz,1H),3.32(dd,J＝10.5,6.3Hz,1H),3.03(dd,J＝8.4,4.4Hz,1H),2.73(s,1H),2.42(d,J＝7.7Hz,1H),2.30(s,4H),1.83(dt,J＝11.8,8.3Hz,1H),1.66(dd,J＝ 14.3,7.1Hz,2H),1.61(d,J＝6.5Hz,1H),1.55(d,J＝6.5Hz,3H),1.32(t,J＝7.1Hz,3H).
实施例41 (R)-1-(2-氯苯基)乙基(1-乙基-5-(4-(((S)-2-(羟甲基)四氢吡咯-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯
Figure PCTCN2021071682-appb-000135
m.p.:63.5-64.7℃；ESI-MS(m/z):539.17[M+H]； 1H NMR(400MHz,DMSO-d 6)δ9.97(s,1H),8.48(s,1H),7.74(d,J＝8.6Hz,1H),7.62(d,J＝7.3Hz,1H),7.56(s,1H),7.52–7.46(m,2H),7.43(t,J＝7.3Hz,1H),7.36(d,J＝7.7Hz,2H),6.09(q,J＝6.4Hz,1H),4.47(s,1H),4.23–4.14(m,2H),4.10(s,1H),3.70(d,J＝14.1Hz,1H),3.47(dd,J＝10.4,4.4Hz,1H),3.32(d,J＝10.3Hz,1H),3.03(d,J＝4.0Hz,1H),2.72(s,1H),2.42(d,J＝7.6Hz,1H),1.84(dd,J＝19.0,8.2Hz,1H),1.64(td,J＝10.2,6.3Hz,2H),1.61(d,J＝6.5Hz,1H)1.56(d,J＝6.4Hz,3H),1.31(t,J＝7.0Hz,3H).
实施例42 苯甲基(S)-(1-乙基-5-(4-((2-(羟甲基)四氢吡咯-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯
Figure PCTCN2021071682-appb-000136
m.p.:64.2-65.5℃；MS(ESI)m/z:491.32[M+H],513.35[M+Na],489.29[M-H]； 1H NMR(400MHz,DMSO-d 6)δ9.87(s,1H),8.45(s,1H),7.73(d,J＝7.7Hz,1H),7.60(s,1H),7.51(d,J＝8.7Hz,1H),7.47(d,J＝6.9Hz,2H),7.44–7.39(m,2H),7.34(dd,J＝15.1,6.2Hz,2H),5.19(s,2H),4.45(s,1H),4.19(dd,J＝14.0,6.9Hz,2H),4.10(d,J＝14.2Hz,1H),3.68(d,J＝14.2Hz,1H),3.46(dd,J＝10.3,4.2Hz,1H),3.30(d,J＝10.5Hz,1H),3.05–2.98(m,1H),2.69(m,1H),2.44–2.33(m,1H),1.82(dd,J＝19.2,8.3Hz,1H),1.70–1.60(m,2H),1.57(dd,J＝12.0,6.0Hz,1H),1.34(t,J＝7.1Hz,3H).
实施例43 苯并[d][1,3]二氧戊环-5-基甲基(S)-(1-乙基-5-(4-((2-(羟甲基)四氢吡咯-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯
Figure PCTCN2021071682-appb-000137
m.p.:129.7-131.8℃；ESI-MS[M+H](m/z):535.26； 1H NMR(400MHz,DMSO-d 6)δ9.81(s,1H),8.44(s,1H),7.74(d,J＝8.5Hz,1H),7.59(s,1H),7.51(d,J＝8.7Hz,1H),7.39(s,1H),7.03(s,1H),6.95(d,J＝3.5Hz,2H),6.03(s,2H),5.08(s,2H),4.57–4.47(m,1H),4.23–4.18(m,2H),4.15(d,J＝16.0Hz,1H),3.76(s,1H),3.48(m,2H)3.07(d,J＝6.1Hz,1H),2.78(s,1H),1.85(dd,J＝19.1,8.2Hz,1H),1.67(d,J＝6.8Hz,2H),1.58(dd,J＝11.8,6.1Hz,2H),1.34(t,J＝7.1Hz,3H).
实施例44 3,5-二氯苄基(1-乙基-5-(4-((4-羟基哌啶-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯
Figure PCTCN2021071682-appb-000138
m.p.:67.9-69.6℃；MS(ESI)m/z:559.39[M+H],581.41[M+Na]； 1H NMR(600MHz,DMSO-d 6)δ9.96(s,1H),8.47(s,1H),7.73(dd,J＝8.6,1.6Hz,1H),7.60(s,2H),7.54(s,2H),7.52(d,J＝8.7Hz,1H),7.35(dd,J＝3.3,2.5Hz,1H),5.20(s,2H),4.56(s,1H),4.20(q,J＝7.2Hz,2H),3.60(s,2H),3.46(s,1H),2.79(s,2H),2.15(s,2H),1.73(d,J＝9.9Hz,2H),1.42(dd,J＝13.1,5.9Hz,2H),1.34(t,J＝7.2Hz,3H).
实施例45 苯并[d][1,3]二氧戊环-5-基甲基(1-乙基-5-(4-((4-羟基哌啶-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯
Figure PCTCN2021071682-appb-000139
m.p.:64.3-65.9℃；ESI-MS[M+H](m/z):535.31； 1H NMR(400MHz,DMSO-d 6)δ9.82(s,1H),8.46(s,1H),7.73(d,J＝8.5Hz,1H),7.59(s,1H),7.50(d,J＝8.6Hz,1H),7.35(s,1H),7.04(s,1H),6.94(s,2H),6.03(s,2H), 5.08(s,2H),4.57(s,1H),4.26–4.10(m,2H),3.63(s,2H),3.47(s,1H),2.80(s,2H),2.18(s,2H),1.73(d,J＝10.0Hz,2H),1.43(d,J＝9.2Hz,2H),1.34(t,J＝7.0Hz,3H).
实施例46 3,4-二氟苄基(1-乙基-5-(4-((4-羟基哌啶-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯
Figure PCTCN2021071682-appb-000140
m.p.:60.0-62.4℃；MS(ESI)m/z:527.26[M+H],525.18[M-H]； 1H NMR(400MHz,DMSO-d 6)δ9.91(s,1H),8.46(s,1H),7.73(d,J＝8.5Hz,1H),7.60(s,1H),7.51(dd,J＝19.8,10.9Hz,3H),7.35(s,2H),5.17(s,2H),4.56(s,1H),4.20(d,J＝6.8Hz,2H),3.61(s,2H),3.47(s,1H),2.79(m,2H),2.16(m,2H),1.72(m,2H),1.42(d,J＝9.4Hz,2H),1.34(t,J＝6.9Hz,3H).
实施例47 (R)-1-(2-氯苯基)乙基(1-乙基-5-(4-((4-羟基哌啶-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯
Figure PCTCN2021071682-appb-000141
m.p.:103.1-105.6℃；MS(ESI)m/z:539.28[M+H],537.31[M-H]； 1H NMR(400MHz,DMSO-d 6)δ9.98(s,1H),8.50(s,1H),7.73(d,J＝8.6Hz,1H),7.62(d,J＝7.4Hz,1H),7.56(s,1H),7.51–7.46(m,2H),7.43(t,J＝7.5Hz,1H),7.34(d,J＝8.7Hz,2H),6.09(q,J＝6.5Hz,1H),4.57(d,J＝2.8Hz,1H),4.16(dd,J＝14.0,6.9Hz,2H),3.62(s,2H),3.48(s,1H),2.81(d,J＝10.3Hz,2H),2.17(s,2H),1.74(d,J＝9.8Hz,2H),1.56(d,J＝6.4Hz,3H),1.43(m,2H),1.31(t,J＝7.1Hz,3H).
实施例48 3,5-二氯苄基(5-(4-((双(2-羟乙基)氨基)甲基)噻唑-2-基)-1-乙基-1H-吲哚-3-基)氨基甲酸酯
Figure PCTCN2021071682-appb-000142
m.p.:112.7-113.6℃； 1H NMR(400MHz,DMSO-d 6)δ7.73(t,J＝12.3Hz,1H),7.60(s,1H),7.53(d,J＝8.7Hz,1H),7.45(d,J＝1.9Hz,1H),7.42(s,2H),7.35(s,1H),7.16(s,1H),6.97(s,1H),4.89(s,2H),4.85(s,2H),4.51(d,J＝5.6Hz,2H),4.25–4.13(m,2H),3.89(s,2H),3.53(s,2H),3.51(s,2H),2.70(s,2H),1.34(t,J＝5.7Hz,3H).
实施例49 3,5-二氯苄基(1-乙基-5-(4-((4-(2-羟乙基)哌嗪-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯
Figure PCTCN2021071682-appb-000143
m.p.:80.5-81.7℃；MS(ESI)m/z:588.13[M+H]； 1H NMR(400MHz,DMSO-d 6)δ9.96(s,1H),8.47(s,1H),7.73(d,J＝8.7Hz,1H),7.60(s,2H),7.54(s,2H),7.52(d,J＝9.0Hz,1H),7.36(s,1H),5.20(s,2H),4.44(s,1H),4.20(q,J＝6.9Hz,2H),3.62(s,2H),3.49(t,J＝6.1Hz,2H),3.42(s,2H),2.49–2.45(m,4H),2.42(t,J＝6.1Hz,4H),1.34(t,J＝7.1Hz,3H).
实施例50 3,4-二氟苄基(1-乙基-5-(4-((4-(2-羟乙基)哌嗪-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯
Figure PCTCN2021071682-appb-000144
m.p.:83.1-85.0℃；MS(ESI)m/z:556.12[M+H]； 1H NMR(400MHz,DMSO-d 6)δ9.91(s,1H),8.46(s,1H),7.73(dd,J＝8.7,1.3Hz,1H),7.59(d,J＝6.5Hz,1H),7.56(s,1H),7.52(s,1H),7.50(s,1H),7.35(s,2H),5.17(s,2H),4.40(s,1H),4.20(q,J＝7.1Hz,2H),3.62(s,2H),3.49(t,J＝6.0Hz,2H),2.49–2.43(m,6H),2.39(t,J＝6.1Hz,4H),1.34(t,J＝7.2Hz,3H).
实施例51 苯甲基(1-乙基-5-(4-((4-(2-羟乙基)哌嗪-1-基)甲基)噻唑-2- 基)-1H-吲哚-3-基)氨基甲酸酯
Figure PCTCN2021071682-appb-000145
m.p.:88.2-89.6℃；MS(ESI)m/z:519.76[M+H]； 1H NMR(400MHz,DMSO-d 6)δ9.88(s,1H),8.47(s,1H),7.73(d,J＝8.6Hz,1H),7.60(s,1H),7.50(d,J＝8.7Hz,1H),7.46(s,2H),7.41(s,2H),7.35(s,2H),5.19(s,2H),4.41(s,1H),4.19(d,J＝6.9Hz,2H),3.61(s,2H),3.49(s,2H),2.48–2.45(m,6H),2.40(m,4H),1.34(t,J＝6.9Hz,3H).
实施例52 1-苯甲基-3-(1-乙基-5-(4-(吗啉甲基)噻唑-2-基)-1H-吲哚-3-基)脲
室温下将中间体3.5g(0.01mol)M 2溶于干燥甲苯中，加入3mL三乙胺和3mL叠氮磷酸二苯酯，搅拌30min后，加入1.6g(0.015mol)苄胺，回流反应3h。反应毕，蒸除溶剂，加入水与二氯甲烷分液，有机层蒸干后得粗产物。粗产物经薄层层析纯化后得目标化合物0.71g，收率15％。
Figure PCTCN2021071682-appb-000146
m.p.:102.9-103.7℃；MS(ESI)m/z:476.75[M+H],474.73[M-H]； 1H NMR(400MHz,DMSO-d 6)δ8.66(s,1H),8.22(s,1H),7.67(d,J＝8.6Hz,1H),7.58(s,1H),7.50(d,J＝8.7Hz,1H),7.39(s,1H),7.37–7.30(m,5H),7.25(d,J＝4.5Hz,1H),6.54(t,J＝5.9Hz,1H),4.34(d,J＝5.9Hz,2H),4.17(q,J＝7.1Hz,2H),3.62(s,2H),3.61–3.58(m,4H),2.47(m,4H),1.33(t,J＝7.1Hz,3H).
按照实施例52的方法，以中间体M 2为原料与苄胺进行Curtius重排反应制备得到实施例53-54的化合物。
实施例53 1-(1-乙基-5-(4-((4-甲基哌啶-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)-3-(4-氟苯甲基)脲
Figure PCTCN2021071682-appb-000147
m.p.:104.7-105.2℃；MS(ESI)m/z:506.83[M+H]； 1H NMR(400MHz,DMSO-d 6)δ8.70(s,1H),8.22(s,1H),7.67(dd,J＝8.6,1.5Hz,1H),7.57(s,1H),7.49(d,J＝8.7Hz,1H),7.37(dd,J＝8.4,5.7Hz,2H),7.32(s,1H),7.16(t,J＝8.9Hz,2H),6.59(t,J＝6.0Hz,1H),4.32(d,J＝5.8Hz,2H),4.16(q,J＝7.1Hz,2H),3.58(s,2H),2.88(d,J＝11.3Hz,2H),2.00(t,J＝10.7Hz,2H),1.57(d,J＝11.9Hz,2H),1.33(t,J＝7.1Hz,3H),1.21(m,J＝12.9,3.2Hz,1H),1.14(m,J＝17.4,8.2Hz,2H),0.88(d,J＝6.4Hz,3H).
实施例54 1-(4-氯苯甲基)-3-(1-乙基-5-(4-((4-甲基哌嗪-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)脲
Figure PCTCN2021071682-appb-000148
m.p.:102.1-103.9℃；MS(ESI)m/z:523.86[M+H]； 1H NMR(400MHz,DMSO-d 6)δ8.70(s,1H),8.22(s,1H),7.67(dd,J＝8.7,1.3Hz,1H),7.57(s,1H),7.50(d,J＝8.7Hz,1H),7.40(d,J＝7.3Hz,1H),7.39(s,1H),7.36(s,2H),7.34(s,1H),6.60(t,J＝6.0Hz,1H),4.33(d,J＝5.9Hz,2H),4.17(q,J＝7.1Hz,2H),3.62(s,2H),2.50–2.44(m,3H),2.37(m,4H),2.17(s,3H),1.33(t,J＝7.2Hz,3H).
实施例55
步骤A 5-(4-((4-乙酰氧基哌啶-1-基)甲基)噻唑-2-基)-1-乙基-1H-吲哚-3-羧酸
Figure PCTCN2021071682-appb-000149
室温下，将中间体3.85g(0.01mol)M 2、2mL乙酸酐、3mL三乙胺和0.1g 4-二甲氨基吡啶依次加入25mL二氯甲烷中，室温反应1.5h。反应毕，加入水与二氯甲烷分液，蒸干有机层得黄色固体3.3g，收率77％。
步骤B 1-((2-(3-(3-(3-氯-4-甲氧基苯基)脲基)-1-乙基-1H-吲哚-5-基)噻唑-4-基)甲基)哌啶-4-基乙酸酯
Figure PCTCN2021071682-appb-000150
室温下，将从步骤A得到的产物3.3g(0.008mol)溶于干燥甲苯中，加入2mL三乙胺和3mL叠氮磷酸二苯酯，搅拌30分钟后加入3-氯-4-甲氧基苄胺，回流反应2h。反应毕，冷却至室温，蒸除甲苯，加入水与二氯甲烷分液，有机层蒸干得油状物3.57g，收率75％。
步骤C 1-(3-氯-4-甲氧基苯甲基)-3-(1-乙基-5-(4-((4-羟基哌啶-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)脲(实施例55)
室温下，将从步骤B得到的产物3.57g溶于15mL二氧六环中，加入2M的氢氧化钠溶液20mL，50℃反应2h。反应毕，加入水30mL，用二氯甲烷萃取(25mL×2)，有机层蒸干得粗产物。粗产物经薄层层析纯化得到目标化合物，收率19％。
Figure PCTCN2021071682-appb-000151
m.p.:103.5-104.6℃；MS(ESI)m/z:555.86[M+H]； 1H NMR(400MHz,DMSO-d 6)δ8.69(s,1H),8.22(s,1H),7.67(dd,J＝8.6,1.4Hz,1H),7.57(s,1H),7.49(d,J＝8.7Hz,1H),7.38(d,J＝1.8Hz,1H),7.33(s,1H),7.26(dd,J＝8.4,1.9Hz,1H),7.10(d,J＝8.5Hz,1H),4.55(s,1H),4.27(d,J＝5.8Hz,2H),4.17(q,J＝7.1Hz,2H),3.83(s,3H),3.59(s,2H),3.46(s,1H),2.78(d,J＝11.3Hz,2H),2.13(t,J＝9.8Hz,2H),1.72(d,J＝9.5Hz,2H),1.41(dd,J＝18.6,8.8Hz,2H),1.33(t,J＝7.2Hz,3H).
实施例56 1-(5-(4-((双(2-羟乙基)氨基)甲基)噻唑-2-基)-1-乙基-1H-吲哚-3-基)-3-(3-氯-4-甲氧基苄基)脲
Figure PCTCN2021071682-appb-000152
m.p.:109.5-110.3℃； 1H NMR(400MHz,DMSO-d 6)δ8.65(s,1H),8.18(s,1H),7.69(dd,J＝8.6,1.4Hz,1H),7.57(s,1H),7.50(d,J＝8.7Hz,1H),7.43(s,1H),7.38(d,J＝1.8Hz,1H),7.27(dd,J＝8.5,1.8Hz,1H),7.11(d,J＝8.5Hz,1H),6.55(t,J＝5.9Hz,1H),4.44(s,2H),4.26(d,J＝5.8Hz,2H),4.17(dd,J＝14.3,7.1Hz,2H),3.86(s,2H),3.83(s,3H),3.51(t,J＝6.0Hz,4H),2.67(t,J＝6.2Hz,4H),1.33(t,J＝7.2Hz,3H).
本发明化合物的ATX抑制活性研究
以FS-3(Echelon Biosciences,Inc.Salt Lake City,UT)为底物，测试本发明化合物和阳性对照药GLPG-1690对于ATX的抑制作用。
从最高浓度20微摩尔开始，在每个孔中加入10微升的系列稀释化合物。糖基化的人ATX蛋白(Echelon Biosciences,Inc.Salt Lake City,UT)，所用最终浓度为0.4或0.64μg/mL，将其稀释在50mM Tris-HCl(2-氨基-2-羟甲基-1,3-丙二醇盐酸盐)中，pH为8，加入氯化钠250毫摩尔，5毫摩尔氯化钾，1毫摩尔氯化镁，1毫摩尔氯化钙和0.1％无脂肪酸BSA(牛血清白蛋白)保持总体积为20μL。在酶混合物中加入化合物，将所得混合物在室温下振动，孵育30分钟。加入稀释在同一缓冲液中的20μL 0.75μM的FS-3(Echelon Biosciences,Inc.,Salt Lake City,UT)，激发荧光反应。在室温下孵育30分钟后(激发波长485nm，发射波长520nm)，从荧光激发设备(PerkinElmer)上读取荧光值，通过Excel软件计算各时间点的斜率值，最后将斜率值导入SPSS软件计算得到IC 50值。
本发明化合物的抗肿瘤活性研究
体外抗肿瘤细胞活性
对本发明的通式Ⅰ所示的吲哚衍生物进行了体外MCF-7乳腺癌细胞活性测试及EGFR高表达的人肺腺癌细胞A549的活性筛选，所用细胞系购自中科院上海细胞库。
(1)细胞复苏并传代2-3次稳定后，用胰蛋白酶溶液(0.25％)使其从培养瓶底部消化下来。将细胞消化液倒入离心管中后，之后加入培养液以终 止消化。将离心管在800r/min下离心10min，弃去上清液后加入5mL培养液，吹打混匀细胞，吸取10μL细胞混悬液加入细胞计数板中计数，调整细胞浓度为104个/孔。96孔板中除A1孔为空白孔不加细胞外，其余皆加入100μL细胞混悬液。将96孔板放入培养箱中培养24h。
(2)用50μL二甲基亚砜溶解受试样品，然后加入适量培养液，使样品溶解成2mg/mL药液，然后在24孔板中将样品稀释为20、4、0.8、0.16、0.032μg/mL。每个浓度加入3孔，其中周围两行两列细胞长势受环境影响较大，只作为空白细胞孔使用。将96孔板放入培养箱中培养72h。
(3)将96孔板中带药培养液弃去，用磷酸缓冲溶液(PBS)将细胞冲洗两遍，在每孔中加入MTT(0.5mg/mL)100μL放入培养箱中4h后，弃去MTT溶液，加入二甲基亚砜100μL。在磁力振荡器上振荡使存活细胞与MTT反应产物甲臜充分溶解，放入酶标仪(Thermo Varioskan Flash)中测定结果。通过Bliss法可求出药物IC 50值。
化合物对ATX抑制活性及乳腺癌细胞MCF-7和肺腺癌细胞A549活性结果见表1。
表1
Figure PCTCN2021071682-appb-000153
Figure PCTCN2021071682-appb-000154
Figure PCTCN2021071682-appb-000155
发明化合物在体内抗纤维化活性研究
本发明所用SPF级小鼠购自辽宁长生生物技术股份有限公司，品系C57BL/6，体重17-20克，性别雄性，均通过辽宁省实验动物质量检测中心认证符合ARRIVE规程，动物体内试验流程符合沈阳药科大学动物伦理委员会规程。
1、采用Masson染色实验方法，考察实施例34的化合物(34)对心肌梗死(MI)模型的抑制作用，评价其抗心肌组织纤维化能力。
建立了大鼠心肌梗死(MI)模型，方法如下：雄性Wistar大鼠、体重200-230g，随机分成2组，每组30只。分别为对照组(假手术组)和心肌梗死组，以10％水合氯醛腹腔注射麻醉后仰卧位固定，于第4-5肋间开胸，剪开心包膜于左心耳下缘2mm处结扎左冠状动脉前降支，随即闭合胸腔，观测心电图及心律失常发生情况。以心电图ST段显著抬高为模型成功标志，假手术组穿线不结扎。
将心肌组织切片脱蜡至蒸馏水，苏木素染色5～10min，盐酸酒精分化，流水蓝化，蒸馏水洗，丽春红酸性品红液中染5～8min，蒸馏水洗，1％磷钼酸中染1～3min，不用水洗直接入苯胺蓝液或亮绿液5min，水速洗，置60℃温箱中烘干，二甲苯透明，封固。胶原纤维呈蓝色(用苯胺蓝复染)或绿色(用亮绿复染)，细胞质、肌纤维和红细胞呈红色，细胞核呈蓝褐色。
实验结果如图1所示，心梗模型中胶原组织明显增多，当用34处理后，胶原组织较心梗模型组相比明显减小。实验结果证明，34有减少胶原组织生成，从而抑制纤维化的作用。
2、采用博来霉素介导的小鼠肺纤维化模型，对本发明的化合物34和46进行了体内活性研究，初步评价了其对于肺纤维化组织的改善作用。对C57BL/6J小鼠通过灌胃给药方式分别给予GLPG-1690(60mg/kg)及化合 物34和46(20/60mg/kg)，每日1次，共31天(第-3天至第28天)。在第4天(+1天)，实验组(包括模型组及给药组，每组5只)气管内给药博来霉素用以建立肺纤维化模型。同时，模型组用生理盐水替代试验化合物，对照组为肺组织正常的未处理组。分别采用H&E染色及Masson染色方法对肺组织切片进行分析，结果见图2和图3。结果表明，所测试的本发明的化合物均表现出较显著的肺组织保护作用，且其保护作用与阳性对照GLPG-1690相当。

Claims (14)

  1. 通式Ⅰ所示的吲哚衍生物或其光学异构体、药学上可接受的盐、溶剂化物或前药，
    Figure PCTCN2021071682-appb-100001
    其中，
    L为
    Figure PCTCN2021071682-appb-100002
    X为O、S或NH；
    R为H、C1-C6烷基、C2-C6烯基或C2-C6炔基；
    R 1和R 2相同或不同，分别独立地任选自氢、羟基、氨基甲酰基、氨基磺酰基、C1-C6酰基或取代的磺酰基，所述取代基为C1-C4烷基、C2-C4烯基或C2-C4炔基；
    或R 1和R 2为任选的被一个或多个如下取代基取代的C1-C6烷基、C2-C6烯基或C2-C6炔基，所述取代基为氢、卤素、卤代C1-C4烃基、卤代C1-C4烷氧基、氨基、氰基、羟基、巯基、羧基、氨基甲酰基、氨基磺酰基、-NR nR o、-OR n、-C(O)R n、-C(O)OR n、-OC(O)R n、-C(O)N(R o)R n、-N(R o)C(O)R n、-S(O) yR n、-SO 2N(R o)R n、-N(R o)SO 2R n或-(CH 2) zNR oR n，其中y是0、1或2，z是1、2或3，R n和R o各自独立地选自H或C1-C4烃基，所述卤素为氟、氯或溴；
    或R 1和R 2与和它们所连接的氮原子一起形成4-7元杂环或5-6元芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子，所述杂环和/或芳杂环可被1-3个相同或不同的R 9取代；
    R 9为氢、羧基、羟基、C1-C4羟烷基、C1-C4烷氧基、C1-C6烃基或取代的C1-C6烷基，所述取代基为：氰基、氨基、C1-C4烷胺基或C1-C4磺酰基，所述烃基为C1-C6烷基、C2-C6烯基或C2-C6炔基；
    R 3为氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、3-6元饱和或不饱和碳环或C1-C6烷氧基；
    R 4不存在，或为C1-C4烷基、C2-C4烯基、C2-C4炔基、取代或未取代的5-6元芳杂环，所述取代基为C1-C4烷基、C2-C4烯基、 C2-C4炔基、C3-C6环烷基、羟基、氰基、C1-C4烷氧基或卤素所取代的(CH 2) n，其中，n是1、2或3，所述芳杂环含有1-3个N、O和/或S；
    R 5、R 6、R 7、R 8分别独立地选自氢、卤素、C1-C4烷基、C2-C4烯基、C2-C4炔基、C1-C4卤代烷基、C1-C4烷氧基、C1-C4烷硫基、羟基、羧基、氰基、C1-C4酰氨基、C1-C4烃基取代的氨甲酰基、C1-C4烃基取代的磺酰氨基、氨基、C1-C4烷基砜、C1-C4烷基亚砜，且其数目及组合不限；
    或R 4与R 5与它们所连接的苯环上的碳原子一起形成4-7元杂环或芳杂环、4-7元不饱和碳环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子；
    或R 5与R 6与它们所连接的苯环上的碳原子一起形成4-7元不饱和碳环、4-7元杂环或芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子；
    或R 6与R 7与它们所连接的苯环上的碳原子一起形成3-7元不饱和碳环、4-7元杂环或芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子；
    或R 7与R 8与它们所连接的苯环上的碳原子一起形成4-7元不饱和碳环、4-7元杂环或芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子。
  2. 权利要求1的通式Ⅰ所示的吲哚衍生物或其光学异构体、药学上可接受的盐、溶剂化物或前药，
    其中，
    R 1和R 2相同或不同，分别独立地任选自氢、羟基、氨基甲酰基、氨基磺酰基、C1-C6酰基、取代的磺酰基，所述取代基为C1-C4烷基、C2-C4烯基或C2-C4炔基；
    或R 1和R 2为任选的被一个或多个如下取代基取代的C1-C6烷基、C2-C6烯基或C2-C6炔基，所述取代基为氢、卤素、卤代C1-C4烷基、卤代甲氧基、氨基、氰基、羟基、巯基、羧基、氨基甲酰基、氨基磺酰基、-NR nR o、-OR n、-C(O)R n、-C(O)OR n、-OC(O)R n、-C(O)N(R o)R n、-N(R o)C(O)R n、-S(O) yR n、-SO 2N(R o)R n、-N(R o)SO 2R n或-(CH 2) zNR oR n，其中y是0、1或2，z是1、2或3，R n和R o各自独立地选自H或C1-C4烷基，所述卤素为氟、氯或溴；
    或R 1和R 2与和它们所连接的氮原子一起形成4-7元杂环或5-6元芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子， 所述杂环和/或芳杂环可被1-3个相同或不同的R 9取代；
    R 9为氢、羧基、羟基、C1-C4羟烷基、C1-C4烷氧基、未取代或取代C1-C6烷基、C2-C6烯基或C2-C6炔基，所述取代基为：氰基、氨基、C1-C4烷胺基或C1-C4磺酰基；
    优选地，R 1和R 2为任选的被羟基、羧基取代的C1-C6烷基、C2-C6烯基或C2-C6炔基，或R 1和R 2与和它们所连接的氮原子一起形成4-7元杂环，所述杂环含有1-3个N、O和/或S的杂原子，或所述杂环可被1-3个相同或不同的R 9取代；
    R 9为氢、羧基、羟基、C1-C6烷基、C1-C4烷氧基、C1-C4羟烷基；
    更优选地，
    R 1和R 2与和它们所连接的氮原子一起形成
    Figure PCTCN2021071682-appb-100003
    Figure PCTCN2021071682-appb-100004
  3. 权利要求1或2的通式Ⅰ所示的吲哚衍生物或其光学异构体、药学上可接受的盐、溶剂化物或前药，
    其中，
    R 3为氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、3-6元饱和或不饱和碳环或C1-C6烷氧基；
    优选地，
    R 3为氢或C1-C4烷基；
    更优选地，
    R 3为甲基或乙基。
  4. 权利要求1-3任何一项的通式Ⅰ所示的吲哚衍生物或其光学异构体、药学上可接受的盐、溶剂化物或前药，
    其中，
    R 4不存在，或为C1-C4烷基、C2-C4烯基、C2-C4炔基、取代或未取代的5-6元芳杂环，所述取代基为C1-C4烷基、C2-C4烯基、C2-C4炔基、C3-C6环烷基、羟基、氰基、C1-C4烷氧基、卤素所取代的(CH 2) n，其中，n是1、2或3，所述芳杂环含有1-3个N、O和/或S；
    优选地，
    R 4不存在，或为5-6元芳杂环，所述芳杂环含有1-3个N、O和/或S，或是任选地被C1-C4烷基、烷氧基、卤素所取代的(CH 2) n， 其中，n是1、2或3；
    更优选地，
    R 4不存在，或为氰基取代的噻唑环，或是(CH 2) n，其中，n是1、2或3。
  5. 权利要求1-4任何一项的通式Ⅰ所示的吲哚衍生物或其光学异构体、药学上可接受的盐、溶剂化物或前药，
    其中，
    R 5、R 6、R 7、R 8分别独立地选自氢、卤素、C1-C4烷基、C2-C4烯基、C2-C4炔基、C1-C4卤代烷基、C1-C4烷氧基、C1-C4烷硫基、羟基、羧基、氰基、C1-C4酰氨基、C1-C4烃基取代的氨甲酰基、C1-C4磺酰氨基、氨基、C1-C4烷基砜、C1-C4烷基亚砜，且其数目及组合不限；
    优选地，
    R 5、R 6、R 7、R 8分别独立地选自氢、卤素、C1-C4烷氧基，且其数目及组合不限。
  6. 权利要求1-5任何一项的通式Ⅰ所示的吲哚衍生物或其光学异构体、药学上可接受的盐、溶剂化物或前药，
    其中，
    R 4与R 5与它们所连接的苯环上的碳原子一起形成4-7元不饱和碳环、4-7元杂环或芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子；
    优选地，
    R 4与R 5与它们所连接的苯环一起形成
    Figure PCTCN2021071682-appb-100005
    或R 4、R 5与L及它们所连接的苯环形成
    Figure PCTCN2021071682-appb-100006
  7. 权利要求1-6任何一项的通式Ⅰ所示的吲哚衍生物或其光学异构体、药学上可接受的盐、溶剂化物或前药，
    其中，
    R 5与R 6与它们所连接的苯环上的碳原子一起形成4-7元不饱和碳环、4-7元杂环或芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子；
    或R 6与R 7与它们所连接的苯环上的碳原子一起形成4-7元不饱和碳环、4-7元杂环或芳杂环，所述杂环或芳杂环含有1-3个N、S和/或O的杂原子；
    或R 7与R 8与它们所连接的苯环上的碳原子一起形成4-7元不 饱和碳环、4-7元杂环或芳杂环，所述杂环或芳杂环含有1-3个N、O和/或S的杂原子。
  8. 权利要求1所述的通式Ⅰ所示的吲哚衍生物或其光学异构体、药学上可接受的盐、溶剂化物或前药，其选自以下化合物：
    (Z)-2-(2-(1-(1-乙基-5-(4-(吗啉基甲基)噻唑-2-基)-1H-吲哚-3-基)-2,2,2-三氟乙叉基)肼基)-4-(4-氟苯基)噻唑-5-甲腈，
    (Z)-((2-(3-(1-(2-(5-氰基-4-(4-氟苯基)噻唑-2-基)肼基)-2,2,2-三氟乙基)-1-乙基-1H-吲哚-5-基)-噻唑-4-基)-甲基)-L-脯氨酸，
    (Z)-((2-(3-(1-(2-(5-氰基-4-(4-甲氧基苯基)噻唑-2-基)肼基)-2,2,2-三氟乙基)-1-乙基-1H-吲哚-5-基)-噻唑-4-基)-甲基)-L-脯氨酸，
    (Z)-2-(2-(1-(1-乙基-5-(4-(吡咯-1-基甲基)噻唑-2-基)-1H-吲哚-3-基)-2,2,2-三氟乙叉基)肼基)-4-(4-氟苯基)噻唑-5-甲腈，
    (Z)-2-(2-(1-(1-乙基-5-(4-(哌啶-1-基甲基)噻唑-2-基)-1H-吲哚-3-基)-2,2,2-三氟乙叉基)肼基)-4-(4-氟苯基)噻唑-5-甲腈，
    (Z)-2-(2-(1-(1-乙基-5-(4-((4-甲基哌啶-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)-2,2,2-三氟乙叉基)肼基)-4-(4-甲氧基苯基)噻唑-5-甲腈，
    (S,Z)-2-(2-(1-(1-乙基-5-(4-((2-(羟甲基)四氢吡咯-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)-2,2,2-三氟乙叉基)肼基)-4-(4-氟苯基)噻唑-5-甲腈，
    (Z)-2-(2-(1-(1-乙基-5-(4-((3-羟基氮杂环丁烷-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)-2,2,2-三氟乙叉基)肼基)-4-(4-氟苯基)噻唑-5-甲腈，
    (Z)-2-(2-(1-(1-乙基-5-(4-((4-(2-羟乙基)哌嗪-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)-2,2,2-三氟乙叉基)肼基)-4-(4-氟苯基)噻唑-5-甲腈，
    (Z)-2-(2-(1-(1-乙基-5-(4-((4-羟基哌啶-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)-2,2,2-三氟乙叉基)肼基)-4-(4-氟苯基)噻唑-5-甲腈，
    (Z)-4-((2-(3-(1-(2-(苯并[d]噻唑-2-基)肼基)-2,2,2-三氟乙叉基)-1-乙基-1H-吲哚-5-基)-噻唑-4-基)甲基)吗啉，
    (Z)-2-(2-(1-(1-乙基-5-(4-(哌啶-1-基甲基)噻唑-2-基)-1H-吲哚-3-基)-2,2,2-三氟乙叉基)肼基)苯并[d]噻唑-5-腈，
    (Z)-1-((2-(3-(1-(2-(苯并[d]噻唑-2-基)肼基)-2,2,2-三氟乙叉 基)-1-乙基-1H-吲哚-5-基)噻唑-4-基)甲基)哌啶-4-醇，
    (E)-1-乙基-N′-(4-氟苯甲叉基)-5-(4-(吗啉基甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼，
    (E)-1-乙基-N′-(4-甲氧基苯甲叉基)-5-(4-(吗啉基甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼，
    (E)-N′-(苯并[d][1,3]二氧戊环-5-基甲叉基)-1-乙基-5-(4-(吗啉基甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼，
    (E)-1-乙基-5-(4-(吗啉基甲基)噻唑-2-基)5-N′-((4-氧-4H-色酮-3-基)甲叉基)-1H-吲哚-3-甲酰肼，
    (E)-N′-(4-氟苯甲叉基)-1-甲基-5-(4-(吗啉基甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼，
    (E)-N′-(苯并[d][1,3]二氧戊环-5-基甲叉基)-1-甲基-5-(4-(吗啉基甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼，
    (E)-1-乙基-N′-(4-氟苯甲叉基)-5-(4-(哌啶-1-基甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼，
    (E)-1-乙基-N′-(4-甲氧基苯甲叉基)-5-(4-(四氢吡咯-1-基甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼，
    (E)-N′-(苯并[d][1,3]二氧戊环-5-基甲叉基)-1-乙基-5-(4-((4-甲基哌嗪-1-基)甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼，
    (E)-N′-(4-氯苯甲叉基)-1-甲基-5-(4-((4-甲基哌嗪-1-基)甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼，
    (E)-1-乙基-N′-(4-氟苯甲叉基)-5-(4-((4-甲基哌啶-1-基)甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼，
    (E)-1-乙基-N′-(4-氟苯甲叉基)-5-(4-((4-羟基哌啶-1-基)甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼，
    (E)-N′-(苯并[d][1,3]二氧戊环-5-基甲叉基)-1-乙基-5-(4-((4-羟基哌啶-1-基)甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼，
    (E)-N′-(4-氯苯甲叉基)-1-乙基-5-(4-((4-羟基哌啶-1-基)甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼，
    (E)-1-乙基-N′-(4-氟苯甲叉基)-5-(4-((2-(羟甲基)四氢吡咯-1-基)甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼，
    (E)-1-乙基-N′-(1-(4-氟苯基)乙叉基)-5-(4-((2-(羟甲基)四氢吡咯-1-基)甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼，
    (E)-N′-(苯并[d][1,3]二氧戊环-5-基甲叉基)-1-乙基-5-(4-((2-(羟甲基)四氢吡咯-1-基)甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼，
    (E)-N′-(4-氯苯甲叉基)-1-乙基-5-(4-((4-(2-羟乙基)哌嗪-1-基)甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼，
    (E)-1-乙基-N′-(4-氟苯甲叉基)-5-(4-((4-(2-(羟乙基)哌嗪-1-基)甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼，
    (E)-N′-(苯并[d][1,3]二氧戊环-5-基甲叉基)-1-乙基-5-(4-((4-(2-羟乙基)哌嗪-1-基)甲基)噻唑-2-基)-1H-吲哚-3-甲酰肼，
    3,5-二氯苯甲基(1-乙基-5-(4-(吗啉基甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯，
    3,5-二氯苯甲基(1-乙基-5-(4-(四氢吡咯-1-基甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯，
    (R)-1-(4-甲基苯基)乙基(1-乙基-5-(4-(四氢吡咯-1-基甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯，
    3,5-二氯苯甲基(1-乙基-5-(4-((4-甲基哌啶-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯，
    3,5-二氯苯甲基(1-乙基-5-(4-((4-甲基哌嗪-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯，
    3,5-二氯苯甲基(S)-(1-乙基-5-(4-((2-(羟甲基)四氢吡咯-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯，
    (R)-1-(对-甲基苯基)乙基(1-乙基-5-(4-(((S)-2-(羟甲基)四氢吡咯-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯，
    (R)-1-(2-氯苯基)乙基(1-乙基-5-(4-(((S)-2-(羟甲基)四氢吡咯-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯，
    苯甲基(S)-(1-乙基-5-(4-((2-(羟甲基)四氢吡咯-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯，
    苯并[d][1,3]二氧戊环-5-基甲基(S)-(1-乙基-5-(4-((2-(羟甲基)四氢吡咯-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯，
    3,5-二氯苄基(1-乙基-5-(4-((4-羟基哌啶-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯，
    苯并[d][1,3]二氧戊环-5-基甲基(1-乙基-5-(4-((4-羟基哌啶-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯，
    3,4-二氟苄基(1-乙基-5-(4-((4-羟基哌啶-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯，
    (R)-1-(2-氯苯基)乙基(1-乙基-5-(4-((4-羟基哌啶-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯，
    3,5-二氯苄基(5-(4-((双(2-羟乙基)氨基)甲基)噻唑-2-基)-1-乙基 -1H-吲哚-3-基)氨基甲酸酯，
    3,5-二氯苄基(1-乙基-5-(4-((4-(2-羟乙基)哌嗪-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯，
    3,4-二氟苄基(1-乙基-5-(4-((4-(2-羟乙基)哌嗪-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯，
    苯甲基(1-乙基-5-(4-((4-(2-羟乙基)哌嗪-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)氨基甲酸酯，
    1-苯甲基-3-(1-乙基-5-(4-(吗啉甲基)噻唑-2-基)-1H-吲哚-3-基)脲，
    1-(1-乙基-5-(4-((4-甲基哌啶-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)-3-(4-氟苯甲基)脲，
    1-(4-氯苯甲基)-3-(1-乙基-5-(4-((4-甲基哌嗪-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)脲，
    1-(3-氯-4-甲氧基苯甲基)-3-(1-乙基-5-(4-((4-羟基哌啶-1-基)甲基)噻唑-2-基)-1H-吲哚-3-基)脲，和
    1-(5-(4-((双(2-羟乙基)氨基)甲基)噻唑-2-基)-1-乙基-1H-吲哚-3-基)-3-(3-氯-4-甲氧基苄基)脲。
  9. 一种药物组合物，包含权利要求1-8任何一项所述的通式Ⅰ所示的吲哚衍生物或其光学异构体、药学上可接受的盐、溶剂化物或前药和药学上可接受的载体。
  10. 权利要求1-8任何一项所述的通式Ⅰ所示的吲哚衍生物或其光学异构体、药学上可接受的盐、溶剂化物或前药或权利要求9所述的药物组合物在制备ATX抑制剂中的应用。
  11. 权利要求1-8任何一项所述的通式Ⅰ所示的吲哚衍生物或其光学异构体、药学上可接受的盐、溶剂化物或前药或权利要求9所述的药物组合物在制备抗肿瘤和/或抗纤维化药物中的应用。
  12. 如权利要求11所述的应用，其特征在于，所述的肿瘤为乳腺癌和/或胶质瘤，所述纤维化疾病为肺纤维化、肝纤维化和/或心肌纤维化。
  13. 一种制备权利要求1至8中任一项所述的通式Ⅰ所示的吲哚衍生物或其光学异构体、药学上可接受的盐、溶剂化物或前药的方法，其包括使用选自以下路线1～路线5中的方法，分别由中间体M1、M2、M2’、M3反应制备而成：
    路线1：
    Figure PCTCN2021071682-appb-100007
    路线2：
    Figure PCTCN2021071682-appb-100008
    路线3：
    Figure PCTCN2021071682-appb-100009
    路线4：
    Figure PCTCN2021071682-appb-100010
    路线5：
    Figure PCTCN2021071682-appb-100011
    其中，所述的通式Ⅰ所示的吲哚衍生物分别为I 1、I 2、I 3、I 4、I 5、I 5’、I 6、I 7、I 8、I 9或I 10所示的化合物，化合物中的L、R 1、R 2、R 3、R 5、R 6、R 7和R 8如权利要求1至8中任一项所定义。
  14. 下式M1、M2、M2’或M3所示的化合物：
    Figure PCTCN2021071682-appb-100012
    其中，化合物中的R 1、R 2和R 3如权利要求1至8中任一项所定义。
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